methyl chloride - who.int · this report contains the collective views of an international group of...

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 28

METHYL CHLORIDE

Note that the layout and pagination of this pdf file are not identical to those of the printedCICAD

First draft prepared by Agneta Löf, National Institute of Working Life, Solna, SwedenMaria Wallén, National Chemicals Inspectorate (KEMI), Solna, Sweden, and Jonny Bard, Åseda, Sweden

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, 2000

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 (ParticipatingOrganizations), following recommendations made by the 1992 UN Conference on Environment andDevelopment to strengthen cooperation and increase coordination in the field of chemical safety. Thepurpose of the IOMC is to promote coordination of the policies and activities pursued by the ParticipatingOrganizations, jointly or separately, to achieve the sound management of chemicals in relation to humanhealth and the environment.

WHO Library Cataloguing-in-Publication Data

Methyl chloride.

(Concise international chemical assessment document ; 28)

1.Methyl chloride - toxicity 2.Risk assessment 3.Environmental exposureI.International Programme on Chemical Safety II.Series

ISBN 92 4 153028 6 (NLM Classification: QV 633) 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 2000

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

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

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY MAMMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117.3 Metabolism and elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117.4 Genetic polymorphism and sex, strain, organ, and species differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.4 Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.5 Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168.6 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

8.6.1 Studies in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188.6.2 Studies in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

8.7 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208.7.1 Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

8.7.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.8 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

9.1 Studies in volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239.2 Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239.3 Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2310.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24


iv

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 11.1.2 Criteria for setting tolerable intakes or guidance values for methyl chloride . . . . . . . . . . . . . . . . . . . . . . 26 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2711.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Methyl chloride

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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.

CICADs are concise documents that providesummaries of the relevant scientific informationconcerning the potential effects of chemicals uponhuman health and/or the environment. They are basedon selected national or regional evaluation documents oron existing EHCs. Before acceptance for publication asCICADs by IPCS, these documents undergo extensivepeer review by internationally selected experts to ensuretheir completeness, accuracy in the way in which theoriginal data are represented, and the validity of theconclusions drawn.

The primary objective of CICADs ischaracterization of hazard and dose–response fromexposure to a chemical. CICADs are not a summary of allavailable data on a particular chemical; rather, theyinclude only that information considered critical forcharacterization of the risk posed by the chemical. Thecritical studies are, however, presented in sufficientdetail to support the conclusions drawn. For additionalinformation, the reader should consult the identifiedsource documents upon which the CICAD has beenbased.

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 areprovided as guidance only. The reader is referred to EHC1701 for advice on the derivation of health-basedtolerable intakes and guidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, newinformation is being developed constantly. Unlessotherwise stated, CICADs are based on a search of thescientific literature to the date shown in the executivesummary. In the event that a reader becomes aware ofnew information that would change the conclusionsdrawn in a CICAD, the reader is requested to contactIPCS to inform it of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures are designed totake advantage of the expertise that exists around theworld — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment.

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 toensure that it meets the specified criteria for CICADs.

The second stage involves 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 draftis submitted to a Final Review Board together with thereviewers’ comments.

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, or

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).


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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)

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industry. 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.


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1. EXECUTIVE SUMMARY

The assessment of human health aspects in thisCICAD on methyl chloride was based primarily on areview prepared by the Nordic Expert Group incollaboration with the Dutch Expert Committee forOccupational Standards (Lundberg, 1992). Relevantdatabases covering the years 1992–1999 were searchedto identify additional data. For the environmental andecotoxicological aspects of methyl chloride, BUA (1986),ATSDR (1990), WMO (1994), and HSDB (1996) wereused as primary sources. ATSDR (1990) was updated in1998; where ATSDR (1998) provided new information,this has been taken into account. Additional data onenvironmental issues were identified in relevantdatabases covering the years 1989–1997. Informationconcerning the nature and availability of the sourcedocuments is presented in Appendix 1. Information onthe peer review of this CICAD is presented in Appendix2. This CICAD was approved as an internationalassessment at a meeting of the Final Review Board, heldin Stockholm, Sweden, on 25–28 May 1999. Participantsat the Final Review Board meeting are listed in Appendix3. The International Chemical Safety Card (ICSC 0419) formethyl chloride, produced by the InternationalProgramme on Chemical Safety (IPCS, 1999), has beenreproduced in this document.

Methyl chloride (CAS No. 74-87-3) is releasedmainly to air during its production and use and byincineration of municipal and industrial wastes. How-ever, natural sources, primarily oceans and biomassburning, clearly dominate over anthropogenic sources.The total global release of methyl chloride from allsources is estimated to be about 5 × 106 tonnes per year.The contribution from natural sources has beenestimated to be well over 90%, and perhaps as much as99%, of the total release. Methyl chloride is present inthe troposphere at a concentration of approximately 1.2µg/m3 (0.6 ppb).

The principal sink for methyl chloride in the tropo-sphere is chemical reaction with hydroxyl radicals, andthe atmospheric lifetime is estimated to be 1–3 years. Acertain amount of methyl chloride reaches the strato-sphere; there, photodissociation generates chlorine radi-cals, which contribute to ozone depletion. Estimates ofthe amount of methyl chloride reaching the stratosphere,and thus depleting ozone, vary widely. As estimatedfrom figures presented by the World MeteorologicalOrganization (WMO), methyl chloride contributesapproximately 15% of the total equivalent effectivestratospheric chlorine. The stratospheric ozonedepletion potential (ODP) of methyl chloride has beendetermined to be 0.02 relative to the reference compound

CFC-11, which has an ODP of 1. Methyl chloride is notthought to contribute significantly to either globalwarming or photochemical air pollution.

The dominant loss mechanism for methyl chloridein water and soil is volatilization. Slow hydrolysis andpossibly biotic degradation may contribute to the loss indeeper soil layers and in groundwater. However, littleinformation is available concerning biodegradation.

The most important route of exposure of methyl

chloride in humans is via the respiratory pathway. Inhumans as well as in experimental animals, methylchloride is readily absorbed through the lungs followinginhalation. Following exposure to 14C-radiolabelledmethyl chloride, the radioactivity is found throughoutthe body. Although a large portion of the radiolabelledsubstance is incorporated into protein through the one-carbon pool, methyl chloride may also bind to protein bydirect alkylation. However, if methyl chloride is analkylating agent, it is so to a very small extent. Methylchloride is metabolized in mammals either by conjugationwith glutathione or, to a lesser extent, through oxidationby cytochrome P-450; the glutathione pathway yieldsmethanethiol, and both pathways yield formaldehydeand formate. Metabolites from methyl chloride areexcreted via the urine and by exhalation. Methyl chlorideis also exhaled unmetabolized.

In humans, there are large interindividual differ-ences in the uptake and metabolism of methyl chloride.These differences depend on the presence or absence ofthe enzyme glutathione transferase T1 (GSTT1), whichdisplays genetic polymorphism. Humans can be pheno-typed as high conjugators, low conjugators, or non-conjugators of GSTT1. However, as it is not evident ifhigh conjugators or non-conjugators incur the highestrisk, one must consider all phenotypes as sensitive tomethyl chloride exposure.

The acute inhalation toxicity of methyl chloride inrats and mice seems to be fairly low, with an LC50 valueabove 4128 mg/m3 (2000 ppm). No data on irritation orsensitizing properties were located in the literature.

The main target organs after short-term inhalationexposure to methyl chloride seem to be the nervoussystem, with functional disturbances and cerebellardegeneration in both rats and mice, as well as testicles,epididymis, and kidneys in rats and kidneys and liver inmice.

In a 2-year inhalation study in mice, axonal swell-ing and degeneration of lumbar spinal nerves wereobserved at 103 mg/m3 (50 ppm) in exposed animalscompared with controls, but without an apparent

Methyl chloride

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dose–response relationship. At the end of the study,cerebellar degeneration in mice of both sexes and renaladenocarcinomas in male mice were observed at2064 mg/m3 (1000 ppm). These effects were not observedin the rat at 2064 mg/m3 (1000 ppm).

Methyl chloride is clearly genotoxic in in vitrosystems in both bacteria and mammalian cells. Althoughthe positive effects seen in a dominant lethal test mostlikely were cytotoxic rather than genotoxic, methylchloride might be considered a very weak mutagen invivo based on some evidence of DNA–protein cross-linking at higher doses.

Testicular lesions and epididymal granulomasfollowed by reduced sperm quality lead to reducedfertility in rats at 980 mg/m3 (475 ppm) and to completeinfertility at higher doses.

Methyl chloride induced heart defects in mousefetuses when dams were exposed to 1032 mg/m3

(500 ppm) during the gestation period.

Effects on humans, especially on the centralnervous system, can be clearly seen after accidentalinhalation exposure. In short-term exposure ofvolunteers to methyl chloride, no significant effects wereseen that could be attributed to the exposure. There areinsufficient epidemiological data available to assess therisk for humans to develop cancer as a result of methylchloride exposure.

In conclusion, the critical end-point for methylchloride inhalation toxicity in humans seems to beneurotoxicity. Guidance values of 0.018 mg/m3

(0.009 ppm) for indirect exposure via the environmentand 1.0 mg/m3 (0.5 ppm) for the working environmentwere derived. Although the nerve lesions were seen atlower exposure levels than those at which infertility inrats (980 mg/m3 [475 ppm]) and renal tumours in malemice (2064 mg/m3 [1000 ppm]) occurred, emphasis shouldalso be laid on these very serious effects in a qualitativerisk characterization of methyl chloride.

Few data were found on the short-term toxicity ofmethyl chloride to both aquatic and terrestrial organisms.No data were found on long-term toxicity. The existingdata indicate that methyl chloride has a low acutetoxicity to aquatic organisms. The lowest LC50 value forfish is 270 mg/litre. As measured concentrations ofmethyl chloride in surface waters are generally severalorders of magnitude less than those demonstrated tocause effects, it is likely that methyl chloride poses a lowrisk of acute effects on aquatic organisms. Only verylimited data are available on the effects of methylchloride on terrestrial organisms.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Methyl chloride (CAS No. 74-87-3; CH3Cl; chloro-methane) is a colourless gas at ambient temperatures. Itcan be compressed to a liquid, which has a weak etherealsmell. The odour threshold has been estimated to be 21mg/m3 (10 ppm) (ASTM, 1973). Methyl chloridedecomposes in water with a half-time of 4.66 h at 100 °C(IARC, 1986).

Methyl chloride is marketed as a liquefied gas

under pressure. The purity of a representative technicalgrade of methyl chloride is close to 100%. Impuritiesinclude water, hydrochloric acid, methyl ether, methanol,and acetone (Holbrook, 1992).

Methyl chloride has a very high vapour pressureand a high solubility in water. The value of its Henry’slaw constant is high, which suggests that volatilizationof methyl chloride will be significant in surface waters.The calculated octanol/water partition coefficient (logKow) is low, indicating a low potential for bio-accumulation and low tendency of adsorption to soil andsediment.

Some relevant physical and chemical properties ofmethyl chloride are listed in Table 1. Additionalphysical/chemical properties are presented in theInternational Chemical Safety Card, reproduced in thisdocument.

3. ANALYTICAL METHODS

In air, methyl chloride can be analysed by Method

1001 of the US National Institute for Occupational Safetyand Health (NIOSH, 1994). Analysis is performed by gaschromatography (GC), and the sample detection limit is3.1 µg/m3 (1.5 ppb). Using the method of Oliver et al.(1996), the detection limit is 1.1 µg/m3 (0.53 ppb).

The use of carbon disulfide at dry ice temperaturefor desorbing the analyte has also been described, aswell as a thermal desorption technique as an alternative(Severs & Skory, 1975). A thermally desorbable diffu-sional dosimeter for monitoring methyl chloride in theworkplace has also been described (Hahne, 1990). Verylow concentrations (0.006–0.1 µg/m3 [0.003–0.05 ppb]) ofmethyl chloride (in ambient air) can be analysed by theuse of photoionization, flame ionization, and electroncapture detectors in series (Rudolph & Jebsen, 1983).


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Table 1: Identity and physical/chemical properties of methylchloride.

Property Value Reference

Relative molecular mass 50.49

Melting point !97.7 °C!97.1 °C

Holbrook,1992 Weast, 1988

Boiling point !23.73 °C!24.2 °C

Holbrook,1992 Weast, 1988

Density liquid at 20/4 °C gas at 0 °C, 101.3 kPa

0.920 g/ml2.3045 g/litre

Holbrook,1992Holbrook,1992

Specific gravity 1.74 (air = 1) Holbrook,1992

Solubility in water at 25 °C 5.325 g/litre4.800 g/litre

Horvath, 1982Holbrook,1992

Vapour pressure at 5.5 °C 25 °C

3.04 × 105 Pa5.75 × 105 Pa

BUA, 1986BUA, 1986

Henry’s law constant at 3 °C (seawater, salinity

30.4‰)a

25 °C

0.1977 ± 1.4%

4.15–6.05kPa@m3/mol

Moore et al.,1995BUA, 1986

Log Kow 0.91 Hansch & Leo,1985

Conversion factor ppm (v/v)to mg/m3 in air at 25 °C

1 ppm =2.064 mg/m3

1 mg/m3 =0.4845 ppm

ATSDR, 1990

a Henry’s law constant is defined as the concentration in airdivided by the concentration in water at equilibrium; unit ofHenry’s law constant: dimensionless (Moore et al., 1995).

Exposure to methyl chloride can also be monitoredin air by a direct-reading infrared analyser, at minimumdetectable concentrations of 800–3100 µg/m3 (390–1500 ppb) (IARC, 1985).

Stratospheric air samples are often concentrated bya cryogenic procedure, at liquid nitrogen or argon tem-perature, followed by GC analysis employing electroncapture detection (Rasmussen et al., 1980; Singh et al.,1983, 1992; Rudolph et al., 1992, 1995; Khalil &Rasmussen, 1993; Fabian et al., 1996) or with GC/massspectrometry (MS) (Schauffler et al., 1993). The GC maybe equipped with a flame ionization detector (Evans etal., 1992) or a mass selective detector (Atlas et al., 1993).Almasi et al. (1993) described a modified version of amethod commonly used by the US EnvironmentalProtection Agency (EPA) to analyse low levels ofvolatile organic compounds in air (EPA Method TO-14).It includes sample concentrations on glass beads at

!160 °C, thermal desorption, separation on a GC capil-lary column, and detection with ion trap MS. The detec-tion limit is about 0.06 µg/m3 (0.03 ppb) for methylchloride.

In water, methyl chloride can be analysed by EPAMethod 502.2 at a detection limit of 0.1 µg/litre (US EPA,1986b). Other methods for the detection of volatileorganic substances in water are EPA Method 502.1,which has a detection limit of 0.01 µg/litre (US EPA,1986b), and EPA Method 524.2, with a detection limit of0.05 µg/litre (US EPA, 1986b). Another method involvinga solid-phase micro-extraction technique has a detectionlimit of <25 µg/litre (Shirey, 1995).

EPA Method 601 (purgeable halocarbons) is suit-able for measuring methyl chloride in wastewater. Thedetection limit is 0.06 µg/litre (US EPA, 1982; CFR, 1990).A similar method is EPA Method 624 (purgeables), witha detection limit of 2.8 µg/litre (US EPA, 1982; CFR,1991). A third method used for analysis of wastewater isEPA Method 1624, with a minimum detection level of 50µg/litre (CFR, 1991).

In soil and solid waste, EPA Method 5030 (USEPA, 1986a) may be used to analyse methyl chloride.Analysis is performed by different EPA methods. InMethod 8010B, the limit of detection is 12.5 µg/kg forhigh-concentration soils and sludges (US EPA, 1986a).Gomes et al. (1994) describes another method to collectand analyse methyl chloride, which can also be used toanalyse contaminants in groundwater.

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

Natural sources of methyl chloride dominate overanthropogenic sources. The major source appears to bethe marine/aquatic environment, likely associated withalgal growth. Other sources are biomass burning (forestfires), degradation of wood by fungi, and direct andindirect anthropogenic sources.

Methyl chloride is produced industrially by reac-tion of methanol and hydrogen chloride or by chlorina-tion of methane (Key et al., 1980; Edwards et al., 1982a;Holbrook, 1992). In almost all of the commercial uses,methyl chloride is reacted to form another product(ATSDR, 1998). The current principal uses are in theproduction of silicones and also as a general methylatingagent. The use of methyl chloride in the manufacture ofsynthetic rubber, its refrigerant and extractant applica-tions, and its use as a tetramethyllead intermediate nowhave secondary importance (Holbrook, 1992).

Methyl chloride

7

Indirect sources of methyl chloride are tobaccosmoke, turbine exhaust (Wynder & Hoffmann, 1967;Graedel, 1978; Häsänen et al., 1990), incineration ofmunicipal and industrial waste (Graedel & Keene, 1995),chlorination of drinking-water, and sewage effluent(Abrams et al., 1975).

The current production capacity of methyl chloridein the USA has been estimated to be about 0.417 × 106

tonnes per year (CMR, 1995). The production in Japan in1996 was 0.13 × 106 tonnes (Chemical Daily Co. Ltd.,1998).

It has been concluded that well over 90%, andperhaps as much as 99%, of ambient air concentrationson a global scale appear to originate from naturalsources rather than from anthropogenic sources(ATSDR, 1998). Edwards et al. (1982b) estimated theemissions of methyl chloride during production,transport, storage, and use to be approximately 0.02 × 106

tonnes per year, corresponding to nearly 6% of theamount produced. According to this estimate,anthropogenic sources would account for 1–2% of thetotal release, including natural sources. Other estimatesof the global yearly release from anthropogenic sourcesare in the range of 0.024–0.6 × 106 tonnes (Watson et al.,1980; Gribble, 1992; Dowdell et al., 1994), the higherestimate including indirect anthropogenic sources andpossibly also biomass burning.

