IPCS INCHEM Home

    CYHEXATIN: Addendum

    First draft prepared by
    A. Moretto
    Institute of Occupational Medicine,
    University of Padua, Padua, Italy

         Explanation
         Evaluation for acceptable daily intake
              Biochemical aspects
                   Absorption, distribution and excretion
              Toxicological studies
                   Acute toxicity
                   Reproductive toxicity
                   Embryotoxicity and teratogenicity
              Observations in humans
              Comments
              Toxicological evaluation
         References

    Explanation

         The toxicological data on cyhexatin (tricyclohexyltin
    hydroxide) were reviewed by the Joint Meeting in 1970, 1973, 1978,
    1980, 1981, 1988, 1989 and 1991 (Annex I, references 14, 20, 30, 34,
    36, 53, 56 and 62). The 1991 Meeting reviewed draft reports of
    several toxicokinetic studies with both technical and micronized
    cyhexatin and of a multigeneration study in rats; final reports of a
    teratogenicity study in rabbits and a multigeneration study in rats
    were also reviewed. An ADI was established at 0-0.001 mg/kg bw on
    the basis of the multigeneration study in rats. The 1991 Meeting
    recommended that cyhexatin be reviewed again in 1994 when the
    following additional information would become available: (i)
    observations in humans; (ii) clarification of the influence of
    particle size on the toxicokinetics and toxicity of cyhexatin; (iii)
    determination of the effect of restricted food intake on
    reproduction parameters, preferably by a limited paired-feeding
    study in rats during gestation and lactation; and (iv) information
    on the particle size of cyhexatin residues in food.

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    Absorption, distribution and excretion

    Mice

         Absorption of uniformly labelled 14C-cyhexatin applied at 1
    mg/kg bw to a 1.2-cm2 area of the skin of the upper back of
    7-8-week-old Dublin ICR mice was slow. The geometric mean percentage
    dermal penetration was 0.7 after 1 h, 1.4 after 6 h and 5.5 after 24
    h (Grissom  et al., 1985).

    Rats

         Two Wistar rats weighing about 200 g were given a single oral
    dose of 5 mg of 119Sn-cyhexatin in a gelatin capsule, and urine
    and faeces were collected for 10 consecutive days after dosing.
    Total radioactivity was recovered quantitatively in excreta; 75-85%
    was excreted within the first four days after administration. Most
    of the radiolabel (97.5-98.1%) was found in the faeces, suggesting
    little absorption from the gastrointestinal tract. This assumption
    was confirmed in guinea-pigs given 2 mg of 119Sn-cyhexatin in
    gelatin capsules, since little radiolabel was found in the bile
    (Smith & Fischer, 1970).

         Radiolabel concentrations were measured in 53 Wistar rats fed
    diets containing 100 ppm of 119Sn-cyhexatin for 90 days and
    sacrificed periodically during treatment and up to 115 days after
    the end of treatment. The tissue 119Sn content increased during
    the first two weeks of feeding and then remained substantially
    unchanged. After 90 days of feeding, kidney, liver, brain, heart,
    spleen and muscle had the highest concentrations of 119Sn (0.4-0.8
    ppm). After cyhexatin was withdrawn from the diet, the level of
    119Sn in the tissues decreased slowly, with a half-life of about
    10 days, except in muscle and brain where the half-life was about 40
    days. Trace amounts were still present after 115 days. Animals that
    received comparable amounts of 119Sn as stannic chloride had much
    lower tissue levels of 119Sn. About 60% of total radiolabel in
    muscle tissue soon after withdrawal of cyhexatin was 119Sn, but
    the level decreased to about 25% after 80 days;
    119Sn-dicyclohexyltin oxide represented about 20 and 70% of total
    radiolabel, respectively (Smith & Fischer, 1970).

         Forty OFA-SD (10PS Caw) female rats were administered 3 mg/kg
    bw of technical-grade or micronized cyhexatin (purity, 96%)
    suspended in carboxymethylcellulose in 5 mg/ml water by gastric
    intubation. Five female rats served as controls. Groups of five
    treated rats were bled 0.5, 1, 3, 4, 6, 8, 12 and 24 h after dosing;
    controls were bled at 24 h only. Urine and faeces were collected
    throughout the 24-h period from five treated animals and the
    controls. No deaths or clinical signs were observed. The mean
    urinary levels of tin over 24 h were 9.0 g/l in controls and 69
    g/l in rats treated with technical-grade cyhexatin and 8.5 g/l in
    controls and 85 g/l in rats treated with micronized compound. The
    mean faecal levels were 1.9 g/g in controls and 177 g/g in rats
    given the technical grade, and 2.4 g/g in controls and 203 g/g in
    rats receiving micronized compound (Barrow, 1991a,b,c,d).

