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    Concise International Chemical Assessment Document 13








    TRIPHENYLTIN COMPOUNDS








    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 13



    TRIPHENYLTIN COMPOUNDS



    First draft prepared by Dr J. Sekizawa, National Institute of Health
    Sciences, Tokyo, Japan



    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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    WHO Library Cataloguing-in-Publication Data

    Triphenyltin compounds.

         (Concise international chemical assessment document ; 13)

         1.Organotin compounds - adverse effects   
         2.Organotin compounds - toxicity
         3.Environmental exposure   4.Maximum permissible exposure level
         I.International Programme on Chemical Safety   II.Series

         ISBN 92 4 153013 8            (NLM classification: QV 290)
         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
         8.8. Mode of action

    9. EFFECTS ON HUMANS

         9.1. Case reports
         9.2. Epidemiological studies

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         10.1. Aquatic environment
         10.2. Terrestrial environment

    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 triphenyltin
              11.1.3. Sample risk characterization
         11.2. Evaluation of environmental effects

    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 and disposal

    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
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    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.

    FIGURE 

         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.

    1.  EXECUTIVE SUMMARY

         This CICAD on triphenyltin compounds was based on a review
    prepared by the National Committee for Concise International Chemical
    Assessment Documents of Japan (CICAD National Committee, 1997). Many
    critical studies on health effects in this review were cited from
    monographs on pesticide residues prepared by the Food and Agriculture
    Organisation of the United Nations (FAO, 1991a,b) and the World Health
    Organization (WHO, 1992). These monographs report summaries of the
    many studies submitted to WHO by manufacturers for evaluation, in
    addition to summaries of published papers. In the case of studies
    submitted by manufacturers, original papers are proprietary and were
    not available to authors of the review prepared by the CICAD National
    Committee (1997), to authors of the CICAD draft, or to the CICAD Final
    Review Board. Therefore, this CICAD inevitably relies on the
    evaluations made by the Joint FAO/WHO Meeting on Pesticide Residues
    (JMPR) for those studies cited from summaries of proprietary data.

         Extensive information on environmental effects was obtained from
    a review of the environmental effects of triorganotin compounds,
    prepared by the Advisory Committee on Pesticides of the Health and
    Safety Executive of the United Kingdom (HSE, 1992). Additional data
    were obtained through a search of Medline and Toxline Plus databases
    up to October 1997. Information on the nature of the review processes
    and the availability of the source documents is presented 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
    1283) for triphenyltin hydroxide (TPTH), produced by the International
    Programme on Chemical Safety (IPCS, 1996), has also been reproduced in
    this document.

         Triphenyltin compounds are triphenyl derivatives of tetravalent
    tin. They are colourless solids with low vapour pressures. They are
    lipophilic and have low solubility in water.

         Triphenyltin and tributyltin compounds have been used extensively
    as algicides and molluscicides in antifouling products since the
    1960s. Use of triorganotins in antifouling paints has been restricted
    in many countries because of their catastrophic effects on the oyster
    industry and more general effects on the aquatic ecosystem.
    Triphenyltin is used as a non-systemic fungicide with mainly
    protective action.

         Triphenyltin is strongly adsorbed to sediment and soil, and
    little desorption occurs. Its half-life in water has been estimated to
    be several days in June and 2-3 weeks in November. Although
    triphenyltin compounds can be degraded by stepwise dephenylation and
    excreted in conjugated forms, they bioaccumulate in fish and snails,
    with bioconcentration factors (BCFs) ranging from several hundred to
    32 500 (in the intestinal sac of  Lymnaea stagnalis).

         Environmental concentrations of triphenyltin compounds vary
    depending upon how, when, and where the compounds were used.
    Concentrations ranging from 0 ng/litre to nearly 200 ng/litre have
    been detected in bay areas or marinas as a result of leaching from
    ships treated with triphenyltin-based antifouling paints.
    Environmental concentrations of triphenyltin compounds have decreased
    in recent years as a result of tightening restrictions on their use in
    antifouling paints.

         Triphenyltin compounds given orally to rats are not readily
    absorbed and are excreted primarily in faeces and partly in urine.
    They are metabolized to diphenyltin, monophenyltin, and
    non-extractable bound residues. Absorbed triphenyltin compounds
    accumulate in kidney and liver to the greatest extent, with smaller
    amounts in other organs. Triphenyltin compounds applied dermally can
    penetrate through the skin in a time- and dose-dependent manner.

         Triphenyltin exerts a variety of health effects in various animal
    species, including effects on the immune system,
    reproductive/developmental effects at levels near those that are
    maternally toxic (most lowest-observed-adverse-effect levels, or
    LOAELs, are in the several mg/kg range or lower), hyperplasia/adenomas
    in endocrine organs, apoptosis in thymus cells, calcium release in
    sarcoplasmic reticulum cells, and eye irritation. The underlying
    mechanisms of these effects are under investigation; a common
    mechanism may explain this toxicity profile.

         Triphenyltin compounds are moderately acutely toxic to rats. They
    are not carcinogenic, but some data show that they are co-clastogenic.

         Reproductive and developmental effects include a decrease in the
    number of implantations and live fetuses (at 1.0 mg triphenyltin
    acetate [TPTA]/kg body weight per day in a rabbit gavage study),
    reduction in litter size/pup weight and in relative thymus or spleen
    weight in the weanlings (at 1.5 mg TPTH/kg body weight per day in the
    diet in a two-generation reproduction study in rats;
    no-observed-adverse-effect level, or NOAEL, 0.4 mg/kg body weight per
    day), and abortion and reduction in fetal weight (at 0.9 mg TPTH/kg
    body weight per day in a rabbit gavage study). 

         The lowest NOAEL detected in the toxicity tests was 0.1 mg
    TPTH/kg body weight per day for maternal toxicity in a rabbit gavage
    study, based on decreased food consumption and body weight gain at 0.3
    mg/kg body weight per day. The same value was obtained in an early
    2-year rat study in which a slight decrease in white blood cells was
    seen at higher doses. In a 52-week dog study, the NOAEL was estimated
    to be 0.21 mg TPTH/kg body weight per day based on a decrease in
    relative liver weight in females at higher doses.

         Triphenyltin compounds affect the immune system. A decrease in
    immunoglobulin (Ig) concentrations (even at the lowest dose level,
    i.e., 0.3 mg TPTH/kg body weight per day in a 2-year feeding study in
    rats), lymphopenia (at 0.3 mg TPTH/kg body weight per day in another
    2-year feeding study in rats or at 0.338 mg TPTH/m3 in a 13-week
    inhalation study in rats), thymus atrophy (at 1.5 mg triphenyltin
    chloride [TPTCl]/kg body weight per day in a 2-week feeding study with
    weanling rats), and splenic atrophy (at 5 mg TPTH/kg body weight per
    day in a 28-day feeding study in mice) have been observed. Females are
    generally more susceptible than males.

         Several end-points were taken into consideration by JMPR in
    establishing the acceptable daily intake (ADI) of triphenyltin for
    oral exposure (FAO, 1991b; WHO, 1992). First, a 200-fold uncertainty
    factor was applied to the no-observed-effect level (NOEL) of 0.1 mg/kg
    body weight per day (based on a finding of reduced white blood cell
    counts at higher doses in a 2-year study in rats) to arrive at an ADI
    of 0-0.5 µg/kg body weight. Secondly, a 500-fold uncertainty factor
    was applied to a LOAEL of 0.3 mg/kg body weight per day in a 2-year
    study in rats in which increased mortality and reduced serum
    immunoglobulin levels were noted. Other NOAELs that were taken into
    consideration together with the above effect levels are 0.4 mg/kg body
    weight per day in a two-generation reproduction study with rats (a
    dose-related decrease in spleen and thymus weights in F1 and F2 male
    and female weanlings was observed at higher levels), 0.3 mg/kg body
    weight per day in a short-term study in rats (reduction in white blood
    cells, decrease in IgG, and increase in relative testes weight were
    seen at higher levels), 0.21 mg/kg body weight per day in a short-term
    dog study (increase in relative liver weight and decrease in serum
    albumin/globulin ratio were seen at higher levels), and 0.1 mg/kg body
    weight per day in a teratology study in rabbits (maternal toxicity was
    seen at higher levels).

         There are no data concerning occupational exposure to
    triphenyltin compounds. A few poisoning case reports describe
    neurotoxic effects, which appeared to persist. Exposure of the general
    public to triphenyltin compounds occurs mostly from ingestion of
    contaminated seafood, which in some cases has been found to contain
    triphenyltin levels as high as 1 µg/g (in muscle of some fish
    species). Triphenyltin intake from contaminated foods in Japan in 1997
    was estimated to be around 11% of the ADI (i.e., 2.75 µg/day for a
    50-kg person) established by JMPR.

         Triphenyltin compounds exert deleterious effects on aquatic
    organisms at very low concentrations. For example, imposex of rock
    shells (Japanese gastropods) was seen at around 1 ng/litre
    (no-observed-effect concentration, or NOEC, not determined), and
    chronic toxicity to fathead minnow ( Pimephales promelas) larvae was
    observed at 0.23 µg/litre (lowest-observed-effect concentration, or
    LOEC). Triphenyltin is considered to be an endocrine disruptor,
    because imposex, a phenomenon in which female gastropods develop male
    sex organs, is probably caused by hormonal disturbance.

         No NOEC for triphenyltin has been established for imposex in
    molluscs. Experimentally, by injection, triphenyltin has a potency
    similar to that of tributyltin in the genus  Thais. Triphenyltin is
    less potent than tributyltin in  Nucella; however, triphenyltin shows
    greater bioaccumulation than tributyltin. From this, it can be
    estimated that the NOEC for triphenyltin will be a few ng/litre or
    lower. The observed prevalence of imposex in  Thais in the field with
    ambient concentrations supports this estimate. Because residues of
    triphenyltin and tributyltin occur together in the environment, their
    relative contribution to observed imposex cannot be assessed for
     Thais species. Use of either triphenyltin or tributyltin in
    antifouling paint would lead to population declines of marine
    invertebrates on this basis.
    

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         Triphenyltin compounds are triphenyl derivatives of tetravalent
    tin. They conform to the general formula (C6H5)3Sn-X, where X is an
    anion or an anionic group, such as chloride, hydroxide, and acetate.

    CHEMICAL STRUCTURE 

         Physical and chemical properties of triphenyltin compounds vary
    depending upon the anion linked to tin. At ambient temperatures in the
    pH range of 3-8, TPTA and TPTCl are hydrolysed to TPTH within 1 min;
    as a consequence, the results of most studies with TPTA or TPTCl can
    be applied to TPTH. Triphenyltin compounds are colourless solids with
    low vapour pressures (<2 mPa at 50°C). The compounds are lipophilic
    and have low water solubility (typically a few mg/litre at neutral
    pH).

         The identity and physical/chemical properties of TPTH, TPTA, and
    TPTCl are given in Table 1. Additional properties of TPTH are
    presented in the International Chemical Safety Card (ICSC 1283)
    reproduced in this document.


        Table 1: Identity and physical/chemical properties of some triphenyltin compounds.a
                                                                                                                                         

                                   Triphenyltin hydroxide              Triphenyltin acetate                    Triphenyltin chloride
                                                                                                                                         

    Synonyms                       Fentin hydroxide; TPTH              Fentin acetate; TPTA                    Fentin chloride; TPTCl

    Chemical Abstracts             76-87-9                             900-95-8                                639-58-7
    Service (CAS) Registry No.

    Molecular formula              C18H16OSn                           C20H18O2Sn                              C18H15ClSn

    Molecular weight               367.0                               409.1                                   385.5

    Melting point                  122-123.5°C                         122-124°C                               106°C

    Solubility in water (20°C)     1 mg/litre at pH 7                  9 mg/litre at pH 5                      40 mg/litre 
                                   greater at lower pH                                                         (pH not given)

    Solubility in other            10 g/litre (ethanol)                22 g/litre (ethanol)                    moderately soluble
    solvents (20°C)                171 g/litre (dichloromethane)       82 g/litre (ethyl acetate)              in organic solvents
                                   28 g/litre (diethyl ether)          5 g/litre (hexane)
                                   50 g/litre (acetone)                460 g/litre (dichloromethane)
                                                                       89 g/litre (toluene)

    Vapour pressure                0.047 mPa (50°C)                    1.9 mPa (60°C)                          0.021 mPa
    Log Kow                        3.43                                3.43                                    -
                                                                                                                                        

    a From Tomlin (1997); NLM (1998).
        


    3.  ANALYTICAL METHODS

         Triphenyltin compounds and their degradation products can be
    analysed in food commodities and in environmental or biological media
    using several techniques, depending upon type of medium and
    sensitivity required. The procedure usually starts with either liquid
    extraction or adsorption onto a solid matrix, followed by
    re-extraction and/or concentration. Quantification is then performed
    using flame or flameless atomic absorption spectrometry, gas
    chromatography with flame photometric or mass spectrometric detection,
    or normal-phase high-performance liquid chromatography with
    ultraviolet or fluorescence detection (Hattori et al., 1984; Ishizaka
    et al., 1989; Fent & Hunn, 1991; Gomez-Ariza et al., 1992; Staeb et
    al., 1992; Tsunoda, 1993; Kohri et al., 1995; Suzuki et al., 1996).

         The detection limits of these techniques are in the range of
    ng/litre for water and <1 µg/kg for sediments and biological samples.
    Triphenyltin can also be separated from samples by capillary
    supercritical fluid chromatography and measured by inductively coupled
    plasma mass spectrometry. A detection limit of 12.0 pg was obtained
    for triphenyltin using this method (Vela & Caruso, 1993).

         Triphenyltin in water, sediment, and biological samples, as well
    as inorganic tin that is excreted in urine following exposure to
    triphenyltin, can be extracted with hydrogen chloride and
     n-hexane/benzene (3:2 v/v) in the presence of tropolone, then
    pentylated with a Grignard reagent prior to gas chromatography with
    flame photometric detection. Quantification limits by this method were
    found to be 3 ng/litre for water, 0.5 µg/kg for sediments and
    biological samples, and 3 pg as tin for urine (Ohhira & Matsui, 1991,
    1993; Harino et al., 1992).
    

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         Triphenyltin compounds have been used extensively as algicides
    and molluscicides in antifouling products since the 1960s (HSE, 1992).

         TPTA and TPTH are used mainly as fungicides with a preventive
    action on potatoes, sugar beets, hops, and celery (FAO, 1991a).
    Triphenyltin compounds are used on rice against fungal diseases,
    algae, and molluscs.

         Use of triorganotins in antifouling paints has been restricted in
    many countries because of their catastrophic effects on the oyster
    industry and more general effects on the aquatic ecosystem.

         Information on amounts of triphenyltins used has been obtained
    only from Japan. Use of triphenyltin compounds for antifouling paints
    in Japan decreased from 4835 tonnes in 1983 to 346 tonnes (formulation
    basis) in 1989 (Sugita, 1992). Their use for antifouling paints was 40
    tonnes (active ingredient) in 1989 and stopped after 1990 in Japan
    (MITI, 1998). About 120-140 tonnes (active ingredient) were produced
    each year between 1994 and 1996 in Japan for export (MITI, 1998).

         Between 1978 and 1990, 33-75 tonnes (active ingredient) of
    phenyltin compounds were produced in Japan for use as a fungicide;
    production ceased in 1990 (JPPA, 1982-1996).
    

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         Degradation of triphenyltin occurs through sequential
    dephenylation resulting from cleavage of the tin-carbon bond through
    biological, ultraviolet irradiation, chemical, or thermal mechanisms;
    biological cleavage and cleavage by ultraviolet irradiation are
    considered to be the most significant processes. Abiotic factors, such
    as elevated temperatures, increased intensity of sunlight, and aerobic
    conditions, seem to enhance triphenyltin degradation in the
    environment (CICAD National Committee, 1997).

         Hydrolysis of triphenyltin compounds in water leads to the
    formation of principally TPTH and various hydrated oxides (Beurkle,
    1985). It has been demonstrated that the presence of chloride from
    seawater lowers the solubility of triphenyltin compounds by reaction
    with the hydrated cation to form the covalent organotin chloride
    (Ozcan & Good, 1980).

         In plants, no translocation occurs from treated leaves (FAO,
    1991a). TPTA and TPTCl are spontaneously hydrolysed to form TPTH.
    Phenyl groups are split off from TPTH to form diphenyl and monophenyl
    compounds. Both parent compound and metabolites conjugate to form
    glycosides or glutathione conjugates.

