Calculating the dermal flux of chemicals with OELs based on their molecular structure: An attempt to assign the skin notation

Abstract

Our objectives included calculating the permeability coefficient and dermal penetration rates (flux value) for 112 chemicals with occupational exposure limits (OELs) according to the LFER (linear free-energy relationship) model developed using published methods. We also attempted to assign skin notations based on each chemical's molecular structure. There are many studies available where formulae for coefficients of permeability from saturated aqueous solutions ( K p) have been related to physicochemical characteristics of chemicals. The LFER model is based on the solvation equation, which contains five main descriptors predicted from chemical structure: solute excess molar refractivity, dipolarity/polarisability, summation hydrogen bond acidity and basicity, and the McGowan characteristic volume. Descriptor values, available for about 5000 compounds in the Pharma Algorithms Database were used to calculate permeability coefficients. Dermal penetration rate was estimated as a ratio of permeability coefficient and concentration of chemical in saturated aqueous solution. Finally, estimated dermal penetration rates were used to assign the skin notation to chemicals. Defined critical fluxes defined from the literature were recommended as reference values for skin notation. The application of Abraham descriptors predicted from chemical structure and LFER analysis in calculation of permeability coefficients and flux values for chemicals with OELs was successful. Comparison of calculated K p values with data obtained earlier from other models showed that LFER predictions were comparable to those obtained by some previously published models, but the differences were much more significant for others. It seems reasonable to conclude that skin should not be characterised as a simple lipophilic barrier alone. Both lipophilic and polar pathways of permeation exist across the stratum corneum. It is feasible to predict skin notation on the basis of the LFER and other published models; from among 112 chemicals 94 (84%) should have the skin notation in the OEL list based on the LFER calculations. The skin notation had been estimated by other published models for almost 94% of the chemicals. Twenty-nine (25.8%) chemicals were identified to have significant absorption and 65 (58%) the potential for dermal toxicity. We found major differences between alternative published analytical models and their ability to determine whether particular chemicals were potentially dermotoxic.