These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.
Toxicology studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to 1,2,4,5-tetrachlorobenzene (greater than 99% pure) at various concentrations in formulated diets for 14 days or 13 weeks.
Dietary concentrations were 0, 30, 100, 300, 1,000, or 3,000 ppm 1,2,4,5-tetrachlorobenzene in the 14 day studies. All rats survived to the end of the studies, but all mice in the 3,000-ppm groups died (five animals per group). Histologically, exposed male rats had an accumulation of abnormal hyaline droplets in the renal cortical epithelium. Significant histologic lesions were not seen in female rats or in mice of either sex.
Dietary concentrations were 0, 30, 100, 300, 1,000, or 2,000 ppm 1,2,4,5-tetrachlorobenzene in the 13-week studies (10 animals per group). All rats survived to the end of the studies; two female mice in the 2,000-ppm group were killed in a moribund condition. Body weight gains in the higher dose groups of rats and mice were less than those of controls. In exposed male rats, lesions included renal cortical tubular epithelial hyaline droplet formation, cortical tubular regeneration, and medullary granular casts and mineralization. This spectrum of renal lesions in male rats is consistent with the entity described as "hydrocarbon or hyaline droplet nephropathy." In some exposed female rats (30- to 2,000-ppm groups), there was renal cortical tubular cell regeneration plus accumulation of an unidentified yellow-brown pigment in the renal cortical epithelium.
Centrilobular hepatocellular hypertrophy was observed in the livers of exposed male and female rats. In mice, minimal-to-mild centrilobular hepatocellular hypertrophy was present in males in the 1,000 and 2,000-ppm groups and in females in the 2,000-ppm group. Minimal-to-mild individual hepatocyte degeneration occurred in mice of each sex in the 2,000-ppm groups. Increased serum sorbitol dehydrogenase and alanine aminotransferase activity was observed in the two highest dose groups of male and female mice and indicated hepatocellular injury. Thyroid follicular cell hypertrophy was present in male rats in the 300- to 2,000-ppm groups and in female rats in the 100- to 2,000-ppm groups. Decreased free thyroxin and total thyroxin concentrations in male rats in the 300- to 2,000 ppm groups and female rats in the 30- to 2,000-ppm groups indicated a primary hypothyroid state. Hematologic findings for rats that received 1,000 or 2,000 ppm included significantly decreased hematocrit values, hemoglobin concentration, and erythrocyte counts for males and decreased mean cell volume for females; for mice, decreased hemoglobin concentrations, mean corpuscular hemoglobin, hematocrit, and mean cell volume were observed in males in the 2,000-ppm group and in females in the 1,000- and 2,000-ppm groups. These findings suggest a poorly regenerative anemia in both species.
The no-observed-effect level (NOEL) for histologic lesions was 30 ppm for male and female rats. The NOEL for histologic lesions in male and female mice was 300 ppm.