For female mice, ovarian atrophy was observed in 48/50 low dose and 49/50 high dose mice but not in 

 controls. Tubular cell adenomas of the ovary (0/50; 0/50; 5/50), benign mixed tumors (tubular and 

 stromal) (0/50; 0/50; 4/50), and granulosa cell tumors (0/50; 3/50; 2/50) were observed in dosed female 

 mice. One granulosa cell tumor in the high dose group was malignant. Ovarian abscesses (18/50) and 

 suppurative inflammation of the uterus ( 1 1/50) were observed in control female mice but not in dosed 

 female mice and are believed to be related to indigenous microbial infections and most likely were the 

 cause of early deaths in this group Adenocarcinomas of the uterus were seen in one low dose and in 

 one high dose mouse. 



Testicular aspermatogenesis ( 1/49; 1/49; 16/50), degeneration of the germinal epithelium (0/49; 3/49; 

 23/50), and atypical cells (0/50; 0/49; 26/50) and depletion ( 1/50; 1/49, 15/50) of the epididymis were ob- 

 served at increased incidences in high dose male mice. 



Spindle cell hyperplasia of the adrenal cortex was observed in dosed female mice (3/50, 41/50, 45/50). 

 A spindle cell adenoma (adrenal capsule adenoma) was seen in one low dose female mouse, and a 

 spindle cell carcinoma (adrenal capsule carcinoma) was seen in one low dose male mouse. 



Mineralization of the renal medulla (male: 0/50; 0/50; 17/50; female: 0/50; 0/50; 7/50) and dilatation 

 of the renal tubules (male: 0/50; 0/50; 14/50) were observed in high dose mice. 



Hepatocellular neoplasms (adenomas or carcinomas, combined) were observed at an increased inci- 

 dence in high dose female mice (2/50; 2/50; 8/50) An Ito cell tumor of the liver was observed in one 

 low dose and one high dose female mouse Malignant lymphomas occurred in female mice (12/50; 

 19/50; 24/50). 



Genetic Toxicology: Nitrofurantoin was mutagenic in Salmonella typhimurium strains TA98 and 

 TAIOO, with and without metabolic activation, but was not mutagenic for strains TA1535 or TA1537. 

 Nitrofurantoin induced forward mutations at the TK"^'" locus of L5178Y mouse lymphoma cells in 

 the absence of metabolic activation (it was not tested with activation). Nitrofurantoin induced in- 

 creased numbers of sister chromatid exchanges and chromosomal aberrations in cultured Chinese 

 hamster ovary cells with and without metabolic activation. Results of the sex-linked recessive lethal 

 assay in Drosophila were negative after administration of nitrofurantoin by feeding or by injection. 



Conclusions: Under the conditions of these 2-year feed studies, there was some evidence of carcino- 

 genic activity* of nitrofurantoin for male [''344/N rats as shown by increased incidences of uncommon 

 kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcuta- 

 neous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis 

 and neoplasms of the preputial gland were decreased in the 2,500 ppm group of male rats. There was 

 no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 

 ppm or 1 ,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no 

 evidence of carcinogenic activity of nitrofurantoin for male B6C3Fi mice fed diets containing 1,300 

 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for 

 female B6C3Fi mice as shown by increased incidences of tubular adenomas, benign mixed tumors, 

 and granulosa cell tumors of the ovary. 



Nonneoplastic lesions considered related to nitrofurantoin exposure were chronic nephropathy and 

 associated lesions (hyperplasia of the parathyroid gland, fibrous osteodystrophy of the bone, and 

 mineralization of the glandular stomach) in male rats and testicular degeneration in male rats and 

 mice. Ovarian atrophy and hyperplasia of the adrenal cortex spindle cells were observed in dosed fe- 

 male mice. 



*Explanationof Levels of Evidence of Carcinogenic Activity is on page 7. 



A summary of the Peer Review comments and the pub he discussion on this Technical Report appears on pages 11-13. 



Nitrofurantoin, NTPTK341 