         The most relevant results are reported in Table 1. The
    bioavailability and peak blood concentrations (measured as tin) of
    micronized cyhexatin were about twice those of technical-grade
    cyhexatin, but the bioavailability of both formulations was low (1.2
    and 0.5%, respectively). The half-life in blood was about 2 h.


    
    Table 1.  Pharmacokinetics of technical-grade and micronized cyhexatin in female OFA-SD rats
    after oral and intravenous administration
                                                                                                    
    Treatment     Bioavailability  Half-life  Peak blood    Peak time  Excretion at 24 h (% of dose)
                  (% of dose)      (h)        conc. of tin  in blood                                
                                              (g/l)        (h)        Urine          Faeces
                                                                                                    

    3 mg/kg bw    0.53             1.16       4.56          2          0.3            14
    technical-
    grade, oral

    3 mg/kg bw    1.2              1.55       8.1           2.5        0.5            25
    micronized,
    oral

    0.5 mg/kg bw  (100)            3.35       2019.6a                  0.8            35
    micronized,
    intravenous
                                                                                                    

    From Barrow (1991a,b,c,d); 1 g of tin corresponds to 3.25 g of cyhexatin.
    a At t = 0

    

    Rabbits

         Cyhexatin (purity not reported) was administered by either
    gavage (in 0.5% w/v methylcellulose) or topically (in 2.0% w/v
    methylcellulose mucilage; 6 h) to groups of six pregnant New Zealand
    white rabbits on days 6-19 of gestation at doses of 0.1 or 1 mg/kg
    bw per day. On days 6 and 19, 14C-labelled cyhexatin
    (radiochemical purity, > 96%) was administered; blood samples were
    taken 0, 0.5, 1, 2, 4, 8, 12 and 24 h after treatment on day 6 and
    0, 1, 4, 8, 12 and 24 h after treatment on day 18. Samples were than
    taken every 24 h. All samples were assayed for total radioactivity.
    The animals were killed on day 28 of gestation and their state of
    pregnancy assessed. A fifth group of nine pregnant rabbits received
    cyhexatin by gavage on days 6-19 of gestation at a dose of 1 mg/kg
    per day, a dose of 14C-cyhexatin being administered on day 19 of
    gestation only. At that time, five females were killed 1 h after
    treatment and four were killed 24 h after treatment; maternal blood,
    fetuses, placentae and amniotic fluid were assayed for total
    radioactivity.

         The maximal blood concentration of 14C-cyhexatin was reached
    within 1 h after gavage and within 48-78 h after topical
    application, on both days 6 and 19. The mean peak blood
    concentrations were 24-31 g/l after gavage of 1 mg/kg bw, 1.4-2.5
    g/l after gavage of 0.1 mg/kg bw and 2.6-2.8 g/l after topical
    application of 1 mg/kg bw; cyhexatin was not detected after topical
    application of 0.1 mg/kg bw. The rate of decay of blood
    concentrations was biphasic: the initial half-lives after
    administration of 1 mg/kg per day by gavage were essentially similar
    on days 6 and 19 of gestation (about 8 h). The levels of cyhexatin
    in fetuses and placentae at 24 h were greater (about 1.5 and 3.5
    times, respectively) than the corresponding blood levels, while at 1
    h they were lower. The levels in amniotic fluid were always lessthan
    35% of those in blood (Bailey  et al., 1992).

         Technical-grade cyhexatin (purity, 96%) in
    carboxymethylcellulose was administered by gavage at 0 or 3 mg/kg bw
    per day to pregnant Hy/Cr New Zealand white rabbits on days 6-18 of
    gestation. Blood samples were taken 2, 3 and 4 h after
    administration on day 18 from six treated and six control animals
    for determination of tin. These animals were sacrificed the
    following day. All surviving animals were sacrificed on day 26 of
    gestation, and selected organs and tissues were taken from dams and
    fetuses and weighed. The tin levels in maternal blood peaked 3 h
    after dosing (day 18), with a mean concentration after subtraction
    of control levels of 11.3 g/l, and had returned nearly to control
    levels by 24 h. By day 26, the blood tin levels in treated animals
    were only slightly higher than those in controls. Tin was found in
    the brain, liver and kidney on days 19 (dams only) and 26 (dams and
    fetuses) and in placenta (days 19 and 26) and whole fetuses (day
    19). There was no apparent increase in tin levels in treated

    animals, but high interindividual variability precluded meaningful
    comparisons. In amniotic fluid, the tin levels were about fivefold
    higher than those in controls on day 19 but not on day 26 (Woehrle,
    1991).

