TRIPHENYLTIN COMPOUNDS
This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.
Concise International Chemical Assessment Document 13
TRIPHENYLTIN COMPOUNDS
First draft prepared by Dr J. Sekizawa, National Institute of Health Sciences, Tokyo, Japan
Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization Geneva, 1999
The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.
The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.
WHO Library Cataloguing-in-Publication Data
Triphenyltin compounds.
(Concise international chemical assessment document ; 13)
1.Organotin compounds - adverse effects 2.Organotin compounds - toxicity 3.Environmental exposure 4.Maximum permissible exposure level I.International Programme on Chemical Safety II.Series
ISBN 92 4 153013 8 (NLM classification: QV 290) ISSN 1020-6167
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TABLE OF CONTENTS
FOREWORD
1. EXECUTIVE SUMMARY
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
3. ANALYTICAL METHODS
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6.1. Environmental levels 6.2. Human exposure
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
8.1. Single exposure 8.2. Irritation and sensitization 8.3. Short-term exposure 8.4. Long-term exposure 8.4.1. Subchronic exposure 8.4.2. Chronic exposure and carcinogenicity 8.5. Genotoxicity and related end-points 8.6. Reproductive and developmental toxicity 8.7. Immunological and neurological effects 8.8. Mode of action
9. EFFECTS ON HUMANS
9.1. Case reports 9.2. Epidemiological studies
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
10.1. Aquatic environment 10.2. Terrestrial environment
11. EFFECTS EVALUATION
11.1. Evaluation of health effects 11.1.1. Hazard identification and dose-response assessment 11.1.2. Criteria for setting guidance values for triphenyltin 11.1.3. Sample risk characterization 11.2. Evaluation of environmental effects
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION
13.1. Human health hazards 13.2. Advice to physicians 13.3. Health surveillance advice 13.4. Spillage and disposal
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
INTERNATIONAL CHEMICAL SAFETY CARD
REFERENCES
APPENDIX 1 -- SOURCE DOCUMENTS
APPENDIX 2 -- CICAD PEER REVIEW
APPENDIX 3 -- CICAD FINAL REVIEW BOARD
RÉSUMÉ D'ORIENTATION
RESUMEN DE ORIENTACION
FOREWORD
Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) -- a cooperative programme of the World Health Organization (WHO), the International Labour Organisation (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals.
CICADs are concise documents that provide summaries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their completeness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn.
The primary objective of CICADs is characterization of hazard and dose-response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based.
Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 1701 for advice on the derivation of health-based guidance values.
While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new information that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.
1 International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: deriviation of guidance values for health-based exposure limits. Geneva, World Health Organization (Environmental Health Criteria 170).
Procedures
The flow chart shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world -- expertise that is required to produce the high-quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment.
The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS to ensure that it meets the specified criteria for CICADs.
The second stage involves international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers' comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers' comments.
The CICAD Final Review Board has several important functions:
- to ensure that each CICAD has been subjected to an appropriate and thorough peer review;
- to verify that the peer reviewers' comments have been addressed appropriately;
- to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and
- to approve CICADs as international assessments.
Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.
Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.
1. EXECUTIVE SUMMARY
This CICAD on triphenyltin compounds was based on a review prepared by the National Committee for Concise International Chemical Assessment Documents of Japan (CICAD National Committee, 1997). Many critical studies on health effects in this review were cited from monographs on pesticide residues prepared by the Food and Agriculture Organisation of the United Nations (FAO, 1991a,b) and the World Health Organization (WHO, 1992). These monographs report summaries of the many studies submitted to WHO by manufacturers for evaluation, in addition to summaries of published papers. In the case of studies submitted by manufacturers, original papers are proprietary and were not available to authors of the review prepared by the CICAD National Committee (1997), to authors of the CICAD draft, or to the CICAD Final Review Board. Therefore, this CICAD inevitably relies on the evaluations made by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) for those studies cited from summaries of proprietary data.
Extensive information on environmental effects was obtained from a review of the environmental effects of triorganotin compounds, prepared by the Advisory Committee on Pesticides of the Health and Safety Executive of the United Kingdom (HSE, 1992). Additional data were obtained through a search of Medline and Toxline Plus databases up to October 1997. Information on the nature of the review processes and the availability of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Tokyo, Japan, on 30 June - 2 July 1998. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Card (ICSC 1283) for triphenyltin hydroxide (TPTH), produced by the International Programme on Chemical Safety (IPCS, 1996), has also been reproduced in this document.
Triphenyltin compounds are triphenyl derivatives of tetravalent tin. They are colourless solids with low vapour pressures. They are lipophilic and have low solubility in water.
Triphenyltin and tributyltin compounds have been used extensively as algicides and molluscicides in antifouling products since the 1960s. Use of triorganotins in antifouling paints has been restricted in many countries because of their catastrophic effects on the oyster industry and more general effects on the aquatic ecosystem. Triphenyltin is used as a non-systemic fungicide with mainly protective action.
Triphenyltin is strongly adsorbed to sediment and soil, and little desorption occurs. Its half-life in water has been estimated to be several days in June and 2-3 weeks in November. Although triphenyltin compounds can be degraded by stepwise dephenylation and excreted in conjugated forms, they bioaccumulate in fish and snails, with bioconcentration factors (BCFs) ranging from several hundred to 32 500 (in the intestinal sac of Lymnaea stagnalis).
Environmental concentrations of triphenyltin compounds vary depending upon how, when, and where the compounds were used. Concentrations ranging from 0 ng/litre to nearly 200 ng/litre have been detected in bay areas or marinas as a result of leaching from ships treated with triphenyltin-based antifouling paints. Environmental concentrations of triphenyltin compounds have decreased in recent years as a result of tightening restrictions on their use in antifouling paints.
Triphenyltin compounds given orally to rats are not readily absorbed and are excreted primarily in faeces and partly in urine. They are metabolized to diphenyltin, monophenyltin, and non-extractable bound residues. Absorbed triphenyltin compounds accumulate in kidney and liver to the greatest extent, with smaller amounts in other organs. Triphenyltin compounds applied dermally can penetrate through the skin in a time- and dose-dependent manner.
Triphenyltin exerts a variety of health effects in various animal species, including effects on the immune system, reproductive/developmental effects at levels near those that are maternally toxic (most lowest-observed-adverse-effect levels, or LOAELs, are in the several mg/kg range or lower), hyperplasia/adenomas in endocrine organs, apoptosis in thymus cells, calcium release in sarcoplasmic reticulum cells, and eye irritation. The underlying mechanisms of these effects are under investigation; a common mechanism may explain this toxicity profile.
Triphenyltin compounds are moderately acutely toxic to rats. They are not carcinogenic, but some data show that they are co-clastogenic.
Reproductive and developmental effects include a decrease in the number of implantations and live fetuses (at 1.0 mg triphenyltin acetate [TPTA]/kg body weight per day in a rabbit gavage study), reduction in litter size/pup weight and in relative thymus or spleen weight in the weanlings (at 1.5 mg TPTH/kg body weight per day in the diet in a two-generation reproduction study in rats; no-observed-adverse-effect level, or NOAEL, 0.4 mg/kg body weight per day), and abortion and reduction in fetal weight (at 0.9 mg TPTH/kg body weight per day in a rabbit gavage study).
The lowest NOAEL detected in the toxicity tests was 0.1 mg TPTH/kg body weight per day for maternal toxicity in a rabbit gavage study, based on decreased food consumption and body weight gain at 0.3 mg/kg body weight per day. The same value was obtained in an early 2-year rat study in which a slight decrease in white blood cells was seen at higher doses. In a 52-week dog study, the NOAEL was estimated to be 0.21 mg TPTH/kg body weight per day based on a decrease in relative liver weight in females at higher doses.
Triphenyltin compounds affect the immune system. A decrease in immunoglobulin (Ig) concentrations (even at the lowest dose level, i.e., 0.3 mg TPTH/kg body weight per day in a 2-year feeding study in rats), lymphopenia (at 0.3 mg TPTH/kg body weight per day in another 2-year feeding study in rats or at 0.338 mg TPTH/m3 in a 13-week inhalation study in rats), thymus atrophy (at 1.5 mg triphenyltin chloride [TPTCl]/kg body weight per day in a 2-week feeding study with weanling rats), and splenic atrophy (at 5 mg TPTH/kg body weight per day in a 28-day feeding study in mice) have been observed. Females are generally more susceptible than males.
Several end-points were taken into consideration by JMPR in establishing the acceptable daily intake (ADI) of triphenyltin for oral exposure (FAO, 1991b; WHO, 1992). First, a 200-fold uncertainty factor was applied to the no-observed-effect level (NOEL) of 0.1 mg/kg body weight per day (based on a finding of reduced white blood cell counts at higher doses in a 2-year study in rats) to arrive at an ADI of 0-0.5 µg/kg body weight. Secondly, a 500-fold uncertainty factor was applied to a LOAEL of 0.3 mg/kg body weight per day in a 2-year study in rats in which increased mortality and reduced serum immunoglobulin levels were noted. Other NOAELs that were taken into consideration together with the above effect levels are 0.4 mg/kg body weight per day in a two-generation reproduction study with rats (a dose-related decrease in spleen and thymus weights in F1 and F2 male and female weanlings was observed at higher levels), 0.3 mg/kg body weight per day in a short-term study in rats (reduction in white blood cells, decrease in IgG, and increase in relative testes weight were seen at higher levels), 0.21 mg/kg body weight per day in a short-term dog study (increase in relative liver weight and decrease in serum albumin/globulin ratio were seen at higher levels), and 0.1 mg/kg body weight per day in a teratology study in rabbits (maternal toxicity was seen at higher levels).
There are no data concerning occupational exposure to triphenyltin compounds. A few poisoning case reports describe neurotoxic effects, which appeared to persist. Exposure of the general public to triphenyltin compounds occurs mostly from ingestion of contaminated seafood, which in some cases has been found to contain triphenyltin levels as high as 1 µg/g (in muscle of some fish species). Triphenyltin intake from contaminated foods in Japan in 1997 was estimated to be around 11% of the ADI (i.e., 2.75 µg/day for a 50-kg person) established by JMPR.
Triphenyltin compounds exert deleterious effects on aquatic organisms at very low concentrations. For example, imposex of rock shells (Japanese gastropods) was seen at around 1 ng/litre (no-observed-effect concentration, or NOEC, not determined), and chronic toxicity to fathead minnow ( Pimephales promelas) larvae was observed at 0.23 µg/litre (lowest-observed-effect concentration, or LOEC). Triphenyltin is considered to be an endocrine disruptor, because imposex, a phenomenon in which female gastropods develop male sex organs, is probably caused by hormonal disturbance.
No NOEC for triphenyltin has been established for imposex in molluscs. Experimentally, by injection, triphenyltin has a potency similar to that of tributyltin in the genus Thais. Triphenyltin is less potent than tributyltin in Nucella; however, triphenyltin shows greater bioaccumulation than tributyltin. From this, it can be estimated that the NOEC for triphenyltin will be a few ng/litre or lower. The observed prevalence of imposex in Thais in the field with ambient concentrations supports this estimate. Because residues of triphenyltin and tributyltin occur together in the environment, their relative contribution to observed imposex cannot be assessed for Thais species. Use of either triphenyltin or tributyltin in antifouling paint would lead to population declines of marine invertebrates on this basis.
