ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 75, 448-457 (2003)
Copyright © 2003 by the Society of Toxicology
SAFETY EVALUATION |
Developmental Toxicity and Genotoxicity Studies of 1,1,1,3,3,3-Hexachloropropane (HCC-230fa) in Rats
* Environ, Health Sciences Institute, Arlington, Virginia 22203;
E. I. DuPont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware 19714;
Vulcan Chemicals, Birmingham, Alabama 35238;
Pfizer Inc., Corporate Affairs, Morris Plains, New Jersey 07950; and
¶ Pfizer Inc. Global Research & Development, Eastern Point Road, Groton, Connecticut 06340
The potential developmental toxicity and the in vitro and in vivo genotoxicity of HCC-230fa were assessed. In the developmental toxicity study, groups of 25 mated Crl:CD®(SD)BR rats were exposed (whole body) by inhalation to HCC-230fa over days 7–21 of gestation; the day of confirmed mating was designated as gestation day 1 (GD1). Exposures were 6 h per day at concentrations of 0, 0.5, 2.5, or 25 ppm. Body weight, food consumption, and clinical observation data were collected during the study. On day 22 of gestation, the dams were euthanized and examined grossly. The fetuses were removed and subsequently weighed, sexed, and examined for external, visceral, head, and skeletal alterations. Evidence of maternal and developmental toxicity was observed at 25 ppm and was noted as significant, compound-related reductions in mean maternal body weight, weight change, and food consumption. Significant fetal effects also were observed at 25 ppm as compound-related reductions in mean fetal weight and increased fetal malformations (filamentous tail, situs inversus, absent vertebrae) and variations (rudimentary cervical ribs, delayed sternebral ossification). There was no evidence of either maternal or developmental toxicity at 0.5 or 2.5 ppm. The genotoxicity of HCC-230fa was examined in a bacterial reversion assay and in erythrocyte micronucleus studies in two species by different routes of administration. No increases in the number of revertants were observed in the bacterial reversion assay. In one micronucleus study, HCC-230fa was administered by inhalation to rats as part of a 90-day study at doses indicated above. For the second study, ICR mice were given a single ip dose at 0, 166, 330, or 660 mg/kg. In both micronucleus studies, a significant increase in micronucleated erythrocytes was observed. The results of these studies suggest that HCC-230fa affects rapidly dividing cells and may have long-term consequences for occupational exposures.
Key Words: halogenated hydrocarbons; chlorinated alkanes; inhalation; developmental toxicity; genotoxicity.