Methyl chloride, which is the most prevalent halo-genated methane in the atmosphere, is present in thetroposphere at a concentration of about 1.2 µg/m3

(0.6 ppb) (WMO, 1994). It has been calculated that at aproduction rate of about 3.5 × 106 tonnes per year, thesteady-state mixing ratio of 1.2 µg/m3 (0.6 ppb) ismaintained given an atmospheric lifetime in the order of 2years (WMO, 1994). Estimates of the total global annualrelease of methyl chloride from all sources are around 5 ×106 tonnes (Rasmussen et al., 1980; Logan et al., 1981;Edwards et al., 1982b; Dowdell et al., 1994; WMO, 1994;Fabian et al., 1996). According to ATSDR (1998), thetotal release from all sources amounts to approximately3.2–8.2 × 106 tonnes per year.

Over the Pacific Ocean, the concentration ofmethyl chloride is higher in the lower troposphere thanin the higher layers. However, over the continents, theconcentration is independent of the altitude. Thus, theocean seems to be a source of methyl chloride (Geckeler& Eberhardt, 1995). In the oceans, algae, especiallyplanktonic algae, are considered to be responsible formost of the methyl chloride production. However, thishas not been fully proven. Phytoplankton have beenshown to produce methyl chloride in laboratory studies(Tait & Moore, 1995). An alternative model is that methylchloride is formed as a result of exchange processesbetween methyl iodide and chlorine ions in seawater

(Isidorov, 1990). Estimates of the global yearly release ofmethyl chloride from marine sources are in the range 1–8× 106 tonnes (Watson et al., 1980; Singh et al., 1983;Isidorov, 1990).

Terrestrial species also produce methyl chloride.The activity of methyltransferases, believed to beresponsible for methyl chloride production, has beenobserved in several herbaceous species (Saini, 1995).According to Harper et al. (1988), 34 species of fungi arealso known to biosynthesize methyl chloride.

Estimates of the global annual release of methylchloride from biomass burning are in the range 0.4–1.8 ×106 tonnes (Watson et al., 1980; Andreae, 1991, 1993;Lobert et al., 1991; Rudolph et al., 1994, 1995). The majorpart of the methyl chloride released from biomassburning originates from forest fires in the tropics(Andreae et al., 1994). The estimated global release ofmethyl chloride from temperate and boreal biomass fireshas been calculated to be 0.012 × 106 tonnes per year(Laursen et al., 1992). Low-intensity, inefficient combus-tion and high chlorine content of the biomass promotemethyl chloride formation (Reinhardt & Ward, 1995).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

Most methyl chloride discharged to the environ-ment will be released to air. The principal sink for methylchloride in the troposphere is chemical reaction withhydroxyl radicals (ASTDR, 1990; Graedel & Keene, 1995;Fabian et al., 1996). The rate constant for this reaction isapproximately 4.3 × 10–14 cm3/s per molecule at 25 °C(NASA, 1981; Atkinson, 1985). Atmospheric lifetimeestimates range from 1 to 3 years (Atkinson, 1985; BUA,1986; Warneck, 1988; ATSDR, 1990; WMO, 1990, 1994;Fabian et al., 1996; Houghton et al., 1996). Surfacedeposition, rainout, and washout are unimportant sinksfor methyl chloride (Graedel & Keene, 1995).

Estimates of the amount of methyl chloridereaching the stratosphere vary considerably. Borchers etal. (1994) claim that the contribution of methyl chloride tothe stratospheric chlorine budget is significant. Crutzen& Gidel (1983) estimated the flux of methyl chloride tothe stratosphere to be about 2 × 106 tonnes per year or20–25% of the total annual stratospheric chlorine input.According to Fabian et al. (1996), only a fraction (lessthan 10%) of the amount of methyl chloride emittedreaches the stratosphere. Edwards et al. (1982b) claimthat about 6% of the methyl chloride released reachesthe stratosphere (corresponding to 0.3 × 106 tonnes peryear). According to Graedel & Crutzen


8

Figure 1. Global budget for tropospheric methyl chloride (as tonnes chlorine per year). The budget is based on an averageconcentration of methyl chloride in the troposphere of 1.3 µg/m3 (0.62 ppb), a lifetime of 1.5 years, and a tropospheric burden of

about 3.7 × 106 tonnes chlorine per year (adapted from Graedel & Keene, 1995).

(1993) and Graedel & Keene (1995), only 0.8% (corres-ponding to 0.03 × 106 tonnes chlorine per year) isexpected to reach the stratosphere. A global budget fortropospheric methyl chloride is shown in Figure 1.

The ability of the ozone layer to absorb ultravioletradiation shorter than 290 nm should exclude directphotolysis in the troposphere, because methyl chloridedoes not absorb any radiation above 290 nm (BUA,1986). In the stratosphere, photodissociation will occurat a rate approximately equal to its reaction with hydroxylradicals (Robbins, 1976). The chlorine radicals that aregenerated contribute to ozone depletion. Methylchloride has been shown to photochemically decomposeat 185 nm. Photooxidation products in the gas phasewere carbon dioxide, carbon monoxide, formic acid,formyl chloride, water, and hydrogen chloride (Gürtler &Kleinermanns, 1994).

The stratospheric steady-state ODP of methylchloride has been determined to be 0.02 relative to CFC-11 (ODP = 1) (Solomon et al., 1992; WMO, 1994; Fabianet al., 1996). Estimates of the amount of methyl chloridereaching the stratosphere, and thereby also itscontribution to ozone depletion, vary considerably.However, as estimated from figures presented by WMO(1994), methyl chloride contributes approximately 15%(0.5 ppb) of the total (3.3 ppb) equivalent effectivestratospheric chlorine. The term “equivalent effectivestratospheric chlorine” includes both stratosphericchlorine and bromine ("1 = 40) and also considers the

dissociation rate of each compound involved in ozonedepletion.

A radiative forcing value of 0.0053 W/m2 per partper billion has been determined for methyl chloride. Thisvalue is about 2% of the forcing of CFC-11 and about300 times the forcing of carbon dioxide, on a permolecule basis (Grossman et al., 1994). Houghton et al.(1996) gave the radiative forcing value as 0 W/m2 formethyl chloride. The global warming potential (GWP)has been calculated to be about 25, relative to carbondioxide (GWP = 1), at a time scale of 20 years (Grossmanet al., 1994).

As the current concentration of methyl chloride

in the atmosphere is relatively low, approximately1.2 µg/m3 (0.6 ppb), the contribution of this substance tothe greenhouse effect will not become a problem unlesslarge releases of this gas occur (Grossman et al., 1994).WMO (1994) also considers that the contribution ofmethyl chloride to climate forcing is minimal.

The contribution of methyl chloride to the creationof photochemical air pollution is not significant becauseof its relatively low reactivity and low amounts emitted.The photochemical ozone creation potential (POCP)of methyl chloride has been determined to be 3.5(integrated ozone formation over 5 days) relative to thatof ethylene (POCP = 100) (Derwent et al., 1996).

Reactive chlorine in the lower atmosphere (asdistinguished from chlorofluorocarbon-derived chlorine

1 In the stratosphere, each bromine atom is assumed tobe 40 times more damaging to ozone than each chlorine atom (WMO, 1994).

CH3Clβ= 3.7x106 tonnes

∆≈ 0

Rainout/washout≈ 0.0012 x 106 tonnes

β= Tropospheric burden∆= Tropospheric growth rate

Marine algae4 ± 2 x 106 tonnes

Biomass combustion0.5 ± 0.2 x 106 tonnes

Industrial0.3 ± 0.1 x 106 tonnes

HO-reaction4 ± 1 x 106 tonnes

Ocean hydrolysis0.3 ± 0.6 x 106 tonnes

Transport to the stratosphere0.03 ± 0.01 x 106 tonnes

Methyl chloride

9

in the stratosphere) is supposed to be important inconsiderations of precipitation acidity, corrosion ofmetals and alloys, foliar damage, and chemistry of themarine boundary layer. The tropospheric reactivechlorine burden of approximately 8.3 × 106 tonneschlorine is dominated by methyl chloride (~45%) andtrichloroethane (~25%) (Graedel & Keene, 1995).

If methyl chloride is released into water, it will belost primarily by volatilization. The volatilization half-lifehas been calculated to be 2.1 h in a model river (Lyman etal., 1982). The volatilization half-lives of methyl chloridein a pond and in a lake have been estimated to be 25 hand 18 days, respectively, using the model EXAMS(ATSDR, 1990). The low log Kow (0.91) of methyl chlorideindicates that the substance does not tend toconcentrate in sediments.

The transformation of methyl chloride by hydrol-ysis is probably negligible under acid and neutral condi-tions. Under basic conditions, slow hydrolysis takesplace, yielding methanol as a transformation product(Simon, 1989). Hydrolytic half-lives range from 31 days(pH 11) to 2.5 years (pH not given) at 20–25 °C (Zafiriou,1975; Mabey & Mill, 1976, 1978; Simon, 1989). Thehydrolytic half-life of methyl chloride in seawater varieswith temperature (0–30 °C) from 0.5 to 77 years (Elliott &Rowland, 1995). Laboratory data indicate that thephotochemical transformation of methyl chloride in wateris negligible (Mabey & Mill, 1976).

Methyl chloride was not readily biodegraded in astandardized “closed bottle test” (MITI, 1992). However,several isolated bacterial strains have been shown todegrade methyl chloride under both aerobic (Stirling &Dalton, 1979; Hartmans et al., 1986; Bartnicki & Castro,1994; Chang & Alvarez-Cohen, 1996) and anaerobicconditions (Traunecker et al., 1991; Braus-Stromeyer etal., 1993; Dolfing et al., 1993; Leisinger & Braus-Stromeyer, 1995). A half-life of less than 11 days wasestimated for the anaerobic biodegradation of methylchloride in groundwater, based on laboratory dataobtained under conditions favourable for anaerobicbiodegradation (Wood et al., 1985).

The very low log Kow (0.91) of methyl chlorideindicates that it will not tend to adsorb to soil (Lyman etal., 1982). The adsorption coefficient, Koc, has beencalculated to be 5, based on physical/chemical data(ATSDR, 1990). The very high vapour pressure and lowadsorption to soil suggest that methyl chloride presentnear the soil surface will rapidly be lost by volatilization(ATSDR, 1990; HSDB, 1996). As it is not expected toadsorb to soil, methyl chloride present in deeper soil

layers may to some extent leach into the groundwater, aswell as diffuse to the surface and volatilize (ATSDR,1990; HSDB, 1996). In groundwater, methyl chloride isexpected to biodegrade or hydrolyse very slowly(ATSDR, 1990; HSDB, 1996). The cumulative volatili-zation loss of methyl chloride, from a depth of 1 mbeneath ground, has been calculated to be at least 70%and 22% in 1 year for a sandy soil and a clay soil,respectively (Jury et al., 1990).

There are no experimental studies on bioaccumu-

lation. However, only a minor accumulation in biotawould be expected on the basis of the low log Kow. Abioconcentration factor of 2.9 has been calculated basedon the log Kow (ATSDR, 1990).

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

Background concentrations of methyl chloride inthe troposphere are around 1.2 µg/m3 (0.6 ppb), rangingfrom about 1.0 to 1.4 µg/m3 (from 0.5 to 0.7 ppb) (Cox etal., 1976; Cronn et al., 1976, 1977; Pierotti & Rasmussen,1976; Singh et al., 1977, 1979, 1983; Graedel, 1978; Khalil& Rasmussen, 1981, 1993; Guicherit & Schulting, 1985;Gregory et al., 1986; Warneck, 1988; Rudolph et al., 1992;Singh et al., 1992; Atlas et al., 1993; WMO, 1994; Graedel& Keene, 1995; Fabian et al., 1996). In the stratosphere,the concentration of methyl chloride decreases withaltitude. Concentrations in the Arctic stratosphere inMarch 1992 ranged from 0.60 to 0.082 µg/m3 (from 0.29 to0.04 ppb) at altitudes of 11–22 km (von Clarmann et al.,1995). In May 1985, at a latitude of 26–30 °N, Zander etal. (1992) found methyl chloride concentrations rangingfrom 0.12 to 0.050 µg/m3 (from 0.058 to 0.024 ppb) ataltitudes of 12–22 km. Near the tropical tropopause(23.8–25.3 °N, 15–17 km altitude), the mean methylchloride concentration was measured to be 1.1 µg/m3

(0.531 ppb) during January–March 1992 (Schauffler et al.,1993).

Numerous measurements of methyl chloride levelsin air have been performed, especially in the USA. Themean or median concentrations of methyl chloridemeasured in the air of rural/remote sites in the USA wereabout 1.0–2.7 µg/m3 (0.5–1.3 ppb), with the majority ofthe values below 2.1 µg/m3 (1.0 ppb); the maximumconcentration measured was 4.3 µg/m3 (2.1 ppb)(Grimsrud & Rasmussen, 1975; Robinson et al., 1977;


10

Singh et al., 1977, 1981b; Brodzinsky & Singh, 1983;Rasmussen & Khalil, 1983; Shah & Singh, 1988). Insamples from urban/suburban areas in the USA, themean/median concentrations were in the range of 0.27–6.2 µg/m3 (0.13–3.0 ppb), with the majority of the valuesin the range 1.0–2.3 µg/m3 (0.5–1.1 ppb); the highestconcentration found was 25.0 µg/m3 (12.1 ppb) (Singh etal., 1977, 1979, 1981a, 1982, 1992; Brodzinsky & Singh,1983; Edgerton et al., 1984; Shah & Singh, 1988; Rice etal., 1990; US EPA, 1991a, 1991b; Evans et al., 1992; Kellyet al., 1994; Spicer et al., 1996). Methyl chlorideconcentrations in three Japanese cities ranged from 4.5to 35 µg/m3 (from 2.2 to 17 ppb) (Furutani, 1979). In Delft,the Netherlands, and Lisbon, Portugal, concentrations of6.2 µg/m3 (3.0 ppb) (Guicherit & Schulting, 1985) and 4.5µg/m3 (2.2 ppb) (Singh et al., 1979), respectively, werefound.

From these data, it appears that the concentrationsof methyl chloride are slightly higher in the air of urban/suburban sites than at rural/remote sites. However, adirect comparison is difficult, because samples in urban/suburban areas were probably often taken at groundlevel, while several measurements of rural/remote areaswere made at higher altitudes.

Methyl chloride has also been occasionallydetected in water, soil, and biota. A few studies onmeasurements of methyl chloride in drinking-water wereidentified, most of them performed in the USA andCanada (Abrams et al., 1975; Coleman et al., 1976;Burmaster, 1982; Mariich et al., 1982; Otson et al., 1982;Otson, 1987). A maximum concentration of 44 µg/litrewas measured in a drinking-water well (Burmaster, 1982).

In measurements of groundwaters in the USA,

concentrations of methyl chloride ranged from notdetectable up to 100 µg/litre, found at a former waste siteof a chemical factory (Page, 1981; Burmaster, 1982;Sabele & Clark, 1984; Lesage et al., 1990; Plumb, 1991;Rosenfeld & Plumb, 1991). The substance was detectedin groundwaters at 20 of 479 waste disposal sites in 1991(Plumb, 1991).

In surface water samples in North America, theconcentrations ranged from not detectable up to224 µg/litre, the highest value reported from New Jersey,USA, in the 1970s (Page, 1981; Otson et al., 1982; GreatLakes Water Quality Board, 1983; Granstrom et al., 1984;Staples et al., 1985; Otson, 1987). In the only Europeanstudy found (Hendriks & Stouten, 1993), a maximumconcentration of 12 µg/litre in the river Rhine wasreported. In seawater samples collected near the surface,

methyl chloride was mostly found at 0.01–0.05 µg/litre(Lovelock, 1975; Pearson & McConnell, 1975; NAS,1978; Singh et al., 1979, 1983; Edwards et al, 1982b);however, a higher concentration of 1.2 µg/litre wasreported from a measurement near the shore of California,USA (Singh et al., 1979).

Methyl chloride was detected in soils at 34 wastesites and in sediments at 13 waste sites in the USA(HazDat, 1998) and in 1 of 345 sampling stations of theUS EPA STORET database, at a concentration of<5 µg/kg (Staples et al., 1985). Methyl chloride was alsodetected in soil at an electronic industrial site in SãoPaulo, Brazil (Gomes et al., 1994). No data were found onmethyl chloride levels in sediment. According to the USEPA STORET database, methyl chloride was detected in1% of analysed samples of fish and seafood (Staples etal., 1985).

6.2 Human exposure

Data given in section 6.1 suggest that humans areexposed to methyl chloride in ambient air. Backgroundconcentrations are around 1.2 µg/m3 (0.6 ppb). In urbanareas, mean and median concentrations generally seemto be slightly higher, 1.0–2.3 µg/m3 (0.5–1.1 ppb). How-ever, individual measurements may be much higher. Thehighest value found in the literature was 35 µg/m3

(17 ppb).