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
Triphenyltin compounds are triphenyl derivatives of tetravalent tin. They conform to the general formula (C6H5)3Sn-X, where X is an anion or an anionic group, such as chloride, hydroxide, and acetate.
Physical and chemical properties of triphenyltin compounds vary depending upon the anion linked to tin. At ambient temperatures in the pH range of 3-8, TPTA and TPTCl are hydrolysed to TPTH within 1 min; as a consequence, the results of most studies with TPTA or TPTCl can be applied to TPTH. Triphenyltin compounds are colourless solids with low vapour pressures (<2 mPa at 50°C). The compounds are lipophilic and have low water solubility (typically a few mg/litre at neutral pH).
The identity and physical/chemical properties of TPTH, TPTA, and TPTCl are given in Table 1. Additional properties of TPTH are presented in the International Chemical Safety Card (ICSC 1283) reproduced in this document.
Table 1: Identity and physical/chemical properties of some triphenyltin compounds.a
Triphenyltin hydroxide Triphenyltin acetate Triphenyltin chloride
Synonyms Fentin hydroxide; TPTH Fentin acetate; TPTA Fentin chloride; TPTCl
Chemical Abstracts 76-87-9 900-95-8 639-58-7 Service (CAS) Registry No.
Molecular formula C18H16OSn C20H18O2Sn C18H15ClSn
Molecular weight 367.0 409.1 385.5
Melting point 122-123.5°C 122-124°C 106°C
Solubility in water (20°C) 1 mg/litre at pH 7 9 mg/litre at pH 5 40 mg/litre greater at lower pH (pH not given)
Solubility in other 10 g/litre (ethanol) 22 g/litre (ethanol) moderately soluble solvents (20°C) 171 g/litre (dichloromethane) 82 g/litre (ethyl acetate) in organic solvents 28 g/litre (diethyl ether) 5 g/litre (hexane) 50 g/litre (acetone) 460 g/litre (dichloromethane) 89 g/litre (toluene)
Vapour pressure 0.047 mPa (50°C) 1.9 mPa (60°C) 0.021 mPa Log Kow 3.43 3.43 -
a From Tomlin (1997); NLM (1998).
3. ANALYTICAL METHODS
Triphenyltin compounds and their degradation products can be analysed in food commodities and in environmental or biological media using several techniques, depending upon type of medium and sensitivity required. The procedure usually starts with either liquid extraction or adsorption onto a solid matrix, followed by re-extraction and/or concentration. Quantification is then performed using flame or flameless atomic absorption spectrometry, gas chromatography with flame photometric or mass spectrometric detection, or normal-phase high-performance liquid chromatography with ultraviolet or fluorescence detection (Hattori et al., 1984; Ishizaka et al., 1989; Fent & Hunn, 1991; Gomez-Ariza et al., 1992; Staeb et al., 1992; Tsunoda, 1993; Kohri et al., 1995; Suzuki et al., 1996).
The detection limits of these techniques are in the range of ng/litre for water and <1 µg/kg for sediments and biological samples. Triphenyltin can also be separated from samples by capillary supercritical fluid chromatography and measured by inductively coupled plasma mass spectrometry. A detection limit of 12.0 pg was obtained for triphenyltin using this method (Vela & Caruso, 1993).
Triphenyltin in water, sediment, and biological samples, as well as inorganic tin that is excreted in urine following exposure to triphenyltin, can be extracted with hydrogen chloride and n-hexane/benzene (3:2 v/v) in the presence of tropolone, then pentylated with a Grignard reagent prior to gas chromatography with flame photometric detection. Quantification limits by this method were found to be 3 ng/litre for water, 0.5 µg/kg for sediments and biological samples, and 3 pg as tin for urine (Ohhira & Matsui, 1991, 1993; Harino et al., 1992).
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
Triphenyltin compounds have been used extensively as algicides and molluscicides in antifouling products since the 1960s (HSE, 1992).
TPTA and TPTH are used mainly as fungicides with a preventive action on potatoes, sugar beets, hops, and celery (FAO, 1991a). Triphenyltin compounds are used on rice against fungal diseases, algae, and molluscs.
Use of triorganotins in antifouling paints has been restricted in many countries because of their catastrophic effects on the oyster industry and more general effects on the aquatic ecosystem.
Information on amounts of triphenyltins used has been obtained only from Japan. Use of triphenyltin compounds for antifouling paints in Japan decreased from 4835 tonnes in 1983 to 346 tonnes (formulation basis) in 1989 (Sugita, 1992). Their use for antifouling paints was 40 tonnes (active ingredient) in 1989 and stopped after 1990 in Japan (MITI, 1998). About 120-140 tonnes (active ingredient) were produced each year between 1994 and 1996 in Japan for export (MITI, 1998).
Between 1978 and 1990, 33-75 tonnes (active ingredient) of phenyltin compounds were produced in Japan for use as a fungicide; production ceased in 1990 (JPPA, 1982-1996).
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
Degradation of triphenyltin occurs through sequential dephenylation resulting from cleavage of the tin-carbon bond through biological, ultraviolet irradiation, chemical, or thermal mechanisms; biological cleavage and cleavage by ultraviolet irradiation are considered to be the most significant processes. Abiotic factors, such as elevated temperatures, increased intensity of sunlight, and aerobic conditions, seem to enhance triphenyltin degradation in the environment (CICAD National Committee, 1997).
Hydrolysis of triphenyltin compounds in water leads to the formation of principally TPTH and various hydrated oxides (Beurkle, 1985). It has been demonstrated that the presence of chloride from seawater lowers the solubility of triphenyltin compounds by reaction with the hydrated cation to form the covalent organotin chloride (Ozcan & Good, 1980).
In plants, no translocation occurs from treated leaves (FAO, 1991a). TPTA and TPTCl are spontaneously hydrolysed to form TPTH. Phenyl groups are split off from TPTH to form diphenyl and monophenyl compounds. Both parent compound and metabolites conjugate to form glycosides or glutathione conjugates.
The persistence of TPTA and TPTH depends on soil type and pH. TPTH is strongly adsorbed to sediment and soil, and little desorption occurs. Therefore, uptake into plants via roots may be expected to be extremely low.
14C-labelled TPTA in soil degraded to inorganic tin with evolution of 14C-labelled carbon dioxide. Similar experiments on sterile soil showed insignificant evolution of labelled carbon dioxide, which suggests that degradation can be attributed to microorganisms (Barnes et al., 1971). Soil respiration was slightly enhanced after treatment with TPTA, indicating that there were no adverse effects on aerobic microorganisms (Suess & Eben, 1973).
A half-life of 1-3 months has been reported for TPTH in sandy and silt loam soils and 126 days in flooded silt loam (US EPA, 1987). The half-life of triphenyltin in water was estimated to be several days in June and 2-3 weeks in November (Soderquist & Crosby, 1980).
Half-lives of triphenyltin in mussels ( Mytilus edulis) taken in the summer of 1989 in Yokohama (a busy port, heavily contaminated with triphenyltin) and Urayasu (a river mouth, about 10 times less polluted than Yokohama) in Japan were estimated to be 139 and 127 days, respectively (Shiraishi & Soma, 1992). Biological half-lives of triphenyltin in short-necked clams ( Tapes [ Amygdala] japonica) and guppy ( Poecilia reticulata) were estimated to be approximately 30 days and 48 days, respectively (Takeuchi et al., 1989; Tas et al., 1990). The ecological half-life of triphenyltin in gastropods was estimated to be 347 days (Mensink et al., 1996).
Temporal variations of phenyltin concentrations in zebra mussels ( Dreissena polymorpha) were studied at two locations near potato fields during and after the triphenyltin fungicide spraying season in the Netherlands (Staeb et al., 1995). Phenyltin concentrations in zebra mussels were high in the period before and during harvesting but not during the spraying season, which suggests that phenyltin compounds in some foliage ended up in the water and were taken up by the mussels. Although higher concentrations were detected in locations near areas of spray operation, marinas, and harbours, the widespread presence of triphenyltin residues in mussels collected in 56 locations all over the Netherlands suggests the contribution of transport via the air.
An extensive study on the presence of nine organotin compounds in a freshwater food-web (zebra mussel, eel, roach bream, pike, perch, pike perch, and cormorant; details and scientific names of species not given in the report) revealed that phenyltin concentrations in benthic species were higher than butyltin concentrations in lower trophic levels (Staeb et al., 1996). This suggests that triphenyltin is to a large extent taken up from the sediment by benthic organisms. At higher trophic levels, net bioaccumulation of triphenyltin compounds was greater than that of tributyltins, resulting in relatively higher triphenyltin concentrations. With birds, the highest concentrations of organotins were in liver and kidney and not in subcutaneous fat, which shows that organotins accumulate via mechanisms different from those of traditional lipophilic compounds.
BCFs in daphnids did not exceed 300 (Filenko & Isakova, 1979). In fish, BCFs ranged from 257 to 4100. The highest value (4100) was estimated for filefish ( Rudarius ercodes) cultivated in water containing 148 ng triphenyltin/litre for 56 days (Yamada & Takayanagi, 1992). When Lymnaea stagnalis (a freshwater snail) was exposed to 2 µg TPTH/litre for 5 weeks, tin accumulated to the greatest extent in the intestinal sac, to a level of 65.1 mg/kg (i.e., BCF of 32 500; Van der Maas et al., 1972).
Tissue concentrations of triphenyltin in common carp ( Cyprinus carpio) exposed to 5.6 µg TPTCl/litre for 10 days, which reached a plateau after 7 days, were examined. The BCFs were highest in the kidney (2090), followed by liver (912), muscle (269), and gall bladder (257) (Tsuda et al., 1987).
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6.1 Environmental levels
Triphenyltin levels in ambient water, sediment, and organisms were surveyed in about 30 locations (estuaries and bay) in Japan between 1982 and 1995 (Japan Environment Agency, 1983, 1996). Triphenyltin levels in water (detection limit 5 ng/litre) and sediment (detection limit 1.0 ng/g) of bay and inshore areas decreased from 2.7-8.0 ng/litre and 3.3-7.8 ng/g in 1988-1991 to 2.5-3.0 ng/litre and 1.5-2.3 ng/g in 1992-1995, respectively.
Triphenyltin levels in ambient water and sediment in the Tokyo bay area gradually decreased from peak levels (geometric means: 25.1 ng/litre in water, 4.3 ng/g in sediment) to 1.8 ng/litre (water) and 0.19 ng/g (sediment) in 1993 because of consecutive tightening of regulations and voluntary withdrawal of use by coastal fishery industries (Takeuchi et al., 1991).
Triphenyltin levels were measured in fish and shellfish obtained from the Tokyo Central Fish Wholesale Market from April 1988 to March 1991 (Takeuchi et al., 1991; see section 6.2). The finding of triphenyltin in coastal fish, as well as in open-ocean or pelagic fish, is suggestive of biomagnification through the food-chain. High levels in clams and oysters showed that direct uptake from water or sediment also plays an important role for these species.
