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This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, 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 Institute of 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 the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 2002
Transcript

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, theInternational 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

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 chemicalsafety, 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 itspublications, 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 theprovisions 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 theexpression 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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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, AND ACCUMULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.6.2 In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.7 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.7.1 Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.7.1.1 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 Hazard identification and exposure–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Uncertainties in the evaluation of human health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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

Diethylene glycol dimethyl ether

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FOREWORD

Concise International Chemical AssessmentDocuments (CICADs) are the latest in a family ofpublications from the International Programme onChemical Safety (IPCS) — a cooperative programme ofthe 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 ofchemicals.

International Chemical Safety Cards on therelevant chemical(s) are attached at the end of theCICAD, to provide the reader with concise informationon the protection of human health and on emergencyaction. They are produced in a separate peer-reviewedprocedure at IPCS. They may be complemented byinformation from IPCS Poison Information Monographs(PIM), similarly produced separately from the CICADprocess.

CICADs are concise documents that provide sum-maries of the relevant scientific information concerningthe potential effects of chemicals upon human healthand/or the environment. They are based on selectednational or regional evaluation documents or on existingEHCs. Before acceptance for publication as CICADs byIPCS, these documents undergo extensive peer reviewby internationally selected experts to ensure theircompleteness, 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 achemical. 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 critical 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 environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered 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 that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new informa-tion that would change the conclusions drawn in aCICAD, 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 environment. The IPCS RiskAssessment Steering Group advises the Co-ordinator,IPCS, on the selection of chemicals for an IPCS riskassessment, 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 andone or more experienced authors of criteria documents toensure that it meets the specified criteria for CICADs.

The draft is then sent to an international peerreview by scientists known for their particular expertiseand by scientists selected from an international rostercompiled 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 second draft

1 International Programme on Chemical Safety (1994)Assessing human health risks of chemicals: derivationof guidance values for health-based exposure limits.Geneva, World Health Organization (EnvironmentalHealth Criteria 170).

Concise International Chemical Assessment Document 41

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S E L E C T I O N O F H I G H Q U A L I T YN 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 (PRODUCER/RESPONSIBLE OFFICER),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)

Diethylene glycol dimethyl ether

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

A consultative group may be necessary to adviseon specific issues in the risk assessment document.

The CICAD Final Review Board has severalimportant functions:

– to ensure that each CICAD has been subjected toan appropriate and thorough peer review;

– to verify that the peer reviewers’ comments havebeen addressed appropriately;

– to provide guidance to those responsible for thepreparation 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 approve CICADs as international assessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of theirexperience in the regulation of chemicals. Boards arechosen according to the range of expertise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion 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 notparticipate in the final decision-making process.

Concise International Chemical Assessment Document 41

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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 forreview in the CICAD series owing to concerns 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 review 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 liquidwith a slight, pleasant odour. It is miscible with waterand a number of common organic solvents. In thepresence 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 ofdiglyme.

The main targets in male animals after repeatedintake of diglyme are the reproductive organs. In 2-weekinhalation studies in male rats, dose-dependentdecreases 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 100ppm (558 mg/m3). Experiments with mice showedmorphologically altered sperm, mainly with amorphousheads, after exposure to 1000 ppm (5580 mg/m3). Afterexposure 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 for 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 ofdiglyme in vitro. Nor was the number of chromosomalaberrations increased in bone marrow cells in vivo.

In a dominant lethal test with rats, the number ofpregnancies was significantly reduced after exposure to1000 ppm (5580 mg/m3) but not to 250 ppm (1395 mg/m3).The positive results may be due to the effects of diglymeon fertility.

In teratogenicity studies with rats, rabbits, andmice, diglyme showed dose-dependent effects on fetalweights, number of resorptions, and incidence of varia-tions and malformations in a wide variety of tissues andorgan 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 minormetabolite 2-methoxyacetic acid.

Epidemiological studies of female semiconductorworkers occupationally exposed to ethylene glycolethers (EGEs), including diglyme, have found anincreased risk of spontaneous abortions and lowerfecundity. Workers in the semiconductor industry 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 ofmetals, organic solvents, and other chemicals, including2-methoxyethanol, a metabolite of diglyme, but not todiglyme itself, were found to have an increased risk ofoligospermia.

The main environmental target compartment ofdiglyme is the hydrosphere. The chemical is hydrolyti-cally stable. The half-life in air for the reaction of diglyme

Diethylene glycol dimethyl ether

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with hydroxyl radicals is calculated to be about 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 thewater miscibility of the chemical, a negligible potentialfor bioaccumulation and geoaccumulation is derived.

From valid test results available on the toxicity ofdiglyme 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 fordaphnia (Daphnia magna) and the 72-h EC10 value foralgae (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 humanhealth effects. Exposure of the general population todiglyme should be avoided.

The available data do not indicate a significant riskassociated with exposure of aquatic organisms todiglyme. Due to the lack of measured exposure levels, asample risk characterization with respect to terrestrialorganisms cannot be performed. However, from the usepattern of diglyme, significant exposure of terrestrialorganisms is not to be expected.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Diglyme (CAS No. 111-96-6; relative molecularmass 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. Itbelongs to the group of ethylene glycol ethers (EGEs).The molecular structure of diglyme (C6H14O3) is shownbelow:

CH3 – O – CH2 – CH2 – O – CH2 – CH2 – O – CH3

Diglyme is a colourless liquid of low viscosity witha slight, pleasant odour. The chemical freezes at about!64 °C. Depending on the presence of impurities, itsboiling point is between 155 and 165 °C (Hoechst, 1990).Diglyme is miscible with water and with a number ofcommon organic solvents. It dissolves numerous

compounds, such as vegetable oils, waxes and resins,boron hydrides, organic boron compounds, sulfur, sulfurdioxide, hydrogen peroxide, and carbon dioxide. Withwater, azeotrope formation is observed at aconcentration ratio of 23 wt. % diglyme and 77 wt. %water (BUA, 1993a). Diglyme has an n-octanol/waterpartition coefficient (log Kow) of !0.36, determined by ashake flask experiment (Funasaki et al., 1984). Its vapourpressure at 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 as0.041 PaAm3/mol (J. Gmehling, personal communication,1991).

The conversion factors for diglyme for the gasphase (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 ofstrong oxidation agents, peroxide may form. Commercialproducts typically contain peroxides at a concentrationof 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 ofdiglyme are presented in the International ChemicalSafety 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, synthetic polymers 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) orgas chromatography/mass spectrometric detection(GC/MSD) (NIOSH, 1990, 1991, 1996; Stolz et al., 1999).For the determination of diglyme in indoor air, thechemical 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 isalso in general carried out by adsorption onto XAD 4 orXAD 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 notavailable. A detection limit of 0.01 µg/litre is reported(Morra et al., 1979).

Analytical methods for the determination ofdiglyme 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 capillary 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 rates92.0–125.2% (at 2, 5, and 10 mg/litre) (Hubner et al.,1992). [14C]Diglyme was determined in rat urine formetabolism studies by high-performance liquid chroma-tography/scintillation detection on a reversed-phase C18column (gradient elution with methanol/acetic acid) afteracidification of the sample (Cheever et al., 1988). Infor-mation on detection methods for other biological mater-ials is not available.