Workplace concentrations have been measured infour US chemical plants (NIOSH, 1980). Three of theplants produced methyl chloride. The personal 8-h time-weighted average concentrations in the three plantsranged from 18.4 to 25.6 mg/m3 (from 8.9 to 12.4 ppm),from <0.4 to 15.5 mg/m3 (from <0.2 to 7.5 ppm), and from<0.2 to 26.2 mg/m3 (from <0.1 to 12.7 ppm), respectively.In the fourth plant, where methyl chloride was used as ablowing agent in the production of polystyrene foam,the personal exposures ranged from 6.2 to 44.2 mg/m3

(from 3.0 to 21.4 ppm). In a Dutch methyl chlorideproduction plant, individual 8-h time-weighted averagesof methyl chloride exposure in the air ranged from 62 to186 mg/m3 (from 30 to 90 ppm) (van Doorn et al., 1980).

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY

MAMMALS AND HUMANS

The most important route of exposure of methylchloride in humans is via the respiratory pathway. Data

Methyl chloride

11

on methyl chloride toxicokinetics cover only inhalation;no relevant information on other routes of administrationwas located in the literature.

7.1 Absorption

In humans as well as in experimental animals,methyl chloride is readily absorbed through the lungsfollowing inhalation (Andersen et al., 1980; Stewart et al.,1980; Landry et al., 1983; Nolan et al., 1985; Löf et al.,2000). In human volunteers exposed to 21 or 103 mgmethyl chloride/m3 (10 or 50 ppm) for 6 h or to 21 mg/m3

(10 ppm) for 2 h, steady state was reached during thefirst exposure hour (Nolan et al., 1985; Löf et al., 2000). Inrats, equilibrium between uptake and elimination wasalso obtained within 1 h (Landry et al., 1983).

7.2 Distribution

After rats were exposed to 14C-labelled methylchloride by inhalation, radioactivity was found to thelargest extent in the liver, kidneys, and testes and to asmaller extent in the brain and lungs (Redford-Ellis &Gowenlock, 1971; Kornbrust et al., 1982; Landry et al.,1983). The presence of residues was, however, attributedto the metabolism of methyl chloride to formaldehydeand formate and subsequent incorporation of the radio-labelled carbon atom into tissue macromolecules throughsingle-carbon anabolic pathways (Kornbrust & Bus,1982; Kornbrust et al., 1982). Methyl chloride may alsobind to macromolecules, especially protein, and to aminimal extent probably also to DNA (Kornbrust et al.,1982; Vaughan et al., 1993).

7.3 Metabolism and elimination

In humans as well as in animals, methyl chlorideis mainly metabolized by conjugation with glutathione.S-Methylglutathione can then be further metabolized toS-methylcysteine and methanethiol (Redford-Ellis &Gowenlock, 1971; Bus, 1982; Landry et al., 1983). To alesser extent, methyl chloride is also metabolized micro-somally via cytochrome P-450 in rat liver, resulting in theformation of formaldehyde and formate (Kornbrust &Bus, 1983). Formaldehyde and formate may also beformed via the glutathione pathway (Kornbrust & Bus,1983).

Inhalation of methyl chloride by male B6C3F1 miceresulted in a concentration-dependent depletion ofglutathione in liver, kidney, and brain. The depletion wasmost pronounced in the liver, where a 6-h inhalationexposure to 206 mg/m3 (100 ppm) decreased the gluta-thione level by 45%, and exposure to 5160 mg/m3

(2500 ppm) reduced the glutathione content to 2% ofcontrol levels (Kornbrust & Bus, 1984).

Metabolites from methyl chloride are excreted inthe urine and in the expired air. S-Methylcysteine hasbeen identified in the urine of occupationally exposedhumans and rats (van Doorn et al., 1980; Landry et al.,1983), and formic acid has been found in rat urine(Kornbrust & Bus, 1983). Further, carbon dioxide hasbeen shown to be the major final metabolite of methylchloride, accounting for nearly 50% of the radiolabelledmaterial recovered after a 6-h exposure of rats to methylchloride (Kornbrust & Bus, 1983). Methyl chloride isalso excreted unmetabolized via the lungs, as seen instudies in volunteers (Stewart et al., 1980; Nolan et al.,1985; Löf et al., 2000).

The plausible metabolic pathways of methylchloride in mammals are shown in Figure 2.

7.4 Genetic polymorphism and sex,strain, organ, and species differences

In several studies in volunteers, large inter-individual differences in concentrations of methylchloride in breath and blood and amounts of excretedurinary metabolites have been observed (Stewart et al.,1980; van Doorn et al., 1980; Putz-Anderson et al., 1981a;Nolan et al., 1985; Löf et al., 2000).

One explanation for the large interindividualdifferences in uptake and elimination of methyl chloridein humans is the presence or absence of the enzymeGSTT1 (Coles & Ketterer, 1990). The presence of theGSTT1 gene leads to conjugation between glutathioneand methyl chloride (GSTT1+), and the absence of thegene leads to no conjugation (GSTT1!) (Pemble et al.,1994).

About 60% of blood samples from a Germanpopulation showed a significant metabolic elimination ofmethyl chloride, whereas 40% did not (Peter et al., 1989).In a Swedish population, Warholm et al. (1994) found alarge interindividual variation in the glutathionetransferase activity in erythrocytes treated with methylchloride, as 43% had a high activity, 46% had a mediumactivity, and 11% lacked activity. Nelson and co-workers(1995) mapped the ethnic differences in the prevalence ofthe null genotype (GSTT1!) and found the highestprevalence among Chinese (64%), followed by Koreans(60%), African-Americans (22%), and Caucasians (20%),and the lowest among Mexican-Americans (10%).Warholm et al. (1994) concluded that the GSTT1polymorphism leads to three different phenotypes inhumans — namely, non-conjugators (NC), low conjuga-tors (LC), and high conjugators (HC). In a comparisoninvolving the three human phenotypes and experimentalanimals, Thier et al. (1998) established that GSTT1activity towards methyl chloride in human erythrocytes


12

Figure 2: Metabolic pathways for methyl chloride (slightly modified after Bus, 1982).

CH3 ClMethyl chloride in exhaled air

CH3 Clexcretion of

especially proteins

alkylation ofmacromolecules,

excretionvia urine

HCHOFormaldehyde

HCOOHFormic acid

GS CH3S-Methylglutathione

S-MethylcysteineCH3SCH2CHCOOH

NH2

2-via metabolism

incorporationin the tissues

exhalationCO2

H2SHydrogensulphide

CH3 SHMethanethiol

one carbonpool

+ glutathione+glutathione transferase

+Cytochrome P450

SO4

Methyl chloride

13

(HC, LC, or NC) and in liver and kidney cytosol inexperimental animals decreased in the following order:female mouse (B6C3F1) > male mouse (B6C3F1) > HC >rat (Fischer 344) > LC > hamster (Syrian golden) > NC. Inanimals, GSTT1 activity towards methyl chloride was 2–7times higher in liver cytosol than in kidney cytosol(Thier et al., 1998).

The human GSTT1 polymorphism was illustrated ina study on the toxicokinetics of methyl chloride involunteers phenotyped for GSTT1 activity (HC, LC, andNC) (Löf et al., 2000). It was seen that conjugators withthe fast GSTT1 activity (HC) had the highest respiratorynet uptake (respiratory net uptake equals the differencebetween the amount of methyl chloride in inhaled andexhaled air during exposure) of methyl chloride, whereassubjects with no GSTT1 activity (NC) had a smallerrespiratory net uptake. At the end of the exposure, theconcentration of methyl chloride in blood declined morerapidly among volunteers with high (HC) and intermedi-ate (LC) GSTT1 activity than in those with no activity(NC). The area under the curve for NC was higher thanthose for HC and LC, and the area under the curve for LCwas higher than that for HC. Further, the clearance ofmethyl chloride by metabolism was high in fast conjuga-tors (HC) and close to zero in subjects with no GSTT1activity (NC).

In an investigation by Dekant et al. (1995), sex-,strain-, and species-specific bioactivation of methylchloride by cytochrome P-450 2E1 (CYP2E1) was seen inthe liver and kidneys of rats and mice. In kidneymicrosomes, the rate of oxidation of methyl chloride wassignificantly higher in male mice than in female mice andin rats of both sexes than in mice. It was also observedthat the rate of oxidation in kidney microsomes wasfaster in CD-1 mice and NMRI mice than in C3H/He andC57BL/6J mice. In erythrocytes from other species —rats, mice, cows, pigs, sheep, and rhesus monkeys — noconversion of methyl chloride was seen in erythrocytecytoplasm (Peter et al., 1989).

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

In B6C3F1 mice, the LC50 of methyl chloride viainhalation for 6 h was reported to be 4644 mg/m3

(2250 ppm) in males and 17 544 mg/m3 (8500 ppm) infemales (White et al., 1982). The data on lethal doseswere obtained from an abstract without any further

details. In another experimental series, where no clinicalacute toxicity symptoms except for lethality werereported, five male B6C3F1 mice were exposed (wholebody) to methyl chloride at concentrations of 1032–5160 mg/m3 (500–2500 ppm) in increments of 1032 mg/m3

(500 ppm) (Chellman et al., 1986a). The6-h LC50 value was determined to be 4540 mg/m3

(2200 ppm). In this study, lethality as well as hepato-toxicity, renal toxicity, and cerebellar degeneration wereprevented in mice exposed to 5160 mg/m3 (2500 ppm) for6 h by pretreatment with the glutathione synthesisinhibitor L-buthionine-S,R-sulfoximine, indicating thatmetabolism of methyl chloride by glutathione conjuga-tion increases the toxicity.

Although other single-exposure inhalation toxicitystudies in small rodents exist, they are very old (pub-lished before 1950) and do not meet current standards,and they are therefore not included in the presentevaluation on methyl chloride. In any case, the resultsare similar to those reported here.

No single-exposure studies on methyl chloridetoxicity following other routes of administration werelocated in the literature.

In conclusion, based on scarce data, the acuteinhalation toxicity in male mice seems to be fairly low,with an LC50 value above 4128 mg/m3 (2000 ppm). Inmice, a sex difference in susceptibility to methyl chloridewas indicated.

8.2 Irritation and sensitization

No data on irritation or sensitization were available.

8.3 Short-term exposure

The toxic response to methyl chloride was studiedin Fischer 344 rats (10 animals per sex per group)exposed by inhalation to 0, 4128, 7224, or 10 320 mgmethyl chloride/m3 (0, 2000, 3500, or 5000 ppm) for6 h/day for 9 days (5 days of exposure followed by a 2-day break in exposure, then a further 4 days’ exposure)and in C3H, C57BL/6, or B6C3F1 mice (5 animals perstrain per sex per group) exposed by inhalation to 0,1032, 2064, or 4128 mg methyl chloride/m3 (0, 500, 1000, or2000 ppm) for 6 h/day for 12 days (Morgan et al., 1982).The animals were sacrificed 18 h after their last exposureor immediately after the day’s exposure if they werefound to be moribund. Clinical observations andhistopathological investigations of the brain, liver,kidneys, and adrenal glands in both species and oftestes and epididymis of rats were reported. As a resultof high intoxication, some rats from the two highest dosegroups were sacrificed in extremis (6 males, 5 females:


14

10 320 mg/m3 [5000 ppm]; 2 females: 7224 mg/m3 [3500ppm]). No information was given on whether effectswere seen in animals with a fulfilled exposure scheme orwith an interrupted scheme.

Clinically, especially in the higher dose groups, therats were seriously affected by the exposure, and symp-toms such as lack of coordination of the forelimbs, paral-ysis of the hindlimbs, convulsive seizures, perineal urinestaining, and diarrhoea were recorded. In the kidneys,concentration-related degeneration and necrosis of theproximal convoluted tubules could be seen (lowest-observed-adverse-effect level or LOAEL [males] =4128 mg/m3 [2000 ppm]; LOAEL [females] = 7224 mg/m3

[3500 ppm]). Testicular degeneration in the seminiferoustubules (LOAEL = 4128 mg/m3 [2000 ppm]) and adrenalfatty degeneration (LOAEL [males and females] = 7224mg/m3 [3500 ppm]) were also concentration related. Mostanimals showed minimal hepatocellular response,including loss of normal areas of cytoplasmic basophiliaand variable degeneration. Rats in the 10 320 mg/m3 (5000ppm) group showed degeneration of the cerebellargranular layer.

All mice in the highest dose group died before orwere moribund at exposure day 5. No apparent straindifferences could be seen from available mortality data.Prior to death, some of the animals developed moderateto severe ataxia, and all females developed haematurea.In the 2064 mg/m3 (1000 ppm) group, females developedhaematurea to a much larger extent than males. Cerebellardegeneration of the same type as in rats was seen at the2064 and 4128 mg/m3 (1000 and 2000 ppm) concentrationlevels in female C57BL/6 mice only. The other two mousestrains did not develop brain lesions. On the contrary, inall three mouse strains, degeneration in the kidneys wasfound at 4128 mg/m3 (2000 ppm), and basophilic renaltubules were observed at 2064 mg/m3 (1000 ppm).Hepatocellular necrosis was confined to the 4128 mg/m3

(2000 ppm) group in male C57BL/6 and B6C3F1 mice.Hepatocellular degeneration was seen in lower dosegroups, mainly in the 1032 and 2064 mg/m3 (500 and 1000ppm) groups of male and female C57BL/6 mice. Liverdamage in the low dose groups was considered mild andconsisted of, for example, variable degrees of glycogendepletion and cytoplasmic vacuolization.

From these studies, which highlight species andsex differences in methyl chloride-induced toxicity, a ratLOAEL of 4128 mg/m3 (2000 ppm) could be derived fromthe testicular, epididymal, renal, and to some extenthepatocellular findings, and a mouse LOAEL of1032 mg/m3 (500 ppm) could be derived from the hepato

cellular effects. A no-effect level could not be obtainedfor either species.

The ultrastructure of the methyl chloride-inducedcerebellar lesions observed in mice and rats by Morganand co-workers (1982) and in guinea-pigs (reportedunder section 8.4) by von Kolkmann & Volk (1975) wasfurther studied by Jiang et al. (1985) in female C57BL/6mice. The mice were exposed for 6 h/day, 5 days/week,for 2 weeks to 0 or 3096 mg methyl chloride/m3 (0 or 1500ppm). In all treated mice, degenerative changes ofvarying severity were observed in the granular cell layerof the cerebellum. The lesions in the granular cells werecharacterized by nuclear and cytoplasmic condensationof scattered granule cells and also by watery swellingand disruption of granule cell perikarya. From poorlyreported clinical observations, neurological deficiency inmotor coordination was seen. Few kidney abnormalitieswere detected, indicating that the cerebellar degenera-tions were not secondary to kidney lesions.

In a study primarily designed to investigate thecorrelation between neurotoxicity and continuousversus intermittent exposure to methyl chloride, Landryet al. (1985) exposed female C57BL/6 mice for 11 dayseither continuously (22.5 h/day) to 31, 103, 206, 310, or413 mg/m3 (15, 50, 100, 150, or 200 ppm) or intermittently(5.5 h/day) to 310, 826, 1651, 3302, or 4954 mg/m3 (150,400, 800, 1600, or 2400 ppm). A quantitative relationshipbetween neurotoxicity and continuous and intermittentexposure was not observed. The lowest effect level forclinical observations, similar to those reported earlier byDunn & Smith (1947) and later by von Kolkmann & Volk(1975), Morgan et al. (1982), and Jiang et al. (1985), was206 mg/m3 (100 ppm) for continuous exposure and 3302mg/m3 (1600 ppm) for intermittent exposure. Cerebellarlesions were recorded at 206 and 826 mg/m3 (100 and 400ppm) for continuous and intermittent exposure,respectively. A statistically significant decrease wasobserved in relative and absolute thymus weights at the31, 103, and 310 mg/m3 (15, 50, and 150 ppm) exposurelevels (continuous exposure) and also at the 3302 and4954 mg/m3 (1600 and 2400 ppm) levels (intermittentexposure). Although the decrease in thymus weight at31 mg/m3 (15 ppm) suggests that this level might be aLOAEL, the absence of a methyl chloride-induced effecton the thymus or its function in long-term studiesindicates that these weight decreases are of uncertainsignificance. From the results, a LOAEL of 826 mg/m3

(400 ppm) for intermittent exposure (cerebellar lesions)and of 206 mg/m3 (100 ppm) for continuous exposure canbe concluded.

To assess the role of inflammation in the toxicity ofmethyl chloride, especially to sperm, Chellman et al.

Methyl chloride

15

(1986b) exposed male Fischer 344 rats for 5 days, 6 h/day,to 0 or 10 320 mg methyl chloride/m3 (0 or 5000 ppm) withand without the presence of the anti-inflammatory agent3-amino-1-(m-[trifluoromethyl]phenyl)-2-pyrazoline(BW755C), an inhibitor of leucotriene and prostaglandinsynthesis. Lesions that were induced by exposure tomethyl chloride alone were epididymal spermgranulomas, degeneration of cerebellar granule cells,necrosis of renal proximal tubules, cloudy swelling ofhepatocytes, and vacuolization of cell cytoplasm in theouter region of zona fasciculata in the adrenal glands.Virtually none of these effects was seen when BW755Cwas given in parallel with methyl chloride, stronglysuggesting an inflammatory response.

