1,2-dichloroethane - who | world health …2-dichloroethane first draft prepared by ms k. hughes and...

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 Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 1

1,2-DICHLOROETHANE

First draft prepared by Ms K. Hughes and Ms M.E. Meek,Environmental Health Directorate,Health Canada

Please note that thelayout and pagination of this pdf file are not identical to the printedCICAD

Published under the joint sponsorship of the United Nations Environment Programme, theInternational Labour Organisation, and the World Health Organization, and produced within theframework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health OrganizationGeneva, 1998

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organisation (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, and the Organisation for Economic Co-operationand Development (Participating Organizations), following recommendations made by the 1992 UNConference on Environment and Development to strengthen cooperation and increase coordination in thefield of chemical safety. The purpose of the IOMC is to promote coordination of the policies andactivities pursued by the Participating Organizations, jointly or separately, to achieve the soundmanagement of chemicals in relation to human health and the environment.

WHO Library Cataloguing in Publication Data

1,2-Dichloroethane.

(Concise international chemical assessment document ; 1)

1.Ethylene dichlorides – toxicity 2.Ethylene dichlorides –administration and dosage 3.Dose-response relationship, Drug4.Environmental exposure I.International Programme forChemical Safety II.Series

ISBN 92 4 153001 4 (NLM Classification: QV 633) ISSN 1020-6167

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©World Health Organization 1998

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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.

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

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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

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

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . 7

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

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

9.1 Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99.2 Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . 9

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11.1.2 Criteria for setting guidance values for 1,2-dichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . 12 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13


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13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

13.1 Human health hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313.2 Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313.3 Health surveillance advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413.4 Explosion and fire hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 13.4.1 Explosion hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

13.4.2 Fire hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413.4.3 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

13.5 Spillage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

APPENDIX 2 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

1,2-Dichloroethane

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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 Organisation (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 have undergoneextensive peer review by internationally selected expertsto ensure their completeness, accuracy in the way inwhich the original data are represented, and the validityof the conclusions drawn.

The primary objective of CICADs is character-ization of hazard and dose–response from exposure to achemical. CICADs are not a summary of all available dataon a particular chemical; rather, they include only thatinformation considered critical for characterization of therisk posed by the chemical. The critical studies are,however, presented in sufficient detail to support theconclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environment will

vary 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 toEHC 1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new infor-mation that would change the conclusions drawn in aCICAD, the reader is requested to contact the IPCS toinform 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 andone or more experienced authors of criteria documents 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 seconddraft is submitted to a Final Review Board together withthe reviewers’ 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.

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

P R I M A R Y R E V I E W A T P R O D U C E R L E V E L

( 1-2 OTHER DOCUMENT PRODUCERS) 1

P R O D U C E R

REVIEW BY IPCS CONTACT POINTS

FINAL REVIEW BOARD 3

FINAL DRAFT 4

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

R E S P O N S I B L E

O F F I C E R

( R O )

SELECTION OF PRIORITY CHEMICAL

1 Revision as necessary.2 Taking into account the comments from reviewers.3 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments (6-10 CICADs are usually reviewed atthe Final Review Board). In the case of pesticides the role of the Final Review Board is fulfilled by a joint meeting on pesticides.4 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RO ),PREPARATION

OF SECOND DRAFT 2

1,2-Dichloroethane

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

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board. Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the final decision-making process.


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1. EXECUTIVE SUMMARY

This CICAD on 1,2-dichloroethane was preparedby the Environmental Health Directorate of HealthCanada based on an International Programme onChemical Safety (IPCS) Environmental Health Criteria(EHC) document (IPCS, 1995), which assesses thepotential effects on human health of indirect exposure to1,2-dichloroethane in the general environment as well asthe chemical’s environmental effects. Data identified asof May 1993 (human health effects) and October 1994(environmental effects) were considered in thesereviews. Information on the nature of the peer reviewprocess and the availability of the EHC document ispresented in Appendix 1. For this CICAD, the peerreview process prior to consideration by the FinalReview Board was covered by the peer review carriedout for the EHC. This CICAD on 1,2-dichloroethane wasfinalized and approved for publication, throughcorrespondence, by members of the Final Review Board,who also considered the peer review comments providedduring the development of the EHC. The composition ofthe Final Review Board is outlined in Appendix 2. TheInternational Chemical Safety Card (ICSC 0250) producedby the IPCS (1993) has also been reproduced in thisdocument.

1,2-Dichloroethane (CAS no. 107-06-2) is a volatile,synthetic hydrocarbon that is used principally in thesynthesis of vinyl chloride monomer and otherchlorinated solvents. It has also been used as a leadedgasoline additive and a fumigant, although its use as agasoline additive is declining. The majority of environ-mental releases are to ambient air, where it is moderatelypersistent. However, it is not expected to contribute toozone depletion. 1,2-Dichloroethane has a low potentialfor bioaccumulation; inhalation in air is likely the primarysource of human exposure.

Little information is available on the effects of 1,2-dichloroethane in humans. The few identifiedepidemiological investigations on its potential carcino-genicity are inconclusive.

1,2-Dichloroethane is moderately acutely toxic inexperimental animals. Limited information on non-neoplastic effects presented in short-term, subchronic,and chronic studies indicates that the liver and kidneysare the principal target organs; lowest reported effectlevels for ingestion and inhalation were 49–82 mg/kgbody weight per day (increases in liver weight in ratsexposed for 13 weeks) and 202 mg/m3 (effects on liverand kidney function in rats exposed for 12 months),respectively. Based on the results of a limited number ofstudies, there is no evidence that 1,2-dichloroethane is

teratogenic in experimental animals or that it inducesreproductive or developmental effects at levels ofexposure lower than those that cause other systemiceffects.

Exposure to 1,2-dichloroethane by gavage for78 weeks induced a significant increase in the incidenceof tumours at several sites (including haemangiosar-comas and tumours of the stomach, mammary gland,liver, lung, and endometrium) in both rats and mice. Although there were no significant increases in tumourincidence in rats or mice exposed via inhalation, repeateddermal or intraperitoneal application of 1,2-dichloroethane resulted in an increase in lung tumours inmice. 1,2-Dichloroethane has been consistently geno-toxic in numerous in vitro assays in prokaryotes, fungi,and mammalian (including human) cells. Similarly,results were consistently positive for genotoxic activity(as well as binding to DNA) in in vivo studies in rats,mice, and insects.

The lowest reported IC50s and EC50s for variousend-points in aquatic organisms were 25 and 105mg/litre, respectively. The lowest reported LC50 value forDaphnia was 220 mg/litre, whereas effects onreproduction occurred at 20.7 mg/litre. The mostsensitive freshwater vertebrate tested was the north-western salamander (Ambystoma gracile), in whichreduced larval survival was observed at 2.5 mg/litre. Only limited data are available on the effects of 1,2-dichloroethane on terrestrial species.

Based on available data, 1,2-dichloroethane isconsidered to be a probable human carcinogen, andtherefore exposure should be reduced to the extentpossible. The carcinogenic potency (expressed as thedose associated with a 5% increase in tumour incidence),derived on the basis of studies in which animals wereexposed by gavage, was calculated to be 6.2–34 mg/kgbody weight per day. Guidance values for air (theprincipal source of human exposure) of 3.6–20 :g/m3 or0.36–2.0 :g/m3, calculated on the basis of a margin 5000-or 50 000-fold less than the estimated carcinogenicpotency, have been derived; however, it should benoted that risks are overestimated on this basis, asavailable data indicate that 1,2-dichloroethane is lesspotent when inhaled. (Corresponding values foringestion are 1.2–6.8 :g/kg body weight per day or0.12–0.68 :g/kg body weight per day.) These valuescorrespond to those considered by some agencies torepresent “essentially negligible” risk (i.e. 10–5 to 10–6 fora genotoxic carcinogen). Based on a sample estimate,indirect exposure in the general environment is up toapproximately 300 times less than these values.

1,2-Dichloroethane

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2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

1,2-Dichloroethane (CAS no. 107-06-2; ethylenedichloride, dichloro-1,2-ethane; see structural diagrambelow) is a synthetic chemical that is a colourless liquidat room temperature. It is also highly volatile, with avapour pressure of 8.5 kPa (at 20ºC), and soluble inwater, with a solubility of 8690 mg/litre (at 20ºC). The logoctanol/water partition coefficient of 1,2-dichloroethaneis 1.76. Additional physical/chemical properties arepresented in the International Chemical Safety Card,reproduced in this document.

H H * * Cl ) C ) C ) Cl * * H H

3. ANALYTICAL METHODS

Analysis for 1,2-dichloroethane in environmentalmedia is usually by gas chromatography, in combinationwith electron capture detection, flame ionization detec-tion, or mass spectrometry. Detection limits range from0.016 to >4 :g/m3 for air, from 0.001 to 4.7 :g/litre forwater, and from 6 to 10 :g/kg for various foodstuffs(ATSDR, 1992).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

There are no known natural sources of 1,2-

dichloroethane. The principal use for 1,2-dichloroethaneis in the synthesis of vinyl chloride monomer and, to alesser extent, in the manufacture of various chlorinatedsolvents. It is also incorporated into antiknock gasolineadditives (although this use is declining with the phase-out of leaded gasoline in some countries) and has beenused as a fumigant. Total annual production of 1,2-dichloroethane in Canada (1990) and the USA (1991) isabout 922 and 6318 kt, respectively (CPI, 1991; ChemicalMarketing Reporter, 1992).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

The majority of 1,2-dichloroethane released to theenvironment is in emissions to air. 1,2-Dichloroethane ismoderately persistent in air; its estimated atmosphericlifetime is between 43 and 111 days. Small amounts of1,2-dichloroethane are transported to the stratosphere,where photolysis may produce chlorine radicals, whichmay in turn react with ozone (Spence & Hanst, 1978;Callaghan et al., 1979). Some 1,2-dichloroethane may bereleased in industrial effluents to the aquatic environ-ment, from where it is removed rapidly by volatilization(Dilling et al., 1975). 1,2-Dichloroethane may also leachto groundwater near industrial waste sites. It is notexpected to bioconcentrate in aquatic or terrestrialspecies.

