This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 15

1,2-DIAMINOETHANE (ETHYLENEDIAMINE)

First draft prepared by Mr R. Cary, Health and Safety Executive, Merseyside, United Kingdom, Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United Kingdom, and Dr 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 the printed CICAD

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

World Health Organization Geneva, 1999 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of 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 the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established 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 and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and 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 assessment I.International Programme on Chemical Safety II.Series

ISBN 92 4 153015 4 (NLM classification: QV 275) ISSN 1020-6167

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Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 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 ...... 7 6.2 Human exposure ...... 7

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

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

8.1 Single exposure ...... 9 8.2 Irritation and sensitization ...... 9 8.3 Short-term exposure ...... 9 8.4 Long-term exposure ...... 10 8.4.1 Subchronic exposure ...... 10 8.4.2 Chronic exposure and carcinogenicity ...... 10 8.5 Genotoxicity and related end-points ...... 10 8.6 Reproductive and developmental toxicity ...... 11 8.7 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 ...... 16 11.2 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 ...... 18 13.2 Advice to physicians ...... 18 13.3 Health surveillance advice ...... 18 13.4 Spillage ...... 18

iii Concise International Chemical Assessment Document 15

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

iv 1,2-Diaminoethane (Ethylenediamine)

FOREWORD While every effort is made to ensure that CICADs represent the current status of knowledge, new Concise International Chemical Assessment information is being developed constantly. Unless Documents (CICADs) are the latest in a family of otherwise stated, CICADs are based on a search of the publications from the International Programme on scientific literature to the date shown in the executive Chemical Safety (IPCS) — a cooperative programme of summary. In the event that a reader becomes aware of the World Health Organization (WHO), the International new information that would change the conclusions Labour Organisation (ILO), and the United Nations drawn in a CICAD, the reader is requested to contact Environment Programme (UNEP). CICADs join the IPCS to inform it of the new information. Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of Procedures chemicals. The flow chart shows the procedures followed to CICADs are concise documents that provide produce a CICAD. These procedures are designed to summaries of the relevant scientific information take advantage of the expertise that exists around the concerning the potential effects of chemicals upon world — expertise that is required to produce the high- human health and/or the environment. They are based quality evaluations of toxicological, exposure, and other on selected national or regional evaluation documents or data that are necessary for assessing risks to human on existing EHCs. Before acceptance for publication as health and/or the environment. CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure The first draft is based on an existing national, their completeness, accuracy in the way in which the regional, or international review. Authors of the first original data are represented, and the validity of the draft are usually, but not necessarily, from the institution conclusions drawn. that developed the original review. A standard outline has been developed to encourage consistency in form. The primary objective of CICADs is The first draft undergoes primary review by IPCS to characterization of hazard and dose–response from ensure that it meets the specified criteria for CICADs. exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they The second stage involves international peer include only that information considered critical for review by scientists known for their particular expertise characterization of the risk posed by the chemical. The and by scientists selected from an international roster critical studies are, however, presented in sufficient compiled by IPCS through recommendations from IPCS detail to support the conclusions drawn. For additional national Contact Points and from IPCS Participating information, the reader should consult the identified Institutions. Adequate time is allowed for the selected source documents upon which the CICAD has been experts to undertake a thorough review. Authors are based. required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft Risks to human health and the environment will is submitted to a Final Review Board together with the vary considerably depending upon the type and extent reviewers’ comments. of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally The CICAD Final Review Board has several measured or predicted exposure scenarios. To assist the important functions: reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever – to ensure that each CICAD has been subjected to possible. These examples cannot be considered as an appropriate and thorough peer review; representing all possible exposure situations, but are – to verify that the peer reviewers’ comments have provided as guidance only. The reader is referred to EHC been addressed appropriately; 1701 for advice on the derivation of health-based – to provide guidance to those responsible for the guidance values. preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and – to approve CICADs as international assessments. 1 International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: derivation Board members serve in their personal capacity, not as of guidance values for health-based exposure limits. representatives of any organization, government, or Geneva, World Health Organization (Environmental Health industry. They are selected because of their expertise in Criteria 170). human and environmental toxicology or because of their

1 Concise International Chemical Assessment Document 15

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)

FIRST DRAFT PREPARED

PRIMARY REVIEW BY IPCS ( REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/ SPECIALIZED EXPERTS

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER), PREPARATION OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

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.

2 1,2-Diaminoethane (Ethylenediamine)

experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

3 Concise International Chemical Assessment Document 15

1. EXECUTIVE SUMMARY of microorganisms may improve degradation. Breakdown is less rapid in seawater than in fresh water. Bioaccumu- lation is unlikely. This CICAD on 1,2-diaminoethane (ethylenedi- amine) was based on a review of human health concerns EDA has moderate acute toxicity in animals. It is a (primarily occupational, but also including an environ- primary irritant, being corrosive when undiluted, and is mental assessment) prepared by the United Kingdom’s also a skin sensitizer. EDA has not been tested for muta- Health and Safety Executive (Brooke et al., 1997). Data genicity to current regulatory standards, and there are identified up to the end of 1994 were covered in the origi- no assays for clastogenic activity or for the potential to nal review. An additional literature search up to July express activity in somatic cells in vivo. Thus, there is 1997 was conducted to identify any new information that insufficient information to draw firm conclusions regard- had been published since the review was completed. ing the mutagenic potential of EDA. EDA was not Information on environmental fate and effects was based carcinogenic in animals. Non-neoplastic effects on the on the report of the German Chemical Society’s Adviso- liver (pleomorphic changes to hepatocytes) have been ry Committee on Existing Chemicals of Environmental observed in rats following oral dosing for 2 years at Relevance (BUA, 1997). The preparation and peer review 45 mg EDA/kg body weight per day and above, with of the source documents are described in Appendix 1. no effects seen at 9 mg EDA/kg body weight per day. Information on the peer review of this CICAD is Although the significance of these hepatic cell changes presented in Appendix 2. This CICAD was approved as for human health is unclear, as well as whether or not an international assessment at a meeting of the Final they are a consequence of oral exposure (i.e., they might Review Board, held in Tokyo, Japan, on 30 June – 2 July not occur via other routes, as they may be related to 1998. Participants at the Final Review Board meeting are first-pass effects), they cannot be discounted, and the listed in Appendix 3. The International Chemical Safety risk of their development should be characterized. In oral Card (ICSC 0269) produced by the International Pro- gavage dosing studies, effects on the rat eye (retinal gramme on Chemical Safety (IPCS, 1993) has also been atrophy and, at higher doses, cataract formation) were reproduced in this document. observed at doses of 100 mg EDA/kg body weight per day and above. Doses of 200 and 100 mg EDA/kg body 1,2-Diaminoethane (CAS No. 107-15-3), commonly weight per day and above were associated with renal known as ethylenediamine (EDA), is a synthetic colour- damage in rats and mice, respectively. There was also less to yellowish liquid at normal temperature and some indication of effects in the spleen in mice and rats pressure. It is strongly alkaline and is miscible with water at doses of 400 mg EDA/kg body weight per day and and alcohol. The main use for EDA is as an intermediate above and in the thymus in rats at 800 mg/kg body in the manufacture of tetraacetyl ethylenediamine, weight per day. In inhalation studies, no effects were ethylenediaminetetraacetic acid (EDTA), organic seen in rats at about 150 mg/m3 (60 ppm), and slight flocculants, urea resins, and fatty bisamides. It is also depilation was the only treatment-related effect observed used, to a much smaller extent, in the production of for- at about 330 mg/m3 (132 ppm). mulations for use in the printed circuit board and metal finishing industries, as an accelerator/curing agent in Because diluted EDA is a skin irritant and a skin epoxy coatings/resins, and in the manufacture of phar- sensitizer, there may be a risk of developing irritant maceutical products. EDA is present as a contaminant and/or allergic dermatitis if suitable personal protective (<0.5%) in commercially supplied fatty amines, which are equipment is not used in the occupational environment used as wetting agents in bituminous emulsions. It is where skin contact can occur. EDA is also capable of also used in the synthesis of carbamate fungicides, in inducing a state of respiratory tract hypersensitivity and surfactant and dye manufacture, and in photography provoking asthma in the occupational environment, and development chemicals and cutting oils. EDA is a degra- this is considered to be the major health effect of con- dation product of ethylenebis(dithiocarbamate) fungi- cern. cides. The mechanism for the induction of the hypersen- No atmospheric effects are expected, as reaction of sitive state is not proven, although the skin sensitizing EDA with hydroxyl radicals is likely to be rapid (half-life potential of EDA and the limited evidence of immuno- 8.9 h), and washout of volatilized EDA is expected. logical involvement in workers with EDA-provoked Volatilization to the atmosphere is likely from soil but not asthma are suggestive of an immunological mechanism. from water. Adsorption to soil particulates is strong However, irrespective of the mechanism involved, the through electrostatic binding; leaching through soil available data do not allow either elucidation of dose– profiles to groundwater is not expected. Complex response relationships or identification of the thresholds formation with metals and humic acids is expected. Bio- for induction of the hypersensitive state or provocation degradation is the most likely source of breakdown in of an asthmatic response. The sample risk characteriza- the environment and should be quite rapid; adaptation tion in this document has, in order to assess the risks of

4 1,2-Diaminoethane (Ethylenediamine)

other systemic effects, evaluated the risk of hepatic and alcohol. The log octanol/water partition coefficient effects in occupationally exposed individuals. It con- (log Kow) ranges from !1.2 to !1.52. pKa1 and pKa2 cludes that when EDA is used in closed systems, the (calculated) are 10.71 and 7.56, respectively, indicating exposure, both measured and predicted from models, is protonation at environmentally relevant pH. Additional substantially (by 100-fold or greater) less than the no- physical/chemical properties are presented in the observed-effect level (NOEL) in rats; thus, adverse International Chemical Safety Card reproduced in this effects on the liver are unlikely. document.

Exposure of the general public to EDA could not Conversion factors for EDA at 20 °C and 101.3 kPa be evaluated owing to the lack of available data. are as follows:

Toxic thresholds for microorganisms may be as 1 ppm = 2.50 mg/m3 low as 0.1 mg EDA/litre. However, toxicity tests in cul- 1 mg/m3 = 0.40 ppm ture media should be treated with caution, as the EDA may complex with metal ions. Effects may therefore be indirect, resulting from the loss of bioavailability of essential elements. LC50s for invertebrates and fish range 3. ANALYTICAL METHODS from 14 to >1000 mg/litre. A no-observed-effect concen- tration (NOEC) for Daphnia reproduction has been reported at 0.16 mg/litre. For monitoring concentrations of EDA in work- place air, NIOSH (1984–1989) uses a method that Given the wide range of acute and chronic test employs adsorption on silica gel and analysis by gas results, a predicted no-effect concentration (PNEC) for chromatography with flame ionization detection. A aquatic organisms was taken as 16 :g/litre, based on solvent-free sampling system is preferable because of application of an uncertainty factor of 10 to the lowest more convenient handling, and it is a great advantage if reported NOEC for Daphnia reproduction. Conservative derivatization can be achieved directly on the absorbent. assumptions for predicted environmental concentration The Health and Safety Laboratories of the United King- (PEC) produce PEC/PNEC ratios indicating some concern dom’s Health and Safety Executive have evaluated a from initial concentrations (i.e., at first release into the published method (Andersson et al., 1985; Levin et al., river or estuary). However, more refined exposure 1989; Patel & Rimmer, 1996). Air is sampled onto 1- estimates indicate low risk to aquatic organisms. naphthyl-isothiocyanate-impregnated filters, desorbed by acetonitrile, and analysed by high-performance liquid chromatography with ultraviolet detection. The method has a working range between 2.5 and 50 mg/m3 for a 2. IDENTITY AND PHYSICAL/CHEMICAL 5-litre air sample. The detection limit was found to be PROPERTIES 0.08 mg/m3. The method generally meets the Comité Européen de Normalisation requirements on the overall uncertainty. Although the Comité Européen de Normali- 1,2-Diaminoethane (CAS No. 107-15-3) is more sation requirements for desorption efficiency were not commonly known as ethylenediamine, with EDA used as satisfied at 25 and 50 mg/m3, a smaller sample can be a common abbreviation. Other common synonyms taken if necessary. include dimethylenediamine, 1,2-ethanediamine, 1,2- ethylenediamine, beta-aminoethylamine, and ethane-1,2- There are no reported methods for the biological diamine. EDA’s structural formula is shown below: monitoring of occupational exposure to EDA. However, analytical techniques based on solvent extraction of H H H H EDA and high-performance liquid chromatography have

NCCN been reported and used in pharmacological studies H H (Cotgreave & Caldwell, 1983c), and these might form the H H basis for biological monitoring methods.