The question as to whether methyl chloride-induced renal tumours in male mice are evoked by themetabolic intermediate formaldehyde was studied byJäger et al. (1988). Fischer 344 rats and B6C3F1 miceof both sexes in groups of five were exposed to 0 or 2064mg methyl chloride/m3 (0 or 1000 ppm) for 6 days, andDNA lesions (cross-links and single-strand breaks),glutathione transferase (GST) activity, and formaldehydedehydrogenase (FDH) activity were measured. It wasshown that the tumour formation in male mice is notbased on any obvious biochemical sex differences inenzymatic transformation with respect to FDH. Neither isthe metabolically formed formaldehyde likely to be theeffective carcinogen, as the characteristic formaldehyde-induced genetic damage is absent. However, the signifi-cant species difference between mice and rats — in thatmice, due to higher GST activity, especially in the kid-neys, seem to be more susceptible to methyl chloridetreatment — could not be ruled out. It was, for example,not shown if toxicity caused by the glutathione conjuga-tion pathway was due to a metabolite formed or to gluta-thione depletion, as suggested by Jäger et al. (1988).

In conclusion, after short-term exposure, the targetorgan in both rats and mice is the nervous system, withfunctional disturbances and cerebellar degeneration. TheLOAELs in mice are 206 and 826 mg/m3 (100 and400 ppm) upon continuous and intermittent exposure,respectively. Higher levels of exposure caused toxicity inthe kidney and liver in mice and in the testes, epididymis,and kidney in rats. A mouse LOAEL of 1032 mg/m3 (500ppm) could be derived from liver toxicity data. Thedecrease in thymus weight, unaccompanied byhistopathological changes, in mice exposed to 31 mg/m3

(15 ppm) was not corroborated by either a 90-day (CIIT,1979) or a 2-year study (CIIT, 1981) (reported in sections8.4 and 8.5, respectively). Because of this lack ofcorroboration, the decrease in thymus weight will not beforwarded to the sample risk characterization.

No toxicity data for short-term exposures otherthan those obtained from administration via the respira-tory pathway were located in the literature.

8.4 Medium-term exposure

To investigate methyl chloride-induced neurotox-icity, von Kolkmann & Volk (1975) exposed 19 guinea-pigs to 41 280 mg methyl chloride/m3 (20 000 ppm; 2vol% in a pressurized vessel) by inhalation for 61–70 days (10 min/day, 6 times/week). Clinically, inapproximately half of the animals in the treated group,ataxia, paresis of the hind legs, staggering, atacticmoving of the head, and retardation in spontaneousreaction and mobility were observed. No animal diedduring the exposure period. Histopathologically,necroses were seen in the cerebellar cortex in thegranular cell layer. Further, Purkinje’s cell necrosisoccurred. Considering the extremely high exposureconcentrations, the study can be used for descriptivepurposes only.

In a subchronic toxicity study, 80 Fischer 344 rats(40 per sex) and 80 B6C3F1 mice (40 per sex) wereexposed to methyl chloride by inhalation at concentra-tions of 0, 774, 1548, or 3096 mg/m3 (0, 375, 750, or 1500ppm) for 90 days (CIIT, 1979). Clinical observations anddata on food consumption, body and organ weights,haematology, clinical chemistry, urinalysis,ophthalmoscopic examination, gross pathology, andhistopathology were recorded.

Female mice in the 3096 mg/m3 (1500 ppm) dosegroup had significantly depressed total body weight atthe end of the exposure period. Absolute and/or relativeorgan weights were increased for heart, brain, spleen,liver, kidneys, and lungs in female mice (mainly in thehighest dose group) and in pancreas in male mice. Cyto-plasmic vacuolization of hepatocytes occurred in the twohighest dose groups and was considered compoundrelated. In the 1548 mg/m3 (750 ppm) dose group, vacuo-lization was seen 5 times as frequently in females as inmales. Exposure-related fluctuations in haematology andin clinical chemistry were observed but not consideredsignificant, as they were within the control range.Further, the methyl chloride-exposed mice had a highincidence of a mucopurulent conjunctivitis. However,this effect was probably not related to methyl chlorideexposure, as it was seen mainly in the 774 mg/m3 (375ppm) dose group. The available results indicate thatfemale mice are more sensitive than male mice to methylchloride exposure.

Male rats in all dose groups and females in the twohighest dose groups showed significantly decreasedabsolute body weight. In rats (males and/or females;mainly in the highest dose group), absolute and/or rela-


16

tive organ weights were increased for heart, brain, testes,ovaries, spleen, liver, kidney, pancreas, and adrenals.

In the 1979 CIIT study (which served as a pilot forthe 2-year chronic toxicity/carcinogenicity study by CIIT[1981]), no compound-related lesions were reported fromgross pathology or histopathology on kidneys, heart, ortestes. The absence of recorded organ lesions in micecould be due to a fairly high mortality, especially in thehighest dose group, in combination with the histologicalexamination applied. In the histopathologicalexamination, as a first step, the highest dose group wascompared with the control group. In the case of positivefindings, the control animals were thereafter comparedwith the 1548 mg/m3 (750 ppm) dose group and then the375 ppm (774 mg/m3) dose group. This procedure mightsuffer from a high mortality in the 3096 mg/m3 (1500 ppm)dose group and give rise to false negatives. No similarexplanation could be given for rats, as the mortalityduring the exposure period was low.

8.5 Long-term exposure andcarcinogenicity

In a 2-year inhalation study, Fischer 344 rats andB6C3F1 mice (120 animals per sex per group) wereexposed to 0, 103, 464, or 2064 mg methyl chloride/m3 (0,50, 225, or 1000 ppm) for 6 h/day, 5 days/week, with theobjective of determining the potential toxicological andoncogenic effects (CIIT, 1981). Planned interimnecropsies of the experimental animals were completed at6, 12, 18, and 24 months following initiation of exposure.As a result of high mortality in the mouse high-dosegroup, the scheduled 24-month sacrifice was carried outafter 21 or 22 months of exposure. After 6 or 12 months,10 rats per sex per dose group were scheduled to besacrificed, and after 18 or 24 months, 20 and 80 rats persex per dose group, respectively. Mice were scheduledfor sacrifice in groups of 10 per sex per dose group after6, 12, or 18 months and in groups of 90 per sex per dosegroup after 24 (or 21, 22 months). Data on body weights,clinical signs of toxic effects, clinical chemical analyses,gross pathology, and histopathology were recorded.

During the exposure period, rat survival was notaffected by methyl chloride exposure. However, mousesurvival was low in the 2064 mg/m3 (1000 ppm) dosegroup compared with the control animals. The highmortality occurred predominantly during the first6 months and was attributed by CIIT (1981) to fightingfor dominance. The number of rats and mice that diedduring the 2-year study for reasons other than plannedsacrifice is given in Table 2.

Total body weight gain was significantly reducedthroughout the exposure period for male and female ratsin the 2064 mg/m3 (1000 ppm) exposure group. Althoughfemale rats in the 464 mg/m3 (225 ppm) group and femalemice in the 2064 mg/m3 (1000 ppm) group also hadsignificantly decreased growth rates, these occurredperiodically and were not observed at the end ofexposure. The relative heart weight was increased infemale mice and male and female rats at 2064 mg/m3 (1000ppm). Otherwise, changes in relative or absolute organweights were seen at the 2064 mg/m3 (1000 ppm)exposure level for kidney, liver, heart, and brain in bothspecies and in testes in rats. For comparison with theshort-term exposure study by Landry et al. (1985),thymus weight was not affected by methyl chlorideexposure in the 2-year study.

Clinical observations on toxicity to the centralnervous system (hunched posture, tremor, andparalysis) were seen in mice in the highest dose groupbut not in rats.

In mice, statistically significant hepatocellularchanges (vacuolization, karyomegaly, cytomegaly, anddegeneration) were seen in male and female mice fromthe 2064 mg/m3 (1000 ppm) group. In male mice exposedto 2064 mg methyl chloride/m3 (1000 ppm), significantlyelevated serum glutamic–pyruvic transaminase (SGPT)values were seen, coupled with histopathologicalfindings in the liver. Elevated SGPT values were alsoobserved in the lower dose groups but were notcorrelated with any histopathological findings.

In the 2064 mg/m3 (1000 ppm) dose group in malemice, a large, statistically significant increase (P > 0.05)in the development of renal tubuloepithelial hyperplasia,hypertrophy, and/or karyomegaly, with onset at12 months, was observed. Further, in the same group,significant exposure-related increases (P < 0.05) innumbers of observed renal cortical adenomas as well asrenal adenocarcinomas (including those designed asrenal cortical adenocarcinomas and renal corticalpapillary cystadenocarcinomas) were noted in animalssacrificed or dying between 12 and 21 months (inci-dences of cortical renal lesions are found in Table 3).Cortical adenomas were also seen in two male mice in the464 mg/m3 (225 ppm) group. Although this increase wasnot of statistical significance, the adenomas were similarto those that occurred in the 2064 mg/m3 (1000 ppm)group and were therefore judged to be associated withthe methyl chloride exposure. In the 103 mg/m3 (50 ppm)group, there was a slightly increased incidence of renalcortical microcysts in male mice sacrificed at 24 monthscompared with the control males (6/32 vs. 1/20). Renalmicrocysts were also observed in the 464 mg/m3 (225ppm) group; the

Methyl chloride

17

Table 2: Number of rodents that died during the exposure period for reasons other than scheduled sacrifice.

Number of rodents that died

0 ppm 50 ppm 225 ppm 1000 ppm

Species male female

male female male female male female

Rats 15 23 12 19 12 23 14 19

Mice 75 33 62 34 62 25 93 73

Table 3: Total number of significant cortical renal lesions (malign and benign) observed in male B6C3F1 miceexposed to methyl chloride for 2 years.

Number of renal lesions/number of animals necropsied


Renal lesions m f m f m f m f

Cortex, adenocarcinoma 0/120 0/120 0/118 0/100 0/117 0/123 5/120 0/109

Cortex, papillary cysts,adenocarcinoma

0/120 0/120 0/118 0/100 0/117 0/123 1/120 0/109

Cortex, adenoma 0/120 0/120 0/118 0/100 2/117 0/123 12/120 0/109

Cortex, papillary cysts, adenoma 0/120 0/120 0/118 0/100 0/117 0/123 2/120 0/109

Cortex tubuloepithelium, hypertrophy,hyperplasia, and/or karyomegaly

0/120 0/120 0/118 0/100 0/117 0/123 44/120 0/109

increase, as compared with the control group, was not,however, significant in either males or females. Theincidence of renal cortical microcysts was not reported inanimals from the highest dose group. Since the micro-cysts appear to be variations of the same lesionobserved at higher exposure levels, they should beconsidered to be related to methyl chloride, although noconcentration dependence could be established.

Further, at 2064 mg/m3 (1000 ppm), degenerationand atrophy of the seminiferous tubules were seen, aswell as lymphoid depletion and splenic atrophy.

At the 18-month sacrifice, cerebellar lesions(degeneration and atrophy of the cerebellar granularlayer) were noted in male and female mice at the2064 mg/m3 (1000 ppm) level. Mice from the control, low,and intermediate exposure groups did not have lesionsin the granular cell layer of the cerebellum. At the 22-month sacrifice, similar but more extensive observationsin 17/18 females were reported from the 2064 mg/m3 (1000ppm) group (the only group examined at this timeperiod).

At the 18-month sacrifice, axonal swelling anddegeneration of minor severity were observed in thespinal nerves and cauda equina associated with thelumbar spinal cord. The effects occurred in most treatedanimals in all dose groups (controls: 1/5 males and 2/10females; 103 mg/m3 [50 ppm]: 4/5 males and 10/10females; 464 mg/m3 [225 ppm]: 5/5 males and 5/5 females;

2064 mg/m3 [1000 ppm]: 3/7 males and no data onfemales). The effects at each exposure level weresignificantly increased in each dose group as comparedwith control animals. However, no concentration–response relationship could be established. In the2064 mg/m3 (1000 ppm) dose group sacrificed at22 months, minimal to moderate swelling and degener-ation of the lumbar spinal nerves were recorded in 13 of18 female mice. Twelve of 18 females had similar lesionsin the thoracic spinal cord, and 6/18 females in thecervical spinal cord. Histopathological examinations ofmice in the 2064 mg/m3 (1000 ppm) dose group withunscheduled death showed high incidences of cerebellarlesions and axonal degeneration of lumbar spinal nerves,lesions similar to those found at the 18-month sacrifice.

In rats, exposure to methyl chloride at 2064 mg/m3

(1000 ppm) caused testicular lesions (bilateral, P > 0.05,and unilateral, P > 0.05, diffuse degenerations andatrophies of the seminiferous tubules). These lesionswere statistically significant as compared with thecontrol group and were first observed at the 6-monthsacrifice. Sperm granulomas were noted in three male ratsat 2064 mg/m3 (1000 ppm). No statistically significantchanges other than the effects on body weight gain wereseen in female rats. This indicates that the maximumtolerated dose used in the CIIT (1981) study might havebeen too low to induce toxicity in female rats.

Significant findings from the long-term studies inmice are disturbances of the nervous system and


18

induction of tumours and microcysts in male mice.Axonal swelling and degeneration of spinal nerves in allexposure groups suggest a LOAEL of 103 mg/m3

(50 ppm). This LOAEL is forwarded to the sample riskcharacterization. The observation of renal microcysts inthe 103 mg/m3 (50 ppm) dose group (although not con-centration related) supports the LOAEL of 103 mg/m3

(50 ppm). Further significant findings are the testicularlesions in rats. In male rats, testicular lesions occurred at2064 mg/m3 (1000 ppm). No toxic effects in females werereported.

No toxicity data from long-term exposure to methylchloride other than those obtained from administrationvia the respiratory pathway were located in the literature.

8.6 Genotoxicity and related end-points

For an overview of, and details on, the geno-toxicity studies, see Table 4. In all studies referred tobelow, methyl chloride was administered by inhalation,unless otherwise noted.

8.6.1 Studies in vitro

Using the Ames assay, methyl chloride was shownto induce gene mutations in Salmonella typhimuriumTA100 (Simmon et al., 1977) and in S. typhimuriumTA1535 (Andrews et al., 1976) in both the presence andabsence of metabolic activation. Further, a concentra-tion-related increase in the 8-azaguanine-resistantfraction in S. typhimurium was observed (Fostel et al.,1985).

Methyl chloride induced the adaptive response toalkylation damage in Escherichia coli regulated by theada protein, which suggests that methyl chloride is adirect DNA-alkylating agent (Vaughan et al., 1993).

Methyl chloride caused gene mutations in vitro inTK6 human lymphoblasts, as shown by a dose-relatedincrease in the mutant fraction (Fostel et al., 1985).

In the study by Fostel and co-workers (1985), noincrease in DNA strand breaks as measured by alkalineelution was observed. However, the outcome from thepositive control (methyl methane sulfonate [MMS]) wasquestionable, as unexpectedly high doses were neededfor a positive result. Thus, the mutagenic lesions pro-duced by methyl chloride might be either different fromthose produced by MMS or formed at a level below thethreshold of detection of alkaline solution.

DNA damage following methyl chloride exposurewas shown as a statistically significant enhancedtransformation of Syrian hamster embryo cells by SA7adenovirus (Hatch et al., 1983).

In vitro, 1–10% methyl chloride caused inductionof unscheduled DNA synthesis (UDS) in rat spermato-cytes and hepatocytes (Working et al., 1986).

Methyl chloride was shown to directly bind tobovine serum albumin. No further details were available(Kornbrust et al., 1982).

In TK/6 human lymphoblasts, methyl chlorideinduced a statistically significant concentration-relatedinduction of sister chromatid exchange (SCE) frequencyas well as significantly declined mitotic index and asignificant concentration-related increase in second-division metaphases (Fostel et al., 1985).

8.6.2 Studies in vivo

In vivo, methyl chloride did not cause induction ofUDS in rat spermatocytes, hepatocytes, or trachealepithelial cells at exposure concentrations of 6192–7224 mg/m3 (3000–3500 ppm) for 6 h/day for 5 days.However, exposure to 30 960 mg/m3 (15 000 ppm) for 3 hdid cause a marginal increase in UDS in hepatocytes(Working et al., 1986). The doses used were consideredbelow, but close to, the maximum tolerated dose.

In a macromolecular binding study, male rats wereexposed to 14C-labelled methyl chloride (specific activity25–70 dpm/nmol = 11.2–31.4 × 10–3 mCi/mmol), andaccumulation of 14C was measured in lipid, RNA, DNA,and protein from isolated liver, kidneys, lungs, andtestes (Kornbrust et al., 1982). Radiolabelled carbon wasfound in all tissues and fractions studied; however,methylation was not found. Pretreatment with the proteinsynthesis inhibitor cycloheximide or the folic acidantagonist methotrexate, which interferes with single-carbon metabolism, to a large extent inhibited most of the14C-incorporation in proteins and macromolecules,respectively. Further, the extent of incorporation ofmethyl chloride into proteins and lipids was consistentwith the rates of turnovers in these macromolecules.Therefore, the most likely mechanism for uptake ofmethyl chloride into macromolecules is via the one-carbon pool. However, this does not exclude thepossibility that methyl chloride might bind directly tomacromolecules to a lesser extent.

In a DNA binding assay, in which Peter et al.(1985) exposed rats and mice to 14C-labelled methylchloride, no methylation of guanine in DNA at N7 and/orO6 in liver and kidneys by methyl chloride was found.The specific activity in this study (13 mCi/mmol = 2.9 ×104 dpm/nmol) was about 3 orders of magnitude higherthan that used by Kornbrust et al. (1982).

Methyl chloride

19

Table 4: Genotoxicity of methyl chloride and related end-points.