         Groups of 20 female Hy/Cr hybrid New Zealand white rabbits were
    administered 3 mg/kg bw of technical-grade or micronized cyhexatin
    (purity, 96%) by gavage or percutaneously. Blood samples were taken
    from two rabbits in each group after 0.25 (only those treated by
    gavage), 0.5, 1, 4, 8, 24, 32, 48 and 56 h (the last only for those
    treated percutaneously). Urine and faeces were collected from four
    animals after 48 (gavage) or 56 h (percutaneous). A further group of
    20 animals was given a single intravenous bolus of 0.5 mg/kg bw
    micronized cyhexatin. The dose was chosen on the basis of the
    results of a preliminary experiment in which all animals given 3
    mg/kg bw and one of four animals given 1 mg/kg bw died within a few
    hours of treatment (Woehrle, 1992a). Blood samples were taken from
    five rabbits 5, 10, 15, 20 and 30 min and 1, 2, 4, 6, 8 and 24 h
    after treatment. Urine and faeces were collected from five animals
    24 h before and 24 and 48 h after treatment.

         Treatment had marked respiratory and circulatory effects: four
    animals died after blood sampling, and two died 2-5 min after
    dosing. In all of the studies, tin levels were assumed to mirror
    cyhexatin concentrations. The most relevant results are reported in
    Table 2. Absorption was slower after percutaneous exposure, but
    bioavailability was similar after oral and percutaneous
    administration (7-10% of the dose). Administration of micronized
    cyhexatin resulted more quickly in slightly higher peak blood
    concentrations than the technical-grade formulation given by the
    same route. The half-life in blood was about 2 h in animals given
    micronized cyhexatin orally or intravenously and 9-22 h for the
    other preparation, possibly because of slower absorption (Barrow,
    1991e,f,g,h; Woehrle, 1992b).


        Table 2.  Pharmacokinetics of technical-grade and micronized cyhexatin in female New Zealand
    white rabbits after oral, percutaneous and intravenous administration
                                                                                                          
    Treatment      Bioavailability   Half-life   Peak blood     Peak time   Excretion at 24 h (% of dose)
                   (% of dose)       (h)         conc. of tin   in blood                                  
                                                 (g/l)         (h)         Urine             Faeces
                                                                                                          

    3 mg/kg bw     9.2               9           8.1            5.5         0.4               23
     technical-
     grade, oral

    3 mg/kg bw     7.7               2           11.5           3.5         0.6               27
     micronized,
     oral

    3 mg/kg bw     7.7               22          3.4            11.7        0.2               0
     technical-
     grade, skin

    3 mg/kg bw     6.9               14          4.3            9.1         0.3               0
     micronized,
     skin

    0.5 mg/kg bw   (100)             2           316a           -           0.6               ?b
     micronized,
     intravenous
                                                                                                          

    From Barrow (1991e,f,g,h; Woehrle, 1992a); 1 g of tin corresponds to 3.25 g of cyhexatin.
    a At t = 0
    b Severe constipation precluded meaningful analysis.


    

    2.  Toxicological studies

    (a)  Acute toxicity

         The LD50 of micronized cyhexatin (purity, 96%) in
    Sprague-Dawley CD rats treated by gavage was 265 mg/kg bw (95%
    confidence interval, 124-569) in females and 501 (192-1307) mg/kg bw
    in males (Denton, 1993a). Higher LD50s were found for
    technical-grade cyhexatin, i.e. 654 (446-1454) mg/kg bw in females
    and 627 (478-1120) mg/kg bw in males (Denton, 1993b).

         The LD50s in CD(SD)BR rats after gavage of technical-grade
    and micronized cyhexatin (purity, 95-96%) from another source were
    274 (189-397) mg/kg bw for technical-grade and 411 (293-577) mg/kg
    bw for micronized cyhexatin in females and 425 (260-693) mg/kg bw
    for technical-grade and 407 mg/kg bw (confidence interval not
    calculable) for micronized cyhexatin in males (Longobardi, 1994a,b).