The metabolite 2-methoxyacetic acid is assumed toplay a major role in the toxic effects of diglyme (seesections 8 and 9). Therefore, common detection methodsfor this compound in urine after inhalation exposure torelated EGEs are described briefly here. The basis ofthese 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 inboth cases with a GC/FID using a capillary column. Therecovery rates were reported to be 31% (Groeseneken etal., 1986) and 98% (Sakai et al., 1993). The detection limitswere 0.15 mg/litre (Groeseneken et al., 1986) and 0.05mg/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 closed system by thecatalytic 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-massethylene glycol dimethyl ether are separated byfractional distillation (Hoechst, 1991). This process isbased on the classic Williamson ether synthesis(Rebsdat & Mayer, 1999).

In 1982, about 47 200 tonnes of diglyme wereproduced 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 countries arenot available. Diglyme is registered as a high-production-volume chemical by the Organisation forEconomic 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 itschemical 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, suchas 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 manufacture of inte-grated circuit boards, primarily as a solvent for thephotoresists. These are used as photosensitive materialsfor the coating of the wafer during microlithographicpatterning in the photo/apply process (Messner, 1988;Correa et al., 1996; Gray et al., 1996) and in theproduction of semiconductors (Corn & Cohen, 1993).

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Diglyme is included in the European Inventory ofCosmetics Ingredients in the solvent category (EC, 1996).Its use in cosmetics in Germany and Canada was notreported (BUA, 1993a; Clariant GmbH, personalcommunication, 2000; IKW [German Trade Associationon Cosmetic and Detergent Preparations], personalcommunication, 2000; R. Gomes, Health Canada,personal communication, 2001). Data for 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-basedpaints for consumer use.

4.4 Estimated global release

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

The releases from the production of diglyme at theGerman 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 releasedwith solid wastes. The liquid wastes are disposed of inapproved chemical waste incinerators (BUA, 1993a).

Data on the degree of recycling of diglyme from itsapplication as a solvent or as an inert reaction medium inindustrial processes are not available.

Information on the content of diglyme in consumerproducts such as cosmetics or paints and lacquers is notavailable. 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 lowHenry’s law constant (see section 2), leading to a lowvolatility 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 solutionof 47.2 g diglyme/litre (5% v/v) kept in the dark for21 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 ofminor importance due to diglyme’s weak absorption 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 KOH of 1.7 × 10–11 cm3/moleculeper second (Dagaut et al., 1988). Assuming an averagetropospheric hydroxyl radical concentration of about6 × 105 molecules/cm3 (BUA, 1993b), the half-life ofdiglyme 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 reactions,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 activated sludgewas 17% after 3 h, and total removal was 42% after28 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 anelectrolytic respirometer test with industrial wastewaterfrom a manufacturer of synthetic organic chemicals. In afurther experiment in which diglyme was tested togetherwith dioxane and other unspecified organic chemicals,the degree of biodegradation was significantly higherthan 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. Highsalt 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 arenot available.

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5.3 Accumulation

The log Kow of diglyme (!0.36; see section 2) indi-cates a negligible potential for bioaccumulation.

Measurements concerning the geoaccumulation ofdiglyme 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 ofadsorption onto soil. It is to be expected that the oxygenatoms 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 Kow; 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 orto adsorb to soil constituents, diglyme may reachgroundwater. EGEs were detected particularly in anoxicgroundwater in the vicinity of US landfill sites (Ross etal., 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 ambientor workplace air are not available.

Diglyme was detected in surface water in theDutch parts of the river Rhine at concentrations rangingbetween 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 notquantified in 1992 in wastewater samples, from a Germanoil reclaiming company, that had been pretreated byequalization, neutralization, adsorption to activatedsludge, flocculation, and flotation (Gulyas et al., 1994).

Data on the concentration of diglyme in soil orsediment are not available.

Data on the concentration of diglyme in biologicalmaterial are not available.

6.2 Human exposure

6.2.1 Workplaces

There is a potential for inhalation or dermal contactin the chemical and allied product industries wherediglyme is used as a solvent.

During the diglyme production process and its useas 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 data are available on diglyme exposure con-centrations at the workplace. Data on other EGEs that areproduced in the same way and that have a comparableuse pattern and similar volatilization behaviour mayserve as a rough approximation.

ECETOC (1995) reported time-weighted average(TWA) exposures for several other EGEs between 0.01and 6.5 ppm for the production process. This wouldcorrespond to airborne diglyme concentrations betweenabout 0.06 and 36 mg/m3, taking its conversion factor forthe gas phase into account (see section 2). The dermalexposure to diglyme can be estimated with the calcu-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 furtherthat exclusively the palms (an area about 420 cm2) areexposed, this would lead to a maximum dermal body doseof 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 diglymeconcentrations between about 0.06 and 3.1 mg/m3. Asdiglyme 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

Diethylene glycol dimethyl ether

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permeation of protective gloves of different materials byEGEs. Gloves made of nitrile and butyl rubber or neo-prene provide the best protection (breakthrough rates$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 professionalpainting operations, 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). Fordiglyme, 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 estimated forthe production and solvent use of diglyme in chemicalsynthesis (incidental contact during transferring/weighing/mixing or cleaning and maintenanceprocedures, 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 inherentlybiodegradable with a rather long log phase and a signifi-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 generalpopulation to diglyme is likely via the ingestion ofdrinking-water and via dermal contact with the respec-tive consumer products.

The database is not sufficient to estimate the dailyintake of diglyme by the general population.

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

Quantitative information on dermal exposure todiglyme via cosmetic products is not available. Althoughdiglyme is included in the European Union’s Inventoryon Cosmetics Ingredients, its use was not reported forGermany 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 exposure is assumed tobe of minor importance. Dermal exposure cannot bequantified with the available data.

6.2.3 Biological monitoring

As dermal exposure is significant, measurement ofdiglyme in air is not sufficient for exposure monitoring.Therefore, biological monitoring of the metabolite 2-methoxyacetic acid, which belongs to the metabolicpathway that is responsible for the developmentaleffects and effects on the reproductive system, ispreferable. 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 diglyme in rats showthat diglyme is absorbed from the gastrointestinal tract(Cheever et al., 1986, 1988). Absorption followinginhalation can be concluded from the observation ofpoisoning symptoms in studies on single- and repeated-dose exposure to diglyme and in analogy with otherglycol ethers.

In an in vitro study with human skin, the highpercutaneous 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 orvapours 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 5920 mg in a study withhuman volunteers (Kezic et al., 1997).

7.2 Distribution and accumulation

No studies are available that investigate the dis-tribution of radioactively labelled diglyme within thebody. Glycol ethers in general are readily distributedthroughout 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

Application at day of gestation – – – – – 12 11

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

Pretreatment – – 22 daysdiglyme

22 daysphenobarbital

– – –

% 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 calculated 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 ofdiglyme involves O-demethylation with subsequentoxidation to form the main metabolite 2-methoxyethoxy-acetic acid, which accounts 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 et 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% ofthe dose in the urine of rats after 48–96 h (Cheever et al.,1988, 1989a). In the urine of pregnant mice, it was foundin higher concentrations (26–28% of the dose; Daniel etal., 1986, 1991) (see Table 1). Also, humans may form thismetabolite in higher concentrations. Based on nmol 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 withphenobarbital or ethanol increases the cleavage of thecentral ether linkage of diglyme as a result of cytochromeP-450 enzyme induction in the liver (Cheever et 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 fetuseither) after dosing diglyme to mice at day 11 or 12 ofpregnancy (Daniel et al., 1986, 1991). The highest levelsfor the average embryo (whole embryos analysed) weredetected at 6 h after dosing. Significantly lower amountswere detected in blood taken from the dam at that timepoint (Daniel et al., 1991).

