CHRONIC TOXICITY STUDIES OF SERTACONAZOLE AFTER ORAL-ADMINISTRATION TO RATS AND FERRETS

Six-month chronic oral toxicity studies of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy-methyl] benzo[b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2) were carried out in rats and ferrets. The dose levels used were 50, 150 and 300 mg/kg in rats and 50, 150 and 250 mg/kg in ferrets. There was no mortality associated with the drug in either of the two species. The results obtained show that the toxic effects may be summarized as a smaller body weight increase in rats at 150 and 300 mg/kg and in male ferrets at 250 mg/kg. Food consumption decreased significantly in rats at 300 mg/kg, and was not proportional to the doses of 150 and 50 mg/kg. In serum biochemistry, increases in alkaline phosphatase in rats, ALT in male ferrets at 150 and 250 mg/kg and AST only at 250 mg/kg were observed. BUN increased at 150 and 250 mg/kg in ferrets. Organ weights did not show hepatomegalia in either of the two species. In ferrets, the ovaries significantly increased in weight. The histopathological study in the rats showed some very characteristic microvacuolization changes in the hepatocytary cytoplasm, possibly associated with the induction of microsomal enzymes described for imidazoles. In the ferrets, persistent large corpora lutea were found in the ovaries of the animals treated with doses of 250 and 150 mg/kg, responsible for the increase in ovary weight, and also for the ductal hyperplasia of the mammary gland and endometrium, due to the known inhibitory effect on the synthesis of adrenal steroids caused by these derivatives. Since all these effects, common to imidazoles, were observed in doses of over 50 mg/kg, sertaconazole may be considered to be very safe, far more so than other antifungals of this group.