    (b)  Reproductive toxicity

    Rats

         The following additional information was available from the
    multigeneration study in rats that was reviewed by the 1991 JMPR
    (Annex I, reference 64): The purity of the micronized cyhexatin was
    96%. Analysis of diets at weeks 1, 2, 4 and 6-45 indicates a median
    (range) percentage of nominal concentration of 104% (82-120) at 10
    ppm, 104% (86-120) at 30 ppm and 101% (89-122) at 100 ppm. Diets
    were prepared weekly; in one test for stability, it was shown that
    there was no loss of compound over eight days. The mean intakes of
    compound before mating were 0.7, 2.1 and 7 mg/kg bw per day for
    males and 0.7, 2.4 and 7.5 mg/kg bw per day for females fed 10, 30
    and 100 ppm, respectively. The intakes of F0 females during
    gestation were 1, 2 and 6.7 mg/kg bw per day, and those during
    lactation were 1.7, 4.8 and 12.8 mg/kg bw per day in the same
    groups, respectively. The food intakes of the F1 generation before
    mating were 0.8, 2.8 and 10.6 mg/kg bw per day for males and 1.0,
    2.9 and 10.5 mg/kg bw per day for females, respectively. The intakes
    of F1 females were 1, 2 and 7.3 mg/kg bw per day during the first
    gestation, 1.7, 4.8 and 11.8 mg/kg bw per day during lactation and
    1, 2 and 6.3 mg/kg bw per day during the second gestation. The NOAEL
    was 10 ppm, equal to 0.7 mg/kg bw per day.

         A draft report describing a one-generation pair-feeding study
    of reproductive toxicity in rats was available. Groups of 25 male
    and 25 female OFA SD rats were given a diet containing 30 ppm
    cyhexatin (purity and formulation not reported)  ad libitum for a
    four-week period before mating, during mating, during gestation and
    during lactation. Pair-fed groups received the same quantity of diet

    as that consumed by the treated groups. Diets were prepared weekly.
    One test for stability showed no loss of compound over eight days.
    Analysis of the diet on day 1 and at weeks 5 and 10 showed
    analytical concentrations within 90% of the target, except on one
    occasion when it was about 80%. Food consumption was recorded daily,
    and animals were observed for signs of toxicity. Body weights were
    recorded weekly; those of females were also recorded on days 0, 7,
    14 and 20 of gestation and on days 1, 4, 7, 14 and 21 of lactation.

         Neither deaths nor signs of toxicity were observed. Mean
    body-weight gain was slightly reduced (- 5%) in treated animals and
    more so (- 11%) in the group fed only during gestation. The treated
    males consumed about 9% less food during the first week of
    treatment, and the treated females consumed about 10% less food
    during the first two weeks of gestation and, occasionally, during
    the last two weeks of lactation. The intakes of cyhexatin were
    1.9-2.5 mg/kg bw per day until the end of gestation and had
    increased to a maximum of 5.9 mg/kg bw per day by the end of
    lactation. Mating performance, fertility, length of gestation and
    pup viability were similar in all groups. Pup weight gain was
    slightly lower in both the treated (- 19%) and pair-fed groups (-
    13%) than in concurrent controls, but was similar to that of
    historical controls in the laboratory. The difference between the
    treated and control groups was statistically significant on days 14
    (females) and 21 (males and females). Physical and functional
    development of offspring (assessed by pinna infolding, incisor
    eruption and eye opening) was marginally delayed in the treated
    group; in general, however, it was comparable in all groups. No
    significant observations were made at necropsy in any group. The
    weights of the epididymes and testes were not altered by the
    treatment. It was concluded that cyhexatin at 30 ppm in the diet has
    some effect on pup growth, which cannot be explained solely on the
    basis of reduced food intake due to unpalatability of the diet. This
    effect was only partially diminished by pair-feeding. The reduced
    food intake is likely to be the cause of the reduced body-weight
    gain seen in females of the F0 generation (Barrow, 1993).

    (c)  Embryotoxicity and teratogenicity

    Rabbits

         Groups of 25-26 pregnant New Zealand white rabbits were
    administered 0, 0.5, 1 or 3 mg/kg bw per day of technical-grade
    cyhexatin (purity, 95.1%) in 0.5% carboxymethyl-cellulose in a
    volume of 0.25 ml/kg on one of six clipped, 30-cm2 sites on the
    back during days 6-18 of gestation. The sites were used in rotation.
    Solutions were prepared daily. Analyses of the formulations showed

