Dicyclanil (Veterinary Medicinal Products)

Food Safety Commission of Japan (FSCJ) conducted a risk assessment of dicycranil (CAS No. 112636-83-6), a pyrimidine-derived insect growth regulator, using the evaluation reports from the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the European Medicines Agency (EMEA), and also the Australian government. In an 18-month chronic toxicity/carcinogenicity study in mice, increased incidences of hepatocellular adenomas and carcinomas were observed in females in the 500 ppm group. In spite of a recent experiment implying the possible indirect genotoxicity of dicyclanil on the carcinogenicity, dicyclanil is unlikely to exert the carcinogenicity in vivo through the genotoxic mechanism judging from other studies. FSCJ recognized it as feasible to set the threshold value. Adverse effects detected at the lowest dose in various toxicological studies were the increased plasma levels of cholesterol and phospholipid at 100 ppm (equivalent to 2.7 mg/kg bw/day in males and 3.5 mg/kg bw/day in females) in a 90-day subacute toxicity study in dogs. No-observed-adverse-effect level (NOAEL) of this study was 20 ppm (equivalent to 0.61 mg/kg bw/day in males and 0.71 mg/kg bw/day in females). On the other hand, the NOAEL in a long term study, a 12-month chronic toxicity study in dogs was 25 ppm (equivalent to 0.71 mg/kg bw/day in males) based on increased level of plasma cholesterol observed only in males at 150 ppm (equivalent to 4.4 mg/kg bw/day in males and 5.1 mg/kg bw/day in females). The increased cholesterol levels in plasma were common in both studies in dogs. It was appropriate to choose the NOAEL for the effect on cholesterol in the longer term treatment, and thus FSCJ adopted the NOAEL of 0.71 mg/kg bw/day. Consequently, FSCJ specified the ADI of 0.0071 mg/kg bw/day for dicyclanil based on the NOAEL of 0.71 mg/kg bw/day in the 12-month chronic toxicity study in dogs, by applying a safety factor of 100.