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

Concise International Chemical Assessment Document 15

1,2-DIAMINOETHANE (ETHYLENEDIAMINE)

First draft prepared byMr R. Cary, Health and Safety Executive, Merseyside, United Kingdom, Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United Kingdom, andDr J. Delic, Health and Safety Executive, Merseyside, United Kingdom

Please note that the layout and pagination of this pdf file are not identical to those of theprinted CICAD

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, 1999

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, 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

1,2-Diaminoethane (Ethylenediamine).

(Concise international chemical assessment document ; 15)

1.Ethylenediamines 2.Environmental exposure 3.Risk assessmentI.International Programme on Chemical Safety II.Series

ISBN 92 4 153015 4 (NLM classification: QV 275) 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 1999

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 . . . . . . . . . . . . . . . . . . . 6

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . 9

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . 14

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 11.1.2 Criteria for setting guidance values for EDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

13.1 Human health hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1813.2 Advice to physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1813.3 Health surveillance advice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1813.4 Spillage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18


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14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

1,2-Diaminoethane (Ethylenediamine)

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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 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-basedguidance 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, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of their

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 (Environmental HealthCriteria 170).


2

S E L E C T I O N O F H I G H Q U A L I T YNATIONAL/REGIONAL

ASSESSMENT DOCUMENT(S)

CICAD PREPARATION FLOW CHART

FIRST DRAFTPREPARED

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

PRIMARY REVIEW BY IPCS (REVISIONS AS NECESSARY)


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experience 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-diaminoethane (ethylenedi-amine) was based on a review of human health concerns(primarily occupational, but also including an environ-mental assessment) prepared by the United Kingdom’sHealth and Safety Executive (Brooke et al., 1997). Dataidentified up to the end of 1994 were covered in the origi-nal review. An additional literature search up to July1997 was conducted to identify any new information thathad been published since the review was completed.Information on environmental fate and effects was basedon the report of the German Chemical Society’s Adviso-ry Committee on Existing Chemicals of EnvironmentalRelevance (BUA, 1997). The preparation and peer reviewof the source documents are described in Appendix 1.Information on the peer review of this CICAD ispresented in Appendix 2. This CICAD was approved asan international assessment at a meeting of the FinalReview Board, held in Tokyo, Japan, on 30 June – 2 July1998. Participants at the Final Review Board meeting arelisted in Appendix 3. The International Chemical SafetyCard (ICSC 0269) produced by the International Pro-gramme on Chemical Safety (IPCS, 1993) has also beenreproduced in this document.

1,2-Diaminoethane (CAS No. 107-15-3), commonlyknown as ethylenediamine (EDA), is a synthetic colour-less to yellowish liquid at normal temperature andpressure. It is strongly alkaline and is miscible with waterand alcohol. The main use for EDA is as an intermediatein the manufacture of tetraacetyl ethylenediamine,ethylenediaminetetraacetic acid (EDTA), organicflocculants, urea resins, and fatty bisamides. It is alsoused, to a much smaller extent, in the production of for-mulations for use in the printed circuit board and metalfinishing industries, as an accelerator/curing agent inepoxy coatings/resins, and in the manufacture of phar-maceutical products. EDA is present as a contaminant(<0.5%) in commercially supplied fatty amines, which areused as wetting agents in bituminous emulsions. It isalso used in the synthesis of carbamate fungicides, insurfactant and dye manufacture, and in photographydevelopment chemicals and cutting oils. EDA is a degra-dation product of ethylenebis(dithiocarbamate) fungi-cides.

No atmospheric effects are expected, as reaction ofEDA with hydroxyl radicals is likely to be rapid (half-life8.9 h), and washout of volatilized EDA is expected.Volatilization to the atmosphere is likely from soil but notfrom water. Adsorption to soil particulates is strongthrough electrostatic binding; leaching through soilprofiles to groundwater is not expected. Complexformation with metals and humic acids is expected. Bio-degradation is the most likely source of breakdown inthe environment and should be quite rapid; adaptation

of microorganisms may improve degradation. Breakdownis less rapid in seawater than in fresh water. Bioaccumu-lation is unlikely.

EDA has moderate acute toxicity in animals. It is aprimary irritant, being corrosive when undiluted, and isalso a skin sensitizer. EDA has not been tested for muta-genicity to current regulatory standards, and there areno assays for clastogenic activity or for the potential toexpress activity in somatic cells in vivo. Thus, there isinsufficient information to draw firm conclusions regard-ing the mutagenic potential of EDA. EDA was notcarcinogenic in animals. Non-neoplastic effects on theliver (pleomorphic changes to hepatocytes) have beenobserved in rats following oral dosing for 2 years at45 mg EDA/kg body weight per day and above, withno effects seen at 9 mg EDA/kg body weight per day.Although the significance of these hepatic cell changesfor human health is unclear, as well as whether or notthey are a consequence of oral exposure (i.e., they mightnot occur via other routes, as they may be related tofirst-pass effects), they cannot be discounted, and therisk of their development should be characterized. In oralgavage dosing studies, effects on the rat eye (retinalatrophy and, at higher doses, cataract formation) wereobserved at doses of 100 mg EDA/kg body weight perday and above. Doses of 200 and 100 mg EDA/kg bodyweight per day and above were associated with renaldamage in rats and mice, respectively. There was alsosome indication of effects in the spleen in mice and ratsat doses of 400 mg EDA/kg body weight per day andabove and in the thymus in rats at 800 mg/kg bodyweight per day. In inhalation studies, no effects wereseen in rats at about 150 mg/m3 (60 ppm), and slightdepilation was the only treatment-related effect observedat about 330 mg/m3 (132 ppm).

Because diluted EDA is a skin irritant and a skinsensitizer, there may be a risk of developing irritantand/or allergic dermatitis if suitable personal protectiveequipment is not used in the occupational environmentwhere skin contact can occur. EDA is also capable ofinducing a state of respiratory tract hypersensitivity andprovoking asthma in the occupational environment, andthis is considered to be the major health effect of con-cern.

The mechanism for the induction of the hypersen-sitive state is not proven, although the skin sensitizingpotential of EDA and the limited evidence of immuno-logical involvement in workers with EDA-provokedasthma are suggestive of an immunological mechanism.However, irrespective of the mechanism involved, theavailable data do not allow either elucidation of dose–response relationships or identification of the thresholdsfor induction of the hypersensitive state or provocationof an asthmatic response. The sample risk characteriza-tion in this document has, in order to assess the risks of


5

other systemic effects, evaluated the risk of hepaticeffects in occupationally exposed individuals. It con-cludes that when EDA is used in closed systems, theexposure, both measured and predicted from models, issubstantially (by 100-fold or greater) less than the no-observed-effect level (NOEL) in rats; thus, adverseeffects on the liver are unlikely.

Exposure of the general public to EDA could notbe evaluated owing to the lack of available data.

Toxic thresholds for microorganisms may be aslow as 0.1 mg EDA/litre. However, toxicity tests in cul-ture media should be treated with caution, as the EDAmay complex with metal ions. Effects may therefore beindirect, resulting from the loss of bioavailability ofessential elements. LC50s for invertebrates and fish rangefrom 14 to >1000 mg/litre. A no-observed-effect concen-tration (NOEC) for Daphnia reproduction has beenreported at 0.16 mg/litre.

Given the wide range of acute and chronic testresults, a predicted no-effect concentration (PNEC) foraquatic organisms was taken as 16 :g/litre, based onapplication of an uncertainty factor of 10 to the lowestreported NOEC for Daphnia reproduction. Conservativeassumptions for predicted environmental concentration(PEC) produce PEC/PNEC ratios indicating some concernfrom initial concentrations (i.e., at first release into theriver or estuary). However, more refined exposureestimates indicate low risk to aquatic organisms.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

1,2-Diaminoethane (CAS No. 107-15-3) is morecommonly known as ethylenediamine, with EDA used asa common abbreviation. Other common synonymsinclude dimethylenediamine, 1,2-ethanediamine, 1,2-ethylenediamine, beta-aminoethylamine, and ethane-1,2-diamine. EDA’s structural formula is shown below:

EDA is a colourless to yellowish hygroscopicliquid with an ammonia-like odour. Its molecular weightis 60.12. It is a strongly alkaline (pH of 25% EDA in wateris 11.9), very volatile, pungent material, which fumesprofusely in air. It has a melting point of about 8.5 °C, aboiling point of 116 °C (at 101.3 kPa), and a vapourpressure of 1.7 kPa at 25°C. EDA is miscible with water

and alcohol. The log octanol/water partition coefficient(log Kow) ranges from !1.2 to !1.52. pKa1 and pKa2

(calculated) are 10.71 and 7.56, respectively, indicatingprotonation at environmentally relevant pH. Additionalphysical/chemical properties are presented in theInternational Chemical Safety Card reproduced in thisdocument.

Conversion factors for EDA at 20 °C and 101.3 kPaare as follows:

1 ppm = 2.50 mg/m3

1 mg/m3 = 0.40 ppm

3. ANALYTICAL METHODS

For monitoring concentrations of EDA in work-place air, NIOSH (1984–1989) uses a method thatemploys adsorption on silica gel and analysis by gaschromatography with flame ionization detection. Asolvent-free sampling system is preferable because ofmore convenient handling, and it is a great advantage ifderivatization can be achieved directly on the absorbent.The Health and Safety Laboratories of the United King-dom’s Health and Safety Executive have evaluated apublished method (Andersson et al., 1985; Levin et al.,1989; Patel & Rimmer, 1996). Air is sampled onto 1-naphthyl-isothiocyanate-impregnated filters, desorbedby acetonitrile, and analysed by high-performance liquidchromatography with ultraviolet detection. The methodhas a working range between 2.5 and 50 mg/m3 for a5-litre air sample. The detection limit was found to be0.08 mg/m3. The method generally meets the ComitéEuropéen de Normalisation requirements on the overalluncertainty. Although the Comité Européen de Normali-sation requirements for desorption efficiency were notsatisfied at 25 and 50 mg/m3, a smaller sample can betaken if necessary.

There are no reported methods for the biologicalmonitoring of occupational exposure to EDA. However,analytical techniques based on solvent extraction ofEDA and high-performance liquid chromatography havebeen reported and used in pharmacological studies(Cotgreave & Caldwell, 1983c), and these might form thebasis for biological monitoring methods.

EDA can be measured in water using reverse-phase high-performance liquid chromatography withultraviolet detection at 315 nm, following derivatizationwith acetylacetone. The limit of detection was reportedto be 0.26 :g/litre (Nishikawa, 1987).

N CH

HC N

H

H

H

H

H

H


6

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

EDA is not known to occur naturally. The mainuse for EDA is as an intermediate in the manufacture oftetraacetyl ethylenediamine, EDTA, organic flocculants,urea resins, and fatty bisamides. It is also used, to amuch smaller extent, in the production of formulationsfor use in the printed circuit board and metal finishingindustries, as an accelerator/curing agent in epoxy coat-ings/resins, and in the manufacture of pharmaceuticalproducts. EDA is also present as a contaminant (<0.5%)in commercially supplied fatty amines, which are used aswetting agents in bituminous emulsions. It is also usedin the synthesis of carbamate fungicides, in surfactantand dye manufacture, and in photography developmentchemicals and cutting oils. These are believed to beminor uses in the United Kingdom and were not inves-tigated in this review. EDA is a degradation product ofethylenebis(dithiocarbamate) fungicides.