    concentrations that were 78-103% of the target at week 1; after
    adjustment of the formulating procedures, the concentrations were
    91-103% of the target at week 2. Homogeneity was reported to be
    within acceptable limits (no data), and the concentration 6 h after
    preparation was > 90% of the initial level. Animals were observed
    daily for clinical signs and were weighed on days 0, 6-19, 23, 26
    and 29; their food consumption was determined daily. On day 18, 3-4
    h after treatment, blood samples were taken from three animals
    selected randomly from each group, which were then sacrificed to
    verify their pregnancy status. Plasma cyhexatin levels on day 18
    were below the levels of linearity of the method (0.26 mg/l) in some
    samples and undetectable in others. No relevant clinical signs were
    observed, except for erythema, oedema, eschar and fissuration
    (dose-related) at the application sites. Two of the animals at the
    low dose and one at the high dose died, and one at the low dose and
    one at the middle dose aborted. The body weight and food consumption
    of dams were not affected by treatment, and the findings in females
    at necropsy were unremarkable. The numbers of corpora lutea,
    implantations, intra-uterine deaths and live young, the percentage
    of implantation loss, and litter weights were similar in all groups.
    No visceral malformations were recorded, except for spina bifida in
    two control fetuses. One fetus of a dam at the middle dose was
    missing part of the cerebral hemisphere. Differences in the
    incidences of enlargement of the anterior fontanelle of the cranium
    and of incomplete or non-ossification of the fifth sternebrae were
    not statistically significant. The Meeting concluded that cyhexatin
    at percutaneous doses up to 3 mg/kg bw per day had no maternally
    toxic effect and was not teratogenic (Jamieson, 1991).

         An expert review of a study of teratogenicity in rabbits (Ross,
    1990 [reported as Bailey  et al., 1990 by the 1991 JMPR]; Annex I,
    reference 64) was available to the present Meeting. The observations
    are summarized in Table 3. The range of incidence of folded retinas
    in control groups in studies performed six months before or after
    the period of the reported study during which the animals were alive
    was 2.4-33.3% for unilateral and 2.2-18.9% for bilateral folded
    retina. Since the folding was classified as slight, artefacts of
    fixation could not be ruled out. Given the absence of a clear
    dose-response relationship, the historical control data and the
    possibility of some fixation artefacts, the Meeting concluded that
    the NOAEL in this study was 0.75 mg/kg bw day on the basis of
    possible maternal toxicity at higher doses (Tesh, 1994).

        Table 3.  Incidence (%) of slightly folded retina in rabbits treated with cyhexatin
    from two sources
                                                                                          
    Treatment                           From Kentucky (USA)  From Vlissingen (Netherlands)
    (mg/kg per day)                     (97% pure)           (98% pure)
                                                                                          

    Unilateral slightly folded retina
    0                                   14.3                 14.3
    0.75                                21.1                 20.7
    1.5                                 18.2                 20.6
    3.0                                 32.3                 15.8

    Bilateral slightly folded retina
    0                                   11.9                 11.9
    0.75                                21.7                 10.3
    1.5                                 31.8                 14.7
    3.0                                 16.1                 21.1
                                                                                          

    From Ross, 1990 [reported as Bailey  et al., 1990 by the 1991 JMPR]
    
    3.  Observations in humans

         A study was conducted to evaluate potential exposure to
    cyhexatin of people mixing and spraying Plictran 50W Miticide in
    orchards and re-entering the treated orchards to pick fruit. The
    formulation was applied from commercial two-directional orchard
    sprayers towed behind tractors which had either open or enclosed
    cabs. Treated orchards were re-entered in order to harvest or thin
    fruit 0, 7 and 14 days after application. Operators wore half-face
    air-purifying respirators with pesticide cartridges, chemically
    resistant gloves, goggles and long-sleeved, long-legged clothing for
    both mixing and spraying. The operators of open-cab tractors wore
    protective rubber suits, and pickers wore long-sleeved, long-legged
    clothing. The average concentrations of cyhexatin measured in the
    breathing zone of drivers of open- and enclosed-cab tractors were
    0.039 mg/m3 during mixing and 0.027 mg/m3 during spraying.
    Potential dermal exposure was assessed by the method suggested in
    the US Environmental Protection Agency Pesticide Assessment
    Guidelines, on the basis of estimates of surface deposition of
    cyhexatin on exposed body surfaces and 16% of surface deposition on
    clothed body surfaces. The average potential dermal exposure during
    mixing and spraying was 0.7-7 mg/day. Potential dermal exposures
    during picking were 21 mg on the day of application to 0.83 mg 14
    days after application. The percentage of the potential dermal
    exposure that occurred on the hands was 81% on the day of
    application and 25% 14 days after application (Scortichini & Bohl,
    1988).

