III. RESULTS: RATS 



Subcutaneous Tissue: The incidences of fibro- 

 mas and fibromas or fibrosarcomas (combined) 

 in low dose male rats were significantly greater 

 than those in controls (Table 14). 



Testis and Epididymis: Aspermatogenesis and 

 atrophy are frequently observed in the testis of 

 2-year-old F344/N rats and are usually associ- 

 ated with the occurrence of interstitial cell tu- 

 mors. Although these lesions were present in 

 control and dosed male rats, the incidence and 

 severity were higher in dosed rats. Degenera- 

 tion of the spermatogenic (germinal) epithelium, 

 fibrinoid necrosis of arterioles, and perivascular 

 infiltration of mononuclear infiammatory cells 

 also occurred at increased incidences in dosed 

 rats (Table 15). The degeneration of the 



spermatogenic epithelium was characterized by 

 a decrease in the number of cells, nuclear pykno- 

 sis (necrosis), cytoplasmic vacuolization, forma- 

 tion of spermatid giant cells, and accumulation 

 of cellular debris in the tubular lumens. The 

 fibrinoid necrosis involved small arteries and ar- 

 terioles and consisted of the deposition of hya- 

 line material within the intima and media. This 

 was usually accompanied by perivascular ac- 

 cumulations of lymphocytes, plasma cells, and 

 macrophages. Atypical cells occurred in the epi- 

 didymis of dosed rats. 



Interstitial cell adenomas of the testis occurred 

 with a significant negative trend, and the inci- 

 dence in the high dose group was significantly 

 lower than that in the controls (Table 16). 



TABLE 14. SUBCUTANEOUS TISSUE TUMORS IN MALE RATS [N THE TWO YEAR FEED STUDY OF 



NITROFURANTOIN 



Control 



1,300 ppni 



2,500 ppm 



Fibroma 



Overall Rates 

 Adjusted Rates 

 Terminal Rates 

 Day of First Observation 

 Life Table Tests 

 Logistic Regression Tests 



Fibrosarcoma 



Overall Rates 



Fibroma or Fibrosarcoma (a) 



Overall Rates 

 Adjusted Rates 

 Terminal Rates 

 Day of First Observation 

 Life Table Tests 

 Logistic Regression Tests 



(a) Historical incidence of fibromas, fibrosarcomas, sarcomas, neurofibromas, or neurofibrosarcomas (combined) at study 

 laboratory (mean ± SD): 28/439(6% ± 4%); historical incidence in NTP studies: 144/1,937(7% ± 4%) 



45 



Nitrofurantoin, NTP TR 341 



