Comparative Toxicities of o-, m-, and p-Nitrotoluene in 13-Week Feed Studies in F344 Rats and B6C3F1 Mice

Nitrotoluenes are high-production-volume chemicals used in thesynthesis of agricultural chemicals and in various dyes. Becauseof differences in the metabolism of the three isomers and theircapabilities to bind to DNA, comparative toxicity studies ofo-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F₁mice. o-, m-, and p-Nitrotoluene was administered in the feedto male and female rats and mice at doses ranging from 625 to10,000 ppm for 13 weeks. These doses delivered approximately40 to 700 mg/kg body wt/day for rats and 100 to 1700 mg/kg/dayfor mice. There were no treatment-related effects on survivalin any of the studies. Decreased body weights relative to controlsoccurred in dosed rats and mice in all studies at the higherdose levels and were most pronounced in rats receiving o-nitrotoluene.Mesotheliomas of the tunica vaginalis were observed in 3 of10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelialcell hyperplasia was observed in 2 of 10 male rats receivingo-nitrotoluene at 10,000 ppm. Kidney toxicity was observed inmale rats receiving o-, m-, or p-nitrotoluene and included hyalinedroplet nephropathy and an associated increase in the renalconcentration of _2U-globulin Evidence of liver toxicity in themale rats receiving o-nitrotoluene included hepatocyte vacuolization,oval cell hyperplasia, and increased serum bile acids, sorbitoldehydrogenase, and alanine aminotransferase. Although therewas no histopathologic evidence of hepatic toxicity in maleor female rats given the m- or p-isomers or in female rats giventhe o-isomer, treatment-related hepatic effects were detectedin these groups, as measured by an increase in the relativeliver weights and by elevations in serumbile acids and liver-specificenzymes. The spleens of treated male and female rats had a mildincrease in hematopoiesis, hemosiderin deposition, and/or congestion.These splenic changes were slightly more prominent in rats administeredthe o- and p- isomers. Administration of o-, m-, or p-nitrotolueneimpaired testicular function in the rat, as shown by testiculardegeneration and reduction in the density, motility, and numberof sperm cells. Administration of each isomer to rats causedincreases in the length of the estrus cycle. The only histopathologicevidence for treatment-related toxicity in mice in the 13-weekstudies occurred in animals receiving the o-nitrotoluene isomerwhere the chemical caused degeneration and metaplasia of theolfactory epithelium. These comparative toxicity studies ofo-, m-, or p-nitrotoluene showed that all three chemicals causedtoxicity in the kidney, spleen, liver, and/or reproductive systemin rats. In general, toxicity was most severe with the ortho-isomer.In mice, olfactory epithelium degeneration was the only treatment-relatedlesion induced by o-nitrotoluene. Elevations in liver weightswere observed at the higher dose levels in rats and mice treatedwith any of the three isomers. o-Nitrotoluene was car cinogenicin male rats, as indicated by the occurrence of mesotheliomasat 5000 ppm and mesothelial cell hyperplasia at 10,000 ppm.