Table 4 (contd)

Species Protocol Result Reference

Gene mutation in vitro; bacteria

S. typhimurium TA100 Ames test2.5–20%; 8 h; ± S9 mix

positive Simmon et al., 1977

S. typhimurium TA1535 Ames test0.5–20.7%; ± S9 mix

positive Andrews et al., 1976

S. typhimurium TM677(8-azaguanineresistance)

bacterial forward mutation assay 0, 5, 10, 20, or 30%; 3 h; strain deficient in metabolizingxenobiotics; no metabolizing system was added

positive Fostel etal., 1985

DNA damage in vitro; bacteria

E. coli B F26 adaptive response to alkylation damage (ada gene) positive Vaughan et al., 1993

Gene mutation in vitro; mammalian cells

human lymphoblastsTK6 (trifluorothymidineresistance)

gene mutation0, 1, 2, 3, 4, or 5%; 3 hpositive controls: ethyl methane sulfonate (EMS) or methylmethane sulfonate (MMS)

positive Fostel et al.,1985

DNA damage in vitro; mammalian cells

human lymphoblastsTK6

alkaline elution 0, 1, 3, or 5%positive controls: EMS or MMS

negative Fostel et al.,1985

Syrian hamster embryocells (primary SHE cells)

DNA damage and repair assay (DNA adenovirus SA7 transformation)0, 6000, 12 000, 27 000, 52 000, or 103 000 mg/m3 (0,3000, 6000, 13 000, 25 000, or 50 000 ppm); 2–20 h

positive Hatch et al.,1983

rat, F-344hepatocytesspermatocytes

unscheduled DNA synthesis1–10%

positive Working etal., 1986

bovine serum albumin protein binding assay positive Kornbrust etal., 1982

Chromosomal effects in vitro; mammalian cells

human lymphoblastsTK6

sister chromatid exchange assay0, 0.3, 1.0, or 3.0%positive control: EMS

positive Fostel et al.,1985

DNA damage in vivo; mammals

rat, F-344hepatocytesspermatocytestracheal epithelial cells

unscheduled DNA synthesis6192–7224 mg/m3 (3000–3500 ppm), 5 days, 6 h/day

negative Working etal., 1986

unscheduled DNA synthesis30 960 mg/m3 (15 000 ppm); 3 h

weaklypositive

rat, F-344, males3 or 6 animals per group(no further informationon groups was available)

DNA binding study1032, 3096 mg/m3 (500, 1500 ppm); 6 h + 24 hpostexposurespecific radioactivity: 25–70 dpm/nmol = 11.2–31.4 × 10–3

mCi/mmolliver, kidney, lung, testes

negative Kornbrust etal., 1982

mouse, B6F3C1, malesand females6 animals per group

DNA–protein cross-links0 or 2064 mg/m3 (0 or 1000 ppm); 8 h

indications(malemice)

Ristau et al.,1989


Table 4 (contd)

Species Protocol Result Reference

20

rat, F-344, males andfemales 5 animals per group

DNA binding studyexposure for 4 h of rats in a closed chamber; initialconcentration approximately 2064 mg/m3 (1000 ppm)(reading off from graphs)specific radioactivity: 13 mCi/mmol = 2.9 × 104 dpm/nmol

negative Peter et al.,1985

mouse, B6C3F1, malesand females25 animals per group

DNA binding studyexposure for 4 h of rats in a closed chamber; initialconcentration approximately 2064 mg/m3 (1000 ppm)(reading off from graphs)specific radioactivity: 13 mCi/mmol = 2.9 x 104 dpm/nmol

ngative Peter et al.,1985

rat, F-344, males andfemales5 animals per group

mouse, B6F3C1, malesand females5 animals per group

DNA–protein cross-links2064 mg/m3 (1000 ppm)approximately 6 h/day for 6 days

2064 mg/m3 (1000 ppm)approximately 6 h/day for 6 daysanimals sacrificed 6 h postexposure

indication Jäger et al.,1988

Chromosomal effects in vivo; mammals

rat, Fischer 344,males80 animals per group

dominant lethal test6 h/day for 5 days + 17 exposure-free weeks0, 2064, 6192 mg/m3 (0, 1000, 3000 ppm) + positivecontrol triethylenemelamine (TEM)

negative(probably acytotoxiceffect)

Working etal., 1985a

Using the alkaline elution technique, no cross-linksin male mouse kidneys could be detected after exposureto 2064 mg methyl chloride/m3 (1000 ppm) for 6 days, butsome indications of DNA single-strand breaks wereobtained (Jäger et al., 1988). However, when mice wereexposed to 2064 mg/m3 (1000 ppm) for 8 h only, DNAcross-links were seen in renal tissue of male mice but notin female mice or in hepatic tissues (Ristau et al., 1989).In an attempt to investigate the time-course of the DNAlesions, Ristau et al. (1990) again exposed male mice to2064 mg methyl chloride/m3 (1000 ppm) for 8 h. In renaltissue, it was observed that DNA–protein cross-linkswere removed at a fast rate, whereas single-strand breaksappeared to accumulate. At 48 h postexposure, alllesions had disappeared.

In a dominant lethal assay, performed according toOrganisation for Economic Co-operation and Develop-ment (OECD) test guidelines, male rats were exposed tomethyl chloride (Working et al., 1985a). The numbers oflive and total implants were decreased, there was anincrease in the percentage of preimplantation loss atweeks 2, 4, 6, and 8 postexposure, and there was anincrease in the percentage of postimplantation loss atweek 1 postexposure. The changes observed were notconcentration related. A true dominant lethal effect ofgenetic origin could be questioned, as the time-coursesof the pre- and postimplantation losses after methylchloride exposure were not the same as those obtainedafter administration of the positive control, triethylene-melamine (TEM). The development of sperm granulomasin the epididymis, the effects seen in the dominant lethalassay, seems to be cytotoxic rather than genotoxic in

origin. However, a genotoxic effect should not be totallyexcluded.

The role of epididymal inflammation in the induc-tion of lethal mutations was studied by Chellman et al.(1986c) in an assay with a test protocol similar to theOECD test guideline for dominant lethal mutations. Ratswere exposed to methyl chloride in the presence orabsence of the anti-inflammatory agent BW755C.BW755C was effective against the postimplantationlosses induced by methyl chloride, but not against pre-implantation losses. The authors’ conclusions, based onunpublished data mentioned in Chellman et al. (1986c),are that the increase in preimplantation losses might be aconsequence of testicular lesions caused by methylchloride and that BW755C is effective againstepididymal injuries only, thus indicating that epididymalinflammation has a role in the induced infertility.

In conclusion, methyl chloride is clearly genotoxicin in vitro systems, in both bacteria and mammalian cells.Methyl chloride binds to protein. Methyl chloride ispossibly an alkylating agent; however, the availablestudies do not allow any quantification. Although thepositive effects seen in a dominant lethal test were mostlikely cytotoxic rather than genotoxic, methyl chloridemight be considered a very weak mutagen in vivo basedon some evidence of DNA–protein cross-linking athigher doses.

Methyl chloride

21

8.7 Reproductive and developmentaltoxicity

8.7.1 Effects on fertility

In the 1981 CIIT study, referred to in section 8.5,exposure to methyl chloride at 2064 mg/m3 (1000 ppm)caused testicular lesions in rats. The lesions seen werebilateral and consisted of diffuse degeneration andatrophy of the seminiferous tubules.

Chapin et al. (1984) investigated the developmentof lesions induced in testes and epididymis and effectson reproductive hormones in F-344 rats after exposure to0 or 6192 mg methyl chloride/m3 (0 or 3000 ppm) for atotal of 9 days (6 h/day; approximately 60 exposed ani-mals and 16 control animals). Testicular lesions in theform of delay in spermiation, germinal epithelial vacuo-lization, and cellular exfoliation as well as bilateral epidid-ymal granulomas were seen. The effects were observedin most animals, with the onset at day 9 or 11 after thebeginning of the exposure. In general, lesions seen in

Table 5: Breeding results in rats in the F0 and F2 generations after methyl chloride exposure.

Breeding results


F0 generation: number of exposed males provenfertile when mated to exposed females

18/40 (45%) 20/39 (51%) 12/40 (30%) 0/40 (0%)

F0 generation: number of exposed males provenfertile when mated to unexposed females

23/28 (82%) 21/28 (75%) 12/28 (43%) 0/26 (0%)

F1 generation: number of exposed males provenfertile when mated to exposed females

31/40 (78%) 26/40 (65%) 14/23 (61%) –

animals at day 19 were of higher severity than thoseseen earlier. In rats killed 70 days or more after the onsetof the exposure, 70–90% of the seminiferous tubuleslacked any germinal cells; in 10–30% of the tubules,varying degrees of recovery of spermiation wereobserved. The LOAEL in this study must be set at6192 mg/m3 (3000 ppm).

A two-generation inhalation study in Fischer 344rats was carried out at methyl chloride concentrations of0, 310, 980, or 3096 mg/m3 (0, 150, 475, or 1500 ppm)(Hamm et al., 1985). The F0 generation (40 males and 80females per exposure group) was exposed for 10 weeksand during a 2-week mating period (6 h/day,5 days/week, and 6 h/day, 7 days/week, respectively). Asimilar exposure schedule was used for the F1 genera-tion, with the exclusion of the 3096 mg/m3 (1500 ppm)exposure level. In the high-dose F0-generation malessacrificed immediately after 12 weeks of exposure,treatment-related lesions were found, consisting ofminimal to severe atrophy of the seminiferous tubules(10/10 males examined) and granulomas in the epididymis(3/10). Severely affected tubules were lined by Sertoli’scells and by occasional stem cell spermatogonia. In theless affected tubules, decreased numbers ofspermatogonia, primary spermatocytes, and/orsecondary spermatocytes were found.

Further, in the F0 generation, no litters were bornwhen high-dose males were mated to exposed or unex-posed females, and significantly fewer litters were bornto unexposed females mated to the males in the980 mg/m3 (475 ppm) dose group. No differences in litter

size, sex ratio, pup viability, or pup growth were foundamong the 980 mg/m3 (475 ppm) and 310 mg/m3 (150 ppm)groups compared with the control F0 group. A trendtowards decreased fertility was also found in the 980mg/m3 (475 ppm) dose group in the F1 generation. ALOAEL of 980 mg/m3 (475 ppm) (infertility) was derivedfrom the two-generation study. Breeding results in ratsin the F0 and F2 generations after methyl chlorideexposure are shown in Table 5.

In a dominant lethal assay in rats exposed tomethyl chloride for 5 days, described in section 8.6,visible sperm granulomas in the epididymis were presentin the 6192 mg/m3 (3000 ppm) group 17 weeks post-exposure but not in the 2064 mg/m3 (1000 ppm) group orin the control group. After exposure to 6192 mg/m3 (3000ppm), the number of live and total implants wasdecreased, and there was an increase in postimplantationloss. In both treated groups, there was an increase inpreimplantation losses (Working et al., 1985a). TheLOAEL for preimplantation loss was 2064 mg/m3

(1000 ppm).

In a subsequent study, Working et al. (1985b)characterized the effect of methyl chloride exposure onsperm quality and histopathology in rats in more detail.Male Fischer 344 rats (80 animals per group) wereexposed to 0, 2064, or 6192 mg methyl chloride/m3 (0,1000, or 3000 ppm) for 5 days, 6 h/day. Besides signifi-cantly decreased testis weights in the high-dose group3–8 weeks postexposure and the findings that more than50% of the treated animals showed sperm granulomas inthe epididymis in the same dose group, observationsindicating cytotoxic effects on sperm quality were made.


22

Observations made at the 6192 mg/m3 (3000 ppm) levelincluded significant decreases in testicular spermatidhead counts, delay in spermiation, epithelial vacuoliza-tion, luminal exfoliation of spermatogenic cells, andmultinucleated giant cells. Further, sperm isolated fromthe vasa deferentia had significantly depressed numbersand an elevated frequency of abnormal sperm headmorphology by week 1 postexposure and significantlydepressed sperm motility and increased frequency ofheadless tails by week 3 postexposure. These changeswere all within or close to the normal range by week 16postexposure. A LOAEL of 6192 mg/m3 (3000 ppm) couldbe derived based on the histopathological findings.

The cause of preimplantation loss induced bymethyl chloride was further investigated in rats byWorking & Bus (1986). Fischer 344 rats (10–30 animalsper group) inhaled 0, 2064, or 6192 mg methyl chloride/m3

(0, 1000, or 3000 ppm) 6 h/day for 5 days or received asingle injection of TEM as a positive control forgenotoxicity. At weeks 1–3 postexposure in the6192 mg/m3 (3000 ppm) group, preimplantation losses didnot exceed unfertilized ova, which was the case for thepositive control. From these data, the authors suggestedthat preimplantation losses are due to a failure infertilization rather than to an increase in embryonaldeaths.

In conclusion, testicular lesions and epididymalgranulomas followed by reduced sperm quality lead toreduced fertility as well as complete infertility in rats. ALOAEL of 980 mg/m3 (475 ppm) and a no-observed-adverse-effect level (NOAEL) of 310 mg/m3 (150 ppm)were identified from the two-generation study of Hammet al. (1985).

8.7.2 Developmental toxicity

In a study designed to study structural teratogen-icity, pregnant Fischer 344 rats (25 rats per dose group)were exposed to 0, 206, 1032, or 3096 mg methyl chloride/m3 (0, 100, 500, or 1500 ppm) for 6 h/day throughgestation days 7–19 (Wolkowski-Tyl et al., 1983a). In thehighest dose group, significant reductions in fetal bodyweight and female crown–rump length were observed.Further, skeletal immaturities such as reducedossification (metatarsals and phalanges of the anteriorlimbs, thoracic vertebral centra, pubis of pelvic girdle,and metatarsals of the hindlimbs) were seen. Althoughthese findings were seen in the presence of significantlydecreased maternal food consumption, body weight, andweight gain in the same dose group, they should beconsidered as serious and exposure related. A fetalLOAEL for skeletal immaturities as well as a maternalLOAEL for effects on body weight and food consump-tion of 3096 mg/m3 (1500 ppm) were obtained. No othereffects, including heart defects, were reported from the206 and 1032 mg/m3 (100 and 500 ppm) dose groups.

In parallel with the rat study, Wolkowski-Tyl et al.(1983a) also evaluated teratogenicity in pregnantC57BL/6 mice (33 mice per dose group) carrying B6C3F1fetuses exposed through gestation days 6–17 followingthe same exposure schedule as the rats. Dams in the 3096mg/m3 (1500 ppm) group died or were killed in extremisdue to very high toxicity (tremor, hunched appearance,difficulty in righting, vaginal bleeding, bloody urine,cerebellar granular cell necrosis and degeneration, etc.).No other maternal toxicity was observed in the otherexposure groups. In the 1032 mg/m3 (500 ppm) group, thefetuses (male and female) had a small but significantincrease in heart defects (reduction or absence of theatrioventricular valves, chordae tendineae, and papillarymuscles). In both the 1032 and 206 mg/m3 (500 and 100ppm) groups, a significant increase in degree ofossification in the hindlimbs was seen as compared withcontrol animals. A LOAEL for heart defects in fetuses of1032 mg/m3 (500 ppm) was obtained.

In a subsequent study, Wolkowski-Tyl et al.(1983b) again exposed pregnant C57BL/6 mice carryingB6C3F1 fetuses with the aim of confirming the earlierfindings, elucidating the nature of the heart defects moreclearly, and establishing a concentration–effect relation-ship. Approximately 75 mice per dose group wereexposed to 0, 516, 1032, or 1548 mg methyl chloride/m3 (0,250, 500, or 750 ppm) for 6 h/day during gestation days6–18. In the 1032 and 1548 mg/m3 (500 and 750 ppm)groups, an exposure-related increase in heart defects(involving effects on the atrioventricular valves, chordaetendineae, and papillary muscles) was observed. Damswere affected at the 1548 mg/m3 (750 ppm) exposure level(decrease in body weight and body weight gain). Nomaternal toxicity, embryotoxicity, fetotoxicity, orteratogenicity was associated with exposure to methylchloride at 516 mg/m3 (250 ppm). In this study, theLOAEL for heart defects was 1032 mg/m3 (500 ppm), theNOAEL was 516 mg/m3 (250 ppm), and the maternalLOAEL was 1548 mg/m3 (750 ppm).

In a number of different experiments on smallnumbers of animals, pregnant C57BL/6 mice carryingB6C3F1 fetuses were exposed to methyl chloride atconcentrations of 516, 619, or 2064 mg/m3 (250, 300, or1000 ppm) for 12–24 h during gestation day 11.5–12.5(John-Greene et al., 1985). The exposure time was chosenas a critical period in development of cardiac defects.The authors found heart defects when the test was non-blind but not when the technician was unaware of whichfetuses were exposed. Further, John-Greene et al. (1985)had concerns regarding the technique used byWolkowski-Tyl et al. (1983a). However, the investigationby John-Greene et al. (1985) is difficult to evaluate, as asmall number of animals were used and as the exposureperiod was not similar to those in the Wolkowski-Tyl etal. (1983a, 1983b) studies. No LOAEL could beestablished.

Methyl chloride

23

In conclusion, from the studies by Wolkowski-Tyland co-workers (1983a, 1983b), it seems that methylchloride could induce heart defects in mice exposed to1032 mg/m3 (500 ppm) when dams were exposed throughgestation days 6–18. A NOAEL of 206 mg/m3 (100 ppm)was established from the developmental toxicity studies.

8.8 Immunological and neurologicaleffects

No specific reports on immunological or neuro-logical effects caused by methyl chloride were found inthe literature.