Approximately 11 000 tonnes of EDA are importedinto the United Kingdom each year, with very little beingre-exported (Brooke et al., 1997). World productionamounts to 100 000–500 000 tonnes annually.1 In 1992,annual production capacities were 18 000 tonnes forGermany, 54 000 tonnes for the Netherlands,30 000 tonnes for Belgium, 25 000 tonnes for Sweden,about 159 000 tonnes for the United States, and15 000 tonnes for Japan (BUA, 1997).

No measured concentrations of EDA in wastewaterstreams from manufacture and use are available.However, estimates of EDA entering waste treatmentfrom four European manufacturing plants were 200, 287,5000–10 000, and 1000 kg/year. Use in photochemicalswas estimated to lead to 1.1 tonnes being introducedinto municipal sewage treatment plants in Germany. Allfigures are for 1992 or 1993 (BUA, 1997).

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

Few experimental data are available on the distri-bution, transport, or fate of EDA in the environment.However, qualitative, and some quantitative, estimateshave been made on the basis of its physicochemicalproperties.

EDA has a moderately high vapour pressure and isexpected to volatilize from soil (HSDB, 1997). In theatmosphere, it should react rapidly with photochemicallyproduced hydroxyl radicals; no experimental rates areavailable for this proposed reaction, but a half-life of8.9 h has been calculated.1 EDA may react with carbondioxide to form an insoluble carbamate. The high watersolubility of EDA means that volatilized chemical is alsolikely to be washed out by rain.2 The calculated dimen-sionless Henry’s law constant (air/water partition coeffi-cient) is extremely low (7.08 × 10–8); therefore, littleevaporation would be expected from water. A half-life forvolatilization of 45 years was estimated for a model river1 m deep.2 An approximate Henry’s law constant is givenin BUA (1997) as 1.77 × 10–4 PaAm3/mol.

Photodegradation is not expected, as the moleculecontains no chromophores, which absorb radiation(HSDB, 1997).

Despite their miscibility with water, ethylene-amines can bind strongly to soil. There was a wide rangeof determined adsorption coefficients in experimentalstudies on six soil types (Table 1). Some reduction invariability occurred when results were normalized fororganic carbon content, although this was less markedwith EDA than with the other ethyleneamine studied.Sorption to soil was rapid, with equilibrium occurringwithin a few hours. Electrostatic interaction between thepositively charged ethyleneamine and negativelycharged soils appeared to be the dominant factor inbinding. Complex formation with metals and humic acidsis expected. Sorption is greater to soils with high cationexchange capacity (Davis, 1993).

EDA at 200 mg/litre was incubated with adapted

sewage sludge until there was no further decrease inchemical oxygen demand (COD); at that time (unspeci-fied), 97.5% of the chemical had been degraded. The rateof degradation was 9.8 mg COD/g per hour (Pitter, 1976).

EDA at 3, 7, and 10 mg/litre was incubated withsewage sludge (adapted and non-adapted), and percentbiodegradation was determined 5, 10, 15, and 20 dayslater. Degradation rates were comparable for adapted andnon-adapted sludge up to 15 days (at 56% and 55%,respectively); at 20 days, however, the values were 70%and 47%, respectively. Based on this single point, it isnot possible to conclude definitively that adaptationimproves degradation. Nitrate and nitrite were measuredthroughout the incubation to correct for oxygen demanddue to conversion of ammonia or organic nitrogen tothese species. Such a correction was necessary for EDA

1 IUCLID (European Union database), 1st ed., 1996.

2 Syracuse Research Corporation modelling, summarized inHSDB (1997).


7

Table 1: Sorption of EDA to various soil types.a

Soil type pHCation exchange

capacity (meq/100 g)Fraction of organic

carbon (Foc)b

Freundlichadsorption

coefficient (Kd)b

Adsorption coefficientnormalized for organic

carbon (K = Kd/Foc)c

Sandy loam (Londo) 7.2 9.2 0.026 69 2700

Sandy clay loam 7.3 16.4 0.039 220 5600

Sandy loam (Cecil) 6.0 3.0 0.014 29 2100

Silty loam 6.0 15.6 0.034 238 7100

Clay 7.9 11.9 0.014 70 5000

Aquifer sand 9.6 6.9 0.0024 15 6200

a Data from Davis (1993).b Values rounded.c Mean 4800 ± 2000 (SD).

alone out of more than 50 compounds tested. Degrada-tion was also tested in a salt-water system using non-adapted sludge; EDA was degraded less effectively,with 16% of theoretical degradation after 20 days (Priceet al., 1974). A comparable value at 16.6% was measuredin seawater by Takemoto et al. (1981). EDA incubatedwith microorganisms isolated from river water andadapted to the compound over 28 days showed >80%degradation relative to theoretical oxygen demand over10 days (Mills & Stack, 1955).

Brief descriptions of the following degradationtests were also identified. EDA incubated with activatedsludge at 100 mg/litre for 28 days showed 93–95% degra-dation relative to theoretical oxygen demand in amodified Ministry of International Trade and Industry(MITI) test (Japan Chemical Industry Ecology-Toxicology Information Center, 1992). Incubation withactivated sludge at a concentration of 50 mg/litre led todegradation of 10%, 87.5%, and 94% after 5, 15, and28 days, respectively.1

The high water solubility and low octanol/waterpartition coefficient indicate that bioaccumulation inorganisms is unlikely.

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

There are no reports of monitoring of EDA levelsin the aquatic environment or of measurements ineffluents.

Residues of EDA in soil, 15 days post-treatmentwith the fungicide maneb, have been reported at0.119 mg/kg for the top 1 cm (approximately) and at 0.044mg/kg down to about 5 cm. Residues on tomatoes andbeans were 0.053 and 0.239 mg/kg, respectively,immediately after spraying, falling to 0.047 and0.094 mg/kg, respectively, after 14 days (Newsome et al.,1975).

6.2 Human exposure

The data available to the authors of this documentare restricted mainly to the occupational environment.The exposure assessments used in this report are basedon either limited data or data modelled using the Esti-mation and Assessment of Substance Exposure (EASE)model. This is a general-purpose predictive modeldeveloped by the United Kingdom’s Health and SafetyExecutive for exposure assessment in the workplace. Inits present form, the model is in widespread use acrossthe European Union for the occupational exposureassessment of new and existing substances. Similarly,information on control measures has been derived fromUnited Kingdom industry sources. Where data gapsexist, professional judgement has been used.

The number of employees exposed to EDA in theUnited Kingdom is not accurately known. For use as anintermediate in the manufacture of tetraacetyl ethylene-diamine, EDTA, organic flocculants, urea resins, andfatty bisamides, it is estimated that 140 employees will bepotentially exposed. During the production of formu-lations for use in the printed circuit board and metalfinishing industries and in the manufacture of epoxycoatings/resins and pharmaceutical products, it is esti-mated that 200 employees will be regularly exposed toEDA. The number of employees potentially exposedfrom use of EDA-based formulations in the printedcircuit board and metal finishing industries is estimatedto be about 100. EDA can also be released when indus-trial epoxy coatings/adhesives are applied, and this1 Unpublished report from Akzo Research to Delamine, 1989

(cited in IUCLID).


8

activity has the potential to expose several thousandemployees across a wide range of industries.

There are very few measured occupational expo-sure data available. EDA’s use as an intermediate inchemical synthesis takes place in closed systems. Meas-ured exposures for these manufacturing processes showthat control is achieved to a level of less than 1.25 mg/m3

(0.5 ppm) 8-h time-weighted average (Hansen et al.,1984). Modelled data (EASE) are in good agreement,predicting comparable values of 0.53–1.3 mg/m3 (0.21–0.52 ppm). Short-term peak exposures (sampling andhose uncoupling operations) were predicted to rangebetween 16.8 and 33.3 mg/m3 (6.7 and 13.3 ppm), 15-mintime-weighted average.

EDA’s use in the production of formulations usu-ally takes place in well-ventilated enclosed systems.Measured exposure data are not available for these proc-esses. However, modelled exposure data indicate expo-sure levels of 5–20 mg/m3 (2–8 ppm) 8-h time-weightedaverage in the presence of local exhaust ventilation and38–75 mg/m3 (15–30 ppm) 8-h time-weighted average inthe absence of local exhaust ventilation. Correspondingshort-term peak exposures during mixer charging oper-ations were estimated to be 5–25 mg/m3 (2–10 ppm)15-min time-weighted average in the presence of localexhaust ventilation and 50–103 mg/m3 (20–41 ppm)15-min time-weighted average in the absence of localexhaust ventilation.

The potential for exposure during the use of EDAformulations will be moderated by the low concentrationof EDA present in the formulations. Very few exposuredata are available, and there is scope for widely differentuse scenarios. There will be no appreciable occupationalexposure if these products are used in enclosed venti-lated systems as indicated by measured exposure data(<2.5 mg/m3 [<1 ppm] 8-h time-weighted average) andmodelled exposure data (0–0.25 mg/m3 [0–0.1 ppm] 8-htime-weighted average). Modelled exposure data forimmersion processes, in the presence of local exhaustventilation, predicted inhalation exposures of 0.5–2.5 mg/m3 (0.2–1 ppm) 8-h time-weighted average. The potentialfor greatest inhalation exposure was predicted forsituations where these formulations are brushed in opensystems with only general dilution ventilation or sprayedin open systems in the presence of local exhaustventilation. Under these conditions, modelled exposuredata predict exposures in the range 2.5–5 mg/m3 (1–2 ppm) 8-h time-weighted average. Short-term peakexposures during mixing and loading operations wereestimated to be 5–10 mg/m3 (2–4 ppm) 15-min time-weighted average. Polyamines and alkanol polyamines,including EDA, have been reported to be released fromhot bitumen during road paving (Levin et al., 1994). EDAconcentrations generated during road paving werebelow 0.025 mg/m3 (0.01 ppm).

There will also be a potential for dermal exposureacross the full range of industries handling EDA. Mod-elled data estimate dermal exposures in the range0–0.15 mg/cm2 per day. However, the use of personalprotective equipment is standard practice in all indus-tries using EDA. Therefore, in practice, dermal exposurewill be considerably reduced by the use of personalprotective equipment.

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

The toxicokinetics of EDA has received onlylimited study, and there are no studies followinginhalation exposure. Studies in humans have beenrelated to the clinical application of EDA and havedemonstrated rapid absorption via the gastrointestinaltract, with at least 50% absorbed within the first 7 h;absorbed EDA is rapidly removed from the plasma(Caldwell & Cotgreave, 1983; Cotgreave & Caldwell,1983a,b, 1985). At least half the amount absorbed isexcreted in the urine, largely as the acetylated metaboliteN-acetylethylenediamine and, in smaller amounts, as theunchanged compound.

This toxicokinetic picture is supported and extend-ed by data from studies in experimental animals. Studiesin rats and mice have demonstrated rapid and extensiveuptake via the oral route and also via the respiratorytract following intratracheal instillation (about 70% ormore of the applied dose was absorbed within 48 h)(McKelvey et al., 1982; Yang & Tallant, 1982; Yang et al.,1984b). Some (about 12% of the applied dose over 24 h)dermal absorption has also been observed in rats at non-irritant concentrations, with greater absorption at higher,skin-damaging concentrations (Yang et al., 1987). Theseanimal studies have also demonstrated that EDA and/orits metabolites are widely distributed throughout thebody and are rapidly eliminated, largely via the urine butalso as carbon dioxide in the breath and a small amountvia the faeces, providing evidence for some biliaryexcretion. It would seem reasonable to conclude that asimilar situation with respect to distribution andexcretion would pertain in humans. Examination ofurinary metabolites in these animal studies demonstratedthat EDA is also found in an acetylated conjugate formin the rat and mouse. There is evidence that thispathway may become saturated with increasing doseand that alternative metabolic pathways may be involvedat higher doses in the mouse.