         The persistence of TPTA and TPTH depends on soil type and pH.
    TPTH is strongly adsorbed to sediment and soil, and little desorption
    occurs. Therefore, uptake into plants via roots may be expected to be
    extremely low.

         14C-labelled TPTA in soil degraded to inorganic tin with
    evolution of 14C-labelled carbon dioxide. Similar experiments on
    sterile soil showed insignificant evolution of labelled carbon
    dioxide, which suggests that degradation can be attributed to
    microorganisms (Barnes et al., 1971). Soil respiration was slightly
    enhanced after treatment with TPTA, indicating that there were no
    adverse effects on aerobic microorganisms (Suess & Eben, 1973).

         A half-life of 1-3 months has been reported for TPTH in sandy and
    silt loam soils and 126 days in flooded silt loam (US EPA, 1987). The
    half-life of triphenyltin in water was estimated to be several days in
    June and 2-3 weeks in November (Soderquist & Crosby, 1980).

         Half-lives of triphenyltin in mussels ( Mytilus edulis) taken in
    the summer of 1989 in Yokohama (a busy port, heavily contaminated with
    triphenyltin) and Urayasu (a river mouth, about 10 times less polluted
    than Yokohama) in Japan were estimated to be 139 and 127 days,
    respectively (Shiraishi & Soma, 1992). Biological half-lives of
    triphenyltin in short-necked clams ( Tapes [ Amygdala]  japonica)
    and guppy ( Poecilia reticulata) were estimated to be approximately
    30 days and 48 days, respectively (Takeuchi et al., 1989; Tas et al.,
    1990). The ecological half-life of triphenyltin in gastropods was
    estimated to be 347 days (Mensink et al., 1996).

         Temporal variations of phenyltin concentrations in zebra mussels
    ( Dreissena polymorpha) were studied at two locations near potato
    fields during and after the triphenyltin fungicide spraying season in
    the Netherlands (Staeb et al., 1995). Phenyltin concentrations in
    zebra mussels were high in the period before and during harvesting but
    not during the spraying season, which suggests that phenyltin
    compounds in some foliage ended up in the water and were taken up by
    the mussels. Although higher concentrations were detected in locations
    near areas of spray operation, marinas, and harbours, the widespread
    presence of triphenyltin residues in mussels collected in 56 locations
    all over the Netherlands suggests the contribution of transport via
    the air.

         An extensive study on the presence of nine organotin compounds in
    a freshwater food-web (zebra mussel, eel, roach bream, pike, perch,
    pike perch, and cormorant; details and scientific names of species not
    given in the report) revealed that phenyltin concentrations in benthic
    species were higher than butyltin concentrations in lower trophic
    levels (Staeb et al., 1996). This suggests that triphenyltin is to a
    large extent taken up from the sediment by benthic organisms. At
    higher trophic levels, net bioaccumulation of triphenyltin compounds
    was greater than that of tributyltins, resulting in relatively higher
    triphenyltin concentrations. With birds, the highest concentrations of
    organotins were in liver and kidney and not in subcutaneous fat, which
    shows that organotins accumulate via mechanisms different from those
    of traditional lipophilic compounds.

         BCFs in daphnids did not exceed 300 (Filenko & Isakova, 1979). In
    fish, BCFs ranged from 257 to 4100. The highest value (4100) was
    estimated for filefish ( Rudarius ercodes) cultivated in water
    containing 148 ng triphenyltin/litre for 56 days (Yamada & Takayanagi,
    1992). When  Lymnaea stagnalis (a freshwater snail) was exposed to 2
    µg TPTH/litre for 5 weeks, tin accumulated to the greatest extent in
    the intestinal sac, to a level of 65.1 mg/kg (i.e., BCF of 32 500; Van
    der Maas et al., 1972).

         Tissue concentrations of triphenyltin in common carp ( Cyprinus
     carpio) exposed to 5.6 µg TPTCl/litre for 10 days, which reached a
    plateau after 7 days, were examined. The BCFs were highest in the
    kidney (2090), followed by liver (912), muscle (269), and gall bladder
    (257) (Tsuda et al., 1987).
    

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

         Triphenyltin levels in ambient water, sediment, and organisms
    were surveyed in about 30 locations (estuaries and bay) in Japan
    between 1982 and 1995 (Japan Environment Agency, 1983, 1996).
    Triphenyltin levels in water (detection limit 5 ng/litre) and sediment
    (detection limit 1.0 ng/g) of bay and inshore areas decreased from
    2.7-8.0 ng/litre and 3.3-7.8 ng/g in 1988-1991 to 2.5-3.0 ng/litre and
    1.5-2.3 ng/g in 1992-1995, respectively.

         Triphenyltin levels in ambient water and sediment in the Tokyo
    bay area gradually decreased from peak levels (geometric means: 25.1
    ng/litre in water, 4.3 ng/g in sediment) to 1.8 ng/litre (water) and
    0.19 ng/g (sediment) in 1993 because of consecutive tightening of
    regulations and voluntary withdrawal of use by coastal fishery
    industries (Takeuchi et al., 1991).

         Triphenyltin levels were measured in fish and shellfish obtained
    from the Tokyo Central Fish Wholesale Market from April 1988 to March
    1991 (Takeuchi et al., 1991; see section 6.2). The finding of
    triphenyltin in coastal fish, as well as in open-ocean or pelagic
    fish, is suggestive of biomagnification through the food-chain. High
    levels in clams and oysters showed that direct uptake from water or
    sediment also plays an important role for these species.

         In the Netherlands, up to 920 ng triphenyltin (as tin)/g sediment
    was found in the Westinder lake system in 1993, whereas no
    triphenyltin was found in the water (detection limit 5 ng/litre)
    (Staeb et al., 1996). In freshwater marinas in Switzerland, up to 191
    ng triphenyltin/litre was detected in 1988-1990, whereas 107 ng/g dry
    weight was the highest value measured in vertical sediment core
    profiles, and concentrations up to 11 ng triphenyltin/litre were
    measured in the river system (Fent & Hunn, 1991, 1995). In  Dreissena
    mussels of the same marinas, up to 3.88 µg triphenyltin/g wet weight
    was detected (Fent & Hunn, 1991), whereas up to 0.31 µg triphenyltin
    (as tin)/g dry weight in  Mytilus mussels and up to 0.24 µg
    triphenyltin/g in  Thais snails were detected in a Spanish marina
    area in 1995 (Morcillo et al., 1997).

         Biological monitoring of triphenyltin concentrations in fish from
    coastal areas of Japan showed that concentrations decreased between
    1989 (detected in 40 out of 65 samples, maximum concentration 2.6 µg/g
    wet weight in muscle, detection limit 20 ng/g) and 1995 (detected in
    21 out of 70 samples, maximum concentration 0.25 µg/g) (Japan
    Environment Agency, 1996). Similarly, triphenyltin levels in mussels
    and birds decreased over the same period: triphenyl was detected in 17
    out of 25 samples of mussels (maximum concentration 0.45 µg/g) and in
    5 out of 10 samples of birds (maximum concentration 0.05 µg/g) in
    1989, compared with 0 out of 35 samples of mussels and 0 out of 10
    samples of birds in 1995 (detection limit 0.02 µg/g in both years)
    (Japan Environment Agency, 1996).

         Zebra mussels were used as a biomonitor to evaluate organotin
    pollution in Dutch fresh waters (Staeb et al., 1995). High
    concentrations (1700-3200 ng tin/g dry weight) were found near
    locations where triphenyltin fungicide had been sprayed. Degradation
    products (di- and monophenyltins) were also detected in nearly all
    mussels.

         In pecan orchards (Georgia, USA) where triphenyltin fungicides
    were sprayed, triphenyltin concentrations in foliage and soils were
    8.5-37 µg/g dry weight and 1.2-12 µg/g dry weight, respectively
    (Kannan & Lee, 1996). Although triphenyltin was absent in surface soil
    where the fungicide had been sprayed 8-10 times a year until 2 years
    earlier, monophenyltin was detected at approximately the same
    concentration as in recently sprayed orchards. Fish (bluegill
    [ Lepomis macrochirus], largemouth bass [ Micropterus salmoides],
    and channel catfish [ Ictalurus punctatus]) from a pond near a
    recently sprayed orchard contained predominantly monophenyltin (with
    the highest concentration of 22 µg/g wet weight in the liver of
    catfish) in addition to smaller amounts of triphenyltin and
    diphenyltin.

    6.2  Human exposure

         No data are available on occupational exposure to triphenyltin
    compounds. There are also no data on levels of triphenyltin in indoor
    or ambient air or in drinking-water.

         The residue data available in support of registration of
    triphenyltin compounds in the United Kingdom, obtained using various
    colorimetric methods, ranged between 0.013 and 0.016 mg/kg in 3 out of
    25 samples of potatoes provided by the Potato Marketing Board and
    known to have been treated with a triphenyltin fungicide. The
    remaining samples contained residues below 0.013 mg/kg, which is the
    limit of detection (ACP, 1990). In supervised trials of triphenyltin
    formulations (wettable powder; 54%; 216-324 g active ingredient/ha) on
    potatoes in Germany, residues ranged from 0.3 mg/kg to less than the
    detection limit (0.01 mg/kg) 7 days after application (FAO, 1991a).
    Supervised trials of triphenyltin formulations (wettable powder; 50 or
    54%; 216-324 g active ingredient/ha) in Germany on sugar beets showed
    residues ranging from 0.1 to 1.9 mg/kg in leaves and less than the
    detection limit (0.05 mg/kg) in beets 35 days after application. In
    supervised trials of triphenyltin formulations (wettable powder) on
    rice in the USA, residues ranged from less than the detection limit
    (0.01 mg/kg) to 0.03 mg/kg 22-23 days after application (57.5%; 536 g
    active ingredient/ha, twice) and from less than the detection limit
    (0.01 mg/kg) in milled rice or bran 22-46 days after application
    (47.5%; 250 or 500 g active ingredient/ha) (FAO, 1991a).

         When 14C-labelled TPTH was administered orally to dairy cows
    over a period of 60 days at doses of 1.13, 5.61, or 22.44 mg
    triphenyltin/kg diet (dry matter), residues were 0.08, 0.31, and 0.9
    g/kg in meat and 0.006, 0.026, and 0.41 mg/kg in milk, corresponding
    to transfer factors of 0.038-0.068 in meat and 0.004-0.006 in milk
    (Smith, 1981).

         Triphenyltin levels were measured in fish, clams, and shrimps
    obtained from the Tokyo Central Fish Wholesale Market from April 1988
    to March 1991. Levels were higher in cultured fish and in fish from
    coastal or bay areas than in pelagic fish (mean concentration 0.048
    µg/g) (Takeuchi et al., 1991). Freshwater fish were relatively
    uncontaminated. Fish obtained from bay or inshore areas were the most
    contaminated; the highest concentration measured in 82 samples of four
    fish species was >1.0 µg triphenyltin/g muscle (mean 0.317 µg/g).
    Triphenyltin levels in clams and shrimps ranged from 0 to 0.83 µg/g
    edible portion (mean 0.113 µg/g). Triphenyltin intake from pelagic
    fish was estimated based on analyses of fish samples in 1988-1991 by a
    market basket study in Tokyo as 3.15 µg (mean concentration of 0.048
    µg/g times 65.6 g intake of pelagic fish by a Japanese person per
    day). Although tributyltin was used more abundantly than triphenyltin
    in antifouling paints, residue levels in fish and shellfish were
    mostly comparable, with several differences among fish groups.

         National market basket studies, including the above study, have
    estimated daily intakes of triphenyltin per 50-kg person in Japan
    (expressed as TPTCl) to be 4.3, 10.4, 2.7, 0.6, 1.2, 1.4, 0.7, and 2.7
    µg in 1990, 1991, 1992, 1993, 1994, 1995, 1996, and 1997, respectively
    (NIHS, 1998). Triphenyltin compounds were found mostly in seafood. As
    about a twofold difference was observed between the above estimated
    daily intakes (averages of 10 local laboratories, including the Shiga
    Prefecture) and estimated intakes in the Shiga Prefecture (Tsuda et
    al., 1995), this implies that differences in food intake patterns or
    some other factor may influence estimates of daily intake. This fact
    and coincidental contamination with tributyltin must be taken into
    account in any risk estimation for exposure by the oral route.

         Another report of a market basket survey estimated the intake of
    triphenyltin from raw and processed seafood in Nagasaki Prefecture (a
    southern part of Japan) in 1989-1991 to be 8.51 µg/day per person
    (Baba et al., 1991). TPTCl concentrations in fish, shellfish, seaweed,
    canned fish/shellfish, fish paste product, and salted/dried fish were
    274, 80, 21, 12, 16, and 22 ng/g (averages), respectively. Cooking did
    not reduce the triphenyltin content of fish and shellfish samples.
    

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         Several studies have shown that TPTH orally administered to rats
    is eliminated mainly via the faeces, with smaller amounts in the
    urine. Metabolites found in faeces included di- and monophenyltin as
    well as a significant portion of non-extractable bound residues (the
    sulfate conjugates of hydroquinone, catechol, and phenol). In faeces,
    the major substance present was unchanged parent compound.

         TPTA was rapidly and completely hydrolysed to TPTH at pH 3-8 and
    23-24°C (Beurkle, 1985).

         Seven days after oral administration to rats, TPTH residues
    (approximately 3% of the administered dose) were distributed mainly in
    the kidneys, followed by liver, brain, and heart (Eckert et al., 1989;
    Kellner & Eckert, 1989). Similar results were obtained after chronic
    exposure for 104 weeks (Dorn & Werner, 1989; Tennekes et al., 1989a).

         Species differences in the metabolism of triphenyltin were
    investigated by Ohhira & Matsui (1996). Dearylation of triphenyltin
    was slower in hamsters than in rats, and pancreatic accumulation of
    triphenyltin was higher in hamsters. There was a good correlation
    between tin concentrations in the pancreas and plasma glucose levels,
    indicating that triphenyltin-induced hyperglycaemia depends upon the
    amount of tin compounds absorbed into the pancreas. Most of the tin
    compounds in the brains of both species were triphenyltin.

         Percutaneously absorbed TPTA in guinea-pigs was distributed to
    the highest extent in the liver, followed by the adrenal glands,
    kidneys, brain, spinal cord, and pancreas (Nagamatsu et al., 1978).
    Triphenyltin, diphenyltin, and monophenyltin were detected in faeces
    in a ratio of 15:6:2. The biological half-life of triphenyltin was
    estimated to be 9.4 days.
    

    8.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         Because TPTA and TPTCl are hydrolysed rapidly to TPTH in aqueous
    media, the results of oral toxicity studies with these triphenyltin
    compounds can be applied to TPTH. Many critical studies described
    below were cited from WHO (1992), which summarizes evaluations of the
    original proprietary reports; as details of these original proprietary
    reports were not available to the CICAD authors, we have relied on the
    WHO evaluation for these studies.

    8.1  Single exposure

         After a single oral administration of triphenyltin, toxic signs
    observed in various species include anorexia, emesis, tremor, and
    diarrhoea, followed by drowsiness and ataxia (WHO, 1992). No further
    details were provided. Clinical signs appeared a day after
    administration and were exacerbated over the following 3 days or so
    (CICAD National Committee, 1997). Oral LD50s for TPTH were
    approximately 160 mg/kg body weight in rats and 100-245 mg/kg body
    weight in mice; oral LD50s for TPTA were 140-298 mg/kg body weight in
    rats and 81-93 mg/kg body weight in mice (Ueda & Iijima, 1961; Scholz
    & Weigand, 1969; Hollander & Weigand, 1974; Ikeda, 1977; Leist &
    Weigand, 1981a,b).

         Dermal LD50s were 127 mg/kg body weight in rabbits and 1600
    mg/kg body weight in rats for TPTH (Leist & Weigand, 1981c,d) and 350
    mg/kg body weight in mice and >2000 mg/kg body weight in rats for
    TPTA (Ueda & Iijima, 1961; Diehl & Leist, 1986a). Inhalation LC50s
    were 44-69 mg/m3 in rats for TPTH and TPTA (Hollander & Weigand,
    1981, 1986).

    8.2  Irritation and sensitization

         TPTA was not irritating to the skin of rabbits (Diehl & Leist,
    1986b). However, severe ocular lesions developed in rabbits; these
    were not reversible (Diehl & Leist, 1986c).