EDA can be measured in water using reverse- EDA is a colourless to yellowish hygroscopic phase high-performance liquid chromatography with liquid with an ammonia-like odour. Its molecular weight ultraviolet detection at 315 nm, following derivatization is 60.12. It is a strongly alkaline (pH of 25% EDA in water with acetylacetone. The limit of detection was reported is 11.9), very volatile, pungent material, which fumes to be 0.26 : profusely in air. It has a melting point of about 8.5 °C, a g/litre (Nishikawa, 1987). boiling point of 116 °C (at 101.3 kPa), and a vapour pressure of 1.7 kPa at 25°C. EDA is miscible with water

5 Concise International Chemical Assessment Document 15

4. SOURCES OF HUMAN AND EDA has a moderately high vapour pressure and is ENVIRONMENTAL EXPOSURE expected to volatilize from soil (HSDB, 1997). In the atmosphere, it should react rapidly with photochemically produced hydroxyl radicals; no experimental rates are EDA is not known to occur naturally. The main available for this proposed reaction, but a half-life of 1 use for EDA is as an intermediate in the manufacture of 8.9 h has been calculated. EDA may react with carbon tetraacetyl ethylenediamine, EDTA, organic flocculants, dioxide to form an insoluble carbamate. The high water urea resins, and fatty bisamides. It is also used, to a solubility of EDA means that volatilized chemical is also 2 much smaller extent, in the production of formulations likely to be washed out by rain. The calculated dimen- for use in the printed circuit board and metal finishing sionless Henry’s law constant (air/water partition coeffi- –8 industries, as an accelerator/curing agent in epoxy coat- cient) is extremely low (7.08 × 10 ); therefore, little ings/resins, and in the manufacture of pharmaceutical evaporation would be expected from water. A half-life for products. EDA is also present as a contaminant (<0.5%) volatilization of 45 years was estimated for a model river 2 in commercially supplied fatty amines, which are used as 1 m deep. An approximate Henry’s law constant is given –4 3 wetting agents in bituminous emulsions. It is also used in BUA (1997) as 1.77 × 10 PaAm /mol. in the synthesis of carbamate fungicides, in surfactant and dye manufacture, and in photography development Photodegradation is not expected, as the molecule chemicals and cutting oils. These are believed to be contains no chromophores, which absorb radiation minor uses in the United Kingdom and were not inves- (HSDB, 1997). tigated in this review. EDA is a degradation product of ethylenebis(dithiocarbamate) fungicides. Despite their miscibility with water, ethylene- amines can bind strongly to soil. There was a wide range Approximately 11 000 tonnes of EDA are imported of determined adsorption coefficients in experimental into the United Kingdom each year, with very little being studies on six soil types (Table 1). Some reduction in re-exported (Brooke et al., 1997). World production variability occurred when results were normalized for amounts to 100 000–500 000 tonnes annually.1 In 1992, organic carbon content, although this was less marked annual production capacities were 18 000 tonnes for with EDA than with the other ethyleneamine studied. Germany, 54 000 tonnes for the Netherlands, Sorption to soil was rapid, with equilibrium occurring 30 000 tonnes for Belgium, 25 000 tonnes for Sweden, within a few hours. Electrostatic interaction between the about 159 000 tonnes for the United States, and positively charged ethyleneamine and negatively 15 000 tonnes for Japan (BUA, 1997). charged soils appeared to be the dominant factor in binding. Complex formation with metals and humic acids No measured concentrations of EDA in wastewater is expected. Sorption is greater to soils with high cation streams from manufacture and use are available. exchange capacity (Davis, 1993). However, estimates of EDA entering waste treatment from four European manufacturing plants were 200, 287, EDA at 200 mg/litre was incubated with adapted 5000–10 000, and 1000 kg/year. Use in photochemicals sewage sludge until there was no further decrease in was estimated to lead to 1.1 tonnes being introduced chemical oxygen demand (COD); at that time (unspeci- into municipal sewage treatment plants in Germany. All fied), 97.5% of the chemical had been degraded. The rate figures are for 1992 or 1993 (BUA, 1997). of degradation was 9.8 mg COD/g per hour (Pitter, 1976).

EDA at 3, 7, and 10 mg/litre was incubated with sewage sludge (adapted and non-adapted), and percent 5. ENVIRONMENTAL TRANSPORT, biodegradation was determined 5, 10, 15, and 20 days DISTRIBUTION, AND TRANSFORMATION later. Degradation rates were comparable for adapted and non-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 is Few experimental data are available on the distri- not possible to conclude definitively that adaptation bution, transport, or fate of EDA in the environment. improves degradation. Nitrate and nitrite were measured However, qualitative, and some quantitative, estimates throughout the incubation to correct for oxygen demand have been made on the basis of its physicochemical due to conversion of ammonia or organic nitrogen to properties. these species. Such a correction was necessary for EDA

2 Syracuse Research Corporation modelling, summarized in 1 IUCLID (European Union database), 1st ed., 1996. HSDB (1997).

6 1,2-Diaminoethane (Ethylenediamine)

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

Freundlich Adsorption coefficient Cation exchange Fraction of organic adsorption normalized for organic b b c Soil type pH capacity (meq/100 g) carbon (Foc) coefficient (Kd) carbon (K = Kd/Foc)

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- Residues of EDA in soil, 15 days post-treatment tion was also tested in a salt-water system using non- with the fungicide maneb, have been reported at adapted sludge; EDA was degraded less effectively, 0.119 mg/kg for the top 1 cm (approximately) and at 0.044 with 16% of theoretical degradation after 20 days (Price mg/kg down to about 5 cm. Residues on tomatoes and et al., 1974). A comparable value at 16.6% was measured beans were 0.053 and 0.239 mg/kg, respectively, in seawater by Takemoto et al. (1981). EDA incubated immediately after spraying, falling to 0.047 and with microorganisms isolated from river water and 0.094 mg/kg, respectively, after 14 days (Newsome et al., adapted to the compound over 28 days showed >80% 1975). degradation relative to theoretical oxygen demand over 10 days (Mills & Stack, 1955). 6.2 Human exposure

Brief descriptions of the following degradation The data available to the authors of this document tests were also identified. EDA incubated with activated are restricted mainly to the occupational environment. sludge at 100 mg/litre for 28 days showed 93–95% degra- The exposure assessments used in this report are based dation relative to theoretical oxygen demand in a on either limited data or data modelled using the Esti- modified Ministry of International Trade and Industry mation and Assessment of Substance Exposure (EASE) (MITI) test (Japan Chemical Industry Ecology- model. This is a general-purpose predictive model Toxicology Information Center, 1992). Incubation with developed by the United Kingdom’s Health and Safety activated sludge at a concentration of 50 mg/litre led to Executive for exposure assessment in the workplace. In degradation of 10%, 87.5%, and 94% after 5, 15, and its present form, the model is in widespread use across 28 days, respectively.1 the European Union for the occupational exposure assessment of new and existing substances. Similarly, The high water solubility and low octanol/water information on control measures has been derived from partition coefficient indicate that bioaccumulation in United Kingdom industry sources. Where data gaps organisms is unlikely. exist, professional judgement has been used.

The number of employees exposed to EDA in the United Kingdom is not accurately known. For use as an 6. ENVIRONMENTAL LEVELS AND intermediate in the manufacture of tetraacetyl ethylene- HUMAN EXPOSURE diamine, EDTA, organic flocculants, urea resins, and fatty bisamides, it is estimated that 140 employees will be potentially exposed. During the production of formu- 6.1 Environmental levels lations for use in the printed circuit board and metal finishing industries and in the manufacture of epoxy There are no reports of monitoring of EDA levels coatings/resins and pharmaceutical products, it is esti- in the aquatic environment or of measurements in mated that 200 employees will be regularly exposed to effluents. EDA. The number of employees potentially exposed from use of EDA-based formulations in the printed circuit board and metal finishing industries is estimated to be about 100. EDA can also be released when indus- 1 Unpublished report from Akzo Research to Delamine, 1989 trial epoxy coatings/adhesives are applied, and this (cited in IUCLID).

7 Concise International Chemical Assessment Document 15

activity has the potential to expose several thousand There will also be a potential for dermal exposure employees across a wide range of industries. across the full range of industries handling EDA. Mod- elled data estimate dermal exposures in the range There are very few measured occupational expo- 0–0.15 mg/cm2 per day. However, the use of personal sure data available. EDA’s use as an intermediate in protective equipment is standard practice in all indus- chemical synthesis takes place in closed systems. Meas- tries using EDA. Therefore, in practice, dermal exposure ured exposures for these manufacturing processes show will be considerably reduced by the use of personal that control is achieved to a level of less than 1.25 mg/m3 protective equipment. (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 and 7. COMPARATIVE KINETICS AND hose uncoupling operations) were predicted to range METABOLISM IN LABORATORY ANIMALS between 16.8 and 33.3 mg/m3 (6.7 and 13.3 ppm), 15-min AND HUMANS time-weighted average.

EDA’s use in the production of formulations usu- The toxicokinetics of EDA has received only ally takes place in well-ventilated enclosed systems. limited study, and there are no studies following Measured exposure data are not available for these proc- inhalation exposure. Studies in humans have been esses. However, modelled exposure data indicate expo- 3 related to the clinical application of EDA and have sure levels of 5–20 mg/m (2–8 ppm) 8-h time-weighted demonstrated rapid absorption via the gastrointestinal average in the presence of local exhaust ventilation and 3 tract, with at least 50% absorbed within the first 7 h; 38–75 mg/m (15–30 ppm) 8-h time-weighted average in absorbed EDA is rapidly removed from the plasma the absence of local exhaust ventilation. Corresponding (Caldwell & Cotgreave, 1983; Cotgreave & Caldwell, short-term peak exposures during mixer charging oper- 1983a,b, 1985). At least half the amount absorbed is 3 ations were estimated to be 5–25 mg/m (2–10 ppm) excreted in the urine, largely as the acetylated metabolite 15-min time-weighted average in the presence of local N-acetylethylenediamine and, in smaller amounts, as the 3 exhaust ventilation and 50–103 mg/m (20–41 ppm) unchanged compound. 15-min time-weighted average in the absence of local exhaust ventilation. This toxicokinetic picture is supported and extend- ed by data from studies in experimental animals. Studies The potential for exposure during the use of EDA in rats and mice have demonstrated rapid and extensive formulations will be moderated by the low concentration uptake via the oral route and also via the respiratory of EDA present in the formulations. Very few exposure tract following intratracheal instillation (about 70% or data are available, and there is scope for widely different more of the applied dose was absorbed within 48 h) use scenarios. There will be no appreciable occupational (McKelvey et al., 1982; Yang & Tallant, 1982; Yang et al., exposure if these products are used in enclosed venti- 1984b). Some (about 12% of the applied dose over 24 h) lated systems as indicated by measured exposure data dermal absorption has also been observed in rats at non- 3 (<2.5 mg/m [<1 ppm] 8-h time-weighted average) and irritant concentrations, with greater absorption at higher, 3 modelled exposure data (0–0.25 mg/m [0–0.1 ppm] 8-h skin-damaging concentrations (Yang et al., 1987). These time-weighted average). Modelled exposure data for animal studies have also demonstrated that EDA and/or immersion processes, in the presence of local exhaust its metabolites are widely distributed throughout the ventilation, predicted inhalation exposures of 0.5–2.5 mg/ 3 body and are rapidly eliminated, largely via the urine but m (0.2–1 ppm) 8-h time-weighted average. The potential also as carbon dioxide in the breath and a small amount for greatest inhalation exposure was predicted for via the faeces, providing evidence for some biliary situations where these formulations are brushed in open excretion. It would seem reasonable to conclude that a systems with only general dilution ventilation or sprayed similar situation with respect to distribution and in open systems in the presence of local exhaust excretion would pertain in humans. Examination of ventilation. Under these conditions, modelled exposure urinary metabolites in these animal studies demonstrated 3 data predict exposures in the range 2.5–5 mg/m (1– that EDA is also found in an acetylated conjugate form 2 ppm) 8-h time-weighted average. Short-term peak in the rat and mouse. There is evidence that this exposures during mixing and loading operations were pathway may become saturated with increasing dose 3 estimated to be 5–10 mg/m (2–4 ppm) 15-min time- and that alternative metabolic pathways may be involved weighted average. Polyamines and alkanol polyamines, at higher doses in the mouse. including EDA, have been reported to be released from hot bitumen during road paving (Levin et al., 1994). EDA concentrations generated during road paving were below 0.025 mg/m3 (0.01 ppm).

