Concise International Chemical Assessment Document 14


    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 14


    First draft prepared by Dr Robert Benson, United States Environmental
    Protection Agency, Denver, Colorado, USA

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

    World Health Organization
    Geneva, 1999

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO). The overall objectives
    of the IPCS are to establish the scientific basis for assessment of
    the risk to human health and the environment from exposure to
    chemicals, through international peer review processes, as a
    prerequisite for the promotion of chemical safety, and to provide
    technical assistance in strengthening national capacities for the
    sound management of chemicals.

         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    Nations Industrial Development Organization, the United Nations
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    field of chemical safety. The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
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    sound management of chemicals in relation to human health and the

    WHO Library Cataloguing-in-Publication Data

    Tributyltin oxide.

         (Concise international chemical assessment document ; 14)

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

         ISBN 92 4 153014 6        (NLM classification: QV 290)
         ISSN 1020-6167

         The World Health Organization welcomes requests for permission to
    reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
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    (c) World Health Organization 1999

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material in
    this publication do not imply the expression of any opinion whatsoever
    on the part of the Secretariat of the World Health Organization
    concerning the legal status of any country, territory, city, or area
    or of its authorities, or concerning the delimitation of its frontiers
    or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar nature
    that are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.









         6.1. Environmental levels
         6.2. Human exposure



         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
                   8.7.1. Immunotoxicity
                   8.7.2. Neurotoxicity



         10.1. Aquatic environment
         10.2. Terrestrial environment


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



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










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    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).


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         This CICAD on tributyltin oxide (TBTO) was prepared by the United
    States Environmental Protection Agency (US EPA) and is based on an
    International Programme on Chemical Safety Environmental Health
    Criteria document on tributyltin compounds (IPCS, 1990) and on the US
    EPA's  Toxicological review on tributyltin oxide (US EPA, 1997). Data
    identified as of 1989 and 1996, respectively, were considered in these
    reviews. Additional information identified as of June 1998 has been
    included in this document. 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
    1282) for TBTO, produced by the International Programme on Chemical
    Safety (IPCS, 1996), has also been reproduced in this document.

         In this document, the term TBTO is used when that specific
    chemical is intended. In the environment, however, tributyltin
    compounds are expected to exist mainly as tributyltin hydroxide,
    tributyltin chloride, and tributyltin carbonate. In those cases or
    when the identity of the specific chemical is not clear, the general
    term tributyltin is used.

         TBTO is an effective biocidal preservative for wood, cotton
    textiles, paper, and paints and stains for residential homes. It is
    added as an antifouling agent in numerous formulations of marine
    paints. Tributyltin is present in most of these antifouling
    formulations as an organometallic copolymer. Tributyltin is slowly
    released from the painted surface as the polymer is hydrolysed in
    seawater, providing protection against encrustations for as long as
    4-5 years.

         As a result of its low water solubility and lipophilic character,
    tributyltin adsorbs readily onto particles. Its half-life in the water
    column ranges from a few days to weeks. Tributyltin may persist in
    sediments for several years. It bioaccumulates in organisms, with the
    highest concentrations found in liver and kidney. Uptake from food is
    more important than uptake directly from water.

         No information is available on the toxicity of TBTO in humans
    following long-term exposure. Some data and case reports indicate that
    TBTO is a severe dermal and respiratory irritant. The data, however,
    are not adequate to characterize the exposure-response relationships.
    Some studies have quantified human exposure to tributyltin from the
    diet in Japan.

         TBTO is moderately to highly acutely toxic to laboratory mammals
    in short-term studies. In numerous well-conducted studies, both short
    term and long term, the critical effect of TBTO is immunotoxicity
    (depression of immune functions dependent on the thymus). The
    no-observed-adverse-effect level (NOAEL) for immunosuppression in rats
    following long-term exposure is 0.025 mg/kg body weight per day.
    Benchmark dose analysis shows that the exposure corresponding to the
    lower confidence limit (95%) on dose for a 10% decrease in
    immunoglobulin (Ig) E titre in rats is 0.034 mg/kg body weight per
    day. In a carcinogenicity study in rats, there was an increased
    incidence of some tumours in some endocrine tissues. These tumours
    occur spontaneously with variable incidence in the strain of rat used
    in the study and are of unknown significance for a human health risk
    assessment. TBTO is not carcinogenic in mice. The weight of evidence
    shows that TBTO is not genotoxic. There is no indication that
    reproductive or developmental effects occur at an exposure below that
    identified as the NOAEL for immunotoxicity. Effects on reproduction
    and development occur only at exposures near those causing maternal
    toxicity. Data show that TBTO is a severe respiratory tract and skin
    irritant. Based on the NOAEL for immunotoxicity and an uncertainty
    factor of 100, a guidance value for oral exposure is 0.0003 mg/kg body
    weight per day. No adequate data are available to derive a guidance
    value for inhalation exposure.

         TBTO is extremely hazardous to some aquatic organisms. It is an
    endocrine disruptor in some organisms. The concentration of
    tributyltin in some coastal waters is above a concentration causing
    severe adverse effects. Adverse effects have been sufficiently severe
    to lead to reproductive failure and population decline in some areas.
    The general hazard to the terrestrial environment is likely to be low.


         Tributyltin oxide (CAS No. 56-35-9; C24H54OSn2;
    bis-[tri- n-butyltin]-oxide; tri- n-butyltin oxide; TBTO; hexabutyl
    distannoxane) has the structural formula
    (CH3CH2CH2CH2)3Sn-O-Sn(CH2CH2CH2CH3)3. It is flammable but
    does not form explosive mixtures with air. TBTO is a mild oxidizing
    agent. In the presence of oxygen, light, or heat, slow breakdown
    occurs. The solubility of TBTO in water ranges from <1 to >100 mg/
    litre, depending on temperature and pH. TBTO is soluble in lipids and
    very soluble in a number of organic solvents (e.g., ethanol, ether,
    halogenated hydrocarbons). Its octanol/water partition coefficient
    (log  Kow) lies between 3.19 and 3.84 for distilled water and is
    3.54 for seawater. Additional physical/chemical properties are
    presented in the International Chemical Safety Card reproduced in this


         Several methods are used for measuring tributyltin derivatives in
    water, sediment, and biota (IPCS, 1990). Atomic absorption
    spectrometry is the most common method used for all media. Flame
    atomic absorption spectrometry has a detection limit of 0.1 mg/litre
    in water. Flameless atomic absorption spectrometry, using atomization
    in an electric furnace with graphite, is more sensitive and allows
    detection limits of between 0.1 and 1.0 µg/litre. Recent modifications
    using a gas chromatograph equipped with a flame photometric detector
    allow a detection limit of 1 ng/litre (Tolosa et al., 1996).
    Tributyltin can be separated from the sample matrix by capillary
    supercritical fluid chromatography and determined by inductively
    coupled plasma mass spectrometry. A detection limit of 12.5 pg was
    obtained (Vela & Caruso, 1993). There are several different methods of
    extracting tributyltin from sediment and biota and forming volatile
    derivatives. The detection limits are 0.5 and 5.0 µg/kg for sediment
    and biota, respectively (Vela & Caruso, 1993).


         Tributyltin compounds have been registered as molluscicides; as
    antifoulants on boats, ships, quays, buoys, crab pots, fish nets, and
    cages; as wood preservatives; as slimicides on masonry; as
    disinfectants; and as biocides for cooling systems, power station
    cooling towers, pulp and paper mills, breweries, and leather
    processing and textile mills. Tributyltin in antifouling paints was
    first marketed in a form that allowed free release of the compound.
    More recently, controlled-release paints, in which the tributyltin is
    incorporated in a copolymer matrix, have become available. Rubber
    matrices have also been developed to give long-term slow release and
    lasting effectiveness for antifouling paints and molluscicides.
    Government restrictions have decreased the global use of tributyltin
    compounds in antifouling paints on small boats.


         As a result of its low water solubility and lipophilic character,
    tributyltin adsorbs readily onto particles (IPCS, 1990). Between 10%
    and 95% of TBTO introduced into water is estimated to undergo
    adsorption onto particulate matter. Progressive disappearance of
    adsorbed TBTO is due to degradation, not desorption. The degree of
    adsorption depends on the salinity of the water, the nature and size
    of particles in suspension, the amount of suspended matter,
    temperature, and the presence of dissolved organic matter.

         The degradation of TBTO involves the splitting of the carbon-tin
    bond (IPCS, 1990). This can result from various processes -- both
    physicochemical (hydrolysis and photodegradation) and biological
    (degradation by microorganisms and metabolism by higher organisms)
    -- occurring simultaneously in the environment. Although the
    hydrolysis of organotin compounds occurs under conditions of extreme
    pH, it is barely evident under normal environmental conditions.
    Photodegradation occurs during laboratory exposures of solutions to
    ultraviolet light at 300 nm (and to a lesser extent at 350 nm). Under
    natural conditions, photolysis is limited by the wavelength range of
    sunlight and by the limited penetration of ultraviolet light into
    water. The presence of photosensitizing substances can accelerate
    photodegradation. Biodegradation depends on environmental conditions
    such as temperature, oxygenation, pH, the level of mineral elements,
    the presence of easily biodegradable organic substances for
    co-metabolism, and the nature of the microflora and its capacity for
    adaptation. It also depends on whether the TBTO concentration is lower
    or higher than the lethal or inhibitory threshold for the
    microorganisms. As with abiotic degradation, biotic breakdown of
    tributyltin is a progressive oxidative debutylization founded on the
    splitting of the carbon-tin bond. Dibutyltin derivatives, which are
    more readily degraded than tributyltin, are formed. Monobutyltins are
    mineralized slowly. Although anaerobic degradation occurs, there is a
    lack of agreement as to its importance; some consider it to be slow,
    whereas others believe that it is more rapid than aerobic degradation.
    Species of bacteria, algae, and wood-degrading fungi have been
    identified that can degrade TBTO. Estimates of the half-life of
    tributyltin in the environment vary widely. The half-life in the water
    column ranges from a few days to weeks. Tributyltin can persist in
    sediments for several years.

         Bioconcentration factors (BCFs) of up to 7000 have been reported
    in laboratory investigations with molluscs and fish, and higher values
    have been reported in field studies (IPCS, 1990). Bioaccumulation in
    bivalves is especially high because of the low capacity for
    metabolism. In molluscs, uptake from food is more important than
    uptake directly from water. Higher BCFs in microorganisms (between 100
    and 30 000) may reflect adsorption rather than uptake into cells
    (IPCS, 1990). A recent publication reported a range of BCFs in the
    Pacific oyster ( Crassostrea gigas) of 2400-7800 (Li et al., 1997).
    Another recent publication reported a range of biomagnification
    factors in marine mammals of 0.6-6.0 (Madhusree et al., 1997).