In the Netherlands, up to 920 ng triphenyltin (as tin)/g sediment was found in the Westinder lake system in 1993, whereas no triphenyltin was found in the water (detection limit 5 ng/litre) (Staeb et al., 1996). In freshwater marinas in Switzerland, up to 191 ng triphenyltin/litre was detected in 1988-1990, whereas 107 ng/g dry weight was the highest value measured in vertical sediment core profiles, and concentrations up to 11 ng triphenyltin/litre were measured in the river system (Fent & Hunn, 1991, 1995). In Dreissena mussels of the same marinas, up to 3.88 µg triphenyltin/g wet weight was detected (Fent & Hunn, 1991), whereas up to 0.31 µg triphenyltin (as tin)/g dry weight in Mytilus mussels and up to 0.24 µg triphenyltin/g in Thais snails were detected in a Spanish marina area in 1995 (Morcillo et al., 1997).
Biological monitoring of triphenyltin concentrations in fish from coastal areas of Japan showed that concentrations decreased between 1989 (detected in 40 out of 65 samples, maximum concentration 2.6 µg/g wet weight in muscle, detection limit 20 ng/g) and 1995 (detected in 21 out of 70 samples, maximum concentration 0.25 µg/g) (Japan Environment Agency, 1996). Similarly, triphenyltin levels in mussels and birds decreased over the same period: triphenyl was detected in 17 out of 25 samples of mussels (maximum concentration 0.45 µg/g) and in 5 out of 10 samples of birds (maximum concentration 0.05 µg/g) in 1989, compared with 0 out of 35 samples of mussels and 0 out of 10 samples of birds in 1995 (detection limit 0.02 µg/g in both years) (Japan Environment Agency, 1996).
Zebra mussels were used as a biomonitor to evaluate organotin pollution in Dutch fresh waters (Staeb et al., 1995). High concentrations (1700-3200 ng tin/g dry weight) were found near locations where triphenyltin fungicide had been sprayed. Degradation products (di- and monophenyltins) were also detected in nearly all mussels.
In pecan orchards (Georgia, USA) where triphenyltin fungicides were sprayed, triphenyltin concentrations in foliage and soils were 8.5-37 µg/g dry weight and 1.2-12 µg/g dry weight, respectively (Kannan & Lee, 1996). Although triphenyltin was absent in surface soil where the fungicide had been sprayed 8-10 times a year until 2 years earlier, monophenyltin was detected at approximately the same concentration as in recently sprayed orchards. Fish (bluegill [ Lepomis macrochirus], largemouth bass [ Micropterus salmoides], and channel catfish [ Ictalurus punctatus]) from a pond near a recently sprayed orchard contained predominantly monophenyltin (with the highest concentration of 22 µg/g wet weight in the liver of catfish) in addition to smaller amounts of triphenyltin and diphenyltin.
6.2 Human exposure
No data are available on occupational exposure to triphenyltin compounds. There are also no data on levels of triphenyltin in indoor or ambient air or in drinking-water.
The residue data available in support of registration of triphenyltin compounds in the United Kingdom, obtained using various colorimetric methods, ranged between 0.013 and 0.016 mg/kg in 3 out of 25 samples of potatoes provided by the Potato Marketing Board and known to have been treated with a triphenyltin fungicide. The remaining samples contained residues below 0.013 mg/kg, which is the limit of detection (ACP, 1990). In supervised trials of triphenyltin formulations (wettable powder; 54%; 216-324 g active ingredient/ha) on potatoes in Germany, residues ranged from 0.3 mg/kg to less than the detection limit (0.01 mg/kg) 7 days after application (FAO, 1991a). Supervised trials of triphenyltin formulations (wettable powder; 50 or 54%; 216-324 g active ingredient/ha) in Germany on sugar beets showed residues ranging from 0.1 to 1.9 mg/kg in leaves and less than the detection limit (0.05 mg/kg) in beets 35 days after application. In supervised trials of triphenyltin formulations (wettable powder) on rice in the USA, residues ranged from less than the detection limit (0.01 mg/kg) to 0.03 mg/kg 22-23 days after application (57.5%; 536 g active ingredient/ha, twice) and from less than the detection limit (0.01 mg/kg) in milled rice or bran 22-46 days after application (47.5%; 250 or 500 g active ingredient/ha) (FAO, 1991a).
When 14C-labelled TPTH was administered orally to dairy cows over a period of 60 days at doses of 1.13, 5.61, or 22.44 mg triphenyltin/kg diet (dry matter), residues were 0.08, 0.31, and 0.9 g/kg in meat and 0.006, 0.026, and 0.41 mg/kg in milk, corresponding to transfer factors of 0.038-0.068 in meat and 0.004-0.006 in milk (Smith, 1981).
Triphenyltin levels were measured in fish, clams, and shrimps obtained from the Tokyo Central Fish Wholesale Market from April 1988 to March 1991. Levels were higher in cultured fish and in fish from coastal or bay areas than in pelagic fish (mean concentration 0.048 µg/g) (Takeuchi et al., 1991). Freshwater fish were relatively uncontaminated. Fish obtained from bay or inshore areas were the most contaminated; the highest concentration measured in 82 samples of four fish species was >1.0 µg triphenyltin/g muscle (mean 0.317 µg/g). Triphenyltin levels in clams and shrimps ranged from 0 to 0.83 µg/g edible portion (mean 0.113 µg/g). Triphenyltin intake from pelagic fish was estimated based on analyses of fish samples in 1988-1991 by a market basket study in Tokyo as 3.15 µg (mean concentration of 0.048 µg/g times 65.6 g intake of pelagic fish by a Japanese person per day). Although tributyltin was used more abundantly than triphenyltin in antifouling paints, residue levels in fish and shellfish were mostly comparable, with several differences among fish groups.
National market basket studies, including the above study, have estimated daily intakes of triphenyltin per 50-kg person in Japan (expressed as TPTCl) to be 4.3, 10.4, 2.7, 0.6, 1.2, 1.4, 0.7, and 2.7 µg in 1990, 1991, 1992, 1993, 1994, 1995, 1996, and 1997, respectively (NIHS, 1998). Triphenyltin compounds were found mostly in seafood. As about a twofold difference was observed between the above estimated daily intakes (averages of 10 local laboratories, including the Shiga Prefecture) and estimated intakes in the Shiga Prefecture (Tsuda et al., 1995), this implies that differences in food intake patterns or some other factor may influence estimates of daily intake. This fact and coincidental contamination with tributyltin must be taken into account in any risk estimation for exposure by the oral route.
Another report of a market basket survey estimated the intake of triphenyltin from raw and processed seafood in Nagasaki Prefecture (a southern part of Japan) in 1989-1991 to be 8.51 µg/day per person (Baba et al., 1991). TPTCl concentrations in fish, shellfish, seaweed, canned fish/shellfish, fish paste product, and salted/dried fish were 274, 80, 21, 12, 16, and 22 ng/g (averages), respectively. Cooking did not reduce the triphenyltin content of fish and shellfish samples.
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
Several studies have shown that TPTH orally administered to rats is eliminated mainly via the faeces, with smaller amounts in the urine. Metabolites found in faeces included di- and monophenyltin as well as a significant portion of non-extractable bound residues (the sulfate conjugates of hydroquinone, catechol, and phenol). In faeces, the major substance present was unchanged parent compound.
TPTA was rapidly and completely hydrolysed to TPTH at pH 3-8 and 23-24°C (Beurkle, 1985).
Seven days after oral administration to rats, TPTH residues (approximately 3% of the administered dose) were distributed mainly in the kidneys, followed by liver, brain, and heart (Eckert et al., 1989; Kellner & Eckert, 1989). Similar results were obtained after chronic exposure for 104 weeks (Dorn & Werner, 1989; Tennekes et al., 1989a).
Species differences in the metabolism of triphenyltin were investigated by Ohhira & Matsui (1996). Dearylation of triphenyltin was slower in hamsters than in rats, and pancreatic accumulation of triphenyltin was higher in hamsters. There was a good correlation between tin concentrations in the pancreas and plasma glucose levels, indicating that triphenyltin-induced hyperglycaemia depends upon the amount of tin compounds absorbed into the pancreas. Most of the tin compounds in the brains of both species were triphenyltin.
Percutaneously absorbed TPTA in guinea-pigs was distributed to the highest extent in the liver, followed by the adrenal glands, kidneys, brain, spinal cord, and pancreas (Nagamatsu et al., 1978). Triphenyltin, diphenyltin, and monophenyltin were detected in faeces in a ratio of 15:6:2. The biological half-life of triphenyltin was estimated to be 9.4 days.
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
Because TPTA and TPTCl are hydrolysed rapidly to TPTH in aqueous media, the results of oral toxicity studies with these triphenyltin compounds can be applied to TPTH. Many critical studies described below were cited from WHO (1992), which summarizes evaluations of the original proprietary reports; as details of these original proprietary reports were not available to the CICAD authors, we have relied on the WHO evaluation for these studies.
8.1 Single exposure
After a single oral administration of triphenyltin, toxic signs observed in various species include anorexia, emesis, tremor, and diarrhoea, followed by drowsiness and ataxia (WHO, 1992). No further details were provided. Clinical signs appeared a day after administration and were exacerbated over the following 3 days or so (CICAD National Committee, 1997). Oral LD50s for TPTH were approximately 160 mg/kg body weight in rats and 100-245 mg/kg body weight in mice; oral LD50s for TPTA were 140-298 mg/kg body weight in rats and 81-93 mg/kg body weight in mice (Ueda & Iijima, 1961; Scholz & Weigand, 1969; Hollander & Weigand, 1974; Ikeda, 1977; Leist & Weigand, 1981a,b).
Dermal LD50s were 127 mg/kg body weight in rabbits and 1600 mg/kg body weight in rats for TPTH (Leist & Weigand, 1981c,d) and 350 mg/kg body weight in mice and >2000 mg/kg body weight in rats for TPTA (Ueda & Iijima, 1961; Diehl & Leist, 1986a). Inhalation LC50s were 44-69 mg/m3 in rats for TPTH and TPTA (Hollander & Weigand, 1981, 1986).
8.2 Irritation and sensitization
TPTA was not irritating to the skin of rabbits (Diehl & Leist, 1986b). However, severe ocular lesions developed in rabbits; these were not reversible (Diehl & Leist, 1986c).
At concentrations that were irritating to skin, TPTH (purity 97.0%) showed no skin sensitization in guinea-pigs in the Buehler test (Leist & Weigand, 1981e; Schollmeier & Leist, 1989) or in the maximization test (Diehl & Leist, 1987). TPTA gave a positive response when tested for skin sensitization in guinea-pigs in the Buehler test (Diehl & Leist, 1986d). Further details were not given.
8.3 Short-term exposure
One unpublished dermal exposure study in rats submitted to WHO (1992) is described in Table 2. A NOAEL of 10 mg/kg body weight was identified in this study. Additional short-term studies that examined effects on the immune system are discussed in section 8.7.
8.4 Long-term exposure
8.4.1 Subchronic exposure
Several subchronic studies on the effects of TPTH on several animal species exposed by various routes have been performed (WHO, 1992). Studies that show effects at the lowest doses in each animal species are summarized in Table 2. Further studies and details are available in WHO (1992) and CICAD National Committee (1997).
Dietary studies with rats, mice, and dogs showed a decrease in immunoglobulin levels, body weight gain, and white blood cells and an increase in liver weights and death. Decreases in immunoglobulin levels and white blood cells were observed consistently at lowest effect levels in all tests. NOAELs for dietary studies were identified as 3.4-4.1 mg/kg body weight per day in mice (3-month exposure), 0.30-0.35 mg/kg body weight per day in rats (13-week exposure), and 0.21 mg/kg body weight per day in dogs (52-week exposure) (Table 2). Several species were affected in a similar way, although mice appeared to be least sensitive.