8 1,2-Diaminoethane (Ethylenediamine)

8. EFFECTS ON LABORATORY al. (1997) stated that inflammatory responses in the rabbit MAMMALS AND IN VITRO TEST SYSTEMS eye were induced by “one drop” of EDA.

Overall, from the reports that are available, togeth- A number of the available studies on both the er with a consideration of its alkaline properties, it is toxicokinetics and toxicity of EDA have employed the reasonable to conclude that EDA is corrosive, with the base substance (EDA) and/or the hydrochloride salt capacity to produce severe chemical burns to the skin (EDAA2HCl). The latter is used in pharmaceutical prepa- and eye. rations as a solubilizer to increase uptake of theophylline (this complex being known as aminophylline) and has EDA has been demonstrated to possess skin been used as a preservative in skin creams (although it is sensitizing potential in guinea-pig studies, generally unclear whether or not this still occurs). In general, the using standard methodologies such as the Magnusson presence of the hydrochloride has little qualitative effect and Kligman maximization and Buehler tests on the toxicokinetic or systemic toxicity properties of (Thorgeirsson, 1978; Erikson, 1979; Maurer et al., 1979; EDA, particularly following oral dosing, as it is likely that Henck et al., 1980; Goodwin et al., 1981; Babiuk et al., the hydrochloride salt would be formed anyway in the 1987; Robinson et al., 1990; Dubinina et al., 1997; Leung acidic environment of the stomach. However, the & Auletta, 1997). In four of these studies (Goodwin et al., hydrochloride does seem to act in a neutralizing capacity 1981; Babiuk et al., 1987; Robinson et al., 1990; Leung & to reduce the significant irritancy potential of EDA. Auletta, 1997), the investigators ensured that non-irritant Studies using both forms of EDA are included in this challenge concentrations of EDA were used, providing review. clear evidence for a sensitization response. EDA also produced positive results in the local lymph node assay 8.1 Single exposure (Basketter & Scholes, 1992). In contrast to these positive results, EDA consistently produced negative results in Studies in various animal species have shown the mouse ear swelling test (Gad et al., 1986; Cornacoff et EDA to be of moderate acute toxicity by the inhalation al., 1988; Dunn et al., 1990). One study demonstrated the potential for EDA to cross-react with other alkylamines (rat 8-h LC50 estimated to be in the range of 4916– 3 either as the inducing or as the challenge agent (Leung 9832 mg/m [1966–3933 ppm]), oral (rat LD50 values of & Auletta, 1997). 1160–3250 mg/kg body weight), and dermal (rabbit LD50 values of 550–2880 mg/kg body weight) routes of exposure (Smyth et al., 1941, 1951; Boyd & Seymour, No studies are available on respiratory sensitiza- 1946; Carpenter et al., 1948; NTP, 1982a,b; Yang et al., tion in animals. 1983; Dubinina et al., 1997). Few details exist of the toxic signs observed or of target organs. 8.3 Short-term exposure

8.2 Irritation and sensitization In a 12-day study (NTP, 1982b), mice received gavage doses of between 50 and 600 mg EDA/kg body There are a number of reports available on skin weight per day (administered as EDAA2HCl). Deaths were irritation in animals, but in general they all repeat the observed at 400 and 600 mg EDA/kg body weight per information from one original study (Smyth et al., 1951). day. No effects were seen at 50 mg EDA/kg body weight In that study, 0.01 ml undiluted EDA applied to the per day. Renal effects (nephrosis and tubule shaved backs of albino rabbits produced skin necrosis regeneration) were observed at 100 mg EDA/kg body within 24 h. A recent report has also indicated EDA to be weight per day and above. Lymphoid depletion in and a skin irritant (Dubinina et al., 1997). Although no further necrosis of splenic follicles were observed at 400 mg information is available, such a response is consistent EDA/kg body weight per day. with EDA being strongly alkaline. Studies using EDAA2HCl have also resulted in skin irritation, although A 7 h/day, 30-day inhalation study in rats indicat- the neutralizing action of the hydrochloride may have ed that the liver and kidney are potential target tissues, influenced the severity of effects, particularly on dilution with local effects in the lungs also likely (Pozzanni & (Yang et al., 1983, 1987). Carpenter, 1954). No effects were observed in this study at an airborne exposure concentration of about 150 mg/ 3 As with skin irritation, the reports that are available m (60 ppm). Slight depilatory effects were seen at 3 for eye irritation all largely reproduce data from one 330 mg/m (132 ppm), becoming more marked at higher original study (Carpenter & Smyth, 1946). In this study, exposure concentrations. Treatment-related deaths were 3 3 0.005-ml solutions of 5% EDA or greater caused corneal observed at 563 mg/m (225 ppm) and 1210 mg/m 3 injury, which again would be expected, given the alkaline (484 ppm) (all animals died at 1210 mg/m [484 ppm]). properties of the substance. More recently, Dubinina et Cloudy swelling of cells in the liver and convoluted tubules of the kidneys were also observed at these expo-

9 Concise International Chemical Assessment Document 15

sure concentrations. Degeneration of the convoluted degeneration and/or necrosis) were observed at 200 and tubules was seen in animals exposed to 1210 mg/m3 (484 400 mg EDA/kg body weight per day. ppm), as was congestion of the lungs and adrenals. 8.4.2 Chronic exposure and carcinogenicity 8.4 Long-term exposure There are two carcinogenicity studies in animals. 8.4.1 Subchronic exposure Both studies were performed to reasonably adequate standards, including extensive histopathology, and were Dietary studies in rats have also indicated that the negative for carcinogenic activity. liver is a target tissue, with changes in the size and shape of hepatocytes and their nuclei being noted at In the first study, groups of 99–225 F344 rats were 1000 mg/kg body weight per day in a 90-day study (Yang orally dosed with 0, 20, 100, or 350 mg EDAA2HCl et al., 1983). (equivalent to 0, 9, 45, or 158 mg EDA/kg body weight per day) for 2 years (Yang et al., 1984a). Non-neoplastic Oral gavage studies using doses of between 100 effects were similar to those described in studies of and 1600 mg EDA/kg body weight per day (administered shorter duration (Yang et al., 1993), as indicated above as EDAA2HCl) have been carried out in rats (NTP, 1982a). (section 8.4.1). Effects were seen at 45 mg EDA/kg body Deaths were observed after 12 doses at 800 and 1600 mg weight per day, with a NOAEL of 9 mg EDA/kg body EDA/kg body weight per day and after 800 mg EDA/kg weight per day. Tracheitis was also observed, probably body weight per day for 90 days. Renal tubular lesions as a consequence of exposure to EDA in airborne dust (dilation of the lumen, necrosis, degeneration and derived from the diet. regeneration of the epithelium) were seen at 200 mg EDA/kg body weight per day and above after 12 doses. In the second study, groups of 40–50 C3H/HeJ Similar renal lesions but of a less severe nature were mice were dermally administered 0 or 0.25 mg aqueous seen only at 600 mg EDA/kg body weight per day and EDA 3 times per week for a lifetime (DePass et al., 1984). above after 90 days. This indicates recovery in the kid- The dermal study included a positive control group that ney, probably as a consequence of compensatory regen- received 3-methylcholanthrene. Skin fibrosis and hyper- eration. No effects were seen on the kidney at 100 mg keratosis were observed in EDA-treated mice. EDA/kg body weight per day in either study. Ocular effects including cataract formation and retinal atrophy 8.5 Genotoxicity and related end-points were observed in all dose groups. Minimal to moderate focal retinal atrophy was observed in 3 out of 10 females Only limited information is available on the geno- at 100 mg EDA/kg body weight per day; 2 males had mild toxic potential of EDA. There is some evidence that EDA to moderate retinal atrophy and 1 male had severe retinal may be mutagenic in bacteria with and without metabolic atrophy at 200 mg EDA/kg body weight per day. activation (Hedenstedt, 1978; Hulla et al., 1981; Haworth Lymphoid depletion and/or necrosis in spleen were et al., 1983; Leung, 1994). Although the most recent observed at 800 mg EDA/kg body weight per day and in study (Leung, 1994) appears to be negative, there was a all decedents following 12 doses, and thymus weight small response in Salmonella typhimurium TA100 and a was reduced at 800 mg EDA/kg body weight per day in positive, but not reproducible, response in TA1535. the 90-day study. Uterine lesions (reduced uterine horn Positive results have also been reported in these strains size and atrophy of the myometrium and endometrium) from the other studies, although only one of these were seen after dosing for 90 days with 600 or 800 mg (Haworth et al., 1983) was adequately reported. The only EDA/kg body weight per day, and reduced ovarian size series of studies performed on mammalian cell systems was seen after 800 mg EDA/kg body weight per day for in vitro (gene mutation and sister chromatid exchange in 90 days. Overall, a no-observed-adverse-effect level Chinese hamster ovary cells; unscheduled DNA (NOAEL) was not identified from these studies, as synthesis in rat primary hepatocytes) were consistently effects on the eyes were seen at all dose levels. Only negative (Slesinski et al., 1983), although there has been ocular effects were seen at the lowest-observed-adverse- no assay for clastogenic activity. A sex-linked recessive effect level (LOAEL) of 100 mg EDA/kg body weight per lethal test in Drosophila melanogaster was negative day, and these were of a minimal to mild nature, following dosing by feeding or injection (Zimmering et suggesting that this dose represented the lower end of al., 1985). There are no in vivo studies on somatic cells, the dose–response relationship for these effects. but a dominant lethal study in rats up to doses inducing signs of toxicity (up to 500 mg EDAA2HCl/kg body In a 90-day study, mice received oral gavage doses weight per day in the diet) was negative (Slesinski et al., of 25–400 mg EDA/kg body weight per day (NTP, 1983). 1982b). No effects were seen at 100 mg EDA/kg body weight per day. Renal lesions (cortical tubular Although there has been some evidence of muta- genicity in bacterial systems in a few limited studies, the

10 1,2-Diaminoethane (Ethylenediamine)

available evidence indicates that EDA is not genotoxic, 8.7 Immunological and neurological with all results in mammalian cells in vitro and in vivo effects (dominant lethal assay) being negative. It should be noted that the overall database is limited, with no assays No studies are available that have specifically available for clastogenic activity or for genotoxic poten- investigated the potential immunotoxicity of EDA. tial in somatic cells in vivo. Effects on lymphoid tissue in the spleen in mice and rats (see sections 8.3 and 8.4.1, respectively) and on the 8.6 Reproductive and developmental thymus in rats (see section 8.4.1) were observed in oral toxicity gavage dosing studies.

