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This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organization, or the World Health Organization.

Concise International Chemical Assessment Document 41

DIETHYLENE GLYCOL DIMETHYL ETHER

Please note that the lay out and pagination of this pdf file are not necessarily identical

to those of the printed CICAD

First draft prepared by Drs I. Mangelsdorf, A. Boehncke, and G. Könnecker, Fraunhofer Instituteof Toxicology and Aerosol Research, Hanover, Germany

Published under the joint sponsorship of the United Nations Environment Programme, the

International Labour Organization, and the World Health Organization, and produced within theframework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health OrganizationGeneva, 2002

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The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organization (ILO),and the World Health Organization (WHO). The overall objectives of the IPCS are to establish thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemical

safety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, the United Nations Institute for Training andResearch, and the Organisation for Economic Co-operation and Development (Participating Organiza-tions), following recommendations made by the 1992 UN Conference on Environment and Developmentto strengthen cooperation and increase coordination in the field of chemical safety. The purpose of theIOMC is to promote coordination of the policies and activities pursued by the Participating Organizations,

jointly or separately, to achieve the sound management of chemicals in relation to human health and theenvironment.

WHO Library Cataloguing-in-Publication Data

Diethylene glycol dimethyl ether.

(Concise international chemical assessment document ; 41)

1.Ethylene glycols - adverse effects 2.Ethylene glycols - toxicity 3.Methyl ethers -adverse effects 4.Methyl ethers - toxicity 5.Risk assessment 6.Environmentalexposure I.International Programme on Chemical Safety II.Series

ISBN 92 4 153041 3 (NLM Classification: QV 81) ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information onany changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 2002

Publications of the World Health Organization enjoy copyright protection in accordance with the

provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.The designations employed and the presentation of the material in this publication do not imply the

expression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany, provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

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iii

TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.2 Anthropogenic sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.3 Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.4 Estimated global release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, TRANSFORMATION, ANDACCUMULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

5.1 Transport and distribution between media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75.2 Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75.3 Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

6.2.1 Workplaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86.2.2 Consumer exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.2.3 Biological monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

7.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97.2 Distribution and accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . 11

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.1.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.1.2 Oral administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.1.3 Dermal administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.2.1 Irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.2.2 Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.3.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.3.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.4 Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

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8.5 Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.6 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.6.1 In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.6.2 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.7 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.7.1 Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.7.1.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.7.1.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8.7.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.7.2.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.7.2.2 Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8.8 Other toxicity/mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

9.1 Reproductive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189.2 Haematological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 11.1.1 Ha za rd id en ti fi ca ti on an d e xpo su re –re sp on se a sse ssm en t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for diglyme . . . . . . . . 20 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 11.1.4 Unce rtaint ies in th e e valu atio n of hu man h ea lth e ffe cts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2111.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

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Diethylene glycol dimethyl ether

1

FOREWORD

Concise International Chemical Assessment

Documents (CICADs) are the latest in a family of

publications from the In ternational Programme onChemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the InternationalLabour Organization (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment of chemicals.

International Chemical Safety Cards on therelevant chemical(s) are attached at the end of theCICAD, to provide the reader with concise information

on the protection of human health and on emergencyaction. They are produced in a separate peer-reviewed procedure at IPCS. They may be complemented byinformation from IPCS Poison Information Monographs(PIM), similarly produced separately from the CICAD pr oc es s.

CICADs are concise documents that provide sum-maries of the relevant scientific information concerning

the potential effects of chemicals upon human healthand/or the environment. They are based on selectednational or regional evaluation docume nts or on existingEHCs. Before acceptance for publication as CICADs by

IPCS, these documents undergo extensive peer review by internat ionally selected experts to ensure their completeness, accuracy in the way in which the originaldata are represented, and the validity of the conclusionsdrawn.

The primary objective of CICADs is characteri-

zation of hazard and dose–response from exposure to a

chemical. CICADs are not a summary of all available dataon a particular chemical; rather, they include only thatinformation considered critical for characterization of therisk posed by the chemical. The critica l studies are,

however, presented in sufficient detail to support theconclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environme nt willvary considerably depending upon the type and ex tentof exposure. Responsible authorities are stronglyencouraged to characterize risk on t he basis of locally

measured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and risk characterization are provided in CICADs, whenever

poss ible . These examples cannot be cons idered asrepresenting all possible exposure situations, but are

provided as guidance only. The reader is referred to EHC1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure th at CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scien tificliterature to the date shown in the executive summary. Inthe event that a reader bec omes aware of new informa-tion that would change the conclusions drawn in a

CICAD, the reader is requested to contact IPCS to informit of the new information.

Procedures

The flow chart on page 2 shows the proceduresfollowed to produce a CICAD. These procedures aredesigned to take advantage of the expertise that existsaround the world — expertise that is required to producethe high-quality evaluations of toxicological, exposure,and other data that are necessary for assessing risks tohuman health and/or the environme nt. The IPCS Risk Assessment Steering Group advises the Co-ordinator,

IPCS, on the selection of chemicals for an IPCS risk assessment, the appropriate form of the document (i.e.,EHC or CICAD), and which institution bears theresponsibility of the document production, as well as onthe type and extent of the international peer review.

The first draft is based on an existing national ,

regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outlinehas been developed to encourage consistency in form.The first draft undergoes primary review by IPCS and

one or more experienced authors of criteria documents toensure that it meets the specified criteria for CICADs.

The draft is then sent to an international peer review by scientists known for their particular expertise

and by scientists selected from an international roster compiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers’ comments into account andrevise their draft, if necessary. The resulting secon d draft

1 International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: derivation

of guidance values for health-based exposure limits.

Geneva, World Health Organization (EnvironmentalHealth Criteria 170).

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Concise Internat ional Chemical Assessm ent Document 41

2

S E L E C T I O N O F H I G H Q U A L I T Y N A T I O N A L / R E G I O N A L

A S S E S S M E N T D O C U M E N T ( S )

CICAD PREPARATION FLOW CHART

F I R S T D R A F T

P R E P A R E D

REVIEW BY IPCS CONTACT POINTS/SPECIALIZED EXPERTS

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

SELECTION OF PRIORITY CHEMICAL

1 Taking into account the comments from reviewers.2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.3 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS ( PR OD UC ER /R ES PO NS IB LE OF FI CE R),PREPARATION

OF SECOND DRAFT 1

P R I M A R Y R E V I E W B Y I P C S( REVISIONS AS NECESSARY )

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3

is submitted to a Final Review Board together with thereviewers’ comments.

A consultative group may be necessary to advise

on specific issues in the risk assessment document.

The CICAD Final Review Board has several

important functions:

– to ensure that each CICAD has been subjected to

an appropriate and thorough peer review;

– to verify that the peer reviewers’ comments have be en addressed appropr ia te ly ;

– to prov ide guidanc e to those responsible for the preparat ion of CICADs on how to resolve anyremaining issues if, in the opinion of the Board, theauthor has not adequately addressed all commentsof the reviewers; and

– to ap prove CICADs as interna tional as sessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, or industry. They are selected because of their expertise inhuman and environmental toxicology or because of their

experience in the regulation of chemicals. Boards arechosen according to the range of expert ise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the prep aration of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects under discussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board.

Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may not participate in the fin al decision-making process.

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4

1. EXECUTIVE SUMMARY

This CICAD on diethylene glycol dimethyl ether

(in the following called diglyme) was prepared by theFraunhofer Institute of Toxicology and AerosolResearch, Hanover, Germany. Diglyme was selected for review in the CICAD series owing to concern s for humanhealth, notably potential reproductive effects. TheCICAD is based on reports compiled by the GDChAdvisory Committee on Existing Chemicals of Environ-mental Relevance (BUA, 1993a) and the German MAK-

Kommission (Greim, 1994). A comprehensive literaturesearch of relevant databases was conducted in March2000 to identify any relevant references publishedsubsequent to those incorporated in these reports.

Information on the preparation and peer revie w of thesource documents is presented in Appendix 1. Informa-tion on the peer review of this CICAD is presented inAppendix 2. This CICAD was approved as an interna-tional assessment at a meeting of the Final ReviewBoard, held in Geneva, Switzerland, on 8–12 January2001. Participants at the Final Review Board meeting arelisted in Appendix 3. The International Chemical SafetyCard on diglyme (ICSC 1357), produced by the Inter-

national Programme on Chemical Safety (IPCS, 2000), hasalso been reproduced in this document.

Diglyme (CAS No. 111-96-6) is a colourless liquid

with a slight, pleasant odour. It is miscible with water and a number of common organic solvents. In the presence of oxidation agents, peroxide may form. Due toits dipolar aprotic properties, diglyme is used mainly as asolvent (semiconductor industry, chemical synthesis,lacquers), as an inert reaction medium in chemicalsynthesis, and as a separating agent in distillations.

Diglyme liquid or vapour is readily absorbed byany route of exposure, metabolized, and excreted mainlyin the urine. The main metabolite is 2-methoxyethoxy-acetic acid. 2-Methoxyacetic acid is a minor metabolite;

in rats, it amounts to about 5–15% in the urine .

The acute toxicity of diglyme is low after oralexposure or inhalation.

Diglyme is slightly irritating to the skin or eye. Noinvestigations are available on the sensitizing effects of diglyme.

The main targets in male animals after repeated

intake of diglyme are the reproductive organs. In 2-week inhalation studies in male rats, dose-dependent

decreases in weights of testes, epididymides, prostate,and seminal vesicles were observed. The testes were

atrophic, and damage of the spermatocytes wasobserved. The no-observed-adverse-effect level(NOAEL) in these studies was 30 ppm (167 mg/m3); thelowest-observed-adverse-effect level (LOAEL) was 100

ppm (558 mg/m3

). Experiments with mice showedmorphologically altered sperm, mainly with amorphousheads, after exposure to 1000 ppm (5580 mg/m3). After exposure by inhalation to high concentrations, male andfemale animals also showed effects on thehaematopoietic system, such as changes in leukocytecounts and atrophy in spleen and thymus.

No long-term studies are available fo r diglyme;therefore, all end-points cannot be reliably assessed.Several Ames tests as well as an unscheduled DNAsynthesis test did not reveal a genotoxic potential of diglyme in vitro. Nor was the number of chromosomalaberrations increased in bone marrow cells in vivo.

In a dominant lethal test with rats, the number of pregnanc ies wa s significant ly reduced a fter exposure to1000 ppm (5580 mg/m3) but not to 250 ppm (1395 mg/m3).The positive results may be due to the eff ects of diglymeon fertility.

In teratogenicity studies with rats, rabbits, and

mice, diglyme showed dose-dependent effects on fetalweights, number of resorptions, and incidence of varia-tions and malformations in a wide variety of tissues and

organ systems, at concentrations that were notmaternally toxic. The LOAEL for developmental effectsin an inhalation study with rats was 25 ppm (140 mg/m3);the NOAEL for the oral route was 25 mg/kg body weightin rabbits and 62.5 mg/kg body weight in mice. Thereproductive toxicity of diglyme is attributed to the minor metabolite 2-methoxyacetic acid.

Epidemiological studies of female semiconductor workers occupationally exposed to ethylene glycolethers (EGEs), including diglyme, have found anincreased risk of spontaneous abortions and lower

fecundity. Workers in the semiconductor indust ry areexposed to a number of potential reproductive toxicants,however, including EGEs and other chemicals. Fromthese data, it is not possible to determine thecontribution of diglyme to the increased risk of adversereproductive effects. Painters exposed to a variety of metals, organic solvents, and other chemicals, including2-methoxyethanol, a metabolite of diglyme, but not to

diglyme itself, were found to have an inc reased risk of oligospermia.

The main environmental target compartment of

diglyme is the hydrosphere. The chemical is hydrolyti-cally stable. The half-life in air for the reaction of diglyme

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with hydroxyl radicals is calculated to be a bout 19 h.Diglyme is inherently biodegradable, with a rather longlog phase and significant adsorption to activated sludge.From the n-octanol/water partition coefficient and the

water miscibility of the chemical, a negligible potentialfor bioaccumulation and geoaccumulation is derived.

From valid test results available on the toxicity of

diglyme to various aquatic organisms, this compoundcan be classified as a chemical exhibiting low acute tox-icity in the aquatic compartment. The 48-h EC0 value for

daphnia ( Daphnia magna) and the 72-h EC10 value for algae (Scenedesmus subspicatus) were $1000 mg/litre(highest measured concentration). For the golden orfe( Leuciscus idus), a 96-h LC0 of $2000 mg/litre wasdetermined. Only very few studies concerning the tox-icity of diglyme towards terrestrial species are available.The fungus Cladosporium resinae exhibited a toxicthreshold concentration of about 9.4 g/litre.

From the sample risk characterization for theworkplace, there is high concern for possible huma nhealth effects. Exposure of the general popula tion todiglyme should be avoided.

The available data do not indicate a significant risk

associated with exposure of aquatic organisms todiglyme. Due to the lack of measured exposure levels, asample risk characterization with respect to terrestrial

organisms cannot be performed. However, from the use patte rn of d iglyme, significant exposure o f te rrestria lorganisms is not to be expected.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Diglyme (CAS No. 111-96-6; relative molecular mass 134.17) is also known as bis(2-methoxyethyl)ether

(IUPAC name), diethylene glycol dimethyl ether,DEGDM(E), dimethyl carbitol, and 2,5,8-trioxynonane. It belongs to the group of ethylene glycol ethers (EGEs).The molecular structure of diglyme (C6H14O3) is shown below:

CH3 – O – CH2 – CH 2 – O – CH2 – CH2 – O – CH3

Diglyme is a colourless liquid of low viscosity witha slight, pleasant odour. The chemical free zes at about

!64 °C. Depending on the presence of impurities, its boi ling po int is between 155 and 165 °C (Hoechs t, 1990).

