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    AZOCYCLOTIN

    EXPLANATION

         Azocyclotin is an organic tin compound that was reviewed by the
    Joint Meeting of Pesticide Residues (JMPR) in 1979 and 1981
    (Annex 1, FAO/WHO, 1980a; 1982a).  The compound underwent
    toxicological evaluation in 1981 and a Toxicological Monograph was
    prepared at that time (Annex 1, FAO/WHO, 1982b).

         The 1981 JMPR estimated that the acceptable daily intake (ADI)
    for man was 0-0.003 mg/kg bw, based upon no-effect observed in
    2-year studies in the rat (5 ppm in the diet equivalent to
    0.25 mg/kg bw/day) and the dog (10 ppm in the diet equivalent to
    0.25 mg/kg bw/day).  In addition, further information to permit
    adequate evaluation in the future was considered to be desirable. 
    This information included studies to determine the potential for
    central nervous system toxicity.

         Azocyclotin has recently been studied for its ability to
    produce potential embryotoxic and teratogenic effects after oral and
    dermal application to rabbits.  The results of these tests are
    discussed below.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Special studies on teratogenicity

    Rabbits

         In an oral range finding study four groups of 4 artificially
    inseminated New Zealand White rabbits received 0 (1% cremophor) 1, 3
    or 10 mg/kg bw/day by gavage on days 6-18 of pregnancy (Day 0 of
    pregnancy was the day of artificial insemination).  No rabbits
    carried to term at 3 and 10 mg/kg bw/day, two animals in each group
    being killed in extremis, and 2 in each group aborting.  Stomach
    ulceration in 3/4 at 10 and 2/4 at 3 mg/kg bw/day was noted.  One
    abortion occurred at 1 mg/kg bw/day attributed to maternal
    infection.  One animal at this dose lost weight, and 3 showed
    reduced food intake.  Mean fetal weight was reduced at 1 mg/kg
    bw/day.  No malformations recorded (Tesh & Rose, 1981).

         In the main oral study, 4 groups of artificially inseminated
    New Zealand White rabbits received 0 (1% cremophor); 0.1, 0.3 or
    1.9 mg/kg bw/day, by gavage of 93.1% pure azocyclotin on days 6-18
    of pregnancy (Day 0 was the day of insemination).  The incidence of
    mortality at these dose levels was 1, 0, 3, and 2, respectively. The
    deaths in the control rabbit and in one rabbit at 0.3 mg/kg bw/day
    were not compound-related effects.

         Compound-related effects (gastrointestinal disturbances) cannot
    be ruled out in the remaining animals at 0.3 mg/kg bw/day.  Data are
    not available on the necropsies of the 1 mg/kg bw/day animals which
    died.  Decreased body weight gain was observed at 1 mg/kg bw/day,
    and slightly reduced at 0.3 mg/kg bw/day.  Abortions (2) were
    observed at 1 mg/kg bw/day in animals which showed evidence of
    gastrointestinal tract disturbances.  There were no observed effects
    on litter size, number of viable young, resorption incidence, pre-
    or post-implantation losses, fetal weight or placental weight.  No
    major malformations were recorded.  However, an increased incidence
    of variants (fissures in ovarial boxes, thickened ribs, incomplete
    ossification of digits) was observed in pups from the 1 mg/kg bw/day
    dose level, which may have been indicative of minimal fetotoxicity. 
    The NOAEL for maternal toxicity was 0.1 mg/kg bw/day, and for
    teratogenicity, 1 mg/kg bw/day (the highest dose tested) (Tesh
     et al. 1981).

         Groups of female CHBB Himalayan rabbits (15/dose) received
    dermal applications of 0, 30, 100, or 300 mg/kg bodyweight
    (concentrations of 0, 3, 10, and 30%, respectively) of azocyclotin
    (3.9% pure) from days 6 to 18 of gestation (Day 0 = day of mating). 
    The compound was applied for 6 hours/day to shaved areas on the
    backs of the animals using occulusive methods.  On gestation day 29,

    dams were sacrificed and fetuses delivered by C-section.  The
    fetuses were dissected and examined for visceral anomalies, and
    subsequently cleared and stained for skeletal observations.

         One pregnant dam in the 300 mg/kg bw/day group died on day 21
    due to unknown causes;  the animal had a full, distended gall
    bladder and the intestines were filled with gases.  Adverse effects
    on the skin as well as digestive problems occurred in the dams at
    all of the doses tested.  The treated skin areas were clearly
    injured as indicated by the presence of moderate to severe erythema
    and edema, dehydration, and roughened surfaces.  Digestive problems
    occurred in 9/15 controls, 12/15 low dose, 12/15 mid dose, and 15/15
    high dose animals, and were said to be related to stress; there was
    a greater incidence (generally dose-related) of reduced nutritional
    intake, soft feces, and a smaller amount of feces in all treated
    groups compared to the controls.  In addition, a few high dose dams
    were emaciated, had distended gall bladders and empty intestines
    filled with gases, or had diarrhea.  Other findings in dams included
    the occurrence of hemorrhagic excretions and abortions of placentas
    and fetuses (0/15 controls, 1/15 low dose, 0/15 mid dose, and 4/15
    high dose) and cysts on the fallopian tubes of ovaries (1/15
    controls, 0/15 low dose, 2/15 mid dose, and 4/15 high dose).  The
    pregnancy rate was reduced at the high dose level as a result of
    dams who had completely resorbed (see below); the percentage of
    pregnant (expressed as a percentage of those that were fertilized)
    was 100% in controls, 85.7% low dose, 92.3% mid dose, and 61.5% high
    dose.  The weight gain of the dams was reduced at 100 mg/kg/day but
    the response did not appear to be dose-related.