The potential of EDA to affect fertility and There are a few, mainly in vitro, studies on the development has been studied in rats in investigations effects of EDA on the release of (-aminobutyric acid conducted to modern regulatory standards. In a two- from the retina, gut, and brain (Perkins & Stone, 1980; generation study in F344 rats, no effects on fertility or Forster et al., 1981; Lloyd et al., 1982; Morgan & Stone, development in any of the generations were observed up 1982; Sarthy, 1983; Kerr & Ong, 1984; Strain et al., 1984; to a dose level (225 mg EDA/kg body weight per day) Hill, 1985; Erdo et al., 1986; Krantis et al., 1990; McKay & that induced signs of parental toxicity (Yang et al., Krantis, 1991). The general conclusion that can be drawn 1984b). Dose levels used in this study were 0, 50, 150, or from these studies is that EDA can cause a calcium- 500 mg EDAA2HCl/kg body weight per day (equivalent to independent release of (-aminobutyric acid that is 0, 23, 68, and 225 mg EDA/kg body weight per day). insensitive to the presence of tetrodotoxin. EDA was Effects on the uterus and ovaries have been seen also shown to have (-aminobutyric acid mimetic proper- following gavage dosing of rats with 600 and 800 mg ties (i.e., reduction of neuronal firing rate). This suggests EDA/kg body weight per day for 90 days (see section that EDA could have a central nervous system depres- 8.4.1; NTP, 1982a). In a series of developmental toxicity sant effect, but studies were not performed to address studies in F344 rats, EDA was found to produce signs of this possibility. It was reported that EDA elicited con- fetotoxicity (increased resorptions) and delays in devel- traction of the guinea-pig ileum that was mediated via opment at high dose levels (450 mg EDA/kg body weight neuronal release of (-aminobutyric acid. However, in the per day) that induced clear signs of toxicity in the dams rat ileum, EDA acted directly on the mucosa, resulting in (DePass et al., 1987). Dose levels used in this study were relaxation. Although these are interesting results, the 0, 50, 250, or 1000 mg EDAA2HCl/kg body weight per day toxicological significance of these findings is unclear; (equivalent to 0, 23, 113, and 450 mg EDA/kg body they may, however, partly explain the central nervous weight per day). Some of the developmental effects system depressant and gastrointestinal effects seen in appear to have been related, at least in part, to the some of the animal studies at high doses. reduced nutritional status of the animals. However, a clear NOAEL for developmental toxicity of 113 mg EDA/kg body weight per day was observed in these studies. 9. EFFECTS ON HUMANS

The results of a preliminary screening study in mice indicated no significant effects on development in No studies are available in which the effects, other the offspring of dams exposed to toxic doses of EDA than the respiratory effects summarized below, of repeat- (400 mg/kg body weight per day) by oral gavage (Hardin ed exposure of humans to EDA are examined. No reports et al., 1987). have been found in which genotoxicity, carcinogenicity, or reproductive toxicity following exposure to EDA in No effects on development were seen in the off- human populations has been studied. spring of New Zealand white rabbits dosed during preg- nancy with up to 178 mg EDAA2HCl/kg body weight per A case report exists concerning a 36-year-old day (equivalent to 80 mg EDA/kg body weight per day), worker who died from cardiac collapse 55 h after being a dose that did not induce maternal toxicity (NTP, 1991; splashed by an accidental spillage of EDA (Niveau & Price et al., 1993). In a preliminary study, 2/20 pregnant Painchaux, 1973). Exposure to an unquantified amount of rabbits receiving 100 mg EDA/kg body weight per day EDA was in the order of a few minutes prior to the by gavage died, and decreased body weight was seen in patient being washed. Four hours after the exposure, he survivors. At 400 mg/kg body weight per day, all the presented with tachycardia (100 beats/min), anuria, and dams died. red/brown generalized erythema. The tachycardia increased (up to 140 beats/min), anuria persisted, and an expectorant cough, abdominal cramps, diarrhoea, and blackish vomiting appeared. The patient became hyper- kalaemic, and his red blood cell count decreased. Overall,

11 Concise International Chemical Assessment Document 15

given the lack of information with respect to levels of eruption following, in all but one of the cases, an initial exposure, few useful conclusions can be drawn from this improvement upon using the cream. Patch testing was case report. conducted using a 1% aqueous solution of EDA, producing skin reactions in all patients ranging from The only information available on skin irritation in erythema and oedema to erythema vesiculation and humans either is anecdotal or does not involve direct oedema vesiculation, which extended beyond the patch surface skin contact with EDA. In a brief report on the test site. Other substances tested also induced physicochemical properties of EDA, it is noted anecdot- responses, but not in a consistent manner, with at most ally that “the liquid, if not washed from the skin, causes only four individuals responding in any one test. blistering” (Boas-Traube et al., 1948). The other report available documents the results of intradermal skin tests As well as the original reports in pharmacists with solutions (0.1–1%) of EDA on three individuals working with EDA, cases of skin sensitization to EDA being tested for hypersensitivity following treatment have been reported in the occupational environment in a with aminophylline (Kradjan & Lakshminarayan, 1981). number of different settings, including use of floor The skin response in two patients consisted of blistering polish remover (English & Rycroft, 1989), use of coolant rather than a weal and flare reaction, which normally oils (Crow et al., 1978), and in wire-drawing (Matthieu et typifies a sensitization response. Punch biopsies were al., 1993; Sasseville & Al-Khenaizan, 1997). Positive obtained from one patient, and histopathological exami- responses to patch testing with EDA have also been nation of these indicated tissue necrosis and oedema of observed in other occupational settings, such as the the epidermis and dermis. These responses suggested a offshore oil industry (Ormerod et al., 1989), but positive direct corrosive effect of EDA. responses to other substances, including other polyamines, were also seen in such cases. Thus, it is No specific reports were found of the effects of unclear whether EDA had been responsible for inducing EDA on the eyes of humans. In the original reports of the sensitized state and/or cross-reacting following the animal eye irritation study (see section 8.3), it is sensitization to another polyamine. claimed that EDA is known to have produced loss of vision or slowly healing corneal burns in industrial use A large number of cases of occupational asthma (Carpenter & Smyth, 1946). However, no further infor- reported to have been caused by exposure to EDA are mation or references were given. available in the literature (Dernehl, 1951; Gelfand, 1963; Popa et al., 1969; Valeyeva et al., 1975; Lam & EDA has been known for many years to be capable Chan-Yeung, 1980; Chan-Yeung, 1982; Hagmar et al., of inducing allergic skin reactions in humans. This has 1982; Matsui et al., 1986; Aldrich et al., 1987; Nakazawa been observed both in the workplace and, most notably, & Matsui, 1990; Lewinsohn & Ott, 1991; Ng et al., 1991, in patients treated with aminophylline or with skin 1995). There are a few studies in which the potential for creams in which EDA was used as a stabilizer (Epstein & EDA to cause respiratory hypersensitivity has been Maibach, 1968; Petrozzi & Shore, 1976; Booth et al., 1979; examined using bronchial provocation testing and Wall, 1982; Hardy et al., 1983; Balato et al., 1984; Edman investigation of antibody formation. As EDA is & Moller, 1986; Nielsen & Jorgensen, 1987; Terzian & corrosive, the vapour would be predicted to be a respi- Simon, 1992; Toal et al., 1992; Dias et al., 1995; Simon et ratory tract irritant, which is a complicating factor in al., 1995; Sasseville & Al-Khenaizan, 1997). The first interpreting the data available and in elucidating the reports of skin sensitizing effects in humans date back to underlying mechanism for any asthmatic responses the late 1950s, when cases were described of eczematous seen. reactions in pharmacists who came into contact with EDA when using aminophylline (Baer et al., 1958; Tas & Popa et al. (1969), in a well-conducted study, Weissberg, 1958). investigated 48 subjects with asthmatic symptoms caused by exposure to a number of low molecular weight Subsequent to these early reports, numerous stud- chemicals, including EDA. None of the subjects had a ies and case reports have been published documenting history of respiratory disorder prior to occupational the skin sensitizing properties of EDA both following exposure, and the asthmatic response was associated clinical use and within the occupational setting, such only with occupational exposure in all cases. No informa- that the substance has become incorporated into stan- tion was given in the report on the workplace airborne dard series for patch testing (Fregert, 1981; Shehade et concentrations of EDA to which these workers were al., 1991). An example from the clinical setting is that of exposed. A series of tests were performed in all subjects, the report on a series of 13 patients who had used skin including skin and inhalation tests with the test agent at cream containing EDA for, paradoxically, dermatitic sub-irritant concentrations; skin and inhalation tests to conditions (Provost & Jillson, 1967). Use of the cream in common allergens; skin tests (intradermal, scratch, and 11 of these patients had resulted in the sudden patch tests) using sub-irritant concentrations of the test appearance of a severe generalized patchy eczematous substance; Prausnitz-Kustner transfer reaction (to test

12 1,2-Diaminoethane (Ethylenediamine)

for the presence of immunoglobulin E antibodies); and the work shift and subsided at weekends. There was no determination of precipitating antibodies to EDA. For the previous history of asthma. No information was given in inhalation test, the sub-irritant concentration was the report of the airborne concentrations of EDA (or determined in control asthmatic subjects, and a 2- to 10- other substances) to which the man was exposed at fold dilution of this was used for the bronchial challenge. work. A series of controlled inhalation challenge expo- No information was given on the airborne exposure sures, designed to mimic work exposure conditions, were concentrations generated under these test conditions. conducted with each of the chemicals to which the Control inhalation tests with the diluent, physiological subject was exposed at work. The duration of exposure saline, were also conducted. It is not stated in the report was determined by the patient’s tolerance, and exposure whether or not the inhalation challenge tests were was terminated when eye irritation or cough was experi- conducted in a blind manner. enced. No information on the airborne exposure concen- trations of EDA generated under these test conditions Six subjects had an immediate, positive reaction to was given in the report. A methacholine inhalation test EDA in the workplace. Of these, four showed an immedi- for bronchial hyperreactivity was also performed. Pul- ate, positive response following inhalation testing with monary function tests were conducted pre- and post- sub-irritant concentrations of EDA. These subjects challenge, and blood samples were taken before, during, developed marked bronchoconstriction following inhala- and after each challenge. The subject showed marked tion exposure to EDA, with a reduction in forced expi- bronchial reactivity to methacholine. ratory volume in 1 s (FEV1) of 62% and an increase in respiratory resistance of 44%, compared with controls. Exposure to an unknown concentration of vapour Although not stated in the report, these values are pre- from a 1:25 solution of EDA was tolerated for 15 min. sumed to be average changes. Intradermal skin tests with This exposure produced a marked bronchoconstriction. EDA were positive in these four subjects, whereas patch A late asthmatic response developed 4 h after the expo- tests were negative. Inhalation challenges with common sure, at which time FEV1 was reduced by 26% and allergens were negative. The Prausnitz-Kustner test was continued to decrease over the next 3 h towards a 40% positive in all subjects, and all had eosinophilia, deter- reduction. A 26% reduction was still apparent after 24 h, mined in the sputum, although not, except in one case, in despite treatment with bronchodilator drugs. This pat- the blood. No precipitating antibodies were found. In the tern of response to EDA was reproducible. The patient two other subjects, the inhalation challenge test was did not respond similarly to any of the other chemicals negative. No precipitating antibodies were found, and tested: formaldehyde, sulfur dioxide, and two colour the Prausnitz-Kustner test was negative in both developing agents that were stated to be irritants. Expo- subjects. Eosinophilia was absent. Inhalation challenges sure to formaldehyde (vapour from a 1:4 solution) with other common allergens were also negative. produced an immediate small (<20%), transient reduction

in FEV1, whereas exposure to sulfur dioxide caused These data provide evidence that EDA may elicit coughing and chest tightness and an immediate an asthmatic response at sub-irritant concentrations and transient reduction of 25% in FEV1. There was no that the response is specific to EDA. Four out of six increase in plasma histamine concentration during the subjects responsive to EDA in the workplace also had a period of bronchoconstriction, although EDA was positive response to inhaled EDA at sub-irritant concen- shown to cause in vitro histamine release from whole trations. This demonstrates that the reaction is not a blood taken from the patient and from two control generalized response to an irritant. The positive subjects. A skin test using 1:100 EDA and a precipitin Prausnitz-Kustner reaction may be indicative of an test for antibodies to EDA were both negative. The immunological component, but the test is not specific, patient subsequently had to give up work because of and no firm conclusions can be drawn from it. It provides respiratory symptoms and became asymptomatic after supporting evidence in this case. The evidence suggests 2 weeks. Subsequent testing with methacholine, 2.4 that the subjects were hypersensitive to inhaled EDA months after ceasing work, showed that the subject had and that a state of respiratory hypersensitivity had been a reduction in the previous bronchial hyperreactivity. induced by the substance. In conclusion, the subject showed an asthmatic Although a number of other studies are available, response to EDA but not to formaldehyde or the colour the information is of poor quality. Lam & Chan-Yeung developing agents. The pattern of response to sulfur (1980) and Chan-Yeung (1982) describe the case of one dioxide was more immediate and suggestive of an worker in a photographic laboratory who developed irritation response. Overall, a clear pattern of asthmatic asthma after 2.5 years of exposure to a variety of chemi- response that was specific to EDA was observed in this cals, including EDA, but also other irritant substances. study. However, it is not possible to distinguish with The worker developed symptoms of sneezing, nasal certainty between an irritant response and a sensitization discharge, productive cough and nocturnal cough, response, because it is possible that an irritant concen- wheezing, and dyspnoea. The symptoms coincided with tration was used for the bronchial challenge exposure,