9. EFFECTS ON HUMANS

9.1 Studies in volunteers

In order to monitor the physiological response tomethyl chloride in healthy volunteers (eight men andnine women) with no previous methyl chloride exposure,Stewart et al. (1980) exposed the volunteers to methylchloride at concentrations of 0, 41, 206, or (men only) 310mg/m3 (0, 20, 100, or [men only] 150 ppm), 1, 3, and 7.5h/day, 5 days/week, for 6 weeks in an exposure chamber.Using a wide battery of behavioural, neurological,electromyographic, and clinical tests, no significantdecrements were found in the exposed volunteers ascompared with controls. For interindividual differencesin methyl chloride concentrations in blood and expiredair, see section 7.

In volunteers, Putyz-Anderson and co-workers(1981a, 1981b) found minimal or no effects onperformance after exposure to methyl chloride at 206 or413 mg/m3 (100 or 200 ppm) for 3h (n=56) and at 413mg/m3 (200 ppm) for 3.5 h (n=84), respectively

9.2 Case reports

Available information related to the toxic effects onhumans exposed to high concentrations of methylchloride is mainly derived from accidental exposures inconnection with the use of methyl chloride in theproduction of polystyrene foams and also fromrefrigerator leakages. Among symptoms described incase reports (see, for example, MacDonald, 1946;McNally, 1946; Hansen et al., 1953; Thordarson et al.,1964; Scharnweber et al., 1974; Spevak et al., 1976;Gudmundsson, 1977; Lanham, 1982) are effects on thenervous system, such as dizziness, weakness, blurredvision, muscular incoordination, drowsiness, sleep

disturbances, mental confusion, and paraesthesis.Neurotic and depressive symptoms are also described.Further, gastrointestinal symptoms (nausea, vomiting,abdominal pain, etc.) have been observed, as well asjaundice. In general, the symptoms seem to developsoon after the exposure. However, recovery periods varyto a large extent; for example, in seamen highly exposedto methyl chloride, effects on the nervous system wereobserved 13 years after the accident (Gudmundsson,1977).

9.3 Epidemiological studies

Performance and cognitive functions wereadversely affected in workers manufacturing foamproducts. There was also an increase in the magnitudeof finger tremors. The workers were exposed for 2 yearsto approximately 72 mg methyl chloride/m3 (35 ppm), aswell as other chemicals (NIOSH, 1976). However,insufficient information was available on exposure to theother chemicals and lifestyle factors, and no relationshipcould be established between methyl chloride exposureand the various psychological and personality testsemployed.

A mortality follow-up study was conducted of852 male workers employed for at least 1 month betweenthe years 1943 and 1978 in a butyl rubber manufacturingplant using methyl chloride (Holmes et al., 1986). Foreach cohort member, complete work history and deathinformation were obtained. No information on lifestylefactors was reported. The exposure to methyl chlorideand other compounds used in the butyl rubber manufac-turing plant was estimated in three categories (high,medium, and low). No detectable excess mortality fromany specific cause of death including all cancers wasfound in the study population after analysis by leveland duration of exposure.

In a 32-year follow-up study by Rafnsson &Gudmundsson (1997), indications of elevated mortalityfrom cardiovascular disease after high accidental methylchloride exposure were seen in Icelandic seamen (deck-hands: relative risk [RR] = 3.9, 95% confidence interval[CI] = 1.0–14.4; officers: RR = 1.7, 95% CI = 0.3–6.4). Thesmall number of observed cancers (all cancers and lungcancers) in the exposed group provides an insufficientbasis for assessing the cancer risk in humans. Thereference group used was controlled for age,occupation, social class, and lifestyle factors.

In conclusion, effects on humans, especially onthe central nervous system, can clearly be seen afteraccidental (mostly high) exposure or after normal workexposure levels. A rough estimation of the degree ofexposure from case reports might be in the order ofapproximately 200–2000 mg/m3 (100–1000 ppm). In short-term exposure of volunteers, no significant effects were


24

Table 6: Short-term toxicity to aquatic organisms.

Organism End-point Toxicity (mg/litre) Reference

Cyanobacteria

Microcystis aeruginosa Toxicity threshold, EC3 (cell multiplication inhibition test)

550 Bringmann & Kühn,1976

Green algae

Scenedesmus quadricauda Toxicity threshold, EC3 (cell multiplication inhibition test)

1450 Bringmann & Kühn,1980

Protozoa

Entosiphon sulcatum Toxicity threshold, EC5 (cell multiplication inhibition test)

>8000 Bringmann & Kühn,1980

Fish

Bluegill sunfish (Lepomis macrochirus) 96-h LC50 550 Dawson et al., 1977

Tidewater silverside (Menidia

beryllina)96-h LC50 270 Dawson et al., 1977

Table 7: Short-term toxicity to terrestrial organisms.

Organism End-point Toxicity Reference

Bacteria

Methanogenic bacteria (35 °C,pH 7, anaerobic conditions)

48-h IC50 (inhibition of gas production)

50 mg/litre Blum & Speece, 1991

Nitrobacter

(25 °C, pH 9.1)24-h IC50 (inhibition of NO2-N production)

2010 mg/litre Tang et al., 1992

Pseudomonas putida Toxicity threshold, EC3 (cell multiplication inhibitiontest)

500 mg/litre Bringmann & Kühn,1976

Higher plants

Several speciesa (3-h exposure in gas phase)

Visible symptoms Photosynthesis Transpiration

5000–10 000 mg/m3 (2400–4800ppm)

>5000 mg/m3 (>2400 ppm)>5000 mg/m3 (>2400 ppm)

Christ, 1996

a Tested plant species were tomatoes (Lycopersicum esculentum Miller), sunflower (Helianthus annuus L.), bush bean (Phaseolus

vulgaris L.), nasturtium (Tropaeolum majus L.), sugar-beet (Beta vulgaris L.), soya bean (Glycine maxima (L.) Merill), and wheat(Triticum aestivum L.).

seen. There are insufficient data available to assess therisk for humans to develop cancer as a result of methylchloride exposure.

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

Few data were found on the short-term toxicity ofmethyl chloride to aquatic organisms, and no data werefound on long-term toxicity. The existing data for acyanobacterium, a green alga, a protozoan, and two fishspecies indicate a low acute toxicity to aquatic species

(see Table 6). The acute toxicity to the two fish specieswas determined under static conditions, and the concen-tration of the test substance was not measured. Thismeans that the toxicity may have been underestimatedby the test, if significant amounts of the test substancevolatilized during the test. The 96-h LC50 values for thefreshwater species, bluegill sunfish (Lepomis macro-chirus), and the saltwater species, tidewater silverside(Menidia beryllina), were determined to be 550 and270 mg/litre, respectively (Dawson et al., 1977).

10.2 Terrestrial environment

Data on the short-term toxicity of methyl chloridewere found only for three species of bacteria and somehigher plants (see Table 7). No chronic toxicity data werefound for terrestrial organisms.

Methyl chloride

25

Table 8: Summary of animal inhalation toxicity studies with relevance for risk characterization.

SpeciesStudyduration End-point

LOAEL,mg/m3 (ppm)

NOAEL,mg/m3 (ppm) Reference

Short-term exposure

mouse, C3H,females;C57BL/6,males andfemales

12 days hepatocellular necrosis anddegeneration

1032 (500) – Morgan et al., 1982

mouse,C57BL/6,females

11 days,continuousexposure

cerebellar lesions 206 (100) – Landry et al., 1985

intermittentexposure

826 (400) –

Long-term exposure

rat, F-344 2 years testicular lesions 2064 (1000) 464 (225) CIIT, 1981

mouse,B6C3F1

2 years renal tumours in males; significantincrease at 2064 mg/m3 (1000 ppm)

2064 (1000) 464 (225) CIIT, 1981

development of renal microcysts inmales; also seen at 464 mg/m3 (225ppm); no dose–response

103 (50)

nerve axonal swelling anddegeneration; seen in all treatedgroups; effects significant as comparedwith control

103 (50)

Reproductive toxicity — fertility

rat, F-344 9 days testicular lesions and epididymalgranulomas

6192 (3000) – Chapin et al., 1984

rat, F-344 two-generation

infertility; dose dependence or trend 980 (475) 310 (150) Hamm et al., 1985

rat, F-344 5 days preimplantation loss 2064 (1000) – Working et al., 1985a

rat, F-344 5 days effects on sperm quality 6192 (3000) 2064 (1000) Working et al., 1985b

Reproductive toxicity — development

rat, F-344 gestationdays 7–19

skeletal immaturities in the presenceof effects of maternal body weight andfood consumption

3096 (1500) 1032 (500) Wolkowski-Tyl et al.,1983a

mouse,B6C3F1

gestationdays 6–17

heart defects in fetuses; significantincrease as compared with controlanimals

1032 (500) 206 (100) Wolkowski-Tyl et al.,1983a

mouse,B6C3F1

gestationdays 6–18

heart defects in fetuses; dosedependence

1032 (500) 516 (250) Wolkowski-Tyl et al.,1983b

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification anddose–response assessment

The database for methyl chloride risk assessmentis in general acceptable in terms of toxicity afterinhalation exposure. Few data could be located in theliterature on methyl chloride toxicity after dermal or oral

administration. However, as the major route of humanexposure to methyl chloride seems to be by therespiratory pathway, the lack of data from other routes ofadministration is of minor concern. It should be pointedout that there are surprisingly few recent investigationsof methyl chloride toxicity for all end-points exceptgenotoxicity. In Table 8, data from inhalation toxicitystudies on methyl chloride in experimental animals aresummarized.

Considering the human GSTT1 polymorphism andthe suggested metabolic pathways of methyl chloride(Figure 2), it is not possible to conclude whether a rapidmetabolic clearance of methyl chloride as in high


26

conjugators (HC) leads to a higher or lower risk than alonger retention of methyl chloride in the body as in lowconjugators (LC) or non-conjugators (NC). Further, asthe GSTT1 activity decreases in the order mouse liverand kidney cytosol > HC > rat > LC > hamster > NC, it isimpossible to select one species of experimental animalas preferable in the risk assessment of methyl chloridewhen extrapolating animal effects data to humans.Because of these uncertainties, no species ofexperimental animal can be ruled out in favour ofanother, and human high conjugators, low conjugators,and non-conjugators must be considered as sensitive tomethyl chloride. Consequently, the lowest appropriateLOAEL or NOAEL from any species could be chosen forfurther risk characterization.

Data on single exposures are poor for methylchloride, and no firm conclusions can be drawn.However, the acute inhalation toxicity in rats and malemice after single exposure seems to be fairly low, with anLC50 value above 4128 mg/m3 (2000 ppm). In mice, theremight be a sex difference in susceptibility to methylchloride, as the LC50 value obtained for female mice was17 544 mg/m3 (8500 ppm).

No data on irritation and sensitization wereavailable. However, from short- and long-term exposuredata, no indications of respiratory irritation caused bymethyl chloride exposure have been reported. Thus,methyl chloride is probably not a strong respiratoryirritant.

The principal target in both rats and mice uponshort-term exposure is the nervous system, with animalsexhibiting functional disturbances and cerebellardegeneration. The LOAEL (based on cerebellardegeneration) in mice is 206 mg/m3 (100 ppm) uponcontinuous exposure. Higher levels of exposure causedtoxicity in the kidney and liver in mice and in the testes,epididymis, and kidney in rats. The decrease in thymusweight, unaccompanied by histopathological changes, inmice exposed to 31 mg/m3 (15 ppm) was not corroboratedby either a 90-day or a 2-year study.

In the long-term studies, exposure to 103 mg/m3 (50ppm) caused nerve lesions, such as axonal swelling anddegeneration. The effects at each exposure level weresignificantly increased in each dose group as comparedwith control animals. However, no concen-tration–response relationship could be established.Significant degenerative effects on nerve fibres werealso seen at higher doses, although the observationswere not concentration related. Further, testicular lesionsin rats and renal lesions in male mice were importantfindings obtained from the 2-year toxicity study. Renaltumours as well as testicular lesions were seen at the2064 mg/m3 (1000 ppm) exposure level, and, although notof statistical significance, cortical adenoma was also

seen at 464 mg/m3 (225 ppm). Development of renalcortical microcysts in mice was seen in the 103 mg/m3 (50ppm) dose group and to some extent in the 464 mg/m3

(225 ppm) group (CIIT, 1981); however, no concentra-tion–response relationship could be establishedAlthough there are indications of low CYP2E1 activity inmale human kidney microsomes as compared with maleCD-1 mice, as shown by Speerschneider & Dekant(1995), the presence of human renal CYP2E1 cannot beexcluded. Further, the presence of CYP2E1 in humantissues other than kidneys might lead to the induction oftumours in other organs. Therefore, the findings of renaltumours in male mice should be considered as relevantfor humans.

Methyl chloride is clearly genotoxic in in vitrosystems in both bacteria and mammalian cells. Methylchloride can bind to protein. However, if methyl chlorideis an alkylating agent, it is so to a very small extent.Further, methyl chloride might be considered only a veryweak mutagen in vivo.

Testicular lesions and epididymal granulomasfollowed by reduced sperm quality lead to reducedfertility as well as complete infertility in rats. A LOAEL of980 mg/m3 (475 ppm) could be derived from the repro-ductive toxicity data where a concentration–responsecould be established (NOAEL = 310 mg/m3 [150 ppm]).

It seems from the Wolkowski-Tyl et al. (1983a,1983b) studies that methyl chloride could induce heartdefects in mice exposed to 1032 mg/m3 (500 ppm) whendams are exposed through gestation days 6–18. Thedevelopment of heart defects was concentration depen-dent. A NOAEL of 206 mg/m3 (100 ppm) could beestimated from the developmental toxicity studies.

Effects on humans, especially on the centralnervous system, can clearly be seen after accidental ornormal work exposure levels. A rough estimation of thedegree of exposure from case reports might be in theorder of approximately 200–2000 mg/m3 (100–1000 ppm).In short-term exposures of volunteers, no significanteffects on the nervous system were seen. There areinsufficient data available to assess the risk for humansto develop cancer as a result of methyl chlorideexposure.

11.1.2 Criteria for setting tolerable intakes orguidance values for methyl chloride

Human data supplemented by data from short-,medium-, and long-term studies in laboratory animals,principally the mouse, clearly indicate that the nervoussystem is a particularly vulnerable target of methylchloride exposure. Histopathological effects in spinalcord nerves were observed in a 2-year exposure of mice(CIIT, 1981) at a LOAEL of 103 mg/m3 (50 ppm), in the

Methyl chloride

27

absence of renal and hepatic effects. At 2064 mg/m3

(1000 ppm), cerebellar degeneration was noted. Thislatter lesion, which appears to be of a progressive andpersistent nature, has also been observed in miceexposed in other studies (e.g., Landry et al., 1985) formuch shorter periods of time. In addition, evidence offunctional impairment noted in short-term studies isconsistent with the spinal cord and the brain beingpotential sites of injury under chronic exposure condi-tions.

Consequently, the LOAEL of 103 mg/m3 (50 ppm),

derived from the 2-year study by CIIT (1981) for effectson the nervous system, was chosen to be used in therisk characterization.

As no estimation from the available exposuredatabase can be made on the allocation of the tolerableintake from environmental air and from air in the workingenvironment, two separate guidance values werederived.

A guidance value for indirect inhalation exposureto methyl chloride via the environment for the generalpopulation was estimated to be:

(103 mg/m3 × 1.0 × 6/24 × 5/7) / 1000

= 0.018 mg/m3 (0.009 ppm)

where: • 103 mg/m3 (50 ppm) is the LOAEL,• 1.0 refers to 100% allocation of the tolerable intake to

intake via the environmental air, • 6/24 and 5/7 are the conversion of 6 h/day and 5

days/week to continuous exposure, and• 1000 is the uncertainty factor (×10 for intraspecies

variation, ×10 for interspecies variation, and ×10 forthe poor database and the use of a LOAEL instead ofa NOAEL).

A guidance value for occupational inhalationexposure was estimated to be:

(103 mg/m3 × 1.0) / 100 = 1.0 mg/m3 (0.5 ppm)

where: • 103 mg/m3 (50 ppm) is the LOAEL,• 1.0 refers to 100% allocation of the tolerable intake to

intake via workplace air, and• 100 is the uncertainty factor (×10 for interspecies

variation and ×10 for the poor database and the use ofa LOAEL instead of a NOAEL).

No correction was made for continuous exposure in theworking environment.

11.1.3 Sample risk characterization

Based on the sample estimate of exposure, indirectexposure via the ambient air, 0.0012 mg/m3 (0.6 ppb), is 15times below the guidance value of 0.018 mg/m3 (0.009ppm). Also, the sample median exposure estimate forurban air, 0.0010–0.0023 mg/m3 (0.5–1.1 ppb), is 18 to 8times below the guidance value. Finally, the maximumvalue obtained from individual measurements in urbanair, 0.035 mg/m3 (17 ppb), is 2 times above the guidancevalue. From the available exposure data, a risk wasidentified from exposure in urban air but not ambient air.

The quality of human exposure data in the presentreport is fairly poor, which will contribute to uncertain-ties in the outcome of the sample risk characterization foroccupational exposure. However, when more applicableexposure data can be used, the quality of the riskassessment will improve.

The range of the sample estimate of workplaceexposure, 0.2–186 mg/m3 (0.1–90 ppm), is 5 times belowand 180 times above the guidance value of 1.0 mg/m3 (0.5ppm), respectively. Thus, a comparison of the availablemethyl chloride exposure concentrations in the workingenvironment and the guidance value derived from effectson the nervous system leads to the identification of arisk. Although the nerve lesions were seen at lowerexposure levels than those at which infertility in rats (980mg/m3 [475 ppm]) and renal tumours in male mice (2064mg/m3 [1000 ppm]) occurred, emphasis should also belaid on these very serious effects in a qualitative riskcharacterization of methyl chloride.

