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

Abstract

Nitrotoluenes are high-production-volume chemicals used in the synthesis of agricultural chemicals and in various dyes. Because of differences in the metabolism of the three isomers and their capabilities to bind to DNA, comparative toxicity studies of o-, m-, and p-nitrotoluene were conducted in F344 rats and B6C3F1 mice. o-, m-, and p-Nitrotoluene was administered in the feed to male and female rats and mice at doses 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 occurred in dosed rats and mice in all studies at the higher dose levels and were most pronounced in rats receiving o-nitrotoluene. Mesotheliomas of the tunica vaginalis were observed in 3 of 10 male rats receiving o-nitrotoluene at 5000 ppm, and mesothelial cell hyperplasia was observed in 2 of 10 male rats receiving o-nitrotoluene at 10,000 ppm. Kidney toxicity was observed in male rats receiving o-, m-, or p-nitrotoluene and included hyaline droplet nephropathy and an associated increase in the renal concentration of α2U-globulin Evidence of liver toxicity in the male rats receiving o-nitrotoluene included hepatocyte 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 measured by an increase in the relative liver weights and by elevations in serumbile acids and liver-specific enzymes. The spleens of treated male and female rats had a mild increase in hematopoiesis, hemosiderin deposition, and/or congestion. These splenic changes were slightly more prominent in rats administered the o- and p- isomers. Administration of o-, m-, or p-nitrotoluene impaired testicular function in the rat, as shown by testicular degeneration and reduction in the density, motility, and number of sperm cells. Administration of each isomer to rats caused increases in the length of the estrus cycle. The only histopathologic evidence for treatment-related toxicity in mice in the 13-week studies occurred in animals receiving the o-nitrotoluene isomer where the chemical caused degeneration and metaplasia of the olfactory epithelium. These comparative toxicity studies of o-, m-, or p-nitrotoluene showed that all three chemicals caused toxicity in the kidney, spleen, liver, and/or reproductive system in rats. In general, toxicity was most severe with the ortho-isomer. In mice, olfactory epithelium degeneration was the only treatment-related lesion induced by o-nitrotoluene. Elevations in liver weights were observed at the higher dose levels in rats and mice treated with any of the three isomers. o-Nitrotoluene was car cinogenic in male rats, as indicated by the occurrence of mesotheliomas at 5000 ppm and mesothelial cell hyperplasia at 10,000 ppm.