Impact of solvent dry down, phase change, vehicle pH and slowly reversible keratin binding on skin penetration of cosmetic relevant compounds: II. Solids.

We extended a mechanistic, physics-based framework of the dry down process, previously developed for liquids and electrolytes, to solids and coded it into the latest UB/UC/P&G skin permeation model, herein renamed DigiSkin. The framework accounts for the phase change of the permeant from dissolved in a solvent (liquid) to precipitated on the skin surface (solid). The evaporation rate for the solid is reduced due to lower vapor pressure for the solid state versus subcooled liquid. These vapor pressures may differ by two orders of magnitude. The solid may gradually redissolve and penetrate the skin. The framework was tested by simulating the in vitro human skin permeation of the 38 cosmetically relevant solid compounds reported by Hewitt et al., J. Appl. Toxicol. 2019, 1-13. The more detailed handling of the evaporation process greatly improved DigiSkin evaporation predictions (r = 0.89). Further, we developed a model reliability prediction score classification using diverse protein reactivity data and identified that 15 of 38 compounds are out of model scope. Dermal delivery predictions for the remaining chemicals have excellent agreement with experimental data. The analysis highlighted the sensitivity of water solubility and equilibrium vapor pressure values on the DigiSkin predictions outcomes influencing agreement with the experimental observations.