In an inhalation study in rats exposed to TPTH, macroscopic lesions in the lungs were observed at 2.0 mg/m3 in most of the dead rats (all males and one female died at this dose), and histopathology revealed severe effects in lower air passages and in the lungs. The NOAEL was 0.014 mg/m3.
8.4.2 Chronic exposure and carcinogenicity
Chronic toxicity/carcinogenicity studies in rats and mice exposed to TPTH (WHO, 1992) are summarized in Table 3. There were indications that the doses received by animals in the US National Toxicology Program (NTP) studies may have been lower than intended owing to instability of the test compound in the diet. The size of the control group (small compared with test groups) in the NTP mouse study limits interpretation of the results. Consistent findings in all studies are a decrease in immunoglobulin concentrations at lowest effect levels and a higher susceptibility of females, as seen in a higher mortality rate and reduced body weight gain at low doses.
Effects on immunoglobulin levels were reported with both rats and mice. In an 80-week feeding study in mice, a decrease in immunoglobulin concentrations was seen at dose levels of 5, 20, and 80 ppm TPTH in the diet. The incidence of hepatocellular adenoma in both sexes and the incidence of hepatocellular carcinoma in females only were increased at the highest dose (80 ppm) (Tennekes et al., 1989a; Table 3). The NOAEL in this study was 5 ppm, equivalent to 0.85 mg/kg body weight per day for males and 1.36 mg/kg body weight per day for females, based on decreased body weight gain in females.
Table 2: Short-term and subchronic studies on TPTH.
Study type, Dose Species Observed effects (mostly at lowest effect Reference duration (purity; %) (strain, number/dose) level) and NOAEL values
Diet 0, 4, 20, 100 ppm Mouse At 100 ppm, haematological and biochemical Suter & Horst, 3 months (97.2%) (NMRI, 10/group) parameters were affected, including a reduction 1986a in erythrocyte count and haemoglobin level, an increase in platelet count, and a decrease in IgG, IgA, and IgM (females only). Liver weight was increased in both sexes, and relative weights of ovaries, adrenals, kidneys, heart, and brain were decreased in females at this dose. NOAEL: 20 ppm (3.4 mg/kg body weight per day for males, 4.1 mg/kg body weight per day for females).
Diet 0, 4, 20, 100 ppm Rat Relative testis weight was significantly higher in Suter & Horst, 13 weeks, (97.2%) (Wistar, 15/group) high-dose males, whereas no effects on spleen and 1986b 4-week thymus weights were observed. In females, white blood recovery cells decreased at 20 ppm (corresponding to 1.75 mg/kg body weight per day) and 100 ppm. After the recovery period, IgG decreased significantly in females at all dose levels. NOAEL: 4 ppm (0.30 mg/kg body weight per day for males, 0.35 mg/kg body weight per day for females).
Diet 0, 2, 6, 18 ppm Dog At 18 ppm, relative liver weight was increased in Sachose et al., 1987 52 weeks (97.2%) (beagle, 10/group) females and serum albumin/globulin ratio was decreased in males. NOAEL: 6 ppm (0.21 mg/kg body weight per day).
Table 2 (continued)
Study type, Dose Species Observed effects (mostly at lowest effect Reference duration (purity; %) (strain, number/dose) level) and NOAEL values
Dermal 0, 5, 10, 20 Rat Dose-related increase in erythema and scale Leist, 1988 21 applications mg/kg body (unknown, formation was seen. At 20 mg/kg body weight, four in 29 days, weight each 6-12/group) rats died. Lymphocytes decreased in both sexes and 14-day recovery time (97.1%) monocytes increased in females at 20 mg/kg body weight. NOAEL for systemic toxicity: 10 mg/kg body weight.
Inhalation 0.014, 0.338, Rat All males and one female died at the highest dose. At Duchosal et 6 h/day, 1.997 mg/m3, (Wistar, 0.338 mg/m3, a decrease in white blood cells and al., 1989 5 days/week, nose-only 10/group) biochemical and haematological changes were seen in 13 weeks, exposurea (96.2%) females. IgM increase was seen in males at 0.338 4-week recovery mg/m3. Histopathology revealed degenerative and inflammatory lesions in the anterior part of the nasal cavity, in the trachea, and in the lungs in the highest dose group of both sexes. NOAEL: 0.014 mg/m3.
a Mass median aerodynamic diameter: 3 µm.
In a 2-year rat feeding study with dietary concentrations of 0, 5, 20, and 80 ppm TPTH (Tennekes et al., 1989b), a decrease in immunoglobulin concentrations was observed in all triphenyltin-dosed groups. An increase in the incidence of pituitary adenoma in females and an increase in testicular Leydig cell tumours at higher doses were accompanied by non-neoplastic lesions in these organs. Low survival at higher doses limits interpretation of the results in females. A NOAEL could not be established at the lowest concentration of 5 ppm (equivalent to 0.3 and 0.4 mg/kg body weight per day in males and females, respectively) because of increased mortality in females and reduced serum immunoglobulin levels at this dose.
Although some tumours were detected in the above studies, the WHO expert group apparently evaluated those as being not significant (WHO, 1992). No detailed explanation of the reasons for this or results of statistical analysis were provided in the report. Recently, Clegg et al. (1997) critically examined the human relevance of Leydig cell hyperplasia and adenoma formation in rodents after chronic exposure and suggested that a hormonal mode of action, which may be of little relevance to humans, either mechanistically or quantitatively, could be operating. They also pointed out the very low incidence of Leydig cell adenomas in humans (age-adjusted occurrence of 0.4 per million).
An early 2-year rat study showed a reduction in white blood cell count at a TPTH dietary level of 5 ppm (corresponding to 0.3 mg/kg body weight per day) (Til et al., 1970). The NOEL was chosen as 2 ppm in the diet (equivalent to 0.1 mg/kg body weight per day) based on this finding.
8.5 Genotoxicity and related end-points
Most in vitro and in vivo genotoxicity tests, such as the Salmonella mutagenicity test, yeast forward mutation test, mitotic gene conversion assay, mouse lymphoma forward mutation assay, chromosomal aberration assay, unscheduled DNA synthesis, micronucleus test in mice, cytogenetic assay in Chinese hamster, and dominant lethal assay in rats, showed negative results at the maximum doses tested, based on studies reviewed in WHO (1992).
There are no new data that impact on the conclusion in WHO (1992) that triphenyltin is not genotoxic. Recent data indicate, however, that triphenyltin potentiates the genotoxicity of other substances. Triphenyltin showed potentiation of mitomycin C-induced breakage-type chromosomal aberrations in cultured hamster cells when cells were treated during the G2 phase (Sasaki et al., 1993). Similarly, the frequency of micronuclei induction by mitomycin C (1 mg/kg intraperitoneal injection) in mouse peripheral reticulocytes was enhanced by treatment with TPTCl, although TPTCl itself did not induce micronuclei (Yamada & Sasaki, 1993). Positive responses in these
assays may be related to the toxic effects of triphenyltin on lymphocytes, because two in vivo studies for chromosomal aberrations (a micronucleus test in mice and a cytogenetic test in Chinese hamsters) were negative. These data support the conclusion of the WHO (1992) group.
It is therefore concluded that triphenyltin does not present a genotoxic hazard.
8.6 Reproductive and developmental toxicity
Triphenyltin appears to cause reproductive effects in rats and developmental toxicity in rats, rabbits, and hamsters at low doses (around 1 mg/kg body weight and higher) at which maternal toxicity is observed. Studies that show effects at the lowest doses for various end-points in experimental animals are summarized in Table 4 (WHO, 1992; CICAD National Committee, 1997). Decreases in number of implantations, live fetuses, and mean fetal weight and increases in resorption were the consistent findings observed at lowest effect doses.
An increase in the number of dead F1 pups and a decrease in mean litter size, pup weight, and relative spleen and thymus weights in the weanlings were observed in a two-generation rat study at 18.5 ppm TPTH in the diet (approximately 1.5 mg/kg body weight per day); at this concentration, body weight gain and food consumption of the parents were not affected (Young, 1986). The NOAEL in this study was 5 ppm (equivalent to 0.4 mg/kg body weight per day).
A general paucity of mature sperm was seen in rats treated with TPTA and TPTCl in the diet (20 mg/kg body weight per day) for 20 days, and spermatogenic anomalies were observed in histological sections (Snow & Hays, 1983). Reduced food intake and the resultant decrease in weight gain were suspected as the cause, as malnutrition is known to precede gonadal dysfunction and even atrophy. However, differences in the distribution of spermatogenic phases in rats treated with TPTA and TPTCl do not support this explanation.
TPTCl prevented implantation in rats in a dose-dependent manner when administered at 0, 3.1, 4.7, or 6.3 mg/kg body weight per day on days 0-3 and at 0, 6.3, 12.5, or 25.0 mg/kg body weight per day on days 4-6. The compound caused larger implantation failures when administered during earlier stages of blastogenesis (Ema et al., 1997). Implantation failure was observed at 4.7 and 6.3 mg/kg body weight per day on days 0-3 and at 12.5 and 25.0 mg/kg body weight per day on days 4-6. The effects of TPTCl on uterine function, as a cause of implantation failure, were determined using pseudopregnant rats dosed at 0, 3.1, 4.7, or 6.3 mg/kg body weight per day on days 0-3 (Ema et al., 1998). A significant suppression of the uterine decidualization and decrease in the serum progesterone levels were
Table 3: Chronic exposure and carcinogenicity studies on TPTH.
Duration Chemical dose Species Effects, NOAEL Reference (purity; %) (strain, number/dose)
78 weeks with 0, 37.5, 75 ppm Mouse No treatment-related effects were seen in NTP, 1978 26-week (not stated) (B6C3F1, clinical signs or body weight, although survival observation After 1 week, 50/group) decreased in females with increased dose. No period only 57.9% of tumour incidence was found histopathologically. the initial dose The size of the control group (20 mice of recovered each sex) limits interpretation of the results.
80 weeks 0, 5, 20, 80 ppm Mouse (KFM-Han, Body weight gain decreased at 80 ppm for males and Tennekes et (97.2% prepared NMRI, 50/group) at 20 and 80 ppm for females. Decreases in al., 1989a daily) immunoglobulin concentrations were observed at various levels. An increased relative number of lymphoid cells was detected in femoral bone marrow myelogram for all treated groups. Incidence of hepatocellular adenomas was 12.2, 20, 26, and 32% at 0, 5, 20, and 80 ppm, respectively, for males and 0, 0, 0, and 18% at 0, 5, 20, and 80 ppm, respectively, for females. At 80 ppm, increased incidence of hepatocellular carcinoma was seen in females (6% compared with 0% at other doses). Based on reduced body weight gain, NOAEL was 5 ppm (corresponding to 0.85 mg/kg body weight per day for males and 1.36 mg/kg body weight per day for females).