13 Concise International Chemical Assessment Document 15 although little immediate response was observed. In 10. EFFECTS ON OTHER ORGANISMS IN addition, although exposure to irritant concentrations of THE LABORATORY AND FIELD the other workplace chemicals did not elicit the same pattern, magnitude, or severity of response as that seen with EDA, since accurate exposure levels were not Results of acute ecotoxicity tests are given in given, it is not possible to determine whether or not the Table 2. EDA concentration used had the greatest irritant poten- tial. No evidence for any immunological involvement was A 21-day Daphnia magna reproduction test was found. In conclusion, this study provides only conducted according to the German Federal Environment circumstantial evidence that EDA caused a state of Agency (Umweltbundesamt) guidelines in a closed respiratory hypersensitivity in this subject. vessel. End-points measured included adult mortality, onset of production of young, and reproduction rate. A number of other case reports are available of The most sensitive end-point was for reproductive rate, individuals who exhibited asthmatic signs and symptoms and a NOEC of 0.16 mg/litre was established (Kuhn et al., associated with exposure to EDA in the workplace 1989). In a second study conducted according to Organ- (Gelfand, 1963; Valeyeva et al., 1975; Matsui et al., 1986; isation for Economic Co-operation and Development Nakazawa & Matsui, 1990; Ng et al., 1991). Although (OECD) guidelines, a NOEC for reproduction was bronchial challenge testing with EDA produced reported at 2 mg/litre (Mark & Hantink-de Rooy, 1992). asthmatic responses in these subjects, they had personal An early life stage test conducted under OECD guide- and/or family histories of allergic disease and/or they lines on three-spined stickleback (Gasterosteus acule- had worked with and responded on challenge to other atus) showed no effects of EDA at 10 mg/litre (the substances. Retrospective studies using the medical highest concentration tested) over 28 days (Mark & records of populations of workers using EDA have Arends, 1992). indicated that about 10% of such populations developed signs and symptoms of occupational asthma (Aldrich et Growth of lettuce (Lactuca sativa) plants over al., 1987; Lewinsohn & Ott, 1991). No challenge tests 7 days was studied in tests conducted under OECD were carried out with these surveys. Thus, these case Guideline 208; EC50 concentrations for EDA in soil reports and population-based studies provide only sup- (nominal) were >1000 mg/kg for 7-day and 692 mg/kg for porting circumstantial evidence for the involvement of 14-day growth periods (Hulzebos et al., 1993). EDA in producing occupational asthma.

Although it is clear from these reports that EDA can provoke an asthma attack, in many cases there is 11. EFFECTS EVALUATION insufficient information to indicate whether or not the hypersensitive state was induced specifically by EDA. However, from one well-conducted study, there is 11.1 Evaluation of health effects evidence that a hypersensitive state specific to EDA has been induced in workers and that an asthmatic response 11.1.1 Hazard identification and dose–response was provoked by sub-irritant concentrations of the assessment substance. Overall, the results of this study, taken together with the supporting data from a substantial EDA is of moderate acute toxicity by all routes. In number of other reports of occupational asthma, indicate studies in animals, EDA is a primary skin and eye irritant, that EDA is capable of inducing a state of hypersensitiv- being corrosive when undiluted. It is also a skin ity in the airways, such that subsequent exposure may sensitizer. In repeated-dose toxicity studies by the oral trigger asthma. The mechanism by which the hypersensi- and inhalation routes, effects on the liver and kidney tive state is induced is not proven. Given the skin sen- have been observed, with pleomorphic changes to sitizing potential of EDA and the limited evidence of hepatocytes in rats being reported at the lowest oral immunological involvement in workers with EDA- doses used (45 mg/kg body weight per day and above provoked occupational asthma, an immunological for 2 years; NOAEL, 9 mg/kg body weight per day). In mechanism would seem plausible. Irrespective of the inhalation studies, there were no effects at 150 mg/m3 (60 mechanism involved, the data available (specifically the ppm), although slight depilation was observed at the lack of information on airborne exposure concentrations next highest concentration (330 mg/m3 [132 ppm]) and under both work and challenge test conditions) do not effects on the liver and kidney at higher concentrations allow elucidation of a dose–response relationship or the still (approximately 500 mg/m3 [200 ppm] and above). identification of levels of EDA that are not capable of inducing a hypersensitive state or of provoking an There has been some evidence of mutagenicity in asthmatic response. bacterial systems in a few limited studies. However, much of the available evidence is negative, although the

14 1,2-Diaminoethane (Ethylenediamine)

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

Concentration Species End-point (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 96-h LC50 115.7 Curtis & Ward, 1981 promelas)

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 for mechanism involved, the available data (particularly lack clastogenic activity or for genotoxic potential in somatic of information on exposure conditions either in the cells in vivo. EDA was not carcinogenic in adequate workplace or on bronchial challenge testing) do not studies in animals. allow either elucidation of dose–response relationships or identification of the thresholds for induction of the In humans, EDA has the potential to induce hypersensitive state or provocation of an asthmatic respiratory tract hypersensitivity, and provocation of response. asthma is the major health effect of concern in the occupational environment. The mechanism of induction 11.1.2 Criteria for setting guidance values for of the hypersensitive state is unknown, although the EDA skin sensitizing potential of EDA and limited evidence in workers with EDA-provoked asthma are suggestive of an Available data are inadequate to serve as a basis immunological mechanism. However, irrespective of the for characterization of the dose–response relationship

15 Concise International Chemical Assessment Document 15 for provocation of an asthmatic response, the effect of 70-kg worker breathing 10 m3 of air containing 1.25 mg greatest concern in the occupational environment. As it EDA/m3 [0.5 ppm] per day, with 100% absorption; and is not possible to identify a level of exposure that is 10% absorption from unprotected, undamaged skin for a without adverse effect, it is recommended that levels be standard hand area of 840 cm2). This is 30-fold less than reduced to the extent possible. the NOAEL for hepatic effects in the oral studies.

With respect to systemic effects, the lowest Available data on indirect exposure in the general NOAELs of 150 mg/m3 (60 ppm) (inhalation) and 9 mg/kg environment or from consumer products are inadequate body weight per day (oral) can serve as a basis for to serve as a basis for a sample characterization of risk comparison with estimated exposure for characterization for these scenarios. of risk, either with application of appropriate uncertainty factors or directly. An example of the latter (margin of 11.2 Evaluation of environmental effects exposure) approach is presented in section 11.1.3. No atmospheric effects are expected, as reaction 11.1.3 Sample risk characterization with hydroxyl radicals is likely to be rapid, and washout of volatilized EDA is expected. Volatilization to the Available data are inadequate to serve as a basis atmosphere is likely from soil but not from water. for characterization of the dose–response relationship, and hence risk, for provocation of an asthmatic Adsorption to soil particulates is strong through response, the effect of greatest concern in the occupa- electrostatic binding; leaching through soil profiles to tional environment. For substances that are asthmagens, groundwater is not expected. EDA is readily bio- it is also advisable to restrict peak exposures, as they degradable, and this is the most likely source of break- may have a role in the induction and triggering of down in the environment; adaptation of microorganisms asthmatic phenomena. However, to help assess the risk may improve degradation. Breakdown is less rapid in to human health arising from occupational exposures, a seawater than in fresh water. Bioaccumulation is comparison is made with the NOAELs for systemic unlikely. effects from animal studies. Toxic thresholds for microorganisms may be as It should also be noted that because diluted EDA low as 0.1 mg/litre. However, toxicity tests in culture is a skin irritant and sensitizer, there is a risk of devel- media should be treated with caution, as the EDA may oping irritant and/or allergic dermatitis if suitable per- complex with metal ions. Effects may therefore be sonal protective equipment is not used. indirect, from loss of bioavailability of essential ele- ments. The “toxic thresholds” reported are lowest- A sample risk characterization for systemic effects observed-effect concentrations (LOECs) for small in the occupational environment in the United Kingdom changes in sublethal end-points; the exact degree of is provided here. Measured data on exposure to EDA effect at the reported concentrations is not always clear, (generally used in closed systems) indicate that levels in and these have not been used in the risk assessment. industry in the United Kingdom are less than 1.25 mg/m3 (0.5 ppm), 8-h time-weighted average. Modelled data The principal receiving compartment in the (EASE) are in good agreement, predicting comparable environment is the hydrosphere, and this is the only values of 0.53–1.3 mg/m3 (0.21–0.52 ppm). Short-term compartment for which a quantitative risk assessment peak exposures (sampling and hose uncoupling opera- can be attempted. tions) were predicted to be 16.8–33.3 mg/m3 (6.7– 13.3 ppm), 15-min time-weighted average. The EASE The distribution of acute (from Table 2) and model predicts dermal exposures in the range of 0– chronic test results is plotted in Figure 1. Chronic test 0.15 mg/cm2 per day for an operator transferring EDA results are available for fish (a limit test only) and into closed systems once a day (although coveralls and Daphnia (NOECs from 21-day reproduction tests). well-maintained plastic gloves will significantly reduce Chronic EC50s for algal growth or biomass are also exposure from this source). available, but no NOEC was reported for these studies. Given the range of chronic test results across three With respect to systemic effects, worst-case esti- trophic levels, it is proposed that an uncertainty factor of mated and measured exposures of 1.25 mg/m3 (0.5 ppm), 10 be applied to the lowest reported NOEC (for Daphnia 8-h time-weighted average, are substantially less (by 100- reproduction at 0.16 mg/litre) to derive an estimated fold or greater) than the NOAEL in the inhalation study PNEC for aquatic organisms of 0.016 mg/litre. This is in in rats. The combined body burden from inhalation and accord with OECD, European Union, and US dermal exposure for chemical synthesis can be estimated Environmental Protection Agency guidelines. There are to be about 0.3 mg/kg body weight per day (assuming a no reported test results for estuarine/marine organisms;

16 1,2-Diaminoethane (Ethylenediamine)

* 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 test results (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 for • PEClocal (water) is the predicted environmental these species. concentration (g/litre)

No measured concentrations of EDA in surface • Ceffluent is the concentration of the chemical in the waters have been reported. A single quantitative risk wastewater treatment plant effluent (g/litre), assessment has been reported (van Wijk, 1992) based on calculated as Ceffluent = W × (100 ! P)/(100 × Q), discharges into the Ems-Dollard estuary in the Nether- where: lands. The figure of 75 kg/day for release of EDA at this W = emission rate (75 kg/day) site has been used here as a representative estimate of P = percent removal in the wastewater release; no information on releases from industrial plants treatment plant (91%, based on a elsewhere is available. classification of the chemical as “readily biodegradable”) Based on this emission rate, and using default Q = volume of wastewater in m3/day values from the OECD Technical Guidance Manual, the (default 200 litres [0.2 m3] per person initial concentration in river water would be as follows: per day for a population of 10 000 inhabitants)

PEClocal (water) = Ceffluent/[(1 + Kp(susp) × C(susp)) × D] • Kp(susp) is the suspended matter/water adsorption

= 337.5 :g/litre coefficient, calculated as Kp(susp) = Foc(susp) × Koc, where: where: Foc(susp) = the fraction of organic carbon in suspended matter (0.01)

17 Concise International Chemical Assessment Document 15

Koc = 0.411 × Kow 13. HUMAN HEALTH PROTECTION AND where: EMERGENCY ACTION Kow = the octanol/water partition coefficient (0.063) Human health hazards, together with preventive • C(susp) is the concentration of suspended matter in and protective measures and first aid recommendations, the river water in kg/litre (default concentration 15 are presented in the International Chemical Safety Card mg/litre) (ICSC 0269) reproduced in this document.