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

Data considered to be most representative ofcurrent levels of 1,2-dichloroethane in environmentalmedia are summarized in Table 1. Mean concentrationsof 1,2-dichloroethane in surveys of ambient air in non-source-dominated areas in cities are 0.07–0.28 :g/m3 inCanada, <0.004–3.8 :g/m3 in Japan, and 1.2 :g/m3 in theUnited Kingdom and the Netherlands. Earlier surveys inthe USA reported mean levels of 0.33–6.05 :g/m3;however, peak levels near chemical manufacturing plantshave ranged as high as 736 :g/m3 (US EPA, 1985). Mean levels in residential indoor air are reported to be<0.1 :g/m3 in Canada, 0.1–0.5 :g/m3 in the USA, and 3.4:g/m3 in the Netherlands.

In drinking-water, mean 1,2-dichloroethane con-centrations are generally less than 0.5 :g/litre, based onthe results of surveys in Canada, the USA, Japan, andSpain. Although there are few recent data, 1,2-dichloro-ethane has only very rarely been detected in surfacewater at concentrations greater than 10 :g/litre.

1,2-Dichloroethane has only rarely been detectedin foodstuffs in extensive surveys in Canada and theUSA. Also, as 1,2-dichloroethane has low potential forbioaccumulation, food is unlikely to be a major source ofexposure.


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Table 1: Levels of 1,2-dichloroethane in environmental media.

Medium Location Year Concentrations Reference

Ambient air Canada 1988–1990 0.07–0.28 :g/m3 (means) T. Dann, unpublished data,1992

Ambient air Japan 1992 <0.004–3.8 :g/m3 (means) Environment Agency Japan,1993

Ambient air UK 1982, 1983 1.2 :g/m3 (mean) Clark et al., 1984a,b

Ambient air Netherlands 1980 1.2 :g/m3 (mean) Guicherit & Schulting, 1985

Ambient air USA 1980–1982 0.33–6.05 :g/m3 (means) Singh et al., 1980, 1981, 1982

Indoor air (residential) Canada 1991 <0.1 :g/m3 (mean) Fellin et al., 1992

Indoor air (residential) USA 0.1–0.5 :g/m3 (means) US EPA, 1992

Indoor air (residential) Netherlands 1984–1985 3.4 :g/m3 (mean) Kliest et al., 1989Drinking-water Canada 1988–1991

19901982–1983

<0.05–0.139 :g/litre (mean)

<0.2 :g/litre (mean)<0.1 :g/litre (mean)

P. Lachmaniuk, personalcommunication, 1991Ecobichon & Allen, 1990Otson, 1987

Drinking-water USA Early 1980s NDa – 19 :g/litreND – 0.05 :g/litre

Letkiewicz et al., 1982Barkley et al., 1980

Drinking-water Japan 1976 <0.5–0.9 :g/litre Fujii, 1977

Drinking-water Spain 1987 2–22 :g/litre Freiria-Gandara et al., 1992

Surface water Canada 1981–1985 <0.08 :g/litre Kaiser et al., 1983; Comba &Kaiser, 1985; Kaiser & Comba,1986; Lum & Kaiser, 1986

Surface water Japan 1992 0.01–3.4 :g/litre Environment Agency Japan,1993

Food (34 groups) Canada 1991

1992

<50 :g/kg (solids); <1 :g/litre(liquids)<5 :g/kg (solids); <1 :g/litre(liquids)

Enviro-Test Laboratories, 1991

Enviro-Test Laboratories, 1992

Food (19 items) USA Not specifiedNot specified

ND – 0.31 :g/kgND – 8.2 :g/kg

Heikes, 1987, 1990Heikes, 1987

Food (231 items) USA Not specified <9–30 :g/kg Daft, 1988a Detection limit not reported.

6.2 Human exposure

An example of estimated indirect exposure in thegeneral environment is presented here. Exposure of thegeneral population to 1,2-dichloroethane in environ-mental media may be estimated based on concentrationsdetermined in various media and reference values forbody weight and consumption patterns. Owing to theavailability of relevant data, exposure has been estimatedbased primarily on data from North America. However,countries are encouraged to estimate total exposure onthe basis of national data, possibly in a manner similar tothat outlined here.

Based on a daily inhalation volume for adults of 22m3, a mean body weight for males and females of 64 kg,the assumption that 4 of 24 hours are spent outdoors(IPCS, 1994), and the range of mean levels of 1,2-dichloroethane in ambient air of 0.07–0.28 :g/m3 in asurvey of cities across Canada, the mean intake of 1,2-dichloroethane from ambient air for the generalpopulation is estimated to range from 0.004 to 0.02 :g/kgbody weight per day. The mean intake of 1,2-dichloroethane in indoor air, based on the assumption

that 20 of 24 hours are spent indoors (IPCS, 1994) andthe range of concentrations in indoor or “personal” air inCanada and the USA of <0.1–0.5 :g/m3, is estimated torange from <0.03 to 0.1 :g/kg body weight per day. Based on a daily volume of water consumption for adultsof 1.4 litres, a mean body weight of 64 kg (IPCS, 1994),and the mean levels of 1,2-dichloroethane in provincialsurveys in Canada of <0.05–0.139 :g/litre, the meanintake from drinking-water is estimated to range from<0.001 to 0.003 :g/kg body weight per day. Intake of1,2-dichloroethane in food is likely to be negligible, as ithas not been detected in extensive surveys and as it haslow potential for bioaccumulation. Therefore, theprincipal source of exposure of the general population to1,2-dichloroethane is indoor and outdoor air, with onlyminor amounts being contributed by drinking-water.

Few data on occupational exposure to 1,2-dichloroethane were identified. In North America,workers are exposed to 1,2-dichloroethane principally inthe manufacture of other chemical substances; in suchsituations, the principal route of exposure is most likelyinhalation and, possibly, dermal contact.

1,2-Dichloroethane

7

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

1,2-Dichloroethane is readily absorbed followinginhalation, ingestion, and dermal exposure and is rapidlyand widely distributed throughout the body. Relativedistribution of radioactivity (presumably as metabolites)was similar in rats administered a single oral dose of 150 mg/kg body weight and those exposed by inhalationto 150 ppm (600 mg/m3) for 6 hours (Reitz et al., 1982). 1,2-Dichloroethane is rapidly and extensivelymetabolized in rats and mice, with principally sulfur-containing metabolites being eliminated in the urine in adose-dependent manner. Metabolism appears to besaturated or limited in rats at levels of exposure resultingin concentrations in blood of 5–10 :g/ml (Reitz et al.,1982). Levels of DNA alkylation were higher followingexposure to a bolus dose of 150 mg/kg body weight bygavage compared with inhalation of 150 ppm (600 mg/m3)over a 6-hour period (Reitz et al., 1982).

Available data suggest that 1,2-dichloroethane ismetabolized via two principal pathways. The firstinvolves a saturable microsomal oxidation mediated bycytochrome P-450 to 2-chloroacetaldehyde and 2-chloro-ethanol, followed by conjugation with glutathione. Thesecond pathway entails direct conjugation withglutathione to form S-(2-chloroethyl)-glutathione, whichmay be non-enzymatically converted to a glutathioneepisulfonium ion; this ion can form adducts withproteins, DNA, or RNA. Although DNA damage hasbeen induced by the P-450 pathway in vitro (Banerjee etal., 1980; Guengerich et al., 1980; Lin et al., 1985), severallines of evidence indicate that the glutathioneconjugation pathway is probably of greater significancethan the P-450 pathway as the major route for DNAdamage (Guengerich et al., 1980; Rannug, 1980;Sundheimer et al., 1982; Inskeep et al., 1986; Koga et al.,1986; Simula et al., 1993).

8. EFFECTS ON LABORATORY MAMMALSAND IN VITRO TEST SYSTEMS

8.1 Single exposure

1,2-Dichloroethane is moderately acutely toxic inexperimental animals. For example, LC50s for ratsexposed by inhalation for 6 or 7.25 hours ranged from4000 mg/m3 (Spencer et al., 1951) to 6600 mg/m3 (Bonnetet al., 1980), whereas oral LD50s for rats, mice, dogs, andrabbits ranged from 413 to 2500 mg/kg body weight

(Barsoum & Saad, 1934; McCollister et al., 1956; Smyth,1969; Larionov and Kokarovtseva, 1976; Munson et al.,1982; NIOSH, 1994a).

8.2 Irritation and sensitization

Application of 1,2-dichloroethane to the skin ofexperimental animals has resulted in microscopicchanges and moderate oedema (Duprat et al., 1976;Kronevi et al., 1981; Jakobson et al., 1982). Similarly,histological changes and mild irritation in the eye havebeen observed in animals following direct application(Kuwabara et al., 1968; Duprat et al., 1976). Noinformation on the sensitization potential of thissubstance was identified.