Table 3 (continued)
Duration Chemical dose Species Effects, NOAEL Reference (purity; %) (strain, number/dose)
2 years 0, 0.5, 1, 2, 5, Rat (not stated, A slight decrease in white blood cells was seen Til et 10 ppm (not stated) 25/group) at the highest dose in the first year. This effect al., 1970 was less often seen at 5 ppm (corresponding to 0.3 mg/kg body weight per day), and only once at 2 ppm in the males. The relative thyroid weight was slightly decreased at 10 ppm in the females only. Average relative weights of other organs, gross autopsy findings, and microscopic examinations did not reveal significant differences between treated and control groups. NOEL was 2 ppm in the diet, equivalent to 0.1 mg/kg body weight per day.
78 weeks with 0, 37.5, 75 ppm Rat (Fischer 344, No effects were observed on clinical signs, NTP, 1978 26-week (not stated) 50/group) mortality, food consumption, macroscopy, or observation After 1 week, only histopathology. No increase in tumour incidence. period 57.9% of the initial dose recovered
104 weeks 0, 5, 20, 80 ppm Rat (SPF KFM-Han In females, mortality was increased (survival Tennekes et prepared twice Wistar, 70/group) was 75, 51, 36, and 23%, respectively, with al., 1989b monthly from frozen increasing dose). Immunoglobulin decrease stock (IgG1 and IgG2a for females, and IgG2c for males) was observed at all doses. IgA levels for males decreased, and IgM levels increased for both sexes at 20 and 80 ppm. Leydig cell tumours were 1.7, 8.5, 5.0, and 16.7% at 0, 5, 20, and 80 ppm, respectively. The incidence of pituitary adenomas was increased in females at 20 and 80 ppm. These changes were accompanied by non-neoplastic lesions in the pituitary and testis. NOAEL was not established because of observations of mortality increase in females and
Table 3 (continued)
Duration Chemical dose Species Effects, NOAEL Reference (purity; %) (strain, number/dose)
104 weeks serum immunoglobulin decrease at the lowest level, (continued) 5 ppm (equal to 0.3 mg/kg body weight per day for males and 0.4 mg/kg body weight per day for females).
Table 4. Reproductive and developmental toxicity studies on triphenyltin.
Species Study design Effects Reference (strain, number/sex/dose)
Rat In a two-generation reproduction study, rats The number of dead F1 pups was Young, 1986 (Wistar, were given TPTH in diet (0, 5, 18.5, or 50 increased and mean litter size 30/sex/group) ppm) during growth, mating, gestation, and decreased at 18.5 and 50 ppm. In lactation for one litter per generation. Fo parents, the body weight gains Clinical signs, body weight, food consumption, and food consumption of both sexes mating performance, and reproductive parameters were lower at 50 ppm. At 50 ppm, the were observed. Organ weights of parents relative weights of brain, testes, and pups were recorded. Pups were ovaries, adrenals, kidneys, spleen, sexed and examined for gross malformations and heart were increased in F0 and the number of stillborn and live pups. and/or in F1 adults and/or F1 and F2 weanlings. A dose-related decrease was observed in spleen and thymus weight in F1 and F2 weanlings at 50 and 18.5 ppm (equal to 1.5 mg/kg body weight per day). The NOAEL was 5 ppm, equal to 0.4 mg/kg body weight per day.
Table 4 (continued)
Species Study design Effects Reference (strain, number/sex/dose)
Rat TPTA or TPTCl (0 or 20 mg/kg body weight per In rats sacrificed after 21 days, all Snow & Hays, (Holtzman, day in diet) was dosed for 20 days. Four eight spermatogenic phases were seen, 1983 13 males/group) animals from each group were sacrificed on but there was a general paucity of mature day 21, and the remaining animals were sperm, and the distribution showed some sacrificed after 4 more days with test diets predominance of immature sperm. Recovery and a recovery period (70 days). Distribution was seen after the 70-day control diet. of the eight phases of spermatogenesis was Treated animals ate about two-thirds as observed. much food as the controls.
Pregnant rat TPTCl was dosed by gavage at 0, 3.1, 4.7, or In successfully mated females, TPTCl Ema et al., (Wistar, 6.3 mg/kg body weight per day on day 0 to day prevented implantation in a dose-dependent 1997 10-13/group) 3 of gestation or at 0, 6.3, 12.5 or 25.0 mg/kg manner. The pregnancy rate was significantly body weight per day on day 4 to day 6 of decreased after administration of TPTCl on gestation. Dams were sacrificed on day 20 of days 0 to 3 at 4.7 and 6.3 mg/kg body weight gestation. Numbers of live/dead fetuses and per day, and days 4 to 6 at 12.5 and 25.0 resorptions were counted. Live fetuses were mg/kg body weight per day. TPTCl caused larger sexed, weighed, and inspected for malformations failures in implantations when administered externally. during earlier stages of blastogenesis.
Pregnant rat TPTH was dosed at 0, 0.35, 1, 2.8, or 8 A dose-related decrease in body weight gain Rodwell, (Sprague-Dawley, mg/kg body weight per day on day 6 through and food consumption was seen in the 2.8 and 1985 45/group) day 15 of gestation. On day 20 of gestation, 8 mg/kg body weight per day groups. At 8 all rats were sacrificed. Clinical signs, body mg/kg body weight per day, an abortion in one weights, and food consumption were examined. dam, increase of number of non-gravid dams, After sacrifice, the dams were observed for total litter resorptions, early resorptions, number and location of viable and non-viable and significant decrease of number of viable fetuses, early and late resorptions, and the fetuses and fetal weight were observed. The number of implantation sites. The corpora lutea incidence of absent/delayed ossification was were counted. Fetuses were weighted, sexed, and increased in high-dose litters. The percentage examined for external, internal, and skeletal of fetuses with hydrocephaly was 0.4, 0, 0, anomalies. 0.4, and 1%, and with omphalocele 0.2, 0.2, 0.2 0, and 0.5%, respectively, for the 0, 0.35, 1,
Table 4 (continued)
Species Study design Effects Reference (strain, number/sex/dose)
2.8, and 8 mg/kg body weight per day groups. There was no evidence for TPTH-induced irreversible structural effects. The NOAEL for maternal toxicity was 1 mg/kg body weight per day, and for embrytoxicity, 2.8 mg/kg body weight per day.
Pregnant hamster TPTH was dosed by gavage (0, 2.25, 5.08, or The 12 mg/kg body weight per day group showed Carlton & (Syrian, 12 mg/kg body weight per day) from day 5 to a decrease in mean body weight gain, food Howard, 1982 20-25/group) day 14. All dams were sacrificed on gestation consumption, pup weight, and death (4 animals). day 15. The gravid uterus was weighed, and Two animals died in each of the 2.25 and 5.08 corpora lutea were counted. Fetuses and mg/kg body weight per day groups. The average resorption sites were noted. Fetuses were number of minor anomalies of fetuses per litter weighed and observed for external, visceral, and delayed ossifications were significantly and skeletal malformations. greater among the 12 mg/kg body weight per day group. Three cases of hydronephrosis were seen at 5.08 mg/kg body weight per day and one case of hydrocephalus was seen at 12 mg/kg body weight per day.
Pregnant TPTA (0, 0.1, 0.32, or 1.0 mg/kg body weight In the 1.0 mg/kg body weight per day Baeder, rabbit per day) was dosed by gavage from day 6 to group, one dam died, three dams aborted, 1987 (Himalayan, day 18 of gestation. On day 29 of gestation, one dam gave a premature delivery, and 15/group) the dams were sacrificed. Dams were observed two dams had intrauterine deaths. The for clinical signs, body weight, food number of implantations and of live consumption, number of resorptions, fetuses decreased at 1.0 mg/kg body implantations, corpora lutea, viable and weight per day. Mean fetal weight, non-viable tissues, organ weights, and crown/rump length, and placental weight macroscopy. Fetuses were weighed and examined decreased in pups at 1.0 mg/kg body weight for sex, length, and external, internal, and per day. At 1.0 mg/kg body weight per day, skeletal anomalies. four pups showed omphalocele with protrusion
Table 4 (continued)
Species Study design Effects Reference (strain, number/sex/dose)
of intestinal coils or liver tissue. Slight retardation of skeletal ossification was detected at 1.0 mg/kg body weight per day. An increase in the number of fetuses with fewer ossified caudal vertebrae, weak ossification of the hyoid bone, and non-/only slight ossification of the os pubis in some fetuses were shown. NOAEL for maternal and embryo toxicity was 0.32 mg/kg body weight per day.
Pregnant TPTH was dosed by gavage at 0, 0.1, 0.3, or Two rabbits from the 0.9 mg/kg body weight Rodwell, rabbit 0.9 mg/kg body weight per day on day 6 to day per day group aborted. A dose-related decrease 1987 (New Zealand 18 of gestation. Dams were sacrificed on day 29 in mean body weight gain and food consumption white, 22/group) of gestation. Corpora lutea, early/late was observed in the 0.3 and 0.9 mg/kg body resorptions, and number of implantations were weight per day groups. Mean fetal weight was counted. Fetuses were weighed, sexed, and lower in the 0.9 mg/kg body weight per day examined for external, skeletal, and visceral group. The NOAEL for maternal toxicity was anomalies and developmental variations. 0.1 mg/kg body weight per day, and the NOAEL for embryotoxicity was 0.3 mg/kg body weight per day.
found at 4.7 and 6.3 mg/kg body weight per day, at which doses implantation failure was caused in pregnant rats. These findings suggest that implantation failure due to TPTCl may be mediated via the suppression of uterine decidualization correlated with the reduction in serum progesterone levels.
In hamsters administered TPTH by gavage where death was observed (2.25 mg/kg body weight per day and higher), anomalies such as hydronephrosis, hydrocephalus, and delayed ossification were detected in the pups at 5.08 mg/kg body weight per day and higher (Carlton & Howard, 1982). Although delayed ossification was observed in rabbits, which are the most sensitive species, when TPTA was dosed at 1.0 mg/kg body weight per day by gavage during gestation days 6 through 18, maternal effects were also detected at this dose level (Baeder, 1987). The percentages of fetuses with hydrocephaly and omphalocele were not significantly higher in rats dosed with TPTH (0-8 mg/kg body weight per day on gestation days 6-15), and it was concluded that there was no evidence for TPTH-induced irreversible structural effects in rats (Rodwell, 1985).
The lowest NOAEL for maternal toxicity was seen in rabbits -- 0.1 mg/kg body weight per day, above which dose reductions in body weight gain and food consumption were observed. The lowest NOAEL for embryo-toxicity in rabbits was 0.3 mg/kg body weight per day, above which abortion and a decrease in mean fetal weight were observed (Rodwell, 1987).
8.7 Immunological and neurological effects
Effects on the immune system were observed in short-term as well as long-term toxicity studies (WHO, 1992; CICAD National Committee, 1997). Effects of organotin compounds on lymphoid organs and lymphoid functions were reviewed (Penninks et al., 1990). Like other organotin compounds, triphenyltin showed immunosuppressive properties (lymphopenia and a decrease in spleen and thymus weights), resulting in altered humoral and cellular immunity in rats, mice, and guinea-pigs, although effects were usually less severe than those observed with tributyltin.
When weanling male SPF Wistar rats were fed diets containing TPTCl at 0, 15, 50, or 150 ppm for 2 weeks, thymus weight was decreased at 15 ppm (corresponding to 1.5 mg/kg body weight per day) or above, and spleen weight was decreased dose dependently (Snoeij et al., 1985). At 150 ppm, decreases in body weight and brain weight were seen, and the liver was enlarged. The effects of TPTCl were similar to those of tributyltin chloride or tripropyltin chloride in a parallel test, but less severe.