Diglyme is miscible with water and with a number of common organic solvents. It dissolves numerous

compounds, such as vegetable oils, waxes and resins, boron hydrides, organic boron compounds, su lfur , sulfur dioxide, hydrogen peroxide, and carbon dioxide. Withwater, azeotrope formation is observed at a

concentration ratio of 23 wt. % diglyme and 77 wt. %water (BUA, 1993a). Diglyme has an n-octanol/water par tit ion coeff icient ( log K ow) of !0.36, determined by ashake flask experiment (Funasaki et al., 1984). Its vapour pressure a t 20 °C ranges from 0.23 to 1.1 kPa. Thechemical is volatile with water vapour (BUA, 1993a). Thecalculated Henry’s law constant is given as

0.041 PaAm3/mol (J. Gmehling, personal communication,1991).

The conversion factors for diglyme for the gas phase (101.3 kPa, 20 °C) are as follows:

1 mg/m3 = 0.18 ppm 1 ppm = 5.58 mg/m3

Diglyme is chemically stable. In the presence of strong oxidation agents, peroxide may form. Commercial products typically conta in peroxides at a concentrat ionof 5 mg/kg. To avoid the further formation of peroxides,

commercial products may contain antioxidants, such as2,6-di-tert -butyl-4-methylphenol (BUA, 1993a).

Additional physical and chemical properties of

diglyme are presented in the International Chemical

Safety Card (ICSC 1357) reproduced in this document.

3. ANALYTICAL METHODS

Two general methods for the determination of

glycol derivatives in ambient and workplace air aredescribed:

# adsorption onto modified silica containing cyano-

propyl groups , syn thet ic po lyme rs such as XAD 2or XAD 7, or modified activated charcoal, withsubsequent solvent elution (e.g., acetone,dichloromethane, dichloromethane/methanol); and

# adsorption onto TENAX TA with subsequentthermal desorption.

In either case, detection is carried out via gaschromatography/flame ionization detection (GC/FID) or

gas chromatography/mass spectrometric detection(GC/MSD) (NIOSH, 1990, 1991, 1996; Stolz et al., 1999).For the determination of diglyme in indoor air, the

chemical was adsorbed onto activated charcoal, elutedwith dichloromethane/methanol, and determined by

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capillary GC/MSD (internal standard toluene-d8and 1,2,3-trichloropropane). The detection limit was3 µg/m3; data on recovery rate and standard deviationare not available (Plieninger & Marchl, 1999).

The enrichment of diglyme from water samples is

also in general carried out by adsorption onto XAD 4 or XAD 8 material with subsequent solvent elution (e.g.,diethylether, dichloromethane) and determination bycapillary GC/MSD (Morra et al., 1979; Lauret et al., 1989).Recovery rates and standard deviations are not

available. A detection limit of 0.01 µg/litre is reported(Morra et al., 1979).

Analytical methods for the determination of diglyme in soil or sediment are not available.

Diglyme was determined together with other glycolethers in human urine by enrichment on diatomaceousearth, extraction with dichloromethane/acetone (90:10),and detection by ca pillary GC/FID. The validation resultsof the method are given only as ranges for total glycolethers: detection limits 0.25–1 mg/litre, standarddeviation 1.5–17.1% (at 5 mg/litre), and recovery rates

92.0–125.2% (at 2, 5, and 10 mg/litre) (Hubner et al.,1992). [14C]Diglyme was determined in rat urine for metabolism studies by high-performance liquid chroma-tography/scintillation detection on a reversed-phase C18column (gradient elution with methanol/acetic acid) after

acidification of the sample (Cheever e t al., 1988). Infor-mation on detection methods for other biological mater-ials is not available.

The metabolite 2-methoxyacetic acid is assumed to

play a major ro le in the toxic effects of diglyme (seesections 8 and 9). Therefore, common detection methods

for this compound in urine after inhalation exposure torelated EGEs are described briefly here. The basis of these methods is an esterification of 2-methoxyaceticacid with diazomethane after lyophilization of the alkalineurine solution and uptake in hydrochloric acid/dichloro-

methane (Groeseneken et al., 1986) or withtrimethylsilyldiazomethane after extraction of the acidurine solution with dichloromethane/isopropyl alcohol(Sakai et al., 1993). The determination was carried out in both cases wi th a GC/FID us ing a capillary column. Therecovery rates were reported to be 31% (Groesenek en etal., 1986) and 98% (Sakai et al., 1993). The detection limitswere 0.15 mg/litre (Groeseneken et al., 1986) and 0.05

mg/litre (Sakai et al., 1993).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

4.1 Naturalsources

There are no known natural sources of diglyme.

4.2 Anthropogenic sources

Diglyme is manufactured in a clo sed system by the

catalytic conversion of dimethyl ether and ethyleneoxide under elevated pressure (1000–1500 kPa) andtemperatures (50–60 °C) with a maximum yield of 60%.

The by-products tri- and tetraethylene glycol dimethylether and small amounts of a high-molecular-mass

ethylene glycol dimethyl ether are separated byfractional distillation (Hoechst, 1991). This process is based on the classic Wil liamson e ther synthesis(Rebsdat & Mayer, 1999).

In 1982, about 47 200 tonnes of diglyme were produced in the USA (HSDB, 1983). In 1990, about400 tonnes of the chemical were manufactured inGermany, of which 200 tonnes were exported (BUA,1993a). More recent data or data from other c ountries arenot available. Diglyme is registered as a high-

production-volume chemical by the Organisat ion for

Economic Co-operation and Development (OECD) (i.e.,its production volume in at least one OECD member stateis $1000 tonnes/year) (OECD, 1997).

4.3 Uses

Because of its dipolar aprotic properties and its

chemical stability (see sections 2 and 5.2), diglyme isused mainly as a solvent, as an inert reaction medium inchemical synthesis, and as a separating agent in distilla-tions. These uses include industrial applications, such

as polymerization reactions (e.g., of isoprene, styrene),the manufacture of perfluorinated organic compounds

(BUA, 1993a), reactions in boron chemistry (Brothertonet al., 1999; Rittmeyer & Wietelmann, 1999), and itsapplication as a solvent for, for example, textile dyes,lacquers, and cosmetics (BUA, 1993a; Baumann & Muth,1997).

Diglyme is also used in the manufactu re of inte-grated circuit boards, primarily as a solvent for the photores is ts . These are used as photosens it ive mater ialsfor the coating of the wafer during microlithographic patterning in the photo/apply process (Messner, 1988;

Correa et al., 1996; Gray et al., 1996) and in the

production of semiconductors (Corn & Cohen, 1993).

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Diglyme is included in the European Inven tory of

Cosmetics Ingredients in the solvent category (EC, 1996).Its use in cosmetics in Germany and Canada was not

reported (BUA, 1993a; Clariant GmbH, personalcommunication, 2000; IKW [German Trade Associationon Cosmetic and Detergent Preparations], personalcommunication, 2000; R. Gomes, Health Canada, personal communicat ion , 2001). Data fo r other countriesare also not available.

EGEs in general are also used as auxiliary solventsin water-based paints that are industrially applied (e.g.,in the spraying of automobiles, metal furniture, house-hold appliances, and machines) (Karsten & Lueckert,1992; Baumann & Muth, 1997). It is not possible with theavailable data to estimate the annual amount of diglymein this field of use or its application in water-based pa in ts fo r consume r use .

4.4 Estimated global release

The global releases of diglyme cannot be estimatedwith the available data.

The releases from the production of diglym e at the

German manufacturer for the year 1990 are estimated asfollows: <2.5 g/tonne released into air, about 133–188 g/tonne released into water, and <7.5 kg/tonne released

with solid wastes. The liquid wastes are disposed of inapproved chemical waste incinerators (BUA, 1993a).

Data on the degree of recycling of diglyme from its

application as a solvent or as an inert reaction medium inindustrial processes are not available.

Information on the content of diglyme in consumer prod ucts such as co smet ics o r pai nt s and la cq uers is no tavailable. It is assumed that any diglyme used in thisway will end up in ambient air or domestic wastewater.

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, TRANSFORMATION, AND

ACCUMULATION

5.1 Transport and distribution betweenmedia

Diglyme is miscible with water and has a low

Henry’s law constant (see section 2), leading to a low

volatility from aqueous solutions (Thomas, 1990). From

this and its use pattern, it is expected that the main targetcompartment of the chemical will be the hydrosphere.

5.2 Transformation

From GC measurements with an aqueous solution

of 47.2 g diglyme/litre (5% v/v) kept in the dark for 21 days (NTP, 1987), it has been concluded that thechemical is hydrolytically stable. This is also to beexpected from diglyme’s chemical structure (Harris,1990).

Direct photolysis of diglyme is assumed to be of minor importance due to diglyme’s weak absorptio n atwavelengths above 230 nm (Ogata et al., 1978a,b). NTP(1987) determined no decrease in the concentration of anaqueous solution of diglyme (47.2 g/litre) exposed toroom light for 72 h.

The reaction of gaseous diglyme with hydroxylradicals in the atmosphere has an experimentally deter-mined rate constant K OH of 1.7 × 10 –11 cm3/molecule per se cond (Dagaut et al. , 1988). Assuming an averagetropospheric hydroxyl radical concentration of about

6 × 105 molecules/cm3 (BUA, 1993b), the half-life of diglyme can be calculated to about 19 h. Due to themiscibility of diglyme with water and its low Henry’s lawconstant (see section 2), diglyme is furthermore expectedto be deposited easily with rain or other wet deposition.

From this and its short half-life in atmospheric rea ctions,long-distance transport of diglyme in ambient air isassumed to be negligible.

From a Zahn-Wellens test following OECD Guide-

line 302B, adsorption of diglyme onto activate d sludgewas 17% after 3 h, and total removal was 42% after

28 days. The degree of elimination and the degradationcurve are indicative of inherent primary degradation,according to OECD criteria (Hoechst, 1989a).

Roy et al. (1994) achieved a similar result in an

electrolytic respirometer test with industrial wastewater from a manufacturer of synthetic organic chemicals. In afurther experiment in which diglyme was tested together with dioxane and other unspecified organic chemicals,the degree of biodegradation was significantly higher than in the test with diglyme alone (80% after 32 days),suggesting that the biodegradation of diglyme is moreefficient in the presence of other carbon sources. High

salt concentrations in the wastewater, however, result ina decrease in biodegradation, indicated by a significantincrease in the lag phase.

Data on the anaerobic degradation of diglyme are

not available.

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5.3 Accumulation

The log K ow of diglyme (!0.36; see section 2) indi-

cates a negligible potential for bioaccumulation.

Measurements concerning the geoaccumulation of

diglyme are not available . Data on the adsorption of thechemical onto activated sludge in the Zahn-Wellens test(see section 5.2) cannot be used for the estimation of adsorption onto soil. It is to be expected that the oxygen

atoms in the diglyme molecule will lead to a high affinityfor the microorganisms of the activated sludge but notfor the humic acids or inorganic components of soils.From the physicochemical properties of the substance(miscibility with water, low log K ow; see section 2), a lowtendency to sorption onto inorganic and organic soilsubstances is to be expected.

As a result of its highly hydrophilic character andits low tendency to volatilize from aqueous solutions or to adsorb to soil constituents, diglyme may reachgroundwater. EGEs were detected particularly in anoxicgroundwater in the vicinity of US landfill sites (Ross et

al., 1992). The possibility that the chemical will subse-quently enter wells and drinking-water cannot beexcluded.

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

Data on the concentrations of diglyme in ambient

or workplace air are not available.

Diglyme was detected in surface water in theDutch parts of the river Rhine at concentrations ranging

between 0.1 and 0.3 µg/litre (1978; five samples), 0.03 and0.3 µg/litre (1979; five samples), and 0.5 and 5 µg/litre(1985; six samples) (Morra et al., 1979; Linders et al.,1981; KIWA, 1986). More recent data or data fromsurface waters in other countries are not available.

In 1987, the chemical was determined in the bio-logically treated leakage from two French landfills atconcentrations in the order of 2–20 µg/litre (Lauret et al.,1989). Diglyme was furthermore determined but not

quantified in 1992 in wastewater samples, from a Germanoil reclaiming company, that had been pretreate d by

equalization, neutralization, adsorption to activatedsludge, flocculation, and flotation (Gulyas et al., 1994).

Data on the concentratio n of diglyme in soil or

sediment are not available.

Data on the concentration of diglyme in biological

material are not available.

6.2 Human exposure

6.2.1 Workp laces

There is a potential for inhalation or dermal contact

in the chemical and allied product industries wherediglyme is used as a solvent.

During the diglyme production process and its use

as a solvent in chemical synthesis, inhalation and dermalcontact are assumed to occur mainly during cleaning andmaintenance operations, as solvents are handled mainlyin closed systems.

No d ata are available on diglyme exposure con-

centrations at the workplace. Data on other EGEs that are produced in the same way and tha t have a comparab le

use pattern and similar volatilization behaviour mayserve as a rough approximation.

ECETOC (1995) reported time-weighted average(TWA) exposures for several other EGEs between 0.01

and 6.5 ppm for the production pro cess. This wouldcorrespond to airborne diglyme concentrations betweenabout 0.06 and 36 mg/m3, taking its conversion factor for the gas phase into account (see section 2). The dermalexposure to diglyme can be estimated with the cal cu-lation model Estimation and Assessment of SubstanceExposure (EASE) to be a maximum of 0.1 mg/cm2 per day, based on the assumption that trained workers inci-

dentally have direct skin contact with diglyme duringcleaning and maintenance operations. Assuming further that exclusively the palms (an area about 420 cm2) areexposed, this would lead to a maximum dermal body dose

of 0.6 mg/kg body weight per day (assuming a bodyweight of 70 kg).

