Nitrofurazone, a widely used antimicrobial agent, was evaluated for potential developmental toxicity. Artificially-inseminated New Zealand White rabbits were exposed to NF (O, 5, 10, 15 or 20 mg/kg/day , po) in corn oil vehicle throughout major organogenesis [gestational days 6-19]. At scheduled sacrifice (gd 30), the uterine contents of 121 confirmed pregnant does were evaluated (22-27 per group).
No maternal deaths occurred at 0, 5, 10 or 15 mg NF/kg/day; an 8% (2/26) mortality rate was observed at the high dose. Clinical signs were observed more frequently in NF-exposed animals, but no clear dose-related pattern was associated with these findings. No differences among groups were observed for maternal body weight (gd 0, 6, 12 or 30), maternal weight gain during gestation, or corrected gestational weight gain. On the final day of dosing (gd 19), a significant downward trend for maternal body weight was observed due to minor reductions at 10, 15 and 20 mg/kg/day (98.5%, 95.7% and 94.1% of controls, respectively). In addition, a significant downward trend for gravid uterine weight was observed due to reductions at 20 mg/kg/day . The 20 mg/kg/day group exhibited significantly decreased maternal weight gain during treatment, and increased maternal liver weight (both absolute and relative), but no clear treatment-related effects were observed for these paremeters at 5-15 mg/kg/day .
Among live litters, NF exposure did not affect the number of live fetuses per litter, percentage of male fetuses per litter, or average fetal body weight per litter. Among all pregnant females, however, a significant increase was observed in the high-dose group for the percentage of resorptions per litter. The mean percentage of resorptions per litter was 7.49%, 2.74%, 13.15%, 8.67% and 30.86% in the vehicle through high-dose groups, respectively. The percentage of live fetuses malformed per litter was also increased at the high dose (2. 68%, 6.15%, 0.38%, 4.84% and 14.60% for the control through high-dose groups, respectively). A sex-selective effect of nitrofurazone upon morphological development was observed in which male fetuses were not affected, and female fetuses exhibited a significant increase in malformation incidence at 20 mg/kg/day .
In summary, no definitive evidence of maternal or embryo/fetal toxicity was observed following administration of NF at 5, 10 or 15 mg/kg/day , po. NF exposure at 20 mg/kg/day was associated with 8% (2/26) maternal mortality, reduced maternal weight gain during treatment, increased maternal liver weight (both absolute and relative), increased resorption of implanted conceptuses and an increased incidence of malformed live fetuses per litter Thus, the present investigation provided evidence of adverse embryo/fetal effects only at a dose which was lethal to 8% of the pregnant females.