Groups of mice were given 0, 1, 5, 25, 50, or 125 ppm TPTH in the diet for 28 days. Twelve male and 12 female mice were killed on day 29, and the remaining mice were returned to control diets and killed on day 57. A significantly decreased body weight gain was observed in male and female mice at 125 ppm, from which they recovered after 28 days. Food consumption was significantly decreased at 50 and 125 ppm. Relative liver weight was increased at 25 (females only), 50, and 125 ppm, relative spleen weight was clearly decreased in males at 50 and 125 ppm and in females at 25 ppm (corresponding to 5 mg/kg body weight per day) and higher, and relative thymus weight was decreased at 125 ppm in males. At histopathology, lymphoid depletion in the thymus and spleen was observed in mice at 125 ppm. A decrease in total white blood cells, neutrophils, and lymphocytes at 50 and 125 ppm in males and females was noted. At the highest dose, a decrease in total cells in spleen and splenic B-cells was observed, and a decrease in total cells in thymus and splenic T-cells was seen in males. IgM levels were decreased in females at 25 ppm and higher, but the decrease was not clearly dose related. All effects were reversible. The NOAEL was 5 ppm, equal to 1 mg/kg body weight per day for males and 1.15 mg/kg body weight per day for females (MacCormick & Thomas, 1990).
When triphenyltin was injected intraperitoneally into mice at doses of 0, 1, 3, or 10 mg/kg body weight per day for 14 days, it inhibited the T-cell-dependent humoral (IgM and IgE production) and cellular (induction of cytotoxic T-cell or induction of delayed hypersensitivity) immune response at 3 mg/kg body weight per day and above (Nishida et al., 1990).
In a long-term study with female guinea-pigs fed 15 ppm TPTA in the diet (corresponding to approximately 1.5 mg/kg body weight per day), decreases in thymus weight and in the number of plasma cells of the spleen and lymph nodes were seen in guinea-pigs examined on days 47 and 77. Repeated dosing for 104 days inhibited the immunological reaction against tetanus toxoids (Verschuuren et al., 1970). The dosed group had a lower antibody count and fewer antitoxoid-producing cells at the popliteal fossa than the controls when examined immunohistologically.
Triphenyltin showed relatively slight neurotoxicological effects at relatively high doses compared with other trialkyltin compounds (i.e., triethyltin, trimethyltin, tributyltin, tripropyltin) (Bouldin et al., 1981; Wada et al., 1982). In neonatal rats dosed orally with 30 mg TPTA/kg body weight per day from day 3 to day 30, no light microscopic or electron microscopic changes were observed in the hippocampus or pyriform cortex/lobe, which are susceptible to neuronal necrosis with trimethyltin (Bouldin et al., 1981). In addition, triphenyltin did not cause oedema in the myelin sheath, as was usually induced by triethyltin (Bouldin et al., 1981).
In the maze learning test, rats orally given Tinestan (a product containing 60% TPTA) at doses of 0.6 (corresponding to 0.36 mg TPTA/kg body weight per day) or 6 mg/kg body weight per day, 6 days/week for 6 weeks, made many mistakes and showed slow reaction speed (Lehotzky et al., 1982). In the conditioned avoidance response test, no difference was observed between the dose groups and the control group; however, extinction of behaviour was delayed in the high-dose group (6 mg/kg body weight per day) after discontinuation of the stimulus. Resting time during swimming tests was shortened by treatment with amphetamine; in rats given 23 mg Tinestan/kg body weight per day for 20 days, however, amphetamine-induced hyperkinesis was antagonized on the 20th day. Tin levels in the brain tissues increased in some of the rats after administration of triphenyltin.
8.8 Mode of action
Treatment of rat thymocytes with immunotoxic organotins (TPTCl, tributyltin, dibutyltin) at 5 µmol/litre, but not non-immunotoxic organotins (trimethyltin, triethyltin), caused a rapid decrease in the F-actin content, resulting in the depolymerization of thymocyte F-actin (Chow & Orrenius, 1994). Immunotoxic effects of organotin compounds may involve cytoskeletal modification in addition to the perturbation of thymocyte calcium homeostasis.
Triphenyltin at concentrations of 0.5-10 µmol/litre induced calcium overload in rat pheochromocytoma cells, which caused internucleosomal DNA cleavage typical of apoptotic cell death (Viviani et al., 1995). Triethyltin or trimethyltin, which did not modify cell viability, did not enhance or showed little effect on calcium influx.
Triphenyltin induced calcium release in ruthenium red (a calcium release channel blocker) sensitive and insensitive ways, with EC50 values of 75 and 270 µmol/litre, respectively. The Ca2+-ATPase activity and calcium uptake of sarcoplasmic reticulum were also inhibited by triphenyltin. The study suggested that the internal calcium store of skeletal muscle could be depleted by triphenyltin through the inhibition of calcium uptake and the induction of calcium release by acting on the Ca2+-ATPase and calcium release channel. Development of muscle weakness in organotin intoxication could be partly explained by this peripheral myopathy-related finding (Kang et al., 1997).
Oral administration of a single dose of TPTCl (60 mg/kg body weight) induced diabetes with decreased insulin secretion in hamsters after 2-3 days, without morphological changes in pancreatic islets. Administration of TPTCl strongly inhibited a rise in cytoplasmic calcium concentration induced by 27.8 mmol glucose/litre, 100 µmol acetylcholine/litre in the presence of 5.5 mmol glucose/litre, and 100 nmol gastric inhibitory polypeptide/litre in the presence of 5.5 mmol glucose/litre. TPTCl administration impaired the insulin secretion in islet cells induced by 27.8 mmol glucose/litre, 100 nmol gastric
inhibitory polypeptide/litre in the presence of 5.5 mmol glucose/litre, and 100 µmol acetylcholine/litre in the presence of 5.5 mmol glucose/litre. The pathology of triphenyltin-induced diabetes in hamsters involves a defect in cellular calcium response due to a reduced calcium influx through voltage-gated calcium channels (Miura et al., 1997).
9. EFFECTS ON HUMANS
Major complaints concerning toxic effects experienced during the spraying of TPTA formulations involved the central nervous system, including headache, nausea, vomiting, and photophobia, and were exacerbated 1 day after exposure.
9.1 Case reports
Two cases of poisoning by TPTA were reported (Manzo et al., 1981). A patient who inhaled, 5 days before hospitalization, a certain amount of fungicide powder containing 60% TPTA (Brestan(R)) complained about dizziness, nausea, and photophobia. He had an episode of sudden malaise with dizziness and temporary loss of consciousness 1 day before his visit. He soon recovered; however, he experienced a brief loss of consciousness, nausea, and vomiting. On admission, general appearance and physical examination showed no abnormality except for a mild impairment of body balance. In spite of treatment with various antiemetics, nausea and photophobia persisted until the 4th day. Complete recovery was seen 10 days after hospitalization. Another patient inhaled an unknown amount of Brestan(R) in an aqueous solution 3 h before his visit while spraying that solution onto a rice field. He noted general malaise, weakness, and dryness of the mouth. At the time of admission, the subjective symptoms had totally disappeared. There were no abnormal neurological findings. Severe headache, weakness, and photophobia appeared on the day following hospitalization. All these symptoms disappeared on the 4th day after admission. The mean concentrations of tin in the blood and urine collected in 24 h during his hospital stay were 48 + 29 ng/ml (normal value 2 ng/ml or less) and 113 + 20.6 ng/ml (normal range 10-65 ng/ml), respectively.
9.2 Epidemiological studies
Hypersensitivity reaction to a series of 36 triphenyltin-containing pesticide formulations was surveyed among 652 subjects in Italy (Lisi et al., 1987). Among them, 180 were agricultural and 43 were ex-agricultural workers. Of the 652 subjects, 274 had contact dermatitis, mostly on the hands, and the other 378 were hospitalized for non-allergic skin disorders. Patch tests were performed on the upper back, and irritant and allergic reactions were evaluated. Irritant and allergic reactions were seen in 45 of 350 subjects and in 1 out of 350 subjects, respectively, with a patch of 1% TPTH. At 0.5% TPTH, irritant reactions were seen in 5 of 109 subjects, whereas no allergic reactions were seen in any of the 109 subjects. The report showed that TPTH is a moderately strong irritant among the fungicides used in Italy.
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
10.1 Aquatic environment
Extensive data exist on the toxicity of triphenyltin compounds to organisms in the environment (HSE, 1992; CICAD National Committee, 1997). Data that show the most severe effects on typical species are listed in Tables 5 and 6. Available data show that triphenyltin is extremely toxic to various species of aquatic organisms, although the concentrations of triphenyltin that produce toxic effects vary according to species.
Growth inhibition of yeasts and fungi with TPTCl occurs at 5 µg/litre and above (Hallas & Cooney, 1981).
Reproduction of freshwater algae was inhibited more than 50% at 2-5 µg/litre (Wong et al., 1982). Indigenous algae were more sensitive than pure cultures. EC50s for inhibition of germination or carbon fixation of marine and estuarine algae were 0.92-2 µg/litre (Walsh et al., 1985).
The LC50 in a 96-h exposure for a copepod was 8 µg/litre (Linden et al., 1979). LC50s in a 48-h exposure for Daphnia magna were 10-200 µg/litre (FAO, 1991a). The NOEC for reproduction in the same species in a 21-day exposure was 0.1 µg/litre (FAO, 1991a).
One of the most sensitive effects of triphenyltin on organisms in the environment is imposex (the development of male sex organs in female gastropods) in rock shells (Japanese gastropods, Thais clavigera and T. bronni), which supposedly occurs at levels (1 ng/litre) similar to those that are seen with tributyltin compounds (Horiguchi et al., 1994). When triphenyltin was injected into rock shells, it was approximately as strong as tributyltin in promoting imposex (Horiguchi et al., 1997), although it was less potent than tributyltin for inducing imposex in Nucella. As imposex is probably caused by hormonal disturbance, triphenyltin is considered to be an endocrine disruptor.
Testosterone (500 ng/litre) induces faster and more intensive imposex development in Nucella lapillus than that induced by tributyltin. Simultaneous exposure to tributyltin and to the antiandrogen cyproterone acetate, which suppresses imposex development completely in N. lapillus and reduces imposex development in Hinia reticulatus, proves that the imposex-inducing effects of tributyltin are mediated by an increasing androgen level and are not caused directly by the organotin compound itself. Furthermore, tributyltin-induced imposex development can be suppressed in both snails by adding estrogens to the aqueous medium. These observations suggest that tributyltin causes an inhibition of the cytochrome P-450-dependent aromatase system, which catalyses the aromatization of androgens to estrogens. Artificial inhibition of the cytochrome P-450-dependent aromatase system using SH 489
(1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase inhibitor and flavone as a non-steroidal aromatase inhibitor induces development of imposex in both snails. The same mechanism may apply to triphenyltin (Bettin et al., 1996).
Field surveys in 1990-1992 and in 1993-1995 in Japan showed 100% occurrence of imposex in T. clavigera. In surveys from 1992 to 1995, the incidence of imposex in the common whelk ( Buccinum undatum) was always greater than 90% (Mensink et al., 1996). Concentrations of phenyltin compounds (up to 625 ng tin/g dry weight in the organism) were much higher than those of butyltin compounds.
