FENTIN

    First draft prepared by
    Mrs. M.F.A. Wouters,
    Mrs. J.E.M. van Koten-Vermeulen,
    Mrs. Dr.E.M. den Tonkelaar,
    National Institute of Public Health
    and Environmental Protection,
    Bilthoven, Netherlands

    EXPLANATION

         Fentin toxicity has been reviewed by the Joint Meetings in
    1963, 1965 and 1970 (Annex I, 2, 3 and 14). Data include
    biochemical studies in rats, sheep and cows, acute and short-term
    tests in rats, guinea pigs and dogs, long-term studies in rats and
    guinea pigs, reproduction studies in rats and immunotoxicity
    examinations in rats and guinea pigs. The 1970 Joint meeting
    established an ADI of 0-0.0005 mg/kg bw applicable to
    triphenyltinhydroxide (TPTH), triphenyltinacetate (TPTA) and
    triphenyl-tinchloride (TPTCl) and to the sum of TPTH + TPTA +
    TPTC1. This ADI was based on a NOAEL of 0.1 mg/kg bw in a chronic
    rat study with a safety factor of 200.  New studies have become
    available, which were evaluated by the present Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Rat

         Ten male rats received a single oral dose of 5 mg 14C-TPTH/kg
    bw dissolved in 0.5 ml of ethanol. After 7 days 39.2% of applied
    radioactivity was excreted in the urine and 51.5% in the faeces
    (Bakke  et al., 1982).

         Two female rats received a single oral dose of 10 mg
    14C-TPTH/kg bw. Within 72 hours 71.7% of applied radioactivity was
    excreted in the faeces, 20.8% of the dose in the urine., 6.5%
    remained in the carcass. Exhalation of 14CO2 was below 0.1%
    (Lachmann & Siegemund, 1987).

         Groups of 5 rats/sex received single oral doses of 2 or 10 mg
    14C-TPTH/kg bw.  Additionally repeated application was studied by
    14 daily doses of 2 mg/kg and one dose of 2 mg 14C-TPTH/kg bw. The
    faeces appeared to be the principal route of excretion (32-53% of
    the dose).  Approximately 12-24% was excreted via the urine.
    Excretion was biphasic with half-lives of 9 and 62 hours. After 7
    days concentrations of applied radioactivity were found in the
    liver (0.14-0.16 mg/kg at 2 mg/kg, 0.17-0.21 mg/kg at repeated
    treatment and 0.37-0.42 mg/kg at 10 mg/kg). In the kidneys
    0.023-0.035 mg/kg was found at 2 mg/kg, 0.04-0.06 mg/kg at repeated
    treatment and 0.13-0.25 mg/kg at 10 mg/kg. All other concentrations
    found in  tissues, blood and plasma were below 0.1 mg/kg or the
    detection limit. Absorption was incomplete, with an average of 40%
    of the dose. The recovery rates showed considerable variations,
    ranging from one group to another between 48 and 84%. The expired
    air contained less than 1% of the dose (Kellner & Eckert, 1986).
    The authors explained the low and variable recovery by assuming
    that a volatile metabolite (benzene) was formed and escaped from
    the faeces and during processing of the analytical samples.

         Two groups of rats received a single or seven daily oral
    administrations of 2 mg 113Sn-TPTH/kg bw. Rats were sacrificed
    after 1 and 7 days after the single dose and 1, 3, 7 and 14 days
    after 7 daily doses. The radioactivity was excreted predominantly
    via the faeces (96.2% to 100.8%) independent of sex and number of
    doses. Excretion via the faeces was biphasic with half-lives of 9
    and 53 hours. Only up to 1.4% was excreted via the urine, with a
    half-life of about 45 hours. Seven days after single dosing the
    amount of radioactivity in the examined tissues and organs

    corresponded to about 2.8-3.2% of the administered radioactivity,
    with highest concentrations in the kidneys (0.26-0.37 mg/kg), liver
    (0.15-0.30 mg/kg), brain (0.09-0.11 mg/kg) and heart (0.07-0.10
    mg/kg). One day after the first dose the highest concentrations
    were detected in the liver (1.95 mg/kg), kidneys (1.78 mg/kg) and
    walls of the g.i.t. (1.26 mg/kg). In all other organs the
    concentrations were below 1 mg/kg. Radioactivity increased in the
    organs during repeated dosage. Residues after multiple dosing were
    up to seven times higher than those after single administration,
    indicating accumulation of metabolites. Analysis of these data
    showed that the cumulated residue would reach maximum values in all
    organs after multiple dosing after 20-25 days. The concentrations
    decreased after the last dose and had dropped to 0.67 mg/kg in
    kidneys 14 days after the last administration. In the remaining
    organs levels were below 0.5 mg/kg (liver, brain, skeletal
    musculature, spleen, heart muscle) or 0.1 mg/kg (testes, lungs,
    walls of gastro-intestinal tract) or were below the detection limit
    (fat). The radioactivity in all organs/tissues accounted for 0.29%
    of the administered dose at that time (Eckert  et al, 1989;
    Kellner & Eckert, 1989).

         Three groups of 20 male rats received single dermal
    applications with 0.09, 0.96 and 12.82 mg 14C-labelled TPTH/kg bw
    as aqueous suspension, wrapped with a non-occlusive cover. After
    periods ranging from 0.5 to 10 hours the rats were sacrificed.
    Total radioactivity in excreta (urine) was less than 1% of applied
    radioactivity. The amount excreted increased with increasing
    application time. Measurable radioactivity levels were found in
    blood of the mid and highest dose group. The highest concentration
    was 0.019 mg/kg. Muscle tissue beneath the application site
    contained low levels of residues, the highest concentration found
    was 0.173 ppm. Total recovery in the mid and high dose group was
    90.7 and 101.5%, respectively. The total amount absorbed was 34-38%
    of which a very high percentage (>95%) was bound to the skin
    (Resnis  et al., 1986)

         Three groups of 20 male rats received single dermal
    applications of 0.11, 0.99 or 10.24 mg 14C-TPTH/kg bw as aqueous
    suspension. After 10 hours exposure TPTH was washed from the skin
    and about 45, 60 and 78% of applied radioactivity was removed from
    the groups treated with 0.11, 0.99 or 10.24 mg/kg, respectively.
    The remaining radioactivity is absorbed into the skin. At the
    lowest dose about 2, 3.4, 26, 34 and 28% was penetrated through the
    skin after 10 and 24 hours and 7, 14 and 21 days, respectively.
    From these penetrated amounts 13, 27, 88, 91 and 99% was excreted
    (cumulative). At higher doses the amount which penetrated skin is
    lower, maximal 15 and 10%, respectively (Craine, 1987).

         Rats were fed a diet containing 0, 5, 20 or 80 ppm TPTH for
    104 weeks. Tissue residue levels were recorded after 52 and 104
    weeks. The highest levels were observed in kidneys (up to 25 mg
    total tin/kg after 52 weeks and 10.5 mg/kg after 104 weeks in the
    80 ppm group) and liver (up to 9.5 mg total tin/kg after 52 weeks
    and 3.1 mg/kg after 104 weeks in the 80 ppm group). The lowest
    residue level was observed in blood (up to 0.11 mg total tin/kg in
    the 80 ppm group) (Tennekes  et al, 1989a; Dorn & Werner, 1989b).

    Guinea-pig

         From a single dermal application of 113Sn-TPTA 3.04% and 7.97%
    was absorbed percutaneously through the skin 1 and 2 days after
    application. About 16.3% and 12.4% remained in the applied area,
    respectively (Nagamatsu  et al., 1978)

         After a single subcutaneous injection of 2 mg 113Sn-TPTA to
    guinea-pigs about 21% remained in the body 20 days after
    administration. The biological half-life was estimated as 9.4 days.
    Radioactivity was mainly excreted in the faeces, the daily
    excretion rate was highest in the early stage after injection. The
    absorption of radioactivity from the injection site was rather
    slow. About 18.5%, 4.3% and 0.1% of the dose were retained at the
    injection site after 5, 10 and 20 days, respectively. The highest
    concentration of radioactivity was noted in the liver, adrenal
    glands, kidneys and brain. The parent compound, diphenyltin and
    monophenyltin were identified in the faeces (Nagamatsu  et al.,
    1978).

    Dog

         After feeding a diet containing 0, 2, 6 or 18 ppm for 52 weeks
    highest tin levels were found at the 18 ppm group in the liver (up
    to 12 mg/kg) and kidneys (up to 3.25 mg/kg) while the lowest
    concentration was found in blood (up to 0.04 mg/kg). The residue
    levels were similar after 4 and 52 weeks (Sachsse  et al., 1987)
    (Dorn & Werner, 1989a).

    Biotransformation

         Triphenyltinacetate (TPTA) was rapidly and completely
    hydrolyzed to triphenyltinhydroxide (TPTH) at pH 3-8 and at
    23-24 °C. Therefore it is assumed that it will rapidly hydrolyze to
    TPTH  in vivo (Buerkle, 1985).

         Groups of male and female rats received single oral doses with
    2 or 10 mg 14C-TPTH/kg bw. Additionally repeated application was
    studied by 14 daily administrations of 2 mg/kg were followed by one
    dose of 2 mg 14C-TPTH/kg bw. The applied radioactivity was
    excreted within two days via the faeces (50-70%) and urine

    (10-20%). Repeated administration caused a higher rate of renal
    excretion. In faeces the major radioactive substance present was
    unchanged parent compound. Metabolites found included di- and
    monophenyltin as well as a significant portion of non-extractable
    bound residues. Also benzene has been shown to be evaporated from
    the faeces. Repeated dosage lowered the proportion of TPTH whereas
    the more polar degradation products were increased. The composition
    of renally excreted material revealed a moderate difference between
    the dosage levels. Low dosing resulted in the excretion of the
    sulfate conjugates of hydroquinone, catechol and phenol whereas
    high level dosing led to additional formation of resorcinol sulfate
    and a medium polar metabolite. These metabolites are comparable to
    those formed when benzene is given to warm-blooded animals.
    Phenylmercapturic acid, which is an enzymatic degradation product
    of phenyl glutathionate also occurred in trace amounts. Phenyltin
    compounds were not detected in the urine. The proposed metabolic
    pathway is given in Figure 1 (Buerkle  et al., 1986).

         14C-TPTH (purity 87%) was administered orally at 2 mg/kg bw
    by stomach tube to 3 male rats with a bile fistula. About 2.8% of
    the applied radioactivity was excreted with bile within 30 hours
    after dosing. In addition 11% of applied radioactivity was excreted
    with the urine and 0.4% was detected in the cage wash. The
    radioactivity excreted with the bile consisted of three extremely
    to moderately polar metabolite fractions. Due to acid hydrolysis
    their polarity decreased. Unchanged parent compound was not
    excreted via the bile (Buerkle & Kellner, 1987).