7.4 Elimination

The major route of elimination is through the urine.Ninety-six hours after oral application of 6.84 mgdiglyme/kg body weight to male Sprague-Dawley rats,90% of the dose was excreted via urine, 3.6% as carbondioxide, 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 tem-perature (about 10 g/m3) caused restlessness, narrowingof palpebral fissures, and irregular breathing in rats. Allanimals survived. Necropsy 14 days after exposurerevealed no macroscopic findings (Hoechst, 1979a).

8.1.2 Oral administration

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/kgbody weight (Plasterer et al., 1985). Poisoning symptomswere restlessness and breathing difficulties. Necropsy ofanimals found dead revealed changes in lung and liver(no further information available).

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

Diethylene glycol dimethyl ether

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

2-(2-Methoxyethoxy)ethanol

CH3-O-CH2-CH2-OH

2-Methoxyethanol

CH3-O-CH2-CH2-O-CH 2-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 furtherinformation available).

8.2.2 Sensitization

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 asmean 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 femaleAlderley 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, andhistopathology (of a limited number of organs withouttestes) were also performed. In contrast to the DuPontstudy cited above, no changes in haematologicalparameters 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 totalwhite blood cells was more than doubled compared withcontrols. This increase was not, however, statisticallysignificant (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 orcarcinogenicity.

8.6 Genotoxicity and related end-points

8.6.1 In vitro studies

Results of investigations of genotoxicity in vitroare 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 aberrationsin 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 ofpregnancies and an increase in preimplantation lossesmay be due either to a dominant 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 vitro.

Result

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

Salmonella

mutagenicity teststrain TA1535, TA1537,TA1538, TA98, TA100

0.3–100 µl per plate – – cytotoxicity at100 µl per plate

McGregor et al.,1983

Salmonella

mutagenicity teststrain TA1538, TA98,TA100

20–70 µl per plate not tested – no cytotoxicity McGregor et al.,1983

Salmonella

mutagenicity teststrain TA1535, TA1538,TA98, TA100

0.01–10 mg per plate – – tested with ratand hamster S9,no cytotoxicity

Mortelmans etal., 1986

Salmonella

mutagenicity teststrain TA1535, TA1537,TA1538, TA98, TA100

0.005–50 µl per plate – – cytotoxicity at 25and 50 µl perplate

Hoechst,1979d,e

Unscheduled DNAsynthesis

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

McGregor et al.,1983

A recessive lethal test on Drosophilamelanogaster exposed to 250 ppm (1395 mg/m3) for 2.75h 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 fertility

8.7.1.1 Inhalation

There are several well conducted studies availablein which toxicity to the male reproductive organs hasbeen investigated.

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, or84 days post-exposure. Body weight gain was dosedependently decreased. At 370 and 1100 ppm (2065 and6138 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. At370 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 with110 and 370 ppm (614 and 2065 mg/m3), but not with 1100ppm (6138 mg/m3) (DuPont, 1988b; Lee et al., 1989;Valentine et al., 1999).

In order to identify a NOAEL for effects on thetestes, 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. Meanbody weights of rats exposed to 100 ppm (558 mg/m3)were significantly lower than those of controls at the endof 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 100ppm (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 differentlesions observed occurred in the same or different 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 germcells

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, minimal1, 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 theNOAEL (DuPont, 1989).

In a dominant lethal test, groups of 10 male adultCD rats were exposed to 0, 250, or 1000 ppm (0, 1395, or5580 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, largereductions in pregnancy frequency occurred in the 1000ppm (5580 mg/m3) exposure group in weeks 4 through 9,

but particularly in weeks 5 through 7 after exposure,when frequencies were only about 10%. Further,preimplantation losses in these weeks were large, andthere 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 1000ppm (0, 1395, or 5580 mg/m3) 7 h/day for 4 days, andsperm were isolated 35 days after the exposure. Fourmice of the 1000 ppm (5580 mg/m3) group were founddead on the morning of the 4th exposure day. Mice ofboth exposure groups showed a reduction in body

Diethylene glycol dimethyl ether

15

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 (5580mg/m3) group. All categories of abnormalities wereinvolved to some extent: hook upturned or hookelongated, 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, theauthors concluded that the spermatocytes 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 upto 20 daily oral doses of distilled water or diglyme at684 mg/kg body weight. Testicular changes wereanalysed, including a subsequent recovery over an8-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 were found intesticular weight and the combined weight of seminalvesicles and coagulating gland in four male JCL-ICR micethat 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 Developmental toxicity

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 morphogenesis in a widevariety of tissues and organ systems, and the diversity offetal 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 lateralventricles of the brain, axial skeletal malformations(vertebral fusions, hemivertebrae), and appendicularmalformations (aberrant clavicular and scapularformation, 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 ofskeletal developmental variations), the pattern, type, andincidence of variations were similar to those seen at100 ppm (558 mg/m3), suggesting, according to theauthors, 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 liver weightswere found in the dams at 100 ppm (558 mg/m3), theNOAEL for diglyme exposure in the dams is 25 ppm (140mg/m3).

8.7.2.2 Oral

In an oral application study with rabbits, similareffects 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 ofthe kidneys and axial skeleton and clubbing of the limbswithout underlying skeletal involvement were the mostfrequently presented individual defects. At 50 mg/kgbody weight, percentages of prenatal mortality 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

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, 400 ppm (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, appendicularmalformations [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

NOAEL25 mg/kg body weight

NTP (1987)

NOAEL25 mg/kg body weight

NOAEL50 mg/kg body weight

Schwetz et al.(1992)

miceCD-120–24

gavage in distilledwater, days 6–15

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 appendicularskeleton)500 mg/kg body weight: dams: weight gain (due to decrease in graviduterine weight) 9; resorptions 8

NOAEL 500 mg/kg body weight

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

gavage in distilledwater, days 6–13

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 etal. (1987)

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

Diethylene glycol dimethyl ether

17

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

In mice, the NOAELs were 500 mg/kg body weightfor maternal effects and 62.5 mg/kg body weight fordevelopmental 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 dysmorphogenesisof the axial and appendicular skeleton (NTP, 1985; Price etal., 1987). Further defects of digits and 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 derivedaccording to the benchmark dose approach, was 99 mg/kgbody weight. This was lower 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 ofCheever et al. (1985) with rats, both compounds exhibitedtesticular toxicity primarily affecting pachytene anddividing stages of spermatocytes at lower exposurelevels. In comparing the testicular toxicity of equimolardosages 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 toproduce the same effects. Similarly, in the inhalationstudy of Lee et al. (1989) with rats, the toxic effects of 300ppm (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 highernumber of abnormal sperm than 500 ppm (1550 mg/m3) 2-methoxyethanol; thus, considering equimolarconcentrations, diglyme seems to be somewhat moretoxic. 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 minormetabolite of diglyme, other metabolites or otherpharmacokinetic behaviours of diglyme compared with 2-methoxyethanol may contribute to the toxicity ofdiglyme.