9

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

A number of the available studies on both thetoxicokinetics and toxicity of EDA have employed thebase substance (EDA) and/or the hydrochloride salt(EDAA2HCl). The latter is used in pharmaceutical prepa-rations as a solubilizer to increase uptake of theophylline(this complex being known as aminophylline) and hasbeen used as a preservative in skin creams (although it isunclear whether or not this still occurs). In general, thepresence of the hydrochloride has little qualitative effecton the toxicokinetic or systemic toxicity properties ofEDA, particularly following oral dosing, as it is likely thatthe hydrochloride salt would be formed anyway in theacidic environment of the stomach. However, thehydrochloride does seem to act in a neutralizing capacityto reduce the significant irritancy potential of EDA.Studies using both forms of EDA are included in thisreview.

8.1 Single exposure

Studies in various animal species have shownEDA to be of moderate acute toxicity by the inhalation(rat 8-h LC50 estimated to be in the range of 4916–9832 mg/m3 [1966–3933 ppm]), oral (rat LD50 values of1160–3250 mg/kg body weight), and dermal (rabbit LD50

values of 550–2880 mg/kg body weight) routes ofexposure (Smyth et al., 1941, 1951; Boyd & Seymour,1946; Carpenter et al., 1948; NTP, 1982a,b; Yang et al.,1983; Dubinina et al., 1997). Few details exist of the toxicsigns observed or of target organs.

8.2 Irritation and sensitization

There are a number of reports available on skin

irritation in animals, but in general they all repeat theinformation from one original study (Smyth et al., 1951).In that study, 0.01 ml undiluted EDA applied to theshaved backs of albino rabbits produced skin necrosiswithin 24 h. A recent report has also indicated EDA to bea skin irritant (Dubinina et al., 1997). Although no furtherinformation is available, such a response is consistentwith EDA being strongly alkaline. Studies usingEDAA2HCl have also resulted in skin irritation, althoughthe neutralizing action of the hydrochloride may haveinfluenced the severity of effects, particularly on dilution(Yang et al., 1983, 1987).

As with skin irritation, the reports that are availablefor eye irritation all largely reproduce data from oneoriginal study (Carpenter & Smyth, 1946). In this study,0.005-ml solutions of 5% EDA or greater caused cornealinjury, which again would be expected, given the alkalineproperties of the substance. More recently, Dubinina et

al. (1997) stated that inflammatory responses in the rabbiteye were induced by “one drop” of EDA.

Overall, from the reports that are available, togeth-er with a consideration of its alkaline properties, it isreasonable to conclude that EDA is corrosive, with thecapacity to produce severe chemical burns to the skinand eye.

EDA has been demonstrated to possess skinsensitizing potential in guinea-pig studies, generallyusing standard methodologies such as the Magnussonand Kligman maximization and Buehler tests(Thorgeirsson, 1978; Erikson, 1979; Maurer et al., 1979;Henck et al., 1980; Goodwin et al., 1981; Babiuk et al.,1987; Robinson et al., 1990; Dubinina et al., 1997; Leung& Auletta, 1997). In four of these studies (Goodwin et al.,1981; Babiuk et al., 1987; Robinson et al., 1990; Leung &Auletta, 1997), the investigators ensured that non-irritantchallenge concentrations of EDA were used, providingclear evidence for a sensitization response. EDA alsoproduced positive results in the local lymph node assay(Basketter & Scholes, 1992). In contrast to these positiveresults, EDA consistently produced negative results inthe mouse ear swelling test (Gad et al., 1986; Cornacoff etal., 1988; Dunn et al., 1990). One study demonstrated thepotential for EDA to cross-react with other alkylamineseither as the inducing or as the challenge agent (Leung& Auletta, 1997).

No studies are available on respiratory sensitiza-tion in animals.

8.3 Short-term exposure

In a 12-day study (NTP, 1982b), mice received

gavage doses of between 50 and 600 mg EDA/kg bodyweight per day (administered as EDAA2HCl). Deaths wereobserved at 400 and 600 mg EDA/kg body weight perday. No effects were seen at 50 mg EDA/kg body weightper day. Renal effects (nephrosis and tubuleregeneration) were observed at 100 mg EDA/kg bodyweight per day and above. Lymphoid depletion in andnecrosis of splenic follicles were observed at 400 mgEDA/kg body weight per day.

A 7 h/day, 30-day inhalation study in rats indicat-ed that the liver and kidney are potential target tissues,with local effects in the lungs also likely (Pozzanni &Carpenter, 1954). No effects were observed in this studyat an airborne exposure concentration of about 150 mg/m3 (60 ppm). Slight depilatory effects were seen at330 mg/m3 (132 ppm), becoming more marked at higherexposure concentrations. Treatment-related deaths wereobserved at 563 mg/m3 (225 ppm) and 1210 mg/m3

(484 ppm) (all animals died at 1210 mg/m3 [484 ppm]).Cloudy swelling of cells in the liver and convolutedtubules of the kidneys were also observed at these expo-


10

sure concentrations. Degeneration of the convolutedtubules was seen in animals exposed to 1210 mg/m3 (484ppm), as was congestion of the lungs and adrenals.

8.4 Long-term exposure

8.4.1 Subchronic exposure

Dietary studies in rats have also indicated that theliver is a target tissue, with changes in the size andshape of hepatocytes and their nuclei being noted at1000 mg/kg body weight per day in a 90-day study (Yanget al., 1983).

Oral gavage studies using doses of between 100and 1600 mg EDA/kg body weight per day (administeredas EDAA2HCl) have been carried out in rats (NTP, 1982a).Deaths were observed after 12 doses at 800 and 1600 mgEDA/kg body weight per day and after 800 mg EDA/kgbody weight per day for 90 days. Renal tubular lesions(dilation of the lumen, necrosis, degeneration andregeneration of the epithelium) were seen at 200 mgEDA/kg body weight per day and above after 12 doses.Similar renal lesions but of a less severe nature wereseen only at 600 mg EDA/kg body weight per day andabove after 90 days. This indicates recovery in the kid-ney, probably as a consequence of compensatory regen-eration. No effects were seen on the kidney at 100 mgEDA/kg body weight per day in either study. Oculareffects including cataract formation and retinal atrophywere observed in all dose groups. Minimal to moderatefocal retinal atrophy was observed in 3 out of 10 femalesat 100 mg EDA/kg body weight per day; 2 males had mildto moderate retinal atrophy and 1 male had severe retinalatrophy at 200 mg EDA/kg body weight per day.Lymphoid depletion and/or necrosis in spleen wereobserved at 800 mg EDA/kg body weight per day and inall decedents following 12 doses, and thymus weightwas reduced at 800 mg EDA/kg body weight per day inthe 90-day study. Uterine lesions (reduced uterine hornsize and atrophy of the myometrium and endometrium)were seen after dosing for 90 days with 600 or 800 mgEDA/kg body weight per day, and reduced ovarian sizewas seen after 800 mg EDA/kg body weight per day for90 days. Overall, a no-observed-adverse-effect level(NOAEL) was not identified from these studies, aseffects on the eyes were seen at all dose levels. Onlyocular effects were seen at the lowest-observed-adverse-effect level (LOAEL) of 100 mg EDA/kg body weight perday, and these were of a minimal to mild nature,suggesting that this dose represented the lower end ofthe dose–response relationship for these effects.

In a 90-day study, mice received oral gavage dosesof 25–400 mg EDA/kg body weight per day (NTP,1982b). No effects were seen at 100 mg EDA/kg bodyweight per day. Renal lesions (cortical tubular

degeneration and/or necrosis) were observed at 200 and400 mg EDA/kg body weight per day.

8.4.2 Chronic exposure and carcinogenicity

There are two carcinogenicity studies in animals.Both studies were performed to reasonably adequatestandards, including extensive histopathology, and werenegative for carcinogenic activity.

In the first study, groups of 99–225 F344 rats wereorally dosed with 0, 20, 100, or 350 mg EDAA2HCl(equivalent to 0, 9, 45, or 158 mg EDA/kg body weightper day) for 2 years (Yang et al., 1984a). Non-neoplasticeffects were similar to those described in studies ofshorter duration (Yang et al., 1993), as indicated above(section 8.4.1). Effects were seen at 45 mg EDA/kg bodyweight per day, with a NOAEL of 9 mg EDA/kg bodyweight per day. Tracheitis was also observed, probablyas a consequence of exposure to EDA in airborne dustderived from the diet.

In the second study, groups of 40–50 C3H/HeJmice were dermally administered 0 or 0.25 mg aqueousEDA 3 times per week for a lifetime (DePass et al., 1984).The dermal study included a positive control group thatreceived 3-methylcholanthrene. Skin fibrosis and hyper-keratosis were observed in EDA-treated mice.

8.5 Genotoxicity and related end-points

Only limited information is available on the geno-toxic potential of EDA. There is some evidence that EDAmay be mutagenic in bacteria with and without metabolicactivation (Hedenstedt, 1978; Hulla et al., 1981; Haworthet al., 1983; Leung, 1994). Although the most recentstudy (Leung, 1994) appears to be negative, there was asmall response in Salmonella typhimurium TA100 and apositive, but not reproducible, response in TA1535.Positive results have also been reported in these strainsfrom the other studies, although only one of these(Haworth et al., 1983) was adequately reported. The onlyseries of studies performed on mammalian cell systemsin vitro (gene mutation and sister chromatid exchange inChinese hamster ovary cells; unscheduled DNAsynthesis in rat primary hepatocytes) were consistentlynegative (Slesinski et al., 1983), although there has beenno assay for clastogenic activity. A sex-linked recessivelethal test in Drosophila melanogaster was negativefollowing dosing by feeding or injection (Zimmering etal., 1985). There are no in vivo studies on somatic cells,but a dominant lethal study in rats up to doses inducingsigns of toxicity (up to 500 mg EDAA2HCl/kg bodyweight per day in the diet) was negative (Slesinski et al.,1983).

Although there has been some evidence of muta-genicity in bacterial systems in a few limited studies, the


11

available evidence indicates that EDA is not genotoxic,with all results in mammalian cells in vitro and in vivo(dominant lethal assay) being negative. It should benoted that the overall database is limited, with no assaysavailable for clastogenic activity or for genotoxic poten-tial in somatic cells in vivo.

8.6 Reproductive and developmentaltoxicity

The potential of EDA to affect fertility and

development has been studied in rats in investigationsconducted to modern regulatory standards. In a two-generation study in F344 rats, no effects on fertility ordevelopment in any of the generations were observed upto a dose level (225 mg EDA/kg body weight per day)that induced signs of parental toxicity (Yang et al.,1984b). Dose levels used in this study were 0, 50, 150, or500 mg EDAA2HCl/kg body weight per day (equivalent to0, 23, 68, and 225 mg EDA/kg body weight per day).Effects on the uterus and ovaries have been seenfollowing gavage dosing of rats with 600 and 800 mgEDA/kg body weight per day for 90 days (see section8.4.1; NTP, 1982a). In a series of developmental toxicitystudies in F344 rats, EDA was found to produce signs offetotoxicity (increased resorptions) and delays in devel-opment at high dose levels (450 mg EDA/kg body weightper day) that induced clear signs of toxicity in the dams(DePass et al., 1987). Dose levels used in this study were0, 50, 250, or 1000 mg EDAA2HCl/kg body weight per day(equivalent to 0, 23, 113, and 450 mg EDA/kg bodyweight per day). Some of the developmental effectsappear to have been related, at least in part, to thereduced nutritional status of the animals. However, aclear NOAEL for developmental toxicity of 113 mgEDA/kg body weight per day was observed in thesestudies.

