benzyl alcohol (cas #100-51-6) greenscreen for safer...

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Benzyl Alcohol (CAS #100-51-6) GreenScreen® for Safer Chemicals (GreenScreen®)

Assessment

Prepared for:

Environmental Defense Fund

February 1, 2016

1367 Connecticut Ave., N.W., Suite 300

Washington, D.C. 20036

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TABLE OF CONTENTS

GreenScreen® Executive Summary for Benzyl Alcohol (CAS #100-51-6) ............................................ i

Chemical Name ...................................................................................................................................... 1

GreenScreen® Summary Rating for Benzyl Alcohol ............................................................................. 2

Transformation Products and Ratings .................................................................................................... 3

Introduction ............................................................................................................................................ 3

GreenScreen® List Translator Screening Results ................................................................................... 4

PhysicoChemical Properties of Benzyl Alcohol .................................................................................... 5

Group I Human Health Effects (Group I Human) ................................................................................. 5

Carcinogenicity (C) Score .................................................................................................................. 5

Mutagenicity/Genotoxicity (M) Score ............................................................................................... 6

Reproductive Toxicity (R) Score ........................................................................................................ 8

Developmental Toxicity incl. Developmental Neurotoxicity (D) Score ............................................ 9

Endocrine Activity (E) Score ........................................................................................................... 10

Group II and II* Human Health Effects (Group II and II* Human) .................................................... 10

Acute Mammalian Toxicity (AT) Group II Score ............................................................................ 10

Systemic Toxicity/Organ Effects incl. Immunotoxicity (ST) .......................................................... 11

Group II Score (single dose) ......................................................................................................... 11

Group II* Score (repeated dose) ................................................................................................... 12

Neurotoxicity (N) ............................................................................................................................. 13

Group II Score (single dose) ......................................................................................................... 13

Group II* Score (repeated dose) ................................................................................................... 13

Skin Sensitization (SnS) Group II* Score ........................................................................................ 14

Respiratory Sensitization (SnR) Group II* Score ............................................................................ 16

Skin Irritation/Corrosivity (IrS) Group II Score ............................................................................... 16

Eye Irritation/Corrosivity (IrE) Group II Score ................................................................................ 17

Ecotoxicity (Ecotox) ............................................................................................................................ 18

Acute Aquatic Toxicity (AA) Score ................................................................................................. 18

Chronic Aquatic Toxicity (CA) Score .............................................................................................. 19

Environmental Fate (Fate) ................................................................................................................... 20

Persistence (P) Score ........................................................................................................................ 20

Bioaccumulation (B) Score .............................................................................................................. 21

Physical Hazards (Physical) ................................................................................................................. 21

Reactivity (Rx) Score ....................................................................................................................... 21

Flammability (F) Score..................................................................................................................... 21

References ............................................................................................................................................ 23

APPENDIX A: Hazard Benchmark Acronyms ................................................................................... 26

APPENDIX B: Results of Automated GreenScreen® Score Calculation for Benzyl Alcohol

(CAS #100-51-6) ........................................................................................................................... 27





APPENDIX C: Pharos Output for Benzyl Alcohol (CAS #100-51-6) ................................................ 28

Licensed GreenScreen® Profilers ......................................................................................................... 32

TABLE OF FIGURES

Figure 1: GreenScreen® Hazard Ratings for Benzyl Alcohol ................................................................ 3

TABLE OF TABLES

Table 1: Physical and Chemical Properties of Benzyl Alcohol (CAS #100-51-6) ................................ 5




and distribution are expressly prohibited. Page i

GreenScreen® Executive Summary for Benzyl Alcohol (CAS #100-51-6)

Benzyl alcohol is a chemical that functions as a solvent, plasticizer, fragrance and flavoring

component, preservative, viscosity-controlling agent, and degreasing agent.

Benzyl alcohol was assigned a GreenScreen Benchmark™ Score of 2 (“Use but Search for Safer

Substitutes”). This score is based on the following hazard score combinations:

Benchmark 2e (“Moderate T (Group I Human)”)

o Moderate developmental toxicity (D)

Benchmark 2f (“Very High T (Ecotoxicity or Group II Human) or High T (Group II* Human)”)

o High Group II* Human (repeated dose neurotoxicity (Nr*) and skin sensitization (SnS*)

A data gap (DG) exists for endocrine activity (E). As outlined in CPA (2013) Section 12.2 (Step 8 –

Conduct a Data Gap Analysis to assign a final Benchmark score), benzyl alcohol meets requirements

for a GreenScreen® Benchmark Score of 2 despite the hazard data gaps. In a worst-case scenario, if

benzyl alcohol were assigned a High score for the data gap endocrine activity (E), it would be

categorized as a Benchmark 1 Chemical.

GreenScreen® Benchmark Score for Relevant Route of Exposure:

As a standard approach for GreenScreen® evaluations, all exposure routes (oral, dermal and

inhalation) were evaluated together, so the GreenScreen® Benchmark Score of 2 (“Use but Search for

Safer Substitutes”)is applicable for all routes of exposure.

GreenScreen® Hazard Ratings for Benzyl Alcohol

C M R D E AT SnS* SnR* IrS IrE AA CA P B Rx F

single repeated* single repeated*

L L L M DG M DG L M H H DG L H L L vL vL L L

Fate Physical

ST N

Group I Human Group II and II* Human Ecotox

Note: Hazard levels (Very High (vH), High (H), Moderate (M), Low (L), Very Low (vL)) in italics reflect estimated

(modeled) values, authoritative B lists, screening lists, weak analogues, and lower confidence. Hazard levels in

BOLD font are used with good quality data, authoritative A lists, or strong analogues. Group II Human Health

endpoints differ from Group II* Human Health endpoints in that they have four hazard scores (i.e., vH, H, M, and L)

instead of three (i.e., H, M, and L), and are based on single exposures instead of repeated exposures. Please see

Appendix A for a glossary of hazard acronyms.




and distribution are expressly prohibited. Page 1 of 32

GreenScreen® Assessment for Benzyl Alcohol (CAS #100-51-6)

Method Version: GreenScreen® Version 1.21

Assessment Type2: Certified

Chemical Name: Benzyl Alcohol

CAS Number: 100-51-6

GreenScreen® Assessment Prepared By:

Quality Control Performed By:

Name: Zach Guerrette, Ph.D. Name: Bingxuan Wang, Ph.D., D.A.B.T.

Title: Toxicologist Title: Toxicologist

Organization: ToxServices LLC Organization: ToxServices LLC

Date: January 29, 2015 Date: Feb 4, 2015, Dec 4, 2015, Feb 1, 2016

Assessor Type: Licensed GreenScreen® Profiler Assessor Type: Licensed GreenScreen® Profiler

Name: Jennifer Rutkiewicz, Ph.D.

Title: Toxicologist

Organization: ToxServices LLC

Update Date: December 3, 2015

Assessor Type: Licensed GreenScreen® Profiler

Confirm application of the de minimus rule3: N/A (this assessment was conducted for the

theoretically pure substance)

Chemical Structure(s):

Also called:

Benzenemethanol; (Hydroxymethyl)benzene; alpha-Toluenol; Benzenecarbinol; Benzoyl alcohol;

Benzylicum; EINECS 202-859-9; Hydroxytoluene; Methanol, phenyl-; Phenolcarbinol;

Phenylcarbinol; Phenylcarbinolum; Phenylmethanol; Phenylmethyl alcohol (ChemIDplus 2015)

Chemical Structure(s) of Chemical Surrogates Used in the GreenScreen®:

In the absence of available data for the chemical of interest, ToxServices searched for a suitable

analog or class of analogs using guidance in the U.S. EPA’s procedure for identifying analogs (U.S.

1 Use GreenScreen® Assessment Procedure (Guidance) V1.2 2 GreenScreen® reports are either “UNACCREDITED” (by unaccredited person), “AUTHORIZED” (by Authorized

GreenScreen® Practitioner), “CERTIFIED” (by Licensed GreenScreen® Profiler or equivalent) or “CERTIFIED WITH

VERIFICATION” (Certified or Authorized assessment that has passed GreenScreen® Verification Program) 3 Every chemical in a material or formulation should be assessed if it is:

1. intentionally added and/or

2. present at greater than or equal to 100 ppm





EPA 2010), ECHA’s read across assessment framework (ECHA 2015a) and OECD’s guidance on

grouping of chemicals (OECD 2014). Resources used for the surrogate search included the

ChemIDplus structural similarity search, OECD Toolbox, U.S. EPA’s Analog Identification

Methodology (AIM), and U.S. EPA’s Chemical Assessment Clustering Engine (ChemACE).

Surrogates were considered to be appropriate if they resemble the target in terms of molecular

structure and size, contain a substructure of functional group that may play a critical toxicological

role, share similar physicochemical properties (e.g. water solubility, partition coefficient), or have

common or similar precursors, metabolites, or breakdown products. Where surrogates are used to fill

data gaps or as supporting evidence, the use of a surrogate is clearly indicated for that endpoint.

Benzoic acid was identified as an appropriate surrogate to fill the Data Gap for reproductive toxicity.

As note by UNEP (2001), both benzyl alcohol and benzoic acid share a common metabolic pathway

(benzyl alcohol is oxidized to benzaldehyde and then benzoic acid) and are rapidly and completely

metabolized within 24 hours. Based on the shared metabolic pathways, benzoates including benzyl

alcohol and benzoic acid have similar toxicological profiles.

Benzoic acid (CAS# 65-85-0)

Identify Applications/Functional Uses (HSDB 2009):

1. Solvent

2. Plasticizer

3. Fragrance and flavoring component

4. Preservative

5. Viscosity-controlling agent

6. Degreasing agent

GreenScreen® Summary Rating for Benzyl Alcohol4: Benzyl alcohol was assigned a

GreenScreen Benchmark™ Score of 2 (“Use but Search for Safer Substitutes”). This score is

based on the following hazard score combinations:

Benchmark 2e (“Moderate T (Group I Human)”)

o Moderate developmental toxicity (D)

Benchmark 2f (“Very High T (Ecotoxicity or Group II Human) or High T (Group II* Human)”)

o High Group II* Human (repeated dose neurotoxicity (Nr*) and skin sensitization (SnS*)

A Data gap (DG) exists for endocrine activity (E). As outlined in CPA (2013) Section 12.2 (Step 8 –

Conduct a Data Gap Analysis to assign a final Benchmark score), benzyl alcohol meets requirements

for a GreenScreen® Benchmark Score of 2 despite the hazard data gaps. In a worst-case scenario, if

benzyl alcohol were assigned a High score for the data gap endocrine activity (E), it would be

categorized as a Benchmark 1 Chemical.

