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 pentachlorobenzene (99% pure) in feed for 15 days or 13 weeks.
Exposure concentrations were 0, 100, 330, 1,000, 3,300, or 10,000 ppm pentachlorobenzene in the 15-day studies (five animals of each sex per group per species). All rats that received 10,000 ppm and all mice that received 3,300 or 10,000 ppm died. Of the exposed rats that survived to the end of the studies, males had an accumulation of abnormal hyaline droplets in the renal cortical epithelium and males and females had centrilobular hepatocellular hypertrophy. Chemical-related lesions were not observed in exposed mice.
Exposure concentrations were 0, 33, 100, 330, 1,000, or 2,000 ppm pentachlorobenzene in the 13-week studies (10 animals of each sex per group per species). No compound-related deaths occurred. Body weights of exposed rats but not of mice were lower than those of controls. In male rats, dose-related histologic lesions included renal tubular epithelial hyaline droplet formation 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." Exacerbation of spontaneous nephropathy characterized by renal tubular cell regeneration and homogeneous intratubular protein casts was seen in rats of each sex. Urinary protein concentration was increased in male and female rats in the 1,000- and 2,000-ppm groups; this change was especially prominent in males. Urinary glucose concentration was increased in male rats in the 330- to 2,000-ppm groups and in female rats in the 1,000 and 2,000-ppm groups. Centrilobular hepatocellular hypertrophy was observed in exposed male and female rats. Unidentified yellow-brown pigment granules were present in hepatocytes and renal tubular epithelium in exposed animals of each sex but were more prominent in females. These granules possibly contained porphyrins. The only exposure-related histologic lesion in mice of either sex was centrilobular hepatocellular hypertrophy. Significant, but not dose-related, increases of liver porphyrin concentrations were observed in exposed male rats; female rats in the 2,000-ppm group also had increased liver porphyrin concentrations. Liver porphyrin concentrations were significantly increased in the 1,000- and 2,000-ppm groups of mice of each sex. Increased sorbitol dehydrogenase concentrations in exposed rats and mice of each sex were attributed to mild hepatocyte injury.
Minimal thyroid follicular cell hypertrophy was also present in male and female rats in the 1,000 and 2,000-ppm groups. Free thyroxin and total thyroxin concentrations were significantly decreased in exposed male and female rats; these data indicate moderate hypothyroxinemia in exposed animals.
Hematologic findings in exposed rats included decreased hematocrit, hemoglobin concentration, erythrocyte count (males), mean corpuscular hemoglobin, mean erythrocyte volume, and mean corpuscular hemoglobin concentration; these findings are consistent with a mild-to-moderate anemia that is microcytic (decreased mean cell volume), hypochromic (decreased mean corpuscular hemoglobin concentration, females), and poorly regenerative (slight-to-no change in reticulocyte counts).
The no-observed effect levels (NOELs) for histologic lesions were 33 ppm for male rats and 330 ppm for female rats. The NOEL for histologic lesions in female mice was 100 ppm. An NOEL was not reached for male mice.