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 diglymecompared 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 alterations in the hindpaws, compared with 38% after treatment with 537 mgdiglyme/kg body weight and 0.6 or 0% in concurrentcontrols. Further, monoethylene glycol dimethyl ethershowed 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 ofleukocytes was decreased. This is consistent withstudies on other EGEs, where mechanistic studiesindicate that the immune system is a sensitive target fortoxicity in the rat and that the proximate immunotoxicantis methoxyacetic acid (ECETOC, 1995).

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The metabolite 2-methoxyacetic acid, which isgenerated from 2-methoxyethanol by the action of alcoholdehydrogenase, may be important for the toxic effects. Itcan undergo activation to methoxyacetyl coenzyme Aand 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 causes the testicularlesions 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 oneepidemiological study of painters exposed to 2-methoxy-ethanol is also discussed.

9.1 Reproductive effects

EGEs including diglyme are used in the manufactureof semiconductors. Epidemiological studies of threesemiconductor populations evaluated potential adversereproductive outcomes. It is unclear from the descriptionsprovided by the authors whether these populationsoverlapped. In each of these studies, workers wereexposed to mixtures including diglyme but not to diglymealone. In a single study of painters, exposure included ametabolite of diglyme and EGEs.

One of the semiconductor populations includedworkers from 14 different companies. The study includedboth retrospective and prospective study designs.Exposure to EGEs was determined using questionnairesfrom subjects about the work performed and anassessment of the work environment by industrialhygienists, 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 permenstrual cycle) was conducted 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 tothe comprehensive interview (Eskanazi et al., 1995a,b). Ofthe 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 thephotolithography 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 abortion 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 ofspontaneous 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 amongfemale 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 reportedby Gray et al., 1996). Gray et al. (1996) also reported onthe results of a prospective study of reproductiveoutcomes at the same plants. 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 employees. Therewas a significantly elevated risk of spontaneousabortion (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

Diethylene glycol dimethyl ether

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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 exposurecategories was found for both end-points for EGEexposure. Among wives of male employees exposed toEGEs, there was no evidence of an increased risk ofspontaneous 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 pregnancyand 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 ofspontaneous 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, suchas arsine, phosphine, diborane, xylene, toluene, andhexamethyldisilane.

Semen samples from 73 painters and 40 controlsfrom 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 ofthose with oligospermia differed between the groups.The proportion of men with a sperm density #100million/cm3 was higher in the exposed group than in theunexposed group (33% vs. 20%; P = 0.20). Theproportion 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 ofpainters with azoospermia was 5% compared with 0% inthe controls.

9.2 Haematological effects

The relationship between exposure to EGEs andhaematological 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) found10% of painters with haemoglobin levels consistent withanaemia (P = 0.02) and 3.4% of painters and no controlswith abnormally low levels of polymorphonuclearleukocytes (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 whiteblood 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 ofhealthy donors showed no changes in haemoglobin orerythrocyte 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 isnot always stated whether the cited effect values arebased on nominal or measured concentrations ofdiglyme. In some cases (Hoechst, 1994, 1995), theconcentration of the test substance is detected by thedetermination of dissolved organic carbon or carbon inthe 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 sub-spicatus), 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 ontadpoles of the frog species Rana brevipoda werebetween 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 EC10 of >1000 mg/litre wasdetermined (Hoechst, 1989b).

Only acute toxic effects have been examined in thetests above. One should be aware of possible effects ofdiglyme 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 sporegermination 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 againstoriental and Mediterranean fruit flies (Dacus dorsalisand 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 Hazard identification andexposure–response 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 toxicityof 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 unscheduledDNA synthesis test did not reveal a genotoxic potentialof diglyme in vitro. Further, the number of chromosomalaberrations was not increased in bone marrow cells invivo. The positive results of a dominant lethal test maybe due to the effects of diglyme on fertility.

The main targets of the toxicity of diglyme are thereproductive 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 mainlyaffected. Effects were found in rats and mice in severalexperiments after inhalation and oral exposure. Theeffects were reversible at lower concentrations; atconcentrations of about 1100 ppm (6138 mg/m3), theeffects persisted in the investigated time period of 84days. The NOAEL for reproductive effects in rats was 30ppm (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. Developmentaleffects occur at low concentrations without maternaltoxicity. Effects on fetal weights, an increased numberof resorptions, and an increased incidence of variations/malformations in a wide variety of tissues and organ

Frankfurt am Main, Hoechst AG, 2 pp. (unpublished testresults).

Diethylene glycol dimethyl ether

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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 toxicityindicated 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 ofexposure (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 foundslightly decreased rates; no effects were observed in theother.

Painters exposed to the solvent 2-methoxyethanol,which is also a metabolite of diglyme, were found tohave an increased prevalence of oligospermia andazoospermia. The painters were also exposed to numer-ous other substances, including organic solvents andmetals, however.

11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values fordiglyme

A guidance value for uptake of diglyme viainhalation according to EHC 170 (IPCS, 1994) can bebased 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 thestudy 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 Sample risk characterization

Assuming that exposure concentrations fordiglyme are the same as for other EGEs, the TWA forexposure 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. Theseconcentrations are considerably higher than theguidance value for the general population of 0.6 mg/m3,derived above. In addition, high dermal uptake ofdiglyme has to be taken into consideration. It has to berecognized, furthermore, that protective gloves mayallow significant permeation of diglyme. Gloves made ofnitrile and butyl rubber or neoprene provide the bestprotection.

In conclusion, from the sample risk characterizationfor the workplace, there is high concern for possiblehuman health effects. No information is available on thepresence or concentrations of diglyme in cosmetics;because of its reprotoxic potency, all exposure of thegeneral public to diglyme should be avoided.

11.1.4 Uncertainties in the evaluation of humanhealth effects

There is a high degree of confidence that thereproductive system is the target of the toxicity ofdiglyme. 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 conductedwith 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 ofdiglyme 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 cannotbe quantified with the available data.

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The main target compartment of diglyme is thehydrosphere. The chemical is inherently biodegradablewith a rather long log phase and significant adsorptionto activated sludge. Bioaccumulation andgeoaccumulation are of minor importance.

In the available experimental studies, diglymeexhibited 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 beexceeded 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 usepattern of diglyme, significant exposure of terrestrialorganisms is not to be expected.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

Previous evaluations by international bodies werenot identified.

REFERENCES

Atkinson R (1989) Kinetics and mechanisms of the gas-phasereactions of the hydroxyl radical with organic compounds.Journal of physical and chemical reference data, 1:143.

Baumann W, Muth A (1997) Farben und Lacke: Daten und

Fakten zum Umweltschutz. Berlin, Springer.

Beaumont JJ, Swan SH, Hammond SK, Samuels SJ, Green RS,Hallock MF, Dominguez C, Boyd P, Schenker MB (1995)Historical cohort investigation of spontaneous abortion in thesemiconductor health study: Epidemiologic methods andanalyses of risk in fabrication overall and in fabrication workgroups. American journal of industrial medicine, 28:735–750.

Brooke I, Cocker J, Delic JI, Payne M, Jones K, Gregg NC, DyneD (1998) Dermal uptake of solvents from the vapour phase: anexperimental study in humans. Annals of occupational hygiene,42:531–540.