4 For inorganic chemicals with low human and ecotoxicity across all hazard endpoints and low bioaccumulation potential,

persistence alone will not be deemed problematic. Inorganic chemicals that are only persistent will be evaluated under the

criteria for Benchmark 4.





Figure 1: GreenScreen® Hazard Ratings for Benzyl Alcohol

C M R D E AT SnS* SnR* IrS IrE AA CA P B Rx F

single repeated* single repeated*

L L L M DG M DG L M H H L L H L L vL vL L L

Fate Physical

ST N

Group I Human Group II and II* Human Ecotox

Note: Hazard levels (Very High (vH), High (H), Moderate (M), Low (L), Very Low (vL)) in italics reflect estimated

(modeled) values, authoritative B lists, screening lists, weak analogues, and lower confidence. Hazard levels in

BOLD font are used with good quality data, authoritative A lists, or strong analogues. Group II Human Health

endpoints differ from Group II* Human Health endpoints in that they have four hazard scores (i.e., vH, H, M, and L)

instead of three (i.e., H, M, and L), and are based on single exposures instead of repeated exposures. Please see

Appendix A for a glossary of hazard acronyms.

Transformation Products and Ratings:

Identify feasible and relevant fate and transformation products (i.e., dissociation products,

transformation products, valence states) and/or moieties of concern5

Benzyl alcohol is not likely to undergo hydrolysis as it lacks hydrolysable functional groups (HSDB

2009). Photodegradation of benzyl alcohol has been predicted as calculated rates indicate that 50%

photodegradation would occur after 1.3 to 3 days (UNEP 2001). No photodegradation products were

identified, but as very little is predicted to partition to air and the half-lives are short, any air

photodegradation products would not be considered to be feasible or relevant. In addition, because it

is readily biodegradable, biodegradation products are considered to be transient and are also not

considered to be relevant. Based on these findings, ToxServices concludes that the transformation

products do not modify the Benchmark Score for benzyl alcohol.

Introduction

Benzyl alcohol is used as a solvent, plasticizer, fragrance and flavoring component, preservative,

viscosity-controlling agent, and degreasing agent (HSDB 2009). It is produced via the hydrolysis of

benzyl chloride, catalytic reduction or Cannizzaro reaction of benzaldehyde, or hydrogenation of

benzoic acid. It can also be produced from toluene following oxidation to benzoic acid, esterification

with methanol and hydrogenation of methyl benzoate (HSDB 2009).

Benzyl alcohol is listed in Annex V, Section 34, of EC Regulation No. 1223/2009, and is approved

for use as a preservative in cosmetics sold in the European Union at a maximum use level of 1.0%.

Benzyl alcohol is listed in Annex III, Section 45 of EC Regulation No. 1223/2009 as a solvent,

perfuming, or flavoring agent that is acceptable for use in cosmetic products for purposes other than

inhibiting the development of microorganisms in the product (EC 2009). This purpose has to be

apparent from the presentation of the product. The CIR Expert Panel concluded that benzyl alcohol

is safe in the present practices of use and concentration in cosmetics evaluated by the panel, up to

10% (CIR 2014).

5 A moiety is a discrete chemical entity that is a constituent part or component of a substance. A moiety of concern is often the

parent substance itself for organic compounds. For inorganic compounds, the moiety of concern is typically a dissociated

component of the substance or a transformation product.





ToxServices assessed benzyl alcohol against GreenScreen® Version 1.2 (CPA 2013) following

procedures outlined in ToxServices’ SOP 1.37 (GreenScreen® Hazard Assessment) (ToxServices

2013).

Preservative Spectrum of Effect:

As summarized below, benzyl alcohol displays moderate bacteriostatic and fungistatic activity, with

the best efficacy against gram-positive bacteria.

Benzyl Alcohol’s Preservative Spectrum of Effect

Microorganism Spectrum of Effect Reference

Gram-positive bacteria Good-Moderate Siegert 2014

Gram-negative bacteria Moderate Siegert 2014

Yeasts/Molds Moderate Siegert 2014

Head-space protection Yes Siegert 2014

GreenScreen® List Translator Screening Results

The GreenScreen® List Translator identifies specific authoritative or screening lists that should be

searched to identify GreenScreen® benchmark 1 chemicals (CPA 2012a). Pharos (Pharos 2015) is an

online list-searching tool that is used to screen chemicals against the List Translator electronically. It

checks all of the lists in the List Translator with the exception of the U.S. Department of

Transportation (U.S. DOT) lists (U.S. DOT 2008a,b) and these should be checked separately in

conjunction with running the Pharos query. The output indicates benchmark or possible benchmark

scores for each human health and environmental endpoint. The output for benzyl alcohol can be

found in Appendix B and a summary of the results can be found below:

Neurotoxicity

o Grandjean & Landrigan Neurotoxic Chemicals - Known to be neurotoxic in humans

Acute Mammalian Toxicity

o EC – CLP/GHS

o Associated with H302 – Harmful if swallowed

o Associated with H332 – Harmful if inhaled

o Associated with R20/22 - Harmful by inhalation and if swallowed

o GHS New Zealand – Category 6.1 D (oral and dermal) (equivalent to GHS Category

4) – acutely toxic

o Québec CSST - WHMIS Classifications - Class D2B - Toxic material causing other

toxic effects

Skin Sensitization

o GHS New Zealand Category 6.5B (contact) (equivalent to GHS Category 1) – contact

sensitizer

Eye Irritation

o GHS New Zealand Category 6.4A (equivalent to GHS Category 2A) – Irritating to

the eyes

Acute Aquatic Toxicity

o GHS New Zealand Category 9.1D (fish, crustacean) (equivalent to GHS Category 2-

3) – slightly harmful in the aquatic environment or are otherwise designed for

biocidal action.

Flammability

o Québec CSST - WHMIS Classifications - Class B3 - Combustible liquids





When appropriate, HSNO classifications in New Zealand were converted to the corresponding GHS

classification (EPA 2012).

Physicochemical Properties of Benzyl Alcohol

Benzyl alcohol is a colorless liquid under standard temperature and pressure. It has a high vapor

pressure (0.094 mm Hg) indicating that it has the potential to exist in the vapor phase. It is very

soluble in water (at least 40,000 mg/L) and is more soluble in octanol than in water (log Kow of 1.05).

Its log Kow value indicates that it is not likely to bioaccumulate in the aquatic biota.

Table 1: Physical and Chemical Properties of Benzyl Alcohol (CAS #100-51-6)

Property Value Reference

Molecular formula C7-H8-O ChemIDplus 2015

SMILES Notation c1(ccccc1)CO ChemIDplus 2015

Molecular weight 108.139 g/mol ChemIDplus 2015

Physical state Liquid ECHA 2015b

Appearance Colorless ECHA 2015b

Melting point -15.4°C ECHA 2015b

Vapor pressure 7 Pa (0.053 mm Hg) at 20°C

0.094 mm Hg at 25°C

ECHA 2015b

ChemIDplus 2015

Water solubility 40,000 mg/L at 20°C

42,900 at 25°C

ECHA 2015b

ChemIDplus 2015

Dissociation constant pKa = 15.4 at 25°C ECHA 2015b

Density/specific gravity 1.04 g/cm3 at 22.5°C ECHA 2015b

Partition coefficient Log Kow = 1.05 at 20°C ECHA 2015b

Hazard Classification Summary Section6:

Group I Human Health Effects (Group I Human)

Carcinogenicity (C) Score (H, M, or L): L

Benzyl alcohol was assigned a score of Low for carcinogenicity based on the negative results for

tumor induction observed in two-year cancer bioassays in rats and mice. GreenScreen® criteria

classify chemicals as a Low hazard for carcinogenicity when negative data, no structural alerts, and

no GHS classification are available (CPA 2012b). Confidence in the score is high because it is based

on experimental data from well conducted studies in rats and mice.

Authoritative and Screening Lists

o Authoritative: Not listed on any authoritative lists for this endpoint.

o Screening: Not listed on any authoritative lists for this endpoint.

NTP 1989

o A 103-week carcinogenicity study (identified as GLP-compliant and OECD 451 in

ECHA 2015b) was performed with Fischer 344 rats (50/sex/dose group) administered

oral doses of benzyl alcohol (99% purity) in corn oil at 0, 200, or 400 mg/kg/day via

gavage five days a week. The equivalent doses for a 7-day/week exposure frequency

6 When original study reports were not available, ToxServices summarized study methodology, results, and study author

conclusions as reported in secondary sources. In cases where conclusions were not reported or where ToxServices interpreted the

results differently based on the information presented in the study summary, ToxServices’ conclusions are clearly stated.





were 0, 143, and 286 mg/kg/day, respectively. At the end of the exposure period, the

surviving animals were sacrificed and evaluated for the presence of neoplastic lesions.

No treatment-related induction in the incidences of neoplastic lesions was observed in

this study.

o A 103-week carcinogenicity study (identified as GLP-compliant and OECD 451 in

ECHA 2015b) was performed with B6C3F1 mice (50/sex/dose group) administered oral

doses of benzyl alcohol (99% purity) in corn oil at 0, 100, or 200 mg/kg/day via gavage

five days a week. The equivalent doses for a 7-day/week exposure frequency were 0, 71,

and 143 mg/kg/day, respectively. At the end of the exposure period, the surviving

animals were sacrificed and evaluated for the presence of neoplastic lesions. No

treatment-related induction in the incidences of neoplastic lesions was observed in this

study.

ECHA 2015b

o Two additional studies were identified in the REACH dossier for benzyl alcohol (ECHA

2015b). However, they were assigned a reliability score of 4 (not assignable) and were

viewed by ToxServices as insufficient for inclusion in this assessment as these studies

were performed in vitro or involved an irrelevant exposure route (intraperitoneal).

Mutagenicity/Genotoxicity (M) Score (H, M, or L): L

Benzyl alcohol was assigned a score of Low for mutagenicity/genotoxicity based on ToxServices not

classifying it as a genotoxicant under GHS criteria. GreenScreen® criteria classify chemicals as a

Low hazard for mutagenicity/genotoxicity when negative results, no structural alerts, and no GHS

classification are available (CPA 2012b). Confidence in the score is high because it is based on

experimental data for several well conducted studies.




NTP Undated

o In vitro: A mouse lymphoma forward mutation assay (identified as GLP-compliant and

OECD 476 in ECHA 2015b) was equivocal for mutagenicity. L5178Y (TK+/TK-) cells

were tested at concentrations of 250-4,500 µg/mL in the presence of metabolic activation

and 156-5,000 µg/mL in the absence of metabolic activation. There was a statistically

significant increase in mutations at the thymidine kinase locus at a dose of 4,500 µg/mL

in the absence of metabolic activation. There were no statistically significant increases in

mutations at the thymidine kinase locus at all other dose levels. The study authors

concluded that the results “do not permit a definitive conclusion regarding the genetic

toxicity of benzyl alcohol.”

NTP 1984

o In vitro: An in vitro chromosomal aberration assay was positive for clastogenicity.

Chinese hamster ovary (CHO) cells were tested at concentrations of 50-5,000 µg/mL in

the presence of metabolic activation and 250-5,000 µg/mL in the absence of metabolic

activation. There was a statistically significant increase in chromosomal aberrations in

the presence of but not in the absence of metabolic activation.

o In vitro: An in vitro sister chromatid exchange (SCE) assay was weakly positive for

clastogenicity. CHO cells were tested at concentrations of 16-5,000 µg/mL in the

presence of metabolic activation and 16-1,600 µg/mL in the absence of metabolic

activation. There was a slight increase in the formation of SCEs seen in both the

presence and absence of metabolic activation.





The significance of the SCE assay is controversial, and there is not complete

agreement in the toxicological community as to its ability to predict genotoxicity

(NSF 2011). Therefore, it is ToxServices’ opinion that this study not be given as

much weight as to determining the genotoxicity of benzyl alcohol.

NTP 1987

o In vivo: A sex-linked recessive lethal (SLRL) assay (identified as OECD 477 in ECHA

2015b) was found to be negative for mutagenicity. Drosophila melanogaster were given

doses of 5,000 ppm in food. There were no increases in SLRL mutations seen when

compared to control animals.

UNEP 2001

o In vitro: An Ames reverse mutation assay (identified as GLP-compliant, similar to

OECD 471 in ECHA 2015b) was negative for mutagenicity. Salmonella typhimurium

tester strains TA98, TA100, TA1535, and TA1537 at concentrations of benzyl alcohol

(99.9% purity) at 100-6,666 µg/plate in the presence and absence of metabolic activation.

There were no increases in histidine revertants seen in both the presence and absence of

metabolic activation.

o In vitro: A bacterial reverse mutation assay was negative for mutagenicity. An

Escherichia coli strain was tested at unknown concentrations in both the presence and

absence of metabolic activation. There were no increases in tryptophan revertants seen in

both the presence and absence of metabolic activation.

o In vivo: An in vivo mouse micronucleus assay conducted according to OECD 474 was

performed with ddY mice (6/dose group) administered intraperitoneal injections of

benzyl alcohol (purity not specified) at 50, 100, or 200 mg/kg. The animals were

sacrificed 24 hours after the injection and erythrocyte cells were isolated for the

evaluation of micronuclei. No increase in the frequency of micronuclei was observed

with treatment.

ECHA 2015b

o In vitro: Negative results for DNA damage were obtained in a DNA damage/repair

assay. Primary rat hepatocytes were exposed to benzyl alcohol (purity not specified) in

1% DMSO at 0, 1, 3, or 10 mM without metabolic activation. The highest concentration

of benzyl alcohol produced a positive result in the alkaline elution assay. However, the

cytotoxicity at this concentration was up to 100%. Therefore, authors stated that no

evidence of DNA damage/repair was observed in the absence of significant cytotoxicity.

o In vitro: Negative results for mutagenicity were obtained in an Ames test. S.

typhimurium tester strains TA 98 and TA 1535 were exposed to benzyl alcohol (purity

not specified) at 0.1 to 5.0 µmol/plate without metabolic activation. No increase in the

mutation frequency was observed with treatment in the absence of metabolic activation.

o In vitro: Negative results for clastogenicity were obtained in a chromosome aberration

test conducted in a manner similar to OECD 473 (no metabolic activation). Chinese

hamster lung (CHL) cells were exposed to benzyl alcohol (purity not specified) at 500-

2,000 µg/mL without metabolic activation. No increase in the frequency of chromosome

aberrations was observed with treatment in the absence of metabolic activation.

o In vitro: Negative results for mutagenicity were obtained in an Ames test. S.

typhimurium tester strains TA 92, TA, 94, TA 98, TA 100, TA 1535, and TA 1537 were

exposed to benzyl alcohol (purity not specified) at up to 10 µg/plate with metabolic

activation. No increase in the mutation frequency was observed with treatment in the

presence of metabolic activation.





o In vivo: Positive results for genotoxicity were obtained in a Drosophila wing spot test.

Third instar larvae of Drosophila melanogaster trans-heterozygous for 2 genetic markers

were provided feed containing benzyl alcohol (99% purity) in water at 0.1 to 50 mM until

pupation. Wings of the emerging adult flies were scored for the presence of spots of

mutant cells formed via somatic mutations or mitotic recombination. The highest

concentration of benzyl alcohol produced an increase in the number of wing spots.

o In vivo: Negative results for clastogenicity were obtained in a mouse micronucleus test

conducted according to OECD 474. Male ddY mice (6/dose group) were administered

four intraperitoneal injections of benzyl alcohol (purity not specified) in saline at 100

mg/kg at 24-hour intervals. The animals were sacrificed 24 hours after the last injection

and bone marrow cells were isolation for evaluation of micronuclei. No increase in the

frequency of micronuclei was observed with treatment.

o Additional genotoxicity tests were identified in the REACH dossier for benzyl alcohol.

However, these tests were assigned reliability scores of 4 (not assignable). Therefore,

ToxServices did not include them in this assessment due to the availability of a large

dataset of well conducted and reported studies.

In summary, negative results for mutagenicity were obtained in three Ames tests and one

bacterial reverse mutation assay while positive results for mutagenicity were obtained in a mouse

lymphoma test without metabolic activation (negative results were obtained in the presence of

metabolic activation). Some evidence of chromosomal aberration induction was obtained in the

presence of, but not in the absence of, metabolic activation in one test and a second test found no

evidence of chromosome aberrations in the absence of metabolic activation. Slightly positive

induction of sister chromatid exchanges were obtained in an in vitro test with and without

metabolic activation while no evidence of DNA damage/repair was observed in the absence of

metabolic activation. While mixed results were obtained in vitro, two in vivo mouse

micronucleus tests and one SLRL test in drosophila produced negative results for clastogenicity

and mutagenicity, respectively. A positive result for mutagenicity was obtained in a drosophila

wing test but the relevance of this test to predict genotoxicity potential has not been established.

Based on the negative results obtained in standardized in vivo tests, ToxServices did not classify

benzyl alcohol as a genotoxicant under GHS criteria.

Reproductive Toxicity (R) Score (H, M, or L): L

Benzyl alcohol was assigned a score of Low for reproductive toxicity based on the lack of effects on

reproductive organs of mice and rats administered oral doses of benzyl alcohol for two years or

inhalation exposures for 4 weeks, and a lack of effects on fertility in a 4-generation reproductive

toxicity study in rats for the surrogate benzoic acid. GreenScreen® criteria classify chemicals as a

Low hazard for reproductive toxicity when negative data, no structural alerts, and no GHS

classification are available (CPA 2012b). The confidence in the score is high as it is based on a

functional evaluation of fertility and reproductive output for a strong surrogate with support from a

lack of histopathological changes to reproductive organs in repeated dose studies of benzyl alcohol.




UNEP 2001

o Oral: A GLP-compliant, 103-week study conducted according to OECD 451 was

performed with male and female Fischer 344 rats (50/sex/dose) administered oral doses

of benzyl alcohol (99% purity) at 0, 200, or 400 mg/kg/day via gavage five days a week





for 103 weeks. A NOAEL of 400 mg/kg/day was established, as there were no effects

observed on the testes or ovaries.

o Oral: A GLP-compliant 103-week study conducted according to OECD 451 was

performed with male and female B6C3F1 mice (50/sex/dose) were administered oral

doses of benzyl alcohol (99% purity) at 0, 100, or 200 mg/kg/day via gavage five days a

week for 103 weeks. A NOAEL of 200 mg/kg/day was established, as there were no

effects observed on the testes or ovaries.

ECHA 2015b

o Inhalation: A GLP-compliant repeated inhalation exposure test conducted according to

OECD 412 was performed with Sprague-Dawley rats (10/sex/dose group) administered

nose-only aerosol concentrations of benzyl alcohol (99.9% purity) at 0, 0.041, 0.102,

0.290, or 1.072 mg/L for 6 hours/day, 5 days/week for 4 weeks. The equivalent

concentrations for a 7-day/week exposure frequency are 0, 0.029, 0.073, 0.207, and 0.766

mg/L, respectively. No treatment-related effects were observed on the gross pathological

or histopathological observations of the reproduction organs. A reproductive toxicity

NOAEC of 1.072 mg/L was identified by the study authors.

Surrogate: Benzoic acid (CAS# 65-85-0)

UNEP 2001

o Oral: In a 4-generation reproductive toxicity study in rats, animals (40/sex/dose) were

administered 0.5 or 1% (reported by UNEP to be approximately 375 of 750 mg/kg/day)

benzoic acid (purity not stated) continuously in the diet. The first and second generations

were treated for a lifetime, the third generation was treated for 16 weeks, and the fourth

generation was treated until breeding. No further details were provided regarding the

treatment regimens or mating procedures. There was no evidence of systemic toxicity

based on valuations of weight, food efficiency, organ weights, and histopathology. There

were no effects on fertility or lactation. No additional details were provided. UNEP

identified a reproductive NOAEL of 750 mg/kg/day based on the lack of effects at the

highest dose tested. This study was considered by UNEP of high quality due to the

reputation of the investigators and because it was conducted according to a robust

protocol according to standards at the time.

Although no histopathological effects on reproductive tissues were seen in chronic studies, there

have been no studies evaluating effects of benzyl alcohol on mating and fertility. Therefore data

on the surrogate benzoic acid were also evaluated. Benzoic acid produced no effects on fertility

in a 4-generation study in rats. Therefore a score of Low was assigned.

Developmental Toxicity incl. Developmental Neurotoxicity (D) Score (H, M, or L): M

Benzyl alcohol was assigned a score of Moderate for developmental toxicity based on decreased pup

body weights observed in a mouse developmental toxicity test at a dose of 750 mg/kg/day.

GreenScreen® criteria classify chemicals as a Moderate hazard for developmental toxicity when

limited or marginal evidence of developmental toxicity is observed in animals (CPA 2012b). The

confidence in the score is adjusted as the test used as the basis for the score only evaluated one dose

level and no effects were observed in a second test at a dose of 550 mg/kg/day.




UNEP 2001

o Oral: Pregnant CD-1 mice (n=50) were administered doses of 750 mg/kg/day via gavage

on gestation days (GDs) 7-14. Pups were delivered and raised until postnatal day 3.





Evaluations of maternal body-weight gain and mortality, mating, gestation, numbers of

live and dead pups per litter, total litter weight on days 1 and 2 post partum, litter weight

change between days 1 and 3 post partum, and pup survival were conducted. A maternal

and fetal LOAEL of 750 mg/kg/day was established based on a reduction in maternal

body weight on GD 18 and postnatal day 3 and decreased pup body weights on postnatal

days 1 and 3.

This study was identified as GLP-compliant in ECHA (2015).

o Oral: Pregnant mice (n = 50) were administered doses of 550 mg/kg/day via gavage on

GDs 6-15. A maternal and fetal NOAEL of 550 mg/kg/day was established, as there

were no treatment-related effects observed on maternal weight and weight gain, gestation

index, average number of live pups per litter, and postnatal survival and pup body weight

on days 0 and 3.

ECHA 2015b

o Additional developmental toxicity tests were identified in the REACH dossier for benzyl

alcohol. However, these tests were assigned reliability scores of 4 (not assignable).

ToxServices did not include them in this assessment as they were conducted in non-

mammalian species or no experimental details were provided.

Endocrine Activity (E) Score (H, M, or L): DG

Benzyl alcohol was assigned a score of Data Gap for endocrine activity based on the lack of data

identified for this endpoint.




Not listed as a potential endocrine disruptor on the EU Priority List of Suspected Endocrine

Disruptors.

Not listed as a potential endocrine disruptor on the OSPAR List of Chemicals of Possible

Concern.

No data were identified for this endpoint.

Group II and II* Human Health Effects (Group II and II* Human)

Note: Group II and Group II* endpoints are distinguished in the v 1.2 Benchmark system. For

Systemic Toxicity and Neurotoxicity, Group II and II* are considered sub-endpoints and test data

for single or repeated exposures may be used. If data exist for single OR repeated exposures, then

the endpoint is not considered a data gap. If data are available for both single and repeated

exposures, then the more conservative value is used.

Acute Mammalian Toxicity (AT) Group II Score (vH, H, M, or L): M

Benzyl alcohol was assigned a score of Moderate for acute toxicity based on it being associated with

the EU Risk Phrase R20/22, GHS H-statements H302 and H332, and oral LD50 values of as low as

1,040 mg/kg. GreenScreen® criteria classify chemicals as a Moderate to High hazard for acute

toxicity when they are associated with the EU Risk Phrase R20/22, and a Moderate hazard when

associated with H302 and H332, or the oral LD50 values are between 300 and 2,000 mg/kg (CPA

2012b). Confidence in the score is high because it is based on authoritative listings supported by

data.


o Authoritative:

EC – CLP/GHS





Associated with H302 – Harmful if swallowed

Associated with H332 – Harmful if inhaled

Associated with R20/22 – Harmful by inhalation and if swallowed

o Screening:

GHS New Zealand – Category 6.1 D (oral and dermal) (equivalent to GHS

Category 4) – acutely toxic

o Other:

Québec CSST - WHMIS Classifications - Class D2B - Toxic material causing

other toxic effects

UNEP 2001

o Oral: LD50 values of 1,230-3,100 mg/kg (rat), 1,150- 1,580 mg/kg (mouse), and 1,040

mg/kg (rabbit) have been established for benzyl alcohol.

o Dermal: An LD50 value of 2,000 mg/kg has been established in rabbits.

o Inhalation: 4-hour nose-head only aerosol LC50 of greater than 4.178 mg/L have been

established in Wistar rats (identified as GLP-compliant and OECD 403 in ECHA 2015b).

ECHA 2015b

o Inhalation: 4-hour snout-only aerosol LC50 (CD (remote Sprague-Dawley origin) rat) =

greater than 5.4 mg/mL (GLP-compliant, OECD 403)

Systemic Toxicity/Organ Effects incl. Immunotoxicity (ST)

Group II Score (single dose) (vH, H, M, or L): DG

Benzyl alcohol was assigned a score of Data Gap for systemic toxicity (single dose) based on a lack

of adequate data for this endpoint.




ECHA 2015b

o Oral: In an acute oral toxicity test that identified an oral LD50 of 1,620 mg/kg in male

Wistar rats, bloody eyes, sedation, side and prone-position, and a reduction in general

condition was observed in animals administered at least 1,254 mg/kg. No treatment-

related changes to body weight were observed. No data on gross pathological findings

were presented.

o Inhalation: In the acute inhalation toxicity test that identified a 4-hour LC50 value of

greater than 4,178 mg/L in Wistar rats, slight bradypnea (abnormally slow breathing rate)

and piloerection were observed at 4.78 mg/L. Approximately 3 hours after exposure the

breathing rate returned to normal and all rats were without symptoms on the first day

following exposure onwards. No treatment-related effects were observed on body

weights or gross pathological observations.


greater than 5.4 mg/mL in CD rats, no clinical signs of toxicity were observed with

treatment. Males exhibited a decrease in body weight gain relative to controls on the day

following treatment. No gross pathological changes were observed with treatment.

o Additional acute toxicity tests were identified in the REACH dossier for benzyl alcohol.

However, these tests were assigned reliability scores of 4 (not assignable) or did not

adequately identify the test substance used. ToxServices did not include them in this

assessment as experimental details were not provided.

Based on the weight of evidence, a Data Gap was assigned. Minor transient clinical signs

including effects on general condition, body weight, and respiration were not considered to be





sufficient to assign a hazard classification based on a target organ effect. One oral study in rats

reported “bloody eyes” following exposure to 1,254 mg/kg. Similar effects were not observed in

the inhalation studies, or in subchronic oral studies that tested doses up to 800 mg/kg/day.

Chromodacryorrhea, a condition that resembles hemorrhaging from the eyes, is frequently

reported in rats, and is due to secretion of pigments in response to stress, pain, illness, or restraint

(Merck 2015). Considering the lack of similar effects on the eye in several subchronic oral

studies, the “bloody eyes” observed in the acute oral study are likely to be indicative of

chromodacryorrhea in response to stress rather than a targeted effect on the eye; however based

only on the single acute oral study with very limited study details reported, it is not possible to

exclude the possibility that it is the result of a systemic effect. In the absence of adequate data, a

Data Gap was assigned. Neurological effects such as sedation are considered under

neurotoxicity-single dose, below.

Group II* Score (repeated dose) (H, M, or L): L

Benzyl alcohol was assigned a score of Low for systemic toxicity (repeated dose) based on oral

NOAELs of at least 200 mg/kg/day in subchronic and chronic oral repeated dose studies.

GreenScreen® criteria classify chemicals as a Low hazard for systemic toxicity (repeated dose) when

oral NOAELs are greater than 100 mg/kg/day (CPA 2012b). Confidence in the score is high because

it is based on data from several well conducted studies.




UNEP 2001

o Oral: A 13-week study (identified as GLP-compliant in ECHA 2015b) was conducted in

male and female F344/N rats. Animals (ten/sex/dose) were administered doses of 50,

100, 200, 400, and 800 mg/kg/day via gavage five days a week for 13 weeks. A NOAEL

of 400 mg/kg/day was established, based on clinical signs indicative of neurotoxicity

including staggering, respiratory difficulty, and lethargy.


male and female B6C3F1 mice. Animals (ten/sex/dose) were administered doses of 50,


of 200 mg/kg/day was established, based on reductions in relative weight gain in male

mice.

o Oral: A 103-week study (identified as GLP-compliant and OECD 451 in ECHA 2015b)

was conducted in male and female Fischer 344 rats. Animals (ten/sex/dose) were

administered doses of 200 and 400 mg/kg/day via gavage five days a week for 103

weeks. A NOAEL of 400 mg/kg/day was established, as there were no effects on body

weight gain, mortality, and compound-related non-neoplastic responses.

o Oral: A 103-week study (identified as GLP-compliant and OECD 451 in ECHA 2015b)

was conducted in male and female B6C3F1 mice. Animals (ten/sex/dose) were

administered doses of 100 and 200 mg/kg/day via gavage five days a week for 103

weeks. A NOAEL of 200 mg/kg/day was established, as there were no significant

treatment-related effects seen.

ECHA 2015b

o Inhalation: A GLP-compliant repeated inhalation exposure test conducted according to

OECD 412 was performed with Sprague-Dawley rats (10/sex/dose group) administered

nose-only aerosol concentrations of benzyl alcohol (99.9% purity) at 0, 0.041, 0.102,

0.290, or 1.072 mg/L for 6 hours/day, 5 days/week for 4 weeks. The equivalent





concentrations for a 7-day/week exposure frequency are 0, 0.029, 0.073, 0.207, and 0.766

mg/L, respectively. The animals were evaluated for clinical signs of toxicity, body

weights, food consumption, hematology, clinical chemistry, organ weights, gross

pathology, and histopathology. No treatment-related effects were observed on these

parameters and the study authors identified a NOAEC of 1.072 mg/L (equivalent to 0.766

mg/L for a 7-day/week exposure frequency).

Neurotoxicity (N)

Group II Score (single dose) (vH, H, M, or L): M

Benzyl alcohol was assigned a score of Moderate for neurotoxicity (single dose) based on temporary

sedation and bradypnea (possible signs of narcotic effects) observed in some acute toxicity studies.

GreenScreen® criteria classify chemicals as a Moderate hazard for neurotoxicity (single dose) when

they cause transient narcotic effects that warrants a GHS category 3 classification (CPA 2012b).

Confidence level was reduced due to inconsistent observations across studies




Classified as a developmental neurotoxicant (Grandjean and Landrigan 2006, 2014).

ECHA 2015b

o Oral: In an acute oral toxicity test that identified an oral LD50 of 1,620 mg/kg in male

Wistar rats, sedation, side and prone-position, and a reduction in general condition was

observed in animals administered at least 1,254 mg/kg. No treatment-related changes to

body weight were observed. No data on gross pathological findings were presented.


greater than 4,178 mg/L in Wistar rats, slight bradypnea (abnormally slow breathing rate)

and piloerection were observed at 4.78 mg/L. Approximately 3 hours after exposure the

breathing rate returned to normal and all rats were without symptoms on the first day

following exposure onwards. No treatment-related effects were observed on body

weights or gross pathological observations.


greater than 5.4 mg/mL in CD rats, no clinical signs of toxicity were observed with

treatment. Males exhibited a decrease in body weight gain relative to controls on the day

following treatment. No gross pathological changes were observed with treatment.

o Additional acute toxicity tests were identified in the REACH dossier for benzyl alcohol.

However, these tests were assigned reliability scores of 4 (not assignable) or did not

adequately identify the test substance used. ToxServices did not include them in this

assessment as experimental details were not provided.

Group II* Score (repeated dose) (H, M, or L): H

Benzyl alcohol was assigned a score of High for neurotoxicity (repeated dose) based on symptoms of

gradual neurological deterioration observed in neonates benzyl alcohol poisoning, clinical signs of

neurotoxicity in animal studies at high doses, and being classified as a known neurotoxicant in

humans by Grandjean and Landrigan. GreenScreen® criteria classify chemicals as a Moderate to

High hazard for neurotoxicity (repeated dose) when they are classified as known neurotoxicant in

humans by Grandjean and Landrigan, and as a High hazard when classified to GHS category 1 (CPA

2012b). The confidence in the score is reduced due to insufficient human evidence and lack of

support from animal studies.








Classified as a developmental neurotoxicant (Grandjean and Landrigan 2006, 2014).

UNEP 2001

o Benzyl alcohol poisoning in infants includes neurological symptoms (typically gradual

neurologic deterioration). No further details were identified.


male and female F344/N rats. Animals (ten/sex/dose) were administered doses of 50,


of 400 mg/kg/day was established, based on clinical signs indicative of neurotoxicity

including staggering, respiratory difficulty, and lethargy.

UIC Undated

o `Benzyl alcohol has been reported to cause fatal reactions “gasping syndrome” in

neonates when administered i.v. as a bacteriostatic agent in large volume or multi-dose

injectable products. The symptoms of gasping syndrome include severe metabolic

acidosis, neurologic deterioration and gasping respirations. This was believed to be due to

immature detoxification mechanisms in infants for benzyl alcohol and its metabolites

benzoic acid and hippuric acid. The syndrome was reversed in one surviving infant when

the exposure was discontinued, while in most other cases, it lead to mortality.

In summary, human case reports indicate that benzyl alcohol is capable of causing gasping

syndrome in neonates that includes symptoms of neurological deterioration when administered

intravenously. This route of exposure is not directly relevant to GreenScreen® evaluations, and

benzyl alcohol does not appear to be a specific neurological toxicant in humans (surviving infants

had reduced symptoms). In animals, neurological symptoms such as staggering, respiratory

difficulty and lethargy were observed only at high doses that do not warrant GHS classification.

It is not clear if infants are more sensitive than rodents to the neurological effects of benzyl

alcohol. According to GHS criteria, substances that produced significant toxicity in humans in

case reports or epidemiological studies (regardless of doses) are classified to category 1, while in

exceptional cases, human evidence can warrant category 2 classification when the weight of

evidence in humans is not sufficiently convincing for category 1 classification or the effect is not

severe, and available evidence from animals studies should be consistent with category 2

classification (UN 2013). Benzyl alcohol is classified as a known neurotoxicant in man by

Grandjean and Landrigan, which corresponds to a score of Moderate to High. ToxServices

conservatively classified benzyl alcohol to GHS category 1 based on human evidence, but

confidence level was reduced as no lasting neurological symptoms or neurological tissue

damages were known to be associated with benzyl alcohol administration in human infants.

Skin Sensitization (SnS) Group II* Score (H, M, or L): H

Benzyl alcohol was assigned a score of High for skin sensitization based on positive reactions in

humans, mixed results in animals, and the GHS New Zealand 6.5B classification (equivalent to GHS

Category 1). GreenScreen® criteria classify chemicals as a High hazard for skin sensitization when

they are classified as GHS Category 1A skin sensitizers (CPA 2012b). Confidence in the score is

high because it is based on experimental data in animals and humans, and the SCCNFP’s conclusion

that it is one of the 13 most frequently reported consumer allergens.



o Screening:





GHS New Zealand Category 6.5B (contact) (equivalent to GHS Category 1) –

contact sensitizer

ECHA 2015b

o A modified Draize test was performed with male and female Hartley guinea pigs (10

total, sex distribution not specified) administered dermal doses of benzyl alcohol (purity

not specified). The induction dose was performed with four intradermal injections of

0.25% benzyl alcohol (vehicle not specified) to shaved skin. After 14 days, the challenge

dose was applied as a combination of intradermal injection to one flank at 0.25% and

topical application to the other flank at 10% without coverage (open). The dermal

reactions were scored 24 hours after the challenge dose. A second challenge dose was

applied 7 days later using the same procedure. No positive skin reactions were observed

with treatment and the study authors concluded that benzyl alcohol was not sensitizing to

skin in this study.

o An open epicutaneous test was performed with Himalayan guinea pigs (4-6/dose group)

administered topical applications of 0.1 mL benzyl alcohol (purity not specified)

undiluted up to 3% (no further details available) daily for 21 days. Challenge doses were

applied on day 21 and day 35. Dermal reactions were evaluated 42, 48, and 72 hours

after the challenge dose. Positive skin reactions were observed following the challenge

dose. No further details were provided.

o A Freund's complete adjuvant (FCA) test was performed with Himalayan guinea pigs

(number and sex not specified) administered dermal doses of benzyl alcohol (purity not

specified). The induction doses were applied as intradermal injections of 0.05 ml

volumes of undiluted benzyl alcohol in a 50:50 mixture with FCA to the neck on days 0,

2, 4, 7, and 9 for a total dose of 250 mg. Controls were administered intradermal

injections of FCA alone. The challenge dose was applied as a topical application of

benzyl alcohol (concentration not specified) in petrolatum under occlusive dressing on

day 21 and day 35. Positive skin reactions were observed following the challenge dose.

No further details were provided.

o A Draize test was performed with Himalayan guinea pigs (number and sex not specified)

administered 0.05 mL intradermal injections of 0.1% benzyl alcohol (purity not

specified) in physiological saline. The induction doses were applied on day 0 and then on

9 alternate days for a total dose of 0.95 mg. The challenge doses were applied on days 35

and 49. Positive skin reactions were judged based on the mean diameter of the popular

reactions. No positive skin reactions were observed following the challenge dose. No

further details were provided.

o A guinea pig maximization test conducted according to OECD 406 was performed with

Himalayan guinea pigs (10/dose group, sex distribution not specified) administered

dermal doses of benzyl alcohol (purity not specified). The induction doses were

administered on day 0 as paired intradermal injections of 0.1 ml 5% methyl alcohol, 0.1

ml 5% emulsion of benzyl alcohol in FCA, and 0.1ml of FCA alone. On day 8, a 25%

solution of benzyl alcohol in petrolatum was applied to shaved skin under occlusive

dressing for 48 hours. The challenge dose was applied on day 21 as a sub-irritant

concentration (no further details provided) in petrolatum applied to the skin under

occlusive dressing for 24 hours. The dermal reactions were evaluated 24 and 48 hours

after removal of the dressing. No positive skin reactions were observed following the

challenge dose. No further details were provided.

SCCNFP 1999

o 5% Benzyl alcohol induced positive reactions in 0.5% of tested patients in Japan.





o 5% Benzyl alcohol induced positive reactions in 3/20 patients as a fragrance ingredient.

o 5% Benzyl alcohol tested positive in 2/176 (1.2%) patients in a patch test as a fragrance

ingredient

o 10% Benzyl alcohol tested positive in 3/182 (1.6%) patients suspected of contact allergy

to cosmetics in a patch test with fragrance substances.

o Benzyl alcohol tested positive in 2/156 (1.3%) of patients with contact allergy to

cosmetic products.

o Benzyl alcohol tested positive in 3/578 (0.005%) subjects with sensitization reactions to

cosmetic products in a patch test.

o Benzyl alcohol tested positive in 4/242 (1.6%) patients with contact allergy from

different origins in a patch test.

o Benzyl alcohol is one of the most frequently reported and well-recognized consumer

allergens in the EU, according to existing knowledge (one of 13 allergens identified by

SCCNFP as being of most concern due to high frequency of sensitization reports).

Positive reactions for dermal sensitization were observed in an open epicutaneous test and a FCA

test while negative results were obtained in a guinea pig maximization test, Draize test, and

modified Draize test. These studies have insufficient detail regarding the percent of animals

having positive skin reactions. Positive patch tests were observed in humans and benzyl alcohol

is listed as one of the most frequently reported consumer allergens by SCCNFP. The GHS

criteria classify chemicals to category 1A when the frequency of occurrence for sensitization

reactions is high. Therefore, classification score of High was assigned for this endpoint.

Respiratory Sensitization (SnR) Group II* Score (H, M, or L): DG

Benzyl alcohol was assigned a score of Data Gap for respiratory sensitization based on a lack of

adequate data for this endpoint. Confidence level was reduced due to lack of direct measured data.




UNEP 2001

o In the past several decades, no cases of health complaints, including sensitization

reactions have been reported in workers at manufacturing and application sites of benzoic

acid and its salts as well as benzyl alcohol.

Although there have been no case reports of respiratory sensitization to benzyl alcohol, in the

absence of challenge or animal studies, a lack of case reports was not considered to be sufficient

to assign a Low.

Skin Irritation/Corrosivity (IrS) Group II Score (vH, H, M, or L): L

Benzyl alcohol was assigned a score of Low for skin irritation/corrosivity based on experimental data

indicating that it does not warrant GHS classification as a skin irritant. GreenScreen® criteria

classify chemicals as a Low hazard for skin irritation/corrosivity when negative data, no structural

alerts, and no GHS classification are available (CPA 2012b). Confidence in the score is high because

it is based on experimental data form well conducted studies.




ECHA 2015b

o A GLP-compliant dermal irritation test conducted according to OECD 404 was

performed with New Zealand White rabbits (3 total, sex not specified) administered





topical applications of 0.5 mL undiluted benzyl alcohol (99.99% purity) to shaved skin

under semi-occlusive dressing for 4 hours. An observation period of 7 days followed the

exposure period. The dermal reactions were evaluated at 24, 48, and 72 hours after the

start of the exposure period. The mean erythema score for two of the animals was 0/4,

while the mean score for the third animal was 0.7/4. The mean edema score was 0/4. All

dermal irritation effects were fully reversible within 72 hours.

Based on the results of this study, ToxServices did not classify benzyl alcohol as

a dermal irritant under GHS criteria. GHS guidance (UN 2013) requires that a

chemical produce mean scores of ≥ 1.5 for erythema or edema in at least 2 of 3

tested animals from grades at 24, 48, and 72 hours.

o A dermal irritation test was performed with New Zealand White rabbits (1/sex/dose

group) administered topical applications of 0.5 mL undiluted benzyl alcohol (purity not

specified) to the skin under semi-occlusive dressing for 24 hours. An observation period

of 7 days followed the exposure period. The dermal reactions were evaluated at 24, 48,

and 72 hours after the start of the exposure period. The mean erythema and edema scores

were 0/4.

Based on the results of this study, ToxServices did not classify benzyl alcohol as

a dermal irritant under GHS criteria. GHS guidance (UN 2013) requires that a

chemical produce mean scores of ≥ 1.5 for erythema or edema in at least 2 of 3

tested animals from grades at 24, 48, and 72 hours.

o Additional skin irritation tests were identified in the REACH dossier for benzyl alcohol.

However, these tests were assigned reliability scores of 4 (not assignable) and were not

conducted according to validated methods or were reported with insufficient details could

not be assessed or were in vitro tests that would not be weighed as heavily as the well

conducted in vivo studies. Therefore, ToxServices did not include them in this

assessment.

Eye Irritation/Corrosivity (IrE) Group II Score (vH, H, M, or L): H

Benzyl alcohol was assigned a score of High for eye irritation/corrosivity based on experimental data

indicating that it meets criteria for classification as a Category 2A eye irritant under GHS criteria,

which is in agreement with the classification from GHS New Zealand.. GreenScreen® criteria

classify chemicals as a High hazard for eye irritation/corrosivity when chemicals are classified as

GHS Category 2A eye irritants (CPA 2012b). Confidence in the score is high because it is based on

experimental data.



o Screening:

GHS New Zealand Category 6.4A (equivalent to GHS Category 2A) – Irritating

to the eyes

ECHA 2015b

o A GLP-compliant eye irritation test conducted according to OECD 405 was performed

with New Zealand White rabbits (3 total, sex not specified) administered ocular

instillations of 0.1 mL undiluted benzyl alcohol (99.99% purity). The eyes were rinsed

after 24 hours and the animals were observed for 21 days. The mean corneal score was

1/4, the mean iris score was 0/2 for two of the animals while the third animal had a mean

score of 0.3/2, the mean conjunctival score was 2/3, and the mean chemosis score was

0.7/4 for two of the animals and 1/4 for the third animal. The chemosis effects were fully

reversible within 7 days, and the corneal and conjunctival effects were fully reversible by





21 days at the latest. The study authors concluded that benzyl alcohol was irritating to

the eyes.

Based on the results of this study, ToxServices classified benzyl alcohol as a

Category 2A ocular irritant according to GHS guidelines. GHS criteria (UN

2013) classify chemicals as Category 2A ocular irritants if they produce corneal

opacity scores of ≥ 1, iritis scores of ≥ 1, conjunctival redness scores of ≥ 2,

and/or chemosis scores of ≥ 2 in at least 2 of 3 animals tested at 24, 48, and 72

hours after instillation, and the effects being fully reversible within 21 days.

o An eye irritation test was performed with New Zealand White rabbits (2 total, sex not

specified) administered ocular instillations of 0.1 mL undiluted benzyl alcohol (purity not

specified). An observation period of 7 days followed the instillation. The ocular effects

were evaluated at 1, 24, and 48 hours and 7 days. In both animals the mean corneal score

was 1/4, the iris score ranged from 0-1 (max 2), and the conjunctival score ranged from

0-2 (max 3). One animal had a chemosis score that ranged from 0-1 (max 4) while the

other had a chemosis score that ranged from 0-2 (max 4). All ocular irritation effects

with the exception of the corneal irritation resolved within 7 days. The study authors

concluded that benzyl alcohol causes superficial corrosion of the cornea and was

moderately irritating to the eye.

ToxServices could not assign a classification to benzyl alcohol based on the

results of this test as the mean ocular irritation values were not available for 24,

48, and 72 hours.

o A GLP-compliant ocular irritation test conducted according to OECD 405 was performed

with New Zealand White rabbits (3 total, sex not specified) administered ocular

instillations of 0.1 mL undiluted benzyl alcohol (99.98% purity). An observation period

of 18 days followed the instillation. One animal was sacrificed on day 10 of the study for

ethical reasons; the animal displayed soft feces and hypoactivity although the study

authors state that these clinical signs were not attributed to the treatment. For the two

remaining animals, the mean corneal score was 2/4, the mean iris score was 1/2, the mean

conjunctival score was 2.5/3, and the chemosis score was 3/4 for one animal and ranged

from 1-2 out of 4 for the other animal. The corneal effects were fully reversible within

18 days while the other ocular irritation effects were reversible within 11 days. The study

authors concluded that benzyl alcohol was irritating to the eyes.

Based on the results of this study, ToxServices classified benzyl alcohol as a

Category 2A ocular irritant according to GHS guidelines. GHS criteria (UN

2013) classify chemicals as Category 2A ocular irritants if they produce corneal

opacity scores of ≥ 1, iritis scores of ≥ 1, conjunctival redness scores of ≥ 2,

and/or chemosis scores of ≥ 2 in at least 2 of 3 animals tested at 24, 48, and 72

hours after instillation, and the effects being fully reversible within 21 days.

o Additional eye irritation tests were identified in the REACH dossier for benzyl alcohol.

However, these tests were assigned reliability scores of 4 (not assignable) and were

reported with very limited details. Therefore, ToxServices did not include them in this

assessment given the availability of well conducted and reported studies.

Ecotoxicity (Ecotox)

Acute Aquatic Toxicity (AA) Score (vH, H, M, or L): L

Benzyl alcohol was assigned a score of Low for acute aquatic toxicity based on acute aquatic toxicity

values greater than 100 mg/L in fish, aquatic invertebrates and algae. GreenScreen® criteria classify

chemicals as a Low hazard for acute aquatic toxicity when acute aquatic toxicity values are greater





than 100 mg/L (CPA 2012b). Confidence in the score is high because it is based on experimental

data from several studies.



o Screening:

GHS New Zealand Category 9.1D (fish, crustacean) (equivalent to GHS Category

2-3) – slightly harmful in the aquatic environment or are otherwise designed for

biocidal action.

UNEP 2001

o 48-hour LC50 (Leuciscus idus, ide) = 646 mg/L (DIN 38412 Teil 15)

o 24-hour mobility EC50 (Daphnia magna) = 400 mg/L (DIN 38412 Teil 11)

o 48-hour mobility EC50 (Daphnia magna) = 360 mg/L

ECHA 2015b

o 96-hour LC50 (Pimephales promelas, fathead minnow) = 460 mg/L (non-GLP-compliant,

EPA OPP 72-1)

o 96-hour LC50 (Oryzias latipes, Japanese rice fish) = greater than 100 mg/L (OECD 203)

o 48-hour mobility EC50 (Daphnia magna) = 230 mg/L (GLP-compliant, OECD 202)

o 24-hour mobility EC50 (Daphnia magna) = 55 mg/L (DIN 38412 Teil 11)

o 72-hour growth rate EC50 (Pseudokirchnerella subcapitata, green algae) = 770 mg/L

(GLP-compliant, OECD 201)

o 72-hour area under growth curve EC50 (P. subcapitata, green algae) = 500 mg/L (GLP-

compliant, OECD 201)

o 96-hour cell growth LOAEC (Scenedesmus sp.) = 640 mg/L

o Additional acute aquatic toxicity tests were identified in the REACH dossier for benzyl

alcohol. However, these tests were assigned reliability scores of 3 (not reliable) or 4 (not

assignable). ToxServices did not include them in this assessment as they were provided

with very limited details or did not involve exposures similar to those upon which GHS

criteria are based.

All the reported L/EC50 values are above 100 mg/L except one 24-hour mobility EC50 of 55 mg/L

in daphnia reported in a study conducted according to DIN 38412 Teil 11. Another study

following the same protocol reported a 24-hour mobility EC50 of 400 mg/L in daphnia. The

standard test duration for acute toxicity studies in daphnia is 48 hours, and good quality 48h EC50

values are identified to be 230 and 360 mg/L in two studies in daphnia. Therefore, the weight of

evidence indicates that benzyl alcohol is not highly toxic to aquatic invertebrates. In addition, the

L/EC50 values for fish and algae are > 100 mg/L which corresponds to a Low.

Chronic Aquatic Toxicity (CA) Score (vH, H, M, or L): L

Benzyl alcohol was assigned a score of Low for chronic aquatic toxicity based on the most

conservative chronic aquatic toxicity value of 51 mg/L. GreenScreen® criteria classify chemicals as

a Low hazard for chronic aquatic toxicity when chronic aquatic toxicity values are greater than 10

mg/L (CPA 2012b). Confidence in the score is high because it is based on experimental data.




ECHA 2015b

o 21-day reproduction NOEC (Daphnia magna) = 51 mg/L (GLP-compliant OECD 211)

o 72-hour growth rate and area under growth curve NOEC (P. subcapitata, green algae) =

310 mg/L (GLP-compliant, OECD 201)





A score of Low was assigned based on the NOEC values for daphnia and algae, which are much

greater than the guidance value of 10 mg/L. Although there are no chronic toxicity data for fish,

available acute data (presented above) do not indicate that fish are more sensitive than

invertebrates and plants.

Environmental Fate (Fate)

Persistence (P) Score (vH, H, M, L, or vL): vL

Benzyl alcohol was assigned a score of Very Low for persistence based on it meeting the 10-day

biodegradation window in the OECD 301 A test. GreenScreen® criteria classify chemicals as a Very

Low hazard for persistence when they partition primarily to soil and water and meet the 10-day

biodegradation window in ready biodegradation tests (CPA 2012b). Confidence in the score is high

because it is based on several well conducted biodegradation tests.




ECHA 2015b

o A ready biodegradability test (GLP status unknown) conducted according to OECD 301

C (Modified MITI Test) was performed with activated sludge (adaptation not specified)

exposed to benzyl alcohol (purity not specified) at 100 mg/L for 14 days. At the end of

the exposure period, the level of degradation was 92-96%. The study authors concluded

that benzyl alcohol was readily biodegradable in this test.


A (DOC Die Away Test) was performed with sewage (predominantly domestic,

adaptation not specified) exposed to benzyl alcohol (purity not specified) at 20 mg/L

based on organ carbon content for 21 days. The level of degradation was 92-94% after 7

days, 94-96% after 14 days, and 95-97% after 21 days. The study authors concluded that

benzyl alcohol was readily biodegradable in this test. ToxServices concluded that benzyl

alcohol met the 10-day biodegradation window in this test.


