title: Acute, subacute, and subchronic oral toxicity studies of 1,1-dichloroethane in rats: application to risk evaluation.
abstract: 1,1-Dichloroethane (DCE) is a solvent that is often found as a contaminant of drinking water and a pollutant at hazardous waste sites. Information on its short- and long-term toxicity is so limited that the U.S. EPA and ATSDR have not established oral reference doses or minimal risk levels for the volatile organic chemical (VOC). The acute oral LD(50) in male Sprague-Dawley (S-D) rats was estimated in the present study to be 8.2 g/kg of body weight (bw). Deaths appeared to be due to CNS depression and respiratory failure. In an acute/subacute experiment, male S-D rats were given 0, 1, 2, 4, or 8 g DCE/kg in corn oil by gavage for 1, 5, or 10 consecutive days. The animals were housed in metabolism cages for collection of urine and sacrificed for blood and tissue sampling 24 h after their last dose. There were decreases in body weight gain and relative liver weight at all dosage levels, as well as increased renal nonprotein sulfhydryl levels at 2 and 4 g/kg after 5 and 10 days. Elevated serum enzyme levels, histopathological changes, and abnormal urinalyses were not manifest. For the subchronic study, adult male S-D rats were gavaged with 0.5, 1, 2, or 4 g DCE/kg 5 times weekly for up to 13 weeks. Animals receiving 4 g/kg exhibited pronounced CNS depression, with more than one-half dying by week 11. The 2-g/kg rats exhibited moderate CNS depression. One 2-g/kg rat died during week 6. There were very few manifestations of organ damage in animals that succumbed or in survivors at any dosage level. Decreases in bw gain and transient increases in enzymuria were noted at 2 and 4 g/kg. Serum enzyme levels and blood urea nitrogen were not elevated, nor were glycosuria or proteinuria present. Chemically induced histological changes were not seen in the liver, kidney, lung, brain, adrenal, spleen, stomach, epididymis, or testis. Hepatic microsomal cytochrome P450 experiments revealed that single, high oral doses of DCE did not alter total P450 levels, but did induce CYP2E1 levels and activity and inhibit CYP1A1 activity. These effects were reversible and regressed with repeated DCE exposure. There was no apparent progression of organ damage during the 13-week subchronic study, nor appearance of adverse effects not seen in the short-term exposures. One g/kg orally (po) was found to be the acute, subacute, and subchronic LOAEL for DCE, under the conditions of this investigation. In each instance, 0.5 g/kg was the NOAEL.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2352, USA.
authors.forename: S
authors.initials: S
authors.lastname: Muralidhara
authors.forename: R
authors.initials: R
authors.lastname: Ramanathan
authors.forename: S M
authors.initials: SM
authors.lastname: Mehta
authors.forename: L H
authors.initials: LH
authors.lastname: Lash
authors.forename: D
authors.initials: D
authors.lastname: Acosta
authors.forename: J V
authors.initials: JV
authors.lastname: Bruckner
mesh_terms: D000117:Acetylglucosamine / Q000652:urine; D000135:Acid Phosphatase / Q000652:urine; D000818:Animals; D001835:Body Weight; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004000:Dichloroethylenes; D004785:Environmental Pollutants / Q000633:toxicity; D005018:Ethyl Chloride / Q000031:analogs & derivatives* / Q000633:toxicity*; D005260:Female; D007527:Isoenzymes; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests; D023382:Toxicity Tests, Acute
chemical_list: D004000:Dichloroethylenes; D004785:Environmental Pollutants; D007527:Isoenzymes; C501196:1,1-dichloroethane; C029297:vinylidene chloride; D005018:Ethyl Chloride; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D000135:Acid Phosphatase; D000117:Acetylglucosamine