I. INTRODUCTION 



(Prior and Ferguson, 1950; Nissim, 1957; 

 Montemurro, 1969). 



In a continuous breeding study conducted by the 

 National Toxicology Program (NTP) on nitro- 

 furazone, timed-pregnant CD®-1 mice were fed 

 dietary concentrations of nitrofurazone ranging 

 from 38 to 500 ppm. Exposure was from gesta- 

 tional age of 6-15 days, and observations were 

 continued through day 17. No teratogenic ef- 

 fects were seen in fetuses evaluated on day 17. 

 Selective embryotoxicity, expressed as an in- 

 creased incidence of late fetal death and intra- 

 uterine growth retardation, was observed at ex- 

 posure concentrations that were only marginally 

 toxic to the exposed dams (Price et al., 1985). 



Long-Term Toxicity and Carcinogenicity 



Female Holtzman rats (age not reported) given 

 3,000 ppm nitrofurantoin in feed for either 36 or 

 44.5 weeks (survival and body weights were not 

 reported) did not develop any compound-related 

 tumors (Morris et al., 1969). Similarly, tumors 

 were not induced in young female Sprague 

 Dawley rats (40-72 g) fed nitrofurantoin at 1,870 

 ppm from week to 16, at 1,000 ppm from week 

 16 to 75, and control diets from week 75 to 80 

 (Cohen et al., 1973). Body weights of dosed ani- 

 mals were stated to be reduced, but not signifi- 

 cantly, relative to those of the controls The data 

 indicate that 19/36 nitrofurantoin-dosed rats de- 

 veloped mammary gland tumors (fibroadenomas 

 or adenocarcinomas, combined), whereas 12/30 

 control animals developed these tumors. Six of 

 36 dosed and 6/30 control rats were diagnosed 

 with mammary gland adenocarcinomas. No de- 

 tails were given on survival of the dosed 

 animals. 



Ito et al. (1983) reported that nitrofurantoin ad- 

 ministered in feed to BDFi mice (C57BL/6N X 

 DBA/2N)Fi (50 males and females per dose 

 group, from 9 weeks to 2 years of age) at 0, 750, 

 or 3,000 ppm caused no differences in survival 

 but that the high dose group body weight was 

 significantly lower than that of controls 

 (P<0 05) in each sex. They concluded that there 

 were no differences in tumor incidence between 

 dosed and control animals. However, they 

 stated that negative differences did occur in 

 male mice for liver adenomas (control. 6; low 



dose, 1; high dose, 0); the number of animals ex- 

 amined in each group was not given. In female 

 mice, uterine tumors (reticulum cell sarcoma 

 type A) occurred at incidences of 7, 5, and 12. 

 Metastases from the uterine tumors were re- 

 ported to have been found in the peritoneal cavi- 

 ty, lymph nodes, liver, and lungs at incidences of 

 2, 3, and 5. The earliest uterine tumor was 

 found in the high dose group at week 44. 



Sutton et al. ( 1987a, b) reported in abstracts on 

 studies in which nitrofurantoin was fed to 

 Sprague Dawley rats (50 males and 50 females 

 per dose; 0, 15, 27, or 49 mg/kg per day) and 

 Swiss mice (Crl:CD®-l[ICR]BR; 50 males and 50 

 females per dose; 0, 50, 100, or 200 mg/kg per 

 day). No evidence of compound-related tumor 

 incidences was reported for either rats or mice. 

 The increased number of deaths in high dose 

 male mice indicates that the maximum tolerated 

 dose may have been exceeded in their studies. 



Genetic Toxicology 



Results from a variety of bacterial and fungal as- 

 says have shown that nitrofurantoin is a muta- 

 gen in vitro. Growth inhibition due to DNA 

 damage was noted in Bacillus subtilis 

 (McCarroll et al., 1981; Suter and Jaeger, 1982) 

 and in Escherichia coli (Yahagi et al., 1974; 

 McCalla and Voutsinos, 1974) following expo- 

 sure to nitrofurantoin The mutagenic activity 

 of nitrofurantoin has been demonstrated in nu- 

 merous bacterial gene reversion tests with E. 

 coli (Yahagi et al., 1974; McCalla and Voutsinos, 

 1974; Simmon and Eckford, 1978, Lu et al., 

 1979; Olive, 1979a,b) and Salmonella typhi- 

 murium. particularly strains TA98 and TAIOO, 

 which initiate error-prone DNA repair processes 

 (Wang and Lee, 1976. Goodman et al., 1977; 

 Simmon and Eckford, 1978; De Flora, 1979; 

 Ebringer and Bencova, 1980; Zeiger et al., 1981 ). 

 By comparing the results of nitrofurantoin expo- 

 sure of Salmonella strain TAIOO with those of 

 the nitro reductase-deficient strain TAIOO-FRI, 

 Rosenkranz and Speck (1976) demonstrated that 

 reduction of the nitro group is required to pro- 

 duce a mutagenic response in the absence of 

 metabolic activation. However, they observed 

 significant gene reversion in both strains of 

 Salmonella treated with nitrofurantoin in the 



21 



Nitrofurantoin, NTP TR 341 