• D is the dilution factor for river flow (default value 13.1 Human health hazards of 10) Repeated or prolonged contact with EDA may Calculation of initial PEC in the compartment of the cause skin sensitization and asthma. estuary receiving emissions from the actual plant in the

Netherlands gives a PEC(initial near field) of 10.9 :g/litre. This 13.2 Advice to physicians is based on a local volume at mean tide of 6.9 × 109 litres, a residence time of 1 day, and a wastewater flow from the EDA is corrosive. Inhalation of the vapour may 3 plant of 500 m /day, realistic for the local conditions. cause irritation of the respiratory tract and even lung oedema and could mask asthmatic reaction. More refined modelling, taking into account tidal dilution and expected biodegradation with a half-life of 5 13.3 Health surveillance advice days, predicts a steady-state concentration of 1.3 :g EDA/litre (van Wijk, 1992). This is likely to be a closer Physicians involved in worker health surveillance reflection of the real situation in the estuary. programmes should be aware of the potential of EDA as a human asthmagen. The risk factors shown in Table 3 can be calculated for conservative worst-case and refined estimates of 13.4 Spillage environmental concentrations for a river and estuary. In the case of spillage, emergency crews need to Table 3: PEC/PNEC ratios. wear proper equipment and prevent EDA from reaching drains or watercourses. PEC PNEC PEC/PNEC (:g/litre (:g/litre ratio ) )

River, worst case 337.5 16 21.1 14. CURRENT REGULATIONS,

Estuary, initial worst 10.9 16 0.68 GUIDELINES, AND STANDARDS case

Estuary, refined PEC 1.3 16 0.08 Information on national regulations, guidelines, and standards may be obtained from UNEP Chemicals The PEC/PNEC ratio for the river indicates some (IRPTC), Geneva. cause for concern (ratio greater than 1). However, the PEC is based on very conservative assumptions, and The reader should be aware that regulatory deci- both estimates assume low adsorption to sediment sions about chemicals taken in a certain country can be based on water solubility. Refined estimates for the fully understood only in the framework of the legislation estuary indicate low risk to aquatic organisms. of that country. The regulations and guidelines of all countries are subject to change and should always be verified with appropriate regulatory authorities before application. 12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

Previous evaluations by international bodies were not identified. Information on international hazard classi- fication and labelling is included in the International Chemical Safety Card reproduced in this document.

18 ETHYLENEDIAMINE 0269 June 1999 CAS No: 107-15-3 1,2-Diaminoethane RTECS No: KH8575000 1,2-Ethanediamine

UN No: 1604 H2NCH2CH2NH2 EC No: 612-006-00-6 Molecular mass: 60.1

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Flammable. Gives off irritating or NO open flames, NO sparks, and Powder, alcohol-resistant foam, toxic fumes (or gases) in a fire. NO smoking. water spray, carbon dioxide.

EXPLOSION Above 34°C explosive vapour/air Above 34°C closed system, In case of fire: keep drums, etc., mixtures may be formed. ventilation, and explosion-proof cool by spraying with water. electrical equipment.

EXPOSURE STRICT HYGIENE!

Inhalation Burning sensation. Cough. Ventilation, local exhaust, or Fresh air, rest. Artificial respiration if Laboured breathing. Shortness of breathing protection. indicated. Refer for medical breath. Sore throat. attention.

Skin MAY BE ABSORBED! Redness. Protective gloves. Protective Remove contaminated clothes. Skin burns. Pain. clothing. Rinse skin with plenty of water or shower. Refer for medical attention.

Eyes Redness. Pain. Blurred vision. Face shield. First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then take to a doctor.

Ingestion Abdominal pain. Diarrhoea. Sore Do not eat, drink, or smoke during Rinse mouth. Give plenty of water throat. Vomiting. work. to drink. Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Collect leaking and spilled liquid in sealable C Symbol containers as far as possible. Absorb remaining R: 10-21/22-34-42/43 liquid in sand or inert absorbent and remove to safe S: (1/2-)23-26-36/37/39-45 place. (Extra personal protection: complete UN Hazard Class: 8 protective clothing including self-contained UN Subsidiary Risks: 3 breathing apparatus). UN Pack Group: II

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-77 Fireproof. Separated from incompatible materials (see Chemical Dangers). NFPA Code: H 3; F 2; R 0 Dry.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 2000 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0269 ETHYLENEDIAMINE

IMPORTANT DATA Physical State; Appearance Routes of exposure COLOURLESS TO YELLOW HYGROSCOPIC LIQUID, WITH The substance can be absorbed into the body by inhalation, CHARACTERISTIC ODOUR. through the skin and by ingestion.

Chemical dangers Inhalation risk The substance decomposes on heating producing toxic fumes A harmful contamination of the air can be reached rather (nitrogen oxides). The substance is a medium strong base. quickly on evaporation of this substance at 20°C. Reacts violently with chlorinated organic compounds strong oxidants. Effects of short-term exposure The substance is corrosive to the eyes, the skin and the Occupational exposure limits respiratory tract. Inhalation of vapour or fumes may cause lung TLV (as TWA): 10 ppm; 25 mg/m3 A4 (ACGIH 1999). oedema (see Notes). MAK: 10 ppm; 25 mg/m3; (1995). Effects of long-term or repeated exposure Repeated 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

Boiling point: 116°C Relative density of the vapour/air-mixture at 20°C (air = 1): 1.02 Melting point: 8.5°C Flash point: 34°C (c.c.) Relative density (water = 1): 0.90 Auto-ignition temperature: 385°C Solubility in water: miscible Explosive limits, vol% in air: 2.7-16.6 Vapour pressure, kPa at 20°C: 1.2 Octanol/water partition coefficient as log Pow: -1.2 Relative vapour density (air = 1): 2.1

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 physical effort. 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

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 1,2-Diaminoethane (Ethylenediamine)

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22 1,2-Diaminoethane (Ethylenediamine)

maximization test. Journal of toxicology — Cutaneous and Ng T, Lee H, Malik M, Chee Q, Cheong T, Wang Y (1995) ocular toxicology, 16:189–195. Asthma in chemical workers exposed to aliphatic polyamines. Occupational medicine, 45:45–48. Levin J, Andersson K, Fangmark I, Hallgren C (1989) Determination of gaseous and particulate polyamines in air Nielsen M, Jorgensen J (1987) Persistence of contact sensitivity using sorbent or filter coated with naphthylisothiocyanate. to ethylenediamine. Contact dermatitis, 16:275–276. Applied Industrial Hygiene Association journal, 4:98–100. NIOSH (1984–1989) Manual of analytical methods. Method Levin J, Andersson K, Hallgren C (1994) Exposure to low 3509. Cincinnati, OH, US Department of Health and Human molecular weight polyamines during road paving. Annals of Services, Public Health Service, National Institute for occupational hygiene, 38:257–264. Occupational Safety and Health.

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23 Concise International Chemical Assessment Document 15

Price K, Waggy G, Conway R (1974) Brine shrimp bioassay and especially on amines, nitriles, aromatic nitrogen compounds and seawater BOD of petrochemicals. Journal of the Water Pollution artificial dyes. Journal of toxicological sciences, 7:193–203. Control Federation, 46:63–77. Valeyeva K, Belomyteseva, L, Khafizullin E (1975) Price Q, George J, Marr M, Myers C, Heindel J, Schwetz B Occupational bronchial asthma in employees engaged in the (1993) Developmental toxicity evaluation of ethylenediamine production of ethylenediamine. Aktual'nye Voprosy Gigieny (EDA) in New Zealand white rabbits. Teratology, 47:432–433. Truda Professional' -n Patologii i Toksikologii v Neftyanoi Nefte- khimicheskoi Promyshlennosti, 121–124. Provost T, Jillson O (1967) Ethylenediamine contact dermatitis. Archives of dermatology, 96:231–234. van Ginkel C (1989) Toxicity of ethylenediamine for Pseudomonas putida. Arnhem, Akzo Chemicals (Unpublished Robinson M, Fletcher E, Johnson G, Wyder W, Maurer J (1990) Report No. CRL F89091). Value of cutaneous basophil hypersensitivity (CBH) response for distinguishing weak contact sensitization from irritation reactions van Ginkel CG, Stroo CA (1989) Toxicity of ethylenediamine for in the guinea-pig. Journal of investigative dermatology, activated sludge. Arnhem, Akzo Chemicals (Unpublished Report 94:636–643. No. F89054).

Sarthy P (1983) Release of [3H] (-aminobutyric acid from glial van Ginkel CG, Kroon AGM, Mark U (1990) Algal inhibition test (Muller) cells of the rat retina: effects of K+, veratridine, and with ethylenediamine. Arnhem, Akzo Chemicals (Unpublished ethylenediamine. Journal of neuroscience, 3:2494–2503. Report No. F90086).

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Shehade S, Beck M, Hillier V (1991) Epidemiological survey of van Wijk R (1992) Environmental risk assessment of ethylene- standard series patch test results and observations on day 2 and diamine and diethylenetriamine wastewater discharges in the day 4 readings. Contact dermatitis, 24:119–122. Ems-Dollard estuary. Arnhem, Akzo Chemicals (Unpublished Report No. CRL F92009). Simon P, Terzian C, Frome B (1995) Skin reactions to topical aminophylline. Journal of the American Medical Association, van Wijk R, Postman J, Van Houwelingen H (1994) Joint toxicity 273:1737–1738. of ethyleneamines to algae, daphnids and fish. Environmental toxicology and chemistry, 13:167–171. Slesinski R, Guzzie P, Hengler W, Watanabe P, Woodside M, Yang R (1983) Assessment of genotoxic potential of Wall L (1982) Lymphatoid contact dermatitis due to ethylenedi- ethylenediamine: in vitro and in vivo studies. Mutation research, amine dihydrochloride. Contact dermatitis, 8:51–54. 124:299–314. Woodiwiss F, Fretwell G (1974) The toxicities of sewage Smyth H Jr, Seaton J, Fischer L (1941) The single dose toxicity effluents, industrial discharges and some chemical substances to of some glycols and derivatives. Journal of industrial hygiene brown trout in the Trent River Authority area. Water pollution and toxicology, 23:259–268. control (Great Britain), 73:396.

Smyth H Jr, Carpenter C, Weil C (1951) Range-finding toxicity Yang R, Tallant M (1982) Metabolism and pharmacokinetics of data: List IV. American Medical Association archives of ethylenediamine in the rat following oral, endotracheal or intra- industrial hygiene, 4:119–122. venous administration. Fundamental and applied toxicology, 2:252–260. Strain G, Flory W, Tucker T (1984) Inhibition of synaptosomal uptake of amino acid transmitters by diamines. Neuropharmacol- Yang R, Garman R, Maronpot R, McKelvey J, Weil C, Woodside ogy, 23:971–975. M (1983) Acute and subchronic toxicity of ethylenediamine in laboratory animals. Fundamental and applied toxicology, Takemoto S, Kuge Y, Nakamoto M (1981) The measurement of 3:512–520. BOD in sea water. Suishitsu Okagu Kenkyu [Japanese journal of water pollution research], 4:80–90. Yang R, Garman R, Maronpot R, Mirro E, Woodside M (1984a) Chronic toxicity/carcinogenicity study of ethylenediamine in Tas J, Weissberg D (1958) Allergy to aminophylline. Acta Fischer 344 rats. Toxicologist, 4:53. Allergologica, 12:39–42. Yang R, Tallant M, McKelvey J (1984b) Age-dependent Terzian C, Simon P (1992) Aminophylline hypersensitivity pharmacokinetic changes of ethylenediamine in Fischer 344 rats apparently due to ethylenediamine. Annals of emergency parallel to a two-year chronic toxicity study. Fundamental and medicine, 21:312–314. applied toxicology, 4:663–670.

