title: Studies by the National Toxicology Program on di(2-ethylhexyl)phthalate.
abstract: In a 2-year feed study previously reported by the National Toxicology Program (NTP), the plasticizer di(2-ethylhexyl)phthalate (DEHP) was found to produce increased incidences of hepatocellular neoplasms in both sexes of Fischer 344 (F344) rats and B6C3F1 mice. Further studies by the NTP on this chemical have investigated its genotoxicity, dermal absorption, reproductive and developmental toxicity, and biochemical mechanism of action. DEHP was not mutagenic in Salmonella typhimurium (strains TA98, TA100, TA1535 or TA1537), in L5178Y mouse lymphoma cells, or in Drosophila melanogaster. DEHP did not induce chromosomal aberrations, but did cause a marginal dose-related increase in sister chromatid exchanges in CHO cells. In a dermal absorption study, DEHP was not absorbed well through the skin of F344 rats. In a fertility assessment study, DEHP was shown to be a reproductive toxicant in both male and female CD-1 mice. The teratogenic potential of DEHP was evaluated in F344 rats and CD-1 mice. In the rat study, there were no significant differences in percent fetuses malformed between control and treatment groups, even at dose levels (1.0, 1.5 and 2.0%) which produced significant maternal and fetal toxicity. In the mouse study, the incidence of fetuses with malformations was significantly increased at dose levels which produced maternal and/or fetal toxicity (0.10 and 0.15%), and at a dose level (0.05%) which did not cause maternal or fetal toxicity. The no-observed effect level for developmental toxicity in mice was 0.025% DEHP. Kinetic data on the rates of formation of H2O2 by peroxisomal palmitoyl CoA oxidase, and of degradation of H2O2 by catalase, was used to estimate in vitro steady-state H2O2 concentrations during peroxisomal oxidation of palmitoyl CoA. Increases in steady-state H2O2 in liver homogenates of rats treated with DEHP, di(2-ethylhexyl)adipate, or nafenopin, a hypolipidemic drug, correlated well with the carcinogenic potential of these chemicals determined in previous carcinogenicity studies, and are consistent with but not definitive evidence for the involvement of peroxisome proliferation in the hepatocarcinogenesis of these compounds.
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects; D009153:Mutagens; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D012869:Skin Absorption
chemical_list: D009153:Mutagens; D010795:Phthalic Acids; D010171:Palmitoyl Coenzyme A; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate