food and chemical toxicology contents food and

Food andChemicalToxicology

Editors

J F Borzelleca

A R Boobis

A Safety Assessment of Saturated Branched ChainAlcohols when used as Fragrance Ingredients

Volume 48, Supplement 4, July 2010 ISSN 0278-6915

FOOD AND CHEMICAL TOXICOLOGY

VOLUME 48 (2010) SUPPLEMENT 4CONTENTS

http://www.elsevier.com/locate/foodchemtoxFd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.

ISSN 0278-6915

48(S4) S1–S130 (2010)

Printed by Polestar Wheatons Ltd, Exeter, UK 237

Available online at www.sciencedirect.com

A Safety Assessment of Saturated Branched Chain Alcohols when used asFragrance Ingredients

D. Belsito, D. Bickers, M. Bruze,

P. Calow, H. Greim, J. M. Hanifin,

A. E. Rogers, J. H. Saurat, I. G. Sipes,

H. Tagami, and The RIFM Expert

Panel

S1–S46 A safety assessment of branched chain saturated alcohols when used as

fragrance ingredients

D. McGinty, J. Scognamiglio,

C. S. Letizia and A. M. ApiS47–S50 Fragrance material review on 3,5,5-trimethyl-1-hexanol


C. S. Letizia and A. M. ApiS51–S54 Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol


C. S. Letizia and A. M. ApiS55–S59 Fragrance material review on 4-methyl-2-pentanol


C. S. Letizia and A. M. ApiS60–S62 Fragrance material review on 2-methylundecanol


C. S. Letizia and A. M. ApiS63–S66 Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol


C. S. Letizia and A. M. ApiS67–S69 Fragrance material review on isodecyl alcohol


C. S. Letizia and A. M. ApiS70–S72 Fragrance material review on isooctan-1-ol

D. McGinty, S. P. Bhatia,

J. Scognamiglio, C. S. Letizia and

A. M. Api

S73–S78 Fragrance material review on isotridecan-1-ol (isomeric mixture)


C. S. Letizia and A. M. ApiS79–S81 Fragrance material review on isononyl alcohol


C. S. Letizia and A. M. ApiS82–S84 Fragrance material review on 6,8-dimethylnonan-2-ol

D. McGinty, C. S. Letizia and

A. M. ApiS85–S88 Fragrance material review on 2-ethyl-1-butanol


C. S. Letizia and A. M. ApiS89–S92 Fragrance material review on 2,6-dimethyl-4-heptanol

(Contents continued on inside back cover)

CYAN MAGENTA YELLOW BLACK

48

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OL

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48

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(20

10

)S

1–

S1

30

EL

SE

VIE

R


C. S. Letizia and A. M. Api

S93–S96 Fragrance material review on 3-methyl-1-pentanol



S97–S101 Fragrance material review on 2-methylbutanol

D. McGinty, A. Lapczynski,


A. M. Api

S102–S109 Fragrance materials review on isoamyl alcohol



S110–S114 Fragrance material review on 2,6-dimethyl-2-heptanol



S115–S129 Fragrance material review on 2-ethyl-1-hexanol

(Contents continued from outside back cover)FOOD AND CHEMICAL TOXICOLOGY

Founding Editor

The late Leon Golberg

Editors

JOSEPHOSEPH F. BORZELLECAORZELLECA

Department of Pharmacology andToxicology, Medical College of Virginia,

Richmond, VA 23298-0613, USA

ALANLAN R. BOOBISOOBIS

Section of Experimental Medicine and Toxicology,Division of Medicine, Imperial College, Hammersmith Campus,

Ducane Road, London W12 0NN, UK

Review EditorSUSANUSAN M. BARLOWARLOW

Harrington House, 8 Harrington Road,Brighton, East Sussex BN1 6RE, UK

Associate EditorsJOHNOHN CHRISTIANHRISTIAN LARSENARSEN

National Food Institute, Technical University of Denmark,19 Mørkhøj Bygade, DK-2860 Søborg, Denmark

BRYANRYAN DELANEYELANEY

Senior Research Scientist – Toxicology, Pioneer Hi-Bred International,2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA

GARYARY WILLIAMSILLIAMS

Department of Pathology, New York Medical College, Basic ScienceBuilding, Room 413, Valhalla, NY 10595, USA

SAMUELAMUEL M. COHENOHEN

Department of Pathology and Microbiology, University of NebraskaMedical Center, 983135 Nebraska Medical Center,

Omaha, NE 68198-3135

IVONNEVONNE RIETJENSIETJENS

AFSG/Division of Toxicology, Wageningen University, PO Box 8000,6700 EA Wageningen, The Netherlands

DAVIDAVID J. BRUSICKRUSICK

Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass,Virginia, USA

MICHAELICHAEL W. PARIZAARIZA

Department of Food Microbiology and Toxicology, University ofWisconsin at Madison, 176 Microbial Sciences Building,

1550 Linden Drive Madison, WI 53706, USA

International Editorial Board

P. BALDRICKALDRICK, UKJ. K. CHIPMANHIPMAN, UKT. F. X. COLLINSOLLINS, USAY. P. DRAGANRAGAN, USAL. O. DRAGSTEDRAGSTED, DenmarkL. FERGUSONERGUSON, New ZealandS. J. S. FLORALORA, IndiaH. R. GLATTLATT, GermanyW. H. GLINSMANNLINSMANN, USAY. HASHIMOTOASHIMOTO, JapanA. W. HAYESAYES, USAY. HUAUA, ChinaS. KACEWACEW, Canada

I. KIMBERIMBER, UKS. KNASMULLERNASMULLER, AustriaB. LAKEAKE, UKR. W. LANEANE, USAM. I. LUSTERUSTER, USAD. McGREGORREGOR, FranceP. MAGEEAGEE, UKH. I. MAIBACHAIBACH, USAK. MORGANORGAN, UKR. J. NICOLOSIICOLOSI, USAD. RAYAY, UKK. ROZMANOZMAN, USAW. H. M. SARISARIS, The Netherlands

R. C. SHANKHANK, USAM. SMITHMITH, The NetherlandsY.-J. SURHURH, South KoreaR. G. TARDIFFARDIFF, USAS. L. TAYLORAYLOR, USAJ. A. THOMASHOMAS, USAE. VAVASOURAVASOUR, CanadaH. VERHAGENERHAGEN, The NetherlandsA. VISCONTIISCONTI, ItalyX. WANGANG, People’s Republic of ChinaS. YANNAIANNAI, Israel

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Review

A safety assessment of branched chain saturated alcohols when usedas fragrance ingredients q

D. Belsito a, D. Bickers b, M. Bruze c, P. Calow d, H. Greim e, J.M. Hanifin f, A.E. Rogers g, J.H. Saurat h,I.G. Sipes i, H. Tagami j, The RIFM Expert Panela University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USAb Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USAc Malmo University Hospital, Department of Occupational and Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Swedend Roskilde University, Department of Environmental, Social and Spatial Change, Isafjordvej 66, Roskilde, Denmarke Technical University of Munich, Institute for Toxicology and Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germanyf Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098, USAg Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USAh Dermatotoxicology Swiss Centre for Applied Human Toxicology, University Medical Center, Rue Michel Servet, 1211 Genève 4, Switzerlandi Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USAj 3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan

a r t i c l e i n f o

Keywords:ReviewSafetyFragrance ingredientsBranched chain saturated alcohols

a b s t r a c t

The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. Inhumans, no evidence of skin irritation was found at concentrations of 2–10%. Undiluted, 11 materialsevaluated caused moderate to severe eye irritation. As current end product use levels are between0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. Forindividuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVBlight-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to eli-cit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Followingrepeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSAand three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effectand mode of action to humans is still a matter of debate. The Panel is of the opinion that there are nosafety concerns regarding BCSA under the present levels of use and exposure.


Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22. Chemical identity, regulatory status, and exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2

2.1. Rationale for grouping branched chain saturated alcohols together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22.2. Occurrence and use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72.3. Estimated consumer exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7

3. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S83.1. Primary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S83.2. Secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S83.3. Tertiary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8

4. Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S84.1. Dermal route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S84.2. Oral route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8

0278-6915/$ - see front matter � 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.fct.2010.05.046

q All correspondence should be addressed to: A.M. Api, RIFM, 50 Tice Blvd, Woodcliff Lake, NJ 07677, USA. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address:[email protected].

Food and Chemical Toxicology 48 (2010) S1–S46

Contents lists available at ScienceDirect

Food and Chemical Toxicology

journal homepage: www.elsevier .com/locate / foodchemtox

4.3. Respiratory route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S94.4. Parenteral route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

5. Toxicological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95.1. Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95.2. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

5.2.1. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95.2.2. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105.2.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S11

5.3. Mutagenicity and genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S135.3.1. In vitro mutagenicity studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S135.3.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18

5.4. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S185.4.1. Cell transformation assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S185.4.2. Carcinogenicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18

5.5. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S205.5.1. Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S205.5.2. Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20

5.6. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S325.6.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S325.6.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32

5.7. Mucous membrane irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S325.7.1. Sensory irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S325.7.2. Eye irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33

5.8. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S335.8.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S335.8.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33

5.9. Phototoxicity and photoallergenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S335.10. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S42

1. Introduction

In 2006 complete literature searches were conducted on thebranched chain saturated alcohol group of fragrance ingredients.This document provides a risk assessment of these materials as fra-grance ingredients and is a critical evaluation of the pertinent data.The scientific evaluation focuses on dermal exposure, which is con-sidered to be the primary route for fragrance materials. Where rel-evant, toxicity, metabolism and biological fate data from otherexposures have been considered.

The current format includes a group summary evaluation pa-per and individual Fragrance Material Reviews on discrete chem-icals. The group summary is an evaluation of relevant dataselected from the large bibliography of studies and reports onthe individual chemicals. The selected data were deemed to berelevant based on the currency of protocols, quality of the data,statistical significance and appropriate exposure. These are iden-tified in tabular form in the group summary. Details that areprovided in the tables are not always discussed in the text ofthe group summary. The Fragrance Material Reviews contain acomprehensive summary of all published reports including com-plete bibliographies (McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q).

2. Chemical identity, regulatory status, and exposure

2.1. Rationale for grouping branched chain saturated alcohols together

The group consists of 12 primary, 5 secondary and 3 tertiaryalcohols. Of these materials, three have been previously reviewedin RIFM’s Safety Assessment on Terpene Alcohols (Belsito et al.,2008). The names and structures of the materials reviewed are

shown in Table 1.1 In addition, several noncyclic branched chainalcohols used as examples here have been reviewed in other recentRIFM publications. Information on previously reviewed substancesof this group is not presented again unless it is new or required toevaluate remaining fragrance ingredients. The common characteris-tic structural elements of the alcohols with saturated branched chainare one hydroxyl group per molecule, a C4–C12 carbon chain withone or several methyl side chains. Two members of the group, 2-ethyl-1-butanol and 2-ethyl-1-hexanol, contain an ethyl side chain.One member contains a methoxy group. Metabolism studies arelacking for this compound, however, a methoxy group is enzymati-cally not readily cleaved and if it were so, another primary alcoholgroup would be formed.

As the database for the alcohols under review is limited, addi-tional data for some metabolites of these alcohols have been used.It was demonstrated that 4-methyl-2-pentanol, a group member, ismetabolized to 4-methyl-2-pentanone and 4-hydroxy-4-methyl-2-pentanone is a metabolite of both substances (Gingell et al.,2003). It can also be expected that 2,6-dimethyl-4-heptanol ismetabolized to 2,6-dimethylheptan-4-one. Therefore, studies onpharmacokinetics, metabolism, genotoxicity and systemic toxicityof 4-methyl-2-pentanone, 4-hydroxy-4-methyl-2-pentanone and 2,6-dimethylheptan-4-one have been added to the database. Thesematerials are not used as fragrance ingredients. Due to their struc-tural similarity, these alcohols also share common metabolic path-ways (see below). As metabolism is crucial for pharmacokineticsand toxicity, these alcohols or their metabolites are expected tohave the same primary target organs (liver, kidney, and blood) aswas shown for 2-ethyl-1-hexanol, isoamyl alcohol, isotridecan-1-

1 Isooctan-1-ol, isononyl alcohol, isodecyl alcohol and Isotridecan-1-ol (isomericmixture) are generic names for mixtures of isomers of primary branched alcoholswith an average C-number of 8, 9, 10, or 13, respectively.

S2 D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46

Tabl

e1

Mat

eria

lid

enti

fica

tion

,sum

mar

yof

volu

me

ofus

e,an

dde

rmal

expo

sure

.

Mat

eria

lSy

non

yms

Stru

ctu

reW

orld

wid

em

etri

cto

ns

(an

nu

al)a

Der

mal

syst

emic

expo

sure

inco

smet

icpr

odu

cts

(mg/

kg/d

ay)

Max

imu

msk

inle

vel

(%)b

Subg

roup

:pr

imar

y3,

7-D

imet

hyl-

1-oc

tano

lc

C1

0H

22O

CA

S#10

6-21

-8�D

ihyd

roci

tron

ello

l10

0–10

000.

0005

d0.

02H

enry

’sLa

w:

0.00

0054

7at

mm

3/m

ol25

�C�1

-Oct

anol

,3,7

-dim

eth

yl-

Log

Ko

w:

3.9

at35

�C�P

elar

gol

Mol

ecu

lar

wei

ght:

158.

29�T

etra

hyd

roge

ran

iol

Vap

orpr

essu

re:

0.06

mm

Hg

20�C

Wat

erso

lubi

lity

:17

5.4

mg/

lat

25�C

2-Et

hyl-

1-bu

tano

lC

6H

14O

CA

S#97

-95-

0�1

-Bu

tan

ol,2

-eth

yl-

<0.0

10.

0005

d0.

02H

enry

’sLa

w:

0.00

0017

6at

mm

3/m

ol25

�C�2

-Eth

ylbu

tyl

alco

hol

Log

Ko

w:

1.75

calc

�2-E

thyl

buta

n-1

-ol

Mol

ecu

lar

wei

ght:

102.

18V

apor

pres

sure

:1.

0m

mH

g20

�CW

ater

solu

bili

ty:

11,9

50m

g/l

at25

�C

2-Et

hyl-

1-he

xano

lC

8H

18O

CA

S#10

4-76

-7�2

-Eth

ylh

exan

ol0.

1–1

0.00

050.

008

Hen

ry’s

Law

:0.

0000

31at

mm

3/m

ol25

�C�1

-Hex

anol

,2-e

thyl

-Lo

gK

ow

:2.

73ca

lc�2

-Eth

ylh

exan

-1-o

lM

olec

ula

rw

eigh

t:13

0.23

Vap

orpr

essu

re:

0.06

mm

Hg

20�C

Wat

erso

lubi

lity

:13

79m

g/l

at25

�C

Isoa

myl

alco

hol

0.1–

10.

0002

0.01

C5H

12O

CA

S#12

3-51

-3�1

-Bu

tan

ol,3

-met

hyl

-H

enry

’sLa

w:

0.00

0013

3at

mm

3/m

olat

25�C

�Iso

buty

lca

rbin

olLo

gK

ow

:1.

16�I

sope

nta

nol

Mol

ecu

lar

wei

ght:

88.1

5�I

sope

nty

lal

coh

olV

apor

pres

sure

:3.

84m

mH

g25

�C�3

-Met

hyl

-1-b

uta

nol

Wat

erso

lubi

lity

:41

,580

mg/

lat

25�C

�3-M

eth

ylbu

tan

-1-o

l

Isod

ecyl

alco

hol

C1

0H

22O

CA

S#25

339-

17-7

�Iso

deca

nol

0.1–

10.

0005

d0.

02H

enry

’sLa

w:

0.00

0054

7at

mm

3/m

ol25

�C�8

-Met

hyl

non

an-1

-ol

Log

Ko

w:

3.71

calc

Mol

ecu

lar

wei

ght:

158.

85V

apor

pres

sure

:0.

0204

mm

Hg

25�C

Wat

erso

lubi

lity

:15

1.8

mg/

lat

25�C

Ison

onyl

alco

hol

(iso

mer

unsp

ecifi

ed)

C9H

20O

CA

S#27

458-

94-2

�Iso

non

anol

<0.0

10.

110.

3H

enry

’sLa

w:

0.00

0041

2at

mm

3/m

ol25

�C�7

-Met

hyl

octa

n-1

-ol

Log

Ko

w:

3.22

calc

Mol

ecu

lar

wei

ght:

144.

58V

apor

pres

sure

:0.

0198

mm

Hg

25�C

Wat

erso

lubi

lity

:45

9.7

mg/

lat

25�C

(con

tinu

edon

next

page

)

D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S3

Tabl

e1

(con

tinu

ed)

Mat

eria

lSy

non

yms

Stru

ctu

reW

orld

wid

em

etri

cto

ns

(an

nu

al)a

Der

mal

syst

emic

expo

sure

inco

smet

icpr

odu

cts

(mg/

kg/d

ay)

Max

imu

msk

inle

vel

(%)b

Isoo

ctan

-1-o

lC 8

H1

8O

CA

S#26

952-

21-6

�Iso

octa

nol

<0.0

10.

0005

d0.

02H

enry

’sLa

w:

0.00

0031

atm

m3/m

ol25

C�6

-Met

hyl

hep

tan

-1-o

lLo

gK

ow

:2.

73ca

lcM

olec

ula

rw

eigh

t:13

0.31

Vap

orpr

essu

re:

0.15

1m

mH

g25

CW

ater

solu

bili

ty:

1379

mg/

lat

25�C

Isot

ride

can-

1-ol

(iso

mer

icm

ixtu

re)

C 13H

28O

CA

S#27

458-

92-0

�Iso

trid

ecan

ol10

–100

0.04

0.7

Hen

ry’s

Law

:0.

0001

28at

mm

3/m

ol25

�C�1

1-M

eth

yldo

deca

n-1

-ol

Log

Ko

w:

5.19

calc

Mol

ecu

lar

wei

ght:

200.

66V

apor

pres

sure

:0.

0004

62m

mH

g25

�CW

ater

solu

bili

ty:

5.23

7m

g/l

at25

�C

2-M

ethy

lbut

anol

C 5H

12O

CA

S#13

7-32

-6�A

ctiv

eam

ylal

coh

ol0.

01–0

.10.

0002

0.00

1H

enry

’sLa

w:

0.00

0013

3at

mm

3/m

ol25

�C�1

-Bu

tan

ol,2

-met

hyl

-Lo

gK

ow

:1.

26ca

lc�s

ec-B

uty

lcar

bin

olM

olec

ula

rw

eigh

t:88

.15

�(+/�

)2-

Met

hyl

-1-b

uta

nol

Vap

orpr

essu

re:

2.5

mm

Hg

20�C

�2-M

eth

ylbu

tyl

alco

hol

Wat

erso

lubi

lity

:32

200

mg/

lat

25�C

�2-M

eth

ylbu

tan

-1-o

l

3-M

ethy

l-1-

pent

anol

C 6H

14O

CA

S#58

9-35

-5�2

-Eth

yl-4

-bu

tan

ol<0

.01

0.00

05d

0.02

Hen

ry’s

Law

:0.

0000

176

atm

m3/m

ol25

�C�1

-Pen

tan

ol,3

-met

hyl

-Lo

gK

ow

:1.

75ca

lc�3

-Met

hyl

pen

tan

-1-o

lM

olec

ula

rw

eigh

t:10

2.18

�Met

hyl

Pen

tan

ol-3

Vap

orpr

essu

re:

0.7

mm

Hg

20�C

Wat

erso

lubi

lity

:11

,950

mg/

lat

25�C

2-M

ethy

lund

ecan

olC 1

2H

26O

CA

S#10

522-

26-6

�1-U

nde

can

ol,2

-met

hyl

-<0

.01

0.01

0.04

Hen

ry’s

Law

:0.

0000

963

atm

m3/m

ol25

�C�2

-Met

hyl

un

deca

n-1

-ol

Log

Ko

w:

4.7

calc

Mol

ecu

lar

wei

ght:

186.

39V

apor

pres

sure

:0.

0014

mm

Hg

25�C

Wat

erso

lubi

lity

:16

.18

mg/

lat

25�C

3,5,

5-Tr

imet

hyl-

1-he

xano

lC 9

H2

0O

�1-H

exan

ol,3

,5,5

-tri

met

hyl

-1–

100.

004

0.7

CA

S#34

52-9

7-9

�i-N

onyl

alco

hol

Hen

ry’s

Law

:0.

0000

412

atm

m3/m

ol25

�C�N

onyl

olLo

gK

ow

:3.

11ca

lc�T

rim

eth

ylh

exan

olM

olec

ula

rw

eigh

t:14

4.26

�3,5

,5-T

rim

eth

ylh

exan

olV

apor

pres

sure

:0.

2m

mH

g20

�C�3

,5,5

-Tri

met

hyl

hex

an-1

-ol

Wat

erso

lubi

lity

:57

2m

g/l

at25

�C�3

,5,5

-Tri

met

hyl

hex

ylal

coh

ol


Subg

roup

:se

cond

ary

2,6-

Dim

ethy

l-4-

hept

anol

C 9H

20O

CA

S#10

8-82

-7�D

iiso

buty

lcar

bin

ol10

–100

0.00

05d

0.02

Hen

ry’s

Law

:0.

0000

412

atm

m3/m

ol25

�C�4

-Hep

tan

ol,2

,6-d

imet

hyl

-Lo

gK

ow

3.08

calc

�2,6

-Dim

eth

ylh

epta

n-4

-ol

Mol

ecu

lar

wei

ght:

144.

26V

apor

pres

sure

:0.

0624

mm

Hg

25�C

Wat

erso

lubi

lity

:61

3.8

mg/

lat

25�C

3,7-

Dim

ethy

l-7-

met

hoxy

octa

n-2-

olC 1

1H

24O

2

CA

S#41

890-

92-0

�7-M

eth

oxy-

3,7-

dim

eth

yloc

tan

-2-o

l1–

100.

091.

3H

enry

’sLa

w:

0.00

0000

404

atm

m3/m

ol25

�C�2

-Oct

anol

,7-m

eth

oxy-

3,7-

dim

eth

yl-

Log

Ko

w:

2.76

calc

�Osi

rol

Mol

ecu

lar

wei

ght:

188.

31�O

syro

lV

apor

pres

sure

:0.

0119

mm

Hg

25�C

Wat

erso

lubi

lity

:70

7.1

mg/

lat

25�C

6,8-

Dim

ethy

lnon

an-2

-ol

C 11H

24O

CA

S#70

214-

77-6

�2-N

onan

ol,6

,8-d

imet

hyl

-1–

100.

001

0.00

9Lo

gK

ow

:4.

06ca

lc�N

onad

ylM

olec

ula

rw

eigh

t:17

2.12

Vap

orpr

essu

re:

0.00

0115

mm

Hg

25�C

4-M

ethy

l-2-

pent

anol

C 6H

14O

CA

S#10

8-11

-2�I

sobu

tyl

met

hyl

carb

inol

0.01

–0.1

0.00

05d

0.02

Hen

ry’s

Law

:0.

0000

176

atm

m3/m

ol25

�C�M

eth

ylis

obu

tyl

carb

inol

Log

Ko

w:

1.68

calc

�MIC

Mol

ecu

lar

wei

ght:

102.

18�2

-Pen

tan

ol,4

-met

hyl

-V

apor

pres

sure

:3.

7m

mH

g20

�C�4

-Met

hyl

pen

tan

-2-o

lW

ater

solu

bili

ty:

13,8

00m

g/l

at25

�C

3,4,

5,6,

6-Pe

ntam

ethy

lhep

tan-

2-ol

C 12H

26O

CA

S#87

118-

95-4

�2-H

epta

nol

,3,4

,5,6

,6-p

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ol (isomeric mixture), 3,5,5-trimethyl-1-hexanol, 2,6-dimethylhep-tan-4-one, 4-hydroxy-4-methyl-2-pentanone, 4-methyl-2-pentanol,and 4-methyl-2-pentanone.

Data for 2-ethyl-1-hexanol, 2-ethylbutanol, 4-methyl-2-penta-nol, isoamyl alcohol, 2-methylbutanol and 4-methyl-2-pentanoneshow that the alcohols share common metabolic pathways. Themajor pathways of metabolism and fate are:

– conjugation of the alcohol group with glucuronic acid;– oxidation of the alcohol group;– side-chain oxidation yielding polar metabolites, which may be

conjugated and excreted – or further oxidized to an aldehyde,a carboxylic acid, and to CO2;

– excretion of the unchanged parent compound.

In most cases, metabolism yields innocuous metabolites. Inter-mediary reactive products of oxidation of primary alcohols arealdehydes, which are toxic and possibly genotoxic, although no rel-evant genotoxicity was shown with the primary alcohols tested.

The alcohols under review are summarized in Table 1. CAS No.and synonyms for the alcohols considered in this review are shownin Table 1. The structural formulas are provided in Table 1.

2.2. Occurrence and use

The alcohols under review are used as fragrance ingredients.They may be found in fragrances used in decorative cosmetics, finefragrances, shampoos, toilet soaps, and other toiletries as well as innon-cosmetic products such as household cleaners and detergents.This report summarizes and synthesizes animal and human data,including studies by various routes of exposure, and emphasizesthe risk assessment for use as fragrance ingredients. The scientificevaluation focuses on dermal exposure, which is considered theprimary exposure route for fragrance materials. Where relevantthe metabolism, toxicity, and biological fate data of other routesof exposure have also been considered.

The selected data from published and unpublished reports weredeemed relevant based on the nature of the protocols, quality ofthe data, and appropriate exposure. These data are presented intabular form.

Some of the alcohols assessed in this report have been evaluatedand approved for use as flavor ingredients in foodstuffs. In the Uni-ted States, 2-ethyl-1-hexanol, isoamyl alcohol, and 3-methyl-1-pentanol have been approved for use as food additives or in foodcontact materials by the Food and Drug Administration (FDA). Inaddition, 2,6-dimethyl-4-heptanol, 2-methylbutanol, and 3,5,5-tri-methyl-1-hexanol are listed as food additives (FDA, 2007).

The International Joint FAO/WHO Expert Committee on FoodAdditives (JECFA) has evaluated alicyclic ketones, secondary alco-hols and related esters including 2,6-dimethyl-4-heptanol fromthe group under review and its metabolite 2,6-dimethylheptan-4-one (JECFA, 1999). JECFA also evaluated aliphatic, branched chainsaturated and unsaturated alcohols, aldehydes, acids, and relatedesters including 2-methylbutanol (JECFA, 2004). These materialswere judged by this Committee not to present a safety concernat the current estimated intake levels.

The annual worldwide use of the individual alcohols reviewedherein varies greatly and ranges from <0.01 to 100 metric tons.Compounds with a use volume of >10 metric tons are 2,6-di-methyl-2-heptanol, 2,6-dimethyl-4-heptanol, isotricedan-1-ol,and 3,4,5,6,6-pentamethylheptan-2-ol (IFRA, 2007; Table 1).

2.3. Estimated consumer exposure

Exposure data have been provided by the fragrance industry.Potential consumer exposure to fragrance materials occurs

through the dermal and inhalation routes of exposure. Worst-casescenario calculations indicate that depositions on the surface of theskin following use of cosmetics represents the major route of expo-sure to fragrance ingredients when conservative estimates forevaporation, rinsing and other forms of product removal are em-ployed (Cadby et al., 2002). Therefore, the dermal route was themajor route in assessing the safety of these compounds.

The fragrance industry has developed three types of approachesto estimate potential exposure for consumers to fragrance materials.All three types of exposure are summarized in Table 1. The first is vol-ume of use. The total worldwide volume of use for fragrance materi-als in the branched chain saturated alcohols ranges from <0.01 to>1000 metric tons per year (IFRA, 2004). The reported volume isfor the fragrance ingredient as used in fragrance compounds (mix-tures) in all finished consumer product categories. The volume ofuse is determined by IFRA approximately every 4 years through acomprehensive survey of IFRA and RIFM member companies. As suchthe volume of use data from this survey provides volume of use offragrance ingredients for the majority of the fragrance industry.

The second method estimates the potential percutaneous (totalskin exposure) absorption from the entire body based on the use ofmultiple consumer personal care products containing the same fra-grance ingredient. The dermal systemic exposure in cosmetic prod-ucts is calculated based on the concentrations in 10 types of themost frequently used personal care and cosmetic products (anti-perspirant, bath products, body lotion, eau de toilette, face cream,fragrance cream, hair spray, shampoo, shower gel, and toilet soap).The concentration of the fragrance ingredient in fine fragrances isobtained from examination of several thousand commercial for-mulations. The upper 97.5 percentile concentration is calculatedfrom the data obtained. This upper 97.5 percentile concentrationis then used for all 10 consumer products. These concentrationsare multiplied by the amount of product applied, the number ofapplications per day for each product type, and a ‘‘retention factor”(ranging from 0.001 to 1.0) to account for the length of time aproduct may remain on the skin and/or likelihood of the fragranceingredient being removed by washing. The resultant calculationrepresents the total consumer exposure (mg/kg/day) (Cadbyet al., 2002; Ford et al., 2000). In view of all of the above assump-tions, the total calculated consumer exposure is conservative; it isunlikely that a consumer will consistently use a number of differ-ent consumer products which are all perfumed with the upper 97.5percentile level of the fragrance ingredient from a fine fragrancetype of product (Cadby et al., 2002; Ford et al., 2000). The total con-sumer exposures to fragrance ingredients range from 0.0002 to0.11 mg/kg/body weight (bw)/day for the branched chain satu-rated alcohols fragrance ingredients in high-end users of cosmeticproducts containing these materials (see Table 1) (IFRA, 2004).

The third method provides maximum skin levels. For consider-ation of potential sensitization, the exposure is calculated as thepercent concentration of the fragrance ingredient applied to theskin based on the use of 20% of the fragrance mixture in the finefragrance consumer product (IFRA, 2007). The maximum skinexposure levels of the branched chain saturated alcohol com-pounds that form part of the formulae of fine fragrances varywidely and have been report to range from 0.008% to 1.7%. Themaximum skin exposure for branched chain saturated alcohols infine fragrance products are listed in Table 1 (IFRA, 2007).

In assessing safety, the calculated dermal systemic exposure incosmetic products can then be compared to the indices of systemictoxicity such as NOAEL and LOAEL that are obtained from the re-peat dose subchronic, chronic and reproductive toxicity studiesto derive a margin of exposure (MOE). Systemic exposures (i.e.,the dose absorbed through the skin and available to the systemiccirculation) were estimated based on dermal absorption rates.Where such data were lacking, as a conservative measure, dermal


absorption was considered to be 100% (i.e., the maximum skinexposure value was considered as the estimate of systemicexposure).

All exposure data were provided by the fragrance industry. Fur-ther explanation of how the data were obtained and of how expo-sures were determined has been previously reported by Cadbyet al. (2002) and Ford et al. (2000).

3. Metabolism

3.1. Primary alcohols

When 25 mmoles (2.55 g) of 2-ethyl-1-butanol were adminis-tered by gavage to rabbits, 40% of the dose was excreted in the ur-ine as the glucuronide conjugate. The excretion of glucuronide wascompleted within 24 h (Kamil et al., 1953a). A rabbit was given3.1 ml (2.55 g) 2-ethyl-1-butanol and the 24-h urine was collected.2-Ethyl-1-butanol was excreted mainly as diethylacetylglucuro-nide and a minor amount of methyl n-propyl ketone was alsofound (Kamil et al., 1953b).

Main metabolites of 2-ethyl-1-hexanol identified in the urine ofrats after oral or dermal application were 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, 5-keto-2-ethylhexanoic acid, 2-ethyl-1,6-hexanedioic acid and 6-hydroxy-2-ethylhexanoic acid,mainly as their glucuronides, and expired carbon dioxide. Potentialmetabolites not detected in each study were 2-ethylhexanoic acid,4- and 2-heptanone. One to three percent 2-ethyl-1-hexanol wasexcreted unchanged or as glucuronide. Metabolic saturation wasseen with 500 mg/kg body weight applied (Kamil et al., 1953a,b).This metabolite pattern demonstrates the well-known metabolicpathways of primary alcohols: oxidation of the alcohol group andoxidation of the side chain at various positions, glucuronidationof the oxidation products, and decarboxylation (Fig. 1; Albro,1975; Deisinger et al., 1993, 1994). Induction of metabolism wasnot seen with repeated oral dosing (Deisinger et al., 1994). In rab-bits the glucuronide of 2-ethylhexanoic acid was identified as themain metabolite (87%) after oral application of 2-ethyl-1-hexanol(Kamil et al., 1953a,b). In vitro incubation with mammalian alcoholdehydrogenase resulted in a Vmax of 0.30 lmol/min/mg protein anda Km value of 0.74 mM (Albro, 1975).

Only about 9% of the administered dose was found in the formof the glucuronide when isoamyl alcohol (3-methylbutanol) or 2-methylbutanol was given to rabbits. Other metabolites were notidentified (Kamil et al., 1953a). Age-dependent glucuronidationactivity was demonstrated in vitro in the olfactory mucosa of ratswith isoamyl alcohol (Leclerc et al., 2002). The glucuronidation ofisoamyl alcohol and other short-chained aliphatic alcohols wasinvestigated in vitro with human liver microsomes. The Vmax valuewas 3.3 nmol/min/mg protein and the Km was determined as13.3 mM. The glucuronidation increased with chain length (C2–C5) of the alcohols studied (Jurowich et al., 2004).

Oxidation to the aldehyde and glucuronidation was demon-strated for isoamyl alcohol and 2-methylbutanol with microsomesfrom rats pretreated with ethanol (Iwersen and Schmoldt, 1995).The rate of oxidative metabolism of isoamyl alcohol was about0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g per-fused rat liver (Hedlund and Kiessling, 1969). The rate of oxidationof isoamyl alcohol by human skin alcohol dehydrogenase was183.3 nM/mg protein per minute (Wilkin and Stewart, 1987). TheKm-values of isoamyl alcohol with alcohol dehydrogenase from hu-man and horse liver were 0.07 and 0.08 mM, respectively (Pie-truszko et al., 1973). After intraperitoneal application of 1000 mgisoamyl alcohol or 2-methylbutanol/kg body weight, the corre-sponding aldehydes could not be detected in expired air of rats(Haggard et al., 1945).

3.2. Secondary alcohols

After application of 4-methyl-2-pentanol (methyl isobutyl car-binol in Fig. 2) to rabbits 33.7% of the dose was excreted as the glu-curonide (Kamil et al., 1953a). In mammals, the metabolism ofsecondary alcohols proceeds primarily through their respective ke-tones. 4-Methyl-2-pentanol is metabolized to 4-methyl-2-penta-none (methyl isobutyl ketone in Fig. 2) and further to 4-hydroxy-4-methyl-2-pentanone in rats (Fig. 2; OECD/SIDS, 2007).

Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 hafter oral gavage administration of 5 mmol/kg of 4-methyl-2-pent-anol or 4-methyl-2-pentanone to male rats. After dosing rats by ga-vage with 4-methyl-2-pentanol or 4-methyl-2-pentanone, themajor material in the plasma for both compounds was 4-hydro-xy-4-methyl-2-pentanone. No other metabolites were detected inthe plasma. The extent of metabolism of 4-methyl-2-pentanol to4-methyl-2-pentanone was at least 73%. The reduction of 4-methyl-2-pentanone to 4-methyl-2-pentanol was insignificant(Gingell et al., 2003; Hirota, 1991a).

Similar results were obtained with intraperitoneal applicationof 4-methyl-2-pentanol and 4-methyl-2-pentanone in mice. Afterintraperitoneal administration of 4-hydroxy-4-methyl-2-pentanone,neither 4-methyl-2-pentanol nor 4-methyl-2-pentanone could bedetected in the blood and in the brain (Fig. 2; Granvil et al.,1994). This result shows that in rats and mice 4-methyl-2-pentanolis predominantly oxidized to 4-methyl-2-pentanone and both com-pounds share the same principal metabolite, namely 4-hydroxy-4-methyl-2-pentanone.

In workers exposed to mixed solvents including 4-methyl-2-pentanone and 4-methyl-2-pentanol was identified by GC–MS inthe urine. In a subject exposed to 42.3 ml pure 4-methyl-2-penta-none/m3 for 6 h, 0.42 mg 4-methyl-2-pentanol/g creatinine was ex-creted (Hirota, 1991b). This result confirms, that in humans as well,the reduction of 4-methyl-2-pentanone is insignificant (6 h 42 ml/m3 4-methyl-2-pentanone corresponds to about 320 mg at 66%retention in the lung and a minute volume of 8 l).

3.3. Tertiary alcohols

Data on the tertiary alcohols under review are not available. Atertiary alcohol group cannot be oxidized. Tertiary alcohols are ex-pected to be excreted either via conjugation or unchanged or un-dergo hydroxylation of the carbon chain, which in turn may giverise to a metabolite which can be easily excreted.

4. Pharmacokinetics

4.1. Dermal route of exposure

In vitro absorption rates for 2-ethyl-1-hexanol were 0.22 ± 0.09and 0.038 ± 0.014 mg/cm2/h for rat and human skin, respectively,giving a rat/human ratio of 5.78. The permeability constants were2.59 ± 1.10 � 10�4 cm/h for rats and 4.54 ± 1.66 � 10�5 cm/h forhumans (Barber et al., 1992).

The dermal absorption in the rat was determined to be 5.2% of adose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for 6 h;the absorption rate was calculated to be 0.57 mg/cm2/h. The termi-nal half-life was calculated to be 77 h (Deisinger et al., 1994).

4.2. Oral route of exposure

In rats, oral administration of 2000 mg isoamyl alcohol/kg bodyweight led to a peak concentration of 170 mg/l blood 1 h later. The


authors calculated an oxidation rate of 5 mg/kg body weight/h(Gaillard and Derache, 1965).

After oral administration to rats, 69–75% of a dose of 500 mg14C-labeled 2-ethyl-1-hexanol/kg body weight was excreted inthe urine within 96 h. About 13–15% of the dose was excreted inthe feces and about the same amount was exhaled. More than50% of the dose was excreted within 24 h (Deisinger et al., 1993,1994).

Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 hafter oral gavage administration of 5 mmol/kg of 4-methyl-2-pent-anol or 4-methyl-2-pentanone to male rats. The major material inthe plasma for both compounds was 4-hydroxy-4-methyl-2-penta-none, with similar areas under the curve (AUCs) and Cmax at 9 hafter dosing for both 4-methyl-2-pentanol and 4-methyl-2-penta-none. 4-Methyl-2-pentanone plasma levels and AUC were also sim-ilar after 4-methyl-2-pentanone or 4-methyl-2-pentanoladministration. 4-Methyl-2-pentanol AUC was only about 6% ofthe total material in the blood following 4-methyl-2-pentanoladministration, and insignificant after 4-methyl-2-pentanoneadministration (Gingell et al., 2003).

4.3. Respiratory route of exposure

Respiratory uptake of isoamyl alcohol was investigated in fourhealthy volunteers. Air concentration was 25–200 ppm and expo-sure duration was 10 min. The mean uptake for the last 5 min ofexposure was 63% and the mean respiratory rate was 15.3 min�1

(Kumagai et al., 1998).

4.4. Parenteral route of exposure

After intravenous administration to rats, about 74% of a dose of1 mg 14C-labeled 2-ethyl-1-hexanol/kg body weight was excretedin the urine within 96 h. About 4% of the dose was excreted inthe feces and 23% was exhaled. More than 50% of the dose was ex-creted within 8 h. The terminal half-life was estimated to be 60 h(Deisinger et al., 1993, 1994).

The concentration of isoamyl alcohol in blood declined within5 h to non-detectable levels after intraperitoneal administrationof 1000 mg isoamyl alcohol/kg body weight. Similar values werefound for 2-methylbutanol administered at the same dose. Anelimination half-life was not calculated. For isoamyl alcohol and2-methylbutanol, 1.2% and 7.6%, respectively, were excreted via ur-ine and expired air. Compared to other amyl alcohols tested by theauthors, primary alcohols were eliminated from the blood morequickly than secondary and tertiary alcohols (Haggard et al., 1945).

5. Toxicological studies

5.1. Acute toxicity

Acute dermal toxicity studies have been performed with six pri-mary, three secondary, and three tertiary alcohols, all but one inrabbits. The dermal LD50 values in rabbits and the one in rats arein the range of 1000–>5000 mg/kg body weight. In summary allthe compounds are of low acute toxicity by the dermal route (Ta-ble 2-1).

Eight primary alcohols, four secondary, and three tertiary alco-hols have been tested for oral acute toxicity. The oral LD50 values inrats, mice, and rabbits are in the range of 1000–>5000 mg/kg bodyweight, and therefore, all the compounds exhibit a low toxicitywhen administered via the oral route (Table 2-2).

Lethargy was the most often reported clinical sign after oral ordermal administration, diarrhea and ataxia after oral administra-

tion, and irritation of the skin after dermal administration. Signsof gastrointestinal irritation were noted at necropsy in acute oraltoxicity tests.

In inhalation tests with five primary and two secondary alco-hols, no mortality was observed in rats exposed to air saturatedwith alcohol vapor at room temperature for as long as 8 h. LC50 val-ues were not determined. Local ocular and upper respiratory tractirritation was seen with 2-ethyl-1-hexanol. However, 4-methyl-2-pentanol exposure at 2000 ml/m3 for 8 h resulted in death at14 days of 5/6 rats, and exposure to saturated air at 20 �C resultedin anesthesia at 4 h and death of 6/10 mice after 10 h.

Acute toxicity data obtained from studies with other than oralor dermal exposure are summarized in Table 2-3.

5.2. Repeated dose toxicity

The evaluation of repeated dose systemic toxicity is based onseveral oral studies with mainly primary alcohols and only one sec-ondary alcohol. The metabolic pathways with all the materials inthis group yield innocuous metabolites. The database could bestrengthened by an evaluation of the systemic toxicity of a second-ary and tertiary alcohol. Other studies can be found in Section 5.10.

5.2.1. Dermal studiesDermal studies with branched chain saturated alcohols are

summarized in Table 3-1.

5.2.1.1. Primary alcohols. Over a period of 12 days, rats were treatedwith undiluted 2-ethyl-1-hexanol (2 ml/kg body weight/day, about1600 mg/kg body weight/day) on their shaved backs. At necropsy,the treated animals had decreased absolute and relative thymusweights, liver granulomas, bronchiectasis in the lung, renal tubularepithelial necrosis in the kidneys, edema in heart and testes, de-creased spermatogenesis, and an increase in lipids in adrenals werefound on day 17. These effects were reversed on day 30 (Schmidtet al., 1973).

2-Ethyl-1-hexanol was applied topically under occlusion toFischer 344 rats for 5 days, followed by 2 days untreated, 4 days

Fig. 1. Metabolism of 2-ethyl-1-hexanol in the rat (from Albro, 1975). Metabolitesmarked with asterisks were detected.


treated with 0, 500, or 1000 mg/kg body weight/day. Treatment-related clinical signs of toxicity were restricted to the skin at thetreatment site and included exfoliation (minimal severity) at bothdoses and transient erythema at the high dose. Serum triglycerideswere increased in females at both doses. In high-dose females,peripheral blood lymphocytes and absolute spleen weight were re-duced (RIFM, 1988; Weaver et al., 1989).

Albino rabbits (2/sex/dose) were treated by dermal occludedapplication with 0, 400, or 2000 mg/kg body weight/day of isooct-anol (alcohols C7–9, branched CAS No. 68526-83-0) for 12 dayswith 10 applications, lasting 18–24 h each. Control animals re-ceived isopropyl alcohol. No relevant changes in appearance,behavior, body weight, hematology, and urinalysis were noted intreated animals. Necropsy and microscopic evaluation demon-strated no treatment-related findings. Moderate to severe skin irri-tation at the application site was noted in treated animals withnecrosis in high-dose animals. The systemic NOAEL was2000 mg/kg body weight/day (Esso, 1961a, as cited in ExxonMobilChemical Company, 2001a).

5.2.1.2. Secondary alcohols. New Zealand White rabbits (5/sex/dose)were treated topically by occlusive application of 0 or 1000 mg/kgbody weight/day of 3,4,5,6,6-pentamethylheptan-2-ol for 28 con-secutive days at the same site according to OECD test guideline(TG) 410. Severe skin irritation was induced in rabbits receiving1000 mg/kg body weight/day of 3,4,5,6,6-pentamethylheptan-2-ol. However, no alterations in general health, hematology, bio-chemistry, major organ weights, or histopathology were observed.For systemic effects the NOAEL was 1000 mg/kg body weight/day(RIFM, 1985c).

5.2.1.3. Tertiary alcohols. No studies are available for the membersof this subgroup.

5.2.2. Oral studiesOral toxicity studies with branched chain saturated alcohols are


5.2.2.1. Primary alcohols. Three repeated dose oral toxicity studieswere done with isoamyl alcohol. In a 90-day study according to

OECD TG 408, isoamyl alcohol was administered in the drinkingwater in concentrations of 0, 1000 ppm (about 80 mg/kg/d),4000 ppm (about 340 mg/kg/d), and 16,000 ppm (about 1250 mg/kg/d). The NOAEL of isoamyl alcohol was concluded to be4000 ppm in males (340 mg/kg/d) by the authors because the in-crease of erythrocyte counts at this dose fell within the historicalcontrol range. The NOAEL for females was 16,000 ppm (1250 mg/kg/d) because the increase in prothrombin time was only seen in fe-males and fell within the historical control range (Schilling et al.,1997). Isoamyl alcohol was tested in a 17-week toxicity study withAsh/CSE rats. The test substance was administered by gavage to 15male and 15 female rats per group at dose levels of 0 (vehicle), 150,500, or 1000 mg/kg body weight/day in corn oil. Observationsincluded mortality, behavior, body weight, food and water con-sumption, hematology, serum analysis, urinalysis, renal concentra-tion, organ weights, and gross pathology; microscopic pathologyof 25 organs or tissues on control and top dose only. The only ob-served effect was a statistically significant reduced body weightin males at the highest dose level; food intake was reduced, butnot statistically. The NOAEL was 500 mg/kg body weight/day formales and 1000 mg/kg body weight/day for females (Carpaniniand Gaunt, 1973). Finally, isoamyl alcohol was administered tomale and female Wistar rats as a 2% solution in drinking water(about 2000 mg/kg body weight/day) for 56 weeks. No treatment-related effects on body weight, liver weight, ADH, GOT, GPTactivity, and protein content of the liver were found. Histologicalexaminations of the livers, hearts, spleens, kidneys, and lungs didnot show any significant abnormalities (Johannsen and Purchase,1969).

Several studies in mice (gavage, RIFM, 1992a,b) and rats (ga-vage, RIFM, 1988; Weaver et al., 1989), given 2-ethyl-1-hexanolby gavage or drinking water (RIFM, 1988; Weaver et al., 1989),or feed (RIFM, 1992c) for periods of 9–11 days yielded NOAELs inthe range of 100–150 mg/kg body weight/day. Doses of 330 mg/kg body weight/day and higher resulted in CNS depression, lacri-mation, decreased food consumption, and body weights. 2-Ethyl-1-hexanol was administered by gavage to F344 rats and B6C3F1mice of both sexes as an aqueous solution (0, 25, 125, 250, or500 mg/kg body weight/day) for 13 weeks. Histopathology wasundertaken on tissues recommended in US EPA guidelines. TheNOAEL was 125 mg/kg body weight/day for rats and mice (Astillet al., 1996a). In a carcinogenicity study (see Section 5.4) 2-ethyl-1-hexanol was given to male and female rats and mice by gavage5 times a week in 0.005% aqueous Cremophor EL (rats: 0 (water),0 (vehicle), 50, 150, or 500 mg/kg body weight/day, 2 months;mice: 0 (water), 0 (vehicle), 50, 200, or 750 mg/kg body weight/day, 18 months). The NOAEL for systemic toxicity for mice was200 mg/kg body weight/day. In rats, the NOAEL for systemic toxic-ity was 50 mg/kg body weight/day (Astill et al., 1996b).

An oral study according to OECD TG 422 (combined repeateddose and reproductive/developmental toxicity screening test) wasconducted with 3,5,5-trimethyl-1-hexanol. Twelve SD (Crj:CD) ratsper sex and dose group were gavaged with 0 (vehicle: olive oil), 12,60, or 300 mg/kg body weight/day. Exposure duration in males was46 days and in females from day 14 before mating to day 3 of lacta-tion. Males of all dose groups showed alpha-2u-globulin nephropa-thy. In males and females dosed with 60 or 300 mg/kg body weight/day, systemic effects were seen, including reduced body weight andfood consumption. On the basis of these findings, the NOAEL for re-peated dose toxicity was 12 mg/kg body weight/day for male andfemale rats (MHW, Japan, 1997b as cited in OECD/SIDS, 2003).

In a 90-day study according to OECD TG 408 isotridecanol(isoalcohols C11–14, C13 rich, CAS No. 68526-86-3) was administeredorogastrically (gavage) to Sprague–Dawley rats in doses of 0, 100,500, or 1000 mg/kg body weight/day. No effects were observedonly at the lowest dose. The NOAEL for systemic toxicity was

Fig. 2. Metabolism of 4-methyl-2-pentanol in the rat and mouse (OECD/SIDS,2007).


100 mg/kg body weight/day (Exxon Biomedical Sciences Inc., 1986as cited in ExxonMobil Chemical Company, 2001b).

5.2.2.2. Secondary alcohols. A combined repeated dose and repro-ductive/developmental screening study according to OECD TG422 is available with 4-hydroxy-4-methyl-2-pentanone,a metaboliteof 4-methyl-2-pentanol. Ten rats per sex and group were dosed bygavage with 0, 30, 100, 300, or 1000 mg 4-hydroxy-4-methyl-2-pentanone/kg body weight/day in distilled water. Males weredosed for 44 days and females from day 14 before mating to day3 of lactation (approximately for 45 days). No effects were notedat 30 mg/kg body weight/day. Males treated with at least100 mg/kg body weight/day showed male rat-specific alpha-2u-nephropathy. At both 300 and 1000 mg/kg body weight/day, dele-terious effects were observed, including dilatation of the distal tu-bules and fatty degeneration of the proximal tubular epithelium inkidneys in females (300 mg/kg body weight/day) (MHW, Japan1997, as cited in OECD/SIDS, 2007). The NOAEL was 100 mg/kgbody weight/day due to kidney effects in females at 300 mg/kgbody weight/day. The kidney effects in males at 100 mg/kg bodyweight are not relevant for humans.

2,6-Dimethyl-4-heptanol was tested in a 13-week toxicitystudy in rats. Male and female animals were fed a diet containingthe test substance mixed with five parts of microcrystalline cellu-lose (16/sex/group). The daily intake of the test material was11 mg/kg body weight/day for males and females. Female ratsshowed a statistically significantly lower (�12.1%) body weightgain and reduced food efficiency. The authors concluded that thereduction in body weight gain was most probably of no toxicolog-ical significance since the reduction was not associated with othertoxicologically significant differences between test and control ani-mals (Posternak and Vodoz, 1975). Because only the range of bodyweights at the start of the study is given, it is unclear whether theanimals were adequately randomized to control and test groupsbased on body weight. Only one dose was tested, therefore, it can-not be judged whether the body weight gain reduction is a sub-stance-induced effect. A NOAEL for this study for the females

cannot be deduced because of the reduction in body weight gain.For males the NOAEL is 11 mg/kg body weight/day.

5.2.2.3. Tertiary alcohols. No data available.

5.2.3. Inhalation studiesInhalation studies with branched chain saturated alcohols are


5.2.3.1. Primary alcohols. Male and female Wistar rats (10/group/sex) were exposed 6 h daily on 5 days per week for 90 days to 2-ethyl-1-hexanol (purity 99.9%) in concentrations of 15, 40, or120 ml/m3 (highest vapor concentration at room temperature).Neither local nor systemic effects were found. The NOAEL is120 ml/m3 (Klimisch et al., 1998).

Three female Alderly-Park rats exposed in whole body exposurechambers for 13 six-hour exposure periods to saturated vapor of amixture of branched chain alcohols designated isooctan-1-ol(180 ml/m3) showed no adverse effects (Gage, 1970).

5.2.3.2. Secondary alcohols. A 9-day study in rats (10/sex/group, 5 h/day, 5 days/week) exposed to 98, 300, or 905 ml/m3 2,6-dimethyl-heptan-4-one demonstrated increased liver weights from 300 ml/m3 as well as alpha-2u-globulin accumulation in the kidneys ofmales (Dodd et al., 1987). Considering the increased liver weightsas a sign of enzyme induction, the NOAEL is 98 ml/m3.

In a 6-week inhalation study with 2,6-dimethylheptan-4-one,groups of 30 rats (15/sex) were exposed to 0, 125, 252, 534, 925,or 1654 ml/m3 of 2,6-dimethylheptan-4-one, 7 h/day, 5 days/weekfor 6 weeks. Liver and kidney weights were increased at 252 ml/m3 in females. At 925 ml/m3 ‘‘increased incidence of minor patho-logical change” was reported. At 1654 ml/m3 all females died dur-ing the first exposure whereas 12/15 males survived all exposuresat this concentration. Among surviving males at 1654 ml/m3 therewere no major histopathological changes; ‘‘cloudy swelling” in theliver and the convoluted tubules in the kidneys and lung conges-tion were observed in some surviving males (Carpenter et al.,

Table 2-1Acute dermal toxicity studies.

Material Species No./dose LD50 mg/kg body weightb References

Subgroup: primary2-Ethyl-1-butanol Rabbit 4 1260 (95% C.I. 850–1870) Smyth et al. (1954)

Rabbit n.f.i. 2000 Draize et al. (1944)2-Ethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)

Rabbit 4 (males) 2380 (95% C.I. 1700–3340) Smyth et al. (1969)Rabbit 4 >2600 Scala and Burtis (1973)

Isoamyl alcohol Rabbit 10 >5000 RIFM (1976a)Rabbit 6 4000 RIFM (1979c)Rabbit 4 (males) 3970 (95% C.I. 2930–5370) Smyth et al. (1969)

Isotridecan-1-ol (isomeric mixture) Rabbit 4 (males) 7070 Smyth et al. (1962)Rabbit 4 >2600 Scala and Burtis (1973)

2-Methylbutanol Rabbit 4 (males) 3540 Smyth et al. (1962)Rabbit n.f.i. 3540 RIFM (1979b)

3,5,5-Trimethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)

Subgroup: secondary2,6-Dimethyl-4-heptanol Rabbit 20 (males) 4591 (95% C.I. 2036–10,383) Smyth et al. (1949)4-Methyl-2-pentanol Rabbit 5 3560 (2720–4760) Smyth et al. (1951)3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) >2000 RIFM (1985a)

Subgroup: tertiary2,6-Dimethyl-2-heptanol Rabbit 10 >5000 RIFM (1976a)3,6-Dimethyl-3-octanola Rabbit 8 >5000 RIFM (1973a)3-Methyloctan-3-ola Rabbit 10 >5000 RIFM (1978c)

n.f.i.: no further information.a No relevant use was reported.b Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.


1953). Considering the increased liver weights as a sign of enzymeinduction at 250 ml/m3, the NOAEL is 125 ml/m3.

Wistar rats were whole body exposed to 0, 211, 825, or 3700 mg4-methyl-2 pentanol/m3 (0, 50.5, 198, or 886 ml/m3) (purity > 98%)6 h per day and 5 days per week for 6 weeks, 12 animals per sexand group. In females of all concentration groups and in malestreated with 198 ml/m3 or more, increased levels of ketone bodiesin urine were noted. At the highest concentration, absolute kidneyweights increased in males and proteinuria was detected; an in-crease in serum alkaline phosphatase in females was observed.

There were no exposure-related histopathological effects in thekidneys or other organs. The increases in ketone bodies, kidneyweight, and alkaline phosphatase were not considered adverse tox-icological effects. Therefore, the NOAEL was assessed to be3700 mg/m3 (886 ml/m3) by OECD/SIDs (Blair, 1982 as cited inOECD/SIDS, 2007). However, since the increase in alkaline phos-phatase in high-concentration females was significantly elevatedthe NOAEL is judged to be 198 ml/m3.

A 14-week inhalation study (equivalent to OECD TG 413) wasperformed with the metabolite of 4-methyl-2-pentanol and

Table 2-2Acute oral toxicity studies.

Material Species No./dose LD50 mg/kg body weightb References

Subgroup: primary2-Ethyl-1-butanol Rat 5 1850 (95% C.I. 1520–2240) Smyth et al. (1954)

Rat n.f.i. 1850 Nishimura et al. (1994) and Bar andGriepentrog (1967)

Rabbit n.f.i. 1200 Draize et al. (1944)2-Ethyl-1-hexanol Rat n.f.i. 2049 Nishimura et al. (1994)

Rat 5 2460 (1820–3330) Smyth et al. (1969)Rat 5-15 3200 Hodge (1943)Rat males, n.f.i. 7100 (95% C.I. 5500–9199) Shaffer et al. (1945)Rat 36 total 3290 (95% C.I. 2870–3790) Schmidt et al. (1973)Rat n.f.i. 3290 (95% C.I. 2870–3790) Bar and Griepentrog (1967) and Dave and

Lidman (1978)Rat 5 3730 Scala and Burtis (1973)

Isoamyl alcohol Mouse 4 (2/sex) >2000 (pre-screen for micronucleustest)

RIFM (2008)

Rat 5 males 7100 (4820–10400) Smyth et al. (1969)Rat 4/sex males: 1300 (95% C.I. 670–2410)

females: 4000 (95% C.I. 2450–6170)Purchase (1969)

Rat n.f.i. 4360 Golovinskaia (1976)Rat n.f.i. 1300 Nishimura et al. (1994)Rat n.f.i. >5000 RIFM (1979c)Rabbit 10–35 3438 Munch (1972)

Isodecyl alcohol Rat n.f.i. 6500 Nishimura et al. (1994)Isotridecan-1-ol (isomeric mixture) Rat 5 males 17,200 Smyth et al. (1962); Nishimura et al. (1994)

Rat 5 4750 (ca) Scala and Burtis (1973)Rat 3 2000 RIFM (2002a)Rat n.f.i. >2000 (50% branched, 50% linear

form)ECB (1995) as cited in Greim (2000)

Mouse n.f.i. 6500 RIFM (1963a)Mouse n.f.i. 7257 (mixture of branched saturated

primary isomers, purity > 99.7%)ECB (1995) and Hoechst (1961a) as cited inGreim (2000)

2-Methylbutanol Rat 5 males 4920 (95% C.I. 3750–6460) Smyth et al. (1962)Rat n.f.i. 1000 Nishimura et al. (1994)Rat n.f.i. 4010 Rowe and McCollister (1982)Rat 10 (5/sex) 4170 RIFM (1979b)Rat 10 (5/sex) >5000 RIFM (1985e)

3-Methyl-1-pentanol Mouse 10 >2000 RIFM (1982a)3,5,5-Trimethyl-1-hexanol Rat 10 2300 (95% C.I. 1700–3100) RIFM (1977a)

Rat n.f.i. >2000 MHW, Japan (1997a) as cited in OECD/SIDS(2003)

Subgroup: secondary2,6-Dimethyl-4-heptanol Rat 20 males (5/dose) 3560 (95% C.I. 1430–8860) Smyth et al. (1949)

Rat 32 total (16/sex) 4350 Posternak and Vodoz (1975)Rat 5–11 6500 McOmie and Anderson (1949)Mouse 6–14 5000 (95% C.I. 2500–7500) McOmie and Anderson (1949)

3,7-Dimethyl-7-methoxyoctan-2-ol Rat 5/sex 5000 RIFM (1976a)4-Methyl-2-pentanol Rat n.f.i. 2950 Bar and Griepentrog (1967)

Rat n.f.i. 2590 Nishimura et al. (1994)Rat 5 2590 (2260–2970) Smyth et al. (1951)

3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) 5845 (95% C.I. 5360–6375) RIFM (1984a)

Subgroup: tertiary2,6-Dimethyl-2-heptanol Rat 10 >5000 RIFM (1976a)

Rat n.f.i. 6800 RIFM (1979a)3,6-Dimethyl-3-octanola Rat 10 >5000 RIFM (1973a)3-Methyloctan-3-ola Rat 10 3400 (95% C.I: 2500–4700) RIFM (1978c)

n.f.i.: no further information.a No relevant use was reported.b Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.


4-methyl-2-pentanone. Male and female rats and mice (14 per spe-cies/sex/group) were exposed to 0, 50, 250, or 1000 ml 4-methyl-2-pentanone/m3 (0, 204, 1020, or 4090 mg/m3) 6 h per day and 5 daysper week. Slight, but statistically significant, increases in absoluteand relative liver weight were observed in males of both species atthe highest concentration. As there were no histopathologicalchanges in the livers observed, the changes were considered to beof no toxicological relevance. Male rats demonstrated alpha-2u-globulin ephropathy. The NOAEL was considered to be 1000 ml/m3

(4090 mg/m3) for both species (Phillips et al., 1987).In a two-generation study with rats with 4-methyl-2-pentanone clin-

ical signs in the form of CNS depression were noted during exposures of

adults to 1000 and 2000 ml/m3. The systemic NOAEL was 500 ml/m3 inthis study. Signs of irritation were not reported (Nemec et al., 2004).

5.2.3.3. Tertiary alcohols. No data available.

5.3. Mutagenicity and genotoxicity

5.3.1. In vitro mutagenicity studiesThe available studies are summarized in Table 4-1.

5.3.1.1. Indicator studies. In a study of the cytotoxic and genotoxiceffects of a number of alcohols and ketones, 2-methylbutanol

Table 2-3Acute inhalation and miscellaneous toxicity studies in animals.

Material Dose route Species No./dose LD50 and/or clinical signs References

Subgroup: primary2-Ethyl-1-butanol Inhalation, exposure to

concentrated vaporsRat 6 Maximum time for no death: 8 h Smyth et al. (1954)

2-Ethyl-1-hexanol Inhalation, exposure toconcentrated vapors

Rat 6 Maximum time for no death: 8 h Smyth et al. (1969)

Whole body exposure for 6 h toair bubbled through 2-ethyl-1-hexanol to yield a nominalchamber concentration of227 ml/m3

Rat, mouse,guinea pig

10/species No mortality, irritation of eyes,nose, throat, and respiratorypassages, blinking, lacrimation,preening, nasal discharge,salivation, gasping, and chewingmovements

Scala and Burtis (1973)

Intraperitoneal Rat 5–15 LD50 650 mg/kg body weight Hodge (1943)Intraperitoneal Rat 5/sex LD50 500–1000 mg/kg body

weightDave and Lidman (1978)

Intraperitoneal Mouse 5–15 LD50 780 mg/kg body weight Hodge (1943)Isoamyl alcohol i.v. Mouse Not reported LD50 2.64 mmol/kg body weight

(233 mg/kg body weight)Chvapil et al. (1962)

Isotridecan-1-ol(isomeric mixture)

Inhalation, exposure to airsaturated with alcohol vapor atroom temperature for 8 h

Rat 6 rats/14 days No effects RIFM (1963c) and Smythet al. (1962)

Inhalation to 12 ml/m3

(saturation concentration at30 �C) for 6 h

Rat, mouse,guinea pig

10/species No effects Scala and Burtis (1973)

Intraperitoneal Mouse n.f.i. LD50 600 mg/kg body weight RIFM (1963b)2-Methylbutanol Intraperitoneal Rat n.f.i. 1000 mg/kg body weight:

sedation, irritation of theperitoneum and injury of thelungs; 2000 mg/kg body weight:respiratory arrest and death

Haggard et al. (1945)

Intraperitoneal Mouse 10 (5/sex) LD50 between 200 and700 mg/kg body weight

RIFM (1979b)

Inhalation, saturatedatmosphere at 20 �C (calculated:10,050 mg/m3 bzw. 2744 ml/m3)for 7 h

Rat n.f.i. No mortality, escape behavior,intermittent respiration

RIFM (1979b)

Inhalation, saturated vapor for8 h

Rat 6 No mortality Rowe and McCollister(1982)

3-Methyl-1-pentanol Intraperitoneal Mouse 10 LD50 > 250 mg/kg body weight;P2000 mg/kg body weight:10/10 animals died within30 min (respiratory depression)

RIFM (1982a)

Subgroup: secondary2,6-Dimethyl-4-heptanol Inhalation, exposure to

substantially saturated vapor orcooled mist (400 ml/m3) for 8 h

Rat 12 No mortality Smyth et al. (1949)

Inhalation, exposure to asaturated vapor–air mixture for12 h

Mouse 10 2.0 mg/l: no mortality McOmie and Anderson(1949)

4-Methyl-2-pentanol Inhalation for 8 h at 2000 ppm Rat 6 5/6 animals died within 14 days Carpenter et al. (1949) andSmyth et al. (1951)

Inhalation exposure to asaturated vapor–air at 20 �C for4–15 h

Mouse 10 Somnolence and anesthesiaMortality at 10 h (6/10) and 15 h(8/10)

McOmie and Anderson(1949)

3,4,5,6,6-Pentamethylheptan-2-ol

Intraperitoneal injection at dosesof 50, 166, 500, 750, 1000, 1250,1666, and 3000 mg/kg bodyweight

Mouse 2 One death at 1250 mg/kgClinical signs observed for allmice above 1000 mg/kg

RIFM (1985d)

n.f.i.: no further information.


Tabl

e3-

1Re

peat

eddo

seto

xici

tyst

udie

s–

derm

al.

Mat

eria

lM

eth

odD

ose

Spec

ies

(No.

/dos

e)R

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

Sin

gle

appl

icat

ion

/day

onth

esh

aved

back

for

12da

ys2

ml/

kgbo

dyw

eigh

t/da

y(1

600

mg/

kgbo

dyw

eigh

t/da

y)

Rat

(10)

Abs

olu

tean

dre

lati

veth

ymu

sw

eigh

tsde

crea

sed,

live

rgr

anu

lom

as,b

ron

chie

ctas

isin

the

lun

g,re

nal

tubu

lar

epit

hel

ial

nec

rose

s,ed

emat

ous

hea

rtan

dte

stes

and

decr

ease

dsp

erm

atog

enes

is

Sch

mid

tet

al.(

1973

)

5da

ysoc

clu

sive

trea

tmen

t,2

days

un

trea

ted,

4da

ystr

eate

d

0,50

0,or

1000

mg/

kgbo

dyw

eigh

t/da

yFi

sch

er34

4ra

t(1

0/se

x)P

500

mg/

kgbo

dyw

eigh

t/da

y:ex

foli

atio

n(m

inim

alse

veri

ty),

sple

enw

eigh

tde

crea

sed;

seru

mtr

igly

ceri

des

incr

ease

d(f

emal

es);

1000

mg/

kgbo

dyw

eigh

t:tr

ansi

ent

eryt

hem

a(d

ays

4–7)

(gra

ded

asba

rely

perc

epti

ble)

,dec

reas

edab

solu

tesp

leen

wei

ght,

lym

phoc

ytes

decr

ease

d

RIF

M(1

988)

;W

eave

ret

al.(

1989

)

Isoo

ctan

ol(a

lcoh

ols

C7–

C9

bran

ched

CA

SN

o.68

526-

83-0

)

Occ

lusi

ve,1

8–24

hfo

r12

days

(10

trea

tmen

ts)

0(i

sopr

opyl

alco

hol

),40

0,20

00m

g/kg

body

wei

ght/

day

Rab

bit

(Alb

ino)

(2/s

ex)

Syst

emic

NO

AEL

:20

00m

g/kg

body

wei

ght/

day

400

mg/

kgbo

dyw

eigh

t/da

y:m

oder

ate

tose

vere

irri

tati

on,

fiss

ure

,cor

iace

ous

skin

2000

mg/

kgbo

dyw

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t/da

y:n

ecro

sis

ofth

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in

Esso

Res

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gin

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ng

Com

pan

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961)

asci

ted

inEx

xon

Mob

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hem

ical

Com

pan

y(2

001a

)

Subg

roup

:se

cond

ary

3,4,

5,6,

6-Pe

nta

met

hyl

hep

tan

-2-o

lD

erm

al(o

cclu

sive

),6

h/d

ayfo

r28

days

(OEC

DTG

410)

0(w

ater

),10

00m

g/kg

body

wei

ght/

day

Rab

bit

(New

Zeal

and

Wh

ite)

(5/s

ex)

Syst

emic

NO

AEL

:10

00m

g/kg

body

wei

ght/

day

1000

mg/

kgbo

dyw

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t/da

y:(f

),se

vere

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ons:

wel

lde

fin

edse

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hem

aan

ded

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his

topa

thol

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ofth

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in:

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ive

chan

ges

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mis

,ass

ocia

ted

infl

amm

atio

n,h

yper

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tosi

s,sc

abfo

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ion

RIF

M(1

985c

)

Der

mal

(occ

lusi

ve),

6h

/day

for

28da

ys30

,100

,300

,an

d10

00m

g/kg

/day

Rab

bit

(New

Zeal

and

Wh

ite)

(10/

sex)

Syst

emic

NO

AEL

:10

00m

g/kg

body

wei

ght/

day

Slig

ht

tom

oder

ate

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alir

rita

tion

;sev

ere

irri

tati

onat

hig

h(3

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d10

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/day

)do

ses;

reve

rsib

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ter

8da

ys

RIF

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986b

)

Abb

revi

atio

ns

see

Tabl

e3-

3.


Tabl

e3-

2Re

peat

eddo

seto

xici

tyst

udie

s–

oral

.

Mat

eria

lM

eth

odD

ose

Spec

ies

(No.

/dos

e)R

esu

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Ref

eren

ces

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roup

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y2-

Eth

yl-1

-hex

anol

Gav

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22da

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330,

660,

930

mg/

kgbo

dyw

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tin

sun

flow

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ntr

ols

10m

loi

l/kg

body

wei

ght

Rat

(10)

930

mg/

kg:

body

wei

ght

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y17

decr

ease

d,m

orta

lity

:1/

10Sc

hm

idt

etal

.(19

73)

Gav

age,

9tr

eatm

ents

in11

days

0,10

0,33

0,10

00,1

500

mg/

kgbo

dyw

eigh

t/da

y,te

stsu

bsta

nce

un

dilu

ted

Fisc

her

344

rat

(10/

sex)

Syst

emic

NO

AEL

100

mg/

kgbo

dyw

eigh

t/da

y33

0m

g/kg

body

wei

ght/

day:

hyp

oact

ivit

y,at

axia

,pr

ostr

atio

n,d

elay

edri

ghti

ng

refl

ex,m

usc

letw

itch

,la

crim

atio

n,a

nd

uri

ne-

stai

ned

fur.

Food

con

sum

ptio

nan

dbo

dyw

eigh

tsde

crea

sed

(mal

es),

thym

icat

roph

yan

dly

mph

oid

cell

dege

ner

atio

nin

the

thym

us;

1000

mg/

kgbo

dyw

eigh

t/da

y:fo

odco

nsu

mpt

ion

and

body

wei

ghts

decr

ease

d(f

emal

es),

tota

lpe

riph

eral

bloo

dle

uko

cyte

san

dly

mph

ocyt

es,s

plee

nw

eigh

tde

crea

sed

(fem

ales

),ab

solu

tean

dre

lati

veli

ver

wei

ght

incr

ease

dw

ith

out

his

topa

thol

ogic

alfi

ndi

ngs

,abs

olu

tean

dre

lati

vest

omac

hw

eigh

tin

crea

sed

wit

hh

yper

kera

tosi

s,m

uco

sal

hyp

erpl

asia

,ede

ma,

exoc

ytos

is,a

nd

gast

riti

s;15

00m

g/kg

body

wei

ght/

day:

tota

lpe

riph

eral

bloo

dle

uko

cyte

san

dly

mph

ocyt

es,s

plee

nw

eigh

tde

crea

sed

(mal

es),

abso

lute

and

rela

tive

test

esw

eigh

tsde

crea

sed,

no

his

topa

thol

ogic

alfi

ndi

ngs

inte

stes

orki

dney

sat

any

dose

RIF

M(1

988)

;W

eave

ret

al.

(198

9)

Dri

nki

ng

wat

er,9

days

0,30

8pp

m(h

alf-

satu

rate

d)an

d63

6pp

m(s

atu

rate

d):

61.1

and

151.

1m

g/kg

body

wei

ght/

day

for

mal

esan

d73

.4an

d17

3.5

mg/

kgbo

dyw

eigh

t/da

yfo

rfe

mal

es.

Fisc

her

344

rat

(10/

sex)

No

adve

rse

effe

cts

RIF

M(1

988)

;W

eave

ret

al.

(198

9)

Gav

age,

9do

ses

in11

d0,

100,

330,

1000

,or

1500

mg/

kgbo

dyw

eigh

t/da

y,in

prop

ylen

egl

ycol

B6C

3F1

mic

e(1

0/se

x)Sy

stem

icN

OA

EL10

0m

g/kg

body

wei

ght/

day

330

mg/

kgbo

dyw

eigh

t/da

y:re

lati

veli

ver

and

stom

ach

wei

ghts

(mal

e)in

crea

sed;

1000

mg/

kgbo

dyw

eigh

t/da

y:re

lati

veli

ver

and

stom

ach

wei

ghts

(fem

ale)

incr

ease

d;2/

20de

ath

s;15

00m

g/kg

body

wei

ght/

day:

atax

ia,l

eth

argy

,pil

oere

ctio

n,

dysp

nea

,hyp

oth

erm

y,ab

dom

inal

orla

tera

lpo

siti

onan

dlo

ssof

con

scio

usn

ess,

redu

ctio

nin

food

con

sum

ptio

n(m

ales

),re

lati

vete

stes

wei

ght

decr

ease

d;cl

inic

alch

emis

try

and

hem

atol

ogy

no

subs

tan

ce-r

elat

edch

ange

s.N

oh

isto

path

olog

ical

exam

inat

ion

s;10

/20

deat

hs

RIF

M(1

992a

)

Gav

age,

9do

ses

in11

d0,

100,

330,

1000

,or

1500

mg/

kgbo

dyw

eigh

t/da

y,in

anaq

ueo

us

emu

lsio

nin

Cre

mop

hor

EL

B6C

3F1

mic

e(1

0/se

x)Sy

stem

icN

OA

EL10

0m

g/kg

body

wei

ght/

day

300

mg/

kgbo

dyw

eigh

t/da

y:ac

anth

osis

wit

hh

yper

kera

tosi

sin

the

fore

stom

ach

;P

1000

mg/

kgbo

dyw

eigh

t/da

y:re

lati

veli

ver

(mal

es)

and

stom

ach

wei

ghts

(fem

ale)

incr

ease

d,h

yper

trop

hy

ofh

epat

ocyt

es;

1/20

deat

hs;

1500

mg/

kgbo

dyw

eigh

t/da

y:at

axia

,let

har

gy,p

iloe

rect

ion

,ab

dom

inal

orla

tera

lpo

siti

onan

dlo

ssof

con

scio

usn

ess;

clin

ical

chem

istr

yan

dh

emat

olog

y,n

osu

bsta

nce

-rel

ated

chan

ges;

5/20

deat

hs.

RIF

M(1

992b

)

Die

t,11

days

500,

980,

1430

,or

2590

mg/

kg/d

ay(m

ales

)54

0,10

60,

1580

,or

2820

mg/

kg/d

ay(f

emal

es)

F344

rat

(10/

sex)

NO

AEL

<50

0(m

)or

540

(f)

mg/

kgbo

dyw

eigh

t/da

yP

500

(m)

or54

0(f

)m

g/k

g/d:

rela

tive

stom

ach

wei

ghts

incr

ease

dfe

mal

es(f

);tr

igly

ceri

des

and

alan

ine

amin

otra

nsf

eras

ede

crea

sed,

mal

es(m

);fe

edco

nsu

mpt

ion

sign

ifica

ntl

yde

crea

sed

(m)

RIF

M(1

992c

)

(con

tinu

edon

next

page

)


Tabl

e3-

2(c

onti

nued

)

Mat

eria

lM

eth

odD

ose

Spec

ies

(No.

/dos

e)R

esu

lts

Ref

eren

ces

P98

0(m

)or

1060

(f)

mg/

kg/d

:ab

solu

tean

dre

lati

veli

ver

wei

ghts

incr

ease

d(m

,f);

feed

con

sum

ptio

nde

crea

sed

(m,f

);w

ater

con

sum

ptio

nsi

gnifi

can

tly

decr

ease

d(f

);tr

igly

ceri

dean

dal

anin

eam

inot

ran

sfer

ase

decr

ease

d(m

);P

1430

(m)

or15

80(f

)m

g/kg

/d:

food

con

sum

ptio

nre

duce

d(m

,f),

hyp

ertr

oph

yof

hep

atoc

ytes

;bo

dyw

eigh

tsi

gnifi

can

tly

redu

ced

(m);

wat

erco

nsu

mpt

ion

sign

ifica

ntl

yre

duce

d(m

,f);

trig

lyce

ride

and

alan

ine

amin

otra

nsf

eras

ede

crea

sed

(mal

es);

2590

(m)

or28

20(f

)m

g/kg

/d:

abso

lute

and

rela

tive

live

rw

eigh

tsin

crea

sed

(m,f

);bo

dyw

eigh

tde

crea

sed

(m,f

);fe

edco

nsu

mpt

ion

decr

ease

d(m

,f),

wat

erco

nsu

mpt

ion

sign

ifica

ntl

yde

crea

sed

(m,f

);tr

igly

ceri

dean

dal

anin

eam

inot

ran

sfer

ase

decr

ease

d(m

,f)

Gav

age,

5da

ys/w

eek,

13w

eeks

0,25

,125

,250

or50

0m

g/kg

body

wei

ght/

day

F344

rat,

B6C

3F1

mic

e(1

0/se

x)N

OA

EL:

125

mg/

kgbo

dyw

eigh

t/da

y,ra

tsan

dm

ice

P25

0m

g/kg

body

wei

ght/

day:

rela

tive

live

r,ki

dney

(rat

s,bo

thse

xes)

and

stom

ach

wei

ghts

(fem

ale

rats

)in

crea

se,f

atde

posi

tsin

the

live

rce

lls

(mal

era

ts)

decr

ease

,rel

ativ

eli

ver

and

stom

ach

wei

ghts

(mal

em

ice)

incr

ease

d;50

0m

g/kg

body

wei

ght/

day:

acan

thos

isof

the

fore

stom

ach

(fem

ale

mic

e);

pero

xiso

me

prol

ifer

atio

n(m

arke

r:cy

anid

e-in

sen

siti

vepa

lmit

oylC

oAox

idas

e)(r

ats,

both

sexe

s)in

crea

se

Ast

ill

etal

.(19

96a)

Gav

age,

24m

onth

s,5

days

/wee

k0

(wat

er),

0(v

ehic

le),

50,

150,

500

mg/

kg/b

ody

wei

ght/

day

in0.

005%

Cre

mop

hor

EL

F344

rats

(50/

sex)

Syst

emic

NO

AEL

:50

mg/

kgbo

dyw

eigh

t/da

yP

150

mg/

kgbo

dyw

eigh

t/da

y:bo

dyw

eigh

tga

inde

crea

sed,

poor

clin

ical

stat

e,la

bore

dbr

eath

ing,

pilo

erec

tion

oru

rin

e-st

ain

edge

nit

alre

gion

Ast

ill

etal

.(19

96b)

3w

eeks

,ora

lad

min

istr

atio

n�

833

mg/

kgn

.f.i.

Rat

(n=

5)St

atis

tica

lin

crea

se(p

<.0

5)in

live

rw

asob

serv

edY

amad

a(1

974)

Gav

age,

18m

onth

s,5

days

/wee

k0

(wat

er),

0(v

ehic

le),

50,

200,

750

mg/

kgbo

dyw

eigh

t/da

yin

0.00

5%C

rem

oph

orEL

B6C

3F1

mic

e(5

0/se

x)Sy

stem

icN

OA

EL:

200

mg/

kgbo

dyw

eigh

t/da

y75

0m

g/kg

body

wei

ght/

day:

incr

ease

dm

orta

lity

,bod

yw

eigh

tga

ins

decr

ease

d,fo

odco

nsu

mpt

ion

decr

ease

d,fa

tty

live

r,h

yper

plas

iaof

the

fore

stom

ach

epit

hel

ium

Ast

ill

etal

.(19

96b)

Isoa

myl

alco

hol

Dri

nki

ng

wat

er3

mon

ths

0,10

00,4

000,

16,0

00m

g/l

drin

kin

gw

ater

(pu

rity

>98

.6%

);es

tim

ated

tobe

:0,

80,3

20,1

280

mg/

kgbo

dyw

eigh

t/da

y

Wis

tar

rat

(10/

sex)

NO

AEL

fem

ales

=12

80m

g/kg

body

wei

ght/

day

NO

AEL

mal

es=

320

mg/

kgbo

dyw

eigh

t/da

y12

80m

g/kg

body

wei

ght

(mal

es):

eryt

hro

cyte

valu

ein

crea

sed;

mea

nco

rpu

scu

lar

volu

me

(MC

V)

decr

ease

d;m

ean

corp

usc

ula

rh

emog

lobi

n(M

CH

)de

crea

sed

320

and

1280

mg/

kg/d

ay(f

emal

es):

incr

ease

dpr

oth

rom

bin

tim

e

Sch

illi

ng

etal

.(19

97)

RIF

M(1

991b

)

Gav

age,

dail

yfo

r17

wee

ks0

(veh

icle

),15

0,50

0,10

00m

g/kg

body

wei

ght/

day,

inco

rnoi

l

Ash

/CSE

rat

(15/

sex)

addi

tion

al5

anim

als

exam

ined

afte

r3

and

6w

eeks

,re

spec

tive

ly

NO

AEL

fem

ales

=10

00m

g/kg

body

wei

ght/

day

NO

AEL

mal

es=

500

mg/

kgbo

dyw

eigh

t/da

y10

00m

g/kg

body

wei

ght/

day:

mal

es:

body

wei

ght

gain

decr

ease

Car

pan

ini

and

Gau

nt

(197

3)

Dri

nki

ng

wat

er,

56w

eeks

0,2%

(200

0m

g/kg

body

wei

ght/

day)

Wis

tar

rat

(20/

sex)

No

sign

ifica

nt

effe

cts

Joh

ann

sen

and

Purc

has

e(1

969)

Neu

roto

xici

ty:

Wh

ole

body

expo

sure

sw

ith

a30

min

hab

itu

atio

nan

d4

hex

posu

re

3–4

expo

sure

sto

the

vari

ous

solv

ent

con

cen

trat

ion

s(b

etw

een

25%

and

75%

)

Mal

eal

bin

oSP

Fra

ts16

(4/g

rou

p)Th

eco

nce

ntr

atio

nth

atev

oked

a30

%de

pres

sion

inth

ere

cord

edac

tivi

tyw

asde

term

ined

tobe

1700

ppm

Fran

tik

etal

.(19

94)

Neu

roto

xici

ty:

Wh

ole

body

expo

sure

wit

ha

30m

inh

abit

uat

ion

and

2h

expo

sure

3–4

expo

sure

sto

vari

ous

solv

ent

con

cen

trat

ion

s(b

etw

een

25%

and

75%

)

Fem

ale

mic

eof

the

Hst

rain

32(4

/gro

up)

The

con

cen

trat

ion

that

evok

eda

30%

depr

essi

onin

the

reco

rded

acti

vity

was

dete

rmin

edto

be95

0pp

mFr

anti

ket

al.(

1994

)


Isot

ride

can

ol(A

lcoh

ols,

C11

–14

iso,

C13

rich

,CA

SN

o.68

526-

86-3

)

Gav

age,

7da

ys/w

eek,

for

14w

eeks

,OEC

DTG

408

0(d

isti

lled

wat

er),

100,

500,

1000

mg/

kgbo

dyw

eigh

t/da

y

Spra

gue–

Daw

ley

rat

(20/

sex)

NO

AEL

:10

0m

g/kg

body

wei

ght/

day

P50

0m

g/kg

body

wei

ght/

day:

food

con

sum

ptio

nde

crea

sed

(m),

body

wei

ght

decr

ease

d(m

),m

ean

plat

elet

cou

nts

incr

ease

d(f

),gl

uco

sede

crea

sed

(f),

live

rw

eigh

tin

crea

sed

(m,

f),

1000

mg/

kgbo

dyw

eigh

t/da

y:gl

uco

sede

crea

sed

(m),

chol

este

rol

decr

ease

d(f

),re

l.br

ain

and

test

esw

eigh

tin

crea

sed

(m),

rel.

adre

nal

wei

ght

incr

ease

d(f

)

Exxo

nB

iom

edic

alSc

ien

ces

Inc.

(198

6)as

cite

din

Exxo

nM

obil

Ch

emic

alC

ompa

ny

(200

1b)

3,5,

5-Tr

imet

hyl

-1-

hex

anol

Gav

age,

mal

es:

14da

ys14

4m

g/kg

body

wei

ght/

day

Ald

erly

-Par

kW

ista

rra

tIn

crea

sein

the

rela

tive

live

rw

eigh

tN

odi

ffer

ence

from

con

trol

sin

body

wei

ght,

clin

ical

,or

his

topa

thol

ogic

alsi

gns.

Pero

xiso

me

prol

ifer

atio

n,

hyp

och

oles

tero

lem

ia,a

nd

hyp

ogly

ceri

daem

iaw

ere

not

evid

ent

Rh

odes

etal

.(19

84)

Gav

age,

mal

es:

46da

ys,f

emal

es:

from

14da

ysbe

fore

mat

ing

toda

y3

ofla

ctat

ion

,O

ECD

TG42

2

0,12

,60,

300

mg/

kgbo

dyw

eigh

t/da

yin

oliv

eoi

lSD

(Crj

:CD

)ra

t(1

2/se

x)N

OA

ELsy

stem

icto

xici

tym

ales

and

fem

ales

:12

mg/

kgbo

dyw

eigh

t/da

yP

12m

g/kg

body

wei

ght/

day:

ren

alh

yali

ne

drop

lets

,eo

sin

oph

ilic

bodi

es(m

)P

60m

g/kg

body

wei

ght/

day:

rela

tive

live

ran

dki

dney

wei

ght

incr

ease

(m,f

),re

nal

epit

hel

ial

fatt

ych

ange

(f);

impl

anta

tion

inde

xde

crea

sed

(f)

300

mg/

kgbo

dyw

eigh

t/da

y:1

fdi

ed,3

fki

lled

(wea

knes

s);

body

wei

ghts

incr

ease

(m),

food

con

sum

ptio

nin

crea

sed

(m),

body

wei

ghts

decr

ease

d(f

),fo

odco

nsu

mpt

ion

decr

ease

(f);

tota

lli

tter

loss

in2

dam

s

MH

W,J

apan

(199

7b)

asci

ted

inO

ECD

/SID

S(2

003)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-h

epta

nol

Die

t,13

wee

ks0,

11(f

),11

(m)

mg/

kgbo

dyw

eigh

t/da

ym

ixed

wit

hm

icro

crys

tall

ine

cell

ulo

se

Rat

(16/

sex)

No

NO

AEL

(fem

ales

)ba

sed

onre

duct

ion

sof

body

wei

ght

gain

syst

emic

NO

AEL

(mal

es):

11m

g/kg

body

wei

ght;

11.0

6m

g/kg

body

wei

ght/

day:

(fem

ales

)bo

dyw

eigh

tga

inan

dfo

odef

fici

ency

(wei

ght

gain

ed(g

)/fo

odco

nsu

med

(g)�

100,�

10.8

%)

decr

ease

(bod

yw

eigh

tga

in�

12.1

%).

Hem

atol

ogic

alan

dh

isto

logi

cal

exam

inat

ion

sw

ith

out

any

sign

ifica

nt

diff

eren

ces

betw

een

test

and

con

trol

rats

Post

ern

akan

dV

odoz

(197

5)

4-H

ydro

xy-4

-met

hyl-

2-pe

ntan

one

Gav

age,

mal

es:

44da

ys,f

emal

es:

from

14d

befo

rem

atin

gto

day

3of

lact

atio

n(a

ppro

x.45

days

),O

ECD

TG42

2

0,30

,100

,300

,100

0m

g/kg

body

wei

ght/

day

inw

ater

Crj

:CD

(SD

)ra

t(1

0/se

x)N

OA

EL:

100

mg/

kgbo

dyw

eigh

t/da

yP

100

mg/

kgbo

dyw

eigh

t/da

y:m

ale

alph

a-2u

-nep

hro

path

yP

300

mg/

kgbo

dyw

eigh

t/da

y:lo

com

otor

acti

vity

and

stim

ula

tion

resp

onse

decr

ease

(m,f

);di

lata

tion

ofth

edi

stal

tubu

les

and

fatt

yde

gen

erat

ion

ofth

epr

oxim

altu

bula

rep

ith

eliu

min

kidn

eys

(f)

P10

00m

g/kg

body

wei

ght/

day:

hep

atoc

ellu

lar

hyp

ertr

oph

y(m

,f),

alte

red

bloo

dpa

ram

eter

s(i

ncr

ease

:pl

atel

etco

un

ts,

GO

T,to

tal

prot

ein

,tot

alch

oles

tero

l,to

tal

bili

rubi

n,b

lood

ure

an

itro

gen

,cre

atin

ine,

calc

ium

(m);

decr

ease

:gl

uco

se)

(m),

dila

tati

onof

dist

altu

bule

sof

kidn

eys

(m),

vacu

oliz

atio

nof

the

zon

afa

scic

ula

taof

the

adre

nal

s(m

);bo

dyw

eigh

tga

inde

crea

se(f

),re

l.li

ver

wei

ght

incr

ease

(f)

MH

W,J

apan

(199

7)as

cite

din

OEC

D/S

IDS

(200

7)

Abb

revi

atio

ns

see

Tabl

e3-

3.


and isoamyl alcohol were tested for their potency to induce DNAdamage in V79 Chinese hamster fibroblasts, human lung carci-noma epithelial A549 cells and human peripheral blood cells withthe alkaline comet assay. In V79 and A549 cells 2-methylbutanoland isoamyl alcohol showed DNA damage only at cytotoxic con-centrations. The COMET assay could not be performed in humanperipheral blood cells due to extreme cytotoxicity (cells with com-pletely fragmented DNA) (Kreja and Seidel, 2001, 2002).

2-Methylbutanol and isoamyl alcohol gave negative results in alight absorption umu test and positive results in a luminescentumu test (Nakajima et al., 2006). These tests are based on the abil-ity of DNA damaging agents to induce expression of the umu oper-on, which is responsible for chemical and radiation mutagenesis, inEscherichia coli. The positive result is not plausible in view of theother negative tests for genotoxicity (see below) and the overallnegative results for branched chain saturated alcohols. 2-Ethyl-1-hexanol gave a negative and a positive result in two rec-assays(Saido et al., 2003; Tomita et al., 1982). The results of this test sys-tem are not considered for the evaluation of the genotoxicity of thealcohols under study because positive results were often assessedwith substances, which were negative in other genotoxicity testsystems. A test for induction of unscheduled DNA synthesis with2-ethyl-1-hexanol was negative in primary rat hepatocytes (Hodg-son et al., 1982).

4-Methyl-2-pentanone was negative in a vitro UDS test (no fur-ther information; IPCS, 1990 as cited in OECD/SIDS, 2004).

5.3.1.2. Mutation studies. The primary alcohols 3,5,5-trimethyl-1-hexanol, 2-ethyl-1-hexanol, isotridecan-1-ol (isomeric mixture),the secondary alcohols 4-methyl-2-pentanol, its metabolites 4-methyl-2-pentanone and 4-hydroxy-4-methyl-2-pentanone, 2,6-di-methyl-4-heptanol and its metabolite 2,6-dimethylheptan-4-one,as well as a mixture of the secondary alcohol 3,4,5,6,6-pentameth-ylheptan-2-ol (55–80%) and 3,4,5,6,6-pentamethylheptan-2-on(20-45%) were inactive in Ames tests. Urine from Sprague–Dawleyrats dosed by oral gavage for 15 days with 1000 mg 2-ethyl-1-hex-anol/kg body weight/day was found to be non-mutagenic in Salmo-nella typhimurium with and without addition of rat livermicrosomes or beta-glucuronidase/arylsulfatase (DiVincenzoet al., 1983, 1985). 2-Ethyl-1-hexanol was mutagenic in S. typhimu-rium TA100 using the mutation to resistance to 8-azaguanine (Seed,1982). As this test was performed only in one S. typhimurium strainand the other mutagenicity tests using reversion to histidine inde-pendence were negative, this result seems to be of limitedrelevance.

The primary alcohols 2-methylbutanol, isoamyl alcohol, and 2-ethyl-1-hexanol were also inactive in mammalian cell systems(TK+/� mouse lymphoma mutagenicity assay in L5178Y cells orHPRT assay with Chinese hamster V79 fibroblast cells) (Kirbyet al., 1983; Kreja and Seidel, 2002). For 4-methyl-2-pentanone, amouse lymphoma test was considered equivocal (no further infor-mation; IPCS, 1990 as cited in OECD/SIDS, 2004).

A Saccharomyces cerevisiae mitotic gene conversion assay wasnegative for 2,6-dimethylheptan-4-one (OECD/SIDS, 2004).

The secondary alcohol 4-methyl-2-pentanol tested for genemutation in Saccharomyces cerevisiae gave negative results (Clare,1983 as cited in OECD/SIDS, 2007).

5.3.1.3. Chromosome aberration studies. The primary alcohols 2-ethyl-1-hexanol and 3,5,5-trimethyl-1-hexanol as well as the sec-ondary alcohol 4-methyl-2-pentanol and 2,6-dimethylheptan-4-one, did not induce chromosome aberrations in vitro when incu-bated with Chinese hamster ovary, Chinese hamster lung or rat li-ver cells (Brooks et al., 1985 as cited in OECD/SIDS, 2004; Brookset al., 1988; Clare, 1983 as cited in OECD/SIDS, 2007; MHW, Japan,1997d as cited in OECD/SIDS, 2003; Phillips et al., 1982). 4-Hydro-

xy-4-methyl-2-pentanone, tested for chromosomal aberrations inChinese hamster lung cells, revealed significantly increased poly-ploidy in the two highest doses (600 and 1200 lg/ml). Informationas to whether this was done with or without S9 was not available.This test was considered negative because a trend test showed nodose-dependency (MHW, Japan, 1997 as cited in OECD/SIDS, 2007).

5.3.1.4. Micronucleus studies. The primary alcohols 2-methylbuta-nol and isoamyl alcohol did not induce micronuclei in V79 Chinesehamster fibroblasts, with or without addition of hepatic S9 mixfrom Aroclor induced rats (Kreja and Seidel, 2002).

5.3.2. In vivo studiesThe available studies are summarized in Table 4-2. No indica-

tion for a covalent binding of 2-ethyl-1-hexanol to liver DNA of ratsand mice was noted (Albro et al., 1982; Däniken et al., 1984). 2-Ethyl-1-hexanol was not mutagenic in the dominant lethal test(Rushbrook et al., 1982; only as abstract) and not clastogenic in abone marrow chromosome aberration test (Putman et al., 1983),although this result is not reliable because the doses used failedto induce toxicity. 2-Ethyl-1-hexanol (Astill et al., 1986; Barberet al., 1985; only as abstract, no information on the method, andvalidity cannot be assessed) and 3,4,5,6,6-pentamethylheptan-2-ol were not clastogenic in the mouse bone marrow micronucleustest (RIFM, 1985d). Isoamyl alcohol showed an increase in chromo-somal aberrations in bone marrow cells of rats (Barilyak and Koza-chuk, 1988). The study is invalid as no information is available if apositive control group was used, the definite dose was not men-tioned (1/5 of LD50), only one dose was tested, the control animalsdid not show any chromosomal aberrations, and the purity of thesubstance was not given. The authors also found chromosomalaberrations with propanol, which was not genotoxic in a varietyof tests (Greim, 1996). An in vivo mouse micronucleus assay wasconducted on isoamyl alcohol (RIFM, 2008) at doses of 500, 1000,and 2000 mg/kg there was no increase in the frequency of detectedmicronuclei. Isoamyl alcohol was determined to be non-mutagenicin the micronucleus assay.

Additionally, 4-methyl-2-pentanone was negative in an in vivomicronucleus test (no further information; IPCS, 1990 as cited inOECD/SIDS, 2004).

5.4. Carcinogenicity

The available carcinogenicity studies are summarized in Tables5-1.

5.4.1. Cell transformation assaysIn a cell transformation study with mouse epidermis-derived

JB6 cells 2-ethyl-1-hexanol did not promote JB6 cells to anchorageindependence (Ward et al., 1986). A cell transformation assay withBALB 3T3 cells did not induce a significant number of transformedfoci (Barber et al., 1985; RIFM, 1983b).

5.4.2. Carcinogenicity studies2-Ethyl-1-hexanol was given to male and female rats and mice

by gavage 5 times a week in 0.005% aqueous Cremophor EL (rats: 0(water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg bodyweight/day, 18 months). The incidences of carcinomas and baso-philic foci in the liver increased in female mice with the doseand attained statistical significance in the highest dose group com-pared with the vehicle control group but not with the water con-trol group. The time-adjusted incidence of hepatocellularcarcinomas in female mice (13.1%) was outside the normal range(0–2%), but in male mice (18.8%) was within the historical controlrange at the testing facility (0–22%). No adenomas were observed.


Tabl

e3-

3Re

peat

eddo

seto

xici

tyst

udie

s–

inha

lati

on.

Mat

eria

lM

eth

odC

once

ntr

atio

nSp

ecie

s(N

o./d

ose)

Res

ult

sR

efer

ence

s

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

OEC

DTG

413

90da

ys,

6h

/day

,5da

ys/w

eek

0,15

,40,

or12

0m

l/m

3

(hig

hes

tva

pou

rco

nce

ntr

atio

nat

room

tem

pera

ture

),pu

rity

:99

.9%

Wis

tar

rat

(10/

sex)

Loca

lan

dsy

stem

icN

OA

EL:

120

ml/

m3

Kli

mis

chet

al.(

1998

)

Isoo

ctan

ol13

days

,6h

/day

180

ml/

m3

(hig

hes

tva

pou

rco

nce

ntr

atio

nat

room

tem

pera

ture

)

Ald

erly

-Par

kra

t(3

f)N

om

orta

lity

,cli

nic

alsi

gns,

auto

psy

fin

din

gsan

dh

isto

path

olog

ical

chan

ges

Gag

e(1

970)

Subg

roup

:se

cond

ary

2,6-

Dim

ethy

lhep

tan-

4-on

e2

wee

ks,5

h/d

ay,

5da

ys/w

eek

0,98

,300

,905

ml/

m3

Rat

s(1

0/se

x)N

OA

EL:

98m

l/m

3

P30

0m

l/m

3:

live

rw

eigh

tin

crea

sed,

alph

a-2u

-gl

obu

lin

accu

mu

lati

onin

the

kidn

eys

(m)

Dod

det

al.(

1987

)

6w

eeks

,7h

/day

,5

days

/wee

k0,

125,

252,

534,

925,

1654

ml/

m3

Rat

(15/

sex)

NO

AEL

:12

5m

l/m

3

125

ml/

m3:N

oad

vers

eef

fect

s25

2m

l/m

3:L

iver

and

kidn

eyw

eigh

tsin

crea

sed

(f)

534

ml/

m3:

Live

ran

dki

dney

wei

ghts

incr

ease

d(m

+f)

925

ml/

m3:

Live

ran

dki

dney

wei

ghts

incr

ease

d(m

+f)

1654

ml/

m3:

Mor

tali

tyin

all

fem

ales

and

3/15

mal

es.S

urv

ivin

gm

ales

:bo

dyw

eigh

tga

inde

crea

sed

and

live

ran

dki

dney

wei

ghts

incr

ease

d

Car

pen

ter

etal

.(19

53)

4-M

ethy

l-2-

pent

anon

e14

wee

ks,6

h/d

ay,

5da

ys/w

(OEC

DTG

413)

0,50

,250

,100

0m

l/m

3

(0,2

04,1

020,

4090

mg/

m3)

Fisc

her

344

rat

(14/

sex)

NO

AEL

:25

0m

l/m

3

P25

0m

l/m

3:

hya

lin

edr

ople

tsin

prox

imal

tubu

lar

cell

s(m

)10

00m

l/m

3:

abs.

and

rel.

live

rw

eigh

t(s

ligh

tbu

tst

atis

tica

lly

sign

ifica

nt)

incr

ease

(m)

Phil

lips

etal

.(19

87)

14w

eeks

,6h

/day

,5

days

/w(O

ECD

TG41

3)

0,50

,250

,100

0m

l/m

3

(0,2

04,1

020,

4090

mg/

m3)

B6C

3F1

mou

se(1

4/se

x)N

OA

EL:

50m

l/m

310

00m

l/m

3:

abs.

and

rel.

live

rw

eigh

t(s

ligh

tbu

tst

atis

tica

lly

sign

ifica

nt)

incr

ease

(m)

Phil

lips

etal

.(19

87)

4-M

eth

yl-2

-pen

tan

ol12�

4-h

-exp

osu

res

0,20

,000

mg/

m3

Mou

se(9

)U

ncl

ear

desc

ript

ion

ofef

fect

s,u

ncl

ear

exte

nt

ofh

isto

path

olog

yM

cOm

iean

dA

nde

rson

(194

9)

6w

eeks

,6h

/day

,5

days

/w(O

ECD

TG40

7)

0,50

.5,1

98,8

86m

l/m

3

(0,2

11,8

25,3

700

mg/

m3)

Wis

tar

rat

(12/

sex)

NO

AEL

:19

8m

l/m

3

P50

.5m

l/m

3:

con

cen

trat

ion

ofke

ton

ebo

dies

inu

rin

ein

crea

sed

(f)

P19

8m

l/m

3:

con

cen

trat

ion

ofke

ton

ebo

dies

inu

rin

ein

crea

sed

(m)

886

ml/

m3:

abs.

kidn

eyw

eigh

tin

crea

sed

(m),

seru

mal

kali

ne

phos

phat

ase

incr

ease

d(f

)

Bla

ir(1

982)

asci

ted

inO

ECD

/SI

DS

(200

7)

AD

H:

alco

hol

deh

ydro

gen

ase,

BU

N:

bloo

du

rea

nit

roge

n,G

OT:

glu

tam

ate

oxal

acet

ate

tran

sam

inas

e(n

owre

nam

ed:

AST

aspa

rtat

eam

inot

ran

sfer

ase)

,GPT

:gu

tam

ate

pyru

vate

tran

sam

inas

e(n

owre

nam

ed:

ALT

alan

ine

amin

o-tr

ansf

eras

e),f

:fe

mal

e,m

:m

ale,

n.f.

i.:n

ofu

rth

erin

form

atio

n,n

.s.:

not

stat

isti

call

ysi

gnifi

can

t,s.

a.:

see

abov

e,s.

c.:

subc

uta

neo

us.


The number of basophilic liver foci was increased in male mice inthe mid dose group only. The authors considered the liver tumorsin the mouse to be inconclusive because the incidence of hepato-carcinoma precursors did not significantly increase with the dose.Nevertheless, they concluded that 2-ethylhexanol is weakly orquestionably carcinogenic for the female mouse. Under the condi-tions of this study 2-ethyl-1-hexanol was not oncogenic to rats.Doses of 150 and 500 mg/kg body weight/day led to reduced bodyweight gains and in some animals to lethargy and unkemptnesswhich proves that the maximum tolerated dose was reached. Atthe end of the study the mortality was about 52% in the high-dosegroup females and about 28% in the other groups (Table 5-1; Astillet al., 1996b).

5.5. Reproductive and developmental toxicity

5.5.1. Fertility5.5.1.1. In vitro. 2-Ethyl-1-hexanol (200 lM for 24 h) had no effecton lactate and pyruvate production by Sertoli-cell-enriched cul-tures derived from 28-day old Sprague–Dawley rats, whereasphthalate monoesters known to cause testicular atrophy in vivo in-creased Sertoli cell lactate production and lactate/pyruvate ratio(Moss et al., 1988).

In an in vitro model of rat seminiferous tubules 200 lM 2-ethyl-1-hexanol did not induce dissociation of germinal cells from Sertolicells (Gangolli, 1982).

Ethyl-1-hexanol (200 lM for 24 or 48 h) did not result in an in-crease of germ-cell detachment in rat testicular-cell cultures (Gray,1986; Gray and Beamand, 1984; Sjoberg et al., 1986).

5.5.1.2. In vivo. In vivo studies of reproductive and developmentaltoxicity of the branched chain saturated alcohols are summarizedin Tables 6-1 (dermal), 6-2 (oral), and 6-3 (inhalation).

5.5.1.3. Dermal. Effects on the reproductive organs of rats treateddermally with 1000 mg 3,4,5,6,6-pentamethylheptan-2-ol/kg bodyweight/day for 28 days did not occur (see also Section 5.2.1; RIFM,1985c).

5.5.1.4. Oral.5.5.1.4.1. Primary alcohols. 2-Ethyl-1-hexanol administered by

gavage, 167 mg/kg body weight/day, had no effects on Sertoli cellsand gonocytes of 3-day old CD Sprague–Dawley rats (4/group) (Liet al., 2000). Daily gavage doses of 2.7 mmol 2-ethyl-1-hexanol/kg (350 mg/kg body weight) of for 5 days did not induce testiculardamage in 35-day old male Sprague–Dawley rats (Sjoberg et al.,1986).

In a 90-day gavage systemic toxicity study no effects on repro-ductive organs of rats and mice were noted up to doses of 500 mg2-ethyl-1-hexanol/kg body weight/day (see Section 5.2.1.1, Astillet al., 1996a).

In combined repeated dose and reproductive/developmentaltoxicity screening test (OECD TG 422) with gavage applicationof3,5,5-trimethyl-1-hexanol (see Section 5.2.1.1) no effects on fer-tility were observed in males. In females a dose dependent de-crease in implantation index was noted in the 60 and 300 mg/kggroup (MHW, Japan, 1997b as cited in OECD/SIDS, 2003). Basedon these findings, the NOAELs for fertility were 12 mg/kg bodyweight/day for females and 300 mg/kg body weight/day for males.

5.5.1.4.2. Secondary alcohols. In the combined repeated doseand reproductive/developmental toxicity screening test (OECD TG422) with gavage application of 4-hydroxy-4-methyl-2-pentanone(see Section 5.2.1.1), a metabolite of 4-methyl-2-pentanol, no sta-tistically significant changes in any reproductive parameter at anydose were noted. According to the authors there was a tendency forlower reproductive indices (fertility and implantations, no further

information) at the highest dose of 1000 mg/kg body weight/day.Therefore the NOAEL for fertility was 300 mg/kg body weight/day(MHW, Japan, 1997 as cited in OECD/SIDS, 2007).

2,6-Dimethyl-4-heptanol showed no effects on the reproductiveorgans of rats in a 13-week feeding study with the only tested doseof 11 mg/kg body weight/day (Posternak and Vodoz, 1975). Itsmetabolite 2,6-dimethylheptane-4-one given by gavage has beenassessed in a reproduction/developmental toxicity screen (OECDTG 421) and did not lead to reproductive effects up to the highesttested dose of 1000 mg/kg body weight/day (Shell HSE, 1996 as ci-ted in OECD/SIDS, 2004).

5.5.1.4.3. Tertiary alcohols. No studies were available.

5.5.1.5. Inhalation.5.5.1.5.1. Primary alcohols. In a 90-day inhalation study in rats,

no effects on the reproductive organs were seen at concentrationsup to 120 ml/m3 2-ethyl-1-hexanol (Klimisch et al., 1998).

5.5.1.5.2. Secondary alcohols. With 4-methyl-2-pentanone, themetabolite of 4-methyl-2-pentanol, a two-generation study per-formed in Sprague–Dawley rats (30/sex/group) exposed to 0, 500,1000, or 2000 ml/m3 (0, 2050, 4090, or 8180 mg/m3), for 6 h perday, 7 days per week. Treatment started 70 days prior to matingfor the F0 and F1 generations, continued to the end of the matingperiod for males and to day 20 of gestation for females. Treatmentof females resumed at day 5 of lactation. Because of CNS depres-sion in F1 pups upon initiation of exposures on post-natal day 22and the death of one F1 male pup from the 2000 ml/m3 group,treatment was interrupted and continued on day 28. In males ofall exposure groups alpha-2u-globulin nephropathy was observed.F0 and F1 adults of the mid and high exposure groups showed asedative effect, which was reversible 1 h after exposure. Decreasedbody weight gain and slightly decreased food consumption duringthe first 2 weeks of exposure occurred only at the high concentra-tion in both generations. There were no effects on reproductive anddevelopmental parameters, or on estrous cycle and sperm param-eters. The NOAEL for systemic toxicity was established at 1000 ml/m3 (4090 mg/m3) due to slightly reduced body weight and feedconsumption at 2000 ml/m3. The NOAEL for reproductive toxicitywas 2000 ml/m3 (8180 mg/m3) (Nemec et al., 2004). In view ofthe clinical signs of CNS depression of adults during the exposuresat 1000 and 2000 ml/m3 the systemic parental NOAEL is 500 ml/m3.

Histopathological examinations in the 6-week inhalation studywith 4-methyl-2-pentanol (Blair, 1982 as cited in OECD/SIDS,2007) showed no adverse effects on the reproductive organs ofmale and female rats up to the highest concentration tested(886 ml/m3). For further details see Section 5.2.1.2.


5.5.2. Developmental toxicity5.5.2.1. Dermal. 2-Ethyl-1-hexanol (99.72% pure) was administeredon the clipped dorsal skin by occlusive cover to F344 rats 6 h perday from gestation days 6–15 at doses of 0, 0.5, 1.0, 2.0, or3.0 ml/kg body weight/day (0, 420, 840, 1680, or 2520 mg/kg bodyweight/day) in a range-finding study (8/group). In the main study(25/group) doses of 0, 0.3, 1.0, and 3.0 ml/kg body weight/day (0,252, 840, or 2520 mg/kg body weight/day) were applied. Persistentexfoliation, crusting, and erythema on the application site wereseen in both studies from 840 mg/kg body weight/day. Maternalweight gain was reduced at 1680 and 2520 mg/kg body weight/day. The NOAELs for maternal toxicity were 252 mg/kg bodyweight/day based on skin irritation and 840 mg/kg body weight/day based on systemic toxicity. The developmental NOAEL wasthe highest tested dose of 2520 mg/kg body weight/day (Fisheret al., 1989; Tyl et al., 1992).


Tabl

e4-

1M

utag

enic

ity

and

geno

toxi

city

:in

vitr

ost

udie

s.

Mat

eria

lTe

stsy

stem

Con

cen

trat

ion

Res

ult

sR

efer

ence

s

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

Rec

-ass

ayBa

cillu

ssu

btili

sH

17,M

4550

0l

g/di

skin

DM

SON

egat

ive

Tom

ita

etal

.(19

82)

Rec

-ass

ayBa

cillu

ssu

btili

sH

A10

1,R

ec-4

Dil

ute

din

DM

SOto

mak

eth

ein

hib

itio

nci

rcle

betw

een

I.D.9

and

40m

m

Posi

tive

Said

oet

al.(

2003

)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1537

,TA

1538

,TA

1535

,E.c

oli

WP2

uvrA

1–10

00l

g/pl

ate

inD

MSO

,gro

wth

inh

ibit

ion

P50

0l

g/pl

ate

Not

mu

tage

nic

Shim

izu

etal

.(19

85)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

3.3–

333

lg/

plat

ein

DM

SON

otm

uta

gen

icZe

iger

etal

.(19

82)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

3.3–

220

lg/

plat

ein

DM

SON

otm

uta

gen

icZe

iger

etal

.(19

85)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,153

8,26

3710

0–20

00l

g/pl

ate

inD

MSO

,tes

ted

up

tocy

toto

xic

con

cen

trat

ion

sN

otm

uta

gen

icA

garw

alet

al.(

1985

)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(met

hod

un

spec

ified

)S.

typh

imur

ium

(un

spec

ified

)n

.f.i.

Not

mu

tage

nic

Bar

ber

etal

.(19

85)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,153

80.

01–1

.0l

l/pl

ate

inD

MSO

,cyt

otox

icco

nce

ntr

atio

nP

1.0

ll/

plat

eN

otm

uta

gen

icK

irby

etal

.(19

83)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(pre

incu

bati

onm

eth

od)

S.ty

phim

uriu

mTA

98,T

A10

00.

1–10

.0l

M,n

.f.i.

Not

mu

tage

nic

War

ren

etal

.(19

82)

L517

8YTK

+/�

mou

sely

mph

oma

mu

tage

nic

ity

assa

yL5

178Y

mou

sely

mph

oma

cell

s0.

013–

1.0

ll/

ml

inD

MSO

,cyt

otox

icco

nce

ntr

atio

nP

1.0

ll/

ml

Not

mu

tage

nic

Kir

byet

al.(

1983

)

8-A

zagu

anin

ere

sist

ance

assa

yS.

typh

imur

ium

TA10

00.

5–1.

5l

M,n

.f.i.

Mu

tage

nic

Seed

(198

2)U

DS

assa

yPr

imar

yra

th

epat

ocyt

escu

ltu

res

prep

ared

from

Fisc

her

344

rats

Cel

lsw

ere

trea

ted

sim

ult

aneo

usl

yw

ith

test

com

pou

nd

and

trit

iate

dth

ymid

ine

for

1h

,n.f.

i.

Did

not

indu

cede

tect

able

leve

lsof

UD

SH

odgs

onet

al.(

1982

)

Ch

rom

osom

alab

erra

tion

assa

yC

hin

ese

ham

ster

ovar

yce

lls

1.5–

2.8

mM

Did

not

indu

cean

incr

ease

dfr

equ

ency

ofch

rom

osom

alab

erra

tion

sco

mpa

red

toth

eco

ntr

ol;

50%

kill

at2.

5m

M

Phil

lips

etal

.(19

82)

Uri

ne

of2-

eth

yl-1

-hex

anol

trea

ted

rats

(100

0m

g/kg

body

wei

ght

for

15da

ys)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(sta

nda

rdpl

ate

assa

y)S.

typh

imur

ium

TA98

,TA

100,

TA15

35,

TA15

37,T

A15

38U

pto

2m

lu

ndi

lute

du

rin

e,n

egat

ive

and

posi

tive

cont

rols

:u

rin

eof

un

trea

ted

rats

and

8-h

ydro

xyqu

inol

ine

Not

mu

tage

nic

DiV

ince

nzo

etal

.(19

85)

Isoa

myl

alco

hol

Com

etas

say

Ch

ines

eh

amst

erV

79fi

brob

last

cell

s,h

um

anlu

ng

carc

inom

aep

ith

elia

lce

llli

ne

A54

9,an

dh

um

anpe

riph

eral

bloo

dce

lls

(pB

)

0,23

,46,

91m

MD

NA

dam

age

atat

cyto

toxi

cco

nce

ntr

atio

ns

(91

mM

inV

79an

dA

549

cell

s),e

xtre

mel

ycy

toto

xic

inpB

(an

alys

esn

otpo

ssib

le)

Kre

jaan

dSe

idel

(200

1,20

02)

umu

test

:Li

ght

abso

rpti

onS.

typh

imur

ium

TA15

35/p

SK10

02C

once

ntr

atio

ns

inw

hic

hgr

owth

inh

ibit

ion6

50%

(n.f.

i.)N

egat

ive

Nak

ajim

aet

al.(

2006

)

umu

test

:Lu

min

isce

ntS.

typh

imur

ium

TA15

35/p

TL21

0co

nce

ntr

atio

ns

inw

hic

hgr

owth

inh

ibit

ion6

50%

(n.f.

i.)Po

siti

ve

Mic

ron

ucl

eus

test

wit

han

dw

ith

out

S9ac

tiva

tion

Ch

ines

eh

amst

erV

79fi

brob

last

cell

s0,

5,9,

23m

MN

otge

not

oxic

Kre

jaan

dSe

idel

(200

2)

HPR

Tte

stw

ith

and

wit

hou

tS9

acti

vati

onC

hin

ese

ham

ster

V79

fibr

obla

stce

lls

Up

to51

.5m

M(h

igh

est

non

-tox

icco

nce

ntr

atio

n)

Not

mu

tage

nic

Kre

jaan

dSe

idel

(200

2)

Isot

ride

can

-1-o

l(i

som

eric

mix

ture

)A

mes

assa

yw

ith

and

wit

hou

tS9

acti

vati

onS.

typh

imur

ium

TA98

,TA

100,

TA15

35,

TA15

3720

-500

0l

g/pl

ate

no

cyto

toxi

city

Not

mu

tage

nic

RIF

M(1

989)

2-M

eth

ylbu

tan

olum

ute

st:

Ligh

tab

sorp

tion

S.ty

phim

uriu

mTA

1535

/pSK

1002

Con

cen

trat

ion

sin

wh

ich

grow

thin

hib

itio

n6

50%

(n.f.

i.)N

egat

ive

Nak

ajim

aet

al.(

2006

)um

ute

st:

Lum

inis

cent

S.ty

phim

uriu

mTA

1535

/pTL

210

Posi

tive

Com

etas

say

Ch

ines

eh

amst

erV

79fi

brob

last

cell

s,h

um

anlu

ng

carc

inom

aep

ith

elia

lce

llli

ne

A54

9,an

dh

um

anpe

riph

eral

bloo

dce

lls

(pB

)

0,45

,90

mM

DN

Ada

mag

eat

cyto

toxi

cco

nce

ntr

atio

ns

(45

mM

inA

549,

90m

Min

V79

cell

s),e

xtre

mel

ycy

toto

xic

inpB

(an

alys

esn

otpo

ssib

le)

Kre

jaan

dSe

idel

(200

1,20

02)

(con

tinu

edon

next

page

)


Tabl

e4-

1(c

onti

nued

)

Mat

eria

lTe

stsy

stem

Con

cen

trat

ion

Res

ult

sR

efer

ence

s

Mic

ron

ucl

eus

test

wit

han

dw

ith

out

S9ac

tiva

tion

Ch

ines

eh

amst

erV

79fi

brob

last

cell

s0,

23,4

5m

MN

otge

not

oxic

Kre

jaan

dSe

idel

(200

2)

HPR

Tte

stw

ith

and

wit

hou

tS9

acti

vati

onC

hin

ese

ham

ster

V79

fibr

obla

stce

lls

Up

to46

mM

(hig

hes

tn

on-t

oxic

con

cen

trat

ion

)N

otm

uta

gen

icK

reja

and

Seid

el(2

002)

3,5,

5-Tr

imet

hyl

-1-h

exan

olA

mes

assa

y(p

rein

cuba

tion

assa

y)w

ith

and

wit

hou

tm

etab

olic

acti

vati

onO

ECD

TG47

1,47

2

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,E.c

oli

WP2

uvrA

up

to50

0l

g/pl

ate

cyto

toxi

city

:P

150

lg/

plat

e(±

S9)

Not

mu

tage

nic

MH

W,J

apan

(199

7c)

asci

ted

inO

ECD

/SID

S(2

003)

Ch

rom

osom

alab

erra

tion

and

poly

ploi

dyO

ECD

TG47

3C

hin

ese

ham

ster

lun

gce

lls

(CH

L/IU

)u

pto

100

lg/

ml

cyto

toxi

city

:20

0l

g/m

lN

otge

not

oxic

MH

W,J

apan

(199

7d)

asci

ted

inO

ECD

/SID

S(2

003)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-hep

tan

olA

mes

assa

yw

ith

and

wit

hou

tS9

acti

vati

on(s

tan

dard

plat

eas

say)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1537

,TA

1538

,TA

1535

,E.c

oli

WP2

uvrA

3.33

–100

0l

g/pl

ate

wit

hS9

mix

inD

MSO

,1.

00–5

00l

g/pl

ate

iwit

hS9

mix

inD

MSO

,cyt

otox

icco

nce

ntr

atio

n:

P33

3l

g/pl

ate

Not

mu

tage

nic

Mec

chi

(200

2)as

cite

din

DO

W(2

003)

2,6-

Dim

ethy

lhep

tan-

4-on

eM

itot

icge

ne

con

vers

ion

assa

yw

ith

and

wit

hou

tS9

Sacc

haro

myc

esce

revi

siae

0.01

–5.0

mg/

ml,

cyto

toxi

city

at0.

5m

g/m

lw

ith

S9,a

t5.

0w

ith

out

S9N

egat

ive

Mor

telm

ans

etal

.(19

86)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(sta

nda

rdpl

ate

assa

y)S.

typh

imur

ium

TA98

,TA

100,

TA15

35,

TA15

37,T

A15

38,E

.col

iW

P2uv

rA31

.25-

4000

lg/

plat

ein

DM

SO,

cyto

toxi

cco

nce

ntr

atio

n:

P50

0l

g/pl

ate

Not

mu

tage

nic

Bro

oks

etal

.(19

85)

asci

ted

inO

ECD

/SID

S(2

004)

Bro

oks

etal

.(19

88)

Am

esas

say

wit

han

dw

ith

out

S9ac

tiva

tion

(sta

nda

rdpl

ate

assa

y)S.

typh

imur

ium

n.f.

i.1–

333

lg/

plat

e,n

ocy

toto

xici

tyob

serv

edN

otm

uta

gen

icM

orte

lman

set

al.(

1986

)

Cyt

ogen

etic

assa

yR

atli

ver

cell

(RL4

)62

.5–5

00l

g/m

l,cy

toto

xici

tyat

the

hig

hes

tdo

sele

vel

test

edN

oin

crea

sed

inci

den

ceof

chro

mos

ome

aber

rati

ons

Bro

oks

etal

.(19

85)

asci

ted

inO

ECD

/SID

S(2

004)

Bro

oks

etal

.(19

88)

4-H

ydro

xy-4

-met

hyl

-2-

pen

tan

one

Am

esas

say

wit

han

dw

ith

out

met

abol

icac

tiva

tion

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,E.c

oli

WP2

uvr

A31

3–50

00l

g/pl

ate

no

cyto

toxi

city

was

obse

rved

Not

mu

tage

nic

MH

W,J

apan

(199

7)as

cite

din

OEC

D/S

IDS

(200

7)C

hro

mos

omal

aber

rati

ons

and

poly

ploi

dyO

ECD

TG47

3C

hin

ese

ham

ster

lun

gce

lls

(CH

L/IU

)30

0–12

00l

g/m

ln

ocy

toto

xici

tyob

serv

edat

the

hig

hes

tco

nce

ntr

atio

npo

lypl

oidy

incr

ease

at60

0an

d12

00l

g/m

l,w

ith

out

dose

-de

pen

den

cen

otge

not

oxic

MH

W,J

apan

,199

7,as

cite

din

OEC

D/S

IDS

(200

7)

4-M

ethy

l-2-

pent

anon

eU

DS

n.f.

i.n

.f.i.

Neg

ativ

eIP

CS,

1990

asci

ted

inO

ECD

/SID

S(2

004)

Am

esas

say

n.f.

i.n

.f.i.

Neg

ativ

eIP

CS

(199

0)as

cite

din

OEC

D/S

IDS

(200

4)M

ouse

lym

phom

ate

stn

.f.i.

n.f.

i.Eq

uiv

ocal

IPC

S(1

990)

asci

ted

inO

ECD

/SID

S(2

004)

4-M

eth

yl-2

-pen

tan

olA

mes

assa

yw

ith

and

wit

hou

tS9

acti

vati

onS.

typh

imur

ium

TA98

,TA

100,

TA15

35,

TA15

37,T

A15

38,E

.col

iW

P2uv

rA

up

to50

00l

g/pl

ate

cyto

toxi

city

:50

00l

g/pl

ate

(±S9

)N

otm

uta

gen

icSh

imiz

uet

al.(

1985

)

Am

esas

say

wit

han

dw

ith

out

met

abol

icac

tiva

tion

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,TA

1538

,E.c

oli

WP2

uvr

Apk

m10

1

31.2

5–40

00l

g/pl

ate

no

cyto

toxi

city

was

obse

rved

Not

mu

tage

nic

Cla

re(1

983)

asci

ted

inO

ECD

/SID

S(2

007)

Gen

em

uta

tion

wit

han

dw

ith

out

met

abol

icac

tiva

tion

Sacc

haro

myc

esce

revi

siae

JD1

10–5

000

lg/

plat

ecy

toto

xici

ty:

5000

lg/

plat

eN

otm

uta

gen

icC

lare

(198

3)as

cite

din

OEC

D/S

IDS

(200

7)C

ytog

enet

icas

say

Rat

live

rce

ll(R

L4)

0,0.

5,1,

2m

g/m

lno

cyto

toxi

city

was

obse

rved

Neg

ativ

eC

lare

(198

3)as

cite

din

OEC

D/S

IDS

(200

7)3,

4,5,

6,6-

Pen

tam

eth

ylh

epta

n-2

-ol

(55–

80%

)an

d3,

4,5,

6,6-

pen

tam

eth

ylh

epta

n-2

-on

(20–

45%

)

Am

esas

say

wit

han

dw

ith

out

met

abol

icac

tiva

tion

(pla

tein

corp

orat

ion

test

)

S.ty

phim

uriu

mTA

98,T

A10

0,TA

1535

,TA

1537

,TA

1538

,E.c

oli

WP2

uvrA

1.te

st:

up

to10

00l

g/pl

ate

2.te

st:

up

to10

0l

g/pl

ate

cyto

toxi

city

:P

500

lg/

plat

e

Not

mu

tage

nic

RIF

M(1

985b

)

DM

SO:

dim

eth

ylsu

lfox

ide,

n.f.

i.:n

ofu

rth

erin

form

atio

n,n

.s.:

not

stat

isti

call

ysi

gnifi

can

t.


Tabl

e4-

2M

utag

enic

ity

and

geno

toxi

city

:in

vivo

stud

ies.

Mat

eria

lTe

stsy

stem

Spec

ies

(No.

/dos

e)D

ose/

Con

cen

trat

ion

Res

ult

sR

efer

ence

s

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

DN

Abi

ndi

ng

invi

voby

[14C

]la

bele

d2-

eth

yl-1

-hex

anol

;16

haf

ter

the

adm

inis

trat

ion

ofth

era

diol

abel

edte

stsu

bsta

nce

:is

olat

ion

ofli

ver

DN

Aan

dan

alyz

ing

for

radi

oact

ivit

y

2Fe

mal

eFi

sch

er34

4ra

tsan

d2

fem

ale

NM

RI

mic

eD

iet

con

tain

ing

1%di

(2-e

thyl

hex

yl)

phth

alat

e(r

at)

ordi

(2-e

thyl

hex

yl)

adip

ate

(mou

se)

for

4w

eeks

;ra

diol

abel

ed[1

4C

]2-

eth

yl-1

-hex

anol

was

adm

inis

tere

dby

gava

ge(r

at:

51.1

or53

.4m

g/kg

body

wei

ght;

mou

se:

120.

2or

109.

5m

g/kg

body

wei

ght)

No

indi

cati

onfo

ra

cova

len

tbi

ndi

ng

of2-

eth

yl-1

-hex

anol

toli

ver

DN

Aof

rats

orm

ice;

mos

tif

not

all

radi

oact

ivit

yin

live

rD

NA

was

due

tobi

osyn

thet

icin

corp

orat

ion

Dän

iken

etal

.(19

84)

DN

Abi

ndi

ng

invi

voby

[14C

]la

bele

d2-

eth

yl-1

-hex

anol

,24

haf

ter

the

adm

inis

trat

ion

ofth

era

diol

abel

edte

stsu

bsta

nce

:is

olat

ion

ofli

ver

DN

Aan

dan

alyz

ing

for

radi

oact

ivit

y

Mal

eFi

sch

erra

t,n

.f.i.

An

imal

sw

ere

fed

adi

etco

nta

inin

g1%

di(2

-eth

ylh

exyl

)ph

thal

ate

for

11da

ysad

libi

tum

.On

day

10th

eyw

ere

give

na

sin

gle

oral

dose

of10

0l

Ci[

1-1

4C

]2-

eth

yl-

1-h

exan

olan

don

day

11th

eyw

ere

sacr

ifice

d

No

bin

din

gof

the

labe

led

test

subs

tan

ceto

live

rD

NA

Alb

roet

al.(

1982

)

Bon

em

arro

wm

icro

nu

cleu

sas

say,

n.f.

i.B

6C3F

1m

ouse

,n.f.

i.Te

stpr

otoc

olac

cord

ing

tost

anda

rdte

sts

perf

orm

edby

Litt

onB

ion

etic

sIn

c.,n

.f.i.

Not

gen

otox

ic,n

.f.i.

Ast

ill

etal

.(19

86);

Bar

ber

etal

.(1

985)

Cyt

ogen

etic

assa

yw

ith

bon

em

arro

wce

lls

5Fi

sch

er34

4ra

t/gr

oup

Ora

lga

vage

for

5co

nse

cuti

veda

ysw

ith

0.02

,0.0

7,an

d0.

21m

l/kg

body

wei

ght/

day

(17,

58,1

74m

g/kg

body

wei

ght/

day)

=u

pto

1/10

ofth

e5-

day-

LD50

No

incr

ease

inch

rom

atid

and

chro

mos

ome

brea

ksco

mpa

red

toth

eco

ntr

ols;

mit

otic

inde

xw

asn

otaf

fect

ed,n

oto

xici

tyob

serv

ed,n

ore

liab

len

egat

ive

resu

lt

Putm

anet

al.(

1983

)

Dom

inan

tle

thal

test

Mal

eIC

R/S

IMm

ouse

n.f.

i.25

0,50

0,an

d10

00m

g/kg

body

wei

ght/

day

(bas

edon

5-da

y-LD

50)

for

5co

nse

cuti

veda

ys,a

fter

trea

tmen

tea

chm

ale

was

hou

sed

wit

h2

virg

infe

mal

spe

rw

eek

for

8co

nse

cuti

veda

ys,s

acri

fice

ofth

efe

mal

eson

days

14–1

7of

cagi

ng

wit

hth

em

ales

;po

siti

veco

ntr

ol:

trim

ehty

len

emel

amin

e

No

dom

inan

tle

thal

mu

tati

ons;

fert

ilit

yin

dice

san

dav

erag

en

um

bers

ofde

adan

dto

tal

impl

ants

per

preg

nan

cyw

ere

wit

hin

the

nor

mal

ran

ge

Ru

shbr

ook

etal

.(19

82)

Isoa

myl

alco

hol

Mic

ron

ucl

eus

Test

wit

hbo

ne

mar

row

cell

sN

MR

Im

ice

(5/s

ex/d

ose)

500,

1000

,or

2000

mg/

kgbo

dyw

eigh

t/da

yN

on-m

uta

gen

icR

IFM

(200

8)

Subg

roup

:se

cond

ary

4-M

ethy

l-2-

pent

anon

eM

icro

nu

cleu

ste

stn

.f.i.

n.f.

i.N

egat

ive

IPC

S(1

990)

asci

ted

inO

ECD

/SI

DS

(200

4)3,

4,5,

6,6-

Pen

tam

eth

ylh

epta

n-2

-ol

Bon

em

arro

wm

icro

nu

cleu

sas

say

(i.p

.),s

acri

fied

:30

,48,

72h

afte

rap

plic

atio

n

Mou

se(5

/sex

/dos

e)0,

900

mg/

kgbo

dyw

eigh

tin

corn

oil

Not

gen

otox

icPC

E/N

CE

redu

ced

48an

d72

haf

ter

dosi

ng

RIF

M(1

985d

)

n.f.

i.:n

ofu

rth

erin

form

atio

n,P

CE:

poly

chro

mat

icer

yth

rocy

tes,

NC

E:n

orm

och

rom

atic

eryt

hro

cyte

s.


5.5.2.2. Oral.5.5.2.2.1. Primary alcohols. Wistar rats were given a single dose

of 6.25 or 12.5 mmol 2-ethyl-1-hexanol/kg body weight (833 or1666 mg/kg body weight) by gavage on day 12 of pregnancy, andunderwent caesarean section on day 20 of pregnancy. At the higherdose, 22.2% of the surviving fetuses had malformations (lower dosegroup 2% and controls 0%). These included hydronephrosis (7.8%),tail anomalies (4.9%), malformed limbs (9.7%), and ‘‘others” (1%).In the higher dose group the average fetal weight was reduced.Implantation index, numbers of dead and resorbed fetuses wereunaffected. Although the dose of 1666 mg/kg body weight isaround half of the oral LD50, no maternal toxicity was reported(Ritter et al., 1987).

Pregnant Sprague–Dawley rats (6/group) were gavaged with asingle dose of 0, 6.25, 9.38, or 12.5 mmol 2-ethyl-1-hexanol/kgbody weight (equivalent to 0, 813, 1219, and 1625 mg/kg bodyweight) in corn oil on gestation day 11.5, followed 8 h later by32 lCi 65Zn and killed on gestation day 12.5. From 1219 mg/kgbody weight the maternal food intake was reduced, maternal livermetallothionein and 65Zn concentrations were higher, whereas inthe embryos the 65Zn content was lower than in animals whichdid not receive 2-ethyl-1-hexanol. The percentage of resorptionswas not affected by the test substance (Bui et al., 1998).

2-Ethyl-1-hexanol was administered daily by gavage to Wistarrats (10/group) from gestation days 6 to 19 at doses of 0, 1, 5, or10 mmol/kg body weight/day (equivalent to 0, 130, 650, and1300 mg/kg body weight/day). At the lowest dose no maternaland fetal effects occurred. At 650 mg/kg body weight/day, fetusweights were significantly lower and the incidence of skeletal vari-ations and retardations was increased. At 1300 mg/kg bodyweight/day maternal body weight measured on days 15 and 20was significantly reduced; clinical signs (salivation, CNS depres-sion, nasal discharge) were observed, and 6 dams died. Post-implantation losses, resorptions, number, and percent of fetusesand litters with malformations and variations, and number andpercent of fetuses with retardations were increased. The fetalweight was decreased. The maternal and developmental NOAELwere 130 mg/kg body weight/day each (Hellwig and Jäckh, 1997).

Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-hexanol microencapsulated in their diet at concentrations of 0%,0.009%, 0.03%, and 0.09% from days 0 to 17 of pregnancy. This cor-responded to calculated doses of 0.13, 43, and 129 mg/kg body

weight/day. No maternal toxicity was observed and the birth ratewas 93–96% in all groups. All of the litters survived and all gesta-tional parameters were normal. There were no external, visceral,or skeletal malformations and no increase in variations occurred.The authors concluded that 2-ethyl-1-hexanol plays essentiallyno role in the expression of DEHP-induced maternal and develop-mental toxicity (NTP, 1991; Price et al., 1991). As no toxic doseswere reached, no conclusion on the potential of developmentaltoxicity of 2-ethyl-1-hexanol in mice can be drawn from this study.

In a screening test, mice (Charles River CD-1) were given1525 mg 2-ethyl-1-hexanol/kg body weight/day by gavage fromdays 7 to 14 of pregnancy (50 animals treated and 50 controls).The dams and pups were observed until day 3 of lactation. Signsof toxicity in the dams included significantly reduced body weightand movement, ataxia, hypothermia, unkempt coats, and blood inthe urine. Seventeen animals died of exposure-related causes. Thenumber of live pups and their weight were significantly reduced(Hardin et al., 1987). A NOAEL cannot be deduced from this study.

Twenty-five pregnant Wistar rats were gavaged with 0 (cornoil), 100, 500, or 1000 mg/kg body weight/day on gestation days6–15. The test material was a mixture of C7–9 branched alcohols,with isooctyl alcohol as the main component (CAS No. 68526-83-0). In the mid- and high-dose groups statistically significant in-creases in the number of lumbar ribs were observed. The authorsstate that, due to the lack of embryotoxicity these findings wereattributed to maternal toxicity observed during treatment. How-ever, in the 500 mg/kg body weight/day group no maternal toxicitywas reported. In high-dosed dams emaciation, rales, hypoactivity,decreased food consumption, and body weight gain were observed.The total number of fetuses with skeletal variations and with hypo-plastic skull bones was noted. These findings exceeded the histor-ical control range of the laboratory but were not observed withlitter-based analysis. The maternal NOAEL was set at 500 mg/kgbody weight/day and the fetal NOAEL at 1000 mg/kg bodyweight/day (EBSI, 1994a, as cited in Nishimura et al., 1994). As in-creased incidences of lumbar ribs were seen from 500 mg/kg bodyweight/day at which dose no maternal toxicity was reported, theNOAEL for developmental toxicity should better be evaluated as100 mg/kg body weight/day.

Two different isomeric mixes of isononyl alcohol (isononanoltype 1 and isononanol type 2, CAS No. 68515-81-1 for both) andisodecyl alcohol were administered by gavage to Wistar rats

Table 5-1Carcinogenicity studies.

Material Method Dose Species (No./dose) Results References

Subgroup: primary2-Ethyl-1-hexanol Cell transformation

assay with andwithout metabolicactivation

96–180 nl/ml; survival:31.7–72% in theconcomitant cytotoxicitytest, positive control:cyclophosphamide

BALB 3T3 cells Negative Barber et al. (1985) andRIFM (1983b)

Cell transformation,anchorageindependence,without metabolicactivation

4–77 � 10�7 mM, noinformation on cytotoxicity

JB6 cell line ofmouse epidermiscells

Negative Ward et al. (1986)

Oral (gavage),5 days/week,18 months

0, 50, 200, 750 mg/kg bodyweight/day

B6C3F1 mouse,50/sex/group

750 mg/kg body weight/day:weak hepatocellular carcinomaincrease (f), body weight gaindecrease, mortality increase

Astill et al. (1996b)

Oral (gavage),5 days/w, 24 months

0, 50, 150, 500 mg/kg bodyweight/day

F344 rat, 50/sex/group

P150 mg/kg body weight/day:body weight gain decrease,lethargy, unkemptness 500 mg/kg body weight/day: mortality:52% f



(10/group) daily on gestation days 6–15. The doses for the isononylalcohols were 0, 1, 5, 7.5, and 10 mmol/kg body weight/day (0, 144,720, 1080, and 1440 mg/kg body weight/day), for isodecyl alcohol0, 1, 5, and 10 mmol/kg body weight/day (0, 158, 790, and1580 mg/kg body weight/day). Isononyl alcohol 1 mainly consistsof dimethyl heptanols. Isononyl alcohol 2 mainly consists of di-methyl heptanols and methyl octanols. The test procedure wasaccording to OECD TG 414 with the exception that 10 instead of20 animals per dose level were used. At the lowest dose of isononylalcohol 1 there was an equivocal increase in the incidence of fe-tuses with hydroureter (11%, which was only slightly above thehighest incidence of 4 control groups used in the study, 9.2%).The highest historical control incidence was reported to be 7.7%for studies conducted in the same time interval as the study underquestion. A clear dose–response was not seen. Therefore, a sub-stance-related effect is questionable. At the lowest dose of isononylalcohol 2 no maternal and fetal toxicity was seen. At a dose of720 mg/kg body weight/day and more of isononyl alcohols 1 and2, signs of maternal and developmental toxicity, including de-creased body weight, increased resorption rates, and increasedskeletal variations and retardations were observed. At doses of1080 mg/kg body weight/day and more the incidences of malfor-mations were elevated. For isodecyl alcohol, maternal toxicity (re-duced body weight gain and clinical signs) was evident at 790 mg/kg body weight/day and more. Developmental toxicity includingreduced mean fetal body weight and skeletal retardations were ob-served only in the highest dose group. The maternal NOAEL forisononyl alcohol 1 and isononyl alcohol 2 is 144 mg/kg bodyweight/day and for isodecyl alcohol 158 mg/kg body weight/day.The NOAEL for developmental toxicity for isononyl alcohol 1 and2 is 144 mg/kg body weight/day and for isodecyl alcohol 790 mg/kg body weight/day. Isononyl and isodecyl alcohol are develop-mental toxins only at doses that produce maternal toxicity (Hell-wig and Jäckh, 1997; RIFM, 1991a).

In a combined repeated dose and reproductive/developmentaltoxicity screening test with gavage application of 3,5,5-trimethyl-1-hexanol (OECD TG 422) (see Section 5.2.1.1) the following resultsconcerning developmental toxicity were observed: the number ofpups born alive diminished in the 60 and 300 mg/kg bodyweight/day groups. In the high-dose group total litter loss was ob-served in two dams, the viability of neonates on day 4 of lactationwas lower, and male and female pups showed lower body weightson day 0 of lactation (MHW, Japan, 1997b as cited in OECD/SIDS,2003). Therefore, the NOAEL for systemic toxicity and develop-

mental toxicity were considered 12 mg/kg body weight/day. Skel-etal and visceral effects were not investigated in the pups.

5.5.2.2.2. Secondary alcohols. In the combined repeated doseand reproductive/developmental toxicity screening test with ga-vage application of 4-hydroxy-4-methyl-2-pentanone [OECD TG422] (see Sections 5.2.1.1 and 5.5.2), a tendency for a decrease ofdevelopmental parameters was observed at the highest dose of1000 mg/kg body weight/day. These effects included the totalnumber of pups born, delivery index, live birth index, number ofpups alive and viability index on day 4 of lactation The NOAELfor developmental toxicity was 300 mg/kg body weight/day. TheNOAEL for maternal toxicity was 100 mg/kg body weight/day(MHW, Japan 1997, as cited in OECD/SIDS, 2007). OECD TG 422does not provide for an evaluation of skeletal and visceral effectsin pups.

2,6-Dimethylheptan-4-one has been assessed in a reproduction/developmental toxicity screening test 20 rats (10/sex) were given0, 100, 300, or 1000 mg 2,6-dimethylheptan-4-one/kg bodyweight/day in corn oil by gavage from 2 weeks prior to matingthroughout pregnancy until weaning day 5 post partum whenthe dams and offspring were sacrificed. Two dams at the top doselevel died during lactation due to the test substance. There was noevidence of an effect on any of the reproductive parameters inves-tigated or on any of the surviving litters. The NOAEL for develop-mental effects is the highest tested dose of 1000 mg 2,6-dimethylheptan-4-one/kg body weight/day, with a parental NOAELof 300 mg/kg body weight/day (Shell HSE, 1996 as cited in OECD/SIDS, 2004). OECD TG 421 does not provide for an evaluation ofskeletal and visceral effects in pups.


5.5.2.3. Inhalation.5.5.2.3.1. Primary alcohols. Pregnant Wistar rats (20–25) were

whole body exposed 6 h per day on gestation days 6–15 to 0,510, 2500, or 9800 mg isoamyl alcohol/m3 (0, 138, 675, and2646 ml/m3). Body weight gain was decreased at the highest con-centration between days 6 and 9 but there were no compound-re-lated effects on conception rate, mean number of corpora lutea,implantation sites, pre- and post-implantation losses, and numberof resorptions, viable fetuses, sex ratio, mean fetal, and placentalweight. No external, visceral, or skeletal malformations were ob-served. The NOAEL for maternal toxicity was 2500 mg/m3

(675 ml/m3) and the NOAEL for developmental toxicity 9800 mg/m3 (2646 ml/m3) (Klimisch and Hellwig, 1995).

Table 6-1Reproductive and developmental toxicity studies - dermal.

Material Method Concentration/dose Species (No./dose) Results References

2-Ethyl-1-hexanol Occlusive, 6 h/day,on gestation days6–15, caesareansection at day 21

Range-finding study: 0, 0.5, 1.0,2.0, and 3.0 ml/kg body weight/day (0, 420, 840, 1680, or2520 mg/kg body weight/day)

F344 rats (range-finder:8 f/group; main study:25 f/group)

NOAEL maternal toxicity: 252 mg/kgbody weight/day based on skinirritation and 840 mg/kg bodyweight/day based on systemictoxicity NOAEL developmentaltoxicity: 2520 mg/kg body weight/day

Deisinger et al. (1994);Tyl et al. (1992)

Main study: 25/group 99.72%pure 0, 0.3, 1.0, and 3.0 ml/kgbody weight/day (0, 252, 840, or2520 mg/kg body weight/day)

Maternal: P840 mg/kg body weight/day: Persistent exfoliation andcrusting and erythema at applicationsite; maternal liver, kidney, thymus,spleen, adrenal, and uterine weightsand gestational and fetal parameterswere unaffected by treatment;P1680 mg/kg body weight/day:weight gain decreaseFetal: no treatment-related increasesin incidence of individual or pooledexternal, visceral, or skeletalmalformations or variations


Tabl

e6-

2Re

prod

ucti

vean

dde

velo

pmen

tal

toxi

city

stud

ies

–or

al.

Mat

eria

lM

eth

odC

once

ntr

atio

n/d

ose

Spec

ies

(No.

/dos

e)R

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

Gav

age,

3da

ys/w

eek,

3-da

yol

dm

ales

0,16

7m

g/kg

body

wei

ght/

day

CD

Spra

gue–

Daw

ley

rats

(4m

/gro

up)

No

effe

cton

Sert

oli

cell

san

dgo

noc

ytes

Liet

al.(

2000

)

Gav

age,

5da

ys,3

5-da

yol

dm

ale

rats

2.7

mm

ol/k

gbo

dyw

eigh

t/da

y(3

50m

g/kg

body

wei

ght/

day)

Spra

gue–

Daw

ley

rats

No

test

icu

lar

dam

age

Sjob

erg

etal

.(19

86)

Gav

age

onda

y12

0(u

ntr

eate

d),6

.25

or12

.5m

mol

(833

,16

66m

g/kg

body

wei

ght/

day)

,un

dilu

ted

Wis

tar

rats

(7f/

grou

p)M

ater

nal:

no

mat

ern

alto

xici

tyw

asre

port

edR

itte

ret

al.(

1987

)

Feta

l:16

66m

g/kg

body

wei

ght/

day:

22.2

%of

the

surv

ivin

gfe

tuse

sh

adm

alfo

rmat

ion

s(l

ower

dose

grou

p2%

,co

ntr

ols

0%).

Thes

ein

clu

ded

hyd

ron

eph

rosi

s(7

.8%

),ta

ilan

omal

ies

(4.9

%),

mal

form

edli

mbs

(9.7

%)

and

‘‘oth

ers”

(1%

);av

erag

efe

tal

wei

ght

decr

ease

dIm

plan

tati

onin

dex,

aver

age

feta

lw

eigh

t,n

um

bers

ofde

adan

dre

sorb

edfe

tuse

sw

ere

not

affe

cted

Gav

age,

onge

stat

ion

day

11.5

;af

ter

8h

intu

bate

dw

ith

32l

Ci

65Zn

,kil

led

onge

stat

ion

day

12.5

0,6.

25,9

.38

or12

.5m

mol

2-et

hy-

1-h

exan

ol/k

gbo

dyw

eigh

tin

corn

oil

(equ

ival

ent

to0,

813,

1219

,162

5m

g/kg

body

wei

ght)

Spra

gue–

Daw

ley

rats

(6f/

grou

p)M

ater

nal:

P12

19m

g/kg

body

wei

ght:

mat

ern

alfo

odin

take

decr

ease

d;16

25m

g/kg

body

wei

ght:

perc

enta

geof

65Zn

reta

ined

inm

ater

nal

live

rin

crea

se

Bu

iet

al.(

1998

);Ta

ube

nec

ket

al.

(199

6)

Feta

l:th

epe

rcen

tage

ofre

sorp

tion

sw

asn

otaf

fect

ed16

25m

g/kg

body

wei

ght:

perc

enta

geof

65Zn

reta

ined

inth

eem

bryo

sde

crea

sed

Gav

age

from

days

6to

19of

preg

nan

cy0,

1,5,

and

10m

mol

/kg

body

wei

ght/

day

(0,

130,

650,

and

1300

mg/

kgbo

dyw

eigh

t/da

y)

Wis

tar

rats

(10

f/gr

oup)

NO

AEL

mat

ern

alan

dde

velo

pmen

tal

toxi

city

:13

0m

g/kg

body

wei

ght/

day

Hel

lwig

and

Jäck

h(1

997)

Mat

erna

l:P

650

mg/

kgbo

dyw

eigh

t/da

y:13

00m

g/kg

body

wei

ght/

day:

body

wei

ght

decr

ease

d;m

orta

lity

incr

ease

dFe

tal:

P65

0m

g/kg

body

wei

ght/

day:

wei

ght

decr

ease

d,sk

elet

alva

riat

ion

san

dre

tard

atio

nin

crea

sed

1300

mg/

kgbo

dyw

eigh

t/da

y:po

st-

impl

anta

tion

loss

,res

orpt

ion

s,n

um

ber

and

perc

ent

fetu

ses

and

litt

ers

wit

hm

alfo

rmat

ion

san

dva

riat

ion

s,an

dn

um

ber

and

perc

enta

geof

fetu

ses

wit

hre

tard

atio

ns

incr

ease

d;fe

tal

wei

ght

decr

ease

dD

ays

0–17

ofpr

egn

ancy

Die

t:0%

,0.0

09%

,0.0

3%,

and

0.09

%(m

icro

enca

psu

late

d)(0

.13,

43an

d12

9m

g/kg

body

wei

ght/

day)

CD

-1Sw

iss

mic

e(2

8f/

grou

p)N

OA

ELm

ater

nal

and

deve

lopm

enta

lto

xici

ty:

129

mg/

kgbo

dyw

eigh

t/da

ybu

tn

oto

xic

dose

test

ed

NTP

(199

1)an

dPr

ice

etal

.(19

91)

>99%

pure

test

subs

tan

ceN

om

ater

nal

toxi

city

;al

lof

the

litt

ers

surv

ived

and

all

gest

atio

nal

para

met

ers

wer

en

orm

al


Gav

age

from

days

7to

14of

preg

nan

cy;

the

dam

san

dpu

psw

ere

obse

rved

un

til

day

3of

lact

atio

n

0,15

25m

g/kg

body

wei

ght/

day

inco

rnoi

lC

har

les

Riv

erC

D-1

mic

e(5

0f/

grou

p)N

OA

ELfo

rm

ater

nal

/dev

elop

men

tal

toxi

city

can

not

bede

rive

dH

ardi

net

al.(

1987

)

Mat

erna

l:15

25m

g/kg

/d:

17/4

9di

ed(c

ontr

ols

0),r

edu

ced

mov

emen

t,at

axia

,h

ypot

her

mia

,un

kem

ptco

ats

and

bloo

din

the

uri

ne,

body

wei

ght

and

fert

ilit

yan

dpr

egn

ancy

inde

xde

crea

seFe

tal:

1525

mg/

kg/d

ay:

nu

mbe

rof

live

pups

and

inth

eir

wei

ght

decr

ease

.No

furt

her

para

met

ers

wer

eco

nsi

dere

din

this

stu

dyIs

ooct

ylal

coh

ol(C

7–9

alco

hol

s,br

anch

ed(C

AS

No.

6852

6-83

-0)

)

Gav

age,

days

6–15

p.c.

,ac

cord

ing

toO

ECD

TG41

4

0,10

0,50

0,10

00m

g/kg

body

wei

ght/

day

inco

rnoi

l

Spra

gue–

Daw

ley

rat

(25

f/gr

oup)

NO

AEL

mat

ern

alto

xici

ty:

500

mg/

kgbo

dyw

eigh

t/da

yEB

SI(1

994a

)as

cite

din

Exxo

n(2

001a

)N

OA

ELde

velo

pmen

talt

oxic

ity:

100

mg/

kgbo

dyw

eigh

t/da

yM

ater

nal:

1000

mg/

kg:

food

con

sum

ptio

nde

crea

sed,

body

wei

ght

gain

from

GD

6–9

and

GD

6–15

decr

ease

d,cl

inic

alsi

gns

(em

acia

tion

,ral

es,h

ypoa

ctiv

ity,

abdo

min

al/a

nog

enit

alst

ain

ing,

litt

leor

no

stoo

l)Fe

tal:

P50

0m

g/kg

:nu

mbe

rof

lum

bar

ribs

incr

ease

d10

00m

g/kg

body

wei

ght/

day:

nu

mbe

rof

fetu

ses

wit

hsk

elet

alva

riat

ion

sin

crea

sed,

hyp

opla

stic

sku

llbo

nes

incr

ease

don

lyon

ape

r-fe

tus

basi

sIs

otri

deca

n-1

-ol

(iso

mer

icm

ixtu

re)

Gav

age,

days

6–19

p.c.

0(o

live

oil)

,60,

250,

or75

0W

ista

rra

ts(2

5/f/

grou

p)N

OA

ELfo

rm

ater

nal

toxi

city

:25

0m

g/kg

RIF

M(2

003b

)N

OA

ELfo

rde

velo

pmen

tal

toxi

city

:75

0m

g/kg

Mat

erna

l:75

0m

g/kg

:tr

ansi

ent

sali

vati

on;1

1%re

duct

ion

offo

odco

nsu

mpt

ion

(6–1

0p.

.c);

incr

ease

dal

anin

eam

inot

ran

sfer

ase

valu

es;

incr

ease

dtr

igly

ceri

des

(14%

)an

dre

lati

veli

ver

wei

ghts

(18%

);de

crea

sed

tota

lpr

otei

nan

dgl

obu

lin

con

cen

trat

ion

s25

0m

g/kg

:tr

ansi

ent

sali

vati

onFe

tal:

750

mg/

kgbo

dyw

eigh

t/da

y:n

oef

fect

sIs

onon

ylal

coh

ol(I

son

onan

olty

pe1

(CA

SN

o.68

515-

81-

1))

Gav

age,

days

6–15

p.c.

acco

rdin

gto

OEC

DTG

414

0(c

ontr

ol1:

wat

er,

con

trol

2:w

ater

wit

h0.

005%

Cre

mop

hor

EL),

1,5,

and

10m

mol

/kg

body

wei

ght/

day

(0,

144,

720,

and

1440

mg/

kgbo

dyw

eigh

t/da

y)in

aqu

eou

sC

rem

oph

orEL

Wis

tar

rats

(10

f/gr

oup)

NO

AEL

for

mat

ern

alto

xici

ty:

144

mg/

kgbo

dyw

eigh

t/da

yN

OA

ELfo

rde

velo

pmen

tal

toxi

city

:14

4m

g/kg

body

wei

ght/

day

Hel

lwig

and

Jäck

h(1

997)

and

EPA

,19

91

Supp

lem

enta

ryst

udy

:0

(con

trol

1:w

ater

,co

ntr

ol2:

wat

erw

ith

0.00

5%C

rem

oph

orEL

)an

d7.

5m

mol

/kg

body

wei

ght/

day

(0,

1080

mg/

kgbo

dyw

eigh

t/da

y)be

cau

seof

mor

tali

tyof

alld

ams

at10

mm

ol/k

g(1

440

mg/

kg)

body

wei

ght/

day

Mat

erna

l:P

720

mg/

kg:

food

con

sum

ptio

n(d

ays

6–10

p.c.

)de

crea

sed,

clin

ical

sign

s(a

path

y,n

asal

disc

har

ge)

1080

mg/

kg:

seve

rem

ater

nal

sign

s(n

.f.i.)

,m

orta

lity

(1/1

0)14

40m

g/kg

:m

orta

lity

(10/

10)

Feta

l:14

4m

g/kg

body

wei

ght/

day:

fetu

ses

wit

hh

ydro

ure

ter

(8/7

3;11

.0%

,con

trol

1:0/

68,c

ontr

ol2:

3/69

,4.3

%),

no

furt

her

effe

cts

(con

tinu

edon

next

page

)


Tabl

e6-

2(c

onti

nued

)

Mat

eria

lM

eth

odC

once

ntr

atio

n/d

ose

Spec

ies

(No.

/dos

e)R

esu

lts

Ref

eren

ces

720

mg/

kgbo

dyw

eigh

t/da

y:fe

tuse

sw

ith

hyd

rou

rete

r(8

/67,

12.0

%),

feta

ln

um

ber

decr

ease

dan

d%

fetu

ses

wit

hsk

elet

alva

riat

ion

san

dre

tard

atio

ns

incr

ease

d10

80m

g/kg

:fe

tuse

sw

ith

hyd

rou

rete

r(3

/37

,8.1

%,c

ontr

ol1:

6/65

,9.2

%,c

ontr

ol2:

2/58

,3.4

%);

mea

nu

teri

ne

and

feta

lw

eigh

tsde

crea

sed,

reso

rpti

ons

incr

ease

d,po

st-

impl

anta

tion

loss

incr

ease

d,n

um

ber

and

%fe

tuse

san

dli

tter

sw

ith

mal

form

atio

ns

incr

ease

d(m

ain

lyre

late

dto

the

hea

rt),

nu

mbe

ran

d%

fetu

ses

wit

hre

tard

atio

ns

incr

ease

,ske

leta

lva

riat

ion

incr

ease

(ru

dim

enta

ry-c

ervi

cal

rib(

s)in

crea

sed

(11/

0co

ntr

ol1,

11/1

con

trol

2))

1440

mg/

kgbo

dyw

eigh

t/da

y:ex

amin

atio

nof

fetu

ses

not

poss

ible

beca

use

ofm

ater

nal

deat

hIs

odec

ylal

coh

olG

avag

e,da

ys6–

15p.

c.,

acco

rdin

gto

OEC

DTG

414

(10

inst

ead

of20

reco

mm

ende

dan

imal

s/gr

oup)

0,1,

5,an

d10

mm

ol/k

gbo

dyw

eigh

t/da

y(0

,15

8,79

0,an

d15

80m

g/kg

body

wei

ght/

day)

inaq

ueo

us

Cre

mop

hor

EL

Wis

tar

rats

(10

f/gr

oup)

NO

AEL

mat

ern

alto

xici

ty:

158

mg/

kgbo

dyw

eigh

t/da

yH

ellw

igan

dJä

ckh

(199

7)

NO

AEL

deve

lopm

enta

lto

xici

ty:

790

mg/

kgbo

dyw

eigh

t/da

yM

ater

nal:

P79

0m

g/kg

:fo

odco

nsu

mpt

ion

decr

ease

d,bo

dyw

eigh

ton

days

15an

d20

decr

ease

d,cl

inic

alsy

mpt

oms

(nas

aldi

sch

arge

,sal

ivat

ion

,an

dC

NS

depr

essi

on)

1580

mg/

kg:

mor

tali

tyin

crea

sed

Feta

l:15

80m

g/kg

:m

ean

ute

rin

ean

dfe

tal

wei

ghts

decr

ease

d,re

sorp

tion

sin

crea

sed,

post

impl

anta

tion

loss

incr

ease

d,n

um

ber

and

%fe

tuse

sw

ith

mal

form

atio

ns

and

reta

rdat

ion

sin

crea

sed

3,5,

5-Tr

imet

hyl

-1-

hex

anol

Gav

age,

mal

es:

46da

ys,f

emal

es:

from

14da

ysbe

fore

mat

ing

toda

y3

ofla

ctat

ion

,O

ECD

TG42

2

0,12

,60,

300

mg/

kgbo

dyw

eigh

t/da

yin

oliv

eoi

l

SD(C

rj:C

D)

rat

(12/

sex/

dose

)N

OA

ELsy

stem

icto

xici

tym

ales

and

fem

ales

:12

mg/

kgbo

dyw

eigh

t/da

yM

HW

,Jap

an(1

997b

)as

cite

din

OEC

D/S

IDS

(200

3)N

OA

ELfe

rtil

ity:

12m

g/kg

body

wei

ght/

day

(fem

ales

)30

0m

g/kg

body

wei

ght/

day

(mal

es)

NO

AEL

deve

lopm

enta

lto

xici

ty:

12m

g/kg

body

wei

ght

Pare

ntal

:P

12m

g/kg

body

wei

ght/

day:

ren

alh

yali

ne

drop

lets

,eos

inop

hil

icbo

dies

(m)

P60

mg/

kgbo

dyw

eigh

t/da

y:re

l.li

ver

wei

ght

incr

ease

(m,f

),ab

s.an

dre

l.ki

dney

wei

ght

incr

ease

(m),

pale

disc

olor

atio

nof

kidn

eys

(m),

ren

altu

bula

rep

ith

elia

lre

gen

erat

ion

(m),

form

atio

nof

gran

ula

rca

sts

inki

dney

(m),

ren

alep

ith

elia

lfa

tty

chan

ge(f

);im

plan

tati

onin

dex

decr

ease

(f)

300

mg/

kgbo

dyw

eigh

t/da

y:1

fdi

ed,3

fki

lled

(wea

knes

s);

body

wei

ghts

incr

ease

(m),

food

con

sum

ptio

nin

crea

se(m

),bo

dyw

eigh

tsde

crea

se(f

),fo

odco

nsu

mpt

ion

decr

ease

(f);

uri

ne

volu

me

incr

ease

(m),

wat

erco

nsu

mpt

ion

incr

ease

(m);

red

bloo

dce

llco

un

tsde

crea

se(m

),h

emat

ocri

t


decr

ease

(m),

hem

oglo

bin

decr

ease

(m),

BU

Nde

crea

se(m

),ch

lori

dede

crea

se(m

)ab

s.li

ver

wei

ght

incr

ease

(m,f

),re

l.ki

dney

wei

ght

incr

ease

(f),

swel

lin

gof

kidn

ey(m

),ye

llow

ish

wh

ite

disc

olor

atio

nof

live

r(f

),ir

regu

lari

tyin

shap

eof

foll

icle

s(m

),co

lum

nar

chan

geof

foll

icu

lar

epit

hel

ium

(m),

thyr

oid

coll

oid

decr

ease

(m),

thym

us

atro

phy

(f);

tota

lli

tter

loss

in2

dam

sFe

tal:

P60

mg/

kgbo

dyw

eigh

t/da

y:de

crea

sed

pups

born

aliv

e30

0m

g/kg

body

wei

ght/

day:

viab

ilit

yof

neo

nat

eson

day

4of

lact

atio

nde

crea

sed,

body

wei

ghts

ofm

ale

and

fem

ale

pups

?de

crea

sed

Subg

roup

:se

cond

ary

2,6-

Dim

eth

ylh

epta

n-4

-on

eG

avag

e,fr

om2

wee

kspr

ior

tom

atin

gth

rou

ghou

tpr

egna

ncy

un

til

wea

nin

gda

y5

post

part

um

(OEC

DTG

421)

0(v

ehic

le),

100,

300,

1000

mg/

kgbo

dyw

eigh

t/da

yin

corn

oil

Alp

k:A

pfsS

Dra

ts(1

0/se

x/gr

oup)

NO

AEL

pare

nta

lsy

stem

icto

xici

ty:

300

mg/

kgbo

dyw

eigh

t/da

ySh

ell

HSE

(199

6)as

cite

din

OEC

D/

SID

S(2

003)

NO

AEL

deve

lopm

enta

l/re

prod

uct

ive

effe

cts:

1000

mg/

kgbo

dyw

eigh

t/da

yM

ater

nal:

1000

mg/

kgbo

dyw

eigh

t/da

y:tw

oda

ms

died

duri

ng

lact

atio

n,

attr

ibu

tabl

eto

the

test

subs

tan

ce.T

her

ew

asn

oef

fect

onth

en

um

ber

ofpr

egn

anci

es,p

osit

ive

smea

rs,l

itte

rsbo

rn,

nu

mbe

rof

impl

anta

tion

sor

prop

orti

onof

pups

born

live

inan

ydo

segr

oup

Pate

rnal

:10

00m

g/kg

body

wei

ght/

day:

mal

ebo

dyw

eigh

tga

ins

decr

ease

No

chan

ges

inor

gan

wei

ght

and

no

sign

ifica

nt

his

topa

thol

ogic

alch

ange

sin

the

mal

eor

fem

ale

repr

odu

ctiv

eor

gan

s;n

oev

iden

ceof

anef

fect

onan

yof

the

repr

odu

ctiv

epa

ram

eter

sin

vest

igat

edor

onan

yof

the

surv

ivin

gli

tter

s4-

Hyd

roxy

-4-m

ethy

l-2-

pent

anon

eO

ECD

TG42

2(s

cree

nin

gte

st):

mal

es:

44da

ys,f

emal

es:

from

14da

ysbe

fore

mat

ing

toda

y3

ofla

ctat

ion

0,30

,100

,300

,10

00m

g/kg

body

wei

ght/

day

inw

ater

Crj

:CD

(SD

)ra

t(1

0/se

x/do

se)

NO

AEL

pare

nta

lsy

stem

icto

xici

ty:

100

mg/

kgbo

dyw

eigh

t/da

yM

HW

,Jap

an(1

997)

asci

ted

inO

ECD

/SI

DS

(200

7)N

OA

ELfo

rfe

rtil

ity

and

deve

lopm

enta

lto

xici

ty:

300

mg/

kgbo

dyw

eigh

t/da

yPa

rent

al:

ten

den

cyfo

rlo

wer

repr

odu

ctiv

ein

dice

s(f

erti

lity

and

impl

ants

)(n

.f.i.)

Feta

l:10

00m

g/kg

body

wei

ght/

day:

ten

den

cyfo

rde

crea

seof

the

foll

owin

gpa

ram

eter

s:to

tal

nu

mbe

rof

pups

born

,de

live

ryin

dex,

live

birt

hin

dex,

nu

mbe

rof

pups

aliv

e,vi

abil

ity

inde

xon

day

4of

lact

atio

n(n

.f.i.)

f:fe

mal

e,m

:m

ale,

n.f.

i.:n

ofu

rth

erin

form

atio

n,n

.s.:

not

stat

isti

call

ysi

gnifi

can

t,p.

c.:

post

coit

um


Tabl

e6-

3Re

prod

ucti

vean

dde

velo

pmen

tal

toxi

city

stud

ies

–in

hala

tion

.

Mat

eria

lM

eth

odC

once

ntr

atio

n/d

ose

Spec

ies

(No.

/dos

e)R

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

Wh

ole

body

expo

sure

from

day

0to

19of

preg

nan

cy0,

850

mg/

m3

(160

ml/

m3)

the

max

imu

mva

por

con

cen

trat

ion

that

cou

ldbe

ach

ieve

dw

ith

out

incr

easi

ng

expo

sure

cham

ber

tem

pera

ture

abov

e80

�F

Spra

gue–

Daw

ley

rats

(15

f/gr

oup)

NO

AEL

160

ml/

m3

Nel

son

etal

.(19

89)

Mat

erna

l:16

0m

l/m

3:

no

mat

ern

alto

xici

tyFe

tal:

160

ml/

m3:

no

sign

ifica

nt

diff

eren

ces

inco

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The same test procedure was performed with 14–15 pregnantHimalayan rabbits. The animals were exposed to 0, 510, 2510, or9800 mg isoamyl alcohol/m3 (0, 138, 678, and 2646 ml/m3) fromday 7 to day 19 post-insemination. In dams exposed to the highestconcentration body weight gain was decreased between days 7 and10 post insemination and irritant eye effects (reddish, lid closure,and slight discharge) were noted. Histopathological examinationof the dams revealed no substance-related effects. The reproduc-tion parameters (e.g. mean number of corpora lutea, implantationsites, values calculated for the pre- and post-implantation losses,and number of resorptions) and malformations (external, visceral,or skeletal) were within the levels of the concurrent control groupor of historical control groups. The maternal NOAEL was 2500 mg/m3 (678 ml/m3) and the NOAEL for developmental toxicity was9800 mg/m3 (2646 ml/m3) (Klimisch and Hellwig, 1995).

Fifteen pregnant Sprague–Dawley rats were exposed (wholebody) 7 h per day on gestation days 0–19 to 850 mg 2-ethyl-1-hex-anol/m3 (160 ml/m3), the maximum vapor concentration thatcould be achieved without increasing exposure chamber tempera-ture above 80 � F. After caesarean section on day 20, one-half of thefetuses were examined for skeletal malformations, the other halffor visceral malformations. Aside from a decrease in feed consump-tion in dams compared to control, there were no significant differ-ences in maternal, reproductive, or developmental parameters(Nelson et al., 1989). The NOAEL for maternal and developmentaltoxicity was 850 mg/m3 (160 ml/m3).

5.5.2.3.2. Secondary alcohols. Thirty-five pregnant Fischer 344rats or 30 pregnant CD-1 mice were exposed 6 h per day on gesta-tion days 6–15 to 0, 300, 1000, and 3000 ml 4-methyl-2-pentanone/m3 (0, 1230, 4090, and 12,300 mg/m3). Maternal toxicity (neuro-muscular effects, e.g. loss of coordination or paresis) was observedin both species after exposure to the highest concentration. Ratdams showed reductions in body weights, body weight gain, andfood consumption. The relative kidney weights were elevated. Inmice, three dams died at the first exposure and the relative andabsolute liver weights were increased. Reduced fetal body weightper litter and delayed skeletal ossification was observed in bothspecies at the highest concentration. Rat fetuses showed an in-creased incidence of unilateral rudimentary rib at the first lumbararch. In mice, the number of dead fetuses as well as visceral andskeletal variations was increased. The NOAELs for maternal and fe-tal toxicity were 1000 ml/m3 for both species (Tyl et al., 1987 as ci-ted in OECD/SIDS, 2007).


5.6. Skin irritation

5.6.1. Human studiesSeven alcohols with saturated branched chain under review

with a worldwide use of greater than 0.01 tons per year have beenwell studied for their potential to produce dermal irritation in hu-mans (see Table 7-1).

The following substances did not induce skin irritation in pre-tests for a maximization study with single occlusive applicationfor 48 h with the highest concentrations tested, i.e., 20% 3,6-di-methyl-3-octanol (RIFM, 1972a, 1973c), 10% 3,7-dimethyl-7-meth-oxyoctan-2-ol (RIFM, 1982b), 10% 2,6-dimethyl-2-heptanol (RIFM,1976b, 1983a), 8% isoamyl alcohol (RIFM, 1976b), 8% 3,5,5-tri-methyl-1-hexanol (RIFM, 1977b), and 4% 2-ethyl-1-hexanol (RIFM,1976c).

No irritation was observed with 2% 2,6-dimethyl-2-heptanolduring the induction phase of a human repeat insult patch test(HRIPT) in 10 healthy male and female volunteers (RIFM, 1969).The repeated application of 15% 3,4,5,6,6-pentamethylheptan-2-ol during the induction phase of a HRIPT led to erythema (6 grade1 of 4, 4 grade 2 of 4) in 5 of 51 volunteers (RIFM, 1983c).

A patch test (5 min under occlusion) was conducted on 12healthy volunteers and with 3 or 12 subjects of oriental ancestrywith a 75% aqueous solution of isoamyl alcohol. Irritation reactionswere observed in all volunteers (Wilkin and Fortner, 1985a,b; Wil-kin and Stewart, 1987).

Further details on studies of dermal irritation in humans areprovided in Table 7-1.

5.6.2. Animal studiesTwelve of the alcohols under review with a worldwide use of

greater than 0.01 tons per year have been tested in animal modelsof skin irritation using rabbits, rats, or guinea pigs. Studies withsingle application are summarized in Table 7-2-1 and studies withrepeated application are shown in Table 7-2-2.

A single application of neat 3,4,5,6,6-pentamethylheptan-2-oldid not produce dermal irritation in rabbits (RIFM, 1984b) and rats(RIFM, 1985a). If applied undiluted as a single application, 2-ethyl-1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol,3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol, 4-methyl-2-pentanol, 2,6-dimethyl-2-heptanol, and 3,6-dimethyl-3-octanol(McOmie and Anderson, 1949; RIFM, 1973a, 1976a, 1977a; Scalaand Burtis, 1973; Cornu et al., 1992, 1984, 1978) led to slight ormoderate irritation in all studies with rabbits irrespectively ofthe method used. As an exception undiluted 2,6-dimethyl-2-hept-anol was strongly irritating after 24 h occlusive application (RIFM,1979a). The diluted substances led to no or only slight effects inrabbits or guinea pigs: 3,6-dimethyl-3-octanol 15% no to slightreactions (RIFM, 1970), 2,6-dimethyl-2-heptanol 10% no reaction(RIFM, 1981a), 3,7-dimethyl-7-methoxyoctan-2-ol 1% slight reac-tion (RIFM, 1973e).

Five percent 3,7-dimethyl-7-methoxyoctan-2-ol did not pro-duce dermal irritation in guinea pigs after repeated application(RIFM, 1973d). Repeated application of neat 2-ethyl-1-hexanolled to slight dermal irritation in rats (Schmidt et al., 1973). Moder-ate or strong irritation was observed after repeated applications ofundiluted 2,6-dimethyl-4-heptanol, 4-methyl-2-pentanol, and3,4,5,6,6-pentamethylheptan-2-ol (also diluted) in rabbits (McO-mie and Anderson, 1949; RIFM, 1985c, 1986a). Toxicity studieswith repeated dermal application (see Section 5.2.1) also showeddermal irritation especially with 3,4,5,6,6-pentamethylheptan-2-ol. These studies were performed with high doses under occlusionand are therefore not representative of human exposure.

5.7. Mucous membrane irritation

5.7.1. Sensory irritation5.7.1.1. Human data. The results of the human irritation studies aresummarized in Table 8.

Human male volunteers (with and without self-reported multi-ple chemical sensitivity) were exposed to 2-ethyl-1-hexanol byinhalation for 4 h (exposure chamber). Fluctuating concentrations(time weighted average concentrations: 1.5 (control), 10, and20 ml/m3) were used in the first experiment, and similar but con-stant vapor concentrations in a second experiment. Olfactory- andtrigeminal-mediated symptoms and intensities of odor, eye, andnasal irritation were recorded. Self-reported nasal and eye irrita-tion and perceived odor intensity were increased and concentra-tion-related at concentrations of 10 ml/m3 or more. Self-reportedchemical sensitivity had only minor effects on chemosensorysymptoms in the second experiment (constant concentrations)and no effect on intensity ratings in either experiment (van Thrielet al., 2005).

An average of 12 subjects were exposed by inhalation to 2,6-di-methyl-4-heptanol for 15 min. At 5 ml/m3 or more, eye irritationwas observed, and at 10 ml/m3 nose and throat irritation. The sen-sory response limit was reported to be less than 5 ml/m3 (Silver-


man et al., 1946). In the same study 4-methyl-2-pentanol led toeye irritation at 50 ml/m3 and higher concentrations resulted innose and throat irritation. The NOEL was 25 ml/m3 (Silvermanet al., 1946).

5.7.1.2. Animal data. Sensory irritation was evaluated in 4 Swissmale mice via measurement of changes in respiratory rate duringa 10-min exposure to isoamyl alcohol. The concentration of iso-amyl alcohol that caused a 50% decrease in the respiratory rate(RD50) of mice was 4452 ml/m3 with 95% confidence limits of2885–12,459 ml/m3 (Kane et al., 1980). Another study reported aRD50 value of 2624 mg/m3 (729 ml/m3) (Korpi et al., 1999).

After a 5-min exposure to 4-methyl-2-pentanol the RD50 formice was 420 ml/m3 (6 animals/group) (Muller and Greff, 1984as cited in Greim, 2002).

5.7.2. Eye irritationNo human studies on eye irritation are available. An overview of

in vivo studies on eye irritation in rabbits can be found in Table 9.Several in vitro tests to investigate the eye irritation potential

did show an irritating effect of 2-ethyl-1-hexanol (Adriaens andRemon, 2002; Adriaens et al., 2005; Casterton et al., 1996; Gauth-eron et al., 1994; Gilleron et al., 1997; Goethem et al., 2006; Ken-nah et al., 1989a).

For 3,7-dimethyl-7-methoxyoctan-2-ol only one study with a1% solution in propylene glycol was available, in which the sub-stance did not cause irritating effects (RIFM, 1973e).

In 4 of 5 studies, isotridecan-1-ol (isomeric mixture) elicited noeye irritation in rabbits (Greim, 2000). Further information aboutthe test method and the concentration were not given. The undi-luted substance was moderately irritating to the rabbit eye inone study (Greim, 2000; Scala and Burtis, 1973).

Undiluted 3,6-dimethyl-3-octanol was evaluated as an eye irri-tant. The substance led to redness and chemosis of the conjunctiva,slight corneal opacity, and swelling of the iris. The effects were notreversible within 3 days (RIFM, 1970).

In three studies undiluted 2-ethyl-1-hexanol was moderatelyirritating to the rabbit eye (Carpenter and Smyth, 1946; Schmidtet al., 1973; Smyth et al., 1969). Observed effects were conjunctivalredness and swelling, lacrimation, and discharge. The effects didnot clear within 96 h. Corneal effects were not found (Schmidtet al., 1973). In three other studies, the undiluted substance wasclassified as a severe eye irritant (Kennah et al., 1989b; RIFM,1978b; Scala and Burtis, 1973). These studies resulted in dullnessand vascularization of the cornea (Scala and Burtis, 1973). The cor-neal effects were persistent (RIFM, 1978b). In addition, iritis, con-junctival erythema, chemosis, and discharge appeared (Scala andBurtis, 1973).

Undiluted 2,6-dimethyl-2-heptanol, 2,6-dimethyl-4-heptanol,4-methyl-2-pentanol, and 3,4,5,6,6-pentamethylheptan-2-ol weremoderate eye irritants (McOmie and Anderson, 1949; RIFM,1979a, 1984c; Smyth et al., 1951). The substances caused conjunc-tivitis with edema and corneal injury. The effects disappearedwithin 7 days (McOmie and Anderson, 1949; RIFM, 1984c) exceptfor those caused by 2,6-dimethyl-2-heptanol (RIFM, 1979a).

Undiluted 2-ethyl-1-butanol, isoamyl alcohol, and 2-methylbu-tanol were highly irritating to the rabbit eye (Smyth et al., 1954,1962, 1969).

5.8. Skin sensitization

5.8.1. Human studiesSeven of the alcohols under review with a worldwide use of

greater than 0.01 tons per year have been evaluated for their po-tential to induce sensitization in humans (see Tables 10-1 and10-2).

In both subgroups of primary and secondary alcohols no evi-dence of a sensitizing effect in a maximization test or in a humanrepeated insult patch test (HRIPT) with volunteers was observedwith 4% 2-ethyl-1-hexanol (RIFM, 1976c), 8% isoamyl alcohol(RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b), 10%3,7-dimethyl-7-methoxyoctan-2-ol (RIFM, 1982b), and 15%3,4,5,6,6-pentamethylheptan-2-ol (RIFM, 1983c). In the subgroupof tertiary alcohols 2,6-dimethyl-2-heptanol did not induce posi-tive reactions in a maximization test (10%, RIFM, 1976b) or a HRIPT(2%, RIFM, 1969). In a maximization test with 20% 3,6-dimethyl-3-octanol in petrolatum (RIFM, 1972a), 4 of 25 volunteers exhibitedpositive reactions 24 and 48 h after challenge. However, sincethese four subjects also reacted strongly to a control material itwas concluded that the reactions observed were due to a ‘‘spillover” effect from the other material. In a second test with 10% inpetrolatum, the positive reactions could not be confirmed (RIFM,1973c).

With a sub-irritating concentration (no further information) of3,7-dimethyl-7-methoxyoctan-2-ol in petrolatum, 0.9% positivereactions (2 patients) were found in patch tests with 218 patientswith proven sensitization to fragrance materials (Table 10-2; Lar-sen et al., 2002).

5.8.2. Animal studiesResults of available animal studies are shown in Table 10-3. In

comparison to humans, limited data on sensitization in animalsare available. Only one secondary and one tertiary alcohol weretested.

2,6-Dimethyl-2-heptanol was negative in guinea pigs at a con-centration of 10% (Watanabe et al., 1988). No delayed-type hyper-sensitivity was observed for 3,7-dimethyl-7-methoxyoctan-2-ol inthe same species (RIFM, 1973d).

5.9. Phototoxicity and photoallergenicity

Limited data were available with regard to the phototoxicityand photoallergenicity of the alcohols with saturated branchedchain (see Table 11). From human or animal studies reliable datawere available only on the phototoxicity and photoallergenicityof the tertiary alcohol 2,6-dimethyl-2-heptanol.

No phototoxic reactions were observed in 6 healthy female vol-unteers exposed to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/acetone, followed by irradiation by UVA (RIFM, 1983a).

In the only animal phototoxicity study, 10% 2,6-dimethyl-2-heptanol in ethanol produced no phototoxic reactions after UVAor UVB irradiation in guinea pigs (RIFM, 1981a).

No studies have been performed which investigate the photoal-lergic potential in humans.

2,6-Dimethyl-2-heptanol was tested for its photoallergenicityin a reliable test with guinea pigs (RIFM, 1981b). No photoallerge-nicity was seen in the animals induced with 10% in rectified alco-hol, followed by irradiation with UVB and UVA (9 times in 18 days),and challenged after a 10-day rest with 10% of the test substance inrectified alcohol and irradiation.

As the alcohols under review do not contain double bonds, theycannot absorb UVA or UVB light. Indeed, UV spectra have beenobtained for 12 materials (2-ethyl-1-hexanol, isoamyl alcohol,isotridecan-1-ol (isomeric mixture), 2-methylbutanol, 3-methyl-1-pentanol, 2-methylundecanol, 3,5,5-trimethyl-1-hexanol, 2,6-di-methyl-4-heptanol, 3,7-dimethyl-7-methoxyoctan-2-ol, 6,8-dim-ethylnonan-2-ol, 3,4,5,6,6-pentamethylheptan-2-ol, and 2,6-dimethyl-2-heptanol). Five materials did not absorb UV light, theremaining 5 peaked in the UVC range (<290 nm) and returned tobaseline around 300 nm (see Table 12). 2-Ethyl-1-hexanol and3,7-dimethyl-7-methoxyoctan-2-ol peaked between 200 and 215with minor absorption returning to baseline at 400 nm. Based on


Tabl

e7-

1Sk

inir

rita

tion

stud

ies

inhu

man

s.

Mat

eria

lM

eth

odC

once

ntr

atio

nSu

bjec

tsR

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

48h

,occ

lusi

ve(p

re-

test

for

am

axim

izat

ion

stu

dy)

4%in

petr

olat

um

29h

ealt

hy

mal

evo

lun

teer

sN

oir

rita

tion

RIF

M(1

976c

)

Isoa

myl

alco

hol

48h

,occ

lusi

ve(p

re-

test

for

am

axim

izat

ion

stu

dy)

8%in

petr

olat

um

25h

ealt

hy

volu

nte

ers

No

irri

tati

onR

IFM

(197

6b)

5m

in,o

cclu

sive

75%

inw

ater

12vo

lun

teer

sIr

rita

tion

inal

l12

volu

nte

ers

Wil

kin

and

Stew

art

(198

7)

5m

in,o

cclu

sive

75%

inw

ater

12vo

lun

teer

s(o

rien

tal)

Irri

tati

onin

all

12vo

lun

teer

sW

ilki

nan

dFo

rtn

er(1

985a

)

5m

in,o

cclu

sive

75%

inw

ater

3vo

lun

teer

s(o

rien

tal)

Irri

tati

onin

all

3vo

lun

teer

sW

ilki

nan

dFo

rtn

er(1

985b

)

3-M

eth

yl-1

-pen

tan

ol24

h,o

cclu

sive

(pre

-te

stfo

ra

HR

IPT)

0.5%

inal

coh

olSD

A39

C41

hea

lth

yvo

lun

teer

sLi

ttle

orn

oir

rita

tion

RIF

M(1

973f

)

3,5,

5-Tr

imet

hyl

-1-h

exan

ol48

h,o

cclu

sive

(pre

-te

stfo

ra

max

imiz

atio

nst

udy

)

8%,i

npe

trol

atu

m25

hea

lth

yvo

lun

teer

sN

oir

rita

tion

RIF

M(1

977b

)

Subg

roup

:se

cond

ary

3,7-

Dim

eth

yl-7

-met

hox

yoct

an-2

-ol

48h

,occ

lusi

ve(p

re-

test

for

am

axim

izat

ion

stu

dy)

10%

,pet

rola

tum

27h

ealt

hy

mal

ean

dfe

mal

evo

lun

teer

sN

oir

rita

tion

RIF

M(1

982b

)

3,4,

5,6,

6-Pe

nta

met

hyl

hep

tan

-2-o

lD

uri

ng

the

indu

ctio

nph

ase

ofa

repe

ated

insu

ltpa

tch

test

(HR

IPT)

:9

appl

icat

ion

sw

ith

adu

rati

onof

24h

wit

hin

a3-

wee

kpe

riod

,occ

lusi

ve,

0.2

ml,

obse

rvat

ion

son

the

appl

icat

ion

days

15%

v/v

solu

tion

inet

han

olSD

A39

C(9

9%)

51h

ealt

hy

mal

ean

dfe

mal

evo

lun

teer

s10

/48

posi

tive

reac

tion

s:5

grad

e1

reac

tion

s(e

ryth

ema

con

fin

edto

the

con

tact

site

and

exce

edin

gth

atof

the

un

trea

ted

skin

)an

d5

grad

e2

reac

tion

s(e

ryth

ema

con

fin

edto

the

con

tact

site

and

defi

nit

ely

exce

edin

gth

atof

the

un

trea

ted

skin

;pa

pule

sm

ayor

may

not

bepr

esen

t)

RIF

M(1

983c

)

Subg

roup

:te

rtia

ry2,

6-D

imet

hyl

-2-h

epta

nol

48h

,occ

lusi

ve(p

re-

test

for

am

axim

izat

ion

stu

dy)

10%

inpe

trol

atu

m25

hea

lth

yvo

lun

teer

sN

oir

rita

tion

RIF

M(1

976b

)

0.02

5m

l/2

cm2,

occl

usi

ve,u

pto

72h

10%

in1:

1et

han

ol/a

ceto

ne

6h

ealt

hy

fem

ale

volu

nte

ers

No

irri

tati

onR

IFM

(198

3a)

Indu

ctio

nph

ase

ofH

RIP

T2%

indi

met

hyl

phth

alat

e10

hea

lth

ym

ale

and

fem

ale

volu

nte

ers

No

irri

tati

onR

IFM

(196

9)

3,6-

Dim

eth

yl-3

-oct

anol

a48

h,o

cclu

sive

(pre

-te

stfo

ra

max

imiz

atio

nst

udy

)

10%

inpe

trol

atu

m5

hea

lth

ym

ale

volu

nte

ers

No

irri

tati

onR

IFM

(197

3c)

48h

,occ

lusi

ve(p

re-

test

for

am

axim

izat

ion

stu

dy)

20%

inpe

trol

atu

m5

hea

lth

ym

ale

volu

nte

ers

No

irri

tati

onR

IFM

(197

2a)

3-M

eth

yloc

tan

-3-o

la48

h,o

cclu

sive

(pre

-te

stfo

ra

max

imiz

atio

nst

udy

)

10%

inpe

trol

atu

m29

hea

lth

yvo

lun

teer

sN

oir

rita

tion

RIF

M(1

978a

)

aN

ore

leva

nt

use

was

repo

rted

.


Tabl

e7-

2-1

Skin

irri

tati

onst

udie

sin

anim

als,

sing

leap

plic

atio

n.

Mat

eria

lM

eth

odC

once

ntr

atio

nSp

ecie

sR

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-bu

tan

ol24

h,u

nco

vere

d,0.

01m

lsa

mpl

eon

the

clip

ped

skin

Un

dilu

ted

Rab

bit

(n=

5)A

nav

erag

ere

acti

onto

atr

ace

ofca

pill

ary

inje

ctio

nSm

yth

etal

.(19

54)

2-Et

hyl

-1-h

exan

ol50

00m

g/kg

,n.f.

i.U

ndi

lute

dR

abbi

t(n

=10

)M

oder

ate

redn

ess

and

edem

ain

10/1

0R

IFM

(197

7a)

24h

,un

cove

red,

0.01

ml

sam

ple

onth

ecl

ippe

dsk

inU

ndi

lute

dor

asa

solu

tion

inw

ater

,pr

opyl

ene

glyc

olor

acet

one

Rab

bit

(n=

5)M

oder

ate

irri

tati

onob

serv

edSm

yth

etal

.(19

69)

24h

,occ

lusi

ve,0

.1,0

.316

,1.0

,3.

16m

g/kg

body

wei

ght,

onth

ecl

ippe

din

tact

skin

,obs

erva

tion

sda

ily

up

to7

days

Un

dilu

ted

Rab

bit

(n=

4)M

oder

ate

irri

tati

on:

mod

erat

eer

yth

ema,

mod

erat

eed

ema,

aton

ia,b

lan

chin

g,de

squ

amat

ion

,co

riac

eou

snes

s,n

ecro

sis,

and

esch

ar

Scal

aan

dB

urt

is(1

973)

Isoa

myl

alco

hol

Sin

gle

appl

icat

ion

of5.

0g/

kgU

ndi

lute

dR

abbi

t(n

=10

)M

arke

der

yth

ema

and

mod

erat

eed

ema

RIF

M(1

976a

)Si

ngl

eap

plic

atio

nU

ndi

lute

dR

abbi

t(n

=6)

Ver

yir

rita

ting

RIF

M(1

979c

)24

h,u

nco

vere

d,0.

01m

lsa

mpl

eon

the

clip

ped

skin

Un

dilu

ted

oras

aso

luti

onin

wat

er,

prop

ylen

egl

ycol

orac

eton

eR

abbi

t(n

=5)

Irri

tati

onw

asob

serv

edSm

yth

etal

.(19

69)

isot

ride

can

-1-o

l(m

ixed

isom

ers)

Sin

gle

occl

usi

vepa

tch

for

24h

toin

tact

skin

of4

rabb

its

Un

dilu

ted

Rab

bits

Mod

erat

ely

irri

tati

ng

Scal

aan

dB

urt

is(1

973)

Sin

gle

un

cove

red

appl

icat

ion

of0.

01m

lfo

r24

hU

ndi

lute

dR

abbi

tsM

oder

atel

yir

rita

tin

gSm

yth

etal

.(19

62)

Perc

uta

neo

usl

yto

the

inta

ctdo

rsal

skin

for

20h

Un

dilu

ted

Rab

bits

Seve

reer

yth

ema

and

dist

inct

edem

aat

24h

dist

inct

scar

rin

gan

dse

vere

scal

ing

at8

days

RIF

M(1

963d

,e)

4-h

sem

i-oc

clu

sive

irri

tati

onU

ndi

lute

dR

abbi

tsSl

igh

tto

mar

ked

eryt

hem

a,sl

igh

tor

mod

erat

eed

ema

and

scal

ing

RIF

M(2

003a

)

2-M

eth

ylbu

tan

ol24

h,u

nco

vere

d,0.

01m

lsa

mpl

eon

the

clip

ped

skin

Un

dilu

ted

Rab

bit

(n=

5)Ir

rita

tion

defi

ned

asth

ele

ast

visi

ble

capi

llar

yin

ject

ion

from

the

un

dilu

ted

mat

eria

lSm

yth

etal

.(19

62)

n.f.

i.U

ndi

lute

dR

abbi

t(n

=2)

Mod

erat

ely

irri

tati

ng

RIF

M(1

979b

)3-

Met

hyl

-1-p

enta

nol

0.5

ml

appl

icat

ion

,24

hco

nta

ct,

obse

rved

agai

nat

48h

0.5%

inal

coh

olSD

A39

CR

abbi

t(n

=3)

No

eryt

hem

aan

ded

ema

obse

rved

RIF

M(1

972c

)

3,5,

5-Tr

imet

hyl

-1-h

exan

ol50

00m

g/kg

body

wei

ght,

n.f.

i.U

ndi

lute

dR

abbi

t(n

=10

)R

edn

ess:

mil

d:2/

10,m

oder

ate:

4/10

,sev

ere:

4/10

;ed

ema:

mil

d:1/

10,m

oder

ate:

9/10

,sev

ere:

0/10

RIF

M(1

977a

)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-hep

tan

olN

eat

appl

icat

ion

aspa

rtofl

LD5

0U

ndi

lute

dR

abbi

t(n

=5)

No

irri

tati

onSm

yth

etal

.(19

49)

4h

,sem

i-oc

clu

sive

,3.9

-9.4

ml/

kgbo

dyw

eigh

ton

the

shav

edsk

inU

ndi

lute

dR

abbi

t(n

=5)

2/5

som

eer

yth

ema

and

slig

ht

edem

aM

cOm

iean

dA

nde

rson

(194

9)3,

7-D

imet

hyl

-7-

met

hox

yoct

an-2

-ol

24h

,occ

lusi

ve,0

.5m

l,ab

rade

dan

din

tact

skin

,obs

erva

tion

saf

ter

24,

72h

1%in

prop

ylen

egl

ycol

Rab

bit

(n=

6)M

ildl

yir

rita

tin

g,PI

I0.5

,5/6

very

slig

ht

eryt

hem

ain

the

inta

ctan

dab

rade

dsi

tes

afte

r24

h,1

/6ve

rysl

igh

ter

yth

ema

inth

ein

tact

and

abra

ded

site

saf

ter

72h

RIF

M(1

973e

)

4-M

eth

yl-2

-pen

tan

olD

etai

lsof

the

met

hod

not

repo

rted

Con

cen

trat

ion

and

veh

icle

not

repo

rted

Rab

bit,

n.f.

i.2/

10de

fin

edas

anav

erag

ere

acti

oneq

uiv

alen

tto

atr

ace

ofca

pill

ary

inje

ctio

nSm

yth

etal

.(19

51)

0.25

h,o

bser

vati

onpe

riod

of10

days

,n

.f.i.

Un

dilu

ted

Rab

bit

(n=

3)Im

med

iate

slig

ht

eryt

hem

aan

dde

laye

dm

oder

ate

eryt

hem

aw

ith

dryi

ng

ofsu

rfac

eM

cOm

iean

dA

nde

rson

(194

9)7

appl

icat

ion

s(5

h)

toth

ein

tact

skin

for

21da

ysU

ndi

lute

dR

abbi

ts(n

=2)

Eryt

hem

a,fl

akin

g,an

dcr

acki

ng

ofth

esk

inw

ith

blee

din

gfi

ssu

res

byth

e7t

hex

posu

reM

cOm

iean

dA

nde

rson

(194

9)3,

4,5,

6,6-

Pen

tam

eth

ylh

epta

n-2

-ol

4h

,occ

lusi

ve,0

.5m

l,cl

ippe

dsk

in,

obse

rvat

ion

sat

24,4

8,72

hU

ndi

lute

dR

abbi

t(n

=6)

No

irri

tati

onR

IFM

(198

4b)

24h

,occ

lusi

ve,2

000

mg/

kgbo

dyw

eigh

t,ob

serv

atio

ns

at24

h,a

nd

dail

yfo

r14

days

Un

dilu

ted

Rat

s(n

=5/

sex)

No

irri

tati

onR

IFM

(198

5a)

Subg

roup

:te

rtia

ry2,

6-D

imet

hyl

-2-h

epta

nol

5000

mg/

kgbo

dyw

eigh

t,n

.f.i.

Un

dilu

ted

Rab

bit

(n=

10)

2/10

slig

ht

redn

ess,

8/10

mod

erat

ere

dnes

s,1/

10sl

igh

ted

ema,

9/10

mod

erat

eed

ema

RIF

M(1

976a

)

(con

tinu

edon

next

page

)


the UV spectra and review of phototoxic/photoallergy data, thematerials in this group would not be expected to elicit phototoxic-ity or photoallergy under the current conditions of use as a fra-grance ingredient.

5.10. Miscellaneous studies

To address hepatotoxicity, several miscellaneous studies wereconducted. Ex vivo studies on the mechanism of hepatotoxicitywere conducted with 2-ethyl-1-hexanol, 2-methylbutanol, andisoamyl alcohol, in vitro enzyme induction and peroxisome prolif-eration studies were conducted with 2-ethyl-1-hexanol and iso-amyl alcohol and in vivo repeated dose toxicity studies with 2-ethyl-1-hexanol, isoamyl alcohol, isodecyl alcohol, isononyl alco-hol, isooctane-1-ol (isomeric mixture) and 3,5,5-trimethyl-1-hexa-nol were performed. These studies are not summarized here butmay be found in detail in individual Fragrance Material Reviews(McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q). The data showthat 2-ethyl-1-hexanol is a peroxisome proliferator and that 2-ethyl-1-hexanol, 2-methylbutanol, and isoamyl alcohol induce li-ver enzymes.

6. Conclusion

The compounds assessed in this group have a close structuralrelationship, similar metabolism, and toxicity profiles.

Data on metabolism for the compounds under review are avail-able only for the primary alcohols 2-ethyl-1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol, and for the secondaryalcohol 4-methyl-2-pentanol.

The major pathways of metabolism and fate which are commonto the primary, secondary and tertiary alcohols in this group are:

– conjugation of the alcohol group with glucuronic acid;– oxidation of the alcohol group;– side-chain oxidation yielding polar metabolites, which may be

conjugated and excreted – or further oxidation to an aldehyde,a carboxylic acid, and to CO2;

– excretion of the unchanged parent compound.

In most cases metabolism yields innocuous substances, whichare excreted in the urine and feces.

Because there is insufficient information for many of the 20alcohols with saturated branched chain under review, the databaseis supplemented with studies of 3 metabolites of these alcohols.

The Panel is of the opinion that there are no safety concernsregarding alcohols branched chain saturated under the present de-clared levels of use and exposure. These materials have not beenevaluated at levels other than reported in this group summary.Use of these materials at higher maximum dermal levels or highersystemic exposure levels requires re-evaluation by the Panel. Thisconclusion was based on the following reasons:

� No, or only minimal, evidence of skin irritation in humans wascaused by 6 compounds tested at concentrations of 2–10%. Dueto the structural similarities, compounds not tested for skin irrita-tion in humans are expected to show similar properties withrespect to this endpoint. Therefore, the alcohols under review poseno concern provided concentrations in end products are in therange of 2–10%, which is above the current concentrations of use.� The 11 materials evaluated for eye irritation showed that the

undiluted materials cause moderate to severe eye irritation.However, since these materials are not used undiluted theypose no concern for eye irritation at the concentrations cur-rently in use in end products (0.001–1.7%).Ta

ble

7-2-

1(c

onti

nued

)

Mat

eria

lM

eth

odC

once

ntr

atio

nSp

ecie

sR

esu

lts

Ref

eren

ces

1,5,

15m

in,2

,20

h,i

nta

ctan

dab

rade

dsk

in,o

bser

vati

ons

afte

r24

h,

48h

,8da

ys;

(Fed

eral

Reg

iste

r38

,No.

187,

§15

00.4

1,S.

2701

9,27

.Sep

t.19

73)

Un

dilu

ted

Rab

bit

(n=

6)PI

I5.

1,st

ron

gly

irri

tati

ng,

afte

r24

hon

inta

ctsk

in:

6/6

stro

ng

redn

ess,

5/6

slig

ht

edem

a,1/

6st

ron

ged

ema,

slig

ht

redn

ess

alre

ady

afte

r5

min

reve

rsib

lew

ith

in8

days

,red

nes

saf

ter

24h

appl

icat

ion

not

reve

rsib

lew

ith

in8

days

RIF

M(1

979a

)

4h

,pat

chte

st,o

bser

vati

ons

afte

r4

h,

24h

,48

h(c

ontr

olof

aph

otot

oxic

ity

stu

dy)

10%

inet

han

olA

lbin

ogu

inea

-pig

(n=

8)N

oir

rita

tion

RIF

M(1

981a

)

3,6-

Dim

eth

yl-3

-oct

anol

a50

00m

g/kg

body

wei

ght,

n.f.

i.U

ndi

lute

dR

abbi

t(n

=8)

8/8:

slig

ht

redn

ess,

3/8:

slig

ht

edem

a,4/

8:m

oder

ate

edem

aR

IFM

(197

3a)

24h

,occ

lusi

ve,0

.5m

l,in

tact

and

abra

ded

skin

,obs

erva

tion

sat

24,4

8,72

h

Un

dilu

ted,

15%

indi

stil

led

wat

erR

abbi

t(n

=6)

Un

dilu

ted

PII:

3.4,

very

slig

ht

tom

oder

ate/

seve

reer

yth

ema,

very

slig

ht

tosl

igh

ted

ema,

no

obse

rvat

ion

sw

ere

mad

eaf

ter

3da

ys;

15%

PII:

2.0,

very

slig

ht

tow

ell-

defi

ned

eryt

hem

an

oed

ema

tove

rysl

igh

ted

ema,

3/6

anim

als

wer

en

oten

tire

lyre

cove

red

wit

hin

7da

ysa

scor

eof

5or

mor

eis

rega

rded

assi

gnif

yin

ga

prim

ary

skin

irri

tan

t

RIF

M(1

970)

3-M

eth

yloc

tan

-3-o

la50

00m

g/kg

body

wei

ght

Un

dilu

ted

Rab

bit

(n=

10)

4/10

:sl

igh

tre

dnes

s,4/

10:

mod

erat

ere

dnes

s,2/

10:

slig

ht

edem

a,8/

10:

mod

erat

eed

ema

RIF

M(1

978c

)

n.f.

i.:n

ofu

rth

erin

form

atio

n,P

II:

prim

ary

irri

tati

onin

dex.

aN

ore

leva

nt

use

was

repo

rted

.


Tabl

e7-

2-2

Skin

irri

tati

onst

udie

sin

anim

als,

repe

ated

appl

icat

ion.

Mat

eria

lM

eth

odC

once

ntr

atio

nSp

ecie

sR

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

12ap

plic

atio

ns,

over

ape

riod

of12

days

,un

cove

red,

2m

l/kg

body

wei

ght/

day

onth

esh

aved

skin

,ob

serv

atio

ns

dail

y

Un

dilu

ted

Rat

(n=

10)

Aft

er10

days

slig

ht

redn

ess

and

scab

bin

gSc

hm

idt

etal

.(1

973)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-hep

tan

ol7

appl

icat

ion

s,5–

12h

dura

tion

over

ape

riod

of15

–21

days

,un

cove

red,

3.0

ml/

kgon

100

cm2,

non

abra

ded

skin

,obs

erva

tion

sda

ily

Un

dilu

ted

Rab

bit

(n=

2)de

fin

ite

eryt

hem

aaf

ter

2nd

expo

sure

;ar

eas

offl

akin

gaf

ter

4th

expo

sure

;cr

acki

ng

ofsk

in,fi

ssu

res

wit

hso

me

blee

din

gaf

ter

7th

expo

sure

McO

mie

and

An

ders

on(1

949)

3,7-

Dim

eth

yl-7

-met

hox

yoct

an-2

-ol

10ap

plic

atio

ns,

24h

dura

tion

onal

tern

ate

days

duri

ng

a3-

wee

kpe

riod

,occ

lusi

ve,0

.2m

l,sh

aved

skin

,obs

erva

tion

s

2.5,

5%in

wat

er,

appl

icat

ion

s1–

7:5%

,app

lica

tion

s8–

10:

2.5%

Gu

inea

pig

(n=

10)

No

irri

tati

on,i

sola

ted

occu

ren

ces

ofsl

igh

ter

yth

ema

duri

ng

the

trea

tmen

tpe

riod

RIF

M(1

973d

)

4-M

eth

yl-2

-pen

tan

ol5

appl

icat

ion

s,5–

12h

dura

tion

over

ape

riod

of15

–21

days

,un

cove

red,

3.0

ml/

kgon

100

cm2,

non

abra

ded

skin

,obs

erva

tion

sda

ily

Un

dilu

ted

Rab

bit

(n=

3)Se

vere

dryi

ng

ofth

esk

inw

ith

som

esl

ough

ing

and

crac

kin

gM

cOm

iean

dA

nde

rson

(194

9)

3,4,

5,6,

6-Pe

nta

met

hyl

hep

tan

-2-o

l9–

28ap

plic

atio

ns,

6h

dura

tion

over

ape

riod

of28

days

,occ

lusi

ve,n

onab

rade

dan

dcl

ippe

dsk

in,

obse

rvat

ion

sda

ily

Un

dilu

ted,

1.5%

,5%

,15%

,50%

diss

olve

din

1%w

/vaq

ueo

us

met

hyl

cell

ulo

se(c

a.30

,100

,300

,10

00m

g/kg

body

wei

ght/

daya

y)

Rab

bit

(n=

10/s

ex)

P30

mg/

kgbo

dyw

eigh

t/da

yay:

eryt

hem

aan

ded

ema

incr

ease

ddo

se-d

epen

den

tly;

P30

0m

g/kg

body

wei

ght/

daya

y:af

ter

9tr

eatm

ents

the

trea

tmen

tw

aste

rmin

ated

asa

resu

ltof

irri

tati

on

RIF

M(1

986a

)

Dai

lyap

plic

atio

ns

for

6h

,du

rati

onov

er28

days

,oc

clu

sive

,100

0m

g/kg

body

wei

ght/

daya

y,n

onab

rade

dsk

in,o

bser

vati

ons

dail

y

Un

dilu

ted

Rab

bit

(n=

13/s

ex)

Seve

rean

dpe

rsis

ten

tir

rita

tion

:de

rmal

irri

tati

onpr

ogre

ssed

rapi

dly

inal

lan

imal

sto

wel

lde

fin

edto

mod

erat

eer

yth

ema

and

edem

aw

ith

inon

ew

eek;

irri

tati

onpr

ogre

ssed

furt

her

inse

vera

lrab

bits

beco

min

gse

vere

wit

hin

2w

eeks

oftr

eatm

ent,

scab

form

atio

n

RIF

M(1

985c

)


� These materials have no or low sensitizing potential. Availabledata for five of the substances show that they do not possess asensitization potential. However, for 3,6-dimethyl-3-octanol, alow sensitization potential in humans cannot be excluded. Satu-rated alcohols do not form hydroperoxides. They oxidize andbecome aldehydes or ketones. The use of these materials underthe declared levels of use and exposure will not induce sensitiza-tion. For those individuals who are already sensitized, there is apossibility that an elicitation reaction may occur. The relation-ship between the no effect level for induction and the no effectlevel for elicitation is not known for this group of materials.� Based on the lack of structures, which could absorb UVA or UVB

light, and review of phototoxic/photoallergy data, the alcoholswith saturated branch chains would not be expected to elicitphototoxicity or photoallergy under the current conditions ofuse as a fragrance ingredient.� The 15 compounds tested have a low order of acute toxicity.� The seven branched chain saturated alcohols and three of their

metabolites (see Tables in Section 5.2) tested were of low sys-temic toxicity after repeated application. Changes indicative ofenzyme induction in the liver (liver enlargement), peroxisomeproliferation and alpha-2u-nephropathy in male rats have beenobserved at doses of 60 mg/kg body weight/day and more. Thelowest NOAEL of all the subacute and sub-chronic oral studiesavailable, which were performed with five of the substancesunder review and the metabolite 4-hydroxy-4-methyl-2-penta-none, is 10 mg/kg body weight/day for 3,5,5-trimethyl-1-hexa-nol. This value is taken as representative for all members ofthe group as a worst-case. The database does not allow a defi-nite conclusion that the toxicity after dermal application islower than after oral application by gavage (oral bolus dosevs. slow uptake via the skin). However, at least 3,4,5,6,6-pen-tamethylheptan-2-ol had a much higher systemic NOAEL of1000 mg/kg body weight/day in a subacute dermal study com-pared to the lowest oral NOAEL of 10 mg/kg body weight/daymentioned above. Several subacute and subchronic inhalationstudies showed a lowest NOAEL of 120 ml/m3 for 2-ethyl-1-hexanol corresponding to a dose of 175 mg/kg body weight/day, assuming a body weight of 261 g, a minute volume of0.2 l for a rat (Bide et al., 2000) and 100% retention. Comparingthe oral worst-case NOAEL of 10 mg/kg body weight/day to theworst-case daily uptake of 0.14 mg/kg body weight/day whichwas estimated for 3,4,5,6,6-pentamethylheptan-2-ol (100% der-mal absorption assumed as worst-case) the margin of safety is70 (100% oral absorption is assumed as shown with 2-ethyl-1-hexanol). For the other compounds for which systemic uptakein consumers (Table 1) has been estimated by RIFM, the marginof safety is between 90 and 50,000. There is an adequate marginof safety for the alcohols under review when applied in con-sumer products at the current concentrations.� With 3,5,5-trimethyl-1-hexanol adverse effects on reproduction

were noted at a rather low oral dose (60 mg/kg body weight/day) with a NOAEL of about 10 mg/kg body weight/day. For thiscompound the estimated systemic dose is 0.0036 mg/kg bodyweight for consumers (Table 1), leading to a margin of safetyof 2700. 2-Ethyl-1-hexanol induced fetotoxic and teratogeniceffects at high doses of 1300 mg/kg body weight/day in rats,however, none of the group members tested induced adverseeffects on fertility and development at doses or concentrationsthat were not toxic to the parental animals. It should be notedthat in a dermal study with 2-ethyl-1-hexanol no adverseeffects on development in rats were seen with the highest doseof 2520 mg/kg body weight indicating, that dermal exposure isless effective in producing adverse effects than oral exposuremost probably due to the different pharmacokinetic behaviorfor both application routes.Ta

ble

8Se

nsor

yir

rita

tion

stud

ies

inhu

man

s

Mat

eria

lD

ose

rou

teN

o.su

bjec

ts/

con

cen

trat

ion

grou

p

Cli

nic

alsi

gns

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-hex

anol

Inh

alat

ion

,exp

osu

re,4

h:

con

stan

tco

nce

ntr

atio

ns:

(1.5

,10,

20m

l/m

3)

orfl

uct

uat

ing

con

cen

trat

ion

s(t

ime-

wei

ghte

dav

erag

e1.

5,10

,20

ml/

m3)

Con

stan

tco

nce

ntr

atio

ns:

7m

ales

wit

hou

tan

d12

mal

esw

ith

sMC

S

P10

ml/

m3:

self

-rep

orte

dn

asal

and

eye

irri

tati

onan

dpe

rcei

ved

odor

inte

nsi

tyin

crea

se;

no

diff

eren

cebe

twee

nsu

bjec

tsw

ith

and

wit

hou

tsM

CS

van

Thri

elet

al.(

2005

)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-hep

tan

olIn

hal

atio

n,e

xpos

ure

for

15m

in12

Eye

irri

tati

onat

5an

d10

ml/

m3,n

ose

and

thro

atir

rita

tion

at10

ml/

m3

Silv

erm

anet

al.(

1946

)

4-M

eth

yl-2

-pen

tan

olIn

hal

atio

nex

posu

refo

r15

min

12Ey

eir

rita

tion

at50

ml/

m3,n

ose

and

thro

atir

rita

tion

>50

ml/

m3

Silv

erm

anet

al.(

1946

)

sMC

S:se

lf-r

epor

ted

mu

ltip

lech

emic

alse

nsi

tivi

ty.


Tabl

e9

Eye

irri

tati

onst

udie

sin

rabb

its.

Mat

eria

lM

eth

odR

esu

lts

Ref

eren

ces

Subg

roup

:pr

imar

y2-

Eth

yl-1

-bu

tan

olSi

ngl

eap

plic

atio

n,u

ndi

lute

dor

dilu

ted

inw

ater

ofpr

opyl

ene

glyc

ol,g

radi

ng

afte

r18

–24

h,n

.f.i.

Prod

uce

dan

inju

ryof

nec

rosi

sto

63–8

7%of

the

eye

Smyt

het

al.(

1954

)

2-Et

hyl

-1-h

exan

olSi

ngl

eap

plic

atio

nof

0.00

5m

l,u

ndi

lute

d,gr

adin

gaf

ter

18–2

4h

,n.f.

i.Se

vere

burn

Car

pen

ter

and

Smyt

h(1

946)

Smyt

het

al.(

1969

)Si

ngl

eap

plic

atio

n,o

ne

drop

,un

dilu

ted,

50%

,25%

,12.

5%so

luti

ons

inoi

l,ob

serv

atio

ns

up

to96

h,o

ne

rabb

itpe

rco

nce

ntr

atio

n

Con

jun

ctiv

alre

dnes

san

dsw

elli

ng,

lacr

imat

ion

,di

sch

arge

,no

effe

cts

onth

eco

rnea

Sch

mid

tet

al.(

1973

)

Un

dilu

ted

test

subs

tan

ce:

effe

cts

not

reve

rsib

lew

ith

in96

h12

.5%

no

effe

ctSi

ngl

eap

plic

atio

nof

0.1

ml,

un

dilu

ted,

obse

rvat

ion

saf

ter

1,4,

and

24h

,2,3

,4,a

nd

7da

ys,6

rabb

its

Seve

reey

eir

rita

nt

Scal

aan

dB

urt

is(1

973)

Med

ian

scor

esaf

ter

24,7

2h

,an

d7

days

:19

,20,

0(D

raiz

esc

ores

)C

orn

eal

dull

nes

s,op

acit

y(w

ides

prea

dco

rnea

lop

acit

y),

and

vasc

ula

riza

tion

,iri

titi

s,co

nju

nct

ival

eryt

hem

a,ch

emos

is,a

nd

disc

har

geSi

ngl

eap

plic

atio

nof

0.1

ml,

un

dilu

ted,

obse

rvat

ion

saf

ter

24,4

8,an

d72

h,6

rabb

its

Pers

iste

nt

corn

eal

effe

cts

RIF

M(1

978b

)

Dra

ize

scor

es24

h:

corn

ea:

17.5

,iri

s:2.

5,co

nju

nct

ivae

:7.

048

h:

corn

ea:

10.8

,iri

s:0.

8,co

nju

nct

ivae

:7.

072

h:

corn

ea:

7.5,

iris

:0.

8,co

nju

nct

ivae

:5.

3Si

ngl

eap

plic

atio

nof

0.1

ml,

un

dilu

ted

and

solu

tion

inpr

opyl

ene

glyc

olor

wat

er:

110,

14,a

nd

21da

ys,6

rabb

its

Dra

ize

scor

esK

enn

ahet

al.(

1989

b)

100%

solu

tion

:51

(sev

ere)

,30%

:35

(sev

ere/

mod

erat

e),

10%

:39

(mod

erat

e),3

%:

30(m

oder

ate)

,1%

:9

(mil

d)C

orn

eal

swel

ling

in%

ofco

ntr

ol:

100%

solu

tion

:19

2%;

30%

:19

0%;

10%

:16

2%;

3%:

151%

;1%

:94

%Is

oam

ylal

coh

olSi

ngl

eap

plic

atio

n,u

ndi

lute

dor

solu

tion

inw

ater

orpr

opyl

ene

glyc

ol,n

.f.i.

Seve

rebu

rnSm

yth

etal

.(19

69)

RIF

M(1

979c

)Is

otri

deca

n-1

-ol

(iso

mer

icm

ixtu

re)

Sin

gle

appl

icat

ion

,un

dilu

ted

and

obse

rvat

ion

s1,

24,4

8,72

han

d7

days

afte

rap

plic

atio

nIr

rita

tion

was

obse

rved

.In

one

anim

alsl

igh

tco

rnea

lop

acit

yan

dlo

ssof

corn

eal

tiss

ue

RIF

M(2

002b

)

Sin

gle

appl

icat

ion

,un

dilu

ted,

0.5

ml

Smal

lar

eaof

nec

rosi

son

the

eye

Smyt

het

al.(

1962

)Si

ngl

eap

plic

atio

n,u

ndi

lute

dan

dob

serv

atio

ns

1an

t24

haf

ter

appl

icat

ion

Slig

ht

irri

tati

onR

IFM

(196

3d)

RIF

M(1

963f

)Si

ngl

eap

plic

atio

nof

0.1

ml,

un

dilu

ted,

obse

rvat

ion

saf

ter

1,4,

and

24h

,2,3

,4,a

nd

7da

ys,6

rabb

its

Mod

erat

ely

irri

tati

ng

Scal

aan

dB

urt

is(1

973)

2-M

eth

ylbu

tan

olSi

ngl

eap

plic

atio

n,u

ndi

lute

dor

solu

tion

inw

ater

orpr

opyl

ene

glyc

ol,o

bser

vati

ons

and

grad

ing

afte

r24

h,6

anim

als

Res

ult

edin

inju

ryw

her

eco

rnea

ln

ecro

sis

was

obse

rved

Smyt

het

al.(

1962

)

Sin

gle

appl

icat

ion

,un

dilu

ted

and

obse

rvat

ion

saf

ter

24,

48,a

nd

72h

,6an

imal

sTu

rbid

ity

atth

eco

rnea

,in

flam

mat

ion

onth

eir

is,a

nd

redn

ess,

swel

ling

,or

secr

etio

nof

the

con

jun

ctiv

aeR

IFM

(197

9b)

Subg

roup

:se

cond

ary

2,6-

Dim

eth

yl-4

-hep

tan

olU

ndi

lute

d,0.

5m

lap

plic

atio

n,n

.f.i.

An

aver

age

reac

tion

,at

mos

ta

very

smal

lar

eaof

nec

rosi

sre

sult

ing

from

0.5

ml

ofu

ndi

lute

dch

emic

alin

the

eye

Smyt

het

al.(

1949

)

Sin

gle

appl

icat

ion

,un

dilu

ted,

obse

rvat

ion

saf

ter

24h

,an

d72

h,1

anim

alM

oder

ate;

som

eco

nju

nct

ivit

isw

ith

som

eed

ema

and

corn

eal

inju

ry;

scor

e10

afte

r24

h,r

etu

rned

tosc

ore

0M

cOm

iean

dA

nde

rson

(194

9)

(con

tinu

edon

next

page

)


Tabl

e9

(con

tinu

ed)

Mat

eria

lM

eth

odR

esu

lts

Ref

eren

ces

wit

hin

72h

3,7-

Dim

eth

yl-7

-met

hox

yoct

an-2

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� Available data on genotoxicity for eight alcohols and threemetabolites do not show such a potential in vitro or in vivo.Due to the structural similarities of the members of this groupof alcohols, and because both terpene alcohols (Belsito et al.,2008) and unsaturated branched chain alcohols (Belsito et al.,2008) did not show a genotoxic potential, no genotoxicity isexpected for the other materials of the group.� A valid carcinogenicity study showed that 2-ethyl-1-hexanol is

a weak inducer of liver tumors in female mice. Mechanisticstudies showed that 2-ethyl-1-hexanol is an activator ofPPAR-alpha. These substances can contribute to liver carcino-genesis by increasing tumor promotion. The relevance of thismechanism for humans is still a matter of debate. While this

mechanism cannot be completely discounted, it is reasonableto assume that humans are less sensitive than rodents. In viewof the low use of 2-ethyl-1-hexanol in cosmetic products (0.1–1 tons/y) and the low systemic exposure estimated by RIFM(0.0005 mg/kg body weight/day), the margin of exposure is100,000 compared to the NOAEL for liver carcinomas in miceof 50 mg/kg body weight, which is considered to be sufficientfor a non-genotoxic compound.

Conflict of interest statement

This research was supported by the Research Institute for Fra-grance Materials, an independent research institute that is funded

Table 10-3Skin sensitization studies in animals.

Material Method Concentration Species Results References

Subgroup: secondary3,7-Dimethyl-7-

methoxyoctan-2-ol

According to Food and Drug Administration of theUnited States of America in ‘‘Appraisal of the Safety ofChemicals in Food, Drugs and Cosmetics” 1959, p. 51,except that the test material was applied topically andnot injected: induction: 10 applications with 2.5 or 5%topically, challenge: 2 weeks later with 2.5% in water

Applications 1–7: 5%(irritating),applications 8–10: 2.5%

Guinea pig (n = 10) No delayed-typehypersensitivity

RIFM(1973d)

Subgroup: tertiary2,6-Dimethyl-2-

heptanolMaximization test Induction: 10% in FCA

(intradermal),challenge: 20% in acetone

Guinea pig (10 in testgroup, 10 in controlgroup)

No sensitizationreactions

Watanabeet al.(1988)

FCA: Freund’s complete adjuvant.

Table 10-2Diagnostic patch tests.

Material Method Concentration Subjects Results Reference


methoxyoctan-2-olPatchtest

Concentration and vehicle notreported

218 patients with proven contact dermatitiswere tested with 3,7-dimethyl-7-methoxyoctan-2-ol

2 positivereactions

Larsen et al.(2002)

Table 10-1Skin sensitization studies in humans.

Material Method Concentration Subjects Results References

Subgroup: primary2-Ethyl-1-hexanol Maximization test 4% in petrolatum 29 healthy volunteers No sensitization reactions RIFM (1976c)Isoamyl alcohol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)3-Methyl-1-pentanol HRIPT 0.5% in alcohol SDA 39C 41 healthy volunteers No sensitization reactions RIFM (1973f)3,5,5-Trimethyl-1-hexanol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1977b)


methoxyoctan-2-olMaximization test 10% in petrolatum 27 healthy volunteers No sensitization reactions RIFM (1982b)

3,4,5,6,6-Pentamethylheptan-2-ol

HRIPT 15% v/v solution in ethanolSDA 39C (99%)

51 healthy male andfemale volunteers

No sensitization reactions RIFM (1983c)

Subgroup: tertiary2,6-Dimethyl-2-heptanol Maximization test 10% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)

HRIPT 2% in dimethyl phthalate 53 healthy volunteers(18 males and 35 females)

No sensitization reactions RIFM (1969)

HRIPT 5% in alcohol SDA 39C 45 healthy volunteers(33 females, and 12 males)

No sensitization reactions RIFM (1971, 1972b)

3,6-Dimethyl-3-octanola Maximization test 20% in petrolatum 25 healthy male volunteers Inconclusive because subjectsreacted to other test materialon the same Panel

RIFM (1972a)

Maximization test 10% in petrolatum 25 healthy male volunteers No sensitization reactions(this was a retest)

RIFM (1973c)

3-Methyloctan-3-ola Maximization test 10% in petrolatum 29 healthy male volunteers No sensitization reactions RIFM (1978a)

HRIPT: human repeated insult patch test.a No relevant use was reported.


by the manufacturers of fragrances and consumer products con-taining fragrances. The authors are all members of the Expert Panelof the Research Institute for Fragrance Materials, an independentgroup of experts who evaluate the safety of fragrance materials.

References

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Table 12Summary of UV spectra data.

Material UV spectra range of absorption (nm)

2-Ethyl-1-hexanol Peaked at 210–215Returned to baseline at 400 (with minor absorption 290–400)

Isoamyl alcohol Does not absorb UV light

Isotridecan-1-ol (isomeric mixture) Does not absorb UV light

2-Methylbutanol Peaked at 200–215Returned to baseline at 220–225

3-Methyl-1-pentanol Peaked at 200–210Returned to baseline at 280–290

2-Methylundecanol Peaked at 200–205Returned to baseline at 270–280

3,5,5-Trimethyl-1-hexanol Does not absorb UV light

2,6-Dimethyl-4-heptanol Does not absorb UV light

3,7-Dimethyl-7-methoxyoctan-2-ol Peaked at 200–210Returned to baseline at 400 (with minor absorption 290–400)

6,8-Dimethylnonan-2-ol Peaked at 200–210Returned to baseline 230–240 (with minor absorption 260–320)

3,4,5,6,6-Pentamethylheptan-2-ol Peaked at 200–205Returned to baseline 264–271

2,6-Dimethyl-2-heptanol Does not absorb UV light

Table 11Phototoxicity and photoallergenicity.

Material Method Concentration Species Results References

Subgroup: tertiary2,6-Dimethyl-2-heptanol 0.025 ml/test site on the back (36 test sites, 2 cm2),

covered, 30 min later the test sites were exposed toUVA irradiation (320–400 nm, 1, 2.5, 5, 10, 20 J/cm2),observations 4, 24, 48 and 72 h after irradiation

10% in 1:1ethanol/acetone

6 healthyvolunteers(females)

Not phototoxic RIFM(1983a)

Patch applied 48 h, 4 h after the removal of thepatches the animals did receive:

10% in ethanol Albino guinea pig(n = 8/group)

Not phototoxic, after4 h 1/8 slight reaction(in each group), whichwas cleared within24 h

RIFM(1981a)

Group A: UVA (320–400 nm), 30 minGroup B: UVB (280–370 nm), 15 minGroup C: no irradiation, Group D: not pretreated andRadiated from both light sources, observations 4, 24,48 h after the irradiationPhotoallergy test: induction: 0.1 ml on 8 cm2 of thetest area, 15 min UVB, 4 h UVA (Westinghouse blacklight tubes, from a distance of 25 cm) every 2nd day,total nine times in 18 days, challenge: after restingtime of 10 days 0.025 ml applied on both flanks, leftflank irradiated as for induction, skin reading 24 and48 h after challenge

10% in rectifiedalcohol

Guinea pig(n = 8/sex)

No photoallergenicity RIFM(1981b)


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Review

Fragrance material review on 3,5,5-trimethyl-1-hexanol

D. McGinty *, J. Scognamiglio, C.S. Letizia, A.M. ApiResearch Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA


Keywords:ReviewFragrance

a b s t r a c t

A toxicologic and dermatologic review of 3,5,5-trimethyl-1-hexanol when used as a fragrance ingredientis presented. 3,5,5-Trimethyl-1-hexanol is a member of the fragrance structural group branched chainsaturated alcohols. The common characteristic structural elements of the alcohols with saturatedbranched chain are one hydroxyl group per molecule, and a C4 to C12 carbon chain with one or severalmethyl side chains. This review contains a detailed summary of all available toxicology and dermatologypapers that are related to this individual fragrance ingredient and is not intended as a stand-alone doc-ument. A safety assessment of the entire branched chain saturated alcohol group will be published simul-taneously with this document; please refer to Belsito et al. (2010) for an overall assessment of the safeuse of this material and all other branched chain saturated alcohols in fragrances.

� 2010 Published by Elsevier Ltd.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S481. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S482. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S483. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S484. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

4.7.1. Two to fourteen days studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S494.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50

4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S504.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50

4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S504.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50

0278-6915/$ - see front matter � 2010 Published by Elsevier Ltd.doi:10.1016/j.fct.2010.05.026

* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.E-mail address: [email protected] (D. McGinty).





Introduction

This document provides a summary of the toxicologic review of3,5,5-trimethyl-1-hexanol when used as a fragrance ingredientincluding all human health endpoints. 3,5,5-Trimethyl-1-hexanol(see Fig. 1; CAS Number 3452-97-9) is a fragrance ingredient usedin cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. It is a colorless oily liquid with an oily-herbaceous odor (Arctander, 1969). This material has been reportedto occur in nature, with quantities observed in black currants, crab,and strawberry guava (VCF, 2009).

In 2006, a complete literature search was conducted on 3,5,5-trimethyl-1-hexanol. On-line toxicological databases weresearched including those from the Chemical Abstract Services,[e.g. ToxCenter (which in itself contains 18 databases includingchemical abstracts)], and the National Library of Medicine [e.g.Medline, Toxnet (which contains 14 databases)] as well as 26 addi-tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,fragrance companies were asked to submit all test data.

The safety data on this material was last reviewed by Letizia etal. (2000). All relevant references are included in this document.More details have been provided for unpublished data. The numberof animals, sex and strain are always provided unless they are notgiven in the original report or paper. Any papers in which the vehi-cles and/or the doses are not given have not been included in thisreview. In addition, diagnostic patch test data with fewer than 100consecutive patients have been omitted.

1. Identification

1.1. Synonyms: 1-hexanol, 3,5,5-trimethyl-; i-nonyl alcohol;nonylol; trimethylhexanol; 3,5,5-trimethylhexanol; 3,5,5-trimethylhexan-1-ol; 3,5,5-trimethylhexyl alcohol.

1.2. CAS Registry Number: 3452-97-9.1.3. EINECS Number: 222-376-7.1.4. Formula: C9H20O.1.5. Molecular weight: 144.26.1.6. Council of Europe (2000): 3,5,5-trimethyl-1-hexanol was

included by the Council of Europe in the list of substances

granted B – information required – 28 days oral study(COE No. 702).

1.7. JECFA (1998): The Joint FAO/WHP Expert Committee onFood Additives (JECFA No. 268) concluded that the substancedoes not present a safety concern at current levels of intakewhen used as a flavouring agent.

1.8. FEMA (1970): Flavor and Extract Manufacturers’ Associationstates: generally Recognized as safe as a flavor ingredient –GRAS 5.

2. Physical properties

2.1. Physical form: a colorless oily liquid.2.2. Boiling point (calculated; EPA, 2010): 188.53 �C.2.3. Flash point: 174 �F; CC.2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol

25 �C.2.5. Log Kow (calculated; EPA, 2010): 3.11.2.6. Refractive index: 1.4318.2.7. Specific gravity: 0.832 (20 �C); 0.8252 (25 �C).2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 �C);

0.106 mm Hg (25 �C); 14.1 Pa (25 �C)2.9 water solubility(calculated; EPA, 2010): 572 mg/l (25 �C).

2.9. UV spectra available. Does not absorb UV light.

3. Usage

3,5,5-Trimethyl-1-hexanol is a fragrance ingredient used inmany fragrance compounds. It may be found in fragrances usedin decorative cosmetics, fine fragrances, shampoos, toilet soapsand other toiletries as well as in non-cosmetic products such ashousehold cleaners and detergents. Its use worldwide is in the re-gion of 1–10 metric tons per annum (IFRA, 2004). The reported vol-ume of use is for 3,5,5-trimethyl-1-hexanol as used in fragrancecompounds (mixtures) in all finished consumer product categories.The volume of use is surveyed by IFRA approximately every 4 yearsthrough a comprehensive survey of IFRA and RIFM member com-panies. As such the volume of use data from this survey providesvolume of use of fragrance ingredients for the majority of thefragrance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of sev-eral thousand commercial formulations. The upper 97.5 percentileconcentration is calculated from the data obtained. This upper 97.5

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,5,5-trimethyl-1-hexanol.

Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredient mg/kg/dayb

Anti-perspirant 0.5 1 1 0.01 0.14 0.000100Bath products 17 0.29 0.001 0.02 0.14 0.000001Body lotion 8 0.71 1 0.004 0.14 0.000500Eau de toilette 0.75 1 1 0.08 0.14 0.001400Face cream 0.8 2 1 0.003 0.14 0.000100Fragrance cream 5 0.29 1 0.04 0.14 0.001400Hair spray 5 2 0.01 0.005 0.14 0.000010Shampoo 8 1 0.01 0.005 0.14 0.000010Shower gel 5 1.07 0.01 0.012 0.14 0.000010Toilet soap 0.8 6 0.01 0.015 0.14 0.000020Total 0.0036

a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.b Based on a 60-kg adult.

HO

Fig. 1. 3,5,5-Trimethyl-1-hexanol.

S48 D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50

percentile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to accountfor the length of time a product may remain on the skin and/orlikelihood of the fragrance ingredient being removed by washing.The resultant calculation represents the total consumer exposure(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5% percentile use level in formulae for use in cosmet-ics in general has been reported to be 0.14 (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.0035 mg/kg for high end users.

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be0.68% (IFRA, 2007), assuming use of the fragrance oil at levels upto 20% the final product.

4. Toxicology data

4.1. Acute toxicity (see Table 2)

4.1.1. Oral studiesThe acute oral LD50 of 3,5,5-trimethyl-1-hexanol in rats (10/

dose) was reported to be 2.3 (95% C.I. 1.7–3.1) g/kg. Mortality was0, 0, 7, and 10 of 10 rats at 0.67, 1.31, 2.56, and 5.0 g/kg, respec-tively. Deaths occurred on days 1, 2, or 3. The observation periodwas 14 days. Clinical signs included lethargy, coma, ataxia, diar-rhea, piloerection, ptosis, and chromorhinorrhea. Necropsy obser-vations included red/yellow oral/nasal exudates, yellow/brownanogenital exudates, dark areas/orange lungs, dark/mottled liver,dark/mottled kidneys, red/yellow areas of intestines, stomachbloated/red–yellow areas/fluid filled, spleen mottled (RIFM, 1977a).

4.1.2. Dermal studiesThe acute dermal LD50 of 3,5,5-trimethyl-1-hexanol in rabbits

(10/dose) was reported to be greater than 5.0 g/kg. Mortality was3 of 10 rabbits at 5.0 g/kg. Deaths occurred on days 9, 13, and 14.Observation period was 14 days. Clinical signs included lethargy,diarrhea, and anorexia. Necropsy observations included mild, mod-erate, or severe erythema and mild or moderate edema, yellow/brown anogenital exudates, dark/mottled liver, dark/mottled/mal-formed kidneys, red/yellow areas of intestines, stomach bloated(RIFM, 1977a).


4.2.1. Human studiesIn a human maximization test pre-screen, 8% 3,5,5-trimethyl-1-

hexanol was applied to the volar forearms or backs of 25 healthy

subjects for 48 h under occlusion. No subject had any irritation(RIFM, 1977b).

4.2.2. Animal studiesIrritation was evaluated during the acute dermal study of 3,5,

5-trimethyl-1-hexanol in 10 rabbits. A single dose of 5.0 g/kgresulted in mild, moderate, or severe erythema and mild ormoderate edema (RIFM, 1977a).

4.3. Mucous membrane (eye) irritation

No information available.


4.4.1. Human studies4.4.1.1. Induction studies. In a study involving 25 subjects, a maxi-mization test (Kligman, 1966; Kligman and Epstein, 1975) wascarried out with 3,5,5-trimethyl-1-hexanol in petrolatum on vari-ous panels of volunteers. Application was under occlusion to thesame site on the forearms or backs of all subjects for five alter-nate-day 48 h periods. Patch sites were pre-treated for 24 h with2.5% aqueous sodium lauryl sulfate (SLS) under occlusion. Follow-ing a 10–14 days rest period, challenge patches were applied underocclusion to fresh sites for 48 h. Challenge applications were pre-ceded by 60 min SLS treatment. Reactions were read at patchremoval and again at 24 h. There was no evidence of contactsensitization to 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b).

4.4.1.2. Animal studies. No information available.

4.5. Phototoxicity and photoallergy


4.6. Absorption, distribution and metabolism



4.7.1. Two to fourteen days studies3,5,5-Trimethyl-1-hexanol was included in a repeat dose oral

gavage study of a series of compounds related to diethylhexlphthalate and diethylhexyl adipate in male Alderley Park Wistar-derived rats. Animals were dosed for 14 days with 1 mM/kg/d(�144 mg/kg/d) 3,5,5-trimethyl-1-hexanol dissolved in polyethyl-ene glycol 300. At termination of the study, there was no differencefrom controls in body weight, or any clinical or histopathologicalsigns of hepatotoxicity. At necropsy, relative liver weight was sig-nificantly greater than that of controls, but peroxisome prolifera-tion and hypocholesterolemia and hypotriglyceridaemia were notevident (Rhodes et al., 1984).

4.7.2. Subchronic studiesMale SD (CRJ:CD) rats were given 3,5,5-trimethyl-1-hexanol by

gavage for 46 days at doses of 0, 12, 60, or 300 mg/kg body weight/day in olive oil. Females were dosed 14 days before mating andthrough to day 3 of lactation. Renal hyaline droplets and eosino-philic bodies were observed (slight to moderate) in all dosed malerats, but these findings were not observed in females. The 60 mg/kg body weight/day dose group experienced relative liver and kid-ney weight increases (males and females), renal epithelial fattychanges (females), and a decreased implantation index (females).At 300 mg/kg body weight/day one female died, and three wereput down because of weakness. Body weights increased and food

Table 2Summary of acute toxicity studies.

Route Species No. animals/dose group LD50 (g/kg) References

Oral Rat 10 2.3 RIFM (1977a)Dermal Rabbit 10 >5.0 RIFM (1977a)

D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50 S49

consumption increased in males, but decreased in females. Fe-males showed a litter loss in two dams. On the basis of these find-ings the NOAEL was considered to be 12 mg/kg/day for male andfemale rats (MHW, Japan, 1997b as cited in OECD/SIDS (2003)).

4.7.3. Chronic (90+ days) studiesNo information available.



4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems. 3,5,5-Trimethyl-1-hexanol was notmutagenic in an Ames test (preincubation assay with and withoutmetabolic activation) in Salmonella typhimurium TA98, TA100,TA1535, TA1537 and in E. coli WP2 uvrA assays (MHW, Japan1997c as cited in OECD/SIDS (2003) and Kusakabe et al. (2002)).

4.9.1.2. Studies in mammalian cells. 3,5,5-Trimethyl-1-hexanol up to100 lg/plate (cytotoxicity occurred at 200 lg/plate) with or with-out metabolic activation, did not induce chromosomal aberrationsor polyploidy in an in vitro Chinese hamster lung cell (OECD TG473) study (MHW, Japan 1997c as cited in OECD/SIDS (2003) andKusakabe et al. (2002).

4.9.1.3. In vivo studies. No information available.



This individual fragrance material review is not intended as astand-alone document. Please refer to A Safety Assessment ofBranched Chain Saturated Alcohols When Used as Fragrance Ingre-dients (Belsito et al., 2010) for an overall assessment of thismaterial.


This research was supported by the Research Institute for Fra-grance Materials, an independent research institute that is fundedby the manufacturers of fragrances and consumer products con-taining fragrances. The authors are all employees of the ResearchInstitute for Fragrance Materials.

References

Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. II, No.3006. S. Arctander, Montclair, New Jersey.

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H. 2010. A safety assessment of branched chainsaturated alcohols when used as fragrance ingredients, Food and ChemicalToxicology 48 (S4), S1–S46.

Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:providing estimates for safety evaluation. Regulatory Toxicology andPharmacology 36, 246–252.

Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.Chemically-defined Flavouring Substances. Group 2.1.3 Aliphatic Alcohols,Branched Chain. Number 702. Council of Europe Publishing, Strasbourg. p. 59.

EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, v 4.00 or insert version used. United StatesEnvironmental Protection Agency, Washington, DC, USA.

FEMA (Flavor, Extract Manufacturers Association), 1970. Recent progress in theconsideration of flavoring ingredients under the food additives amendment 4.GRAS substances. Food Technology 24 (5), 25–34.

Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria fordevelopment of a database for safety evaluation of fragrance ingredients.Regulatory Toxicology and Pharmacology 31, 166–181.


2007.JECFA (Joint Expert Committee on Food Additives), 1998. Safety Evaluation of

Certain Food Additives. WHO Food Additives Series: 40. Prepared by the Forty-ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives(JECFA). World Health Organization, Geneva, 1998.

Kligman, A.M., 1966. The identification of contact allergens by human assay. III. Themaximization test. A procedure for screening and rating contact sensitizers.Journal of Investigative Dermatology 47, 393–409.

Kligman, A.M., Epstein, W., 1975. Updating the maximization test for identifyingcontact allergens. Contact Dermatitis 1, 231–239.

Kusakabe, H., Yamakage, K., Wakuri, S., Sasaki, K., Nakagawa, Y., Watanabe, M.,Hayashi, M., Sofuni, T., Ono, H., Tanaka, N., 2002. Relevance of chemicalstructure and cytotoxicity to the induction of chromosome aberrations based onthe testing results of 98 high production volume industrial chemicals. MutationResearch 517 (1–2), 187–198.

Letizia, C.S., Cocchiara, J., Wellington, G.A., Funk, C., Api, A.M., 2000. Monographs onfragrance raw materials, 3,5,5-trimethyl-1-hexanol. Food and ChemicalToxicology 38 (Suppl. 3), S223–S235.

OECD and Screening Information Datasets (SIDS), (2003). High Production VolumeChemicals 3,5,50-trimethyl-1-hexanol (CAS No.: 3452-97-9). Processed byUnited Nations Environmental Program, (UNEP). Available online: <http://www.chem.unep.ch/irptc/sids/OECDSIDS/indexcasnumb.htm>.

Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,1984. The absence of testicular atrophy and in vivo and in vitro effects onhepatocyte morphology and peroxisomal enzyme activities in male ratsfollowing the administration of several alkanols. Toxicology Letters 21, 103–109.

RIFM (Research Institute for Fragrance Materials, Inc.), 1977a. Acute Toxicity Studyin Rats, Rabbits and Guinea Pigs. RIFM Report Number 1695, July 25 (RIFM,Woodcliff Lake, NJ, USA).

RIFM (Research Institute for Fragrance Materials, Inc.), 1977b. Report on HumanMaximization Studies. RIFM Report Number 1702, May 09 (RIFM, WoodcliffLake, NJ, USA).

VCF (Volatile Compounds in Food): database. In: Nijssen, L.M., Ingen-Visscher, C.A.van, Donders, J.J.H. (Eds.), Version 11.1.1 – Zeist (The Netherlands): TNO Qualityof Life, 1963–2009.


Review

Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol




a b s t r a c t

A toxicologic and dermatologic review of 3,7-dimethyl-7-methoxyoctan-2-ol when used as a fragranceingredient is presented. 3,7-Dimethyl-7-methoxyoctan-2-ol is a member of the fragrance structuralgroup branched chain saturated alcohols. The common characteristic structural elements of the alcoholswith saturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with oneor several methyl side chains. This review contains a detailed summary of all available toxicology anddermatology papers that are related to this individual fragrance ingredient and is not intended as astand-alone document. A safety assessment of the entire branched chain saturated alcohol group willbe published simultaneously with this document; please refer to Belsito et al. (2010) for an overall assess-ment of the safe use of this material and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.2.2. Animal studies (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.4.2. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S534.4.3. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S544.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S544.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S544.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S544.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54

4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54







Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 3,7-dimethyl-7-meth-oxyoctan-2-ol when used as a fragrance ingredient. 3,7-Dimethyl-7-methoxyoctan-2-ol (see Fig. 1; CAS Number 41890-92-0) is afragrance ingredient used in cosmetics, fine fragrances, shampoos,toilet soaps and other toiletries as well as in non-cosmetic productssuch as household cleaners and detergents. It is an almost colorlessliquid and has a sandalwood odor with a flowery, woodsy note.

In 2006, a complete literature search was conducted on 3,7-Di-methyl-7-methoxyoctan-2-ol. On-line toxicological databaseswere searched including those from the Chemical Abstract Ser-vices, [e.g. ToxCenter (which in itself contains 18 databases includ-ing Chemical Abstracts)], and the National Library of Medicine [e.g.Medline, Toxnet (which contains 14 databases)] as well as 26 addi-tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,fragrance companies were asked to submit all test data.

The safety data on this material was last reviewed by Ford et al.,1992. All relevant references are included in this document. Moredetails have been provided for unpublished data. The number ofanimals, sex and strain are always provided unless they are not gi-ven in the original report or paper. Any papers in which the vehi-cles and/or the doses are not given have not been included in thisreview. In addition, diagnostic patch test data with fewer than 100consecutive patients have been omitted.

1. Identification

1.1. Synonyms: 7-Methoxy-3,7-dimethyloctan-2-ol; 2-Octanol,7-methoxy-3,7-dimethyl; Osirol; Osyrol; 7-Methoxy-3,7-dimethyloctan-2-ol.

1.2. CAS Registry number: 41890-92-0.

1.3. EINECS number: 255-574-7.1.4. Formula: C11H24O2.

1.5. Molecular weight: 188.31.


2.1. Physical form: An almost colorless liquid.2.2. Boiling point (calculated; EPA, 2010): 229.67 �C.2.3. Flash point:>110 �C (230�F).2.4. Henry’s law (calculated; EPA, 2010): 0.000000404 atm m3/

mol 25 �C.2.5. Log Kow (calculated; EPA, 2010): 2.76.2.6. Refractive index: 1.446.2.7. Specific gravity: 0.898.2.8. Vapor pressure (calculated; EPA, 2010): 0.0119 mm Hg;

1.58 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 707.1 mg/l (25 �C).

2.10. UV spectra available at RIFM, peaks at 200–210 nm andreturns to baseline at 400 nm. Minor absorption from 290–400 nm.

3. Usage

3,7-Dimethyl-7-methoxyoctan-2-ol is a fragrance ingredientused in many fragrance compounds. It may be found in fragrancesused in decorative cosmetics, fine fragrances, shampoos, toiletsoaps and other toiletries as well as in non-cosmetic products suchas household cleaners and detergents. Its use worldwide is in theregion of 1–10 metric tons per annum (IFRA, 2004). The reportedvolume of use is for 3,7-dimethyl-7-methoxyoctan-2-ol as usedin fragrance compounds (mixtures) in all finished consumer prod-uct categories. The volume of use is surveyed by IFRA approxi-mately every 4 years through a comprehensive survey of IFRAand RIFM member companies. As such the volume of use data fromthis survey provides volume of use of fragrance ingredients for themajority of the fragrance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of severalthousand commercial formulations. The upper 97.5 percentile con-centration is calculated from the data obtained. This upper 97.5 per-centile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for

HO

O

Fig. 1. 3,7-Dimethyl-7-methoxyoctan-2-ol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,7-dimethyl-7-methoxyoctan-2-ol.





the length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).



4. Toxicology data

4.1. Acute toxicity

4.1.1. Oral studiesThe acute oral LD50 of 3,7-dimethyl-7-methoxyoctan-2-ol in

rats was reported to be approximately 5.0 g/kg. Mortality was 2/5 males at less than 4 h after dosing and 3/5 females at less than23 h after dosing. Symptoms included lethargy, piloerection, diure-sis, salivation, and ataxia. Necropsy revealed darkening of the liverand injection of blood vessels of the abdominal viscera. Recovery ofsurvivors was apparently complete within 8 days of dosing.Slightly depressed body weight gains were observed during thefirst week after dosing in male rats, but returned to normal duringthe second week of observation. Terminal necropsy findings of sur-vivors were normal (RIFM, 1976).

4.1.2. Dermal studiesNo available information.


4.2.1. Human studiesIn a human maximization test pre-screen, 10% 3,7-Dimethyl-7-

methoxyoctan-2-ol (6900 lg/cm2) was applied under occlusion tothe backs of 27 healthy subjects for 48 h. No significant evidence ofirritation was observed (RIFM, 1982).

4.2.2. Animal studies (see Table 2)In a rabbit (n = 6) dermal irritation study conducted according

to US FDA Guidelines, 0.5 ml of 1% 3,7-Dimethyl-7-methoxyoc-tan-2-ol in propylene glycol on an occlusive 24 h patch was consid-ered mildly irritating. Very slight erythema was observed in theintact and abraded sites of 5 animals at 24 h. In one animal there

was no observable response to treatment. At 72 h, the reactionshad ameliorated. One animal showed very slight erythema at theintact and abraded sites. There was no observable response totreatment in the remaining 5 animals. The Primary Irritation Indexwas calculated to be 0.5 (RIFM, 1973a).

In a guinea pig (n = 10) sensitization study conducted accordingto US FDA Guidelines, irritation was not induced by 0.2 ml of 2.5%or 5% 3,7-Dimethyl-7-methoxyoctan-2-ol in water applied underocclusion to a 0.5 inch square to the shaved area of the shoulder24 h per day on alternate days during a 3 week period for a totalof 10 applications. Applications 1 – 7 were at 5% and applications8 – 10 were at 2.5%. Challenge dose was applied in the same man-ner using 2.5% 14 days after the last induction dose. Three animalsexhibited 1 grade 1 response for erythema once each during theinduction period and 1 animal exhibited 2 grade 1 erythema re-sponses during induction. There were no positive responses fol-lowing challenge (RIFM, 1973b).


In a rabbit (n = 6) eye irritation study conducted according to USFDA Guidelines, 0.1 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol inpropylene glycol produced only temporary mild conjuctival reac-tions in 5 animals. In one animal chemosis of the conjunctivawas observed. No corneal or iris involvement occurred and all ef-fects cleared within 3 days (RIFM, 1973c).


4.4.1. Human studies4.4.1.1. Induction studies. In a human Maximization study involving27 subjects, there was no evidence of contact sensitization to 10%3,7-Dimethyl-7-methoxyoctan-2-ol (6900 lg/cm2). Test materialwas applied in petrolatum under occlusion to the forearms for a to-tal of five alternate day, 48 h periods. Each application was pre-ceded by a 24 h occlusive treatment of the patch sites with 7.5%aqueous sodium lauryl sulfate. Following a 10–14 day rest period,challenge patches were applied under occlusion to fresh sites for48 h. Challenge applications were preceded by 30 min applicationsof 7.5% sodium lauryl sulfate under occlusion on the left side andno pretreatment on the right side. Challenge sites were evaluatedat removal of the patches and 24 h later (RIFM, 1982).

4.4.1.2. Cross-sensitization. No available information.

4.4.2. Diagnostic studiesIn a diagnostic patch test study, there were positive responses

to 3,7-dimethyl-7-methoxyoctan-2-ol (concentration not speci-fied) in 2 of 218 dermatology patients with previous positive reac-tion to at least one fragrance material (Larsen et al., 2002).

4.4.3. Animal studies4.4.3.1. Maximization Test. No available information.

4.4.3.2. Other studies. In a guinea pig (n = 10) sensitization studyconducted according to US FDA Guidelines, sensitization was not

Table 2Summary of animal irritation studies.

Method Dose Species Results References

Dermal application 1% Rabbit Slight erythema RIFM (1973a)Occluded dermal application Induction Guinea pig During the induction, three animals exhibited slight

erythema and one was moderateNo response to challenge

RIFM (1973b)5%2.5%Challenge2.5%


induced by 0.2 ml of 2.5% or 5% 3,7-dimethyl-7-methoxyoctan-2-olin water applied under occlusion to a 0.5 inch square to the shavedarea of the shoulder 24 h per day on alternate days during a 3 weekperiod for a total of 10 applications. Applications 1–7 were at 5%and applications 8–10 were at 2.5%. Challenge dose was appliedin the same manner using 2.5% 14 days after the last inductiondose. Three animals exhibited 1 grade 1 response for erythemaonce each during the induction period and 1 animal exhibitedgrade 1 erythema responses twice during induction. There wereno positive responses following challenge (RIFM, 1973b).

4.4.3.3. Local Lymph Node Assay (LLNA). No available information.


No available information.







4.9. Genotoxicity




This individual Fragrance Material Review is not intended as astand-alone document. Please refer to A Safety Assessment ofBranched Chain Saturated Alcohols When Used as Fragrance Ingre-dients (Belsito et al., 2010) for an overall assessment of thismaterial.



References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chainsaturated alcohols when used as fragrance ingredients. Food and ChemicalToxicology 48 (S4), S1–S46.


EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, V 4.00 or Insert Version Used. United StatesEnvironmental Protection Agency, Washington, DC, USA.

Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monograph on 3,7-dimethyl-7-methoxyoctan-2-ol. Food and Chemical Toxicology 30 (Suppl.), 25S.



2007.Larsen, W., Nakayama, H., Fischer, T., Elsner, P., Frosch, P., Burrows, D., Jordan, W.,

Shaw, S., Wilkinson, J., Marks, J., Sugawara, M., Nethercott, M., Nethercott, J.,2002. Fragrance contact dermatitis – a worldwide multicenter investigation(Part III). Contact Dermatitis 46 (3), 141–144.

RIFM (Research Institute for Fragrance Materials, Inc.), 1973a. Irritant Effects of3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Skin. Unpublished Report fromBush Boake Allen Ltd., 07 June. Report Number 1765. RIFM, Woodcliff Lake,NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1973b. Screening Test forDelayed Dermal Sensitization with 3,7-Dimethyl-7-methoxyoctan-2-ol in theAlbino Guinea Pig. Unpublished Report from Bush Boake Allen Ltd., 03 May.Report Number 1766. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1973c. Irritant effects of 3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Eye Mucosa. Unpublished Reportfrom Bush Boake Allen Ltd., 07 June. Report Number 1767. RIFM, WoodcliffLake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1976. Acute Oral Toxicity ofValanone B, Cytenol, 3,7-Dimethyl-7-methoxyoctan-2-ol, 8-Methoxy-p-menthene and Pinocarvyl Acetate in Rats. Unpublished Report from BushBoake Allen Ltd., 23 March. Report Number 1764. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1982. Report on HumanMaximization Studies. RIFM Report Number 1643, October 05. RIFM, WoodcliffLake, NJ, USA.


Review

Fragrance material review on 4-methyl-2-pentanol

D. McGinty *, J. Scognamiglio, C.S. Letizia, A.M. ApiResearch Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA



a b s t r a c t

A toxicologic and dermatologic review of 4-methyl-2-pentanol when used as a fragrance ingredient ispresented. 4-Methyl-2-pentanol is a member of the fragrance structural group branched chain saturatedalcohols. The common characteristic structural elements of the alcohols with saturated branched chainare one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains.This review contains a detailed summary of all available toxicology and dermatology papers that arerelated to this individual fragrance ingredient and is not intended as a stand-alone document. A safetyassessment of the entire branched chain saturated alcohol group will be published simultaneously withthis document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this mate-rial and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.1.4. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57

4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57

4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S574.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57

4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S584.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S584.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58

4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S584.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58

4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58







Introduction

This document provides a comprehensive summary of thetoxicologic review, including all human health endpoints, of4-Methyl-2-pentanol when used as a fragrance ingredient.4-Methyl-2-pentanol (see Fig. 1; CAS Number 108-11-2) is a fra-grance ingredient used in cosmetics, fine fragrances, shampoos,toilet soaps and other toiletries as well as in non-cosmetic prod-ucts such as household cleaners and detergents. This materialhas been reported to occur in nature, with highest quantitiesobserved in annatto extract (VCF, 2009).

In 2006, a complete literature search was conducted on 4-Methyl-2-pentanol. On-line toxicological databases were searchedincluding those from the Chemical Abstract Services, [e.g., ToxCen-ter (which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g., Medline,Toxnet (which contains 14 databases)] as well as 26 additionalsources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-grance companies were asked to submit all test data.

The safety data on this material has never been reviewed beforeby RIFM (Research Institute for Fragrance Materials, Inc.). All rele-vant references are included in this document. More details havebeen provided for unpublished data. The number of animals, sexand strain are always provided unless they are not given in the ori-ginal report or paper. Any papers in which the vehicles and/or thedoses are not given have not been included in this review. In addi-tion, diagnostic patch test data with fewer than 100 consecutivepatients have been omitted.

1. Identification

1.1. Synonyms: Isobutyl methyl carbinol; 4-methylpentan-2-ol;methyl isobutyl carbinol; MIC; 2-pentanol, 4-methyl-

1.2. CAS registry number: 108-11-2.1.3. EINECS number: 203-551-7.1.4. Formula: C6H14O.1.5. Molecular weight: 102.18.


2.1. Physical form: no information available.2.2. Boiling point (calculated; EPA, 2010): 124.88 �C.2.3. Flash point: no information available.2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m3/mol

25 �C.2.5. Log Kow (calculated; EPA, 2010): 1.68.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 3.7 mm Hg 20 �C;

3.74 mm Hg (25 �C); 498 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 13,800 mg/l at

25 �C.2.10. UV spectra not available at RIFM.

3. Usage

4-Methyl-2-pentanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of0.01–0.1 metric tons per annum (IFRA, 2004). The reported volumeis for the use of 4-methyl-2-pentanol used in fragrance compounds(mixtures) used in all finished consumer product categories. Thevolume of use is surveyed by IFRA approximately every four yearsthrough a comprehensive survey of IFRA and RIFM member com-panies. As such the volume of use data from this survey providesvolume of use of fragrance ingredients for the majority of the fra-grance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of severalthousand commercial formulations. The upper 97.5 percentile con-centration is calculated from the data obtained. This upper 97.5 per-centile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account forthe length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 4-methyl-2-pentanol.

Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredient (mg/kg/day)b

Anti-perspirant 0.5 1 1 0.01 .02 0.000001Bath products 17 0.29 0.001 0.02 .02 0.000001Body lotion 8 0.71 1 0.004 .02 0.000100Eau de toilette 0.75 1 1 0.08 .02 0.000200Face cream 0.8 2 1 0.003 .02 0.000001Fragrance cream 5 0.29 1 0.04 .02 0.000200Hair spray 5 2 0.01 0.005 .02 0.000001Shampoo 8 1 0.01 0.005 .02 0.000001Shower gel 5 1.07 0.01 0.012 .02 0.000001Toilet soap 0.8 6 0.01 0.015 .02 0.000001Total 0.0005


HO

Fig. 1. 4-Methyl-2-pentanol.


This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,2007), which would result in a maximum daily exposure on theskin of 0.0005 mg/kg for high end users (see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level that re-sults from the use of 4-Methyl-2-pentanol in formulae that go intofine fragrances has not been reported. A default value of 0.02% isused assuming use of the fragrance oils at levels up to 20% in thefinal product.

4. Toxicology data


4.1.1. Oral studiesThe acute oral LD50 of 4-methyl-2-pentanol in five rats was re-

ported to be 2.59 (2.26–2.97) g/kg. No additional details were re-ported (Smyth et al., 1951).

The acute oral LD50 of 4-methyl-2-pentanol in rats was reportedto be 2.95 g/kg. No additional details were reported (Bar and Grie-pentrog, 1967).

The acute oral LD50 of 4-methyl-2-pentanol in rats was reportedto be 2.59 g/kg. No additional details were reported (Nishimuraet al., 1994).

4.1.2. Dermal studiesThe acute dermal LD50 of 4-methyl-2-pentanol in rabbits was

reported to be 3.56 (2.72–4.76) ml/kg (�3.56 g/kg). No additionaldetails were reported (Smyth et al., 1951).

4.1.3. Inhalation studiesThe acute inhalation exposure of six rats to 4-methyl-2-penta-

nol at 2000 ppm for 8 h was reported to result in mortality of5/6. The maximum time for no death was 2 h. No additional detailswere reported (Smyth et al., 1951; Carpenter et al., 1949).

When mice were exposed to 4-methyl-2-pentanol vapor satu-rated air at 20 �C, mortality was 0, 0, 6, and 8 of 10 animals follow-ing 4, 8.5, 10, and 15 h, respectively. The observation period was7 days. Somnolence was induced in 1 h, anesthesia in 4 h, anddeath in 10 h. No additional details were reported (McOmie andAnderson, 1949).

4.1.4. Miscellaneous studiesNo available Information.


4.2.1. Human studiesNo available information.

4.2.2. Animal studies (see Table 3)In a rabbit skin irritation study, 4-methyl-2-pentanol induced

grade 2 irritation defined as an average reaction equivalent to atrace of capillary injection. No additional details were reported(Smyth et al., 1951, 1949).

In a three rabbit skin irritation study, exposure of rabbits to va-pors of 4-methyl-2-pentanol for 0.25 h resulted in immediateslight erythema and delayed moderate erythema with drying ofsurface. Five direct applications of the 3.0 ml/kg over a 100 cm2

area material to the skin of rabbits (n = 3) resulted in severe dryingof skin with some sloughing and cracking (McOmie and Anderson,1949).

4.3. Mucous membrane (eye) irritation (see Table 4)

In a rabbit eye irritation study, 0.005 ml of undiluted 4-methyl-2-pentanol induced injury of up to 5.0 points. A score of five pointsis given for necrosis on 63–87% visible after fluorescein staining,without corneal opacity. No additional details were reported(Smyth et al., 1951, 1949).

In a three rabbit eye irritation study conducted according to themethod of Draize, 4-methyl-2-pentanol produced moderate irrita-tion; some conjunctivitis with some edema and corneal injury butreturned to normal after 7 days (McOmie and Anderson, 1949).






4.6.1. AbsorptionNo available information.

4.6.2. DistributionNo available information.

4.6.3. Metabolism4.6.3.1. In vivo studies in animals. 4-Methyl-2-pentanol (methyl iso-butyl carbinol, MIBC) is an oxygenated solvent that is metabolizedto methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-2-pentanone (HMP). Plasma levels of MIBC, MIBK, and HMP were


Route Species No. animals/dose group

LD50

(g/kg)References

Oral Rat 5 2.59 Smyth et al., 1951Oral Rat N/A 2.95 Bar and Griepentrog, 1967Oral Rat N/A 2.59 Nishimura et al., 1994Dermal Rabbit 5 3.56 Smyth et al., 1951


Method Dose(%)

Species Reactions References

Dermal irritation 100 Rabbit Trace of capillaryinjection

Smyth et al.,1951

Dermal irritation 100 Rabbit Dry skin with somesloughing andcracking

McOmie andAnderson,1949

Table 4Summary of eye irritation studies.

Dose (%) Reactions References

100 Irritation observed Smyth et al., 1951100 Irritation observed McOmie and Anderson, 1949


determined up to 12 h after oral gavage administration of 5 mmol/kg of MIBC or MIBK (510 and 500 mg/kg, respectively) in corn oil tomale Sprague–Dawley rats (n = at least three blood samples persampling time). The major material in the plasma for both testmaterials was HMP, with similar areas under the curve (AUCs)and C-max at 9 h after dosing for both MIBC and MIBK. MIBK plas-ma levels and AUC were also comparable after MIBK or MIBCadministration. MIBC AUC was only about 6% of the total materialin the blood following MIBC administration, and insignificant afterMIBK administration. No other metabolites were detected in theplasma. The extent of metabolism of MIBC to MIBK was at least73% (Gingell et al., 2003; Granvil et al., 1994).

In an occupational exposure study of workers exposed to mixedsolvents including MIBK or MIBK alone, 4-methyl-2-pentanol wasidentified by GCMS in the urine (Hirota, 1991a).

4-Methyl-2-pentanol was identified as a metabolite followingintraperitoneal administration of MIBK to rats (Hirota, 1991b).

Excessive urinary glucuronide excretion, compared to that ofcontrols, by rabbits (n = 3) following oral gavage administrationof 3 ml/rabbit of 4-methyl-2-pentanol, represented 33.7% of theadministered dose (Kamil et al., 1953).

4.6.3.2. In vitro studies in animals. No available information.


4-Methyl-2-pentanol was exposed to nine mice 12 times for 4 hat 20 mg/l. No deaths were observed (McOmie and Anderson,1949).

4-Methyl-2-pentanol was given at doses of 0, 50.5, 198, or886 ml/m3 to Wistar rats (12/sex) for 6 h per day, 5 days a week,over the course of 6 weeks according to OECD guideline TG 407.At the two lowest doses the concentration of ketone bodies inthe urine increased for males and females. At 886 ml/m3 the abso-lute kidney weight increased (males) and the serum alkaline phos-phatase increased (females). The authors concluded a NOAEC at198 ml/m3 (OECD/SIDS 2007).



4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems (see Table 5). 4-Methyl-2-pentanol upto 5000 lg/plate was not mutagenic in Salmonella typhimuriumstrains TA 98, TA 100, TA1535, TA 1537, and TA 1538 and Escerichiacoli strain WP 2 uvrA, Ames with and without addition of S9 liverfractions from KC500 induced rats (Shimizu et al., 1985).

An Ames assay with and without metabolic activation found 4-methyl-2-pentanol as non-mutagenic using Salmonella typhimuri-um TA98, TA100, TA1535, TA1537, TA1538, E. coli WP2 uvr Apkm 101 at 31.25–4000 lg/plate (OECD/SIDS, 2007).

4-Methyl-2-pentanol is not mutagenic according to a genemutation study with and without metabolic activation in saccharo-myces cerevisiae JD1 at 10–5000 lg/plate (OECD/SIDS, 2007).

4.9.1.2. Studies in mammalian cells. Rat liver cells (RL4) were testedin a cytogenetic assay with 0, 0.5, 1, or 2 mg/ml of 4-methyl-2-pentanol. According to the conditions of this study the results werenegative (OECD/SIDS, 2007).

4.9.2. In vivo studiesNo available information.





This research was supported by the Research Institute forFragrance Materials, an independent research institute that isfunded by the manufacturers of fragrances and consumer productscontaining fragrances. The authors are all employees of theResearch Institute for Fragrance Materials.

References


Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilungder Aromatisierungsmittel fur Lebensmittel (where we stand concerning theevaluation of flavoring substances from the viewpoint of health). MedizinErnahr. 8, 244–251.


Carpenter, C.P., Smyth, H.F., Pozzani, U.C., 1949. The assay of acute vapor toxicity,and the grading and interpretation of results on 96 chemical compounds. TheJournal of Industrial Hygiene and Toxicolology 31 (6), 343–346.



Gingell, R., Regnier, J.F., Wilson, D.M., Guillaumat, P.O., Appelqvist, T., 2003.Comparative metabolism of methyl isobutyl carbinol and methyl isobutylketone in male rats. Toxicology Letters 136 (1–2), 199–204.

Granvil, C.P., Sharkawi, M., Plaa, G.L., 1994. Metabolic fate of methyl n-butyl ketone,methyl isobutyl ketone and their metabolites in mice. Toxicology Letters 70 (3),263–267.

Hirota, N., 1991a. The metabolism of methyl isobutyl ketone and biologicalmonitoring: part 2. Qualitative and quantitative study of 4-methyl-2-pentanolexcreted in the urine of workers exposed to methyl isobutyl ketone. OkayamaIgakkai Zasshi 103 (4), 327–336.

Table 5Summary of bacterial studies.

Test system Concentration Results References

Ames assay with and without S9 activation Salmonella typhimuriumTA98, TA100, TA 1535, TA1537 and TA 1538Escerichia coli WP 2 uvrA

Up to 5000 lg/plate Not mutagenic Shimizu et al., 1985

Ames assay with and without S9 activation Salmonella typhimuriumTA98, TA100, TA 1535, TA1537 and TA 1538Escerichia coli WP 2 uvrA pkm 101

31.25–4000 lg/plate Not mutagenic OECD/SIDS, 2007

Mutation assay Saccharomyces cerevisiae JD1 10–5000 lg/plate Not mutagenic OECD/SIDS, 2007


Hirota, N., 1991b. The metabolism of methyl isobutyl ketone and its biologicalmonitoring: part 1. Qualitative and quantitative studies of methyl isobutylketone exhaled from the lungs and excreted in the urine, and the metabolites inthe urine of rats inject. Okayama Igakkai Zasshi 103 (4), 315–326.

IFRA (International Fragrance Association), 2004. Use level survey, August 2004.IFRA (International Fragrance Association), 2007. Volume of use survey, February

2007.Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The

metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclicaliphatic alcohols. Biochemical Journal 53, 129–136.


Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity(LD50-value) of organic chemicals to mammals by solubility parameter (delta).

1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323. Japanese JournalIndustrial Health.

OECD and Screening Information Datasets (SIDS), (2007). High production volumechemicals 4-methylpentan-2-ol (Cas no: 108-11-2). Processed by UnitedNations Environmental Program, (UNEP) available online: <http://www.chem.unep.ch/irptc/sids/OECDSIDS/indexcasnumb.htm>.



Smyth, H.F., Carpenter, C.P., Weil, C.S., 1951. Range finding toxicity data: List IV.Archives of Industrial Hygiene and Occupational Medicine 4, 119–122.

VCF, 2009. (Volatile Compounds in Food): database/Nijssen, L.M., Ingen-Visscher,C.A. van, Donders, J.J.H. (Eds.). – Version 11.1.1 – TNO Quality of Life, Zeist, TheNetherlands, 1963–2009.


Review

Fragrance material review on 2-methylundecanol




a b s t r a c t

A toxicologic and dermatologic review of 2-methylundecanol when used as a fragrance ingredient is pre-sented. 2-Methylundecanol is a member of the fragrance structural group branched chain saturated alco-hols. The common characteristic structural elements of the alcohols with saturated branched chain areone hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains the information available on this individual fragrance ingredient and is not intended as astand-alone document. A safety assessment of the entire branched chain saturated alcohol group will bepublished simultaneously with this document; please refer to Belsito et al. (2010) for an overall assess-ment of the safe use of this material and all other branched chain saturated alcohols in fragrances.


Contents


Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S62References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S62

Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 2-methylundecanol whenused as a fragrance ingredient. 2-Methylundecanol (see Fig. 1; CASNumber 10522-26-6) is a fragrance ingredient used in cosmetics,fine fragrances, shampoos, toilet soaps and other toiletries as wellas in non-cosmetic products such as household cleaners anddetergents.

In 2006, a complete literature search was conducted on 2-Meth-ylundecanol. On-line toxicological databases were searchedincluding those from the Chemical Abstract services, [e.g., ToxCen-ter (which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g., Medline,Toxnet (which contains 14 databases)] as well as 26 additionalsources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-grance companies were asked to submit all test data.


1. Identification

1.1 Synonyms: 1-undecanol, 2-methyl-; 2-methylundecan-1-ol1.2 CAS registry number: 10522-26-61.3 EINECS number: 234-067-41.4 Formula: C12H26O1.5 Molecular weight: 186.39


2.1 Physical form: no information available2.2 Boiling point (calculated; EPA, 2010): 262.99 �C






journal homepage: www.elsevier .com/locate/ foodchemtox

2.3 Flash point: no information available2.4 Henry’s law (calculated; EPA, 2010): 0.0000963 atm m3/mol

25 �C2.5 Log Kow (calculated; EPA, 2010): 4.72.6 Refractive index: no information available2.7 Specific gravity: no information available2.8 Vapor pressure (calculated; EPA, 2010): 0.0014 mm Hg;

0.186 Pa (25 �C)2.9 Water solubility (calculated; EPA, 2010): 16.18 mg/l (25 �C)

2.10 UV spectra available at RIFM, peaks at 200–205 nm andreturns to baseline at 270–280 nm

3. Usage

2-Methylundecanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of<0.01 metric tons per annum (IFRA, 2004). The reported volumeof use is for 2-methylundecanol as used in fragrance compounds(mixtures) in all finished consumer product categories. The volumeof use is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies. Assuch the volume of use data from this survey provides volume of

use of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (see Ta-ble 1) is calculated based on the concentrations of the same fra-grance ingredient in ten types of the most frequently usedpersonal care and cosmetic products (anti-perspirant, bath prod-ucts, body lotion, eau de toilette, face cream, fragrance cream, hairspray, shampoo, shower gel, and toilet soap). The concentration ofthe fragrance ingredient in fine fragrances is obtained from exam-ination of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayfor each product type, and a ‘‘retention factor” (ranging from0.001 to 1.0) to account for the length of time a product may re-main on the skin and/or likelihood of the fragrance ingredientbeing removed by washing. The resultant calculation representsthe total consumer exposure (mg/kg/day) (Cadby et al., 2002; Fordet al., 2000).


A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be0.04% (IFRA, 2007), assuming use of the fragrance oil at levels upto 20% in the final product.

4. Toxicology data

No data available on this material.


Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylundecanol.




Fig. 1. 2-Methylundecanol.




References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic

assessment of alcohols branched chain saturated when used as fragranceingredients. Food and Chemical Toxicology, this issue 48 (S4), S1–S46.


EPA (Environmental Protection Agency), 2010. Estimation programs interfacesuite™ for Microsoft� Windows, v 4.00 or insert version used]. United StatesEnvironmental Protection Agency, Washington, DC, USA.



2007.


Review

Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol




a b s t r a c t

A toxicologic and dermatologic review of 3,4,5,6,6-pentamethylheptan-2-ol when used as a fragranceingredient is presented. 3,4,5,6,6-Pentamethylheptan-2-ol is a member of the fragrance structural groupbranched chain saturated alcohols. The common characteristic structural elements of the alcohols withsaturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one orseveral methyl side chains. This review contains a detailed summary of all available toxicology and der-matology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will be pub-lished simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessmentof the safe use of this material and all other branched chain saturated alcohols in fragrances.


Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S641. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S642. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S643. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S644. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.1.3. Intraperitoneal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

4.2. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

4.3. Mucous membrane (eye) irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.4. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

4.5. Phototoxicity and photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S654.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S664.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

4.7.1. Two to fourteen day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S664.7.2. Subchronic studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S664.7.3. Chronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S664.9. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S664.9.2. In vivo studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66







Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 3,4,5,6,6-pentamethyl-heptan-2-ol when used as a fragrance ingredient. 3,4,5,6,6-Pen-tamethylheptan-2-ol (see Fig. 1; CAS Number 87118-95-4) is afragrance ingredient used in cosmetics, fine fragrances, shampoos,toilet soaps and other toiletries as well as in non-cosmetic prod-ucts such as household cleaners and detergents.

In 2006, a complete literature search was conducted on3,4,5,6,6-pentamethylheptan-2-ol. On-line toxicological databaseswere searched including those from the Chemical Abstract Services[e.g. ToxCenter (which in itself contains 18 databases includingChemical Abstracts)], and the National Library of Medicine [e.g.Medline, Toxnet (which contains 14 databases)] as well as 26 addi-tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,fragrance companies were asked to submit all test data.


1. Identification

1.1. Synonyms: 2-heptanol, 3,4,5,6,6-pentamethyl-; Koavol DH.1.2. CAS Registry Number: 87118-95-4.1.3. EINECS Number: 401-030-0.1.4. Formula: C12H26O.1.5. Molecular weight: 186.39.


2.1. Physical form: no information available.2.2. Boiling point: 220.2–231.7 �C.2.3. Flash point: 365.5 K (92.5 �C).

2.4. Henry’s law (calculated; EPA, 2010): 0.0000963 atm m3/mole.2.5. Log Kow: 4.0587 at 19 �C.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure: 2.088 Pa at 298 K.2.9. Water solubility: 0.066 g/l at 19 �C.

2.10. UV spectra available at RIFM, peaks at 200–205 nm andreturns to baseline 264–271 nm.

3. Usage

3,4,5,6,6-Pentamethylheptan-2-ol is a fragrance ingredient usedin many fragrance compounds. It may be found in fragrances usedin decorative cosmetics, fine fragrances, shampoos, toilet soaps andother toiletries as well as in non-cosmetic products such as house-hold cleaners and detergents. Its use worldwide is in the range of10–100 metric tons per annum (IFRA, 2004). The reported volumeof use is for 3,4,5,6,6-pentamethylheptan-2-ol as used in fragrancecompounds (mixtures) in all finished consumer product categories.The volume of use is surveyed by IFRA approximately every fouryears through a comprehensive survey of IFRA and RIFM membercompanies. As such the volume of use data from this survey pro-vides volume of use of fragrance ingredients for the majority ofthe fragrance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in 10 types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of sev-eral thousand commercial formulations. The upper 97.5 percentileconcentration is calculated from the data obtained. This upper97.5 percentile concentration is then used for all 10 consumer prod-ucts. These concentrations are multiplied by the amount of productapplied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account forthe length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been reported to be 5.5% (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.1403 mg/kg for high end users.Fig. 1. 3,4,5,6,6-Pentamethylheptan-2-ol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,4,5,6,6-pentamethylheptan-2-ol.


Anti-perspirant 0.5 1 1 0.01 5.5 0.0046Bath products 17 0.29 0.001 0.02 5.5 0.0001Body lotion 8 0.71 1 0.004 5.5 0.0208Eau de toilette 0.75 1 1 0.08 5.5 0.0550Face cream 0.8 2 1 0.003 5.5 0.0044Fragrance cream 5 0.29 1 0.04 5.5 0.0532Hair spray 5 2 0.01 0.005 5.5 0.0005Shampoo 8 1 0.01 0.005 5.5 0.0004Shower gel 5 1.07 0.01 0.012 5.5 0.0006Toilet soap 0.8 6 0.01 0.015 5.5 0.0007

Total 0.1401




4. Toxicology data


4.1.1. Oral studiesSprague–Dawley albino rats were divided into three groups of

10 animals, consisting of five males and five females per group.The three dose levels of undiluted 3,4,5,6,6-pentamethylheptan-2-ol was orally administered (via gavage) at 7.81, 6.25, or 5.0 g/kg bodyweight. Animals were observed immediately after dosing,at 1 and 4 h, and twice daily thereafter for 14 days. At 5.0 g/kg 1of 10 died, and clinical signs included moderate salivation, piloe-rection, lethargy, lacrimation, hunched posture, and epistaxis. At6.25 g/kg, 8 of 10 died with clinical signs including diarrhea,hunched posture, lethargy, piloerection, ataxia, moderate tremors,lacrimation, and epistaxis. In the highest dosage group (7.81 g/kg)9 of 10 died, and clinical signs were the same as above. No controlswere used and the LD50 was calculated to be 5.845 (5.36–6.375) g/kg bodyweight (RIFM, 1984a).

4.1.2. Dermal studiesA group of 10 (5/sex) HC/CFY (remote Sprague–Dawley) rats

were treated with the 3,4,5,6,6-pentamethylheptan-2-ol at 2.0 g/kg bodyweight. A dermal application was made to the dorso-lum-bar region (which had been previously clipped free of fur), coveredwith a gauze patch, and held in place with an impermeable dress-ing. All animals were observed soon after dosing, frequently on day1, and at least twice per day for 14 days after dosing. There were nomortalities, clinical signs of toxicity, or skin reactions at the site ofapplication. The acute LD50 was determined to be greater than2.0 g/kg bodyweight (RIFM, 1985c).

4.1.3. Intraperitoneal studiesIn a preliminary dose range finding study, 3,4,5,6,6-pentameth-

ylheptan-2-ol was administered intraperitoneally to eight groups(2/sex/group) of CD-1 mice at doses of 50, 166, 500, 750, 1000,1250, 1666 and 3000 mg/kg bodyweight. Signs were observed atall levels of 1000 mg/kg and higher. One animal died at 1250 mg/kg and all animals at the two highest dosage levels. Due to theseverity of the signs and mortality, 900 mg/kg was selected asthe maximum tolerated dose (RIFM, 1985a).


4.2.1. Human studiesIrritation was evaluated during the induction phase in a human

repeated insult patch test (HRIPT). A 0.2 ml aliquot of a 15% solu-tion in alcohol SDA-39C was applied to clear plastic patches,1.5 � 1.5 in. (Parke–Davis Readi–Bandages). The patches were

placed on the subjects’ skin between the left scapula and spinalmid-line for 24 h under occlusion. After a 24–48 h rest period, sub-jects were again patched at the same site. Nine applications weremade in a three week period. Slight irritation was observed in 5of the 51 male and female volunteers (RIFM, 1983).

4.2.2. Animal studiesA group of six male albino New Zealand rabbits were given

0.5 ml of the undiluted 3,4,5,6,6-pentamethylheptan-2-ol and ob-served for up to 72 h. Erythema and edema were not observed inany of the six rabbits tested (RIFM, 1984b).


3,4,5,6,6-Pentamethylheptan-2-ol was evaluated for eye irrita-tion in nine healthy albino rabbits. Undiluted aliquots of 0.1 mlwere instilled into one eye. The untreated eye of each animalserved as a control. Observations were made at 1 h, and dailythereafter for a week. Irritation was observed in the cornea andconjunctiva, but cleared by the seventh day (RIFM, 1984c).


4.4.1. Human studies4.4.1.1. Induction studies. A repeated insult patch tests was con-ducted to determine if 15% 3,4,5,6,6-pentamethylheptan-2-ol inalcohol SDA-39C would induce dermal sensitization in 51 humanvolunteers. During the induction phase 0.2 ml was applied ontoParke–Davis Readi–Bandages and applied to the backs of each vol-unteer for 24 h. Induction applications were made for a total ofnine applications during three week period. Following a one weekrest period, a challenge patch was applied to a site previously un-exposed on the upper back. Patches were applied as in the induc-tion phase and kept in place for 24 h after which time they wereremoved. Reactions to the challenge were scored at 24, 48, and72 h after application. There were no sensitization reactions duringthe challenge phase (RIFM, 1983).

4.4.2. Animal studiesNo information available.






4.7.1. Two to fourteen day studiesNo information available.

4.7.2. Subchronic studies (see Table 3)3,4,5,6,6-Pentamethylheptan-2-ol was assessed for its toxicity

to 10 New Zealand white rabbits (5/sex) when administered tothe occluded skin. Applications of 1000 mg/kg were made for 6 heach day for 28 consecutive days. Irritation progressed rapidly inall rabbits and within two weeks severe erythema and edema wereobserved. Histopathological examination revealed the treated skinto have acanthotic and focal ulcerative changes in the epidermis,along with associated inflammation, hyperkeratosis, and scab for-mation. A systemic NOAEL of 1000 mg/kg bodyweight/day wasdecided for 3,4,5,6,6-pentamethylheptan-2-ol although severe irri-tation was observed (RIFM, 1985d).

At concentrations of 1.5%, 5.0%, 15%, and 50% 3,4,5,6,6-pentam-ethylheptan-2-ol in 1% aqueous methylcellulose (equivalent to 30,100, 300, and 1000 mg/kg/day) was applied to the intact skin of


Route Species Number ofanimals/dose group

LD50 (g/kg) References

Oral Rat 10 5.8 RIFM (1984a)Dermal Rat 10 >2.0 RIFM (1985a)


New Zealand white rabbits (10/sex). The two lowest dosages (30and 100 mg/kg/day) were allowed to run for 6 h per day, and 28consecutive days under an occlusive patch. Slight to moderate der-mal irritation developed for both dosages but ameliorated by day16 for 30 mg/kg/day, and persisted to termination for 100 mg/kg/day. Treatment of the two highest dosages (300 and 1000 mg/kg/day) was terminated after nine applications because of the severityof the dermal reactions. However, after 8 days irritation subsidedand the data suggests the dermal reactions are reversible. A sys-temic NOAEL of 1000 mg/kg bodyweight/day was decided for3,4,5,6,6-pentamethylheptan-2-ol although severe irritation wasobserved (RIFM, 1986).

4.7.3. Chronic studiesNo information available.



4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems. An Ames test using 0.1 ml of3,4,5,6,6-pentamethylheptan-2-ol was added to Escherichia coliWP2 uvrA, Salmonella typhimurium TA 98, 100, 1535, 1537, and1538 cultures at concentrations up to 1000 lg/plate with andwithout S9 activation. Toxicity was observed with tester strainsTA 98, 100, and 1535 at the higher dose levels. A second roundof tests, up to 100 lg/plate, did not show any substantial increasesin revertant colony numbers. It was concluded that the test mate-rial showed no evidence of mutagenic activity in these bacterialsystems (RIFM, 1985b).

4.9.1.2. Studies in mammalian cells. No information available.

4.9.2. In vivo studiesIn a CD-1 mouse micronucleus test, three groups of 10 animals

(5 males and 5 females per group) were given single doses of3,4,5,6,6-pentamethylheptan-2-ol in corn oil by intraperitonealinjection at 900 mg/kg and sacrificed at 30, 48, and 72 h. All groupsshowed significantly lower ratios of polychromatic erythrocytes tonormochromatic erythrocytes (PCE/NCE) suggesting the bioavail-ability of the test article. Statistically significant increases in theincidence of micronuclei of experimental animals were not ob-served. Based upon the inability of the test article to produce a sig-nificant increase in the incidence of micronuclei per 1000polychromatic erythrocytes in the treated versus the negative con-trol groups, 3,4,5,6,6-pentamethylheptan-2-ol was determined tobe negative in the micronucleus test (RIFM, 1985c).



This individual Fragrance Material Review is not intended as astand-alone document. Please refer to A Safety Assessment ofBranched Chain Saturated Alcohols When Used as Fragrance Ingre-

dients (Belsito et al., 2010) for an overall assessment of thismaterial.



References



EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, v 4.00 or Insert Version Used. United StatesEnvironmental Protection Agency, Washington, DC, USA.



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Irritation and Sensitization Hazards by Dermal Contact: Repeated Insult PatchTest with 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report fromInternational Flavors and Fragrances, 27 October. Report Number 48462,RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1984a. Acute Oral LD50Determination in the Rat on 3,4,5,6,6-Pentamethylheptan-2-ol. UnpublishedReport from International Flavors and Fragrances, Report Number 47552, RIFM,Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1984b. Primary DermalIrritation Test of 3,4,5,6,6-Pentamethylheptan-2-ol on the Rabbit. UnpublishedReport from International Flavors and Fragrances, Report Number 47792, RIFM,Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1984c. Acute Eye Irritation/Corrosion Test to the Rabbit of 3,4,5,6,6-Pentamethylheptan-2-ol. UnpublishedReport from International Flavors and Fragrances, Report Number 47677, RIFM,Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1985a. Acute DermalToxicity to the Rat of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Reportfrom International Flavors and Fragrances, Report Number 47587, RIFM,Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1985b. Microbial MetabolicActivation Test to Assess the Potential Mutagenic Effect of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from International Flavors andFragrances, Report Number 48164, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1985c. Micronucleus Test(MNT) OECD on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report fromInternational Flavors and Fragrances, Report Number 48252, RIFM, WoodcliffLake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1985d. Twenty-eight DayDermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.Unpublished Report from International Flavors and Fragrances, ReportNumber 47793, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1986. Twenty-eight DayDermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.Unpublished Report from International Flavors and Fragrances, ReportNumber 48027, RIFM, Woodcliff Lake, NJ, USA.

Table 3Summary of subchronic studies.

Method Dose(mg/kg/day)

Species Results References

Dermal application under occlusion 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1985d)Severe irritation; associated inflammation,hyperkeratosis, and scabbing

Dermal application under occlusion Up to 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1986)Slight to moderate dermal irritation; severeirritation at high doses; reversible after 8 days


Review

Fragrance material review on isodecyl alcohol




a b s t r a c t

A toxicologic and dermatologic review of isodecyl alcohol when used as a fragrance ingredient is pre-sented. Isodecyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.The common characteristic structural elements of the alcohols with saturated branched chain are onehydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains a detailed summary of all available toxicology and dermatology papers that are relatedto this individual fragrance ingredient and is not intended as a stand-alone document. A safety assess-ment of the entire branched chain saturated alcohol group will be published simultaneously with thisdocument; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this materialand all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S694.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69


Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of isodecyl alcohol whenused as a fragrance ingredient. Isodecyl alcohol (see Fig. 1; CAS

Number 25339-17-7) is a fragrance ingredient used in cosmetics,fine fragrances, shampoos, toilet soaps and other toiletries as wellas in non-cosmetic products such as household cleaners anddetergents.

In 2006, a complete literature search was conducted on isodecylalcohol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services [e.g. ToxCenter (whichin itself contains 18 databases including Chemical Abstracts)],







and the National Library of Medicine [e.g. Medline, Toxnet(which contains 14 databases)] as well as 26 additional sources(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrancecompanies were asked to submit all test data.


1. Identification

1.1. Synonyms: isodecanol; 8-methylnonan-1-ol.1.2. CAS Registry Number: 25339-17-7.1.3. EINECS Number: 246-869-1.1.4. Formula: C10H22O.1.5. Molecular weight: 158.85.



(25 �C).2.5. Log Kow (calculated; EPA, 2010): 3.71.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 0.0204 mm Hg;

2.72 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 151.8 mg/l (25 �C).

2.10. UV spectra not available at RIFM.

3. Usage

Isodecyl alcohol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of0.1–1.0 metric tons per annum (IFRA, 2004). The reported volumeof use is for isodecyl alcohol as used in fragrance compounds (mix-tures) in all finished consumer product categories. The volume ofuse is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies.As such the volume of use data from this survey provides volumeof use of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (seeTable 1) is calculated based on the concentrations of the same fra-grance ingredient in 10 types of the most frequently used personalcare and cosmetic products (anti-perspirant, bath products, bodylotion, eau de toilette, face cream, fragrance cream, hair spray,shampoo, shower gel, and toilet soap). The concentration of thefragrance ingredient in fine fragrances is obtained from examina-tion of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayfor each product type, and a ‘‘retention factor” (ranging from0.001 to 1.0) to account for the length of time a product may re-main on the skin and/or likelihood of the fragrance ingredientbeing removed by washing. The resultant calculation representsthe total consumer exposure (mg/kg/day) (Cadby et al., 2002; Fordet al., 2000).

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing isodecyl alcohol.



Total 0.00002


Fig. 1. Isodecyl alcohol.


This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been not been reported. As such the default valueof 0.02% is used to calculate the maximum daily exposure on theskin of 0.00002 mg/kg for high end users.

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has not been reported. Adefault value of 0.02% is used, assuming use of the fragrance oillevels up to 20% in the final product.

4. Toxicology data

4.1. Acute toxicity

4.1.1. Oral studiesThe acute oral LD50 of isodecyl alcohol in rats was reported to be

6.5 g/kg. No additional details available (Article in Japanese)(Nishimura et al., 1994).

4.1.2. Dermal studiesNo information available.














In a comparative developmental toxicity study, isodecyl alcoholwas administered by gavage to Wistar rats (10/group) at 0, 1, 5,

and 10 mmol/kg (0, 158, 790, and 1580 mg/kg/day) on gestationdays 6–15. Maternal toxicity and incidences of fetal retardationsand rare malformations were observed at 10 mmol/kg. Maternalmortality was 4/10 in this dose group. Body weight on days 15and 20, uterus weight, and fetal weights were all significantly low-er than controls in the 10 mmol/kg group. Post-implantation loss,resorptions, and number of fetuses with malformations were allhigher than controls at 10 mmol/kg. There was no maternal mor-tality in any of the other groups. Some maternal signs, but no fetalsigns were observed at 5 mmol/kg. The clinical signs included nasaldischarge, salivation, and signs of CNS depression. None of themeasured maternal or fetal parameters were significantly differentthan controls at this dose. The NOEL for maternal effects was1 mmol/kg and for fetal effects 5 mmol/kg (Hellwig and Jackh,1997).

4.9. Genotoxicity







References



EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows v 4.00 or Insert Version Used. United StatesEnvironmental Protection Agency, Washington, DC, USA.


Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain andfive branched-chain primary alcohols in rats. Food and Chemical Toxicology 35(5), 489–500.


2007.Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity

(LD50-value) of organic chemicals to mammals by solubility parameter (delta).1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese JournalIndustrial Health).


Review

Fragrance material review on isooctan-1-ol




a b s t r a c t

A toxicologic and dermatologic review of isooctan-1-ol when used as a fragrance ingredient is presented.Isooctan-1-ol is a member of the fragrance structural group branched chain saturated alcohols. The com-mon characteristic structural elements of the alcohols with saturated branched chain are one hydroxylgroup per molecule, and a C4–C12 carbon chain with one or several methyl side chains. This review con-tains a detailed summary of all available toxicology and dermatology papers that are related to this indi-vidual fragrance ingredient and is not intended as a stand-alone document. A safety assessment of theentire branched chain saturated alcohol group will be published simultaneously with this document;please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material and all otherbranched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S724.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S72


Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of isooctan-1-ol when usedas a fragrance ingredient. Isooctan-1-ol (see Fig. 1; CAS Number26952-21-6) is a fragrance ingredient used in cosmetics, fine fra-

grances, shampoos, toilet soaps and other toiletries as well as innon-cosmetic products such as household cleaners and detergents.

In 2006, a complete literature search was conducted on isooc-tan-1-ol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services [e.g. ToxCenter (whichin itself contains 18 databases including Chemical Abstracts)],and the National Library of Medicine [e.g. Medline, Toxnet (whichcontains 14 databases)] as well as 26 additional sources (e.g. BIO-SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companieswere asked to submit all test data.








1. Identification

1.1. Synonyms: isooctanol; 6-methylheptan-1-ol.1.2. CAS Registry Number: 26952-21-6.1.3. EINECS Number: 248-133-5.1.4. Formula: C8H18O.1.5. Molecular weight: 130.31.


2.1. Physical form: no information available.2.2. Boiling point (calculated; EPA, 2010): 188.52 �C.2.3. Flash point: no information available.2.4. Henry’s law (calculated; EPA, 2010): 0.000031 m3/mol

(25 �C).2.5. Log Kow (calculated; EPA, 2010): 2.73.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 0.151 mm Hg;

20.1 Pa (25 �C).

2.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 �C).2.10. UV spectra are not available at RIFM.

3. Usage

Isooctan-1-ol is a fragrance ingredient used in many fragrancecompounds. It may be found in fragrances used in decorative cos-metics, fine fragrances, shampoos, toilet soaps and other toiletriesas well as in non-cosmetic products such as household cleanersand detergents. Its use worldwide is in the region of less than0.01 metric tons per annum (IFRA, 2004). The reported volume ofuse is for isooctan-1-ol as used in fragrance compounds (mixtures)in all finished consumer product categories. The volume of use issurveyed by IFRA approximately every four years through a com-prehensive survey of IFRA and RIFM member companies. As suchthe volume of use data from this survey provides volume of useof fragrance ingredients for the majority of the fragrance industry.


This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has not been reported. As such the default value of0.02% is used to calculate the maximum daily exposure on the skinof 0.0005 mg/kg for high end users of these products (see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level that

Fig. 1. Isooctan-1-ol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing isooctan-1-ol.


Anti-perspirant 0.5 1 1 0.01 .02 0.000001Bath products 17 0.29 0.001 0.02 .02 0.000001Body lotion 8 0.71 1 0.004 .02 0.000100Eau de toilette 0.75 1 1 0.08 .02 0.000200Face cream 0.8 2 1 0.003 .02 0.000001Fragrance cream 5 0.29 1 0.04 .02 0.000200Hair spray 5 2 0.01 0.005 .02 0.000001Shampoo 8 1 0.01 0.005 .02 0.000001Shower gel 5 1.07 0.01 0.012 .02 0.000001Toilet soap 0.8 6 0.01 0.015 .02 0.000001

Total 0.0005



results from the use of isooctan-1-ol in formulae that go into finefragrances has been not been reported. A default value of 0.02%is used assuming use of the fragrance oils at levels up to 20% inthe final product.

4. Toxicology data

4.1. Acute toxicity

4.1.1. Oral studiesNo information available.


4.1.3. Inhalation studiesThere was no mortality, clinical signs, or autopsy findings when

three female Alderly-Park rats were exposed in whole body expo-sure chambers. Animals were exposed for up to 6 h a day, 5 days aweeks (a total of 13 over 4 weeks) to saturated vapor of a mixtureof branched chain alcohols designated isooctan-1-ol, with a boilingpoint of 185–189 �C. Concentration was 1 mg/l or 188 ppm (Gage,1970).















4.9. Genotoxicity







References





Gage, J.C., 1970. The subacute inhalation toxicity of 109 industrial chemicals. BritishJournal of Industrial Medicine 27, 1–18.


2007.


Review

Fragrance material review on isotridecan-1-ol (isomeric mixture)

D. McGinty *, S.P. Bhatia, J. Scognamiglio, C.S. Letizia, A.M. ApiResearch Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA



a b s t r a c t

A toxicologic and dermatologic review of isotridecan-1-ol (isomeric mixture) when used as a fragranceingredient is presented. Isotridecan-1-ol (isomeric mixture) is a member of the fragrance structural groupbranched chain saturated alcohols. The common characteristic structural elements of the alcohols withsaturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one orseveral methyl side chains. This review contains a detailed summary of all available toxicology and der-matology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will be pub-lished simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessmentof the safe use of this material and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S754.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S754.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S754.1.3. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S754.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75


4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S764.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S764.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S764.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S764.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S764.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S774.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77



Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of isotridecan-1-ol (isomeric







mixture) when used as a fragrance ingredient. Isotridecan-1-ol (seeFig. 1; CAS Number 27458-92-0) is a fragrance ingredient used incosmetics, fine fragrances, shampoos, toilet soaps and other toilet-ries as well as in non-cosmetic products such as household clean-ers and detergents. This material has been reported to occur innature within beef (VCF, 2009).

In 2006, a complete literature search was conducted on Isotrid-ecan-1-ol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services, [e.g., ToxCenter (whichin itself contains 18 databases including Chemical Abstracts)], andthe National Library of Medicine [e.g., Medline, Toxnet (which con-tains 14 databases)] as well as 26 additional sources (e.g., BIOSIS,Embase, RTECS, OSHA, ESIS). In addition, fragrance companies wereasked to submit all test data.


1. Identification

1.1 Synonyms: Isotridecanol; 11-methyldodecan-1-ol1.2 CAS registry number: 27458-92-01.3 EINECS number: 248-469-21.4 Formula: C13H28O1.5 Molecular weight: 200.66


2.1 Physical form: no information available2.2 Boiling point (calculated; EPA, 2010): 279.35 �C2.3 Flash point: no information available2.4 Henry’s law (calculated; EPA, 2010): 0.000128 atm m3/mol


0.0615 Pa (25 �C)2.9 Water solubility (calculated; EPA, 2010): 5.237 mg/l at 25�

2.10 UV spectra available at RIFM. Does not absorb UV light.

3. Usage

Isotridecan-1-ol (isomeric mixture) is a fragrance ingredientused in many fragrance compounds. It may be found in fragrancesused in decorative cosmetics, fine fragrances, shampoos, toiletsoaps and other toiletries as well as in non-cosmetic products suchas household cleaners and detergents. Its use worldwide is in theregion of 10–100 metric tons per annum (IFRA, 2004). The reportedvolume of use is for isotridecan-1-ol as used in fragrance com-pounds (mixtures) in all finished consumer product categories.The volume of use is surveyed by IFRA approximately every fouryears through a comprehensive survey of IFRA and RIFM membercompanies. As such the volume of use data from this survey pro-vides volume of use of fragrance ingredients for the majority ofthe fragrance industry.

The dermal systemic exposure in cosmetic products (seeTable 1) is calculated based on the concentrations of the same fra-grance ingredient in ten types of the most frequently used personalcare and cosmetic products (anti-perspirant, bath products, bodylotion, eau de toilette, face cream, fragrance cream, hair spray,shampoo, shower gel, and toilet soap). The concentration of thefragrance ingredient in fine fragrances is obtained from examina-tion of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10Fig. 1. Isotridecan-1-ol (isomeric mixture).

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing isotridecan-1-ol (isomeric mixture).





consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayfor each product type, and a ‘‘retention factor” (ranging from0.001 to 1.0) to account for the length of time a product may re-main on the skin and/or likelihood of the fragrance ingredientbeing removed by washing. The resultant calculation representsthe total consumer exposure (mg/kg/day) (Cadby et al., 2002; Fordet al., 2000).



4. Toxicology data


4.1.1. Oral studiesThe acute oral LD50 of isotridecan-1-ol (1-tridecanol: mixed pri-

mary isomers) in male rats (n = 5) was reported to be 17.2 (12.3–23.9) ml/kg (�17.2; 12.3–23.6 g/kg). No additional details were re-ported (Smyth et al., 1962; Nishimura et al., 1994).

Scala and Burtis (1973) reported an LD50 for isotridecan-1-ol (1-tridecanol: mixed primary isomers) of 4.75 g/kg in Sprague–Daw-ley rats (five/dose). The principal clinical signs were central ner-vous system depression and labored respiration. The depressionincluded inactivity, ataxia, limb sprawling, depressed rightingand placement reflexes, prostration, and coma. The intensity ofthe signs was related to dose. The signs of effect had an early onset,and recovery was complete by the second or third day. Wheredeaths occurred, they were seen as late as 4 days.

The LD50 of isotridecan-1-ol in Wistar rats was found to begreater than 2 g/kg body weight for male and female rats. Singlegavage doses of 2.0 g/kg body weight of isotridecan-1-ol in oliveoil were given to six (three/sex/group) fasted animals. No mortalityoccurred in the 2 g/kg groups. Piloerection was the only clinicalsign observed, in males, 5 h after administration. No clinical signsand findings were observed in the females of the 2 g/kg adminis-tration group. The mean body weights of the administration groupsincreased throughout the study period. No macroscopic pathologic

abnormalities were observed. This study was based on the OECD,EU and US EPA OPPTS guidelines (RIFM, 2002a).

Greim (2000) reported acute oral an LD50 value of isotridecan-1-ol (isomeric mixture: 50% branched, 50% linear form) as greaterthan 2.0 g/kg in rats (further information not obtained, ECB, 1995).

The acute oral LD50 in mice with 30% isotridecan-1-ol (isomericmixture) as an aqueous emulsion with tragacanth gum was re-ported to be >6.5 ml (�6.5 g/kg) body weight. Observations weremade for 7 days. The clinical signs noted were staggering, acceler-ated respiration, tremors, and slow recovery. The mortalities weresporadic and late (RIFM, 1963a).

Greim (2000) reported acute oral an LD50 value of isotridecan-1-ol (isomeric mixture) as 7.257 g/kg in mice (further informationnot obtained, ECB, 1995; Hoechst, 1961a).

4.1.2. Dermal studiesThe acute dermal LD50 of isotridecan-1-ol (Tridecanol: mixed

primary isomers) in male rabbits (n = 4) was reported to be 7.07(2.33–21.4) ml/kg (�7.07; 2.33–24.4 g/kg). Contact time was 24 hand observation time was 14 days. No additional details were re-ported (Smyth et al., 1962).

The dermal LD50 for isotridecan-1-ol (Tridecanol: mixed pri-mary isomers) applied occlusively for 24 h to rabbits (four/dose)was reported to be >2.6 g/kg. There were no clinical signs indica-tive of systemic effects at the highest level tested. Dermal irritationwas dose dependent (Scala and Burtis, 1973).

4.1.3. Intraperitoneal studiesThe intraperitoneal LD50 of mice with 8% isotridecan-1-ol

(mixed isomers) as an aqueous emulsion with tragacanth gumwas reported to be about 0.6 ml/kg body weight (�0.6 g/kg).Observations included staggering, accelerated respiration, tremors,and slow recovery. Mortalities were sporadic and late. Necropsyfindings included adhesions in the abdominal cavity (RIFM, 1963b).

4.1.4. Inhalation studiesThe study of the acute inhalation hazard of isotridecan-1-ol

(isomeric mixture) in rats resulted in no deaths (0/12) and noabnormalities. Animals were exposed for 8 h to atmosphere satu-rated with vapor at 20 �C (room temperature). For saturation, airwas conducted through a layer of about 5 cm of the product (RIFM,1963c; Smyth et al., 1962).

No deaths were reported when 10 rats, mice, and guinea pigswere exposed by whole body inhalation for 6 h to air bubbledthrough isotridecan-1-ol (mixed isomers) to yield a nominal cham-ber concentration of 12 ppm (12 ml/m3) at 30 �C. Clinical signsindicated moderate local irritation and slight to moderate systemiceffects. Local irritation involved the mucous membranes of theeyes, nose, throat, and respiratory passages and was manifest asblinking, lacrimation, preening, nasal discharge, salivation, gasp-ing, and chewing movements. Responses were temporary and allanimals had recovered within 1 h after termination of exposure.


Route Species No. animals/dose group LD50 (g/kg) References

Oral Rat 5 17.2 Smyth et al., 1962; Nishimura, 1994Oral Rat 5 4.75 Scala and Burtis, 1973Oral Rat 3 >2.0 RIFM, 2002aOral Rat N/A >2.0 ECB, 1995 as cited in Greim, 2000Oral Mouse N/A 6.5 RIFM, 1963aOral Mouse N/A 7.257 ECB, 1995; Hoechst, 1961a; as cited in Greim, 2000Dermal Rabbit 4 7.07 Smyth et al., 1962Dermal Rabbit 4 >2.6 Scala and Burtis, 1973Intraperitoneal Mouse N/A 0.6 RIFM, 1963b


Gross necropsy findings were normal in appearance (Scala andBurtis, 1973).


4.2.1. Human studiesIn an in vitro human study it was concluded that isotridecan-1-

ol (mixed isomers) does not show a corrosive potential in the Epi-Derm™ skin corrosivity test (RIFM, 2003a).

4.2.2. Animal studies (see Table 3)Isotridecan-1-ol (mixed isomers) was applied ‘‘at full-strength”

to the closely clipped, intact abdominal skin of albino rabbits (four/group). The exposed area was then covered with an occlusive patchfor 24 h. Doses of 0.10, 0.316, 1.0, or 3.16 ml/kg were administeredvolumetrically and observations for signs of toxicity were madeonce daily for 7 days. Moderate irritation was observed (Scalaand Burtis, 1973).

A primary skin irritation evaluation was done on the clippedskin (uncovered) of five albino rabbits with undiluted isotridec-an-1-ol (mixed isomers) and resulted in grade 4 (moderate) irrita-tion (Smyth et al., 1962).

Undiluted isotridecan-1-ol (mixed isomers) produced irritationwhen administered percutaneously to the intact dorsal and earskin of rabbits. The time of exposure on the dorsal skin was 1, 5,15, and 20 h, and 20 h for the ears. The skin was checked after24 h and after 8 days. After 20 h of exposure, the dorsal skin re-sulted in severe erythema and distinct edema when observed at24 h, then distinct scarring and severe scaling at 8 days. Whenthe dorsal skin was exposed for 1, 5, or 15 h severe erythemawas observed at 24 h, then scaling at 8 days. Exposure of 20 h tothe ear resulted in severe erythema at 24 h and severe erythemaand scaring at 8 days (RIFM, 1963d,e).

In order to assess the acute skin irritation potential of isotridec-anol-1-ol in White New Zealand rabbits a dermal irritation/corro-sion test was performed according to the method described inOECD guideline 404. A 0.5 ml sample of the isotridecanol-1-olwas applied for 4 h to the intact skin of three rabbits, using a patchof 2.5 cm � 2.5 cm, covered with semi-occlusive dressing. After re-moval of the patch the application area was washed off. The skinreactions were assessed immediately after removal of the patch,approximately 1, 24, 48 and 72 h after removal and then winweekly intervals until day 14. Slight to marked erythema, slightor moderate edema and scaling were observed in almost all ani-mals during the course of the study. Additionally the describedfindings above were partly extended beyond the area of exposure.Moreover severe scaling and petechiae, both extending beyond thearea of exposure and thickening of the skin in the regions of theapplication area were noted in a single animal. The cutaneous reac-tions (such as slight erythema) were not reversible in all animalswithin study termination of day 14. The average score (24 to72 h) for irritation was calculated to be 3.0 for erythema and 0.3for edema (RIFM, 2003b).


An eye irritation test was conducted in three White New Zea-land rabbits subjected to a single dose ocular application of0.1 ml of undiluted isotridecan-1-ol (mixed isomers). The ocularreactions were assessed approximately 1, 24, 48, 72 h and 7 daysafter application. Slight to moderate conjunctival redness, slightconjunctival chemosis and moderate to severe discharge were ob-served during the course of the study. In addition in one animalslight corneal opacity and loss of corneal tissue was noted duringthe observation period (RIFM, 2002b).

An eye irritation test was conducted in rabbits. Undiluted iso-tridecan-1-ol (mixed isomers) was applied (1 � 50 mm3 or50 mg) to the conjunctival sac of the eyelid. The findings after1 h included slight redness. The findings after 24 h and 8 days werenonirritating. No further information (RIFM, 1963d; RIFM, 1963f).

Application of to the eyes isotridecan-1-ol (mixed isomers) ofrabbits produced irritation grade 2 on a ten-grade scale with Grade1 a very small area of necrosis from 0.5 ml of an undiluted chem-ical in the eye and Grade 5 representing a severe burn from0.005 ml (Smyth et al., 1962).

Six rabbits were given single 0.1 ml application of isotridecan-1-ol (mixed isomers) undiluted. Observations were made after 1,4, and 24 h, 2, 3, 4, and 7 days. Moderate irritation was observed(Scala and Burtis, 1973).


No data available.


No data available.


No data available.


Isotridecan-1-ol (isomeric mixture) in polyethylene glycol wasgiven to Alderley Park Wistar-derived rats, five rats treated and10 controls, by gavage for 14 days. At 1 mmol/kg body weight/


Method Dose(%)

Species Reactions References

Single occlusive patch for 24 h to intact skin offour rabbits

100 Rabbits Moderately irritating Scala and Burtis,1973

Single uncovered application of 0.01 ml for 24 h 100 Rabbits Moderately irritating Smyth et al., 1962Percutaneously to the intact dorsal skin for 20 h 100 Rabbits Severe erythema and distinct edema at 24 h. Distinct scarring and severe

scaling at 8 daysRIFM, 1963e

4-h semi-occlusive irritation 100 Rabbits Slight to marked erythema, slight or moderate edema and scaling RIFM, 2003b


Dose(%)

Reactions References

100 Irritation was observed. In one animal slightcorneal opacity and loss of corneal tissue

RIFM, 2002b

100 Slight irritation RIFM, 1963f100 Small area of necrosis on the eye Smyth et al., 1962100 Moderately irritating Scala and

Burtis, 1973


day (200 mg/kg body weight/day) the liver weight was unaffected,no hepatomegaly, peroxisome proliferation, hypolipidemia, or tes-ticular atrophy was observed (Rhodes et al., 1984).


Isotridecan-1-ol (isomeric mixture) was tested for its prenataldevelopmental toxicity in 25 mated female Wistar rats as a solu-tion in olive oil. Gavage administration of 0, 60, 250, or 750 mg/kg body weight were given on days 6 through day 19 post coitum(p.c.). A standard dose volume of 5 ml/kg body weight was used foreach group. Food consumption and body weights of the animalswere recorded regularly throughout the study period. On day 20p.c., blood was taken from all females, then sacrificed and assessedby gross pathology (including weight determinations of the uno-pened uterus, the liver, the kidneys, the spleen and the placentae).For each dam, corpora lutea were counted and number and distri-bution of implantation sites (differentiated as resorptions, live anddead fetuses) were determined. The fetuses were removed fromthe uterus, sexed, weighed and further investigated for any exter-nal findings soft tissue and skeletal findings. In the 750 mg/kg bodyweight/day dose: transient salivation was noted in all rats betweentreatment days 7–19 p.c.; urine-smeared fur in 4 females on gesta-tion days 10–13 and 17–20 p.c.; statistically significant reductionof food consumption on days 6–10 p.c. (up to about 11% belowthe corresponding control value); statistically significant increasedalanine aminotransferase values; statistically significant increasedtriglycerides and relative liver weights (about 14% or 18%, respec-tively above control values) were noted; statistically significant de-creased total protein and globulin concentrations; no substance-related effects on gestational parameters or fetuses. Substance re-lated findings in the 250 mg/kg body weight/day group included:transient salivation in 17/25 rats immediately after gavaging be-tween treatment days 12–19 p.c.; no substance-related effects ongestational parameters or fetuses were noted. No substance-re-lated effects on dams, gestational parameters or fetuses werenoted the 60 mg/kg body weight/day group.

Under the conditions of this prenatal developmental toxicitystudy, the oral administration of isotridecan-1-ol (isomeric mix-ture) to pregnant Wistar rats from implantation to one day priorto the expected day of parturition (days 6–19 p.c.) elicited somesigns of maternal toxicity at 750 mg/kg body weight/day. Placentaland fetal body weights, the external, soft tissue and/or skeletal(including cartilage) examinations of the fetuses revealed no bio-logically relevant differences between the control and the sub-stance-treated groups. Based on these results, the no observedadverse effect level (NOAEL) for maternal toxicity is 250 mg/kgbody weight/day, while it is 750 mg/kg body weight/day for prena-tal developmental toxicity (RIFM, 2003c).

4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems. Isotridecan-1-ol (isomeric mixture)in DMSO was tested for mutagenicity in the Ames test (Ameset al., 1975) (standard plate test and preincubation test) at dosesup to 5000 lg/plate both in the presence and absence of a metab-olizing system obtained from rat liver (S-9 mix) using Salmonellatyphimurium strains TA1537, TA 1535, TA100, and TA98. No muta-genicity was observed (RIFM, 1989).

4.9.1.2. Studies in mammalian cells. No data available.

4.9.2. In vivo studiesNo data available.


No data available.




References

Ames, B.N., McCann, J., Yamasaki, E., 1975. Methods for detecting carcinogens andmutagens with the salmonella/mammalian-mincrosome mutagenicity test.Mutation Research 31, 347–363.

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologicassessment of Alcohols Branched Chain Saturated when used as fragranceingredients. Food and Chemical Toxicology 48 (S4), S1–S46.




Greim, H. (ed.), 2000. iso-Tridecanol (Isomerengemisch verzweigter primärer C10-C14-Alkohole). Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, 30. Lieferung, Wiley-VCH, Weinheim.


2007.Nishimura, H., Saito, S., Kishida, F.,Matsuo, M., 1994. Analysis of acute toxicity

(LD50-value) of organic chemicals to mammals by solubility parameter (delta).1. Acute oral toxicity to rats. Sangyo Igaku, 36(5), 314–323 (Japanese JournalIndustrial Health).

Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,1984. The absence of testicular atrophy & in vivo & in vitro effects onhepatocyte morphology and peroxisomal enzyme activities in male ratsfollowing the administration of several alkanols. Toxicology Letters 21, 103–109.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963a. Report on the studyof the acute oral toxicity of isotridecan-1-ol in mice. Unpublished report fromBASF, Report number 55417, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963b. Report on the studyof the acute intraperitoneal toxicity of isotridecan-1-ol in mice. Unpublishedreport from BASF, Report number 55414, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963c. Report on the studyof the acute inhalation hazard of isotridecan-1-ol in rats (inhalation hazardtest). Unpublished report from BASF, Report number 55415, RIFM, WoodcliffLake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963d. Results of theanalytical toxicology tests with isotridecan-1-ol. Unpublished report from BASF,Report number 55424, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963e. Report on the studyof the primary irritation/corrosion of isotridecan-1-ol to the intact skin ofrabbits. Unpublished report from BASF, Report number 55426, RIFM, WoodcliffLake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1963f. Report on the study ofthe primary irritation of isotridecan-1-ol to the eye of rabbits. Unpublishedreport from BASF, Report number 55431, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1989. Report on the study ofIsotridecan-1-ol in the AMES test. Unpublished report from BASF, Reportnumber 55420, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 2002a. Isotridecan-1-ol:Acute oral toxicity study in Wistar rats. Unpublished report from BASF, Reportnumber 55416, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 2002b. Isotridecan-1-ol:Acute eye irritation in rabbits. Unpublished report from BASF, Report number55430, RIFM, Woodcliff Lake, NJ, USA.


RIFM (Research Institute for Fragrance Materials, Inc.), 2003a Isotridecan-1-ol:EpiDerm skin corrosivity test. Unpublished report from BASF, Report number55423, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 2003b. Isotridecan-1-ol:Acute dermal irritation/corrosion in rabbits. Unpublished report from BASF,Report number 55427, RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 2003c. Isotridecan-1-ol:prenatal developmental toxicity study in Wistar rats by oral administration(gavage). Unpublished report from BASF, Report number 55432, RIFM,Woodcliff Lake, NJ, USA.

Scala, R.A., Burtis, E.G., 1973. Acute toxicity of a homologous series of branched-chain primary alcohols. American Industrial Hygiene Association Journal(AIHAJ) 34 (11), 493–499.

Smyth, F., Carpenter, C.P., Weil, M.A., Pozzani, U.C., Striegel, J.A., 1962. Range-findingtoxicity data: List VI. Industrial Hygiene Association Journal 23, 95–107.

VCF (Volatile Compounds in Food): database. In: Nijssen, L.M.; Ingen-Visscher, C.A.van; Donders, J.J.H. (Eds), – Version 11.1.1 – TNO Quality of Life, Zeist, TheNetherlands, 1963–2009.


Review

Fragrance material review on isononyl alcohol




a b s t r a c t

A toxicologic and dermatologic review of isononyl alcohol when used as a fragrance ingredient is pre-sented. Isononyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.The common characteristic structural elements of the alcohols with saturated branched chain are onehydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains a detailed summary of all available toxicology and dermatology papers that are relatedto this individual fragrance ingredient and is not intended as a stand-alone document. A safety assess-ment of the entire branched chain saturated alcohol group will be published simultaneously with thisdocument; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this materialand all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.6. Absorption, distribution, and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S814.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81


Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of isononyl alcohol when usedas a fragrance ingredient. Isononyl alcohol (see Fig. 1; CAS Number27458-94-2) is a fragrance ingredient used in cosmetics, fine fra-grances, shampoos, toilet soaps and other toiletries as well as innon-cosmetic products such as household cleaners and detergents.

In 2006, a complete literature search was conducted on isono-nyl alcohol. On-line toxicological databases were searched includ-ing those from the Chemical Abstract Services [e.g., ToxCenter(which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g., Medline, Tox-net (which contains 14 databases)] as well as 26 additional sources(e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrancecompanies were asked to submit all test data.

The safety data on this material has never been reviewed beforeby RIFM (Research Institute for Fragrance Materials, Inc.). All rele-vant references are included in this document. More details have







been provided for unpublished data. The number of animals, sexand strain are always provided unless they are not given in the ori-ginal report or paper. Any papers in which the vehicles and/or thedoses are not given have not been included in this review. In addi-tion, diagnostic patch test data with fewer than 100 consecutivepatients have been omitted.

1. Identification

1.1 Synonyms: isononanol; 7-methyloctan-1-ol1.2 CAS registry number: 27458-94-21.3 EINECS number: 248-471-31.4 Formula: C9H20O1.5 Molecular weight: 144.58


2.1 Physical form: no information available2.2 Boiling point (calculated; EPA, 2010): 208.492.3 Flash point: no information available2.4 Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol


2.63 Pa (25 �C)2.9 Water solubility (calculated; EPA, 2010): 459.7 mg/l (25 �C)

2.10 UV spectra not available at RIFM

3. Usage

Isononyl alcohol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of 1–10 metric tons per annum (IFRA, 2004). The reported volume ofuse is for isononyl alcohol as used in fragrance compounds (mix-tures) in all finished consumer product categories. The volume ofuse is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies.As such the volume of use data from this survey provides volumeof use of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (seeTable 1) is calculated based on the concentrations of the same fra-grance ingredient in ten types of the most frequently used personalcare and cosmetic products (anti-perspirant, bath products, bodylotion, eau de toilette, face cream, fragrance cream, hair spray,shampoo, shower gel, and toilet soap). The concentration of thefragrance ingredient in fine fragrances is obtained from examina-tion of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayfor each product type, and a ‘‘retention factor” (ranging from0.001 to 1.0) to account for the length of time a product may re-main on the skin and/or likelihood of the fragrance ingredientbeing removed by washing. The resultant calculation representsthe total consumer exposure (mg/kg/day) (Cadby et al., 2002; Fordet al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been reported to be 4.46% (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.1137 mg/kg for high end users.

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing isononyl alcohol.


Anti-perspirant 0.5 1 1 0.01 4.46 0.0037Bath products 17 0.29 0.001 0.02 4.46 0.0001Body lotion 8 0.71 1 0.004 4.46 0.0169Eau de toilette 0.75 1 1 0.08 4.46 0.0446Face cream 0.8 2 1 0.003 4.46 0.0036Fragrance cream 5 0.29 1 0.04 4.46 0.0431Hair spray 5 2 0.01 0.005 4.46 0.0004Shampoo 8 1 0.01 0.005 4.46 0.0003shower gel 5 1.07 0.01 0.012 4.46 0.0005Toilet soap 0.8 6 0.01 0.015 4.46 0.0005Total 0.1136


Fig. 1. Isononyl alcohol.


0.30% (IFRA, 2007), assuming use of the fragrance oil at levels up to20% of the final product.

4. Toxicology data

4.1. Acute toxicity










4.6. Absorption, distribution, and metabolism





In a comparative developmental toxicity (OECD TG 414) twodifferent isomeric mixes of isononyl alcohol were administeredby gavage to Wistar rats (10 per group) at 144, 720, 1080, and1440 mg/kg/d (0, 1, 5, 7.5, and 10 mmol/kg/d) on gestation days6–15. The 1080 mg/kg group was a supplemental group with sup-plemental control due to high maternal mortality at 1440 mg/kg/din the original study. Both types of isononyl alcohols exhibited amarked degree of maternal and fetal toxicity at 1080, and1440 mg/kg/d and slight effects at 720 mg/kg. Maternal mortalitywas 10/10 for mixture 1 and 3/10 for mixture 2 at 1440 mg/kg/d.Fetal observations for the 1080 mg/kg groups showed increasesin resorptions, post-implantation loss, and the number/percent offetuses/litters with malformations or retardations. At 720 mg/kg,

the maternal clinical signs included reduced body weight gain,apathy, and nasal discharge. Fetal observations included an in-creased number of skeletal variations and delayed ossifications.There were no significant differences from control at 144 mg/kgin either maternal or fetal parameters (Hellwig and Jackh, 1997,and EPA, 1991).

4.9. Genotoxicity



No available information.This individual Fragrance Material Review is not intended as a

stand-alone document. Please refer to A Toxicologic and Dermato-logic Assessment of Alcohols Branched Chain Saturated When Usedas Fragrance Ingredients (Belsito et al., 2010) for an overall assess-ment of this material.



References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologicassessment of alcohols branched chain saturated when used as fragranceingredients. Food and Chemical Toxicology 48 (S4), S1–S46.


EPA (Environmental Protection Agency), 1991. Study of the prenatal toxicity ofisononylalcohol 1 and isononylalcohol 2 in rats after oral administration(gavage). Unpublished report. Report number 34403 (RIFM, Woodcliff Lake, NJ,USA).

EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, v 4.00 or insert version used]. United StatesEnvironmental Protection Agency, Washington, DC, USA.




2007.


Review

Fragrance material review on 6,8-dimethylnonan-2-ol




a b s t r a c t

A toxicologic and dermatologic review of 6,8-dimethylnonan-2-ol when used as a fragrance ingredient ispresented. 6,8-Dimethylnonan-2-ol is a member of the fragrance structural group branched chain satu-rated alcohols. The common characteristic structural elements of the alcohols with saturated branchedchain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl sidechains. This review contains the information available on this individual fragrance ingredient and isnot intended as a stand-alone document. A safety assessment of the entire branched chain saturated alco-hol group will be published simultaneously with this document; please refer to Belsito et al. (2010) for anoverall assessment of the safe use of this material and all other branched chain saturated alcohols infragrances.


Contents


Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S83References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S84

Introduction

This document provides a summary of the toxicologic review,all human health endpoints, of 6,8-dimethylnonan-2-ol when usedas a fragrance ingredient. 6,8-Dimethylnonan-2-ol (see Fig. 1; CASNumber 70214-77-6) is a fragrance ingredient used in cosmetics,fine fragrances, shampoos, toilet soaps and other toiletries as wellas in non-cosmetic products such as household cleaners anddetergents.

In 2006, a complete literature search was conducted on 6,8-dimethylnonan-2-ol. On-line toxicological databases weresearched including those from the Chemical Abstract Services[e.g. ToxCenter (which in itself contains 18 databases includingChemical Abstracts], and the National Library of Medicine [e.g.Medline, Toxnet (which contains 14 databases)] as well as 26 addi-

tional sources (e.g. BIOSIS, Embase, RTECS, OSHA and ESIS). In addi-tion, fragrance companies were asked to submit all test data.

The safety data on this material has never been reviewed beforeby RIFM (Research Institute for Fragrance Materials Inc.). All rele-vant references are included in this document. More details havebeen provided for unpublished data. The number of animals, sexand strain are always provided unless they are not given in the ori-ginal report or paper. Any papers in which the vehicles and/or thedoses are not given have not been included in this review. In addi-tion, diagnostic patch test data with fewer than 100 consecutivepatients have been omitted.

1. Identification

1.1. Synonyms: 2-Nonanol, 6,8-dimethyl-; Nonadyl.1.2. CAS Registry number: 70214-77-6.1.3. EINECS number: 274-447-7.1.4. Formula: C11H24O.1.5. Molecular weight: 172.12.


* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.E-mail address: [email protected] (D. McGinty).






2.1. Physical form: no information available.2.2. Boiling point (calculated; EPA, 2010): 217.59.2.3. Flash point: no information available.2.4. Henry’s law (calculated; EPA, 2010): 0.0000726 atm m3/

mole.2.5. Log Kow (calculated; EPA, 2010): 4.06.2.6. Refractive index: no information available.2.7. Specific gravity: 0.827 g/ml at 20 �C.2.8. Vapor pressure (calculated; EPA, 2010): 0.0252 mm Hg;

3.36 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): no information

available.2.10. UV spectra available at RIFM, peaks at 200–210 nm and

returns to baseline 230–240 nm. Minor absorption from260 to 320 nm.

3. Usage

6,8-Dimethylnonan-2-ol is a fragrance ingredient used in manyfragrance compounds. It may be found in fragrances used in deco-rative cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of 1–10 metric tons per annum (IFRA, 2004). The reported volume ofuse is for 6,8-dimethylnonan-2-ol as used in fragrance compounds(mixtures) in all finished consumer product categories. The volumeof use is surveyed by IFRA approximately every 4 years through acomprehensive survey of IFRA and RIFM member companies. Assuch the volume of use data from this survey provides volume ofuse of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (seeTable 1) is calculated based on the concentrations of the samefragrance ingredient in 10 types of the most frequently usedpersonal care and cosmetic products (anti-perspirant, bath prod-ucts, body lotion, eau de toilette, face cream, fragrance cream, hairspray, shampoo, shower gel and toilet soap). The concentration ofthe fragrance ingredient in fine fragrances is obtained from exam-

ination of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayfor each product type, and a ‘‘retention factor” (ranging from0.001 to 1.0) to account for the length of time a product may re-main on the skin and/or likelihood of the fragrance ingredientbeing removed by washing. The resultant calculation representsthe total consumer exposure (mg/kg/day) (Cadby et al., 2002; Fordet al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al. 2002, Ford et al.2000). The 97.5% percentile use level in formulae for use in cosmet-ics in general has been reported to be 0.5% (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.0012 mg/kg for high end users (see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be0.009% (IFRA, 2007), assuming use of the fragrance oil at levelsup to 20% in the final product.

4. Toxicology data


This individual Fragrance Material Review is not intended as astand-alone document. Please refer to A Safety Assessment ofBranched Chain Saturated Alcohols When Used as Fragrance Ingre-dients Belsito et al. (2010) for an overall assessment of thismaterial.



Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 6,8-dimethylnonan-2-ol.



Total 0.0012


OH

Fig. 1. 6,8-Dimethylnonan-2-ol.


References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologicassessment of Alcohols Branched Chain Saturated when used as fragranceingredients. Food and Chemical Toxicology 48 (S4), S1–S46.





2007.


Review

Fragrance material review on 2-ethyl-1-butanol

D. McGinty *, C.S. Letizia, A.M. ApiResearch Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA



a b s t r a c t

A toxicologic and dermatologic review of 2-ethyl-1-butanol when used as a fragrance ingredient is pre-sented. 2-Ethyl-1-butanol is a member of the fragrance structural group branched chain saturated alco-hols. The common characteristic structural elements of the alcohols with saturated branched chain areone hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains a detailed summary of all available toxicology and dermatology papers that are related tothis individual fragrance ingredient and is not intended as a stand-alone document. A safety assessmentof the entire branched chain saturated alcohol group will be published simultaneously with this docu-ment; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material andall other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.1.4. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87


4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.4. Skin densitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S874.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87










Introduction

This document provides a comprehensive summary of the tox-icologic review of 2-ethyl-1-butanol when used as a fragranceingredient including all human health endpoints. 2-Ethyl-1-buta-nol (see Fig. 1; CAS Number 97-95-0) is a fragrance ingredient usedin cosmetics, fine fragrances, shampoos, toilet soaps and other toi-letries as well as in non-cosmetic products such as householdcleaners and detergents. This material has been reported to occurin nature, with highest quantities observed in mushrooms (VCF,2009).

In 2006, a complete literature search was conducted on isoamylalcohol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services [e.g. ToxCenter [whichin itself contains 18 databases including Chemical Abstracts)] andthe National Library of Medicine [e.g. Medline, Toxnet (which con-tains 14 databases)] as well as 26 additional sources (e.g. BIOSIS,Embase, RTECS, OSHA, ESIS). In addition, fragrance companies wereasked to submit all test data.


1. Identification

1.1. Synonyms: 1-butanol, 2-ethyl-, 2-ethylbutyl alcohol, 2-eth-ylbutan-1-ol.

1.2. CAS Registry Number: 97-95-0.1.3. EINECS Number: 202-621-4.

1.4. Formula: C6H14O.1.5. Molecular weight: 102.18.1.6. Council of Europe (2000): 2-ethyl-1-butanol was included

by the Council of Europe in the list of substances granted B– information required – 28 day oral study (COE No. 543).



25 �C.2.5. Log Kow (calculated; EPA, 2010): 1.75.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 1.0 mm Hg (20 �C);

1.6 mm Hg (25 �C); 213 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 �C).

2.10. UV spectra not available at RIFM.

3. Usage

2-Ethyl-1-butanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of lessthan 0.01 metric tons per annum (IFRA, 2004). The reported vol-ume of use is for 2-ethyl-1-butanol as used in fragrance com-pounds (mixtures) in all finished consumer product categories.The volume of use is surveyed by IFRA approximately every fouryears through a comprehensive survey of IFRA and RIFM membercompanies. As such the volume of use data from this survey pro-vides volume of use of fragrance ingredients for the majority ofthe fragrance industry.

The dermal systemic exposure in cosmetic products (see Ta-ble 1) is calculated based on the concentrations of the same fra-grance ingredient in 10 types of the most frequently usedpersonal care and cosmetic products (anti-perspirant, bath prod-ucts, body lotion, eau de toilette, face cream, fragrance cream, hairspray, shampoo, shower gel, and toilet soap). The concentration ofthe fragrance ingredient in fine fragrances is obtained from exam-ination of several thousand commercial formulations. The upper97.5 percentile concentration is calculated from the data obtained.This upper 97.5 percentile concentration is then used for all 10consumer products. These concentrations are multiplied by theamount of product applied, the number of applications per dayFig. 1. 2-Ethyl-1-butanol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-butanol.

Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredientb (mg/kg/day)




for each product type, and a ‘‘retention factor” (ranging from 0.001to 1.0) to account for the length of time a product may remain onthe skin and/or likelihood of the fragrance ingredient being re-moved by washing. The resultant calculation represents the totalconsumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al.,2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al. 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,2007), which would result in a maximum daily exposure on theskin of 0.0005 mg/kg for high end users (see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level that re-sults from the use of 2-ethyl-1-butanol in formulae that go intofine fragrances has been not been reported.

4. Toxicology data

4.1. Acute toxicity

Summary of acute toxicity studies is given in Table 2.

4.1.1. Oral studiesThe acute oral LD50 of 2-ethyl-1-butanol in Carworth-Wistar

male or female rats (5/group) was reported to be 1.85 (1.52–2.24) g/kg. Observations were made for 14 days. No additional de-tails were reported (Smyth et al., 1954).

The acute oral LD50 of 2-ethyl-1-butanol in rats was reported tobe 1.85 g/kg. No additional details were reported (Bar and Griepen-trog, 1967; Nishimura et al., 1994).

The acute oral LD50 of 2-ethyl-1-butanol in rabbits was reportedto be 1.2 ml/kg (�1.2 g/kg). No additional details were reported(Draize et al., 1944).

4.1.2. Dermal studiesThe acute dermal LD50 of 2-ethyl-1-butanol in rabbits (4/group)

was reported to be 1.26 (0.85–1.87) g/kg. Observations were madefor 14 days. No additional details were reported (Smyth et al.,1954).

The acute dermal LD50 of 2-ethyl-1-butanol in rabbits was re-ported to be 2.0 ml/kg (�2.0 g/kg). No additional details were re-ported (Draize et al., 1944).

4.1.3. Inhalation studiesIn an acute inhalation study of 2-ethyl-1-butanol in male rats

(6/group), the maximum time to death of exposure to concentrated

vapors was reported to be 8 h. No additional details were reported(Smyth et al., 1954).

4.1.4. Other studiesThe acute intraperitoneal ED3 for induction of pronounced

ataxia in rats was reported to be 2.3 mmol/kg (�0.24 g/kg) (McCre-ery and Hunt, 1978).



4.2.2. Animal studiesIn a group of 5 rabbits (giant albino, New Zealand rabbits) der-

mal irritation study for 24 h uncovered neat 2-ethyl-1-butanol wasapplied at 0.1 ml to clipped skin. Slight to moderate irritation(grade 2) was reported (Smyth et al., 1954).


In a rabbit eye irritation study, a 1% of 2-ethyl-1-butanol solu-tion was reported to produce necrosis of the eye (Smyth et al.,1954).

4.4. Skin densitization







4.6.3. Metabolism4.6.3.1. In vivo studies in animals. Kamil et al. (1953a) reported thatwhen 25 mmol (2.55 g) of 2-ethyl-1-butanol was administered byoral gavage to 3.0 kg rabbits (n = 3), 40% of the administered dosewas excreted in the urine as the glucuronide within 24 h.

Furthermore, Kamil et al. (1953b) reported that 2-ethyl-1-buta-nol, 2.55 g (3.1 ml), administered by oral gavage to a rabbit was ex-creted in the urine (24 h) as diethylacetylglucuronide. A smallamount of methyl-n-propyl ketone was also excreted.

4.6.3.2. In vitro studies in animals. No available information.





4.9. Genotoxicity




LD50

(g/kg)References

Oral Rat 5 1.85 Smyth et al. (1954)Oral Rat N/A 1.85 Nishimura et al. (1994)

Bar and Griepentrog (1967)Oral Rabbit N/A 1.2 Draize et al. (1944)Dermal Rabbit 4 1.26 Smyth et al. (1954)Dermal Rabbit N/A 2.0 Draize et al. (1944)







References

Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilungder Aromatisierungsmittel fur Lebensmittel (where we stand concerning theevaluation of flavoring substances from the viewpoint of health). MedizinErnährung 8, 244–251.



Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.Chemically-defined flavouring substances. Group 2.1.3 Aliphatic Alcohols,branched chain. p. 59, number 543. Council of Europe Publishing, Strasbourg.

Draize, J.H., Woodard, G., Calvery, H.O., 1944. Methods for the study of irritation andtoxicity of substances applied topically to the skin and mucous membranes.Journal of Pharmacology and Experimental Therapeutics 82 (2), 377–390.

EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, v 4.00 or Insert Version used. United StatesEnvironmental Protection Agency, Washington, DC, USA.



2007.Kamil, I.A., Smith, J.N., Williams, R.T., 1953a. Studies in detoxication. 46. The

metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclicaliphatic alcohols. Biochemical Journal 53, 129–136.


McCreery, M.J., Hunt, W.A., 1978. Physico-chemical correlates of alcoholintoxication. Neuropharmacology 17, 451–461.


Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., 1954. Range-finding toxicitydata. List V. Archives of Industrial Hygiene 10, 61–68.

VCF, 2009. Volatile Compounds in Food: Database/Nijssen, L.M., van Ingen-Visscher,C.A., Donders, J.J.H. (Eds.) – Version 11.1.1. TNO Quality of Life, Zeist, TheNetherlands, 1963–2009.


Review

Fragrance material review on 2,6-dimethyl-4-heptanol




a b s t r a c t

A toxicologic and dermatologic review of 2,6-dimethyl-4-heptanol when used as a fragrance ingredient ispresented. 2,6-Dimethyl-4-heptanol is a member of the fragrance structural group branched chain satu-rated alcohols. The common characteristic structural elements of the alcohols with saturated branchedchain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl sidechains. This review contains a detailed summary of all available toxicology and dermatology papers thatare related to this individual fragrance ingredient and is not intended as a stand-alone document. A safetyassessment of the entire branched chain saturated alcohol group will be published simultaneously withthis document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this mate-rial and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S914.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S914.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S914.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91


4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92

4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92

4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S924.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92








Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 2,6-dimethyl-4-heptanolwhen used as a fragrance ingredient. 2,6-Dimethyl-4-heptanol (seeFig. 1; CAS No. 108-82-7) is a fragrance ingredient used in cosmet-ics, fine fragrances, shampoos, toilet soaps and other toiletries aswell as in non-cosmetic products such as household cleaners anddetergents.

In 2006, a complete literature search was conducted on 2,6-di-methyl-4-heptanol. On-line toxicological databases were searchedincluding those from the Chemical Abstract Services, e.g. ToxCenter[which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g. Medline, Toxnet(which contains 14 databases)] as well as 26 additional sources(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrancecompanies were asked to submit all test data.


1. Identification

1.1. Synonyms: diisobutylcarbinol; 4-heptanol, 2,6-dimethyl-;2,6-dimethylheptan-4-ol.

1.2. CAS registry number: 108-82-7.1.3. EINECS number: 203-619-6.1.4. Formula: C9H20O.1.5. Molecular weight: 144.26.1.6. JECFA (2003): The Joint FAO/WHP Expert Committee on

Food Additives (JECFA No. 303) concluded that the substancedoes not present a safety concern at current levels of intakewhen used as a flavouring agent.

1.7. FEMA (1970): Flavor and Extract Manufacturers’ Associationstates: generally Recognized as Safe as a flavor ingredient –GRAS 4. (3140) Hall, 1970.



25 �C.2.5. Log Kow (calculated; EPA, 2010): 3.08.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure: (calculated; EPA, 2010): 0.334 mm Hg;

44.5 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 613.8 mg/l @ 25 �C.

2.10. UV spectra available at RIFM, does not absorb UV light.

3. Usage

2,6-Dimethyl-4-heptanol is a fragrance ingredient used in manyfragrance compounds. It may be found in fragrances used in deco-rative cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of 10–100 metric tons per annum (IFRA, 2004). The reported volume ofuse is for 2,6-dimethyl-4-heptanol as used in fragrance compounds(mixtures) in all finished consumer product categories. The volumeof use is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies. Assuch the volume of use data from this survey provides volume ofuse of fragrance ingredients for the majority of the fragranceindustry.

Fig. 1. 2,6,-Dimethyl-4-heptanol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-4-heptanol.


Anti-perspirant 0.5 1 1 0.01 .02 0.000001Bath products 17 0.29 0.001 0.02 .02 0.000001Body lotion 8 0.71 1 0.004 .02 0.000100Eau de toilette 0.75 1 1 0.08 .02 0.000200Face cream 0.8 2 1 0.003 .02 0.000001Fragrance cream 5 0.29 1 0.04 .02 0.000200Hair spray 5 2 0.01 0.005 .02 0.000001Shampoo 8 1 0.01 0.005 .02 0.000001Shower gel 5 1.07 0.01 0.012 .02 0.000001Toilet soap 0.8 6 0.01 0.015 .02 0.000001Total 0.0005

a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.b Based on a 60 kg adult.



This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5% percentile use level in formulae for use in cosmet-ics in general has not been reported. As such the default value of0.02% is used to calculate the maximum daily exposure on the skinof 0.0005 mg/kg for high end users of these products.

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level that re-sults from the use of 2,6-dimethyl-4-heptanol in formulae thatgo into fine fragrances has not been reported. A default value of0.02% is used, assuming use of the fragrance oil at levels up to20% in the final product.

4. Toxicology data


4.1.1. Oral studiesFive rats per dose were given a single dose of 2,6-dimethyl-4-

heptanol at 1, 2, 4, and 8 g/kg. Observations for mortality and orsystemic effects were made for 14 days. The acute oral LD50 in ratswas calculated to be 3.56 g/kg (95% CI 1.43–8.86) (Smyth et al.,1949).

Sixteen male and sixteen female rats of the Wistar CF/Gif Car-worth strain were given 2,6-dimethyl-4-heptanol with food.Observations for mortality and or systemic effects were made.The acute oral LD50 in rats was calculated to be 4.35 g/kg. Necropsyresults done at week 12 showed organ weights and organ histopa-thology to be within normal limits (Posternak and Vodoz, 1975).

Rats (5, 6, or 11/dose) were dosed intra-gastrically with 2.5, 3.7,5.0, 7.5, 10, and 12.5 g/kg in 1% aqueous Tergitol. Observations formortality and or systemic effects were made. The acute oral LD50 inrats was calculated to be 6.5 ml/kg (6.5 g/kg) (McOmie and Ander-son, 1949).

In the same study as above, mice (6 or 14/dose) were dosed in-tra-gastrically with 2.5, 5.0, and 10 g/kg in 1% Tergitol. Observa-tions for mortality and systemic effects were made. The LD50 inmice was calculated to be 5.0 g/kg (95% CI 2.5–7.5) (McOmie andAnderson, 1949).

4.1.2. Dermal studiesFive rabbits received a single dermal application of 1, 2, 4 or 8 g/

kg 2,6-dimethyl-4-heptanol. Observations for mortality and/or sys-temic effects were made for 14 days. The acute dermal LD50 in rab-bits was calculated to be 5.66 g/kg (95% CI 2.51–12.80) (Smythet al., 1949).

4.1.3. Inhalation studiesA group of male and female subjects (n = 12) were exposed by

inhalation to 2,6-dimethyl-4-heptanol for 15 min. The sensory re-sponse limit and the concentration that produced irritation of themucus membranes of the eyes, nose, or throat were determined.Less than 5 ppm produced eye irritation in the majority of subjects.At 10 ppm nose and throat were irritated as well (Silverman et al.,1946).

Groups of an unspecified number of rats were exposed to a sat-urated vapor of two samples of 2,6-dimethyl-4-heptanol. The max-imum period of exposure to both samples one and two that did notresult in any deaths was 8 h (Smyth et al., 1949).

Ten mice were exposed by inhalation to 2 mg/l of 2,6-dimethyl-4-heptanol as a saturated vapor-air mixture. No deaths were re-ported after the 12-h exposure (McOmie and Anderson, 1949).



4.2.2. Animal studies (see Table 3)The primary skin irritation of neat 2,6-dimethyl-4-heptanol was

evaluated on groups of five rabbits. Scoring similar to the Draizemethod was used, with grades ranging from 1 to 10. A grade of 1was observed; this indicates there was no irritation from the undi-luted material (Smyth et al., 1949).

Seven 5 h applications of neat 2,6-dimethyl-4-heptanol weremade to the intact skin of two rabbits over a period of 21 days.Observations included definite erythema after the 2nd exposure,areas of flaking after the 4th exposure, and cracking of the skinwith bleeding fissures after the 7th exposure (McOmie andAnderson, 1949).



LD50

(g/kg)References

Oral Rats 5 3.56 Smyth et al. (1949)Oral Rats 32 4.35 Posternak and Vodoz (1975)Oral Rats 5,6 or 11 6.5 McOmie and Anderson (1949)Oral Mice 6 or 14 5 McOmie and Anderson (1949)Dermal Rabbit 5 5.66 Smyth et al. (1949)


Method Dose (%) Species Reactions References

Dermal application 100% Rabbit 0/5 No irritation Smyth et al. (1949)Dermal application 100% Rabbit Definite erythema, flaking, and bleeding fissures McOmie and Anderson (1949)Dermal application 100% Rabbit 2/5 erythema and slight edema McOmie and Anderson (1949)


The cuff method was used for acute dermal exposure in five rab-bits. Animals were given 4 h semi-occlusive applications of neat2,6-dimethyl-4-heptanol from 3.9–9.4 ml/kg. Two of the five rab-bits showed some erythema and slight edema (McOmie andAnderson, 1949).


An ocular irritation study was conducted with two samples ofneat 2,6-dimethyl-4-heptanol. Groups of five rabbits per dose wereused, and the test material was applied to the corneas. The re-tracted eyelids were released approximately 1 min after the instil-lation, and the eyes were stained with fluorescein 18–24 h later.The eyes were examined and scored according to a 10-point scale.Both samples of 2,6-dimethyl-4-heptanol were assigned a score of2, which was equivalent to 0.5 ml of the neat material producinginjury of 1–5 points. Prior to the fluorescein staining, an injury ofone point was equivalent to iritis and five points was equivalentto corneal opacity. After fluorescein staining, one point was equiv-alent to necrosis on less than 5% of the cornea and five points wasequivalent to necrosis on 63–87% of the cornea (Smyth et al.,1949).

2,6-Dimethyl-4-heptanol was tested in one rabbit. ModerateIrritation was observed within the first 24 h, but returned to nor-mal by the 72nd hour (McOmie and Anderson, 1949).








4.7.1. Two to 30-day studiesNo available information.

4.7.2. Subchronic studiesNo available information.

4.7.3. Chronic (90+ days) studiesA 12-week oral study was conducted on groups of 32 Wistar CF/

Gif Carworth strain rats (16 per sex), and the treated animals werefed a diet containing 2,6-dimethyl-4-heptanol mixed with micro-crystalline cellulose. The controls were only fed the basic diet,but both the test and control animals were allowed access to foodad libitum. The daily intake of the test material was estimated tobe 11 mg/kg bodyweight per day. Individual body weights were re-corded prior to the test and weekly thereafter. Observations ofphysical appearance and behavior were made daily. Food con-

sumption was measured on a weekly basis, and efficiency of foodutilization (EFU) was calculated for pairs of rats (as housed). Hema-tological examinations and blood urea determinations were car-ried out on 50% of the animals at week seven, and on all theanimals at the end of the treatment period. All animals were sacri-ficed at the end of the study, and a gross necropsy was conductedat that time. The liver and kidneys were weighed, and a histologicalexamination was conducted. No adverse effects were observed,and no changes of any biological significance were observed (Pos-ternak and Vodoz, 1975).



4.9. Genotoxicity




This individual Fragrance Material Review is not intended as astand-alone document. Please refer to A Safety Assessment of Alco-hols Branched Chain Saturated when used as fragrance ingredients(Belsito et al., 2010) for an overall assessment of this material.



References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chainsaturated alcohols when used as fragrance ingredients. Food and ChemistryToxicology 48 (S4), S1–46.


EPA (Environmental Protection Agency), 2010. Estimation programs interfacesuite™ for Microsoft� Windows, v 4.00 or insert version used. United StatesEnvironmental Protection Agency, Washington, DC, USA.

FEMA (Flavor and Extract Manufacturers Association), 1970. Recent progress in theconsideration of flavoring ingredients under the food additives amendment 4.GRAS substances. Food Technology, 24(5), 25–34.



2007.JECFA (Joint Expert Committee on Food Additives), 2003. Safety evaluation of

certain food additives. Who Food Additives Series:42. Prepared by the Fifty-FirstMeeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).World Health Organization, Geneva 1999.


Posternak, J.M., Vodoz, C.A., 1975. Toxicology tests on flavouring matters. II.Pyrazines and other compounds. Food and Cosmetics Toxicology 13, 487–490.

Silverman, L., Schultz, H.F., First, M.W., 1946. Further studies on sensory response tocertain industrial solvent vapors. The Journal of Industrial Hygiene andToxicolology 28, 262–266.



Dose (%) Vehicle Reactions References

100% NA Irritation observed Smyth et al. (1949)NA NA Irritation observed McOmie and Anderson (1949)


Review

Fragrance material review on 3-methyl-1-pentanol




a b s t r a c t

A toxicologic and dermatologic review of 3-methyl-1-pentanol when used as a fragrance ingredient ispresented. 3-Methyl-1-pentanol is a member of the fragrance structural group branched chain saturatedalcohols. The common characteristic structural elements of the alcohols with saturated branched chainare one hydroxyl group per molecule, and a C4 to C12 carbon chain with one or several methyl side chains.This review contains a detailed summary of all available toxicology and dermatology papers that arerelated to this individual fragrance ingredient and is not intended as a stand-alone document. A safetyassessment of the entire branched chain saturated alcohol group will be published simultaneously withthis document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this mate-rial and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.1.3. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95


4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95

4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S954.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95








Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 3-methyl-1-pentanolwhen used as a fragrance ingredient. 3-Methyl-1-pentanol (seeFig. 1; CAS Number 589-35-5) is a fragrance ingredient used in cos-metics, fine fragrances, shampoos, toilet soaps and other toiletriesas well as in non-cosmetic products such as household cleanersand detergents. This material has been reported to occur in nature,with quantities observed in the mangifera species of mango (VCF,2009).

In 2006, a complete literature search was conducted on 3-methyl-1-pentanol. On-line toxicological databases were searchedincluding those from the Chemical Abstract Services [e.g. ToxCen-ter [which in itself contains 18 databases including Chemical Ab-stracts)] and the National Library of Medicine [e.g. Medline,Toxnet (which contains 14 databases)] as well as 26 additionalsources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-grance companies were asked to submit all test data.


1. Identification

1.1. Synonyms: 2-ethyl-4-butanol; 1-pentanol, 3-methyl;methyl pentanol-3.

1.2. CAS Registry Number: 589-35-5.1.3. EINECS Number: 209-644-9.1.4. Formula: C6H14O.1.5. Molecular weight: 102.18.

1.6. JECFA (1998): The Joint FAO/WHP Expert Committee onFood Additives (JECFA No. 263) concluded that the substancedoes not present a safety concern at current levels of intakewhen used as a flavoring agent.

1.7. FEMA (1990): Flavor and Extract Manufacturers’ Associationstates: Generally Recognized as Safe as a flavor ingredient –GRAS 15 (3762).



25 �C.2.5. Log Kow (calculated; EPA, 2010): 1.75.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 0.7 mm Hg (20 �C);

1.7 mm Hg (25 �C); 227 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 �C).

2.10. UV spectra available at RIFM, peaks at 200–210 nm andreturns to baseline at 280–290 nm.

3. Usage

3-Methyl-1-pentanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of lessthan 0.01 metric tons per annum (IFRA, 2004). The reported vol-ume of use is for 3-methyl-1-pentanol as used in fragrance com-pounds (mixtures) in all finished consumer product categories.The volume of use is surveyed by IFRA approximately every fouryears through a comprehensive survey of IFRA and RIFM membercompanies. As such the volume of use data from this survey pro-vides volume of use of fragrance ingredients for the majority ofthe fragrance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in 10 types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of severalthousand commercial formulations. The upper 97.5 percentileconcentration is calculated from the data obtained. This upper 97.5

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3-methyl-1-pentanol.

Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredientb (mg/kg/day)



Fig. 1. 3-Methyl-1-pentanol.


percentile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account forthe length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been reported to be 0.0006 (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.00002 mg/kg for high end users of these products (Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level in formu-lae that go into fine fragrances has been reported to be 0.0002%(IFRA, 2007), assuming use of the fragrance oil at levels up to20% in the final product.

4. Toxicology data


4.1.1. Oral studiesThe acute oral LD50 of 3-methyl-1-pentanol in mice was re-

ported to be >2 g/kg. Mortality was 0, 0, 1, and 10 of 10 mice at0.5, 1.0, 2.0, and 4.0 g/kg. At the top dose 8/10 animals died within24 h. Surviving animals were observed for 14 days post-dosing(RIFM, 1982).


4.1.3. Other studiesThe acute intraperitoneal LD50 of 3-methyl-1-pentanol in mice

was reported to be >0.25 g/kg. Mortality was 0, 0, 8, 9, 10, and 10of 10 mice at 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 g/kg. At the 0.5,1.0, 2.0, and 4.0 g/kg, 7, 9, 10, and 10 animals, respectively, diedwithin 24 h. Surviving animals were observed for 14 days post-dosing (RIFM, 1982).


4.2.1. Human studiesIrritation was evaluated during the induction phase in a human

repeated insult patch test (HRIPT). An application of 0.5 ml with0.5% 3-methyl-1-pentanol in 99.5% alcohol SDA 39C on a 1 � 1-inch Webril patch was administered to the upper arms of thepanelists and removed after 24 h. Irritation was scored 48 h afterinitial application and a new patch reapplied at that time. Nine

applications were made in a three week period. Little or no irrita-tion was found in all 41 male and female volunteers (RIFM, 1973).

4.2.2. Animal studiesA group of three albino rabbits were given 0.5 ml of 0.5% 3-

methyl-1-pentanol in 99.5% Alcohol SDA 39C and observed at theend of the 24 h contact period and again 48 h later. Erythemaand edema were not observed in any of the three rabbits testedand therefore 3-methyl-1-pentanol cannot be considered a pri-mary irritant (RIFM, 1972).




4.4.1. Human studies4.4.1.1. Induction studies. A repeated insult patch test was con-ducted to determine if 3-methyl-1-pentanol would induce dermalsensitization in human volunteers. During the induction phase0.5 ml was applied onto a Webril swatch and applied to the upperarms of each volunteer for 24 h. Induction applications were madefor a total of 9 applications during 3 week period. Following a twoweek rest period, a challenge patch was applied to the original siteas well as a fresh site. Patches were applied as in the inductionphase and kept in place for 24 h after which time they were re-moved. Reactions to the challenge were scored at 48 and 72 h afterapplication. There was no sensitization reactions observed duringthe challenge phase (RIFM, 1973).

4.4.1.2. Cross-sensitization. No information available.

4.4.1.3. Diagnostic studies. No information available.










4.9. Genotoxicity




This individual Fragrance Material Review is not intended as astand-alone document. Please refer to A Safety Assessment ofBranched Chain Saturated Alcohols When Used as Fragrance




Oral Mice 10 >2.0 RIFM (1982)Intraperitoneal Mice 10 >0.25 RIFM (1982)


Ingredients (Belsito et al., 2010) for an overall assessment of thismaterial.



References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chainsaturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48(S4), S1–S46.

Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:providing estimates for safety evaluation. Regul. Toxicol. Pharma. 36, 246–252.

EPA (Environmental Protection Agency), 2010. Estimation Programs InterfaceSuite™ for Microsoft� Windows, v 4.00 or Insert Version used. United StatesEnvironmental Protection Agency, Washington, DC, USA.

FEMA (Flavor and Extract Manufacturers Association), 1990. Recent progress in theconsideration of flavoring ingredients under the food additives amendment. 15.GRAS substances. Food Technol. 44 (2). 78, 80, 82, 84, 86.

Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria forDevelopment of a database for safety evaluation of fragrance ingredients. Regul.Toxicol. Pharm. 31, 166–181.


2007.JECFA (Joint Expert Committee on Food Additives), 1998. Safety Evaluation of

Certain Food Additives. Who Food Additives Series: 40. Prepared by the Forty-ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives(JECFA). World Health Organization, Geneva.

RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Skin Irritation Studywith 3-Methyl-1-pentanol in Rabbits. Unpublished Report from InternationalFlavors and Fragrances. Report Number 53594. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1973. Repeated Insult PatchTest with 3-Methyl-1-pentanol. Unpublished Report from International Flavorsand Fragrances. Report Number 53593 RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1982. 14-Day LD50 Study on3-Methyl-1-pentanolin Mice. Private Communication to FEMA. UnpublishedReport from H.W. Engler B. Bahler. Report Number 9019. RIFM, Woodcliff Lake,NJ, USA.

VCF, 2009. (Volatile Compounds in Food): Database/Nijssen, L.M., van Ingen-Visscher, C.A., Donders, J.J.H. (Eds.), – Version 11.1.1. TNO Quality of Life, Zeist,The Netherlands, 1963–2009.


Review

Fragrance material review on 2-methylbutanol




a b s t r a c t

A toxicologic and dermatologic review of 2-methylbutanol when used as a fragrance ingredient is pre-sented. 2-Methylbutanol is a member of the fragrance structural group branched chain saturated alco-hols. The common characteristic structural elements of the alcohols with saturated branched chain areone hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains a detailed summary of all available toxicology and dermatology papers that are related tothis individual fragrance ingredient and is not intended as a stand-alone document. A safety assessmentof the entire branched chain saturated alcohol group will be published simultaneously with this docu-ment; please refer to Belsito et al., 2010 for an overall assessment of the safe use of this material andall other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S994.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S994.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S994.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S994.1.4. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S994.1.5. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99


4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1004.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1004.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1004.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100




* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.E-mail address: [email protected] (D. McGinty).







Introduction

This document provides a comprehensive summary of the tox-icologic review, including all human health endpoints, of 2-meth-ylbutanol when used as a fragrance ingredient. 2-Methylbutanol(see Fig. 1; CAS Number 137-32-6) is a fragrance ingredient usedin cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. This material has been reported to occurin nature, with highest quantities observed in hop oil (VCF,2009).

In 2006, a complete literature search was conducted on 2-meth-ylbutanol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services, [e.g., ToxCenter (whichin itself contains 18 databases including Chemical Abstracts)], andthe National Library of Medicine [e.g., Medline, Toxnet (which con-tains 14 databases)] as well as 26 additional sources (e.g., BIOSIS,Embase, RTECS, OSHA, ESIS). In addition, fragrance companies wereasked to submit all test data.

The safety data on this material has never been reviewed byRIFM (Research Institute for Fragrance Materials, Inc.). All relevantreferences are included in this document. More details have beenprovided for unpublished data. The number of animals, sex andstrain are always provided unless they are not given in the originalreport or paper. Any papers in which the vehicles and/or the dosesare not given have not been included in this review. In addition,

diagnostic patch test data with fewer than 100 consecutive pa-tients have been omitted.

1. Identification

1.1. Synonyms: active amyl alcohol; 1-butanol, 2-methyl-; sec-butylcarbinol; (±) 2-methyl-1-butanol; 2-methylbutyl alco-hol; 2-methylbutan-1-ol.

1.2. CAS registry number: 137-32-6.1.3. EINECS number: 205-289-9.1.4. Formula: C5H12O.1.5. Molecular weight: 88.15.1.6. Council of Europe (2000): 2-methylbutanol was included

by the Council of Europe in the list of substances grantedB – information required – 28 day oral study (COE No. 2346).

1.7. FEMA (2001): Flavor and Extract Manufacturers’ Associationstates: Generally Recognized as Safe as a flavor ingredient –GRAS 20.

1.8. JECFA (2004): The Joint FAO/WHO Expert Committee onFood Additives (JECFA No. 1199) concluded that the sub-stance does not present a safety concern at current levelsof intake when used as a flavouring agent.



(25 �C).2.5. Log Kow (calculated; EPA, 2010): 1.26.2.6. Refractive index: no information available.2.7. Specific gravity: no information available.2.8. Vapor pressure (calculated; EPA, 2010): 2.5 mm Hg (20 �C);

4.54 mm Hg (25 �C); 606 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 32,200 mg/l

(25 �C).2.10. UV spectra available at RIFM, peaked at 200–215 nm range

and returns to baseline at 220–225 nm.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylbutanol.




Fig. 1. 2-Methylbutanol.


3. Usage

2-Methylbutanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decorativecosmetics, fine fragrances, shampoos, toilet soaps and other toilet-ries as well as in non-cosmetic products such as household cleanersand detergents. Its use worldwide is in the region of 0.01–0.1 metrictons per annum (IFRA, 2004). The reported volume of use is for 2-methylbutanol as used in fragrance compounds (mixtures) in allfinished consumer product categories. The volume of use is sur-veyed by IFRA approximately every 4 years through a comprehen-sive survey of IFRA and RIFM member companies. As such thevolume of use data from this survey provides volume of use of fra-grance ingredients for the majority of the fragrance industry.

The dermal systemic exposure in cosmetic products (see Table1) is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of sev-eral thousand commercial formulations. The upper 97.5 percentileconcentration is calculated from the data obtained. This upper 97.5percentile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to accountfor the length of time a product may remain on the skin and/orlikelihood of the fragrance ingredient being removed by washing.The resultant calculation represents the total consumer exposure(mg/kg/day) (Cadby et al., 2002, Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002, Ford et al.,2000). The 97.5% percentile use level in formulae for use in cosmet-ics in general has been reported to be 0.007% (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.0002 mg/kg for high end users.

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be0.001% (IFRA, 2007), assuming use of the fragrance oil at levelsup to 20% in the final product.

4. Toxicology data


4.1.1. Oral studiesThe acute oral LD50 of 2-methylbutanol in rats (n = 5) was

reported to be 4.92 (3.75–6.46) ml/kg (�4.92 g/kg). No additionaldetails were reported (Smyth et al., 1962).

The acute oral LD50 of 2-methylbutanol in rats (not specified)was reported to be 1000 mg/kg. No additional details were re-ported (Nishimura et al., 1994).

The acute oral LD50 of 2-methylbutanol in rats (not specified)was reported to be 4.01 g/kg. No additional details were reported(Rowe and McCollister, 1982).

2-Methylbutanol was given to Sprague dawley rats (5/sex) atdoses of 1.47, 2.15, 3.16, or 5.0 g/kg and observed for 14 days.

The acute oral LD50 was reported to be 4.17 g/kg based on mortal-ity (1/10) at 3.16 g/kg and (8/10) at 5.0 g/kg (RIFM, 1979).

Wistar rats (5/sex) were given a single oral dose 3.0 or 5.0 g/kgof 2-methylbutanol by gavage and observed for 14 days. No ani-mals died, and the LD50 was determined to be greater than 5.0 g/kg (RIFM, 1985).

4.1.2. Dermal studiesThe acute dermal LD50 of 2-methylbutanol in rabbits (n = 4) was

reported to be 3.54 ml/kg (�3.54 g/kg). Contact time was 24 h andobservation time was 14 days. No additional details were reported(Smyth et al., 1962; RIFM, 1979).

An acute dermal LD50 value was reported to be 2.89 for 2-methyl-1-butanol (Rowe and McCollister, 1982).

4.1.3. Inhalation studiesThe maximum time for exposure of rats (6/dose) to concen-

trated vapors of 2-methylbutanol without mortality was 8 h. Thechemical was administered undiluted, unless a lesser concentra-tion was necessary. Then the solution was made in water, or cornoil (Smyth et al., 1962).

Rats were exposed to 2-methylbutanol by inhalation of satu-rated atmosphere at 20 �C for 7 h. Mortality was not observed,but escape behavior and intermittent respiration was noted (RIFM,1979).

No mortality was observed when six rats were exposed to 2-methylbutanol by inhalation of saturated vapors for 8 h. No furtherinformation available (Rowe and McCollister, 1982).

4.1.4. Intraperitoneal studiesMice were given 2-methylbutanol at doses of 200, 700, or

2000 mg/kg by intraperitoneal injection and observed for 14 days.All animals in the 2000 mg/kg and 9/10 at 700 mg/kg died. TheLD50 was estimated to be greater than 200 mg/kg but less than700 mg/kg (RIFM, 1979).

Rats were given 2-methylbutanol at doses of 1000, or 2000 mg/kg by intraperitoneal injection and observed for 14 days. Animalsin the 2000 mg/kg showed respiratory arrest and death. At1000 mg/kg the rats showed sedation, irritation of the peritoneumand injury of the lungs (Haggard et al., 1945 as cited in Greim,2008).

4.1.5. Other studiesIn isolated perfused livers of rats, 65.1 mmol 2-methylbutanol/l

were cytotoxic as evidenced by the release of liver enzymes intothe perfusate. The alcohols decreased the content of ATP in the li-ver. The content of oxidized glutathione was increased. Lipid per-oxidation was not observed (Strubelt et al., 1999).




Route Species NO. animals/dose group

LD50

(g/kg)References

Oral Rat 5 4.92 Smyth et al. (1962)Oral Rat N/A 1.00 Nishimura et al. (1994)Oral Rat N/A 4.01 Rowe and McCollister (1982)Oral Rat 10 (5/sex) 4.17 RIFM (1979)Oral Rat 10 (5/sex) >5.0 RIFM (1985)Dermal Rabbit 4 3.54 Smyth et al. (1962)Dermal Rabbit N/A 3.54 RIFM (1979)


4.2.2. Animal studiesIn a rabbit dermal irritation study (n = 5) undiluted 2-methyl-

butanol resulted in Grade 2 irritation defined as the least visiblecapillary injection from the undiluted material (Smyth et al., 1962).

In a rabbit dermal irritation study with two rabbits, undiluted2-methylbutanol resulted in Grade 4.7 or moderate irritation withsome necrosis observed (RIFM, 1979).


In a rabbit eye irritation study, 2-methylbutanol resulted inGrade 8 injury where corneal necrosis was observed (Smythet al., 1962).

In a rabbit eye irritation study (n = 6), undiluted 2-methylbuta-nol resulted in some turbidity at the cornea, inflammation on theiris, and redness of the conjunctivae after observations for 72 h(RIFM, 1979).

When a 0.005 ml of undiluted 2-methylbutanol (or an excess ofa 15% solution in propylene glycol; not specified) was instilled intothe eyes of rabbits moderate to severe burns and corneal necrosiswas observed (Rowe and McCollister, 1982).








4.6.3. Metabolism4.6.3.1. In vivo studies in animals (see Table 3). Following intraperi-toneal administration of 1 g/kg undiluted 2-methylbutanol to rats;blood was drawn for analysis 1 h after the first administration andat subsequent intervals. There was total elimination of 7.6%, 5.6%was recovered unchanged in the expired air and 2.0% unchangedin the urine. Disappearance from blood was rapid, with neitheralcohol nor aldehyde detected after 10 h (Haggard et al., 1945).

Oxidation to the aldehyde and glucuronidation was demon-strated for 2-methylbutanol with microsomes from rats pre-trea-ted with ethanol (Iwersen and Schmoldt, 1995).

2-Methylbutanol was administered to large chinchilla rabbits(n = 3) by oral gavage at 25 m-mol/rabbit. Collected urine did not

contain aldehydes or ketones, but did yield 9.6% of non-reducingglucuronide (Kamil et al., 1953).

4.6.3.2. In vitro studies in animals. Rat liver microsomes metabo-lized 2-methylbutanol to yield approximately 8 nmol aldehydeper minute per mg protein and 13 nmol glucuronide per min permg protein. The km and Vmax for glucuronidation were 2 mmol/land 18 nmol/min/mg protein, respectively. The km and Vmax formicrosomal oxidation were 4.6 mmol/l and 3.6 nmol/min/mg pro-tein, respectively. The microsomes were obtained from male Spra-gue–Dawley rats that had been pre-treated for 2 weeks with 10%ethanol in the drinking water (Iwersen and Schmoldt, 1995).





4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems. Light absorption and luminescentumu tests were used to investigate the genotoxicity of 2-methylbu-tanol with Salmonella typhimurium TA1535/pSK1002 and TA1535/pTL210. Results showed the umu test for light absorption ofTA1535/pSK102 to be negative, where as the umu test for lumines-cent TA1535/pTL210 to be positive (Nakajima et al., 2006).

4.9.1.2. Studies in mammalian cells. In a study of the cytotoxic andgenotoxic effects of a number of alcohols and ketones, 2-methylbu-tanol had an IC50 (Inhibitory concentration resulting in 50% reduc-tion in colony formation) of 31 mM for human lung carcinoma cellline A549. At 45 and 90 mM concentration of 2-methylbutanol,there was no difference from controls in alkaline comet assay tailmoment in either A549 cells or Chinese hamster V79 cells. The co-met assay could not be performed in human peripheral blood cellsdue to cytotoxicity. At methylbutanol concentrations of 23 and45 mM, there was no difference, in the micronucleus test, fromcontrols in induction of micronuclei in V79 cells with or withoutthe addition of hepatic S-9 from Aroclor induced rats. Finally anHPRT with Chinese hamster V70 fibroblast cells at concentrationsup to 46 mM (the highest non-toxic concentration) mutagenicitywas not observed (Kreja and Seidel, 2001, 2002a,b).

4.9.2. In vivo studiesNo available information.





This research was supported by the Research Institute for Fra-grance Materials, an independent research institute that is fundedby the manufacturers of fragrances and consumer products con-

Table 3Summary of in vivo animal studies.

Route Species Results References

Intraperitoneal Rat 5.6% was recovered unchanged inthe expired air and 2.0%unchanged in the urine

Haggardet al. (1945)

Oral (drinkingwater)

Rat Oxidation to the aldehyde andglucuronidation wasdemonstrated

Iwersen andSchmoldt(1995)

Oral (gavage) Rabbit Excess glucuronide excretionrepresented 9.6% of theadministered dose

Kamil et al.(1953)


taining fragrances. The authors are all employees of the ResearchInstitute for Fragrance Materials.

References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branchedchain saturated alcohols when used as fragrance ingredients. Food ChemToxicol. 48 (S4), S1–S46.

Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:providing estimates for safety evaluation. Regul.Toxicol. Pharm. 36, 246–252.

Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.Chemically-defined flavouring substances. Group 2.1.3 Aliphatic alcohols,branched chain. p. 60, number 2346. Council of Europe Publishing, Strasbourg.


FEMA (Flavor and Extract Manufacturers Association), 2001. GRAS flavoringsubstances 20. Food Technol. 55 (12), 1-17.

Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria fordevelopment of a database for safety evaluation of fragrance ingredients. Regul.Toxicol. Pharm. 31, 166–181.

Greim, H. (Ed.), 2008. Pentanol-Isomeren. Toxikologisch-arbeitsmedizinischeBegründungen von MAK-Werten, Lieferung 44. Wiley-VCH, Weinheim.

Haggard, H.W., Miller, D.P., Greenberg, L.A., 1945. The amyl alcohols and theirketones: their metabolic fates and comparative toxicities. J. Ind. Hyg. Toxicol. 27(1), 1–14.


2007.Iwersen, S., Schmoldt, A., 1995. ADH Independent metabolism of aliphatic alcohols:

comparison of oxidation and glucuronidation. Adv. Forensic Sci. 13 (4), 19–22.JECFA, 2004. Safety evaluation of certain food additives. Aliphatic branched-chain

saturated and unsaturated alcohols, aldehydes, acids, and related esters.

Prepared by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).WHO Food Additives Series: 52. IPCS, WHO, Geneva.

Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. Themetabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclicaliphatic alcohols. Biochem. J. 53, 129–136.

Kreja, L., Seidel, H.J., 2001. Toxicology study of some often detected microbialvolatile organic compounds (MVOC). Umweltmed Forsch Prax. 6 (3), 159–163.

Kreja, L., Seidel, H.J., 2002a. Evaluation of the genotoxic potential of some microbialvolatile organic compounds (MVOC) with the comet assay, the micronucleusassay and the HPRT gene mutation assay. Mutat. Res. 513 (1–2), 143–150.

Kreja, L., Seidel, H.J., 2002b. On the cytotoxicity of some microbial volatile organiccompounds as studied in the human lung cell line A549. Chemosphere 49 (1),105–110.

Nakajima, D., Ishii, R., Kageyama, S., Onji, Y., Mineki, S., Morooka, N., Takatori, K.,Goto, S., 2006. Genotoxicity of microbial volatile organic compounds. J. HealthSci. 52 (2), 148–153.


RIFM (Research Institute for Fragrance Materials, Inc.), 1979. Acute toxicity studieson 2-methylbutanol. Unpublished report from BASF, Report number 55366.RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1985. Report on the acuteoral toxicity of 2-methylbutanol in rats. Unpublished report from BASF, Reportnumber 55365. RIFM, Woodcliff Lake, NJ, USA.

Rowe, V.K., McCollister, S.B, 1982. Alcohols. In: Industrial Hygiene and Toxicology,third ed., vol. 11C, pp. 4527–4708 (Chapter 55).

Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., Striegel, J.A., 1962. Range-finding toxicity data: list VI. Am. Ind. Hyg. Assoc. J. (AIHAJ) 23, 95–107.

Strubelt, O., Deters, M., Pentz, R., Siegers, C.P., Younes, M., 1999. The toxic andmetabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver.Toxicol. Sci. (formerly Fundam. Appl. Toxicol.) 49 (1), 133–142.

VCF, 2009. Volatile compounds in food: database. In: Nijssen, L.M., Ingen-Visscher,C.A. van., Donders, J.J.H. (Eds.), Version 11.1.1 – Zeist. TNO Quality of Life, TheNetherlands, pp. 1963–2009.


Review

Fragrance materials review on isoamyl alcohol

D. McGinty *, A. Lapczynski, J. Scognamiglio, C.S. Letizia, A.M. ApiResearch Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA


Keywords:ReviewFrangrance

a b s t r a c t

A toxicologic and dermatologic review of isoamyl alcohol when used as a fragrance ingredient is pre-sented. Isoamyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.The common characteristic structural elements of the alcohols with saturated branched chain are onehydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. Thisreview contains a detailed summary of all available toxicology and dermatology papers that are relatedto this individual fragrance ingredient and is not intended as a stand-alone document. A safety assess-ment of the entire branched chain saturated alcohol group will be published simultaneously with thisdocument; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this materialand all other branched chain saturated alcohols in fragrances.


Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1031. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1032. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1033. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1034. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S104

4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1044.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1044.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.1.3. Intravenous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105

4.2. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.2.1. Human studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105

4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.4. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105

4.5. Phototoxicity and photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.6. Absorption, distribution, and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S105

4.6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1054.6.2. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106

4.7. Repeated dose toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1064.7.1. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1064.7.2. Chronic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S106

4.8. Reproductive and developmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1074.9. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107

4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1074.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107







4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1074.11. Neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108

Introduction

This document provides a comprehensive summary of the tox-icologic review of isoamyl alcohol when used as a fragrance ingre-dient including all human health endpoints. Isoamyl alcohol (seeFig. 1; CAS Number 123-51-3) is a fragrance ingredient used in cos-metics, fine fragrances, shampoos, toilet soaps, and other toiletriesas well as in non-cosmetic products such as household cleanersand detergents. It is a colorless liquid with a disagreeable alcoholodor only becoming a pleasant fruity-winey odor at high dilutions(Arctander, 1969). This material has been reported to occur in nat-ure, with the highest quantities observed in the brassica species ofmustard (VCF, 2009).

In 2006, a complete literature search was conducted on isoamylalcohol. On-line toxicological databases were searched includingthose from the Chemical Abstract Services [e.g. ToxCenter (whichin itself contains 18 databases including Chemical Abstracts)],and the National Library of Medicine [e.g. Medline, Toxnet (whichcontains 14 databases)] as well as 26 additional sources (e.g. BIO-SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companieswere asked to submit all test data.

The safety data on this material was last reviewed by Opdyke(1979). All relevant references are included in this document. Moredetails have been provided for unpublished data. The number ofanimals, sex, and strain are always provided unless they are not gi-ven in the original report or paper. Any papers in which the vehi-cles and/or the doses are not given have not been included in thisreview. In addition, diagnostic patch test data with fewer than 100consecutive patients have been omitted.

1. Identification

1.1. Synonyms: 1-butanol, 3-methyl-; isobutyl carbinol; isopent-anol; isopentyl alcohol; 3-methyl-1-butanol; 3-methylb-utan-1-ol.

1.2. CAS Registry Number: 123-51-3.1.3. EINECS Number: 204-633-5.1.4. Formula: C5H12O.1.5. Molecular weight: 88.15.1.6. Council of Europe (2000): isoamyl alcohol was included by

the Council of Europe in the list of substances granted A –may be used in foodstuffs (COE Number 51).

1.7. FDA: isoamyl alcohol was approved by the FDA as flavor (21CFR 172.515).


1.9. JECFA (1996): the Joint FAO/WHO Expert Committee onFood Additives (JECFA) concluded that the substance doesnot present a safety concern at current levels of intake whenused as a flavoring agent (52).

1.10. OSHA: isoamyl alcohol was listed by the Occupational Safetyand Health Administration as PEL-TWA 100 ppm, 360 mg/m3 (for primary and secondary).


2.1. Physical form: colorless liquid with a disagreeable alcoholodor and pungent, repulsive taste.

2.2. Flash point: 109 �F; CC.2.3. Boiling point: 132 �C.2.4. Henry’s law (calculated; EPA, 2010): 0.0000133 atm m3/mol

(25 �C).2.5. Log Kow (measured; EPA, 2010): 1.16.2.6. Specific gravity: 0.81.2.7. Refractive index: 1.4.2.8. Vapor pressure (calculated; EPA, 2010): 3.84 mm Hg at

(25 �C); 512 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 41,580 mg/l at

25 �C.2.10. UV spectra available at RIFM. Does not absorb UV light.Fig. 1. Isoamyl alcohol.

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing isoamyl alcohol.



Total 0.0002



3. Usage

Isoamyl alcohol is a fragrance ingredient used in decorative cos-metics, fine fragrances, shampoos, toilet soaps, and other toiletriesas well as in non-cosmetic products such as household cleanersand detergents. Its use worldwide is in the region 0.1–1.0 metrictons/annum (IFRA, 2004). The reported volume of use is for iso-amyl alcohol as used in fragrance compounds (mixtures) in all fin-ished consumer product categories. The volume of use is surveyedby IFRA approximately every four years through a comprehensivesurvey of IFRA and RIFM member companies. As such the volumeof use data from this survey provides volume of use of fragranceingredients for the majority of the fragrance industry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in 10 types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of severalthousand commercial formulations. The upper 97.5 percentile con-centration is calculated from the data obtained. This upper 97.5 per-centile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account forthe length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been reported to be 0.01% (IFRA, 2007), whichwould result in a conservative calculated maximum daily exposureon the skin of 0.0002 mg/kg for high end users of these products(see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The maximum skin level that re-sults from the use of isoamyl alcohol in formulae that go into finefragrances has been reported to be 0.012% (IFRA, 2007), assuminguse of the fragrance oil at levels up to 20% in the final product.

4. Toxicology data


4.1.1. Oral studiesAs a preliminary study for a mouse micronucleus test, acute oral

toxicity was evaluated with four (2/sex) animals. The NMRI micewere treated orally with the 0.1, 0.5, 1.0, or 2.0 g/kg of isoamylalcohol and examined for acute toxic symptoms at intervals ofaround 1, 2–4, 6, 24, 30, and 48 h after administration. At the high-est dose of 2.0 g/kg bodyweight the toxic effects observed were areduction in spontaneous activity, eyelid closure, and ruffled fur.No mortality was observed at the highest dose which indicatedthe LD50 to be greater than 2.0 g/kg (RIFM, 2008).

The acute oral LD50 of isoamyl alcohol in rats was reported to be4.36 g/kg (no further details provided) (Golovinskaya, 1976).

The oral LD50 of isoamyl alcohol in rats was reported to be 1.3 g/kg (no further details provided) (Nishimura et al., 1994).

The acute oral (gavage) LD50 was evaluated in groups of 4 ratswith isoamyl alcohol at a dose range of 0.325–4.95 and 0.81–12.0 g/kg (concentration not reported) in polyethylene glycol 200for male and female, respectively. Deaths in female rats occurred4 h after high doses (4.95 and 12.0 g/kg); none died in the 10 daysafter the lower doses (0.81 and 2.0 g/kg). Males receiving the high-est doses of 4.95 g/kg and a group receiving 12.0 g/kg died within4 h, and several at the lower doses of 0.81 and 2.0 g/kg died1–5 days later. Histological examination of the liver revealedhyperemia but very few degenerative changes. Females receiving4.95 g/kg showed cloudy swelling and cast formation in the cortex


Route Species Numberof animals/dose group


Oral Mice 4 >2.0 RIFM (2008)Oral Rat N/A 4.36 Golovinskaya (1976)Oral Rat N/A 1.3 Nishimura et al. (1994)Oral Rat 4 1.3 (male) Purchase (1969)

4.0 (female)Oral Rat 5 7.1 Smyth et al. (1969)Oral Rat N/A >5.0 RIFM (1979)Oral Rabbit 10–35 3.44 Munch (1972)Dermal Rabbit 10 >5.0 RIFM (1976a)Dermal Rabbit 4 3.97 Smyth et al. (1969)Dermal Rabbit 6 4.0 RIFM (1979)Intravenous Mice N/A 0.23 Chvapil et al. (1962)

Table 3Summary of human skin irritation studies.

Method Concentration Results References

Reactions Frequency (%)

48 h closed patch test 8% in petrolatum 0/25 0 RIFM (1976b)5 min, occlusive patch test 75% in water 12/12 100 Wilkin and Fortner (1985a)5 min, occlusive patch test 75% in water 3/3 100 Wilkin and Fortner (1985b)5 min, occlusive patch test 75% in a hydrophilic ointment 12/12 100 Wilkin and Stewart (1987)



Single application of 5.0 g/kg 100 Rabbit Marked erythema and moderate edema RIFM (1976)0.01 ml aliquot applied to the clipped skin 100 Rabbit Irritation observed Smyth et al. (1969)Single application 100 Rabbit Very irritating RIFM (1979)


and a few pyknotic tubular cells in the medulla section of the kid-ney. In females receiving 12.0 g/kg, the cortex showed signs ofnecrosis with some tubular cells showing pyknosis. In males pyk-nosis and hyperemia were seen in the outer zone of the medullain all groups, and tubular necrosis was seen in the cortex afterthe two highest doses (2.0 and 4.95 g/kg). The calculated LD50

was 4.0 g/kg (95% limits: 2.45–6.17 g/kg) for female and 1.3 g/kg(95% limits: 0.67–2.41 g/kg) for male (Purchase, 1969).

Groups of five Carworth-Wistar male rats were administered asingle dose of undiluted isoamyl alcohol by gavage. The oral LD50

of was reported to be 7.1 g/kg with limits of 4.82–10.4 g/kg (Smythet al., 1969).

Isoamyl alcohol was reported to have an LD50 greater than 5.0 g/kg in Sprague Dawley rats. The animals were given doses of 2.15 or5.0 g/kg and observed for 14 days (RIFM, 1979).

The acute oral (gavage) LD50 of isoamyl alcohol was reported tobe 39 mmol/kg (3.45 g/kg). Administration was via stomach tubefrom a 50 ml syringe to groups of 10–35 rabbits (Munch, 1972).

4.1.2. Dermal studiesThe acute dermal LD50 of isoamyl alcohol was evaluated in 10

rabbits. Each animal received a single dermal application of undi-luted isoamyl alcohol at a dose of 5.0 g/kg. Clinical signs and/ormortality were observed over a 14 day period. No deaths were ob-served. Clinical signs included flaccidity, ataxia, loss of righting re-flex and diarrhea. The LD50 was reported to be greater than 5.0 g/kg(RIFM, 1976a).

The acute dermal LD50 was evaluated in groups of four male al-bino New Zealand rabbits. Undiluted isoamyl alcohol at 0.1 ml wasapplied to the clipped trunk, and kept in place beneath an imper-vious plastic film for 24 h (doses and skin area not provided). TheLD50 was reported to be 3.97 g/kg with limits of 2.93–5.37 g/kg(Smyth et al., 1969).

Isoamyl alcohol was reported to have a dermal LD50 of 4 ml/kg(�4 g/kg) in rabbits. The animals were given undiluted doses ofisoamyl alcohol and observed for 8 days (RIFM, 1979).

4.1.3. Intravenous studiesThe intravenous LD50 of isoamyl alcohol in water was deter-

mined in female white H strain mice. Using an approximate gra-phic probit method, the LD50 was calculated to be 2.64 mmol/kg(�233 mg/kg; no further details provided) (Chvapil et al., 1962).

The hemodynamic effects of isoamyl alcohol were studied in 56anesthetized, open chest dogs. The material was administered i.v.at a constant rate for 40–150 min. The infusion of 20 mg/kg/mindecreased heart rate, systemic arterial pressure, and myocardialcontraction force progressively and markedly. All dogs died duringthe first hour of infusion (Nakano and Kessinger, 1972).

Isoamyl alcohol was injected into the vein of cat, under a lightether anesthesia, to determine the lethal dose. In terms of the purealcohol of 0.26 ml/kg (�260 mg/kg) was determined to be lethal(Macht, 1920).

4.1.4. Inhalation studiesSmyth et al. (1969) reported no death up to 8 h when concen-

trated vapors of isoamyl alcohol were exposed to rats byinhalation.

Sensory irritation was evaluated in four Swiss male mice viameasurement of changes in respiratory rate during a 10 min expo-sure to isoamyl alcohol. The concentration of isoamyl alcohol thatcaused a 50% decrease in the respiratory rate (RD50) of mice was4452 ppm with 95% confidence limits of 2885–12,459 (Kaneet al., 1980).

Rats inhaled isoamyl alcohol as a steam vapor in an enrichedatmosphere at 20 �C. After a 7 h exposure, no animals died (RIFM,1979).


4.2.1. Human studies (see Table 3)In a pre-test for a human maximization study, a 48 h closed

patch test was conducted on the volar forearms or backs of 25 vol-unteers with 8% isoamyl alcohol in petrolatum. No irritation wasobserved (RIFM, 1976b).

Patch tests were conducted on 27 (groups of 12, 12, and 3)healthy volunteers with 75% aqueous solution of isoamyl alcohol.Patches were applied to the subjects’ forearms, and were removedafter being occluded for 5 min. Irritation reactions were observedin all volunteers (Wilkin and Fortner, 1985a,b; Wilkin and Stewart,1987).

4.2.2. Animal studies (see Table 4)Irritation was evaluated during a dermal LD50 study. A single

application of 5.0 g/kg of neat isoamyl alcohol was made to 10 rab-bits. Marked or moderate edema were observed in 10/10 rabbits(RIFM, 1976a).

Primary skin irritation was determined using groups of five al-bino rabbits. A 0.01 ml aliquot of isoamyl alcohol was applied tothe clipped skin of the animals undiluted or as a solution in water,propylene glycol or acetone. Irritation reactions were observed(Smyth et al., 1969).

Isoamyl alcohol was reported to be very irritating when appliedundiluted to the skin of six rabbits. Irritation resolved after 8 days(RIFM, 1979).


An eye irritation test was conducted in five rabbits per dose. Iso-amyl alcohol (0.5 ml aliquot) was tested undiluted or as a solutionin propylene glycol and water. Irritant effects were observed(Smyth et al., 1969).

An eye irritation test was conducted in two rabbits with undi-luted isoamyl alcohol. Irritation was observed up to 8 days in onerabbit (RIFM, 1979).


4.4.1. Human studiesA maximization study was conducted on 25 (5 male, 20 female)

volunteers. Isoamyl alcohol at 8% in petrolatum was applied underocclusion to the volar forearms or backs for five alternate days,48 h periods. The sites were pre-treated for 24 h with 2.5% aqueoussodium lauryl sulfate (SLS) under occlusion. The challenge phasewas conducted after a rest period of 10–14 days at sites pre-treatedfor 1 h with 5–10% SLS. The challenge patch was removed after48 h, and the site was read at the patch removal and 24 h afterthe patch removal. No reactions were observed (RIFM, 1976b).

4.4.2. Animal studiesNo data available.


No data available.

4.6. Absorption, distribution, and metabolism

4.6.1. Distribution4.6.1.1. Human studies. Respiratory uptake of isoamyl alcohol wasinvestigated in four healthy volunteers. Test air concentrationwas 25–200 ppm and it was inhaled for 10 min. The mean uptake(determined using calculations based on exhalation percentages ofisoamyl alcohol to mixed exhaled air) for the last 5 min of the test


respiration was 63% and the mean respiratory rate was 15.3 min�1

(Kumagai et al., 1998).

4.6.1.2. Animal studies. Groups of 10 rats per dose received 600 mgof 20% isoamyl alcohol/l solution (either in ethanol or water) byintraperitoneal injection in four equally divided portions of2.5 ml/100 g of bodyweight, at 15 min intervals. Two hours afteradministration, the blood concentration of isoamyl alcohol withethanol was maximal. It declined thereafter and was still detect-able at 10 h but not at 12 h. When isoamyl alcohol was adminis-tered in water, its presence in the blood was discernible 2 h afteradministration but not thereafter (Greenberg, 1970).

A single dose of 2.0 g/kg of isoamyl alcohol, in an aqueous solu-tion of 20%, was given orally to fasted six Wistar WAG rats. Bloodand urine were collected for up to 8 h for measurement of testmaterial levels. The blood level in mg/100 ml was 7 at 15 min, 9at 30 min, 17 at 1 h, 8 at 1.5 h, 7 at 2 h, 3 at 4 h, and 1 at 8 h. Uri-nary excretion was 0 (Gaillard and Derache, 1965).

After intraperitoneal administration of 1000 mg bodyweight,the concentration of isoamyl alcohol in blood declined within 5 hto non-detectable levels. An elimination half-life was not calcu-lated. For isoamyl alcohol 1.2% was excreted via urine and expiredair. Compared to other amyl alcohols tested by the authors, pri-mary alcohols were eliminated from the blood more quickly thansecondary and tertiary alcohols (Haggard et al., 1945).

4.6.2. Metabolism4.6.2.1. Human studies. The glucuronidation of isoamyl alcohol andother short-chained aliphatic alcohols was investigated in vitrowith human liver microsomes. The Vmax value was 3.3 nmol/min/mg protein and the Km was determined as 13.3 mM. The glucuron-idation increased with chain length (C2–C5) of the alcohols studied(Jurowich et al., 2004).

The rate of oxidation of isoamyl alcohol by human skin alcoholdehydrogenase was 183.3 nM/mg protein/min (Wilkin and Stew-art, 1987).

4.6.2.2. Animal studies. A single oral (gavage) dose of 25 mmol/3 kgrabbit (�734.6 mg/kg) of isoamyl alcohol in water was given tothree chinchilla rabbits. Increases in the urinary excretion of glucu-ronides were monitored. Of the dose, 9% was excreted in the urine(at 24 h) as the glucuronide. The urine did not contain aldehydes orketones (Kamil et al., 1953).

In isolated perfused livers of rats, 65.1 mmol isoamyl alcohol/lwere cytotoxic as evidenced by the release of liver enzymes intothe perfusate. The alcohols decreased the content of ATP in the li-ver. The content of oxidized glutathione was increased. Lipid per-oxidation was not observed (Strubelt et al., 1999).

Age-dependent glucuronidation activity was demonstratedin vitro in the olfactory mucosa of 1 day, 1 week, 2 week, 3 month,12 month, and 24 month old male Wistar rats with isoamyl alcohol(Leclerc et al., 2002).

Oxidation to the aldehyde and glucuronidation was demon-strated for isoamyl alcohol with microsomes from rats pre-treatedwith ethanol (Iwersen and Schmoldt, 1995).

The rate of oxidative metabolism of isoamyl alcohol was about0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g per-fused rat liver (Hedlund and Kiessling, 1969).

The Km-values of isoamyl alcohol with alcohol dehydrogenasefrom human and horse liver were 0.07 and 0.08 mM, respectively(Pietruszko et al., 1973).


4.7.1. Subchronic studiesGroups of 10 Ash/CSE rats (5/sex) were administered 500 or

1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,7 days a week for 6 weeks. A group of 10 controls (5/sex) wereadministered corn oil alone. Observations included mortality,behavior, bodyweight, food and water consumption, renal concen-tration, organ weights, and gross pathology. Blood was examinedfor hemoglobin content, packed cell volume, and counts of erythro-cytes, reticulocytes, as well as total and differential leukocytes. Ser-um was analyzed for the content of urea, glucose, total protein, andalbumin as well as activities of glutanic–oxalacetic and glutamic–pyruvic trasaminases and lactic dehydrogenase. With 500 mg/kg,a significant increase in the hemoglobin concentration and redblood cell count of test females was observed when compared tothe controls, but the increases were not dose-related. With1000 mg/kg, a lower pituitary weight in males was observed, butwhen expressed relative to bodyweight, the decrease was not evi-dent. At both doses, red patches on the lungs of male and femaletreated animals and control animals were found at the necropsy.Histopathological examination of the lungs revealed lymphocytecuffing of the bronchi, but the incidence and severity were similarin both the test and control animals. The authors have concludedthe NOAEL to be 1000 mg/kg in females and 500 mg/kg in males(Carpanini et al., 1973).

Groups of 20 SPF-Wistar, Chbb:THOM rats (10/sex) wereadministered isoamyl alcohol in drinking water at 1000 ppm(�80 mg/kg), 4000 ppm (�320 mg/kg), and 16,000 ppm(�1280 mg/kg) for 90 days. A group of 20 controls (10/sex) wereadministered drinking water alone. Parameters evaluated includedbodyweight, food and water consumption, clinical signs, mortality,hematology, clinical chemistry, gross and microscopic pathology.The erythrocyte count was slightly elevated in males treated with4000 ppm (320 mg/kg). With 16,000 ppm (1280 mg/kg), an in-crease in the erythrocyte count, a decrease in the mean corpuscularvolume, and a decrease in the mean corpuscular hemoglobin con-tent of the blood in male rats were observed. Compared to the con-trols, a significant deviation from the control group leukocytecount was observed in males at 1000 ppm (80 mg/kg), and in theprothrombin time in females treated with 4000 and 16,000 ppm(320 and 1280 mg/kg). However, these observed effects did not ap-pear to be relevant to the treatment. Ectopia of thymus tissue inthe region of the thyroid gland was observed in five males treatedwith 16,000 ppm (1680 mg/kg). The no-observable-adverse-effect-level (NOAEL) of isoamyl alcohol was concluded to be 4000 ppm(320 mg/kg) in males and 16,000 ppm (1680 mg/kg) in females(Schilling et al., 1997; RIFM, 1991).

4.7.2. Chronic studiesGroups of 30 Ash/CSE rats (15/sex) were administered 150, 500,

and 1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,7 days a week for 17 weeks. A group of 30 controls (15/sex) wereadministered corn oil alone. Observations included mortality,behavior, bodyweight, food and water consumption, hematology,serum analysis, urinalysis, renal concentration, organ weights,and gross pathology. Microscopic pathology was examined forthe highest dose only. There were no effects associated with treat-ment in the results of the hematological examinations, serum anal-yses, urinary cell counts, renal concentration tests, or organweights. A slight reduced rate of bodyweight gain at the highestdose level was shown to be due to a reduced food intake. Two ratsin the highest dose level died, but histopathological examinationshowed that these deaths were due to dosing into the lungs andnot to any toxic effects of isoamyl alcohol. A female rat given500 mg/kg/day developed a lipoma, which was not considered to


be due to treatment. The other histopathological changes seenwere related to mild infections in the animals and not to isoamylalcohol. The NOAEL was concluded to be 1000 mg/kg/day (Carpa-nini et al., 1973).

Astill et al. (1996) gave 0 (water), 0 (vehicle), 50, 200, or750 mg/kg bodyweight/day in 0.005% cremophor EL to B6C3F1mice (50/sex). For 18 months, 5 days a week, animals were treatedwith isoamyl alcohol by gavage. Increased mortality, and decreasesin bodyweight gains, and food consumption were observed at750 mg/kg as well as fatty liver and hyperplasia of the forestomachepithelium. A systemic NOAEL of 200 mg/kg bodyweight wasdetermined.

4.8. Reproductive and developmental

Groups of 25 pregnant rats were exposed to a vapor–air mixtureof isoamyl alcohol at concentrations of 0.5, 2.5, and 10 mg/l, 6 h/day from gestation day (GD) 6–15. In rats exposed to 10 mg/l body-weight gain was decreased between GD 6 and 9 and increased be-tween GD 12–15, however no biologically relevant orconcentration related differences were apparent among thegroups. At 0.5 mg/l fetal examination revealed skeletal changes:malformations of the sternebrae and/or the vertebral column. With2.5 mg/l, the observed fetal anomalies included soft tissue changessuch as a globular shaped heart and dextrocardia, and skeletalchanges: malformations of the sternebrae and/or the vertebral col-umn. At 10 mg/l observed fetal anomalies included externalchanges such as polydactyly and skeletal changes: malformationsof the sternebrae and/or the vertebral column. With all the testedconcentrations, retardations such as incomplete or missing ossifi-cation of hyoid, skull bones, metacarpal or metatarsal bones, verte-bral bodies, and/or sternebrae were observed. The NOAEL for damswas 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig, 1995;RIFM, 1990a).

As a part of the same experiment, groups of 15 pregnant Hima-layan rabbits Chbbb:HM per dose were exposed to 0.5, 2.5, and10 mg/l isoamyl alcohol on gestation days 7–19. At 10 mg/l a slightretardation of bodyweight increase was observed throughout thewhole exposure period and was significant on GD 7–10. Also, at10 mg/l an indication of an irritant eye effect (reddish, lid closure,or slight discharge) was also observed during the exposure period.In fetuses pseudoankylosis and soft tissue changes such as hypo-plasia of the gall bladder, bipartite ovary, dilated renal pelvis,and/or separate origin of carotids were observed at all doses. How-ever, it was noted that these findings occurred at a similar inci-dence rate in historical controls. Observed skeletal changesincluded malformations of the sternebrae and/or the vertebral col-umn, the sternum and the ribs. They were seen in all groups with-out apparent dose relationships or statistically significantdifferences between the groups. The only significant differencesof note were due to the increased incidence of two specific typesof soft tissue variation (the separated origin of carotids and tracesof interventricular foramen/septum membranaceum) which oc-curred without a clear concentration relationship. The NOAEL fordams was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig,1995; RIFM, 1990b).

4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems. Isoamyl alcohol was negative in aumu test for light absorption in Salmonella typhimurium TA1535/pSK1002 at concentrations in which growth inhibition was 650%.However, isoamyl alcohol was positive when tested in a umu testfor luminescence with S. typhimurium TA1535/pTL210 at concen-trations in which growth inhibition was 650% (Nakajima et al.,2006).

4.9.1.2. Studies in mammalian cells (see Table 5). A Comet assay wasconducted on human lung carcinoma A549 cells and humanperipheral blood pB cells. Induced DNA damage was only observedat cytotoxic concentrations of isoamyl alcohol such as 23, 46, and91 mM (Kreja and Seidel, 2002).

An alkaline single cell gel electrophorese assay (comet assay)was conducted on Chinese hamster V79 fibroblasts, and DNA dam-age induced by isoamyl alcohol was observed at cytotoxic concen-trations of 23, 46, and 91 mM (Kreja and Seidel, 2002).

A micronucleus assay was conducted on Chinese hamster fibro-blast V79 cells, with isoamyl alcohol at concentrations of 5, 9, and23 mM in the presence and absence of metabolic activation (S9).No genotoxic effects were produced at any of the tested concentra-tions (Kreja and Seidel, 2002).

No mutagenicity was produced in a hypoxanthine–guaninephosphoribosyltransferase (HPRT) assay conducted on Chinesehamster lung fibroblast cell line V79, with 51.5 mM of isoamylalcohol in the presence or absence of metabolic activation (S9)(Kreja and Seidel, 2002).

4.9.2. In vivo studiesAn in vivo micronucleus assay was conducted with bone mar-

row cells of NMRI mice with isoamyl alcohol at doses of 500,1000, and 2000 mg/kg. Ten animals (5/sex) were evaluated at 24and 48 h after a single administration for the occurrence of micro-nuclei. There was no increase in the frequency of detected micro-nuclei. Isoamyl alcohol was determined to be non-mutagenic inthe micronucleus assay (RIFM, 2008).


A group of 15 Wistar rats were administered 0.1 ml/kg (�0.1 g/kg) of isoamyl alcohol by gavage, twice a week up to the time oftheir spontaneous deaths. The average total dosage was 27 ml(�27 g). The 25 controls were treated with 1 ml/kg (�1 g/kg) of a0.9% NaCl solution, twice weekly. The animals were weighed atregular intervals, and most were subjected to hematological test-ing. At the time of spontaneous death, a necropsy, histologicalexaminations of all organs, vertebrae, and femur, and additionalhematological tests were conducted. The average survival time ofthe control animals was 643 days. A wide spectrum of tumorswas observed from bladder carcinoma, carcinoma of the kidneypelvis, adenocarcinoma of the proventriculum to benign tumorssuch as papillomae and occasional incipient infiltrative growth.The number of malignant and benign tumors found was 0 and 3,

Table 5Summary of studies in mammalian cells.

Test system Concentration (mM) Results References

Comet assay Human lung carcinoma A549 cells 23, 46, and 91 Not genotoxic Kreja and Seidel (2002)Comet assay Human lung peripheral blood pB cells 46 and 91 Not genotoxic Kreja and Seidel (2002)Comet assay Chinese hamster fibroblast V79 cells 23 and 91 Not genotoxic Kreja and Seidel (2002)Micronucleus assay Chinese hamster fibroblast V79 cells 5, 9, and 23 Not genotoxic Kreja and Seidel (2002)HPRT assay Chinese hamster lunch fibroblast V79 cells 51.5 Not genotoxic Kreja and Seidel (2002)


respectively. The average survival time of test animals was527 days, and the number of malignant and benign tumors foundwas 4 and 3, respectively (Gibel et al., 1975).

As a part of the same experiment group of 24 Wistar rats weresubcutaneously administered 0.04 ml/kg (�0.04 g/kg) of isoamylalcohol, once a week up to the time of their spontaneous deaths.The average total dosage was 3.8 ml (�3.8 g/kg). The controls weresubcutaneously treated with 1 ml/kg (�1 g/kg) of a 0.9% NaCl solu-tion, twice weekly. The average survival time of the control ani-mals was 643 days, and the number of malignant and benigntumors found was 0 and 2, respectively. The average survival timeof test animals was 592 days, and the number of malignant and be-nign tumors found was 10 and 5, respectively. The tumors con-sisted of pancreas adenomas, adenomas of the proventriculusand of suprarenal glands, spleen fibromas to the benign small pap-illomas or fibroadenomas (Gibel et al., 1975).

4.11. Neurotoxicity

Male albino SPF rats derived from the Wistar strain, or femalemice of the H strain were used to study the neurotoxicity of iso-amyl alcohol. Whole body exposures were carried out in 80-l glasschambers with 1 rat or 2 mice. In total 16 rats (4/group) or 32 micewere exposed. Less than 1 min after removal from the exposurebox, a short electrical impulse was applied through ear electrodesto the animals to measure the biological effect of isoamyl alcohol.Of the six time characteristics recorded, duration of toxic extensionof hind limbs was measured, as this was considered the most sen-sitive and reproducible response measures. All animals were giventhree control tests at weekly intervals before the 1st exposure.Most animals went through 3–4 exposure to each concentration,and the interval between exposures was at least 3 weeks. The con-centration that evoked a 30% depression in the recorded activity(M) was determined to be 1700 ppm in rats and 950 ppm in mice(Frantik et al., 1994).

Male Sprague–Dawley rats were divided into groups of four orfive and orally administered 325 mg/kg of isoamyl alcohol. Twohours after administration acetylcholine, 3,4-dihydroxyphenylala-nine (DOPA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxy-phenylglycol (MHPG), serotonin, and 5-hydroxyindoleacetic acid(5HIAA) contents in the small-brain regions were measured. Underthe conditions of this study, a single dose of 325 mg/kg adminis-tered by gavage to rats resulted in increases in 5HIAA in the mid-brain and MHPG in the medulla oblongata. Decreases occurred innorepinephrine in the midbrain and in 5HIAA in the hypothalamus(Kanada et al., 1994).




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Review

Fragrance material review on 2,6-dimethyl-2-heptanol




a b s t r a c t

A toxicologic and dermatologic review of 2,6-dimethyl-2-heptanol when used as a fragrance ingredient ispresented. 2,6-Dimethyl-2-heptanol is a member of the fragrance structural group branched chain satu-rated alcohols. The common characteristic structural elements of the alcohols with saturated branchedchain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl sidechains. This review contains a detailed summary of all available toxicology and dermatology papers thatare related to this individual fragrance ingredient and is not intended as a stand-alone document. A safetyassessment of the entire branched chain saturated alcohol group will be published simultaneously withthis document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this mate-rial and all other branched chain saturated alcohols in fragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1124.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1124.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1124.2.1. Human studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1124.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S112

4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.4.2. Maximization studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.4.3. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.4.4. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S113

4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.5.1. Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1134.5.2. Photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114

4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1144.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1144.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1144.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114

4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S114







Introduction

This document provides a summary, including all human healthendpoints, of the toxicologic review of 2,6-dimethyl-2-heptanolwhen used as a fragrance ingredient. 2,6-Dimethyl-2-heptanol(see Fig. 1; CAS Number 13254-34-7) is a fragrance ingredient usedin cosmetics, fine fragrances, shampoos, toilet soaps and other toi-letries as well as in non-cosmetic products such as householdcleaners and detergents. It is a colorless liquid with a fresh, woody,floral odor.

In 2006, a complete literature search was conducted on 2,6-di-methyl-2-heptanol. On-line toxicological databases were searchedincluding those from the Chemical Abstract Services, [e.g., ToxCen-ter (which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g., Medline,Toxnet (which contains 14 databases)] as well as 26 additionalsources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-grance companies were asked to submit all test data.

The safety data on this material was last reviewed by Ford et al.(1992). All relevant references are included in this document. Moredetails have been provided for unpublished data. The number ofanimals, sex and strain are always provided unless they are not gi-ven in the original report or paper. Any papers in which the vehi-cles and/or the doses are not given have not been included in thisreview. In addition, diagnostic patch test data with fewer than 100consecutive patients have been omitted.

1. Identification

1.1. Synonyms: dimetol; freesiol; 2-heptanol, 2,6-dimethyl-; lol-itol; 2,6-dimethylheptan-2-ol.

1.2. CAS Registry number: 13254-34-7.1.3. EINECS number: 236-244-1.1.4. Formula: C9H20O.1.5. Molecular weight: 144.26.


2.1. Physical form: a colorless liquid with a fresh, woody, floralodor.

2.2. Boiling point (calculated; EPA, 2010): 172.11 �C.2.3. Flash point: 145�F; CC.2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol

25 �C.2.5. Log Kow: 3.0 at 45 �C.2.6. Refractive index: 1.4259.2.7. Specific gravity: 0.8135.2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 �C);

0.364 mm Hg (25 �C); 48.5 Pa (25 �C).2.9. Water solubility (calculated; EPA, 2010): 572 mg/l (25 �C).

2.10. UV spectra available at RIFM, does not absorb UV light.

3. Usage

2,6-Dimethyl-2-heptanol is a fragrance ingredient used in manyfragrance compounds. It may be found in fragrances used in deco-rative cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of 10–100 metric tons per annum (IFRA, 2004). The reported volume ofuse is for 2,6-dimethyl-2-heptanol as used in fragrance compounds(mixtures) in all finished consumer product categories. The volumeof use is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies. Assuch the volume of use data from this survey provides volume ofuse of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of severalthousand commercial formulations. The upper 97.5 percentile con-centration is calculated from the data obtained. This upper 97.5 per-centile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account forthe length of time a product may remain on the skin and/or likeli-hood of the fragrance ingredient being removed by washing. Theresultant calculation represents the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-2-heptanol.




HO

Fig. 1. 2,6-Dimethyl-2-heptanol.


This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-ics in general has been reported to be 2.41 (IFRA, 2007), whichwould result in a maximum daily exposure on the skin of0.0614 mg/kg for high end users (see Table 1).


4. Toxicology data


4.1.1. Oral studiesTen rats were given a single dose of 2,6-dimethyl-2-heptanol at

5.0 g/kg. Observations for mortality and or systemic effects weremade. At 5.0 g/kg, 2/10 deaths occurred within the first day. Symp-toms observed between 2 and 24 h were lethargy (in 3/8 rats),ataxia, piloerection (in 2/8 rats), and some loss of righting reflex.At necropsy two of the rats showed redness through the lungsand stomach. The acute oral LD50 in rats was resolved to be greaterthan 5.0 g/kg (RIFM, 1976a).

Rats were orally given 2,6-dimethyl-2-heptanol as a 31.6–50%emulsion in olive oil. Observations for mortality and/or systemiceffects were made. The acute oral LD50 in rats was calculated tobe greater than 6.8 g/kg (RIFM, 1979).

4.1.2. Dermal studiesThe acute LD50 in rabbits exceeded 5.0 g/kg based on 0 deaths in

10 animals tested at that dose. Ten rabbits received a single dermalapplication at a dose level of 5.0 g/kg bodyweight. Mortality and/orsystemic effects were not observed (RIFM, 1976a).


4.2.1. Human studies (see Table 3)In an irritation screen for a maximization test, 10% 2,6-di-

methyl-2-heptanol in petrolatum was applied to the forearms orbacks of 25 subjects for 48 h under occlusion. No irritation was ob-served (RIFM, 1976b).

Irritation was assessed during an associated phototoxicitystudy. Six healthy female volunteers, 20–40 years old were used.The vehicle was 1:1 ethanol/acetone. Prior to the application of2,6-dimethyl-2-heptanol, 36 test sites (each 2 cm2) were markedon the back (1.5 cm apart). 2,6-Dimethyl-2-heptanol was then ap-plied in a dose volume of 0.025 ml/2 cm2 in 1:1 ethanol/acetone.The right hand test site was covered and served as an irritancy con-

trol site. No effects were observed in any of the subject’s exposedto 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/acetone withoutirradiation (irritancy control sites) (RIFM, 1983).

A preliminary primary irritation study was conducted prior tothe associated Human Repeated Insult Patch Test (HRIPT) todetermine irritation potential of 2,6-dimethyl-2-heptanol. A pilotgroup of 10 healthy male and female subjects, ranging in agefrom 18 to 72 were used. The 10 subjects in the pilot group be-came part of the full complement of 57 subjects that startedthe associated HRIPT. By the end of the induction period, these10 individuals had had 11 induction applications as comparedto the remaining individuals who were subjected to 10 inductionapplications. At 2% 2,6-dimethyl-2-heptanol no effects were ob-served (RIFM, 1969).

Irritation was assessed with a panel of 10 volunteers duringpreliminary test for an HRIPT. The test patch consisted of a 1 � 1inch Webril swatch and 0.5 ml aliquot of 5% 2,6-dimethyl-2-hept-anol in alcohol SDA 39C. A series of nine 24 h exposures over threesuccessive weeks caused little to no irritation (RIFM, 1971a).

A preliminary primary irritation study was conducted prior tothe associated Repeated Insult Patch Test to determine irritationpotential. Thirty-five subjects (10 males and 25 females) com-pleted the study. The test patch was a 1 inch square of Webrilswatch with 0.5 ml of 5% 2,6-dimethyl-2-heptanol in alcohol SDA39C. A series of nine 24 h exposures over three successive weekscaused little to no irritation (RIFM, 1972).

4.2.2. Animal studies (see Table 4)As part of an associated acute toxicity study with a 5 g/kg neat

application of 2,6-dimethyl-2-heptanol, rabbits were observed forirritation. Slight redness in 2, moderate redness in 8, slight edemain 1, and moderate edema in 9 animals was observed (RIFM,1976a).

2,6-Dimethyl-2-heptanol was applied to the intact and abradedskin of six rabbits. The undiluted material produced strong irrita-tion. The Primary Irritation Index was reported as 5.13. (RIFM,1979).

To determine the degree of irritation with 5% 2,6-dimethyl-2-heptanol, dermal occluded patches (0.5 ml) were applied to theclipped intact and abraded skin of three rabbits. Animals were




Oral Rats 10 5.0 RIFM (1976a)Oral Rats NA 6.8 RIFM (1979)Dermal Rabbits 10 5.0 RIFM (1976a)

Table 3Summary of human irritation studies.

Method Dose(%)

Vehicle Results References

Maximization(pre-test)

10 Petrolatum No irritation RIFM (1976b)

Phototoxicity(control)

10 1:1 Ethanol/acetone No irritation RIFM (1983)

HRIPT (pre-test) 2 Dimethyl phthalate No irritation RIFM (1969)HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1971a)HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1972)


Method Dose(%)

Species Results References

Dermalapplication

100 Rabbits Slight to moderateerythema and edema

RIFM (1976a)

Dermalapplication

100 Rabbits Strong irritationobserved

RIFM (1979)

Dermalapplication

5 Rabbits No irritation RIFM (1972)

Phototoxicity(control)

10 GuineaPigs

No irritation RIFM (1981a,b)


immobilized for the 24 h exposure, and then evaluated 48 h afterremoval. Irritation was not observed (RIFM, 1971b).

A minimum of four groups of four albino guinea pigs were patchtested to both flanks for a reaction time of 48 h. Four hours afterthe removal of the patches, the left flanks of the two experimentalgroups (A and B) were irradiated with UV-A or UV-B light. Groups Cand D were controls, where C did not receive radiation and group Dwas not pre-treated. No reactions were observed in the controlGroup C where animals were treated with 10% 2,6-diemthyl-2-heptanol but not irradiated (RIFM, 1981a,b).


Undiluted 2,6-dimethyl-2-heptanol produced strong irritationwhen applied to the surface of the rabbit eye. The Primary Irrita-tion Index was reported as 29.8. Further details reported in Ger-man (RIFM, 1979).

Aliquots of 0.1 ml 2,6-dimethyl-2-heptanol at 5% in alcohol SDA39C were instilled into the eyes of three healthy albino rabbits.Both the treated and control eyes were examined every 24 h for4 days, then again on the 7th day. Moderate conjunctival irritationsuch as redness, chemosis, and discharge were observed, but re-turned to normal by day 7 (RIFM, 1971c).


4.4.1. Human studies4.4.1.1. Induction studies (see Table 5).

4.4.1.2. Human repeated insult patch test. Human Repeated InsultPatch Tests (HRIPT) were conducted to determine if 2,6-di-methyl-2-heptanol would induce dermal sensitization in humanvolunteers. Patches were applied to the inner surface of the rightand left deltoid area of each subject. Patches were occluded and re-mained in place for 48 h. The patches were then removed and readfor any reactions. Alternating rotation of the sites was made for atotal of 10 applications. A 2-week rest period followed the applica-tion of the last patch. After the rest period, the challenge patch wasapplied in the identical manner that the previous patches were ap-plied, except that the test patch was applied in duplicate, one tothe inner surface of each deltoid area. Patches remain in place for48 h after which time they were removed and scored for reactions.

Fifty-three subjects (35 female and 18 male) ranging in agefrom 18 to 72, completed the study. 2,6-Dimethyl-2-heptanol(0.5 cc) in dimethyl phthalate was applied to individual absorbentpatches. At 72 and 144 h readings were made to detect any de-layed/retarded responses. Five minor adhesive tape reactions wererecorded but not repeated during the challenge tests. There wereno sensitization reactions observed in any of the 53 subjects duringthe challenge phase of the study. Under the conditions of the study,2% 2,6-dimethyl-2-heptanol in dimethyl phthalate was not consid-ered a sensitizer in humans subjects (RIFM, 1969).

A 1 � 1 inch Webril swatch with 0.5 ml of 5% 2,6-dimethyl-2-heptanol was applied to the upper arms of 45 subjects (33 female,12 male) ranging in age from 16 to 60. There were no sensitizationreactions observed in any of the 45 subjects during the challenge

phases of these studies. Under these conditions, 5% 2,6-dimethyl-2-heptanol in alcohol SDA 39C was not considered a sensitizer inhumans subjects (RIFM, 1971b, 1972).

4.4.2. Maximization studiesA human maximization (MAX) test was conducted on 25 healthy

volunteers (19 female and 6 males), ages 18–43 years old. Applica-tion was on the volar forearm or back of all subjects for five alternatedays, 48 h periods. The patch site was pre-treated for 24 h with 2.5%aqueous SLS under occlusion. Following a 10-day rest period, a chal-lenge patch of 10% 2,6-dimethyl-2-heptanol was applied to a differ-ent site for a 48 h period under occlusion. Prior to challenge, 5–10%SLS was applied to the site for one hour before application of 2,6-di-methyl-2-heptanol. The challenge site was read at patch removaland 24 h thereafter. There were no instances of contact sensitizationby 2,6-dimethyl-2-heptanol (RIFM, 1976a).

4.4.2.1. Cross-sensitization. No data available on this material.

4.4.3. Diagnostic studiesNo data available on this material.

4.4.4. Animal studies4.4.4.1. Maximization test. A guinea pig maximization test accord-ing to the Kligman (1969) method was conducted. Induction con-sisted of a series of six intradermal injections of 10% 2,6-dimethyl-2-heptanol with and without FCA, followed six to eightdays later with a 48 h occluded patch application. Animals werechallenged 12–14 days later by an occluded 24 h (20% in acetone)patch application. Reactions were read 24 and 48 h after patch re-moval. Positive reactions were not observed (Watanabe et al.,1988).

4.4.4.2. Local Lymph Node Assay (LLNA). No data available on thismaterial.


4.5.1. Phototoxicity4.5.1.1. Human studies. A test was performed on six female volun-teers to determine the phototoxic potential of 2,6-dimethyl-2-heptanol. The light source was a bank of four ‘blacklight’ fluores-cent tubes with an emission spectrum of 320–400 mm housed ina reflector unit. Prior to the application 36 test sites (2 cm2) witha 1.5 separation between each were marked on the back using ametal stamp and Gentian Violent solution. The sites were loadedby micro-pipette with the test material at a dose of 0.25 ml per2 cm2 area. Thirty minutes later the sites were exposed to UV A-irradiation. Observations were made at 4, 24, 48, and 72 h afterthe application. No evidence was noted to indicate that at a con-centration of 10% the material will produce a phototoxic reactionin humans (RIFM, 1983).

4.5.1.2. Animal studies. A minimum of four groups of four albinoguinea pigs were patch tested on both flanks for a reaction timeof 48 h. Four hours after the removal of the patches, the left flanksof the two experimental groups (A and B) were irradiated with UV-A or UV-B light. Groups C and D were controls, where C did not re-ceive radiation and group D was not pre-treated. The light sourceswere both Westinghouse FS 40. The ‘‘black lamp” had a spectrumbetween 320 and 400 nm and a radiation time of 30 min; whereasthe ‘‘sunlamp” had a spectrum of 280–370 nm and radiation timeof 15 min. Skin reactions were measured 4, 24, and 48 h after radi-ation. Slight irritation was observed 4 h after application of 10%2,6-dimethyl-2-heptanol in ethanol in 1/8 animals in Group A, Band D. However, by 48 h all irritation had cleared (RIFM, 1981a).

Table 5Summary of human skin sensitization studies.

Test method Test concentration Results References

HRIPT 2 0/53 RIFM (1969)HRIPT 5 0/10 RIFM (1971)

0/35 RIFM (1972)MAX 10 0/25 RIFM (1976a)


4.5.2. Photoallergy4.5.2.1. Human studies. No data available on this material.

4.5.2.2. Animal studies. Guinea pigs of both sexes, divided in groupsof eight animals each, were shaved on the upper dorsal area. Aboutone hour later, 0.1 ml of 10% 2,6-dimethyl-2-heptanol in rectifiedalcohol was applied to 8 cm2 of the test area. After this pretreat-ment, the animals were exposed to the UV B-irradiation for 150

and thereafter to UV A-irradiation for 4 h (Westinghouse blacklight tubes) from a distance of 25 cm. The application of the testmaterial and the following irradiation were performed every sec-ond day, a total of nine times in 18 days. Observations for irritationwere made 24 h after each application. After a 10-day rest periodthe guinea pigs were again shaved on both flanks and the test areawas marked. A 0.025 ml sample was applied to a 2 cm2 area. Thenonly the left flank was irradiated. Observations were made and 24and 48 h after the challenge. At 10% 2,6-dimethyl-2-heptanol inrectified alcohol showed no photosensitizing potential under theconditions of this test (RIFM, 1981b).







4.9. Genotoxicity






This research was supported by the Research Institute for Fra-grance Materials, an independent research institute that is funded

by the manufacturers of fragrances and consumer products con-taining fragrances. The authors are all employees of the ResearchInstitute for Fragrance Materials.

References

Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chainsaturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48(S4), S1–S46.

Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:providing estimates for safety evaluation. Regul. Toxicol. Pharm. 36, 246–252.


Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monographs on fragrance raw materials, 2,6-dimethyl-2-heptanol. Food Chem. Toxicol. 30 (Suppl.), 23.

Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria fordevelopment of a database for safety evaluation of fragrance ingredients. Regul.Toxicol. Pharm. 31, 166–181.


2007.Kligman, A.M., 1969. The identification of contact allergens by animal assay. The

guinea pig maximization test. J. Invest. Dermatol. 52 (3), 268–276.RIFM (Research Institute for Fragrance Materials, Inc.), 1969. Sensitization and

irritation studies of 2,6-dimethyl-2-heptanol. Unpublished report fromGivaudan, 30 June. Report number 41345. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1971a. Eye irritation studywith 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from InternationalFlavors and Fragrances, Report number 53500. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1971b. Repeated insult patchtest with 2,6-dimethyl-2-heptanol. Unpublished report from InternationalFlavors and Fragrances, Report number 53498. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1971c. Skin irritation studywith 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from InternationalFlavors and Fragrances, Report number 53501. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Repeated insult patchtest with 2,6-dimethyl-2-heptanol. Unpublished report from InternationalFlavors and Fragrances, Report number 53499. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1976a. Acute toxicity studiesin rats, mice, rabbits and guinea pigs. RIFM report number 2019, October 08.RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1976b. Report on humanmaximization studies. RIFM report number 1797, November 04. RIFM,Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1979. Acute toxicity studieson 2,6-dimethyl-2-heptanol. Unpublished report from BASF, 08 February.Report number 4458. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1981a. Guinea pig assay ofphotosensitizing potential of 2,6-dimethyl-2-heptanol. Unpublished reportfrom Givaudan, 09 July. Report number 41343. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1981b. Determination ofphototoxicity of 2,6-dimethyl-2-heptanol in guinea pigs. Unpublished reportfrom Givaudan, 07 April. Report number 41346. RIFM, Woodcliff Lake, NJ, USA.

RIFM (Research Institute for Fragrance Materials, Inc.), 1983. 2,6-Dimethyl-2-heptanol: Phototoxicity test on a fragrance raw material in humans.Unpublished report from Givaudan, 23 September. Report number 41344.RIFM, Woodcliff Lake, NJ, USA.

Watanabe, S., Kinosaki, A., Kawasaki, M., Yoshida, T., Kaidbey, K., 1988. The contactsensitizing potential of (+)- and (�)-hydroxycitronellal. In flavors andfragrances: a world perspective. Proceedings of 10th International Congress ofEssential Oils, 11/86, pp. 1029–1038.


Review

Fragrance material review on 2-ethyl-1-hexanol




a b s t r a c t

A summary of the safety data available for 2-ethyl-1-hexanol when used as a fragrance ingredient is pre-sented. 2-Ethyl-1-hexanol is a member of the fragrance structural group branched chain saturated alco-hols in which the common characteristic structural element is one hydroxyl group per molecule, and a C4

to C12 carbon chain with one or several methyl side chains. This review contains a detailed summary of allavailable toxicology and dermatology papers that are related to this individual fragrance ingredient and isnot intended as a stand-alone document. A safety assessment of the entire branched chain saturated alco-hol group will be published simultaneously with this document; please refer to Belsito et al. (2010) for anoverall assessment of the safe use of this material and all other branched chain saturated alcohols infragrances.


Contents


4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1174.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1174.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1174.1.3. Intraperitoneal (ip) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1174.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118

4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1184.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1184.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118

4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1184.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118

4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1184.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119

4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1194.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119

4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1194.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1194.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119

4.7. Repeated dose toxicity (see Table 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1204.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1204.7.2. Subchronic (31–90 days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1224.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122

4.8. Reproductive and developmental toxicity (see Table 7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1234.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S124

4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1244.9.2. In vivo studies (see Table 10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125







4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1254.10.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1254.10.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125

4.11. Miscellaneous studies (see Table 12) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S127References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S127

Introduction

This document provides a summary of the toxicologic review,including all human health endpoints, of 2-ethyl-1-hexanol whenused as a fragrance ingredient. 2-Ethyl-1-hexanol (see Fig. 1; CASNumber 104-76-7) is a fragrance ingredient used in cosmetics, finefragrances, shampoos, toilet soaps and other toiletries as well as innon-cosmetic products such as household cleaners and detergents.It is a colorless, oily liquid with mild, sweet and slightly floral-rosyodor of considerable tenacity (Arctander, 1969). This material hasbeen reported to occur in nature, with highest quantities observedin tea (VCF, 2009).

In 2007, a complete literature search was conducted on 2-ethyl-1-hexanol. On-line toxicological databases were searched includ-ing those from the Chemical Abstract Services, [e.g. ToxCenter(which in itself contains 18 databases including Chemical Ab-stracts)], and the National Library of Medicine [e.g. Medline, Toxnet(which contains 14 databases)] as well as 26 additional sources(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrancecompanies were asked to submit all test data.

The safety data on this material was last reviewed by Opdyke,1978. All relevant references are included in this document. Moredetails have been provided for unpublished data. The number ofanimals, sex and strain are always provided unless they are not gi-ven in the original report or paper. Any papers in which the vehi-cles and/or the doses are not given have not been included in thisreview. In addition, diagnostic patch test data with fewer than 100consecutive patients have been omitted.

1. Identification

1.1. Synonyms: 2-Ethylhexanol; 1-hexanol, 2-ethyl-1.2. CAS registry number: 104-76-7.1.3. EINECS number: 203-234-3.1.4. Formula: C8H18O.1.5. Molecular weight: 130.23.1.6. JECFA (1998): The Joint FAO/WHO Expert Committee on

Food Additives (JECFA No. 267) concluded that the substancedoes not present a safety concern at current levels of intakewhen used as a flavoring agent.



1.1. Physical form: Colorless, oily liquid with mild, sweet andslightly floral-rosy odor.

1.2. Boiling point (calculated; EPA, 2010): 188.52 �C.1.3. Flash point: 167�F;CC.1.4. Henry’s law (calculated; EPA, 2010): 0.000031 atm m3/mol

25 �C.1.5. Log Kow (calculated): 2.73.1.6. Refractive index: no information available.1.7. Specific gravity: 0.833.1.8. Vapor pressure (calculated; EPA, 2010): 0.06 mm Hg (20 �C);

0.185 mm Hg (25 �C); 24.6 Pa (25 �C).1.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 �C).

1.10. UV spectra available at RIFM, peaks at 210–215 nm andreturns to baseline at 400 nm; minor absorption from 290–400 nm.

3. Usage

2-Ethyl-1-hexanol is a fragrance ingredient used in many fra-grance compounds. It may be found in fragrances used in decora-tive cosmetics, fine fragrances, shampoos, toilet soaps and othertoiletries as well as in non-cosmetic products such as householdcleaners and detergents. Its use worldwide is in the region of0.1–1.0 metric tons per annum (IFRA, 2004). The reported volumeof use is for 2-ethyl-1-hexanol as used in fragrance compounds(mixtures) in all finished consumer product categories. The volumeof use is surveyed by IFRA approximately every four years througha comprehensive survey of IFRA and RIFM member companies. Assuch the volume of use data from this survey provides volume ofuse of fragrance ingredients for the majority of the fragranceindustry.

The dermal systemic exposure in cosmetic products (see Table 1)is calculated based on the concentrations of the same fragranceingredient in ten types of the most frequently used personal careand cosmetic products (anti-perspirant, bath products, body lotion,eau de toilette, face cream, fragrance cream, hair spray, shampoo,shower gel, and toilet soap). The concentration of the fragranceingredient in fine fragrances is obtained from examination of sev-eral thousand commercial formulations. The upper 97.5 percentileconcentration is calculated from the data obtained. This upper 97.5percentile concentration is then used for all 10 consumer products.These concentrations are multiplied by the amount of product ap-plied, the number of applications per day for each product type,and a ‘‘retention factor” (ranging from 0.001 to 1.0) to accountfor the length of time a product may remain on the skin and/orlikelihood of the fragrance ingredient being removed by washing.The resultant calculation represents the total consumer exposure(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).

This is a conservative calculation of dermal systemic exposurebecause it makes the unlikely assumption that a consumer willuse these 10 products containing; which are all perfumed withthe upper 97.5 percentile level of the fragrance ingredient from afine fragrance type of product (Cadby et al., 2002; Ford et al.,2000). The 97.5 percentile use level in formulae for use in cosmet-

HO

Fig. 1. 2-Ethyl-1-hexanol.


ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,2007), which would result in a maximum daily exposure on theskin of 0.0005 mg/kg for high end users (see Table 1).

A maximum skin level is then determined for consideration ofpotential sensitization. The exposure is calculated as the percentconcentration of the fragrance ingredient applied to the skin basedon the use of 20% of the fragrance mixture in the fine fragranceconsumer product (IFRA, 2007). The average maximum use levelin formulae that go into fine fragrances has been reported to be0.008% (IFRA, 2007), assuming use of the fragrance oil at levelsup to 20% of the final product.

4. Toxicology data


4.1.1. Oral studiesIn a study with a total of 85 rats, it was determined that the

lethal dose of 2-ethyl-1-hexanol by oral gavage was 3.2 g/kg(Hodge, 1943).

In a structure–activity study of a large number of organic sol-vents, it was reported that the oral LD50 of 2-ethyl-1-hexanol inrats was 2.049 g/kg (Nishimura et al., 1994).

The acute oral LD50 of 2-ethyl-1-hexanol in groups of fivenon-fasted, Carworth–Wistar male rats was reported to be 2.46(1.82–3.33) g/kg. No additional details were reported (Smythet al., 1969).

In a study primarily addressing the toxicity of diethylhexylphthalate, it was reported that the oral LD50 of 2-ethyl-1-hexanolin 90–120 g male Wistar rats is 7.1 (5.5–9.1) g/kg. No additionaldetails are reported (Shaffer et al., 1945).

The oral LD50 of 2-ethyl-1-hexanol in rats was reported to be3.2 g/kg. No additional details are reported (Bar and Griepentrog,1967; Dave and Lidman, 1978).

The oral LD50 of 2-ethyl-1-hexanol in rats was reported to be3.29 (2.87–3.79) g/kg (Schmidt et al., 1973).

The oral LD50 for 2-ethyl-1-hexanol in Sprague–Dawley rats (5/dose) was reported to be 3.73 g/kg. The principal clinical signswere central nervous system depression and labored respiration.The depression included inactivity, ataxia, limb sprawling, de-pressed righting and placement reflexes, prostration, and coma.The intensity of the signs was related to dose. The signs of effecthad an early onset, and recovery was complete by the second orthird day. Where deaths occurred, they were seen in the first24 h. Gross necropsy revealed some evidence of gastrointestinalirritation (Scala and Burtis, 1973).

In a study to investigate the mechanism of action for inductionof peroxisome proliferation by several compounds including 2-ethyl-1-hexanol, it was reported that a single dose of 100 mg/kgadministered by oral gavage to Fischer 344 rats resulted in no dif-ference from controls in hepatic acyl CoA oxidase or catalase activ-ity 5 h after dosing (Bojes and Thurman, 1994).

4.1.2. Dermal studiesThe dermal LD50 of 2-ethyl-1-hexanol in groups of four male al-

bino New Zealand rabbits was reported to be 2.38 (1.7–3.34) g/kg.No additional details are reported (Smyth et al., 1969).

The dermal LD50 of 2-ethyl-1-hexanol in 10 rabbits was re-ported to be >5.0 g/kg. One of 10 animals died on day 12, but thenecropsy was reported to be normal in the animal that died. Skinirritation with moderate redness and edema was reported in all10 animals (RIFM, 1977).

The dermal LD50 for 2-ethyl-1-hexanol applied occlusively for24 h to rabbits (4/dose) was reported to be >2.6 g/kg. There wereno clinical signs indicative of systemic effects at the highest leveltested. Dermal irritation was dose-dependent (Scala and Burtis,1973).

4.1.3. Intraperitoneal (ip) studiesIn a study with 102 mice, it was determined that the lethal ip

dose in mice was approximately 0.78 g/kg. 2-Ethyl-1-hexanolwas also administered to 101 rats as ip injections to determinean LD50 of 0.65 g/kg. Clinical signs included irregular gait, draggingof hind limbs, gasping without cyanosis, insensibility and sleepi-ness at high doses. The 2-ethyl-1-hexanol was rapidly anaestheticin mice as well as rats (Hodge, 1943).


Route Species No.animals/dose group

LD50

(g/kg)References

Oral Rat 5–15 3.2 Hodge (1943)Oral Rat N/A 2.049 Nishimura et al. (1994)Oral Rat 5 2.46 Smyth et al. (1969)Oral Rat N/A 7.1 Shaffer et al. (1945)Oral Rat N/A 3.2 Bar and Griepentrog

(1967)Dave and Lidman (1978)Schmidt et al. (1973)

Oral Rat 5 3.73 Scala and Burtis (1973)Dermal Rabbit 4 2.38 Smyth (1969)Dermal Rabbit 10 >5.0 RIFM (1977)Dermal Rabbit 4 >2.6 Scala and Burtis (1973)Intraperitoneal Rat 5–15 0.65 Hodge (1943)Intraperitoneal Rat 5 0.5–

1.0Dave and Lidman (1978)

Intraperitoneal Mice 5–15 0.78 Hodge (1943)

Table 1Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-hexanol.



Total 0.0005



Dave and Lidman (1978) reported a literature value from theHandbook of Toxicology of 0.65 g/kg for the ip LD50 of 2-ethyl-1-hexanol in rats. In a separate study, Sprague–Dawley rats (5/sex/dose) were given undiluted 2-ethyl-1-hexanol at doses of 0.05,0.1, 0.5, 1.0, or 5.0 g/kg. Observations were made continuously over14-days. The ip LD50 was reported to be between 0.5 and 1.0 g/kg.At doses of 1.0 and 5.0 g/kg coma and death were observed in therats within two hours. At 0.5 g/kg, the animals went into comas in5 min, but then recovered and survived throughout the experimen-tal period. At the post-mortem examinations, no pathologicalchanges were noted.

4.1.4. Inhalation studiesNo deaths were reported when 10 rats, mice, and guinea pigs

were exposed by whole body inhalation for 6 h to air bubbledthrough 2-ethyl-1-hexanol to yield a nominal chamber concentra-tion of 227 ppm (ml/m3). Clinical signs indicated moderate localirritation and slight to moderate systemic effects. Local irritationinvolved the mucous membranes of the eyes, nose, throat, andrespiratory passages and was manifest as blinking, lacrimation,preening, nasal discharge, salivation, gasping, and chewing move-ments. Responses were temporary and all animals had recoveredwithin 1 h after termination of exposure. Gross necropsy findingswere confined to areas of slight hemorrhage in the lungs. All othertissues and organs were normal in appearance (Scala and Burtis,1973).


4.2.1. Human studiesIn a maximization test pre-screen, 2-ethyl-1-hexanol at 4% was

applied to the backs of 29 healthy male volunteers for 48 h underocclusion. No subject had any irritation (RIFM 1976).

4.2.2. Animal studies (see Table 3)Uncovered application of undiluted 2-ethyl-1-hexanol to the

clipped skin on the underbelly of five rabbits for 24 h producedirritation Grade 3 (moderate) on a 10-Grade scale with Grade 2representing the least visible capillary injection from undilutedmaterial, Grade 6 representing necrosis from undiluted material,and Grade 10 representing necrosis from a 0.01% solution with pro-pylene glycol or water (Smyth et al., 1969).

In an acute dermal toxicity test in which 0.10, 0.316. 1.00, and3.16 mg/kg of undiluted 2-ethyl-1-hexanol was applied occlusivelyfor 24 h to the clipped intact abdominal skin of rabbits, 2-ethyl-1-hexanol was reported to cause moderate dermal irritation (Scalaand Burtis, 1973).

In an acute dermal toxicity test in which 5 g/kg was applied to theskin of rabbits, moderate redness and edema was observed in all 10treated animals. No additional details are reported (RIFM, 1977).


2-Ethyl-1-hexanol was reported to be a severe eye irritant whenapplied undiluted in a 0.1 ml dose to the left eye of each of six

rabbits. Observations were made at 1, 4, and 24 h and 2, 3, 4, and7 days. Median irritation scores according to the Draize systemwere 19, 20, and 0 at 24 h, 72 h, and 7 days, respectively. Cornealdullness, opacity (widespread corneal opacity), vascularization,irritates, conjunctival erythema, chemosis, and discharge were allobserved (Scala and Burtis, 1973).

Application of 2-ethyl-1-hexanol to the eyes of rabbits pro-duced irritation Grade 5 on a 10-Grade scale with Grade 5 repre-senting ‘‘severe burn” from 0.005 ml of undiluted material andGrade 10 representing severe burn from 0.5 ml of a 1% solutionwith propylene glycol or water (Smyth et al., 1969; Carpenter etal., 1946).

In a TSCA 8(e) submission, it was reported that 2-ethyl-1-hexa-nol produced persistent corneal effects in rabbits (EPA, 1991,1992).

Draize rabbit eye irritation scores of 9, 30, 39, 35, and 51 werereported for 1%, 3%, 10%, 30%, and 100% 2-ethyl-1-hexanol, respec-tively, in a study designed to evaluate the predictive value ofchanges in corneal thickness for quantitating eye irritation(Kennah et al., 1989).

Schmidt et al. (1973) conducted an eye irritation study in rab-bits with a single application of 2-ethyl-1-hexanol, undiluted orin solution with oil at 50%, 25%, or 12.5%. Reactions were gradedafter 18–24 h. There were no effects on the cornea for all concen-trations, and at 12.5%. Conjunctival redness, swelling, lacrimation,and discharge were observed at remaining concentrations. Theseeffects did not reverse within 96 h with the undiluted concentra-tion (Schmidt et al., 1973).


4.4.1. Human studies4.4.1.1. Induction studies.

4.4.1.1.1. Human repeated insult patch test (HRIPT). No informa-tion available.

4.4.1.1.2. Maximization studies. In a human maximization studyinvolving 29 subjects, 2-ethyl-1-hexanol was applied in petrola-tum at 4% under occlusion to the forearms for a total of five alter-nate days, 48 h periods. Each application was preceded by a 24 hocclusive treatment of the patch sites with 5% aqueous sodium lau-ryl sulfate. Following a 10–14 day rest period, challenge patcheswere applied to fresh sites on the scapular back under occlusionfor 48 h. The challenge sites were pretreated for 30 min with a5% aqueous sodium lauryl sulfate solution. Challenge sites wereevaluated at 48 and 72 h, there were no positive reactions to 2-ethyl-1-hexanol (RIFM, 1976).



Patch test 100 Rabbits Moderateirritation

Smyth et al. (1969)

Patch test 100 Rabbits Moderateirritation

Scala and Burtis (1973)

Patch test 100 Rabbits Moderateerythema andedema

RIFM (1977)


Dose (%) Vehicle Reactions References

100 – Severe eye irritant Scala and Burtis(1973)

100 – Severe burn Smyth et al.(1969)Carpenter andSmyth (1946)

N/A N/A Persistent corneal effects EPA (1992)100, 30, 10,

3, or 1PEGa Eye irritation observed at all

concentrationsKennah et al.(1989)

100, 50, 25,12.5

N/A No effects to the corneaConjunctival redness, swelling,lacrimation, and discharge100%: not reversed at 96h12.5%: no effects observed

Schmidt et al.(1973)

a PEG, polyethylene glycol.


