Dexamethasone (Veterinary medicinal products)

Abstract

Food Safety Commission of Japan (FSCJ) conducted a risk assessment of dexamethasone (CAS No. 50-02-2), a synthetic adrenocortical hormone, using mainly the evaluation reports from the Joint FAO/WHO Expert Committee on Food Additives (JECFA), and the European Medicines Agency (EMEA). Major adverse effects of dexamethasone were observed in the decrease in white blood cell count (WBC), atrophy of thymus and spleen as well as the decrease in adrenal weights, which were found in various toxicity studies. These effects are attributable to the glucocorticoid action. FSCJ supported the EMEA's judgment "dexamethasone lacks structural similarity with known carcinogens", and concluded that this drug is unlikely to be carcinogenic. Teratogenicity was observed in rats developmental toxicity studies and the no-observed-adverse-effect level (NOAEL) for fetus was 10 μg/kg bw/day. The effect observed at the lowest dose in various toxicological studies was decreased WBC in rats in an endocrinological study. The NOAEL in this study was 1μg/kg bw/day. JECFA and EMEA specified an acceptable daily intake (ADI) based on the pharmacological action, the induction of tyrosine aminotransferase activity (TAT), in rat liver. However FSCJ judged this endpoint is not appropriate to establish an ADI, because the increase of TAT in response to glucocorticoid was a physiological response, and the relationship of changes in TAT with the toxicological findings was obscure. Consequently, FSCJ specified the ADI for dexamethasone at 0.01μg/kg bw/day, based on NOAEL of 1μg/kg bw/day, which was obtained in rats in an endocrinological study, applying a safety factor of 100.