The results of a preliminary screening study inmice indicated no significant effects on development inthe offspring of dams exposed to toxic doses of EDA(400 mg/kg body weight per day) by oral gavage (Hardinet al., 1987).

No effects on development were seen in the off-spring of New Zealand white rabbits dosed during preg-nancy with up to 178 mg EDAA2HCl/kg body weight perday (equivalent to 80 mg EDA/kg body weight per day),a dose that did not induce maternal toxicity (NTP, 1991;Price et al., 1993). In a preliminary study, 2/20 pregnantrabbits receiving 100 mg EDA/kg body weight per dayby gavage died, and decreased body weight was seen insurvivors. At 400 mg/kg body weight per day, all thedams died.

8.7 Immunological and neurologicaleffects

No studies are available that have specificallyinvestigated the potential immunotoxicity of EDA.Effects on lymphoid tissue in the spleen in mice and rats(see sections 8.3 and 8.4.1, respectively) and on thethymus in rats (see section 8.4.1) were observed in oralgavage dosing studies.

There are a few, mainly in vitro, studies on the

effects of EDA on the release of (-aminobutyric acidfrom the retina, gut, and brain (Perkins & Stone, 1980;Forster et al., 1981; Lloyd et al., 1982; Morgan & Stone,1982; Sarthy, 1983; Kerr & Ong, 1984; Strain et al., 1984;Hill, 1985; Erdo et al., 1986; Krantis et al., 1990; McKay &Krantis, 1991). The general conclusion that can be drawnfrom these studies is that EDA can cause a calcium-independent release of (-aminobutyric acid that isinsensitive to the presence of tetrodotoxin. EDA wasalso shown to have (-aminobutyric acid mimetic proper-ties (i.e., reduction of neuronal firing rate). This suggeststhat EDA could have a central nervous system depres-sant effect, but studies were not performed to addressthis possibility. It was reported that EDA elicited con-traction of the guinea-pig ileum that was mediated vianeuronal release of (-aminobutyric acid. However, in therat ileum, EDA acted directly on the mucosa, resulting inrelaxation. Although these are interesting results, thetoxicological significance of these findings is unclear;they may, however, partly explain the central nervoussystem depressant and gastrointestinal effects seen insome of the animal studies at high doses.

9. EFFECTS ON HUMANS

No studies are available in which the effects, otherthan the respiratory effects summarized below, of repeat-ed exposure of humans to EDA are examined. No reportshave been found in which genotoxicity, carcinogenicity,or reproductive toxicity following exposure to EDA inhuman populations has been studied.

A case report exists concerning a 36-year-oldworker who died from cardiac collapse 55 h after beingsplashed by an accidental spillage of EDA (Niveau &Painchaux, 1973). Exposure to an unquantified amount ofEDA was in the order of a few minutes prior to thepatient being washed. Four hours after the exposure, hepresented with tachycardia (100 beats/min), anuria, andred/brown generalized erythema. The tachycardiaincreased (up to 140 beats/min), anuria persisted, and anexpectorant cough, abdominal cramps, diarrhoea, andblackish vomiting appeared. The patient became hyper-kalaemic, and his red blood cell count decreased. Overall,


12

given the lack of information with respect to levels ofexposure, few useful conclusions can be drawn from thiscase report.

The only information available on skin irritation inhumans either is anecdotal or does not involve directsurface skin contact with EDA. In a brief report on thephysicochemical properties of EDA, it is noted anecdot-ally that “the liquid, if not washed from the skin, causesblistering” (Boas-Traube et al., 1948). The other reportavailable documents the results of intradermal skin testswith solutions (0.1–1%) of EDA on three individualsbeing tested for hypersensitivity following treatmentwith aminophylline (Kradjan & Lakshminarayan, 1981).The skin response in two patients consisted of blisteringrather than a weal and flare reaction, which normallytypifies a sensitization response. Punch biopsies wereobtained from one patient, and histopathological exami-nation of these indicated tissue necrosis and oedema ofthe epidermis and dermis. These responses suggested adirect corrosive effect of EDA.

No specific reports were found of the effects ofEDA on the eyes of humans. In the original reports ofthe animal eye irritation study (see section 8.3), it isclaimed that EDA is known to have produced loss ofvision or slowly healing corneal burns in industrial use(Carpenter & Smyth, 1946). However, no further infor-mation or references were given.

EDA has been known for many years to be capableof inducing allergic skin reactions in humans. This hasbeen observed both in the workplace and, most notably,in patients treated with aminophylline or with skincreams in which EDA was used as a stabilizer (Epstein &Maibach, 1968; Petrozzi & Shore, 1976; Booth et al., 1979;Wall, 1982; Hardy et al., 1983; Balato et al., 1984; Edman& Moller, 1986; Nielsen & Jorgensen, 1987; Terzian &Simon, 1992; Toal et al., 1992; Dias et al., 1995; Simon etal., 1995; Sasseville & Al-Khenaizan, 1997). The firstreports of skin sensitizing effects in humans date back tothe late 1950s, when cases were described of eczematousreactions in pharmacists who came into contact withEDA when using aminophylline (Baer et al., 1958; Tas &Weissberg, 1958).

Subsequent to these early reports, numerous stud-ies and case reports have been published documentingthe skin sensitizing properties of EDA both followingclinical use and within the occupational setting, suchthat the substance has become incorporated into stan-dard series for patch testing (Fregert, 1981; Shehade etal., 1991). An example from the clinical setting is that ofthe report on a series of 13 patients who had used skincream containing EDA for, paradoxically, dermatiticconditions (Provost & Jillson, 1967). Use of the cream in11 of these patients had resulted in the suddenappearance of a severe generalized patchy eczematous

eruption following, in all but one of the cases, an initialimprovement upon using the cream. Patch testing wasconducted using a 1% aqueous solution of EDA,producing skin reactions in all patients ranging fromerythema and oedema to erythema vesiculation andoedema vesiculation, which extended beyond the patchtest site. Other substances tested also inducedresponses, but not in a consistent manner, with at mostonly four individuals responding in any one test.

As well as the original reports in pharmacists

working with EDA, cases of skin sensitization to EDAhave been reported in the occupational environment in anumber of different settings, including use of floorpolish remover (English & Rycroft, 1989), use of coolantoils (Crow et al., 1978), and in wire-drawing (Matthieu etal., 1993; Sasseville & Al-Khenaizan, 1997). Positiveresponses to patch testing with EDA have also beenobserved in other occupational settings, such as theoffshore oil industry (Ormerod et al., 1989), but positiveresponses to other substances, including otherpolyamines, were also seen in such cases. Thus, it isunclear whether EDA had been responsible for inducingthe sensitized state and/or cross-reacting followingsensitization to another polyamine.

A large number of cases of occupational asthmareported to have been caused by exposure to EDA areavailable in the literature (Dernehl, 1951; Gelfand, 1963;Popa et al., 1969; Valeyeva et al., 1975; Lam &Chan-Yeung, 1980; Chan-Yeung, 1982; Hagmar et al.,1982; Matsui et al., 1986; Aldrich et al., 1987; Nakazawa& Matsui, 1990; Lewinsohn & Ott, 1991; Ng et al., 1991,1995). There are a few studies in which the potential forEDA to cause respiratory hypersensitivity has beenexamined using bronchial provocation testing andinvestigation of antibody formation. As EDA iscorrosive, the vapour would be predicted to be a respi-ratory tract irritant, which is a complicating factor ininterpreting the data available and in elucidating theunderlying mechanism for any asthmatic responsesseen.

Popa et al. (1969), in a well-conducted study,investigated 48 subjects with asthmatic symptomscaused by exposure to a number of low molecular weightchemicals, including EDA. None of the subjects had ahistory of respiratory disorder prior to occupationalexposure, and the asthmatic response was associatedonly with occupational exposure in all cases. No informa-tion was given in the report on the workplace airborneconcentrations of EDA to which these workers wereexposed. A series of tests were performed in all subjects,including skin and inhalation tests with the test agent atsub-irritant concentrations; skin and inhalation tests tocommon allergens; skin tests (intradermal, scratch, andpatch tests) using sub-irritant concentrations of the testsubstance; Prausnitz-Kustner transfer reaction (to test


13

for the presence of immunoglobulin E antibodies); anddetermination of precipitating antibodies to EDA. For theinhalation test, the sub-irritant concentration wasdetermined in control asthmatic subjects, and a 2- to 10-fold dilution of this was used for the bronchial challenge.No information was given on the airborne exposureconcentrations generated under these test conditions.Control inhalation tests with the diluent, physiologicalsaline, were also conducted. It is not stated in the reportwhether or not the inhalation challenge tests wereconducted in a blind manner.

Six subjects had an immediate, positive reaction toEDA in the workplace. Of these, four showed an immedi-ate, positive response following inhalation testing withsub-irritant concentrations of EDA. These subjectsdeveloped marked bronchoconstriction following inhala-tion exposure to EDA, with a reduction in forced expi-ratory volume in 1 s (FEV1) of 62% and an increase inrespiratory resistance of 44%, compared with controls.Although not stated in the report, these values are pre-sumed to be average changes. Intradermal skin tests withEDA were positive in these four subjects, whereas patchtests were negative. Inhalation challenges with commonallergens were negative. The Prausnitz-Kustner test waspositive in all subjects, and all had eosinophilia, deter-mined in the sputum, although not, except in one case, inthe blood. No precipitating antibodies were found. In thetwo other subjects, the inhalation challenge test wasnegative. No precipitating antibodies were found, andthe Prausnitz-Kustner test was negative in bothsubjects. Eosinophilia was absent. Inhalation challengeswith other common allergens were also negative.

These data provide evidence that EDA may elicitan asthmatic response at sub-irritant concentrations andthat the response is specific to EDA. Four out of sixsubjects responsive to EDA in the workplace also had apositive response to inhaled EDA at sub-irritant concen-trations. This demonstrates that the reaction is not ageneralized response to an irritant. The positivePrausnitz-Kustner reaction may be indicative of animmunological component, but the test is not specific,and no firm conclusions can be drawn from it. It providessupporting evidence in this case. The evidence suggeststhat the subjects were hypersensitive to inhaled EDAand that a state of respiratory hypersensitivity had beeninduced by the substance.

Although a number of other studies are available,the information is of poor quality. Lam & Chan-Yeung(1980) and Chan-Yeung (1982) describe the case of oneworker in a photographic laboratory who developedasthma after 2.5 years of exposure to a variety of chemi-cals, including EDA, but also other irritant substances.The worker developed symptoms of sneezing, nasaldischarge, productive cough and nocturnal cough,wheezing, and dyspnoea. The symptoms coincided with

the work shift and subsided at weekends. There was noprevious history of asthma. No information was given inthe report of the airborne concentrations of EDA (orother substances) to which the man was exposed atwork. A series of controlled inhalation challenge expo-sures, designed to mimic work exposure conditions, wereconducted with each of the chemicals to which thesubject was exposed at work. The duration of exposurewas determined by the patient’s tolerance, and exposurewas terminated when eye irritation or cough was experi-enced. No information on the airborne exposure concen-trations of EDA generated under these test conditionswas given in the report. A methacholine inhalation testfor bronchial hyperreactivity was also performed. Pul-monary function tests were conducted pre- and post-challenge, and blood samples were taken before, during,and after each challenge. The subject showed markedbronchial reactivity to methacholine.

