The effect of formulations and experimental conditions on in vitro human skin permeation—Data from updated EDETOX database

In vitro methods are commonly used in order to estimate the extent of systemic absorption of chemicals through skin. Due to the wide variability of experimental procedures, types of skin and data analytical methods, the resulting permeation measures varies significantly between laboratories and individuals. Inter-laboratory and inter-individual variations with the in vitro measures of skin permeation lead to unreliable extrapolations to in vivo situations. This investigation aimed at a comprehensive assessment of the available data and development of validated models for in vitro skin flux of chemicals under various experimental and vehicle conditions. Following an exhaustive literature review, the human skin flux data were collated and combined with those from EDETOX database resulting in a dataset of a total of 536 flux reports. Quantitative structure–activity relationship techniques combined with data mining tools were used to develop models incorporating the effects of permeant molecular structure, properties of the vehicle, and the experimental conditions including the membrane thickness, finite/infinite exposure, skin pre-hydration and occlusion. The work resulted in statistically valid models for estimation of the skin flux from varying experimental conditions, including relevant real-world mixture exposure scenarios. The models indicated that the most prominent factors influencing flux values were the donor concentration, lipophilicity, size and polarity of the penetrant, and the melting and boiling points of the vehicle, with skin occlusion playing significant role in a non-linear way. The models will aid assessment of the utility of dermal absorption data collected under different conditions with broad implications on transdermal delivery research.