Rat two-generation reproduction and dominant lethal study of acrylamide indrinking water

Fischer 344 (F344) F-0 weanling rats, 30/sex/group, were exposed to acrylam ide in drinking water at 0.0, 0.5, 2.0, or 5.0 mg/kg/day for 10 weeks and t hen mated. Exposure of F-0 females continued through gestation and lactatio n of F-1 litters. F-0 males, after F-0 mating, were removed from exposure a nd mated (one male: two untreated females) for the dominant lethal (DL) ass ay. Thirty F-1 weanlings/sex/group were exposed for 11 weeks to the same do se levels as their parents, and then mated to produce F-2 offspring. F-0 an d F-1 parents and F-1 and F-2 weanlings were necropsied. Prebreeding exposu re of F-0 and F-1 animals resulted in systemic toxicity at 2.0 to 5.0 mg/kg /day, with head tilt and/or foot splay increased at 0.5 to 5.0 mg/kg/day. F -0 and F-1 reproductive indices and gestational length were unaffected. Imp lantations and live pups/litter at birth were reduced at 5.0 mg/kg/day. Sur vival of F-1 and F-2 pups was reduced at 5.0 mg/kg/day for PND 0 through 4 only. In the DL assay, total and live implants were reduced, pre- and posti mplantation loss was increased, and the frequency of DL factors (F-L%) was increased at 5.0 mg/kg/day. At 5.0 mg/kg/day, adult F-1 male peripheral ner ves exhibited axonal fragmentation and/or swelling; F-1 female spinal cord sections were unremarkable. The NOEL for prenatal DL was 2.0 mg/kg/day; the NOEL for adult systemic toxicity, including neurotoxicity, was less than o r equal to 0.5 mg/kg/day. Therefore, neurotoxicity and DL were differential ly affected. (C) 2000 Elsevier Science Inc. All rights reserved.