         Groups of rats received a single oral dose of 2 mg
    113Sn-TPTH/kg bw.  Within 30 hours after administration 6.2% (male)
    and 2.8% (female) of applied radioactivity was excreted via the
    bile. Urinary excretion was low and amounted up to 0.07%. After 30
    hours the carcass of male rats (excluding gastrointestinal tract)
    contained 21.6% of the dose and the carcass of female rats
    contained 8.9%. Bile contained besides 14% parent compound, 40%
    diphenyltin, 21%  monophenyltin, and 25% soluble inorganic tin
    (Kellner  et al., 1989).

    

         A 576 kg milk cow received a single oral dose of 5055 g
    14C-TPTH and a 74 kg ewe received a dose of 1011 g 14C-TPTH, in
    capsules. In the cow after 6 days 12.9% of radioactivity was
    excreted in urine and 78% in the faeces. Tissues contained 5.1%.
    Maximum radioactivity levels were found in the liver (5.5 mg/kg),
    kidney and adrenals (both 2.2 mg/kg). In the sheep, 32.6% of
    applied radioactivity was found in urine and 47.5% in the faeces 
    after 8 days. Tissues contained 3.1%. The liver showed highest
    level of radioactivity, 6.6 mg/kg. Triphenyltinchloride was
    identified as the major faecal excretion product. Phenol,
    hydroquinone, catechol and resorcinol were isolated from the urine
    (Bakke  et al., 1982).

    Toxicological studies

    Acute toxicity

         The LD50 and LC50 values for TPTH and TPTA in various species
    are given in Tables 1 and 2, respectively.

         The observed intoxication signs following oral exposure
    include anorexia, emesis, tremor and diarrhoea followed by
    drowsiness and ataxia. After dermal exposure to TPTH, skin
    irritation was observed.

         Five applications of 50 mg TPTA (purity not stated)/kg applied
    to the nuchal skin of 5 rats caused no mortality but some signs of
    local irritation. Five applications of 100 mg/kg to 5 rats caused
    death of one animal and local signs of irritation. Five
    applications of 200 mg/kg were lethal to rats. (Summary only)
    (Hollander & Weigand, 1974d).

         A single dermal application of 12.5 mg TPTA/kg to 3 rabbits
    was lethal for 2 rabbits and caused black coloration of the skin
    and scarcely pilous sites of the body. (Summary only) (Hollander &
    Weigand 1974d).


    
    Table 1.  Acute toxicity of TPTH

                                                                                             

    Species    Sex       Route     Purity      LD50       LC50      References
                                            (mg/kg bw)   (mg/m3)
                                                                                             

    Rat         M        oral         ?        165                  Leist & Weigand (1981a)
                F        oral         ?        156                  Leist & Weigand (1981b)
                F        perc.        ?       1600                  Leist & Weigand (1981c)
               M&F      inhal.a     97.0%                60.3       Hollander & Weigand (1981)

    Rabbit      M        perc.        ?        127                  Leist & Weigand (1981d)

    Dog        M&F       oral         ?       »100                  Brunk & Weigand (1981)
                                                                                             

         a  indicates 4 hour exposure

    Table 2.  Acute toxicity of TPTA

                                                                                             

    Species       Sex     Route    Purity      LD50       LC50      Reference
                                      %     (mg/kg bw)   (mg/m3)
                                                                                             

    Mouse          M       oral      99        81.0                 Ueda & Iijima (1961)
                   M       oral      99        93.3                 Ueda & Iijima (1961)
                   M       s.c.      99        44.0                 Ueda & Iijima (1961)
                   M      dermal     99       350                   Ueda & Iijima (1961)

    Rat            F       oral       ?       298                   Scholz & Weigand (1969b)
                   F       oral       ?       140                   Hollander & Weigand (1974a)
                  M&F     dermal     97     >2000                   Diehl & Leist (1986b)
                   M       i.p.      97         3.6                 Diehl & Leist (1986a)
                   F       i.p.      97        12.7                 Diehl & Leist (1986a)
                   M      inhal.     97                   44a       Hollander & Weigand (1986)
                   F      inhal.     97                   69a       Hollander & Weigand (1986)  

    Guinea pig     ?       oral       ?        25                   Hollander & Weigand (1974b)

    Rabbit         M       oral       ?        80                   Hollander & Weigand (1980)
                                                                                             

         a  indicates 4 hour exposure, whole body exposure, dust inhalation
    

    Short-term studies

    Mice

         Male and female NMRI mice (10/sex/group) were fed diets
    containing 0, 4, 20 or 100 ppm TPTH technical (purity 97.2%) for
    three months. No compound-related effects were observed on
    mortality, clinical signs, food consumption, body weight,
    macroscopy and histopathology. At 100 ppm several haematological
    and biochemical parameters were affected. Erythrocyte count and Hb
    were decreased and platelet count increased in males and females.
    The incidence of Heinz bodies was increased in males and MCH and
    MCHC were decreased in females. Mouse immunoglobulins (IgA and IgG)
    were decreased, IgM levels were decreased in females only. In
    female mice total protein, albumin and alpha-globulin were
    increased and gammaglobulin was decreased. Liver weight was
    increased in males and females and a decrease was observed in the
    relative weights of ovaries, adrenals, kidneys, heart and brain in
    females. The NOAEL in this study is 20 ppm, equal to 3.4 mg/kg bw
    (males) and 4.1 mg/kg bw (females) (Suter & Horst, 1986a).

    Rats

         In a range-finding study groups of rats (Hoe: WISKf;
    10/sex/group) were fed diets containing 0, 5, 10, 20, 40 or 80 ppm
    TPTH (97.0%) for 30 days. No compound-related effects were observed
    on clinical signs, water consumption, urinalysis, organ weight,
    macroscopy nor histopathology. In male rats at 80 ppm body weight
    gain was decreased. Food consumption was decreased during the first
    weeks in males at 80 ppm and females at 40 and 80 ppm. An increase
    in thrombocyte count was observed in female rats at 40 and 80 ppm;
    at the highest dose a decrease in Hb was observed in males and a
    decrease in haematocrit was observed in females. At the highest
    dose bilirubin, creatinin (males only), SGPT and urea (males only)
    were increased. SAP was increased in a non dose-related manner in
    males at 20 ppm and higher and in high-dose females. There was no
    effect on spleen weight. The NOAEL in this study is 20 ppm equal to
    2.01 mg/kg bw (males) or 1.83 mg/kg bw (females) (Leist  et al.,
    1982).

         Groups of Wistar rats (15/sex/group) received dietary
    concentrations of 0, 4, 20 or 100 ppm TPTH-technical (purity 97.2%)
    for 13 weeks. The treatment period was followed by a 4-week
    recovery period (5 male and 5 female rats/group). Observations
    included clinical signs, food consumption, body weight,
    ophthalmoscopy, hearing tests, haematology, clinical chemistry,
    organ weights, macroscopy and histopathology (54 tissues; only in
    control and high-dose rats). After 13 weeks of treatment the
    following parameters were significantly affected; mean body weight
    gain and food consumption were slightly decreased in high-dose
    rats. RBC was increased, MCV (in males also at 20 ppm) and MCH were

    decreased. In females WBC decreased at 20 and 100 ppm. Most
    biochemical parameters were significantly affected at the highest
    dose. The observed increase in ASAT was also apparent at 20 ppm as
    was the decrease in albumin in females (also at 4 ppm). IgG was
    slightly lower. The 18-hour urine volume was increased and the
    specific gravity was decreased at 100 ppm. Relative testes weight
    was significantly higher in high-dose males. After the recovery
    period ASAT was still increased at 100 ppm and IgG was decreased in
    males and significantly in females at all dose levels. No effects
    were observed on spleen and thymus weights. The NOAEL in this study
    is 4 ppm equal to 0.30 mg/kg bw (males) or 0.35 mg/kg bw (females)
    (Suter & Horst, 1986b).

         Four different experimental groups received 21 dermal
    applications of 0, 5, 10 or 20 mg TPTA (purity unknown)/kg bw/day
    in a 29-day period. Dosage groups consisted of 12 rats/sex in the
    0 and 20 mg/kg groups and of 6 rats/sex in the 5 and 10 mg/kg
    groups. At the end of the treatment period 6 rats/sex of the 0 and
    20 mg/kg groups were kept for a 14 day recovery period. Rats were
    observed for clinical signs, body weight, food consumption,
    haematology, blood chemistry, urinalysis, organ weights, macroscopy
    and histopathology. Piloerection, mydriasis, increased muscle tones
    and dyspnoea were observed in high dose rats. Dose-related increase
    in erythema and scale formation was observed in all treated groups.
    Dose-related cracked skin and thickening of the skin fold was
    observed at 10 and 20 mg/kg groups. Crusts and slight oedema were
    observed in some animals at 20 mg/kg. At 20 mg/kg 4 animals died.
    Lymphocytes decreased in males and females at 20 mg/kg. Monocytes
    increased in females at 20 mg/kg. Sodium level decreased in all
    treated males (n.d.r.) and females. Potassium decreased in 20 mg/kg
    females. Inorganic phosphorus and total protein increased in 20
    mg/kg females. A/G-ratio and albumin increased in 20 mg/kg males.
    A1-globulins decreased in 20 mg/kg males. Macroscopy and
    microscopy showed dose-related skin lesions such as hyperkeratosis
    and epidermal hyperplasia in all treated groups. All effects were
    reversible. No effects on spleen weights were observed. The NOAEL
    for systemic toxicity in this study is 10 mg/kg bw (Leist, 1988).

         TPTH (purity 97.1%) was applied to the shaven unabraded backs
    of Charles River rats (10/sex/group) at doses of 0, 5, 10 or 20
    mg/kg bw for 15 applications in 3 weeks. No treatment-related
    effects were observed on food consumption, haematology, clinical
    chemistry, urinalysis nor organ weights. Male body weight gain was
    very slightly decreased in all treated groups and significantly
    decreased during the first week at the highest dose. Dermal
    irritation, increasing with each application, was observed in all
    treated rats during the first 2 weeks. At the third week the
    irritation was less severe and severe erythema was not present any
    more. At macroscopy an increased incidence in ulcerated, exfoliated
    and thickened skin was observed in all treated groups. Microscopic

    evaluation of the treated skin revealed acanthosis and
    hyperkeratosis. Also changes such as focal ulceration and mild
    dermal inflammatory changes correlated with the observed dermal
    irritation were seen. No systemic toxicity was observed (Laveglia
     et al., 1985).