For the use of EGEs in the semiconductor industry,

TWA exposure values between 0.01 and 0.55 ppm arereported (workplace operation not specified; ECETOC,1995). This would correspond to airborne diglymeconcentration s between about 0.06 and 3.1 mg/m3. A s

diglyme is obviously used in mixtures with other EGEs(see, for example, Messner, 1988), the diglyme exposurelevels cannot be estimated from these data.The maximumdermal dose could be assumed to be equal to the doseestimated for the production process (0.6 mg/kg bodyweight per day). Some authors report significant

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permeation of protective gloves of diffe rent materia ls byEGEs. Gloves made of nitrile and butyl rubber or neoprene provide the bes t p rotect ion (breakthrough ra tes$45 min) and are now the ones being used most fre-

quently in the semiconductor industry (for review, seePaustenbach, 1988).

For the use of glycol ethers in professional

pain ting operat ions , the geometric means of the TWAexposure values were between 1.7 and 5.6 ppm, withmaximum concentrations up to about 37.6 ppm

(workplace operation not specified; ECETOC, 1995). For diglyme, this would correspond to airborneconcentrations between 9.5 and 31 mg/m3, with amaximum of 210 mg/m3. The maximum dermal exposurecould be assumed to be equal to the dose e stimated for the production and solvent use of diglyme in chemicalsynthesis (incidental contact during transferring/weighing/mixing or cleaning and maintenance pro cedures, exposure of palms [420 cm2] only: 0.1 mglacquer/cm2 per day). Assuming a maximum diglymecontent of the lacquer of 25% (Baumann & Muth, 1997),this results in a maximum dermal body dose of about 0.15mg diglyme/kg body weight per day.

6.2.2 Consumer exposure

The main target compartment of diglyme is thehydrosphere (see section 5.1). The chemical is inherently

biodegradable with a rather long log phase and a signif i-cant tendency to adsorb onto activated sludge (seesection 5.2). From this and from its suspected use as asolvent in consumer products such as lacquers andcosmetics, the main route of exposure of the general population to diglyme is l ikely via the ingestion of drinking-water and via dermal contact with the re spec-tive consumer products.

The database is not sufficient to estimate the daily

intake of diglyme by the general population.

Data on the concentration of diglyme in drinking-water are not available.

Quantitative information on dermal exposure to

diglyme via cosmetic products is not available. Althoughdiglyme is included in the European Union’s Inventoryon Cosmetics Ingredients, its use was not reported for Germany or Canada (see section 4.3). For other countries,

data are also not available.

Measured data on exposure to diglyme-containingwater-based paints and lacquers for consumer use arenot available. Furthermore, the relevance of diglyme asan auxiliary solvent in paints for consumer use cannot beestimated with the available data. Due to the low ten-dency of volatilization of diglyme from aqueous solu-

tions (see section 5.1), inhalation exp osure is assumed to be of minor importance. Dermal exposure c annot bequantified with the available data.

6.2.3 Biological m onitoring

As dermal exposure is significant, measurement of diglyme in air is not sufficient for exposure monitoring.Therefore, biological monitoring of the metabolite 2-methoxyacetic acid, which belongs to the metabolic pa thway tha t i s responsib le for the deve lopmentaleffects and effects on the reproductive system, is

preferable. Methods for detecting this metabolite in urineare described in section 3.

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

7.1 Absorption

Studies on the metabolism of digl yme in rats show

that diglyme is absorbed from the gastrointestinal tract(Cheever et al., 1986, 1988). Absorption followinginhalation can be concluded from the observation of po ison ing symptoms in s tudies on sing le - and repeated -

dose exposure to diglyme and in analogy with other glycol ethers.

In an in vitro study with human skin, the high percutaneous absorption of glycol ethers (ECETOC,1995; Johanson, 1996) was confirmed. The permeabilityconstant was 1 × 10 –3 cm/h, and the lag time was approxi-mately half an hour. With these findings, diglyme wasamong the glycol ethers with the highest absorption rate(Filon et al., 1999).

Dermal absorption of glycol ether liquids or vapours is very high (Johanson & Boman, 1991;

ECETOC, 1995; Kezic et al., 1997; Brooke et al., 1998;

Johanson, 2000). With 2-methoxyethanol, for example,dermal absorption of the vapour is approximately as highas absorption via inhalation. Dermal uptake of the liquidis very high: exposure of an area of 2000 cm2 for 1 hresulted in a body dose of 592 0 mg in a study withhuman volunteers (Kezic et al., 1997).

7.2 Distribution and accumulation

No studies are avai lable that inves tigate the dis -

tribution of radioactively labelled diglyme within the

body. Glycol ethers in general are readily distributed

throughout the body (ECETOC, 1995).

The metabolite 2-methoxyacetic acid has shownevidence of accumulation in animals and humans. In

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Table 1: Metabolites in the urine after single oral application of diglyme.

Male Sprague-Dawley rats Pregnant CD-1 mice

Cheever et al. (1988)

Cheever et al.(1989a)

Richards etal. (1993)

Daniel et al.(1986)

Daniel etal. (1991)

Dose (mg/kg body weight) 6.84 684 684 684 684 300 500

Appl icat ion at day of gestation – – – – – 12 11

Duration of urine collection (h) 96 96 96 96 48 48 48

Pretreatment – – 22 days

diglyme

22 days

phenobarbital

– – –

% of dose

Metabolite I (not identified) <0.1 0.3 0.4 0.7 n.g.a n.g. n.g.

N -(Methoxyacetyl)glycine 0.1 0.3 0.7 0.9 n.g. n.g. n.g.

Diglycolic acid 6.7 3.9 2.2 4.6 n.g. n.g. n.g.

Metabolite IV (not identified) 2.5 1.0 1.1 1.6 n.g. n.g. n.g.

2-Methoxyacetic acidb 5.8 6.2 10.0 13.4 n.g. 26.1–27.0 28.0

2-Methoxyethanol 2.2 0.8 2.1 1.5 n.g. n.g. n.g.

2-Methoxyethoxyacetic acidb 70.3 67.9 68.5 64.2 67.0 64.5–67.1 63.0

Metabolite VIII (not identified) 0.4 1.2 2.3 1.0 n.g. n.g. n.g.

2-(2-Methoxyethoxy)ethanol 0.3 <0.1 1.2 0.7 n.g. n.g. n.g.

Diglyme 0.4 1.8 1.3 0.3 n.g. n.g. n.g.

Total 88.7 83.4 88.8 88.9 81.0 n.g. n.g.

a n.g. = not given.b Bold indicates main metabolites.

humans, its half-life was calcula ted as 77.1 h (ECETOC,1995).

7.3 Metabolism

The metabolites identified in the urine followingoral application in different studies are given in Table 1.The metabolic pathway of diglyme is shown in Figure 1.

The principal pathway of biotransformation of

diglyme involves O-demethylation with subsequent

oxidation to form the main metabolite 2-methoxyethoxy-acetic acid, which accou nts for about 60–70% of thedose in the urine of rats and pregnant mice after 48 –96 h(Daniel et al., 1986; Cheever et al., 1988; Toraason e t al.,1996) (see Table 1).

In addition, cleavage (O-dealkylation) of the cen-

tral ether bond results in the formation of 2-methoxy-ethanol, which is subsequently oxidized to 2-methoxy-acetic acid. This metabolite accounts for about 5–15% of

the dose in the urine of rats a fter 48–96 h (Cheever et al.,1988, 1989a). In the urine of pregnant mice, it was found

in higher concentrations (26–28 % of the dose; Daniel etal., 1986, 1991) (see Table 1). Also, humans may form thismetabolite in higher concentrations. Based on n mol 2-methoxyethanol generated per nmol P-450, human

microsomes were found to be 7 times more effective thanrat microsomes in converting diglyme to 2-methoxy-ethanol (Tirmenstein, 1993; Toraason et al., 1996).

There is no apparent quantitative difference in thespectrum of metabolites, including 2-methoxyethoxy-acetic acid and 2-methoxyacetic acid, over a 100-folddose range (6.84–684 mg/kg body weight; see Table 1).

Repeated doses of diglyme or induction with

phenobarbi tal o r ethanol increases the cleavage of the

central ether linkage of diglyme as a result of cytochromeP-450 enzyme induction in the liver (Cheever e t al., 1988,1989a; Tirmenstein, 1993; ECETOC, 1995; Toraason et al.,1996).

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Figure 1: Metabolism and disposition of diethylene glycol dimethyl ether (bis(2-methoxyethyl)ether).

Although the main metabolite in rat urine is 2-methoxyethoxyacetic acid, numerous studies indicatethat 2-methoxyacetic acid is the metabolite responsiblefor the toxicity of diglyme for the male reproductiveorgans (see also section 8.7) (Cheever et al., 1985, 1988;BUA, 1993a). Further, 2-methoxyacetic acid was trans-ferred to the fetus and found as the sole metabolite inthe fetus (no parent compound was detected in the fetu s

either) after dosing diglyme to mice at day 11 or 12 of pregnancy (Daniel et al. , 1986, 1991). The highest levelsfor the average embryo (whole embryos analysed) weredetected at 6 h after dosing. Significantly lower amounts

were detected in blood taken from the dam at that time point (Daniel et al. , 1991).

7.4 Elimination

The major route of elimination is through the urine. Ninety-six hours after oral app lication of 6.84 mgdiglyme/kg body weight to male Sprague -Dawley rats,90% of the dose was excreted via urine, 3.6% as carbon

dioxide, and 2.9% in the faeces. Only 1.7% of the doseremained in the carcass (Cheever et al., 1988).

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

8.1.1 Inhalation

A 7-h nose-only exposure (inhalation hazard test)to an atmosphere saturated with diglyme at room temperature (about 10 g/m3) caused restlessness, narrowing

of palpebral fissures, and irregular breathing in rats. All

animals survived. Necropsy 14 days after exposurerevealed no macroscopic findings (Hoechst, 1979a).

8.1.2 Oral adm in istration

The acute oral toxicity of diglyme is low. The oralLD50 for the female rat is 4760 mg/kg body weight(Hoechst, 1979b) and for the female mouse is 2978 mg/kg body weigh t (Plasterer et al ., 1985). Poisoning symptomswere restlessness and breathing difficulties. Necropsy of animals found dead revealed changes in lung and liver (no further information available).

CH3-O-CH2-CH2-O-CH2-CH 2-O-CH3


CH3-O-CH2-CH2-O-CH2-CH 2-O H

2-(2-Methoxyethoxy)ethanol

CH3-O-CH2-CH2-OH

2-Methoxyethanol

CH3-O-CH2-CH2-O-CH2-COOH

2-(2-Methoxyethoxy)acetic acid

CH3-O-CH2-COOH

Methoxyacetic acid

HOOC-CH 2-O-CH2-COOH

Diglycolic acid

CH3-O-CH2-CO-NH-CH2-COOH

N -Methoxyacetyl glycine

U R I N E

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irritation after 24 h (Hoechst, 1979c; no further information available).

8.2.2 Sens itization

There are no data available.

8.3 Short-term exposure

8.3.1 Inhalation

Groups of 20 male and 10 female Crl:CD rats were

exposed to 0, 110, 370, or 1100 ppm (0, 614, 2065, or 6138mg/m3) diglyme, 6 h/day, 5 days/week, for 2 weeks. Malerats were killed after 10 days of exposure and 14, 42, or 84days post-exposure, respectively. Female rats were killedafter the 10th exposure and 14 days post-exposure. Urineanalysis, haematological analyses, and histopathologywere performed. Changes in the haematopoietic systemoccurred in both sexes and involved the bone marrow,spleen, thymus, leukocytes, and erythrocytes.According to the authors, the no-observed-adverse-effect level (NOAEL) for female rats was 370 ppm (2065mg/m3). Males were more sensitive than females:compared with controls, body weight gain as well as

mean leukocyte counts were dose dependentlydecreased in all dose groups. Further, stage-specificgerm cell damage occurred at all concentrations and wasconcentration and time dependent (see section 8.7.1.1).

Thus, for male rats, a NOAEL could not be established inthis study (DuPont, 1988b; Lee et al., 1989; Valentine etal., 1999).

In another study with four male and four female

Alderley Park rats per group exposed for 3 weeks,6 h/day, to 200 and 600 ppm (1116 and 3348 mg/m3)diglyme, urine analysis, haematological analyses, and

histopathology (of a limited numbe r of organs withouttestes) were also performed . In contrast to the DuPontstudy cited above, no changes in haematological parameters were noted after exposure to 600 ppm

(3348 mg/m3

). However, similar to the observations inthat study, body weight gain was affected and thymuswas atrophied. Further, adrenals were congested. Noeffects were found in the 200 ppm (1116 mg/m3) dosegroup (Gage, 1970).

8.3.2 Oral

In four male JCL-ICR mice that received diglyme in

the drinking-water for 25 days at a level of 2% (approx-

imately 7000 mg/kg body weight, assuming an intake of 7ml/day and a body weight of 20 g), the number of tota lwhite blood cells was more than doubled comp ared withcontrols. This increase was not, however, statistically

significant (Nagano et al., 1984). For repeated-dosestudies on effects of diglyme on male reproductiveorgans, see section 8.7.

8.4 Medium-term exposure

There are no medium-term exposure studies

available.