No NOEC was established for the effects of triphenyltin on imposex; however, from the above observations, the NOEC can be assumed to be around 1 ng/litre or lower.
Another sensitive effect of triphenyltin was the inhibition of arm regeneration in brittle star ( Ophioderma brevispina) at 0.01 µg/litre. Neurotoxicological action of triphenyltin was suggested as the cause (Walsh et al., 1986).
The 96-h LC50s of triphenyltin in fish were 7.1 µg/litre (fathead minnow) and higher (Jarvinen et al., 1988). A subchronic toxicity study with fathead minnow larvae showed the strong toxicity of triphenyltin, with a 30-day LC50 of 1.5 µg/litre and a 30-day NOEC of 0.15 µg/litre (LOEC 0.23 µg/litre). The need for studies of cumulative effects in a full life cycle at lower concentrations was suggested.
Beginning with yolk sac fry, rainbow trout ( Oncorhynchus mykiss) was continuously exposed for 110 days to TPTCl at concentrations of 0.12-15 nmol/litre or to diphenyltin chloride at 160-4000 nmol/litre. Diphenyltin chloride was about 3 orders of magnitude less toxic than TPTCl. A NOEC of 160 nmol/litre (corresponding to 60 µg/litre) was established for diphenyltin chloride, and a NOEC of 0.12 nmol/litre (corresponding to 50 ng/litre) was established for TPTCl. Histopathological examination revealed depletion of glycogen in liver cells of both di- and triphenyltin-exposed fish. At the end of the exposure period, resistance to infection was examined by an intraperitoneal challenge with Aeromonas hydrophila, a secondary pathogenic bacterium in fish. Resistance to bacterial challenge was found to be decreased even at the lowest-effect concentration of both di- and triphenyltin compounds (de Vries et al., 1991).
Because thymus reduction, decrease in numbers of lymphocytes, and inhibition of gonad development in fish species exposed to tributyltin have been reported, triphenyltin may have similar effects on the immune and reproductive systems of fish (Shimizu & Kimura, 1992).
Table 5: Acute toxicity to aquatic organisms.
Compound Organism Criterion Levels/remarks Reference
TPTCl Debaryomyces hansenii Minimum inhibitory 5 µg/ml Hallas & Cooney, 1981 (yeast) concentration
TPTCl Ankistrodesmus 4-h IC50 for primary 10 µg/litre, Wong et al., 1982 (freshwater alga) productivity static, 20 °C
TPTCl Skeletonema costatum, EC50 for 0.92 µg/litre Walsh et al., 1985 a major component of carbon fixation 13.8 µg/litre fouling slimea LC50
TPTH Daphnia magna (water 48-h LC50 10 µg/litre FAO, 1991a flea)
TPTFb Nitrocra spinipes 96-h LC50 8 µg/litre Linden et al., 1979 (harpacticoid copepod)
TPTH Eight fish species 96-h LC50 Pimephales promelas Javienen et al., 1988 (fathead minnow) was the most sensitive species, 7.1 µg/litre
TPTCl Pagrus major 48-h LC50 12.6 µg/litre Yamada & Takayanagi, 1992 (red sea bream)a
a Marine and estuarine species. b Triphenyltin fluoride.
Table 6: Chronic/subchronic toxicity to aquatic organisms.
Compound Organism Criterion Levels/remarks Reference
TPTCl Natural community of 50% reduction of 2 µg/litre, Wong et al., 1982 freshwater algae reproduction and indigenous algae primary production more sensitive than pure cultures
Ankistrodesmus falcatus 85% inhibition of 5 µg/litre reproduction
TPTH Daphnia magna 21-day NOEC 0.1 µg/litre FAO, 1991a
TPTH Lymnaea stagnalis: 9-day LC100, or 10 µg/litre for Van der Maas et a freshwater sludge deficiencies in LC100, 2 µg/litre al., 1972 snail growth, mobility, for deficiencies and embryo development after 5 weeks of exposure
TPTCl Thais clavigera Relative penis length Relative penis length Horiguchi et al., 1997 (Japanese rock shell)a in female significantly increased with injection of 0.1 µg triphenyltin/g wet tissue and culture for 30 days
TPTH Pimephales promelas 30-day LC50, NOEC, 1.5, 0.15, and 0.23 Jarvinen et al., 1988 (fathead minnow) larvae and LOEC µg/litre, respectively
a Marine and estuarine species.
10.2 Terrestrial environment
Triphenyltin compounds applied to crops at the recommended dosage rate did not harm wild animals, birds, or non-target insects (HSE, 1992). The EC50 for honey bees ( Apis mellifera) was many times higher than that for a range of common pesticides (Eisler, 1989).
LD50s for triphenyltin compounds were 46.5-114 mg/kg body weight in Japanese quail ( Coturnix japonica) and bobwhite quail ( Colinus virginianus) and 285-378 mg/kg body weight in mallards ( Anas platyrhynchos) (Booth et al., 1980; Ebert & Weigand, 1982; Ebert & Leist, 1987, 1988).
Gavage administration of 2 mg TPTCl/kg body weight to chickens ( Gallus domesticus) from the 19th day after hatching for 10 days resulted in atrophy of the thymus and the bursa of Fabricius (Guta-Socaciu et al., 1986).
Female Peking ducks ( Anas platyrhynchos v. domestica) (30 weeks old) administered 25 mg TPTH/kg body weight per day by gavage for 4 weeks showed a decrease in body weight, a gradual decrease in the number of eggs or total lack of egg production, mild anaemia, enlargement of the spleen, liver, and kidneys, and atrophy of the reproductive organs (Masoud et al., 1985). Changes to the spleen, liver, and kidneys reversed within 4 weeks after the end of the exposure, but the uterine tube and ovaries did not completely return to normal.
11. EFFECTS EVALUATION
As tributyltin compounds have been used more abundantly and more extensively than triphenyltin compounds in many locations, and as tributyltin and triphenyltin compounds have similar effects on humans and organisms in the environment, risk from exposure to triphenyltin must be considered together with risk from exposure to tributyltin (IPCS, 1990; Sekizawa, 1998). There are many uncertainties in the potential risk posed by triphenyltin and its metabolites and in the mechanism underlying the immunotoxicological and reproductive effects caused by these compounds, and further studies on these aspects are necessary to improve the risk assessment on triphenyltin.
11.1 Evaluation of health effects
11.1.1 Hazard identification and dose-response assessment
No quantitative data on humans are available. In two poisoning case reports of inhalation exposure to TPTA formulations, neurotoxic effects appeared to persist for a few days. A moderate level of irritant action was detected in a patch test study.
Triphenyltin compounds given orally to rats are not readily absorbed and are excreted primarily in faeces and to a lesser extent in urine. Triphenyltin compounds are metabolized to diphenyltin, monophenyltin, and non-extractable bound residues. Absorbed triphenyltin compounds accumulate to the greatest extent in kidney and liver and to a smaller degree in other organs. Triphenyltin compounds applied dermally can penetrate through the skin in a time- and dose-dependent manner.
Triphenyltin exerts a variety of effects on several animal species, including effects on the immune system, reproductive/developmental effects at levels near those that are maternally toxic (most LOAELs are in the several mg/kg range or lower), hyperplasia/adenomas in endocrine organs, apoptosis in thymus cells, calcium release in sarcoplasmic reticulum cells, and eye irritation. The underlying mechanism of these effects is under investigation; a common mechanism may explain this toxicity profile.
Health effects observed in laboratory animals and toxicological criteria for setting guidance values are summarized in Table 7. Triphenyltin compounds are moderately toxic in acute tests, and the lowest NOAELs for the oral, dermal, and inhalation routes in short-term and subchronic studies were 0.21 mg/kg body weight per day in dog (52-week exposure), 10 mg/kg body weight per day in rat (29-day exposure), and 0.014 mg/m3 in rat (4-week exposure), respectively. Triphenyltin is not carcinogenic or genotoxic.
Table 7: Toxicological criteria for setting guidance values for dietary and non-dietary exposure to triphenyltin compounds.
Type of test Organisms (route of exposure, Results/remarks duration of test)
Single exposure Rat LD50: 160 mg TPTH/kg body weight
Short-term Dog (oral, 52 weeks), rat NOAEL for oral, dog: 0.21 mg TPTH/kg body (dermal, 29 days), rat weight per day, based on relative liver (inhalation, 4 weeks) weight decrease at effect levels; NOAEL for dermal, rat: 10 mg TPTH/kg body weight per day, based on erythema, mortality, lymphocyte decrease at effect levels; NOAEL for inhalation, rat: 0.014 mg TPTH/m3, based on IgM increase at effect levels
Long-term Mouse (80 weeks), rat NOAEL for mouse: 0.85-1.36 mg TPTH/kg body (104 weeks) weight per day, based on decreased body weight at effect levels; NOAEL for rat: 0.1 mg TPTH/kg body weight per day, based on reduction in white blood cell counts at effect levels
Genotoxicity In vivo/in vitro Mostly negative
Reproduction Rat NOAEL: 0.4 mg TPTH/kg body weight per day, based on decreased litter size, pup weight, relative spleen/thymus weight in weanlings at effect levels
Teratogenicity Rabbit NOAEL for maternal toxicity: 0.1 mg TPTH/kg body weight per day, based on decreased body weight gain at effect levels
Table 7 (continued)
Type of test Organisms (route of exposure, Results/remarks duration of test)
Immunotoxicity Mouse/rat/guinea-pig Immunosuppressive; LOAEL: 0.3 mg TPTH/kg body weight per day in rat
Neurotoxicity Rat (6 weeks) Toxic at 0.36 mg TPTA/kg body weight per day in maze learning test
Reproductive and developmental effects include a decrease in the number of implantations and live fetuses (at 1.0 mg TPTA/kg body weight per day in a rabbit gavage study), a reduction in litter size/pup weight and in relative thymus or spleen weight in the weanlings (at 1.5 mg TPTH/kg body weight per day in diet in a two-generation reproduction study in rats; NOAEL 0.4 mg/kg body weight per day), and abortion and a reduction in fetal weight (at 0.9 mg TPTH/kg body weight per day in a rabbit gavage study).
Triphenyltin compounds show effects on the immune system, such as a decrease in immunoglobulin concentrations (even at the lowest dose level, i.e., 0.3 mg TPTH/kg body weight per day in a 2-year rat feeding study), lymphopenia (at 1.75 mg TPTH/kg body weight per day in a 13-week dietary study in rats or at 0.338 mg/m3 in a 13-week inhalation study in rats), and thymus or splenic atrophy (at 1.5 mg TPTCl/kg body weight per day in a 2-week feeding study with weanling rats or at 5 mg TPTH/kg body weight per day in a 28-day feeding study in mice, respectively). Females are generally more susceptible than males with respect to these effects.
The lowest NOAEL detected in the toxicity tests was 0.1 mg/kg body weight per day for maternal toxicity in a rabbit gavage study, based on decreased food consumption and body weight gain at 0.3 mg/kg body weight per day; the same NOAEL was obtained in an early 2-year rat study in which a slight decrease in white blood cells was seen at higher doses.