         At concentrations that were irritating to skin, TPTH (purity
    97.0%) showed no skin sensitization in guinea-pigs in the Buehler test
    (Leist & Weigand, 1981e; Schollmeier & Leist, 1989) or in the
    maximization test (Diehl & Leist, 1987). TPTA gave a positive response
    when tested for skin sensitization in guinea-pigs in the Buehler test
    (Diehl & Leist, 1986d). Further details were not given.

    8.3  Short-term exposure

         One unpublished dermal exposure study in rats submitted to WHO
    (1992) is described in Table 2. A NOAEL of 10 mg/kg body weight was
    identified in this study. Additional short-term studies that examined
    effects on the immune system are discussed in section 8.7.

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         Several subchronic studies on the effects of TPTH on several
    animal species exposed by various routes have been performed (WHO,
    1992). Studies that show effects at the lowest doses in each animal
    species are summarized in Table 2. Further studies and details are
    available in WHO (1992) and CICAD National Committee (1997).

         Dietary studies with rats, mice, and dogs showed a decrease in
    immunoglobulin levels, body weight gain, and white blood cells and an
    increase in liver weights and death. Decreases in immunoglobulin
    levels and white blood cells were observed consistently at lowest
    effect levels in all tests. NOAELs for dietary studies were identified
    as 3.4-4.1 mg/kg body weight per day in mice (3-month exposure),
    0.30-0.35 mg/kg body weight per day in rats (13-week exposure), and
    0.21 mg/kg body weight per day in dogs (52-week exposure) (Table 2).
    Several species were affected in a similar way, although mice appeared
    to be least sensitive.

         In an inhalation study in rats exposed to TPTH, macroscopic
    lesions in the lungs were observed at 2.0 mg/m3 in most of the dead
    rats (all males and one female died at this dose), and histopathology
    revealed severe effects in lower air passages and in the lungs. The
    NOAEL was 0.014 mg/m3.

    8.4.2  Chronic exposure and carcinogenicity

         Chronic toxicity/carcinogenicity studies in rats and mice exposed
    to TPTH (WHO, 1992) are summarized in Table 3. There were indications
    that the doses received by animals in the US National Toxicology
    Program (NTP) studies may have been lower than intended owing to
    instability of the test compound in the diet. The size of the control
    group (small compared with test groups) in the NTP mouse study limits
    interpretation of the results. Consistent findings in all studies are
    a decrease in immunoglobulin concentrations at lowest effect levels
    and a higher susceptibility of females, as seen in a higher mortality
    rate and reduced body weight gain at low doses.

         Effects on immunoglobulin levels were reported with both rats and
    mice. In an 80-week feeding study in mice, a decrease in
    immunoglobulin concentrations was seen at dose levels of 5, 20, and 80
    ppm TPTH in the diet. The incidence of hepatocellular adenoma in both
    sexes and the incidence of hepatocellular carcinoma in females only
    were increased at the highest dose (80 ppm) (Tennekes et al., 1989a;
    Table 3). The NOAEL in this study was 5 ppm, equivalent to 0.85 mg/kg
    body weight per day for males and 1.36 mg/kg body weight per day for
    females, based on decreased body weight gain in females.


        Table 2: Short-term and subchronic studies on TPTH.
                                                                                                                                    

    Study type,      Dose               Species                Observed effects (mostly at lowest effect               Reference
    duration         (purity; %)        (strain, number/dose)  level) and NOAEL values
                                                                                                                                    

    Diet             0, 4, 20, 100 ppm  Mouse                  At 100 ppm, haematological and biochemical              Suter & Horst,
    3 months         (97.2%)            (NMRI, 10/group)       parameters were affected, including a reduction         1986a
                                                               in erythrocyte count and haemoglobin level,
                                                               an increase in platelet count, and a decrease
                                                               in IgG, IgA, and IgM (females only). Liver
                                                               weight was increased in both sexes, and
                                                               relative weights of ovaries, adrenals, kidneys,
                                                               heart, and brain were decreased in females at
                                                               this dose. NOAEL: 20 ppm (3.4 mg/kg body weight
                                                               per day for males, 4.1 mg/kg body weight per day
                                                               for females).

    Diet             0, 4, 20, 100 ppm  Rat                    Relative testis weight was significantly higher in      Suter & Horst,
    13 weeks,        (97.2%)            (Wistar, 15/group)     high-dose males, whereas no effects on spleen and       1986b
    4-week                                                     thymus weights were observed. In females, white blood
    recovery                                                   cells decreased at 20 ppm (corresponding to 1.75 mg/kg
                                                               body weight per day) and 100 ppm. After the recovery
                                                               period, IgG decreased significantly in females at
                                                               all dose levels. NOAEL: 4 ppm (0.30 mg/kg body
                                                               weight per day for males, 0.35 mg/kg body weight per
                                                               day for females).

    Diet             0, 2, 6, 18 ppm    Dog                    At 18 ppm, relative liver weight was increased in       Sachose et al., 1987
    52 weeks         (97.2%)            (beagle, 10/group)     females and serum albumin/globulin ratio was
                                                               decreased in males. NOAEL: 6 ppm (0.21 mg/kg body
                                                               weight per day).

    Table 2 (continued)
                                                                                                                                    

    Study type,      Dose               Species                Observed effects (mostly at lowest effect               Reference
    duration         (purity; %)        (strain, number/dose)  level) and NOAEL values
                                                                                                                                    

    Dermal           0, 5, 10, 20       Rat                    Dose-related increase in erythema and scale             Leist, 1988
    21 applications  mg/kg body         (unknown,              formation was seen. At 20 mg/kg body weight, four
    in 29 days,      weight each        6-12/group)            rats died. Lymphocytes decreased in both sexes and
    14-day recovery  time (97.1%)                              monocytes increased in females at 20 mg/kg body 
                                                               weight. NOAEL for systemic toxicity: 10 mg/kg body
                                                               weight.

    Inhalation       0.014, 0.338,      Rat                    All males and one female died at the highest dose. At   Duchosal et 
    6 h/day,         1.997 mg/m3,       (Wistar,               0.338 mg/m3, a decrease in white blood cells and        al., 1989
    5 days/week,     nose-only          10/group)              biochemical and haematological changes were seen in
    13 weeks,        exposurea (96.2%)                         females. IgM increase was seen in males at 0.338
    4-week recovery                                            mg/m3. Histopathology revealed degenerative and
                                                               inflammatory lesions in the anterior part of the nasal
                                                               cavity, in the trachea, and in the lungs in the 
                                                               highest dose group of both sexes. NOAEL: 0.014 mg/m3.
                                                                                                                                    
    a Mass median aerodynamic diameter: 3 µm.
    

         In a 2-year rat feeding study with dietary concentrations of 0,
    5, 20, and 80 ppm TPTH (Tennekes et al., 1989b), a decrease in
    immunoglobulin concentrations was observed in all triphenyltin-dosed
    groups. An increase in the incidence of pituitary adenoma in females
    and an increase in testicular Leydig cell tumours at higher doses were
    accompanied by non-neoplastic lesions in these organs. Low survival at
    higher doses limits interpretation of the results in females. A NOAEL
    could not be established at the lowest concentration of 5 ppm
    (equivalent to 0.3 and 0.4 mg/kg body weight per day in males and
    females, respectively) because of increased mortality in females and
    reduced serum immunoglobulin levels at this dose.

         Although some tumours were detected in the above studies, the WHO
    expert group apparently evaluated those as being not significant (WHO,
    1992). No detailed explanation of the reasons for this or results of
    statistical analysis were provided in the report. Recently, Clegg et
    al. (1997) critically examined the human relevance of Leydig cell
    hyperplasia and adenoma formation in rodents after chronic exposure
    and suggested that a hormonal mode of action, which may be of little
    relevance to humans, either mechanistically or quantitatively, could
    be operating. They also pointed out the very low incidence of Leydig
    cell adenomas in humans (age-adjusted occurrence of 0.4 per million).

         An early 2-year rat study showed a reduction in white blood cell
    count at a TPTH dietary level of 5 ppm (corresponding to 0.3 mg/kg
    body weight per day) (Til et al., 1970). The NOEL was chosen as 2 ppm
    in the diet (equivalent to 0.1 mg/kg body weight per day) based on
    this finding.

    8.5  Genotoxicity and related end-points

         Most  in vitro and  in vivo genotoxicity tests, such as the
     Salmonella mutagenicity test, yeast forward mutation test, mitotic
    gene conversion assay, mouse lymphoma forward mutation assay,
    chromosomal aberration assay, unscheduled DNA synthesis, micronucleus
    test in mice, cytogenetic assay in Chinese hamster, and dominant
    lethal assay in rats, showed negative results at the maximum doses
    tested, based on studies reviewed in WHO (1992).

         There are no new data that impact on the conclusion in WHO (1992)
    that triphenyltin is not genotoxic. Recent data indicate, however,
    that triphenyltin potentiates the genotoxicity of other substances.
    Triphenyltin showed potentiation of mitomycin C-induced breakage-type
    chromosomal aberrations in cultured hamster cells when cells were
    treated during the G2 phase (Sasaki et al., 1993). Similarly, the
    frequency of micronuclei induction by mitomycin C (1 mg/kg
    intraperitoneal injection) in mouse peripheral reticulocytes was
    enhanced by treatment with TPTCl, although TPTCl itself did not induce
    micronuclei (Yamada & Sasaki, 1993). Positive responses in these

    assays may be related to the toxic effects of triphenyltin on
    lymphocytes, because two  in vivo studies for chromosomal aberrations
    (a micronucleus test in mice and a cytogenetic test in Chinese
    hamsters) were negative. These data support the conclusion of the WHO
    (1992) group.

         It is therefore concluded that triphenyltin does not present a
    genotoxic hazard.

    8.6  Reproductive and developmental toxicity

         Triphenyltin appears to cause reproductive effects in rats and
    developmental toxicity in rats, rabbits, and hamsters at low doses
    (around 1 mg/kg body weight and higher) at which maternal toxicity is
    observed. Studies that show effects at the lowest doses for various
    end-points in experimental animals are summarized in Table 4 (WHO,
    1992; CICAD National Committee, 1997). Decreases in number of
    implantations, live fetuses, and mean fetal weight and increases in
    resorption were the consistent findings observed at lowest effect
    doses.

         An increase in the number of dead F1 pups and a decrease in mean
    litter size, pup weight, and relative spleen and thymus weights in the
    weanlings were observed in a two-generation rat study at 18.5 ppm TPTH
    in the diet (approximately 1.5 mg/kg body weight per day); at this
    concentration, body weight gain and food consumption of the parents
    were not affected (Young, 1986). The NOAEL in this study was 5 ppm
    (equivalent to 0.4 mg/kg body weight per day).

         A general paucity of mature sperm was seen in rats treated with
    TPTA and TPTCl in the diet (20 mg/kg body weight per day) for 20 days,
    and spermatogenic anomalies were observed in histological sections
    (Snow & Hays, 1983). Reduced food intake and the resultant decrease in
    weight gain were suspected as the cause, as malnutrition is known to
    precede gonadal dysfunction and even atrophy. However, differences in
    the distribution of spermatogenic phases in rats treated with TPTA and
    TPTCl do not support this explanation.

         TPTCl prevented implantation in rats in a dose-dependent manner
    when administered at 0, 3.1, 4.7, or 6.3 mg/kg body weight per day on
    days 0-3 and at 0, 6.3, 12.5, or 25.0 mg/kg body weight per day on
    days 4-6. The compound caused larger implantation failures when
    administered during earlier stages of blastogenesis (Ema et al.,
    1997). Implantation failure was observed at 4.7 and 6.3 mg/kg body
    weight per day on days 0-3 and at 12.5 and 25.0 mg/kg body weight per
    day on days 4-6. The effects of TPTCl on uterine function, as a cause
    of implantation failure, were determined using pseudopregnant rats
    dosed at 0, 3.1, 4.7, or 6.3 mg/kg body weight per day on days 0-3
    (Ema et al., 1998). A significant suppression of the uterine
    decidualization and decrease in the serum progesterone levels were


        Table 3: Chronic exposure and carcinogenicity studies on TPTH.
                                                                                                                                      

    Duration              Chemical dose         Species             Effects, NOAEL                                         Reference
                          (purity; %)           (strain,
                                                number/dose)
                                                                                                                                      

    78 weeks with         0, 37.5, 75 ppm       Mouse               No treatment-related effects were seen in              NTP, 1978
    26-week               (not stated)          (B6C3F1,            clinical signs or body weight, although survival
    observation           After 1 week,         50/group)           decreased in females with increased dose. No
    period                only 57.9% of                             tumour incidence was found histopathologically.
                          the initial dose                          The size of the control group (20 mice of
                          recovered                                 each sex) limits interpretation of the results.

    80 weeks              0, 5, 20, 80 ppm      Mouse (KFM-Han,     Body weight gain decreased at 80 ppm for males and     Tennekes et 
                          (97.2% prepared       NMRI, 50/group)     at 20 and 80 ppm for females. Decreases in             al., 1989a
                          daily)                                    immunoglobulin concentrations were observed at
                                                                    various levels. An increased relative number of
                                                                    lymphoid cells was detected in femoral bone
                                                                    marrow myelogram for all treated groups.
                                                                    Incidence of hepatocellular adenomas was 12.2,
                                                                    20, 26, and 32% at 0, 5, 20, and 80 ppm,
                                                                    respectively, for males and 0, 0, 0, and 18%
                                                                    at 0, 5, 20, and 80 ppm, respectively, for
                                                                    females. At 80 ppm, increased incidence of
                                                                    hepatocellular carcinoma was seen in females
                                                                    (6% compared with 0% at other doses). Based on
                                                                    reduced body weight gain, NOAEL was 5 ppm
                                                                    (corresponding to 0.85 mg/kg body weight per day
                                                                    for males and 1.36 mg/kg body weight per day for
                                                                    females).

    Table 3 (continued)
                                                                                                                                      

    Duration              Chemical dose         Species             Effects, NOAEL                                         Reference
                          (purity; %)           (strain,
                                                number/dose)
                                                                                                                                      

    2 years               0, 0.5, 1, 2, 5,      Rat (not stated,    A slight decrease in white blood cells was seen        Til et 
                          10 ppm (not stated)   25/group)           at the highest dose in the first year. This effect     al., 1970
                                                                    was less often seen at 5 ppm (corresponding to
                                                                    0.3 mg/kg body weight per day), and only once at
                                                                    2 ppm in the males. The relative thyroid weight
                                                                    was slightly decreased at 10 ppm in the females
                                                                    only. Average relative weights of other organs,
                                                                    gross autopsy findings, and microscopic
                                                                    examinations did not reveal significant differences
                                                                    between treated and control groups. NOEL was
                                                                    2 ppm in the diet, equivalent to 0.1 mg/kg body
                                                                    weight per day.