         Although it has been suggested that tributyltin accumulates in
    organisms because of its solubility in fat (IPCS, 1990), recent work
    suggests that this might not be the case. Although tributyltin
    residues in blubber of marine mammals have been reported (Iwata et
    al., 1994, 1995, 1997), levels were considerably higher in other
    tissues, notably liver (Iwata et al., 1994, 1995, 1997; Kannan et al.,
    1996, 1997, 1998; Kim et al., 1996a,b; Madhusree et al., 1997; Tanabe,
    1998; Tanabe et al., 1998). Comparison of patterns of tributyltin
    residues with those of fat-soluble organochlorines in marine mammals
    showed marked differences. Unlike the organochlorines, tributyltin
    residues were the same in both sexes and remained constant after
    animals reached maturity. It has been suggested that transfer through
    milk to offspring, a marked trend with the organochlorines, does not
    occur with tributyltin. Cetaceans showed greater bioaccumulation than
    pinnipeds (Kim et al., 1996c). There has also been a report of
    accumulation in liver and kidney of seabirds (Guruge et al., 1997).
    Stäb et al. (1996) recently determined organotin compounds in the food
    web of a shallow freshwater lake; in birds in the food web, the
    highest concentrations of organotin compounds were also in liver and
    kidney, not in subcutaneous fat. The various authors cited suggest
    protein binding in liver to be the major mechanism of bioaccumulation.


    6.1  Environmental levels

         Tributyltin compounds have been found in water, sediment, and
    biota in areas close to pleasure boating activity, especially in or
    near marinas, boat yards, and dry docks; in fish nets and cages
    treated with antifouling paints; and in areas near cooling systems
    (IPCS, 1990). The degree of tidal flushing and the turbidity of the
    water influence tributyltin concentrations. As reported in IPCS
    (1990), tributyltin levels have been found to reach 1.58 µg/litre in
    seawater and estuaries; 7.1 µg/litre in fresh water; 26.3 mg/kg in
    coastal sediments; 3.7 mg/kg in freshwater sediments; 6.39 mg/kg in
    bivalves; 1.92 mg/kg in gastropods; and 11 mg/kg in fish. However,
    these maximum concentrations of tributyltin should not be taken as
    representative, because a number of factors, such as paint particles
    in water and sediment samples, may give rise to anomalously high
    values. It has been found that measured tributyltin concentrations in
    the surface microlayer of both fresh water and seawater are up to two
    orders of magnitude above those measured just below the surface.
    However, it should be noted that recorded levels of tributyltin in
    surface microlayers may be highly affected by the method of sampling.

         More recent data (collected up to the mid-1990s) have documented
    a decline in tributyltin levels in the environment, presumably due to
    the restrictions placed on the use of antifouling paints on vessels
    (CEFIC, 1994; Ruiz et al., 1996; Stronkhorst, 1996; Tolosa et al.,
    1996; NIVA, 1997; dela Cruz & Molander, 1998). Recent data have also
    documented a seasonal variation in the concentration of tributyltin in
    a freshwater marina; the concentration was highest in late spring and
    showed a progressive decline until winter (Fent & Hunn, 1991). This
    same study also documented that the tributyltin concentration in
    sediment decreased progressively with depth. In areas where the
    tributyltin concentrations in water and sediment have been monitored
    in the same location, the concentration of tributyltin in the water
    has declined more rapidly than the concentration of tributyltin in
    sediment (Stronkhorst, 1996). The range of concentrations reported in
    coastal waters and estuaries is 1-10 ng/litre; the range reported for
    water in marinas and major ports is 20-460 ng/litre. Most of the
    sediment samples analysed contained less than 100 µg/kg, although some
    samples exceeded 1000 µg/kg. The highest value reported for a sediment
    sample obtained from a port in Sweden was 10 940 µg/kg. The range of
    concentrations reported in biota is 0.01-3 mg/kg (dela Cruz &
    Molander, 1998).

         There are a number of reports on the occurrence of tributyltin
    residues in marine organisms. Levels of total butyltin residues (the
    sum of detected tributyltin, dibutyltin, and monobutyltin) of 5-230
    ng/g in muscle of fish (Kannan et al., 1995, 1996, 1997), 300 ng/g in
    liver and kidney of marine birds (Guruge et al., 1997), and 13-395

    ng/g in muscle of marine mammals have been reported (Iwata et al.,
    1994, 1995, 1997; Kannan et al., 1997). In marine mammals, much higher
    total butyltin residues were reported for blubber (48-744 ng/g),
    kidney (25-3210 ng/g), and liver (40-11 340 ng/g) (Iwata et al., 1994,
    1995, 1997; Kannan et al., 1996, 1997, 1998; Kim et al., 1996a,b,c;
    Madhusree et al., 1997; Tanabe, 1998; Tanabe et al., 1998).
    Geographical comparisons showed greater accumulation of residues close
    to coasts compared with the open sea and in the vicinity of developed
    compared with developing countries.

    6.2  Human exposure

         Information on tributyltin concentrations in various media that
    are relevant to estimation of human exposure is extremely limited,
    being restricted to data from Japan.1 It is unknown if this
    information is representative of other areas, and additional
    investigation is desirable.

         Tsuda et al. (1995) investigated the daily intakes of tributyltin
    compounds from meals in Shiga Prefecture, Japan. Daily intakes of TBTO
    determined by the duplicate-portion method were 4.7 + 7.0 µg/day in
    1991 ( n = 39) and 2.2 + 2.2 µg/day in 1992 ( n = 40). Using the
    market basket method, the daily intake was estimated at 6-9 µg/day in
    1991 and 6-7 µg/day in 1992. The TBTO was found mostly in seafood.

         Market basket studies in 10 local regions in Japan have shown
    that the national average daily intake of tributyltin (expressed as
    tributyltin chloride) was 3.7, 9.9, 5.4, 3.6, 2.9, 1.6, 1.5, and 2.3
    µg/day in 1990, 1991, 1992, 1993, 1994, 1995, 1996, and 1997,
    respectively.1 Variation among the local regions reflects differences
    in food intake patterns as well as differences in tributyltin levels
    in local fisheries.

         Recent preliminary data (Takahashi et al., 1998) suggest the
    potential for non-food sources of exposure -- for example, consumer
    products such as rubber gloves and baking sheets.
    1 Dr J. Sekizawa's (National Institute of Health Sciences, Tokyo,
       Japan) review of unpublished data.



         Little definitive information is available on the
    pharmacokinetics of TBTO (see IPCS, 1990, and references therein).
    TBTO is absorbed from the gut (20-50%, depending on the vehicle) and
    via the skin of mammals (approximately 10%). Other data suggest
    absorption in the 1-5% range via the skin.1 TBTO can be transferred
    across the blood-brain barrier and from the placenta to the fetus.
    Following 14 days of oral administration, steady-state levels in
    tissue are reached after 3-4 weeks. Absorbed material is rapidly and
    widely distributed among tissues (principally the liver and kidney).
    Metabolism in mammals is rapid; metabolites are detectable in the
    blood within 3 h of TBTO administration. The principal metabolite
    appears to be the hydroxybutyl compound, which is unstable and rapidly
    splits to form the dibutyl derivative and butanol. In  in vitro
    studies, it has been shown that TBTO is a substrate for mixed-function
    oxidases, but these enzymes are inhibited by very high concentrations
    of TBTO. The rate of TBTO loss differs with different tissues. TBTO
    and its metabolites are eliminated principally via the bile. The
    calculated half-time for elimination of TBTO residues in mice is 29
    days (Brown et al., 1977).

         Tributyltin metabolism also occurs in lower organisms, but it is
    slower, particularly in molluscs, than in mammals. The capacity for
    bioaccumulation is, therefore, much greater in lower organisms than in

         There are some recent preliminary data (Takahashi et al., 1998)
    on the occurrence of total butyltin residues in human liver. The
    average concentration in four samples was 84 ng/g wet weight (range
    59-96 ng/g). The concentration of tributyltin was less than the
    detection limit of 2 ng/g. The concentration of dibutyltin was 79% of
    the total.
    1 Letter and attachments from J.A. Jonker, Elf Atochem, to D.J.
      Stenhouse, Health and Safety Executive, United Kingdom, dated
      3 February 1997.



         Extensive data are available on the toxicity of TBTO. Detailed
    descriptions of studies critical to the evaluation of TBTO follow; all
    other studies are described in US EPA (1997) or IPCS (1990).
    Collectively, these data establish that immunotoxicity is the critical
    effect of TBTO. A detailed evaluation of these effects is found in
    section 8.7. All studies involving repeated oral exposure are listed
    in Table 1.

    8.1  Single exposure

         TBTO is moderately to highly acutely toxic to laboratory mammals.
    Acute oral LD50 values range from 127 to 234 mg/kg body weight for
    the rat and average 85 mg/kg body weight for the mouse (IPCS, 1990).
    TBTO exhibits greater lethal potential when administered parenterally
    (20 and 16 mg/kg body weight in the rat and mouse, respectively) as
    opposed to orally, probably as a result of only partial absorption
    from the gut. Single-exposure studies using 100 mg TBTO/kg body weight
    by oral gavage (Funahashi et al., 1980) demonstrated a transient
    increase in adrenal weight shortly after exposure (returning to normal
    within 2 days) and a transient effect on thyroid follicles (distension
    with flat epithelial cells). In addition, there were reversible
    effects on the pituitary and on levels of adrenocorticotrophic
    hormones, thyroid-stimulating hormone, thyroxine, and serum cortisol.
    The acute dermal LD50 in rabbits is about 9000 mg/kg body weight.

         Truhaut et al. (1979) exposed mice to an aerosol of TBTO in olive
    oil for either a single 1-h period or seven 1-h periods on successive
    days, using TBTO concentrations in air ranging between 50 and 400
    mg/m3. Exploratory behaviour was scored over 5-min periods 2 h after
    the single exposure was complete or 24 h after the last of the seven
    exposure periods. The lower two exposures caused a significant
    increase in exploratory behaviour (17% and 5% for 42 and 84 mg/kg body
    weight, respectively), whereas the higher exposures reduced
    exploratory behaviour (-18% and -38% for 170 and 340 mg/kg body
    weight, respectively).

         Schweinfurth & Gunzel (1987) summarized the results of several
    inhalation studies in laboratory animals. After a single 4-h exposure
    of rats to aerosols of TBTO, signs of irritation (nasal discharge,
    lung oedema, and congestion of the pulmonary circulation) and
    enteritis were observed. The LC50 was 77 mg/m3 (total particles) or
    65 mg/m3 (particles with a diameter <10 µm). In guinea-pigs exposed
    to aerosols of TBTO in olive oil at 200 mg/m3 and above, death
    occurred within 1 h of exposure. Ten male and 10 female rats were
    exposed to almost saturated vapours of TBTO (concentration not
    specified) without a single death occurring during exposure for 7 h or
    the following 14-day observation period. Only minor clinical signs
    (slight nasal discharge directly after exposure) were noted. For this
    study, the authors reported no information on particle size or the
    end-points evaluated.

        Table 1: Summary of oral toxicity studies on TBTO.