11.2 Evaluation of environmental effects

The troposphere, where methyl chloride reactswith hydroxyl radicals, is the main environmental sink forthe chemical. A certain amount of the troposphericmethyl chloride reaches the stratosphere. In the strato-sphere, photolysis produces chlorine radicals, which inturn will react with ozone. Estimates of the amount ofmethyl chloride reaching the stratosphere, and therebyalso its contribution to ozone depletion, vary consider-ably. However, as estimated from figures presented bythe WMO, methyl chloride contributes approximately15% of the total equivalent effective stratosphericchlorine.1 The relative contribution from methyl chlorideto the depletion of the ozone layer will probably increase

1 The term “equivalent effective stratospheric chlorine”includes both stratospheric chlorine and bromine andalso considers the dissociation rate of each compoundinvolved in ozone depletion (e.g., chlorofluorocarbons).In the stratosphere, each bromine atom is assumed to be40 times more damaging to ozone than each chlorineatom.


28

in the future, as the use of chlorofluorocarbons andhydrochlorofluorocarbons is expected to decrease. Thestratospheric ODP of methyl chloride has been deter-mined to be 0.02 relative to that of CFC-11 (ODP = 1).

Methyl chloride is not thought to contributesignificantly to global warming or to the creation ofphotochemical air pollution.

The dominant loss mechanism for methyl chloridein water and soil is volatilization. Slow hydrolysis andpossibly biotic degradation may contribute at deeper soildepths and in groundwater. However, little information isavailable concerning biodegradation.

Data on short-term toxicity to both aquatic andterrestrial organisms are sparse. No information wasfound on long-term toxicity. The available data showthat methyl chloride has a low acute toxicity to testedaquatic organisms (e.g., protozoa, green algae, and fish).The lowest LC50 value for fish is 270 mg/litre. As concen-trations of methyl chloride in surface waters (maximum0.22 mg/litre) are generally several orders of magnitudeless than those demonstrated to cause effects, it is likelythat methyl chloride poses a low risk of acute effects onaquatic organisms. Data on terrestrial organisms areeven more sparse than data on aquatic organisms. Theonly information found shows that methyl chloridecauses acute effects (i.e., visible symptoms and effectson photosynthesis and transpiration) on higher plants atconcentrations above 5000 mg/m3 (2400 ppm), which isabout 105 times higher than the highest concentrationfound in urban air (i.e., 0.035 mg/m3 [0.017 ppm]).

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

In its series of monographs, the InternationalAgency for Research on Cancer (IARC, 1986) hasevaluated methyl chloride. Based on the data available,the Task Group concluded that there is inadequateevidence for the carcinogenicity of methyl chloride toexperimental animals and to humans. In the overallassessment of data from short-term tests, the TaskGroup concluded that there is sufficient evidence forgenotoxic activity. In the overall evaluation (IARC,1987), methyl chloride was placed in group 3 as beingnot classifiable as to its carcinogenicity to humans.

Methyl chloride

29

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34

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36

APPENDIX 1 — SOURCE DOCUMENTS

Lundberg P (1992) Methyl chloride. NEG andDECOS basis for an occupational standard.Solna, National Institute of OccupationalHealth, Nordic Council of Ministers (Arbete ochHälsa 27)

Copies of the Arbete och Hälsa document on methylchloride (ISSN 0346-7821; ISBN 91-7045-179-6) may beobtained from:

National Institute for Working LifePublications DepartmentS-171 84 SolnaSweden

The document, which is focused on health effects only,was prepared in the series of criteria documents from the NordicExpert Group for Documentation of Occupational ExposureLimits (NEG) in collaboration with the Dutch Expert Committeefor Occupational Standards (DECOS) of the Dutch Directorate-General of Labor. The draft was reviewed by the Dutch ExpertCommittee as well as by the Nordic Expert Group. The reviewerswere industrial and academic specialists who were chosen eitherbecause they have an extended knowledge of methyl chlorideitself or because they are specialists in the critical effect area ofthe chemical.

ATSDR (1990) Toxicological profile forchloromethane. Atlanta, GA, US Department ofHealth and Human Services, Public HealthService, Agency for Toxic Substances andDisease Registry (Report No. TP-90-07)

ATSDR (1998) Toxicological profile forchloromethane (update). Atlanta, GA, USDepartment of Health and Human Services,Public Health Service, Agency for ToxicSubstances and Disease Registry (Report No.205-93-0606)

Copies of the ATSDR Toxicological profile for

chloromethane may be obtained from:

Agency for Toxic Substances and Disease RegistryDivision of Toxicology1600 Clifton Road NE, E-29Atlanta, Georgia 30333USA

A peer review panel was assembled for the Toxicological

profile on chloromethane (1990), including Dr Anthony DeCaprioand Dr Nancy Reiches (private consultants), Dr Theodore Mill(SRI International), and Dr Nancy Tooney (Department ofBiochemistry, Polytechnic University). A joint panel of scientistsfrom ATSDR and EPA reviewed the peer reviewers’ commentsand determined which ones to include in the profile.

For the updated profile (1998), the panel consisted of DrHerbert Cornish (private consultant), Dr Anthony DeCaprio(Associate Professor, State University of New York at Albany), DrTheodore Mill (Senior Scientist, SRI International), and DrNancy Tooney (Associate Professor, Brooklyn, NY). Scientists

from the ATSDR reviewed the peer reviewers’ comments anddetermined which ones to include in the profile.

The responsibility for the content of the profiles lies withthe ATSDR.

BUA (1986) Chloromethane. GDCh-AdvisoryCommittee on Existing Chemicals ofEnvironmental Relevance (BUA). Weinheim,VCH Verlagsgesellschaft mbH; and New York,NY, VCH Publishers, Inc. (BUA Report 7)

Copies of the BUA report on chloromethane (ISBN 3-527-28558-X [Weinheim] and 1-56081-734-8 [New York]) may beobtained from VCH in Weinheim, Basel, Cambridge, and NewYork.

BUA reports are written by the largest German producer ofthe chemical. The draft is examined by BUA (GDCh-AdvisoryCommittee for Existing Chemicals of Environmental Relevance),which consists of representatives from government agencies,industry, and the scientific community. Resulting questions areclarified by the authors as well as by further research (resulting inupdated reports). After an average of two readings in the workgroup and discussions with experts, the BUA plenum debates thereport before it is published. More detailed information on theBUA reports is found in Assessment of existing chemicals. A

contribution toward improving the environment, a 1993 report byBUA.

HSDB (1996) Hazardous substances data bank .Bethesda, MD, US National Library of Medicine

The version of HSDB used for this CICAD is included inthe CD-ROM CHEM-BANK (July 1996), published by:

Silver Platter Information Inc.100 River Ridge DriveNorwood, MA 02062-5043USA

HSDB is also available on CD-ROM from the CanadianCentre for Occupational Health and Safety (CCINFOdisc 2) andon-line by Data-Star, DIMDI, STN International, Toxicology DataNetwork (TOXNET). HSDB is built, reviewed, and maintained onthe National Library of Medicine’s TOXNET. HSDB is a factualdata bank, referenced and peer reviewed by a committee ofexperts (the Scientific Review Panel). All data extracted fromHSDB for use in this CICAD were preceded by the symboldenoting the highest level of peer review.

The date for the last revision or modification of the recordon methyl chloride was June 1996.

Methyl chloride

37

WMO (1994) Montreal protocol on substancesthat deplete the ozone layer — Scientificassessment of ozone depletion: 1994. Geneva,World Meteorological Organization (GlobalOzone Research and Monitoring Project ReportNo. 37)

Copies of this report (ISBN 92-807-1449-X) for scientificusers may be obtained from:

World Meteorological Organizationattn. Dr Rumen BojkovP.O. Box 23001211-GenevaSwitzerland

The WMO (1994) report was the latest in a series ofscientific assessments of ozone depletion, prepared under theauspices of WMO and UNEP, that was available during thepreparation of the CICAD on methyl chloride. The genesis of theWMO (1994) report occurred at the 4th meeting of theConference of the Parties to the Montreal Protocol held inCopenhagen, Denmark, in 1992, at which the scope of thescientific needs was defined. In 1993, an international steeringgroup outlined the report and suggested scientists to serve asauthors. The first draft was examined by the authors and a smallgroup of experts, and the second draft was sent to a largenumber of scientists worldwide for review. At a Panel ReviewMeeting in July 1994, final changes were discussed and decidedupon. The scientists who prepared the report (230) andparticipated in the peer review process (147) are listed in thereport.

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on methyl chloride was sent for review toinstitutions and organizations identified by IPCS after contactwith IPCS national Contact Points and Participating Institutions,as well as to identified experts. Comments were received from:

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

R. Benson, US Environmental Protection Agency, Denver,CO, USA

R. Cary, Health and Safety Executive, Bootle, UnitedKingdom

R. Chhabra, Department of Health and Human Services,National Institute of Environmental Health Sciences,Research Triangle Park, NC, USA

P. Edwards, Department of Health, Protection of HealthDivision, London, United Kingdom

M. Greenberg, US Environmental Protection Agency,Research Triangle Park, NC, USA

Martin Matisons Environmental Health Service, HealthDepartment of Western Australia

H. Nagy, National Institute for Occupational Safety andHealth, Cincinnati, OH, USA

W. Rawson and L. Neuwirth, Methyl Chloride IndustryAssociation, Washington, DC, USA

M. Warholm, Institute of Environmental Medicine,Karolinska Institute, Stockholm, Sweden

P. Yao, Ministry of Health, Institute of OccupationalMedicine, Chinese Academy of Preventive Medicine,Ministry of Health, Beijing, People’s Republic of China

K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umweltund Gesundheit, Neuherberg, Oberschleissheim,Germany


38

APPENDIX 3 — CICAD FINAL REVIEWBOARD

Stockholm, Sweden, 25–28 May 1999

Members

Mr H. Abadin, Agency for Toxic Substances and DiseaseRegistry, Centers for Disease Control and Prevention, Atlanta,GA, USA

Dr B. Åkesson, Department of Occupational and EnvironmentalHealth, University Hospital, Lund, Sweden

Dr T. Berzins (Chairperson), National Chemicals Inspectorate(KEMI), Solna, Sweden

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

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

Dr S. Dobson (Rapporteur), Institute of Terrestrial Ecology,Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire,United Kingdom

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 G. Koennecker, Chemical Risk Assessment, FraunhoferInstitute for Toxicology and Aerosol Research, Hannover,Germany

Dr A. Nishikawa, National Institute of Health Sciences, Divisionof Pathology, Tokyo, Japan

Professor K. Savolainen, Finnish Institute of OccupationalHealth, Helsinki, Finland

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

Ms D. Willcocks (Vice-Chairperson), Chemical AssessmentDivision, National Occupational Health and Safety Commission(Worksafe Australia), Sydney, Australia

Professor P. Yao, Institute of Occupational Medicine, ChineseAcademy of Preventive Medicine, Ministry of Health, Beijing,People’s Republic of China

Observers

Dr N. Drouot (representing ECETOC), Elf Atochem, DSE-PIndustrial Toxicology Department, Paris, France

Ms S. Karlsson, National Chemicals Inspectorate (KEMI), Solna,Sweden

Dr A. Löf, National Institute of Working Life, Solna, Sweden

Dr A. Poole (representing CEFIC), Dow Europe S.A., Horgen,Switzerland

Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt undGesundheit, Institut für Toxikologie, Neuherberg,Oberschleissheim, Germany

Secretariat

Dr A. Aitio, Programme for the Promotion of Chemical Safety,World Health Organization, Geneva, Switzerland

Ms M. Godden, Health and Safety Executive, Bootle, UnitedKingdom

Ms L. Regis, Programme for the Promotion of Chemical Safety,World Health Organization, Geneva, Switzerland

Dr P. Toft, Division of Health and Environment, World HealthOrganization, Regional Office for the Americas/Pan AmericanSanitary Bureau, Washington, DC, USA

Dr M. Younes, Programme for the Promotion of ChemicalSafety, 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

METHYL CHLORIDE 0419March 1999

CAS No: 74-87-3RTECS No: PA6300000UN No: 1063EC No: 602-001-00-7

ChloromethaneMonochloromethaneCH3ClMolecular mass: 50.5

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Highly flammable. Heating willcause rise in pressure with risk ofbursting.

NO open flames, NO sparks, andNO smoking.

Shut off supply; if not possible andno risk to surroundings, let the fireburn itself out; in other casesextinguish with water spray.

EXPLOSION Gas/air mixtures are explosive. Closed system, ventilation,explosion-proof electrical equipmentand lighting. Use non-sparkinghandtools.

In case of fire: keep cylinder cool byspraying with water. Combat firefrom a sheltered position.

EXPOSURE STRICT HYGIENE!

Inhalation Staggering gait. Dizziness.Headache. Nausea. Vomiting.Convulsions. Unconsciousness.See Notes.

Ventilation, local exhaust, orbreathing protection.

Fresh air, rest. Artificial respiration ifindicated. Refer for medicalattention.

Skin MAY BE ABSORBED! ONCONTACT WITH LIQUID:FROSTBITE.

Cold-insulating gloves. Protectiveclothing.

ON FROSTBITE: rinse with plentyof water, do NOT remove clothes.

Eyes (See Skin). Safety goggles, face shield, or eyeprotection in combination withbreathing protection.

Ingestion

SPILLAGE DISPOSAL PACKAGING & LABELLING

Evacuate danger area! Consult an expert!Ventilation. NEVER direct water jet on liquid. (Extrapersonal protection: complete protective clothingincluding self-contained breathing apparatus).

F+ SymbolXn SymbolR: 12-40-48/20S: (2-)9-16-33UN Hazard Class: 2.1

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-41/20G41NFPA Code: H2; F4; R0

Fireproof. Ventilation along the floor.

Boiling point: -24.2°CMelting point: -97.6°CRelative density (water = 1): 0.92Solubility in water, g/100 ml at 25°C: 0.5Vapour pressure, kPa at 21°C: 506

Relative vapour density (air = 1): 1.8Flash point: Flammable GasAuto-ignition temperature: 632°CExplosive limits, vol% in air: 8.1-17.4Octanol/water partition coefficient as log Pow: 0.91

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

0419 METHYL CHLORIDE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS LIQUEFIED GAS.

Physical dangersThe gas is heavier than air and may travel along the ground;distant ignition possible, and may accumulate in low ceilingspaces causing deficiency of oxygen. See Notes.

Chemical dangersThe substance decomposes on burning producing toxic andcorrosive fumes including hydrogen chloride and phosgene.Reacts violently with powdered aluminium, powdered zinc,aluminium trichloride and ethylene causing fire and explosionhazard. Attacks many metals in the presence of moisture.

Occupational exposure limitsTLV: 50 ppm; (skin) (ACGIH 1998).TLV (as (STEL) ): 100 ppm; (skin) (ACGIH 1998).

Routes of exposureThe substance can be absorbed into the body by inhalation andthrough the skin.

Inhalation riskA harmful concentration of this gas in the air will be reachedvery quickly on loss of containment.

Effects of short-term exposureThe liquid may cause frostbite. The substance may causeeffects on the central nervous system. Exposure may result inunconsciousness. Exposure far above OEL may result in liver,cardiovascular system and kidney damage. Medicalobservation is indicated.

Effects of long-term or repeated exposureThe substance may have effects on the central nervoussystem, resulting in effects measured using behavioural tests.Animal tests show that this substance possibly causes toxiceffects upon human reproduction.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

NOTES

Following intoxication patient should be observed carefully for 48 hours.Check oxygen content before entering area.

ADDITIONAL INFORMATION

Methyl chloride

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RÉSUMÉ D’ORIENTATION

L’évaluation des effets du chlorure de méthyle surla santé humaine qui figure dans le présent CICADrepose principalement sur une mise au point rédigée parle Groupe nordique d’experts en collaboration avec leComité néerlandais pour les normes d’hygiène sur leslieux de travail (Lundberg, 1992). Un dépouillement desbanques de données couvrant la période 1992-1999 a étéeffectué afin de compléter les données disponibles. Ence qui concerne les effets environnementaux etécotoxicologiques du chlorure de méthyle, lesprincipales sources d’information utilisées sont lessuivantes : BUA (1986), ATDSR (1990) et WMO/OMM(1994). La banque de données ATDSR a été mise à jouren 1998; chaque fois que cette banque de donnéescontenait de nouvelles informations, elles ont été prisesen compte. La consultation des banques de donnéespertinentes couvrant la période 1989-1997 a permisd’obtenir des données supplémentaires sur lesquestions d’ordre écologique. On trouvera à l’appendice1 des renseignements sur la nature des sourcesdocumentaires existantes. Des informations sur l’examenpar des pairs du présent CICAD sont données àl’appendice 2. Ce CICAD a été approuvé en tantqu’évaluation internationale lors d’une réunion duComité d’évaluation finale qui s’est tenue à Stockholm(Suède) du 25 au 28 mai 1999. La liste des participants auComité d’évaluation finale figure à l’appendice 3. Lafiche internationale sur la sécurité chimique (ICSC 0419)du chlorure de méthyle, établie par le Programmeinternational sur la sécurité chimique (IPCS, 1999), estégalement reproduite dans le présent document.

