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    Concise International Chemical Assessment Document 15








    1,2-DIAMINOETHANE (ETHYLENEDIAMINE)









    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



    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),
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    Environment Programme (UNEP), the International Labour Organisation
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    the risk to human health and the environment from exposure to
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    sound management of chemicals in relation to human health and the
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    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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    TABLE OF CONTENTS

    FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels
         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure
         8.2. Irritation and sensitization
         8.3. Short-term exposure
         8.4. Long-term exposure
              8.4.1. Subchronic exposure
              8.4.2. Chronic exposure and carcinogenicity
         8.5. Genotoxicity and related end-points
         8.6. Reproductive and developmental toxicity
         8.7. Immunological and neurological effects

    9. EFFECTS ON HUMANS

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    11. EFFECTS EVALUATION

         11.1. Evaluation of health effects
              11.1.1. Hazard identification and dose-response assessment
              11.1.2. Criteria for setting guidance values for EDA
              11.1.3. Sample risk characterization
         11.2. Evaluation of environmental effect

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         13.1. Human health hazards
         13.2. Advice to physicians
         13.3. Health surveillance advice
         13.4. Spillage

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

    INTERNATIONAL CHEMICAL SAFETY CARD

    REFERENCES

    APPENDIX 1 -- SOURCE DOCUMENTS

    APPENDIX 2 -- CICAD PEER REVIEW

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    RÉSUMÉ D'ORIENTATION

    RESUMEN DE ORIENTACION
    

    FOREWORD

         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
    Programme on Chemical Safety (IPCS) -- a cooperative programme of the
    World Health Organization (WHO), the International Labour Organisation
    (ILO), and the United Nations Environment Programme (UNEP). CICADs
    join the Environmental Health Criteria documents (EHCs) as
    authoritative documents on the risk assessment of chemicals.

         CICADs are concise documents that provide summaries of the
    relevant scientific information concerning the potential effects of
    chemicals upon human health and/or the environment. They are based on
    selected national or regional evaluation documents or on existing
    EHCs. Before acceptance for publication as CICADs by IPCS, these
    documents undergo extensive peer review by internationally selected
    experts to ensure their completeness, accuracy in the way in which the
    original data are represented, and the validity of the conclusions
    drawn.

         The primary objective of CICADs is characterization of hazard and
    dose-response from exposure to a chemical. CICADs are not a summary of
    all available data on a particular chemical; rather, they include only
    that information considered critical for characterization of the risk
    posed by the chemical. The critical studies are, however, presented in
    sufficient detail to support the conclusions drawn. For additional
    information, the reader should consult the identified source documents
    upon which the CICAD has been based.

         Risks to human health and the environment will vary considerably
    depending upon the type and extent of exposure. Responsible
    authorities are strongly encouraged to characterize risk on the basis
    of locally measured or predicted exposure scenarios. To assist the
    reader, examples of exposure estimation and risk characterization are
    provided in CICADs, whenever possible. These examples cannot be
    considered as representing all possible exposure situations, but are
    provided as guidance only. The reader is referred to EHC 1701 for
    advice on the derivation of health-based guidance values.

         While every effort is made to ensure that CICADs represent the
    current status of knowledge, new information is being developed
    constantly. Unless otherwise stated, CICADs are based on a search of
    the scientific literature to the date shown in the executive summary.
    In the event that a reader becomes aware of new information that would
    change the conclusions drawn in a CICAD, the reader is requested to
    contact IPCS to inform it of the new information.
                 
    1 International Programme on Chemical Safety (1994)
        Assessing human health risks of chemicals: deriviation of guidance
        values for health-based exposure limits. Geneva, World Health
       Organization (Environmental Health Criteria 170).

    Procedures

         The flow chart shows the procedures followed to produce a CICAD.
    These procedures are designed to take advantage of the expertise that
    exists around the world -- expertise that is required to produce the
    high-quality evaluations of toxicological, exposure, and other data
    that are necessary for assessing risks to human health and/or the
    environment.

         The first draft is based on an existing national, regional, or
    international review. Authors of the first draft are usually, but not
    necessarily, from the institution that developed the original review.
    A standard outline has been developed to encourage consistency in
    form. The first draft undergoes primary review by IPCS to ensure that
    it meets the specified criteria for CICADs.

         The second stage involves international peer review by scientists
    known for their particular expertise and by scientists selected from
    an international roster compiled by IPCS through recommendations from
    IPCS national Contact Points and from IPCS Participating Institutions.
    Adequate time is allowed for the selected experts to undertake a
    thorough review. Authors are required to take reviewers' comments into
    account and revise their draft, if necessary. The resulting second
    draft is submitted to a Final Review Board together with the
    reviewers' comments.

         The CICAD Final Review Board has several important functions:

    -    to ensure that each CICAD has been subjected to an appropriate
         and thorough peer review;
    -    to verify that the peer reviewers' comments have been addressed
         appropriately;
    -    to provide guidance to those responsible for the 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.

    Board members serve in their personal capacity, not as representatives
    of any organization, government, or industry. They are selected
    because of their expertise in human and environmental toxicology or
    because of their 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
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    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.

    FIGURE 

    1.  EXECUTIVE SUMMARY


         This CICAD on 1,2-diaminoethane (ethylenediamine) was based on a
    review of human health concerns (primarily occupational, but also
    including an environmental assessment) prepared by the United
    Kingdom's Health and Safety Executive (Brooke et al., 1997). Data
    identified up to the end of 1994 were covered in the original review.
    An additional literature search up to July 1997 was conducted to
    identify any new information that had been published since the review
    was completed. Information on environmental fate and effects was based
    on the report of the German Chemical Society's Advisory Committee on
    Existing Chemicals of Environmental Relevance (BUA, 1997). The
    preparation and peer review of the source documents are described in
    Appendix 1. Information on the peer review of this CICAD is presented
    in Appendix 2. This CICAD was approved as an international assessment
    at a meeting of the Final Review Board, held in Tokyo, Japan, on
    30 June - 2 July 1998. Participants at the Final Review Board meeting
    are listed in Appendix 3. The International Chemical Safety Card (ICSC
    0269) produced by the International Programme on Chemical Safety
    (IPCS, 1993) has also been reproduced in this document. 

         1,2-Diaminoethane (CAS No. 107-15-3), commonly known as
    ethylenediamine (EDA), is a synthetic colourless to yellowish liquid
    at normal temperature and pressure. It is strongly alkaline and is
    miscible with water and alcohol. The main use for EDA is as an
    intermediate in the manufacture of tetraacetyl ethylenediamine,
    ethylenediaminetetraacetic acid (EDTA), organic flocculants, urea
    resins, and fatty bisamides. It is also used, to a much smaller
    extent, in the production of formulations for use in the printed
    circuit board and metal finishing industries, as an accelerator/curing
    agent in epoxy coatings/resins, and in the manufacture of
    pharmaceutical products. EDA is present as a contaminant (<0.5%) in
    commercially supplied fatty amines, which are used as wetting agents
    in bituminous emulsions. It is also used in the synthesis of carbamate
    fungicides, in surfactant and dye manufacture, and in photography
    development chemicals and cutting oils. EDA is a degradation product
    of ethylenebis(dithiocarbamate) fungicides.

         No atmospheric effects are expected, as reaction of EDA with
    hydroxyl radicals is likely to be rapid (half-life 8.9 h), and washout
    of volatilized EDA is expected. Volatilization to the atmosphere is
    likely from soil but not from water. Adsorption to soil particulates
    is strong through electrostatic binding; leaching through soil
    profiles to groundwater is not expected. Complex formation with metals
    and humic acids is expected. Biodegradation is the most likely source
    of breakdown in the environment and should be quite rapid; adaptation
    of microorganisms may improve degradation. Breakdown is less rapid in
    seawater than in fresh water. Bioaccumulation is unlikely.

         EDA has moderate acute toxicity in animals. It is a primary
    irritant, being corrosive when undiluted, and is also a skin
    sensitizer. EDA has not been tested for mutagenicity to current
    regulatory standards, and there are no assays for clastogenic activity
    or for the potential to express activity in somatic cells  in vivo.
    Thus, there is insufficient information to draw firm conclusions
    regarding the mutagenic potential of EDA. EDA was not carcinogenic in
    animals. Non-neoplastic effects on the liver (pleomorphic changes to
    hepatocytes) have been observed in rats following oral dosing for 2
    years at 45 mg EDA/kg body weight per day and above, with no effects
    seen at 9 mg EDA/kg body weight per day. Although the significance of
    these hepatic cell changes for human health is unclear, as well as
    whether or not they are a consequence of oral exposure (i.e., they
    might not occur via other routes, as they may be related to first-pass
    effects), they cannot be discounted, and the risk of their development
    should be characterized. In oral gavage dosing studies, effects on the
    rat eye (retinal atrophy and, at higher doses, cataract formation)
    were observed at doses of 100 mg EDA/kg body weight per day and above.
    Doses of 200 and 100 mg EDA/kg body weight per day and above were
    associated with renal damage in rats and mice, respectively. There was
    also some indication of effects in the spleen in mice and rats at
    doses of 400 mg EDA/kg body weight per day and above and in the thymus
    in rats at 800 mg/kg body weight per day. In inhalation studies, no
    effects were seen in rats at about 150 mg/m3 (60 ppm), and slight
    depilation was the only treatment-related effect observed at about 330
    mg/m3 (132 ppm).

         Because diluted EDA is a skin irritant and a skin sensitizer,
    there may be a risk of developing irritant and/or allergic dermatitis
    if suitable personal protective equipment is not used in the
    occupational environment where skin contact can occur. EDA is also
    capable of inducing a state of respiratory tract hypersensitivity and
    provoking asthma in the occupational environment, and this is
    considered to be the major health effect of concern.

         The mechanism for the induction of the hypersensitive state is
    not proven, although the skin sensitizing potential of EDA and the
    limited evidence of immunological involvement in workers with
    EDA-provoked asthma are suggestive of an immunological mechanism.
    However, irrespective of the mechanism involved, the available data do
    not allow either elucidation of dose-response relationships or
    identification of the thresholds for induction of the hypersensitive
    state or provocation of an asthmatic response. The sample risk
    characterization in this document has, in order to assess the risks of
    other systemic effects, evaluated the risk of hepatic effects in
    occupationally exposed individuals. It concludes that when EDA is used
    in closed systems, the exposure, both measured and predicted from
    models, is substantially (by 100-fold or greater) less than the
    no-observed-effect level (NOEL) in rats; thus, adverse effects on the
    liver are unlikely.

         Exposure of the general public to EDA could not be evaluated
    owing to the lack of available data.

         Toxic thresholds for microorganisms may be as low as 0.1 mg
    EDA/litre. However, toxicity tests in culture 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 from 14 to
    >1000 mg/litre. A no-observed-effect concentration (NOEC) for
     Daphnia reproduction has been reported at 0.16 mg/litre.

         Given the wide range of acute and chronic test results, a
    predicted no-effect concentration (PNEC) for aquatic organisms was
    taken as 16 µg/litre, based on application of an uncertainty factor of
    10 to the lowest reported NOEC for  Daphnia reproduction.
    Conservative assumptions for predicted environmental concentration
    (PEC) produce PEC/PNEC ratios indicating some concern from initial
    concentrations (i.e., at first release into the river or estuary).
    However, more refined exposure estimates indicate low risk to aquatic
    organisms.
    

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         1,2-Diaminoethane (CAS No. 107-15-3) is more commonly known as
    ethylenediamine, with EDA used as a common abbreviation. Other common
    synonyms include dimethylenediamine, 1,2-ethanediamine,
    1,2-ethylenediamine, beta-aminoethylamine, and ethane-1,2-diamine.
    EDA's structural formula is shown below:

    CHEMICAL STRUCTURE 

         EDA is a colourless to yellowish hygroscopic liquid with an
    ammonia-like odour. Its molecular weight is 60.12. It is a strongly
    alkaline (pH of 25% EDA in water is 11.9), very volatile, pungent
    material, which fumes profusely in air. It has a melting point of
    about 8.5°C, a 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 and alcohol.
    The log octanol/water partition coefficient (log  Kow) ranges from
    -1.2 to -1.52. p Ka1 and p Ka2 (calculated) are 10.71 and 7.56,
    respectively, indicating protonation at environmentally relevant pH.
    Additional physical/chemical properties are presented in the
    International Chemical Safety Card reproduced in this document.

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

         1 ppm = 2.50 mg/m3
         1 mg/m3 = 0.40 ppm
    

    3.  ANALYTICAL METHODS

         For monitoring concentrations of EDA in workplace air, NIOSH
    (1984-1989) uses a method that employs adsorption on silica gel and
    analysis by gas chromatography with flame ionization detection. A
    solvent-free sampling system is preferable because of more convenient
    handling, and it is a great advantage if derivatization can be
    achieved directly on the absorbent. The Health and Safety Laboratories
    of the United Kingdom's Health and Safety Executive have evaluated a
    published method (Andersson et al., 1985; Levin et al., 1989; Patel &
    Rimmer, 1996). Air is sampled onto
    1-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 5-litre air sample. The detection limit was found
    to be 0.08 mg/m3. The method generally meets the Comité Européen de
    Normalisation requirements on the overall uncertainty. Although the
    Comité Européen de Normalisation requirements for desorption
    efficiency were not satisfied at 25 and 50 mg/m3, a smaller sample
    can be taken if necessary.

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

         EDA can be measured in water using reverse-phase high-performance
    liquid chromatography with ultraviolet detection at 315 nm, following
    derivatization with acetylacetone. The limit of detection was reported
    to be 0.26 µg/litre (Nishikawa, 1987).
    

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         EDA is not known to occur naturally. The main use for EDA is as
    an intermediate in the manufacture of tetraacetyl ethylenediamine,
    EDTA, organic flocculants, urea resins, and fatty bisamides. It is
    also used, to a much smaller extent, in the production of formulations
    for use in the printed circuit board and metal finishing industries,
    as an accelerator/curing agent in epoxy coatings/resins, and in the
    manufacture of pharmaceutical products. EDA is also present as a
    contaminant (<0.5%) in commercially supplied fatty amines, which are
    used as wetting agents in bituminous emulsions. It is also used in the
    synthesis of carbamate fungicides, in surfactant and dye manufacture,
    and in photography development chemicals and cutting oils. These are
    believed to be minor uses in the United Kingdom and were not
    investigated in this review. EDA is a degradation product of
    ethylenebis(dithiocarbamate) fungicides.

         Approximately 11 000 tonnes of EDA are imported into the United
    Kingdom each year, with very little being re-exported (Brooke et al.,
    1997). World production amounts to 100 000-500 000 tonnes annually.1
    In 1992, annual production capacities were 18 000 tonnes for Germany,
    54 000 tonnes for the Netherlands, 30 000 tonnes for Belgium, 25 000
    tonnes for Sweden, about 159 000 tonnes for the United States, and
    15 000 tonnes for Japan (BUA, 1997).

         No measured concentrations of EDA in wastewater streams from
    manufacture and use are available. However, estimates of EDA entering
    waste treatment from four European manufacturing plants were 200, 287,
    5000-10 000, and 1000 kg/year. Use in photochemicals was estimated to
    lead to 1.1 tonnes being introduced into municipal sewage treatment
    plants in Germany. All figures are for 1992 or 1993 (BUA, 1997).

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


    

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         Few experimental data are available on the distribution,
    transport, or fate of EDA in the environment. However, qualitative,
    and some quantitative, estimates have been made on the basis of its
    physicochemical properties.

         EDA has a moderately high vapour pressure and is expected to
    volatilize from soil (HSDB, 1997). In the atmosphere, it should react
    rapidly with photochemically produced hydroxyl radicals; no
    experimental rates are available for this proposed reaction, but a
    half-life of 8.9 h has been calculated.1 EDA may react with carbon
    dioxide to form an insoluble carbamate. The high water solubility of
    EDA means that volatilized chemical is also likely to be washed out by
    rain.2 The calculated dimensionless Henry's law constant (air/water
    partition coefficient) is extremely low (7.08 × 10-8); therefore,
    little evaporation would be expected from water. A half-life for
    volatilization of 45 years was estimated for a model river 1 m
    deep.2 An approximate Henry's law constant is given in BUA (1997) as
    1.77 × 10-4 Pa.m3/mol.

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

         Despite their miscibility with water, ethyleneamines can bind
    strongly to soil. There was a wide range of determined adsorption
    coefficients in experimental studies on six soil types (Table 1). Some
    reduction in variability occurred when results were normalized for
    organic carbon content, although this was less marked with EDA than
    with the other ethyleneamine studied. Sorption to soil was rapid, with
    equilibrium occurring within a few hours. Electrostatic interaction
    between the positively charged ethyleneamine and negatively charged
    soils appeared to be the dominant factor in binding. Complex formation
    with metals and humic acids is expected. Sorption is greater to soils
    with high cation exchange capacity (Davis, 1993).

         EDA at 200 mg/litre was incubated with adapted sewage sludge
    until there was no further decrease in chemical oxygen demand (COD);
    at that time (unspecified), 97.5% of the chemical had been degraded.
    The rate 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 biodegradation was determined
    5, 10, 15, and 20 days 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 not possible to
    conclude definitively that adaptation improves degradation. Nitrate
    and nitrite were measured throughout the incubation to correct for
                          
    1  IUCLID (European Union database), 1st ed., 1996.
    2  Syracuse Research Corporation modelling, summarized in HSDB
       (1997).

    oxygen demand due to conversion of ammonia or organic nitrogen to 
    these species. Such a correction was necessary for EDA alone out of
    more than 50 compounds tested. Degradation was also tested in a
    salt-water system using non-adapted sludge; EDA was degraded less
    effectively, with 16% of theoretical degradation after 20 days (Price
    et al., 1974). A comparable value at 16.6% was measured in seawater by
    Takemoto et al. (1981). EDA incubated with microorganisms isolated
    from river water and adapted to the compound over 28 days showed >80%
    degradation relative to theoretical oxygen demand over 10 days (Mills
    & Stack, 1955).

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

         The high water solubility and low octanol/water partition
    coefficient indicate that bioaccumulation in organisms is unlikely.

                  
    1  Unpublished report from Akzo Research to Delamine, 1989 (cited in
       IUCLID).


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

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

    Sandy loam (Londo)          7.2        9.2                              0.026             69                      2700
    Sandy clay loam             7.3        16.4                             0.039             220                     5600
    Sandy loam (Cecil)          6.0        3.0                              0.014             29                      2100
    Silty loam                  6.0        15.6                             0.034             238                     7100
    Clay                        7.9        11.9                             0.014             70                      5000
    Aquifer sand                9.6        6.9                              0.0024            15                      6200
                                                                                                                                               

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


    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

         There are no reports of monitoring of EDA levels in the aquatic
    environment or of measurements in effluents.

         Residues of EDA in soil, 15 days post-treatment with the
    fungicide maneb, have been reported at 0.119 mg/kg for the top 1 cm
    (approximately) and at 0.044 mg/kg down to about 5 cm. Residues on
    tomatoes and beans were 0.053 and 0.239 mg/kg, respectively,
    immediately after spraying, falling to 0.047 and 0.094 mg/kg,
    respectively, after 14 days (Newsome et al., 1975).

    6.2  Human exposure

         The data available to the authors of this document are restricted
    mainly to the occupational environment. The exposure assessments used
    in this report are based on either limited data or data modelled using
    the Estimation and Assessment of Substance Exposure (EASE) model. This
    is a general-purpose predictive model developed by the United
    Kingdom's Health and Safety Executive for exposure assessment in the
    workplace. In its present form, the model is in widespread use across
    the European Union for the occupational exposure assessment of new and
    existing substances. Similarly, information on control measures has
    been derived from United Kingdom industry sources. Where data gaps
    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 intermediate in the manufacture of
    tetraacetyl ethylenediamine, EDTA, organic flocculants, urea resins,
    and fatty bisamides, it is estimated that 140 employees will be
    potentially exposed. During the production of formulations for use in
    the printed circuit board and metal finishing industries and in the
    manufacture of epoxy coatings/resins and pharmaceutical products, it
    is estimated that 200 employees will be regularly exposed to 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
    industrial epoxy coatings/adhesives are applied, and this activity has
    the potential to expose several thousand employees across a wide range
    of industries.

         There are very few measured occupational exposure data available.
    EDA's use as an intermediate in chemical synthesis takes place in
    closed systems. Measured exposures for these manufacturing processes
    show that control is achieved to a level of less than 1.25 mg/m3
    (0.5 ppm) 8-h time-weighted average (Hansen et al., 1984). Modelled
    data (EASE) are in good agreement, predicting comparable values of
    0.53-1.3 mg/m3 (0.21-0.52 ppm). Short-term peak exposures (sampling
    and hose uncoupling operations) were predicted to range between 16.8
    and 33.3 mg/m3 (6.7 and 13.3 ppm), 15-min time-weighted average.

         EDA's use in the production of formulations usually takes place
    in well-ventilated enclosed systems. Measured exposure data are not
    available for these processes. However, modelled exposure data
    indicate exposure levels of 5-20 mg/m3 (2-8 ppm) 8-h time-weighted
    average in the presence of local exhaust ventilation and 38-75 mg/m3
    (15-30 ppm) 8-h time-weighted average in the absence of local exhaust
    ventilation. Corresponding short-term peak exposures during mixer
    charging operations were estimated to be 5-25 mg/m3 (2-10 ppm) 15-min
    time-weighted average in the presence of local exhaust ventilation and
    50-103 mg/m3 (20-41 ppm) 15-min time-weighted average in the absence
    of local exhaust ventilation.

         The potential for exposure during the use of EDA formulations
    will be moderated by the low concentration of EDA present in the
    formulations. Very few exposure data are available, and there is scope
    for widely different use scenarios. There will be no appreciable
    occupational exposure if these products are used in enclosed
    ventilated systems as indicated by measured exposure data 
    (<2.5 mg/m3 [<1 ppm] 8-h time-weighted average) and modelled exposure 
    data (0-0.25 mg/m3 [0-0.1 ppm] 8-h time-weighted average). Modelled
    exposure data for immersion processes, in the presence of local
    exhaust ventilation, predicted inhalation exposures of 0.5-2.5 mg/m3
    (0.2-1 ppm) 8-h time-weighted average. The potential for greatest
    inhalation exposure was predicted for situations where these
    formulations are brushed in open systems with only general dilution
    ventilation or sprayed in open systems in the presence of local
    exhaust ventilation. Under these conditions, modelled exposure data
    predict exposures in the range 2.5-5 mg/m3 (1-2 ppm) 8-h
    time-weighted average. Short-term peak exposures during mixing and
    loading operations were estimated to be 5-10 mg/m3 (2-4 ppm) 15-min
    time-weighted average. Polyamines and alkanol polyamines, including
    EDA, have been reported to be released 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).

         There will also be a potential for dermal exposure across the
    full range of industries handling EDA. Modelled data estimate dermal
    exposures in the range 0-0.15 mg/cm2 per day. However, the use of
    personal protective equipment is standard practice in all industries
    using EDA. Therefore, in practice, dermal exposure will be
    considerably reduced by the use of personal protective equipment.
    

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         The toxicokinetics of EDA has received only limited study, and
    there are no studies following inhalation exposure. Studies in humans
    have been related to the clinical application of EDA and have
    demonstrated rapid absorption via the gastrointestinal tract, with at
    least 50% absorbed within the first 7 h; absorbed EDA is rapidly
    removed from the plasma (Caldwell & Cotgreave, 1983; Cotgreave &
    Caldwell, 1983a,b, 1985). At least half the amount absorbed is
    excreted in the urine, largely as the acetylated metabolite
     N-acetylethylenediamine and, in smaller amounts, as the unchanged
    compound.

         This toxicokinetic picture is supported and extended by data from
    studies in experimental animals. Studies in rats and mice have
    demonstrated rapid and extensive uptake via the oral route and also
    via the respiratory tract following intratracheal instillation (about
    70% or more of the applied dose was absorbed within 48 h) (McKelvey et
    al., 1982; Yang & Tallant, 1982; Yang et al., 1984b). Some (about 12%
    of the applied dose over 24 h) dermal absorption has also been
    observed in rats at non-irritant concentrations, with greater
    absorption at higher, skin-damaging concentrations (Yang et al.,
    1987). These animal studies have also demonstrated that EDA and/or its
    metabolites are widely distributed throughout the body and are rapidly
    eliminated, largely via the urine but also as carbon dioxide in the
    breath and a small amount via the faeces, providing evidence for some
    biliary excretion. It would seem reasonable to conclude that a similar
    situation with respect to distribution and excretion would pertain in
    humans. Examination of urinary metabolites in these animal studies
    demonstrated that EDA is also found in an acetylated conjugate form in
    the rat and mouse. There is evidence that this pathway may become
    saturated with increasing dose and that alternative metabolic pathways
    may be involved at higher doses in the mouse.
    

    8.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         A number of the available studies on both the toxicokinetics and
    toxicity of EDA have employed the base substance (EDA) and/or the
    hydrochloride salt (EDA.2HCl). The latter is used in pharmaceutical
    preparations as a solubilizer to increase uptake of theophylline (this
    complex being known as aminophylline) and has been used as a
    preservative in skin creams (although it is unclear whether or not
    this still occurs). In general, the presence of the hydrochloride has
    little qualitative effect on the toxicokinetic or systemic toxicity
    properties of EDA, particularly following oral dosing, as it is likely
    that the hydrochloride salt would be formed anyway in the acidic
    environment of the stomach. However, the hydrochloride does seem to
    act in a neutralizing capacity to reduce the significant irritancy
    potential of EDA. Studies using both forms of EDA are included in this
    review.

    8.1  Single exposure

         Studies in various animal species have shown EDA to be of
    moderate acute toxicity by the inhalation (rat 8-h LC50 estimated to
    be in the range of 4916-9832 mg/m3 [1966-3933 ppm]), oral (rat LD50
    values of 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, 1946; Carpenter et al., 1948; NTP,
    1982a,b; Yang et al., 1983; Dubinina et al., 1997). Few details exist
    of the toxic signs observed or of target organs.

    8.2  Irritation and sensitization

         There are a number of reports available on skin irritation in
    animals, but in general they all repeat the information from one
    original study (Smyth et al., 1951). In that study, 0.01 ml undiluted
    EDA applied to the shaved backs of albino rabbits produced skin
    necrosis within 24 h. A recent report has also indicated EDA to be a
    skin irritant (Dubinina et al., 1997). Although no further information
    is available, such a response is consistent with EDA being strongly
    alkaline. Studies using EDA.2HCl have also resulted in skin
    irritation, although the neutralizing action of the hydrochloride may
    have influenced the severity of effects, particularly on dilution
    (Yang et al., 1983, 1987).

         As with skin irritation, the reports that are available for eye
    irritation all largely reproduce data from one original study
    (Carpenter & Smyth, 1946). In this study, 0.005-ml solutions of 5% EDA
    or greater caused corneal injury, which again would be expected, given
    the alkaline properties of the substance. More recently, Dubinina et
    al. (1997) stated that inflammatory responses in the rabbit eye were
    induced by "one drop" of EDA.

         Overall, from the reports that are available, together with a
    consideration of its alkaline properties, it is reasonable to conclude
    that EDA is corrosive, with the capacity to produce severe chemical
    burns to the skin and eye.

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

         No studies are available on respiratory sensitization in animals.

    8.3  Short-term exposure

         In a 12-day study (NTP, 1982b), mice received gavage doses of
    between 50 and 600 mg EDA/kg body weight per day (administered as
    EDA.2HCl). Deaths were observed at 400 and 600 mg EDA/kg body weight
    per day. No effects were seen at 50 mg EDA/kg body weight per day.
    Renal effects (nephrosis and tubule regeneration) were observed at 100
    mg EDA/kg body weight per day and above. Lymphoid depletion in and
    necrosis of splenic follicles were observed at 400 mg EDA/kg body
    weight per day.

         A 7 h/day, 30-day inhalation study in rats indicated that the
    liver and kidney are potential target tissues, with local effects in
    the lungs also likely (Pozzanni & Carpenter, 1954). No effects were
    observed in this study at an airborne exposure concentration of about
    150 mg/m3 (60 ppm). Slight depilatory effects were seen at 330 mg/m3
    (132 ppm), becoming more marked at higher exposure concentrations.
    Treatment-related deaths were observed at 563 mg/m3 (225 ppm) and
    1210 mg/m3 (484 ppm) (all animals died at 1210 mg/m3 [484 ppm]).
    Cloudy swelling of cells in the liver and convoluted tubules of the
    kidneys were also observed at these exposure concentrations.
    Degeneration of the convoluted tubules was seen in animals exposed to
    1210 mg/m3 (484 ppm), as was congestion of the lungs and adrenals.

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         Dietary studies in rats have also indicated that the liver is a
    target tissue, with changes in the size and shape of hepatocytes and
    their nuclei being noted at 1000 mg/kg body weight per day in a 90-day
    study (Yang et al., 1983).

         Oral gavage studies using doses of between 100 and 1600 mg EDA/kg
    body weight per day (administered as EDA.2HCl) have been carried out
    in rats (NTP, 1982a). Deaths were observed after 12 doses at 800 and
    1600 mg EDA/kg body weight per day and after 800 mg EDA/kg body weight
    per day for 90 days. Renal tubular lesions (dilation of the lumen,
    necrosis, degeneration and regeneration of the epithelium) were seen
    at 200 mg EDA/kg body weight per day and above after 12 doses. Similar
    renal lesions but of a less severe nature were seen only at 600 mg
    EDA/kg body weight per day and above after 90 days. This indicates
    recovery in the kidney, probably as a consequence of compensatory
    regeneration. No effects were seen on the kidney at 100 mg EDA/kg body
    weight per day in either study. Ocular effects including cataract
    formation and retinal atrophy were observed in all dose groups.
    Minimal to moderate focal retinal atrophy was observed in 3 out of 10
    females at 100 mg EDA/kg body weight per day; 2 males had mild to
    moderate retinal atrophy and 1 male had severe retinal atrophy at 200
    mg EDA/kg body weight per day. Lymphoid depletion and/or necrosis in
    spleen were observed at 800 mg EDA/kg body weight per day and in all
    decedents following 12 doses, and thymus weight was reduced at 800 mg
    EDA/kg body weight per day in the 90-day study. Uterine lesions
    (reduced uterine horn size and atrophy of the myometrium and
    endometrium) were seen after dosing for 90 days with 600 or 800 mg
    EDA/kg body weight per day, and reduced ovarian size was seen after
    800 mg EDA/kg body weight per day for 90 days. Overall, a
    no-observed-adverse-effect level (NOAEL) was not identified from these
    studies, as effects on the eyes were seen at all dose levels. Only
    ocular effects were seen at the lowest-observed-adverse-effect level
    (LOAEL) of 100 mg EDA/kg body weight per day, and these were of a
    minimal to mild nature, suggesting that this dose represented the
    lower end of the dose-response relationship for these effects.

         In a 90-day study, mice received oral gavage doses of 25-400 mg
    EDA/kg body weight per day (NTP, 1982b). No effects were seen at 100
    mg EDA/kg body weight per day. Renal lesions (cortical tubular
    degeneration and/or necrosis) were observed at 200 and 400 mg EDA/kg
    body weight per day.

    8.4.2  Chronic exposure and carcinogenicity

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

         In the first study, groups of 99-225 F344 rats were orally dosed
    with 0, 20, 100, or 350 mg EDA.2HCl (equivalent to 0, 9, 45, or 158
    mg EDA/kg body weight per day) for 2 years (Yang et al., 1984a).
    Non-neoplastic effects were similar to those described in studies of
    shorter duration (Yang et al., 1993), as indicated above (section
    8.4.1). Effects were seen at 45 mg EDA/kg body weight per day, with a
    NOAEL of 9 mg EDA/kg body weight per day. Tracheitis was also
    observed, probably as a consequence of exposure to EDA in airborne
    dust derived from the diet.

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

    8.5  Genotoxicity and related end-points

         Only limited information is available on the genotoxic potential
    of EDA. There is some evidence that EDA may be mutagenic in bacteria
    with and without metabolic activation (Hedenstedt, 1978; Hulla et al.,
    1981; Haworth et al., 1983; Leung, 1994). Although the most recent
    study (Leung, 1994) appears to be negative, there was a small response
    in  Salmonella typhimurium TA100 and a positive, but not
    reproducible, response in TA1535. Positive results have also been
    reported in these strains from the other studies, although only one of
    these (Haworth et al., 1983) was adequately reported. The only series
    of studies performed on mammalian cell systems  in vitro  (gene
    mutation and sister chromatid exchange in Chinese hamster ovary cells;
    unscheduled DNA synthesis in rat primary hepatocytes) were
    consistently negative (Slesinski et al., 1983), although there has
    been no assay for clastogenic activity. A sex-linked recessive lethal
    test in  Drosophila melanogaster was negative following dosing by
    feeding or injection (Zimmering et al., 1985). There are no  in vivo
    studies on somatic cells, but a dominant lethal study in rats up to
    doses inducing signs of toxicity (up to 500 mg EDA.2HCl/kg body
    weight per day in the diet) was negative (Slesinski et al., 1983).

         Although there has been some evidence of mutagenicity in
    bacterial systems in a few limited studies, the available evidence
    indicates that EDA is not genotoxic, with all results in mammalian
    cells  in vitro and  in vivo (dominant lethal assay) being negative.
    It should be noted that the overall database is limited, with no
    assays available for clastogenic activity or for genotoxic potential
    in somatic cells  in vivo.

    8.6  Reproductive and developmental toxicity

         The potential of EDA to affect fertility and development has been
    studied in rats in investigations conducted to modern regulatory
    standards. In a two-generation study in F344 rats, no effects on

    fertility or development in any of the generations were observed up to
    a dose level (225 mg EDA/kg body weight per day) that induced signs of
    parental toxicity (Yang et al., 1984b). Dose levels used in this study
    were 0, 50, 150, or 500 mg EDA.2HCl/kg body weight per day (equivalent
    to 0, 23, 68, and 225 mg EDA/kg body weight per day). Effects on the
    uterus and ovaries have been seen following gavage dosing of rats with
    600 and 800 mg EDA/kg body weight per day for 90 days (see section
    8.4.1; NTP, 1982a). In a series of developmental toxicity studies in
    F344 rats, EDA was found to produce signs of fetotoxicity (increased
    resorptions) and delays in development at high dose levels (450 mg
    EDA/kg body weight per day) that induced clear signs of toxicity in
    the dams (DePass et al., 1987). Dose levels used in this study were 0,
    50, 250, or 1000 mg EDA.2HCl/kg body weight per day (equivalent to 0,
    23, 113, and 450 mg EDA/kg body weight per day). Some of the
    developmental effects appear to have been related, at least in part,
    to the 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.

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

         No effects on development were seen in the offspring of New
    Zealand white rabbits dosed during pregnancy with up to 178 mg
    EDA.2HCl/kg body weight per day (equivalent to 80 mg EDA/kg body
    weight per day), a dose that did not induce maternal toxicity (NTP,
    1991; Price et al., 1993). In a preliminary study, 2/20 pregnant
    rabbits receiving 100 mg EDA/kg body weight per day by gavage died,
    and decreased body weight was seen in survivors. At 400 mg/kg body
    weight per day, all the dams died.

    8.7  Immunological and neurological effects

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

         There are a few, mainly  in vitro, studies on the effects of EDA
    on the release of gamma-aminobutyric acid from the retina, gut, and
    brain (Perkins & Stone, 1980; Forster et al., 1981; Lloyd et al.,
    1982; Morgan & Stone, 1982; Sarthy, 1983; Kerr & Ong, 1984; Strain et
    al., 1984; Hill, 1985; Erdo et al., 1986; Krantis et al., 1990; McKay
    & Krantis, 1991). The general conclusion that can be drawn from these
    studies is that EDA can cause a calcium-independent release of
    gamma-minobutyric acid that is insensitive to the presence of
    tetrodotoxin. EDA was also shown to have gamma-minobutyric acid

    mimetic properties (i.e., reduction of neuronal firing rate). This
    suggests that EDA could have a central nervous system depressant
    effect, but studies were not performed to address this possibility. It
    was reported that EDA elicited contraction of the guinea-pig ileum
    that was mediated via neuronal release of gamma-aminobutyric acid.
    However, in the rat ileum, EDA acted directly on the mucosa, resulting
    in relaxation. Although these are interesting results, the
    toxicological significance of these findings is unclear; they may,
    however, partly explain the central nervous system depressant and
    gastrointestinal effects seen in some of the animal studies at high
    doses.
    

    9.  EFFECTS ON HUMANS

         No studies are available in which the effects, other than the
    respiratory effects summarized below, of repeated exposure of humans
    to EDA are examined. No reports have been found in which genotoxicity,
    carcinogenicity, or reproductive toxicity following exposure to EDA in
    human populations has been studied.

         A case report exists concerning a 36-year-old worker who died
    from cardiac collapse 55 h after being splashed by an accidental
    spillage of EDA (Niveau & Painchaux, 1973). Exposure to an
    unquantified amount of EDA was in the order of a few minutes prior to
    the patient being washed. Four hours after the exposure, he presented
    with tachycardia (100 beats/min), anuria, and 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 hyperkalaemic, and his
    red blood cell count decreased. Overall, given the lack of information
    with respect to levels of exposure, few useful conclusions can be
    drawn from this case report.

         The only information available on skin irritation in humans
    either is anecdotal or does not involve direct surface skin contact
    with EDA. In a brief report on the physicochemical properties of EDA,
    it is noted anecdotally that "the liquid, if not washed from the skin,
    causes blistering" (Boas-Traube et al., 1948). The other report
    available documents the results of intradermal skin tests with
    solutions (0.1-1%) of EDA on three individuals being tested for
    hypersensitivity following treatment with aminophylline (Kradjan &
    Lakshminarayan, 1981). The skin response in two patients consisted of
    blistering rather than a weal and flare reaction, which normally
    typifies a sensitization response. Punch biopsies were obtained from
    one patient, and histopathological examination of these indicated
    tissue necrosis and oedema of the epidermis and dermis. These
    responses suggested a direct corrosive effect of EDA.

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

         EDA has been known for many years to be capable of inducing
    allergic skin reactions in humans. This has been observed both in the
    workplace and, most notably, in patients treated with aminophylline or
    with skin creams in which EDA was used as a stabilizer (Epstein &
    Maibach, 1968; Petrozzi & Shore, 1976; Booth et al., 1979; Wall, 1982;
    Hardy et al., 1983; Balato et al., 1984; Edman & Moller, 1986; Nielsen
    & Jorgensen, 1987; Terzian & Simon, 1992; Toal et al., 1992; Dias et
    al., 1995; Simon et al., 1995; Sasseville & Al-Khenaizan, 1997). The

    first reports of skin sensitizing effects in humans date back to the
    late 1950s, when cases were described of eczematous reactions in
    pharmacists who came into contact with EDA when using aminophylline
    (Baer et al., 1958; Tas & Weissberg, 1958).

         Subsequent to these early reports, numerous studies and case
    reports have been published documenting the skin sensitizing
    properties of EDA both following clinical use and within the
    occupational setting, such that the substance has become incorporated
    into standard series for patch testing (Fregert, 1981; Shehade et al.,
    1991). An example from the clinical setting is that of the report on a
    series of 13 patients who had used skin cream containing EDA for,
    paradoxically, dermatitic conditions (Provost & Jillson, 1967). Use of
    the cream in 11 of these patients had resulted in the sudden
    appearance of a severe generalized patchy eczematous eruption
    following, in all but one of the cases, an initial improvement upon
    using the cream. Patch testing was conducted using a 1% aqueous
    solution of EDA, producing skin reactions in all patients ranging from
    erythema and oedema to erythema vesiculation and oedema vesiculation,
    which extended beyond the patch test site. Other substances tested
    also induced responses, but not in a consistent manner, with at most
    only four individuals responding in any one test.

         As well as the original reports in pharmacists working with EDA,
    cases of skin sensitization to EDA have been reported in the
    occupational environment in a number of different settings, including
    use of floor polish remover (English & Rycroft, 1989), use of coolant
    oils (Crow et al., 1978), and in wire-drawing (Matthieu et al., 1993;
    Sasseville & Al-Khenaizan, 1997). Positive responses to patch testing
    with EDA have also been observed in other occupational settings, such
    as the offshore oil industry (Ormerod et al., 1989), but positive
    responses to other substances, including other polyamines, were also
    seen in such cases. Thus, it is unclear whether EDA had been
    responsible for inducing the sensitized state and/or cross-reacting
    following sensitization to another polyamine.

