Subchronic urinary bladder toxicity evaluation of N-Nitrosodiphenylamine in Fischer 344 rats.
Female Fischer 344 (F344) rats were exposed to N-nitrosodiphenylamine (NDPA) by dietary feed at concentrations of 0, 250, 1000, 2000, 3000 or 4000 ppm for 5 days, 2, 4 and 13 weeks duration. Endpoints evaluated included clinical observations, body weights, urinary bladder weights, blood NDPA, gross pathology and urinary bladder histopathology. There were no NDPA exposure-related clinical signs of toxicity. The mean body weight decreased 3% to 5% compared with the control in the 4000 ppm group during study weeks 2 through to 13. Statistically significant increases in urinary bladder weight were observed as early as after 5 days exposure and were concentration dependent at ≥ 3000 ppm. NDPA-related urinary bladder microscopic alterations consisted of mixed cell infiltrates, increased mitosis, increased necrosis of epithelial cells, diffuse and/or nodular transitional epithelial hyperplasia and squamous metaplasia of transitional epithelium. These changes affected only rats exposed to NDPA concentrations ≥ 2000 ppm. Blood NDPA concentrations were negligible in animals exposed to ≤ 1000 ppm and ranged from 0.12 to 0.19 µg ml(-1) in rats of the ≥ 2000 ppm groups at the 5 days and 2 weeks time points. A no observable adverse effect level (NOAEL) of 1000 ppm NDPA (60 mg kg(-1) day(-1) ) was selected based on the absence of urinary bladder histopathology.
The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA.
Darol E
DE
Dodd
Linda J
LJ
Pluta
Mark A
MA
Sochaski
Kathleen A
KA
Funk
Russell S
RS
Thomas
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D008297:Male; D009602:Nitrosamines / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D059550:Toxicity Tests, Subchronic; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D009602:Nitrosamines; C023649:N-nitrosodiphenylamine