IV. DISCUSSION AND CONCLUSIONS 



potential metabolic reaction could involve hy 

 drolysis of the carbon-nitrogen bond, resulting 

 in production of a furfuraldehyde and an imida- 

 zole. Aldehydes, hydrazines, semicarbazides, 

 imidazoles, and related compounds have clasto- 

 genic potential. However, nitrofurantoin has 

 not demonstrated mutagenic activity in any of 

 the in vivo somatic and germ cell test systems in 

 which it has been studied. 



The experimental and tabulated data for the 

 NTP Technical Report on nitrofurantoin were 

 examined for accuracy, consistency, complete- 

 ness, and compliance with Good Laboratory 

 Practice regulations. As summarized in Appen- 

 dix I, the audit revealed no major problems with 

 the conduct of the studies or with collection and 

 documentation of the experimental data. No dis- 

 crepancies were found that influenced the final 

 interpretation of the results of these studies. 



Under the conditions of these 2-year feed stud- 

 ies, there was some evidence of carcinogenic 

 activity* of nitrofurantoin for male F344/N rats 

 as shown by increased incidences of uncommon 

 kidney tubular cell neoplasms. Uncommon 



osteosarcomas of the bone and neoplasms of the 

 subcutaneous tissue were observed in dosed 

 male rats. Incidences of interstitial cell adeno- 

 mas 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 tol- 

 erate higher doses. There was no evidence of car- 

 cinogenic 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 fe- 

 male B6C3P'i mice as shown by increased inci- 

 dences of tubular adenomas, benign mixed tu- 

 mors, and granulosa cell tumors of the ovary. 



Nonneoplastic lesions considered related to ni- 

 trofurantoin exposure were chronic nephropathy 

 and associated lesions (hyperplasia of the para- 

 thyroid gland, fibrous osteodystrophy of the 

 bone, and mineralization of the glandular stom- 

 ach) in male rats and testicular degeneration in 

 male rats and mice. Ovarian atrophy and hy- 

 perplasia of the adrenal cortex spindle cells were 

 observed in dosed female mice. 



•Explanation of Levels of Evidence of Carcinogenic Activity is on page 7. 



A summary of the Peer Review comments and the public discussion on this Technical Report appears on pages 1113. 



Nitrofurantoin, NTP TR 34 1 



66 



