Chronic toxicity of di(2-ethylhexyl)phthalate in mice.

B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at Weeks 26, 52, 78, and 104 from 10 animals per sex per group. Body weights and food consumption were measured weekly for the first 16 weeks, then monthly thereafter. Survival was reduced for mice receiving 6000 ppm DEHP. Overall weight gains were significantly lower for the 6000-ppm male group, but there was no difference among female groups. Food consumption was not affected by exposure. No biologically significant changes in clinical chemistry, hematology, or urinalysis were observed. After 104 weeks of exposure, kidney weights for the 500- and 1500-ppm male, and 6000-ppm male/female groups were significantly lower than for the controls. Significantly higher liver weight was seen for the 500-, 1500-, and 6000-ppm male groups and the 6000-ppm female group of mice. Testis weights for the 500-, 1500-, and 6000-ppm males were significantly lower than for the controls. Uterine weights for the 6000-ppm group were significantly lower than for the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately (R. M. David et al., 1999. Toxicol. Sci. 50, 195-205). Tumors were observed at > or = 500-ppm dosages, where peroxisome proliferation was significantly increased. A NOEL for both tumors and peroxisome proliferation was 100 ppm. In the study presented here, bilateral hypospermia in the testes of male mice, hepatocyte pigmentation and cytoplasmic eosinophilia in the liver, and chronic progressive nephropathy of male and female mice were observed at 6000 ppm. Hypospermia and chronic progressive nephropathy were also observed at 1500 ppm, where peroxisome proliferation was 2.7-6.8-fold higher than controls. Many lesions observed in rats were not seen in mice. A dose level of 500 ppm (98.5-116.8 mg/kg/day) was identified as a no-observed-adverse-effect level (NOAEL) for noncarcinogenic effects.