Lorsque du chlorure de méthyle (No CAS 74-87-3) estlibéré dans l’atmosphère, c’est surtout au cours de saproduction, de son utilisation ou encore lors del’incinération de déchets municipaux ou industriels. Quoiqu’il en soit, les sources naturelles de chlorure deméthyle (en premier lieu les océans et la combustion dela biomasse) l’emportent largement en importance sur lessources d’origine humaine. On estime que l’ensemble deces sources libère chaque année quelque 5 × 106 tonnesde chlorure de méthyle. La part des sources naturellesdans ce bilan dépasse largement 90 % selon les esti-mations et pourrait même atteindre 99 %. Le composé estprésent dans la troposphère à une concentrationapproximativement égale à 1,2 µg/m3 (0,6 parties parmilliard).

Dans la troposphère, le piégeage du chlorure deméthyle s’effectue principalement par sa réaction sur lesradicaux hydroxyle et l’on estime que sa demi-vieatmosphérique est de 1 à 3 ans. Une fraction s’échappedans la stratosphère où le composé subit unephotodissociation donnant naissance à des radicauxchlore qui attaquent la couche d’ozone. Les estimations

relatives à la proportion de chlorure de méthyle quiatteint la stratosphère et contribue par là à la destructionde la couche d’ozone, sont très variables. Selon leschiffres donnés par l’Organisation météorologiquemondiale (OMM), le chlorure de méthyle contribue àhauteur de 15 % à la teneur totale de la stratosphère enchlore actif. Le chlorure de méthyle a un potentiel dedestruction de l’ozone stratosphérique de 0,02 parrapport au composé de référence, le CFC-11 dont lepotentiel est égal à 1 par définition. On ne pense pas quele chlorure de méthyle ait une influence sensible sur leréchauffement climatique ou sur la pollution de l’aird’origine photochimique.

Le chlorure de méthyle disparaît principalement del’eau et du sol par évaporation. Dans les couches pro-fondes du sol et dans les eaux souterraines, sadisparition pourrait s’expliquer notamment par une lentehydrolyse et éventuellement par une biodégradation. Onsait cependant peu de choses sur ce dernier point.

La voie la plus importante d’exposition humaine auchlorure de méthyle est la voie respiratoire. Chezl’Homme comme chez l’animal de laboratoire, il estrapidement absorbé au niveau des poumons aprèsinhalation. Après exposition à du chlorure de méthylemarqué au 14C, la radioactivité se répartit dans l’ensemblede l’organisme. Le produit radiomarqué est incorporé engrande partie aux protéines par le canal du pool dessubstances à un atome de carbone, mais le chlorure deméthyle peut également se fixer aux protéines paralkylation directe. Toutefois, si le composé se comportecomme un agent alkylant, c’est en très faible proportion.Chez les mammifères, il est métabolisé par conjugaisonavec le glutathion et, dans une moindre mesure, paroxydation au niveau du cytochrome P-450. Laconjugaison avec le glutathion conduit à la formation deméthanethiol et les deux voies métaboliques ont pourpoint d’aboutissement le formaldéhyde et le formiate.Les métabolites du chlorure de méthyle sont excrétésdans les urines ainsi que dans l’air expiré, qui contientégalement une certaine proportion du composé initial.

Chez l’Homme, on observe d’importantesdifférences individuelles concernant l’absorption et lamétabolisation du chlorure de méthyle. Ces différencessont dues à la présence ou à l’absence d’une enzyme, laglutathion-transférase T1 (GSTT1), qui présente unpolymorphisme génétique. On distingue en effet 3phénotypes chez l’Homme qui correspondent à uneconjugaison forte, faible ou nulle. De toute manière,comme on voit pas très bien si le risque le plus élevécorrespond à une conjugaison forte ou à uneconjugaison nulle, il faut considérer que tous lesphénotypes ont la même sensibilité au chlorure deméthyle.


42

La toxicité aiguë du chlorure de méthyle aprèsinhalation semble assez faible pour le rat et la souris,puisque la CL50 est supérieure à 4128 mg/m3 (2000 ppm).On n’a pas trouvé dans la littérature de données quiindiquent que le composé soit irritant ou sensibilisant.

Il semble qu’après inhalation, les principauxorganes cibles du chlorure de méthyle soient le systèmenerveux (avec des troubles fonctionnels ainsi qu’unedégénérescence du cervelet chez le rat et la souris) ainsique les testicules, l’épididyme et le rein chez le rat ouencore le rein et le foie chez la souris.

Lors d’une étude de 2 ans au cours de laquelle ona fait inhaler du chlorure de méthyle à des souris, on aconstaté qu’à la concentration de 103 mg/m3 (50 ppm),les nerfs rachidiens lombaires présentaient un gonfle-ment de l’axone et des signes de dégénérescence parcomparaison aux animaux témoins, sans qu’on puissetoutefois mettre en évidence une relation dose-réponse.Au terme de cette étude, on a observé chez les sourisdes deux sexes une dégénérescence du cervelet et chezles mâles, des adénocarcinomes rénaux à laconcentration de 2064 mg/m3 (1000 ppm). Ces effetsn’ont pas été observés chez le rat à cette concentration.

Le chlorure de méthyle se révèle nettementgénotoxique in vitro, tant vis-à-vis des bactéries que descellules mammaliennes. Même si les effets observés lorsd’un test de létalité dominante étaient très vraisemblable-ment plutôt cytotoxiques que génotoxiques, on pourraitconsidérer le chlorure de méthyle comme très faiblementmutagène in vivo, eu égard à certains signes témoignantde la présence de pontages ADN–protéines aux dosesélevées.

Chez des rats soumis à une concentration de

980 mg/m3 (475 ppm), on a observé la présence delésions testiculaires et notamment de granulomesépididymaires, puis une réduction de la vitalité desspermatozoïdes qui a conduit à une baisse de la fertilitéaboutissant à une stérilité totale à plus forte dose.

Le chlorure de méthyle a produit des anomaliescardiaques chez des foetus de souris dont la mère avaitété exposée à une concentration de 1032 mg/m3

(500 ppm) pendant la gestation.

Après inhalation accidentelle de chlorure deméthyle, les effets sont nets chez l’Homme, notammentau niveau du système nerveux central. Chez des volon-taires brièvement exposés à du chlorure de méthyle, onn’a pas constaté d’effets sensibles qui puissent êtreattribués à ce composé. On n’a pas suffisamment dedonnées épidémiologiques pour évaluer le risque decancer chez l’Homme par suite d’une exposition auchlorure de méthyle.

En conclusion, on peut dire que chez l’Homme, lepoint d’aboutissement de l’action toxique du chlorure deméthyle est vraisemblablement le système nerveuxcentral. On a pu en tirer des valeurs-guides de0,018 mg/m3 (0,009 ppm) pour une exposition indirectedans l’environnement et de 1,0 mg/m3 (0,5 ppm) pour uneexposition sur le lieu de travail. Bien que les lésionsnerveuses aient été constatées chez le rat à des dosesplus faibles que celles qui provoquaient la stérilité desmâles (980 mg/m3, soit 475 ppm) ou des lésions rénaleschez des souris mâles (à la concentration de 2064 mg/m3,soit 1000 ppm), c’est ces très graves effets qui sont àprendre en compte pour toute caractérisation qualitativedu risque que comporte une exposition au chlorure deméthyle.

On n’a guère trouvé de données sur la toxicité àcourt terme du chlorure de méthyle pour les organismesaquatiques ou terrestres. Dans le cas de la toxicité à longterme, c’est même une absence totale. Les donnéesexistantes indiquent que le composé n’a qu’une faibletoxicité aiguë pour les organismes aquatiques. Chez lespoissons, la plus faible valeur de la CL50qui ait étéobtenue est de 270 mg/litre. Comme les dosages donnentpour les eaux de surface des concentrations de chlorurede méthyle généralement inférieures de plusieurs ordrede grandeur à celles qui produisent effectivement deseffets, il est vraisemblable que ce composé ne présentepas de risque important d’intoxication aiguë pour lesorganismes aquatiques. On ne possède que des donnéestrès limitées concernant les effets du chlorure de méthylesur les organismes terrestres.

Methyl chloride

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RESUMEN DE ORIENTACIÓN

La evaluación de los aspectos relativos a la saludhumana de este CICAD sobre el cloruro de metilo sebasó fundamentalmente en un estudio preparado por elGrupo de Expertos Nórdicos en colaboración con elComité de Expertos Neerlandeses en Normas del Trabajo(Lundberg, 1992). Se realizó una búsqueda en las basesde datos pertinentes para el período de 1992-1999 conobjeto de obtener datos adicionales. Se utilizaron comofuentes principales para los aspectos ambientales yecotoxicológicos del cloruro de metilo BUA (1986),ATSDR (1990), WMO/OMM (1994) y HSDB (1996). Lapublicación ATSDR (1990) se actualizó en 1998; cuandoesta versión actualizada proporcionaba información, seha tenido en cuenta. Se obtuvieron datos adicionalessobre cuestiones ambientales en bases de datospertinentes para el período 1989-1997. La informaciónrelativa al carácter y a la disponibilidad de losdocumentos originales se presenta en el apéndice 1. Lainformación sobre el examen colegiado de este CICADfigura en el apéndice 2. Este CICAD se aprobó comoevaluación internacional en una reunión de la Junta deEvaluación Final, celebrada en Estocolmo (Suecia) del 25al 28 de mayo de 1999. La lista de participantes en estareunión figura en el apéndice 3. La Ficha internacional deseguridad química (ICSC 0419) para el cloruro de metilo,preparada por el Programa Internacional de Seguridad delas Sustancias Químicas (IPCS, 1999), se reproduce en elpresente documento.

El cloruro de metilo (CAS Nº 74-87-3) se liberafundamentalmente en el aire durante su producción yuso y por la incineración de residuos municipales eindustriales. Sin embargo, las fuentes naturales, enparticular los océanos y la combustión de biomasa,predominan claramente sobre las fuentesantropogénicas. La emisión mundial total de cloruro demetilo de todas las fuentes se estima en alrededor de 5 ×106 toneladas al año. Se ha calculado que la contribuciónde las fuentes naturales es muy superior al 90%, y tal vezhasta del 99%, de la emisión total. El cloruro de metiloestá presente en la troposfera en una concentraciónaproximada de 1,2 µg/m3 (0,6 ppmm).

El principal medio de absorción del cloruro demetilo en la troposfera es la reacción química con losradicales hidroxilo y su vida en la atmósfera se estimaque es de uno a tres años. Cierta cantidad de cloruro demetilo llega a la estratosfera; allí, la fotodisociacióngenera radicales de cloro, que contribuyen a ladestrucción de la capa de ozono. Las estimaciones de lacantidad de cloruro de metilo que llega a la estratosfera ydestruye pues la capa de ozono varían ampliamente. Apartir de las cifras presentadas por la OrganizaciónMeteorológica Mundial (OMM), se estima que el clorurode metilo contribuye con alrededor del 15% al

equivalente total de cloro estratosférico efectivo. Se hadeterminado que el cloruro de metilo tiene un potencialde destrucción del ozono estratosférico de 0,02 enrelación con el compuesto de referencia, el CFC-11, cuyopotencial es igual a 1. No parece que el cloruro de metilocontribuya de manera significativa al calentamientomundial o a la contaminación fotoquímica del aire.

El mecanismo predominante de eliminación delcloruro de metilo en el agua y el suelo es la volatiliza-ción. La hidrólisis lenta y posiblemente la degradaciónbiótica pueden contribuir a su desaparición en las capasmás profundas del suelo y en el agua freática. Sin embar-go, hay poca información sobre su biodegradación.

La ruta de exposición más importante del serhumano al cloruro de metilo son las vías respiratorias. Enlas personas, así como en los animales de experi-mentación, el cloruro de metilo se absorbe con rapidez através de los pulmones después de la inhalación. Tras laexposición a cloruro de metilo marcado con 14C, sedetecta radiactividad en todo el organismo. Aunque unagran parte de la sustancia marcada se incorpora a lasproteínas a través del “pool” de moléculas de un átomode carbono, el cloruro de metilo también se puede unir aproteínas por alquilación directa. Sin embargo, si bien esun agente alquilante, lo es en un grado muy pequeño. Elcloruro de metilo se metaboliza en los mamíferos porconjugación con el glutatión, y en menor proporciónmediante oxidación por el citocromo P-450; la vía delglutatión produce metanotiol y ambas vías dan lugar aformaldehído y formato. Los metabolitos del cloruro demetilo se eliminan con la orina y por exhalación. Tambiénse exhala cloruro de metilo sin metabolizar.

En las personas, hay grandes diferenciasindividuales en la absorción y el metabolismo del clorurode metilo. Estas diferencias dependen de la presencia oausencia de la enzima glutatión transferasa T1 (GSTT1),que presenta polimorfismo genético. Se distinguen en elser humano tres fenotipos, correspondientes a unaconjugación alta, baja o nula de la GSTT1. Sin embargo,como no está claro si el mayor riesgo corresponde a unaconjugación alta o a una conjugación nula, hay queconsiderar que todos los fenotipos son sensibles a laexposición al cloruro de metilo.

La toxicidad aguda por inhalación de cloruro demetilo en ratas y ratones parece ser bastante baja, conun valor de la CL50 superior a 4128 mg/m3 (2000 ppm). Nose han encontrado en la bibliografía datos indicativos deque el compuesto sea irritante o sensibilizante.

Los principales órganos destinatarios tras unaexposición breve por inhalación al cloruro de metiloparecen ser el sistema nervioso, con trastornosfuncionales y degeneración cerebelar tanto en las ratascomo en los ratones, así como los testículos, el


44

epidídimo y los riñones en las ratas y los riñones y elhígado en los ratones.

En un estudio por inhalación de dos años conratones se observaron inflamación y degeneraciónaxonal de los nervios de la médula espinal lumbar con103 mg/m3 (50 ppm) en los animales expuestos encomparación con los testigos, pero sin una relacióndosis-respuesta aparente. Al final del estudio sedetectaron degeneración cerebelar en los ratones deambos sexos y adenocarcinomas renales en los ratonesmachos con 2064 mg/m3 (1000 ppm). Estos efectos no seobservaron en las ratas con 2064 mg/m3 (1000 ppm).

El cloruro de metilo es claramente genotóxico ensistemas in vitro, tanto en bacterias como en células demamífero. Aunque los efectos positivos observados enuna prueba de dominancia letal fueron con todaprobabilidad citotóxicos más que genotóxicos, el clorurode metilo podría considerarse un mutágeno muy débil invivo sobre la base de algunos signos deentrecruzamiento proteína-ADN a dosis más altas.

Las lesiones testiculares y los granulomas epididi-males seguidos de una disminución de la calidad delesperma dieron lugar a una reducción de la fecundidaden las ratas con 980 mg/m3 (475 ppm) y a su pérdidacompleta a dosis superiores.

El cloruro de metilo indujo afecciones cardíacas enfetos de ratones cuyas madres estuvieron expuestas a1032 mg/m3 (500 ppm) durante el período de gestación.

Se pueden observar claramente efectos en laspersonas, especialmente en el sistema nervioso central,tras la exposición accidental por inhalación. En laexposición breve de voluntarios al cloruro de metilo nose observaron efectos significativos que pudieranatribuirse a ella. Hay pocos datos epidemiológicos quepermitan evaluar el riesgo de aparición de cáncer para laspersonas como resultado de la exposición al cloruro demetilo.

En conclusión, el efecto final crítico para latoxicidad por inhalación de cloruro de metilo en laspersonas parece ser la neurotoxicidad. Se obtuvieronvalores guía de 0,018 mg/m3 (0,009 ppm) para laexposición indirecta a través del medio ambiente y de1,0 mg/m3 (0,5 ppm) para el entorno de trabajo. Aunquelas lesiones nerviosas se observaron a niveles deexposición inferiores a los que provocaron la pérdida defecundidad en las ratas (980 mg/m3 [475 ppm]) y lostumores renales en los ratones macho (2064 mg/m3 [1000ppm]), en la caracterización del riesgo cualitativo delcloruro de metilo se debe hacer hincapié también en esosefectos muy graves.

Se encontraron pocos datos sobre la toxicidad acorto plazo del cloruro de metilo para los organismosacuáticos o terrestres. No se obtuvo ningún dato sobrela toxicidad a largo plazo. Los datos disponibles indicanque el cloruro de metilo tiene una toxicidad aguda bajapara los organismos acuáticos. El valor más bajo de laCL50 para los peces es de 270 mg/litro. Teniendo encuenta que las concentraciones de cloruro de metilo quese han determinado en las aguas superficiales songeneralmente varios órdenes de magnitud inferiores a lasque se ha demostrado que son causantes de esosefectos, es probable que el cloruro de metilo representeun riesgo bajo de efectos agudos para los organismosacuáticos. Solamente se dispone de datos muy limitadossobre los efectos del cloruro de metilo en los organismosterrestres.

THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Azodicarbonamide (No. 16, 1999)Benzoic acid and sodium benzoate (No. 26, 2000)Benzyl butyl phthalate (No. 17, 1999)Biphenyl (No. 6, 1999)2-Butoxyethanol (No. 10, 1998)Chloral hydrate (No. 25, 2000)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)Diphenylmethane diisocyanate (MDI) (No. 27, 2000)Ethylenediamine (No. 15, 1999)Ethylene glycol: environmental aspects (No. 22, 2000)2-Furaldehyde (No. 21, 2000)HCFC-123 (No. 23, 2000)Limonene (No. 5, 1998)Manganese and its compounds (No. 12, 1999)Methyl methacrylate (No. 4, 1998)Mononitrophenols (No. 20, 2000)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)

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