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

         Popa et al. (1969), in a well-conducted study, investigated 48
    subjects with asthmatic symptoms caused by exposure to a number of low
    molecular weight chemicals, including EDA. None of the subjects had a
    history of respiratory disorder prior to occupational exposure, and
    the asthmatic response was associated only with occupational exposure
    in all cases. No information was given in the report on the workplace
    airborne concentrations of EDA to which these workers were exposed. A
    series of tests were performed in all subjects, including skin and
    inhalation tests with the test agent at sub-irritant concentrations;
    skin and inhalation tests to common allergens; skin tests
    (intradermal, scratch, and patch tests) using sub-irritant
    concentrations of the test substance; Prausnitz-Kustner transfer
    reaction (to test for the presence of immunoglobulin E antibodies);
    and determination of precipitating antibodies to EDA. For the
    inhalation test, the sub-irritant concentration was determined in
    control asthmatic subjects, and a 2- to 10-fold dilution of this was
    used for the bronchial challenge. No information was given on the
    airborne exposure concentrations generated under these test
    conditions. Control inhalation tests with the diluent, physiological
    saline, were also conducted. It is not stated in the report whether or
    not the inhalation challenge tests were conducted in a blind manner.

         Six subjects had an immediate, positive reaction to EDA in the
    workplace. Of these, four showed an immediate, positive response
    following inhalation testing with sub-irritant concentrations of EDA.
    These subjects developed marked bronchoconstriction following
    inhalation exposure to EDA, with a reduction in forced expiratory
    volume in 1 s (FEV1) of 62% and an increase in respiratory resistance
    of 44%, compared with controls. Although not stated in the report,
    these values are presumed to be average changes. Intradermal skin
    tests with EDA were positive in these four subjects, whereas patch
    tests were negative. Inhalation challenges with common allergens were
    negative. The Prausnitz-Kustner test was positive in all subjects, and
    all had eosinophilia, determined in the sputum, although not, except
    in one case, in the blood. No precipitating antibodies were found. In
    the two other subjects, the inhalation challenge test was negative. No
    precipitating antibodies were found, and the Prausnitz-Kustner test
    was negative in both subjects. Eosinophilia was absent. Inhalation
    challenges with other common allergens were also negative.

         These data provide evidence that EDA may elicit an asthmatic
    response at sub-irritant concentrations and that the response is
    specific to EDA. Four out of six subjects responsive to EDA in the
    workplace also had a positive response to inhaled EDA at sub-irritant
    concentrations. This demonstrates that the reaction is not a
    generalized response to an irritant. The positive Prausnitz-Kustner
    reaction may be indicative of an immunological component, but the test
    is not specific, and no firm conclusions can be drawn from it. It
    provides supporting evidence in this case. The evidence suggests that
    the subjects were hypersensitive to inhaled EDA and that a state of
    respiratory hypersensitivity had been induced by the substance.

         Although a number of other studies are available, the information
    is of poor quality. Lam & Chan-Yeung (1980) and Chan-Yeung (1982)
    describe the case of one worker in a photographic laboratory who
    developed asthma after 2.5 years of exposure to a variety of
    chemicals, including EDA, but also other irritant substances. The
    worker developed symptoms of sneezing, nasal discharge, productive
    cough and nocturnal cough, wheezing, and dyspnoea. The symptoms
    coincided with the work shift and subsided at weekends. There was no
    previous history of asthma. No information was given in the report of
    the airborne concentrations of EDA (or other substances) to which the
    man was exposed at work. A series of controlled inhalation challenge
    exposures, designed to mimic work exposure conditions, were conducted
    with each of the chemicals to which the subject was exposed at work.
    The duration of exposure was determined by the patient's tolerance,
    and exposure was terminated when eye irritation or cough was
    experienced. No information on the airborne exposure concentrations of
    EDA generated under these test conditions was given in the report. A
    methacholine inhalation test for bronchial hyperreactivity was also
    performed. Pulmonary function tests were conducted pre- and
    post-challenge, and blood samples were taken before, during, and after
    each challenge. The subject showed marked bronchial reactivity to
    methacholine.

         Exposure to an unknown concentration of vapour from a 1:25
    solution of EDA was tolerated for 15 min. This exposure produced a
    marked bronchoconstriction. A late asthmatic response developed 4 h
    after the exposure, at which time FEV1 was reduced by 26% and
    continued to decrease over the next 3 h towards a 40% reduction. A 26%
    reduction was still apparent after 24 h, despite treatment with
    bronchodilator drugs. This pattern of response to EDA was
    reproducible. The patient did not respond similarly to any of the
    other chemicals tested: formaldehyde, sulfur dioxide, and two colour
    developing agents that were stated to be irritants. Exposure to
    formaldehyde (vapour from a 1:4 solution) produced an immediate small
    (<20%), transient reduction in FEV1, whereas exposure to sulfur
    dioxide caused coughing and chest tightness and an immediate transient
    reduction of 25% in FEV1. There was no increase in plasma histamine
    concentration during the period of bronchoconstriction, although EDA
    was shown to cause  in vitro histamine release from whole blood taken
    from the patient and from two control subjects. A skin test using
    1:100 EDA and a precipitin test for antibodies to EDA were both
    negative. The patient subsequently had to give up work because of
    respiratory symptoms and became asymptomatic after 2 weeks. Subsequent
    testing with methacholine, 2.4 months after ceasing work, showed that
    the subject had a reduction in the previous bronchial hyperreactivity.

         In conclusion, the subject showed an asthmatic response to EDA
    but not to formaldehyde or the colour developing agents. The pattern
    of response to sulfur dioxide was more immediate and suggestive of an
    irritation response. Overall, a clear pattern of asthmatic response
    that was specific to EDA was observed in this study. However, it is

    not possible to distinguish with certainty between an irritant
    response and a sensitization response, because it is possible that an
    irritant concentration was used for the bronchial challenge exposure,
    although little immediate response was observed. In addition, although
    exposure to irritant concentrations of 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 given, it
    is not possible to determine whether or not the EDA concentration used
    had the greatest irritant potential. No evidence for any immunological
    involvement was found. In conclusion, this study provides only
    circumstantial evidence that EDA caused a state of respiratory
    hypersensitivity in this subject.

         A number of other case reports are available of individuals who
    exhibited asthmatic signs and symptoms associated with exposure to EDA
    in the workplace (Gelfand, 1963; Valeyeva et al., 1975; Matsui et al.,
    1986; Nakazawa & Matsui, 1990; Ng et al., 1991). Although bronchial
    challenge testing with EDA produced asthmatic responses in these
    subjects, they had personal and/or family histories of allergic
    disease and/or they had worked with and responded on challenge to
    other substances. Retrospective studies using the medical records of
    populations of workers using EDA have indicated that about 10% of such
    populations developed signs and symptoms of occupational asthma
    (Aldrich et al., 1987; Lewinsohn & Ott, 1991). No challenge tests were
    carried out with these surveys. Thus, these case reports and
    population-based studies provide only supporting circumstantial
    evidence for the involvement of EDA in producing occupational asthma.

         Although it is clear from these reports that EDA can provoke an
    asthma attack, in many cases there is insufficient information to
    indicate whether or not the hypersensitive state was induced
    specifically by EDA. However, from one well-conducted study, there is
    evidence that a hypersensitive state specific to EDA has been induced
    in workers and that an asthmatic response was provoked by sub-irritant
    concentrations of the substance. Overall, the results of this study,
    taken together with the supporting data from a substantial number of
    other reports of occupational asthma, indicate that EDA is capable of
    inducing a state of hypersensitivity in the airways, such that
    subsequent exposure may trigger asthma. The mechanism by which the
    hypersensitive state is induced is not proven. Given the skin
    sensitizing potential of EDA and the limited evidence of immunological
    involvement in workers with EDA-provoked occupational asthma, an
    immunological mechanism would seem plausible. Irrespective of the
    mechanism involved, the data available (specifically the lack of
    information on airborne exposure concentrations under both work and
    challenge test conditions) do not allow elucidation of a dose-response
    relationship or the identification of levels of EDA that are not
    capable of inducing a hypersensitive state or of provoking an
    asthmatic response.
    

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Results of acute ecotoxicity tests are given in Table 2.

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

         Growth of lettuce ( Lactuca  sativa) plants over 7 days was
    studied in tests conducted under OECD Guideline 208; EC50
    concentrations for EDA in soil (nominal) were >1000 mg/kg for 7-day
    and 692 mg/kg for 14-day growth periods (Hulzebos et al., 1993).
    

    11.  EFFECTS EVALUATION

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         EDA is of moderate acute toxicity by all routes. In studies in
    animals, EDA is a primary skin and eye irritant, being corrosive when
    undiluted. It is also a skin sensitizer. In repeated-dose toxicity
    studies by the oral and inhalation routes, effects on the liver and
    kidney have been observed, with pleomorphic changes to hepatocytes in
    rats being reported at the lowest oral doses used (45 mg/kg body
    weight per day and above for 2 years; NOAEL, 9 mg/kg body weight per
    day). In inhalation studies, there were no effects at 150 mg/m3 (60
    ppm), although slight depilation was observed at the next highest
    concentration (330 mg/m3 [132 ppm]) and effects on the liver and
    kidney at higher concentrations still (approximately 500 mg/m3 [200
    ppm] and above).

         There has been some evidence of mutagenicity in bacterial systems
    in a few limited studies. However, much of the available evidence is
    negative, although the overall database is limited, there being no
    assays for clastogenic activity or for genotoxic potential in somatic
    cells  in vivo. EDA was not carcinogenic in adequate studies in
    animals.

         In humans, EDA has the potential to induce respiratory tract
    hypersensitivity, and provocation of asthma is the major health effect
    of concern in the occupational environment. The mechanism of induction
    of the hypersensitive state is unknown, although the skin sensitizing
    potential of EDA and limited evidence in workers with EDA-provoked
    asthma are suggestive of an immunological mechanism. However,
    irrespective of the mechanism involved, the available data
    (particularly lack of information on exposure conditions either in the
    workplace or on bronchial challenge testing) do not allow either
    elucidation of dose-response relationships or identification of the
    thresholds for induction of the hypersensitive state or provocation of
    an asthmatic response.

