The potential health effects of phthalate esters in children's toys: a review and risk assessment.

Diisononyl phthalate (DINP) is one of several dialkyl phthalate esters that are widely used as plasticizers to impart softness and flexibility to normally rigid polyvinyl chloride (PVC) products. During the past 2 years, concern has been voiced by public interest groups and regulatory agencies in Europe, Canada, and the United States regarding the potential adverse health effects of DINP migrating from children's toys during mouthing activities. Concern has focused on potential chronic effects on the kidney and liver. In chronic high-dose studies with rodents, DINP causes a dose-related decrease in body weight, an increase in liver weight, and changes in liver cell histopathology (hypertrophy). To a lesser extent, the rodent kidney is also a target for prolonged high-level exposures of DINP. Prolonged high-level exposure of rodents to DINP leads to an increased incidence of liver tumors (adenomas and carcinomas). The chronic cancer and noncancer effects of DINP on rodent liver are consistent with its known action as a peroxisome proliferator. Peroxisome proliferation is a threshold-based effect that is reversible on cessation of exposure to proliferators such as DINP. Because rodents are uniquely responsive and humans and nonhuman primates are particularly nonresponsive to peroxisome proliferators, rodents are very poor animal models for use in human risk assessment of adverse effects mediated through peroxisome proliferation. Because DINP exerts its effects on rodent liver through a known threshold-based mechanism of little, if any, relevance to humans, a highly conservative risk assessment can be conducted using a NOAEL uncertainty factor approach. Chronic rodent no-observed-effect levels (NOELs) based on end points such as increased liver weight and changes in liver pathology that are early indicators of peroxisome proliferation but should not be considered adverse range from about 100 to 400 mg/kg/day. Application of a 100-fold uncertainty factor yields acceptable daily intakes (ADIs) ranging from 1 to 4 mg/kg/day. Estimates of DINP migration from soft PVC materials have been obtained from a variety of in vitro methods (simulated saliva and controlled agitation) as well as in vivo methods (controlled chewing) that more closely resemble child chewing and mouthing activities. Recent estimates by the Consumer Product Safety Commission (CPSC) suggest that maximum exposures occur in infants 3-12 months of age. The geometric mean (50th percentile) exposure is 5.7 microg/kg/day and the 95th percentile is 94.3 microg/kg/day. These exposure values are 17,500-70,000 and 1100-4200 times, respectively, lower than the chronic rodent NOAEL for DINP and 175-700 and 11-42 times lower than the corresponding ADI of 1-4 mg/kg/day. It is concluded, with a high degree of confidence, that the use of DINP in soft PVC toys and other children's products does not present a significant risk to children. The scientific evidence supports the continued use of DINP as a plasticizer in children's products. Copyright 1999 Academic Press.