Evaluation of subchronic (13 week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene).

Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene) in commercial sunscreen products has increased considerably in recent years. To support larger scale human exposure to this compound, additional toxicological information was needed in several key areas. The present studies evaluated subchronic toxicity, developmental toxicity, and in vitro genotoxic potential of Octocrylene. In the subchronic study, male and female New Zealand white (NZW) rabbits treated topically with concentrations of octocrylene up to 534 mg/kg/day for 13 weeks showed slight to moderate dose-dependent skin irritation that correlated positively with a mild depression in body weight gain. Lack of associated histopathologic or clinical hematology abnormalities suggested that the body weight effect probably reflected a nonspecific response to topical irritation. In percutaneous developmental toxicity studies, NZW does were treated topically with Octocrylene at levels up to 267 mg/kg/day on Days 6 through 18 of gestation. Body weight gain, food consumption, and all maternal, reproductive, and offspring parameters evaluated were comparable between Octocrylene-treated and control animals. In the oral developmental toxicity assay, female CD-1 mice received oral doses of Octocrylene up to 1000 mg/kg/day on Days 8-12 of gestation. No evidence of maternal or developmental toxicity was seen at any dose tested. Genotoxicity was evaluated in vitro using the Chinese hamster ovary cell assay to assess clastogenicity and the mouse lymphoma cell assay to assess forward gene mutations. Octocrylene did not induce any significant increase in genotoxicity. This evaluation of toxicological potential supports the use of Octocrylene as a human photoprotectant.

The interactive toxicity of CHCl3 and BrCCl3 in precision-cut rat liver slices.

The interactive toxicity of two nontoxic concentrations of chloroform (CHCl3) and bromotrichloromethane (BrCCl3) was examined in precision-cut rat liver slices. Liver slices were prepared from male Sprague-Dawley rats (220-250 g) pretreated with phenobarbital for 4 days. Toxicants were administered 1 hr apart. Intracellular K+ levels were similar to untreated controls in slices treated with 0.2 mM CHCl3 or 0.125 microliters (0.25 mg, 1.26 mumol) BrCCl3 alone, indicating that these concentrations were nontoxic. However, addition of both toxicants, irrespective of order, resulted in a time-dependent loss of intracellular K+ which was significant at 9 hr following administration. This was interpreted as evidence of synergistic toxicity. Cytochrome P450 loss was significant as early as 3 hr following exposure to BrCCl3, alone or when added with CHCl3. This loss may be attributed to BrCCl3-induced suicide inactivation of cytochrome P450. Centrilobular hepatocytes may be more susceptible to the interactive toxicity of CHCl3 and BrCCl3. Activity of enzymes found predominantly in this area was significantly decreased in slices exposed to both toxicants relative to controls. Conversely, activity of enzymes found predominantly in the periportal region was similar to that of untreated and treated controls. Interactive toxicity of BrCCl3 and CHCl3 was not a consequence of increased lipid peroxidation or depletion of slice glutathione content. Further studies need to be conducted to elucidate the mechanisms mediating the interactive toxicity of BrCCl3 and CHCl3.

The hepatotoxicity of chloroform in precision-cut rat liver slices.

Chloroform hepatotoxicity was investigated in precision-cut liver slices from male Sprague-Dawley rats pretreated with phenobarbital to predispose animals to CHCl3 intoxication. Liver slices were exposed to 0.2, 0.5 and 1.0 mM chloroform for a total of 9 h in a roller culture system. Intracellular K+ loss was found to be concentration- and time-dependent over the duration of the experiment. Histopathological changes were also evident. Glucose 6-phosphate dehydrogenase and beta-glucuronidase were significantly decreased at 3 h relative to controls where a loss of 61% and 36% occurred, respectively. Enzyme levels of alanine aminotransferase and lactate dehydrogenase, both found predominantly in periportal hepatocytes, remained identical to controls over the duration of the experiment. A significant time-dependent depletion of glutathione occurred as early as 3 h following the administration of 0.5 mM chloroform. Mitochondrial viability, measured by the reduction of a specific dye, was significantly lower than controls in treated slices at 6 h following chloroform administration. Precision-cut liver slices appear to be especially useful for the biochemical and histopathological examination of site-specific hepatotoxicants such as CHCl3.