    Toxicity/         Study length       End-point            LOAEL             NOAEL              Reference
    species                                                   (mg/kg body       (mg/kg body
                                                              weight per day)   weight per day)


    Monkey            22 weeks           Decreased leukocyte  0.14              -                  Karrer et 
                                         counts                                                    al., 1992

    Rat               24 months          Decreased survival,  2.1               0.19               Wester et al.,
                                         changes in kidney                                         1987, 1988, 1990
                                         and organ weights,
                                         increased serum
                                         IgA and IgM

    Mouse             18 months          Decreased survival   0.7 (frank        -                  Daly, 1992
                                                              effect level)

    Rat               2 generations      Reproduction         -                 4.42               Schroeder, 1990
                                         Decreased pup        3.43              0.34


    Rat               gestation days     Decreased maternal   9                 5                  Schroeder, 1981
                      6-19               Increased            5                 -

    Rat               gestation days     Decreased maternal   10                5                  Crofton et al., 1989
                      6-20               Decreased pup        10                5
                                         weight and survival

    Table 1 (continued)

    Toxicity/         Study length       End-point            LOAEL             NOAEL              Reference
    species                                                   (mg/kg body       (mg/kg body
                                                              weight per day)   weight per day)

    Mouse             gestation days     Decreased maternal   11.7              5.8                Davis et al., 1987
                      6-15               Decreased fetal      23.4              11.7
                                         weight; increased

    Mouse             gestation days     Decreased maternal   40                20                 Baroncelli et al., 1990
                      6-15               Increased            40                20
                                         decreased fetal

    Mouse             gestation days     Haematology          -                 20                 Karrer et al., 1995


    Rat               28 days            Thymus-dependent     5                 0.5                Verdier et al., 1991

    Rat               4 weeks            Lymph node           0.5               -                  Krajnc et al., 1984;
                                         haemorrhage                                               Vos et al., 1984

    Rat               1 week;            Lymph node           0.4               -                  Bressa et al., 1991
                      4 weeks            haemorrhage

    Rat               6 weeks            Virus titres         2                 -                  Garssen et al.,

    Table 1 (continued)

    Toxicity/         Study length       End-point            LOAEL             NOAEL              Reference
    species                                                   (mg/kg body       (mg/kg body
                                                              weight per day)   weight per day)

    Rat               6 weeks            Reduced thymus       8                 2                  Van Loveren et al., 
                                         weight                                                    1990

    Rat               6 weeks            Reduced              2                 -                  Vos et al., 1984
                                         immunity and

    Rat               6 weeks            Decreased IL+2R      0.5               -                  Vandebriel et al.,
                                         alpha mRNA;                                               1998
                                         reduced CD25

    Rat               13-26 weeks        Reduced thymus       3                 -                  Funahashi et al.,
                                         weight                                                    1980

    Rat               18 weeks           Reduced thymus       16                -                  Carthew et al., 
                                         weight                                                    1992

    Rat, aged         5 months           Thymus-dependent     2.5               0.25               Vos et al., 1990

    Rat, weanling     4.5 or             Thymus-dependent     0.25              0.025              Vos et al., 1990
                      18 months          immunity

    Mouse             gestation days     Humoral and          0.1               -                  Buckiova et al., 
                      4-17 or 11-17      cell-mediated                                             1992

    Rat               10 doses to        Depressed mitogen    5                 2.5                Smialowicz et al.,
                      pre-weanlings      response                                                  1989

    8.2  Irritation and sensitization

         TBTO is a potent skin irritant and an extreme eye irritant (IPCS,
    1990). It is not a skin sensitizer (IPCS, 1990). Poitou et al. (1978)
    investigated the skin-sensitizing potential of TBTO in guinea-pigs
    using the Magnussen-Kligman method. The concentrations used for
    sensitization were 1% (intradermal phase) and 5% (topical phase).
    Using challenge concentrations of 0.25% and 0.1%, no sensitizing
    action was demonstrated in the 20 test animals. It is not clear from
    IPCS (1990) whether these challenge concentrations represented the
    maximum non-irritant concentrations or what positive control
    substances were used to verify the sensitivity of the assay. A recent
    study (Stringer et al., 1991) demonstrated contact sensitivity in the

    8.3  Short-term exposure

         Short-term studies focusing on effects on the immune system
    following oral exposure are listed in Table 1.

         In the only study involving repeated inhalation exposure that
    reported effects in the respiratory tract, rats (10 males and 10
    females per dose) were exposed in "nose-only" chambers for 4 h to TBTO
    doses of 0, 0.03 (vapour), 0.16 (vapour), or 2.8 (aerosol) mg/m3, 5
    days/week, for a total of 21-24 treatments (Schweinfurth & Gunzel,
    1987). At the highest dose, severe toxic effects were produced.
    Mortality was 5/10 in males and 6/10 in females. In addition,
    inflammatory reactions (not further specified) in the total
    respiratory tract and histological changes (not further specified) in
    the lymphatic organs were observed. No local or systemic changes were
    observed at the lower doses. The authors did not, however, report what
    end-points were evaluated.

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         A large number of well-conducted subchronic studies have been
    conducted in rats focusing on toxicity to the immune system. These
    studies and their NOAELs and lowest-observed-adverse-effect levels
    (LOAELs) are listed in Table 1 and summarized in section 8.7.

         Effects of TBTO (purity 96%) on haematology and serum chemistry
    were assessed in groups of three and four adult male cynomolgus
    monkeys that ingested doses of 0 or 0.160 mg/kg body weight per day,
    respectively, 6 days/week for 22 weeks (0 and 0.14 mg/kg body weight
    per day, actual intake) (Karrer et al., 1992). The TBTO was dissolved
    in vegetable oil and added to Tween 80-augmented pear juice, which the
    monkeys drank. Study end-points consisted of clinical observations,
    body weight, and standard haematology and clinical chemistry indices,
    including serum immunoglobulin (IgM and IgG) levels. A progressive

    decrease in total leukocyte counts occurred during the first 10 weeks
    of exposure (significantly [ P < 0.05] lower than controls at weeks
    8 and 10; 67% of control value at week 10). Leukocytes subsequently
    increased and were similar to controls between weeks 10 and 16, but
    decreased again between weeks 16 and 20 (61.5% of control value at
    week 20;  P < 0.05). No significant alterations in differential
    leukocyte count, serum immunoglobulins, or other study parameters were
    observed. Based on decreased total leukocyte levels, 0.14 mg/kg body
    weight per day (the only dose tested) is a LOAEL in monkeys.

    8.4.2  Chronic exposure and carcinogenicity

         Well-conducted studies are available in rats and mice. A study in
    dogs (Schuh, 1992) is fatally flawed and is not reported. Long-term
    studies assessing effects on the immune system are reported in section
    8.7 and listed in Table 1.

         In a chronic toxicity/carcinogenicity study, groups of 60 male
    and 60 female Wistar rats were exposed to dietary TBTO (0.5, 5, and 50
    mg/kg diet) for 2 years (Wester et al., 1987, 1988, 1990). Based on
    estimates of average body weight and food consumption from reported
    data, ingested dosages were approximately 0.019, 0.19, or 2.1 mg/kg
    body weight per day in males and 0.025, 0.25, or 2.5 mg/kg body weight
    per day in females. End-points that were evaluated included clinical
    abnormalities, survival, body weight, food and water consumption, and
    the incidence of neoplastic lesions. Haematology, urinalysis, clinical
    chemistry (including immunoglobulins IgG, IgM, and IgA), and
    endocrinology (total thyroxine and free thyroxine, thyrotropin,
    luteinizing hormone, follicle-stimulating hormone, insulin) were
    evaluated in 10 rats per sex per dose after approximately 3, 12, and
    24 months (endocrinology not assessed at 3 months). Organ weights and
    histology were evaluated in 10 rats per sex per dose after 12 and 24
    months, and histology was also evaluated in all moribund rats as well
    as rats surviving until 24 months.

         No treatment-related adverse changes were found in males or
    females at the lowest dose. Serum immunoglobulin levels were
    significantly ( P < 0.05, Student's  t-test) increased in the
    high-dose group. Concentrations of IgA were increased in both sexes
    after 12 and 24 months; at 24 months, levels of IgA were 508% of the
    control value in males ( P < 0.001) and 294% of the control value in
    females ( P < 0.01). Concentrations of IgG were significantly 
    ( P < 0.01) reduced in females after 3 months (42% of the standard 
    serum value compared with 69-71% in controls and other treated groups) 
    and 12 months (80% compared with 124-127%), but not after 24 months or 
    in males. Concentrations of IgM were increased in both sexes after 3, 
    12, and 24 months; at 24 months, the IgM level was 258% of the 
    standard serum value in males ( P < 0.01) and 240% of the standard 
    value in females ( P < 0.01).

         Other effects occurred predominantly in high-dose rats, including
    decreased survival, decreased body weight, and changes in organ
    weights. At termination, survival in females in the high-dose group
    was 54% versus 74% in controls; survival in males in the high-dose
    group was 40% versus 60% in controls. Terminal body weights at this
    dose were approximately 13% (male) and 9% (female) lower than
    controls. Absolute liver, kidney, adrenal gland (male only), and heart
    (male only) weights were increased and thyroid weight (female only)
    was decreased in high-dose rats at study termination; relative organ
    weights were not reported. The liver weight was increased 36% and 29%
    in males and females, respectively; the kidney weight was increased
    29% and 33% in males and females, respectively; the adrenal weight in
    males and females was increased 630% and 44%, respectively; the heart
    weight in males was increased 13%; and the thyroid weight in females
    was decreased 26%.

         Treatment-related non-neoplastic histological changes occurred in
    the liver, spleen, and thyroid of high-dose males and females.
    Histological effects after 12 months included slight bile duct changes
    (characterized by hyperplasia, cellular hypertrophy, and minimal
    infiltration of mononuclear cells or by cholangiofibrosis), decreased
    haemosiderin content in spleen (qualitative analysis only), and
    decreased thyroid follicular epithelial cell height. Examination after
    24 months showed that only the histological changes in the thyroid
    persisted. There were no accompanying significant changes in
    concentrations of serum thyroid hormones. The incidence and severity
    of age-related degenerative changes in the kidney (nephrosis and
    vacuolation and pigmentation of the proximal tubular epithelium,
    suggestive of iron and/or lipofuscin) were increased in high-dose
    males and females after 24 months.

         Neoplastic lesions were examined in the control and high-dose
    groups; if differences were observed, the intermediate-dose groups
    were also examined for those tumour types. Increased incidences of
    benign pituitary tumours, pheochromocytomas in the adrenal medulla,
    and parathyroid adenomas were noted. These data are shown in Table 2.

         There are increases in the incidence of some benign spontaneous
    tumours at the high dose in some endocrine tissues. According to the
    authors, these tumours normally occur in this strain of rats with high
    and variable background incidence (Kroes et al., 1981; Wester et al.,
    1985). In the two data sets available for these tumour types in the
    strain of Wistar rats used by Wester et al. (1990), the reported
    background occurrence of pituitary tumours (adenomas plus carcinomas)
    in females was 52% and 55% and in males was 34% and 87%; the reported
    background incidence of pheochromocytomas (benign plus malignant) in
    females was 8% and 16% and in males was 22% and 58%. The authors
    reported no data on the background occurrence of parathyroid tumours.

         There was no significant endocrine imbalance documented in the
    study. No significant change was observed in the serum levels of
    thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating
    hormone, insulin, total thyroxine, or free thyroxine. There was,
    however, a decrease in the free thyroxine: total thyroxine ratio for
    both sexes at 12 and 24 months in the high-dose group and after 12
    months in the mid-dose group. Although the pituitary tumours stained
    for the presence of prolactin, there was no correlation between the
    serum level of prolactin or the occurrence of hyperplastic or
    neoplastic mammary tissue and the presence of pituitary tumour.