Thorgeirsson A (1978) Sensitization capacity of epoxy resin Yang R, Anuszkiewicz C, Chu S, Garman R, McKelvey J, Tallant hardeners in the guinea pig. Acta Dermatologica, 58:332–336. M (1987) Biochemical and morphological studies on the percutaneous uptake of [14C]ethylenediamine in the rat. Journal Toal M, Kinney A, Fulton R (1992) Allergy to the of toxicology and environmental health, 20:261–272. ethylenediamine component of aminophylline. Ulster medical journal, 61:205–206. Zimmering S, Mason M, Valencia R, Woodruff R (1985) Chemical mutagenesis testing in Drosophila. II. Results of 20 Tonogai Y, Ogawa S, Ito Y, Iwaida M (1982) Actual survey on coded compounds tested for the National Toxicology Program. Tlm (median tolerance limit) values of environmental pollutants, Environmental mutagenesis, 7:87–100.

24 1,2-Diaminoethane (Ethylenediamine)

APPENDIX 1 — SOURCE DOCUMENTS APPENDIX 2 — CICAD PEER REVIEW

Brooke et al. (1997): 1,2-Diaminoethane (Risk The draft CICAD on 1,2-diaminoethane Assessment Document EH72/7) (ethylenediamine) was sent for review to institutions and organizations identified by IPCS after contact with IPCS national Contact Points and Participating Institutions, as well as The authors’ draft version of this Health and Safety to identified experts. Comments were received from: Executive report was initially reviewed internally by a group of approximately 10 Health and Safety Executive experts (mainly Akzo Novel nv, Arnhem, Netherlands toxicologists, but also scientists from other relevant disciplines, such as epidemiology and occupational hygiene). The Department of Health, London, United Kingdom toxicology section of the amended draft was then reviewed by toxicologists from the United Kingdom Department of Health. Environment Agency, Wallingford, United Kingdom Subsequently, the entire risk assessment document was reviewed by a tripartite advisory committee to the United Kingdom Health Ethyleneamines Product Stewardship Discussion Group, and Safety Commission, the Working Group for the Assessment Michigan, USA of Toxic Chemicals (WATCH). This committee is composed of experts in toxicology and occupational health and hygiene from Health Canada, Ottawa, Canada industry, trade unions, and academia. International Agency for Research on Cancer, Lyon, The members of the WATCH committee at the time of France the peer review were Mr Steve Bailey, Independent Consultant; Dr Hilary Cross, Trade Unions Congress; Mr David Farrar, National Chemicals Inspectorate (KEMI), Solna, Sweden Independent Consultant; Dr Tony Fletcher, Trade Unions Congress; Dr Alastair Hay, Trade Unions Congress; Dr Jenny National Institute for Working Life, Solna, Sweden Leeser, Chemical Industries Association; Dr Len Levy, Institute of Occupational Hygiene, Birmingham; Dr Mike Molyneux, National Institute of Public Health and Environmental Chemical Industries Association; Mr Alan Moses, Chemical Protection, Bilthoven, The Netherlands Industries Association; and Mr Jim Sanderson, Independent Consultant. Nofer Institute of Occupational Medicine, Lodz, Poland

United States Department of Health and Human Services BUA (1997): Ethylenediamine (GDCh-Advisory (National Institute for Occupational Safety and Health, Cincinnati, USA; National Institute of Environmental Committee on Existing Chemicals of Environ- Health Sciences, Research Triangle Park, USA) mental Relevance Report No. 184) United States Environmental Protection Agency (Office of For the BUA review process, the company that is in Research and Development, Washington, DC, USA) charge of writing the report (usually the largest producer in Germany) prepares a draft report using literature from an extensive literature search as well as internal company studies. This draft is subject to a peer review during several readings of a working group consisting of representatives from government agencies, the scientific community, and industry.

25 Concise International Chemical Assessment Document 15

APPENDIX 3 — CICAD FINAL REVIEW Dr B. Hansen,1 European Chemicals Bureau, European BOARD Commission, Ispra, Italy Mr T. Jacob,1 Dupont, Washington, DC, USA Tokyo, Japan, 30 June – 2 July 1998 Dr H. Koeter, Organisation for Economic Co-operation and Development, Paris, France Members Mr H. Kondo, Chemical Safety Policy Office, Ministry of International Trade and Industry, Tokyo, Japan Dr R. Benson, Drinking Water Program, United States Environ- mental Protection Agency, Denver, CO, USA Ms J. Matsui, Chemical Safety Policy Office, Ministry of International Trade and Industry, Tokyo, Japan Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden Mr R. Montaigne,1 European Chemical Industry Council (CEFIC), Brussels, Belgium Mr R. Cary, Health Directorate, Health and Safety Executive, Merseyside, United Kingdom Dr A. Nishikawa, Division of Pathology, National Institute of Health Sciences, Tokyo, Japan Dr C. DeRosa, Agency for Toxic Substances and Disease Registry, Center for Disease Control and Prevention, Atlanta, Dr H. Nishimura, Environmental Health Science Laboratory, GA, USA National Institute of Health Sciences, Osaka, Japan Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, Ms C. Ohtake, Chem-Bio Informatics, National Institute of Health United Kingdom Sciences, Tokyo, Japan Dr H. Gibb, National Center for Environmental Assessment, Dr T. Suzuki, Division of Food, National Institute of Health United States Environmental Protection Agency, Washington, Sciences, Tokyo, Japan DC, USA Dr K. Takeda, Mitsubishikasei Institute of Toxicological and Dr R.F. Hertel, Federal Institute for Health Protection of Environmental Sciences, Yokohama, Japan Consumers & Veterinary Medicine, Berlin, Germany Dr K. Tasaka, Department of Chemistry, International Christian Dr I. Mangelsdorf, Documentation and Assessment of Chemicals, University, Tokyo, Japan Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany Dr H. Yamada, Environment Conservation Division, National Research Institute of Fisheries Science, Kanagawa, Japan Ms M.E. Meek, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada (Chairperson) Dr M. Yamamoto, Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan (Vice-Chairperson) Dr M. Yasuno, School of Environmental Science, The University of Shiga Prefecture, Hikone, Japan Professor S.A. Soliman, Department of Pesticide Chemistry, Alexandria University, Alexandria, Egypt Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Ms D. Willcocks, Chemical Assessment Division, Worksafe Germany Australia, Camperdown, Australia (Rapporteur)

Professor P. Yao, Chinese Academy of Preventive Medicine, Institute of Occupational Medicine, Beijing, People’s Republic Secretariat of China Ms L. Regis, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Observers Mr A. Strawson, Health and Safety Executive, London, United Kingdom Professor F.M.C. Carpanini,1 Secretary-General, ECETOC (European Centre for Ecotoxicology and Toxicology of Dr P. Toft, Associate Director, International Programme on Chemicals), Brussels, Belgium Chemical Safety, World Health Organization, Geneva, Switzerland Dr M. Ema, Division of Biological Evaluation, National Institute of Health Sciences, Osakai, Japan

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

1 Invited but unable to attend.

26 1,2-Diaminoethane (Ethylenediamine)

RÉSUMÉ D’ORIENTATION ique et d’huiles de coupe. L’EDA est un produit de décomposition des éthylènebis(dithiocarbamates) utilisés comme fongicides. Ce CICAD relatif au 1,2-diaminoéthane (éthylène- diamine) a été préparé à partir d’une étude du Health and Il ne devrait pas y avoir d’effets atmosphériques Safety Executive du Royaume-Uni sur les risques pour la puisque la réaction de l’EDA avec les radicaux santé humaine (risques professionnels pour l’essentiel, hydroxyles est vraisemblablement rapide (demi-vie 8,9 h) mais comportant également un volet écologique) (Brooke et que la fraction volatilisée devrait être éliminée par les et al., 1997). La bibliographie sur laquelle s’appuie précipitations. Ce passage dans l’atmosphère à l’état de l’étude originale a été arrêtée à fin 1994. Une analyse de vapeur est probable à partir du sol, mais pas à partir de la littérature a été ensuite effectuée jusqu’à juillet 1997 à l’eau. L’EDA adhère fortement aux particules du sol par la recherche de données qui auraient pu être publiées attraction électrostatique; on pense qu’il ne devrait donc depuis la fin de l’étude. Les données relatives à la pas y avoir de passage dans les eaux souterraines par destinée du composé dans l’environnement et à son lessivage des sols. Il peut sans doute former des impact écologique sont tirées d’un rapport du Comité complexes avec les métaux et les acides humiques. La consultatif de la Société allemande de Chimie pour les voie de décomposition la plus probable dans substances chimiques d’intérêt écologique (BUA, 1997). l’environnement est la voie biologique et elle devrait être On trouvera à l’appendice 1 des indications sur les assez rapide; l’adaptation des microorganismes pourrait sources documentaires utilisées et sur leur mode de accélérer le processus. La décomposition est plus lente dépouillement. Les renseignements concernant l’examen dans l’eau de mer que dans l’eau douce. Il n’y a du CICAD par des pairs font l’objet de l’appendice 2. Ce probablement pas de bioaccumulation. CICAD a été approuvé en tant qu’évaluation internationale lors d’une réunion du Comité d’évaluation L’EDA présente une toxicité aiguë modérée pour finale qui s’est tenue à Tokyo (Japon) du 30 juin au 2 les animaux. C’est surtout une substance irritante, qui juillet 1998. La liste des participants à cette réunion est corrosive quand elle n’est pas diluée et qui provoque figure à l’appendice 3. La fiche d’information également une sensibilisation cutanée. On n’a pas internationale sur la sécurité chimique (ICSC No 0269) procédé à la recherche de son pouvoir mutagène dans établie par le Programme international sur la Sécurité les conditions prescrites par la réglementation actuelle et chimique (IPCS, 1993) est également reproduite dans ce on ne dispose pas non plus d’études sur son activité document. clastogène ou sur une action qui s’exercerait sur les cellules somatiques in vivo. Il n’existe donc pas de Le 1,2-diaminoéthane (No CAS 107-15-3), données suffisantes pour que l’on puisse se prononcer couramment désigné sous le nom d’éthylènediamine avec certitude sur le pouvoir mutagène éventuel de (EDA), est un produit de synthèse qui se présente sous l’EDA. Quoi qu’il en soit, le composé ne s’est pas révélé la forme d’un liquide incolore à jaunâtre dans les condi- cancérogène chez l’animal. On a observé des effets non tions normales de température et de pression. Il présente néoplasiques au niveau du foie (modifications pléo- une réaction fortement alcaline et il est miscible à l’eau et morphes des hépatocytes) chez des rats auxquels on à l’alcool. On l’utilise principalement comme intermé- avait fait ingérer du 1,2-diaminoéthane pendant 2 ans. diaire dans la fabrication de la tétra-acétyl-éthylène- Ces effets ont été observés à des doses quotidiennes diamine, de l’acide éthylènediamine-tétra-acétique supérieures ou égales à 45 mg d’EDA par kg de poids (EDTA), des floculants organiques, des résines à base corporel, aucune anomalie ne se manifestant à la dose d’urée et des diamides gras. Dans des proportions beau- quotidienne de 9 mg par kg de poids corporel. On voit coup plus faibles, il entre également dans la composition pas très clairement ce que cette observation peut de formulations destinées à la fabrication des supports signifier pour la santé humaine et l’on ne peut d’ailleurs de circuits imprimés ou utilisées dans l’industrie de pas se prononcer non plus sur le point de savoir si les finissage des métaux. Il peut aussi être utilisé comme effets rapportés sont effectivement dus à l’ingestion de accélérateur ou agent de réticulation dans les résines l’EDA (par exemple, ils pourraient ne pas se produire si époxy employées notamment comme revêtements ainsi on changeait la voie d’administration ou être liés à des que pour la préparation de certains produits pharma- effets de premier passage), mais on ne peut les négliger ceutiques. L’EDA est présent sous la forme d’impureté pour autant et il faut déterminer les conditions de leur (<0,5 %) dans les amines grasses du commerce utilisées apparition. Lors d’études où le composé a été administré comme agents mouillants dans les émulsions bitumi- par gavage, on a observé des effets oculaires chez le rat neuses. On l’emploie également dans la synthèse des (atrophie rétinienne et à dose élevée, formation de fongicides à base de carbamates, dans la fabrication des cataractes) à des doses quotidiennes supérieures ou agents de surface et des colorants ainsi que dans la égales à 100 mg par kg de poids corporel. Chez des rats préparation de produits de développement photograph- et des souris, on a constaté la présence de lésions