Brotherton RJ, Weber CJ, Guibert CR, Little JL (1999) Boroncompounds. In: Ullmann’s encyclopedia of industrial chemistry,6th ed. Weinheim, Wiley VCH (electronic release).

BUA (1993a) Diethylene glycol dimethyl ether (bis(2-

methoxyethyl)-ether). GDCh Advisory Committee on ExistingChemicals of Environmental Relevance (BUA). Stuttgart, Hirzel,pp. 1–64 (BUA Report 67).

BUA (1993b) OH-Radikale in der Troposphäre; Konzentration

und Auswirkung. GDCh Advisory Committee on ExistingChemicals of Environmental Relevance (BUA). Stuttgart, Hirzel,pp. 1–163 (BUA-Report 100).

Burditt AK Jr, Hinman FG, Balock JW (1963) Screening of fumi-gants for toxicity to eggs and larvae of the oriental fruit fly andMediterranean fruit fly. Journal of economic entomology,56:261–265.

Catalano PJ, Scharfstein DO, Ryan LM, Kimmel CA, Kimmel GL(1993) Statistical model for fetal death, fetal weight, and malfor-mation in developmental toxicity studies. Teratology, 47(4):281–290.

Cheever KL, Weigel WW, Richards DE, Lal JB, Plotnick HB(1985) Testicular effects of bis(2-methoxyethyl) ether in the adultmale rat: equimolar dose comparison with 2-methoxyethanoland 2-ethoxyethanol. Toxicologist, 5:140.

Cheever KL, Richards DE, Weigel WW, Lal JB, Dinsmore AM,Daniel FB (1986) Metabolism of a testicular toxin, bis(2-methoxyethyl) ether, in the rat. Toxicologist, 6:32.

Cheever KL, Richards DE, Weigel WW, Lal JB, Dinsmore AM,Daniel FB (1988) Metabolism of bis(2-methoxyethyl) ether in theadult male rat: evaluation of the principal metabolite as atesticular toxicant. Toxicology and applied pharmacology,94:150–159.

Cheever KL, Richards DE, Weigel WW, Begley KB (1989a) Therole of enzyme induction on metabolite formation of bis(2-methoxyethyl) ether in the rat. Toxicology and industrial health,5:601–607.

Diethylene glycol dimethyl ether

23

Cheever KL, Weigel WW, Richards DE, Lal JB, Plotnick HB(1989b) Testicular effects of bis(2-methoxyethyl)ether in theadult male rat. Toxicology and industrial health, 5:1099–1109.

Cook RR, Bodner KM, Kolesar RC, Uhlmann CS, VanPeenenPFD, Dickson GS, Flanagan K (1982) A cross-sectional study ofethylene glycol monomethyl ether process employees. Archives

of environmental health, 37(6):346–351.

Corn M, Cohen R (1993) Real-time measurement of sub-ppmconcentrations of airborne chemicals in semiconductormanufacturing. Journal of exposure analysis and environmental

epidemiology, 3(S1):37–49.

Correa A, Gray RH, Cohen R, Rothman N, Shah F, Seacat H,Corn M (1996) Ethylene glycol ethers and risks of spontaneousabortion and subfertility. American journal of epidemiology,143(7):707–717.

Dagaut P, Wallington IJ, Liu R, Kurylo MJ (1988) 22nd

International Symposium on Combustion, Seattle, WA [cited inAtkinson, 1989].

Daniel FB, Eisenmann C, Cheever KL, Richards DE, Weigel WW(1986) Metabolism of a reproductive toxin bis-2-methoxyethylether in the pregnant mouse. Teratology, 33:75C.

Daniel FB, Cheever KL, Begley KB, Richards DE, Weigel WW,Eisenmann CJ (1991) Bis(2-methoxyethyl)ether: metabolism andembryonic disposition of a developmental toxicant in thepregnant CD-1 mouse. Fundamental and applied toxicology,16(3):567–575.

Denkhaus W, Steldern DV, Botzenhardt U, Konietzko H (1986)Lymphocyte subpopulations in solvent-exposed workers. Inter-

national archives of occupational and environmental health,57:109–115.

Driscoll CD, Valentine R, Staples RE, Chromey NC, Kennedy GLJr (1998) Developmental toxicity of diglyme by inhalation in therat. Drug and chemical toxicology, 21(2):119–136.

DuPont (1988a) Teratogenicity study of diglyme in the rat.Newark, NJ, E.I. Du Pont de Nemours & Co., 289 pp.

DuPont (1988b) Subchronic inhalation toxicity study with

diglyme. Newark, NJ, E.I. Du Pont de Nemours & Co., 445 pp.

DuPont (1989) Subchronic inhalation toxicity study with

diglyme. Newark, NJ, E.I. Du Pont de Nemours & Co., 187 pp.

EC (1996) The international nomenclature of cosmetic

ingredients. European Commission (http://www.cosmetic-world.com/inci/default.htm).

ECETOC (1995) The toxicology of glycol ethers and its

relevance to man. Brussels, European Centre for Ecotoxicologyand Toxicology of Chemicals, pp. 1–350 (Technical Report No.64).

Eskenazi B, Gold EB, Lasley BL, Samuels SJ, Hammond SK,Wight S, O’Neill Rasor M, Hines CJ, Schenker MB (1995a)Prospective monitoring of early fetal loss and clinicalspontaneous abortion among female semiconductor workers.American journal of industrial medicine, 28(6):833–846.

Eskenazi B, Gold EB, Samuels SJ, Wight S, Lasley BL,Hammond SK, O’Neill Rasor M, Schenker MB (1995b)

Prospective assessment of fecundability of femalesemiconductor workers. American journal of industrial medicine,28(6):817–831.

Filon FL, Fiorito A, Adami G, Barbiere P, Coceani N, Bussar R,Reisenhofer E (1999) Skin absorption in vitro of glycol ethers.International archives of occupational and environmental health,72:480–484.

Funasaki N, Hada S, Neya S, Machida K (1984) Intramolecularhydrophobic association of two alkyl chains of oligoethyleneglycol diethers and diesters in water. Journal of physical

chemistry, 88:5786–5790.

Gage JC (1970) The subacute inhalation toxicity of 109industrial chemicals. British journal of industrial medicine,27:1–18.

Gray RH, Correa A, Hakim R, Cohen R, Corn M, Shah F,Rothman N, Hou W, Secat H (1996) Ethylene glycol ethers andreproductive health in semiconductor workers. Occupational

hygiene, 2(1–6):331–338.

Greim H, ed. (1994) Diethylene glycol dimethyl ether. In:Occupational toxicants. Critical data evaluation for MAK values

and classification of carcinogens. Weinheim, Wiley-VCH, pp.41–50.

Groeseneken D, van Vlem E, Veulemans H, Masschelein R(1986) Gas chromatographic determination of methoxyaceticand ethoxyacetic acid in urine. British journal of industrial

medicine, 43:62–65.

Gulyas H, Reich M, Sekoulov I (1994) Characterisation of abiologically treated wastewater from oil reclaiming: recording oflow molecular weight organics and estimation of humicsubstances. Water science and technology, 29(9):195–198.

Hammond SK, Hines CJ, Hallock MF, Woskie SR,Abdollahzadeh S, Iden CR, Anson E, Ramsey F, Schenker MB(1995) Tiered exposure-assessment strategy in the semiconductorhealth study. American journal of industrial medicine,28(6):661–680.