         Groups of SPF-Wistar rats (10/sex/group) were exposed to 0.05,
    0.5 and 2.0 mg TPTH (purity 96.2%)/m3 for 6 hours/day, 5 days/week
    for 13 weeks (nose only exposure).  Analytical concentrations were:
    0.014, 0.338 or 1.997 mg/m3. The MMAD was 3 µm. The reversibility
    of treatment-related changes was studied after a 4-week recovery
    period in the control and highest dose group with 10 additional
    animals/sex. Observations were made for clinical signs, body
    weight, food consumption, ophthalmoscopy, haematology and clinical
    chemistry, organ weights (6), macroscopy and histopathology. In the
    highest dose group 10 males and 1 female died between test weeks
    2-13 compared to none in the other groups. Laboured respiration and
    rales were observed only in the highest exposure group. These signs
    were still noted during the first week of recovery. RBC, Hb and Hc
    were decreased in high exposed females, while platelet count was
    increased. WBC was decreased in females at 0.5 and 2.0 mg/m3.
    Glucose and total bilirubin were decreased in females at 0.5 and
    2.0 mg/m3. Creatinine, albumin, gamma-glutamyltransferase and
    potassium levels were decreased in females at 2.0 mg/m3. Calcium
    and phosphorus level were decreased in all exposed female groups.
    Calcium level decreased also in males at 0.5 and 2.0 mg/m3.  IgG
    increased in females at the high exposure level and IgM increased
    in males at 0.5 and 2.0 mg/m3. Relative lung weights increased in
    high exposed males, but no effect on thymus or spleen weight was
    observed. Macroscopic examination showed lesions in the form of
    multiple red foci in the lungs of most dead rats. Histopathology
    revealed in both sexes at 2.0 mg/m3 degenerative and/or
    inflammatory lesions in the anterior part of the nasal cavity, in
    the trachea and in the lungs. The lower air passages and in
    particular the lungs were severely affected. The pathomorphologic
    sequence of events in the lungs seemed to start with degeneration
    and multifocal necrosis of the bronchial epithelium followed by
    multifocal or lobular fibrinous bronchopneumonia. The NOAEL in this
    study is 0.05 mg/m3 (Duchosal  et al., 1989).

         Groups of 10 rats/sex were fed diets containing TPTA (purity
    not given) at a rate of 0, 37.5, 150 or 625 ppm, during 30 days. No
    effects were found on haematology and urinalysis. Seven rats/sex
    from the 625 ppm group died during the study. Signs in this group
    were piloerection and deterioration of the general condition. At
    150 and 625 ppm temporary body weight gain decreases were seen.
    Histopathology showed gastrointestinal haemorrhages and hepatic
    changes (effects on cell metabolism) in the 625 ppm group. The
    NOAEL in this study is 37.5 ppm, equivalent to 1.9 mg/kg bw.
    (Summary only) (Hollander & Weigand, 1974c).

    Guinea-pigs

         Groups of guinea pigs (10/sex/group) were fed a diet
    containing TPTA (purity not given) at a rate of 0, 7.5, 30.0 or 125
    ppm. No effects were found on haematology nor urinalysis. In the
    125 ppm group 8 male and 5 female guinea pigs died during
    treatment. Effects found in this group included poor general
    condition, piloerection and decrease in body weight gain.
    Histological evaluation revealed fatty changes in the livers of
    guinea-pigs treated with the highest dose (summary only) (Hollander
    & Weigand, 1974c)

    Dogs

         Male and female dogs (beagle, 10/sex/group) received a diet
    containing 0, 2, 6 or 18 ppm TPTH (purity 97.2%) for 52 weeks.
    Interim necropsy on 2 dogs/sex/group was performed after 4, 13 and
    27 weeks. Observations were made for clinical signs, food
    consumption, body weight, hearing, ophthalmoscopy, haematology,
    clinical chemistry (including immunoglobulins) and urinalysis. The
    weights of 12 organs/animal were recorded (including spleen and
    thymus). Gross necropsy and histopathology (about 40
    tissues/animal) were carried out. A/G-ratio decreased in males at
    18 ppm after 26 and 52 weeks. In females albumin decreased at 6 and
    18 ppm after 52 weeks. In females at 18 ppm relative liver weight
    was increased. The NOAEL in this study is 6 ppm, equal to 0.21
    mg/kg bw (Sachsse  et al., 1987)

    Long-term/carcinogenicity studies

    Mice

         Groups of B6C3F1 mice (50/sex/group) were fed diets containing
    37.5 or 75 ppm TPTH (purity ?) for 78 weeks. There was an
    additional observation period of 26 weeks for both groups. Twenty
    male and 20 female mice were used as controls.  Dosed feed
    preparations containing 37.5 or 75 ppm TPTH were analyzed
    spectrophotometrically. 88% of the theoretical amount of TPTH was
    recovered immediately after preparation but after 1 week only 57.9%
    was recovered. The data were not corrected for any loss which may
    have been due to the instability of TPTH.  No treatment-related
    effects were observed on clinical signs and body weight. Survival
    was decreased in female mice (survival for males was: 65%, 72% and
    76% and for females 95%, 74% and 66% for 0, 37.5 and 75 ppm,
    respectively). At histopathology no increase in tumour incidence
    was observed (NTP, 1978)

         Groups of CD1-Charles River mice (60/sex/group) were fed diets
    (prepared at weekly intervals) containing 0, 7, 28 or 52 ppm
    technical TPTH (purity 96.3%) for 18 months. Observations included
    clinical signs, mortality, body weight, food consumption,

    macroscopy and histopathology (19 tissues). Survival rate was
    significantly decreased in male mice in the mid and highest dose
    groups (70%, 70%, 41% and 41% at 0, 7, 28 and 52 ppm,
    respectively). Survival rates for females were 55%, 71.7%, 53.3%
    and 58.3% at 0, 7, 28 and 52 ppm, respectively). The frequency of
    aggression, alopecia, irritation, laceration and scabs was
    dose-relatedly increased in both males and females. Food
    consumption was reduced during some short periods in all treated
    females. At histopathology an increase in the occurrence of
    endometrial hyperplasia with cyst formation of the uterus was
    observed at 28 and 52 ppm. The tumour incidence was not increased
    (Terrel & Reddy, 1978). Extensive histomorphologic examination of
    the uterus revealed that the observed cystic endometrial
    hyperplasia was considered to be a hyperplastic reaction and not
    neoplastic (Brown, 1985).

         Groups of 50 male and 50 female mice (KFM-Han. NMRI) were fed
    diets (prepared fresh daily) containing 0, 5, 20, 80 ppm TPTH
    (purity 97.2%) for 80 weeks. Observations were made for clinical
    signs, body weight, food consumption, ophthalmoscopy, haematology
    (differential wbc count), clinical chemistry (including
    immunoglobulin classes and subclasses) and organ weights (no spleen
    weight). Gross pathology and histopathology (35 tissues including
    bone marrow smears) were carried out. Intercurrent mortality was
    significantly increased for 80 ppm females. At 80 ppm mice showed
    ruffled fur towards the end of the study as well as skin lesions.
    Body weight gain was reduced for 80 ppm males and 20 and 80 ppm
    females. IgG, IgA, IgM, IgG4(f), IgG2a(f), IgG2b and IgG3 were
    slightly or moderately decreased at 80 ppm. The decrease in IgA was
    also found at 20 and 5 ppm (n.d.r.) and in IgM at 20 and 5 ppm in
    male mice. Relative liver weight was markedly increased and
    relative brain weight slightly increased at 80 ppm males and
    females. Relative kidney weight was decreased at 80 ppm in males
    and females. Macroscopic examination showed nodules, foci and
    nodular lesions in the livers of mice in 80 ppm males. Skin lesions
    were observed in both sexes at 80 ppm. Microscopy showed a higher
    incidence of slight to moderate, focal to multifocal, nodular
    hyperplasia in the liver of 80 ppm males and females. A higher
    incidence of hepatocellular adenomas was observed at 80 ppm
    (incidence: 12.2%, 20%, 26% and 32% for 0, 5, 20 and 80 ppm,
    respectively, for male mice, and 0% in 0, 5 and 20 ppm females and
    18% in 80 ppm females; only significant at 80 ppm). An increased
    incidence in hepatocellular carcinomas was observed in 80 ppm
    females. The incidence was 6% compared to 0% in the 0, 5 and 20 ppm
    groups. An increased incidence of chronic suppurative dermatitis
    and related non-specific skin lesions including acanthosis and
    hyperkeratosis was observed in 80 ppm males and females. An
    increased relative number of lymphoid cells was detected in femoral
    bone marrow myelograms for all treated groups. The relative numbers
    of granulocytes were significantly decreased for females at 5 ppm

    and both sexes at 20 and 80 ppm. The relative numbers of
    erythrocyte precursors were significantly  decreased for males at
    20 and 80 ppm.  However, it is difficult to evaluate these data in
    the absence of red cell counts in peripheral blood.  Although a
    reduction in serum immunoglobulin concentrations was reported,  the
    Meeting noted that there was no corresponding effect on
    haematological parameters and that the method of analysis has not
    been validated in rodents. The data on serum immunoglobulin
    concentrations was therefore not utilized in the determination of
    the NOAEL for this study.  Based on reduced body weight gain, the
    NOAEL is 5 ppm, equal to 1 mg/kg bw/day (Tennekes  et al., 1989a).

    Rats

         Groups of Fischer 344 rats (50/sex/group) were fed diets
    prepared weekly containing 37.5 or 75 ppm TPTH (purity not stated)
    for 78 weeks. There was an additional observation period of 26
    weeks for both groups.  Twenty male and 20 female rats were used as
    controls.  Feed preparations containing 37.5 or 75 ppm TPTH were
    analyzed spectrophotometrically.  Of the theoretical amount of
    TPTH, 80% was recovered immediately after preparation but after 1
    week only 57.9% was recovered. The data were not corrected for any
    loss which may have been due to the instability of TPTH. No effects
    were observed on clinical signs, mortality, food consumption,
    macroscopy nor histopathology (31 tissues including pituitary gland
    and testes). Body weight was slightly but dose dependently
    decreased in male rats after week 40. Survival rates were 75%, 76%
    and 84% for males and 90%, 80% and 90% for females at 0, 37.5 and
    75 ppm TPTH. The tumour incidence was not enhanced (NTP, 1978).

         Groups of 70 rats/sex (SPF-bred KFM-Han. Wistar) rats received
    a diet containing 0, 5, 20 or 80 ppm TPTH (purity 97.2%) for 104
    weeks. The diets were prepared twice monthly and frozen.  A fresh
    amount of diet was given daily.  Observations were made for
    clinical signs, food consumption, body weight, ophthalmoscopy,
    haematology, clinical chemistry (including immunoglobulin classes
    and subclasses), urinalysis, organ weights, macroscopy and
    histopathology (about 40 tissues/animal, including bone marrow
    smears). Mortality was increased (dose-related) in all treated
    females. The survival was 75, 51, 36 and 23%, respectively.
    Preceding mortality clinical signs were ruffled fur, reduced
    activity, ataxia, stiff gait and hunched posture. Due to this
    excess mortality no laboratory investigations could be made for the
    80 ppm female group at 104 weeks. Group mean food intake was
    reduced for males and females at 80 ppm. Body weight gain was
    dose-relatedly decreased in males and females at 20 and 80 ppm.
    Ophthalmoscopy showed an increased incidence of unilateral or
    bilateral corneal opacity in males at 20 and 80 ppm at 104 weeks.
    Hb and haematocrit were decreased in female rats at 20 and 80 ppm.