D (Closed Bottle Test) was performed with adapted, activated sludge exposed to benzyl

alcohol (purity not specified) at greater than 2 and less than 5 mg/L for 28 days. At the

end of the exposure period, the level of degradation was 95% based on theoretical oxygen

demand (ThOD). The study authors concluded that benzyl alcohol was readily

biodegradable in this test.

o U.S. EPA 2012

The BIOWIN modeling Ready Biodegradable Predictor indicates that benzyl

alcohol is expected to be readily biodegradable (see Appendix D). Fugacity

modeling predicts 64.8% will partition to soil with a half-life of 30 days, 34%

will partition to water with a half-life of 15 days, and 1.03% will partition to air

with a half-life of 11.2 days hours.

o Additional biodegradation tests were identified in the REACH dossier for benzyl alcohol.

However, these tests evaluated the anaerobic degradation or inherent biodegradability of

benzyl alcohol or were not conducted according to or comparable to guideline protocols

and thus could not be compared to GHS criteria. Given the availability of several well

conducted ready biodegradation studies producing positive results, ToxServices did not

include them in this assessment.





Bioaccumulation (B) Score (vH, H, M, L, or vL): vL

Benzyl alcohol was assigned a score of Very Low for bioaccumulation based on an estimated BCF of

0.31 and a measured log Kow of 1.05. GreenScreen® criteria classify chemicals as a Very Low hazard

for bioaccumulation when BCF values are no greater than 100 and log Kow values are no greater than

4.0 (CPA 2012b). Confidence in the score is high because it is based on an experimental log Kow

value.




UNEP 2001

o Benzyl alcohol does not bioaccumulate, with an estimated bioconcentration factor (BCF)

of 0.31.

ECHA 2015b

o Benzyl alcohol has a log Kow value of 1.05 at 20°C in a shake-flask and HPLC method

test.

Physical Hazards (Physical)

Reactivity (Rx) Score (vH, H, M, or L): L

Benzyl alcohol was assigned a score of Low for reactivity based on reports that it is not oxidizing

and an HMIS rating that it is not explosive, self-reactive, or otherwise reactive. GreenScreen®

criteria classify chemicals as a Low hazard for reactivity when no GHS classifications are available

for any of the reactivity sub-endpoints (CPA 2012b). The confidence in the score is adjusted as it is

not based on data or authoritative lists.




ECHA 2015b

o Benzyl alcohol does not contain any functional groups associated with explosive or

oxidizing properties.

Sigma-Aldrich 2014

o A material safety data sheet for benzyl alcohol states that it has a reactivity rating of 0

from the National Fire Protection Association (NFPA) (“Normally stable, even under fire

exposure conditions, and is not reactive with water”) (NFPA 2012) and Hazardous

Materials Identification System (HMIS) (“Materials that are normally stable, even under

fire conditions, and will not react with water, polymerize, decompose, condense, or self-

react. Non-explosives”) (Paint.org 2015).

Based on the MSDS identified above stating that benzyl alcohol is nonreactive and the

conclusion in the REACH dossier that it lacks functional groups associated with oxidative and

explosive properties, ToxServices did not classify benzyl alcohol as a reactive chemical based on

GHS criteria (UN 2013).

Flammability (F) Score (vH, H, M, or L): L

Benzyl alcohol was assigned a score of Low for flammability based on its measured flash points of

94-101°C GreenScreen® criteria classify chemicals as a Low hazard for flammability when they are

not classifiable under GHS as a flammable liquid based on a flash point of greater than 93°C (CPA

2012b). Confidence in the score is high because it is based on experimental data.







o Screening:

Québec CSST - WHMIS Classifications - Class B3 - Combustible liquids

ECHA 2015b

o A flash point of 100.4°C was identified for benzyl alcohol in an open cup test.

o A flash point of 94°C was identified for benzyl alcohol (method not reported).

UNEP 2001

o A flash point of 101°C was identified for benzyl alcohol in a closed cup test (DIN

51758).

Based on the above data, ToxServices did not classify benzyl alcohol as a flammable liquid under

GHS criteria (UN 2013). GHS criteria specify that flammable liquids have flash points of no

greater than 93°C. WHMIS class B3 includes combustible materials that must be heated before

catching fire (at 37.8ºC – 93.3ºC). The measured flash point of greater than 100ºC does not

warrant a WHMIS B3 classification, and it was not clear how Environment Canada came to this

classification. Therefore, ToxServices relied on experimental data rather than the screening list

for this endpoint.





References

ChemIDplus. 2015. Entry for Benzyl alcohol (CAS #100-51-6). United States National Library of

Medicine. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/100-51-6.

Clean Production Action (CPA). 2012a. List Translator. Dated February 2012. Available at:

http://www.greenscreenchemicals.org/.

Clean Production Action (CPA). 2012b. The GreenScreen® for Safer Chemicals Version 1.2

Criteria. Dated: November 2012. Available at: http://www.greenscreenchemicals.org/.

Clean Production Action (CPA). 2013. The GreenScreen® for Safer Chemicals Chemical Hazard

Assessment Procedure. Version 1.2 Guidance. Dated August 31, 2013. Available at:

http://www.greenscreenchemicals.org/.

Cosmetic Ingredient Review (CIR). 2014. CIR Compendium.

Environmental Protection Authority (EPA). 2009. Correlation between GHS and New Zealand

HSNO Hazard Classes and Categories Information Sheet. Third Revised Edition. Available

at: http://www.epa.govt.nz/Publications/hsnogen-ghs-nz-hazard.pdf.

European Chemicals Agency (ECHA). 2015a. Read-Across Assessment Framework (RAAF).

Available: http://echa.europa.eu/documents/10162/13628/raaf_en.pdf.

European Chemicals Agency (ECHA). 2015b. REACH Dossier for Benzyl Alcohol (CAS #100-51-

6). Available at: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d9b1369-7454-687c-

e044-00144f67d249/DISS-9d9b1369-7454-687c-e044-00144f67d249_DISS-9d9b1369-7454-687c-

e044-00144f67d249.html.

European Union (EU). 2009. Regulation (EC) No. 1223/2009 of the European Parliament and of the

Council of 30 November 2009 on cosmetic products. Recast. Official Journal of the European Union.

L342/39. Dated December 22, 2009.

Grandjean, P. and P.J. Landrigan. 2006. Developmental neurotoxicity of industrial chemicals.

Lancet 368: 2167-2178.

Grandjean, P. and P.J. Landrigan. 2014. Neurobehavioral effects of developmental toxicity. The

Lancet 13: 330-338.

Hazardous Substances Data Bank (HSDB). 2009. Entry for Benzyl Alcohol (CAS #100-51-6).

HSDB Number 46. Last revision date April 20, 2009. United States National Library of Medicine.

Available at: http://toxnet.nlm.nih.gov/newtoxnet/hsdb.htm.

The Merck Veterinary Manual. 2015. Mice and Rats as Pets. Available:

http://www.merckvetmanual.com/mvm/exotic_and_laboratory_animals/rodents/mice_and_rats_as_p

ets.html.


http://chem.sis.nlm.nih.gov/chemidplus/rn/100-51-6

http://www.greenscreenchemicals.org/



http://echa.europa.eu/documents/10162/13628/raaf_en.pdf

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d9b1369-7454-687c-e044-00144f67d249/DISS-9d9b1369-7454-687c-e044-00144f67d249_DISS-9d9b1369-7454-687c-e044-00144f67d249.html



http://toxnet.nlm.nih.gov/newtoxnet/hsdb.htm

http://www.merckvetmanual.com/mvm/exotic_and_laboratory_animals/rodents/mice_and_rats_as_pets.html

http://www.merckvetmanual.com/mvm/exotic_and_laboratory_animals/rodents/mice_and_rats_as_pets.html




National Fire Protection Association (NFPA). 2012. NFPA 704: Standard System for the

Identification of Hazards of Materials for Emergency Response. Available at:

http://www.nfpa.org/codes-and-standards/free-access

National Toxicology Program (NTP). Undated. Benzyl alcohol mouse lymphoma assay. Study

Number 464779. National Institute of Environmental Health Sciences, Department of Health and

Human Services. Available at: http://tools.niehs.nih.gov/cebs3/ntpViews/?studyNumber=002-

01714-0009-0000-4.

National Toxicology Program (NTP). 1984. Benzyl alcohol in vitro cytogenetics assays. Study



01714-0002-0000-7 and http://tools.niehs.nih.gov/cebs3/ntpViews/?studyNumber=002-01714-0001-

0000-6.

National Toxicology Program (NTP). 1987. Benzyl alcohol sex linked recessive lethal assay. Study



01714-0008-0000-3.

National Toxicology Program (NTP). 1989. NTP Technical Report on the Toxicology and

Carcinogenesis Studies of Benzyl Alcohol (CAS No. 100-51-6) in F344/N Rats and B6C3F1 Mice

(Gavage Studies). NTP TR 343, NIH Publication No. 89-2599. National Institutes of Health, Public

Health Service, U.S. Department of Health and Human Services. Available at:

http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr343.pdf.

NSF. 2011. NSF/ANSI Standard 61: Drinking Water System Components – Health Effects.

Organisation for Economic Co-operation and Development (OECD). 2014. Guidance on Grouping

of Chemicals, Second Edition. Series on Testing and Assessment No. 194. Available:

http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2014)4&docl

anguage=en.

Paint.org. 2015. HMIS® Ratings. Available at:

http://www.paint.org/component/docman/cat_view/49-hmis.html.

Pharos. 2015. Pharos Chemical and Material Library Entry for Benzyl Alcohol (CAS #100-51-6).

Available at: http://www.pharosproject.net/material/.

The Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers

(SCCNFP). 1999. Opinion conserning fragrance allergy in consumers. A review of the problem.

Analysis of the need for appropriate consumer information and identification of consumer allergens.

SCCNFP/0017/98 Final. Available at: www.expub.com.

Siegert, W. 2014. Approved Preservatives for Cosmetics. Berlin: Schülke & Mayer GmbH.

Sigma-Aldrich. 2014. Safety Data Sheet for Benzyl Alcohol (CAS #100-51-6). Product Number

80708. Version 5.9. Revision date July 31, 2014. Available at:

http://www.sigmaaldrich.com/catalog/product/fluka/80708?lang=en&region=US.


http://www.nfpa.org/codes-and-standards/free-access

http://tools.niehs.nih.gov/cebs3/ntpViews/?studyNumber=002-01714-0009-0000-4








http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr343.pdf

http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2014)4&doclanguage=en

http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2014)4&doclanguage=en

http://www.paint.org/component/docman/cat_view/49-hmis.html

http://www.pharosproject.net/material/

http://www.expub.com/

http://www.sigmaaldrich.com/catalog/product/fluka/80708?lang=en&region=US




ToxServices. 2013. SOP 1.37: GreenScreen® Hazard Assessments. Dated: April 24, 2013.

University of Illinois at Chicago (UIC). Undated. Drug information updates. Benzyl alcohol

toxicity in neonates. Available at: https://www.uic.edu/pharmacy/services/di/benzyl.htm.

