Thirteen-week inhalation toxicity of p-dichlorobenzene in mice and rats

Subchronic inhalation toxicity of p-dichlorobenzene (p-DCB) was examined by exposing BDF1 mice and F344 rats of both sexes (6 h/d and 5 d/wk) to inhalation of 25, 55, 120, 270 or 600 ppm (v/v) p-DCB vapor for 13 wk. The exposure to p-DCB vapor retarded the growth rate in the male mice, and induced hepatotoxicity in the mice and rats of both sexes and renal and hematological toxicity in the male rats. Hepatotoxicity was characterized by increased liver weight, hepatocellular hypertrophy, and increased serum levels of total cholesterol. Liver necrosis and increased serum levels of AST and ALT were observed in the exposed mice, whereas these changes, which indicate hepatocellular death, did not occur in any of the exposed rats. p-DCB-induced renal lesions occurred only in the male rats. Hyaline droplets were observed in the proximal tubular epithelial cells, and were stained positively with anti-alpha2u-globulin, suggesting excessive accumulation of alpha2u-globulin in the epithelial cells. Granular casts were formed in the tubular lumen, resulting from the necrotic desquamation of the renal tubular epithelium. Papillary mineralization in the renal pelvis and increased serum levels of BUN and creatinine were noted. These renal changes indicated alpha2u-globulin nephropathy. Decreases in red blood cell counts, hemoglobin concentration, hematocrit and mean corpuscular volume and increased spleen weight occurred in the exposed male rats. The NOAEL was 120 ppm for the hepatic endpoint in mice and for the renal endpoint in rats. The maximum tolerated dose for a 2-yr bioassay inhalation study of rodent carcinogenicity was estimated to be 300 ppm, based on the present results.