Nitrofurazone (NTFZ) was evaluated for reproductive toxicity in CD-1 (Swiss) mice using Reproductive Assessment by Continuous Breeding Protocol (RACB). Male and female mice were exposed to NTFZ in feed at doses of 0, 100, 375, and 750 ppm (15 to 124 mg/kg/day).
At 750 ppm in female F0 animals. increased relative kidney plus adrenal weight and hepatic centrilobular hypertrophy were seen. For males, doses of equal to or greater than 375 ppm increased kidney effects. Reproductive toxicity was observed in the F0 generation at all dose levels and increased in a dose-related manner. In all NTFZ-treated groups, testicular degeneration, increase in the percent abnormal sperm, and reduced relative ovary plus oviduct weight were observed. At 375 and 750 ppm, fertility and fecundity were reduced, as were sperm concentration and testis and/or epididymis weight. At the high dose, males were infertile and exhibited testicular hypospermia and epididymal hypo- or azoospermia, and elevated relative intratesticular testosterone concentration. During Task 2, adverse effects of treatment on delivery and postnatal care were noted, primarily at 375 ppm NTFZ, and included live or dead pups left inside the amniotic sac or with the placenta attached, pups born prematurely, or an extended (more than 24 hours) delivery period.
In Task 3, the treated males were infertile, whereas the treated females exhibited reduced litter size and adjusted pup body weight.
For F1 males, 100 ppm produced a borderline increase in nephropathy. For F1 females, 375 ppm decreased postnatal survival and decreased female body weight. Reproductive toxicity, including a decrease in the proportion of pups born alive. secondary to a decrease in the number of live-born female pups per litter, and a shortened gestational period were observed at 375 ppm. Relative cauda epididymis weight was decreased at both 100 and 375 ppm NTFZ, whereas a decrease in sperm concentration and increase in the percent abnormal sperm, and significant testicular degeneration were observed at 375 ppm. Absolute and relative intratesticular testosterone concentrations were unaffected. Estrous cycle length and pattern were significantly affected at both 100 and 375 ppm.
In summary, the MTD for generalized toxicity was 375 ppm for the F0 generation and 100 ppm for the F1 generation. The No- Observed-Adverse-Effect- Level (NOAEL) for systemic toxicity was 100 ppm for the F0 generation. A NOAEL for the F1 generation could not be determined . Reproductive toxicity was observed at all treatment levels tested for both generations. Thus, there was no NOAEL for reproductive toxicity in this study. NTFZ was a reproductive toxicant to CD-1 mice in both the Fn and F1 generations at doses at and below those which caused systemic toxicity.
NTIS # PB92-217694