United Nations (UN). 2013. Globally Harmonized System of Classification and Labeling of

Chemicals (GHS). Fifth Revised Edition. ST/SG/AC/10/30/Rev.5. Available at:

http://www.unece.org/trans/danger/publi/ghs/ghs_rev05/05files_e.html.

United Nations Environment Programme (UNEP). 2001. Screening Information Dataset (SDIS)

Initial Assessment for Benzoates: Benzoic acid, Sodium benzoate, Potassium benzoate, Benzyl

alcohol. Organization for Economic Cooperation and Development (OECD) SIDS. Available at:

http://www.chem.unep.ch/irptc/sids/OECDSIDS/BENZOATES.pdf

United States Environmental Protection Agency (U.S. EPA). 2010. The Use of Structure-Activity

Relationships (SAR) in the High Production Volume Chemicals Challenge Program.

United States Environmental Protection Agency (U.S. EPA). 2012. Estimation Programs Interface

(EPI) SuiteTM Web, v4.11, Washington, DC, USA. Available at:

http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.


https://www.uic.edu/pharmacy/services/di/benzyl.htm

http://www.unece.org/trans/danger/publi/ghs/ghs_rev05/05files_e.html

http://www.chem.unep.ch/irptc/sids/OECDSIDS/BENZOATES.pdf

http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm




APPENDIX A: Hazard Benchmark Acronyms

(in alphabetical order)

(AA) Acute Aquatic Toxicity

(AT) Acute Mammalian Toxicity

(B) Bioaccumulation

(C) Carcinogenicity

(CA) Chronic Aquatic Toxicity

(D) Developmental Toxicity

(E) Endocrine Activity

(F) Flammability

(IrE) Eye Irritation/Corrosivity

(IrS) Skin Irritation/Corrosivity

(M) Mutagenicity and Genotoxicity

(N) Neurotoxicity

(P) Persistence

(R) Reproductive Toxicity

(Rx) Reactivity

(SnS) Sensitization- Skin

(SnR) Sensitization- Respiratory

(ST) Systemic/Organ Toxicity



Limited license provided to EDF for posting via EDF’s website at https://www.edf.org/. Further copying, resale, and distribution are expressly prohibited. Page 27 of 25

APPENDIX B: Results of Automated GreenScreen® Score Calculation for Benzyl Alcohol (CAS #100-51-6)

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Chemical

NameCAS# C M R D E AT STs STr Ns Nr SNS* SNR* IrS IrE AA CA P B Rx F

No Benzyl Alcohol 100-51-6 L L L M DG M DG L M H H DG L H L L vL vL L L

a b c d e f g

No No No No No

No No No No Yes Yes No

STOP

STOP

a b c d e f g h i j bm4End

Result

Yes Yes Yes Yes Yes 2

Final

GreenScreen®

Benchmark Score

1Benzyl Alcohol 2

GreenScreen® Score Inspector

Table 1: Hazard Table

Group I Human Group II and II* Human Ecotox Fate Physical

Sy

stem

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Table 2: Chemical Details

Table 3: Hazard Summary Table Table 6

Benchmark Chemical Name

Preliminary

GreenScreen®

Benchmark Score

Chemical Name

Table 4

2

3

4

22

Note: Chemical has not undergone a data gap

assessment. Not a Final GreenScreenTM

Score

After Data gap Assessment

Note: No Data gap Assessment Done if Preliminary

GS Benchmark Score is 1.4

Table 5: Data Gap Assessment Table

Datagap Criteria

3

Benzyl Alcohol

1





APPENDIX C: Pharos Output for Benzyl Alcohol (CAS #100-51-6)





APPENDIX D: EPISuite Modeling Results for Benzyl Alcohol (CAS #100-51-6)

CAS Number: 100-51-6

SMILES : OCc(cccc1)c1

CHEM : Benzenemethanol

MOL FOR: C7 H8 O1

MOL WT : 108.14

------------------------------ EPI SUMMARY (v4.11) --------------------------

Physical Property Inputs:

Log Kow (octanol-water): 1.05

Boiling Point (deg C) : ------

Melting Point (deg C) : -15.40

Vapor Pressure (mm Hg) : 0.053

Water Solubility (mg/L): 40000

Henry LC (atm-m3/mole) : ------

Log Octanol-Water Partition Coef (SRC):

Log Kow (KOWWIN v1.68 estimate) = 1.08

Log Kow (Exper. database match) = 1.10

Exper. Ref: HANSCH,C ET AL. (1995)

Boiling Pt, Melting Pt, Vapor Pressure Estimations (MPBPVP v1.43):

Boiling Pt (deg C): 205.65 (Adapted Stein & Brown method)

Melting Pt (deg C): -5.43 (Mean or Weighted MP)

VP(mm Hg,25 deg C): 0.0535 (Mean VP of Antoine & Grain methods)

VP (Pa, 25 deg C) : 7.14 (Mean VP of Antoine & Grain methods)

MP (exp database): -15.2 deg C

BP (exp database): 205.3 deg C

VP (exp database): 9.40E-02 mm Hg (1.25E+001 Pa) at 25 deg C

Water Solubility Estimate from Log Kow (WSKOW v1.42):

Water Solubility at 25 deg C (mg/L): 6.36e+004

log Kow used: 1.05 (user entered)

melt pt used: -15.40 deg C

Water Sol (Exper. database match) = 4.29e+004 mg/L (25 deg C)

Exper. Ref: YALKOWSKY,SH & DANNENFELSER,RM (1992)

Water Sol Estimate from Fragments:

Wat Sol (v1.01 est) = 32322 mg/L

ECOSAR Class Program (ECOSAR v1.11):

Class(es) found:

Benzyl Alcohols

Henrys Law Constant (25 deg C) [HENRYWIN v3.20]:

Bond Method : 2.17E-007 atm-m3/mole (2.20E-002 Pa-m3/mole)

Group Method: 4.66E-008 atm-m3/mole (4.72E-003 Pa-m3/mole)

Exper Database: 3.37E-07 atm-m3/mole (3.41E-002 Pa-m3/mole)

For Henry LC Comparison Purposes:





User-Entered Henry LC: not entered

Henrys LC [via VP/WSol estimate using User-Entered or Estimated values]:

HLC: 1.885E-007 atm-m3/mole (1.910E-002 Pa-m3/mole)

VP: 0.053 mm Hg (source: User-Entered)

WS: 4E+004 mg/L (source: User-Entered)

Log Octanol-Air Partition Coefficient (25 deg C) [KOAWIN v1.10]:

Log Kow used: 1.05 (user entered)

Log Kaw used: -4.861 (exp database)

Log Koa (KOAWIN v1.10 estimate): 5.911

Log Koa (experimental database): None

Probability of Rapid Biodegradation (BIOWIN v4.10):

Biowin1 (Linear Model) : 0.9829

Biowin2 (Non-Linear Model) : 0.9878

Expert Survey Biodegradation Results:

Biowin3 (Ultimate Survey Model): 3.1422 (weeks )

Biowin4 (Primary Survey Model) : 3.8261 (days )

MITI Biodegradation Probability:

Biowin5 (MITI Linear Model) : 0.5370

Biowin6 (MITI Non-Linear Model): 0.7077

Anaerobic Biodegradation Probability:

Biowin7 (Anaerobic Linear Model): 0.7025

Ready Biodegradability Prediction: YES

Hydrocarbon Biodegradation (BioHCwin v1.01):

Structure incompatible with current estimation method!

Sorption to aerosols (25 Dec C)[AEROWIN v1.00]:

Vapor pressure (liquid/subcooled): 7.07 Pa (0.053 mm Hg)

Log Koa (Koawin est ): 5.911

Kp (particle/gas partition coef. (m3/ug)):

Mackay model : 4.25E-007

Octanol/air (Koa) model: 2E-007

Fraction sorbed to airborne particulates (phi):

Junge-Pankow model : 1.53E-005

Mackay model : 3.4E-005

Octanol/air (Koa) model: 1.6E-005

Atmospheric Oxidation (25 deg C) [AopWin v1.92]:

Hydroxyl Radicals Reaction:

OVERALL OH Rate Constant = 8.2541 E-12 cm3/molecule-sec

Half-Life = 1.296 Days (12-hr day; 1.5E6 OH/cm3)

Half-Life = 15.550 Hrs

Ozone Reaction:

No Ozone Reaction Estimation

Fraction sorbed to airborne particulates (phi):

2.46E-005 (Junge-Pankow, Mackay avg)

1.6E-005 (Koa method)





Note: the sorbed fraction may be resistant to atmospheric oxidation

Soil Adsorption Coefficient (KOCWIN v2.00):

Koc : 21.46 L/kg (MCI method)

Log Koc: 1.332 (MCI method)

Koc : 12.43 L/kg (Kow method)

Log Koc: 1.094 (Kow method)

Experimental Log Koc: 1.1 (database)

Aqueous Base/Acid-Catalyzed Hydrolysis (25 deg C) [HYDROWIN v2.00]:

Rate constants can NOT be estimated for this structure!

Bioaccumulation Estimates (BCFBAF v3.01):

Log BCF from regression-based method = 0.104 (BCF = 1.271 L/kg wet-wt)

Log Biotransformation Half-life (HL) = -1.5888 days (HL = 0.02578 days)

Log BCF Arnot-Gobas method (upper trophic) = 0.167 (BCF = 1.47)

Log BAF Arnot-Gobas method (upper trophic) = 0.167 (BAF = 1.47)

log Kow used: 1.05 (user entered)

Volatilization from Water:

Henry LC: 3.37E-007 atm-m3/mole (Henry experimental database)

Half-Life from Model River: 1808 hours (75.32 days)

Half-Life from Model Lake : 1.981E+004 hours (825.3 days)

Removal In Wastewater Treatment:

Total removal: 1.91 percent

Total biodegradation: 0.09 percent

Total sludge adsorption: 1.80 percent

Total to Air: 0.02 percent

(using 10000 hr Bio P,A,S)

Level III Fugacity Model:

Mass Amount Half-Life Emissions

(percent) (hr) (kg/hr)

Air 1.03 11.2 1000

Water 34 360 1000

Soil 64.8 720 1000

Sediment 0.0929 3.24e+003 0

Persistence Time: 424 hr





Licensed GreenScreen® Profilers

Benzyl Alcohol GreenScreen® Evaluation Prepared by:

Zach Guerrette, Ph.D.

Toxicologist

ToxServices LLC

Benzyl Alcohol GreenScreen® Evaluation QC’d by:

Bingxuan Wang, Ph.D.

Toxicologist

ToxServices LLC


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