27 Concise International Chemical Assessment Document 15 rénales aux doses quotidiennes respectives de 200 et 100 de former des complexes avec les ions métalliques. Ses mg de composé par kg de poids corporel et au-delà. On a effets pourraient donc être indirects et résulter de ce que également trouvé quelques indices d’effets sur la rate certains éléments essentiels cessent alors d’être biodis- chez des souris et des rats à des doses quotidiennes ponibles. Pour les invertébrés et les poissons, la valeur supérieures ou égales à 400 mg d’EDA par kg de poids de la CL50 va de 14 à >1000 mg/litre. On a trouvé une corporel, de même que chez des rats, au niveau du valeur de 0,16 mg/litre pour la dose sans effet observable thymus, à la dose quotidienne de 800 mg/kg de poids (NOEC) sur la reproduction de Daphnia. corporel. Les études d’inhalation effectuées sur des rats n’ont pas permis d’observer d’effets à la dose d’environ Etant donné que les résultats des épreuves de 150 mg/m3 (60 ppm) et le seul effet imputable au traite- toxicité aiguë et chronique varient très largement, on a ment a été une légère dépilation à la dose d’environ fixé à 16 :g/litre la valeur de la concentration sans effet 330 mg/m3 (132 ppm). observable prévisible (PNEC), en appliquant un coeffi- cient d’incertitude de 10 à la valeur publiée la plus faible Comme l’EDA a un effet irritant et sensibilisateur de la concentration sans effet observable (NOEC) sur la sur l’épiderme, il pourrait y avoir un risque d’apparition reproduction de Daphnia. Des hypothèses prudentes de dermatites d’irritation ou de dermatites allergiques si relatives à la concentration prévisible dans l’environne- l’on porte pas d’équipement protecteur individuel sur les ment (PEC) permettent d’aboutir à une valeur du rapport lieux de travail où il y a possibilité de contact cutané. PEC/PNEC justifiant quelques craintes eu égard aux L’EDA peut également provoquer une hypersensibilité concentrations initiales (par ex. lors de la décharge des voies respiratoires et de l’asthme chez les personnes initiale dans un cours d’eau ou un estuaire). Néanmoins, professionnellement exposées et c’est d’ailleurs cet effet une estimation plus élaborée de l’exposition probable que l’on considère comme le plus préoccupant sur le indique un faible risque pour les organismes aquatiques. plan sanitaire.

On ne sait pas avec exactement par quel mécan- isme se développe cet état d’hypersensibilité, mais le pouvoir sensibilisateur cutané de l’EDA et les quelques indications dont on dispose sur l’existence d’une com- posante immunologique chez les ouvriers souffrant d’un asthme provoqué par ce composé, incitent à penser que ce mécanisme serait justement de nature immunologique. Quoi qu’il en soit et quel que puisse être la nature du mécanisme en question, les données disponibles ne permettent pas de mettre en évidence une relation dose- réponse ou de déterminer le seuil d’apparition d’un état d’hypersensibilité ou d’une réaction asthmatiforme. Dans le présent document, le risque imputable au composé est caractérisé par des effets hépatiques dont on a évalué la probabilité chez des sujets exposés à l’EDA de par leur profession, le but étant d’apprécier le risque d’autres effets généraux. La conclusion en est que lorsque 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 valeur sans effet observable (NOEL) chez le rat et que, par conséquent, des effets hépatiques indésirables sont improbables.

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

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

28 1,2-Diaminoethane (Ethylenediamine)

RESUMEN DE ORIENTACIÓN No cabe prever efectos atmosféricos, puesto que la reacción de la EDA con los radicales hidroxilo es probablemente rápida (semivida de 8,9 horas) y se Este CICAD sobre el 1,2 diaminoetano (etilen- supone que la EDA volatilizada se arrastra. Es probable diamina) se basa en un examen de los problemas la volatilización a la atmósfera a partir del suelo, pero no relativos a la salud humana (fundamentalmente del agua. Se adsorbe fuertemente a las partículas del ocupacional, pero con la inclusión también de una suelo mediante enlaces electrostáticos; no parece haber evaluación en el medio ambiente) preparado por la lixiviación a través de los perfiles del suelo hacia el agua Dirección de Salud y Seguridad del Reino Unido (Brooke freática. Es posible la formación de complejos con et al., 1997). En el documento original se incorporaron los metales y ácidos húmicos. La biodegradación es el datos obtenidos hasta el final de 1994. Se realizó mecanismo más probable de descomposición en el medio asimismo una búsqueda bibliográfica amplia hasta julio ambiente y debería ser bastante rápida; la adaptación de de 1997 para identificar cualquier información que se los microorganismos puede aumentar la degradación. La hubiera publicado después de la terminación del informe. descomposición es menos rápida en el agua de mar que La información sobre el destino y los efectos en el medio en el agua dulce. No es probable la bioacumulación. ambiente se basa en el informe del Comité Consultivo sobre Sustancias Químicas Existentes Importantes para La toxicidad aguda de la EDA en los animales es el Medio Ambiente de la Sociedad Alemana de Química moderada. Es irritante primario, de propiedades corrosi- (BUA, 1997). La información sobre la preparación del vas cuando no está diluido, y es también sensibilizador documento original y su examen colegiado figura en el cutáneo. La EDA no se ha sometido a pruebas de apéndice 1. La información acerca del examen colegiado mutagenicidad con arreglo a las normas reglamentarias de este CICAD se presenta en el apéndice 2. Este CICAD actuales y no se han realizado valoraciones para se aprobó como evaluación internacional en una reunión determinar la actividad clastogénica o el potencial para de la Junta de Evaluación Final celebrada en Tokio, expresar su actividad en células somáticas in vivo. Así Japón, del 30 de junio al 2 de julio de 1998. La lista de pues, no se dispone de información suficiente para llegar participantes en esta reunión figura en el apéndice 3. La a conclusiones firmes sobre el potencial mutagénico de Ficha internacional de seguridad química (ICSC 0269), la EDA. No fue carcinogénico en animales. Se han preparada por el Programa Internacional de Seguridad de observado efectos no neoplásicos en el hígado de ratas las Sustancia Químicas (IPCS, 1993), también se (cambios pleomórficos a hepatocitos), tras la administra- reproduce en este documento. ción oral durante dos años con concentraciones de 45 mg de EDA/kg de peso corporal al día y superiores, El 1,2-diaminoetano (CAS Nº 107-15-3), conocido sin que se vieran efectos con 9 mg EDA/kg de peso normalmente como etilendiamina (EDA), es un líquido corporal al día. Aunque no está clara la importancia de sintético entre incoloro y amarillento a temperatura y estos cambios de las células hepáticas para la salud presión normales. Es fuertemente alcalino y miscible con humana, así como si son consecuencia de la exposición agua y con alcohol. Se utiliza fundamentalmente como oral o no (es decir, podrían no producirse por otras vías, intermediario en la fabricación de tetracetil etilendiamina, porque pueden estar relacionados con los efectos del ácido etilendiaminotetracético (EDTA), floculantes primer paso), no se pueden ignorar y se debería orgánicos, resinas de urea y bisamidas grasas. También caracterizar el riesgo de su aparición. En estudios de se usa, en proporción mucho menor, en la producción de administración oral por sonda se observaron efectos formulaciones con destino a las industrias de tarjetas de oculares en las ratas (atrofia de la retina y con dosis más circuitos impresos y acabado de metales, como agente altas formación de cataratas) con dosis de 100 mg de acelerador o de curado en revestimientos/resinas de EDA/kg de peso corporal al día y superiores. Las dosis epóxido y en la fabricación de productos farmacéuticos. de 200 mg y 100 mg de EDA/kg de peso corporal al día y Se encuentra como contaminante (<0,5%) en las aminas superiores se asociaron con daños renales en ratas y grasas de suministro comercial, que se utilizan como ratones, respectivamente. También se encontraron agentes humectantes en emulsiones bituminosas. signos de efectos en el bazo de ratones y ratas con dosis También se emplea en la síntesis de fungicidas a base de de 400 mg de EDA/kg de peso corporal al día y carbamato, en la fabricación de surfactantes y tintes y en superiores y en el timo de ratas con 800 mg/kg de peso productos químicos para el revelado fotográfico, así corporal al día. En estudios de inhalación realizados con como en lubricantes para cuchillas. La EDA es un ratas no se detectaron efectos con concentraciones de producto de la degradación de los fungicidas de unos 150 mg/m3 (60 ppm), y con 330 mg/m3 (132 ppm) el etilenbis(ditiocarbamato). único efecto relacionado con la dosis fue una ligera depilación.

29 Concise International Chemical Assessment Document 15

Puesto que la EDA diluida es irritante y sensibi- PEC/PNEC que ponen de manifiesto alguna preocu- lizador cutáneo, si en el lugar de trabajo no se utiliza un pación a partir de concentraciones iniciales (es decir, en equipo de protección personal adecuado y se produce el primer vertido en el río o el estuario). Sin embargo, un contacto cutáneo se corre el riesgo de contraer una estimaciones más precisas de la exposición indican un dermatitis irritante y/o alérgica. La EDA puede inducir riesgo escaso para los organismos acuáticos. además un estado de hipersensibilidad de las vías respiratorias y provocar asma en el entorno ocupacional, y se considera que éste es el efecto en la salud que despierta mayor preocupación.

No se ha demostrado el mecanismo de inducción de la hipersensibilidad, aunque el potencial de sensibi- lización cutánea de la EDA y las pruebas limitadas de actuación inmunitaria en los trabajadores con asma a causa de esta sustancia hacen pensar en un mecanismo inmunitario. Sin embargo, con independencia del mecanismo de que se trate, los datos disponibles no permiten dilucidar las relaciones dosis-respuesta o identificar los umbrales para la inducción del estado de hipersensibilidad o la provocación de una respuesta asmática. A fin de determinar los riesgos de otros efectos sistémicos, en la caracterización del riesgo de muestras en este documento se evaluó el riesgo de efectos hepáticos en personas con exposición ocupacional. Se ha llegado a la conclusión de que, cuando la EDA se utiliza en sistemas cerrados, la exposición, tanto medida como pronosticada a partir de modelos, es fundamentalmente inferior (100 veces o más) a la concentración sin efectos observados (NOEL) en ratas; así pues, son poco probables los efectos hepáticos adversos.

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

El umbral tóxico para los microorganismos puede ser de sólo 0,1 mg de EDA/litro. Sin embargo, las pruebas de toxicidad en medios de cultivo se han de interpretar con precaución, porque la EDA puede formar complejos con iones metálicos. Por consiguiente, los efectos pueden ser indirectos debido a una pérdida de biodisponibilidad de elementos esenciales. Las CL50 para invertebrados y peces oscila entre 14 y >1000 mg/litro. Se ha notificado una concentración sin efectos observados (NOEC) para la reproducción en Daphnia de 0,16 mg/litro.

Habida cuenta de la gran variedad de resultados de las pruebas de toxicidad aguda y crónica, se determinó una concentración prevista sin efectos observados (PNEC) para los organismos acuáticos de 16 :g/litro, basada en la aplicación de un factor de incertidumbre de 10 a la NOEC más baja notificada para la reproducción de Daphnia. Hipótesis prudentes para la concentración prevista en el medio ambiente (PEC) establecen razones

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