title: Carcinogenesis Bioassay of Di(2-ethylhexyl)phthalate (CAS No. 117-81-7) in F344 Rats and B6C3F1 Mice (Feed Studies).
abstract: A bioassay of di(2-ethylhexyl)phthalate, the most commonly used plasticizer for polyvinylchloride polymers, for possible carcinogenicity was conducted by feeding diets containing 6,000 or 12,000 ppm of the test chemical to groups of 50 male and 50 female F344 rats and 3,000 or 6,000 ppm to groups of 50 male and 50 female B6C3F1 mice for 103 weeks. Controls consisted of 50 untreated rats and 50 untreated mice of either sex. Mean body weights of dosed male rats (high- and low-dose), high-dose female rats, and dosed female mice (high- and low-dose) were marginally-to-moderately lower than those of the corresponding controls at the end of the chronic study, reflecting a decrease in body weight gain. Food consumption was reduced slightly in rats of either sex, whereas there was no apparent difference among the mouse groups. Female rats and male and female mice administered di(2-ethylhexyl)phthalate had significantly higher incidences of hepatocellular carcinomas than those observed in the controls (rats -- males: 1/50, 2%; 1/49, 2%; 5/49, 10%; females -- 0/50, 0%; 2/49, 4%; 8/50, 16%, P=0.003; mice -- males: 9/50, 18%; 14/48, 29%; 19/50, 38%, P=0.022; females: 0/50, 0%; 7/50, 14%; P=0.006, 17/50, 34%, P<0.001). Further, a statistically significant positive trend for hepatocellular carcinomas occurred in female rats (P=0.002) and in male (P=0.018) and female (P<0.001) mice. In addition, di(2-ethylhexyl)phthalate caused a statistically significant increased incidence of male rats with either hepatocellular carcinomas or neoplastic nodules (3/50, 6%; 6/49, 12%; 12/49, 24%; P=0.010). Degeneration of the seminiferous tubules was observed in the high-dose male rats (1/49, 2%; 2/44, 5%; 43/48, 90%) and in the high-dose male mice (1/49, 2%; 2/48 4%; 7/49, 14%). Hypertrophy of cells in the anterior pituitary was also found at increased incidences in the high-dose male rats (1/46, 2%; 0/43, 0%; 22/49, 45%). Under the conditions of this bioassay, di(2-ethylhexyl)phthalate was carcinogenic for F344 rats and B6C3F1 mice, causing increased incidences of female rats and male and female mice with hepatocellular carcinomas, and inducing an increased incidence of male rats with either hepatocellular carcinomas or neoplastic nodules. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: DEHP