    ASAT, ALAT, ALP were increased in males and females at 80 ppm. The
    following changes in immunoglobulin levels were observed only after
    50 weeks: IgG1 levels were reduced for all treated females and 80
    ppm males, IgG2a levels were reduced for all treated females and
    IgG2c levels were reduced for all treated males, IgA levels were
    reduced for males at 20 and 80 ppm and IgM levels were increased
    for both sexes at 20 and 80 ppm. At termination most relative organ
    weights were increased in the 80 ppm groups, including spleen
    weight. An increased incidence of pituitary adenomas was diagnosed
    in females at 20 and 80 ppm. The recorded incidences were 64.4%,
    63.2%, 76.8% and 93.1% for 0, 5, 20 and 80 ppm groups,
    respectively. An increased incidence of testicular Leydig cell
    tumours was diagnosed at 80 ppm. The recorded incidences were 1.7%,
    8.5%, 5.0% and 16.7% for 0, 5, 20 and 80 ppm, respectively.
    Non-neoplastic lesions observed included an increase in hyperplasia
    of the pars intermedia of the pituitary gland in males at 80 ppm.
    An increased incidence of cystoid change of the pars intermedia of
    the pituitary gland was noted in males at 20 and males and females
    at 80 ppm at 52 weeks. Increased incidences of testicular Leydig
    cell hyperplasia and tubular atrophy were noted in rats at 80 ppm
    after 104 weeks. Increased incidences of hepatic bile duct
    proliferations and portal sclerosis were noted in females at 20 and
    80 ppm after 52 and 104 weeks of treatment. An increased incidence
    of skeletal muscle atrophy was noted in male rats at 80 ppm after
    104 weeks of treatment.  Because mortality was increased in females
    and serum immunoglobulins were decreased at the lowest dose level
    of 5 ppm (equal to 0.3 (males) 0.4 (females) mg/kg bw no NOAEL
    could be established (Tennekes  et al., 1989b).

    Reproduction studies

         In a range-finding study Wistar rats (10/sex/group) were
    administered 0, 12.5, 25, 50, 100 or 200 ppm TPTH (weekly prepared,
    purity not stated) in the diet for in total 90 days (from 59 day
    pre-mating period up to 21 day gestation period). All animals were
    killed following weaning. Observations included clinical signs,
    mortality, body weight, organ weight and food consumption. Parents
    were observed haematologically and histopathologically. Pups were
    sexed, weighed and observed for gross abnormalities. Severe
    clinical signs like rough coat, hunched back, lethargy, nasal
    discharge and alopecia were observed in rats at 200 ppm. At 200 ppm
    body weight gain was significantly reduced in males and food
    consumption was slightly reduced in male and female rats. White
    blood cell count was significantly decreased in high dose females.
    A lower pregnancy rate (4/10) was observed in females at 200 ppm,
    no viable offspring resulted. At 100 ppm pup survival, pupweight
    and litter size (at 50 ppm not significantly) were dose-relatedly
    decreased. At histopathology necrosis of the renal papilla or
    medulla was observed in males at 100 and 200 ppm. One high-dose

    male rat that died after six weeks showed hepatic, thymic and
    testicular necrosis (Carlton & Crisp, 1982).

         In a two-generation reproduction study groups of Wistar
    (Crl:(WI)BR)COBS rats (30/sex/group) were given diets (prepared
    every 5-7 days) containing 0, 0', 5, 18.5 or 50 ppm TPTH (purity
    97.2%) during growth, mating, gestation and lactation for one
    litter per generation. Observations included clinical signs, body
    weight, food consumption, mating performance and reproductive
    parameters. Organ weights (including spleen and thymus) of parents
    and pups were recorded and the parents were examined histologically
    (control group 1 and 50 ppm groups only).  Pups were sexed, and
    examined for gross malformations and the number of stillborn and
    live pups were recorded.

         Body weight gain and food consumption were occasionally
    decreased in F0 parents at 50 ppm. The number of dead F1 pups
    increased and mean litter size decreased at 50 ppm. Mean pup weight
    was decreased at 50 ppm on lactation days 14 and 21. In F0 parents
    the body weight gains and food consumption of both sexes were lower
    at 50 ppm and occasionally at 18.5 ppm. Mean litter size decreased
    at 18.5 and 50 ppm. Viability of F2 pups at 50 ppm, prior to
    culling was slightly decreased. Mean pup weight was decreased at 50
    ppm on lactation days 7, 14 and 21. At 18.5 mg/kg a slight decrease
    was seen. Pups from one litter at 50 ppm appeared emaciated on
    lactation day 21. Several pups in another litter in this group had
    wet yellow urogenital staining on lactation day 21. At 50 ppm the
    relative weights of brain, testes, ovaries, adrenals, kidneys
    spleen and heart were increased at several occasions in F0 and/or
    in F1 adults and/or F1 and F2 weanlings (males and females). At
    18.5 ppm increases were also observed for kidneys, testes and heart
    weights, whereas at 5 ppm only relative heart weight was increased
    in male F1 adults.  A dose-related decrease was observed in spleen
    and thymus weight in F2 male and female weanlings at 50 and 18.5
    ppm.  In F1 weanlings the same trend was observed.  The NOAEL in
    this study is 5 ppm, equal to 0.4 mg/kg bw/day (Young, 1986).

         Two groups of 13 male rats (29 days old) received a diet
    containing 0 or 20 mg TPTA/kg bw for 25 days. Four animals from
    each group were sacrificed on day 21 and the remaining animals
    received the test diet for another 4 days and a control diet for an
    additional 70 days at which time they were sacrificed. Observations
    were made for the distribution of the eight phases of
    spermatogenesis. In rats sacrificed after 21 days all 8
    spermatogenic phases were seen, but there was a general paucity of
    mature sperm and the distribution showed some predominance of
    immature sperm. Recovery was seen after the 70 days control diet
    (Snow & Hays, 1983).

    Special studies on embryotoxicity and/or teratogenicity

    Rat

         Pregnant Sprague-Dawley rats (20/group) received by gavage 0,
    1.25, 5, 8.75 or 12.5 mg/kg TPTH (purity unknown) bw/day, day 6
    through 15 of gestation. The rats were sacrificed on day 20 of
    gestation. Observations were made for body weight, number of
    implantations, number of live and dead fetuses, number of
    resorptions and number of corpora lutea. The fetuses were weighed
    and examined for external, visceral and skeletal abnormalities. 
    Three animals each in the 8.75 and 12 mg/kg groups aborted. Only
    those animals showed abnormal behavioural reaction. One female in
    the 12.5 mg/kg group died. Females at 8.75 and 12.5 mg/kg showed a
    lower food consumption and lower body weight gain (dose-
    relatedly). In the 8.75 and 12.5 mg/kg groups an increase in
    resorptions was observed. Fetuses from these groups also exhibited
    a lower weight and a decrease in viable fetuses. A non dose-related
    increase in hydrocephalus and hydronephrosis was seen in all
    treated groups (2%, 5%, 12%, 16% and 6%, respectively) (Ravert &
    Parke, 1976).

         In a teratogenicity study (Segment II + III) groups of 25
    pregnant Sprague-Dawley rats were given oral daily doses of 0,
    0.35, 1, 2.8 or 8 mg TPTH (purity 97.1%)/kg b.w. in corn oil from
    day 6 or 15 of gestation. All animals were allowed to deliver
    naturally and rear the offspring to weaning on lactation day 21. At
    lactation day 4, 10 pups/litter were selected and killed on the
    28th day. The dams were killed on day 21 of lactation. Dams were
    observed for mortality, clinical signs and body weight. Litters
    were examined for gross malformations and the number of live and
    dead fetuses was recorded. Fetuses were observed for bodyweight and
    examined for haematology, clinical chemistry and urinalysis,
    macroscopy, kidney weight and histopathology of the kidney. Dams at
    8 mg/kg bw showed lethargy, yellow staining in the urogenital area,
    and a more extensive hairloss than dams in the other groups. At the
    same dose group maternal body weight gain was significantly
    decreased (only during treatment) and gestation length was
    significantly increased, and pup survival was decreased on
    lactation day 0. Only LDH values in blood decreased in pups at 1,
    2.8 and 8 mg TPTH/kg bw and ASAT was decreased in females pups at
    all doses. Globulin levels were significantly decreased in female
    pups at 2.8 and 8.0 mg/kg bw and A/G ratio was increased at the
    highest dose. Relative kidney weight in pups was significantly
    increased at 2.8 and 8 mg/kg bw.  The dose of 1 mg/kg bw can be
    regarded as a NOAEL for embryotoxicity (Rodwell, 1985a).

         Twenty to 26 pregnant rats per group received by gavage 0,
    1.0, 2.8 and 8 mg TPTH (purity unknown)/kg bw/day suspended in corn
    oil, day 5 through 19 of gestation. On day 20 all females were
    sacrificed. Uterus weight was determined and corpora lutea were

    counted. Fetuses and resorption sites were noted. Fetuses were
    weighed, sexed and observed for external, internal and skeletal
    malformations. In the 2.8 and 8 mg/kg groups a dose-related nasal
    and oral discharge were observed. In the highest group two animals
    died. Body weight gain was significantly reduced at 8 mg/kg. The
    number of dead or resorbed fetuses was higher at 8 mg/kg. Pup
    weight was depressed in the 8 mg/kg group. The occurrence of
    hydro-ureter was increased at the highest dose (Carlton & Connell,
    1981; Carlton, 1985).

         In order to clarify the occurrence of hydronephrosis,
    hydrocephalus and hydroureter, another rat study was carried out.
    Groups of 45 pregnant rats received 0, 0.35, 1, 2.8 and 8 mg TPTH
    (purity 97.1%)/kg bw/day day 6 through 15 of gestation. Day 20 of
    gestation all rats were sacrificed. Throughout gestation
    observations were made for clinical signs, body weights and food
    consumption. After sacrifice the dams were observed for number and
    location of viable and nonviable fetuses, early and late
    resorptions and the number of implantation sites. The corpora lutea
    were counted. Fetuses were weighed, sexed and examined for
    external, internal and skeletal anomalies. During the treatment
    period, hair loss was more extensive in the 8 mg/kg group. A few
    animals in this group were emaciated, lethargic and had yellow
    staining in the urogenital area. One female in this group had an
    abortion. A dose-related decrease in body weight gain and food
    consumption was apparent in the 2.8 and 8 mg/kg groups. Number of
    nongravid females, number of total litter resorptions and early
    resorptions increased at 8 mg/kg. Number of viable fetuses and
    fetal weight decreased significantly at 8 mg/kg. The incidence of
    absent or delayed ossification in high dosed litters was increased.
    The percentage of fetuses with hydrocephaly was 0.4, 0, 0, 0.4 and
    1%, respectively, and for fetuses with omphalocele 0.2, 0.2, 0.2 0,
    and 0.5%, respectively for the 0, 0.35, 1, 2.8 and 8 mg/kg groups.
    The NOAEL for maternal toxicity was 1 mg/kg bw and the NOAEL for
    embrytoxicity was 2.8 mg/kg bw. There was no evidence for
    TPTH-induced irreversible structural effects (Rodwell, 1985b).

