Abstract
The skin permeability (Kp) defines the rate of a chemical penetrating across the stratum corneum. This value is widely used to quantitatively describe the transport of molecules in the outermost layer of epidermal skin and indicate the significance of skin absorption. This study defined a Kp quantitative structure-activity relationship (QSAR) based on 106 chemical substances of Kp measured using human skin and interpreted the molecular interactions underlying transport behavior of small molecules in the stratum corneum. The Kp QSAR developed in this study identified four molecular descriptors that described the molecular cyclicity in the molecule reflecting local geometrical environments, topological distances between pairs of oxygen and chlorine atoms, lipophilicity, and similarity to antineoplastics in molecular properties. This Kp QSAR considered the octanol-water partition coefficient to be a direct influence on transdermal movement of molecules. Moreover, the Kp QSAR identified a sub-domain of molecular properties initially defined to describe the antineoplastic resemblance of a compound as a significant factor in affecting transdermal permeation of solutes. This finding suggests that the influence of molecular size on the chemical’s skin-permeating capability should be interpreted with other relevant physicochemical properties rather than being represented by molecular weight alone.
Highlights
As the pool of candidates to select the descriptors from was significant, the p values assigned in the hypotheses for the addition of regressors to the model and for the removal from the model were crucial to the number of descriptors to include in the final quantitative structure-activity relationship (QSAR)
The rate of chemicals permeating through the stratum corneum, the Kp, is widely used to quantitatively describe the potential of dermal absorption for manmade and naturally derived compounds
This study developed a four-descriptor Kp QSAR based on 106 compounds of Kp determined using human skin
Summary
Identification of Transdermal Penetration for Manmade and Natural Chemicals. The exposure of the skin to manmade and naturally derived chemicals is an issue of rising concern, in the workplace, where dermal absorption represents a prominent route by which significant uptake of hazardous chemicals may occur [1,2]. Molecules 2018, 23, 911 exposure, as robust data reporting systemic/target organ toxicity as a direct result of skin absorption are required to support the hazard identification of toxic compounds [2,4]. The lack of sufficient data from biological tests in vivo and in vitro to demonstrate potential dermal penetration and absorption of toxic compounds has been a major factor impeding the development of quantitative standards in the management of occupational skin exposure
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