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.
Two-week and 13-week toxicity studies of hexachloro-1,3-butadiene incorporated in the diet were conducted in B6C3F1 mice. Groups of five mice of each sex received diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm hexachloro-1,3-butadiene for 15 days. Toxic responses in the 2-week studies, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough hair coats, light sensitivity, and/or in coordination), deaths (all mice in the two highest dose groups died by day 7), body and organ weight depression, and gross and histopathologic changes. The most prevalent microscopic lesion, seen in all hexachloro-1,3-butadiene-dosed mice, was renal tubular cell necrosis and/or regeneration. Regeneration was seen in lower dose groups. In addition to kidney lesions, histopathologic changes were also seen in the liver (hepatocyte necrosis, cytoplasmic vacuolization), lymphoid tissues (lymphnode necrosis, depletion), and testis (seminiferous tubule giant cells) of mice in the two highest dose groups which died during the first week of the studies.
Thirteen-week studies were conducted in which groups of 10 mice per sex received 0, 1, 3, 10, 30, or 100 ppm hexachloro-1,3-butadiene in feed(corresponding to doses of 0, 0.1, 0.4, 1.5, 4.9, or 16.8 mg/kg per day for males and 0.2, 0.5, 1.8, 4.5, or 19.2 mg/kg per day for females). No compound-related clinical signs or deaths were observed. Compared with controls, body weight gain was reduced in males receiving 30 and 100 ppm (-49% and -56%, respectively) and females receiving 100 ppm (-47%). Kidney weights were reduced in the males receiving 30 and 100 ppm and females receiving 100 ppm. A compound-related increase in tubular cell regeneration in the renal cortex occurred in male and female mice. This lesion, characterized by a diffuse increase in basophilia of the tubular epithelial cytoplasm and an increase in the number of nuclei, increased in severity with increased dose. The motility of sperm from dosed mice was lower, though not dose related, than that from controls. Female mice were more susceptible to the toxicity of hexachloro-1,3-butadiene than male mice. Based on the histopathologic evaluations, the no-observed-adverse-effect level appeared to be 10 ppm for the male mice in this 13-week study; no such level was identified for the female mice.