         In a special study consisting of three tests the potential of
    TPTH to induce alterations in the urogenital tract of exposed rat
    fetuses was investigated. In test I pregnant Sprague Dawley rats
    received 0, 4 or 8 mg TPTH (purity unknown)/kg bw by gavage during
    day 7 through 20 of gestation. In test II (a and b) doses of 0 and
    4 mg/kg bw were given. All females from test I and IIa were
    sacrificed on day 21 of gestation. The uteri were removed, weighed,
    and examined to determine the number of live, dead and resorbed
    fetuses. Live fetuses were examined for gross external anomalies.
    In test IIb the animals delivered normally and weaned their young
    for 28 days. In these young animals renal morphology and function
    were examined. At 8 mg/kg bw maternal (death and reduced

    extra-uterine weight gain during pregnancy) and fetal (mortality
    and decreased body weight) toxicity were observed. There was no
    effect on cerebral ventricles. At 4 mg/kg bw only slightly dilated
    renal pelvis was seen and at 4 and 8 mg/kg bw (n.d.r.) dilated
    ureter was observed. In a replicate test (IIa) these effects were
    hardly observed. In test IIb no effects at all where found for the
    renal function or morphology. Only the treated pups only showed a
    lower pup weight (Kavlock, 1985).

         Four groups of 12 pregnant rats (Sprague Dawley) received from
    day 6 through 15 of gestation 0, 5, 10 or 15 mg TPTA (purity
    97.1%)/kg bw/day. Females were sacrificed on day 21 of gestation.
    Dams were observed for number of resorptions, number of
    implantations, post-implantation loss, viable and non viable
    fetuses. Fetuses were weighed and examined for external, visceral
    and skeletal anomalies. Two rats treated with 15 mg/kg died during
    the study and 4 had complete resorptions. Average maternal weight
    gain decreased at 5 mg/kg and significantly 10 and 15 mg/kg.
    Post-implantation loss increased significantly at 15 mg/kg. A
    significant reduction of some ossification centers, mainly at the
    level of the metacarpus and caudal vertebrae, was seen in all
    treated groups. Minor anomalies (hydroureter, vertebrae missing or
    bipartite) increased significantly at 15 mg/kg (Giavini  et al.,
    1980).

         Groups of pregnant rats (Wistar) received during day 7 through
    16 of gravidity 0, 1.25, 3.2 or 8 mg TPTA/kg bw/day. TPTA (purity
    97.0%) was dissolved in sesame oil. The females were sacrificed and
    delivered on day 21 of gestation. The dams were observed for
    clinical signs, body weight, food consumption, number of
    implantations, resorptions and corpora lutea, viable and non viable
    fetuses, organ weights (heart, liver, kidneys and spleen) and
    macroscopy. Fetuses were weighed, and examined for length, sex,
    external, internal and visceral anomalies. Ten dams at 8 mg/kg had
    abortions. Dams at 8 mg/kg showed signs of clinical intolerance as
    piloerection, bloody nose secretion, local hair loss accompanied by
    scab formation. Body weight gain and food consumption were
    decreased in this group. At 8 mg/kg early and total intrauterine
    deaths increased and number of implantations, total live fetuses,
    fetal body weight and crown/rump length decreased. At 8.0 mg/kg an
    increase in fetuses with non ossification or only weak ossification
    of the sternebrae was observed. At 8 mg/kg also an increase (5%) in
    distended uni- or bilateral ureter was observed. The NOAEL in this
    study is 3.2 mg TPTA/kg bw (Baeder, 1987a).

    Hamsters

         Four groups of 20-25 pregnant Syrian hamsters received by
    gavage 0, 2.25, 5.08, or 12 mg TPTH (purity not given)/kg bw in
    0.3% hydroxypropyl cellulose in saline from day 5 through 14.

    Vitamin A palmitate was administered by gavage on day 8. All dams
    were sacrificed on gestation day 15. The weight of the gravid
    uterus was determined and corpora lutea were counted. Fetuses and
    resorption sites were noted. Fetuses were weighed and observed for
    external, visceral and skeletal malformations. Four animals died in
    the highest-dose group and several animals showed an abnormal
    behaviour. In the mid-dose group and in the lowest-dose group 2
    animals died. Hamsters from the highest-dose group showed a
    decreased mean body weight gain and a decreased food consumption.
    Fetuses from this group showed also a decreased pup weight. The
    average number of minor anomalies (such as kinky tail, haematomas
    and anaemic appearance) of fetuses per litter was significantly
    greater among the 12 mg/kg group. A significantly greater number of
    skeletal variations (poorly ossified, missing metatarsals or
    missing sternebrae) was observed among the 12 mg/kg group. Three
    cases of hydrone-phrosis were seen at 5.08 mg/kg bw and 1 case of
    hydrocephalus was seen at 12 mg/kg bw (Carlton & Howard, 1982;
    Carlton, 1985).

    Rabbits

         Three groups of 22 pregnant New Zealand White rabbits received
    by gavage 0, 0.1, 0.3 or 0.9 mg TPTH/kg bw/day mixed in 1% aqueous
    CMC, day 6 through 18 of gestation. Dams were sacrificed day 29 of
    gestation. Observations were made for clinical signs, body weight
    and food consumption.  After sacrifice corpora lutea, early and
    late resorptions and number of implantations were counted. All
    fetuses were weighed, sexed and examined for external, skeletal and
    visceral anomalies and developmental variations. Two rabbits from
    the 0.9 mg/kg group aborted. A dose-related decrease in mean body
    weight gain and food consumption was observed in the 0.3 and 0.9
    mg/kg groups. Mean fetal weight was lower in the 0.9 mg/kg group.
    The NOAEL for maternal toxicity was 0.1 mg/kg bw and the NOAEL for
    embryotoxicity was 0.3 mg/kg bw (Rodwell, 1987).

         TPTA (purity 97.0%) was dissolved in sesame oil and
    administered orally by gavage to groups of 15 pregnant rabbits
    during day 6 through 18 of gestation. The dose levels were 0, 0.1,
    0.32 or 1.0 mg/kg bw/day. On day 29 of gestation the dams were
    sacrificed. Dams were observed for clinical signs, body weights,
    food consumption, number of resorptions, number of implantations,
    number of corpora lutea, viable and non viable tissues, organ
    weights (heart, liver kidney, spleen) and macroscopy. Fetuses were
    weighed and examined for sex, length, external, internal and
    skeletal anomalies. In the 1.0 mg/kg group 1 dam died, 3 dams
    aborted, 1 dam was sacrificed due to a premature delivery and 2
    dams had only intra-uterine deaths. Three dams showed vaginal
    haemorrhages. The water consumption and food consumption of dams at

    1 mg/kg decreased. The number of implantations and of live fetuses
    decreased at 1 mg/kg. Mean fetal weight, mean crown/rump length
    and mean placental weight decreased in pups at 1 mg/kg. At 1 mg/kg
    4 pups (15.4%) showed omphalocele with protrusion of intestinal
    coils or liver tissue. Slight retardation of skeletal ossification
    was detected in the 1.0 mg/kg group. There was an increase in the
    number of fetuses with fewer than 13 ossified caudal vertebrae and
    some fetuses showed weak ossification of the hyoid bone or non
    ossification or only slight ossification of the  os pubis. The
    NOAEL for maternal and embryotoxicity in this study is 0.32 mg/kg
    bw/day (Baeder, 1987b).

    Special studies on immunotoxicity

         Seinen and Penninks (1987) reviewed the available data on
    immunotoxic properties of TPTH from the published literature and
    confidential studies provided by the manufacturer.  They concluded
    that subacute treatment with TPTH resulted in lymphopenia and
    lymphocyte depletion of spleen and thymus. After treatment up to 13
    weeks these effects appeared to be transient. Rats fed 25 ppm TPTH
    (not 5 ppm) showed cell mediated immunity as measured by slightly
    suppressed DTH (delayed type hypersensitivity) to ovalbumin and
    tuberculin. The humoral immunity was not affected at doses up to 25
    ppm. However in mice dosed with TPTH up to 20 mg/kg bw for 14 days
    DTH response to keyhole limpet haemocyanin was not affected,
    whereas the humural activity was suppressed at 20 mg/kg bw. In
    various other immune function tests no disturbances were observed. 
    The authors concluded therefore that TPT-compounds display weak
    immunosuppressive potential. This immunosuppressive activity is
    observed at dose levels that markedly reduce the numbers of blood
    lymphocytes and the weight of the lymphoid organs (Seinen &
    Penninks, 1987).  The original data for certain studies in this
    review were not available to the JMPR.

    Mice

         In a limited experiment young and mature mice were fed a diet
    containing TPTA (purity >99%) at a rate of 30, 100 or 300 ppm for
    4 days. Feeding resulted in a dose-related decrease in spleen,
    heart and liver weight and number of blood leucocytes (Ishaaya
     et al., 1976; Seinen & Penninks, 1987).

         Groups of B6C3F1/CrlBR mice (18/sex/group) were administered
    0, 1, 5, 25, 50 or 125 ppm TPTH (purity 96.4%) for 28 days.  A
    positive control group (18/sex) was fed control diet and received
    a single i.p. injection of 180 mg cyclophosphamide/kg bw 48 hours
    prior to the end of the treatment period.  Twelve male and 12
    female mice were killed at day 29 and the remaining mice were

    returned to control diets and were killed on day 57.  Observations
    were made on survival and clinical signs, body weight, food
    consumption, haematology, liver, spleen, and thymus weight,
    macroscopy and histopathology. Special immunotoxicological
    parameters as splenocyte counts, thymocyte counts, number of
    splenic T- and B-cells and basal serum immunoglobulin levels were
    recorded and the bone marrow was examined. 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 250 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 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. No
    dose-related effects were observed on any of the bone marrow
    parameters (note: only 50% of the smears could be evaluated,
    because of technical problems). The main haematological effects
    were a decrease in total white blood cells, neutrophils and
    lymphocytes at 50 and 125 ppm in males and females.  Dose-related
    changes in haematological parameters were observed in males at 25,
    50 and 125 ppm and in females in all dose levels (MCH and MCHC). At
    the highest dose a decrease in total cells/spleen  and splenic
    B-cells were observed and a decrease in total cells/thymus and
    splenic T-cells were seen in males. IgM levels were decreased in
    females at 25 ppm and higher, but were not clearly dose-related.
    All effects were reversible. Mice fed cyclophosphamide showed
    decreased spleen and thymus weight accompanied by histologic
    evidence of lymphoid depletion. Cyclophosphamide also altered the
    % T- and % B-cells in both sexes and reduced the spleen and thymus
    cellularity. The effects were not reversible. The NOAEL for
    immunotoxicity is 5 ppm, equal to 1 mg/kg bw for males and 1.15 for
    females (McCormick & Thomas, 1990a).