    78 weeks with         0, 37.5, 75 ppm       Rat (Fischer 344,   No effects were observed on clinical signs,            NTP, 1978
    26-week               (not stated)          50/group)           mortality, food consumption, macroscopy, or
    observation           After 1 week, only                        histopathology. No increase in tumour incidence.
    period                57.9% of the initial
                          dose recovered

    104 weeks             0, 5, 20, 80 ppm      Rat (SPF KFM-Han    In females, mortality was increased (survival          Tennekes et 
                          prepared twice        Wistar, 70/group)   was 75, 51, 36, and 23%, respectively, with            al., 1989b
                          monthly from frozen                       increasing dose). Immunoglobulin decrease
                          stock                                     (IgG1 and IgG2a for females, and IgG2c for
                                                                    males) was observed at all doses. IgA levels
                                                                    for males decreased, and IgM levels increased
                                                                    for both sexes at 20 and 80 ppm. Leydig cell
                                                                    tumours were 1.7, 8.5, 5.0, and 16.7% at 0, 5,
                                                                    20, and 80 ppm, respectively. The incidence of
                                                                    pituitary adenomas was increased in females at
                                                                    20 and 80 ppm. These changes were accompanied by
                                                                    non-neoplastic lesions in the pituitary and
                                                                    testis. NOAEL was not established because of
                                                                    observations of mortality increase in females and

    Table 3 (continued)
                                                                                                                                      

    Duration              Chemical dose         Species             Effects, NOAEL                                         Reference
                          (purity; %)           (strain,
                                                number/dose)
                                                                                                                                      

    104 weeks                                                       serum immunoglobulin decrease at the lowest level,
    (continued)                                                     5 ppm (equal to 0.3 mg/kg body weight per day for
                                                                    males and 0.4 mg/kg body weight per day for females).
                                                                                                                                      


    Table 4. Reproductive and developmental toxicity studies on triphenyltin.
                                                                                                                                      

    Species             Study design                                      Effects                                           Reference
    (strain,
    number/sex/dose)
                                                                                                                                      


    Rat                 In a two-generation reproduction study, rats      The number of dead F1 pups was                    Young, 1986
    (Wistar,            were given TPTH in diet (0, 5, 18.5, or 50        increased and mean litter size
    30/sex/group)       ppm) during growth, mating, gestation, and        decreased at 18.5 and 50 ppm. In
                        lactation for one litter per generation.          Fo parents, the body weight gains
                        Clinical signs, body weight, food consumption,    and food consumption of both sexes
                        mating performance, and reproductive parameters   were lower at 50 ppm. At 50 ppm, the
                        were observed. Organ weights of parents           relative weights of brain, testes,
                        and pups were recorded. Pups were                 ovaries, adrenals, kidneys, spleen,
                       sexed and examined for gross malformations        and heart were increased in F0
                        and the number of stillborn and live pups.        and/or in F1 adults and/or F1 and F2 
                                                                          weanlings. A dose-related decrease was
                                                                          observed in spleen and thymus weight
                                                                          in F1 and F2 weanlings at 50 and 18.5
                                                                          ppm (equal to 1.5 mg/kg body weight 
                                                                          per day). The NOAEL was 5 ppm, equal to
                                                                          0.4 mg/kg body weight per day.

    Table 4 (continued)
                                                                                                                                      

    Species             Study design                                      Effects                                           Reference
    (strain,
    number/sex/dose)
                                                                                                                                      

    Rat                 TPTA or TPTCl (0 or 20 mg/kg body weight per      In rats sacrificed after 21 days, all             Snow & Hays,
    (Holtzman,          day in diet) was dosed for 20 days. Four          eight spermatogenic phases were seen,             1983
    13 males/group)     animals from each group were sacrificed on        but there was a general paucity of mature
                        day 21, and the remaining animals were            sperm, and the distribution showed some
                        sacrificed after 4 more days with test diets      predominance of immature sperm. Recovery
                        and a recovery period (70 days). Distribution     was seen after the 70-day control diet.
                        of the eight phases of spermatogenesis was        Treated animals ate about two-thirds as
                        observed.                                         much food as the controls.

    Pregnant rat        TPTCl was dosed by gavage at 0, 3.1, 4.7, or      In successfully mated females, TPTCl              Ema et al.,
    (Wistar,            6.3 mg/kg body weight per day on day 0 to day     prevented implantation in a dose-dependent        1997
    10-13/group)        3 of gestation or at 0, 6.3, 12.5 or 25.0 mg/kg   manner. The pregnancy rate was significantly
                        body weight per day on day 4 to day 6 of          decreased after administration of TPTCl on
                        gestation. Dams were sacrificed on day 20 of      days 0 to 3 at 4.7 and 6.3 mg/kg body weight
                        gestation. Numbers of live/dead fetuses and       per day, and days 4 to 6 at 12.5 and 25.0
                        resorptions were counted. Live fetuses were       mg/kg body weight per day. TPTCl caused larger
                        sexed, weighed, and inspected for malformations   failures in implantations when administered
                        externally.                                       during earlier stages of blastogenesis.

    Pregnant rat        TPTH was dosed at 0, 0.35, 1, 2.8, or 8           A dose-related decrease in body weight gain       Rodwell,
    (Sprague-Dawley,    mg/kg body weight per day on day 6 through        and food consumption was seen in the 2.8 and      1985
    45/group)           day 15 of gestation. On day 20 of gestation,      8 mg/kg body weight per day groups. At 8
                        all rats were sacrificed. Clinical signs, body    mg/kg body weight per day, an abortion in one
                        weights, and food consumption were examined.      dam, increase of number of non-gravid dams,
                        After sacrifice, the dams were observed for       total litter resorptions, early resorptions,
                        number and location of viable and non-viable      and significant decrease of number of viable
                        fetuses, early and late resorptions, and the      fetuses and fetal weight were observed. The
                        number of implantation sites. The corpora lutea   incidence of absent/delayed ossification was
                        were counted. Fetuses were weighted, sexed, and   increased in high-dose litters. The percentage
                        examined for external, internal, and skeletal     of fetuses with hydrocephaly was 0.4, 0, 0,
                        anomalies.                                        0.4, and 1%, and with omphalocele 0.2, 0.2, 0.2
                                                                          0, and 0.5%, respectively, for the 0, 0.35, 1,

    Table 4 (continued)
                                                                                                                                      

    Species             Study design                                      Effects                                           Reference
    (strain,
    number/sex/dose)
                                                                                                                                      
                                                                          2.8, and 8 mg/kg body weight per day groups.
                                                                          There was no evidence for TPTH-induced
                                                                          irreversible structural effects. The NOAEL for
                                                                          maternal toxicity was 1 mg/kg body weight per
                                                                          day, and for embrytoxicity, 2.8 mg/kg body weight
                                                                          per day.

    Pregnant hamster    TPTH was dosed by gavage (0, 2.25, 5.08, or       The 12 mg/kg body weight per day group showed     Carlton & 
    (Syrian,            12 mg/kg body weight per day) from day 5 to       a decrease in mean body weight gain, food         Howard, 1982
    20-25/group)        day 14. All dams were sacrificed on gestation     consumption, pup weight, and death (4 animals).
                        day 15. The gravid uterus was weighed, and        Two animals died in each of the 2.25 and 5.08
                        corpora lutea were counted. Fetuses and           mg/kg body weight per day groups. The average
                        resorption sites were noted. Fetuses were         number of minor anomalies of fetuses per litter
                        weighed and observed for external, visceral,      and delayed ossifications were significantly
                        and skeletal malformations.                       greater among the 12 mg/kg body weight per day
                                                                          group. Three cases of hydronephrosis were seen
                                                                          at 5.08 mg/kg body weight per day and one case
                                                                          of hydrocephalus was seen at 12 mg/kg body weight
                                                                          per day.

    Pregnant            TPTA (0, 0.1, 0.32, or 1.0 mg/kg body weight      In the 1.0 mg/kg body weight per day              Baeder,
    rabbit              per day) was dosed by gavage from day 6 to        group, one dam died, three dams aborted,          1987
    (Himalayan,         day 18 of gestation. On day 29 of gestation,      one dam gave a premature delivery, and
    15/group)           the dams were sacrificed. Dams were observed      two dams had intrauterine deaths. The
                        for clinical signs, body weight, food             number of implantations and of live
                        consumption, number of resorptions,               fetuses decreased at 1.0 mg/kg body
                        implantations, corpora lutea, viable and          weight per day. Mean fetal weight,
                        non-viable tissues, organ weights, and            crown/rump length, and placental weight
                        macroscopy. Fetuses were weighed and examined     decreased in pups at 1.0 mg/kg body weight
                        for sex, length, and external, internal, and      per day. At 1.0 mg/kg body weight per day,
                        skeletal anomalies.                               four pups showed omphalocele with protrusion

    Table 4 (continued)
                                                                                                                                      

    Species             Study design                                      Effects                                           Reference
    (strain,
    number/sex/dose)
                                                                                                                                      
                                                                          of intestinal coils or liver tissue. Slight
                                                                          retardation of skeletal ossification was
                                                                          detected at 1.0 mg/kg body weight per day.
                                                                          An increase in the number of fetuses with
                                                                          fewer ossified caudal vertebrae, weak
                                                                          ossification of the hyoid bone, and non-/only
                                                                          slight ossification of the os pubis in some
                                                                          fetuses were shown. NOAEL for maternal and
                                                                          embryo toxicity was 0.32 mg/kg body weight
                                                                          per day.


    Pregnant            TPTH was dosed by gavage at 0, 0.1, 0.3, or       Two rabbits from the 0.9 mg/kg body weight        Rodwell,
    rabbit              0.9 mg/kg body weight per day on day 6 to day     per day group aborted. A dose-related decrease    1987
    (New Zealand        18 of gestation. Dams were sacrificed on day 29   in mean body weight gain and food consumption
    white, 22/group)    of gestation. Corpora lutea, early/late           was observed in the 0.3 and 0.9 mg/kg body
                        resorptions, and number of implantations were     weight per day groups. Mean fetal weight was
                        counted. Fetuses were weighed, sexed, and         lower in the 0.9 mg/kg body weight per day
                        examined for external, skeletal, and visceral     group. The NOAEL for maternal toxicity was
                        anomalies and developmental variations.           0.1 mg/kg body weight per day, and the NOAEL
                                                                          for embryotoxicity was 0.3 mg/kg body weight
                                                                          per day.
                                                                                                                                      
    

    found at 4.7 and 6.3 mg/kg body weight per day, at which doses
    implantation failure was caused in pregnant rats. These findings
    suggest that implantation failure due to TPTCl may be mediated via the
    suppression of uterine decidualization correlated with the reduction
    in serum progesterone levels.

         In hamsters administered TPTH by gavage where death was observed
    (2.25 mg/kg body weight per day and higher), anomalies such as
    hydronephrosis, hydrocephalus, and delayed ossification were detected
    in the pups at 5.08 mg/kg body weight per day and higher (Carlton &
    Howard, 1982). Although delayed ossification was observed in rabbits,
    which are the most sensitive species, when TPTA was dosed at 1.0 mg/kg
    body weight per day by gavage during gestation days 6 through 18,
    maternal effects were also detected at this dose level (Baeder, 1987).
    The percentages of fetuses with hydrocephaly and omphalocele were not
    significantly higher in rats dosed with TPTH (0-8 mg/kg body weight
    per day on gestation days 6-15), and it was concluded that there was
    no evidence for TPTH-induced irreversible structural effects in rats
    (Rodwell, 1985).

         The lowest NOAEL for maternal toxicity was seen in rabbits -- 0.1
    mg/kg body weight per day, above which dose reductions in body weight
    gain and food consumption were observed. The lowest NOAEL for
    embryo-toxicity in rabbits was 0.3 mg/kg body weight per day, above
    which abortion and a decrease in mean fetal weight were observed
    (Rodwell, 1987).

    8.7  Immunological and neurological effects

         Effects on the immune system were observed in short-term as well
    as long-term toxicity studies (WHO, 1992; CICAD National Committee,
    1997). Effects of organotin compounds on lymphoid organs and lymphoid
    functions were reviewed (Penninks et al., 1990). Like other organotin
    compounds, triphenyltin showed immunosuppressive properties
    (lymphopenia and a decrease in spleen and thymus weights), resulting
    in altered humoral and cellular immunity in rats, mice, and
    guinea-pigs, although effects were usually less severe than those
    observed with tributyltin.

         When weanling male SPF Wistar rats were fed diets containing
    TPTCl at 0, 15, 50, or 150 ppm for 2 weeks, thymus weight was
    decreased at 15 ppm (corresponding to 1.5 mg/kg body weight per day)
    or above, and spleen weight was decreased dose dependently (Snoeij et
    al., 1985). At 150 ppm, decreases in body weight and brain weight were
    seen, and the liver was enlarged. The effects of TPTCl were similar to
    those of tributyltin chloride or tripropyltin chloride in a parallel
    test, but less severe.

         Groups of mice were given 0, 1, 5, 25, 50, or 125 ppm TPTH in the
    diet for 28 days. Twelve male and 12 female mice were killed on day
    29, and the remaining mice were returned to control diets and killed
    on day 57. A significantly decreased body weight gain was observed in
    male and female mice at 125 ppm, from which they recovered after 28
    days. Food consumption was significantly decreased at 50 and 125 ppm.
    Relative liver weight was increased at 25 (females only), 50, and 125
    ppm, relative spleen weight was clearly decreased in males at 50 and
    125 ppm and in females at 25 ppm (corresponding to 5 mg/kg body weight
    per day) and higher, and relative thymus weight was decreased at
    125 ppm in males. At histopathology, lymphoid depletion in the thymus
    and spleen was observed in mice at 125 ppm. A decrease in total white
    blood cells, neutrophils, and lymphocytes at 50 and 125 ppm in males
    and females was noted. At the highest dose, a decrease in total cells
    in spleen and splenic B-cells was observed, and a decrease in total
    cells in thymus and splenic T-cells was seen in males. IgM levels were
    decreased in females at 25 ppm and higher, but the decrease was not
    clearly dose related. All effects were reversible. The NOAEL was 5
    ppm, equal to 1 mg/kg body weight per day for males and 1.15 mg/kg
    body weight per day for females (MacCormick & Thomas, 1990).

         When triphenyltin was injected intraperitoneally into mice at
    doses of 0, 1, 3, or 10 mg/kg body weight per day for 14 days, it
    inhibited the T-cell-dependent humoral (IgM and IgE production) and
    cellular (induction of cytotoxic T-cell or induction of delayed
    hypersensitivity) immune response at 3 mg/kg body weight per day and
    above (Nishida et al., 1990).

         In a long-term study with female guinea-pigs fed 15 ppm TPTA in
    the diet (corresponding to approximately 1.5 mg/kg body weight per
    day), decreases in thymus weight and in the number of plasma cells of
    the spleen and lymph nodes were seen in guinea-pigs examined on days
    47 and 77. Repeated dosing for 104 days inhibited the immunological
    reaction against tetanus toxoids (Verschuuren et al., 1970). The dosed
    group had a lower antibody count and fewer antitoxoid-producing cells
    at the popliteal fossa than the controls when examined
    immunohistologically.

         Triphenyltin showed relatively slight neurotoxicological effects
    at relatively high doses compared with other trialkyltin compounds
    (i.e., triethyltin, trimethyltin, tributyltin, tripropyltin) (Bouldin
    et al., 1981; Wada et al., 1982). In neonatal rats dosed orally with
    30 mg TPTA/kg body weight per day from day 3 to day 30, no light
    microscopic or electron microscopic changes were observed in the
    hippocampus or pyriform cortex/lobe, which are susceptible to neuronal
    necrosis with trimethyltin (Bouldin et al., 1981). In addition,
    triphenyltin did not cause oedema in the myelin sheath, as was usually
    induced by triethyltin (Bouldin et al., 1981).

         In the maze learning test, rats orally given Tinestan (a product
    containing 60% TPTA) at doses of 0.6 (corresponding to 0.36 mg TPTA/kg
    body weight per day) or 6 mg/kg body weight per day, 6 days/week for 6
    weeks, made many mistakes and showed slow reaction speed (Lehotzky et
    al., 1982). In the conditioned avoidance response test, no difference
    was observed between the dose groups and the control group; however,
    extinction of behaviour was delayed in the high-dose group (6 mg/kg
    body weight per day) after discontinuation of the stimulus. Resting
    time during swimming tests was shortened by treatment with
    amphetamine; in rats given 23 mg Tinestan/kg body weight per day for
    20 days, however, amphetamine-induced hyperkinesis was antagonized on
    the 20th day. Tin levels in the brain tissues increased in some of the
    rats after administration of triphenyltin.

    8.8  Mode of action

         Treatment of rat thymocytes with immunotoxic organotins (TPTCl,
    tributyltin, dibutyltin) at 5 µmol/litre, but not non-immunotoxic
    organotins (trimethyltin, triethyltin), caused a rapid decrease in the
    F-actin content, resulting in the depolymerization of thymocyte
    F-actin (Chow & Orrenius, 1994). Immunotoxic effects of organotin
    compounds may involve cytoskeletal modification in addition to the
    perturbation of thymocyte calcium homeostasis.

         Triphenyltin at concentrations of 0.5-10 µmol/litre induced
    calcium overload in rat pheochromocytoma cells, which caused
    internucleosomal DNA cleavage typical of apoptotic cell death (Viviani
    et al., 1995). Triethyltin or trimethyltin, which did not modify cell
    viability, did not enhance or showed little effect on calcium influx.

         Triphenyltin induced calcium release in ruthenium red (a calcium
    release channel blocker) sensitive and insensitive ways, with EC50
    values of 75 and 270 µmol/litre, respectively. The Ca2+-ATPase
    activity and calcium uptake of sarcoplasmic reticulum were also
    inhibited by triphenyltin. The study suggested that the internal
    calcium store of skeletal muscle could be depleted by triphenyltin
    through the inhibition of calcium uptake and the induction of calcium
    release by acting on the Ca2+-ATPase and calcium release channel.
    Development of muscle weakness in organotin intoxication could be
    partly explained by this peripheral myopathy-related finding (Kang et
    al., 1997).