         Based on the constellation of changes (increased mortality,
    increased serum immunoglobulins, changes in organ weight, and
    histopathological changes) observed at the highest dose, the LOAEL is
    2.1 mg/kg body weight per day and the NOAEL is 0.19 mg/kg body weight
    per day (Wester et al., 1987, 1988, 1990).

         TBTO (purity 97.1%) was fed to groups of 50 male and 50 female
    CD-1 mice in dietary concentrations of 0, 5, 25, or 50 mg/kg for 18
    months in a study primarily designed to assess carcinogenicity (Daly,
    1992). Based on food consumption and body weight data, mean compound
    intake was reported to be 0, 0.7, 3.7, or 7.7 mg/kg body weight per
    day in males and 0, 0.9, 4.8, or 9.2 mg/kg body weight per day in

         Statistically significant decreases in survival occurred in
    treated mice of both sexes. In males, survival after 18 months was 67,
    52, 42, and 42% in the control, low-, mid-, and high-dose groups,
    respectively ( P < 0.05, all doses). Survival in females at 18
    months was 59, 48, 40, and 27% in the control, low-, mid-, and
    high-dose groups, respectively ( P < 0.05 except for low-dose
    group). No information on cause of death was available. Other
    treatment-related effects included significantly decreased food
    consumption and increased absolute and relative liver weights in
    females at the high dose. Incidences of gross liver enlargement and
    discoloration were slightly increased in both sexes in all dose
    groups. The gross liver changes are not considered biologically
    significant because of the slight changes and absence of hepatic
    histopathological alterations. Increased incidences of common
    spontaneous non-neoplastic lesions, particularly
    glomerular/interstitial amyloidosis of the kidney, were found.
    Incidences of renal amyloidosis were increased in females in all dose
    groups (50, 67.7, and 78.4%, respectively, compared with 34.8% in
    controls) but not in males. The progression of this lesion appeared to
    be more rapid in both sexes at the two highest doses, indicating a
    compound-related effect. There were no statistically significant
    increases in the incidence of any tumours or groups of tumours in
    males or females. TBTO was not carcinogenic in this study in mice.
    This study identified an effect level for mortality at 0.7 mg/kg body
    weight per day (the lowest dose tested) (Daly, 1992).

        Table 2: Neoplastic lesions in rats.a
                           Incidence of                 Incidence of                 Incidence of
                           pituitary tumoursb           adrenal                      parathyroid
                                                        pheochromocytomasb           adenomas

    Concentration       Female         Male           Female         Male           Female         Male
    of TBTO
    (mg/kg diet)

    0                   22/50          34/50          3/50           16/50          0/64           0/39
    0.5                 32/50*         39/50*         3/50           13/50          0/4            42/50
    5                   22/50          29/50          3/50           14/50          1/40           1/51
    50                  35/50**        43/50***       34/50***       33/50***       1/44           6/43c

    a  From Wester et al. (1990).
    b  Statistical analysis was carried out according to Peto et al. (1980), one tailed. Values marked
       with asterisks differ significantly from the corresponding control values (* P < 0.05; ** P < 0.01;
       *** P < 0.001).
    c  The value differs significantly (chi-square test) from the corresponding control (P < 0.01).

    8.5  Genotoxicity and related end-points

         The genetic effects of TBTO were evaluated in multiple  in vivo
    and  in vitro short-term tests (Davis et al., 1987). TBTO was not
    mutagenic in the rec assay in  Bacillus subtilis, did not induce
    reverse mutations in  Klebsiella pneumoniae, and did not produce
    point mutations in  Salmonella typhimurium strains TA1530, TA1535,
    TA1538, TA97, TA98, or TA100 in the presence or absence of a rat liver
    activation system (Davis et al., 1987). TBTO was mutagenic in
     S. typhimurium strain TA100 in a fluctuation test, but only in the
    presence of rat liver S9 (Aroclor-induced) and at cytotoxic
    concentrations. TBTO did not induce gene mutations in
     Schizosaccharomyces pombe, mitotic gene conversions in
     Saccharomyces cerevisiae, or sister chromatid exchange in Chinese
    hamster ovary cells in the presence or absence of rat or mouse liver
    S9. Structural chromosomal aberrations, endoreduplicated and polyploid
    cells, were observed in Chinese hamster ovary cells. The aberrations
    were observed only at 8 h after treatment (not at 15 or 24 h) and only
    at the highest concentration tested in the presence of S9.
    Cytotoxicity was also observed at this concentration. TBTO did not
    induce gene mutations in V79 Chinese hamster cells or in mouse
    lymphoma cells. It did not induce recessive lethal mutations in adult
    male  Drosophila melanogaster by either feeding or injection. Doses
    of 0.37 or 0.74 mmol/litre did not increase the number of X-linked
    recessive mutations. An increased number of micronuclei was observed
    in polychromatic erythrocytes of male BALB/c mice 48 h after a single
    oral dose of TBTO (60 mg/kg body weight). A reanalysis of the slides
    from the high-dose group, however, failed to confirm the increase in
    micronuclei (IPCS, 1990). A lower dose (30 mg/kg body weight) was
    ineffective. Neither dose induced micronuclei 30 h after treatment. 

         One report demonstrated that TBTO and triphenyltin chloride are
    co-clastogens in a whole mammalian system (Yamada & Sasaki, 1993). The
    frequency of micronuclei induced by mitomycin C in mouse peripheral
    reticulocytes was enhanced approximately 50% when 50 mg TBTO/kg body
    weight and 100 mg triphenyltin chloride/kg body weight were given
    orally to mice. No effect was observed when the chemicals were
    administered separately.

         In aggregate, despite the limited positive findings at cytotoxic
    concentrations, the weight of evidence shows that TBTO is not
    genotoxic. This conclusion remains consistent with the previous
    evaluation by IPCS (1990).

    8.6  Reproductive and developmental toxicity

         Several well-conducted studies are available that investigated
    the effects of TBTO on the reproductive system and fetal development
    in rats and mice. The results of these studies are listed in Table 1.
    These studies show no evidence that TBTO is a significant reproductive
    or developmental toxicant in rodents. The developmental effects noted

    in the various studies occur at or near the exposure that also causes
    maternal toxicity (depressed body weight or impaired weight gain
    during pregnancy). The LOAELs for maternal toxicity in rats and mice
    are approximately 10 mg/kg body weight per day, with NOAELs of
    approximately 5 mg/kg body weight per day.

    8.7  Immunological and neurological effects

    8.7.1  Immunotoxicity

         A large number of well-conducted studies have shown that TBTO
    causes depression of immune functions dependent on the thymus. Results
    from a number of short-term studies are listed in Table 1. Subchronic
    and chronic studies (Vos et al., 1990) are summarized in detail below
    and are listed in Table 1. The chronic study conducted by Vos et al.
    (1990) shows effects on thymus-dependent immune responses at a dose
    lower than that at which any other toxic effects have been observed.
    The Vos et al. (1990) study also establishes that weanling animals are
    more sensitive than adults to the effects of TBTO. For example,
    following subchronic exposure, the LOAEL in weanling rats was 0.25
    mg/kg body weight per day, whereas the LOAEL in aged rats was 2.5
    mg/kg body weight per day. The NOAELs were 0.025 and 0.25 mg/kg body
    weight per day, respectively. Data from Buckiova et al. (1992) and
    Smialowicz et al. (1989) also show that exposure of mice  in utero
    and exposure of rat pups prior to weaning cause effects at exposures
    lower than those required for the same effects in adult animals.

         In a subchronic immunotoxicity study (Vos et al., 1990; a
    companion to the chronic study summarized below), aged (1-year-old)
    male Wistar rats were exposed for 5 months to the same diets used in
    the principal study. Based on the authors' statement from the chronic
    study (see below), estimated compound intake was 0, 0.025, 0.25, or
    2.5 mg/kg body weight per day. End-points were the same as some of
    those evaluated in the chronic study.

         Compound-related effects occurred only in the high-dose group and
    consisted of significantly decreased thymus weight (39% lower than
    controls,  P < 0.01), impaired resistance to  Trichinella spiralis
    (indicated by increased recovery of adult worms from the small
    intestine [780% higher than controls;  P < 0.01] and number of
    larvae in muscle [80% higher;  P < 0.001]), and impaired resistance
    to  Listeria monocytogenes (indicated by approximately 300% increased
    splenic bacterial count;  P < 0.05).

         Subchronic and chronic immunotoxicity studies were conducted in
    which weanling SPF-derived Riv:TOX Wistar rats were fed TBTO (purity
    95.3%) at concentrations of 0, 0.5, 5, or 50 mg/kg. Male rats (females
    not tested) were evaluated following exposure to TBTO for up to 18
    months (Krajnc et al., 1987; Vos et al., 1990). The authors reported
    the 5 mg/kg dietary concentration to be equivalent to a dose of 0.25
    mg/kg body weight per day, indicating that estimated test doses were

    0.025, 0.25, and 2.5 mg/kg body weight per day. Body weight, absolute
    thymus weight, and absolute spleen weight were measured in groups of
    18, 12, and 12 rats, respectively, following exposure for 4.5 months.

         Immunological function studies for specific and non-specific
    resistance were performed in 9-12 rats per group after 4-6 or 15-17
    months of exposure. Antigen-specific functional assays evaluated IgM
    and IgG responses to sheep red blood cells (immunized after
    16 months); IgM and IgG responses to ovalbumin and delayed-type
    hypersensitivity (24-, 48-, and 72-h) responses to ovalbumin and
     Mycobacterium tuberculosis (immunized after 6 or 15 months of
    exposure); and resistance to oral infection by  T. spiralis larvae
    (infected after 5.5 or 16.5 months).

         Non-specific resistance was assessed by splenic clearance of
    intravenously injected  L. monocytogenes bacteria (after 5 or 17
    months of exposure) and natural cell-mediated cytotoxicity of spleen
    cells (after 4.5 or 16 months of exposure) and peritoneal cells (after
    4.5 months of exposure only) using a 4-h 51Cr-release assay with
    YAC-lymphoma target cells. Non-specific end-points included the
    numbers of viable nucleated thymus and spleen cells and responses of
    thymus and spleen cells to T-cell and/or B-cell mitogens
    (phytohaemagglutinin, concanavalin A, pokeweed mitogen, and/or
     Escherichia coli lipopolysaccharide) after exposure for 4.5 months
    (thymus and spleen) or 16 months (spleen only); and numbers of viable
    nucleated mesenteric lymph node cells with cell surface marker
    analysis (after 6 and 18 months of exposure; low-dose group not tested
    in this assay).

         No significant effects were observed in the IgM or IgG responses
    to sheep red blood cells, the IgM or IgG responses to  T. spiralis,
    the IgM or IgG responses to ovalbumin, or the delayed-type
    hypersensitivity responses to ovalbumin and  M. tuberculosis.

         Thymus weight was significantly reduced in the high-dose group
    (17% lower than controls,  P < 0.05), although the response of
    thymocytes to T-cell mitogens was unaltered. No significant
    alterations in spleen weight, response of spleen cells to T- and
    B-cell mitogens, or body weight were found at any dose. Statistically
    significant changes occurred in the percentage of mesenteric lymph
    node T-lymphocytes in the high-dose group (20% lower than controls
    after 18 months of exposure) and B-lymphocytes in the mid-dose (60%
    higher than controls after 18 months) and high-dose (48% higher than
    controls after 18 months) groups; however, the absolute number of
    T-lymphocytes and B-lymphocytes per lymph node was not significantly
    altered. The low-dose group was not tested with these assays. The
    B-cell increase was an increase in the percentage of B-cells, but the
    interpretation of these data is equivocal, because they are
    counter-intuitive when viewed in context with the other effects,
    especially the IgE titres.