    Rats

         A similar study was conducted in 18 male and 18 female Wistar
    rats. A positive control group was fed a diet containing 125 mg
    DOTDC (dioctyltin-dichloride)/kg. No effects were observed on
    mortality, clinical signs, body weight, organ weight, macroscopy.
    Food consumption was decreased in female rats at 125 ppm. No
    dose-related effects were seen at histopathology (note only 50% of
    the bone marrow smears could be used in the histopathological
    evaluation). In both males and females red blood cell parameters
    were affected at the highest groups. The white blood cells and
    lymphocytes were significantly decreased in males at 125 ppm and
    females showed a tendency to a decrease at 50 and 125 ppm. In male
    rats at 50 and 25 ppm platelet count was increased. No effect was
    observed on the viability of the thymus or spleen cells nor on the

    percentages of splenic T- and B-cells in either sex. IgG levels
    were significantly reduced in females at 50 and 125 ppm. All
    effects were reversible. The effects in the positive control group
    were as expected. These effects were largely reversible following
    cessation of DOTDC exposure. The NOAEL for immunotoxicity is 25 ppm
    equal to 1.82 mg/kg bw for females and 1.71 mg/kg bw for males
    (McCormick & Thomas 1990b).

         In order to investigate the reaction of rats to infection with
     Trichinella spiralis female rats were administered 2.5 mg TPTH
    (purity 97.2%)/kg bw over a 10 day period. This administration had
    no effect on host resistance in contrast to the positive controls
    dexamethasone and cyclophosphamide. There are also no effects on
    additional parameters, i.e., thymus weights, percentage of
    lymphocytes in the differential blood count, and body weight gains
    (Diehl & Leist, 1987b).

    Special studies on genotoxicity

         TPTH as well as TPTA were tested in various genotoxicity
    assays. See Tables 3 and 4 respectively, for a summary of the
    studies considered. In most of the assays negative results were
    obtained. The positive results in the chromosome aberration assays
    are probably related to the toxic effect of the compound on
    T-lymphocytes and not to a genotoxic action of TPTH.

    Special studies on sensitization

         At concentrations which were irritant to the skin, TPTH
    (purity 97.0%) showed no skin sensitization in guinea-pigs in the
    Buehler test (Leist & Weigand, 1981f; Schollmeier & Leist, 1989)
    nor in the maximization test (Diehl & Leist, 1987a).

         TPTA gave a positive response when tested for skin
    sensitization in guinea-pigs in the Buehler test (Diehl & Leist,
    1986e).


        Table 3.  Results of genotoxicity assays on TPTH

                                                                                                                                

    Test system           Test object            Concentration of           Purity    Results     Reference
                                                       TPTH                   (%)
                                                                                                                                

    Ames test a,b         S. typhimurium         0.31-5 µg/pl                97.0     Negative    Richold et al. (1981)
                          TA 1535, TA100,        in DMSO
                          TA1537, TA98,
                          TA1538

                          E. coli WP2 uvra       313-5000 µg/pl              97.0     Negative
                                                 in DMSO

    Yeast forward         S. pombe p1            0.05-1 µg/ml                97.2     Negative    Milone & Hirsch (1985b)
    mutation test                                in DMSOa

    Mitotic gene          Saccharomyces          0.1, 1, 3 or                97.2     Negativec   Milone & Hirsch (1985a)
    conversion assay      cerevisiae D4          5 µg/mla
                                                 1, 5, 10 or
                                                 15 µg/mlb

    Mouse lymphoma        L5178Y mouse           10-150 ng/mla               97.2     Negative    DenBoer & Hoorn (1985)
    forward mutation      lymphoma cells         (>80 ng/ml toxic)                    Weakly
    assay (TK +/-)                               40-600 ng/mlb                        positive
                                                 (>300 ng/ml toxic)

    Mouse lymphoma        L5178Y mouse           0.01-2 µg/1a                  ?      Positive    NCI (1984)
    forward mutation      lymphoma cells         (>0.1 toxic)                         Negative
    assay (TK +/-)                               1.7-8 µg/1b

    Chromosome            Human lymphocytes      31.25-1000 ng/mla                    Positive    Kirkland (1985)
    aberration assay                             250-2000 ng/mlb
                                                 both in DMSO
                                                                                                                                

    Table 3 (contd).

                                                                                                                                

    Test system           Test object            Concentration of           Purity    Results     Reference
                                                       TPTH                   (%)
                                                                                                                                

    Chromosome            Human lymphocytes      0.681-1.47 µg/mla           96.2     Negative    Nunziata & Conzonni (1988)
    aberration assay                             in DMSO                              Positive
                                                 0.316-1.47 µg/mlb
                                                 in DMSO

    Unscheduled           Rat hepatocytes        0.01-2.0 µg/ml in DMSO      97.2    Negativec    Cifone & Myhr (1985)
    DNA synthesis                                >0.25 µg/ml toxic

    Survival (cell        Rat embryo cells       0.019 µg/5.2 x 104 cells      ?     Positived    Traul et al. (1981)
    transformation)       infected with          or 0.0145 µg/5.2 x 104
    assay                 leukaemia virus
                          (2FR450 cells)

    Micronucleus test     NMRI mouse bone        35, 70 or 140 mg/kg bw po   97.2    Negative     Banduhn et al. (1985)
    NMRI                  marrow cells

    Cytogenic assay       Chinese hamster bone   20, 50 or 80 mg/kg bw po    96.2    Negative     Mueller (1987)
                          marrow cells
                                                                                                                                

    Table 3 (contd).

                                                                                                                                

    Test system           Test object            Concentration of           Purity    Results     Reference
                                                       TPTH                   (%)
                                                                                                                                

    Dominant lethal       Sprague-Dawley rats    daily ip injections         94.8     Negative    Ravert et al. (1978)
    assay                                        with 3, 20, 38
                                                 or 150 mg/kg bw in
                                                 corn oil; 150 mg/kg
                                                 bw toxic (8/10
                                                 died). Concentration
                                                 of TPTA
                                                                                                                                

    a  without metabolic activation
    b  with metabolic activation
    c  positive control yielded positive results
    d  only summary available

    Table 4.  Results of genotoxicity assays on TPTA

                                                                                                                                

    Test system           Test object            Concentration of           Purity    Results     Reference
                                                       TPTA                   (%)
                                                                                                                                

    Ames testa,b          S. typhimurium         0.032-1000 µg/plate         97.1     Negative    Jung & Weigand (1986)
                          TA100, TA1535,         in DMSO
                          TA1537, TA1538,
                          TA98
                          E. coli WP2 uvra

    Gene conversiona,b    S. cerevisiae D4       1-50 µg/ml in DMSO          97.1     Negative    Milone & Hirsch (1986a)

    Dominant              Sprague-Dawley rats    daily i.p. injections       94.8     Negative    Ravert et al. (1978)
    lethal assay                                 with 3, 20, 38 or
                                                 150 mg/kg bw in corn oil;
                                                 150 mg/kg bw toxic (8/10
                                                 died)).  Concentration of
                                                 TPTA
                                                                                                                                

    a  without metabolic activation
    b  with metabolic activation
    

    Special studies on skin and eye irritation

         A dose of 500 mg TPTH (purity not stated) diluted in a 0.9%
    NaCl solution was slightly irritant when applied under occlusive
    conditions to the shaven intact and shaven abraded skin of 6 New
    Zealand rabbits for 24 hours (Leist & Weigand, 1981e).

         Dilutions of 1:10, 1:100 and 1:1000 prepared from 2.5 g TPTA
    (purity not stated) in 0.9% NaCl were examined in the Barail
    Intracutaneous test by intracutaneous injections of 0.02 ml
    administered to the skin of rabbits. No irritation was seen. Five
    applications of 0.5 ml of the TPTA solution to depilated and intact
    rabbits skin caused slight local irritation. (Summary only)
    (Hollander & Weigand, 1974e).

         A dose of 500 mg TPTA (purity 97%) moistened with
    physiological saline was applied under semi-occlusive conditions to
    the shaven intact skin of 6 New Zealand rabbits for 54 hours. No
    irritation was observed up to 72 hours after application (Diehl &
    Leist, 1986c).

         Application of 100 mg TPTH (purity not stated) diluted in a
    0.9% NaCl-solution into the eyes of 9 New Zealand rabbits caused
    severe irritation; increasing adverse effects resulted in a
    discontinuation of the experiment after 72 hours (Leist & Weigand,
    1981e).

         Rabbits received an instillation of 0.1 ml of a solution of
    2.5 g TPTA (purity not stated) in 0.9% NaCl into one eye. After 24
    hours slight local irritation was observed (Summary only)
    (Hollander & Weigand, 1974e).

         Nine New Zealand rabbits received an instillation of 100 mg
    TPTA (purity 97%) into one eye. All rabbits developed severe ocular
    lesions (swollen conjunctivae, markedly injected blood vessels,
    diffusely crimson red colouring, nacreous opacity and whitish and
    reddish brown discharge). After 72 hours all animals were
    sacrificed because the lesions were non-reversible (Diehl & Leist,
    1986d).

    Observations in humans

         Two cases of poisoning with Brestan 60 (60% TPTA and 15%
    Maneb) have been reported. In both cases (farmers of 75 and 53
    years) inhalation of the powder took probably place during
    preparation of the spray solution. Symptoms observed were nausea,
    dizziness, transient loss of consciousness, convulsions, persistent
    headache, and photophobia, as well as impaired liver functions.
    Both patients were discharged in good health after 10 and 15 days
    (Manzo & Richelmi, 1981).

         Acute severe intoxication was reported in a 23-year old male
    in an attempted suicide with a TPT-compound (molluscicidal agent,
    no specifications given). The patient was suffering from abdominal
    pains, diarrhoea and vomiting and also showed reversible acute or
    delayed neurological symptoms. The patient's health was completely
    recovered within 3 1/2 months (Wu  et al., 1990).

    COMMENTS

         Most toxicological studies on fentin were carried out with
    triphenyltin hydroxide (TPTH). Since triphenyltin acetate (TPTA) is
    hydrolysed rapidly to TPTH in an aqueous medium, studies with both
    compounds have been used for the evaluation of fentin.