8.3 Short-term exposure

Few data were identified on the toxicity of 1,2-dichloroethane following short-term exposure. Degener-ation and necrosis of the liver and kidneys, accompaniedby congestion and haemorrhage of the lungs andadrenal glands, were observed in small groups of rats,rabbits, guinea-pigs, dogs, and pigs exposed to 1,2-dichloroethane by inhalation at 6000 mg/m3, 7 hours/day,for 6 days (Heppel et al., 1945). No effects on body ororgan weights, histology, or clinical chemistry werenoted in rats administered oral doses of up to 150 mg/kgbody weight per day for 2 weeks (van Esch et al., 1977;Reitz et al., 1982).

8.4 Long-term exposure

8.4.1 Subchronic exposure

The results of subchronic studies in severalspecies of experimental animals indicate that the liverand kidneys are the target organs of 1,2-dichloroethaneexposure; however, most of these studies were inade-quate to serve as a basis for establishing reliable no-observed-effect levels or lowest-observed-effect levels,generally because of the inadequate documentation andthe limited range of end-points examined in small groupsof animals. In a series of early limited studies,morphological changes in the liver were observed inseveral species following subchronic exposure (7hours/day) to airborne concentrations as low as 800mg/m3 (Heppel et al., 1946; Spencer et al., 1951; Hofmannet al., 1971). Increases in relative liver weight have beenobserved in rats following subchronic oraladministration of doses of 49–82 mg/kg body weight perday and above for 13 weeks (van Esch et al., 1977; NTP,1991).


8

8.4.2 Chronic exposure and carcinogenicity

Little information was presented on non-neoplasticeffects in available chronic studies. Changes in serumparameters indicative of liver and kidney toxicity wereobserved in groups of 8–10 male or female Sprague-Dawley rats exposed to airborne concentrations as lowas 202 mg/m3 for 12 months, although histopathologicalexaminations were not conducted in this study(Spreafico et al., 1980).

The carcinogenicity of 1,2-dichloroethane hasbeen investigated in a few limited bioassays in experi-mental animals (limitations include short duration ofexposure and high mortality). In an inhalation study, nosignificant increase in the incidence of any type oftumour was reported in groups of 90 male or femaleSprague-Dawley rats exposed to concentrations of 1,2-dichloroethane up to 150 ppm (607 mg/m3), 7 hours/day, 5 days/week, for 78 weeks and observed untilspontaneous death (Maltoni et al., 1980). However,mortality was high in this study, although it was notrelated to concentration, and incidence rates were notadjusted for differential mortality among groups. Therewas a non-significant increase in the incidence ofmammary gland adenomas and fibroadenomas in femaleSprague-Dawley rats (n = 50) exposed to 1,2-dichloro-ethane at 50 ppm (200 mg/m3), 7 hours/day, 5 days/ week,for 2 years in an assay in which no other compound-related toxicity was observed (Cheever et al., 1990). Noincrease in the incidence of any type of tumour wasobserved in groups of 90 male or female Swiss miceexposed to concentrations of 1,2-dichloroethane up to150 ppm (607 mg/m3), 7 hours/day, 5 days/ week, for 78weeks and observed until spontaneous death (Maltoniet al., 1980).

In contrast, there has been convincing evidence ofincreases in tumour incidence in two species followingingestion. There were significant increases in theincidence of tumours at several sites in Osborne-Mendelrats (n = 50 of each sex in exposed groups; n = 20matched controls; n = 60 pooled controls) administeredtime-weighted-average doses of 47 or 95 mg/kg bodyweight per day in corn oil by gavage, 5 days/week, for 78weeks, followed by 32 weeks of observation. Theincidence of squamous cell carcinomas of the stomachwas significantly increased in both groups of exposedmales (0/60, 0/20, 3/50, and 9/50 in pooled [fromconcurrent studies] vehicle controls, matched vehiclecontrols, low-dose group, and high-dose group,respectively). There were also significant increases inthe incidence of haemangiosarcomas in exposed males(1/60, 0/20, 9/50, and 7/50) and females (0/59, 0/20, 4/50,and 4/50). The incidence of fibromas of thesubcutaneous tissue was significantly increased inexposed males (0/60, 0/20, 5/50, and 6/50). In females,

there were significant increases in the incidences ofadenocarcinomas and fibroadenomas (combined) of themammary gland (6/59, 0/20, 15/50, and 24/50). Mortalitywas significantly higher in both males and females in thehigh-dose group, and there was a greater frequency ofclinical signs of toxicity in exposed rats compared withcontrols. Chronic murine pneumonia was present in60–94% of rats in each group, although the incidencewas not related to dose (NCI, 1978).

In a similar bioassay, B6C3F1 mice (n = 50 of each

sex in exposed groups; n = 20 matched controls; n = 60 pooled controls) were administered time-weighted-average doses of 97 or 195 mg/kg body weightper day (males) and 149 or 299 mg/kg body weight perday (females) in corn oil by gavage, 5 days/week, for 78weeks, followed by 13 weeks of observation. Theincidence of hepatocellular carcinomas was significantlyincreased in exposed males (4/59, 1/19, 6/47, and 12/48 inpooled vehicle controls, matched vehicle controls, low-dose group, and high-dose group, respectively),although the authors noted that the increase in theincidence of this tumour could not be convincinglyattributed to the test chemical, owing to the highvariability of hepatocellular neoplasms among historicalcontrols. The incidence of alveolar/bronchiolaradenomas was significantly increased in males in thehigh-dose group (0/59, 0/19, 1/47, and 15/48) and in bothgroups of exposed females (2/60, 1/20, 7/50, and 15/48);one female in the high-dose group had analveolar/bronchiolar carcinoma. The incidence ofmammary gland adenocarcinomas was significantlyincreased in females at both doses (0/60, 0/20, 9/50, and7/48). The incidence of endometrial stromal polyp orendometrial stromal sarcoma (combined) in females wassignificantly elevated at both doses (0/60, 0/20, 5/49, and5/47). There was a dose-related increase in mortality infemales, but not in males; in addition, body weight wasdecreased in females receiving the higher dose (NCI,1978).

The incidence of lung tumours (benign lung papil-lomas) was significantly increased in female non-inbredHa:ICR mice (n = 30) following repeated dermal applica-tion of 1,2-dichloroethane, 3 times/week, for 440–594days (van Duuren et al., 1979). Repeated intraperitonealinjections of 1,2-dichloroethane resulted in a dose-related increase in the number of pulmonary adenomasper mouse in a screening bioassay in a susceptible strain(A/St), although none of these increases was significant(Theiss et al., 1977). Concomitant exposure to inhaled1,2-dichloroethane and disulfiram in the diet resulted inan increased incidence of intrahepatic bile ductcholangiomas and cysts, subcutaneous fibromas,hepatic neoplastic nodules, interstitial cell tumours in thetestes, and mammary adenocarcinomas in rats, comparedwith rats administered either compound alone or

1,2-Dichloroethane

9

untreated controls (Cheever et al., 1990). No potential toinitiate or promote tumour development was evident inthree bioassays (van Duuren et al., 1979; Klaunig et al.,1986; Story et al., 1986; Milman et al., 1988), although theextent of histopathological examination was limited inthese studies.

8.5 Genotoxicity and related end-points

1,2-Dichloroethane has been consistently

demonstrated to be genotoxic in numerous in vitro(Table 2) and in vivo (Table 3) assays for a wide range ofend-points. It has been mutagenic in Salmonellatyphimurium, especially in the presence of an exogenousactivation system, and induces unscheduled DNAsynthesis, induces gene mutation, and forms adductswith DNA in mammalian cells in vitro. It binds to DNAin all reported in vivo studies in rats and mice. 1,2-Dichloroethane has also induced somatic cell and sex-linked recessive lethal mutations in Drosophilamelanogaster.

Available data on genotoxicity are consistent with the hypothesis that the glutathione pathway ofconjugation (i.e. production of the glutathione epi-sulfonium ion) is probably of greater significance thanthe P-450 pathway as the major route for DNA damage(Guengerich et al., 1980; Rannug, 1980; Sundheimer et al.,1982; Inskeep et al., 1986; Koga et al., 1986; Simula et al.,1993); mutation frequency in human cell lines has beencorrelated with variations in levels of glutathione-S-transferase activities (Crespi et al., 1985).

8.6 Reproductive and developmentaltoxicity

Based on the results of a limited number of studies, there is no evidence that 1,2-dichloroethane isteratogenic in experimental animals and little convincingevidence that it induces reproductive or developmentaleffects at doses below those that cause other systemiceffects (Alumot et al., 1976; Vozovaya, 1977; Kavlock etal., 1979; Rao et al., 1980; Lane et al., 1982).

8.7 Immunological and neurologicaleffects

Immunological effects, including reducedresistance to streptococcal challenge, decreasedpulmonary bactericidal activity in mice, and altered levelsof antibody production in rabbits, have been observedfollowing acute or subchronic exposure to 1,2-dichloroethane at 20 and 10 mg/m3 and above,respectively (Shmuter, 1977; Sherwood et al., 1987),whereas there were no effects in rats exposed to up to800 mg/m3 for several days (Sherwood et al., 1987).