         Exposure to cyhexatin (determined as tin) was monitored in one
    mixer/loader, one tractor driver and two sprayers on three
    consecutive working days and two subsequent rest days. Exposure by
    inhalation was low (6-1070 g/day). Dermal exposure was 0.8-19
    mg/day. The concentration of tin in blood increased by up to 20
    times after exposure; the peak level in one subject was 20.5 g/l.
    There was a poor correlation of blood levels with cutaneous
    exposure, except on day 1. Blood tin concentrations had not returned
    to normal values two days after the end of exposure, and in one
    subject it was normal one day after exposure but much higher the
    following day. The authors gave no explanation for this finding.
    Sample contamination during blood drawing could not be discounted.
    Urinary and faecal levels were not determined (Maroni, 1993).

         Medical surveillance of workers exposed to organotin compounds,
    including cyhexatin, showed no adverse effects on haematological,
    clinical chemical or immunological parameters. The urinary tin
    levels of exposed workers were no higher than those of unexposed
    controls (Baaijens, 1992).

    Comments

         Cyhexatin is poorly absorbed after oral administration to rats
    and rabbits or dermal application on rabbits. In rabbits, the
    bioavailability was similar after treatment by either route,
    although a higher peak blood concentration was reached after oral
    administration. The bioavailability after oral administration was
    much greater in rabbits (7-9%) than in rats (0.5-1.2%). Micronized
    cyhexatin had greater bioavailability than the technical formulation
    in female rats but not in female rabbits.

         The disposition of cyhexatin is slow: 75-85% was eliminated in
    rats within four days after treatment, and the administered dose was
    recovered completely within about 10 days. After rats were fed diets
    containing 100 ppm of 119Sn-cyhexatin for 90 days, the tissue
    content of 119Sn reached a steady state within about two weeks.
    When cyhexatin was removed from the diet, the half-life of 119Sn
    in most tissues was about 10 days, except in the brain and muscle
    where it was about 40 days. 119Sn was present in muscles mainly as
    cyhexatin and, later, as dicyclohexyltin.

         In pregnant rabbits given 14C-cyhexatin either orally or
    dermally, peak blood concentrations were found to be higher than
    those expected from results obtained in non-pregnant animals.
    Contrasting results were obtained in fetus, placenta and amniotic
    fluid in two studies.

         Comparative studies in rats showed that micronized cyhexatin
    has greater acute oral toxicity (LD50 = 265 mg/kg bw) than
    technical-grade cyhexatin (LD50 = 654 mg/kg bw) in females but not
    in males (LD50 = 501 and 599 mg/kg bw, respectively). This finding
    is consistent with data on kinetics from the same laboratory using
    the same source of cyhexatin, in which the bioavailability of
    micronized cyhexatin was greater than that of technical-grade
    cyhexatin in female rats. In studies of acute toxicity in female
    rats performed in another laboratory using cyhexatin from another
    source, however, lower acute toxicity was seen with micronized
    (LD50 = 411 mg/kg bw) than with technical-grade (LD50 = 274
    mg/kg bw) cyhexatin. WHO (1992) has classified cyhexatin as slightly
    hazardous.

         More information has been provided from the multigeneration
    study (reviewed by the 1991 Meeting) in rats fed diets containing 0,
    10, 30 or 100 ppm of micronized cyhexatin. The NOAEL in this study
    was 10 ppm, equal to 0.7 mg/kg bw per day, on the basis of decreased
    body-weight gain in pups during lactation and reduced survival of
    F0 and F1 offspring at 30 ppm.

         A one-generation study of reproductive toxicity was conducted
    in pair-fed rats. Animals were given control diet  ad libitum, a
    diet containing 30 ppm of micronized cyhexatin or the same amount of

    control diet as that consumed by the cyhexatin group. Pup growth was
    affected by both cyhexatin and the control diet but to a greater
    extent by the former. Therefore, reduced food intake accounted only
    partially for the effects. In a study of reproductive toxicity
    reviewed by the 1991 Meeting, rats were administered diets
    containing cyhexatin at concentrations that yielded 0, 0.1, 0.5 or
    6.0 mg/kg bw per day. A slight effect on body weight, associated
    with reduced food intake, was observed in F0 females at 0.5 mg/kg
    bw per day, and the NOAEL was 0.1 mg/kg bw per day. Taking into
    consideration the results of the pair-feeding study and the other
    multigeneration study in rats, the Meeting considered that the
    effect seen at 0.5 mg/kg bw per day might be due to diet
    unpalability. The Meeting concluded that the NOAEL was 0.5 mg/kg bw
    per day.