         After oral administration of 14C-labelled TPTH the
    radioactivity was mainly eliminated via the faeces (50-70%), but
    also via the urine (20-25%). Biliary excretion was also
    demonstrated. After 7 days residual radioactivity was present with
    the highest concentration in the liver and the next highest in the
    kidneys. After oral administration of 113Sn-labelled TPTH,
    elimination was almost exclusively via faeces. In both cases faecal
    elimination was biphasic with half-lives of 9 and 50-60 hours. With
    113Sn-labelled TPTH the highest concentration was found in the
    kidneys. After administration of the 14C-labelled compound,
    radioactivity in the faeces of the rat consisted of parent compound
    and di- and monophenyltin as well as non-extractable bound residues
    and tin (measured as Sn). It was reported that benzene was found in
    the faeces.  Sulfate conjugates of phenol, hydroquinone, catechol
    and resorcinol as well as phenylmercapturic acid were present in
    the urine. Phenyltin compounds were not found in the urine.

         TPTH is toxic to rats after acute oral administration with
    LD50 values of about 160 mg/kg bw.  TPTA showed similar acute
    toxicity.

         In a 3-month study in mice at dietary concentrations of TPTH
    of 0, 4, 20 or 100 ppm, a number of effects were observed at 100
    ppm.  The main effects were a decrease in haemoglobin concentration
    and erythrocyte count and an increase in Heinz bodies. 
    Immunoglobulins were decreased and liver weight was increased.  The
    NOAEL was 20 ppm, equal to 3.4 and 4.1 mg/kg bw/day for males and
    females, respectively.

         Dietary concentrations of TPTH of 0, 4, 20 or 100 ppm were
    tested in a 13-week study in rats.  The NOAEL was 4 ppm, equal to
    0.30 and 0.35 mg/kg bw/day for males and females respectively,
    based on a decrease in white blood cells and plasma albumin and an
    increase in plasma aspartate aminotransferase at 20 ppm.

         In a 52-week study in dogs (dietary concentrations of TPTH of
    0, 2, 6 or 18 ppm) the NOAEL was 6 ppm, equal to 0.2 mg/kg bw/day,
    based on a decreased albumin level and an increase in relative
    liver weight at 18 ppm.

         Two long-term/carcinogenicity studies in mice and one in rats
    were performed in which there was no evidence of carcinogenicity.
    However, there were indications in each of these studies that the

    doses received by the animals may have been lower than intended
    owing to instability of the test compound in the diet.

         In a third long-term/carcinogenicity study in mice at dietary
    concentrations of TPTH of 0, 5, 20 or 80 ppm, increased liver and
    decreased kidney weights, increased nodular hyperplasia and
    hepatocellular adenoma and carcinoma occurred at 80 ppm only.  The
    NOAEL was 5 ppm, equal to 0.85 mg/kg bw/day for males and 1.36
    mg/kg bw/day for females, based on decreased body-weight gain at 20
    ppm.

         In a second long-term/carcinogenicity study in rats (with
    dietary concentrations of TPTH of 0, 5, 20 or 80 ppm), an increase
    in mortality was observed at all dose levels.  A  NOAEL could not
    be established at the lowest concentration of 5 ppm, equal to 0.3
    and 0.4 mg/kg bw/day for males and females respectively.  The
    incidence of pituitary adenomas was increased in females at 20 and
    80 ppm.  At 80 ppm, the incidence of Leydig cell tumours was
    increased.  These changes were accompanied by non-neoplastic
    lesions in the pituitary and the testes.

         In a 2-generation reproduction study in rats with one litter
    per generation (dietary concentrations of TPTH of 0, 5, 18.5 or 50
    ppm) fertility was not affected.  The NOAEL was 5 ppm (equal to 0.4
    mg/kg bw/day) based on decreased litter size, decreased pup weight
    and decreased relative spleen and thymus weight in the weanlings.

         In several teratogenicity studies with rats, hamsters, and
    rabbits, TPTA or TPTH caused maternal and embryo toxicity, but
    irreversible structural effects were not observed.  In rabbits, the
    most sensitive species, the NOAEL for embryo/fetotoxicity was 0.3
    mg/kg bw/day in a study that utilized doses of 0, 0.1, 0.3 or 0.9
    mg/kg bw/day TPTA. In this study the NOAEL for maternal toxicity
    was 0.1 mg/kg bw/day.

         Most  in vitro and  in vivo genotoxicity tests were
    negative.  However, two human lymphocyte chromosomal aberration
    assays and two mouse lymphoma mutation assays were positive.  The
    latter responses may have been caused by a variety of effects,
    including chromosomal aberrations.  Since two  in vivo studies for
    chromosomal aberrations (a micronucleus test in mice and a
    cytogenetic test in Chinese hamsters) were negative, it would
    appear that any genotoxic properties are of low potency.  It was
    therefore concluded that fentin does not present a genotoxic hazard
    for man.

         Effects on the immune system were observed in short- as well
    as in long-term toxicity studies. In special studies with mice and
    rats, TPTH showed immunosuppressive properties (lymphopenia and
    lymphocyte depletion of spleen and thymus), resulting in altered
    humoral and cellular immunity.  The NOAEL in mice was 5 ppm, equal

    to 1 mg/kg bw/day, based on a decrease in splenic weight  found at
    25 ppm.  In rats, the NOAEL was 25 ppm, equal to 1.7 and 1.8 mg/kg
    bw/day for males and females respectively, based upon a significant
    decrease in immunoglobulin G and a marginal decrease in leucocyte
    and lymphocyte counts at 50 ppm.

         The Meeting noted that there was increased mortality at the
    lowest dose tested in the most recent long-term study in rats (0.3
    mg/kg bw/day).  Applying a 500-fold safety factor to this LOAEL
    would result in approximately the same ADI as the previously
    established ADI based upon a NOAEL of 0.1 mg/kg bw/day in an
    earlier long-term study in rats.  The previous ADI was therefore
    retained.  This ADI is supported by NOAELs derived from recent
    studies, including the NOAEL of 0.4 mg/kg bw/day in the
    2-generation reproduction study, the NOAELs in short-term studies
    in rats (0.3 mg/kg bw/day) and dogs (0.2 mg/kg bw/day) and in a
    teratology study in rabbits (0.1 mg/kg bw/day for maternal
    toxicity).

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    5 ppm in the diet, equal to 1 mg/kg bw/day
         Rat:      <5 ppm in the diet, equal to <0.3 mg/kg bw/day
                   (long-term/carcinogenicity study)
                   5 ppm in the diet, equal to 0.4 mg/kg bw/day
                   (multigeneration reproduction study)
         Dog:      6 ppm, equal to 0.2 mg/kg bw/day
         Rabbit:   0.1 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.0005 mg/kg bw

    Studies which will provide information valuable in the
    continued evaluation of the compound

    1.   Ongoing studies on the endocrinological effects of fentin

    2.   Observations in humans.

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    Laboratory for mutagenicity testing. Submitted to WHO by Hoechst
    AG., Frankfurt-am-Main.

    Jung, R. & Weigand, W. (1986) Fentin acetate - substance technical,
    Code: Hoe 002782 OF ZD97 0002. Study of the mutagenic potential in
    strains of  Salmonella typhimurium (Ames test) and  Escherichia
     coli. Unpublished Report 86.0042 (A33021) of Hoechst Pharma
    Research Toxicology. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Kavlock, R.J. (1985) Triphenyltin hydroxide developmental
    toxicology study. Unpublished Report of United States Environmental
    Protection Agency (A31424). Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Kellner, H.M. & Eckert, H.G. (1986) Kinetics in the rats following
    single and repeated administration of 2 mg/kg and single
    administration of 10 mg/kg body weight. Unpublished Report
    01-L42-0489-86 (A34186) of Hoechst Radiochemisches Laboratorium.
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Kellner, H.M. & Eckert, H.G. (1989) Addendum to report
    01-L42-0565-89. Hoe 029664 (TPTH)-113Sn. Accumulation and depletion
    study in rats after single and repeated oral administration of 2
    mg/kg body weight. Unpublished Report 01-L42-582-90 (A43434) of

    Pharma Forschung GB-L Radiochemisches Laboratorium Hoechst,
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Kellner, H.M., Eckert, H.G. & Bürkle, W.L. (1989) Hoe 029664
    (TPTH)-113Sn. Absorption studies in rats with bile fistula after
    a single oral dose of approx. 2 mg/kg body weight. Unpublished
    Report 01-L42-0564-89 (A41409) of Hoechst Pharma Foreschung
    Radiochemisches Laboratorium Productent-wicklung GB-C, Submitted to
    WHO by Hoechst AG., Frankfurt-am-Main.

    Kirkland, D.J. (1985) Study to evaluate the chromosome damaging
    potential of HOE 029664 - substance technical by its effects on
    cultured human lymphocytes using an  in vitro cytogenetics assay.
    Unpublished Report A31614 from Microtest Research Limited, UK.
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Lachmann, G. & Siegemund, B. (1987) Exhalation experiment with
    triphenyltinhydroxide (Hoe 029664) in rats. Unpublished Report
    (A34601) of Battelle-Institute. V., Frankfurt-am-Main. Submitted to
    WHO by Hoechst AG., Frankfurt-am-Main.

    Laveglia, J., Hagen, C.A. & Nemec, M.D. (1985)  21-Day dermal
    toxicity study in rats with triphenyltin hydroxide (Code: Hoe
    029664 OF ZD97 0001 technical substance). Unpublished Final Report
    (A31616) project no WIL-39018 from American Hoechst Company, New
    Jersey. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Leist, K.H. (1988) Fentin acetate-substance technical (Code HOE
    002782 OF ZD97 0002). Repeated dose dermal toxicity study (21
    applications in 29 days) with a 14 day withdrawal period.
    Unpublished Report (A39231) 3104 TSR of Pharma Forschung
    Toxicologie und Pathologie. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981a) Acute oral toxicity of HOE 29664
    - Active ingredient (Code: HOE 29664 O F AT201) to the male rat.
    Unpublished Report (A22115) no 182/81 from Hoechst Pharma Forschung
    Toxikologie. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981b) Acute oral toxicity of HOE 29664
    - Active ingredient (Code: HOE 19664 O F AT201) to the female rat.
    Unpublished Report (A22114) 183/81 from Hoechst Pharma Forschung
    Toxikologie. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981c) Acute percutaneous toxicity of
    HOE 29664 -active ingredient (Code: HOE 29664 O F AT201) to the
    female rat. Unpublished Report (A22292) 184/81 from Hoechst Pharma
    Forschung Toxikologie. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981d) Acute percutaneous toxicity of
    HOE 29664 -active ingredient (Code: HOE 29664 OF AT201) to the male
    rabbit. Unpublished Report (A22112) 229/81 from Hoechst Pharma
    Forschung Toxicologie. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981e) HOE 29664 - active ingredient
    (Code: HOE 29664 O F AT201). Irritance to the rabbit skin and eye
    mucosa. Unpublished Report (A22113) 104/81 from Hoechst Pharma
    Forschung Toxikologie. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Leist, K.H. & Weigand, W. (1981f) Test for sensitizing properties
    of Fentin hydroxide-technical (Code : HOE 29664 O F AT201) in
    guinea-pig (according to Buehler). Unpublished Report (A22433)
    724/81 from Hoechst Pharma Forschung Toxicologie. Submitted to WHO
    by Hoechst AG., Frankfurt-am-Main.