4.4.1.1.3. Cross-sensitization. No information available.4.4.1.1.4. Diagnostic studies. No information available.





4.6.1. AbsorptionIn a comparison of in vitro percutaneous absorption in rat and

human skin (n = 12 for rat and human skin), it was reported thatthe absorption rates were 0.22 ± 0.09 and 0.038 ± 0.014 mg/cm2/hin rat and human skin. The permeability constants were 2.59 ±1.10 � 10�4 cm/h for rats and 4.54 ± 1.66 � 10�5 cm/h for humans.The ratio of the permeability constants (rat/human) of 5.78 indi-cates that 2-ethyl-1-hexanol penetrated full thickness rat skinmore rapidly than it penetrated human stratum corneum (Barberet al., 1992).

Dermal absorption in the rat was determined to be 5.2% of adose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for6 h. An absorption rate of 0.57 mg/cm2/h and a terminal half-lifeof 77 h were calculated (Deisinger et al., 1994).

4.6.2. DistributionNo information available.

4.6.3. Metabolism4.6.3.1. In vivo studies in animals. Single oral gavage administrationof 14C labeled 2-ethyl-1-hexanol was given to Fischer 344 rats (4/group) at 50 mg/kg so that absorption, distribution, metabolism,and elimination (ADME) could be studied. A repeated oral doseof 50 mg/kg (unlabeled 2-ethyl-1-hexanol) was also given to ratsfor 14 consecutive days. On the final (15th day) the rats were givena 50 mg/kg dose of 14C labeled 2-ethyl-1-hexanol. All applicationswere neat. The oral doses were eliminated rapidly, predominantlyin urine and feces. Urinary excretion accounted for 56–60% of theadministered dose, with all but about 2% of administered dose ex-creted in the first 24 h. Urinary metabolites eliminated were pre-dominately glucuronides of oxidized metabolites, includingglucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydro-xy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic acid. Fe-cal excretion accounted for 13–15% of the dose, primarily between8 and 24 h after dosing. Sodium hydroxide breath traps accountedfor 8–14% of the dose, primarily in the first 24 h. Silica gel breathtraps accounted 0.25–0.28% following oral dosing. There was someevidence of metabolic saturation at the high dose, and no evidenceof metabolic induction following pretreatment with unlabeledcompound for 14 days. The total recovery for the low, high, and re-peated doses ranged was 94–97% (Deisinger et al., 1994, 1993).

Single oral gavage administration of 14C labeled 2-ethyl-1-hex-anol was given to Fischer 344 rats (4/group) at 500 mg/kg so thatabsorption, distribution, metabolism, and elimination (ADME)could be studied. After oral administration to rats, 69–75% of adose of 500 mg 14C-labeled 2-ethyl-1-hexanol/kg body weightwas excreted in the urine within 96 h. About 13–15% of the dosewas excreted in the feces and about the same amount was exhaled.More than 50% of the dose was excreted within 24 h (Deisingeret al., 1993, 1994).

2-Ethyl-1-hexanol was efficiently absorbed following oraladministration of a 14C labeled dose and was rapidly excreted inrespiratory CO2 (6–7%), feces (8–9%), and urine (80–82%) withessentially complete elimination in 28 h. The amount of radiolabel

recovered in CO2 matched the amount of unlabeled 2-heptanoneplus 4-heptanone recovered from urine in study in which both la-beled and unlabeled compound were administered, suggestingthat both types of metabolite may have been derived from the ma-jor urinary metabolite, 2-ethylhexanoic acid, by decarboxylation,following partial beta-oxidation. The radio-labeled CO2 appearednot to be derived from acetate (urinary acetic acid and liver andbrain cholesterol were not labeled) or by reductive decarboxyl-ation (heptane was not present). Other identified metabolites were2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and2-ethyl-1,6-hexadecanoic acid. Only about 3% of the dose was ex-creted unchanged. In vitro incubation with mammalian alcoholdehydrogenase resulted in a Vmax of 0.30 lmol/min/mg proteinand a Km value of 0.74 mM (Albro, 1975).

In a study of DNA binding of diethylhexylphthalates and relatedcompounds, it was reported that radio-labeled 2-ethyl-1-hexanolwas not bound to hepatic DNA of Fischer 344 rats 24 h followingoral gavage administration (Albro et al., 1982).

It was reported that oral administration of 2.55 g of 2-ethyl-1-hexanol to a rabbit resulted in urinary excretion (24 h) of the glu-curonide of alpha-ethylhexanoic acid (Kamil et al., 1953).

It was reported that urinary glucuronide ester accounted for86.9% of a 25 mMol dose of 2-ethyl-1-hexanol administered by ga-vage to a rabbit weighing approximately 3 kg (Kamil et al., 1953).

In the same ADME study, two groups of Fischer 344 rats (4/group) received a 6 h dermal application (1 g/kg) of 14C labeled2-ethyl-1-hexanol. Pyrex glass containment cells (exposure areaof 2.27 cm2) were covered and adhered to the clipped back of eightrats. Blood pharmacokinetics were studied on four of the eight rats.Dermal dosing resulted in only about 5% absorption of the applieddose. Dermal dosing led to a recovery of 1.41% of the dose in silicagel breath traps compared to 0.25–0.28% following oral dosing. Thesmall portion of the dose that was absorbed dermally was elimi-nated primarily in the urine, with smaller amounts eliminated inthe feces, and as 14CO2 in the breath. Urinary metabolites elimi-nated were predominately glucuronides of oxidized metabolites,including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid,5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoicacid (Deisinger et al., 1994, 1993).

An i.v. injection of 2-ethyl-1-hexanol (1 mg/kg in saline) was gi-ven to two groups of Fischer 344 rats (4/group). Blood pharmaco-kinetics was studied on four of the eight rats; on the other four ratsADME was evaluated. Urinary excretion was rapid with 53% of thedose recovered within 8 h of dosing. The next largest portionsrecovered were from the sodium hydroxide breath traps at 22.9%and fecal excretion at 3.8%. The terminal half-life was estimatedto be 60 h (Deisinger et al., 1993, 1994).

Asano and Yamakawa (1950) reported that following a subcuta-neous injection to rabbits with 11 g of 2-ethyl-1-hexanol over10 days, a volatile urinary metabolite (believed to be 2-ethylcapro-ic acid) and a non-volatile metabolite (believed to be the bis-p-phenylphenacyl ester of 2-ethyl adipic acid) was formed. Theirassessment was based on comparison of the melting points ofthe isolated metabolites and synthesized compounds.

4.6.3.2. In vitro studies in animals (see Table 5). Primary rat hepato-cyte cultures were used to compare the effects of some alkyl phthal-ate esters on peroxisomal enzyme activities. Linear diesters andtheir constituent monoesters and alcohols were compared withbranched chain 2-eythylhexyl derivatives. There was no significantdifference between 2-ethyl-1-hexanol treated and control cells inactivities of cyanide-insensitive palmitoyl-CoA oxidation, a specificperoxisomal marker. Yet, there was a six fold increase with 1 mM 2-ethyl-1-hexanol on carnitine acyl transferase activity (P < 0.01). Theauthors concluded that the measurement of carnitine acyl transfer-


ase alone was not an adequate criterion for assessing peroxisomaleffects in cultured hepatocytes (Gray et al., 1983).

It was reported that 2-ethyl-1-hexanol is one of the metabolitesproduced from diethylhexyl phthalate by rat liver, lung, and kidneyhomogenates (Carter et al., 1974).

4.7. Repeated dose toxicity (see Table 6)

4.7.1. Two to 30-day studies4.7.1.1. Dermal studies. 2-Ethyl-1-hexanol was administered by oc-cluded patch doses to Fischer 344 rats for five days, followed by2 days untreated, followed by 4 days treated at 0, 500, or1000 mg/kg/day. Treatment-related clinical signs of toxicity wererestricted to the skin at the treatment site and included exfoliation(minimal severity) at both doses and transient erythema (days4–7) (graded as barely perceptible) at the high dose. There wereno differences from control in food consumption, water consump-tion, body weight, or weight gain. There was a statistically signifi-cant decrease in lymphocytes compared to control for females atthe high dose and statistically significant increases in triglyceridesfor both males and females at both doses. There was a statisticallysignificant reduction in absolute spleen weight at 1000 mg/kg/dayand in females only at 500 mg/kg/day. Spleen weight relative toboth body weight and brain weight were also reduced in femalesat both 500 and 1000 mg/kg/day. There were no other effects onabsolute or relative organ weights in males. There is no discussionof gross necropsy or histopathological findings. (EPA, 1992b;Weaver et al., 1989).

For 12 days, 2-ethyl-1-hexanol was applied to the shaved backsof 10 rats at 2 ml/kg body weight/day (1600 mg/kg body weight/day). Observations included a decrease in absolute and relativethymus weights, liver granulomas, bronchiectasis in the lung, renaltubular epithelial necroses, edematous heart and testes, as well asdecreased spermatogenesis (Schmidt et al., 1973).

4.7.1.2. Oral studies. 2-Ethyl-1-hexanol was included in a study tofurther investigate the relationship between peroxisome prolifera-tion and induction of cytosolic epoxide hydrolase in mouse liver.Male C57BI/6 mice were given 10,000 ppm (1500 mg/kg bodyweight/day) of 2-ethyl-1-hexanol in their diet for 4 days. At thisdose microsomal epoxide hydrolases were unaffected, but activityof the cytosolic epoxide hydrolases increased (Lundgren et al., 1988).

In a study of the hepatic effects of DEHP and its metabolites,2-ethyl-1-hexanol was administered by oral gavage to male Wistarrats for 7 days at 850, 1335, and 1425 mg/kg/day. Livers were ex-cised for biochemical and histological evaluations. 2-Ethyl-1-hexa-nol, like DEHP, resulted in decreased glucose-6-phosphataseactivity. An increase in relative liver weight, biphenyl-4-hydroxy-lase activity, and cytochrome P-450 content per mg microsomalprotein, was observed when compared to controls. Additionally,there was a similar increase in histochemical alcohol dehydroge-nase activity in the centrilobular area of the liver lobule, and elec-tronmicroscopy studies showed an increase in microbodies anddilation of the endoplasmic reticulum. In contrast to DEHP,succinate dehydrogenase activity was not decreased and aniline-4-hydroxylase activity was not increased by 2-ethyl-1-hexanoltreatment compared to controls (Lake, 1974, 1975).

In contrast to treatment with DEHP and MEHP, treatment with2-ethyl-1-hexanol at dietary levels of 50–2500 ppm (5–250 mg/kgbody weight/day) for 7 days did not prevent orotic acid inducedhepatic triglyceride accumulation. Also, the hepatic enzymes in-volved in lipid transport and metabolism did not increase (Mortonand Rubin, 1979).

Fischer 344 rats (10/sex/dose) were treated by oral gavage withundiluted 2-ethyl-1-hexanol for 5 days, followed by 2 days un-treated, followed by 4 days treated at 0, 100, 330, 1000, or1500 mg/kg/day. The NOEL was 100 mg/kg/d. At 100 mg/kg/day,no treatment related effects were observed for any in-life, clinicalpathology, gross necropsy, or histopathology parameters. Treat-ment-related dose-dependent effects seen at 330 mg/kg/day andhigher included hypoactivity, ataxia, prostration, delayed rightingreflex, muscle twitch, lacrimation, and urine stained fur. Food con-sumption and body weights were decreased. Total leukocytes andlymphocytes and spleen weight and size were decreased. Lymphoidnecrosis in the spleen and thymic atrophy and lymphoid cell degen-eration in the thymus were also observed. Liver weight was in-creased. Stomach weight was increased and histopathologicalfindings of the stomach included hyperkeratosis, mucosal hyper-plasia, edema, exocytosis, and gastritis. Absolute and relative testesweights were decreased at the highest dose. Absolute and relativekidney weights were increased at 1000 mg/kg/day, and relative kid-ney weight was increased at 1500 mg/kg/day. However, there wereno histopathological findings in testes or kidneys (EPA, 1992b).

2-Ethyl-1-hexanol was administered to Fischer 344 rats via thedrinking water continuously for 9 days at 0, 308 ppm (half-satu-rated) and 636 ppm (saturated). Mean intake was estimated tobe 61.1 and 151.1 mg/kg/day for males and 73.4 and 173.5 mg/kg/day for females at the low and high doses, respectively. Therewere no clinical signs of toxicity and no differences from controlin food consumption, body weight, or weight gain. There were sta-tistically significant increases in water consumption for both doselevels. There were no alterations in hematology or clinical chemis-try parameters. There were no effects on absolute or relative organweights. Exposure of Fischer 344 rats to 2-ethyl-1-hexanol indrinking water for 9 days at the maximum possible concentrationdid not result in any significant toxicological changes (EPA, 1992b;Weaver et al., 1989).

The administration of 2-ethyl-1-hexanol to male Swiss–Web-ster mice (6/group) in the diet at a concentration of 2%(2857 mg/kg body weight/day) for 10 days resulted in a significantincrease in absolute liver weight, significantly raised activities ofcytoplasmic and microsomal epoxide hydrolases and glutathione-S-transferase and a significant increase in the cytoplasmic andmicrosomal protein content of the liver (Hammock and Ota, 1983).

2-Ethyl-1-hexanol was microencapsulated in the diet at dosesof 0.46%, 0.92%, 1.38% or 2.75% (a mean daily substance intake of500, 980, 1430, or 2590 mg/kg body weight/day in 10 males and540, 1060, 1580, or 2820 mg/kg body weight/day in 10 females)for 11 days. All groups exhibited reductions in feed consumption,cholesterol, triglycerides and alanine-aminotransferases. Increasedrelative stomach and liver weights were also observed. Overall theauthors felt the NOEL under these study conditions was less than0.46% (500, or 540 mg/kg/day) microcapsules in the feed of maleand female rats (EPA, 1992c).

Table 5Summary of in vitro animal studies.

Test system in vitro Species Concentration Results References

Hepatocyte cultures Rat 0.2 or 1 mM (DMSO) No significant differences in peroxisomal enzyme activities Gray et al. (1983)Liver, lung, and kidney

homogenatesRat 40 mg (DEHP) and 20 mg Tween

80Hydrolyses DEHP to mono-(2-ethylhexyl)phthalate and 2-ethylhexanol

Carter et al.(1974)


At doses of 100, 330, 1000, or 1500 mg/kg body weight/day 2-ethyl-1-hexanol (in propylene glycol) was administered nine timesby gavage to 10 male and 10 female B6C3F1 mice over a period of

11 days. Toxic effects, such as gross lesions in the forestomach, in-creased relative and absolute stomach and liver weights, or clinicalsigns (ataxia, lethargy, piloerection, hypothermy, and loss of

Table 6Summary of repeated dose studies.

Method Dose Species Results References

9 day Dermal(occluded)

0, 500, or 1000 mg/kg/day Rat P500 mg/kg Body weight/day: exfoliation (minimal severity),spleen weight decreased; serum triglycerides increased (females);1000 mg/kg body weight: transient erythema (days 4–7) (gradedas barely perceptible), decreased absolute spleen weight,lymphocytes decreased

EPA (1992b)Weaver et al. (1989)

12 day Dermal 2 ml/kg Body weight/day(1600 mg/kg body weight/day)

Rat Absolute and relative thymus weights decreased, livergranulomas, bronchiectasis in the lung, renal tubular epithelialnecroses, edematous heart and testes and decreasedspermatogenesis

Schmidt et al. (1973)

4 day Oral (In food) 10,000 ppm (1500 mg/kgbody weight/day)

Mice Activity of the cytosolic epoxide hydrolases increased. Lundgren et al. (1988)

7 day Oral (gavage) 800, 1335, or 1425 mg/kg/day

Rat Decreased: glucose-6-phosphatase activityIncreased: liver weight, biphenyl-4-hydroxylase activity, andcytochrome P-450

Lake (1974, 1975)

7 day Oral (In food) 5–250 mg/kg/day Rat No effects Morton and Rubin(1979)

9 day Oral (gavage) 0, 100, 330, 1000, 1500 mg/kg/day

Rat NOEL 100 mg/kg/day EPA (1992b)

9 day Oral (drinkingwater)

61.1 or 151.1 mg/kg/day(males)73.4 or 173.5 mg/kg/day(females)

Rat Significant increase in water consumption EPA (1992b), Weaveret al. (1989)

10 days Oral (in food) 2857 mg/kg body weight/day

Mice 2857 mg/kg body weight/day: absolute liver weight, activities ofcytoplasmic and microsomal epoxide hydrolase and glutathione-S-transferase and the cytoplasmic and microsomal proteincontent of the liver increased

Hammock and Ota(1983)

11 day Oral (in food) 500, 980, 1430, or 2590 mg/kg/day (males)540, 1060, 1580, or2820 mg/kg/day (females)

Rat NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day P 500 (m) or540 (f) mg /kg/d: relative stomach weights increased females (f);triglycerides and alanine aminotransferase decreased, males (m);feed consumption significantly decreased (m)

EPA (1992c)

11 day Oral (gavage) Nine doses in propyleneglycol of 100, 330, 1000, or1500 mg/kg/day

Mice NOEL between 100 and 330 mg/kg body weight/dayToxic effects in the 330 – 1500 mg/kg dosage groups

EPA (1992d)

11 day Oral (gavage) 0, 100, 330, 1000 or1500 mg/kg/day

Rats and Mice Decreased (rat) body weights at 1500 mg/kgIncreased relative liver/stomach weights, and gross lesions (rats)at 1000 and 1500 mg/kg/day. Kidney weights were increased infemales at 330 mg/kg/day.

Astill et al. (1996a)

11 day Oral (gavage) Nine doses: 0, 100, 330,1000, or 1500 mg/kg bodyweight/day, in an aqueousemulsion in Cremophor EL

B6C3F1 mice(10/sex)

Systemic NOAEL 100 mg/kg body weight/day300 mg/kg body weight/day: acanthosis with hyperkeratosis inthe forestomach; P 1000 mg/kg body weight/day: relative liver(males) and stomach weights (female) increased, hypertrophy ofhepatocytes; 1/20 deaths.1500 mg/kg body weight/day: ataxia, lethargy, piloerection,abdominal or lateral position and loss of consciousness; clinicalchemistry and hematology, no substance-related changes; 5/20deaths.

EPA (1992e)

14 day Oral (gavage) 0–1750 mg/kg/day Rats and mice Marked toxicity at the highest dose Kieth et al. (1992)14 day Oral (gavage) 130 mg/kg/day Rat No hepatomegaly, peroxisome proliferation, hypolipidemia, or

testicular atrophyRhodes et al. (1984)

21 day Oral (In food) 20 mg/kg/day Rat Decreased serum cholesterol and triglyceride levels Moody and Reddy(1982)

21 day Oral 833 mg/kg/day Rat Increased liver weights Yamada (1974)21 day Oral (gavage) 950 mg/kg/day Rat Increased absolute and relative liver weights. Slightly increased

hepatic peroxisome levels and pCoA activityHodgson (1987)

21 day Oral (gavage 1000, 1500 mg/kg bodyweight/day

Rat 1000 mg/kg body weight/day: 30% increase in liver-to-body-weight ratio; peroxisome cell fraction and peroxisome density inthe liver increase 500 mg/kg body weight/day: mortality

Barber and Topping(1995)

22 day Oral (gavage) 0, 330, 660, 930 mg/kg bodyweight in sunflower oil,controls 10 ml oil/kg bodyweight

Rat 930 mg/kg: body weight on day 17 decreased, mortality: 1/10 Schmidt et al. (1973)

90 day (inhaled) 15, 40, 120 ppm Rat No substance-related effects were observed NOAEL: 120 ppm Klimisch et al. (1998)91 day Oral (gavage) 0, 25, 250 or 500 mg/kg

(five consecutive days aweek)

Rats and Mice NOEL: 125 mg/kg/dayDecreased body weight gain, gross lesions, serum ALT activities,total protein, albumin concentration, and serum cholesterolIncreased pCoA activity (rats) at 500 mg/kg

Astill et al. (1996a)

18 months Oral(gavage)

50, 200, or 750 (fiveconsecutive days a week)

Mice Lethargy, unkemptness, reductions in body weight gain, andincreased mortality compared to controls


24 months Oral(gavage)

50, 150, or 500 (fiveconsecutive days a week)

Rats Astill et al. (1996b)


consciousness) were observed in the 330–1500 mg/kg bodyweight/day dosage groups. The authors felt the NOEL was between100 and 330 mg/kg bodyweight/day (EPA, 1992d).

In a preliminary study 2-ethyl-1-hexanol was administered asan aqueous emulsion by oral gavage for 11 days to 10 male and fe-male Fischer 344 rats and B6C3F1 mice at 0, 100, 330, 1000, or1500 mg/kg/day. Clinical signs in treated animals were ataxia,lethargy, and lateral/abdominal posturing in rats (at 1000 and1500 mg/kg/day) and mice (1500 mg/kg/day). One female mousefrom the 1000 mg/kg/day dose group died, and 5/10 died at1500 mg/kg/day. There were no mortalities in rats. Significant de-creases in mean rat body weights were observed at 1500 mg/kg onday 10. Significant increases were observed in relative liver andstomach weights of both male and female rats at 1000 and1500 mg/kg/day. Kidney weights were significantly increased infemales at 330 mg/kg/day. Gross lesions in the rats were observedin 2/10 males at 1000 mg/kg/day and 4/10 males and 7/10 femalesat 1500 mg/kg/day. The dose level of 500 mg/kg/day was selectedas a tolerable upper dose based on this 11 day study (Astill,1996a).

Oral toxicity of 2-ethyl-1-hexanol was studied in B6C3F1 miceafter administration by gavage (aqueous emulsion) for 11 days.In total, nine applications of 0, 100, 330, 1000, or 1500 mg/kg weregiven to 10 male and 10 female mice per group. Some toxic effectswere observed, such as increases in liver and stomach weights(absolute and relative), foci in the forestomach, hyperkeratosisand focal/multifocal acanthosis, or clinical signs (ataxia, lethargy,piloerection, abdominal/lateral position, and loss of consciousness)in the 330–1500 mg/kg dosage groups. The authors reported theNOEL was between 100 and 330 mg/kg of 2-ethyl-1-hexanol(EPA, 1992e).

Kieth et al. (1992) studied the dose response for peroxisomeproliferation due to 2-ethyl-1-hexanol in rats and mice. Rats andmice, 5/sex/dose, were dosed by oral gavage for 14 days with upto 6.74 mmol/kg (2500 mg/kg/day) diethylhexyl adipate (DEHA)or 13.5 mmol/day (1750 mg/kg/day) of 2-ethyl-1-hexanol. 2-Ethyl-1-hexanol exhibited marked toxicity in male and female ratsat doses of 8 mmol/kg/day (1160 mg/kg/day) and higher; the ani-mals were killed in extremis. Such toxicity was not noted for DEHA.Both compounds resulted in dose-dependent increased liverweights and peroxisome proliferation in both rats and mice, withDEHA being about twice as potent, on a molar basis, as 2-ethyl-1-hexanol. Since DEHA is metabolized to 2 M equivalents of 2-ethyl-1-hexanol. These data suggest that 2-ethyl-1-hexanol is theproximate peroxisome proliferator of DEHA.

Rhodes et al. (1984) reported that in contrast to results frompreviously reported high dose studies, treatment of male Wistar-derived rats by oral gavage with 1 mmol/kg/day (130 mg/kg/day)2-ethyl-1-hexanol for 14 days resulted in no hepatomegaly, perox-isome proliferation, hypolipidemia, or testicular atrophy. In con-trast, diethylhexylphthalte at 1 mmol/kg/day (390 mg/kg/day)produced hepatic effects.

It was reported that serum cholesterol and triglyceride levelswere significantly decreased in male F-344 rats fed ground ratchow diet containing 2% v/w (20 mg/kg body weight/day) 2-ethyl-1-hexanol for three weeks (Moody and Reddy, 1982).

The subacute toxicity was tested in 2-ethyl-1-hexanol for threeweeks by oral administration. Five rats were dosed at 1 ml/kg(�833 mg/kg) and a statistical increase (p < 0.05) in liver weightwas observed (no further details given) (Yamada, 1974).

Fischer 344 rats were given doses of 2-ethyl-1-hexanol at 100,320, and 950 mg/kg/day in a 21-day gavage study. There was noapparent treatment affect on food intake, although there was a sig-nificant decrease in body weight gain in the 950 mg/kg/day group.A dose-related increase in cyanide-insensitive pamitoyl CoA oxida-tion was observed at 320 and 950 mg/kg/day (Hodgson, 1987).

Male and female rats were given 1000 mg 2-ethyl-1-hexanol/kgbody weight/day by gavage for 3 weeks. The test substance causeda 30% increase in liver-to-body-weight ratio, an increase in the per-oxisome cell fraction and peroxisome density in the liver (Barberand Topping, 1995).

Ten rats were given 0, 330, 660, 930 mg/kg body weight in sun-flower oil by gavage 5 days per week for 22 days. At the highestdose, 930 mg/kg, one animal died and body weight was decreasedon day 17 (Schmidt et al., 1973).

4.7.2. Subchronic (31–90 days) studiesA 90 day subchronic inhalation study was performed on Wistar

rats (10/sex/group) at concentrations of 15, 40, and 120 ppm. Therats were put into an inhalation chamber of glass/steel construc-tion (manufactured by BASF AG, Ludwigshafen Germany). Pressure(�10.2 to 10.1 P) and temperature (23.1–23.8 �C) were measuredcontinuously. Females of the 40 and 120 ppm exposure grouphad a decreased body weight gain, whereas the males of the15 ppm group showed an increase. No clinical signs or mortalitywere observed throughout the study. The authors stated that thedifferences in body weight/body weight gain are incidental, notdose-related and therefore of no toxicological significance. Therewere no macroscopic findings attributable to the material, or in-crease in the cyanice-insensitive palmitoyl Co A oxidation in anytreatment group. Based on the results of this test the NOAEL of in-haled 2-ethyl-1-hexanol was 120 ppm (corresponding to638.4 mg/m3) (Klimisch, 1998).

4.7.3. Chronic (90+ days) studiesMale and female F344 rats and B63F1 mice (10/sex/dose) were

administered 2-ethyl-1-hexanol by oral gavage at doses of 0, 25,250, or 500 mg/kg/day for 13 weeks. One female mouse at250 mg/kg/day died during treatment, but there were no othermortalities in rats or mice. Decreased body weight gain, 7% in maleand 6% in female rats, was observed at 500 mg/kg starting at week4 (males) and week 11 (females). Decreases in serum ALT activities,and serum cholesterol concentrations were observed. Males, at500 mg/kg, had a decrease in total protein and albumin concentra-tion. Significant differences in the relative organ weights from thecontrol rats were moderate and limited to the brain, kidney, liver,stomach, and testes at 250 and 500 mg/kg/day. Gross lesions inboth rats and mice were seen at 500 mg/kg/day only. Dose-relatedmicroscopic findings were limited to the forestomach and liver at500 mg/kg/day in rats and mice. No increases in palmitoyl Coen-zyme A activity were seen in the livers of any mice. Increased activ-ity was observed in rats of the 500 mg/kg/day group. A NOEL of125 mg/kg/day was concluded (Astill, 1996a).

2-Ethyl-1-hexanol was given by oral gavage to B6C3F1 mice andFischer 344 rats (50/sex) as an emulsion with Cremophor in dou-ble-distilled water. Mice received 50, 200, or 750 mg/kg/day for18 months in a volume of 10 ml/kg body weight. Rats received50, 150, or 500 mg/kg/day for 24 months in a volume of 10 ml/kgbody weight. Mortality in male rats (38%) was not dose related,however female mortality in the 500 mg/kg/day amounted to52% of the animals in the group. Mice showed a marked increasein male and female mortality at 750 mg/kg/day, so dosing stoppedat week 78. Weight gains were significantly different from controlsto treated rats at 50, 150, and 500 mg/kg/day (males), as well as150, and 500 mg/kg/day (females). Weight gains were significantlydifferent from control to treated mice at 200, and 750 mg/kg/day(males), as well as 750 mg/kg/day (females). Male and female ratsdid not show any differences in food consumption, but mice had asignificant decrease at 750 mg/kg/day. Clinical observations re-vealed poor general condition, lethargy, poor grooming, and la-bored breathing in rats. There were no instances of poor generalcondition or labored breathing in mice. Moderate increase in focal


lesions and discolorations of the lung were observed in rats of thehigh dose. In the rat only the 50 mg/kg/day group was associatedwith small statistically significant increases in relative femalestomach weight. The mice showed no changes, besides a slight in-crease in testes weight, in relative organ weights at 50 and 200 mg/kg/day (Astill, 1996b).

4.8. Reproductive and developmental toxicity (see Table 7)

In a study of potential teratogenic effects of DEHP and itsmetabolites, 2-ethyl-1-hexanol was administered to pregnantWistar rats by oral gavage on gestation day 12, and fetuses wereexamined on day 20. A dose of 6.25 mmol/kg (1 ml/kg; 833 mg/kg) 2-ethyl-1-hexanol resulted in 2.0% fetuses with malformations,compared to 22.2% at 12.5 mmol/kg (2 ml/kg; 1666 mg/kg) and 0%for controls. At 1666 mg/kg, the percent survivors with hydrone-phrosis or malformations of the cardiovascular system, tail, limbs,or other were 7.8, 0, 4.9, 9.7, and 1.0, respectively (Ritter et al.,1987).

In a preliminary developmental toxicity test of 60 chemicals infemale CD-1 mice, it was reported that 2-ethyl-1-hexanol adminis-tered by oral gavage at 1525 mg/kg/day on gestation days 6–15 re-sulted in 17/49 maternal deaths, and values significantly lowerthan control values for maternal weight gain, viable litters, livebirths per litter, and fetal percent survival, birth weight and weightgain (Hardin et al., 1987).

In a study of differential prenatal toxicity of a series of alcohols,2-ethyl-1-hexanol was administered by oral gavage to Wistar ratson gestation days 6 to 19 at doses of 0, 1, 5, and 10 mmol/kg/day,equivalent to 0, 130, 650, and 1300 mg/kg/day. Maternal toxicitywas evident at 650 and 1300 mg/kg/day, with significant differ-ences from control in maternal body weight on days 15 and 20.There was one death at 650 mg/kg/day attributed to gavage error.In the 1300 mg/kg/day group there were six deaths attributed totreatment, on days 9, 10, and 13. Fetuses were also affected atthe maternally toxic doses, with significant differences from con-trol in post-implantation loss, resorptions, fetal weight, numberand percent fetuses and litters with malformations and variations,and number and percent fetuses with developmental retardations.

The maternal and the fetal NOAEL in this study were 130 mg/kg/day (Hellwig and Jackh, 1997).

In a study of the effects of DEHP and its major metabolites onSertoli cells and gonocytes of 3-day old CD Sprague Dawley rats(4/group), it was reported that 2-ethyl-1-hexanol administeredby oral gavage at 1.28 mmol/kg (�167 mg/kg) had no effects, whileDEHP and MEHP at equimolar doses resulted in large, multinucle-ated gonocytes and a decrease in the number of BrdU labeled Ser-toli cells. (Li et al., 2000).

In a study of the effects of DEHP and its metabolites on rat testisin vivo and in vitro, it was reported that oral gavage doses daily forfive days of 2.7 mmol/kg (�350 mg/kg) of 2-ethyl-1-hexanol didnot induce testicular damage in 35 day old male Sprague Dawleyrats and in vitro administration of 2-ethyl-1-hexanol did not en-hance germ-cell detachment from mixed primary cultures of Ser-toli and germ cells from 35-day old male Sprague Dawley rats,while MEHP had effects on these parameters. 2-Ethyl-1-hexanol(200 lM for 24 or 48 h) did not result in an increase of germ-celldetachment in rat testicular-cell cultures (Gray, 1986; Gray andBeamand, 1984; Sjöberg et al., 1986).

Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-hexanol microencapsulated in their diet at concentrations of 0,0.009, 0.03, and 0.09% from days 0–17 of pregnancy. This corre-sponded to calculated doses of 0.13, 43, and 129 mg/kg bodyweight/day. No maternal toxicity was observed and the birth ratewas 93–96% in all groups. All of the litters survived and all gesta-tional parameters were normal. There were no external, visceral,or skeletal malformations and no increase in variations occurred.The authors concluded that 2-ethyl-1-hexanol plays essentiallyno role in the expression of DEHP-induced maternal and develop-mental toxicity (NTP, 1991; Price et al., 1991).

2-Ethyl-1-hexanol was given to female Sprague Dawley rats (6/group) by gavage so that developmental toxicity could be evalu-ated. On gestation day (GD) 11.5 dosed administration of 0, 6.25,9.38, or 12.5 mmol in corn oil (�0, 813, 1219, 1625 mg/kg bodyweight) was followed by an 8 h intubation with 32 lCi 65Zn.Maternal food intake decreased, and the 65Zn was retained in theliver. The percentage of resorptions was not affected. The authorsconcluded that 2-ethyl-1-hexanol did not elicit a profile of

Table 7Summary of reproductive and developmental toxicity studies.

Method Dose mg/kg body weight/day Species Results References

Oral 833, and 1666 Rat 2% malformations (833 mg/kg)22.2% malformations (1666 mg/kg)

Ritter et al. (1987)

Oral 1525 Mouse 17/49 maternal deathsSignificantly lower maternal weight gain, viable litters, live births/litter, fetal survival, and fetal weight

Hardin et al. (1987)

Oral 0, 130, 650, and 1300 Rat Maternal toxicity at 650 and 1300 mg/kg/day.Maternal and fetal NOAEL 130 mg/kg/day

Hellwig and Jackh (1997)

Oral 167 Rat No effects Li et al. (2000)Oral 350 Rat Did not induce testicular damage Sjöberg et al. (1986)

Gray et al. (1984)Gray (1986)

Oral 0.13, 43 and 129 CD-1 Swiss mice(28 f/group)

NOAEL maternal and developmental toxicity: 129 mg/kg body weight/day but no toxic dose testedno maternal toxicity; all of the litters survived and all gestationalparameters were normal.

NTP (1991), Price et al.(1991)

Oral 0, 813, 1219, 1625 Rat P1219 mg/kg body weight: maternal food intake decreased; 1625 mg/kg body weight: percentage of 65Zn retained in maternal liver increaseThe percentage of resorptions was not affected; 1625 mg/kg bodyweight: percentage of 65Zn retained in the embryos decreased

Bui et al. (1998),Taubeneck (1996)

Wholebody

850 mg/m3 Rat No effects Nelson et al. (1989)

Dermal 0, 420, 840, 1680, 2520 Rat NOAEL was 2520 mg/kg/day Fisher et al. (1989)Tyl et al. (1992)

In vitro 200 uM Rat No effect Moss et al. (1988)In vitro 200 uM Rat Did not induce dissociation of germinal cells from Sertoli Cells Gangolli (1982)


maternal or developmental toxicity compared to that of its parentcompound, DEHP (Bui et al., 1998; Taubeneck, 1996).

When pregnant Sprague Dawley rats were exposed by wholebody exposure 7 h per day on gestation days 1–19 to 850 mg/m3

2-ethyl-1-hexanol, the maximum vapor concentration that couldbe achieved without increasing exposure chamber temperatureabove 80� F, overall mean food consumption was decreased com-pared to control, but there were no significant differences inmaternal weight, water intake, corpora lutea per ovary, resorptionsper litter, numbers of females or males per litter, or fetal weight offemales or males, and no external, visceral, or skeletal malforma-tions were observed (Nelson et al., 1989).

There were no developmental effects when 2-ethyl-1-hexanolwas administered by occluded cutaneous application to Fischer344 rats 6 h per day on gestation days 6–15 at doses of 0, 0.5,1.0, 2.0, and 3.0 ml/kg/d (0, 420, 840, 1680, or 2520 mg/kg/day)in a range-finding study (8/group) or at 0, 0.3, 1.0, and 3.0 ml/kg/day (0, 252, 840, or 2520 mg/kg/day) in the main study (25/group).Maternal weight gain was reduced at 1680 mg/kg and 2520 mg/kg/day. Persistent exfoliation and crusting and erythema were seen inboth studies at 840, 1680, and 2520 mg/kg/day. Maternal liver, kid-ney, thymus, spleen, adrenal, and uterine weights and gestationaland fetal parameters were unaffected by treatment. There wereno treatment related increases in incidence of individual or pooledexternal, visceral, or skeletal malformations or variations. TheNOAELs for maternal toxicity were 252 mg/kg/day based on skinirritation and 840 mg/kg/day based on systemic toxicity. Thedevelopmental NOAEL was at least 2520 mg/kg/day, with no tera-togenicity (Fisher et al., 1989; Tyl et al., 1992).

It was reported that 2-ethyl-1-hexanol had no effect in vitro onlactate and pyruvate production by Sertoli cell enriched culturesderived from 28 day old Sprague Dawley rats, whereas phthalatemonoesters known to cause testicular atrophy in vivo increasedSertoli cell lactate production and lactate/pyruvate ratio (Mosset al., 1988).

It was reported that 200 lM 2-ethyl-1-hexanol in vitro did notinduce dissociation of germinal cells from Sertoli cells in culturesof rat seminiferous tubules (Gangolli, 1982).

4.9. Genotoxicity

4.9.1. In vitro studies4.9.1.1. Bacterial test systems (see Table 8). In Salmonella typhimuri-um (strains TA98, TA100, TA1535, TA1537, and TA1538 andEschericia coli (strain WP2uvrA) 2-ethyl-1-hexanol was found tobe non-mutagenic with and without addition of the S9 mix fromthe livers of male Sprague–Dawley rats (Shimizu et al., 1985).

In a study of 34 phthalates and related chemicals, 2-ethyl-1-hexanol was found to be non-mutagenic in S. typhimurium strainsTA98, TA100, TA1535, and TA1537 with and without addition ofmicrosomes from Aroclor induced rats and Syrian hamsters (Zeigeret al., 1982).

2-Ethyl-1-hexanol was found to be non-mutagenic inS. typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538,and TA2637 with and without metabolic activation (Agarwal etal., 1985).

Salmonella typhimurium (strains not specified), 2-ethyl-1-hexa-nol was found to be non-mutagenic with and without addition ofrat liver microsomes (Barber et al., 1985).

2-Ethyl-1-hexanol was not mutagenic in S. typhimurium (strainsTA98, TA100, TA1535, TA1537, and TA1538) tested with and with-out addition of microsomes from Aroclor induced rats (Kirby et al.,1983).

2-Ethyl-1-hexanol was found to be non-mutagenic inS. typhimurium strains TA98 and TA100 with and without additionof rat liver microsomes (Warren et al., 1982).

At 500 ug/disk, 2-ethyl-1-hexanol was found to be non-muta-genic in the Rec-assay with Bacillus subtilis strains H17 and M45(Tomita et al., 1982).

Urine from Sprague–Dawley rats dosed by oral gavage for15 days with 1000 mg/kg 2-ethyl-1-hexanol was found to benon-mutagenic in S. typhimurium strains TA98, TA100, TA1535,TA1537, and TA1538 with and without addition of rat liver micro-somes or beta-glucuronidase/arylsulfatase (DiVincenzo et al., 1983,1985).

2-Ethyl-1-hexanol was found to be mutagenic S. typhimuriumstrain TA 100 in an 8-azaguanine resistance assay (Seed, 1982).

In a study of the thermal decomposition products of phthalatesand poly(vinyl) chloride, 2-ethyl-1-hexanol was reported to causeDNA damage in the Rec-assay with B. subtilis strains HA101(rec+)and Rec-4 (rec�) (Saido et al., 2003).

4.9.1.2. Studies in mammalian cells (see Table 9). 2-Ethyl-1-hexanolwas found to be non-mutagenic in the L5178Y TK ± mouse lym-phoma cell mutagenicity assay. Doses of 0.01, 0.05, 0.25, 0.5, and1.0 ul/plate representing nontoxic, toxic, and/or maximum toler-ated doses were selected based on preliminary toxicity studies(Kirby et al., 1983).

Table 8Summary of bacterial studies.

Method Bacterial strains Results References

Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 and E. coli WP2uvrA Non-mutagenic Shimizu et al. (1985)Ames test S. typhimurium TA 98, 100, 1535, 1537 Non-mutagenic Zeiger et al. (1982)Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538, 2637 Non-mutagenic Agarwal et al. (1985)Ames test S. typhimurium (unspecified) Non-mutagenic Barber et al. (1985)Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic Kirby et al. (1983)Ames test S. typhimurium TA 98, 100, Non-mutagenic Warren et al. (1982)Rec-assay B. subtilis H17 and M45 Non-mutagenic Tomita et al. (1982)Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic DiVincenzo et al. (1983), (1985)Resistance assay S. typhimurium TA 100 Mutagenic Seed (1982)Rec-assay B. subtilis HA101 (rec+) and Rec-4 (rec-) Mutagenic Saido et al. (2003)

Table 9Summary of mammalian cell studies.

Method Species Results References

Mouse lymphoma cellmutagenicity assay

Mouse Non-mutagenic Kirby et al.(1983)

Cytogenetic assay Rat Did not induceunscheduled DNAsynthesis

Hodgsonet al.(1982)

Balb 3T3transformationassay

Rat Did not inducetransformation

EPA (1983)

Chromosomalaberration assay

Hamster Did not increase frequencyof chromosomalaberrations

Phillipset al.(1982)


2-Ethyl-1-hexanol was evaluated for its ability to induceunscheduled DNA synthesis (UDS) in primary rat hepatocytescultures prepared from Fischer 344 rats. Cells were treated simul-taneously with test compound and tritiated thymidine for 1 h.2-ethyl-1-hexanol did not induce UDS in this assay (Hodgsonet al., 1982, abstract).

2-Ethyl-1-hexanol was tested and found to not induce transfor-mation in an assay for in vitro transformation of Balb 3T3 cells withmetabolic activation by primary rat hepatocytes obtained fromFischer 344 rats. The compound was tested over the concentrationrange of 96–180 nl/ml. This concentration range corresponded toapproximately 31.7–72% survival in the concomitant cytotoxicitytest. The positive control treatments of cyclophosphamide induceda total of 26 foci among 18 flasks; therefore, the sensitivity of theassay appeared normal (EPA, 1983).

2-Ethyl-1-hexanol over a 1.5–2.8 mM concentration range didnot cause a statistically significant increase in frequency of chro-mosomal aberrations compared to control in Chinese Hamsterovary cells (Phillips et al., 1982).

4.9.2. In vivo studies (see Table 10)In the in vivo mouse micronucleus assay using the B6C3F1

mouse and in the Balb 3T3 transformation assay, 2-ethyl-1-hexa-nol was found to be non-mutagenic in the presence and absenceof a co-cultivated rat hepatocyte activation system (Barber et al.,1985; Astill et al., 1986).

Male Fischer 344 rats were dosed by oral gavage for five consec-utive days with 0.02, 0.07, and 0.21 ml/kg/day of 2-ethyl-1-hexa-nol. When compared to controls, there was no increase inchromatid and chromosome breaks. The mitotic index was alsonot affected in bone marrow cells (Putman et al., 1983).

A dominant lethal study was conducted in ICR/SIM mice treatedorally with 2-ethyl-1-hexanol. Dose levels of 250, 500, and1000 mg/kg/day representing the MTD, were selected based on apreliminary acute toxicity study. The animals were treated by oralgavage daily for five consecutive days. After treatment, each malewas housed with two virgin females per week for eight consecutiveweeks to span the spermatogenic cycle. Females were sacrificed onday 14–17 of caging with males and scored for pregnancy, livingfetuses, and early and late fetal deaths. Fertility indices and aver-age numbers of dead and total implants per pregnancy were withinthe normal range. It was concluded that 2-ethyl-1-hexanol did notinduce dominant lethal mutations after oral administration(Rushbrook et al., 1982).


4.10.1. In vitro studiesIn a tumor initiation/promotion study of diethylhexyl phthalate

and its hydrolysis products, 2-ethyl-1-hexanol was evaluated in an

in vitro promotion potential study with mouse epidermis-derivedJB6 cells. 2-Ethyl-1-hexanol did not promote JB6 cells to anchorageindependence (Ward et al., 1986).

A cell transformation assay with BALB 3T3 cells did not induce asignificant number of transformed foci (Barber et al., 1985).

4.10.2. In vivo studies2-Ethyl-1-hexanol was given to male and female rats and mice

by gavage five times a week in 0.005% aqueous Cremophor EL (rats:0 (water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg bodyweight/day, 18 months). The incidences of carcinomas and baso-philic foci in the liver increased in female mice with the doseand attained statistical significance in the highest dose group com-pared with the vehicle control group but not with the water con-trol group. The time-adjusted incidence of hepatocellularcarcinomas in female mice (13.1%) was outside the normal range(0–2%), but in male mice (18.8%) was within the historical controlrange at the testing facility (0–22%). No adenomas were observed.The number of basophilic liver foci was increased in male mice inthe mid dose group only (Table 5). The authors considered the livertumors in the mouse to be inconclusive because the incidence ofhepatocarcinoma precursors did not significantly increase withthe dose. Nevertheless, they concluded that 2-ethylhexanol isweakly or questionably carcinogenic for the female mouse. Underthe conditions of this study 2-ethyl-1-hexanol was not oncogenicto rats. Doses of 150 and 500 mg/kg body weight/day led to re-duced body weight gains and in some animals to lethargy and poorgrooming which proves that the maximum tolerated dose wasreached. At the end of the study the mortality was about 52% inthe high dose group females and about 28% in the other groups(Table 11; Astill et al., 1996b).

4.11. Miscellaneous studies (see Table 12)

In studies in perfused livers from starved female Sprague–Daw-ley rats, 2-ethyl-1-hexanol (3 mM or �0.39 g) in the perfusionmedia (Krebs–Henseleit buffer pH 7.4, 37 �C saturated with 95%O2: 5% CO2) inhibited oxygen uptake in periportal, but not centri-lobular regions, and caused damage primarily in the periportal re-gions, as reflected by trypan blue staining. 2-Ethyl-1-hexanolperfusion also resulted in lactate dehydrogenase release into theperfusion effluent. In isolated mitochondria from the treated livers,oxygen uptake was inhibited in the presence of succinate with ADPand stimulated in the presence of succinate without ADP, indicat-ing an uncoupling of oxidative phosphorylation. It was proposedthat peroxisome proliferators accumulate in the liver due to theirlipophilicity where they inhibit actively respiring mitochondriain periportal regions of the liver lobule and cause local toxicity(Keller et al., 1990, 1992).

In an investigation of the effect of 2-ethyl-1-hexanol on fattyacid metabolism, it was reported that rates of ketone body pro-duction by perfused livers from starved female Sprague–Dawleyrats were decreased about 60% by 200 uM (�0.026 g) 2-ethyl-1-hexanol in the perfusion media (Krebs–Henseleit buffer pH 7.4,37 �C saturated with 95% O2: 5% CO2). Studies were conductedto determine the site of inhibition of fatty acid oxidation. Ratesof ketone body production in the presence of oleate, which re-quires transport of the corresponding CoA compound into themitochondria, were reduced by 2-ethyl-1-hexanol. In contrast, ke-tone body production from hexanoate, which is activated in themitochondria, was not affected by 2-ethyl-1-hexanol. Basal andoleate-stimulated H2O2 productions were not affected by 2-ethyl-1-hexanol, indicating that beta-oxidation was not alteredby the compound. Based on these data, it was concluded that2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in

Table 10Summary of in vivo studies.

Method Species Results References

Mousemicronucleusassay

B6C3F1mouse

Non-mutagenic Barber et al.(1985)Astill et al.(1986)Balb 3T3

transformationassay

Rat Non-mutagenic

Cytogenetic assay Rat No effects Putman et al.(1983)

Dominant lethalstudy

Mouse Did not induce dominantlethal mutations

Rushbrooket al. (1982)


Table 11Study of the carcinogenicity of 2-ethyl-1-hexanol administered to B6C3F1 mice by oral gavage for 18 months (Astill et al., 1996b) – liver findings.

Dose (mg/kg body weight/day) Water control Vehicle control 50 mg/kg 200 mg/kg 750 mg/kg

Congestion m 1/50 0/50 0/50 0/50 7/502

f 1/50 0/50 0/50 3/50 2/50

Peripheral fatty infiltration m 0/50 0/50 0/50 1/50 31/503

f 0/50 1/50 0/50 3/50 22/503

Basophilic foci m 4/50 4/50 5/50 12/501 6/50f 2/50 1/50 2/50 4/50 6/501

Focal hyperplasia m 2/50 7/50 4/50 9/50 10/50f 1/50 0/50 3/50 4/501 1/50

Adenomas m 0/50 0/50 0/50 0/50 1/50

Carcinomas m 4/50 6/50 6/50 7/50 9/50f 1/50 0/50 1/50 3/50 5/501

Compared with the vehicle control (Fisher’s exact test).1 p < 0.05,2 p < 0.01,3 p < 0.001, f, female; m, male.

Table 12studies on the mechanism of hepatotoxicity of 2-ethyl-1-hexanol.

Test system Concentration Results References

Isolation of mitochondria fromperfused rat livers

70 lM, 3 mM in theperfusion medium

2-Ethyl-1-hexanol in the perfusion media: inhibition of the oxygen uptake inperiportal, but not centrilobular regions; damage primarily in the periportal regions,as reflected by trypan blue staining; lactate dehydrogenase release into the perfusioneffluent.Isolated mitochondria from the perfused livers: inhibition of the oxygen uptake in thepresence of succinate with ADP and stimulation in the presence of succinate withoutADP, indicating an uncoupling of oxidative phosphorylation.It was proposed that peroxisome proliferators accumulate in the liver due to theirlipophilicity where they inhibit actively respiring mitochondria in periportal regionsof the liver lobule and cause local toxicity.

Keller et al.(1990, 1991,1992)

Perfused livers 200 lM in theperfusion medium

2-Ethyl-1-hexanol in the perfusion media: rates of ketone body production weredecreased about 60%; rates of ketone body production in the presence of oleate, whichrequires transport of the corresponding CoA compound into the mitochondria, werereduced by 2-ethyl-1-hexanol; in contrast, ketone body production from hexanoate,which is activated in the mitochondria, was not affected by 2-ethyl-1-hexanol; basaland oleate-stimulated H2O2 productions were not affected by 2-ethyl-1-hexanol,indicating that beta-oxidation was not altered by the compound;Based on these data,it was concluded that 2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids inmitochondria but not in peroxisomes.

Badr et al.(1990)

Isolated cylinders of periportal andpericentral regions of the liverlobule

0.1–3 mM:incubation of plugs

Incubation of plugs with 0.1 to 3 mM 2-ethyl-1-hexanol: extensive cell damageassessed from LDH leakage in incubations at 800 lM O2 but significantly less injury at200 lM O2; Concomitantly, inhibition of urea synthesis by over 80% at 800 lM O2, butless than 50% at 200 lM O2; Plugs isolated from both regions of the liver were affectedsimilarly by 2-ethyl-1-hexanol and O2.The authors concluded that these data indicate that 2-ethyl-1-hexanol toxicity isdependent on oxygen tension in isolated sublobular regions of the liver lobule, andtherefore it is unlikely that drug delivery can explain the selective injury to periportalregions in studies with perfused liver.

Liang et al.(1991)

GST from rats and mice Up to 15 mM Cytosolic GST activity (substrates: 1,2-dichloro-4-nitrobenzene- or 1,2-epoxy-3-(p-nitrophenoxy)-propane) was only weakly inhibited in rats (IC50 70 mM or noinhibition up to 10 mM) and mice (IC50 23 mM or 15 mM), in contrast to the effects ofother peroxisome proliferators (e.g. DEHP, MEHP)

Law and Moody(1989, 1991)

Rat liver homogenates 2.5 to 15 mM Concentration-dependent reduction in the activities of aniline hydroxylase andaminopyrine-N-demethylase

Agarwal et al.(1982) Seth(1982)

Kupffer cells in culture Up to 0.9 mM No effect on the Kupffer cell superoxide production Rose et al.(1999)

Kupffer cells in culture Up to 3 mM No effect on the cytosolic free calcium concentrations in Kupffer cells up to 2 mM(Wy-16,643 had an effect at 1,25 mM), only at 3 mM increase of the free calciumconcentration

Hijioka et al.(1991)

Mitochondrial fraction from rat liver 1% Little inhibitory effect on mitochondrial respiration at a concentration of 1% Takahashi(1977)

Cultured hepatocytes 10, 100, 500 lM Inhibition of GJIC was observed, no cytotoxicity in the tested concentration range, aNOEL for GJIC was observed, n.f.i.

Lington et al.(1994)

ADP, adenosine diphosphate; CoA, Coenzyme A; DEHP, di(2-ethylhexyl) phthalate; GJIC, gap junctional intercellular communication; GST, glutathione-S-transferase; MEHP,mono-(2-ethylhexyl) phthalate; n.f.i., no further information; LDH, lactate dehydrogenase.


mitochondria but not in peroxisomes. Treatment of rats ip with0.32 g/kg 2-ethyl-1-hexanol deceased plasma ketone bodies, in-creased hepatic triglycerides, and increased lipid predominantlyin periportal regions of the liver lobule. It was concluded, dataindicates that alterations in hepatic fatty acid metabolism in per-iportal regions of the liver lobule may be early events in peroxi-some proliferation (Badr et al., 1990).

To determine whether the selective toxicity of 2-ethyl-1-hexa-nol for the periportal region in the perfused rat liver (fasted femaleSprague–Dawley rats, pretreated with phenobarbital 1 mg/l for atleast 7 days) was due to local oxygen tension or drug delivery,isolated cylinders of periportal and pericentral regions of the liverlobule were collected with a micropunch following brief perfusionof the organ. Incubation of liver punch biopsy samples with0.1–3 mM (0.01–0.39 g) 2-ethyl-1-hexanol caused extensive celldamage assessed from lactose dehydrogenase (LDH) leakage inincubations at 800 uM O2 but significantly less injury at 200 uMO2. Concomitantly, urea synthesis was inhibited by over 80% at800 uM O2, but less than 50% at 200 uM O2. Liver punch biopsysamples isolated from both regions of the liver were affected sim-ilarly by 2-ethyl-1-hexanol and O2. The authors concluded thatthese data indicate that 2-ethyl-1-hexanol toxicity is dependenton oxygen tension in isolated sublobular regions of the liver lobule,and therefore it is unlikely that drug delivery can explain the selec-tive injury to periportal regions in studies with perfuse liver (Lianget al., 1991).

A study was conducted to determine how peroxisome prolifer-ators and 2-ethyl-1-hexanol, up to 15 mM, would affect mouse andrat liver glutathione S-transferases (GST) in vitro. Cytosolic GSTactivity was only weakly inhibited in rats and mice when com-pared to the effects of other peroxisome proliferators (Law andMoody, 1989, 1991).

The in vitro effects of 2-ethyl-a-hexanol on the activity of ami-nopyrine N-demethylase and aniline hydroxylase were studied.Aliquots of 2.5–15 mM were used the enzyme assay. A concentra-tion dependent reduction in the activities of aniline hydroxylaseand aminopyrine-N-demthylase was observed (Agarwal et al.,1982; Seth, 1982).

Kupffer cells and hepatocytes were isolated to study cell prolif-eration. Incubation of 2-ethyl-1-hexanol with Kupffer cells in cul-ture up to 0.9 mM had no effect of the superoxide production(Rose et al., 1999). Furthermore, there were no effects on the cyto-solic free calcium concentrations in Kupffer cells up to 2 mM. At3 mM an increase of free calcium concentration was observed,whereas, Wy-16,643 had an effect at 1.25 mM (Hijioka et al., 1991).

The effects of 2-ethyl-1-hexanol at 1% on mitochondrial respira-tion of Wistar rat livers were investigated. Little inhibitory effectswere observed (Takahashi, 1977).

Inhibition of gap junctional intercellular communication (GJIC)was observed for 2-ethyl-1-hexanol in cultured hepatocytes fromB6C3F1 female mice and F344 female rats. Reversible effects wereobserved following the removal of the compound, and 2-ethyl-1-hexanol was not considered the most potent metabolite for inhibi-tion to the GJIC (Lington et al., 1994).

This individual Fragrance Material Review is not intended asa stand-alone document. Please refer to a safety assessmentof branched chain saturated alcohols when used as fragranceingredients (Belsito et al., 2010) for an overall assessment of thismaterial.


This research was supported by the Research Institute forFragrance Materials, an independent research institute that isfunded by the manufacturers of fragrances and consumer products

containing fragrances. The authors are all employees of the Re-search Institute for Fragrance Materials.

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S93–S96 Fragrance material review on 3-methyl-1-pentanol



S97–S101 Fragrance material review on 2-methylbutanol

D. McGinty, A. Lapczynski,


A. M. Api

S102–S109 Fragrance materials review on isoamyl alcohol



S110–S114 Fragrance material review on 2,6-dimethyl-2-heptanol



S115–S129 Fragrance material review on 2-ethyl-1-hexanol

(Contents continued from outside back cover)FOOD AND CHEMICAL TOXICOLOGY

Founding Editor

The late Leon Golberg

Editors

JOSEPHOSEPH F. BORZELLECAORZELLECA

Department of Pharmacology andToxicology, Medical College of Virginia,

Richmond, VA 23298-0613, USA

ALANLAN R. BOOBISOOBIS

Section of Experimental Medicine and Toxicology,Division of Medicine, Imperial College, Hammersmith Campus,

Ducane Road, London W12 0NN, UK

Review EditorSUSANUSAN M. BARLOWARLOW

Harrington House, 8 Harrington Road,Brighton, East Sussex BN1 6RE, UK

Associate EditorsJOHNOHN CHRISTIANHRISTIAN LARSENARSEN

National Food Institute, Technical University of Denmark,19 Mørkhøj Bygade, DK-2860 Søborg, Denmark

BRYANRYAN DELANEYELANEY

Senior Research Scientist – Toxicology, Pioneer Hi-Bred International,2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA

GARYARY WILLIAMSILLIAMS

Department of Pathology, New York Medical College, Basic ScienceBuilding, Room 413, Valhalla, NY 10595, USA

SAMUELAMUEL M. COHENOHEN

Department of Pathology and Microbiology, University of NebraskaMedical Center, 983135 Nebraska Medical Center,

Omaha, NE 68198-3135

IVONNEVONNE RIETJENSIETJENS

AFSG/Division of Toxicology, Wageningen University, PO Box 8000,6700 EA Wageningen, The Netherlands

DAVIDAVID J. BRUSICKRUSICK

Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass,Virginia, USA

MICHAELICHAEL W. PARIZAARIZA

Department of Food Microbiology and Toxicology, University ofWisconsin at Madison, 176 Microbial Sciences Building,

1550 Linden Drive Madison, WI 53706, USA

International Editorial Board

P. BALDRICKALDRICK, UKJ. K. CHIPMANHIPMAN, UKT. F. X. COLLINSOLLINS, USAY. P. DRAGANRAGAN, USAL. O. DRAGSTEDRAGSTED, DenmarkL. FERGUSONERGUSON, New ZealandS. J. S. FLORALORA, IndiaH. R. GLATTLATT, GermanyW. H. GLINSMANNLINSMANN, USAY. HASHIMOTOASHIMOTO, JapanA. W. HAYESAYES, USAY. HUAUA, ChinaS. KACEWACEW, Canada

I. KIMBERIMBER, UKS. KNASMULLERNASMULLER, AustriaB. LAKEAKE, UKR. W. LANEANE, USAM. I. LUSTERUSTER, USAD. McGREGORREGOR, FranceP. MAGEEAGEE, UKH. I. MAIBACHAIBACH, USAK. MORGANORGAN, UKR. J. NICOLOSIICOLOSI, USAD. RAYAY, UKK. ROZMANOZMAN, USAW. H. M. SARISARIS, The Netherlands

R. C. SHANKHANK, USAM. SMITHMITH, The NetherlandsY.-J. SURHURH, South KoreaR. G. TARDIFFARDIFF, USAS. L. TAYLORAYLOR, USAJ. A. THOMASHOMAS, USAE. VAVASOURAVASOUR, CanadaH. VERHAGENERHAGEN, The NetherlandsA. VISCONTIISCONTI, ItalyX. WANGANG, People’s Republic of ChinaS. YANNAIANNAI, Israel


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Editors

J F Borzelleca

A R Boobis


Volume 48, Supplement 4, July 2010 ISSN 0278-6915

FOOD AND CHEMICAL TOXICOLOGY

VOLUME 48 (2010) SUPPLEMENT 4CONTENTS

http://www.elsevier.com/locate/foodchemtoxFd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.

ISSN 0278-6915

48(S4) S1–S130 (2010)

Printed by Polestar Wheatons Ltd, Exeter, UK 237

Available online at www.sciencedirect.com

A Safety Assessment of Saturated Branched Chain Alcohols when used asFragrance Ingredients

D. Belsito, D. Bickers, M. Bruze,

P. Calow, H. Greim, J. M. Hanifin,

A. E. Rogers, J. H. Saurat, I. G. Sipes,

H. Tagami, and The RIFM Expert

Panel

S1–S46 A safety assessment of branched chain saturated alcohols when used as

fragrance ingredients


C. S. Letizia and A. M. ApiS47–S50 Fragrance material review on 3,5,5-trimethyl-1-hexanol


C. S. Letizia and A. M. ApiS51–S54 Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol


C. S. Letizia and A. M. ApiS55–S59 Fragrance material review on 4-methyl-2-pentanol


C. S. Letizia and A. M. ApiS60–S62 Fragrance material review on 2-methylundecanol


C. S. Letizia and A. M. ApiS63–S66 Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol


C. S. Letizia and A. M. ApiS67–S69 Fragrance material review on isodecyl alcohol


C. S. Letizia and A. M. ApiS70–S72 Fragrance material review on isooctan-1-ol

D. McGinty, S. P. Bhatia,


A. M. Api

S73–S78 Fragrance material review on isotridecan-1-ol (isomeric mixture)


C. S. Letizia and A. M. ApiS79–S81 Fragrance material review on isononyl alcohol


C. S. Letizia and A. M. ApiS82–S84 Fragrance material review on 6,8-dimethylnonan-2-ol

D. McGinty, C. S. Letizia and

A. M. ApiS85–S88 Fragrance material review on 2-ethyl-1-butanol


C. S. Letizia and A. M. ApiS89–S92 Fragrance material review on 2,6-dimethyl-4-heptanol

(Contents continued on inside back cover)

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