Effects on antibody levels and reversible effects on cell-mediated responses were also noted in mice exposed to1,2-dichloroethane in drinking-water at concentrationsequivalent to doses of 3 mg/kg body weight per day andabove for 14 or 90 days (Munson et al., 1982).

Data on the neurological effects of 1,2-dichloro-ethane have not been identified.

9. EFFECTS ON HUMANS

9.1 Case reports

Acute incidental exposure to 1,2-dichloroethane byinhalation or ingestion has resulted in a variety of effectsin humans, including effects on the central nervoussystem, liver, kidney, lung, and cardiovascular system(e.g. Hinkel, 1965; Suveev & Babichenko, 1969; Dorndorfet al., 1975; Andriukin, 1979; Nouchi et al., 1984). Basedon limited available data in humans, the lethal oral doseof 1,2-dichloroethane has been estimated to be between20 and 50 ml.

9.2 Epidemiological studies

The potential carcinogenicity of 1,2-dichloroethanein exposed human populations has not been extensivelyinvestigated. Mortality due to pancreatic cancer wassignificantly increased (standardized mortality ratio[SMR] = 492, based on eight cases) in a group of 278workers at a chemical production plant who had beenprincipally exposed to 1,2-dichloroethane in combinationwith other chemicals. Mortality due to this causeincreased with duration of exposure. In addition,although the number of cases was small (i.e. four) andthe association with duration of exposure was lessconsistent, mortality due to leukaemia was alsoincreased in these workers (Benson & Teta, 1993).

No association between occupational exposure to1,2-dichloroethane and brain cancer was noted in a smallcase–control study (Austin & Schnatter, 1983). Although the incidence of colon and rectal cancerincreased with concentration of 1,2-dichloroethane indrinking-water in an inherently limited ecological study,concomitant exposure to other substances may havecontributed to the observed effects (Isacson et al., 1985).


10

Table 2: Genotoxicity of 1,2-dichloroethane in vitro (modified from ATSDR, 1992).

Result

Species (test system) End-pointWith

activationWithout

activation Reference

PROKARYOTIC SYSTEMS

Salmonella typhimurium Gene mutation + + Milman et al., 1988

+ + Barber et al., 1981

+ + Kanada & Uyeta, 1978

+ + Nestmann et al., 1980

+ + Rannug et al., 1978

+ + van Bladeren et al., 1981

+ NT Rannug & Beije, 1979

+ – Cheh et al., 1980

+ – Moriya et al., 1983

– – King et al., 1979

+ + Strobel & Grummt, 1987

NT +a Simula et al., 1993

S. typhimurium/spot test Gene mutation NT (+) Brem et al., 1974

(+) – Principe et al., 1981

NT – Buijs et al., 1984

S. typhimurium/Ara test (standard) Gene mutation + – Roldan-Arjona et al., 1991

S. typhimurium/Ara test (liquid) Gene mutation (+) (+) Roldan-Arjona et al., 1991

Streptomyces coelicolor Gene mutation NT – Principe et al., 1981

Escherichia coli K12/343/113 Gene mutation – – King et al., 1979

E. coli wp2 Gene mutation NT (+) Hemminki et al., 1980

– – Moriya et al., 1983

E. coli Pol A DNA damage NT (+) Brem et al., 1974

Bacillus subtilis/rec– assay DNA damage NT – Kanada & Uyeta, 1978

EUKARYOTIC ORGANISMS

— FUNGIAspergillus nidulans Gene mutation NT – Crebelli & Carere, 1988

NT – Principe et al., 1981

A. nidulans Mitotic segregation aberrations NT + Crebelli et al., 1984

A. nidulans Aneuploidy induction NT + Crebelli et al., 1988

Saccharomyces cerevisiae Mitotic recombination NT (+) Simmon, 1980

— ANIMAL SYSTEMSHamster CHO/HGPRT Gene mutation + (+) Tan & Hsie, 1981

+ (+) Zamora et al., 1983

Rat hepatocytes Unscheduled DNA synthesis NT + Williams et al., 1989

Mouse hepatocytes Unscheduled DNA synthesis NT + Milman et al., 1988

Mouse liver DNA DNA binding + NT Banerjee, 1988

Calf thymus DNA DNA binding + NT Prodi et al., 1986

Salmon sperm DNA DND binding + – Banerjee & van Duuren,1979; Banerjee et al., 1980

Mouse BALB/c-3T3 Cell transformation NT – Milman et al., 1988

NT – Tu et al., 1985

Mouse C3H1OT½ Cell transformation NT +b Schultz et al., 1992

Syrian hamster embryo cells Cell transformation NT + Hatch et al., 1983

— HUMAN CELLSHuman lymphoblasts AHH-1 Gene mutation NT + Crespi et al., 1985

Human lymphoblasts TK6 Gene mutation NT + Crespi et al., 1985

Human embryo epithelial-like EUEcells

Gene mutation NT + Ferreri et al., 1983

Human peripheral lymphocytes Unscheduled DNA synthesis + – Perocco & Prodi, 1981

NT = not tested – = negative result + = positive result (+) = weakly positive or marginal resulta Increase in cells expressing GSTA1-1.b Transformed cells induced tumours in nude mice.

1,2-Dichloroethane

11

Table 3: Genotoxicity of 1,2-dichloroethane in vivo(modified from ATSDR, 1992).

Species (test system) End-point Results Reference

MAMMALIAN ASSAYS

Mouse Dominant lethal mutations – Lane et al., 1982

Mouse/spot test Gene mutation (+) Gocke et al., 1983

Mouse bone marrow Sister chromatid exchange + Giri & Que Hee, 1988

Mouse bone marrow Micronuclei – King et al., 1979; Jenssen & Ramal, 1980

Mouse peripheral erythrocytes Micronuclei – Armstrong & Galloway, 1993

Mouse liver, kidney, lung, and stomach DNA binding + Prodi et al., 1986

Mouse liver, kidney, lung, and stomach DNA binding + Arfellini et al., 1984

Mouse forestomach and kidney DNA binding + Hellman & Brandt, 1986

Mouse liver DNA binding + Banerjee, 1988

Rat liver, kidney, spleen, lung, forestomach,and stomach

DNA binding + Reitz et al., 1982

Rat liver, kidney, lung, and stomach DNA binding + Arfellini et al., 1984

Rat liver, kidney, lung, and stomach DNA binding + Prodi et al., 1986

Rat liver and kidney DNA binding + Inskeep et al., 1986

Rat liver and lung DNA binding + Baertsch et al., 1991

Rat liver DNA binding + Banerjee, 1988

Rat liver DNA binding + Cheever et al., 1990

Mouse liver DNA damage + Storer & Conolly 1983, 1985; Storer et al., 1984

Mouse liver DNA damage + Taningher et al., 1991

INSECT ASSAYS

Drosophila melanogaster /somatic mutation Gene mutation + Nylander et al., 1978

D. melanogaster/somatic mutation Gene mutation + Romert et al., 1990

D. melanogaster/somatic mutation Gene mutation + Kramers et al., 1991

D. melanogaster/somatic mutation Gene mutation (+) Ballering et al., 1993

D. melanogaster/recessive lethal Gene mutation + Ballering et al., 1993

D. melanogaster/vermilion locus Gene mutation + Ballering et al., 1993

D. melanogaster/sex-linked recessive Gene mutation + King et al., 1979

D. melanogaster/sex-linked recessive Gene mutation + Kramers et al., 1991

D. melanogaster Chromosomal loss/gain +/+ Valencia et al., 1984

HOST-MEDIATED ASSAYS

Escherichia coli K12/343/113 mouse host-mediated assay

Gene mutation – King et al., 1979

– = negative result + = positive result (+) = weakly positive or marginal result

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

The effects of exposure to 1,2-dichloroethane on anumber of aquatic organisms in the laboratory and fieldhave also been investigated. In bacteria, the lowestreported IC50s for inhibition of gas production andammonia consumption were 25 and 29 mg/litre inmethanogens and Nitrosomonas, respectively (Blum &Speece, 1991). The most sensitive freshwater algastudied was Microcystis aeruginosa, in which an EC50

for inhibition of cell multiplication of 105 mg/litre wasobserved (Bringmann & Kühn, 1978); in the only

identified study in marine algae, an EC50 for carbonuptake of 340 mg/litre was reported in Phaeodactylumtricornutum (Pearson & McConnell, 1975). Toxicitythresholds (cell multiplication inhibition) were above 800mg/litre for three species of aquatic protozoa (Bringmann& Kühn, 1980).

The lowest reported LC50 value for Daphnia was220 mg/litre (Leblanc, 1980), whereas the lowest EC50 (for10% immobilization) was 150 mg/litre (Freitag et al., 1994). Effects on reproductive success and growth wereobserved in Daphnia at 20.7 and 71.7 mg/litre,respectively. There were no effects on these end-pointsat 10.6 and 41.6 mg/litre, respectively (Richter et al.,1983).


12

Based on available data, the most sensitivefreshwater vertebrate species appears to be the north-western salamander, in which 9-day larval survival (4days post-hatch) was reduced at 2.5 mg/litre (Black et al.,1982).

10.2 Terrestrial environment

Identified data on the toxicity of 1,2-dichloro-ethane to terrestrial organisms are inadequate to permitassessment.

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

Based on limited available data in humans, thelethal oral dose of 1,2-dichloroethane has been estimatedto be between 20 and 50 ml. 1,2-Dichloroethane ismoderately acutely toxic by inhalation, based on theresults of studies in experimental animals. Skin and eyeirritation may also be induced by 1,2-dichloroethane.

