COMPARATIVE TOXICITIES OF O-NITROTOLUENE, M-NITROTOLUENE, AND P-NITROTOLUENE IN 13-WEEK FEED STUDIES IN F344 RATS AND B6C3F(1) MICE

Nitrotoluenes are high-production-volume chemicals used in the synthes is of agricultural chemicals and in various dyes. Because of differenc es in the metabolism of the three isomers and their capabilities to bi nd to DNA, comparative toxicity studies of o-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F(1) mice. o-, m-, or p-Nitrotolue ne was administered in the feed to male and female rats and mice at do ses ranging from 625 to 10,000 ppm for 13 weeks. These doses delivered approximately 40 to 700 mg/kg body wt/day for rats and 100 to 1700 mg /kg/day for mice. There were no treatment-related effects on survival in any of the studies. Decreased body weights relative to controls occ urred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. Mesotheliom as of the tunica vaginalis were observed in 3 of 10 male rats receivin g o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was obs erved in 2 of 10 male rats receiving o-nitrotoluene at 10,000 ppm. Kid ney toxicity was observed in male rats receiving o-, m-, or p-nitrotol uene and included hyaline droplet nephropathy and an associated increa se in the renal concentration of alpha(2U)-globulin. Evidence of liver toxicity in the male rats receiving o-nitrotoluene included hepatocyt e vacuolization, oval cell hyperplasia, and increased serum bile acids , sorbitol dehydrogenase, and alanine aminotransferase. Although there was no histopathologic evidence of hepatic toxicity in male or female rats given the m- or p-isomers or in female rats given the o-isomer, treatment-related hepatic effects were detected in these groups, as me asured by an increase in the relative liver weights and by elevations in serum bile acids and liver-specific enzymes. The spleens of treated male and female rats had a mild increase in hematopoiesis, hemosideri n deposition, and/or congestion. These splenic changes were slightly m ore prominent in rats administered the o- and p-isomers. Administratio n of o-, m-, or p-nitrotoluene impaired testicular function in the rat , as shown by testicular degeneration and reduction in the density, mo tility, and number of sperm cells. Administration of each isomer to ra ts caused increases in the length of the estrus cycle. The only histop athologic evidence for treatment-related toxicity in mice in the 13-we ek studies occurred in animals receiving the o-nitrotoluene isomer whe re the chemical caused degeneration and metaplasia of the olfactory ep ithelium. These comparative toxicity studies of o-, m-, or p-nitrotolu ene showed that all three chemicals caused toxicity in the kidney, spl een, liver, and/or reproductive system in rats. In general, toxicity w as most severe with the ortho-isomer. In mice, olfactory epithelium de generation was the only treatment-related lesion induced by o-nitrotol uene. Elevations in liver weights were observed at the higher dose lev els in rats and mice treated with any of the three isomers. o-Nitrotol uene was carcinogenic in male rats, as indicated by the occurrence of mesotheliomas at 5000 ppm and mesothelial cell hyperplasia at 10,000 p pm. (C) 1994 Society of Toxicology.