8.5 Long-term exposure andcarcinogenicity

No studies are available on long-term exposure or carcinogenicity.

8.6 Genotoxicity and related end-points

8.6.1 In vi tro studies

Results of investigations of genotoxicity in vitro

are given in Table 2. Diglyme was not mutagenic inseveral Ames tests with or without S9 mix (Hoechst,1979d,e; McGregor et al., 1983; Mortelmans et al., 1986).

Diglyme also had no effect in a test for unsched-

uled DNA synthesis in human embryo fibroblasts(McGregor et al., 1983).

8.6.2 In vivo studies

Diglyme did not induce chromosomal aberrations

in bone marrow cells in groups of 10 male and 10 femaleCD rats exposed to 250 or 1000 ppm (1395 or 5580 mg/m3)

diglyme 7 h/day for 1 or 5 days (McGregor et al., 1983).

A dominant lethal test is described in section8.7.1.1 (McGregor et al., 1983). The reduced number of

pregnancies and an increase in preimplantat ion lossesmay be due either to a domina nt lethal effect or toreduced fertility of the males. Considering the knowneffects of diglyme on fertility, the authors of the studyassume that reduced fertility is a cause of the effects.Also, the post-implantation losses may be due toreduced fertility instead of a dominant lethal effect, as itis known that early deaths may be a consequence of alow number of implantations.

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Table 2: Genotoxicity of diglyme in v i t ro .

Result

Test system Strain/cell type Concentrations tested !!S9 +S9 Remarks Reference

Salmonella

mutagenicity test

strain TA1535, TA1537,

TA1538, TA98, TA100

0.3–100 µl per plate – – cytotoxicity at

100 µl per plate

McGregor et al.,

1983

Salmonella

mutagenicity test


TA100

20–70 µl per plate not tested – no cytotoxicity McGregor et al.,

1983

Salmonella

mutagenicity test


TA98, TA100

0.01–10 mg per plate – – tested with rat

and hamster S9,

no cytotoxicity

Mortelmans et

al., 1986

Salmonella

mutagenicity test


TA1538, TA98, TA100

0.005–50 µl per plate – – cytotoxicity at 25

and 50 µl per

plate

Hoechst,

1979d,e

Unscheduled DNA

synthesis

human embryo fibroblasts 0.148–19 mg/ml – – no information on

cytotoxicity

available

McGregor et al.,

1983

A recessive lethal test on Drosophila

melanogaster exposed to 250 ppm (1395 mg/m3) for 2.75

h could not be evaluated because of an unusually highdeath rate in a control group (McGregor et al., 1983).

8.7 Reproductive toxicity

8.7.1 Effects on fer t i l ity

8.7.1.1 Inhalation

There are several well conducted studies availablein which toxicity to the male reproductive organs has been invest igated .

Groups of 20 male Crl:CD rats were exposed to 0,

110, 370, or 1100 ppm (0, 614, 2065, or 6138 mg/m3)diglyme, 6 h/day, 5 days/week, for 2 weeks. Exposed ratswere killed after 10 days of exposure and 14, 42, or

84 days post-exposure. Body weight gain was dosedependently decreased. At 370 and 1100 ppm (2065 a nd6138 mg/m3), absolute weights of testes, epididymides,seminal vesicles, and prostrate were reduced; relativeweights of testes were reduced at 1100 ppm(6138 mg/m3). Stage-specific germ cell damage was doseand time dependent: at 110 ppm (614 mg/m3) diglyme,spermatocytes in pachytene and meiotic division atspermatogenic stages XII–XIV were mainly affected. At

370 ppm (2065 mg/m3) diglyme, affected germ cells weresimilar to those seen at 110 ppm (614 mg/m3) diglyme, butround spermatids at spermatogenic stages I–VIII were

also affected. At 1100 ppm (6138 mg/m3) diglyme, markedtesticular atrophy was found affecting all spermatogenicstages. The effects were reversible within 84 days with

110 and 370 ppm (614 and 2065 mg/m3), but not with 1100 ppm (6138 mg/m3) (DuPont, 1988b; Lee et al., 1989;Valentine et al., 1999).

In order to identify a NOAEL for effects on the

testes, a second study was performed with the samestudy design but using lower concentrations of diglyme — 0, 3, 10, 30, and 100 ppm (0, 16.7, 55.8, 167, and558 mg/m3) (measured concentrations: 0, 3.1, 9.9, 30, and98 ppm, corresponding to 0, 17.3, 55.2, 167, and 547mg/m3). The post-exposure period was 14 days. Mean body wei ghts of rats exposed to 100 ppm (558 mg/m3)were significantly lower than those of controls at the end

of the exposure period. The weights of testes, seminalvesicles, prostate, and epididymides were similar tothose of controls. Microscopic examination of the testesrevealed minimal or mild testicular atrophy in the 100

ppm (558 mg/m3

) group. As is demonstrated in Table 3,some effects, such as degenerative germ cells in epidid-ymal tubules, spermatic granuloma in the epididymis,and prostatitis, also occurred at lower concentrations(10 ppm [55.8 mg/m3] and higher) at the end of theexposure as well as after the 14-day recovery period.Most lesions were minimal to mild and occurred in 1/10animals. However, it is not clear whether the different

lesions observed occurred in the same or differe nt ani-mals. Taking into consideration results from historicalcontrols (no data given) as well, the authors of

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Table 3: Effects of diglyme on the male reproductive tract in rats.a

Effect dayb 0 ppm 3 ppm 10 ppm 30 ppm 100 ppm

Body weight gain (g)

day 1–12 63.4 58.1 57.4 57.1 51.2c

day 15–26 68.8 70.0 68.2 64.5 62.8

Number of animals affected, severity of lesion

Testicular atrophy

Sertoli cell only 12

26 1, minimal

Bilateral 12

26 1, minimal

Unilateral 12 1, minimal 1, minimal 1, minimal

26 1, mild

Epididymides

Degenerative germ

cells

12 1, minimal 1, minimal

26 1, minimal

Spermatic granuloma 12 1, minimal

26 1, moderate

Prostate

Prostatitis 12 1, moderate 1, minimal

26 1, mild 1, mild 2, minimal

1, mild

Seminal vesicles

Atrophy acini 12

26 1, minimal

a From DuPont (1989).b Day 12: end of exposure; day 26: after 14 days of recovery.c Statistically significant.

this study considered 30 ppm (167 mg/m3) to be the NOAEL (DuPont, 1989).

In a dominant lethal test, groups of 10 male adultCD rats were exposed to 0, 250, or 1000 ppm (0, 1395, or 5580 mg/m3) diglyme for 7 h/day on 5 consecutive days,then serially mated at weekly intervals for 10 weeks tountreated virgin females in the ratio 1 male:2 females.Male rats exposed to 1000 ppm (5580 mg/m3) showed areduction in body weight. The female rats were killed andexamined 17 days after they were first caged with themales. No effect on frequency of pregnancy was seen inthe 250 ppm (1395 mg/m3) group. However, large

reductions in pregnancy frequency occurred in the 1000 ppm (5580 mg/m3) exposure group in weeks 4 through 9,

but particularly in we eks 5 through 7 after exposure,when frequencies were only about 10%. Further, preimplantat ion losses in these weeks we re large, and

there was evidence of post-implantation losses.Recovery from the influence of diglyme in exposed maleswas complete in week 10 (McGregor et al., 1981, 1983;Hardin, 1983).

Changes in sperm shape were investigated in mice:groups of 10 B6C3F1 mice were exposed to 0, 250, or 1000 ppm (0, 1395, or 5580 mg/m3) 7 h/day for 4 days, andsperm were isolated 35 days after the exposure. Four mice of the 1000 ppm (5580 mg/m3) group were found

dead on the morning of the 4th exposure day. Mice of bo th ex posure grou ps showed a r ed uc tion in bo dy

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weight gain. While no changes compared with thecontrols were observed in the 250 ppm (1395 mg/m3)group, a significant increase in morphologically alteredsperm (32%; control 5%) was found in the 1000 ppm (5580

mg/m3

) group. All categories of abnormalities wereinvolved to some extent: hook upturned or hook elongated, banana-shaped head, amorphous head, foldedtail, and others. Most frequent were amorphous heads,which were increased to 20.87% in the 1000 ppm (5580mg/m3) group compared with 2.18% in the air control.From the timing of exposure and investigations, the

authors concluded that the spermatocyte s had beendamaged (McGregor et al., 1981, 1983).

In conclusion, from these studies, the NOAELfor effects on the testes/spermatocytes is 30 ppm(167 mg/m3).

8.7.1.2 Oral

Groups of five Sprague-Dawley rats received up

to 20 daily oral doses of distilled water or diglyme at684 mg/kg body weight. Testicular changes wereanalysed, including a subsequent recovery over an

8-week period. Primary and secondary spermatocytedegeneration and spermatidic giant cells were observedafter 6–8 treatments. From day 12 of treatment until8 weeks after cessation of exposure, the testes to bodyweight ratio was significantly reduced (Cheever et al.,

1985, 1986, 1988). Testicular LDH-X activity, a pachytenespermatocyte marker enzyme, was significantly decreasedin animals by day 18 of treatment (Cheever et al., 1985,1989b).

No changes compared with controls we re found intesticular weight and the combined weight of seminalvesicles and coagulating gland in four male JCL-ICR mice

that received diglyme in the drinking-water for 25 days ata level of 2% (approximately 7000 mg/kg body weight,assuming an uptake of 7 ml/day and a body weight of 20g) (Nagano et al., 1984).

8.7.2 Develop mental to xic ity

Studies on the developmental toxicity of diglyme,including experimental details, are summarized in Table 4.Diglyme was a developmental toxicant both via inhalationand by the oral route in rats, rabbits, and mice. It iscapable of disrupting normal morphoge nesis in a widevariety of tissues and organ systems, and the diversity of

fetal malformations observed was hypothesized to be dueto a general toxic effect upon proliferating cells, whichwas also evident from the studies on male fertility

(Nagano et al., 1984; Price et al., 1987; Schwetz et al.,1992).

8.7.2.1 Inhalation

In a teratogenicity study, rats exposed by inhala-tion to 25, 100, or 400 ppm (140, 558, or 2232 mg/m3)diglyme during days 7–16 of gestation, the highestconcentration of 400 ppm (2232 mg/m3) caused 100%resorptions (DuPont, 1988a; Driscoll et al., 1998).Malformations found in low incidences at all dosagesincluded abnormally formed tails, distended lateral

ventricles of the brain, axial skeletal malformations(vertebral fusions, hemivertebrae), and appendicular malformations (aberrant clavicular and scapular formation, bent fibula, radius, tibia, and ulna). Further,structural variations, primarily delayed ossification, werefound. The lowest dose of 25 ppm (140 mg/m3) caused aslightly increased incidence of variations. Althoughthese defects were not significantly different fromcontrol values (with the exception of the incidence of skeletal developmental variations), the pattern, type, andincidence of variations were similar to those seen at100 ppm (558 mg/m3), suggesting, according to the

authors, that 25 ppm (140 mg/m3) was an effect level thatapproaches the lower end of the developmental toxicityresponse curve. Therefore, the authors of the studyconcluded that a NOAEL could not clearly be demon-strated for the fetus. As increased relative live r weights

were found in the dams at 100 ppm (558 mg/m3), the NOAEL for diglyme exposure in the dams is 25 ppm (140mg/m3).

8.7.2.2 Oral

In an oral application study with rabbits, similar

effects were noted as after inhalation (NTP, 1987;

Schwetz et al., 1992). The number of resorptions as wellas the number of malformations were increased at dosesof $100 mg/kg body weight. Abnormal development of the kidneys and axial skeleton and clubbing of the limbs

without underlying skeletal involvement were the mostfrequently presented individual defects. At 50 mg/kg body weight , percentages of prenatal mortal ity andmalformed fetuses per litter were both (statistically non-significantly) increased but accounted for a significantoverall increase in the percentage of adversely affectedimplants per litter. In the NTP (1987) study as well as inthe analysis by Kimmel (1996), 50 mg/kg body weight isconsidered as the lowest-observed-adverse-effect level

(LOAEL), and 25 mg/kg body weight as the NOAEL. Incontrast, in the subsequent publication by Schwetz et al.(1992), the authors discussed that 50 mg/kg body weight

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Table 4: Developmental toxicity of diglyme.