         Remarkable changes in the fetuses included a dose-related
    increase in resorptions in all treatment groups. As a consequence of
    this there were reductions in the number of surviving female fetuses
    at all 3 dose levels, male fetuses at the high dose level, and
    combined male and female fetuses at the two highest dose levels. 
    There did not appear to be any other changes in the fetuses with
    respect to mean fetal and placental weights/litter, number of
    corpora lutea, crown-rump length, number of runts/litter, or the
    number of fetuses with bone changes or malformations/litter.  No
    teratogenic effects were observed.  A NOAEL could not be determined
    for either the dams or the fetuses over the dose range of 30 to
    300 mg/kg by dermal application.  A dermal dose of 300 mg/kg was a
    NOAEL for teratogenicity (Renhof, 1989a).

         A second dermal teratogenicity study similar to the one above
    was performed in female DHBB Himalayan rabbits (15/dose) using
    azocyclotin (94.9% pure) in doses of 0 and 10 mg/kg bodyweight.  The
    purpose of the study was to determine a NOAEL for the fetuses.  The
    only treatment-related effect in this study appeared to be injury of
    the treated skin areas in the dams as indicated by the presence of
    very slight to moderate erythema and edema, dehydration and
    roughened surfaces.  One death occurred in a pregnant control dam on

    day 27.  The weight development of the treated dams was reduced
    during application but the change was not statistically significant
    and was similar in magnitude to that seen with the 30 and 300 mg/kg
    bw/day doses of azocyclotin in the above described study.  The
    weight development of the dams was said to be adversely affected by
    the method of compound application.  In regard to malformations, one
    fetus had a split gall bladder, another had a bifurcated rib, and a
    third had fused ribs; all of the fetuses were from different dams. 
    The malformations were within normal historical control ranges, and
    none were seen at doses of 30 to 300 mg/kg bw/day in the first
    dermal study except for fused ribs in one fetus at 30 mg/kg bw/day. 
    No other changes (including digestive problems, hemorrhagic
    excretions/abortions, ovarian cysts, changes in the pregnancy rate,
    resorptions, or changes in the numbers of surviving fetuses) were
    observed after treatment with 10 mg/kg in this study.  The NOAEL for
    the fetuses was 10 mg/kg bw/day after dermal application (Renhof,
    1989b).

    Observations in humans

         No information available.

    COMMENTS

         An oral teratology study in New Zealand White rabbits indicated
    maternal toxicity at 0.3 mg/kg bw/day and above and no evidence of
    teratogenicity at 1 mg/kg bw/day.  There was minimal indication of
    embryo/fetotoxicity at this dose. The NOAEL for the study was
    0.1 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0-0.1 mg/kg bw.

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

         Further observations in humans.

    REFERENCES

    Renhof, M. (1989a)  BUE 1452.  Investigations into the dermal
    embryotoxic effects on rabbits after dermal administration. 
    Unpublished Report No. 17698 from Institute of Toxicology, Bayer AG. 
    Submitted to WHO by Bayer, AG, Wuppertal, FRG.

    Renhof, M. (1989b)  BUE 1452.  Investigations into the embryotoxic
    effects on rabbits after dermal administration.  Unpublished Report
    No. 17686 from Institute of Toxicology, Bayer AG.  Submitted to WHO
    by Bayer, AG, Wuppertal, FRG.

    Tesh, J.M., Rose, F.W. (1981)  BUE 1452.  Effects of oral
    administration upon pregnancy in the rabbit. 1. Dosage range-finding
    study.  Unpublished Report No. 81/BAG 008/097 from Life Science
    Research, England.  Submitted to WHO by Bayer AG, Wuppertal, FRG.

    Tesh, J.M., Rose, F.W., Secker, R.C., Wilby, O.K. (1981)  BUE 1452. 
    Effects of oral administration upon pregnancy in the rabbit. 2. Main
    study.  Unpublished Report No. 81/BAG 009/4617 from Life Science
    Research, England.  Submitted to WHO by Bayer AG, Wuppertal, FRG.


    See Also:
       Toxicological Abbreviations
       Azocyclotin (Pesticide residues in food: 1979 evaluations)
       Azocyclotin (Pesticide residues in food: 1981 evaluations)
       Azocyclotin (Pesticide residues in food: 1983 evaluations)
       Azocyclotin (JMPR Evaluations 2005 Part II Toxicological)