         Oral administration of a single dose of TPTCl (60 mg/kg body
    weight) induced diabetes with decreased insulin secretion in hamsters
    after 2-3 days, without morphological changes in pancreatic islets.
    Administration of TPTCl strongly inhibited a rise in cytoplasmic
    calcium concentration induced by 27.8 mmol glucose/litre, 100 µmol
    acetylcholine/litre in the presence of 5.5 mmol glucose/litre, and 100
    nmol gastric inhibitory polypeptide/litre in the presence of 5.5 mmol
    glucose/litre. TPTCl administration impaired the insulin secretion in
    islet cells induced by 27.8 mmol glucose/litre, 100 nmol gastric

    inhibitory polypeptide/litre in the presence of 5.5 mmol
    glucose/litre, and 100 µmol acetylcholine/litre in the presence of
    5.5 mmol glucose/litre. The pathology of triphenyltin-induced diabetes
    in hamsters involves a defect in cellular calcium response due to a
    reduced calcium influx through voltage-gated calcium channels (Miura
    et al., 1997).
    

    9.  EFFECTS ON HUMANS

         Major complaints concerning toxic effects experienced during the
    spraying of TPTA formulations involved the central nervous system,
    including headache, nausea, vomiting, and photophobia, and were
    exacerbated 1 day after exposure.

    9.1  Case reports

         Two cases of poisoning by TPTA were reported (Manzo et al.,
    1981). A patient who inhaled, 5 days before hospitalization, a certain
    amount of fungicide powder containing 60% TPTA (Brestan(R)) complained
    about dizziness, nausea, and photophobia. He had an episode of sudden
    malaise with dizziness and temporary loss of consciousness 1 day
    before his visit. He soon recovered; however, he experienced a brief
    loss of consciousness, nausea, and vomiting. On admission, general
    appearance and physical examination showed no abnormality except for a
    mild impairment of body balance. In spite of treatment with various
    antiemetics, nausea and photophobia persisted until the 4th day.
    Complete recovery was seen 10 days after hospitalization. Another
    patient inhaled an unknown amount of Brestan(R) in an aqueous solution
    3 h before his visit while spraying that solution onto a rice field.
    He noted general malaise, weakness, and dryness of the mouth. At the
    time of admission, the subjective symptoms had totally disappeared.
    There were no abnormal neurological findings. Severe headache,
    weakness, and photophobia appeared on the day following
    hospitalization. All these symptoms disappeared on the 4th day after
    admission. The mean concentrations of tin in the blood and urine
    collected in 24 h during his hospital stay were 48 + 29 ng/ml
    (normal value 2 ng/ml or less) and 113 + 20.6 ng/ml (normal range
    10-65 ng/ml), respectively.

    9.2  Epidemiological studies

         Hypersensitivity reaction to a series of 36
    triphenyltin-containing pesticide formulations was surveyed among 652
    subjects in Italy (Lisi et al., 1987). Among them, 180 were
    agricultural and 43 were ex-agricultural workers. Of the 652 subjects,
    274 had contact dermatitis, mostly on the hands, and the other 378
    were hospitalized for non-allergic skin disorders. Patch tests were
    performed on the upper back, and irritant and allergic reactions were
    evaluated. Irritant and allergic reactions were seen in 45 of 350
    subjects and in 1 out of 350 subjects, respectively, with a patch of
    1% TPTH. At 0.5% TPTH, irritant reactions were seen in 5 of 109
    subjects, whereas no allergic reactions were seen in any of the 109
    subjects. The report showed that TPTH is a moderately strong irritant
    among the fungicides used in Italy.
    

    10.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    10.1  Aquatic environment

         Extensive data exist on the toxicity of triphenyltin compounds to
    organisms in the environment (HSE, 1992; CICAD National Committee,
    1997). Data that show the most severe effects on typical species are
    listed in Tables 5 and 6. Available data show that triphenyltin is
    extremely toxic to various species of aquatic organisms, although the
    concentrations of triphenyltin that produce toxic effects vary
    according to species.

         Growth inhibition of yeasts and fungi with TPTCl occurs at 5
    µg/litre and above (Hallas & Cooney, 1981).

         Reproduction of freshwater algae was inhibited more than 50% at
    2-5 µg/litre (Wong et al., 1982). Indigenous algae were more sensitive
    than pure cultures. EC50s for inhibition of germination or carbon
    fixation of marine and estuarine algae were 0.92-2 µg/litre (Walsh et
    al., 1985).

         The LC50 in a 96-h exposure for a copepod was 8 µg/litre (Linden
    et al., 1979). LC50s in a 48-h exposure for  Daphnia magna were
    10-200 µg/litre (FAO, 1991a). The NOEC for reproduction in the same
    species in a 21-day exposure was 0.1 µg/litre (FAO, 1991a).

         One of the most sensitive effects of triphenyltin on organisms in
    the environment is imposex (the development of male sex organs in
    female gastropods) in rock shells (Japanese gastropods,
     Thais clavigera and  T. bronni), which supposedly occurs at levels
    (1 ng/litre) similar to those that are seen with tributyltin compounds
    (Horiguchi et al., 1994). When triphenyltin was injected into rock
    shells, it was approximately as strong as tributyltin in promoting
    imposex (Horiguchi et al., 1997), although it was less potent than
    tributyltin for inducing imposex in  Nucella. As imposex is probably
    caused by hormonal disturbance, triphenyltin is considered to be an
    endocrine disruptor.

         Testosterone (500 ng/litre) induces faster and more intensive
    imposex development in  Nucella lapillus than that induced by
    tributyltin. Simultaneous exposure to tributyltin and to the
    antiandrogen cyproterone acetate, which suppresses imposex development
    completely in  N. lapillus and reduces imposex development in  Hinia
    reticulatus, proves that the imposex-inducing effects of tributyltin
    are mediated by an increasing androgen level and are not caused
    directly by the organotin compound itself. Furthermore,
    tributyltin-induced imposex development can be suppressed in both
    snails by adding estrogens to the aqueous medium. These observations
    suggest that tributyltin causes an inhibition of the cytochrome
    P-450-dependent aromatase system, which catalyses the aromatization of
    androgens to estrogens. Artificial inhibition of the cytochrome
    P-450-dependent aromatase system using SH 489

    (1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase
    inhibitor and flavone as a non-steroidal aromatase inhibitor induces
    development of imposex in both snails. The same mechanism may apply to
    triphenyltin (Bettin et al., 1996).

         Field surveys in 1990-1992 and in 1993-1995 in Japan showed 100%
    occurrence of imposex in  T. clavigera. In surveys from 1992 to 1995,
    the incidence of imposex in the common whelk ( Buccinum undatum) was
    always greater than 90% (Mensink et al., 1996). Concentrations of
    phenyltin compounds (up to 625 ng tin/g dry weight in the organism)
    were much higher than those of butyltin compounds.

         No NOEC was established for the effects of triphenyltin on
    imposex; however, from the above observations, the NOEC can be assumed
    to be around 1 ng/litre or lower.

         Another sensitive effect of triphenyltin was the inhibition of
    arm regeneration in brittle star ( Ophioderma brevispina) at 0.01
    µg/litre. Neurotoxicological action of triphenyltin was suggested as
    the cause (Walsh et al., 1986).

         The 96-h LC50s of triphenyltin in fish were 7.1 µg/litre
    (fathead minnow) and higher (Jarvinen et al., 1988). A subchronic
    toxicity study with fathead minnow larvae showed the strong toxicity
    of triphenyltin, with a 30-day LC50 of 1.5 µg/litre and a 30-day NOEC
    of 0.15 µg/litre (LOEC 0.23 µg/litre). The need for studies of
    cumulative effects in a full life cycle at lower concentrations was
    suggested.

         Beginning with yolk sac fry, rainbow trout ( Oncorhynchus
     mykiss) was continuously exposed for 110 days to TPTCl at
    concentrations of 0.12-15 nmol/litre or to diphenyltin chloride at
    160-4000 nmol/litre. Diphenyltin chloride was about 3 orders of
    magnitude less toxic than TPTCl. A NOEC of 160 nmol/litre
    (corresponding to 60 µg/litre) was established for diphenyltin
    chloride, and a NOEC of 0.12 nmol/litre (corresponding to 50 ng/litre)
    was established for TPTCl. Histopathological examination revealed
    depletion of glycogen in liver cells of both di- and
    triphenyltin-exposed fish. At the end of the exposure period,
    resistance to infection was examined by an intraperitoneal challenge
    with  Aeromonas hydrophila, a secondary pathogenic bacterium in fish.
    Resistance to bacterial challenge was found to be decreased even at
    the lowest-effect concentration of both di- and triphenyltin compounds
    (de Vries et al., 1991).

         Because thymus reduction, decrease in numbers of lymphocytes, and
    inhibition of gonad development in fish species exposed to tributyltin
    have been reported, triphenyltin may have similar effects on the
    immune and reproductive systems of fish (Shimizu & Kimura, 1992).


        Table 5: Acute toxicity to aquatic organisms.
                                                                                                                          

    Compound       Organism                    Criterion               Levels/remarks         Reference
                                                                                                                          

    TPTCl          Debaryomyces hansenii       Minimum inhibitory      5 µg/ml                Hallas & Cooney, 1981
                   (yeast)                     concentration

    TPTCl          Ankistrodesmus              4-h IC50 for primary    10 µg/litre,           Wong et al., 1982
                   (freshwater alga)           productivity            static, 20 °C

    TPTCl          Skeletonema costatum,       EC50 for                0.92 µg/litre          Walsh et al., 1985
                   a major component of        carbon fixation         13.8 µg/litre
                   fouling slimea              LC50

    TPTH           Daphnia magna (water        48-h LC50               10 µg/litre            FAO, 1991a
                   flea)

    TPTFb          Nitrocra spinipes           96-h LC50               8 µg/litre             Linden et al., 1979
                   (harpacticoid copepod)

    TPTH           Eight fish species          96-h LC50               Pimephales promelas    Javienen et al., 1988
                                                                       (fathead minnow)
                                                                       was the most
                                                                       sensitive species,
                                                                       7.1 µg/litre

    TPTCl          Pagrus major                48-h LC50               12.6 µg/litre          Yamada & Takayanagi, 1992
                   (red sea bream)a
                                                                                                                          
    a Marine and estuarine species.
    b Triphenyltin fluoride.

    Table 6: Chronic/subchronic toxicity to aquatic organisms.
                                                                                                                                 

    Compound     Organism                    Criterion                      Levels/remarks               Reference
                                                                                                                                 

    TPTCl        Natural community of        50% reduction of               2 µg/litre,                  Wong et al., 1982
                 freshwater algae            reproduction and               indigenous algae
                                             primary production             more sensitive than
                                                                            pure cultures

                 Ankistrodesmus falcatus     85% inhibition of              5 µg/litre
                                             reproduction

    TPTH         Daphnia magna               21-day NOEC                    0.1 µg/litre                 FAO, 1991a

    TPTH         Lymnaea stagnalis:          9-day LC100, or                10 µg/litre for              Van der Maas et
                 a freshwater sludge         deficiencies in                LC100, 2 µg/litre            al., 1972
                 snail                       growth, mobility,              for deficiencies
                                             and embryo development
                                             after 5 weeks of
                                             exposure

    TPTCl        Thais clavigera             Relative penis length          Relative penis length        Horiguchi et al., 1997
                 (Japanese rock shell)a      in female                      significantly increased
                                                                            with injection of 0.1 µg
                                                                            triphenyltin/g wet
                                                                            tissue and culture for
                                                                            30 days

    TPTH         Pimephales promelas         30-day LC50, NOEC,             1.5, 0.15, and 0.23          Jarvinen et al., 1988
                 (fathead minnow) larvae     and LOEC                       µg/litre, respectively
                                                                                                                                 

    a Marine and estuarine species.
    

    10.2  Terrestrial environment

         Triphenyltin compounds applied to crops at the recommended dosage
    rate did not harm wild animals, birds, or non-target insects (HSE,
    1992). The EC50 for honey bees ( Apis mellifera) was many times
    higher than that for a range of common pesticides (Eisler, 1989).

         LD50s for triphenyltin compounds were 46.5-114 mg/kg body weight
    in Japanese quail ( Coturnix japonica) and bobwhite quail ( Colinus
     virginianus) and 285-378 mg/kg body weight in mallards ( Anas
     platyrhynchos) (Booth et al., 1980; Ebert & Weigand, 1982; Ebert &
    Leist, 1987, 1988).

         Gavage administration of 2 mg TPTCl/kg body weight to chickens
    ( Gallus domesticus) from the 19th day after hatching for 10 days
    resulted in atrophy of the thymus and the bursa of Fabricius
    (Guta-Socaciu et al., 1986).

         Female Peking ducks ( Anas platyrhynchos v.  domestica) 
    (30 weeks old) administered 25 mg TPTH/kg body weight per day by 
    gavage for 4 weeks showed a decrease in body weight, a gradual 
    decrease in the number of eggs or total lack of egg production, mild 
    anaemia, enlargement of the spleen, liver, and kidneys, and atrophy 
    of the reproductive organs (Masoud et al., 1985). Changes to the 
    spleen, liver, and kidneys reversed within 4 weeks after the end of 
    the exposure, but the uterine tube and ovaries did not completely 
    return to normal.
    

    11.  EFFECTS EVALUATION

         As tributyltin compounds have been used more abundantly and more
    extensively than triphenyltin compounds in many locations, and as
    tributyltin and triphenyltin compounds have similar effects on humans
    and organisms in the environment, risk from exposure to triphenyltin
    must be considered together with risk from exposure to tributyltin
    (IPCS, 1990; Sekizawa, 1998). There are many uncertainties in the
    potential risk posed by triphenyltin and its metabolites and in the
    mechanism underlying the immunotoxicological and reproductive effects
    caused by these compounds, and further studies on these aspects are
    necessary to improve the risk assessment on triphenyltin.

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         No quantitative data on humans are available. In two poisoning
    case reports of inhalation exposure to TPTA formulations, neurotoxic
    effects appeared to persist for a few days. A moderate level of
    irritant action was detected in a patch test study.

         Triphenyltin compounds given orally to rats are not readily
    absorbed and are excreted primarily in faeces and to a lesser extent
    in urine. Triphenyltin compounds are metabolized to diphenyltin,
    monophenyltin, and non-extractable bound residues. Absorbed
    triphenyltin compounds accumulate to the greatest extent in kidney and
    liver and to a smaller degree in other organs. Triphenyltin compounds
    applied dermally can penetrate through the skin in a time- and 
    dose-dependent manner.

         Triphenyltin exerts a variety of effects on several animal
    species, including effects on the immune system,
    reproductive/developmental effects at levels near those that are
    maternally toxic (most LOAELs are in the several mg/kg range or
    lower), hyperplasia/adenomas in endocrine organs, apoptosis in thymus
    cells, calcium release in sarcoplasmic reticulum cells, and eye
    irritation. The underlying mechanism of these effects is under
    investigation; a common mechanism may explain this toxicity profile.

         Health effects observed in laboratory animals and toxicological
    criteria for setting guidance values are summarized in Table 7.
    Triphenyltin compounds are moderately toxic in acute tests, and the
    lowest NOAELs for the oral, dermal, and inhalation routes in
    short-term and subchronic studies were 0.21 mg/kg body weight per day
    in dog (52-week exposure), 10 mg/kg body weight per day in rat (29-day
    exposure), and 0.014 mg/m3 in rat (4-week exposure), respectively.
    Triphenyltin is not carcinogenic or genotoxic.