         In a study of teratogenicity in rabbits given percutaneous
    doses of technical-grade cyhexatin of 0, 0.5, 1 or 3 mg/kg bw per
    day, neither maternal toxicity nor teratogenic effects were
    observed. In another study, rabbits were given 0, 0.75, 1 or 3 mg/kg
    bw orally. An increased incidence of folded retinas was found in
    treated groups, but a dose-response relationship could not be
    demonstrated and fixation artefacts were considered likely. The
    NOAEL in this study was 0.75 mg/kg bw per day on the basis of
    possible maternal toxicity at higher doses. After taking into
    consideration the results of all the studies of teratogenicity in
    rabbits, the Meeting concluded that cyhexatin is not teratogenic to
    this species.

         Two studies have been carried out of occupational exposure to
    cyhexatin during mixing and spraying. Average exposure by inhalation
    was very low; cutaneous exposure was 0.7-19 mg/day. Cutaneous
    exposure during fruit picking in cyhexatin-treated orchards ranged
    from 21 mg/day at 0 days to 0.8 mg/kg 14 days after application. No
    reliable measurements were reported of tin or cyhexatin in blood or
    urine.

         No information was available on the particle size of cyhexatin
    residues in food because it could not be determined analytically;
    however, it is conceivable that residues are of the same sizes as
    the applied product.

         The Meeting based the ADI on the NOAEL determined in the
    multigeneration study in rats (0.7 mg/kg bw per day), applying a
    100-fold safety factor.

    Toxicological evaluation

    Levels that cause no toxic effect

         Mouse:    3 mg/kg bw per day (two-year study) (Joint Meeting,
                   1981)

         Rat:      0.7 mg/kg bw per day (multigeneration study)

         Rabbit:   0.75 mg/kg bw per day (maternal toxicity in
                   teratogenicity study)

    Estimate of acceptable daily intake for humans

         0-0.007 mg/kg bw

    Studies that would provide information useful for continued
    evaluation of the compound

         Further observations in humans

    References

    Baaijens, P.A. (1992) Medical surveillance of workers exposed to
    organotin-compounds. Unpublished report submitted to WHO by ELF
    Atochem, Agra SA, Plaisir, France.

    Bailey, G.P., Ferguson, E.G.W., Hallifax, D. & Miner, C. (1992)
    Tricyclohexyltin hydroxide: absorption study in the rabbit.
    Unpublished report No. 91/0929 from Life Science Research Ltd, Eye,
    United Kingdom. Submitted to WHO by ELF Atochem Agri SA, Plaisir,
    France.

    Barrow, P.C. (1991a) Cyhexatin technical. pharmacokinetic
    investigation in the rat by the oral route. Unpublished report No.
    457059 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Barrow, P.C. (1991b) Cyhexatin micronised. pharmacokinetic
    investigation in the rat by the oral route. Unpublished report No.
    458059 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Barrow, P.C. (1991c) Cyhexatin technical. Pharmacokinetic
    investigation in the rat by the oral route. Amendment No 1.
    Unpublished report no. 457059 from Pharmakon Europe, Lyon, France.
    Submitted to WHO by Oxon Italia SpA, Milan, Italy.

    Barrow, P.C. (1991d) Cyhexatin micronised. Pharmacokinetic
    investigation in the rat by the oral route. Amendment No 1.
    Unpublished report no. 458059 from Pharmakon Europe, Lyon, France.
    Submitted to WHO by Oxon Italia SpA, Milan, Italy.

    Barrow, P.C. (1991e) Cyhexatin technical. Pharmacokinetic
    investigation in the rabbit by the oral route. Unpublished report
    No. 459059 from Hazleton France. Submitted to WHO by Oxon Italia
    SpA, Milan, Italy.

    Barrow, P.C. (1991f) Cyhexatin micronised. Pharmacokinetic
    investigation in the rabbit by the oral route. Unpublished report
    No. 460059 from Hazleton France. Submitted to WHO by Oxon Italia
    SpA, Milan, Italy.

    Barrow, P.C. (1991g) Cyhexatin technical. Pharmacokinetic
    investigation in the rabbit by the percutaneous route. Unpublished
    report No. 461059 from Hazleton France. Submitted to WHO by Oxon
    Italia SpA, Milan, Italy.

    Barrow, P.C. (1991h) Cyhexatin micronised. Pharmacokinetic
    investigation in the rabbit by the percutaneous route. Unpublished
    report No. 462059 from Hazleton France. Submitted to WHO by Oxon
    Italia SpA, Milan, Italy.