Hardin BD (1983) Reproductive toxicity of the glycol ethers.Toxicology, 27:91–102.

Hardin BD, Eisenmann CJ (1986) Relative potency of fourethylene glycol ethers for induction of paw malformations in themouse. Teratology, 33:85C.

Hardin BD, Eisenmann CJ (1987) Relative potency of fourethylene glycol ethers for induction of paw malformations in theCD-1 mouse. Teratology, 35:321–328.

Hardin BD, Schuler RL, Burg JR, Booth GM, Hazelden KP,MacKenzie KM, Piccirillo VJ, Smith KN (1987) Evaluation of 60chemicals in a preliminary developmental toxicity test. Terato-

genesis, carcinogenesis, mutagenesis, 7:29–48.

Harris JC (1990) Rate of hydrolysis. In: Lyman WJ, Reehl WF,Rosenblatt DH, eds. Handbook of chemical property estimation

methods: Environmental behavior of organic compounds. NewYork, NY, McGraw-Hill Book Company, pp. 7-1–7-48.

Hoechst (1979a) Inhalationstoxizität im Zeitsättigungstest von

Diethylenglykol-dimethylether an männlichen und weiblichen

Concise International Chemical Assessment Document 41

24

SPF-Wistar-Ratten. Frankfurt am Main, Hoechst AG, 10 pp.(Report 488/79; unpublished).

Hoechst (1979b) Akute orale Toxizität von Diethylenglykol-

dimethylether an weiblichen Ratten. Frankfurt am Main, HoechstAG, 4 pp. (Report 376/79; unpublished).

Hoechst (1979c) Haut- und Schleimhautverträglichkeit von

Diethylenglykol-dimethelether an Kaninchen. Frankfurt am Main,Hoechst AG, 10 pp. (Report 447/79; unpublished).

Hoechst (1979d) Test for mutagenicity in bacteria strains in the

absence and presence of a liver preparation. Frankfurt am Main,Hoechst AG, 7 pp. (Report 53/79; unpublished).

Hoechst (1979e) Mutagenicity evaluation of diethyleneglycol-

dimethylether in the Ames Salmonella/microsome plate test.

Frankfurt am Main, Hoechst AG, 15 pp. (Report 743/79,unpublished).

Hoechst (1989a) Prüfberichte: ökologische Untersuchungen.

Frankfurt am Main, Hoechst AG, 4 pp. (unpublished report).

Hoechst (1989b) Untersuchung auf Bakterienschädlichkeit:

Sauerstoff- Zehrungs-Hemmtest. Frankfurt am Main, Hoechst AG,1 p. (unpublished report).

Hoechst (1990) DIN-Sicherheitsdatenblatt vom 06.07.1990.

Frankfurt am Main, Hoechst AG, 2 pp. (unpublished report).

Hoechst (1991) Schriftliche Mitteilung vom 12.09.1991. Frankfurtam Main, Hoechst AG, 8 pp. (unpublished report).

Hoechst (1994) Prüfung der toxischen Wirkung von Diethylen-

glykoldimethylether auf Kleinkrebse (Daphnia magna). HoechstAG, Frankfurt am Main (unpublished report).

Hoechst (1995) Prüfung der Schadwirkung gegenüber Algen

(Algentoxizität) von Diethylenglykoldimethylether. Hoechst AG,Frankfurt am Main (unpublished report).

Hours M, Dananche B, Caillat-Vallet E, Fevotte J, Philippe J,Boiron O, Fabry J (1996) Glycol ethers and myeloid acuteleukemia: a multicenter case control study. Occupational

hygiene, 2:405–410.

HSDB (1983) Hazardous Substances Data Bank. Bethesda, MD,National Library of Medicine.

Hubner B, Geibel K, Angerer J (1992) Gas-chromatographicdetermination of propylene- and diethylene glycol ethers inurine. Fresenius journal of analytical chemistry, 342:746–748.

IPCS (1994) Assessing human health risks of chemicals:

derivation of guidance values for health-based exposure limits.

Geneva, World Health Organization, International Programmeon Chemical Safety (Environmental Health Criteria 170).

IPCS (2000) International Chemical Safety Card — Diethylene

glycol dimethyl ether. Geneva, World Health Organization,International Programme on Chemical Safety (ICSC 1357).

Jenkins-Sumner S, Stedman D, Cheng S, Welsch F, Fennell T(1996) Characterization of urinary metabolites producedfollowing administration of [1,2, methoxy-13C]-2-methoxyethanolto male F-344 rats and pregnant CD-1 mice. Occupational

hygiene, 2:25–31.

Johanson G (1996) An overview of glycol ethers metabolism andtoxicokinetics. Occupational hygiene, 2:5–24.

Johanson G (2000) Toxicity review of ethylene glycolmonomethyl ether and its acetate ester. Critical reviews in

toxicology, 30:307–345.

Johanson G, Boman A (1991) Percutaneous absorption of 2-butoxyethanol vapour in human subjects. British journal of

industrial medicine, 48:788–792.

Karsten E, Lueckert O (1992) Lackrohstofftabellen, 9th ed.Hanover, Curt R. Vincentz Verlag.

Kezic S, Mahieu K, Monster AC, de Wolff FA (1997) Dermalabsorption of vaporous and liquid 2-methoxyethanol and 2-ethoxyethanol in volunteers. Occupational and environmental

medicine, 54:38–43.

Kimmel CA (1996) Reproductive and developmental effects ofdiethylene and triethylene glycol (methyl-, ethyl-) ethers.Occupational hygiene, 2:131–151.

Kiwa (1986) Organische Microverontreinigingen in rijn (Lobith)

en maas (Keizersveer) 1985 — Componentenanalyse en

mutageniteit. Nieuwegein, Kiwa N.V., 4 pp.

Lauret J-M, Prud’homme E, Salmon P (1989) Recherche sur letraitement biologique des lixiviats des centres d’enfouissementtechnique. Techniques sciences methodes, 3:149–158.

Lee KH, Wong HA (1979) Toxic effects of some alcohol andethylene glycol derivatives on Cladosporium resinae. Applied

and environmental microbiology, 38:24–28.

Lee KP, Kinney LA, Valentine R (1989) Comparative testiculartoxicity of bis(2-methoxyethyl)ether and 2-methoxyethanol inrats. Toxicology, 59:239–258.

Linders JBHJ, Morra CFH, den Boer AC, Ruijgrok CTM (1981)Inventory of organic substances in the river Rhine in 1979.

Leidschendam, National Institute for Water Supply, pp. 1–42.

McGregor DB, Willins MJ, McDonald P, Holmstrom M, McDonaldD, Neimeier R (1981) Bis-2-methoxyethyl ether and 2-methoxyethanol results from multiple assay for genotoxic potential.Environmental mutagenesis, 3:381–382.

McGregor DB, Willins MJ, McDonald D, Holmstrom M, McDonaldD, Niemeier RW (1983) Genetic effects of 2-methoxyethanol andbis(2-methoxyethyl)ether. Toxicology and applied pharmacology,70:303–316.

Messner G (1988) Experiences and considerations toenvironmental and working place protection. Processing ofProbimer 52. Galvanotechnik, 79:3072–3079.