Exposure to an unknown concentration of vapourfrom a 1:25 solution of EDA was tolerated for 15 min.This exposure produced a marked bronchoconstriction.A late asthmatic response developed 4 h after the expo-sure, at which time FEV1 was reduced by 26% andcontinued to decrease over the next 3 h towards a 40%reduction. A 26% reduction was still apparent after 24 h,despite treatment with bronchodilator drugs. This pat-tern of response to EDA was reproducible. The patientdid not respond similarly to any of the other chemicalstested: formaldehyde, sulfur dioxide, and two colourdeveloping agents that were stated to be irritants. Expo-sure to formaldehyde (vapour from a 1:4 solution)produced an immediate small (<20%), transient reductionin FEV1, whereas exposure to sulfur dioxide causedcoughing and chest tightness and an immediatetransient reduction of 25% in FEV1. There was noincrease in plasma histamine concentration during theperiod of bronchoconstriction, although EDA wasshown to cause in vitro histamine release from wholeblood taken from the patient and from two controlsubjects. A skin test using 1:100 EDA and a precipitintest for antibodies to EDA were both negative. Thepatient subsequently had to give up work because ofrespiratory symptoms and became asymptomatic after2 weeks. Subsequent testing with methacholine, 2.4months after ceasing work, showed that the subject hada reduction in the previous bronchial hyperreactivity.

In conclusion, the subject showed an asthmaticresponse to EDA but not to formaldehyde or the colourdeveloping agents. The pattern of response to sulfurdioxide was more immediate and suggestive of anirritation response. Overall, a clear pattern of asthmaticresponse that was specific to EDA was observed in thisstudy. However, it is not possible to distinguish withcertainty between an irritant response and a sensitizationresponse, because it is possible that an irritant concen-tration was used for the bronchial challenge exposure,


14

although little immediate response was observed. Inaddition, although exposure to irritant concentrations ofthe other workplace chemicals did not elicit the samepattern, magnitude, or severity of response as that seenwith EDA, since accurate exposure levels were notgiven, it is not possible to determine whether or not theEDA concentration used had the greatest irritant poten-tial. No evidence for any immunological involvement wasfound. In conclusion, this study provides onlycircumstantial evidence that EDA caused a state ofrespiratory hypersensitivity in this subject.

A number of other case reports are available ofindividuals who exhibited asthmatic signs and symptomsassociated with exposure to EDA in the workplace(Gelfand, 1963; Valeyeva et al., 1975; Matsui et al., 1986;Nakazawa & Matsui, 1990; Ng et al., 1991). Althoughbronchial challenge testing with EDA producedasthmatic responses in these subjects, they had personaland/or family histories of allergic disease and/or theyhad worked with and responded on challenge to othersubstances. Retrospective studies using the medicalrecords of populations of workers using EDA haveindicated that about 10% of such populations developedsigns and symptoms of occupational asthma (Aldrich etal., 1987; Lewinsohn & Ott, 1991). No challenge testswere carried out with these surveys. Thus, these casereports and population-based studies provide only sup-porting circumstantial evidence for the involvement ofEDA in producing occupational asthma.

Although it is clear from these reports that EDAcan provoke an asthma attack, in many cases there isinsufficient information to indicate whether or not thehypersensitive state was induced specifically by EDA.However, from one well-conducted study, there isevidence that a hypersensitive state specific to EDA hasbeen induced in workers and that an asthmatic responsewas provoked by sub-irritant concentrations of thesubstance. Overall, the results of this study, takentogether with the supporting data from a substantialnumber of other reports of occupational asthma, indicatethat EDA is capable of inducing a state of hypersensitiv-ity in the airways, such that subsequent exposure maytrigger asthma. The mechanism by which the hypersensi-tive state is induced is not proven. Given the skin sen-sitizing potential of EDA and the limited evidence ofimmunological involvement in workers with EDA-provoked occupational asthma, an immunologicalmechanism would seem plausible. Irrespective of themechanism involved, the data available (specifically thelack of information on airborne exposure concentrationsunder both work and challenge test conditions) do notallow elucidation of a dose–response relationship or theidentification of levels of EDA that are not capable ofinducing a hypersensitive state or of provoking anasthmatic response.

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

Results of acute ecotoxicity tests are given inTable 2.

A 21-day Daphnia magna reproduction test wasconducted according to the German Federal EnvironmentAgency (Umweltbundesamt) guidelines in a closedvessel. End-points measured included adult mortality,onset of production of young, and reproduction rate.The most sensitive end-point was for reproductive rate,and a NOEC of 0.16 mg/litre was established (Kuhn et al.,1989). In a second study conducted according to Organ-isation for Economic Co-operation and Development(OECD) guidelines, a NOEC for reproduction wasreported at 2 mg/litre (Mark & Hantink-de Rooy, 1992).An early life stage test conducted under OECD guide-lines on three-spined stickleback (Gasterosteus acule-atus) showed no effects of EDA at 10 mg/litre (thehighest concentration tested) over 28 days (Mark &Arends, 1992).

Growth of lettuce (Lactuca sativa) plants over7 days was studied in tests conducted under OECDGuideline 208; EC50 concentrations for EDA in soil(nominal) were >1000 mg/kg for 7-day and 692 mg/kg for14-day growth periods (Hulzebos et al., 1993).

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

EDA is of moderate acute toxicity by all routes. Instudies in animals, EDA is a primary skin and eye irritant,being corrosive when undiluted. It is also a skinsensitizer. In repeated-dose toxicity studies by the oraland inhalation routes, effects on the liver and kidneyhave been observed, with pleomorphic changes tohepatocytes in rats being reported at the lowest oraldoses used (45 mg/kg body weight per day and abovefor 2 years; NOAEL, 9 mg/kg body weight per day). Ininhalation studies, there were no effects at 150 mg/m3 (60ppm), although slight depilation was observed at thenext highest concentration (330 mg/m3 [132 ppm]) andeffects on the liver and kidney at higher concentrationsstill (approximately 500 mg/m3 [200 ppm] and above).

There has been some evidence of mutagenicity inbacterial systems in a few limited studies. However,much of the available evidence is negative, although the


15

Table 2: Acute toxicity of EDA to organisms other than laboratory mammals.

Species End-pointConcentration

(mg/litre) Reference

Bacteria and cyanobacteria

Pseudomonas putida Toxic threshold for cell multiplication 0.85 Bringmann & Kuhn, 1980a

Microcystis aeruginosa Toxic threshold for cell multiplication 0.08 Bringmann & Kuhn, 1976

Pseudomonas putida 17-h EC50 (growth rate) 29 (23–35) van Ginkel, 1989

Nitrifying bacteria 3-h EC50 (respiration) 3.2 (0.6–5.7) Balk & Meuwsen, 1989a

NOEC 0.5

Activated sludge bacteria 1-h EC50 (respiration rate) 1600 van Ginkel & Stroo, 1989

Algae

Scenedesmus quadricauda Toxic threshold for cell multiplication 0.85 Bringmann & Kuhn, 1980a

Chlorella pyrenoidosa 96-h EC50 (growth) 100 van Leeuwen, 1986

Selenastrum capricornutum 72-h EC50 (biomass) 71 van Ginkel et al., 1990

72-h EC50 (growth rate) 645

NOEC ~3.2

96-h EC50 (growth rate) 151 van Wijk et al., 1994

Scenedesmus subspicatus 48-h EC50 (biomass and growth rate) >100 Kuhn & Pattard, 1990

Protozoa

Entosiphon sulcatum Toxic threshold for cell multiplication 1.8 Bringmann & Kuhn, 1980a

Uronemia parduczi Toxic threshold for cell multiplication 52 Bringmann & Kuhn, 1980b

Chilomonas paramaecium Toxic threshold for cell multiplication 103 Bringmann & Kuhn, 1980b

Invertebrates

Daphnia magna 48-h LC50 26.5 van Leeuwen, 1986

48-h LC50 46 van Wijk et al., 1994

48-h LC50 16.7 Balk & Meuwsen, 1989b

24-h LC50 14 Kuhn et al., 1989

Brine shrimp (Artemia salina) 24-h LC50 14 Price et al., 1974

Fish

Brown trout (Salmo trutta) 48-h LC50 230 Woodiwiss & Fretwell, 1974

Fathead minnow (Pimephales

promelas)96-h LC50 115.7 Curtis & Ward, 1981

Guppy (Poecilia reticulata) 96-h LC50 275 van Leeuwen, 1986

96-h LC50 640 Balk & Meuwsen, 1989c

96-h LC50 1545 van Wijk et al., 1994

Medaka (Oryzias latipes) 48-h LC50 1000 Tonogai et al., 1982

overall database is limited, there being no assays forclastogenic activity or for genotoxic potential in somaticcells in vivo. EDA was not carcinogenic in adequatestudies in animals.

In humans, EDA has the potential to inducerespiratory tract hypersensitivity, and provocation ofasthma is the major health effect of concern in theoccupational environment. The mechanism of inductionof the hypersensitive state is unknown, although theskin sensitizing potential of EDA and limited evidence inworkers with EDA-provoked asthma are suggestive of animmunological mechanism. However, irrespective of the

mechanism involved, the available data (particularly lackof information on exposure conditions either in theworkplace or on bronchial challenge testing) do notallow either elucidation of dose–response relationshipsor identification of the thresholds for induction of thehypersensitive state or provocation of an asthmaticresponse.

11.1.2 Criteria for setting guidance values forEDA

Available data are inadequate to serve as a basisfor characterization of the dose–response relationship


16

for provocation of an asthmatic response, the effect ofgreatest concern in the occupational environment. As itis not possible to identify a level of exposure that iswithout adverse effect, it is recommended that levels bereduced to the extent possible.

With respect to systemic effects, the lowestNOAELs of 150 mg/m3 (60 ppm) (inhalation) and 9 mg/kgbody weight per day (oral) can serve as a basis forcomparison with estimated exposure for characterizationof risk, either with application of appropriate uncertaintyfactors or directly. An example of the latter (margin ofexposure) approach is presented in section 11.1.3.

11.1.3 Sample risk characterization

Available data are inadequate to serve as a basisfor characterization of the dose–response relationship,and hence risk, for provocation of an asthmaticresponse, the effect of greatest concern in the occupa-tional environment. For substances that are asthmagens,it is also advisable to restrict peak exposures, as theymay have a role in the induction and triggering ofasthmatic phenomena. However, to help assess the riskto human health arising from occupational exposures, acomparison is made with the NOAELs for systemiceffects from animal studies.

It should also be noted that because diluted EDAis a skin irritant and sensitizer, there is a risk of devel-oping irritant and/or allergic dermatitis if suitable per-sonal protective equipment is not used.

A sample risk characterization for systemic effectsin the occupational environment in the United Kingdomis provided here. Measured data on exposure to EDA(generally used in closed systems) indicate that levels inindustry in the United Kingdom are less than 1.25 mg/m3

(0.5 ppm), 8-h time-weighted average. Modelled data(EASE) are in good agreement, predicting comparablevalues of 0.53–1.3 mg/m3 (0.21–0.52 ppm). Short-termpeak exposures (sampling and hose uncoupling opera-tions) were predicted to be 16.8–33.3 mg/m3 (6.7–13.3 ppm), 15-min time-weighted average. The EASEmodel predicts dermal exposures in the range of 0–0.15 mg/cm2 per day for an operator transferring EDAinto closed systems once a day (although coveralls andwell-maintained plastic gloves will significantly reduceexposure from this source).