    11.1.2  Criteria for setting guidance values for EDA

         Available data are inadequate to serve as a basis for
    characterization of the dose-response relationship for provocation of
    an asthmatic response, the effect of greatest concern in the
    occupational environment. As it is not possible to identify a level of
    exposure that is without adverse effect, it is recommended that levels
    be reduced to the extent possible.


        Table 2: Acute toxicity of EDA to organisms other than laboratory mammals.
                                                                                                                                
    Species                          End-point                                     Concentration        Reference
                                                                                      (mg/litre)
                                                                                                                                

    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                                         approx. 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

    Table 2 (continued)
                                                                                                                                
    Species                          End-point                                     Concentration        Reference
                                                                                      (mg/litre)
                                                                                                                                

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

    Fish

    Brown trout (Salmo trutta)       48-h LC50                                            230           Woodiwiss & Fretwell, 1974
    Fathead minnow (Pimephales
    promelas)                        96-h LC50                                          115.7           Curtis & Ward, 1981
    Guppy (Poecilia reticulata)      96-h LC50                                            275           van Leeuwen, 1986
                                     96-h LC50                                            640           Balk & Meuwsen, 1989c
                                     96-h LC50                                           1545           van Wijk et al., 1994
    Medaka (Oryzias latipes)         48-h LC50                                           1000           Tonogai et al., 1982
                                                                                                                                
    

         With respect to systemic effects, the lowest NOAELs of 150 mg/m3
    (60 ppm) (inhalation) and 9 mg/kg body weight per day (oral) can serve
    as a basis for comparison with estimated exposure for characterization
    of risk, either with application of appropriate uncertainty factors or
    directly. An example of the latter (margin of exposure) approach is
    presented in section 11.1.3.

    11.1.3  Sample risk characterization

         Available data are inadequate to serve as a basis for
    characterization of the dose-response relationship, and hence risk,
    for provocation of an asthmatic response, the effect of greatest
    concern in the occupational environment. For substances that are
    asthmagens, it is also advisable to restrict peak exposures, as they
    may have a role in the induction and triggering of asthmatic
    phenomena. However, to help assess the risk to human health arising
    from occupational exposures, a comparison is made with the NOAELs for
    systemic effects from animal studies.

         It should also be noted that because diluted EDA is a skin
    irritant and sensitizer, there is a risk of developing irritant and/or
    allergic dermatitis if suitable personal protective equipment is not
    used.

         A sample risk characterization for systemic effects in the
    occupational environment in the United Kingdom is provided here.
    Measured data on exposure to EDA (generally used in closed systems)
    indicate that levels in industry in the United Kingdom are less than
    1.25 mg/m3 (0.5 ppm), 8-h time-weighted average. Modelled data (EASE)
    are in good agreement, predicting comparable values of 0.53-1.3 mg/m3
    (0.21-0.52 ppm). Short-term peak exposures (sampling and hose
    uncoupling operations) were predicted to be 16.8-33.3 mg/m3 
    (6.7-13.3 ppm), 15-min time-weighted average. The EASE model predicts
    dermal exposures in the range of 0-0.15 mg/cm2 per day for an
    operator transferring EDA into closed systems once a day (although
    coveralls and well-maintained plastic gloves will significantly reduce
    exposure from this source).

         With respect to systemic effects, worst-case estimated and
    measured exposures of 1.25 mg/m3 (0.5 ppm), 8-h time-weighted
    average, are substantially less (by 100-fold or greater) than the
    NOAEL in the inhalation study in rats. The combined body burden from
    inhalation and dermal exposure for chemical synthesis can be estimated
    to be about 0.3 mg/kg body weight per day (assuming a 70-kg worker
    breathing 10 m3 of air containing 1.25 mg EDA/m3 [0.5 ppm] per day,
    with 100% absorption; and 10% absorption from unprotected, undamaged
    skin for a standard hand area of 840 cm2). This is 30-fold less than
    the NOAEL for hepatic effects in the oral studies.

         Available data on indirect exposure in the general environment or
    from consumer products are inadequate to serve as a basis for a sample
    characterization of risk for these scenarios.

    11.2  Evaluation of environmental effects

         No atmospheric effects are expected, as reaction with hydroxyl
    radicals is likely to be rapid, and washout of volatilized EDA is
    expected. Volatilization to the atmosphere is likely from soil but not
    from water.

         Adsorption to soil particulates is strong through electrostatic
    binding; leaching through soil profiles to groundwater is not
    expected. EDA is readily biodegradable, and this is the most likely
    source of breakdown in the environment; adaptation of microorganisms
    may improve degradation. Breakdown is less rapid in seawater than in
    fresh water. Bioaccumulation is unlikely.

         Toxic thresholds for microorganisms may be as low as 0.1
    mg/litre. However, toxicity tests in culture media should be treated
    with caution, as the EDA may complex with metal ions. Effects may
    therefore be indirect, from loss of bioavailability of essential
    elements. The "toxic thresholds" reported are lowest-observed-effect
    concentrations (LOECs) for small changes in sublethal end-points; the
    exact degree of effect at the reported concentrations is not always
    clear, and these have not been used in the risk assessment.

         The principal receiving compartment in the environment is the
    hydrosphere, and this is the only compartment for which a quantitative
    risk assessment can be attempted.

         The distribution of acute (from Table 2) and chronic test results
    is plotted in Figure 1. Chronic test results are available for fish (a
    limit test only) and  Daphnia (NOECs from 21-day reproduction tests).
    Chronic EC50s for algal growth or biomass are also available, but no
    NOEC was reported for these studies. Given the range of chronic test
    results across three trophic levels, it is proposed that an
    uncertainty factor of 10 be applied to the lowest reported NOEC (for
     Daphnia reproduction at 0.16 mg/litre) to derive an estimated PNEC
    for aquatic organisms of 0.016 mg/litre. This is in accord with OECD,
    European Union, and US Environmental Protection Agency guidelines.
    There are no reported test results for estuarine/marine organisms; it
    is assumed that toxicity would be in the same range for these species.

         No measured concentrations of EDA in surface waters have been
    reported. A single quantitative risk assessment has been reported (van
    Wijk, 1992) based on discharges into the Ems-Dollard estuary in the
    Netherlands. The figure of 75 kg/day for release of EDA at this site
    has been used here as a representative estimate of release; no
    information on releases from industrial plants elsewhere is available.

    FIGURE 1

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

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

                     = 337.5 µg/litre

    where:

    *    PEClocal (water) is the predicted environmental concentration (g/litre)

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

               W  =    emission rate (75 kg/day)
               P  =    percent removal in the wastewater treatment plant
                      (91%, based on a classification of the chemical as
                      "readily biodegradable")
               Q  =    volume of wastewater in m3/day (default 200
                      litres [0.2 m3] per person per day for a
                      population of 10 000 inhabitants)

    *     Kp(susp) is the suspended matter/water adsorption coefficient,
         calculated as  Kp(susp) =  Foc(susp) ×  Koc, where:

               Foc(susp)= the fraction of organic carbon in suspended
                         matter (0.01)
               Koc      =    0.411 ×  Kow
              where:
                    Kow = the octanol/water partition coefficient (0.063)
                             

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

    *     D is the dilution factor for river flow (default value of 10)

         Calculation of initial PEC in the compartment of the estuary
    receiving emissions from the actual plant in the Netherlands gives a
    PEC(initial near field) of 10.9 µg/litre. This 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 plant of 500 m3/day, realistic for the
    local conditions.

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

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

    Table 3: PEC/PNEC ratios.
                                                                      

                             PEC (µg/litre)  PNEC (µg/litre)    PEC/PNEC
                                                                ratio
                                                                      

    River, worst case        337.5           16                 21.1
    Estuary, initial
    worst case               10.9            16                 0.68
    Estuary, refined PEC     1.3             16                 0.08
                                                                      

         The PEC/PNEC ratio for the river indicates some cause for concern
    (ratio greater than 1). However, the PEC is based on very conservative
    assumptions, and both estimates assume low adsorption to sediment
    based on water solubility. Refined estimates for the estuary indicate
    low risk to aquatic organisms.
    

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

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

    13.  HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

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

    13.1  Human health hazards

         Repeated or prolonged contact with EDA may cause skin
    sensitization and asthma.

    13.2  Advice to physicians

         EDA is corrosive. Inhalation of the vapour may cause irritation
    of the respiratory tract and even lung oedema and could mask asthmatic
    reaction.

    13.3  Health surveillance advice

         Physicians involved in worker health surveillance programmes
    should be aware of the potential of EDA as a human asthmagen.

    13.4  Spillage

         In the case of spillage, emergency crews need to wear proper
    equipment and prevent EDA from reaching drains or watercourses.
    

    14.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

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

         The reader should be aware that regulatory decisions about
    chemicals taken in a certain country can be fully understood only in
    the framework of the legislation 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.
    


        INTERNATIONAL CHEMICAL SAFETY CARD

                                                                                                                   
    ETHYLENEDIAMINE                                        ICSC: 0269
                                                            June 1999
                                                                                                                   
    CAS #     107-15-3                      1,2-Diaminoethane
    RTECS #   KH8575000                     1,2-Ethanediamine
    UN #      1604                          H2NCH2CH2NH2
    EC #      612-006-00-6                  Molecular mass: 60.1
                                                                                                                   
    TYPES OF HAZARD/     ACUTE HAZARDS/                 PREVENTION                   FIRST AID/
    EXPOSURE             SYMPTOMS                                                    FIRE FIGHTING
                                                                                                                   
    FIRE                 Flammable. Gives off           NO open flames, NO           Powder, alcohol-resistant
                         irritating or toxic            sparks, and NO               foam, water spray, carbon
                         fumes (or gases) in            smoking.                     dioxide.
                         a fire.
                                                                                                                   
    EXPLOSION            Above 34°C explosive           Above 34°C closed            In case of fire: keep drums,
                         vapour/air mixtures            system, ventilation,         etc., cool by spraying with
                         may be formed.                 and explosion-proof          water.
                                                        electrical equipment.
                                                                                                                   
    EXPOSURE                                            STRICT HYGIENE!
                                                                                                                   
    Inhalation           Burning sensation.             Ventilation, local exhaust,  Fresh air, rest. Artificial
                         Cough. Laboured breathing.     or breathing protection.     respiration if indicated.
                         Shortness of breath. Sore                                   Refer for medical attention.
                         Throat.
                                                                                                                   