Species/strain/number per group Exposurea

Concentration/dose Effectsb

MaternalNOAEL/LOAEL

FetalNOAEL/LOAEL Reference

ratsCD25–26

inhalation, 6h/day, days 7–16

0, 25, 100, 400ppm (0, 140,558, 2232mg/m3)

$$25 ppm (140 mg/m3): fetal weights 9, variations (delayed ossification,rudimentary ribs) (mean percentage of fetuses per litter with variations):44.5% versus controls 32.1%100 ppm (558 mg/m3): dams: relative liver weight 8, fetus: structuralmalformations, mainly skeletal (abnormally formed tails, distendedlateral brain ventricles, axial skeletal malformations, appendicular malformations [bent limbs], 6.2% compared with 1.7% in controls); fetalweight 9; variations (mean percentage of fetuses per litter withvariations): 74.5% versus controls 32.1%400 ppm (2232 mg/m3): dams: food consumption 9, body weight gain 9;resorptions 100%

NOAEL25 ppm(140 mg/m3)

LOAEL25 ppm(140 mg/m3)

DuPont (1988a),Driscoll et al. (1998)

rabbitsNew Zealand15–25

gavage in distilledwater, days 6–19

0, 25, 50, 100,175 mg/kg bodyweight

$$50 mg/kg body weight: dams: weight gain 9 (due to decrease in graviduterine weight),adversely affected implants per litter 8 (21.4%, controls 7.9%)$$100 mg/kg body weight: gravid uterine weight 9, prenatal mortality(mainly from resorptions) 8, malformations 8 (mainly abnormaldevelopment of the kidneys and axial skeleton and clubbing of thelimbs)175 mg/kg body weight: dams: faecal output 9, mortality 8 (15%,

controls 4%)

NOAEL100 mg/kg body weight


NTP (1987)



Schwetz et al.(1992)

miceCD-120–24


0, 62.5, 125,250, 500 mg/kgbody weight

$$125 mg/kg body weight: fetal weights 9

$$250 mg/kg body weight: dams: weight gain 9 (due to decrease ingravid uterine weight); late fetal deaths 8, malformations 8 (mainlyneural tube, limbs and digits, craniofacial structures, abdominal wall,cardiovascular system, urogenital organs, axial and appendicular skeleton)500 mg/kg body weight: dams: weight gain (due to decrease in gravid

uterine weight) 9; resorptions 8


NOAEL62.5 mg/kg bodyweight

NTP (1985), Price etal. (1987)

miceCD-1not given

gavage in distilledwater, on day 11

0, 537 mg/kgbody weight

only examination for gross external malformations and fetal body weight537 mg/kg body weight: malformations 8 (paws, digits)

Hardin &Eisenmann (1986,1987)

miceCD-149


0, 3000 mg/kgbody weight

reproductive screening according to Chernoff and Kavlock, no systematicexamination for malformations3000 mg/kg body weight: dams: mortality 8 (20/49); no viable litters

(0/27)

Schuler et al.(1984), Plasterer etal. (1985), Hardin et

al. (1987)

a Days refers to days of pregnancy.b 8 = increased compared with controls; 9 = decreased compared with controls.

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appears to be the bottom end of the dose–response curveand therefore considered 50 mg/kg body weight as the NOAEL.

In mice, the NOAELs were 500 mg/kg body weightfor maternal effects and 62.5 mg/kg body weight for developmental effects. At 125 mg/kg body weight, theonly fetal effects were reduced body weights. Malfor-mations were seen at 250 mg/kg body weight and above.Characteristic malformations associated with diglymewere neural tube closure defects and dysmorphogenesis

of the axial and appendicular skeleton (NTP, 1985; Price etal., 1987). Further defects of digits a nd paws were found,which also occurred in another study with mice (Hardin &Eisenmann, 1986, 1987) dosed with 537 mg/kg bodyweight only on day 11 of pregnancy.

The NTP study in mice (NTP, 1985; Price et al.,1987) has served to illustrate a model that was developedfor assessing the probability of being abnormal byapplying the combination of the parameters fetal death,weight, and malformation (Catalano et al., 1993). TheLED05 (the lower 95% confidence limit of the dosecorresponding to 5% excess risk), which was derived

according to the benchmark dose approach, was 99 mg/kg body weight. This was lowe r than the LED 05 for theindividual parameters, but higher than the NOAEL of 62.5mg/kg body weight.

8.8 Other toxicity/mode of action

The main metabolite of diglyme, 2-methoxyethoxy-

acetic acid, did not show any effect on the testes atequimolar concentrations (Cheever et al., 1986, 1988).Instead, the pattern of diglyme-induced testicular injury isqualitatively similar to that produced by the metabolite 2-

methoxyethanol (McGregor et al., 1981, 1983; Cheever etal., 1985, 1986, 1988; Lee et al., 1989). In the study of Cheever et al. (1985) with rats, both compounds exhibitedtesticular toxicity primarily affecting pachytene anddividing stages of spermatocytes at lower exposure

levels. In comparing the testicular toxicity of equimolar dosages of 2-methoxyethanol (388 mg/kg body weight)and diglyme (684 mg/kg body weight), 2-methoxyethanolwas more potent than diglyme. Spermatocytes wereaffected after only one treatment with 2-methoxyethanol,whereas repeated diglyme treatments were required to produce the same ef fec ts. Simila rly , in the inhalationstudy of Lee et al. (1989) with rats, the toxic effects of 300

ppm (930 mg/m3) 2-methoxyethanol in the testes werevery similar to but more severe than those of 370 ppm(2065 mg/m3) diglyme. In mice, both compounds producedsperm anomalies (McGregor et al., 1981, 1983). A diglyme

concentration of 1000 ppm (5580 mg/m3) caused a higher number of abnormal sperm than 500 ppm (1550 mg/m3) 2-methoxyethanol; thus, considering equimolar concentrations, diglyme seems to be somewhat more

toxic. Mice produce higher concentrations of 2-methoxyacetic acid than rats; therefore, mice may bemore susceptible than rats to the toxic effects of diglyme.Considering that 2-methoxyethanol is only a minor metabolite of diglyme, other metabolites or other pharmacokinetic behaviours o f diglyme compa red with 2-methoxyethanol may contribute to the toxicity of

diglyme.

In both fertility and developmental studies, themetabolite 2-methoxyethanol (DuPont, 1988a; Driscoll etal., 1998) and other ethylene glycol dimethyl ethers(Plasterer et al., 1985; Hardin & Eisenmann, 1986, 1987;Hardin et al., 1987) gave similar results. In the DuPontstudy (DuPont, 1988a; Driscoll et al., 1998), both 25 ppm(78 mg/m3) 2-methoxyethanol and 25 ppm (140 mg/m3)diglyme resulted in significantly more total variationsand variations due to retarded development in rats.Mean percentages of fetuses per litter with variationswere 46% for 2-methoxyethanol and 45% for diglyme

compared with 32% in the control. Similarly, in thestudies of Hardin et al. (Hardin & Eisenmann, 1986, 1987;Hardin et al., 1987), the teratogenic potency for pawdefects in mice was higher with 2-methoxyethanol thanwith diglyme when used in equimolar concentrations.

After treatment with 304 mg 2-methoxyethanol/kg bodyweight, 60.1% of the fetuses had alteration s in the hind paws, compared with 38% afte r treatment with 537 mgdiglyme/kg body weight and 0.6 or 0% in concurrentcontrols. Further, monoethylene glycol dimethyl ether showed a similar toxicity in this study, with 30.4% of thefetuses with alterations of the hind paws, while trieth-

ylene glycol dimethyl ether did not show any effect.Finally, the study of Plasterer et al. (1985) with miceshowed that very high doses of monoethylene glycoldimethyl ether, diglyme, and triethylene glycol dimethylether all caused complete resorptions.

Thymus atrophy has been reported in rats in twoinhalation studies (Gage, 1970; DuPont, 1988b; Lee et al.,1989; Valentine et al., 1999) following exposure to highconcentrations of diglyme. Further, the number of leukocytes was decreased. This is consistent withstudies on other EGEs, where mechanistic studiesindicate that the immune system is a sensitive target for

toxicity in the rat and that the proximate immunotoxicantis methoxyacetic acid (ECETOC, 1995).

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The metabolite 2-methoxyacetic acid, which is

generated from 2-methoxyethanol by the action of alcoholdehydrogenase, may be important for the toxic effects. Itcan undergo activation to methoxyacetyl coenzyme A

and enter the Krebs cycle or fatty acid biosynthesis.Several metabolites of 2-methoxyethanol — for example,2-methoxy- N -acetyl glycine — have been identified thatsupport this pathway (Sumner et al., 1992; Jenkins-Sumner et al., 1996). Thus, 2-methoxyacetic acid mayinterfere with essential metabolic pathways of the cell,and it was hypothetized that this c auses the testicular

lesions and malformations. This is supported by thefinding that simple physiological compounds (e.g., serine,formate, acetate, glycine, and glucose) are able to protectagainst these effects (Johanson, 2000).

9. EFFECTS ON HUMANS

As a consequence of the results of the animalstudies revealing effects on fertility as well as develop-mental toxicity of EGEs, several epidemiological studieshave been carried out to investigate reproductive end-

points in workers with exposure to EGEs. Diglyme is onlyone compound of this substance class, however (see section 2). A metabolite of EGEs and diglyme, 2-methoxyethanol, is also used as a solvent, and one

epidemiological study of painters exposed to 2-methoxy-ethanol is also discussed.

9.1 Reproductive effects

EGEs including diglyme are used in the manufacture

of semiconductors. Epidemiological studies of threesemiconductor populations evaluated potential adverse

reproductive outcomes. It is unclear from the descriptions prov ided by the a ut hors whet he r the se popu la tionsoverlapped. In each of these studies, workers wereexposed to mixtures including diglyme but not to diglyme

alone. In a single study of painters, exposure includ ed ametabolite of diglyme and EGEs.

One of the semiconductor populations includedworkers from 14 different companies. The study included bo th re tr ospe ct iv e a nd pr ospe ct iv e s tu dy de sign s.Exposure to EGEs was determined using questionnairesfrom subjects about the work performed and anassessment of the work environment by industrial

hygienists, but no measurements of personal or areaexposures were made (Hammond et al., 1995). Workers inthe fabrication area were considered exposed to EGEs. For

the retrospective study, information on pregnancyoutcomes and potential confounders (age, smoking,ethnicity, education, income, year of pregnancy, andstress) was obtained through a comprehensive inter-

viewer-administered interview of female employees(Beaumont et al., 1995). The prospective study of earlyfetal loss and fecundity (probability of conception per menstrual cycle) was conducte d in a subset of femaleemployees from five plants. Daily diaries and measure-ments of daily urinary human chorionic gonadotrophin(hCG) levels for 6 months were collected in addition to

the comprehensive interview (Eskanazi et al., 1995a,b). Of the 891 medically verified pregnancies identified for theretrospective study, 774 (86.9%) were live births, 113(12.7%) were spontaneous abortions, and 4 (0.4%) werestillbirths (Beaumont et al., 1995). The overall unadjustedrelative risk (RR) for spontaneous abortions was 1.45(95% confidence interval [CI] = 1.02–2.05) and changedlittle after adjusting for confounders (adjusted RR =1.43;95% CI = 0.95–2.09). When stratified by work group, therisk of spontaneous abortion was statisticallysignificantly increased for female workers in the photolithography group (RR = 1.67; 95% CI = 1.04–2.55)and in the etching group (RR = 2.08; 95% CI = 1.27–3.19).

For women working with higher levels of EGE only inmasking, the risk for spontaneous aborti on wasincreased 3-fold (RR = 3.38; 95% CI = 1.61–5.73) (Swan &Forest, 1996). In the prospective study, no statisticallysignificant differences were detected in the overall rate of

spontaneous abortions between fabrication and non-fabrication workers or when pregnancy outcomes wereexamined by work group (Eskenazi et al., 1995a).However, the ability to conceive was lower amo ngfemale workers exposed to EGEs (fertility rate [FR] = 0.37;95% CI = 0.11–1.19) (Eskenazi et al., 1995b).

Correa et al. (1996) conducted a retrospectiveevaluation of reproductive outcomes among bothwomen employed and wives of men employed at twosemiconductor plants in the eastern USA (also reported by Gray et al ., 1996). Gray et al . (1996) also reported on

the results of a prospective study of reproductiveoutcomes at the same pla nts. Exposure to EGEs in theretrospective study was assessed by questionnaireadministered to the employees in combination withcompany records. There were 115 pregnancies tosemiconductor manufacturing workers — 561 to femaleemployees and 589 to wives of male e mployees. Therewas a significantly elevated risk of spontaneous

abortion (odds ratio [OR] = 2.8; 95% CI = 1.4–5.6) andsubfertility (taking more than 1 year of sexual intercourseto conceive) (OR = 4.6; 95% CI = 1.6–13.3) among femaleemployees in the highest exposure group. The risks of

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spontaneous abortion and subfertility were notsignificantly elevated in the low and medium exposuregroups. A significant ( P = 0.02) dose–responserelationship across low, medium, and high exposure

categories was found for both end-points for EGEexposure. Among wives of male employees exposed toEGEs, there was no evidence of an increased risk of spontaneous abortion but a suggestion of an increasedrisk of subfertility. In the prospective study (Gray et al.1996), early-morning urine samples were assayed for hCGand ovarian steroid hormones to detect early pregnancy

and early pregnancy loss. The study found no evidenceof a decreased conception rate, but there was a non-significantly elevated risk of pregnancy loss.

Pastides et al. (1988) found an increased risk of spontaneous abortion among females employed in thediffusion area of a semiconductor manufacturing plant(RR = 2.2; n = 18 pregnancies; 95% CI = 1.1–3.6) and inthe photolithographic area (RR = 1.8; n = 16 pregnancies;95% CI = 0.8–3.3) compared with unexposed controls (n= 398 pregnancies). No measurements of workplaceexposure were available in this study. Exposuresincluded several glycol ethers and other chemicals, such

as arsine, phosphine, diborane, xylene, toluene, andhexamethyldisilane.

Semen samples from 73 painters and 40 controls

from a shipyard were analysed (Welch et al., 1988).

The painters were exposed by inhalation to 0–17.7 mg2-methoxyethanol/m3 (mean 2.6 mg/m3) and to 0–80.5 mg2-ethoxyethanol (= ethylene glycol monoethyl ether)/m3

(mean 9.9 mg/m3). Skin contact with 2-methoxyethanoland 2-ethoxyethanol was also considered possible.Exposure to numerous other substances, includingorganic solvents and metals, was also known to occur.

