Concise International Chemical Assessment Document 13
TRIPHENYLTIN COMPOUNDS
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Concise International Chemical Assessment Document 13
TRIPHENYLTIN COMPOUNDS
First draft prepared by Dr J. Sekizawa, National Institute of Health
Sciences, Tokyo, Japan
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 1999
The International Programme on Chemical Safety (IPCS),
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
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technical assistance in strengthening national capacities for the
sound management of chemicals.
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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
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field of chemical safety. The purpose of the IOMC is to promote
coordination of the policies and activities pursued by the
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