          In vivo clearance of injected  L. monocytogenes was impaired
    in rats exposed to the high dose for 17 months, as shown by the
    approximately sevenfold increase in number of viable bacteria per
    spleen, indicating that macrophage function was reduced. Resistance to
    infection by  T. spiralis was suppressed in rats exposed to the mid
    or high dose, as shown by significantly reduced serum IgE titres (50
    and 47% lower than controls after 16.5 months of exposure), increased
    numbers of larvae in muscle 42 days after infection (56% and 306%
    higher than controls after 16.5 months), and moderately reduced
    inflammatory reaction around cysts in parasitized musculature
    (qualitative assessment only).

         There was no significant reduction in the activity of natural
    killer cells isolated from the peritoneal cavity following exposure of
    weanling or aged (1-year-old) rats to TBTO for 4.5 months. Also, there
    was no significant reduction in the activity of natural killer cells
    isolated from the spleen following exposure of weanling rats for 4.5
    months. In contrast, the activity of natural killer cells isolated
    from the spleen was suppressed when weanling rats were exposed to all
    doses of TBTO for 16 months (31, 25, and 36% lower than controls,
    respectively, at an effector to target cell ratio of 100, and 32, 18,
    and 30% lower, respectively, at an effector to target cell ratio of
    50). Based on these data, the effect did not progress significantly
    with dose. Because the authors considered these data equivocal in this
    experiment and because there was no clear treatment-related effect,
    the suppression of natural killer cell activity in this study is not
    considered biologically significant.

         Essentially identical results on the immune system were observed
    when weanling rats were exposed for 4.5 or 16.5 months. Based on the
    depression of IgE titres and an increase in  T. spiralis larvae in
    muscle, the LOAEL for immunotoxicity is 0.25 mg/kg body weight per
    day. The NOAEL is 0.025 mg/kg body weight per day (Krajnc et al.,
    1987; Vos et al., 1990).

         Some recent studies suggest that the mechanism of the immunotoxic
    effects is related to induction of apoptosis (programmed cell death)
    within the thymus. Raffray & Cohen (1991) demonstrated that thymocytes
    in culture showed cellular changes consistent with apoptosis at
    concentrations of TBTO that did not affect cell viability. Raffray et
    al. (1993) showed that these effects occur independently of a
    requirement for protein synthesis and do not require fully conserved
    energetics (i.e., the effects occur despite depression of ATP levels
    to less than 20% of control values). Raffray & Cohen (1993)
    demonstrated a correlation between reduction of thymus weight in
    animals given a single oral dose of TBTO and evidence of apoptosis
    (increased DNA fragmentation) in thymic cell isolates (principally
    thymocytes) isolated from the animals during the period of thymic
    involution. These workers also showed that dibutyltin, the major
    metabolite of tributyltin, is less effective in inducing apoptosis
     in vitro, suggesting that the  in vivo toxicity is directly
    attributable to tributyltin.

         A study comparing immunotoxic effects in pre-weanlings and adult
    rats shows that some responses of the developing immune system are
    more sensitive to TBTO (Smialowicz et al., 1989). Adult (9 weeks old)
    male Fischer rats or pre-weanling (3-24 days old) rats were dosed by
    oral gavage 3 times per week for a total of 10 doses. The adults were
    dosed with 5, 10, or 20 mg/kg body weight per dose; the pre-weanlings
    were dosed with 2.5, 5, or 10 mg/kg body weight per dose. Reductions
    in mitogen responses were observed in adults at 10 and 20 mg/kg body
    weight and in pre-weanlings at 5 and 10 mg/kg body weight. The mixed
    lymphocyte reaction was suppressed in adults at 20 mg/kg body weight
    and in pre-weanlings at 10 mg/kg body weight. Finally, natural killer
    cell activity was suppressed only in pre-weanlings at 10 mg/kg body
    weight. In this study, the lowest LOAEL is 5 mg/kg body weight per
    day, and the lowest NOAEL is 2.5 mg/kg body weight per day.

         Pregnant ICR mice were treated with TBTO in Tween
    80:ethanol:saline (1:2:97) by gavage at 0.1 mg/kg body weight per day
    on gestation days 4-17 or 11-17 (Buckiova et al., 1992). Humoral and
    cell-mediated immune responses in offspring were assessed 4 and
    8 weeks after birth. At 0.1 mg/kg body weight per day, the only dose
    tested, effects in the offspring included suppressed primary antibody
    responses to sheep red blood cells, ovalbumin, and lipopolysaccharide
    and increased number of leukocytes. Suppressed delayed-type
    hypersensitivity to sheep red blood cells and unspecified alterations
    in polyclonal proliferative responses of thymocytes and splenocytes
    were also observed. The significance of the LOAEL (0.1 mg/kg body
    weight per day), however, is unclear, because a full publication of
    the results is not available.

    8.7.2  Neurotoxicity

         Triethyltin and trimethyltin compounds have been shown to cause
    severe neurotoxicity (for a summary, see Boyer, 1989). Triethyltin
    causes interstitial oedema throughout the white matter in the spinal
    cord and various regions of the brain; less marked damage occurs in
    the peripheral nervous system. Trimethyltin also causes severe and
    permanent damage to the central nervous system. In this case, however,
    the effect is neuronal necrosis, rather than oedema. TBTO, in
    contrast, causes no severe neurological signs or morphological or
    histopathological changes in brain tissue. In a 4-week study, rats fed
    a dietary concentration of 320 mg/kg (equivalent to 30 mg/kg body
    weight per day) exhibited ptosis or enophthalmia and slight ataxia
    (Krajnc et al., 1984). One chronic study in dogs (Schuh, 1992) also
    gave a slight suggestion of neurotoxicity (atactic gait and apathy).
    As noted above, however, this study is significantly flawed.

         Crofton et al. (1989) measured brain weight and motor activity in
    developmental studies. There was some suggestion of neurotoxicity
    (based on decreased brain weight in pups) at exposures in excess of 10
    mg/kg body weight per day, but no reported effects at 5 mg/kg body
    weight per day.

         Organotin compounds, including tributyltin, have recently been
    shown to induce apoptosis in immortalized neuronal cell lines
    (Thompson et al., 1996) and in pheochromocytoma PC12 cells (Viviani et
    al., 1995). Although TBTO induces apoptosis in neural cells  in
     vitro, it does not cause neurotoxicity in whole animals.

         Although the potential for neurotoxicity has not been completely
    investigated with focused studies, there is no suggestion that
    neurotoxicity is likely a critical or co-critical effect.


         No information was located regarding the toxicity of TBTO in
    humans following long-term exposure. Human data summarized by Boyer
    (1989) suggest that TBTO is a potent non-allergenic dermal irritant.
    There are several case reports claiming irritation of the respiratory
    tract following acute inhalation exposure of people to TBTO (Anon.,
    1991; Hay & Singer, 1991; Shelton et al., 1992; Wax & Dockstader,
    1995). None of these reports, however, contains sufficient information
    to characterize the exposure-response relationship for the reported

         No epidemiological studies on TBTO were located in the


         Tributyltin in the environment is very toxic to most taxa (see
    data cited in IPCS, 1990). Bivalves and gastropods are especially
    sensitive, and larval stages are more vulnerable than adults. The
    lowest reported effect concentrations for tributyltin are 2.4-4.8
    ng/litre for induction of shell deformities in Pacific oyster and
    imposex1 development in dogwhelk ( Nucella lapillus). Other low
    toxicity values reported are no-observed-effect concentrations (NOECs)
    of 80 ng/litre for  Daphnia magna, 40 ng/litre for reduced viability
    of mussel ( Mytilus edulis) larvae, and 10 ng/litre for reduced
    growth of hard-shell clams ( Mercenaria mercenaria) and reduced egg
    production in a marine copepod ( Acartia tonsa).

         In the field, mainly the effects on oysters and prosobranchs have
    been studied. Most studies on imposex have examined populations of
     N. lapillus. It has been suggested that other prosobranchs are even
    more sensitive, and other species have been suggested as indicator
    species (Matthiessen & Gibbs, 1998).

         Matthiessen & Gibbs (1998) reviewed the evidence that
    TBTO-induced imposex and intersex in molluscs are the result of
    endocrine disruption. The effect is most likely the result of elevated
    testosterone titres that masculinize tributyltin-exposed females. The
    precise mechanism has not been fully described, but the weight of
    evidence suggests that TBTO acts as a competitive inhibitor of
    cytochrome P-450-mediated aromatase, leading to increased testosterone
    levels. Additional support for this mechanism has been presented by
    Bettin et al. (1996). Testosterone addition (500 ng/litre) induces
    faster and more intensive imposex development in  N. lapillus than
    that induced by tributyltin. Simultaneous exposure to tributyltin and
    to the antiandrogen cyproterone acetate suppresses imposex development
    completely in  N. lapillus and reduces it in  Hinia reticulata.
    Furthermore, tributyltin-induced imposex development can be suppressed
    by adding estrogens. Inhibition of the cytochrome P-450-dependent
    aromatase using SH 489 (1-methyl-1,4-androstadiene-3,17-dione) and
    flavone induces development of imposex. Some recent data suggest that
    TBTO may also inhibit the formation of sulfur conjugates of
    testosterone and its active metabolites, thus interfering with its

         There is a vast literature on the environmental effects of
    tributyltin. Most of the information below was condensed from IPCS
    (1990). Additional data published since this evaluation have also been
    1 Imposex is the development of male characteristics by female 

    10.1  Aquatic environment

         As tributyltin is used commercially to control bacteria and
    fungi, the substance is toxic to these taxa. The reported minimum
    inhibitory concentrations (MICs) range from 20 to 300 000 µg/litre.
    The MIC for sludge from municipal sewage treatment plants was reported
    as 25 µg/litre (IPCS, 1990). A recent study conducted in yeast
    suggests that the target for TBTO action is the mitochondrial ATPase
    (Veiga et al., 1997). TBTO reduced the respiratory capacity when
    vanillic or benzoic acid was the energy source. The ATP level of the
    cell was severely affected at a concentration of 1.19 mg/litre. The
    mitochondrial ATPase was strongly inhibited at a concentration of 0.3
    mg/litre, whereas the activity of the plasma membrane ATPase was not
    affected by a concentration up to 17.9 mg/litre.

         In the laboratory, effective concentrations for freshwater algae
    ranged from 5 µg/litre (4-h IC50 for growth,  Ankistrodesmus
     falcatus) to 64 µg/litre (96-h EC50,  Scenedesmus pannonicus). A
    4-h IC50 for primary production of 3 µg/litre was reported for a
    natural community from Lake Ontario (IPCS, 1990). For marine and
    estuarine algae, most reported IC50 or EC50/LC50 values range from
    0.1 to 15 µg/litre (IPCS, 1990). For motile spores of the green
    macroalga  Enteromorpha intestinalis, a 5-day EC50 of 0.001 µg/litre
    for spore development and inhibition of settling was indicated (IPCS,
    1990). Effects on community metabolism and nutrient dynamics in
    bladderwrack ( Fucus vesiculosus) have been shown at 0.6 µg
    tributyltin/litre and above (Lindblad et al., 1989). Studies on pure
    cultures of marine algae show that these organisms do not adapt to
    tributyltin; the same EC50 values were obtained for cultures exposed
    for 12 weeks as for naive cells (IPCS, 1990).

