TABLE 12. RENAL TUBULAR CELL LESIONS IN MALE RATS IN THE TWO-YEAR FEED STUDY 

 OF NITROFURANTOIN: ADDITIONAL STEP SECTIONS (a) 



Lesion 



Control 



1,300 ppm 



2.500 ppm 



Hyperplasia 

 Hyperplasia, cystic 

 Adenoma 

 Carcinoma 



9/50(18%) 

 1/50(2%! 

 3/50(6%) 

 0/50(0%) 



9/50(18%) 

 5/50(10%) 

 10/50(20%) 

 0/50(0%) 



7/50(14%) 

 3/50(6%) 

 17/50(34%) 

 1/50(2%) 



(a) Hyperplasia and adenomas observed in one control and three low dose males; hyperplasia, adenoma, and carcinoma 

 observed in one high dose male. 



TABLE 13. RENAL TUBULAR CELL LESIONS IN MALE RATS IN THE TWO-YEAR FEED STUDY 



OF NITROFURANTOIN: COMPOSITE RESULTS 



Lesion 



Control 



1,300 ppm 



2.500 ppm 



Hyperplasia 



Hyperplasia, cystic 



Adenoma 



Carcinoma 



Adenoma and carcinoma (combined) 



Overall Rates 



Terminal Rates 



Day of First Observation 



Lo(;istic Regression Tests 



Tubular cell hyperplasia, adenoma, and carci- 

 noma occurred in the cortex of the kidney and 

 appeared to encompass a morphologic continu- 

 um. Tubular cell hyperplasia generally was 

 characterized by one or two cross-sections of a 

 normal-to-slightly enlarged tubule with strati- 

 fied epithelium that partially or completely oc 

 eluded the tubular lumen. The cells were often 

 enlarged and contained nuclei with prominent 

 nucleoli. Adenomas were circumscribed masses 

 of epithelial cells usually larger than the cross- 

 sectional diameter of three tubules. The epithe- 

 lium formed a solid sheet of cells within the 

 mass or was arranged in packets separated by 

 basement membrane. The cells were generally 

 uniform in appearance and similar to those in 

 hyperplasia. The tubular cell carcinomas were 

 larger than the adenomas and exhibited stjme 

 cellular atypia or pleomorphism. The carcino- 

 mas did not metastasize to other organs. 



Characteristic differences between tubular cell 

 hyperplasia and adenomas in control and dosed 

 male rats are shown in f^igures 5 through 8 The 

 malignant character of the tubular cell carci- 



noma in the high dose male rat is shown in 

 Figures 9 and 10. 



Parathyroid Glands, Glandular Stomach, and 

 Bone: Hyperplasia of the parathyroid glands oc- 

 curred at increased incidences in dosed male rats 

 (male: control, 3/49; low dose, 18/47; high dose, 

 23/49; female: 0/49; 0/50; 1/47) This lesion fre- 

 quently accompanies severe renal disease, and 

 the increased incidence reflects the increased se- 

 verity of the nephropathy in dosed male rats. 

 .Mineralization of the glandular stomach (male: 

 1/49; 8/50; 14/50; female: 0/50; 2/48; 3/50) and fi- 

 brous osteodystrophy of the bone also occurred 

 with increased incidences in dosed male rats 

 (male: 0/50; .5/50; 5/50; female: none observed) 

 and were probably the result of the calcium- 

 phosphate imbalance that accompanies severe 

 renal disease. 



Osteosarcomas were observed in 1/50 low dose 

 and 2/50 high dose male rats. The overall his- 

 torical incidence of osteosarcomas in untreated 

 control male F344/N rats is 8/1,937 (0.4%). The 

 highest incidence observed in an untreated 

 control group is 2/50 



Nitrofurantoin, NTPTR341 



44 