    Barrow, P.C. (1991i) Two generation oral (dietary administration)
    reproduction toxicity study in the rat. Unpublished report No.
    396039 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Barrow, P.C. (1993) One generation oral (dietary admixture)
    reproduction toxicity study in the rat with pair-feeding.
    Unpublished draft report No. 1 from Pharmakon Europe, Lyon, France.
    Submitted to WHO by Oxon Italia SpA, Milan, Italy.

    Denton, S.M. (1993a) Cyhexatin micronised. Acute oral toxicity to
    the rat. Unpublished report from Huntingdon Research Centre Ltd.,
    Huntingdon, United Kingdom. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Denton, S.M. (1993b) Cyhexatin technical. Acute oral toxicity to the
    rat. Unpublished report from Huntingdon Research Centre Ltd.,
    Huntingdon, United Kingdom. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Grissom, R.E., Jr, Brownie, C. & Guthrie, F.E. (1985) Dermal
    absorption of pesticides in mice.  Pestic. Biochem. Physiol., 24,
    119-123.

    Jamieson, H. (1991) Cyhexatin percutaneous teratology study in
    rabbits. Unpublished report No. 737-088-161/T/122/91 from the
    Research Toxicology Centre SpA, Pomezia, Italy. Submitted to WHO by
    Chemia SpA, Ferrara, Italy.

    Longobardi, C. (1994a) Acute oral toxicity study in the albino rat.
    Unpublished report No. 271-010/T/140/93 from the Research Toxicology
    Centre SpA, Pomezia, Italy. Submitted to WHO by Chemia SpA, Ferrara,
    Italy.

    Longobardi, C. (1994b) Acute oral toxicity study in the albino rat.
    Unpublished report No. 271-011/T/129/93 from the Research Toxicology
    Centre SpA, Pomezia, Italy. Submitted to WHO by Chemia SpA, Ferrara,
    Italy.

    Maroni, M. (1993) Personal and biological monitoring of exposure to
    cyhexatin during agricultural use. Unpublished report from the
    International Centre for Pesticide Safety. Submitted to WHO by Oxon
    Italia, Milan, Italy.

    Ross, F.W. (1990) Cyhexatin: Teratology study in rabbit. Unpublished
    report No. 89/0161 from Life Science Research Ltd, Eye, United
    Kingdom. Submitted to WHO by Elf Atochem SA, Plaisir, France.

    Scortichini, B.H. & Bohl, R.W. (1988) Evaluation of tractor/sprayer
    operator and orchard worker exposures to cyhexatin during orchard
    spraying with Plictran 50W miticide and reentry of treated orchards,

    Hartford, Michigan, 28 July 1987. Unpublished report No.
    HEH2.1-1-182(72) from Dow Chemical Co., Midland, MI, USA. Submitted
    to WHO by ELF Atochem Agri SA, Plaisir, France.

    Smith, G.N. & Fischer, F.S. (1970) Metabolism of Plictran miticide.
    Observations on the absorption, distribution, and excretion of
    tricyclohexyltin-Sn119 hydroxide in white rats. Unpublished report
    from Dow Chemical Co., Midland, MI, USA. Submitted to WHO by ELF
    Atochem Agri SA, Plaisir, France.

    Tesh, J.M. (1994) Tricyclohexyltin hydroxide: teratology study in
    the rabbit. Expert review. Unpublished report no. 89/MTC010/0161
    from Pharmaco LSR, Ltd. Submitted to WHO by ELF Atochem Agri SA,
    Plaisir, France.

    WHO (1992) The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.

    Woehrle, F. (1991) Cyhexatin technical. Blood and tissue level
    determination in the pregnant rabbit and its litter after oral
    administrations during the organogenesis period. Unpublished report
    No. 40890 from Hazleton France. Submitted to WHO by Oxon Italia SpA,
    Milan, Italy.

    Woehrle, F. (1992a) Cyhexatin micronised. Pharmacokinetic
    investigation in the rabbit by the intravenous route. Unpublished
    report No. 40790 from Hazleton France. Submitted to WHO by Oxon
    Italia SpA, Milan, Italy.

    Woehrle, F. (1992b) Cyhexatin micronised. Pharmacokinetic
    investigation in the rabbit by the intravenous route. Unpublished
    report No. 49890 from Hazleton France. Submitted to WHO by Oxon
    Italia SpA, Milan, Italy.


    See Also:
       Toxicological Abbreviations