Melengestrol Acetate (Veterinary Medicinal Products)

摘要

Food Safety Commission of Japan (FSCJ) conducted a risk assessment ofmelengestrol acetate (MGA, CAS No. 2919-66-6), a synthetic hormone, based onresults from various studies. MGA was recognized to have no genotoxicityrelevant to human health, and it enabled FSCJ to specify an acceptable dailyintake (ADI) in the assessment. studies using varioushuman hormone-receptors showed that MGA exerts biological action primarily asprogestogens and secondarily as glucocorticoids. Major adverse effects of MGAobserved were mammary gland hyperplasia, endometrial hyperplasia, and a lack ofcorpora lutea, accompanying the elevated level of serum prolactin. Increasedincidence of mammary gland tumor was observed in C3Han/f mice at the dose of1.5 mg/kg bw/day in a carcinogenicity study. The increase was presumably due toMGA-induced hyperprolactinemia, but not a direct effect of MGA from theexperiment, using a prolactin inhibitor. Inhibitions of estrus and ovulation, inaddition to dystocia, were observed in female animals in the reproductive anddevelopmental toxicity studies. Malformations such as cleft palate, clubfoot,umbilical hernia, and defective skeletal ossification were observed in rabbitsat doses of 0.8 and 1.6 mg/kg bw/day in a developmental toxicity study. However,these were likely due to the corticosteroidal (glucocorticoid) action of MGA.The no-observed-adverse-effect level (NOAEL) was obtained from a rhesus monkeystudy given orally 1.5 µg/kg bw/day of MGA over the one menstrual-cycle. Thevalue was, however, the result of the study using the large common ratio of 10.In another study, the lowest-observed-adverse-effect level (LOAEL) of 5 µg/kgbw/day, obtained from a cynomolgus monkey given MGA over the threemenstrual-cycles. The LOAEL value was estimated close to the biologicalthreshold, because of no obvious hormonal disorders despite of minimal change ofmenstrual cycle. Therefore, FSCJ considered it appropriate to specify an ADI onthe basis of the LOAEL obtained from a cynomolgus monkey study over the threemenstrual-cycles, and to add an additional safety factor of 2. Consequently,FSCJ specified the ADI of 0.025 µg/kg bw/day by applying a safety factor of 200to the LOAEL of 5 µg/kg bw/day in a cynomolgus monkey study over the threemenstrual-cycles.