Morra CF, Linders JB, den Boer A, Ruijgrok TM, Zoeteman BC(1979) Organic chemicals measured during 1978 in the river

Rhine in the Netherlands. Leidenschendam, National Institutefor Water Supply, pp. 1–21.

Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, ZeigerE (1986) Salmonella mutagenicity tests: II. Results from thetesting of 270 chemicals. Environmental mutagenesis,8(S7):1–119.

Diethylene glycol dimethyl ether

25

Nagano K, Nakayama E, Oobayashi H, Nishizawa T, Okuda H,Yamazaki K (1984) Experimental studies on toxicity of ethyleneglycol alkyl ethers in Japan. Environmental health perspectives,57:75–84.

NIOSH (1990) Criteria for a recommended standard:

occupational exposure to ethylene glycol monobutyl ether and

ethylene glycol monobutyl acetate. Appendix A. Methods for

sampling and analysis of EGBE and EGBEA in air. Cincinnati,OH, National Institute for Occupational Safety and Health(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 forOccupational Safety and Health (DHHS (NIOSH) Publication No.91-119).

NIOSH (1996) Volatile organic compounds (screening) Method2549. In: NIOSH manual of analytical methods, 4th ed.Cincinnati, OH, National Institute for Occupational Safety andHealth, 8 pp. (http://ehs.clemson.edu/niosh/pdfs/2549.pdf).

Nishiuchi Y (1984) Toxicity of agrochemicals to freshwaterorganisms. 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, NationalToxicology 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 andDevelopment.

Ogata Y, Tomizawa K, Fujii K (1978a) Photo-induced oxidationof diethylene glycol dimethyl ether and analogues with aqueoushydrogen peroxide. Bulletin of the Chemical Society of Japan,51:2628–2633.

Ogata Y, Takagi K, Suzuki T (1978b) Photolytic oxidation ofethylene 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 amongsemiconductor manufacturers. Journal of occupational medicine,30:543–551.

Paustenbach DJ (1988) Assessment of the developmental risksresulting from occupational exposure to selected glycol etherswithin the semiconductor industry. Journal of toxicology and

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

toxicology and environmental health, 15:25–38.

Plieninger P, Marchl D (1999) Occurrence of ester and etherderivatives of polyvalent alcohols in indoor air of 200 Berlinhouseholds. In: Indoor Air ’99, Proceedings of the 8th

International Conference on Indoor Air Quality and Climate,

Edinburgh, Scotland, 8–13 August 1999. Vol. 4. London,Construction Research Communications Ltd., pp. 171–176.

Price CJ, Kimmel CA, George JD, Marr MC (1987) The develop-mental toxicity of diethylene glycol dimethyl ether in mice.Fundamental and applied toxicology, 8:115–126.

Rebsdat S, Mayer D (1999) Ethylene glycol. In: Ullmann’s ency-

clopedia of industrial chemistry, 6th ed. Weinheim, Wiley VCH(electronic release).

Richards DE, Begley KB, DeBord DG, Cheever KL, Weigel WW,Tirmenstein MA, Savage RE Jr (1993) Comparative metabolismof bis(2-methoxyethyl)ether in isolated rat hepatocytes and inthe intact rat: effects of ethanol on in vitro metabolism. Archives

of toxicology, 67(8):531–537.

Rittmeyer P, Wietelmann U (1999) Hydrides. In: Ullmann’s

encyclopedia of industrial chemistry, 6th ed. Weinheim, WileyVCH (electronic release).

Ross B, Johanson G, Foster GD, Eckel WP (1992) Glycol ethersas groundwater contaminants. Applied hydrogeology, 1:66–76.

Roy D, Anagnostu G, Chaphalkar P (1994) Biodegradation ofdioxane and diglyme in industrial waters. Journal of

environmental science and health, Part A, Environmental

science and engineering, 29(1):129–147.

Sakai T, Araki T, Masuyama Y (1993) Determination of urinaryalkoxyacetic acids by a rapid and simple method for biologicalmonitoring of workers exposed to glycol ethers and theiracetates. International archives of occupational and

environmental health, 64:495–498.

Schuler RL, Hardin BD, Niemeier RW, Booth G, Hazelden K,Piccirillo V, Smith K (1984) Results of testing fifteen glycolethers in a short-term in vivo reproductive toxicity assay.Environmental health perspectives, 57:141–146.

Schwetz BA, Price CJ, George JD, Kimmel CA, Morrissey RE,Marr MC (1992) The developmental toxicity of diethylene andtriethylene glycol dimethyl ethers in rabbits. Fundamental and

applied toxicology, 19(2):238–245.

Stolz P, Weis N, Krooss J (1999) Nomenclature and occurrenceof glycols and their derivatives in indoor air. In: Salthammer T,ed. Organic indoor air pollutants, occurrence-measurement-

evaluation. Weinheim, Wiley VCH, pp. 117–125.

Sumner SCJ, Stedman DB, Clarke DO, Welsch F, Fennell TRJ(1992) Characterization of urinary metabolites from [1,2,methoxy-13C]-2-methoxyethanol in mice using 13C nuclearmagnetic resonance spectroscopy. Chemical research in

toxicology, 5:553–560.

Swan SH, Forest W (1996) Reproductive risks of glycol ethers andother agents used in semiconductor manufacturing.Occupational hygiene, 2(1–6):373–385.

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Thomas RG (1990) Volatilization from water. In: Lyman WJ,Reehl WF, Rosenblatt DH, eds. Handbook of chemical property

estimation methods: Environmental behavior of organic

compounds. New York, NY, McGraw-Hill Book Company, pp.15.1–15.34.

Tirmenstein MA (1993) Comparative metabolism of bis(2-methoxyethyl) ether by rat and human hepatic microsomes:Formation of 2-methoxyethanol. Toxicology in vitro ,7(5):645–652.

Toraason M, Richards DE, Tirmenstein MA (1996) Metabolism ofdiglyme by rat hepatocytes and human microsomes.Occupational hygiene, 2(1–6):33–43.

Valentine R, O’Neill AJ, Lee KP, Kennedy GL Jr (1999)Subchronic inhalation toxicity of diglyme. Food and chemical

toxicology, 37(1):75–86.

Welch LS, Cullen MR (1988) Effect of exposure to ethyleneglycol ethers on shipyard painters: III. Hematologic effects.American journal of industrial medicine, 14:527–536.

Welch LS, Schrader SM, Turner TW, Cullen MR (1988) Effects ofexposure to ethylene glycol ethers on shipyard painters: II. Malereproduction. American journal of industrial medicine,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 chargeof writing the report (usually the largest producer in Germany)prepares a draft report using literature from an extensiveliterature search as well as internal company studies. This draft issubject to a peer review in several readings of a working groupconsisting of representatives from government agencies, thescientific community, and industry.

The original German version of this report was publishedin 1991.

Greim H, ed. (1994) Diethylene glycol dimethylether. In: Occupational toxicants. Critical dataevaluation for MAK values and classification ofcarcinogens. Weinheim, Wiley-VCH, pp. 41–50

The scientific documentations of the German Commissionfor the Investigation of Health Hazards of Chemical Compoundsin the Work Area (MAK) are based on critical evaluations of theavailable toxicological and occupational medical data fromextensive literature searches and of well documented industrialdata. The evaluation documents involve a critical examinationof the quality of the database indicating inadequacy or doubtfulvalidity of data and identification of data gaps. This criticalevaluation and the classification of substances are the result ofan extensive discussion process by the members of theCommission proceeding from a draft documentation prepared bymembers of the Commission, by ad hoc experts, or by theScientific Secretariat of the Commission. Scientific expertise isguaranteed by the members of the Commission, consisting ofexperts from the scientific community, industry, and employersassociations.