    Leist, K.H., Weigand, W. & Kramer, Dr. (1982) Range-finding test
    von Hoe 29664-Wirkstoff (Fentinhydroxid) (Code: Hoe 29664 O F
    AT201) im 30-Tage-Fuetterungsversuch and SPF-Wistar-Ratten.
    Unpublished Report (A24003) 426/82 from Hoechst Pharma Forschung
    Toxikologie. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Loquet, C.(1985) Fentin acetate (Code: Hoe 002782 OF ZD97 0001)
    Micronucleus test in mice. Unpublished Report 1592 MAS (A32196) of
    Centre International de Toxicologie at Misery. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    MacCormick, D.L. & Thomas, P.T. (1990a) 28-Day oral diet
    immunotoxicity study of triphenyltin hydroxide (TPTH) substance
    technical (Code HOE 029664 OFZD97 0004) in mice. Unpublished Report
    L08252SN01 (A44053) of Life Science Research. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    MacCormick, D.L. & Thomas, P.T. (1990b) 28-Day oral diet
    immunotoxicity study of triphenyltin hydroxide (TPTH), substance
    technical (Code HOE 029664 OFZD97 0004) in rats. Unpublished Report
    L08252SN02 (A44054) of Life Science Research. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Manzo, L. & Richelmi, P. (1981) Poisoning by triphenyltin acetate.
    Report of two cases and determination of tin in blood and urine by
    neutron activation analysis.  Clinical Toxicology, 18(11)
    1343-1353. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.
    (A44030)

    Milone, M.F. & Hirsch, E. (1985a). Study of the capacity of the
    test article HOE 029664 - Substance technical grade - (Code No. HOE
    029664 OF ZD97 0004) to induce gene conversion in  saccharomyces
     cerevisiae. Unpublished Report (A32085) experiment no.M 890 from

    RBM, Ivrea, Italy. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Milone, M.F. & Hirsch, E. (1985b) Study of the capacity of the test
    article HOE 029664 - Substance technical grade (Code HOE 029664 OF
    ZD97 0004) to induce gene mutation in  Schizosaccharomyces pombe.
    Unpublished Report (A31613) from RBM Italy. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Milone, M.F. & Hirsch, E. (1986a) Study of the capacity of the
    article fentin-acetate-substance technical grade (Code No. Hoe
    002782 OF ZD97 0002) to induce gene conversion in  Saccharomyces
     cerevisiae. Unpublished Report M1023/1-2 (A34018) of Instituto di
    Ricerche Biomedische 'Antoine Marxer'. Submitted to WHO by Hoechst
    AG., Frankfurt-am-Main.

    Milone, M.F. & Hirsch, E. (1986b) Fentin acetate substance
    technical grade. Forward Mutation test in  S. pombe P1.
    Unpublished Report M898 (A32812) of Instituto di Ricerche
    Biomedische 'Antoine Marxer'. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Mueller, W. (1987) Evaluation of HOE 029664 OF ZD97 0004 in the
     in vivo cytogenetic test in bone marrow cells of the Chinese
    hamster - chromosome analysis. Unpublished Report 87.0031 (A36080)
    from Hoechst Pharma research Toxicology and Pathology. Submitted to
    WHO by Hoechst AG., Frankfurt-am-Main.

    Nagamatsu, K., Kido, Y., Urakubo, G., Aida, Y., Ikeda, Y. & Suzuki,
    Y. (1978) Absorption, distribution and excretion of triphenyltin
    acetate and stannic chloride in the guinea pig.  Japanese Journal
     of Hygiene, 33: 486-496.

    NCI (1984) Mouse lymphoma with triphenyltin hydroxide. Unpublished
    Report (A30130), National Cancer Institute. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    NTP (1978) Bioassay of triphenyltin hydroxide for possible
    carcinogenicity. CAS no. 76-87-9 (A199994). Technical report series
    No.139. US Department of Health, Education, and Welfare.

    Nunziata, A. & Consonni, R.F. (1988) Chromosome aberrations in
    human lymphocytes cultured  in vitro. Test substance: HOE 029664
    Fentin hydroxide substance technical (Code: Hoe 029664 OF ZD97
    0004). Unpublished Final Report 157024-M-04487 (A38456) from Life
    Science Research Roma Toxicology Centre S.P.A.  Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Ravert, J. & Parke, G.S.E. (1976) Investigation of teratogenic and
    toxic potential of technical triphenyltinhydroxide (lot #SWRAM-1K).

    Unpublished Report GT85.0797 (31618) of Cannon Laboratories, Inc.
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Ravert, J., Parke, G.S. & Charles, S.J. (1978) The dominant lethal
    assay of technical TPTH (Triphenyltin hydroxide) in Sprague-Dawley
    rats. Unpublished Report (A24394) from Cannon Laboratories Inc.,
    Reading. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Resnis, P., Craine, E.M. & Nemec, M.D. (1986) A dermal absorption
    study in rats with 14C-triphenyltin hydroxide. Unpublished Report
    (WIL-39020) (32810) of WIL Research Laboratories. A subsidiary of
    Great Lakes Chemical Corporation, Ashland. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Richold, M., Jones, E. & Fleming, P.M. (1981) Ames metabolic
    activation test to assess the potential mutagenic effect of HOE
    29664 OF AT201. Unpublished Report 450/81A (A21735) from Huntingdon
    Research Centre, GBR. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Rodwell, D.E. (1985a) One generation teratology and reproductive
    study in rats with triphenyltin hydroxide (Code: HOE 029664 OF ZD97
    0001 Technical substance). Unpublished Final Report project
    WIL-39013 (A31617) from Wil Research Laboratories Inc., Ashland
    USA. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Rodwell, D.E. (1985b) A teratology study in rats with triphenyltin
    hydroxide (Code: HOE 029664 OF ZD97 0001 Technical Substance).
    Unpublished Report  WIL-39011 (A31079) of WIL Research Laboratories
    Inc, Ashland USA. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Rodwell, D.E. (1987) An embryotoxicity study in rabbits with
    triphenyltin hydroxide (Code: HOE 209664 OF ZD97 0004). Unpublished
    Report WIL-39012 (A35220) of WIL Research Laboratories, Ashland.
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Sachsse, K., Frei, T., Luetkemeier, H., Vogel, W., Pappritz, G. &
    Terrier, C. (1987) TPTH - Substance technical (Hoe 029664 OF ZD 97
    0004) Chronic oral toxicity 52-week deeding study in beagle dogs.
    Unpublished Report 047013/047024 (A35733) of RCC Research and
    Consulting Company AG, Itingen, Switzerland. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Schollmeier, U. & Leist, K.H. (1989) Triphenyltin hydroxide -
    active ingredient technical (Code: Hoe 029664 OF ZD97 0004).
    Testing for sensitising properties in the Pirbright-White guinea
    pig according to the technique of Buehler. Unpublished Report
    89.1006 (A42667) of Pharma Research Toxicology and Pathology,
    Hoechst AG. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Scholz & Weigand, W., (1969b) Triphenyltin acetate Study No. 2116.
    Unpublished Data A37396 from Laboratory for Industrial and Drug
    Toxicology. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Seinen, W. & Penninks, A.H. (1987) Immunotoxicity of triphenyltin
    compounds. Department pharmacology, pharmacy and toxicity. Faculty
    of Veterinary Sciences, University of Utrecht, The Netherlands.
    Document A35456. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Snow, R.L. & Hays, R.L. (1983) Phasic distribution of seminiferous
    tubulus in rats treated with triphenyltin compounds.  Bull.
     Environ. Contam. Toxicol. 31: 658-665. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    Suter, P. & Horst, K. (1986a) 13-week oral toxicity (feeding) study
    with TPTH-technical (code: HOE 029664 OF ZD97 0004 in the mouse.
    Unpublished Report project 046991 (A32420) from RCC, Itingen,
    Switzerland. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Suter, P. & Horst, K. (1986b) 13-week oral toxicity (feeding) study
    with TPTH-technical (Code : HOE 029664 OF ZD97 0004) in the rat.
    Unpublished Report  project 046978 (A32419) from RCC, Itingen,
    Switzerland. Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Tennekes, H., Horst, K., Luetkemeier, H., Vogel, W., Vogel, O.,
    Armstrong, J., Ehlers, H.A., Müller, E. & Terrier, Ch. (1989a)
    TPTH-technical (Code: HOE 029664 OF ZD97 0004) oncogenicity 80-week
    feeding study in mice. Unpublished Report 047002 (A40467) of RCC,
    Research and Consulting Company AG., Itingen, Switzerland.
    Submitted to WHO by Hoechst AG., Frankfurt-am-Main.

    Tennekes, H., Horst, K., Luetkemeier, H., Vogel, W., Schlotke, B.,
    Vogel, O., Ehlers, H.A., Mueller, E. & Terrier, Ch. (1989b)
    TPTH-technical (Code: HOE 029664 OF ZD97 0007) chronic
    toxicity/oncogenicity 104-week feeding study in rats. Unpublished
    Report 046980 (A40468) of RCC, Research and Consulting Company AG.,
    Itingen, Switzerland. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Terrel, Y & Reddy, A.K. (1978) Report: 18-month carcinogenicity
    study of technical TPTH 96.3% lot no. SWRAM-1K in CD1 mice.
    Unpublished Report project 6E-725 (A26239) from Cannon
    Laboratories, Inc. Reading. Submitted to WHO by Hoechst AG.,
    Frankfurt-am-Main.

    Traul, K.A., Takayama, K., Kachevsky, V., Hink, R.J. & Wolff, J.S.
    (1981) A rapid  in vitro assay for carcinogenicity of chemical
    substances in mammalian cells utilizing an attachment-independence
    endpoint.  J. Appl. Toxicol. 1(3), 190-195.

    Ueda, K. & Iijima, K. (1961) Acute toxicity of Brestan Technical
    (Triphenyltin Acetate) for mice. Unpublished Report A15046 from
    Laboratory of Hygienics, Tokyo Dental College, Japan. Submitted to
    WHO by Hoechst AG., Frankfurt-am-Main.

    Wu, R,M., Chang, Y.C. & Chiu, H.C. (1990) Acute triphenyltin
    intoxication: a case report.  J. Neurol. Neurosurg. Psych., 53,
    356-357.

    Young, D.L. (1986) A dietary two-generation reproduction study in
    rats with triphenyltin hydroxide (Code: HOE 0.29664 OF ZD97 0004
    technical substance). Final Report project WIL-39022 (A35378) from
    WIL research laboratories, Inc. Ashland USA. Submitted to WHO by
    Hoechst AG., Frankfurt-am-Main.

    See Also:
       Toxicological Abbreviations