female B6C3Fi mice for 103 weeks. Groups of 50 female F344/N rats were fed diets containing 0, 600, 

 or 1 ,300 ppm nitrofurantoin on the same schedule. 



Body Weight and Survival in the Two-Year Studies: Mean body weights and average daily feed con- 

 sumption of dosed male and female rats were similar to those of the controls throughout the studies. 

 The average amount of nitrofurantoin consumed per day was estimated to be 60 and 110 mg/kg for 

 low and high dose male rats and 30 and 60 mg/kg for low and high dose female rats. No significant 

 differences in the number of rats surviving to the end of the studies were observed between any 

 groups of rats of either sex (male: control, 24/50; low dose, 27/50; high dose, 26/50; female: 25/50; 

 26/50; 31/50). 



Mean body weights of high dose male and female mice were up to 12% lower than those of the controls 

 throughout most of the studies. The average daily feed consumption by dosed mice ranged from 93% 

 to 100% that by controls. The average amount of nitrofurantoin consumed per day was estimated to 

 be 280-300 mg/kg and 570-580 mg/kg for low and high dose mice. The survival of the control group of 

 female mice was lower than that of the dosed groups (control, 19/50; low dose, 37/50, high dose, 37/50). 

 The decrease in survival was most likely related to the increase in microbial infection in the repro- 

 ductive tract observed in the controls. Groups of male mice had similar survival (28/50; 29/50; 34/50). 



t^onneoplastic and Neoplastic Effects in the Two-Year Studies: Organs showing toxicity from nitro- 

 furantoin exposure identified in the short term studies were the testis in male rats and mice, the 

 ovary in female rats and mice, and the kidney in male mice. Lesions observed in the 2-year studies 

 were in the testis in male rats and mice, ovary in female mice, and kidney in male rats. 



Chronic nephropathy was observed in nearly all rats, but the severity of the lesions was judged to be 

 greater in dosed male rats Hyperplasia of the transitional cell epithelium (control, 0/50; low dose, 

 5/50; high dose, 2/50) and hydronephrosis of the renal pelvis (0/50; 5/50; 2/50) were also observed in 

 dosed male rats. In the standard single sections of the left and right kidney from each rat, tubular cell 

 adenomas were observed in one low dose and two high dose males; a tubular cell carcinoma was ob- 

 served in another high dose male. Because the number of renal tubular cell neoplasms identified by 

 standard procedures in the dosed male rats was low, additional step-sections of the kidney were eval- 

 uated. The incidences of tubular cell adenomas derived from the step-sections and original sections 

 (combined) were significantly increased in dosed male rats (adenomas: 3/50; 11/50; 19/50); tubular 

 cell carcinomas occurred in two high dose males only. 



Lesions considered to be associated with the nephropathy and nitrofurantoin exposure were observed 

 in male rats and included hyperplasia of the parathyroid glands (3/49; 18/47; 23/49), fibrous osteodys- 

 trophy of the bone (0/50; 5/50; 5/50), and mineralization of the glandular stomach ( 1/49; 8/50; 14/50). 



Atypical cells of the epididymis (0/50; 0/50; 12/50) and degeneration of the testis (0/50; 0/50; 36/50) 

 were observed in high dose male rats. Fibrinoid necrosis of arterioles (1/50; 8/50; 15/50) and perivas- 

 cular infiltration of mononuclear cells (3/50; 9/50, 19/50) were also observed in the testis of male rats. 

 Interstitial cell adenomas of the testis occurred with a negative trend (47/50; 45/50; 21/50), and no 

 adenomas or carcinomas of the preputial gland were seen in high dose male rats (12/48; 11/50; 0/47). 

 The incidence of clitoral gland neoplasms was increased in low dose female rats (5/44; 10/38; 4/42). 



Osteosarcomas were observed in the bone of one low dose and two high dose male rats. The historical 

 incidence of osteosarcomas in untreated male F344/N rats is 8/1,937 (0.4%). The incidences of subcu- 

 taneous tissue neoplasms in dosed male rats were greater than that in the controls (1/50; 7/50; 5/50). 



No neoplastic lesions in dosed female rats or male mice were considered to be compound related at the 

 doses of nitrofurantoin administered. 



Nitrofurantoin, NTP TR 341 



