PESTICIDE RESIDUES IN FOOD - 1983 Sponsored jointly by FAO and WHO EVALUATIONS 1983 Data and recommendations of the joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues Geneva, 5 - 14 December 1983 Food and Agriculture Organization of the United Nations Rome 1985 DAMINOZIDE TOXICOLOGY Explanation The 1977 JMPR was unable to establish an acceptable daily intake (ADI) for daminozide owing to a lack of an adequate long-term rat study and of information on the bio-transformation in animals. The teratogenicity study reviewed by that Meeting was conducted by Industrial Bio-Test Laboratories (IBT) and has been found invalid (FAO/WHO 1978).1 TOXICOLOGICAL STUDIES Special Study on Teratogenicity Daminozide (99 percent pure) was administered daily by gavage at doses of 0, 300, 600 and 1 000 mg/kg to female Wistar rats from day 6 to 15 of gestation. On day 22 the dams were sacrificed and uterine contents were removed and examined before necropsy. No signs of toxicity were observed. Pregnancy rates, numbers of corpora lutea, implantation and resorption rates, foetal deaths, sex ratio, foetal weights and number of live foetuses were not significantly different from control values. Neither the number of foetal anomalies nor the incidence of gross skeletal malformations was found to be significantly increased. Unfortunately, individual animal data were not reported (Khera et al. 1979). Special Studies on Carcinogenicity Mice Daminozide was administered from six weeks of age over the life span of Swiss albino mice as a 2 percent solution in the drinking water. Daily intake averaged 134 mg for males and 170 mg for females, equivalent to 6.7 g/kg/day and 8.5 g/kg/day, respectively. Groups of 100 mice of either sex served as controls. The treatment significantly shortened survival times compared with untreated controls. Significant increases in the incidences of vascular, pulmonary and renal tumours were reported. The incidence of vascular neoplasms, principally hepatic angiosarcomas and angiomas, was reportedly increased from 8 percent (controls) to 72 percent in treated females and from 5 percent to 74 percent in treated males. Similar increases in lung tumours, adenomas and adenosarcomas occurred in treated females (74 percent) 1 See Annex 2 for FAO and WHO documentation. and treated males (72 percent) compared to untreated controls (15 percent and 22 percent, respectively). In addition, 10 percent of treated males developed benign renal adenomas; none were reported in the controls. Further evaluation of this study was not possible as individual animal data was not reported (Toth et al. 1977). Groups of 50 male and 50 female Charles River B6C3F1 mice received daminozide for 104 weeks at 5 000 and 10 000 ppm in the diet, equivalent to 750 and 1 500 mg/kg/day. Twenty animals of either sex were used as controls. The animals were observed for a further week before sacrifice. The mean body weights of high-dose female mice were lower than those of the controls throughout the bioassay. However, mouse mortality was unaffected by daminozide treatment. Male mice exhibited a dose-related increase in hepatocellular carcinomas, which were significantly higher than controls at 10 000 ppm. However, the high incidence of these tumours in historical controls obscures the possible association of hepatocellular carcinomas with daminozide treatment. Furthermore, this trend was not observed in female mice. The incidence of alveolar or bronchiolar adenomas and carcinomas in treated males was not significantly higher than for the matched controls (NCI 1978). Rats Groups of 50 male and 50 female Fischer 344 rats were administered daminozide for 104 weeks at 5 000 and 10 000 ppm in the diet, equivalent to 250 and 500 mg/kg/day. Twenty rats of either sex served as controls. The animals were observed for a further week before sacrifice. Towards the end of the study, the mean body weight of the higher-dosed rats was slightly depressed. However, overall rat survival was not adversely affected by treatment, although male rats had a higher mortality from week 66 to the end of the study. Treated male rats exhibited a higher incidence of interstitial testicular cell tumours than controls. These tumours occur spontaneously at a high incidence in historical controls. Treated female rats had small numbers of endometrial adenocarcinomas and uterine leiomyosarcomas. Although these tumours were not present in the relatively smaller number of controls, the incidence was too low to be statistically significant. Nevertheless, the incidences of these tumours were higher than expected from historical control data (NCI 1978). COMMENTS Daminozide was reviewed by the 1977 Meeting but an ADI was not estimated. The rat teratogenicity study reviewed at that time was carried out by IBT and is invalid. A study subsequently published is inadequate for the evaluation of teratogenicity. Consequently, the Meeting deferred further consideration of this compound. FURTHER WORK OR INFORMATION Required (before an ADI can be estimated) 1. Adequate data to assess the carcinogenicity of daminozide. 2. An adequate teratogenicity study. 3. Information on biotransformation in animals. REFERENCES - TOXICOLOGY Khera, K.S., Whalen, C., Trivett, G. & Anyers, G. Teratologic 1979 assessment of maleic hydrazide and daminozide, and formulations of ethoxyquin, thiabendazole and naled in rats. J. Environ. Sci. Health, B14(6): 1563-77. NCI. Bioassay of daminozide for possible carcinogenicity. CAS No. 1978 1596-84-5. US National Cancer Institute, Bethesda, Md. PB- 285-073. Toth, B., Wallcave, L., Patil, L., Schmeltz, I. & Hoffman, D. 1977 Induction of tumours in mice with the herbicide succinic acid 2,2-dimethylhydrazide. Cancer Res., 37: 3497-3500.
See Also: Toxicological Abbreviations Daminozide (Pesticide residues in food: 1977 evaluations) Daminozide (Pesticide residues in food: 1989 evaluations Part II Toxicology) Daminozide (Pesticide residues in food: 1991 evaluations Part II Toxicology)