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 norm ally rigid polyvinyl chloride (PVC) products. During the past 2 years, conc ern has been voiced by public interest groups and regulatory agencies in Eu rope, 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 fiver. I n chronic high-dose studies with rodents, DINP causes a dose-related decrea se in body weight, an increase in liver weight, and changes in liver cell h istopathology (hypertrophy). To a lesser extent, the rodent kidney is also a target for prolonged high-level exposures of DINP. Prolonged high-level e xposure 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 proli ferator. Peroxisome proliferation is a threshold-based effect that is rever sible on cessation of exposure to proliferators such as DINP. Because roden ts are uniquely responsive and humans and nonhuman primates are particularl y nonresponsive to peroxisome proliferators, rodents are very poor animal m odels for use in human risk assessment of adverse effects mediated through peroxisome proliferation. Because DINP exerts its effects on rodent Liver t hrough a known threshold-based mechanism of Little, if any, relevance to hu mans, a highly conservative risk assessment can be conducted using a NOAEL uncertainty factor approach. Chronic rodent no-observed-effect levels (NOEL s) 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. Applicatio n of a 100-fold uncertainty factor yields acceptable daily intakes (ADIs) r anging fi om I to 4 mg/kg/day. Estimates of DINP migration from soft PVC ma terials have been obtained from a variety of in vitro methods (simulated sa liva and controlled agitation) as well as in vivo methods (controlled chewi ng) that more closely resemble child chewing and mouthing activities. Recen t estimates by the Consumer Product Safety Commission (CPSC) suggest that m aximum exposures occur in infants 3-12 months of age. The geometric mean (5 0th percentile) exposure is 5.7 mu g/kg/day and the 95th percentile is 94.3 mu g/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 conclu ded, with a high degree of confidence, that the use of DINP in soft PVC toy s and other children's products does not present a significant risk to chil dren. The scientific evidence supports the continued use of DINP as a plast icizer in children's products. (C) 1999 Academic Press.