Owing to the limitations of the available studies inhumans, it is necessary to rely on available experimentaldata in animal species as a basis for derivation of no-effect levels or quantitative estimates of carcinogenicpotency. However, in most of the identified short-term and subchronic studies, only a limited range of end-points was examined and documentation wasincomplete. Similarly, little information on non-neoplastic effects was presented in the long-termcarcinogenicity bioassays. Lowest reported effect levelswere 49–82 mg/kg body weight per day for 13 weeks(increases in liver weight in rats) for ingestion (NTP,1991) and 202 mg/m3 (effects on liver and kidneyfunction in rats exposed for 12 months) for inhalation(Spreafico et al., 1980). Based on limited data, there is noevidence that 1,2-dichloroethane is teratogenic inexperimental animals or that it induces reproductive ordevelopmental effects at doses below those that causeother systemic effects.

Based on the limited evidence of carcinogenicity inworkers exposed principally to 1,2-dichloroethane in themost reliable epidemiological study conducted to date(Benson & Teta, 1993), the induction of both rare andcommon tumours in rats and mice exposed by ingestion(NCI, 1978) and supporting evidence in other

limited bioassays, the production of a reactive inter-mediate that alkylates DNA in vivo, and positive resultsin a range of in vitro assays for genotoxicity, 1,2-dichloroethane is considered to be a probable humancarcinogen.

The carcinogenic potency of 1,2-dichloroethanehas been calculated based on the increased incidence ofsquamous cell carcinomas of the stomach, haemangio-sarcomas, fibromas of the subcutaneous tissue, andadenocarcinomas or fibroadenomas (combined) of the mammary gland in Osborne-Mendel rats exposedorally by gavage, as well as the increased incidence ofalveolar/bronchiolar adenomas, hepatocellularcarcinomas, mammary gland adenocarcinomas, andendometrial stromal polyps or sarcomas (combined) insimilarly exposed B6C3F1 mice; data from both thematched (same study) and pooled (concurrent studies)vehicle controls were incorporated. It should be noted,however, that mortality was higher at the high dose infemale mice and rats of both sexes than in other dosegroups in this study. Therefore, these high-dose groupswere not included in the derivation of quantitativeestimates of carcinogenic potency.

Based on multistage modelling of these data,amortized for continuous exposure for a standardduration of 104 weeks and corrected for the expected rateof increase in tumour formation in rodents in a standardbioassay of 104 weeks, the doses associated with a 5%increase in tumour incidence (TD0.05s) range from 6.2 to34 mg/kg body weight per day. Incorporation of ascaling factor for the differences in body surface areabetween rodents and humans was not consideredappropriate, as it is likely that the carcinogenicity of 1,2-dichloroethane is due to a metabolite, rather than to theparent compound.

11.1.2 Criteria for setting guidance values for 1,2-dichloroethane

As available data indicate that 1,2-dichloroethaneis a genotoxic carcinogen, exposure should be reducedto the extent possible. The following guidance isprovided as a possible basis for derivation of limits ofexposure and judgement of the quality of environmentalmedia by relevant authorities, based on the potentialcarcinogenicity of 1,2-dichloroethane in humans. Basedon available data, air is believed to be the principalsource of exposure in the general environment (seesection 6.2) and, therefore, is the principal mediumaddressed here. Available data are consideredinadequate to serve as a basis for development oftolerable intakes for non-neoplastic effects.

1,2-Dichloroethane

13

Although it is desirable to reduce exposure togenotoxic carcinogens to the extent possible, a value, forexample, 5000 or 50 000 times less than the TD0.05s mightbe considered appropriate as a guidance value. Thismargin (5000–50 000) affords protection similar to thatassociated with the range for low-dose risk estimatesgenerally considered by various agencies to be“essentially negligible” (i.e. 10–5 to 10–6). Thiscorresponds to a range of airborne concentrations of3.6–20 :g/m3 or 0.36–2.0 :g/m3. (Corresponding valuesfor ingestion are 1.2–6.8 :g/kg body weight per day or0.12–0.68 :g/kg body weight per day.)

It should be noted, however, that the risk ofexposure in air is most likely overestimated, as theTD0.05s were based on a study in which the experimentalanimals were administered bolus doses of 1,2-dichloro-ethane by gavage, whereas exposure in the generalpopulation is likely to be mostly via inhalation. Basedon available data, the carcinogenic potency of 1,2-dichloroethane appears to be less following inhalationthan following ingestion of bolus doses, most likelybecause of inter-route variations in toxicokinetics.

11.1.3 Sample risk characterization

Non-neoplastic effects in animals have beenobserved only at concentrations more than 700 000 timesgreater than those in the principal medium of exposure(air) in the general environment, based on the sampleestimation of exposure presented in section 6.2 forindirect exposure in the general environment. Identifieddata are inadequate to allow an estimation of exposure to1,2-dichloroethane in the occupational environment.

Although, wherever possible, exposure to geno-toxic carcinogens should be reduced to the extentpossible, indirect population exposure in the generalenvironment, based on the sample estimate presented insection 6.2, is up to approximately 300 times less than aguidance value that might be considered appropriate onthe basis of available dose–response data for carcino-genicity (i.e. 3.6–20 :g/m3 or 0.36–2.0 :g/m3, the TD0.05s divided by 5000 or 50 000). Identified data areinadequate to estimate exposure to 1,2-dichloroethane inthe occupational environment.

11.2 Evaluation of environmental effects

Because 1,2-dichloroethane is released principallyin emissions from industrial sources and because of itshigh volatility, the atmosphere is the predominantenvironmental sink for 1,2-dichloroethane. It ismoderately persistent in air. Stratospheric photolysismay produce chlorine radicals, which may in turn react

with ozone. However, the ozone depleting potential islow (0.001 relative to CFC-11), and the compound is notlisted in the Montreal Protocol on Substances thatDeplete the Ozone Layer.

Terrestrial organisms will have the greatestpotential for exposure to 1,2-dichloroethane in ambientair. However, available data on the effects of 1,2-dichloroethane are inadequate to allow the character-ization of risks in terrestrial species.

Although 1,2-dichloroethane may be released tosurface waters or soil through industrial processes anddisposal, and although hydrolysis and microbialdegradation are slow, the substance is not likely topersist in these media because of its volatility. A rangeof toxicity tests in aquatic species have indicated thateffect levels are generally above 10 mg/litre. Asconcentrations in surface waters are generally severalorders of magnitude less than those demonstrated tocause effects, it is likely that 1,2-dichloroethane posesnegligible risk to aquatic organisms.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

The International Agency for Research on Cancer(IARC, 1979) has classified 1,2-dichloroethane in group2B (possibly carcinogenic to humans) based on suffi-cient evidence of carcinogenicity in experimentalanimals.

The Joint FAO/WHO Expert Committee on FoodAdditives (JECFA) has evaluated 1,2-dichloroethane onthree occasions (WHO, 1971, 1980, 1992). In its lastevaluation, the Committee concluded that this com-pound is genotoxic in both in vitro and in vivo testsystems and carcinogenic in mice and rats whenadministered by the oral route. No acceptable dailyintake (ADI) was therefore allocated. The Committeeexpressed the opinion that 1,2-dichloroethane shouldnot be used in food.

In the current WHO Guidelines for drinking-waterquality (WHO, 1993), the concentrations of 1,2-dichloro-ethane in drinking-water estimated to be associated withexcess risks of 10–4, 10–5, and 10–6 are 300, 30, and 3:g/litre, respectively, based on linear multistagemodelling of the incidence of haemangiosarcomas inmale rats in the NCI (1978) study.

Information on international hazard classificationand labelling is included in the International ChemicalSafety Card reproduced in this document.


14

13. HUMAN HEALTH PROTECTION ANDEMERGENCY ACTION

Human health hazards, together with preventativeand protective measures and first aid recommendations,are presented on the International Chemical Safety Card(ICSC 0250) reproduced in this document.

13.1 Human health hazards

1,2-Dichloroethane is highly flammable. On long-term or repeated exposure, it is considered to be aprobable human carcinogen.

13.2 Advice to physicians

In case of emergency, it is important to wash skinwith soap and water after removing contaminatedclothing. In the event of poisoning, the treatment issymptomatic and supportive. Survival for 48 hoursusually implies complete recovery, although deaths haveoccurred up to 5 days after exposure.

13.3 Health surveillance advice

Monitoring of both liver and kidney functionsshould be included in the health surveillance programmeof humans exposed to 1,2-dichloroethane.

13.4 Explosion and fire hazards

13.4.1 Explosion hazards

1,2-Dichloroethane vapours of between 6 and 12%in air form an explosive mixture.

13.4.2 Fire hazards

1,2-Dichloroethane is highly flammable.

13.4.3 Prevention

Because of its low electroconductivity, 1,2-dichloroethane can generate electrostatic charges as aresult of flow or agitation. Use only closed systems,ventilation, and explosion-proof electrical equipment. All equipment must be grounded.

13.5 Spillage

1,2-Dichloroethane is highly flammable. In theevent of spillage, eliminate all sources of ignition in the

vicinity. Because the substance is absorbed through theskin, do not touch or walk through the spilled materialwithout proper equipment. To avoid the flammabilityhazard, remove wet or contaminated clothing immediate-ly, and use non-sparking tools for clean-up. Do not letthe substance enter the drains or watercourses.