    Skin                 MAY BE ABSORBED! Redness.      Protective gloves.           Remove contaminated
                         Skin burns. Pain.              Protective clothing.         clothes. Rinse skin with
                                                                                     plenty of water or shower.
                                                                                     Refer for medical
                                                                                     attention.
                                                                                                                   

                                                                                                                   
    Eyes                 Redness. Pain. Blurred         Face shield.                 First rinse with plenty
                         vision.                                                     of water for several minutes
                                                                                     (remove contact lenses if 
                                                                                     easily possible), then take to
                                                                                     a doctor.
                                                                                                                   
    Ingestion            Abdominal pain. Diarrhoea.     Do not eat, drink,           Rinse mouth. Give plenty of 
                         Sore throat. Vomiting          or smoke during work.        water to drink. Refer for medical
                                                                                     attention.
                                                                                                                   
    SPILLAGE DISPOSAL                                   PACKAGING & LABELLING
                                                                                                                   
    Collect leaking and spilled liquid in sealable      EU Classification
    containers as far as possible. Absorb remaining     Symbol: C
    liquid in sand or inert absorbent and remove        R: 10-21/22-34-42/43
    to safe place (extra personal protection:           S: (1/2-)23-26-36/37/39-45
    complete protective clothing including              UN Classification
    self-contained breathing apparatus).                UN Hazard Class: 8
                                                        UN Subsidiary Risks: 3
                                                        UN Pack Group: II
                                                                                                                   
    EMERGENCY RESPONSE                                  STORAGE
                                                                                                                   
    Transport Emergency Card: TEC (R)-77                Fireproof. Separated from incompatible materials
    NFPA Code: H 3; F 2; R O;                           (see Chemical Dangers). Dry.
                                                                                                                   
                                           IMPORTANT DATA
                                                                                                                   

    PHYSICAL STATE; APPEARANCE:                         ROUTES OF EXPOSURE:
    COLOURLESS TO YELLOW HYGROSCOPIC LIQUID, WITH       The substance can be absorbed into the body by
    CHARACTERISTIC ODOUR.                               inhalation, through the skin and by ingestion.

    CHEMICAL DANGERS:                                   INHALATION RISK:
    The substance decomposes on heating producing       A harmful contamination of the air can be reached
    toxic fumes (nitrogen oxides). The substance        rather quickly on evaporation of this substance
    is a medium strong base. Reacts violently           at 20°C.
    with chlorinated organic compounds strong
    oxidants.

    OCCUPATIONAL EXPOSURE LIMITS:                       EFFECTS OF SHORT-TERM EXPOSURE:
    TLV (as TWA): 10 ppm; 25 mg/m3 A4                   The substance is corrosive to the eyes, the skin
    (ACGIH 1999).                                       and the respiratory tract. Inhalation of vapour or
                                                        fumes may cause lung oedema (see Notes).

                                                        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                 Auto-ignition temperature:       385°C
    Melting point:                8.5°C                 Explosive limits, vol% in air:   2.7-16.6
    Relative density (water = 1)  0.90                  Octanol/water partition
    Solubility in water:          miscible              coefficient as log Pow:          -1.2
    Vapour pressure, kPa at 20°C: 1.2
    Relative vapour density
    (air = 1):                    2.1
    Relative density of the
    vapour/air-mixture at 20°C
    (air = 1):                    1.02
    Flash point:                  34°C (c.c.)
                                                                                                                   
                                            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 CEC nor the IPCS nor any person acting on behalf of the
                      CEC or the IPCS is responsible for the use which might be made of this
                      information.
                                                                                                                   
    

    REFERENCES

    Aldrich F, Stange A, Geesaman R (1987) Smoking and ethylene diamine
    sensitization in an industrial population.  Journal of occupational
     medicine, 29:311-314.

    Andersson K, Hallgren C, Levin J, Nilsson C (1985) Determination of
    ethylenediamine in air using reagent-coated adsorbent tubes and
    high-performance liquid chromatography on the naphthylisothiourea
    derivative.  American Industrial Hygiene Association journal, 
    46:225-229.

    Babiuk C, Hastings K, Dean J (1987) Induction of ethylenediamine
    hypersensitivity in the guinea-pig and the development of ELISA and
    lymphocyte blastogenesis techniques for its characterisation.
     Fundamental and applied toxicology, 9:623-634.

    Baer R, Cohen H, Neidorff A (1958) Allergic eczematous sensitivity to
    aminophylline.  American Medical Association archives of dermatology,
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    APPENDIX 1 -- SOURCE DOCUMENTS

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

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

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

    BUA (1997):  Ethylenediamine (GDCh-Advisory Committee on Existing
    Chemicals of Environmental Relevance Report No. 184)

         For the BUA review process, the company that is in 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.
    

    APPENDIX 2 -- CICAD PEER REVIEW

         The draft CICAD on 1,2-diaminoethane (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 to identified experts. Comments were received
    from:

         Akzo Novel nv, Arnhem, Netherlands

         Department of Health, London, United Kingdom

         Environment Agency, Wallingford, United Kingdom

         Ethyleneamines Product Stewardship Discussion Group, Michigan,
         USA

         Health Canada, Ottawa, Canada

         International Agency for Research on Cancer, Lyon, France

         National Chemicals Inspectorate (KEMI), Solna, Sweden

         National Institute for Working Life, Solna, Sweden

         National Institute of Public Health and Environmental Protection,
         Bilthoven, The Netherlands

         Nofer Institute of Occupational Medicine, Lodz, Poland

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

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

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    Tokyo, Japan, 30 June - 2 July 1998

    Members

    Dr R. Benson, Drinking Water Program, United States Environmental
    Protection Agency, Denver, CO, USA

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

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

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

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

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

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

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

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

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

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

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

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

    Observers

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


    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

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

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

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

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

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

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

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

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

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

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

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

    Dr K. Tasaka, Department of Chemistry, International Christian
    University, Tokyo, Japan

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

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

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

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

    Secretariat

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

    Mr A. Strawson, Health and Safety Executive, London, United Kingdom

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

    RÉSUMÉ D'ORIENTATION

         Ce CICAD relatif au 1,2-diaminoéthane (éthylènediamine) a été
    préparé à partir d'une étude du Health and Safety Executive du
    Royaume-Uni sur les risques pour la santé humaine (risques
    professionnels pour l'essentiel, mais comportant également un volet
    écologique) (Brooke et al., 1997). La bibliographie sur laquelle
    s'appuie l'étude originale a été arrêtée à fin 1994. Une analyse de la
    littérature a été ensuite effectuée jusqu'à juillet 1997 à la
    recherche de données qui auraient pu être publiées depuis la fin de
    l'étude. Les données relatives à la destinée du composé dans
    l'environnement et à son impact écologique sont tirées d'un rapport du
    Comité consultatif de la Société allemande de Chimie pour les
    substances chimiques d'intérêt écologique (BUA, 1997). On trouvera à
    l'appendice 1 des indications sur les sources documentaires utilisées
    et sur leur mode de dépouillement. Les renseignements concernant
    l'examen du CICAD par des pairs font l'objet de l'appendice 2. Ce
    CICAD a été approuvé en tant qu'évaluation internationale lors d'une
    réunion du Comité d'évaluation finale qui s'est tenue à Tokyo (Japon)
    du 30 juin au 2 juillet 1998. La liste des participants à cette
    réunion figure à l'appendice 3. La fiche d'information internationale
    sur la sécurité chimique (ICSC No 0269) établie par le Programme
    international sur la Sécurité chimique (IPCS, 1993) est également
    reproduite dans ce document.

         Le 1,2-diaminoéthane (No CAS 107-15-3), couramment désigné sous
    le nom d'éthylènediamine (EDA), est un produit de synthèse qui se
    présente sous la forme d'un liquide incolore à jaunâtre dans les
    conditions normales de température et de pression. Il présente une
    réaction fortement alcaline et il est miscible à l'eau et à l'alcool.
    On l'utilise principalement comme intermédiaire dans la fabrication de
    la tétra-acétyl-éthylènediamine, de l'acide
    éthylènediamine-tétra-acétique (EDTA), des floculants organiques, des
    résines à base d'urée et des diamides gras. Dans des proportions
    beaucoup plus faibles, il entre également dans la composition de
    formulations destinées à la fabrication des supports de circuits
    imprimés ou utilisées dans l'industrie de finissage des métaux. Il
    peut aussi être utilisé comme accélérateur ou agent de réticulation
    dans les résines époxy employées notamment comme revêtements ainsi que
    pour la préparation de certains produits pharmaceutiques. L'EDA est
    présent sous la forme d'impureté (<0,5 %) dans les amines grasses du
    commerce utilisées comme agents mouillants dans les émulsions
    bitumineuses. On l'emploie également dans la synthèse des fongicides à
    base de carbamates, dans la fabrication des agents de surface et des
    colorants ainsi que dans la préparation de produits de développement
    photographique et d'huiles de coupe. L'EDA est un produit de
    décomposition des éthylènebis(dithiocarbamates) utilisés comme
    fongicides.

         Il ne devrait pas y avoir d'effets atmosphériques puisque la
    réaction de l'EDA avec les radicaux hydroxyles est vraisemblablement
    rapide (demi-vie 8,9 h) et que la fraction volatilisée devrait être
    éliminée par les précipitations. Ce passage dans l'atmosphère à l'état
    de vapeur est probable à partir du sol, mais pas à partir de l'eau.
    L'EDA adhère fortement aux particules du sol par attraction
    électrostatique; on pense qu'il ne devrait donc pas y avoir de passage
    dans les eaux souterraines par lessivage des sols. Il peut sans doute
    former des complexes avec les métaux et les acides humiques. La voie
    de décomposition la plus probable dans l'environnement est la voie
    biologique et alle devrait être assez rapide; l'adaptation des
    microorganismes pourrait accélérer le processus. La décomposition est
    plus lente dans l'eau de mer que dans l'eau douce. Il n'y a
    probablement pas de bioaccumulation.