        Table 7: Toxicological criteria for setting guidance values for dietary and non-dietary exposure to
             triphenyltin compounds.
                                                                                                                           

    Type of test               Organisms (route of exposure,    Results/remarks
                               duration of test)
                                                                                                                           

    Single exposure            Rat                              LD50: 160 mg TPTH/kg body weight

    Short-term                 Dog (oral, 52 weeks), rat        NOAEL for oral, dog: 0.21 mg TPTH/kg body
                               (dermal, 29 days), rat           weight per day, based on relative liver
                               (inhalation, 4 weeks)            weight decrease at effect levels; NOAEL
                                                                for dermal, rat: 10 mg TPTH/kg body weight
                                                                per day, based on erythema, mortality,
                                                                lymphocyte decrease at effect levels; NOAEL
                                                                for inhalation, rat: 0.014 mg TPTH/m3,
                                                                based on IgM increase at effect levels

    Long-term                  Mouse (80 weeks), rat            NOAEL for mouse: 0.85-1.36 mg TPTH/kg body
                               (104 weeks)                      weight per day, based on decreased body weight
                                                                at effect levels; NOAEL for rat: 0.1 mg TPTH/kg
                                                                body weight per day, based on reduction in white
                                                                blood cell counts at effect levels

    Genotoxicity               In vivo/in vitro                 Mostly negative

    Reproduction               Rat                              NOAEL: 0.4 mg TPTH/kg body weight per day, based
                                                                on decreased litter size, pup weight, relative
                                                                spleen/thymus weight in weanlings at effect levels

    Teratogenicity             Rabbit                           NOAEL for maternal toxicity: 0.1 mg TPTH/kg body
                                                                weight per day, based on decreased body weight
                                                                gain at effect levels

    Table 7 (continued)

                                                                                                                           

    Type of test               Organisms (route of exposure,    Results/remarks
                               duration of test)
                                                                                                                           

    Immunotoxicity             Mouse/rat/guinea-pig             Immunosuppressive; LOAEL: 0.3 mg TPTH/kg body
                                                                weight per day in rat

    Neurotoxicity              Rat (6 weeks)                    Toxic at 0.36 mg TPTA/kg body weight per day in
                                                                maze learning test
                                                                                                                             
    


         Reproductive and developmental effects include a decrease in the
    number of implantations and live fetuses (at 1.0 mg TPTA/kg body
    weight per day in a rabbit gavage study), a reduction in litter
    size/pup weight and in relative thymus or spleen weight in the
    weanlings (at 1.5 mg TPTH/kg body weight per day in diet in a
    two-generation reproduction study in rats; NOAEL 0.4 mg/kg body weight
    per day), and abortion and a reduction in fetal weight (at 0.9 mg
    TPTH/kg body weight per day in a rabbit gavage study).

         Triphenyltin compounds show effects on the immune system, such as
    a decrease in immunoglobulin concentrations (even at the lowest dose
    level, i.e., 0.3 mg TPTH/kg body weight per day in a 2-year rat
    feeding study), lymphopenia (at 1.75 mg TPTH/kg body weight per day in
    a 13-week dietary study in rats or at 0.338 mg/m3 in a 13-week
    inhalation study in rats), and thymus or splenic atrophy (at 1.5 mg
    TPTCl/kg body weight per day in a 2-week feeding study with weanling
    rats or at 5 mg TPTH/kg body weight per day in a 28-day feeding study
    in mice, respectively). Females are generally more susceptible than
    males with respect to these effects.

         The lowest NOAEL detected in the toxicity tests was 0.1 mg/kg
    body weight per day for maternal toxicity in a rabbit gavage study,
    based on decreased food consumption and body weight gain at 0.3 mg/kg
    body weight per day; the same NOAEL was obtained in an early 2-year
    rat study in which a slight decrease in white blood cells was seen at
    higher doses.

    11.1.2  Criteria for setting guidance values for triphenyltin

         No data are available on occupational exposure to triphenyltin.
    Considering its irritant action, neurotoxic symptoms in poisoning, and
    effects on the immune and reproductive systems, care must be taken to
    prevent dermal or inhalation exposure to triphenyltin as much as
    possible.

         Although no data are available on concentrations of triphenyltin
    in air or drinking-water, it is unlikely that triphenyltin would be
    present as a contaminant in these media at detectable levels
    considering its physical/chemical properties and levels of
    triphenyltin that have been detected in ambient water.

         The major exposure route for the general public is through intake
    of foods contaminated with triphenyltin. Estimation of exposure from
    residue data in supervised trials or maximum residue limits in foods
    will lead to overestimates of intake, because not all crops are
    treated with triphenyltin, and residues will not always be at the
    maximum residue limits. Exposure to triphenyltin from treated crops
    and dairy products is considered to be very low to negligible, as long
    as Good Agricultural Practice in the use of pesticides, as defined by
    WHO (1976), is observed. Therefore, the major route of exposure for
    the general public is probably from the ingestion of fish and
    shellfish contaminated with triphenyltin used in antifouling paints.

    Triphenyltin levels found in pelagic fish suggest that pollution from
    offshore boats is not negligible and that triphenyltins are persistent
    in the organisms, probably accumulated through the food-web.

         Several end-points were taken into consideration in establishing
    the ADI for oral exposure by JMPR (FAO, 1991b; WHO, 1992). First, a
    200-fold safety factor (uncertainty factor) was applied to the NOEL of
    0.1 mg/kg body weight per day (based on a finding of reduced white
    blood cell count at higher doses in a 2-year rat study) to arrive at
    an ADI of 0-0.5 µg/kg body weight. Secondly, a 500-fold uncertainty
    factor was applied to a LOAEL of 0.3 mg/kg body weight per day in a
    2-year study in rats in which increased mortality and reduced serum
    immunoglobulins were noted, to derive the same ADI. Other NOAELs taken
    into account are 0.4 mg/kg body weight per day in a two-generation
    reproduction study with rats (a dose-related decrease in spleen and
    thymus weight in F1 and F2 male and female weanlings was observed at
    higher levels), 0.3 mg/kg body weight per day in a 13-week study in
    rats (reduction in white blood cells, IgG decrease, and relative
    testes weight increase seen at higher levels), 0.21 mg/kg body weight
    per day in dogs (relative liver weight increase and serum
    albumin/globulin ratio decrease seen at higher levels), and 0.1 mg/kg
    body weight per day in a teratology study in rabbits (maternal
    toxicity seen at higher levels). No additional information regarding
    derivation of the above two uncertainty factors is available in the
    WHO monograph.

    11.1.3  Sample risk characterization

         Owing to wide variation in the consumption of fish and shellfish
    and local differences in residue levels, only illustrative estimates
    relating to effects and exposure can be made. It should be emphasized
    that local measurements of residues, local estimates of seafood
    consumption, and local decisions on acceptable safety margins must be
    made to assess potential risk. Some examples of risk assessments
    follow.

         Intake of triphenyltin estimated from a market basket survey in
    Japan in 1997 was 2.7 µg/day per person; values fluctuated between 0.6
    and 2.7 µg/day per person over the 1992-1997 period. There was about a
    twofold difference between average daily intake estimates from 10
    local laboratories and intakes estimated by one local government.
    There are people who eat more seafood than the average person. All
    these uncertainties and variations must be taken into account in an
    exposure assessment.

         Triphenyltin intakes can be compared with the high end of the ADI
    of JMPR (0.5 µg/kg body weight per day), which corresponds to 25
    µg/day for a 50-kg Japanese person; intakes are calculated to be 2.4%
    or 10.8% of the ADI for market basket surveys in different periods.

         These data suggest that if actions had not been taken,
    contamination of seafood with triphenyltin may have posed some health
    risks to Japanese consumers. Similar estimates of intake through
    market basket studies in Tokyo reported in 1991 support the above
    estimation.

         The above risk estimation was performed using data on
    triphenyltin compounds alone. Coincidental contamination with
    tributyltin must be taken into account in risk estimation from oral
    exposure. The risk from exposure to triphenyltin compounds will be
    better characterized when combined with risks from other organotin
    compounds that exert similar effects (IPCS, 1990; CICAD National
    Committee, 1997).

    11.2  Evaluation of environmental effects

         Triphenyltins enter the environment through their use in
    antifouling paints for boats and fishnets and as fungicides for
    certain crops.

         Strong adsorption of triphenyltin to soil suggests that organisms
    in treated soil may not be widely affected. The fact that soil
    respiration was not affected significantly suggests that there were no
    adverse effects on aerobic microorganisms.

         Triphenyltins are very toxic to various species in the
    environment at extremely low concentrations. The most sensitive
    effects of triphenyltin are imposex in rock shells (Japanese
    gastropods), supposed to occur at 1 ng/litre, and inhibition of arm
    regeneration in brittle star, at 0.01 µg/litre. The NOEC for
    reproduction (21-day exposure) in  Daphnia magna and the NOEC (30-day
    exposure) for fathead minnow were 0.1 µg/litre and 0.15 µg/litre,
    respectively. The EC50s for carbon fixation, reproduction, and
    primary production in both marine and freshwater algae were in the
    range of 1-2 µg/litre. The LC50 (30-day exposure) for fathead minnow
    was also at a similar level. Acute effects (IC50 for primary
    productivity in algae, 48-h LC50 for daphnid, and 96-h LC50 for fish)
    were seen at 1-10 µg/litre.

         For sensitive invertebrates, critical concentrations are 0.01-0.1
    µg/litre and lower. Sensitive algae and fish species may be
    susceptible at levels below 1 µg/litre.

         Ambient surveys in Japan showed that triphenyltin levels in bay
    and inshore area water and in sediment were 2.5-3.0 ng/litre and
    1.5-2.3 ng/g, respectively, in 1992-1995. Exposure of organisms in the
    environment varies widely depending on where and when the triphenyltin
    compounds were used or discharged.

         No NOEC has been established for triphenyltin-induced imposex in
    molluscs. Experimentally, by injection, triphenyltin has a similar
    potency to tributyltin in the genus  Thais. Triphenyltin is less
    potent than tributyltin in  Nucella; however, triphenyltin shows
    greater bio-accumulation than tributyltin. From this, it can be
    assumed that the NOEC for triphenyltin will be a few ng/litre or
    lower. The observed prevalence of imposex in  Thais in the wild with
    ambient concentrations in this range supports this assumption. Because
    residues of triphenyltin and tributyltin occur together in the
    environment, their relative contribution to observed imposex cannot be
    assessed for  Thais species. Use of either triphenyltin or
    tributyltin in antifouling paint would lead to population declines of
    marine invertebrates on this basis.
    

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Triphenyltin was evaluated by JMPR in 1963, 1965, 1970, and 1991.

         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 preventative and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 1283) reproduced in this
    document.

    13.1  Human health hazards

         Triphenyltin compounds may affect the immune system, resulting in
    impaired function. They have also been found to cause reproductive
    effects and developmental toxicity in animal studies.

    13.2  Advice to physicians

         In case of poisoning, treatment is supportive. Special attention
    should be given to pregnant women exposed to triphenyltin compounds.

    13.3  Health surveillance advice

         Periodic medical examination of the immune system should be
    included in a health surveillance programme.

    13.4  Spillage and disposal

         Triphenyltin compounds are absorbed through the skin. In case of
    spillage, emergency crew should wear proper equipment, including eye
    protection in combination with breathing protection. The compounds
    should not be allowed to enter drains or watercourses.

         Triphenyltin compounds may be disposed of in sealed containers.
    

    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

                                                                                                           

    TRIPHENYLTIN HYDROXIDE                                                  ICSC: 1283
                                                                            November 1998

                                                                                                           

    CAS #   76-87-9               Hydroxytriphenylstannane
    RTECS # WH8575000             Hydroxytriphenylstannate
    UN #    2786                  Fentin hydroxide
    EC #    050-004-00-1          C18H16OSn

                                                                                                           

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

    FIRE               Combustible. Liquid            NO open flames.               Powder, water spray,
                       formulations containing                                      foam, carbon dioxide.
                       organic solvents may be
                       flammable.
                                                                                                           
    EXPLOSION                                                                       In case of fire: keep
                                                                                    drums, etc., cool by
                                                                                    spraying with water.
                                                                                                           
    EXPOSURE                                          PREVENT DISPERSION OF DUST!
                                                      STRICT HYGIENE! AVOID
                                                      EXPOSURE OF (PREGNANT)
                                                      WOMEN!
                                                                                                           
    Inhalation         Cough. Sore throat.            Ventilation, local exhaust,   Fresh air, rest. Refer
                                                      or breathing protection.      for medical attention.
                                                                                                           

                                                                                                           
    Skin               MAY BE ABSORBED! Redness.      Protective gloves.            Remove contaminated
                       Pain.                          Protective clothing.          clothes. Rinse and
                                                                                    then wash skin with
                                                                                    water and soap. Refer
                                                                                    for medical attention.
                                                                                                           
    Eyes               Redness. Pain. Blurred         Safety spectacles, face       First rinse with
                       vision.                        shield, or eye protection     plenty of water for several
                                                      in combination with           minutes (remove contact 
                                                      breathing protection.         lenses if easily 
                                                                                    possible), then take
                                                                                    to a doctor.
                                                                                                           
    Ingestion                                         Do not eat, drink, or smoke   Give plenty of water to
                                                      during work.                  drink. Refer for medical
                                                                                    attention.
                                                                                                           
    SPILLAGE DISPOSAL                                 PACKAGING & LABELLING

                                                                                                           

    Do NOT wash away into sewer. Carefully            Do not transport with food and feedstuffs.
    collect remainder, then remove to safe            Severe marine pollutant.
    place. (Extra personal protection: P3             Symbol: T+, N
    filter respirator for toxic particles).           R: 24/25-26-36/38-50/53
    Use face shield. Chemical protection suit.        S: (1/2-)36/37-45-60-61
                                                      UN Classification
                                                      UN Hazard Class: 6.1
                                                      UN Pack Group: II
                                                                                                           
    EMERGENCY RESPONSE                                STORAGE
                                                                                                           
    Transport Emergency Card: TEC(R)-61G41b           Provision to contain effluent from
                                                      fire extinguishing. Separated from food
                                                      and feedstuffs.
                                                                                                           

                                      IMPORTANT DATA
                                                                                                           
    PHYSICAL STATE; APPEARANCE:                       ROUTES OF EXPOSURE:
    WHITE CRYSTALLINE POWDER                          The substance can be absorbed into
                                                      the body by inhalation, through the
                                                      skin and by ingestion.

    OCCUPATIONAL EXPOSURE LIMITS:                     INHALATION RISK:
    TLV (as organic compounds (tin)): ppm 0.1         Evaporation at 20°C is negligible;
    mg/m3 (skin) (STEL) (ACGIH 1998).                 a harmful concentration of airborne particles
    MAK as tin: ppm, 0.1 mg/m3; skin (D) (1995)       can, however, be reached quickly when dispersed.

                                                      EFFECTS OF SHORT-TERM EXPOSURE:
                                                      The substance irritates the eyes severely, the
                                                      skin and the respiratory tract. The substance
                                                      may cause effects on the immune system, 
                                                      resulting in impaired functions

                                                      EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
                                                      Animal tests show that this substance possibly
                                                      causes malformations in human babies.

                                                                                                           

                                        PHYSICAL PROPERTIES
                                                                                                           
    Decomposes below melting point at 80°C.
    Solubility in water, g/100 ml:    0.008
    Flash point:                      400°C

                                                                                                           

                                        ENVIRONMENTAL DATA
                                                                                                           
    The substance is very toxic to aquatic organisms. In the food chain important to humans,
    bioaccumulation takes place, specifically in molluscs. Avoid release to the
    environment in circumstances different to normal use.

                                                                                                           

                                               NOTES

                                                                                                           

    Carrier solvents used in commercial formulations may change physical and toxicological
    properties. 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

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     Approved or Provisionally Approved Products. York, Ministry of
    Agriculture, Fisheries and Food, Pesticide Safety Directorate,
    Advisory Committee on Pesticides, 18 pp.

    Baba T, Rikioka Y, Toyomura K (1991) Content of tributyltin (TBT) and
    triphenyltin (TPT) compounds in marine products and its processed
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     Prefectural Institute of Public Health and Environmental Sciences
     (Nagasakiken Eisei Kogai Kenkyujo Nenpo), 34:98-102 (in Japanese).

    Baeder C (1987)  Fentin acetate-substance, technical (Code: HOE
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    Barnes RD, Bull AT, Poller RC (1971) Behaviour of triphenyltin acetate
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    Bettin C, Oehlmann J, Stroben E (1996) TBT-induced imposex in marine
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    Beurkle WL (1985)  HOE 002782-14-C (triphenyltin acetate), analysis
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    De Vries H, Penninks AH, Snoeij NJ, Seinen W (1991) Comparative
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    103:229-243.