The IDLH (Immediately Dangerous to Life orHealth) value for this substance is very low, at 50 ppm(200 mg/m3) (NIOSH, 1994b).

14. CURRENT REGULATIONS,GUIDELINES, AND STANDARDS

Information on national regulations, guidelines,and standards is available from the International Registerof Potentially Toxic Chemicals (IRPTC) legal file.

The reader should be aware that regulatorydecisions about chemicals taken in a certain country canbe fully understood only in the framework of thelegislation of that country. The regulations andguidelines of all countries are subject to change andshould always be verified with appropriate regulatoryauthorities before application.

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

© IPCS 1999

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

1,2-DICHLOROETHANE 0250March 1995

CAS No: 107-06-2RTECS No: KI0525000UN No: 1184EC No: 602-012-00-7

Ethylene dichloride1,2-Ethylene dichlorideEthane dichlorideClCH2CH2Cl / C2H4Cl2Molecular mass: 98.96

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Highly flammable. Gives offirritating or toxic fumes (or gases)in a fire.

NO open flames, NO sparks, andNO smoking.

Powder, water spray, foam, carbondioxide.

EXPLOSION Vapour/air mixtures are explosive. Closed system, ventilation,explosion-proof electrical equipmentand lighting. Prevent build-up ofelectrostatic charges (e.g., bygrounding). Do NOT usecompressed air for filling,discharging, or handling.

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

EXPOSURE AVOID ALL CONTACT! IN ALL CASES CONSULT ADOCTOR!

Inhalation Abdominal pain. Cough.Dizziness. Drowsiness. Headache.Nausea. Sore throat.Unconsciousness. Vomiting.Symptoms may be delayed (seeNotes).

Ventilation, local exhaust, orbreathing protection.

Fresh air, rest. Half-uprightposition. Artificial respiration ifindicated. Refer for medicalattention.

Skin Redness. Protective gloves. Remove contaminated clothes.Rinse and then wash skin withwater and soap. Refer for medicalattention.

Eyes Redness. Pain. Blurred vision. Safety goggles, face shield, or eyeprotection in combination withbreathing protection.

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

Ingestion Abdominal cramps. Diarrhoea(further see Inhalation).

Do not eat, drink, or smoke duringwork. Wash hands before eating.

Give nothing to drink. Refer formedical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Evacuate danger area! Collect leaking and spilledliquid in sealable containers as far as possible.Absorb remaining liquid in sand or inert absorbentand remove to safe place. Do NOT wash away intosewer (extra personal protection: self-containedbreathing apparatus).

F SymbolT SymbolR: 45-11-22-36/37/38S: 53-45Note: EUN Hazard Class: 3UN Subsidiary Risks: 6.1UN Pack Group: II

Unbreakable packaging; putbreakable packaging into closedunbreakable container. Do nottransport with food and feedstuffs.Marine pollutant.

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-605NFPA Code: H 2; F 3; R 0;

Fireproof. Separated from strong oxidants, food and feedstuffs and otherincompatible substances (see Chemical Dangers). Cool. Dry.

Boiling point: 83.5�CMelting point: -35.7�CRelative density (water = 1): 1.235Solubility in water, g/100 ml: 0.87Vapour pressure, kPa at 20�C: 8.7Relative vapour density (air = 1): 3.42

Relative density of the vapour/air-mixture at 20�C (air = 1): 1.2Flash point: 13�C c.c. Auto-ignition temperature: 413�CExplosive limits, vol% in air: 6.2-16Octanol/water partition coefficient as log Pow: 1.48

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 1999

0250 1,2-DICHLOROETHANE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS, VISCOUS LIQUID, WITH CHARACTERISTICODOUR. TURNS DARK ON EXPOSURE TO AIR, MOISTUREAND LIGHT.

Physical DangersThe vapour is heavier than air and may travel along the ground;distant ignition possible. As a result of flow, agitation, etc.,electrostatic charges can be generated.

Chemical DangersThe substance decomposes on heating and on burningproducing toxic and corrosive fumes including hydrogenchloride (ICSC # 0163) and phosgene (ICSC # 0007). Reactsviolently with aluminium, alkali metals, alkali amides,ammonia, bases, strong oxidants. Attacks many metals inpresence of water. Attacks plastic.

Occupational Exposure LimitsTLV: 10 ppm; 40 mg/m3 (as TWA) (ACGIH 1994-1995).

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

Inhalation RiskA harmful contamination of the air can be reached very quicklyon evaporation of this substance at 20�C.

Effects of Short-term ExposureThe vapour irritates the eyes, the skin and the respiratory tract.Inhalation of the vapour may cause lung oedema (see Notes).The substance may cause effects on the central nervoussystem, kidneys, liver, resulting in impaired functions.

Effects of Long-term or Repeated ExposureRepeated or prolonged contact with skin may cause dermatitis.This substance is probably carcinogenic to humans.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

NOTES

Depending on the degree of exposure, periodic medical examination is indicated. The symptoms of lung oedema often do notbecome manifest until a few hours have passed and they are aggravated by physical effort. Rest and medical observation aretherefore essential. Immediate administration of an appropriate spray, by a doctor or a person authorized by him/her, should beconsidered.

ADDITIONAL INFORMATION

1,2-Dichloroethane

17

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mutagenesis, 5:795–801.


22

APPENDIX 1 — SOURCE DOCUMENTS

International Programme on Chemical Safety— Environmental Health Criteria MonographNo. 176 (1995)

Copies of the Environmental Health Criteria document on 1,2-

dichloroethane, prepared by the International Programme on ChemicalSafety, as well as the Health and Safety Guide (1991) and theInternational Chemical Safety Card (1993), may be obtained from:

International Programme on Chemical SafetyWorld Health OrganizationGeneva, Switzerland

The first draft of the monograph, prepared by Ms K. Hughes ofthe Environmental Health Directorate, Health Canada, was circulated toIPCS Contact Points (approximately 150 government, industrial,academic, and independent organizations and individuals) for commentin June 1994. The second draft, revised on the basis of the commentsreceived, was also prepared by Ms K. Hughes. Dr E. Smith and DrP.G. Jenkins, both members of the IPCS Central Unit, were responsiblefor the scientific content and technical editing, respectively.

The monograph on 1,2-dichloroethane was finalized by the CoreAssessment Group (CAG) of the Joint Meeting on Pesticides (JMP),which met in Geneva from 25 October to 3 November 1994. The CoreAssessment Group reviewed and revised the draft monograph andmade an evaluation of the risks for human health and the environmentfrom exposure to 1,2-dichloroethane. Participants at the CoreAssessment Group meeting were:

Dr T. Bailey, Ecological Effects Branch, Environmental Fate andEffects Division, US Environmental Protection Agency,Washington, DC, USA

Dr A.L. Black, Department of Human Services and Health,Canberra, ACT, Australia

Mr D.J. Clegg, Carp, Ontario, Canada

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

Dr P.E.T. Douben, Her Majesty’s Inspectorate of Pollution,London, United Kingdom (EHC Joint Rapporteur)

Dr P. Fenner-Crisp, Office of Pesticide Programs, USEnvironmental Protection Agency, Washington, DC, USA

Dr R. Hailey, National Institute of Environmental Health Sciences,National Institutes of Health, Public Health Service, Departmentof Health and Human Services, Research Triangle Park, NC, USA

Ms K. Hughes, Priority Substances Section, Environmental HealthDirectorate, Health Canada, Ottawa, Ontario, Canada (EHC Joint

Rapporteur)

Dr D. Kanungo, Division of Medical Toxicology, CentralInsecticides Laboratory, Government of India, Ministry ofAgriculture & Cooperation, Directorate of Plant Protection,Quarantine & Storage, Faridabad, Haryana, India

Dr L. Landner, MFG, European Environmental Research GroupLtd, Stockholm, Sweden

Dr M.H. Litchfield, Melrose Consultancy, Fontwell, Arundel, WestSussex, United Kingdom

Professor M. Lotti, Institute of Occupational Medicine, Universityof Padua, Padua, Italy (Chairperson)

Dr D.R. Mattison, University of Pittsburgh, Graduate School ofPublic Health, Pittsburgh, PA, USA

Dr J. Sekizawa, Division of Information on Chemical Safety,National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan

Dr P. Sinhaseni, Department of Pharmacology, ChulalongkornUniversity, Bangkok, Thailand

Dr S.A. Soliman, Pesticide Chemicals & Toxicology, King SaudUniversity, Bureidah, Saudi Arabia

Dr M. Tasheva, Department of Toxicology, National Center ofHygiene, Medical Ecology and Nutrition, Sofia, Bulgaria

Mr J.R. Taylor, Pesticides Safety Directorate, Ministry ofAgriculture, Fisheries and Food, York, United Kingdom

Dr H.M. Temmink, Department of Toxicology, WageningenAgricultural Unviersity, Wageningen, The Netherlands

Dr M.I. Willems, Department of Occupational Toxicology, TNONutrition and Food Research Institute, AJ Zeist, The Netherlands

Procedures for the preparation of anEnvironmental Health Criteria document

The order of procedures that result in the publication of an EHCmonograph is shown in the flow chart. A designated staff member ofIPCS, responsible for the scientific quality of the document, serves asResponsible Officer (RO). The IPCS Editor is responsible for layoutand language. The first draft, prepared by consultants or, moreusually, staff from an IPCS Participating Institution, is based initially ondata provided from the International Register of Potentially ToxicChemicals and reference databases such as Medline and Toxline.

