© 1994 Oxford University Press
research-article |
Developmental Toxicity Evaluation of Isopropanol by Gavage in Rats and Rabbits1
*Research Triangle Institute, Research Triangle Park North Carolina 27709-2194
ARCO Chemical Company, Newtown Square Pennsylvania
Shell Oil Company. Houston Texas
BP America, Cleveland Ohio
||Exxon Biomedical Sciences East Millstone, New Jersey
¶Union Carbide Corporation, Danbury Connecticut
Received November 4, 1992; accepted August 2, 1993
Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67–63–0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 mI/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 mI/kg. Maternal body weights, clinical observations, and food consumption were re corded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were re moved from study. In rats, two dams (8%) died at 1200 mg/kg/ day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, ex cept for statistically significantly reduced gestational weight gain (GD 0–20; 89.9% of control value), associated with statisti cally significantly reduced gravid uterine weight at 1200 mg/kg/ day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and lit ter size. Twenty-two to 25 litters were examined per group. Fe tal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mglkg/day. Maternal body weights were statistically significantly re duced during treatment (GD 6–18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0–30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mgI kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of in creased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480mg/kg/day, respectively, in rabbits.