With respect to systemic effects, worst-case esti-mated and measured exposures of 1.25 mg/m3 (0.5 ppm),8-h time-weighted average, are substantially less (by 100-fold or greater) than the NOAEL in the inhalation studyin rats. The combined body burden from inhalation anddermal exposure for chemical synthesis can be estimatedto be about 0.3 mg/kg body weight per day (assuming a

70-kg worker breathing 10 m3 of air containing 1.25 mgEDA/m3 [0.5 ppm] per day, with 100% absorption; and10% absorption from unprotected, undamaged skin for astandard hand area of 840 cm2). This is 30-fold less thanthe NOAEL for hepatic effects in the oral studies.

Available data on indirect exposure in the generalenvironment or from consumer products are inadequateto serve as a basis for a sample characterization of riskfor these scenarios.

11.2 Evaluation of environmental effects

No atmospheric effects are expected, as reactionwith hydroxyl radicals is likely to be rapid, and washoutof volatilized EDA is expected. Volatilization to theatmosphere is likely from soil but not from water.

Adsorption to soil particulates is strong throughelectrostatic binding; leaching through soil profiles togroundwater is not expected. EDA is readily bio-degradable, and this is the most likely source of break-down in the environment; adaptation of microorganismsmay improve degradation. Breakdown is less rapid inseawater than in fresh water. Bioaccumulation isunlikely.

Toxic thresholds for microorganisms may be aslow as 0.1 mg/litre. However, toxicity tests in culturemedia should be treated with caution, as the EDA maycomplex with metal ions. Effects may therefore beindirect, from loss of bioavailability of essential ele-ments. The “toxic thresholds” reported are lowest-observed-effect concentrations (LOECs) for smallchanges in sublethal end-points; the exact degree ofeffect at the reported concentrations is not always clear,and these have not been used in the risk assessment.

The principal receiving compartment in theenvironment is the hydrosphere, and this is the onlycompartment for which a quantitative risk assessmentcan be attempted.

The distribution of acute (from Table 2) andchronic test results is plotted in Figure 1. Chronic testresults are available for fish (a limit test only) andDaphnia (NOECs from 21-day reproduction tests).Chronic EC50s for algal growth or biomass are alsoavailable, but no NOEC was reported for these studies.Given the range of chronic test results across threetrophic levels, it is proposed that an uncertainty factor of10 be applied to the lowest reported NOEC (for Daphniareproduction at 0.16 mg/litre) to derive an estimatedPNEC for aquatic organisms of 0.016 mg/litre. This is inaccord with OECD, European Union, and USEnvironmental Protection Agency guidelines. There areno reported test results for estuarine/marine organisms;


17

* Result of a “limit test” at >10 mg/litre# Predicted NOEC for aquatic organisms (application of a factor of 10 to the lowest reported chronic NOEC)

Figure 1: Distribution of acute toxicity test results (closed circles: various end-points LC50s or EC50s) and chronic toxicity testresults (squares; open NOECs / closed EC50s) for bacteria (B), algae (A), invertebrates (I), and fish (F) in fresh water.

it is assumed that toxicity would be in the same range forthese species.

No measured concentrations of EDA in surfacewaters have been reported. A single quantitative riskassessment has been reported (van Wijk, 1992) based ondischarges into the Ems-Dollard estuary in the Nether-lands. The figure of 75 kg/day for release of EDA at thissite has been used here as a representative estimate ofrelease; no information on releases from industrial plantselsewhere is available.

Based on this emission rate, and using defaultvalues from the OECD Technical Guidance Manual, theinitial concentration in river water would be as follows:

PEClocal (water) = Ceffluent/[(1 + Kp(susp) × C(susp)) × D]

= 337.5 :g/litre

where:

• PEClocal (water) is the predicted environmental

concentration (g/litre)

• Ceffluent is the concentration of the chemical in thewastewater treatment plant effluent (g/litre),calculated as Ceffluent = W × (100 ! P)/(100 × Q),where:

W = emission rate (75 kg/day)P = percent removal in the wastewater

treatment plant (91%, based on aclassification of the chemical as“readily biodegradable”)

Q = volume of wastewater in m3/day(default 200 litres [0.2 m3] per personper day for a population of 10 000inhabitants)

• Kp(susp) is the suspended matter/water adsorptioncoefficient, calculated as Kp(susp) = Foc(susp) × Koc,where:

Foc(susp) = the fraction of organic carbon insuspended matter (0.01)


18

Koc = 0.411 × Kow

where:Kow = the octanol/water partition

coefficient (0.063)

• C(susp) is the concentration of suspended matter inthe river water in kg/litre (default concentration 15mg/litre)

• D is the dilution factor for river flow (default valueof 10)

Calculation of initial PEC in the compartment of theestuary receiving emissions from the actual plant in theNetherlands gives a PEC(initial near field) of 10.9 :g/litre. Thisis based on a local volume at mean tide of 6.9 × 109 litres,a residence time of 1 day, and a wastewater flow from theplant of 500 m3/day, realistic for the local conditions.

More refined modelling, taking into account tidaldilution and expected biodegradation with a half-life of 5days, predicts a steady-state concentration of 1.3 :gEDA/litre (van Wijk, 1992). This is likely to be a closerreflection of the real situation in the estuary.

The risk factors shown in Table 3 can be calculatedfor conservative worst-case and refined estimates ofenvironmental concentrations for a river and estuary.

Table 3: PEC/PNEC ratios.

PEC(:g/litre

)

PNEC(:g/litre

)

PEC/PNECratio

River, worst case 337.5 16 21.1

Estuary, initial worstcase

10.9 16 0.68

Estuary, refined PEC 1.3 16 0.08

The PEC/PNEC ratio for the river indicates somecause for concern (ratio greater than 1). However, thePEC is based on very conservative assumptions, andboth estimates assume low adsorption to sedimentbased on water solubility. Refined estimates for theestuary indicate low risk to aquatic organisms.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

Previous evaluations by international bodies werenot identified. Information on international hazard classi-fication and labelling is included in the InternationalChemical Safety Card reproduced in this document.

13. HUMAN HEALTH PROTECTION ANDEMERGENCY ACTION

Human health hazards, together with preventiveand protective measures and first aid recommendations,are presented in the International Chemical Safety Card(ICSC 0269) reproduced in this document.

13.1 Human health hazards

Repeated or prolonged contact with EDA maycause skin sensitization and asthma.

13.2 Advice to physicians

EDA is corrosive. Inhalation of the vapour maycause irritation of the respiratory tract and even lungoedema and could mask asthmatic reaction.

13.3 Health surveillance advice

Physicians involved in worker health surveillanceprogrammes should be aware of the potential of EDA asa human asthmagen.

13.4 Spillage

In the case of spillage, emergency crews need towear proper equipment and prevent EDA from reachingdrains or watercourses.

14. CURRENT REGULATIONS,GUIDELINES, AND STANDARDS

Information on national regulations, guidelines,and standards may be obtained from UNEP Chemicals(IRPTC), Geneva.

The reader should be aware that regulatory deci-sions about chemicals taken in a certain country can befully understood only in the framework of the legislationof that country. The regulations and guidelines of allcountries are subject to change and should always beverified with appropriate regulatory authorities beforeapplication.

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

ETHYLENEDIAMINE 0269June 1999

CAS No: 107-15-3RTECS No: KH8575000UN No: 1604EC No: 612-006-00-6

1,2-Diaminoethane1,2-EthanediamineH2NCH2CH2NH2

Molecular mass: 60.1

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Flammable. Gives off irritating ortoxic fumes (or gases) in a fire.

NO open flames, NO sparks, andNO smoking.

Powder, alcohol-resistant foam,water spray, carbon dioxide.

EXPLOSION Above 34°C explosive vapour/airmixtures may be formed.

Above 34°C closed system,ventilation, and explosion-proofelectrical equipment.

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

EXPOSURE STRICT HYGIENE!

Inhalation Burning sensation. Cough.Laboured breathing. Shortness ofbreath. Sore throat.

Ventilation, local exhaust, orbreathing protection.

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

Skin MAY BE ABSORBED! Redness.Skin burns. Pain.

Protective gloves. Protectiveclothing.

Remove contaminated clothes.Rinse skin with plenty of water orshower. Refer for medical attention.

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

Ingestion Abdominal pain. Diarrhoea. Sorethroat. Vomiting.

Do not eat, drink, or smoke duringwork.

Rinse mouth. Give plenty of waterto drink. Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Collect leaking and spilled liquid in sealablecontainers as far as possible. Absorb remainingliquid in sand or inert absorbent and remove to safeplace. (Extra personal protection: completeprotective clothing including self-containedbreathing apparatus).

C SymbolR: 10-21/22-34-42/43S: (1/2-)23-26-36/37/39-45UN Hazard Class: 8UN Subsidiary Risks: 3UN Pack Group: II

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-77NFPA Code: H 3; F 2; R 0

Fireproof. Separated from incompatible materials (see Chemical Dangers).Dry.

Boiling point: 116°CMelting point: 8.5°CRelative density (water = 1): 0.90Solubility in water: miscibleVapour pressure, kPa at 20°C: 1.2Relative vapour density (air = 1): 2.1

Relative density of the vapour/air-mixture at 20°C (air = 1): 1.02Flash point: 34°C (c.c.)Auto-ignition temperature: 385°CExplosive limits, vol% in air: 2.7-16.6Octanol/water partition coefficient as log Pow: -1.2

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

0269 ETHYLENEDIAMINE

IMPORTANT DATA

Physical State; AppearanceCOLOURLESS TO YELLOW HYGROSCOPIC LIQUID, WITHCHARACTERISTIC ODOUR.

Chemical dangersThe substance decomposes on heating producing toxic fumes(nitrogen oxides). The substance is a medium strong base.Reacts violently with chlorinated organic compounds strongoxidants.

Occupational exposure limitsTLV (as TWA): 10 ppm; 25 mg/m3 A4 (ACGIH 1999).MAK: 10 ppm; 25 mg/m3; (1995).

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

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

Effects of short-term exposureThe substance is corrosive to the eyes, the skin and therespiratory tract. Inhalation of vapour or fumes may cause lungoedema (see Notes).

Effects of long-term or repeated exposureRepeated or prolonged contact with skin may cause dermatitis.Repeated or prolonged contact may cause skin sensitization.Repeated or prolonged inhalation exposure may cause asthma.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

This substance may be hazardous to the environment; special attention should be given to water organisms.

NOTES

The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physicaleffort. Rest and medical observation are therefore essential.Immediate administration of an appropriate spray, by a doctor or a person authorized by him/her, should be considered.The symptoms of asthma often do not become manifest until a few hours have passed and they are aggravated by physical effort.Rest and medical observation are therefore essential.Anyone who has shown symptoms of asthma due to this substance should never again come into contact with this substance.Do NOT take working clothes home.

ADDITIONAL INFORMATION


21

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APPENDIX 1 — SOURCE DOCUMENTS

Brooke et al. (1997): 1,2-Diaminoethane (RiskAssessment Document EH72/7)

The authors’ draft version of this Health and SafetyExecutive report was initially reviewed internally by a group ofapproximately 10 Health and Safety Executive experts (mainlytoxicologists, but also scientists from other relevant disciplines,such as epidemiology and occupational hygiene). Thetoxicology section of the amended draft was then reviewed bytoxicologists from the United Kingdom Department of Health.Subsequently, the entire risk assessment document was reviewedby a tripartite advisory committee to the United Kingdom Healthand Safety Commission, the Working Group for the Assessmentof Toxic Chemicals (WATCH). This committee is composed ofexperts in toxicology and occupational health and hygiene fromindustry, trade unions, and academia.

