No Significant Risk Level (nsrl) for the Proposition 65 Carcinogen Di(2-ethylhexyl)phthalate

This document provides a basis for the estimation of cancer risk from exposure to di(2­ ethylhexyl)phthalate (DEHP). Epidemiological evidence is uninformative with respect to quantitative estimates of cancer risk to humans from exposure to DEHP. There is evidence that DEHP induces liver tumors in rats and mice by a mode of action common to a class of compounds called “peroxisome proliferators,” involving a specific cellular receptor called the peroxisome proliferator activated receptor-alpha (PPAR-α). Because a cellular receptor having endogenous ligands appears to be central to the hepatocarcinogenic effect in rodents, a nonthreshold model was applied for the estimation of carcinogenic risk. In vitro studies suggest that human cells are not as responsive to the effects of this class of chemicals as rodents, for which the vast majority of experimental evidence is available. Female mice were identified as the most sensitive sex and species to the tumorigenic effects of DEHP. Based on the relative expression levels of the PPAR-α in humans compared to mice, a ten-fold factor was applied to reduce the potency extrapolated from carcinogenicity studies in female mice to account for this assumed lower level of human cellular sensitivity. The application of this scaling factor to the extrapolated cancer potency derived from the experimental animal studies provides a reasonable basis for calculating a level posing no significant risk of cancer to humans. DEHP is metabolized to more active compounds which appear to be primarily responsible for its activity. Rats have exhibited route-dependent differences in metabolism of DEHP which suggest a possible difference in carcinogenic potency by different routes of exposure. Considerably more orally administered DEHP is metabolized by rodents than when given parenterally. Human evidence concerning metabolism of DEHP, while limited, indicates humans metabolize substantially more parenterally administered DEHP than do rodents and does not support significant route specific differences in potency.