The draft document, when received by the RO, may require aninitial review by a small panel of experts to determine its scientificquality and objectivity. Once the RO finds the document acceptable asa first draft, it is distributed, in its unedited form, to well over 150 EHCContact Points throughout the world who are asked to comment on itscompleteness and accuracy and, where necessary, provide additionalmaterial. The Contact Points, usually designated by governments,may be Participating Institutions, IPCS Focal Points, or individualscientists known for their particular expertise. Generally, some fourmonths are allowed before the comments are considered by the RO andauthor(s). A second draft incorporating comments received andapproved by the Director, IPCS, is then distributed to Task Groupmembers, who carry out the peer review, at least six weeks before theirmeeting.

The Task Group members serve as individual scientists, not asrepresentatives of any organization, government, or industry. Theirfunction is to evaluate the accuracy, significance, and relevance of theinformation in the document and to assess the health andenvironmental risks from exposure to the chemical. A summary andrecommendations for further research and improved safety aspects arealso required. The composition of the Task Group is dictated by therange of expertise required for the subject of the meeting and by theneed for a balanced geographical distribution.

The three cooperating organizations of the IPCS recognizethe important role played by nongovernmental organizations. Representatives from relevant national and internationalassociations may be invited to join the Task Group as observers. While observers may provide a valuable contribution to theprocess, they can speak only at the invitation of the Chairperson.

23

C o m m i t m e n t t o d r a f t E H CC o m m i t m e n t t o d r a f t E H C

D o c u m e n t p r e p a r a t i o n i n i t i a t e d

D r a f t s e n t t o I P C S R e s p o n s i b l e O f f i c e r ( R O )

EHC PREPARATION FLOW CHART

R e v i s i o n a sneces sa ry

P o s s i b l e m e e t i n g o f a f e w e x p e r t s t o r e s o l v e c o n t r o v e r s i a l i s s u e s

F i r s t D r a f tF i r s t D r a f t

R e s p o n s i b l e O f f i c e r , E d i t o r c h e c k f o r c o h e r e n c e o f t e x t a n d

r e a d a b i l i t y ( n o t l a n g u a g e e d i t i n g )

R e s p o n s i b l e O f f i c e r , E d i t o r c h e c k f o r c o h e r e n c e o f t e x t a n d

r e a d a b i l i t y ( n o t l a n g u a g e e d i t i n g )

I n t e r n a t i o n a l c i r c u l a t i o n t o C o n t a c t P o i n t s ( 1 5 0 + )

C o m m e n t s t o I P C S ( R O )

R e v i e w o f c o m m e n t s , r e f e r e n c e c r o s s - c h e c k ;p r e p a r a t i o n o f T a s k G r o u p ( T G ) d r a f t

T a s k G r o u p m e e t i n g

I n s e r t i o n o f T G c h a n g e s

Post-TG draft; detailed reference cross-check

EditingEditing

Word-processing

Camera-ready copy

Final editing

Approval by Director, IPCS

WHO Publication Office

Printer Proofs PublicationPublication

Graphics

Library forCIP Data

French/Spanish translations of Summary

Working group,if requiredEditor

routine procedure

optional procedure

Observers do not participate in the final evaluation of thechemical; this is the sole responsibility of the Task Groupmembers. When the Task Group considers it to be appropriate,it may meet in camera .

All individuals who as authors, consultants, or advisersparticipate in the preparation of the EHC monograph must, inaddition to serving in their personal capacity as scientists, informthe RO if at any time a conflict of interest, whether actual orpotential, could be perceived in their work. They are required tosign a conflict of interest statement. Such a procedure ensuresthe transparency and probity of the process.

When the Task Group has completed its review and the ROis satisfied as to the scientific correctness and completeness ofthe document, it then goes for language editing, referencechecking, and preparation of camera-ready copy. After approvalby the Director, IPCS, the monograph is submitted to the WHOOffice of Publications for printing. At this time, a copy of thefinal draft is sent to the Chairperson and Rapporteur of the TaskGroup to check for any errors.


24

APPENDIX 2 — CICAD FINAL REVIEWBOARD

Members

Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland

Dr K. Bentley, Director, Environment Policy Section,Commonwealth Department of Human Services and Health,Canberra, Australia

Mr R. Cary, Toxicology and Existing Substances RegulationUnit, Health and Safety Executive, Merseyside, United Kingdom

Dr J. de Fouw, National Institute of Public Health andEnvironmental Protection, Bilthoven, The Netherlands

Dr C. DeRosa, Director, Division of Toxicology, Agency for ToxicSubstances and Disease Registry, Atlanta, GA, USA

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

Dr W. Farland, Director, National Center for EnvironmentalAssessment, Office of Research and Development, USEnvironmental Protection Agency, Washington, DC, USA(Chairperson)

Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, NationalUniversity of Mexico and Environmental Health Directorate ofthe Health Ministry, Mexico D.F., Mexico

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

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

Mr J.R. Hickman, Environmental Health Directorate, HealthCanada, Ottawa, Ontario, Canada

Dr T. Lakhanisky, Head, Division of Toxicology, Institute ofHygiene and Epidemiology, Brussels, Belgium (Vice-

Chairperson)

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,Fraunhofer Institute for Toxicology and Aerosol Sciences,Hanover, Germany

Ms E. Meek, Head, Priority Substances Section, EnvironmentalHealth Directorate, Health Canada, Ottawa, Ontario, Canada

Dr K. Paksy, National Institute of Occupational Health, Budapest,Hungary

Mr D. Renshaw, Department of Health, London, United Kingdom

Dr J. Sekizawa, Division of Chemo-Bio Informatics, NationalInstitute of Hygienic Sciences, Tokyo, Japan

Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt undGesundheit GmbH, Institut für Toxikologie, Oberschleissheim,Germany

Professor S. Tarkowski, Department of Environmental HealthHazards, The Nofer Institute of Occupational Medicine, Lodz,Poland

Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna,Sweden

Secretariat

Dr M. Baril, International Programme on Chemical Safety, WorldHealth Organization, Geneva, Switzerland

Dr L. Harrison, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Dr M. Mercier, Director, International Programme on ChemicalSafety, World Health Organization, Geneva, Switzerland

Dr P. Toft, Associate Director, International Programme onChemical Safety, World Health Organization, Geneva,Switzerland

1,2-Dichloroethane

25

RÉSUMÉ D’ORIENTATION

La Direction de l’Hygiène du Milieu de SantéCanada a rédigé ce CICAD (Document internationalsuccinct sur l’évaluation des risques chimiques) sur le1,2-dichloréthane en s’inspirant d’un document de lasérie Critères d’hygiène de l’environnement (CHE) duProgramme international sur la Sécurité chimique (PISC)(IPCS, 1995), qui évalue les conséquences potentiellespour la santé humaine d’une exposition indirecte au 1,2-dichloréthane dans l’environnement général ainsi que leseffets de cette substance sur l’environnement. Lesdonnées prises en compte dans cette analyse sont cellesqui étaient disponibles en mai 1993 (effets sur la santéhumaine) ou en octobre 1994 (effets sur l’environne-ment). L’appendice 1 donne des informations sur lanature du processus d’évaluation par les pairs et sur ladisponibilité du document CHE. Pour ce CICAD, c’estl’évaluation pratiquée lors de l’élaboration du documentCHE qui a fait office d’évaluation par les pairs préalable àl’examen du Comité d’évaluation finale. Les membres duComité d’évaluation finale ont apporté les dernièrescorrections à ce CICAD et en ont approuvé lapublication par correspondance, après avoir examiné lesobservations présentées lors de l’élaboration du CHEdans le cadre de l’évaluation par les pairs. Lacomposition du Comité d’évaluation finale est indiquée àl’appendice 2. La fiche internationale sur la sécuritéchimique (ICSC 0250) produite par le PISC (IPCS, 1993)est également reproduite dans ce document.

Le 1,2-dichloréthane (CAS N/ 107-06-2) est unhydrocarbure synthétique volatil utilisé principalementdans la synthèse du chlorure de vinyle monomère etd’autres solvants chlorés. Il a également été utilisécomme additif de l’essence au plomb et comme fumigant,mais son utilisation comme additif de l’essence est endéclin. La plus grande partie du 1,2-dichloréthane libérédans l’environnement se retrouve dans l’air ambiant oùsa persistance est modérée. Toutefois, il ne devrait pascontribuer à la destruction de l’ozone. Le potentiel debioaccumulation du 1,2-dichloréthane est faible; soninhalation avec l’air est probablement la principalesource d’exposition humaine.

On dispose de peu d’information sur les effets du 1,2-dichloréthane chez l’homme. Les quelques étudesépidémiologiques qui ont été faites sur sacancérogénicité potentielle ne sont guère concluantes.

Le 1,2-dichloréthane présente une toxicité aiguëmodérée chez les animaux d’expérience. Les quelquesdonnées que l’on trouve sur ses effets non néoplasiquesdans des études de chronicité à court terme, sub-

chronique ou chronique indiquent que les principauxorganes cibles sont le foie et le rein; les doses les plusfaibles pour lesquelles on ait signalé un effet aprèsingestion et inhalation sont respectivement de 49–82mg/kg de poids corporel par jour (augmentation du poidsdu foie chez des rats exposés pendant 13 semaines) et202 mg/m3 (effets sur les fonctions hépatique et rénalechez des rats exposés pendant 12 mois). D’après lesrésultats d’un petit nombre d’études, il n’y a pas depreuve que le 1,2-dichloréthane soit tératogène chez lesanimaux de laboratoire, ni qu’il induise des effets sur lareproduction ou le développement lorsque les niveauxd’exposition sont inférieurs aux niveaux qui entraînentd’autres effets systémiques.

L’exposition au 1,2-dichloréthane par gavagependant 78 semaines a été suivie d’une augmentationsignificative de l’incidence des tumeurs de différentsorganes (notamment des hémangiosarcomes et destumeurs de l’estomac, des glandes mammaires, du foie,des poumons et de l’endomètre), tant chez le rat quechez la souris. Il n’y a eu aucune augmentationsignificative de l’incidence des tumeurs chez des rats oudes souris exposés par inhalation, mais l’administrationrépétée par voie dermique ou intrapéritonéale aprovoqué une augmentation du nombre des tumeurs despoumons chez la souris. Le 1,2-dichloréthane s’estconstamment révélé génotoxique dans de nombreusesépreuves in vitro sur des cellules de procaryotes, dechampignons et de mammifères (y compris des celluleshumaines). De même, les résultats ont été constammentpositifs en ce qui concerne l’activité génotoxique (ainsique la fixation sur l’ADN) dans des études in vivo chezle rat, la souris et les insectes.

Les valeurs les plus faibles de la CI50s et de la

CE50s qui aient été signalées pour différents effets surdes organismes aquatiques sont respectivement de 25 et105 mg/litre. La CL50 la plus faible pour les daphnies étaitde 220 mg/litre, des effets ayant toutefois été observéssur la reproduction à 20,7 mg/litre. Le vertébré d’eaudouce le plus sensible a été une salamandre (Ambystomagracile) chez laquelle on a constaté une réduction de lasurvie des larves à 2,5 mg/litre. On ne dispose que dedonnées limitées sur la toxicité du 1,2-dichloréthane pourles espèces terrestres.

D’après les données disponibles, le 1,2-dichlor-éthane peut être considéré comme un cancérogèneprobable pour l’homme, de sorte que l’exposition doitêtre réduite dans toute la mesure possible. Le potentielcancérogène (exprimé par la dose associée à une aug-mentation de 5 % de l’incidence des tumeurs), calculé àpartir d’études de gavage, a été évalué à 6,2–34 mg/kg depoids corporel par jour. En appliquant un facteur de


26

sécurité de 5000 ou de 50 000 au potentiel cancérogèneestimé, on arrive à une valeur guide pour l’air (principalesource d’exposition humaine) de 3,6–20 :g/m3 ou0,36–2,0 :g/m3; il faut cependant noter que cetteméthode surestime les risques, car les données dispon-ibles montrent que le 1,2-dichloréthane est moins actiflorsqu’il est inhalé. (Les valeurs correspondantes pourl’ingestion sont respectivement de 1,2–6,8 ou0,12–0,68 :g/kg de poids corporel par jour.) Ces valeurscorrespondent à ce que certains organismes considèrentcomme un risque “pratiquement négligeable” (c’est-à-dire 10!5–10!6 pour un cancérogène génotoxique). D’après une des estimations qui ont été faites,l’exposition indirecte dans un environnement normal estapproximativement 300 fois inférieure à ces valeurs.

1,2-Dichloroethane

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RESUMEN DE ORIENTACIÓN

Esta reseña de la evaluación química internacionaldel 1,2-dicloroetano ha sido preparada por la Direcciónde Higiene del Medio de Health Canada sobre la basede un documento de la serie “Criterios de SaludAmbiental” (EHC) del Programa Internacional deSeguridad de las Sustancias Químicas (IPCS, 1995) en elque se evalúan los efectos potenciales sobre la saludhumana de la exposición indirecta al 1,2-dicloroetano enel medio ambiente general, así como los efectos ambien-tales de dicha sustancia química. En este análisis seexaminan datos obtenidos en mayo de 1993 (efectossobre la salud humana) y octubre de 1994 (efectosambientales). En el apéndice 1 se proporciona infor-mación sobre el proceso de revisión científica y losdocumentos disponibles de la serie EHC. Por lo querespecta a esta reseña de la evaluación química inter-nacional, el proceso de revisión científica previo alexamen realizado por el Comité de Revisión Final se hacumplido mediante la revisión científica efectuada para laelaboración del documento de la serie EHC. Comuni-cándose por correspondencia, los miembros del Comitéde Revisión Final ultimaron esta reseña de la evaluaciónquímica internacional del 1,2-dicloroetano, aprobaron supublicación y examinaron las observaciones dimanantesde la revisión científica efectuada durante la preparacióndel documento de la serie EHC. La composición delComité de Revisión Final figura en el apéndice 2. En elpresente documento también se reproduce la Ficha Inter-nacional de Seguridad Química (ICSC 0250) emitida por elIPCS (1993).

El 1,2-dicloroetano (CAS n/ 107-06-2) es unhidrocarburo sintético volátil que se utiliza principal-mente en la síntesis del monómero cloruro de vinilo y deotros disolventes clorados. También se ha utilizadocomo aditivo de la gasolina con plomo y como fumi-gante, aunque su uso como aditivo de la gasolina se estáreduciendo. La mayor parte de la liberación en elentorno se produce en el aire ambiente, donde es moder-adamente persistente. Sin embargo, no parece quecontribuya al agotamiento de la capa de ozono. El 1,2-dicloroetano tiene un potencial de bioacumulación bajo;la inhalación con el aire probablemente sea la principalfuente de exposición humana.

Se dispone de poca información sobre los efectosdel 1,2-dicloroetano en el ser humano. Las pocasinvestigaciones epidemiológicas conocidas sobre sucarcinogenicidad potencial no son concluyentes.

El 1,2-dicloroetano tiene una toxicidad agudamoderada en animales de experimentación. La escasa

información sobre efectos no neoplásicos presentada enestudios de corta duración, subcrónicos y crónicosindica que los principales órganos afectados son elhígado y los riñones; los niveles mínimos de ingestión einhalación con efectos comunicados fueron de 49–82mg/kg de peso corporal por día (aumento de peso delhígado en las ratas expuestas durante 13 semanas) y 202mg/m3 (efectos sobre la función hepática y renal en lasratas expuestas durante 12 meses), respectivamente. Los resultados de un número limitado de estudios, noaportaron indicios de que el 1,2-dicloroetano seateratogénico en animales de experimentación o que tengaefectos sobre la reproducción o el desarrollo a niveles deexposición inferiores a los que causan otros efectossistémicos.

La exposición al 1,2-dicloroetano administradopor sonda durante 78 semanas produjo un aumentosignificativo de la incidencia de tumores en distintoslugares (hemangiosarcomas y tumores en el estómago,las glándulas mamarias, el hígado, los pulmones y elendometrio) tanto en ratas como en ratones. Aunque nohubo un aumento significativo de la incidencia detumores en las ratas y los ratones expuestos porinhalación, la aplicación cutánea o intraperitonealrepetida de 1,2-dicloroetano se ha revelado sistemática-mente genotóxica en numerosas pruebas realizadas invitro en células de procariotas, hongos y mamíferos(incluidas células humanas). Análogamente, se hanobtenido resultados invariablemente positivos indica-dores de actividad genotóxica (así como enlaces con elADN) en estudios realizados in vivo con ratas, ratones einsectos.

Las CI50 y CE50 más bajas notificadas en relacióncon diversos puntos finales en organismos acuáticosfueron de 25 y 105 mg/litro respectivamente. La CL50 másbaja notificada para Daphnia fue de 220 mg/litro,mientras que los efectos sobre la reproducción seprodujeron con concentraciones de 20,7 mg/litro. Elvertebrado de agua dulce más sensible estudiado fue lasalamandra noroccidental (Ambystoma gracile), en laque se observó una reducción de la supervivencia de laslarvas con niveles de 2,5 mg/litro. Se dispone sólo dedatos limitados sobre los efectos del 1,2-dicloroetano enespecies terrestres.

Teniendo en cuenta los datos disponibles, esprobable que el 1,2-dicloroetano sea carcinógeno para elser humano y, por lo tanto, la exposición a éste deberíareducirse en la medida de lo posible. Sobre la base deestudios realizados en animales expuestos a unaadministración por sonda, se ha calculado que lapotencia carcinogénica (expresada como la dosisasociada a un aumento del 5% en la incidencia de


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tumores) oscila entre 6,2 y 34 mg/kg de peso corporal pordía. Con respecto al aire (fuente principal de exposiciónhumana), se han obtenido valores orientativos 3,6–20g/m3 o 0,36–2,0 g/m3, calculados para un margen 5.000 a50.000 veces inferior a la potencia carcinogénicaestimada; sin embargo, hay que tener en cuenta que sehan sobreestimado los riesgos, ya que los datosdisponibles indican que el 1,2-dicloroetano inhaladoresulta menos potente. (En cuanto a la ingestión, losvalores correspondientes son de 1,2–6,8 g/m3 de pesocorporal por día o 0,12–0,68 g/m3 de peso corporal pordía.) Estos valores comportan lo que algunas entidadesconsideran como un riesgo “prácticamenteinsignificante” (es decir, 10–5 – 10–6 para un carcinógenogenotóxico). Según las estimaciones estadísticas, laexposición indirecta a través del medio ambiente generales aproximadamente 300 veces inferior a esos valores.