IV. DISCUSSION AND CONCLUSIONS 



Nitrofurantoin was studied and evaluated be- 

 cause of its widespread use as a drug for treating 

 urinary tract infections in humans, its struc- 

 tural relationship to known carcinogenic 5-ni- 

 trofuran compounds (lARC, 1974; Cohen, 1978), 

 and the lack of adequate studies to assess its car- 

 cinogenicity. Toxicology and carcinogenesis 

 studies of nitrofurantoin were conducted by ad- 

 ministering USP-grade nitrofurantoin (greater 

 than 99% pure) in feed to groups of F344/N rats 

 and B6C3Fi mice of each sex for 14 days, 13 

 weeks, or 2 years. In the 2-year studies, nitrofu- 

 rantoin was administered in feed at 0, 1,300, or 

 2,500 ppm to male rats and male and female 

 mice and at 0, 600, or 1 ,300 ppm to female rats. 



In the 13-week studies, only one rat (a high dose 

 female) died. Mean body weights relative to 

 those of controls were similar for dosed male and 

 dosed female rats, but because of the lower rela 

 tive mean body weight of females in the 2,500- 

 ppm group, the dietary concentrations selected 

 for the 2-year studies were lower for females 

 than for other groups. P'or mice, two deaths oc- 

 curred in the high dose male group, but final 

 mean body weights relative to those of controls 

 were similar for males and females. Organs af- 

 fected in the 13- week studies were the testis or 

 ovary in rats and mice and the kidney in male 

 mice. 



In the 2-year studies, there were no significant 

 differences in survival between dosed and con- 

 trol groups of rats of either sex or male mice (see 

 Tables 10 and 23). Regarding female mice, the 

 survival of the control group was lower than that 

 of both the low and high dose groups. Ovarian 

 abscesses and suppurative infiammation of the 

 uterus were observed only in control female 

 mice. These infections are believed to be indige- 

 nous and were absent in dosed mice, most likely 

 due to the therapeutic activity of nitrofurantoin. 

 Treatment at the doses used in these studies 

 would be expected to achieve the minimally ef- 

 fective dose level (-30 pg/ml urine) against a 

 broad spectrum of bacteria (Paul, M.F., et al., 

 1960; Buzard et al., 1961; Veronese et al., 1974; 

 Liedtke et al., 1980; Hoener and Patterson, 

 1981). 



Generally, body weights and estimated feed con- 

 sumption values indicate that no or minimal 

 overt toxicity or feed palatability problems were 



encountered in these studies except for female 

 mice. Absorption, metabolism, and excretion of 

 nitrofurantoin are rapid (Paul, M.F , et al., 1960; 

 Buzard et al., 1961; Conklin and Hailey, 1969; 

 Conklin, 1972a,b; Veronese et al., 1974; Maiti 

 and Banerjee, 1978; Wierzba et al., 1982) and 

 change with age in both humans and rats 

 (Braunlich et al., 1978; Wierzba et al., 1982). Af- 

 ter an initial decrease relative to controls, body 

 weight differences between dosed and control 

 rats leveled off. This adaptive response may be 

 due to an age dilTerence in susceptibility to ni- 

 trofurantoin, toxicity, or possible metabolic 

 adaptation (enzyme induction) to chemical expo- 

 sure. High dose male mice demonstrated similar 

 differences in body weight relative to those of 

 controls throughout the study. The exception 

 may be the high dose female mice, whose body 

 weights were decreased relative to those of the 

 controls. Interpretation is made more difficult 

 because of the decreased survival of control fe- 

 male mice. Survival of dosed female mice was 

 not affected, and body weight differences may 

 have been due to palatability of nitrofurantoin 

 or to induced neoplasia. 



The oral (gavage) toxicity of nitrofurantoin var- 

 ies somewhat between rats (LD5() = 604 mg/kg) 

 and mice (LD5o = 360 mg/kg) (Preti, 1970; 

 NIOSH, 1983). The toxicity of nitrofurantoin 

 administered in feed over longer daily time 

 periods is different. The absorption and urinary 

 excretion of macrocrystalline nitrofurantoin (ad- 

 ministered in a capsule) were greater in non- 

 fasting than in fasting volunteers (Bates et al., 

 1974); a much smaller difference was observed 

 for the microcrystalline form (given as a tablet). 

 In the current NTP studies, the doses of nitro- 

 furantoin consumed by rats (up to 110 mg/kg per 

 day) would not be expected to be overtly toxic. 

 In mice, the doses (300 or 570 mg/kg, males; 280 

 or 580 mg/ kg, females) might have been lethal if 

 given as a single bolus but apparently were well 

 tolerated given over a period of 24 hours. The 

 recommended dosage of nitrofurantoin for hu- 

 mans is 50-100 mg, four times a day for 2 weeks 

 (Penn and Griffin, 1982). However, treatment 

 may continue for longer periods (6-30 months) 

 and at higher doses (Simonian et al., 1977; Penn 

 and Griffin, 1982); for an individual weighing 70 

 kg, this is equivalent to approximately 3-6 mg/kg 

 per day up to 10 mg/kg per day. 



Nitrofurantoin, NTP TR 341 



62 



