Oral Toxicity of 1,2-Dichloropropane: Acute, Short-Term, and Long-Term Studies in Rats

Oral Toxicity of 1,2-Dichloropropane: Acute, Short-Term, andLong-Term Studies in Rats. BRUCKNER, J. V., MACKENZIE, W. F.,RAMANATHAN, R., MURALIDHARA, S., KIM, H. J.,AND DALLAS, C. E.(1989). Fundam. Appl. Toxicol 12, 713–730. The objectiveof this investigation was to characterize the acute and short-and long-term toxic potency of orally administered 1,2dichloropropane(DCP). In the acute and short-term studies, male rats of 250–300g were gavaged with 0, 100,250,500, or 1000 mg DCP/kg in cornoil once daily for up to 10 consecutive days. Although ingestionof DCP caused body weight loss and CNS depression, few othertoxic effects were manifest 24 hr after a single dose of thechemical. Morphological changes were limited to liver centrilobularcells in 500 and 1000 mg/kg rats. Similarly, elevated activityof some serum enzymes cccurred only at these two highest doselevels. Hepatic nonprotein sulfhydryl (NPS) levels were decreasedand renal NPS levels increased at 24 hr. In the short-term studyresistance developed to DCP hepatotoxicity over the 10 consecutivedays of exposure, as reflected by progressively lower serumenzyme levels and by decreases in the severity and incidenceof toxic hepatitis and periportal vacuolization. Nucleolar enlargementin hepatocytes, however, was observed at all dosage levels at5 and 10 days. There were a number of manifestations of hemolyticanemia, including erythrophagocytosis in the liver, splenichemosiderosis and hyperplasia of erythropoietic elements ofthe red pulp, renal tubular cell hemosiderosis, and hyperbilirubinemia.Urinalyses and histopathology revealed no evidence of nephrotoxicity.In the long-term study, male rats initially weighing 180–200g were gavaged five times weekly for up to 13 weeks with 0,100,250,500,or 750 mg DCP/kg. As over one-half the 750 mg/kg group diedwithin 10 days, the survivors were sacrificed. Histopathologicalchanges in the 750 mg/kg animals included mild hepatitis andsplenic hemosiderosis, as well as adrenal medullary vacuolizationand cortical lipidosis, testicular degeneration and a reductionin sperm, and increased number of degenerate spermatogonia inthe epididymis in some members of the group. Similar testicularand epididymal degenerative changes also were observed in some500 mg/kg animals after 13 weeks of dosing. There was a progressiveincrease in the number of deaths in the 500 mg/kg group, suchthat more than 50% were dead by 13 weeks. No deaths occurredin the 100 or 250 mg/kg groups. The DCP dosage regimen alsopduced a dose-dependent decrease in body weight gain. DCP exhibitedvery limited hepatotoxic potential and no apparent nephrotoxicpotential in the long-term study. Slight elevations in serumornithine-carbamyl transferase activity, periportal vacuolzation,and active fibroplasia in the liver were seen in the 500 mg/kg