While no effects were seen in hormone levels or in spermviability, motility, and morphology, the prevalence of those with oligospermia differed between the groups.The proportion of men with a sperm density#100million/cm3 was higher in the exposed group than in the

unexposed group (33% vs. 20%; P = 0.20). The proportion of those with oligospermia among painterswho did not smoke compared with controls was 36% vs.16% ( P = 0.05). The proportion of those witholigospermia was similar between painters and controlswho smoked (30% vs. 38%; P = 0.49). The proportion of painters with azoospermia was 5% compared with 0% inthe controls.

9.2 Haematological effects

The relationship between exposure to EGEs and

haematological effects has been evaluated in threeoccupational populations. In none of these studies was

diglyme measured or used alone. In a cross-sectionalstudy of 94 shipyard painters exposed to measurablelevels of 2-ethoxyethanol and 2-methoxyethanol and55 unexposed controls, Welch & Cullen (1988) found

10% of painters with haemoglobin levels consistent withanaemia ( P = 0.02) and 3.4% of painters and no controlswith abnormally low levels of polymorphonuclear leukocytes ( P = 0.07). In a second cross-sectional studyof 40 workers employed in the production of ethyleneglycol monoether, the overall proportion of exposedworkers with abnormal haemoglobin levels or white

blood cell counts did not differ from unexposed controls(n = 25) (Cook et al., 1982). Controlling for potential age,duration, and intensity of exposure using logisticregression suggested a statistically significant decrease(27%) in white blood cell counts. A small study of nineindividuals who laid parquet floors and matched pairs of healthy donors showed no changes in haemoglobin or erythrocyte levels but higher frequencies of NK-cells(anti-Leu7) and B lymphocytes (Denkhaus et al., 1986).Exposures included measurable concentrations of 2- butoxyethanol, 2-ethoxyethanol, 2-methoxyethanol,toluene, xylene, 2-butanone, and other solvents. Noassociation was found between use of products contain-

ing glycol ethers and myeloid acute leukaemia in a studyof 198 matched pairs (Hours et al., 1996).

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

For the toxicity data mentioned in this section, it is

not always stated whether the cited effect values are based on nominal or measured concentrations of

diglyme. In some cases (Hoechst, 1994, 1995), theconcentration of the test substance is detected by thedetermination of dissolved organic carbon or carbon in

the solution. However, due to the water solubility, lowvolatility, and low adsorption potential of diglyme (seesections 2 and 5), all nominal concentrations of the testsubstance are expected to correspond to effectiveconcentrations, even in tests with open systems andlonger exposure periods.

The acute toxicity of diglyme to golden orfes( Leuciscus idus) was determined in a static test, whichgave a 96-h LC0 of $2000 mg/litre.1 An acute toxicity test

1

Hoechst (1979) Abwasserbiologische Untersuchung vonDialkylglykoläthern auf die Goldorfe ( Leuciscus idus).

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with Daphnia magna conducted according to OECDGuideline 202 resulted in no adverse effects at the twotested concentrations of 100 and 1000 mg/litre (48-h EC0

$1000 mg/litre) (Hoechst, 1994). Also, in a test concern-

ing the toxicity of diglyme to algae (Scenedesmus subspicatus), conducted according to OECD Guideline 201,the 72-h EC10 was $1000 mg/litre (highest concentrationtested) (Hoechst, 1995).

The LC50 values for the acute effect of diglyme on

tadpoles of the frog species Rana brevipoda were

between 22 000 and 8300 mg/litre (test periods between 3and 48 h) (Nishiuchi, 1984).

In an activated sludge respiration inhibition testconducted according to EC Guideline 88/302 Part C(OECD Guideline 209), an EC

10 of >1000 mg/litre was

determined (Hoechst, 1989b).

Only acute toxic effects have been examined in thetests above. One should be aware of possible effects of diglyme on reproduction, as observed in tests withmammals (see sections 8.7 and 9.1).

10.2 Terrestrial environment

A study of the effect of diglyme on the spore

germination rate and the mycelial growth rate of theterrestrial fungus Cladosporium resinae (strain 35A)

isolated from Australian soil samples gave a toxicthreshold concentration of 9430 mg/litre (1% v/v) anda concentration for complete inhibition of the mycelialgrowth of 188 600 mg/litre (Lee & Wong, 1979).

In a screening test on fumigating agents against

oriental and Mediterranean fruit flies ( Dacus dorsalis

and Ceratitis capitata), a 48-h LD50 of >98 mg/m3 wasdetermined for 24-h-old shell-less eggs and mature larvaeof each species after a 2-h fumigation (Burditt et al.,1963).

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazar d id en ti fi cat io n and

expos ure–respon se assessment

Diglyme is rapidly absorbed from the gastrointes-

tinal tract, metabolized, and excreted mainly in the urine.In analogy to other EGEs, it is assumed that diglyme isreadily absorbed through the skin. The main metaboliteis 2-methoxyethoxyacetic acid. The reproductive toxicity

of diglyme, however, is attributed to the minor metabolite2-methoxyacetic acid, which is generated from 2-methoxyethanol. There are species differences in theamount metabolized to this metabolite: mice and humansmay produce higher amounts and thus be more suscep-tible than rats.

The acute toxicity of diglyme is low after oralexposure or inhalation. Diglyme is slightly irritating tothe skin or eye. No investigations are available on thesensitizing effects of diglyme.

Several Ames tests as well as an unscheduled

DNA synthesis test did not reveal a genotoxic potentialof diglyme in vitro. Further, the number of chromosomalaberrations was not increased in bone marrow cells in

vivo. The positive results of a dominant lethal test may be due to the effects of diglyme on fertility.

The main targets of the toxicity of diglyme are the

reproductive organs in male animals. Dose-dependentchanges have been shown for weights of testes,epididymides, prostate, and seminal vesicles.Microscopic evaluation revealed atrophy of the testes,with developing spermatocytes being the cells mainly

affected. Effects were found in rats and mice in severalexperiments after inhalation and oral exposure. Theeffects were reversible at lower concentrations; at

concentrations of about 1100 ppm (6138 mg/m3

), theeffects persisted in the investigated time period of 84days. The NOAEL for reproductive effects in rats was 30 ppm (167 mg/m3). In a dominant lethal test, it was shownthat the morphological alterations in the testes were alsoassociated with decreased fertility in the 1000 ppm(5580 mg/m3) group but not in the 250 ppm (1395 mg/m3)group. No long-term studies are available for diglyme.

Diglyme is a strong teratogen. Developmental

effects occur at low concentrations without maternaltoxicity. Effects on fetal weights, an increased number of resorptions, and an increased incidence of variations/malformations in a wide variety of tissues and organFrankfurt am Main, Hoechst AG, 2 pp. (unpublished test

results).

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systems have been found. A LOAEL of 25 ppm(140 mg/m3) has been identified in rats for the inhalationroute, and a NOAEL of 25 mg/kg body weight has beenidentified in rabbits for the oral route. Maternal toxicity

indicated by reduced weight gain was rather low. Therelevance of these findings for humans is shown by thefact that they are found in three different species — rats,rabbits, and mice — and also by different routes of exposure (inhalation and oral).

The risk for spontaneous abortion was evaluated

in two large epidemiological studies of female workers inthe semiconductor industry with exposure to EGEsincluding diglyme. One of these studies also examinedthe risk to wives of male employees with EGE exposure.The studies found an association of the risk of sponta-neous abortion with occupational exposure to EGEs. Oneof these studies found evidence of a dose–responserelationship. The risk of spontaneous abortion fromexposure to diglyme alone could not be evaluated.

The effect of EGEs on conception rates in exposedfemale workers is not clear. The conception rate wasassessed in two prospective studies. One study found

slightly decreased rates; no effects were observed in theother.

Painters exposed to the solvent 2-methoxyethanol,

which is also a metabolite of diglyme, were found to

have an increased prevalence of oligospermia andazoospermia. The painters were also exposed to numer-ous other substances, including organic solvents andmetals, however.

11.1.2 Cr it er ia f or s et ti ng t o ler ab le i nt ak es /

concentrat ions or guidance values for

dig lyme

A guidance value for uptake of diglyme via

inhalation according to EHC 170 (IPCS, 1994) can be based on the developmental toxicity study in rats

(DuPont, 1988a; Driscoll et al., 1998), which gave aLOAEL of 25 ppm (140 mg/m3). As the LOAEL of 25 ppm(140 mg/m3) is, according to the authors, at the bottomend of the dose–response curve, a safety factor of 2seems to be sufficient to extrapolate to a NOAEL.Applying further a safety factor of 10 for interindividualvariability and 10 for interspecies variation, a guidancevalue of about 0.1 ppm (0.6 mg/m3) would be obtained.

For the oral route, no NOAEL from a reliablerepeated-dose toxicity study is available. If one assumes,however, that, as in inhalation studies, developmentaltoxicity is the most relevant end-point, one could use the

study with rabbits, which gave a NOAEL of 25 mg/kg

body weight. Applying safety factors of 10 for inter-individual variability and 10 for interspecies variation, aguidance value of 0.25 mg/kg body weight would beobtained.

11.1.3 Samp le r is k c har ac ter izat io n

Assuming that exposure concentrations for diglyme are the same as for other EGEs, the TWA for exposure in the production process may be up to 36mg/m3, in the semiconductor industry up to 3 mg/m3, andin painting operations up to 31 mg/m3. These

concentrations are considerably higher than theguidance value for the general population of 0.6 mg/m3,derived above. In addition, high dermal uptake of diglyme has to be taken into consideration. It has to berecognized, furthermore, that protective gloves mayallow significant permeation of diglyme. Gloves made of nitrile and butyl rubber or neoprene provide the best protection.

In conclusion, from the sample risk characterization

for the workplace, there is high concern for possiblehuman health effects. No information is available on the

presence or concentrations of diglyme in cosmetics; because of its reprotoxic potency, all exposure of thegeneral public to diglyme should be avoided.

11.1.4 Uncertaint ies in the evaluat ion of h um an

heal th effects

There is a high degree of confidence that thereproductive system is the target of the toxicity of diglyme. This is concluded from consistent results fromexperiments in several animal species with differentroutes of application. Epidemiological studies indicate arisk for humans as well.

No long-term animal studies have been conducted

with diglyme. Therefore, not all end-points could bereliably assessed, and there is some uncertainty con-

cerning the NOAELs derived from short-term studies.

No data are available for the possible use of

diglyme in cosmetics, which may be an important sourceof consumer exposure.

11.2 Evaluation of environmental effects

Diglyme releases into the environment are to be

expected from its use as a solvent, reaction medium, andseparating agent in industrial processes. A minor con-tribution from diglyme-containing consumer products(cosmetics, water-based paints) is possible but cannot

be quantified with the available data.

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The main target compartment of diglyme is the

hydrosphere. The chemical is inherently biodegradablewith a rather long log phase and significant adsorptionto activated sludge. Bioaccumulation and

geoaccumulation are of minor importance.

In the available experimental studies, diglyme

exhibited a low toxicity to aquatic organisms. The 48-hEC0 value for daphnia and the 72-h EC10 value for algaewere both reported to be $1000 mg/litre. It is not to beexpected that the given EC0/EC10 concentrations will be

exceeded in surface waters, where monitoring measure-ments in the early 1980s gave diglyme concentrations of #0.005 mg/litre. Therefore, the available data do notindicate a significant risk of diglyme to aquatic organ-isms.

Due to the lack of measured exposure levels, asample risk characterization with respect to terrestrialorganisms cannot be performed. However, from the use pattern of diglyme, significant exposure of terrestrialorganisms is not to be expected.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

Previous evaluations by international bodies were

not identified.

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(DHHS (NIOSH) Publication No. 90-118;

http://www.cdc.gov/niosh/90-118.html).

NIOSH (1991) Criteria for a recommended standard:

occupational exposure to ethylene glycol monomethyl ether,

ethylene glycol monoethyl ether, and their acetates. Appendix

A. Methods for sampling and analysis of EGME, EGEE, EGMEA,

and EGEEA in air . Cincinnati, OH, National Institute for

Occupational Safety and Health (DHHS (NIOSH) Publication No.

91-119).

NIOSH (1996) Volatile organic compounds (screening) Method

2549. In: NIOSH manual of analytical methods, 4th ed.

Cincinnati, OH, National Institute for Occupational Safety and

Health, 8 pp. (http://ehs.clemson.edu/niosh/pdfs/2549.pdf).

Nishiuchi Y (1984) Toxicity of agrochemicals to freshwater

organisms. III. Solvents. Suisan Zoshoku, 32:115–119.

NTP (1985) Teratologic evaluation of diethylene glycol dimethyl

ether (CAS No. 111-96-6) administered to CD-1 mice on

gestational day 6 through 15. Research Triangle Park, NC,

National Institute of Environmental Health Sciences, National

Toxicology Program (NTP-85-255; PB86-135233).

NTP (1987) Teratologic evaluation of diethylene glycol dimethyl

ether (CAS No. 111-96-6) administered to New Zealand White

rabbits on gestation days 6 through 19. Research Triangle Park,

NC, National Institute of Environmental Health Sciences,

National Toxicology Program (NTP-87-108; PB 87-209532).

OECD (1997) The 1997 OECD list of high production volume

chemicals. Paris, Organisation for Economic Co-operation and

Development.

Ogata Y, Tomizawa K, Fujii K (1978a) Photo-induced oxidation

of diethylene glycol dimethyl ether and analogues with aqueous

hydrogen peroxide. Bulletin of the Chemical Society of Japan,

51:2628–2633.

Ogata Y, Takagi K, Suzuki T (1978b) Photolytic oxidation of

ethylene glycol dimethyl ether and related compounds byaqueous hypochlorite. Journal of the Chemical Society — Perkin

Transactions II , 2:562–567.

