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

B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm di(2-ethylhexy l)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were an alyzed 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 D EHP. Overall weight gains were significantly lower for the 6000-ppm male gr oup, but there was no difference among female groups. Food consumption was not affected by exposure. No biologically significant changes in clinical c hemistry, hematology, or urinalysis were observed. After 104 weeks of expos ure, kidney weights for the 500- and 1500-ppm male, and 6000-ppm male/femal e groups were significantly lower than for the controls. Significantly high er 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 weig hts for the 6000-ppm group were significantly lower than for the controls. All organs were examined for histopathology. The incidence of hepatocellula r lesions has been reported separately (R. M. David et al., 1999. Toxicol. Sci. 50, 195-205). Tumors were observed at greater than or equal to 500-ppm dosages, where peroxisome proliferation was significantly increased. A NOE L for both tumors and peroxisome proliferation was 100 ppm. In the study pr esented here, bilateral hypospermia in the testes of male mice, hepatocyte pigmentation and cytoplasmic eosinophilia in the liver, and chronic progres sive nephropathy of male and female mice were observed at 6000 ppm. Hypospe rmia and chronic progressive nephropathy were also observed at 1500 ppm, wh ere peroxisome proliferation was 2.7-6.8-fold higher than controls. Many le sions 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 (NOA EL) for noncarcinogenic effects.