         L'EDA présente une toxicité aiguë modérée pour les animaux. C'est
    surtout une substance irritante, qui est corrosive quand elle n'est
    pas diluée et qui provoque également une sensibilisation cutanée. On
    n'a pas procédé à la recherche de son pouvoir mutagène dans les
    conditions prescrites par la réglementation actuelle et on ne dispose
    pas non plus d'études sur son activité clastogène ou sur une action
    qui s'exercerait sur les cellules somatiques  in vivo. Il n'existe
    donc pas de données suffisantes pour que l'on puisse se prononcer avec
    certitude sur le pouvoir mutagène éventuel de l'EDA. Quoi qu'il en
    soit, le composé ne s'est pas révélé cancérogène chez l'animal. On a
    observé des effets non néoplasiques au niveau du foie (modifications
    pléomorphes des hépatocytes) chez des rats auxquels on avait fait
    ingérer du 1,2-diaminoéthane pendant 2 ans. Ces effets ont été
    observés à des doses quotidiennes supérieures ou égales à 45 mg d'EDA
    par kg de poids corporel, aucune anomalie ne se manifestant à la dose
    quotidienne de 9 mg par kg de poids corporel. On voit pas très
    clairement ce que cette observation peut signifier pour la santé
    humaine et l'on ne peut d'ailleurs pas se prononcer non plus sur le
    point de savoir si les effets rapportés sont effectivement dus à
    l'ingestion de l'EDA (par exemple, ils pourraient ne pas se produire
    si on changeait la voie d'administration ou être liés à des effets de
    premier passage), mais on ne peut les négliger pour autant et il faut
    déterminer les conditions de leur apparition. Lors d'études où le
    composé a été administré par gavage, on a observé des effets oculaires
    chez le rat (atrophie rétinienne et à dose élevée, formation de
    cataractes) à des doses quotidiennes supérieures ou égales à 100 mg
    par kg de poids corporel. Chez des rats et des souris, on a constaté
    la présence de lésions rénales aux doses quotidiennes respectives de
    200 et 100 mg de composé par kg de poids corporel et au-delà. On a
    également trouvé quelques indices d'effets sur la rate chez des souris
    et des rats à des doses quotidiennes supérieures ou égales à 400 mg
    d'EDA par kg de poids corporel, de même que chez des rats, au niveau
    du thymus, à la dose quotidienne de 800 mg/kg de poids corporel. Les
    études d'inhalation effectuées sur des rats n'ont pas permis
    d'observer d'effets à la dose d'environ 150 mg/m3 (60 ppm) et le seul
    effet imputable au traitement a été une légère dépilation à la dose
    d'environ 330 mg/m3 (132 ppm).

         Comme l'EDA a un effet irritant et sensibilisateur sur
    l'épiderme, il pourrait y avoir un risque d'apparition de dermatites
    d'irritation ou de dermatites allergiques si l'on porte pas
    d'équipement protecteur individuel sur les lieux de travail où il y a
    possibilité de contact cutané. L'EDA peut également provoquer une
    hypersensibilité des voies respiratoires et de l'asthme chez les
    personnes professionnellement exposées et c'est d'ailleurs cet effet
    que l'on considère comme le plus préoccupant sur le plan sanitaire.

         On ne sait pas avec exactement par quel mécanisme 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 composante 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 sensiblement 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 toxicologiques en milieu de culture car l'EDA
    est susceptible de former des complexes avec les ions métalliques. Ses
    effets pourraient donc être indirects et résulter de ce que certains
    éléments essentiels cessent alors d'être biodisponibles. Pour les
    invertébrés et les poissons, la valeur de la CL50 va de 14 à >1000
    mg/litre. On a trouvé une valeur de 0,16 mg/litre pour la dose sans
    effet observable (NOEC) sur la reproduction de  Daphnia.

         Etant donné que les résultats des épreuves de toxicité aiguë et
    chronique varient très largement, on a fixé à 16 µg/litre la valeur de
    la concentration sans effet observable prévisible (PNEC), en
    appliquant un coefficient d'incertitude de 10 à la valeur publiée la
    plus faible de la concentration sans effet observable (NOEC) sur la
    reproduction de  Daphnia. Des hypothèses prudentes relatives à la
    concentration prévisible dans l'environnement (PEC) permettent
    d'aboutir à une valeur du rapport PEC/PNEC justifiant quelques

    craintes eu égard aux concentrations initiales (par ex. lors de la
    décharge initiale dans un cours d'eau ou un estuaire). Néanmoins, une
    estimation plus élaborée de l'exposition probable indique un faible
    risque pour les organismes aquatiques.
    

    RESUMEN DE ORIENTACION

         Este CICAD sobre el 1,2 diaminoetano (etilendiamina) se basa en
    un examen de los problemas relativos a la salud humana
    (fundamentalmente ocupacional, pero con la inclusión también de una
    evaluación en el medio ambiente) preparado por la Dirección de Salud y
    Seguridad del Reino Unido (Brooke et al., 1997). En el documento
    original se incorporaron los datos obtenidos hasta el final de 1994.
    Se realizó asimismo una búsqueda bibliográfica amplia hasta julio de
    1997 para identificar cualquier información que se hubiera publicado
    después de la terminación del informe. La información sobre el destino
    y los efectos en el medio ambiente se basa en el informe del Comité
    Consultivo sobre Sustancias Químicas Existentes Importantes para el
    Medio Ambiente de la Sociedad Alemana de Química (BUA, 1997). La
    información sobre la preparación del documento original y su examen
    colegiado figura en el apéndice 1. La información acerca del examen
    colegiado de este CICAD se presenta en el apéndice 2. Este CICAD se
    aprobó como evaluación internacional en una reunión de la Junta de
    Evaluación Final celebrada en Tokio, Japón, del 30 de junio al 2 de
    julio de 1998. La lista de participantes en esta reunión figura en el
    apéndice 3. La Ficha internacional de seguridad química (ICSC 0269),
    preparada por el Programa Internacional de Seguridad de las Sustancia
    Químicas (IPCS, 1993), también se reproduce en este documento.

         El 1,2-diaminoetano (CAS No 107-15-3), conocido normalmente
    como etilendiamina (EDA), es un líquido sintético entre incoloro y
    amarillento a temperatura y presión normales. Es fuertemente alcalino
    y miscible con agua y con alcohol. Se utiliza fundamentalmente como
    intermediario en la fabricación de tetracetil etilendiamina, ácido
    etilendiaminotetracético (EDTA), floculantes orgánicos, resinas de
    urea y bisamidas grasas. También se usa, en proporción mucho menor, en
    la producción de formulaciones con destino a las industrias de
    tarjetas de circuitos impresos y acabado de metales, como agente
    acelerador o de curado en revestimientos/resinas de epóxido y en la
    fabricación de productos farmacéuticos. Se encuentra como contaminante
    (<0,5%) en las aminas grasas de suministro comercial, que se utilizan
    como agentes humectantes en emulsiones bituminosas. También se emplea
    en la síntesis de fungicidas a base de carbamato, en la fabricación de
    surfactantes y tintes y en productos químicos para el revelado
    fotográfico, así como en lubricantes para cuchillas. La EDA es un
    producto de la degradación de los fungicidas de
    etilenbis(ditiocarbamato).

         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 supone que la EDA volatilizada se arrastra. Es
    probable la volatilización a la atmósfera a partir del suelo, pero no
    del agua. Se adsorbe fuertemente a las partículas del suelo mediante
    enlaces electrostáticos; no parece haber lixiviación a través de los
    perfiles del suelo hacia el agua freática. Es posible la formación de

    complejos con metales y ácidos húmicos. La biodegradación es el
    mecanismo más probable de descomposición en el medio ambiente y
    debería ser bastante rápida; la adaptación de los microorganismos
    puede aumentar la degradación. La descomposición es menos rápida en el
    agua de mar que en el agua dulce. No es probable la bioacumulación.

         La toxicidad aguda de la EDA en los animales es moderada. Es
    irritante primario, de propiedades corrosivas cuando no está diluido,
    y es también sensibilizador cutáneo. La EDA no se ha sometido a
    pruebas de mutagenicidad con arreglo a las normas reglamentarias
    actuales y no se han realizado valoraciones para determinar la
    actividad clastogénica o el potencial para expresar su actividad en
    células somáticas  in vivo. Así pues, no se dispone de información
    suficiente para llegar a conclusiones firmes sobre el potencial
    mutagénico de la EDA. No fue carcinogénico en animales. Se han
    observado efectos no neoplásicos en el hígado de ratas (cambios
    pleomórficos a hepatocitos), tras la administración oral durante dos
    años con concentraciones de 45 mg de EDA/kg de peso corporal al día y
    superiores, sin que se vieran efectos con 9 mg EDA/kg de peso corporal
    al día. Aunque no está clara la importancia de estos cambios de las
    células hepáticas para la salud humana, así como si son consecuencia
    de la exposición oral o no (es decir, podrían no producirse por otras
    vías, porque pueden estar relacionados con los efectos del primer
    paso), no se pueden ignorar y se debería caracterizar el riesgo de su
    aparición. En estudios de administración oral por sonda se observaron
    efectos oculares en las ratas (atrofia de la retina y con dosis más
    altas formación de cataratas) con dosis de 100 mg de EDA/kg de peso
    corporal al día y superiores. Las dosis de 200 mg y 100 mg de EDA/kg
    de peso corporal al día y superiores se asociaron con daños renales en
    ratas y ratones, respectivamente. También se encontraron signos de
    efectos en el bazo de ratones y ratas con dosis de 400 mg de EDA/kg de
    peso corporal al día y superiores y en el timo de ratas con 800 mg/kg
    de peso corporal al día. En estudios de inhalación realizados con
    ratas no se detectaron efectos con concentraciones de unos 150 mg/m3
    (60 ppm), y con 330 mg/m3 (132 ppm) el único efecto relacionado con
    la dosis fue una ligera depilación.

         Puesto que la EDA diluida es irritante y sensibilizador cutáneo,
    si en el lugar de trabajo no se utiliza un equipo de protección
    personal adecuado y se produce un contacto cutáneo se corre el riesgo
    de contraer una dermatitis irritante y/o alérgica. La EDA puede
    inducir 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 sensibilización 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
    µg/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 PEC/PNEC que ponen de manifiesto
    alguna preocupación a partir de concentraciones iniciales (es decir,
    en el primer vertido en el río o el estuario). Sin embargo,
    estimaciones más precisas de la exposición indican un riesgo escaso
    para los organismos acuáticos.
    


    See Also:
       Toxicological Abbreviations
       Ethylenediamine (ICSC)
       Ethylenediamine  (SIDS)