Pastides H, Calabrese EJ, Hosmer DW, Harris DR Jr (1988)

Spontaneous abortion and general illness symptoms among

semiconductor manufacturers. Journal of occupational medicine,

30:543–551.

Paustenbach DJ (1988) Assessment of the developmental risks

resulting from occupational exposure to selected glycol ethers

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environmental health, 23:29–75.

Plasterer MR, Bradshaw WS, Booth GM, Carter MW, Schuler RL,

Hardin BD (1985) Developmental toxicity of nine selected com-pounds following prenatal exposure in the mouse: naphthalene,

p-nitrophenol, sodium selenite, dimethyl phthalate,

ethylenethiourea, and four glycol ether derivatives. Journal of

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Plieninger P, Marchl D (1999) Occurrence of ester and ether

derivatives of polyvalent alcohols in indoor air of 200 Berlinhouseholds. In: Indoor Air ’99, Proceedings of the 8th

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Fundamental and applied toxicology , 8:115–126.

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diglyme by rat hepatocytes and human microsomes.

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14:509–526.

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APPENDIX 1 — SOURCE DOCUMENTS

BUA (1993a) Diethylene glycol dimethyl ether

(bis(2-methoxyethyl)-ether). GDCh AdvisoryCommittee on Existing Chemicals of Environ-mental Relevance (BUA). Stuttgart, Hirzel, pp.1–64 (BUA Report 67)

For the BUA review process, the company that is in charge

of writing the report (usually the largest producer in Germany)

prepares a draft report using literature from an extensive

literature search as well as internal company studies. This draft is

subject to a peer review in several readings of a working group

consisting of representatives from government agencies, the

scientific community, and industry.

The original German version of this report was published

in 1991.

Greim H, ed. (1994) Diethylene glycol dimethylether. In: Occup ational toxicants . Critical data

evaluat ion for MAK values and classi f icat ion of

carcinogens . Weinheim, Wiley-VCH, pp. 41–50

The scientific documentations of the German Commission

for the Investigation of Health Hazards of Chemical Compounds

in the Work Area (MAK) are based on critical evaluations of the

available toxicological and occupational medical data from

extensive literature searches and of well documented industrial

data. The evaluation documents involve a critical examination

of the quality of the database indicating inadequacy or doubtfulvalidity of data and identification of data gaps. This critical

evaluation and the classification of substances are the result of

an extensive discussion process by the members of the

Commission proceeding from a draft documentation prepared by

members of the Commission, by ad hoc experts, or by the

Scientific Secretariat of the Commission. Scientific expertise is

guaranteed by the members of the Commission, consisting of

experts from the scientific community, industry, and employers

associations.

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on diglyme was sent for review to institu-

tions and organizations identified by IPCS after contact withIPCS national contact points and Participating Institutions, as

well as to identified experts. Comments were received from:

M. Baril, International Programme on Chemical Safety/

Institut de Recherche en Santé et en Sécurité du Travail

du Québec, Canada

R. Benson, Drinking Water Program, US Environmental

Protection Agency, USA

R. Cary, Health and Safety Executive, United Kingdom

R. Chhabra, National Institute of Environmental Health

Sciences, National Institutes of Health, USA

J. Gift, National Center for Environmental Assessment, US

Environmental Protection Agency, USA

R. Hertel, Federal Institute for Health Protection of

Consumers and Veterinary Medicine, Germany

C. Hiremath, National Center for Environmental

Assessment, US Environmental Protection Agency, USA

P. Howden, Health and Safety Executive, United

Kingdom

G. Johanson, National Institute for Working Life, Sweden

S. Kristensen, National Industrial Chemicals Notification

and Assessment Scheme, Australia

J. Montelius, National Institute for Working Life, Sweden

H. Savolainen, Ministry of Social Affairs and Health,

Finland

K. Ziegler-Skylakakis, Commission of the European

Communities/European Union, Luxembourg

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APPENDIX 3 — CICAD FINAL REVIEWBOARD

Geneva, Switzerland, 8–12 January 2001

Members

Dr A.E. Ahmed, Molecular Toxicology Laboratory, Department

of Pathology, University of Texas Medical Branch, Galveston,

TX, USA

Mr R. Cary, Health and Safety Executive, Merseyside, United

Kingdom (Chairperson)

Dr R.S. Chhabra, General Toxicology Group, National Institute

of Environmental Health Sciences, National Institutes of Health,

Research Triangle Park, NC, USA

Dr S. Czerczak, Department of Scientific Information, Nofer Institute of Occupational Medicine, Lodz, Poland

Dr S. Dobson, Centre for Ecology and Hydrology,

Cambridgeshire, United Kingdom

Dr O.M. Faroon, Division of Toxicology, Agency for Toxic

Substances and Disease Registry, Atlanta, GA, USA

Dr H. Gibb, National Center for Environmental Assessment, US

Environmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection of

Consumers and Veterinary Medicine, Berlin, Germany

Dr A. Hirose, Division of Risk Assessment, National Institute of Health Sciences, Tokyo, Japan

Dr P.D. Howe, Centre for Ecology and Hydrology,

Cambridgeshire, United Kingdom (Rapporteur )

Dr D. Lison, Industrial Toxicology and Occupational Medicine

Unit, Université Catholique de Louvain, Brussels, Belgium

Dr R. Liteplo, Existing Substances Division, Bureau of Chemical

Hazards, Health Canada, Ottawa, Ontario, Canada

Dr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer

Institute of Toxicology and Aerosol Research, Hanover, Germany

Ms M.E. Meek, Existing Substances Division, Safe EnvironmentsProgram, Health Canada, Ottawa, Ontario, Canada (Vice-

Chairperson)

Dr S. Osterman-Golkar, Department of Molecular Genome

Research, Stockholm University, Stockholm, Sweden

Dr J. Sekizawa, Division of Chem-Bio Informatics, National

Institute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty of

Agriculture, Alexandria Univers ity, El-Shatby, Alexandr ia, Egypt

Dr M. Sweeney, Education and Information Division, National

Institute for Occupational Safety and Health, Cincinnati, OH,

USA

Professor M. van den Berg, Environmental Sciences and

Toxicology, Institute for Risk Assessment Sciences, University of

Utrecht, Utrecht, The Netherlands

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Observers

Dr W.F. ten Berge, DSM Corporate Safety and Environment,

Heerlen, The Netherlands

Dr K. Ziegler-Skylakakis, Commission of the EuropeanCommunities, Luxembourg

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, World

Health Organization, Geneva, Switzerland

Dr Y. Hayashi, International Programme on Chemical Safety,

World Health Organization, Geneva, Switzerland

Dr P.G. Jenkins, International Programme on Chemical Safety,

World Health Organization, Geneva, Switzerland

Dr M. Younes, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

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Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 2000

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

DIETHYLENE GLYCOL DIMETHYL ETHER 1357October 2000

CAS No: 111-96-6RTECS No: KN3339000UN No: 1993

Bis(2-methoxyethyl) etherDiglyme1,1'-Oxybis(2-methoxyethane)Dimethyl carbitolC6H14O3 / (CH3OCH2CH2)2OMolecular mass: 134.2

TYPES OFHAZARD/

EXPOSUREACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Flammable. NO open flames, NO sparks, andNO smoking.

Powder, water spray, foam, carbondioxide.

EXPLOSION Above 51°C explosive vapour/airmixtures may be formed.

Above 51°C use a closed system,ventilation.

In case of fire: keep drums, etc.,cool by spraying with water.

EXPOSURE AVOID EXPOSURE OF(PREGNANT) WOMEN!

Inhalation Cough. Shortness of breath. Venti lat ion, local exhaust, or

breathing protection.

Fresh air, rest.

Skin MAY BE ABSORBED! Redness. Protective gloves. Protectiveclothing.

Remove contaminated clothes.Rinse skin with plenty of water orshower.

Eyes Redness. Pain. Safety spectacles. First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Burning sensation. Do not eat, drink, or smoke duringwork.

Rinse mouth.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Ventilation. Collect leaking liquid in sealablecontainers. Absorb remaining liquid in sand or inertabsorbent and remove to safe place. (Extrapersonal protection: filter respirator for organicgases and vapours).

UN Hazard Class: 3UN Pack Group: III

EMERGENCY RESPONSE STORAGE

NFPA Code: H1; F2; R1 Fireproof. Separated from strong oxidants, strong bases, and strong acids.

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Boiling point: 162°CMelting point: -68°C

Relative density (water = 1): 0.95Solubility in water: miscibleVapour pressure, kPa at 20°C: 0.33Relative vapour density (air = 1): 4.6

Relative density of the vapour/air-mixture at 20°C (air = 1): 1.01Flash point: 51°C c.c.

Auto-ignition temperature: 190°CExplosive limits, vol% in air: 1.5-17.4Octanol/water partition coefficient as log Pow: -0.36

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000

1357 DIETHYLENE GLYCOL DIMETHYL ETHER

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR.

Chemical dangersThe substance can form explosive peroxides. Reacts withstrong acids, strong bases, and strong oxidants.

Occupational exposure limitsTLV not established.MAK: 5 ppm; 27 mg/m3; H (1999)MAK: class II,1 (1999)

Routes of exposureThe substance can be absorbed into the body by inhalation ofits vapour and through the skin.

Inhalation riskA harmful contamination of the air can be reached ratherquickly on evaporation of this substance at 20°C.

Effects of short-term exposureThe substance irritates the eyes, the skin and the respiratorytract.

Effects of long-term or repeated exposureMay cause reproductive toxicity in humans.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

NOTES

Check for peroxides prior to distillation; eliminate if found.

ADDITIONAL INFORMATION

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RÉSUMÉ D’ORIENTATION

Le présent CICAD consacré à l’éther diméthylique

de diéthylène-glycol (désigné sous le nom de diglymedans ce qui suit) a été préparé par l’Institut Fraunhofer de recherche sur la toxicologie et les aérosols, deHanovre (Allemagne). La décision d’inclure le diglymedans la série des CICAD a été prise en raison de lacrainte que l’on peut avoir au sujet d’éventuels effets dece composé sur la santé humaine, notamment en ce quiconcerne la fonction de reproduction. Ce CICAD repose

sur un certain nombre de rapports établis par le Comitéconsultatif GDCh sur les substances chimiques d’impor-tance écologique (BUA, 1993a) ainsi que par la MAK-Komission allemande (Greim, 1994). Il a été procédé en

mars 2000 à un dépouillement bibliographique exhaustif des bases de données existantes, afin de rechercher desréférences à des publications postérieures aux rapportsen question. Des informations sur la préparation etl’examen par des pairs des sources documentairesutilisées sont données à l’appendice 1. L’appendice 2fournit des renseignements sur l’examen par des pairs du présent CICAD. Ce CICAD a été approuvé en tantqu’évaluation internationale lors d’une réunion du

Comité d’évaluation finale qui s’est tenue à Genève du 8au 12 janvier 2001. La liste des participants à cetteréunion figure à l’appendice 3. La Fiche internationalesur la sécurité chimique du diglyme (ICSC 1357), établie

par le Programme international sur la sécurité chimique(IPCS, 2000), est également reproduite dans le présentdocument.

Le diglyme (No CAS 111-96-6) se présente sous la

forme d’un liquide incolore dégageant une odeur légèreet agréable. Il est miscible à l’eau et à un certain nombrede solvants organiques courants. Il peut donner

naissance à des peroxydes en présence d’oxydants.Comme il est dipolaire et aprotique, on l’utilise principalement comme solvant (dans l’industrie dessemi-conducteurs, en synthèse chimique et dans les

laques), comme milieu réactionnel inerte en synthèse et pour certaines séparations par distillation.

A l’état liquide ou sous forme de vapeurs, lediglyme est facilement absorbé quelle que soit la voied’exposition, puis métabolisé et excrété dans les urines.Son principal métabolite est l’acide 2-méthoxyéthoxy-acétique, l’acide 2-méthoxyacétique étant un métabolitesecondaire. Chez le rat, il est présent dans la proportion

de 5 à 15 % dans les urines.

Après exposition par voie orale ou respiratoire, le

diglyme ne présente qu’une faible toxicité aiguë.

Il est légèrement irritant pour la peau et la

muqueuse oculaire. On ne dispose d’aucune étude sur l’effet sensibilisant de ce composé.

L’expérimentation animale montre que chez le mâle,c’est principalement l’appareil reproducteur qui esttouché après exposition répétée. Lors d’une étude aucours de laquelle on a fait inhaler du diglyme pendant2 semaines à des rats mâles, on a observé une diminutiondu poids du testicule, de l’épididyme, de la prostate etdes vésicules séminales. Les testicules étaient atrophiés

et on a constaté une atteinte des spermatocytes. Cesétudes ont permis de fixer à 30 ppm (167 mg/m3) laconcentration sans effet nocif observable (NOAEL) et à100 ppm (558 mg/m3) la concentration la plus faible produisant un effet observable (LOAEL). Des études sur la souris ont révélé des anomalies morphologiquesaffectant les spermatozoïdes et consistant principalementdans la présence d’une tête amorphe, après exposition à1000 ppm (5580 mg/m3). Après avoir été exposés par lavoie respiratoire à de fortes concentrations de diglyme,mâles et femelles ont également présenté des anomaliesaffectant le système hématopoïétique et consistantnotamment en une modification du nombre de

leucocytes et une atrophie splénique et thymique.

On ne dispose d’aucune étude à long terme sur le

diglyme; il n’est donc pas possible d’évaluer tous les points d’aboutissement éventuels de son action toxique.

Aucune génotoxicité n’a été mise en évidence in vitro,que ce soit par divers tests d’Ames ou par recherched’une synthèse non programmée de l’ADN. In vivo, onne constate pas non plus d’augmentation du nombre desaberrations chromosomiques dans les cellules de lamoelle osseuse.