    Diehl KH, Leist KH (1986a)  Fentin acetate-active ingredient
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    Diehl KH, Leist KH (1986b)  Fentin acetate-active ingredient
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    Diehl KH, Leist KH (1986c)  Fentin acetate-active ingredient
     technical. Testing for primary eye irritation in the rabbit.
    Unpublished report 86.0620 (A37382) of Hoechst Pharma Research
    Toxicology and Pathology. Submitted to WHO by Hoechst AG,
    Frankfurt-am-Main [cited in WHO, 1992].

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     of Experts on Pesticide Residues and the WHO Expert Committee on
     Pesticide Residues. Geneva, World Health Organization, 45 pp. (WHO
    Technical Report Series No. 592).

    WHO (1992)  Pesticide residues in food -- 1991, Evaluations 1991 Part
     II -- Toxicology. Geneva, World Health Organization, pp. 173-208.

    WHO/FAO (1971)  1970 evaluation of some pesticide residues in food.
    Rome, World Health Organization/Food and Agriculture Organization of
    the United Nations, pp. 327-366.

    Wong PTS, Chau YK, Kramar O, Bengert GA (1982) Structure toxicity
    relationship of tin compounds on algae.  Canadian journal of
     fisheries and aquatic science, 39:483-488.

    Yamada H, Sasaki YF (1993) Organotins are co-clastogens in a whole
    mammalian system.  Mutation research, 301:195-200.

    Yamada H, Takayanagi K (1992) Bioconcentration and elimination of
    bis(tributyltin) oxide (TBTO) and triphenyltin chloride (TPTC) in
    several marine fish species.  Water research, 26(12):1589-1595.

    Young DL (1986)  A dietary two-generation reproduction study in rats
     with triphenyltin hydroxide (Code: HOE 0.29664 OF ZD97 0004
     technical substance). Final report project WIl-39022 (A35378) of WIL
    Research Laboratories, Inc., Ashland. Submitted to WHO by Hoechst AG,
    Frankfurt-am-Main [cited in WHO, 1992].
    

    APPENDIX 1 -- SOURCE DOCUMENTS

    CICAD National Committee (1997): A critical review on triphenyltin 
    compounds

         The 1997 review on triphenyltin compounds (provisional) was
    developed by the National Committee for Concise International Chemical
    Assessment Documents of Japan (CICAD National Committee, 1997). Much
    important information on health effects was obtained from monographs
    on pesticide residues prepared by the FAO and WHO (FAO, 1991a,b; WHO,
    1992); these monographs describe summary evaluations of data,
    including proprietary information. Extensive information on
    environmental effects was obtained from a 1992 review of the
    environmental effects of triorganotin compounds, prepared by the
    Advisory Committee on Pesticides, Health and Safety Executive, United
    Kingdom (HSE, 1992).

         The CICAD National Committee of Japan is composed of the members
    and observers listed below. Members are experts in the areas of
    toxicology, chemistry, environmental science, occupational safety,
    chemical management, or information science. Observers represent
    divisions related to chemical safety or international activities in
    various ministries and agencies. This committee is independent of
    industry. Its activities are communicated on the homepage of the
    National Institute of Health Sciences.

         The draft review on triphenyltin compounds was prepared by Dr Jun
    Sekizawa and was circulated for comments among members and observers,
    then revised. This review is available by request from Dr Jun
    Sekizawa, National Institute of Health Sciences.

     Members

    Dr S. Hatakeyama, Ecological Hazard Evaluation Team, National
    Institute of Environmental Studies

    Dr T. Kaminuma, Division of Chem-Bio Informatics, National Institute
    of Health Sciences

    Dr J. Kato, Yokohama Laboratory, Mitsubishi-kasei Institute of
    Toxicological and Environmental Sciences

    Dr Y. Kurokawa, Biological Safety Research Centre, National Institute
    of Health Sciences ( Chairperson)

    Dr K. Matsumoto, Department of Chemistry, Waseda University

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

    Mr T. Oshima, Japan Chemical Safety Institute

    Dr H. Sakurai, National Institute for Industrial Health

    Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute
    of Health Sciences

    Mr Y. Shiraishi, Chemical Safety Management Centre, Japan Chemical
    Industry Association

    Dr I. Uchiyama, National Institute of Public Health

    Dr M. Yasuno, Department of Environmental Science, Shiga Prefectural
    University

     Observers1

    Division of Chemical Products Safety, Ministry of International Trade
    and Industry

    Division of Chemical Substance Investigation, Ministry of Labour

    Division of Environmental Chemicals Safety, Ministry of Health and
    Welfare

    Division of Environmental Health and Safety, Environment Agency

    Division of Food Chemicals, Ministry of Health and Welfare

    Division of Foreign Affairs, Ministry of Health and Welfare

    Division of Standards on Drinking Water, Ministry of Health and
    Welfare

    WHO (1992): Pesticide residues in food -- 1991, Evaluations
    1991 Part II -- Toxicology

         The Joint FAO/WHO Meeting on Pesticide Residues, known as JMPR,
    has been evaluating pesticides that are used on food crops and that
    may leave residues on them since 1963. JMPR comprises two groups of
    scientists: namely, the FAO panel, which has responsibility for
    reviewing pesticide residue data and for recommending maximum residue
    limits, and the WHO group, which has responsibility for reviewing
    toxicological data and for recommending acceptable daily intakes
    (ADIs). The principles used by the WHO group for the toxicological
    assessment of pesticide residues in food have been publicized through
    its monographs and reports and in the Environmental Health Criteria of
    the IPCS. Although many of the data come from manufacturers that
    carried out major toxicological studies, the independent nature of the
    JMPR evaluation has been secured through various mechanisms. 
                  
    1  Representatives of the listed divisions in ministries and
       agencies.

         The toxicity of triphenyltin compounds was reviewed by JMPR in
    1963, 1965, 1970, and 1991 (WHO, 1992). At the 1991 meeting, the
    following scientists participated in the WHO group, and 21 other
    experts from various international organizations and countries joined
    in the evaluation (WHO, 1992).

     Members of WHO Expert Group on Pesticide Residues in the 1991 JMPR

    Professor U.G. Ahlborg, Institute of Environmental Medicine, Sweden 

    Dr A.L. Black, Department of Health, Housing and Community Services,
    Australia 

    Dr J.F. Borzelleca, Medical College of Virginia, Virginia Commonwealth
    University, USA

    Mr D.J. Clegg, Health Protection Branch, Health and Welfare Canada,
    Canada

    Professor M. Lotti, Universita di Padova, Istituto di Medicina del
    Lavoro, Italy

    Dr F.R. Puga, Instituto Biologico, Brazil

    Dr P. Yao, Institute of Occupational Medicine, Chinese Academy of
    Preventive Medicine, Ministry of Public Health, People's Republic of
    China

    HSE (1992): A review of the environmental effects of
    triorganotin compounds

         The Health and Safety Executive of the United Kingdom developed
    and published the report entitled  A review of the environmental
     effects of triorganotin compounds (HSE Report No. 111). This review
    was prepared by the Advisory Committee on Pesticides, a tripartite
    committee with representatives from industry, trade unions, and
    academia who give their advice and approve the use under the Control
    of Pesticides Regulations 1986.

         The Health and Safety Executive is responsible for human health
    aspects and pesticide efficacy. The Ministry of Agriculture, Fisheries
    and Food (Pesticides Safety Directorate) is responsible for the
    evaluation of non-human aspects.

         Public access to raw data underlying this publication can be
    arranged by contacting the Pesticide Registration Section, Health and
    Safety Executive, Magdalen House, Stanley Precinct, Bootle,
    Merseyside, United Kingdom L20 3QZ.
    

    APPENDIX 2 -- CICAD PEER REVIEW

         The draft CICAD on triphenyltin compounds 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:

    Department of Health, London, United Kingdom

    Health Canada, Ottawa, Canada

    International Agency for Research on Cancer, Lyon, France

    International Council on Metals and the Environment, Ottawa, Canada

    Karolinska Institute, Stockholm, Sweden

    National Chemicals Inspectorate (KEMI), Solna, Sweden

    National Institute for Occupational Safety and Health, Cincinnati, USA

    National Institute for Working Life, Solna, Sweden 

    United States Department of Health and Human Services (National
    Institute of Environmental Health Sciences, Research Triangle Park,
    USA)

    United States Environmental Protection Agency, Denver, 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, Mitsubishikagaku 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

                  
    1 Invited but unable to attend.

    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 sur les dérivés du triphénylétain a été préparé à partir
    d'une évaluation effectuée par la Commission nationale japonaise des
    CICAD (CICAD National Committee, 1997). De nombreuses études critiques
    sur les effets sanitaires qui sont citées dans cette évaluation sont
    tirées de monographies préparées par l'Organisation des Nations Unies
    pour l'Alimentation et l'Agriculture (FAO, 1991a,b) et par
    l'Organisation mondiale de la Santé (WHO, 1992). Ces monographies
    récapitulent les nombreuses études communiquées à l'OMS par les
    producteurs en vue d'une évaluation, en plus des résumés des articles
    publiés. Dans le cas des études communiquées par les producteurs, les
    documents originaux sont la propriété de leurs auteurs et n'ont pas
    été mis à la disposition des auteurs de l'évaluation préparée par la
    Commission nationale des CICAD (CICAD National Committee, 1997), des
    rédacteurs du projet de CICAD et du Comité d'évaluation finale. Pour
    ce qui concerne les données figurant dans ces documents originaux, les
    rédacteurs du présent CICAD n'ont donc eu d'autre solution que de
    s'appuyer sur les évaluations effectuées lors de la réunion conjointe
    FAO/OMS sur les résidus de pesticides (JMPR).

         De nombreux renseignements concernant les effets environnementaux
    de ce composé ont été tirés d'une étude consacrée aux effets des
    organostanniques sur l'environnement, publiée par l'Advisory Committee
    on Pesticides of the Health and Safety Executive du Royaume-Uni (HSE,
    1992). D'autres informations ont été obtenues en interrogeant les
    bases de données Medline et Toxline Plus jusqu'à octobre 1997.On
    trouvera à l'appendice 1 des indications sur les sources documentaires
    utilisées ainsi que 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 1283) établie pour
    l'hydroxyde de triphénylétain par le Programme international sur la
    sécurité chimique (IPCS, 1996) est également reproduite dans ce
    document.

         Les composés du triphénylétain sont des dérivés triphénylés de
    l'étain IV. Ce sont des solides incolores à faible tension de vapeur.
    Ils sont lipophiles et peu solubles dans l'eau.

         Depuis les années 1960, on fait grand usage des dérivés du
    triphénylétain et du tributylétain comme algicides et molluscicides
    dans les produits antisalissures. L'incorporation de composés
    triorganostanniques dans les peintures marines antisalissures est
    limitée dans de nombreux pays du fait de leurs effets catastrophiques
    sur l'ostréiculture et sur les écosystèmes aquatiques en général. Le
    triphénylétain est utilisé comme fongicide non endothérapique à action
    essentiellement protectrice.

         Le triphénylétain est fortement adsorbé par les solides en
    suspension et le sol et ne se désorbe plus guère ensuite. On estime sa
    demi-vie dans l'eau à quelques jours durant le mois de juin et à 2 ou
    3 semaine en novembre. Bien que susceptibles de se décomposer par
    déphénylation progressive et d'être excrétés sous la forme de
    conjugués, les dérivés du triphénylétain s'accumulent dans l'organisme
    des poissons et des gastéropodes, avec un facteur de bioconcentration
    dont la valeur va de quelques centaines à 32 500 (dans le sac
    intestinal de  Lymnaea stagnalis). 

         La concentration des dérivés du triphénylétain dans
    l'environnement dépend de leur mode, de leur moment et de leur lieu
    d'utilisation. Dans des baies et des marinas, on a trouvé des
    concentrations allant de 0 à près de 200 ng/litre, ces dernières
    valeurs par suite du lessivage des peintures à base de triphénylétain
    utilisées pour protéger la coque des bateaux contre les salissures. La
    concentration des composés du triphénylétain dans l'environnement
    diminue depuis quelques années en raison des restrictions sévères
    imposées à leur utilisation dans les peintures antisalissures.

         Administrés  per os à des rats, les dérivés du triphénylétain ne
    sont pas aisément résorbés et ils sont excrétés principalement dans
    les matières fécales et en partie également dans les urines. Par
    métabolisation, ils sont transformés en diphénylétain, en
    monophénylétain et en résidus liés non extractibles. Une fois
    absorbés, ils s'accumulent en majeure partie au niveau des reins et du
    foie et en plus faible quantité dans d'autres organes. Appliqués sur
    l'épiderme, ils peuvent traverser la peau selon un processus qui est
    fonction du temps et de la dose.

         Le triphénylétain exerce des effets variés sur l'organisme des
    diverses espèces animales, notamment sur le système immunitaire ou sur
    la reproduction et le développement à des des doses proches de celles
    qui sont toxiques pour les mères (la plupart des valeurs de la dose la
    plus faible sans effet observable ou LOAEL, sont de l'ordre de
    quelques mg par kg de poids corporel ou moins). On observe également
    des hyperplasies et des adénomes des glandes endocrines, l'apoptose
    des cellules thymiques, la libération de calcium au niveau des
    cellules du réticulum sarcoplasmique et une irritation oculaire. Les
    mécanismes qui sont à l'origine de ces effets font encore l'objet
    d'investigations et il est possible que ce profil toxicologique
    s'explique par un mécanisme général.

         Les dérivés du triphénylétain sont modérément toxiques pour le
    rat. Ils ne sont pas cancérogènes, mais certaines données montrent
    qu'ils ont une action coclastogène.

         Parmi les effets sur la reproduction et le développement, on peut
    citer la réduction du nombre des nidations et du nombre de foetus
    vivants (à la dose journalière de 1,0 mg/kg p.c. d'acétate de
    triphénylétain, ou TPTA, administré par gavage à des lapins), la

    diminution de la taille des portées et du poids des lapereaux avec
    également une réduction du poids relatif du thymus ou de la rate chez
    des ratons juste sevrés (dans une étude sur deux générations des rats
    recevant une alimentation contenant l'équivalent de 1,5 mg d'hydroxyde
    de triphénylétain - TPTH - par kg de poids corporel et par jour; dans
    cette étude, la dose sans effet nocif observable ou NOAEL, était de
    0,4 mg/kg p.c. par jour) ainsi que des avortements et une diminution
    du poids des foetus (dans une étude sur des lapins recevant
    quotidiennement par gavage une dose de 0,9 mg de TPTH par kg de poids
    corporel).

         La valeur la plus faible de la NOAEL qui ait été obtenue dans une
    étude toxicologique est de 0,1 mg de TPTH par kg p.c. par jour pour la
    toxicité maternelle, les critères de toxicité retenus étant la
    réduction de la consommation de nourriture et du gain de poids à la
    dose quotidienne de 0,3 mg par kg de poids corporel. Une valeur
    identique a été obtenue au début d'une étude de 2 ans sur des rats, au
    cours de laquelle on a observé une légère diminution du nombre de
    leucocytes aux doses élevées. Lors d'une étude de 52 semaines sur des
    chiens, on a trouvé une NOAEL égale à 0,21 mg de TPTH par kg de poids
    corporel par jour, le critère retenu étant la réduction du poids
    relatif du foie chez les femelles soumises à des doses élevées.

         Les dérivés du triphénylétain peuvent affecter le système
    immunitaire. On a observé une diminution de la concentration des
    immunoglobulines (Ig) (même à la dose la plus faible, soit 0,3 mg de
    TPTH par kg p.c. par jour lors d'une étude d'alimentation de 2 ans sur
    des rats), une lymphopénie (à la dose de 0,3 mg par kg p.c. par jour
    dans une autre étude d'alimentation de 2 ans portant également sur des
    rats et à la dose de 0,338 mg/m3 dans une étude d'inhalation sur des
    rats), une atrophie du thymus (à la dose de 1,5 mg de chlorure de
    triphénylétain - TPTCl - par kg p.c. par jour dans une étude
    d'alimentation sur des rats juste sevrés) et enfin une atrophie de la
    rate (à la dose de 5 mg de TPTH par kg p.c. par jour lors d'une étude
    d'alimentation de 28 jours sur des souris). Les femelles sont
    généralement plus sensibles que les mâles.

