TERATOLOGICAL STUDY OF CEFODIZIME SODIUM IN MICE : Intravenous Administration during Period of Organogenesis

Abstract

Cefodizime sodium (THR-221) was intravenously administered at dose levels of 300, 1000 and 3000 mg/kg/day to pregnant mice on days 6-15 of gestation covering the period of organogenesis, and its effects on the dams (F0) and the fetal and postnatal development and fertility of their offspring (F1) were examined. In each group including a control group, 21-24 of the 33-38 F0 dams were submitted to cesarean section on day 18 of gestation, and the remaining 12-14 animals were allowed to litter normally and nurse their offspring until day 21 of lactation. In the F0 dams, no compound effects were seen in general conditions, body weight, food consumption, numbers of corpora lutea and implantations or duration of gestation. The thymus weights of the cesarean sectioned dams at 1000 and 3000 mg/kg/day were less than the control values, but no difference appeared in weights of the other main organs between any treatment group and the control group. No gross visceral abnormalities were noted at any dose. In F1 near-term fetuses, the compound administration exerted no effects on their development at any dose, except the decreased body weight and crown-rump length noted at 3000 mg/kg/day. No difference occurred in incidence of fetuses with external, visceral or skeletal anomalies between any treatment group and the control group. Normally delivered F1 offspring in the treatment groups exhibited no changes from the controls in postnatal development, reflexes, 21-day survival index or behavioral test performance. Skeletal examination on F1 offspring which died during lactation and autopsies on the other animals at the end of study revealed no compound-related abnormalities. The fertility of the F1 mice was normal at all doses, and there were no compound effects on the F1 dams or their near-term fetuses or newborn pups. From the present results, it is considered that the no-effect doses of THR-221 for the maternal mice and their offspring are 300 and 1000 mg/kg/day, respectively.