         For  Lemna and  Elodea species, reduction in growth was
    observed from 0.06 µg/litre following 10 days of exposure to TBTO. For
    the angiosperm  Zostera marina, a NOEC of 0.1 mg/kg sediment was
    reported. The lethal concentration for the salt-marsh species  Aster
     tripholium was 10 µg/kg mud (dry weight) (IPCS, 1990).

         For  Daphnia magna, the 48-h LC50 was 2.3 µg/litre; the NOEC
    has been estimated to be 0.5 µg/litre based on reversal of normal
    response to light (IPCS, 1990). The reported long-term toxicity value
    (21-day NOEC) for  Daphnia magna is 0.19 µg/litre; the 96-h LC50 for
     Tubifex tubifex is 0.1 µg/litre (Fargasova, 1997).

         For target snail adults, the 24-h LC50 was 30-400 µg/litre. The
    sensitivity of snails decreases with age, but eggs are more resistant
    than both young and adults. The lowest-observed-effect concentration
    (LOEC) for reproduction for  Biomphalaria and  Bulinus is 0.001
    µg/litre; the long-term NOEL for  Lymnaea stagnalis is 0.32 µg/litre
    (IPCS, 1990).

         Several field studies on the effects of tributyltin used as a
    molluscicide for schistosomiasis control in tropical areas have been
    reported (IPCS, 1990). For schistosome larvae in the aquatic stages,
    the LC50 was calculated to be 16.8 µg/litre for a 1-h exposure. The
    dose causing 99-100% suppression of cercarial infectivity of mice was
    between 2 and 6 µg/litre (IPCS, 1990).

         Among marine aquatic invertebrates, larval stages are
    considerably more sensitive than adults. For example, the 48-h LC50
    for the Pacific oyster is 1.6 µg/litre for larvae and 1800 µg/litre
    for adults; for the mussel  M. edulis, the same values are 23 and 300
    µg/litre, respectively. The larvae of brown shrimp ( Crangon crangon)
    are also more sensitive than adults, the 96-h LC50s being 1.5 and 41
    µg/litre, respectively (IPCS, 1990).

         For subadults of the copepod  Eurytemora affinis, the 72-h LC50
    was reported as 0.6 µg/litre. For the mysid shrimp ( Acanthomysis
     sculpta), the 96-h LC50 was reported as 0.41 µg/litre. For larvae
    of the lugworm ( Arenicola cristata), the 96-h LC100 was reported as
    4 µg/litre (IPCS, 1990).

         The 144-day EC50 for morbidity and mortality of the copepod
     Acartia tonsa was 0.4 µg/litre (IPCS, 1990). A 6-day NOEC and LOEC
    for  A. tonsa have been reported as 0.011 and 0.023 µg/litre,
    respectively (Kusk & Peterson, 1997). Concentrations of 5-10 µg/litre
    killed all larvae of lobster ( Homarus americanus) within 5-6 days,
    and metamorphosis was affected at 1 µg/litre (IPCS, 1990). A 15-day
    LC50 of mussel ( M. edulis) larvae has been reported as
    approximately 0.1 µg/litre (IPCS, 1990).

         A 22-day LC100 for adult polychaetes  Nereis diversicolor was 4
    µg/litre (IPCS, 1990). In another polychaete,
     Sabellastarte sanctijosephi, mortality occurred at 0.04-1.0 µg/litre
    (Langston, 1995).

         Deformities in regenerated limbs of fiddler crab ( Uca
     pugilator) were observed at 0.5 µg/litre and above. Inhibition of
    the regeneration of arms of brittle star ( Ophioderma brevispina) was
    observed at 0.1 and 0.5 µg/litre (IPCS, 1990).

         It has been suggested that TBTO inhibits calcification of Pacific
    oysters below 2 ng tin/litre (Alzieu, 1991; Langston, 1995). These
    effects have also been observed in the field. In the early 1980s, a
    good correlation was found between field observations of occurrence of
    shell thickening and proximity of ports with large numbers of boats
    (IPCS, 1990).

         Reduced growth of Pacific oyster spat has been shown at all
    concentrations above 20 ng TBTO/litre (IPCS, 1990). Recently
    metamorphosed European oysters ( Ostrea edulis) showed a severe
    reduction in growth rate over 10 days in 0.06 µg/litre. In spats of

     C. gigas,  M. edulis, and carpet shell ( Venerupis ducussata),
    growth was reduced at 0.24 µg/litre over 45 days. For adult mussels
    ( M. edulis), shell length was reduced at 0.31 µg/litre following 66
    days of exposure, and juvenile growth was reduced at 0.07 µg/litre. In
    a study of hard-shell clam ( Mercenaria mercenaria) exposed from
    fertilization to metamorphosis (approximately 14 days), growth was
    reduced at 10 ng/litre and above.

         In the laboratory, all female dogwhelks exposed to TBTO showed
    imposex development at 1-2 ng tin/litre and above (IPCS, 1990). Some
    of the females retained their breeding capacity at the lowest
    concentration, but virtually all females were sterilized at 3-5 ng
    tin/litre. From field observations, the NOEL has been set at less than
    1 ng tributyltin/litre. Imposex has been observed in a number of other
    species in the field. These include  Ocenebra erinacea,
      Ocinebrina aciculata,  Hexaplex trunculus,  Buccinum undatum,
     Littorina littorea, and  Nassarius reticulatus (Oehlmann et al.,
    1996; Matthiessen & Gibbs, 1998).

         In oysters ( O. edulis), severe effects on reproduction occurred
    at 0.24 and 2.6 µg/litre; no larvae were released, gonads were
    undifferentiated, and no females developed (IPCS, 1990). At 0.01
    µg/litre, egg production in exposed  A. tonsa was significantly
    reduced (IPCS, 1990).

         No effect on survival of grass shrimp ( Palaemonetes pugio) was
    found after 96 h of exposure at 1 or 10 mg tributyltin/kg sediment,
    but exposure via water alone resulted in a 96-h LC50 of 20 µg/litre
    (IPCS, 1990). In sediments containing tributyltin, an LC50 of 1-10
    mg/kg sediment was determined for  Amphioxus (IPCS, 1990). No effects
    on survival of the mole crab ( Emerita talpoida) were observed
    following 7 days of exposure at 10 µg/litre seawater and 4.5 mg/kg
    sand (IPCS, 1990). No mortality was observed in mysid shrimp
    ( Acanthomysis sculpta), worms ( Neanthes arenaceodentata), or clams
    ( Macoma nasuta) exposed to concentrations in sediment of 155-610
    µg/kg and concentrations in overlaying water of 0.2 µg/litre over
    10-20 days (IPCS, 1990).

         The reported short-term LC50 values for TBTO in freshwater fish
    obtained under static conditions range from 13 to 240 µg/litre (IPCS,
    1990). The NOEL for the guppy ( Poecilia reticulata) was estimated to
    be 0.01 µg/litre based on thymus atrophy, liver vacuolation, and
    hyperplasia of the haematopoietic tissue (Wester & Canton, 1987).

         The toxicity of TBTO to marine fish is highly variable; 96-h
    LC50 values range between 1.5 and 36 µg/litre, with larval stages
    being more sensitive than adults (IPCS, 1990). Data have been reported
    for bleak ( Alburnus alburnus), sole ( Solea solea), armed bullhead
    ( Agonus cataphractus), girella ( Girella punctata), salt water goby
    ( Chasmichthys dolichograthus), and chinook salmon ( Oncorhynchus
     tshawytscha). There are indications that marine fish avoid TBTO

    concentrations of 1 µg/litre or more (IPCS, 1990). A recent study in
    flounder ( Platichthys flesus) showed that TBTO at 17.3 µg/litre
    caused mortality after 7-12 days, decreased the condition factor,
    resulted in gill lesions, and induced significant reduction of
    non-specific resistance. However, no marked effects on the relative
    thymus volume or on the specific immune system were noted (Grinwis et
    al., 1997).

         Japanese medaka ( Oryzias latipes) fed daily for 3 weeks with
    food containing tributyltin, polychlorinated biphenyls, or a
    combination of the two at 1 mg/kg body weight showed slight
    synergistic effects on reproduction, resulting in reduced spawning
    frequency, number of eggs, and proportion of fertile eggs (Oshima et
    al., 1998).

         No effect on survival was found when eggs and larvae of frog
    ( Rana temporaria) were exposed to TBTO concentrations of 3 µg/litre
    or less; at 30 µg/litre, however, significant mortality was observed
    (IPCS, 1990).

    10.2  Terrestrial environment

         Although the exposure of terrestrial organisms to tributyltin
    results primarily from its use as a wood preservative, tributyltin
    compounds are toxic to insects exposed topically or via feeding on
    treated wood (IPCS, 1990). The LD50 values for tributyltin compounds
    applied topically to the thorax of newly emerged insects range from
    0.48% to 0.72% (dilutions with acetone) for the house fly
    ( Musca domestica), from 0.29% to 0.69% for the mosquito
    ( Anophelese stephensi), and from 0.52% to 0.87% for the cotton
    stainer ( Dysdercus cingulatus). TBTO is toxic to honey bees
    ( Apis mellifera) housed in hives made from TBTO-treated wood
    (1.9 kg/m3). TBTO is toxic to bats ( Pipistrellus pipistrellus)
    housed in roosting cages treated with TBTO, but this result was not
    statistically significant, owing to high mortality in controls. The
    acute toxicity of TBTO to wild mice (deer mice
    [ Peromyscus maniculatus] and house mice [ Mus musculus]) is
    moderate. The estimated dietary LC50 value, based on consumption of
    treated seeds used in repellency tests, is 200 mg/kg diet per day.


    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         A large number of studies have been conducted showing that TBTO
    causes depression of immune functions dependent on the thymus. These
    effects occur at doses lower than those that cause other toxicity (see
    Table 1). Accordingly, the critical effect for TBTO is immunotoxicity.

         Based on the study of Vos et al. (1990), the critical effect is
    immunosuppression (reduced IgE titres and increase in  T. spiralis
    larvae in muscle). The LOAEL is 0.25 mg/kg body weight per day, and
    the NOAEL is 0.025 mg/kg body weight per day. These values were based
    on the authors' report that 5 mg/kg in the diet is equivalent to 0.25
    mg/kg body weight per day. This study tested male animals only. Other
    studies show no evidence of gender differences in the toxic responses
    to TBTO. There is some evidence that a child might be more sensitive
    to the toxic effects of TBTO. For example, Smialowicz et al. (1989)
    showed that pre-weanling rats were more sensitive than adult rats. In
    addition, the principal study (Vos et al., 1990) showed that
    immunotoxic effects were observed when weanling rats were dosed for
    4.5 or 16.5 months, whereas a companion study (Vos et al., 1990)
    showed that these effects were absent or occurred at a higher dose
    when adult (1-year-old) rats were dosed for 5 months.

