Predicting skin permeability of chemical substances using a quantitative structure-activity relationship

The health hazard arising from skin exposure to toxic chemical was conventionally evaluated by determining the skin permeation coefficient (Kp) of chemical in the stratum corneum of human or animal cadaver skin. However, limited by constraints inherent in the technique, to date the Kp evaluation has been performed only insufficiently. This study defined a quantitative structure-activity relationship (QSAR) for Kp prediction and for characterization of, at a molecular level, the physicochemical properties involved in transdermal transport of chemical. One hundred and fifty-eight chemical substances of known Kp determined in vitro using human skin were selected in the QSAR development. The final QSAR consisted of four molecular descriptors, including those describing electrostatic interactions between electric quadrupoles of van der Waals forces, octanol-water partitioning of solute, similarity in antineoplastic property, and frequency of carbon-nitrogen bonding at a constant topological distance. The four-descriptor multiple linear regression model fit the observed Kp data with a R-2 of 0.828 and a mean percentage error of 18.8%, suggesting a capacity of this QSAR to serve as an alterative source of Kp information and a potential tool of dermal hazard characterization, particularly when experimentally determined Kp are not readily available. (C) 2012 The Authors. Published by Elsevier Ltd.