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, aswell as to identified experts. Comments were received from:

M. Baril, International Programme on Chemical Safety/Institut de Recherche en Santé et en Sécurité du Travaildu Québec, Canada

R. Benson, Drinking Water Program, US EnvironmentalProtection Agency, USA

R. Cary, Health and Safety Executive, United Kingdom

R. Chhabra, National Institute of Environmental HealthSciences, National Institutes of Health, USA

J. Gift, National Center for Environmental Assessment, USEnvironmental Protection Agency, USA

R. Hertel, Federal Institute for Health Protection ofConsumers and Veterinary Medicine, Germany

C. Hiremath, National Center for EnvironmentalAssessment, US Environmental Protection Agency, USA

P. Howden, Health and Safety Executive, UnitedKingdom

G. Johanson, National Institute for Working Life, Sweden

S. Kristensen, National Industrial Chemicals Notificationand 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 EuropeanCommunities/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, Departmentof Pathology, University of Texas Medical Branch, Galveston,TX, USA

Mr R. Cary, Health and Safety Executive, Merseyside, UnitedKingdom (Chairperson)

Dr R.S. Chhabra, General Toxicology Group, National Instituteof Environmental Health Sciences, National Institutes of Health,Research Triangle Park, NC, USA

Dr S. Czerczak, Department of Scientific Information, NoferInstitute 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 ToxicSubstances and Disease Registry, Atlanta, GA, USA

Dr H. Gibb, National Center for Environmental Assessment, USEnvironmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection ofConsumers and Veterinary Medicine, Berlin, Germany

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

Dr P.D. Howe, Centre for Ecology and Hydrology,Cambridgeshire, United Kingdom (Rapporteur)

Dr D. Lison, Industrial Toxicology and Occupational MedicineUnit, Université Catholique de Louvain, Brussels, Belgium

Dr R. Liteplo, Existing Substances Division, Bureau of ChemicalHazards, Health Canada, Ottawa, Ontario, Canada

Dr I. Mangelsdorf, Chemical Risk Assessment, FraunhoferInstitute 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 GenomeResearch, Stockholm University, Stockholm, Sweden

Dr J. Sekizawa, Division of Chem-Bio Informatics, NationalInstitute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty ofAgriculture, Alexandria University, El-Shatby, Alexandria, Egypt

Dr M. Sweeney, Education and Information Division, NationalInstitute for Occupational Safety and Health, Cincinnati, OH,USA

Professor M. van den Berg, Environmental Sciences andToxicology, Institute for Risk Assessment Sciences, University ofUtrecht, Utrecht, The Netherlands

Diethylene glycol dimethyl ether

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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, WorldHealth 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

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/EXPOSURE

ACUTE 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. Ventilation, local exhaust, orbreathing 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.

Boiling point: 162°CMelting point: -68°CRelative 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 diméthyliquede diéthylène-glycol (désigné sous le nom de diglymedans ce qui suit) a été préparé par l’Institut Fraunhoferde 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 reposesur 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 enmars 2000 à un dépouillement bibliographique exhaustifdes 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 duprésent CICAD. Ce CICAD a été approuvé en tantqu’évaluation internationale lors d’une réunion duComité 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), établiepar 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 laforme 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 donnernaissance à des peroxydes en présence d’oxydants.Comme il est dipolaire et aprotique, on l’utiliseprincipalement comme solvant (dans l’industrie dessemi-conducteurs, en synthèse chimique et dans leslaques), comme milieu réactionnel inerte en synthèse etpour 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 proportionde 5 à 15 % dans les urines.

Après exposition par voie orale ou respiratoire, lediglyme ne présente qu’une faible toxicité aiguë.

Il est légèrement irritant pour la peau et lamuqueuse oculaire. On ne dispose d’aucune étude surl’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 atrophiéset 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 faibleproduisant un effet observable (LOAEL). Des études surla 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 deleucocytes et une atrophie splénique et thymique.

On ne dispose d’aucune étude à long terme sur lediglyme; il n’est donc pas possible d’évaluer tous lespoints 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 testspourraient 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 etd’organes à des concentrations par ailleurs non toxiquespour 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, laNOAEL était de 25 mg/kg de poids corporel pour le lapin

Diethylene glycol dimethyl ether

33

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 femmestravaillant 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 unebaisse 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 permettentpas 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 dansl’hydrosphère que le diglyme se rassemble. Le composéresiste à l’hydrolyse. Le calcul montre que le t1/2 de laréaction du diglyme avec les radicaux hydroxylesatmosphériques est de 19 h environ. Le diglyme estintrinsèquement 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 considérerce composé comme présentant une faible toxicité aiguëpour 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 audiglyme n’implique pas de risque important pour lesorganismes aquatiques. Comme on ne connaît pas lesniveaux d’exposition, il n’est pas possible de donner unecaractérisation 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 porel 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 particularsus posibles efectos reproductivos. El CICAD se basaen los informes compilados por el Comité ConsultivoAlemán 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 datospertinentes 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 enesta 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 incoloroligeramente aromático. Es miscible en agua y en algunosdisolventes orgánicos comunes. En presencia deagentes oxidantes, puede formar peróxido. Debido a suspropiedades apróticas dipolares, el diglime se utilizaprincipalmente 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 losojos. No se dispone de investigaciones sobre susefectos de sensibilización.

El destino principal en los animales machos trasingestas repetidas de diglime son los órganos reproduc-tores. En estudios de inhalación de dos semanas en ratasmacho, se observó una reducción dependiente de ladosis 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/m3);la concentración más baja con efectos adversosobservados (LOAEL) fue de 100 ppm (558 mg/m3). En losexperimentos 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 variaspruebas de Ames y en una prueba de síntesis de ADNno 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. Enun estudio de inhalación en ratas, la LOAEL para losefectos en el desarrollo fue de 25 ppm (140 mg/m3); laNOAEL 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 laindustria de los semiconductores expuestas en el lugarde 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

Diethylene glycol dimethyl ether

35

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 pintoresexpuestos 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 diglimeen el medio ambiente es la hidrosfera. Esta sustanciaquímica presenta estabilidad hidrolítica. La semivida enel aire para la reacción del diglime con los radicaleshidroxilo se calcula en unas 19 horas. El diglime esbásicamente 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 unpotencial insignificante para la bioacumulación y lageoacumulación.

Teniendo en cuenta los resultados de pruebasválidas disponibles sobre la toxicidad del diglime paradiversos organismos acuáticos, este compuesto sepuede clasificar como sustancia con una toxicidad agudabaja 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 diglimepara las especies terrestres. El hongo Cladosporiumresinae 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 granpreocupación 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 unaexposición importante de los organismos terrestres.

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)

To order further copies of monographs in this series, please contact Marketing and Dissemination,World Health Organization, 1211 Geneva 27, Switzerland(Fax No.: 41-22-7914857; E-mail: [email protected])


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