Des tests de létalité dominante effectués sur desrats ont montré que le nombre de gravidités étaitsensiblement réduit chez le rat après exposition à1000 ppm (5580 mg/m3), mais pas à la concentration de250 ppm (1395 mg/m3). Les résultats positifs de ces tests

pourraient s’expliquer par une action du diglyme sur lafertilité.

Les études de tératogénicité effectuées sur desrats, des lapins et des souris ont révélé des effetsdépendant de la dose sur le poids foetal, le nombre derésorptions et l’incidence des anomalies et desmalformations affectant un grand nombre de tissus et

d’organes à des concentrations par ailleurs non toxiques pour les mères. Lors d’une étude consacrée aux effetssur le développement avec exposition par la voierespiratoire, on a trouvé une LOAEL égale à 25 ppm (140mg/m3); dans le cas d’une exposition par voie orale, la NOAEL était de 25 mg/kg de poids corporel pour le lapin

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et de 62,5 mg/kg de poids corporel pour la souris. Leseffets toxique du diglyme sur la fonction de reproductionsont attribués à son métabolite secondaire, l’acide 2-méthoxyacétique.

Des études épidémiologiques sur des femmes

travaillant dans l’industrie des semi-conducteurs etexposées de par leur profession à des éthers éthyliquesde glycol, dont le diglyme, ont mis en évidence unaccroissement du risque d’avortement spontané et une baisse de la fécondité. D’une façon générale, les travail-

leurs de l’industrie des semi-conducteurs sont exposés àun certain nombre de substances potentiellement tox-iques pour la fonction de reproduction, notamment deséthers éthyliques de glycol. Ces données ne permettent pas de déterminer quelle est la part du diglyme dans cetaccroissement du risque d’effets génésiques nocifs.Chez des peintres exposés à divers métaux, solvantsorganiques et autres substances chimiques, parmilesquels le 2-méthoxyéthanol (qui est également unmétabolite du diglyme), mais pas au diglyme lui-même,on a constaté un accroissement du risqued’oligospermie.

Dans l’environnement, c’est principalement dans

l’hydrosphère que le diglyme se rassemble. Le composéresiste à l’hydrolyse. Le calcul montre que le t 1/2 de laréaction du diglyme avec les radicaux hydroxylesatmosphériques est de 19 h environ. Le diglyme est

intrinsèquement biodégradable avec une phase logarith-mique relativement longue est une adsorption notableaux boues activées. Compte tenu de la valeur de soncoefficient de partage entre le n-octanol et l’eau et de samiscibilité à l’eau, il semble que le potentiel de bio-accumulation et de géoaccumulation du diglyme soitnégligeable.

Les résultats expérimentaux valables dont on peutdisposer au sujet de la toxicité du diglyme vis-à-vis dedivers organismes aquatiques, permettent de considérer ce composé comme présentant une faible toxicité aiguë

pour les biotes de l’hydrosphère. La CE0 à 48 h pour ladaphnie ( Daphnia magna) et la CE10 à 72 h pour lesalgues (Scenedesmus subspicatus) sont $1000 mg/litre(concentration maximale mesurée). Dans le cas de l’iderouge ( Leuciscus idus), on a trouvé une CL0 à 96 h de$2000 mg/litre. On ne dispose que de quelques étudesconcernant la toxicité du diglyme pour les espècesterrestres. Le seuil de toxicité pour un champignon,

Cladosporium resinae, est d’environ 9,4 g/litre.

D’après les exemples représentatifs de caractérisa-

tion du risque sur le lieu de travail, il y a amplement lieude craindre des effets sur la santé humaine. Il faut doncéviter que la population soit exposée au diglyme.

Selon les données disponibles, l’exposition au

diglyme n’implique pas de risque important pour lesorganismes aquatiques. Comme on ne connaît pas lesniveaux d’exposition, il n’est pas possible de donner une

caractérisation représentative du risque couru par lesorganismes terrestres. Toutefois, compte tenu du moded’utilisation du diglyme, il n’y a pas lieu de craindre uneexposition importante.

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RESUMEN DE ORIENTACIÓN

Este CICAD relativo al éter de dietilenglicoldimetilo

(denominado en lo sucesivo diglime) fue preparado por el Instituto Fraunhofer de Toxicología y de Investigaciónsobre los Aerosoles de Hannover, Alemania. Seseleccionó el diglime para someterlo a examen en la seriede los CICAD debido a las preocupaciones quesuscitaba en relación con la salud humana, en particular sus posibles efectos reproductivos. El CICAD se basaen los informes compilados por el Comité Consultivo

Alemán sobre las Sustancias Químicas Importantes parael Medio Ambiente (BUA, 1993a) y la MAK-Kommissionalemana (Greim, 1994). En marzo de 2000 se realizó unainvestigación bibliográfica amplia de bases de datos

pertinentes para buscar cualquier referencia publicadacon posterioridad a las incorporadas a estos informes. Lainformación sobre la preparación de los documentosoriginales y su examen colegiado figura en el Apéndice1. La información acerca del examen colegiado de esteCICAD se presenta en el Apéndice 2. Este CICAD seaprobó como evaluación internacional en una reunión dela Junta de Evaluación Final celebrada en Ginebra (Suiza)del 8 al 12 de enero de 2001. La lista de participantes en

esta reunión figura en el Apéndice 3. La Fichainternacional de seguridad química (ICSC 1357) para eldiglime, preparada por el Programa Internacional deSeguridad de las Sustancias Químicas (IPCS, 2000),

también se reproduce en el presente documento.

El diglime (CAS Nº 111-96-6) es un líquido incoloro

ligeramente aromático. Es miscible en agua y en algunosdisolventes orgánicos comunes. En presencia deagentes oxidantes, puede formar peróxido. Debido a sus propiedades apróticas dipolares, el diglime se utiliza principalmente como disolvente (industria de los semi-

conductores, síntesis química, barnices), como medio dereacción inerte en la síntesis química y como agenteseparador en las destilaciones.

El diglime, en forma líquida o de vapor, se absorbefácilmente por todas las vías de exposición, se metabo-liza y se excreta principalmente en la orina. El metabolitomás importante es el ácido 2-metoxietoxiacético. El ácido2-metoxiacético es un metabolito secundario; en ratas,alcanza un valor aproximado del 5-15% en la orina.

La toxicidad aguda del diglime es baja tras laexposición oral o por inhalación.

El diglime es ligeramente irritante de la piel o los

ojos. No se dispone de investigaciones sobre sus

efectos de sensibilización.

El destino principal en los animales machos tras

ingestas repetidas de diglime son los órganos reproduc-tores. En estudios de inhalación de dos semanas en ratasmacho, se observó una reducción dependiente de la

dosis del peso de los testículos, el epidídimo, la próstatay las vesículas seminales. Se atrofiaron los testículos yse detectaron daños en los espermatocitos. Laconcentración sin efectos adversos observados(NOAEL) en estos estudios fue de 30 ppm (167 mg/m 3);la concentración más baja con efectos adversosobservados (LOAEL) fue de 100 ppm (558 mg/m3). En los

experimentos con ratones se puso de manifiesto unaalteración morfológica del esperma, principalmente concabezas amorfas, tras la exposición a 1000 ppm(5580 mg/m3). Tras la exposición por inhalación aconcentraciones elevadas, también se observaronefectos en el sistema hematopoyético de los animalesmachos y hembras, por ejemplo cambios en el recuentode leucocitos y atrofia del bazo y el timo.

No hay estudios prolongados disponibles deldiglime; por consiguiente, no se pueden evaluar demanera fidedigna todos los efectos finales. En varias pruebas de Ames y en una prueba de síntesis de ADN

no programado no apareció ningún posible efecto geno-tóxico del diglime in vitro. Tampoco se observó unaumento del número de aberraciones cromosómicas enlas células de la médula ósea in vivo.

En una prueba de dominancia letal con ratas, elnúmero de gestaciones se redujo significativamente trasla exposición a 1000 ppm (5580 mg/m3), pero no con250 ppm (1395 mg/m3). Los resultados positivos puedendeberse a los efectos del diglime en la fecundidad.

En estudios de teratogenicidad con ratas, conejos

y ratones se detectaron efectos del diglime dependientesde la dosis en el peso fetal, el número de resorciones y laincidencia de variaciones y malformaciones en unaamplia variedad de tejidos y sistemas de órganos aconcentraciones que no eran tóxicas para la madre. En

un estudio de inhalación en ratas, la LOAEL para losefectos en el desarrollo fue de 25 ppm (140 mg/m3); la NOAEL para la vía oral fue de 25 mg/kg de peso corporalen conejos y de 62,5 mg/kg de peso corporal en ratones.La toxicidad reproductiva del diglime se atribuye al ácido2-metoxiacético, que es un metabolito secundario.

En estudios epidemiológicos de trabajadoras de la

industria de los semiconductores expuestas en el lugar de trabajo a los éteres de etilenglicol, incluido el diglime,se ha registrado un aumento del número de abortosespontáneos y una reducción de la fecundidad. Sinembargo, los trabajadores de esta industria estánexpuestos a varias sustancias con posible toxicidad

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reproductiva, entre ellas los éteres de etilenglicol y otras.A partir de estos datos, no es posible determinar lacontribución del diglime al aumento del riesgo de efectosreproductivos adversos. Se observó que los pintores

expuestos a diversos metales, disolventes orgánicos yotros productos químicos, entre ellos el 2-metoxietanol,metabolito del diglime, pero no al propio diglime, presentaban un mayor riesgo de oligospermia.

El principal compartimento destinatario del diglime

en el medio ambiente es la hidrosfera. Esta sustancia

química presenta estabilidad hidrolítica. La semivida enel aire para la reacción del diglime con los radicaleshidroxilo se calcula en unas 19 horas. El diglime es básicamente biodegradable, con una fase logarítmicalarga y una adsorción importante a los lodos activados.Del coeficiente de reparto n-octanol/agua y lamiscibilidad en agua de esta sustancia se deriva un potencial insignificante para la bioacumulación y lageoacumulación.

Teniendo en cuenta los resultados de pruebasválidas disponibles sobre la toxicidad del diglime paradiversos organismos acuáticos, este compuesto se

puede clasificar como sustancia con una toxicidad aguda baja en el compartimento acuático. El valor de la CE0 a las48 horas para Daphnia magna y el valor de la CE10 a las72 horas para las algas (Scenedesmus subspicatus) fuede $1000 mg/litro (la concentración medida más alta).

Para el cacho ( Leuciscus idus), se determinó una CL0 alas 96 horas de $2000 mg/litro. Son muy pocos losestudios disponibles relativos a la toxicidad del diglime para las especies terrestres. El hongo Cladosporium

resinae mostró una concentración umbral tóxica de unos9,4 g/litro.

Los resultados de la caracterización del riesgo demuestra para el lugar de trabajo suscitan una gran preocupación por sus posibles efectos en la saludhumana. Se debe evitar la exposición de la poblacióngeneral al diglime.

Los datos disponibles no indican un riesgoimportante asociado con la exposición de los organismosacuáticos a esta sustancia. Debido a la falta demediciones de los niveles de exposición, no se puederealizar una caracterización del riesgo de muestra para losorganismos terrestres. Sin embargo, teniendo en cuentalas pautas de uso del diglime, no cabe esperar una

exposición importante de los organismos terrestres.

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THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Acrylonitrile (No. 39, 2002)Azodicarbonamide (No. 16, 1999)Barium and barium compounds (No. 33, 2001)

Benzoic acid and sodium benzoate (No. 26, 2000)Benzyl butyl phthalate (No. 17, 1999)Beryllium and beryllium compounds (No. 32, 2001)Biphenyl (No. 6, 1999)1,3-Butadiene: Human health aspects (No. 30, 2001)2-Butoxyethanol (No. 10, 1998)Chloral hydrate (No. 25, 2000)Chlorinated naphthalenes (No. 34, 2001)Chlorine dioxide (No. 37, 2001)Crystalline silica, Quartz (No. 24, 2000)Cumene (No. 18, 1999)

1,2-Diaminoethane (No. 15, 1999)3,3'-Dichlorobenzidine (No. 2, 1998)1,2-Dichloroethane (No. 1, 1998)2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000) N , N -Dimethylformamide (No. 31, 2001)Diphenylmethane diisocyanate (MDI) (No. 27, 2000)Ethylenediamine (No. 15, 1999)Ethylene glycol: environmental aspects (No. 22, 2000)Formaldehyde (No. 40, 2002)2-Furaldehyde (No. 21, 2000)HCFC-123 (No. 23, 2000)

Limonene (No. 5, 1998)Manganese and its compounds (No. 12, 1999)Methyl and ethyl cyanoacrylates (No. 36, 2001)Methyl chloride (No. 28, 2000)Methyl methacrylate (No. 4, 1998) N -Methyl-2-pyrrolidone (No. 35, 2001)Mononitrophenols (No. 20, 2000) N -Nitrosodimethylamine (No. 38, 2001)Phenylhydrazine (No. 19, 2000) N -Phenyl-1-naphthylamine (No. 9, 1998)1,1,2,2-Tetrachloroethane (No. 3, 1998)

1,1,1,2-Tetrafluoroethane (No. 11, 1998)o-Toluidine (No. 7, 1998)Tributyltin oxide (No. 14, 1999)Triglycidyl isocyanurate (No. 8, 1998)Triphenyltin compounds (No. 13, 1999)Vanadium pentoxide and other inorganic vanadium compounds (No. 29, 2001)