PNNL

Abstract

A physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ) was refined to include an expanded metabolic description of HQ glucuronide metabolites, including measured in vitro rat and human hepatic metabolic parameters, and a description of dermal exposures to support route-to-route and cross-species extrapolation. Total urinary excretion of metabolites (radioactivity) from in vivo rat dermal exposures was used to estimate percutaneous permeability coefficients (Kp) which was the same in male and female rats (3.6x10-5). The human in vivo Kp was estimated to be 1.62´10-4 cm/hr, based on in vitro skin permeability data in rats and humans and the rat in vivo values. This human in vivo Kp estimate corresponds to a moderately slow rate of absorption. A Hazard Index was estimated by comparing the predicted human total multi-substituted glutathione conjugates (as an internal dose surrogate for the toxic glutathione metabolites) following a dermal exposure to the internal total glutathione conjugates in rats following an oral exposure to the rat NOEL of 20 mg/kg. The exposure scenario was based on submersion of both hands in a 5% aqueous solution of HQ (similar to a photographers solution) for 1 hr and is assumed to be a possible worst-case exposure scenario. The Hazard Index was 0.0063, approximately a 160-fold difference. Thus, under more realistic human dermal exposure conditions, it is unlikely that toxic glutathione conjugates (primarily the di- and, to a lesser degree, the tri-glutathione conjugate) will reach significant levels in target tissues.