Summary of mammalian toxicology and health effects of phthalate esters

Abstract

Phthalate esters can be divided into three general categories based on size. These categories are low-MW esters used as solvents in cosmetics or as plasticizers of cellulose acetate polymers, mid-MW esters used as solvents in some PVC products but only in combination with other plasticizers in floor coverings, or as a solvent or plasticizer in the cosmetic and pharmaceutical industries, and high-MW esters used as plasticizers of PVC for wire and cable coverings, medical products, and other consumer products. Phthalate esters are data-rich for effects in laboratory animals, having been the focus of much research because of their effects on the biochemistry of liver cells, the effects on the testes, and the effects on the development of laboratory animals. All phthalate esters have little or no toxicity following single (acute) exposures. These substances are not dermal sensitizers, but may produce minor skin irritation with prolonged exposure to the neat chemical. Long-term hazards from short-term exposures are either minimal or reversible because many long-term effects are observed only following continuous exposure. Long-term effects such as liver cancer only occur in laboratory animals following life-time or near life-time exposure to doses of <100mg kg-1 d-1 of high-MW esters. Cancer is thought to occur through a mechanism that involves biochemical changes in the liver cells of rats and mice. These biochemical changes are not seen in primates. As a result, scientists do not regard humans to be at risk of cancer from exposure to phthalate esters. Reproductive toxicity or developmental effects in the offspring of laboratory animals exposed to mid-MW phthalates during gestation have been reported. Reproductive toxicity is the result of damage to the testes causing lack of sperm production. It is not known if such effects occur in humans, but adult primates have been resistant to the effects seen in adult rodents. Developmental effects can also occur with high exposure to mid-MW esters. The effects include incomplete skeletal formation in the head, spinal cord, tail, and ribs. In addition, male rats demonstrate incomplete formation of the urogenital tract. It is not known if primates or humans are also susceptible to these effects, and the mechanism in laboratory animals is unknown. Exposure to phthalate esters is not thought to cause respiratory diseases such as asthma because these substances are hypoallergenic, but some have tried to associate exposure with an increased sensitivity to respiratory allergens. Sufficient data are lacking to make such a correlation. Phthalate esters are not neurotoxic. In evaluating the concern for humans, many principles of toxicology are discussed to provide the reader with sufficient understanding of species extrapolation. Primates are not as sensitive to phthalate esters as are rodents. There may be a variety of reasons for this lack of sensitivity, for example, lower absorption and different metabolic pathways. There are also intrinsic differences in the responses of primate and human cells to the biochemical effects of phthalate esters. While this difference relates directly to the likelihood of cancer, it may also impact the sensitivity to other effects seen in animals. Thus, predicting the effects in humans must convey some level of uncertainty.