11.1.2 Criteria for setting guidance values for triphenyltin
No data are available on occupational exposure to triphenyltin. Considering its irritant action, neurotoxic symptoms in poisoning, and effects on the immune and reproductive systems, care must be taken to prevent dermal or inhalation exposure to triphenyltin as much as possible.
Although no data are available on concentrations of triphenyltin in air or drinking-water, it is unlikely that triphenyltin would be present as a contaminant in these media at detectable levels considering its physical/chemical properties and levels of triphenyltin that have been detected in ambient water.
The major exposure route for the general public is through intake of foods contaminated with triphenyltin. Estimation of exposure from residue data in supervised trials or maximum residue limits in foods will lead to overestimates of intake, because not all crops are treated with triphenyltin, and residues will not always be at the maximum residue limits. Exposure to triphenyltin from treated crops and dairy products is considered to be very low to negligible, as long as Good Agricultural Practice in the use of pesticides, as defined by WHO (1976), is observed. Therefore, the major route of exposure for the general public is probably from the ingestion of fish and shellfish contaminated with triphenyltin used in antifouling paints.
Triphenyltin levels found in pelagic fish suggest that pollution from offshore boats is not negligible and that triphenyltins are persistent in the organisms, probably accumulated through the food-web.
Several end-points were taken into consideration in establishing the ADI for oral exposure by JMPR (FAO, 1991b; WHO, 1992). First, a 200-fold safety factor (uncertainty factor) was applied to the NOEL of 0.1 mg/kg body weight per day (based on a finding of reduced white blood cell count at higher doses in a 2-year rat study) to arrive at an ADI of 0-0.5 µg/kg body weight. Secondly, a 500-fold uncertainty factor was applied to a LOAEL of 0.3 mg/kg body weight per day in a 2-year study in rats in which increased mortality and reduced serum immunoglobulins were noted, to derive the same ADI. Other NOAELs taken into account are 0.4 mg/kg body weight per day in a two-generation reproduction study with rats (a dose-related decrease in spleen and thymus weight in F1 and F2 male and female weanlings was observed at higher levels), 0.3 mg/kg body weight per day in a 13-week study in rats (reduction in white blood cells, IgG decrease, and relative testes weight increase seen at higher levels), 0.21 mg/kg body weight per day in dogs (relative liver weight increase and serum albumin/globulin ratio decrease seen at higher levels), and 0.1 mg/kg body weight per day in a teratology study in rabbits (maternal toxicity seen at higher levels). No additional information regarding derivation of the above two uncertainty factors is available in the WHO monograph.
11.1.3 Sample risk characterization
Owing to wide variation in the consumption of fish and shellfish and local differences in residue levels, only illustrative estimates relating to effects and exposure can be made. It should be emphasized that local measurements of residues, local estimates of seafood consumption, and local decisions on acceptable safety margins must be made to assess potential risk. Some examples of risk assessments follow.
Intake of triphenyltin estimated from a market basket survey in Japan in 1997 was 2.7 µg/day per person; values fluctuated between 0.6 and 2.7 µg/day per person over the 1992-1997 period. There was about a twofold difference between average daily intake estimates from 10 local laboratories and intakes estimated by one local government. There are people who eat more seafood than the average person. All these uncertainties and variations must be taken into account in an exposure assessment.
Triphenyltin intakes can be compared with the high end of the ADI of JMPR (0.5 µg/kg body weight per day), which corresponds to 25 µg/day for a 50-kg Japanese person; intakes are calculated to be 2.4% or 10.8% of the ADI for market basket surveys in different periods.
These data suggest that if actions had not been taken, contamination of seafood with triphenyltin may have posed some health risks to Japanese consumers. Similar estimates of intake through market basket studies in Tokyo reported in 1991 support the above estimation.
The above risk estimation was performed using data on triphenyltin compounds alone. Coincidental contamination with tributyltin must be taken into account in risk estimation from oral exposure. The risk from exposure to triphenyltin compounds will be better characterized when combined with risks from other organotin compounds that exert similar effects (IPCS, 1990; CICAD National Committee, 1997).
11.2 Evaluation of environmental effects
Triphenyltins enter the environment through their use in antifouling paints for boats and fishnets and as fungicides for certain crops.
Strong adsorption of triphenyltin to soil suggests that organisms in treated soil may not be widely affected. The fact that soil respiration was not affected significantly suggests that there were no adverse effects on aerobic microorganisms.
Triphenyltins are very toxic to various species in the environment at extremely low concentrations. The most sensitive effects of triphenyltin are imposex in rock shells (Japanese gastropods), supposed to occur at 1 ng/litre, and inhibition of arm regeneration in brittle star, at 0.01 µg/litre. The NOEC for reproduction (21-day exposure) in Daphnia magna and the NOEC (30-day exposure) for fathead minnow were 0.1 µg/litre and 0.15 µg/litre, respectively. The EC50s for carbon fixation, reproduction, and primary production in both marine and freshwater algae were in the range of 1-2 µg/litre. The LC50 (30-day exposure) for fathead minnow was also at a similar level. Acute effects (IC50 for primary productivity in algae, 48-h LC50 for daphnid, and 96-h LC50 for fish) were seen at 1-10 µg/litre.
For sensitive invertebrates, critical concentrations are 0.01-0.1 µg/litre and lower. Sensitive algae and fish species may be susceptible at levels below 1 µg/litre.
Ambient surveys in Japan showed that triphenyltin levels in bay and inshore area water and in sediment were 2.5-3.0 ng/litre and 1.5-2.3 ng/g, respectively, in 1992-1995. Exposure of organisms in the environment varies widely depending on where and when the triphenyltin compounds were used or discharged.
No NOEC has been established for triphenyltin-induced imposex in molluscs. Experimentally, by injection, triphenyltin has a similar potency to tributyltin in the genus Thais. Triphenyltin is less potent than tributyltin in Nucella; however, triphenyltin shows greater bio-accumulation than tributyltin. From this, it can be assumed that the NOEC for triphenyltin will be a few ng/litre or lower. The observed prevalence of imposex in Thais in the wild with ambient concentrations in this range supports this assumption. Because residues of triphenyltin and tributyltin occur together in the environment, their relative contribution to observed imposex cannot be assessed for Thais species. Use of either triphenyltin or tributyltin in antifouling paint would lead to population declines of marine invertebrates on this basis.
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
Triphenyltin was evaluated by JMPR in 1963, 1965, 1970, and 1991.
Information on international hazard classification and labelling is included in the International Chemical Safety Card reproduced in this document.
13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION
Human health hazards, together with preventative and protective measures and first aid recommendations, are presented in the International Chemical Safety Card (ICSC 1283) reproduced in this document.
13.1 Human health hazards
Triphenyltin compounds may affect the immune system, resulting in impaired function. They have also been found to cause reproductive effects and developmental toxicity in animal studies.
13.2 Advice to physicians
In case of poisoning, treatment is supportive. Special attention should be given to pregnant women exposed to triphenyltin compounds.
13.3 Health surveillance advice
Periodic medical examination of the immune system should be included in a health surveillance programme.
13.4 Spillage and disposal
Triphenyltin compounds are absorbed through the skin. In case of spillage, emergency crew should wear proper equipment, including eye protection in combination with breathing protection. The compounds should not be allowed to enter drains or watercourses.
Triphenyltin compounds may be disposed of in sealed containers.
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
Information on national regulations, guidelines, and standards may be obtained from UNEP Chemicals (IRPTC), Geneva.
The reader should be aware that regulatory decisions about chemicals taken in a certain country can be fully understood only in the framework of the legislation of that country. The regulations and guidelines of all countries are subject to change and should always be verified with appropriate regulatory authorities before application.
INTERNATIONAL CHEMICAL SAFETY CARD
TRIPHENYLTIN HYDROXIDE ICSC: 1283 November 1998
CAS # 76-87-9 Hydroxytriphenylstannane RTECS # WH8575000 Hydroxytriphenylstannate UN # 2786 Fentin hydroxide EC # 050-004-00-1 C18H16OSn
TYPES OF HAZARD/ ACUTE HAZARDS/ PREVENTION FIRST AID/ EXPOSURE SYMPTOMS FIRE FIGHTING
FIRE Combustible. Liquid NO open flames. Powder, water spray, formulations containing foam, carbon dioxide. organic solvents may be flammable.
EXPLOSION In case of fire: keep drums, etc., cool by spraying with water.
EXPOSURE PREVENT DISPERSION OF DUST! STRICT HYGIENE! AVOID EXPOSURE OF (PREGNANT) WOMEN!
Inhalation Cough. Sore throat. Ventilation, local exhaust, Fresh air, rest. Refer or breathing protection. for medical attention.
Skin MAY BE ABSORBED! Redness. Protective gloves. Remove contaminated Pain. Protective clothing. clothes. Rinse and then wash skin with water and soap. Refer for medical attention.
Eyes Redness. Pain. Blurred Safety spectacles, face First rinse with vision. shield, or eye protection plenty of water for several in combination with minutes (remove contact breathing protection. lenses if easily possible), then take to a doctor.
Ingestion Do not eat, drink, or smoke Give plenty of water to during work. drink. Refer for medical attention.
SPILLAGE DISPOSAL PACKAGING & LABELLING
Do NOT wash away into sewer. Carefully Do not transport with food and feedstuffs. collect remainder, then remove to safe Severe marine pollutant. place. (Extra personal protection: P3 Symbol: T+, N filter respirator for toxic particles). R: 24/25-26-36/38-50/53 Use face shield. Chemical protection suit. S: (1/2-)36/37-45-60-61 UN Classification UN Hazard Class: 6.1 UN Pack Group: II
EMERGENCY RESPONSE STORAGE
Transport Emergency Card: TEC(R)-61G41b Provision to contain effluent from fire extinguishing. Separated from food and feedstuffs.
IMPORTANT DATA
PHYSICAL STATE; APPEARANCE: ROUTES OF EXPOSURE: WHITE CRYSTALLINE POWDER The substance can be absorbed into the body by inhalation, through the skin and by ingestion.
OCCUPATIONAL EXPOSURE LIMITS: INHALATION RISK: TLV (as organic compounds (tin)): ppm 0.1 Evaporation at 20°C is negligible; mg/m3 (skin) (STEL) (ACGIH 1998). a harmful concentration of airborne particles MAK as tin: ppm, 0.1 mg/m3; skin (D) (1995) can, however, be reached quickly when dispersed.
EFFECTS OF SHORT-TERM EXPOSURE: The substance irritates the eyes severely, the skin and the respiratory tract. The substance may cause effects on the immune system, resulting in impaired functions
EFFECTS OF LONG-TERM OR REPEATED EXPOSURE: Animal tests show that this substance possibly causes malformations in human babies.
PHYSICAL PROPERTIES
Decomposes below melting point at 80°C. Solubility in water, g/100 ml: 0.008 Flash point: 400°C
ENVIRONMENTAL DATA
The substance is very toxic to aquatic organisms. In the food chain important to humans, bioaccumulation takes place, specifically in molluscs. Avoid release to the environment in circumstances different to normal use.
NOTES
Carrier solvents used in commercial formulations may change physical and toxicological properties. Do NOT take working clothes home.
ADDITIONAL INFORMATION
LEGAL NOTICE
Neither the CEC nor the IPCS nor any person acting on behalf of the CEC or the IPCS is responsible for the use which might be made of this information.
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