         Adequate data are not available to determine a no-effect or
    effect level following long-term inhalation exposure. The inhalation
    studies that are available document irritation to the respiratory
    system. There are no pharmacokinetic studies available with which to
    conduct a route-to-route extrapolation for extra-respiratory effects.
    TBTO might cause immunosuppression following chronic exposure by

         Cancer bioassays following oral exposure have been conducted in
    rats and mice. The bioassay in rats shows increases in benign
    pituitary tumours, in pheochromocytomas, and in parathyroid tumours at
    the highest dose tested. The significance of these tumours, which
    normally occur in this strain of rat with variable incidence, is
    unclear. The bioassay in mice showed no increase in tumours at any
    site. The weight of evidence shows that TBTO is not genotoxic.

    11.1.2  Criteria for setting guidance values for TBTO

         The no-effect level for immunosuppression (decrease in serum IgE
    titre) following long-term oral exposure in rats is 0.025 mg/kg body
    weight per day. Benchmark dose analysis shows that the exposure
    corresponding to the lower confidence limit (95%) on dose for a 10%
    decrease in serum IgE titre is 0.034 mg/kg body weight per day (US
    EPA, 1997). Application of uncertainty factors of 10 each for
    extrapolation from a laboratory animal species to humans and to

    protect sensitive humans gives a guidance value for oral exposure of
    0.0003 mg/kg body weight per day (rounded from 0.00025 for the
    no-effect level or 0.00034 for the benchmark dose). No appropriate
    data are available to develop a guidance value for inhalation exposure
    or to estimate cancer risk.

    11.1.3  Sample risk characterization

         No human data are available to characterize the toxicity of TBTO,
    but a wealth of data from oral exposure in laboratory animals is
    available. The principal study and a variety of supporting studies
    convincingly demonstrate that the critical effect for TBTO is
    immunotoxicity. Some evidence indicates that young animals are more
    sensitive than adults to the immunotoxic effects. TBTO is not a
    reproductive or developmental toxicant. Insufficient data are
    available to determine the critical effect for TBTO following exposure
    by inhalation. Several case reports document severe irritation of the
    human respiratory system following acute inhalation exposure. The
    potential human hazard for carcinogenicity for TBTO cannot be
    determined. The weight of evidence shows that TBTO is not genotoxic.

         Dietary exposure to tributyltin has been assessed in Japan.
    Consumption of aquatic organisms is the major route of human exposure.
    Data from market basket surveys from 1990 to 1997 estimated the
    average daily intake of tributyltin (expressed as tributyltin
    chloride) at 3.9 µg/day. Using these data, correcting the exposure
    estimate to TBTO by multiplying by the ratio of the molecular weights
    (596/325), and assuming a body weight of 50 kg, the estimated daily
    exposure to TBTO in Japan is 0.00014 mg/kg body weight per day. This
    value is 47% of the guidance value.

         Because of the limited and possibly unrepresentative information
    on human exposure available to the author and reviewers of the CICAD
    and the recent preliminary report (Takahashi et al., 1998) of a
    relatively high burden of tributyltin residues in liver resulting,
    perhaps, from non-food sources, additional investigation is warranted.

    11.2  Evaluation of environmental effects

         Because of their physical/chemical properties, tributyltin
    compounds concentrate in the surface microlayer and in sediments.
    Abiotic degradation does not appear to be a major mechanism of removal
    under environmental conditions. Although TBTO is biodegradable in the
    water column, this process is not rapid enough to prevent the
    occurrence of elevated tributyltin levels in some areas. The half-life
    in the water column ranges from a few days to weeks. Tributyltin may
    persist in sediment for several years. Bioaccumulation occurs in most
    aquatic organisms.

         Tributyltin compounds are extremely hazardous to some aquatic
    organisms because of their toxicity at very low concentrations in
    water. Such concentrations seem to be prevalent in many coastal areas.
    Adverse effects on non-target invertebrates, particularly molluscs,
    have been reported in field studies, and these have been sufficiently
    severe to lead to reproductive failure and population decline. Adverse
    effects on the commercial production of shellfish have been
    successfully reversed by restrictions on the use of antifouling paints
    in some areas, and these restrictions are also leading to the reversal
    of imposex effects in gastropod populations. However, the
    concentrations of tributyltin measured in some coastal waters are
    still above those that induce severe effects in some gastropods. The
    effects on farmed fish indicate that tributyltin-containing paints
    should not be used on restraining nets.

         The general hazard to the terrestrial environment is likely to be
    low. Tributyltin-treated wood could pose a hazard to terrestrial
    organisms living in close contact with it.

         The enhancement of tributyltin concentrations in the surface
    microlayer may present a hazard to littoral organisms, neustonic
    species (including benthic invertebrate and fish larvae), and
    surface-feeding seabirds and wildfowl. Accumulation and low
    biodegradation of tributyltin in sediment may pose a hazard to aquatic
    organisms when these polluted sediments are disturbed by natural
    processes or dredging activities.

         The general decline in tributyltin concentrations in the
    environment has been attributed to the restrictions placed on the use
    of antifouling paints on vessels. However, it should be noted that in
    some locations the concentration of tributyltin in the water is above
    that necessary to elicit severe adverse effects in some sensitive


         Tributyltin compounds were reviewed by the World Health
    Organization in 1989 (IPCS, 1990).

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document.


         Human health hazards, together with preventative and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 1282) reproduced in this

    13.1  Human health hazards

         Effects on the immune system may be observed following acute or
    repeated exposure to tributyltin.

    13.2  Advice to physicians

         In case of poisoning, treatment is supportive. Following
    inhalation of aerosol, symptoms may not be noticeable until a few
    hours have passed. Therefore, rest and medical observation are

    13.3  Health surveillance advice

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

    13.4  Spillage

         TBTO is severely irritating to the skin and eyes. In case of
    spillage, therefore, emergency crew must wear proper equipment,
    including eye protection in combination with breathing protection. The
    compound should not be allowed to enter drains or watercourses.


         Many countries have restricted the use of TBTO. 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.


    TRIBUTYLTIN OXIDE                             ICSC: 1282
                                                  March 1998

    CAS #    56-35-9              Hexabutyldistannoxane
    RTECS #  JN8750000             Tri-n-butylin oxide
    UN #     3020                         TBTO
    EC #     050-008-00-3              C24H54OSn2

                                  Molecular mass: 596.07

    FIRE                          Combustible                   NO open flames           In case of fire in the
                                                                                         surroundings: all 
                                                                                         extinguishing agents allowed.


    EXPOSURE                                                    PREVENT GENERATION
                                                                OF MISTS! STRICT
    Inhalation                    Abdominal cramps. Cough.      Ventilation, local       Fresh air, rest.
                                  Diarrhoea. Laboured           exhaust, or              Half-upright position.
                                  breathing. Nausea. Sore       breathing protection     Refer for medical
                                  throat. Vomiting.                                      attention.
                                  Symptoms may be delayed
                                  (See Notes).

    Skin                          MAY BE ABSORBED! Redness.     Protective gloves.       Rinse and then wash skin
                                  After delay skin burns.       Protective clothing.     with water and soap. Refer
                                                                                         for medical attention.
    Eyes                          Redness. Pain.                Safety spectacles,       First rinse with plenty of
                                                                face shield, or eye      water for several minutes
                                                                protection in            (remove contact lenses if
                                                                combination with         easily possible), then take 
                                                                breathing protection.    to a doctor.
    Ingestion                     Abdominal cramps.             Do not eat, drink or     Induce vomiting (ONLY IN
                                  Diarrhoea. Nausea.            smoke during work.       CONSCIOUS PERSONS!) Give
                                  Vomiting.                     Wash hands before        plenty of water to drink.
                                                                eating.                  Refer for medical attention.
    SPILLAGE DISPOSAL                                           PACKAGING & LABELLING
    Do NOT wash away into sewer. Carefully collect              Severe marine pollutant.
    remainder, then remove to safe place. Do NOT let this       EU Classification
    chemical enter the environment. Chemical protection         Symbol: T
    suit including self-contained breathing apparatus.          R: 21-25-36/38-48/23/25
                                                                S: (1/2)-35-36/37/39-45
                                                                Note: A
                                                                UN Classification
                                                                UN Hazard Class: 6.1
                                                                UN Pack Group: II

    EMERGENCY RESPONSE                                          STORAGE
    Transport Emergency Card: TEC (R)-61G43b                    Provision to contain effluent from fire

                                      IMPORTANT DATA
    PHYSICAL STATE; APPEARANCE:                                 ROUTES OF EXPOSURE:
    LIQUID                                                      The substance can be absorbed into the
                                                                body by inhalation of its aerosol, through
                                                                the skin and by ingestion.

    CHEMICAL DANGERS:                                           INHALATION RISK:
    The substance decomposes on burning                         Evaporation at 20°C is neglible; a harmful
    producing toxic fumes.                                      concentration of airborne particles can, 
                                                                however, be reached quickly.

    TLV (as tin): ppm: 0.1 mg/m3 A4.                        The substance irritates severely the eyes, the skin.
    STEL 0.2 mg/m3 A4 (skin) (ACGIH 1997).                  Inhalation of the aerosol may cause lung oedema (see 
                                                                Notes). The substance may cause effects on the thymus,
                                                                resulting in depression of the immune function.

                                      PHYSICAL PROPERTIES
    Boiling point:                  173°C
    Melting point:                  <-45°C
    Relative density (water = 1):   1.17 at 20°C
    Solubility in water:            poor
    Vapour pressure, Pa at 20°C:    0.001
    Flash point:                    190°C c.c.
    Octanol/water partition coefficient as log Pow: 3.19
                                      ENVIRONMENTAL DATA
    The substance is very toxic to aquatic organisms. In the food chain important to humans,
    bioaccumulation takes place, specifically in fish and molluscs. Avoid release to
    the environment in circumstances different to normal use.

    The symptoms of lung oedema often do not manifest until a few hours have passed and they are
    aggravated by physical effort. Rest and medical observation is therefore essential. Immediate
    administration of an appropriate spray, by a doctor or a person authorized by him/her,
    should be considered.

                                     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.



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    IPCS (1990): Tributyltin compounds 
    (Environmental Health Criteria 116)

         A WHO Task Group meeting on Environmental Health Criteria for
    Tributyltin Compounds was held at the Institute of Terrestrial
    Ecology, Monks Wood, United Kingdom, from 11 to 15 September 1989. The
    Task Group reviewed and revised the draft criteria document and made
    an evaluation of the risks for human health and the environment from
    exposure to tributyltin compounds.

         Copies of this document may be obtained from:

         International Programme on Chemical Safety
         World Health Organization
         Geneva, Switzerland

    US EPA (1997): Toxicological review on tributyltin oxide

         This document received internal peer review by EPA scientists, an
    external peer review by three well-qualified nongovernment scientists,
    and consensus review by EPA Program Offices and the 10 Regional
    Offices. Summaries of significant comments from external peer
    reviewers are included in an appendix to the document.

         Copies of this document may be obtained from:

         EPA Risk Assessment Hotline
         513-569-7254 (phone)
         513-569-7159 (fax)
         rih.iris@epamail.epa.gov (Internet address)
         www.epa.gov/iris (Website)


         The draft CICAD on TBTO 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 and Safety Executive, Bootle, United Kingdom

         Health Canada, Ottawa, Canada

         International Agency for Research on Cancer, Lyon, France

         International Council on Metals and the Environment, Ottawa,

         József Fodor National Center of Public Health, Budapest, Hungary

         Karolinska Institute, Stockholm, Sweden

         National Chemicals Inspectorate (KEMI), Solna, Sweden

         National Institute for Working Life, Solna, Sweden

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

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

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

         World Health Organization, International Programme on Chemical
         Safety, Geneva, Switzerland


    Tokyo, Japan, 30 June - 2 July 1998


    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

    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,

    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


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

    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


    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


         Ce CICAD relatif à l'oxyde de tributyétain (TBTO) a été préparé
    par l'Agence américaine pour la protection de l'environnement (United
    States Environmental Protection Agency, US EPA) à partir d'un document
    sur les dérivés du tributylétain publié par le Programme international
    sur la Sécurité chimique dans la série  Critères d'Hygiène de
     l'Environnement (IPCS, 1990) et d'un document de l'US EPA intitulé
     Toxicological review on tributyltin oxide (US EPA, 1997). Ces deux
    mises au point étaient basées sur des bibliographies arrêtées
    respectivement en 1989 et 1996. Des informations complémentaires dont
    les dernières remontent à juin 1998 ont été incluses dans le présent
    document. 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 aprouvé 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 1282)
    établie pour l'oxyde de tributylétain par le Programme international
    sur la Sécurité chimique (IPCS, 1996) est également reproduite dans ce

         Dans le présent document, on utilise le terme d'oxyde de
    tributylétain chaque fois qu'il est question de ce composé en
    particulier. Toutefois dans l'environnement, les dérivés du
    tributylétain existent selon toute probabilité principalement sous la
    forme d'hydroxyde, de chlorure et de carbonate de tributylétain. Dans
    ce cas et lorsque l'identité du composé est douteuse, on utilise le
    terme général de tributylétain.

         L'oxyde de tributylétain protège efficacement le bois, les
    cotonnades, le papier et les peintures murales contre l'attaque de la
    vermine. Il entre dans la composition de nombreuses peintures marines
    auxquelles on l'ajoute comme agent antisalissures. Il est présent dans
    ces produits sous la forme de copolymère organométallique. Lorsque le
    copolymère est hydrolysé par l'eau de mer, le tributylétain est
    lentement libéré de la surface peinte qu'il protège des incrustations
    pendant des durées pouvant aller jusqu'à 4 ou 5 ans.

         Du fait de sa faible solubilité dans l'eau et de son caractère
    lipophile, le tributylétain s'adsorbe facilement sur les particules.
    Sa demi-vie dans la colonne d'eau va de quelques jours à plusieurs
    semaines. Il peut subsister dans les sédiments pendant plusieurs
    années. Il s'accumule dans l'organisme des animaux, ses organes
    d'élection étant le rein et le foie. L'absorption s'effectue davantage
    à partir des denrées alimentaires que directement à partir de l'eau.

         On ne dispose d'aucun renseignement sur la toxicité du
    tributylétain chez l'Homme à la suite d'une exposition de longue
    durée. D'après un certain nombre de données et d'observations, le
    tributylétain serait fortement irritant pour la peau et les voies
    respiratoires. Ces données ne se prêtent toutefois pas à
    l'établissement de relations dose-réponse bien caractérisées. Des
    études effectuées au Japon ont permis une évaluation quantitative de
    l'exposition au tributylétain présent dans les denrées alimentaires.

         Les études à court terme montrent que l'oxyde de tributylétain
    est modérément à fortement toxique pour les mammifères de laboratoire.
    Des études nombreuses et bien conduites, tant à court qu'à long terme,
    montrent que l'effet essentiel de l'oxyde de tributylétain réside dans
    son immunotoxicité (dépression des fonctions immunitaires
    thymo-dépendantes). La dose sans effet nocif observable (NOAEL) chez
    le rat est de 0,025 mg/kg de poids corporel par jour, le critère
    retenu étant une immunodépression après exposition de longue durée.
    Une analyse des doses de référence montre que l'exposition
    correspondant à la limite inférieure de confiance (95 %) pour une
    réduction de 10 % du titre des anticorps IgE chez le rat est égale à
    0,034 mg/kg de poids corporel par jour. Lors d'une étude de
    cancérogénicité chez le rat, on a constaté une augmentation de
    l'incidence de certaines tumeurs endocriniennes. Ces tumeurs se
    produisent spontanément chez les rats appartenant à l'espèce utilisée
    dans cette étude et on ignore dans quelle mesure on peut les prendre
    en compte dans une évaluation du risque chez l'Homme. L'oxyde de
    tributylétain n'est pas cancérogène pour la souris. L'expérience
    montre qu'il n'est pas non plus génotoxique. Rien n'indique qu'il
    exerce des effets nocifs sur la fonction de reproduction et le
    développement à des doses inférieures à la dose sans effet
    immunotoxique observable. De tels effets ne se produisent que lorsque
    la dose est voisine de celle qui est toxique pour la mère. Comme on
    l'a indiqué plus haut, les données révèlent un effet irritant prononcé
    sur la peau et les voies respiratoires. En s'appuyant sur la valeur de
    la dose sans effet immunotoxique observable et en appliquant un
    coefficient de sécurité de 100, on peut donner une valeur-guide de
    0,0003 mg/kg p.c. par jour pour l'exposition par la voie buccale. On
    ne dispose pas de données suffisantes pour établir une valeur-guide
    dans le cas d'une exposition par inhalation.

         L'oxyde de tributylétain est extrêmement dangereux pour certains
    organismes aquatiques. Dans certains cas, il bloque les fonctions
    endocrines. Dans les eaux littorales de quelques régions, il est
    présent à une concentration supérieure à celle qui produit de graves
    effets nocifs. Dans certaines régions, les effets constatés ont été
    suffisamment graves pour faire chuter la fécondité et réduire
    l'effectif de la population touchée. Le risque global pour
    l'environnement terrestre est vraisemblablement faible.


         Este CICAD sobre el óxido de tributilestaño (TBTO), preparado por
    la Agencia para la Protección del Medio Ambiente de los Estados Unidos
    (EPA), se basa en un documento sobre los Criterios de Salud Ambiental
    del Programa Internacional de Seguridad de las Sustancias Químicas
    relativo a los compuestos de tributilestaño (IPCS, 1990) y en el
     Examen toxicológico sobre el óxido de tributilestaño de la EPA de
    los Estados Unidos (US EPA, 1997). En estos exámenes se analizaron los
    datos identificados hasta 1989 y 1996, respectivamente. En el presente
    documento aparece también la información adicional obtenida hasta
    1998. La información relativa a las características de los proceso 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 de la Junta de Evaluación Final
    aparece en el apéndice 3. La Ficha internacional de seguridad química
    (ICSC 1282), preparada por el Programa Internacional de Seguridad de
    las Sustancias Químicas (IPCS, 1996), también se reproduce en el
    presente documento.

         En este documento, el término de óxido de tributilestaño se
    aplica específicamente a este producto químico. Sin embargo, en el
    medio ambiente es más probable que los compuestos de tributilestaño se
    encuentren como hidróxido, cloruro o carbonato. En esos casos o cuando
    la identidad del producto químico específico no está clara, se utiliza
    el término general de tributilestaño.

         El óxido de tributilestaño es un conservante biocida eficaz de la
    madera, los textiles de algodón, el papel y las pinturas y colorantes
    domésticos. Se añade como agente antiincrustante en numerosas
    formulaciones de pinturas marinas. El tributilestaño está presente en
    la mayoría de esas formulaciones antiincrustantes como copolímero
    organometálico. Se libera lentamente de la superficie pintada a medida
    que el polímero se hidroliza en el agua de mar, proporcionando una
    protección prolongada contra las incrustaciones de hasta cuatro o
    cinco años.

         Debido a su baja solubilidad en agua y a su carácter lipófilo, el
    tributilestaño se adsorbe fácilmente en las partículas. Su semivida en
    la columna de agua oscila entre unos días y varias semanas. Puede
    persistir en los sedimentos durante varios años. Se bioacumula en los
    organismos, alcanzando las concentraciones más altas en el hígado y el
    riñón. La absorción a partir de los alimentos es más importante que la
    procedente directamente del agua.

         No se dispone de información sobre la toxicidad del óxido de
    tributilestaño en el ser humano tras una exposición prolongada.
    Algunos datos e informes de casos ponen de manifiesto que produce

    irritación cutánea y respiratoria grave. Sin embargo, los datos no son
    suficientes para caracterizar la relación exposición-respuesta. En
    algunos estudios realizados en el Japón se ha cuantificado la
    exposición humana al tributilestaño procedente de los alimentos.

         En estudios de corta duración con mamíferos de laboratorio, la
    toxicidad aguda del óxido de tributilestaño es entre moderada y alta.
    En numerosos estudios bien realizados, tanto de corta duración como
    prolongados, su efecto más importante es la inmunotoxicidad (depresión
    de las funciones inmunitarias dependientes del timo). La concentración
    sin efectos adversos observados (NOAEL) para la inmunosupresión en
    ratas tras una exposición prolongada es de 0,025 mg/kg de peso
    corporal al día. El análisis de las dosis de referencia pone de
    manifiesto que la exposición correspondiente al límite de confianza
    más bajo (95%) de la dosis que produce una disminución del 10% en la
    concentración de la inmunoglobulina (Ig) E en ratas es de 0,034 mg/kg
    de peso corporal al día. En un estudio de carcinogenicidad en ratas,
    se observó un aumento en la incidencia de algunos tumores en
    determinados tejidos endocrinos. Estos tumores se producen
    espontáneamente, con una incidencia variable en la estirpe de ratas
    utilizada en el estudio, y se desconoce su importancia en la
    evaluación del riesgo para la salud humana. El óxido de tributilestaño
    no es carcinogénico para los ratones. Las pruebas ponen de manifiesto
    que no es genotóxico. No hay indicios de que se produzcan efectos
    reproductivos o en el desarrollo con una exposición inferior a la
    establecida como NOAEL para la inmunotoxicidad. Estos efectos aparecen
    solamente con exposiciones próximas a las que causan toxicidad
    materna. Los datos demuestran que el óxido de tributilestaño produce
    una irritación cutánea y respiratoria grave. Teniendo en cuenta la
    NOAEL para la inmunotoxicidad y un factor de incertidumbre de 100, el
    valor guía para la exposición oral es de 0,0003 mg/kg de peso corporal
    al día. No se dispone de datos adecuados para extrapolar un valor guía
    aplicable a la exposición por inhalación.

         El óxido de tributilestaño es enormemente peligroso para algunos
    organismos acuáticos. Es un perturbador endocrino en algunos
    organismos. La concentración de tributilestaño en determinadas aguas
    costeras es superior a la que produce efectos adversos graves. Estos
    efectos han sido suficientemente importantes para producir fracaso
    reproductivo y disminución de la población en algunas zonas. El
    peligro general para el medio ambiente terrestre es probablemente

    See Also:
       Toxicological Abbreviations
       Tributyltin oxide (ICSC)