         Pour établir la dose journalière admissible (DJA) de
    triphénylétain en cas d'exposition  per os, le JMPR a pris en
    considération plusieurs points d'aboutissement des effets
    toxicologiques (FAO, 1991b; WHO, 1992). En premier lieu, on a appliqué
    un coefficient d'incertitude de 200 à la dose sans effet observable
    (NOEL) de 0,1 mg/kg p.c. par jour (basée sur l'observation d'une
    diminution du nombre de leucocytes à dose élevée lors d'une étude de 2
    ans sur des rats) pour obtenir une DJA de 0-0,5 µg/kg de poids
    corporel. On a ensuite appliqué un coefficient d'incertitude de 500 à
    la LOAEL de 0,3 mg/kg p.c. par jour tirée d'une étude de 2 ans sur des
    rats, au cours de laquelle on avait noté une augmentation de la
    mortalité et une diminution des taux d'immunoglobulines sériques. Les
    autres valeurs de la NOAEL qui ont été prises en considération

    parallèlement aux résultats précités sont les suivantes : 0,4 mg/kg
    p.c. par jour dans le cas d'une étude sur la reproduction portant sur
    deux générations de rats (cette étude a révélé une réduction du poids
    de la rate et du thymus chez les ratons mâles et femelles juste sevrés
    des générations F1 et F2 aux doses les plus élevées); 0,3 mg/kg p.c.
    par jour à l'occasion d'une étude à court terme sur des rats
    (réduction du nombre de leucocytes, diminution du taux des IgG et
    augmentation du poids relatif des testicules aux doses élevées); 0,21
    mg/kg p.c. par jour lors d'une étude à court terme sur des chiens
    (augmentation du poids relatif du foie et diminution du rapport
    albumine sérique / globulines aux doses élevées); enfin, 0,1 mg/kg
    p.c. lors d'une étude tératologique sur des lapins (toxicité
    maternelle constatée aux doses élevées).

         On ne possède pas de données sur l'exposition professionnelle aux
    dérivés du triphénylétain. Il existe toutefois un certain nombre de
    rapports sur des cas d'intoxication où sont décrits des effets
    neurotoxiques apparemment durables. L'exposition de la population
    générale à ces composés provient essentiellement de l'ingestion de
    produits de la mer contaminés. En effet, on a trouvé des
    concentrations de triphénylétain pouvant atteindre 1 µg/g dans les
    muscles de certaines espèces de poissons. Au Japon, on estime qu'en
    1997 l'absorption de triphénylétain par suite de la consommation
    d'aliments contaminés se situait aux alentours de 11 % de la DJA
    (c'est-à-dire 2,75 µg/jour pour un sujet de 50 kg) établie par le
    JMPR.

         Les dérivés du triphénylétain exercent des effets délétères sur
    les organismes aquatiques à très faible concentration. Par exemple, on
    observé l'apparition d'organes mâles chez des femelles de gastéropodes
    japonais à la concentration d'environ 1 ng/litre (concentration sans
    effet ou NOEC, non déterminée) et des effets toxiques ont été observés
    chez les larves d'une sorte de vairon,  Pimephales promelas, à la
    concentration de 0,23 µg/litre (concentration la plus faible
    produisant un effet ou LOEC). On estime que le triphénylétain perturbe
    les fonctions endocriniennes; en effet, l'apparition d'organes sexuels
    mâles chez les gastéropodes femelles est probablement due à un trouble
    hormonal.

         On n'a pas établi de NOEC relative au changement de sexe chez les
    mollusques par suite d'une exposition au triphénylétain. On a constaté
    expérimentalement, en procédant à des injections, que le
    triphénylétain avait une activité du même ordre que celle du
    tributylétain vis-à-vis du genre  Thais. Chez les mollusques du
    genre  Nucella il est moins actif que le tributylétain, mais sa
    bioaccumulation est supérieure. De ces expérimentations, on peut
    conclure que la NOEC du triphénylétain doit être de quelques ng/litre
    tout au plus. Cette estimation est corroborée par la fréquence de
    l'appartion, en situation réelle, d'organes mâles chez des mollusques
    femelles du genre  Thais exposés aux concentrations ambiantes. Dans
    l'environnement, les résidus de triphénylétain accompagnent ceux de
    tributylétain, aussi ne peut-on évaluer leur contribution respective

    au phénomène d'apparition d'organes mâles chez les gastéropodes
    femelles du genre  Thais. Dans ces conditions, on peut conclure que
    l'utilisation de l'un ou l'autre de ces organostanniques dans les
    peintures antisalissures conduit de tout manière à la décimation des
    invertébrés marins.
    

    RESUMEN DE ORIENTACION

         Este CICAD sobre los compuestos del trifenilestaño se basa en el
    examen preparado por el Comité Nacional para los Documentos
    Internacionales Concisos sobre Evaluación de Sustancias Químicas
    (Comité Nacional para los CICAD, 1997). En el presente examen se citan
    numerosos estudios críticos de los efectos en la salud procedentes de
    monografías sobre residuos de los plaguicidas preparadas por la
    Organización de las Naciones Unidas para la Agricultura y la
    Alimentación (FAO, 1991a,b) y la Organización Mundial de la Salud
    (OMS, 1992). Estas monografías contienen los resúmenes de los
    numerosos estudios que los fabricantes presentaron a la OMS para su
    evaluación, además de resúmenes de los documentos publicados. En el
    caso de los estudios presentados por los fabricantes, los documentos
    originales son privados y los autores del examen preparado por el
    Comité Nacional para los CICAD (1977), los autores del proyecto del
    CICAD o la Junta de Evaluación Final del CICAD no pudieron disponer de
    ellos. Por consiguiente, este CICAD se basa inevitablemente en las
    evaluaciones realizadas en la reunión conjunta FAO/OMS sobre residuos
    de plaguicidas (JMPR) para los estudios citados de los resúmenes de
    datos privados.

         Se obtuvo amplia información sobre los efectos en el medio
    ambiente de un examen acerca de los efectos ecológicos de los
    compuestos de estaño con tres grupos orgánicos, preparado por el
    Comité Consultivo sobre Plaguicidas de la Dirección de Salud y
    Seguridad del Reino Unido (HSE, 1992). Otros datos proceden de una
    búsqueda en las bases de datos Medline y Toxline Plus hasta octubre de
    1997. La información relativa al carácter de los procesos de examen y
    la disponibilidad de los documentos originales figura en el apéndice
    1. La información acerca del examen colegiado de este CICAD se
    presenta en el apéndice 2. Su aprobación tuvo lugar 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 aparece en el apéndice 3. La
    Ficha internacional de seguridad química (ICSC 1283) para el hidróxido
    de trifenilestaño (TPTH), preparada por el Programa Internacional de
    Seguridad de las Sustancias Químicas (IPCS, 1996) también se reproduce
    en el presente documento.

         Los compuestos de trifenilestaño son derivados trifenílicos del
    estaño tetravalente. Son sólidos incoloros con presiones de vapor
    bajas. Son lipófilos y su solubilidad en agua es escasa.

         Los compuestos de trifenilestaño y tributilestaño se han
    utilizado ampliamente desde los años sesenta como alguicidas y
    molusquicidas en los productos antiincrustantes. Se ha restringido el
    empleo de los compuestos de estaño con tres grupos orgánicos en las
    pinturas antiincrustantes debido a sus efectos devastadores en la
    industria de las ostras y a los más generales en el ecosistema
    acuático. El trifenilestaño se utiliza como fungicida no sistémico de
    acción fundamentalmente protectora.

         El trifenilestaño se adsorbe fuertemente al sedimento y al suelo
    y la desorción es escasa. Su semivida en agua se ha estimado en varios
    días en junio y en 2-3 semanas en noviembre. Si bien los compuestos de
    trifenilestaño se pueden degradar mediante defenilación escalonada y
    excretarse en forma conjugada, se ha observado bioacumulación en los
    peces y los caracoles, con factores de bioconcentración que oscilan
    entre varios cientos y 32 500 (en el saco intestinal de  Lymnaea
     stagnalis).

         Las concentraciones de los compuestos de trifenilestaño en el
    medio ambiente varían en función de la manera, el momento y el lugar
    de utilización de esos compuestos. Se han detectado concentraciones
    que oscilan entre 0 ng/litro y casi 200 ng/litro en zonas de bahías o
    puertos deportivos debido a la lixiviación a partir de las
    embarcaciones tratadas con pinturas antiincrustantes que contienen
    trifenilestaño. Las concentraciones de compuestos de trifenilestaño en
    el medio ambiente se han reducido en los últimos años como
    consecuencia del endurecimiento de las restricciones sobre su uso en
    las pinturas antiincrustantes.

         Administrados a ratas por vía oral, los compuestos de
    trifenilestaño no se absorben con facilidad y se excretan
    fundamentalmente en las heces y parcialmente en la orina. Se
    metabolizan a difenilestaño, monofenilestaño y residuos ligados no
    extraíbles. Los compuestos de trifenilestaño absorbidos se acumulan
    sobre todo en el riñón y el hígado y en menor cantidad en otros
    órganos. Tras su aplicación cutánea pueden penetrar a través de la
    piel, de forma dependiente del tiempo y la concentración.

         El trifenilestaño tiene diversos efectos en la salud de las
    distintas especies animales, en particular en el sistema inmunitario,
    efectos en la reproducción/desarrollo, con niveles próximos a los de
    toxicidad materna (las concentraciones más bajas con efectos adversos
    observados o LOAEL son en general del orden de mg/kg o inferiores),
    hiperplasia/adenomas en los órganos endocrinos, apoptosis en las
    células del timo, liberación de calcio en las células del retículo
    sarcoplásmico e irritación ocular. Se están investigando los
    mecanismos que provocan esos efectos; este perfil de toxicidad se
    puede explicar por un mecanismo común.

         Los compuestos de trifenilestaño tienen una toxicidad
    moderadamente aguda en las ratas. No son carcinogénicos, pero algunos
    datos ponen de manifiesto una acción coclastogénica.

         Los efectos reproductivos y en el desarrollo son un aumento en el
    número de implantaciones y fetos vivos (con 1,0 mg de acetato de
    trifenilestaño (TPTA)/kg de peso corporal al día en un estudio de
    administración con sonda realizado en conejos), reducción del tamaño
    de la camada/peso de las crías y del peso relativo del timo o el bazo
    en las crías destetadas (con 1,5 mg de TPTH/kg de peso corporal al día
    en los alimentos en un estudio de reproducción en dos generaciones

    realizado en ratas; la concentración sin efectos adversos observados o
    NOAEL es de 0,4 mg/kg de peso corporal al día) y aborto y reducción
    del peso fetal (con 0,9 mg de TPTH/kg de peso corporal al día en un
    estudio de administración con sonda realizado en conejos).

         La NOAEL más baja detectada en las pruebas de toxicidad fue de
    0,1 mg de TPTH/kg de peso corporal al día para la toxicidad materna en
    un estudio de administración con sonda realizado en conejos, basado en
    la disminución del consumo de alimentos y del aumento del peso
    corporal con 0,3 mg/kg de peso corporal al día. Se obtuvo el mismo
    valor en un estudio inicial de dos años realizado con ratas, en el
    cual se observó que con las dosis más altas se producía una ligera
    disminución de la concentración de leucocitos. En un estudio de 52
    semanas realizado con perros se estimó una NOAEL de 0,21 mg de TPTH/kg
    de peso corporal al día, tomando como base una disminución del peso
    relativo del hígado en las hembras con las dosis más altas.

         Los compuestos de tributilestaño afectan al sistema inmunitario.
    Se ha observado una disminución de la concentración de
    inmunoglobulinas (incluso con la dosis más baja, es decir, 0,3 mg de
    TPTH/kg de peso corporal al día, en un estudio de alimentación de dos
    años realizado con ratas), linfopenia (con 0,3 mg de TPTH/kg de peso
    corporal al día en otro estudio de alimentación de dos años realizado
    con ratas o de 0,338 mg/m3 en un estudio de inhalación de 13 semanas
    con ratas), atrofia del timo (con 1,5 mg de cloruro de trifenilestaño
    (TPTCl)/kg de peso corporal al día en un estudio de alimentación de
    dos semanas realizado con ratas destetadas) y atrofia del bazo (con 5
    mg de TPTH/kg de peso corporal al día en un estudio de alimentación de
    28 días realizado con ratones). En general, las hembras son más
    susceptibles que los machos.

         La JMPR tuvo en cuenta varios efectos finales al establecer la
    ingesta diaria admisible (IDA) de trifenilestaño para la exposición
    oral (FAO, 1991b; OMS, 1992). En primer lugar, se aplicó un factor de
    incertidumbre de 200 a la concentración sin efectos observados (NOEL)
    de 0,1 mg/kg de peso corporal al día (basada en el resultado de la
    disminución de la concentración de leucocitos con las dosis más altas
    obtenido en un estudio de dos años realizado con ratas) para llegar a
    una IDA de 0-0,5 µg/kg de peso corporal. En segundo lugar, se aplicó
    un factor de incertidumbre de 500 a una LOAEL de 0,3 mg/kg de peso
    corporal al día en un estudio de dos años realizado en ratas en el que
    se observó un aumento de la mortalidad y una reducción de la
    concentración de inmunoglobulina sérica. Otras LOAEL que se tuvieron
    en cuenta, junto con los efectos citados más arriba, son 0,4 mg/kg de
    peso corporal al día en un estudio de la reproducción en dos
    generaciones realizado con ratas (con los niveles más altos se observó
    una disminución dependiente de la dosis de los pesos relativos del
    bazo y el timo en los machos y las hembras destetados de la F1 y la
    F2), 0,3 mg/kg de peso corporal al día en un estudio de corta
    duración realizado en ratas (con las dosis más altas se detectó una

    reducción de la concentración de leucocitos y de la IgG y un aumento
    del peso relativo de los testículos), 0,21 mg/kg de peso corporal al
    día en un estudio de corta duración realizado en perros (con las dosis
    más altas se observó un aumento del peso relativo del hígado y una
    disminución de la razón albúmina sérica/globulina) y 0,1 mg/kg de peso
    corporal al día en un estudio de teratología en conejos (con las dosis
    más altas se detectó toxicidad materna).

         No se dispone de datos relativos a la exposición ocupacional a
    los compuestos de trifenilestaño. En un pequeño número de informes de
    casos de intoxicación se describen efectos neurotóxicos, que parecían
    persistir. La exposición del público general a estos compuestos se
    produce fundamentalmente por la ingestión de alimentos marinos
    contaminados, en los cuales se han encontrado a veces concentraciones
    de hasta 1 µg/g (en el músculo de algunas especies de peces). En 1997
    se estimó en el Japón una ingesta de trifenilestaño a partir de
    alimentos contaminados de alrededor del 11% de la IDA (es decir, 2,75
    µg/día para una persona de 50 kg) establecida por la JMPR.

         Los compuestos de trifenilestaño tienen efectos nocivos en los
    organismos acuáticos a concentraciones muy bajas. Por ejemplo, se
    observó imposexo en especies del género  Thais (gasterópodos del
    Japón) con concentraciones de alrededor de 1 ng/litro (no se determinó
    la concentración sin efectos observados o NOEC) y se observó toxicidad
    crónica en las larvas de  Pimephales promelas con 0,23 µg/litro
    (concentración más baja con efectos observados o LOEC). Se considera
    que el trifenilestaño es un perturbador del sistema endocrino a causa
    del imposexo, fenómeno en el cual se forman órganos sexuales
    masculinos en los gasterópodos hembra, probablemente debido a un
    trastorno hormonal.

         No se ha establecido la NOEC del trifenilestaño para el imposexo
    de los moluscos. El trifenilestaño tiene experimentalmente, mediante
    inyección, un efecto semejante al del tributilestaño en el género
     Thais. El primero es menos potente que el segundo en  Nucella; sin
    embargo, su bioacumulación es mayor. A partir de esta información se
    puede estimar que la NOEC para el trifenilestaño será de varios
    ng/litro o más baja. La prevalencia de imposexo en  Thais observada
    sobre el terreno en presencia de determinadas concentraciones en el
    medio ambiente apoya esta estimación. Habida cuenta de que los
    residuos de trifenilestaño y tributilestaño aparecen juntos en el
    medio ambiente, no se puede evaluar su contribución relativa al
    imposexo de las especies de  Thais. Conforme a esta información, el
    uso de trifenilestaño o de tributilestaño en la pintura
    antiincrustante produciría una disminución de la población de los
    invertebrados marinos.
    


    See Also:
       Toxicological Abbreviations
       Triphenyltin compounds (FAO Meeting Report PL/1965/10/1)