The members of the WATCH committee at the time ofthe peer review were Mr Steve Bailey, Independent Consultant;Dr Hilary Cross, Trade Unions Congress; Mr David Farrar,Independent Consultant; Dr Tony Fletcher, Trade UnionsCongress; Dr Alastair Hay, Trade Unions Congress; Dr JennyLeeser, Chemical Industries Association; Dr Len Levy, Institute ofOccupational Hygiene, Birmingham; Dr Mike Molyneux,Chemical Industries Association; Mr Alan Moses, ChemicalIndustries Association; and Mr Jim Sanderson, IndependentConsultant.

BUA (1997): Ethylenediamine (GDCh-AdvisoryCommittee on Existing Chemicals of Environ-mental Relevance Report No. 184)

For the BUA review process, the company that is incharge of writing the report (usually the largest producer inGermany) prepares a draft report using literature from anextensive literature search as well as internal company studies.This draft is subject to a peer review during several readings of aworking group consisting of representatives from governmentagencies, the scientific community, and industry.

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on 1,2-diaminoethane(ethylenediamine) was sent for review to institutions andorganizations identified by IPCS after contact with IPCSnational Contact Points and Participating Institutions, as well asto identified experts. Comments were received from:

Akzo Novel nv, Arnhem, Netherlands

Department of Health, London, United Kingdom

Environment Agency, Wallingford, United Kingdom

Ethyleneamines Product Stewardship Discussion Group,Michigan, USA

Health Canada, Ottawa, Canada

International Agency for Research on Cancer, Lyon,France

National Chemicals Inspectorate (KEMI), Solna, Sweden

National Institute for Working Life, Solna, Sweden

National Institute of Public Health and EnvironmentalProtection, Bilthoven, The Netherlands

Nofer Institute of Occupational Medicine, Lodz, Poland

United States Department of Health and Human Services(National Institute for Occupational Safety and Health,Cincinnati, USA; National Institute of EnvironmentalHealth Sciences, Research Triangle Park, USA)

United States Environmental Protection Agency (Office ofResearch and Development, Washington, DC, USA)


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APPENDIX 3 — CICAD FINAL REVIEWBOARD

Tokyo, Japan, 30 June – 2 July 1998

Members

Dr R. Benson, Drinking Water Program, United States Environ-mental Protection Agency, Denver, CO, USA

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

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

Dr C. DeRosa, Agency for Toxic Substances and DiseaseRegistry, Center for Disease Control and Prevention, Atlanta,GA, USA

Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire,United Kingdom

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

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

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

Ms M.E. Meek, Environmental Health Directorate, HealthCanada, Ottawa, Ontario, Canada (Chairperson)

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

Professor S.A. Soliman, Department of Pesticide Chemistry,Alexandria University, Alexandria, Egypt

Ms D. Willcocks, Chemical Assessment Division, WorksafeAustralia, Camperdown, Australia (Rapporteur)

Professor P. Yao, Chinese Academy of Preventive Medicine,Institute of Occupational Medicine, Beijing, People’s Republicof China

Observers

Professor F.M.C. Carpanini,1 Secretary-General, ECETOC(European Centre for Ecotoxicology and Toxicology ofChemicals), Brussels, Belgium

Dr M. Ema, Division of Biological Evaluation, National Instituteof Health Sciences, Osakai, Japan

Mr R. Green,1 International Federation of Chemical, Energy,Mine and General Workers’ Unions, Brussels, Belgium

Dr B. Hansen,1 European Chemicals Bureau, EuropeanCommission, Ispra, Italy

Mr T. Jacob,1 Dupont, Washington, DC, USA

Dr H. Koeter, Organisation for Economic Co-operation andDevelopment, Paris, France

Mr H. Kondo, Chemical Safety Policy Office, Ministry ofInternational Trade and Industry, Tokyo, Japan

Ms J. Matsui, Chemical Safety Policy Office, Ministry ofInternational Trade and Industry, Tokyo, Japan

Mr R. Montaigne,1 European Chemical Industry Council (CEFIC),Brussels, Belgium

Dr A. Nishikawa, Division of Pathology, National Institute ofHealth Sciences, Tokyo, Japan

Dr H. Nishimura, Environmental Health Science Laboratory,National Institute of Health Sciences, Osaka, Japan

Ms C. Ohtake, Chem-Bio Informatics, National Institute of HealthSciences, Tokyo, Japan

Dr T. Suzuki, Division of Food, National Institute of HealthSciences, Tokyo, Japan

Dr K. Takeda, Mitsubishikasei Institute of Toxicological andEnvironmental Sciences, Yokohama, Japan

Dr K. Tasaka, Department of Chemistry, International ChristianUniversity, Tokyo, Japan

Dr H. Yamada, Environment Conservation Division, NationalResearch Institute of Fisheries Science, Kanagawa, Japan

Dr M. Yamamoto, Chem-Bio Informatics, National Institute ofHealth Sciences, Tokyo, Japan

Dr M. Yasuno, School of Environmental Science, The Universityof Shiga Prefecture, Hikone, Japan

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

Secretariat

Ms L. Regis, International Programme on Chemical Safety,World Health Organization, Geneva, Switzerland

Mr A. Strawson, Health and Safety Executive, London, UnitedKingdom

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

1 Invited but unable to attend.


27

RÉSUMÉ D’ORIENTATION

Ce CICAD relatif au 1,2-diaminoéthane (éthylène-diamine) a été préparé à partir d’une étude du Health andSafety Executive du Royaume-Uni sur les risques pour lasanté humaine (risques professionnels pour l’essentiel,mais comportant également un volet écologique) (Brookeet al., 1997). La bibliographie sur laquelle s’appuiel’étude originale a été arrêtée à fin 1994. Une analyse dela littérature a été ensuite effectuée jusqu’à juillet 1997 àla recherche de données qui auraient pu être publiéesdepuis la fin de l’étude. Les données relatives à ladestinée du composé dans l’environnement et à sonimpact écologique sont tirées d’un rapport du Comitéconsultatif de la Société allemande de Chimie pour lessubstances chimiques d’intérêt écologique (BUA, 1997).On trouvera à l’appendice 1 des indications sur lessources documentaires utilisées et sur leur mode dedépouillement. Les renseignements concernant l’examendu CICAD par des pairs font l’objet de l’appendice 2. CeCICAD a été approuvé en tant qu’évaluationinternationale lors d’une réunion du Comité d’évaluationfinale qui s’est tenue à Tokyo (Japon) du 30 juin au 2juillet 1998. La liste des participants à cette réunionfigure à l’appendice 3. La fiche d’informationinternationale sur la sécurité chimique (ICSC No 0269)établie par le Programme international sur la Sécuritéchimique (IPCS, 1993) est également reproduite dans cedocument.

Le 1,2-diaminoéthane (No CAS 107-15-3),couramment désigné sous le nom d’éthylènediamine(EDA), est un produit de synthèse qui se présente sousla forme d’un liquide incolore à jaunâtre dans les condi-tions normales de température et de pression. Il présenteune réaction fortement alcaline et il est miscible à l’eau età l’alcool. On l’utilise principalement comme intermé-diaire dans la fabrication de la tétra-acétyl-éthylène-diamine, de l’acide éthylènediamine-tétra-acétique(EDTA), des floculants organiques, des résines à based’urée et des diamides gras. Dans des proportions beau-coup plus faibles, il entre également dans la compositionde formulations destinées à la fabrication des supportsde circuits imprimés ou utilisées dans l’industrie definissage des métaux. Il peut aussi être utilisé commeaccélérateur ou agent de réticulation dans les résinesépoxy employées notamment comme revêtements ainsique pour la préparation de certains produits pharma-ceutiques. L’EDA est présent sous la forme d’impureté(<0,5 %) dans les amines grasses du commerce utiliséescomme agents mouillants dans les émulsions bitumi-neuses. On l’emploie également dans la synthèse desfongicides à base de carbamates, dans la fabrication desagents de surface et des colorants ainsi que dans lapréparation de produits de développement photograph-

ique et d’huiles de coupe. L’EDA est un produit dedécomposition des éthylènebis(dithiocarbamates)utilisés comme fongicides.

Il ne devrait pas y avoir d’effets atmosphériques

puisque la réaction de l’EDA avec les radicauxhydroxyles est vraisemblablement rapide (demi-vie 8,9 h)et que la fraction volatilisée devrait être éliminée par lesprécipitations. Ce passage dans l’atmosphère à l’état devapeur est probable à partir du sol, mais pas à partir del’eau. L’EDA adhère fortement aux particules du sol parattraction électrostatique; on pense qu’il ne devrait doncpas y avoir de passage dans les eaux souterraines parlessivage des sols. Il peut sans doute former descomplexes avec les métaux et les acides humiques. Lavoie de décomposition la plus probable dansl’environnement est la voie biologique et elle devrait êtreassez rapide; l’adaptation des microorganismes pourraitaccélérer le processus. La décomposition est plus lentedans l’eau de mer que dans l’eau douce. Il n’y aprobablement pas de bioaccumulation.

L’EDA présente une toxicité aiguë modérée pourles animaux. C’est surtout une substance irritante, quiest corrosive quand elle n’est pas diluée et qui provoqueégalement une sensibilisation cutanée. On n’a pasprocédé à la recherche de son pouvoir mutagène dansles conditions prescrites par la réglementation actuelle eton ne dispose pas non plus d’études sur son activitéclastogène ou sur une action qui s’exercerait sur lescellules somatiques in vivo. Il n’existe donc pas dedonnées suffisantes pour que l’on puisse se prononceravec certitude sur le pouvoir mutagène éventuel del’EDA. Quoi qu’il en soit, le composé ne s’est pas révélécancérogène chez l’animal. On a observé des effets nonnéoplasiques au niveau du foie (modifications pléo-morphes des hépatocytes) chez des rats auxquels onavait fait ingérer du 1,2-diaminoéthane pendant 2 ans.Ces effets ont été observés à des doses quotidiennessupérieures ou égales à 45 mg d’EDA par kg de poidscorporel, aucune anomalie ne se manifestant à la dosequotidienne de 9 mg par kg de poids corporel. On voitpas très clairement ce que cette observation peutsignifier pour la santé humaine et l’on ne peut d’ailleurspas se prononcer non plus sur le point de savoir si leseffets rapportés sont effectivement dus à l’ingestion del’EDA (par exemple, ils pourraient ne pas se produire sion changeait la voie d’administration ou être liés à deseffets de premier passage), mais on ne peut les négligerpour autant et il faut déterminer les conditions de leurapparition. Lors d’études où le composé a été administrépar gavage, on a observé des effets oculaires chez le rat(atrophie rétinienne et à dose élevée, formation decataractes) à des doses quotidiennes supérieures ouégales à 100 mg par kg de poids corporel. Chez des ratset des souris, on a constaté la présence de lésions


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rénales aux doses quotidiennes respectives de 200 et 100mg de composé par kg de poids corporel et au-delà. On aégalement trouvé quelques indices d’effets sur la ratechez des souris et des rats à des doses quotidiennessupérieures ou égales à 400 mg d’EDA par kg de poidscorporel, de même que chez des rats, au niveau duthymus, à la dose quotidienne de 800 mg/kg de poidscorporel. Les études d’inhalation effectuées sur des ratsn’ont pas permis d’observer d’effets à la dose d’environ150 mg/m3 (60 ppm) et le seul effet imputable au traite-ment a été une légère dépilation à la dose d’environ330 mg/m3 (132 ppm).

