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)