Safety evaluation of dermal exposure to phthalates: Metabolism-dependent percutaneous absorption

Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.