Comme l’EDA a un effet irritant et sensibilisateursur l’épiderme, il pourrait y avoir un risque d’apparitionde dermatites d’irritation ou de dermatites allergiques sil’on porte pas d’équipement protecteur individuel sur leslieux de travail où il y a possibilité de contact cutané.L’EDA peut également provoquer une hypersensibilitédes voies respiratoires et de l’asthme chez les personnesprofessionnellement exposées et c’est d’ailleurs cet effetque l’on considère comme le plus préoccupant sur leplan sanitaire.

On ne sait pas avec exactement par quel mécan-isme se développe cet état d’hypersensibilité, mais lepouvoir sensibilisateur cutané de l’EDA et les quelquesindications dont on dispose sur l’existence d’une com-posante immunologique chez les ouvriers souffrant d’unasthme provoqué par ce composé, incitent à penser quece mécanisme serait justement de nature immunologique.Quoi qu’il en soit et quel que puisse être la nature dumécanisme en question, les données disponibles nepermettent pas de mettre en évidence une relation dose-réponse ou de déterminer le seuil d’apparition d’un étatd’hypersensibilité ou d’une réaction asthmatiforme.Dans le présent document, le risque imputable aucomposé est caractérisé par des effets hépatiques donton a évalué la probabilité chez des sujets exposés àl’EDA de par leur profession, le but étant d’apprécier lerisque d’autres effets généraux. La conclusion en est quelorsque l’EDA est utilisé en vase clos, l’exposition –mesurée ou calculée par modélisation – est très sensible-ment inférieure (d’un facteur 100 au moins) à la valeursans effet observable (NOEL) chez le rat et que, parconséquent, des effets hépatiques indésirables sontimprobables.

Faute de données, on ne peut évaluer le niveaud’exposition de la population générale à l’EDA.

Le seuil de toxicité pour les microorganismespourrait ne pas dépasser 0,1 mg/litre. Cependant, il fautinterpréter avec prudence les résultats des tests toxico-logiques en milieu de culture car l’EDA est susceptible

de former des complexes avec les ions métalliques. Seseffets pourraient donc être indirects et résulter de ce quecertains éléments essentiels cessent alors d’être biodis-ponibles. Pour les invertébrés et les poissons, la valeurde la CL50 va de 14 à >1000 mg/litre. On a trouvé unevaleur de 0,16 mg/litre pour la dose sans effet observable(NOEC) sur la reproduction de Daphnia.

Etant donné que les résultats des épreuves detoxicité aiguë et chronique varient très largement, on afixé à 16 :g/litre la valeur de la concentration sans effetobservable prévisible (PNEC), en appliquant un coeffi-cient d’incertitude de 10 à la valeur publiée la plus faiblede la concentration sans effet observable (NOEC) sur lareproduction de Daphnia. Des hypothèses prudentesrelatives à la concentration prévisible dans l’environne-ment (PEC) permettent d’aboutir à une valeur du rapportPEC/PNEC justifiant quelques craintes eu égard auxconcentrations initiales (par ex. lors de la déchargeinitiale dans un cours d’eau ou un estuaire). Néanmoins,une estimation plus élaborée de l’exposition probableindique un faible risque pour les organismes aquatiques.


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RESUMEN DE ORIENTACIÓN

Este CICAD sobre el 1,2 diaminoetano (etilen-diamina) se basa en un examen de los problemasrelativos a la salud humana (fundamentalmenteocupacional, pero con la inclusión también de unaevaluación en el medio ambiente) preparado por laDirección de Salud y Seguridad del Reino Unido (Brookeet al., 1997). En el documento original se incorporaron losdatos obtenidos hasta el final de 1994. Se realizóasimismo una búsqueda bibliográfica amplia hasta juliode 1997 para identificar cualquier información que sehubiera publicado después de la terminación del informe.La información sobre el destino y los efectos en el medioambiente se basa en el informe del Comité Consultivosobre Sustancias Químicas Existentes Importantes parael Medio Ambiente de la Sociedad Alemana de Química(BUA, 1997). La información sobre la preparación deldocumento original y su examen colegiado figura en elapéndice 1. La información acerca del examen colegiadode este CICAD se presenta en el apéndice 2. Este CICADse aprobó como evaluación internacional en una reuniónde la Junta de Evaluación Final celebrada en Tokio,Japón, del 30 de junio al 2 de julio de 1998. La lista departicipantes en esta reunión figura en el apéndice 3. LaFicha internacional de seguridad química (ICSC 0269),preparada por el Programa Internacional de Seguridad delas Sustancia Químicas (IPCS, 1993), también sereproduce en este documento.

El 1,2-diaminoetano (CAS Nº 107-15-3), conocidonormalmente como etilendiamina (EDA), es un líquidosintético entre incoloro y amarillento a temperatura ypresión normales. Es fuertemente alcalino y miscible conagua y con alcohol. Se utiliza fundamentalmente comointermediario en la fabricación de tetracetil etilendiamina,ácido etilendiaminotetracético (EDTA), floculantesorgánicos, resinas de urea y bisamidas grasas. Tambiénse usa, en proporción mucho menor, en la producción deformulaciones con destino a las industrias de tarjetas decircuitos impresos y acabado de metales, como agenteacelerador o de curado en revestimientos/resinas deepóxido y en la fabricación de productos farmacéuticos.Se encuentra como contaminante (<0,5%) en las aminasgrasas de suministro comercial, que se utilizan comoagentes humectantes en emulsiones bituminosas.También se emplea en la síntesis de fungicidas a base decarbamato, en la fabricación de surfactantes y tintes y enproductos químicos para el revelado fotográfico, asícomo en lubricantes para cuchillas. La EDA es unproducto de la degradación de los fungicidas deetilenbis(ditiocarbamato).

No cabe prever efectos atmosféricos, puesto que lareacción de la EDA con los radicales hidroxilo esprobablemente rápida (semivida de 8,9 horas) y sesupone que la EDA volatilizada se arrastra. Es probablela volatilización a la atmósfera a partir del suelo, pero nodel agua. Se adsorbe fuertemente a las partículas delsuelo mediante enlaces electrostáticos; no parece haberlixiviación a través de los perfiles del suelo hacia el aguafreática. Es posible la formación de complejos conmetales y ácidos húmicos. La biodegradación es elmecanismo más probable de descomposición en el medioambiente y debería ser bastante rápida; la adaptación delos microorganismos puede aumentar la degradación. Ladescomposición es menos rápida en el agua de mar queen el agua dulce. No es probable la bioacumulación.

La toxicidad aguda de la EDA en los animales esmoderada. Es irritante primario, de propiedades corrosi-vas cuando no está diluido, y es también sensibilizadorcutáneo. La EDA no se ha sometido a pruebas demutagenicidad con arreglo a las normas reglamentariasactuales y no se han realizado valoraciones paradeterminar la actividad clastogénica o el potencial paraexpresar su actividad en células somáticas in vivo. Asípues, no se dispone de información suficiente para llegara conclusiones firmes sobre el potencial mutagénico dela EDA. No fue carcinogénico en animales. Se hanobservado efectos no neoplásicos en el hígado de ratas(cambios pleomórficos a hepatocitos), tras la administra-ción oral durante dos años con concentraciones de45 mg de EDA/kg de peso corporal al día y superiores,sin que se vieran efectos con 9 mg EDA/kg de pesocorporal al día. Aunque no está clara la importancia deestos cambios de las células hepáticas para la saludhumana, así como si son consecuencia de la exposiciónoral o no (es decir, podrían no producirse por otras vías,porque pueden estar relacionados con los efectos delprimer paso), no se pueden ignorar y se deberíacaracterizar el riesgo de su aparición. En estudios deadministración oral por sonda se observaron efectosoculares en las ratas (atrofia de la retina y con dosis másaltas formación de cataratas) con dosis de 100 mg deEDA/kg de peso corporal al día y superiores. Las dosisde 200 mg y 100 mg de EDA/kg de peso corporal al día ysuperiores se asociaron con daños renales en ratas yratones, respectivamente. También se encontraronsignos de efectos en el bazo de ratones y ratas con dosisde 400 mg de EDA/kg de peso corporal al día ysuperiores y en el timo de ratas con 800 mg/kg de pesocorporal al día. En estudios de inhalación realizados conratas no se detectaron efectos con concentraciones deunos 150 mg/m3 (60 ppm), y con 330 mg/m3 (132 ppm) elúnico efecto relacionado con la dosis fue una ligeradepilación.


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Puesto que la EDA diluida es irritante y sensibi-lizador cutáneo, si en el lugar de trabajo no se utiliza unequipo de protección personal adecuado y se produceun contacto cutáneo se corre el riesgo de contraer unadermatitis irritante y/o alérgica. La EDA puede inducirademás un estado de hipersensibilidad de las víasrespiratorias y provocar asma en el entorno ocupacional,y se considera que éste es el efecto en la salud quedespierta mayor preocupación.

No se ha demostrado el mecanismo de inducciónde la hipersensibilidad, aunque el potencial de sensibi-lización cutánea de la EDA y las pruebas limitadas deactuación inmunitaria en los trabajadores con asma acausa de esta sustancia hacen pensar en un mecanismoinmunitario. Sin embargo, con independencia delmecanismo de que se trate, los datos disponibles nopermiten dilucidar las relaciones dosis-respuesta oidentificar los umbrales para la inducción del estado dehipersensibilidad o la provocación de una respuestaasmática. A fin de determinar los riesgos de otros efectossistémicos, en la caracterización del riesgo de muestrasen este documento se evaluó el riesgo de efectoshepáticos en personas con exposición ocupacional. Seha llegado a la conclusión de que, cuando la EDA seutiliza en sistemas cerrados, la exposición, tanto medidacomo pronosticada a partir de modelos, esfundamentalmente inferior (100 veces o más) a laconcentración sin efectos observados (NOEL) en ratas;así pues, son poco probables los efectos hepáticosadversos.

No se pudo evaluar la exposición del públicogeneral a la EDA debido a la falta de datos disponibles.

El umbral tóxico para los microorganismos puedeser de sólo 0,1 mg de EDA/litro. Sin embargo, laspruebas de toxicidad en medios de cultivo se han deinterpretar con precaución, porque la EDA puede formarcomplejos con iones metálicos. Por consiguiente, losefectos pueden ser indirectos debido a una pérdida debiodisponibilidad de elementos esenciales. Las CL50 parainvertebrados y peces oscila entre 14 y >1000 mg/litro.Se ha notificado una concentración sin efectosobservados (NOEC) para la reproducción en Daphnia de0,16 mg/litro.

Habida cuenta de la gran variedad de resultados delas pruebas de toxicidad aguda y crónica, se determinóuna concentración prevista sin efectos observados(PNEC) para los organismos acuáticos de 16 :g/litro,basada en la aplicación de un factor de incertidumbre de10 a la NOEC más baja notificada para la reproducción deDaphnia. Hipótesis prudentes para la concentraciónprevista en el medio ambiente (PEC) establecen razones

PEC/PNEC que ponen de manifiesto alguna preocu-pación a partir de concentraciones iniciales (es decir, enel primer vertido en el río o el estuario). Sin embargo,estimaciones más precisas de la exposición indican unriesgo escaso para los organismos acuáticos.