What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut‐off: An updated analysis

Abstract

It is widely accepted that substances must have a molecular weight (MW) < 500 to penetrate effectively through the skin to induce sensitization. Roberts et al. (2012. Contact Dermatitis 68: 32-41) evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW > 500, five were sensitizers. This provided good evidence to refute such a MW 500 threshold. While Roberts et al. (2012) made a convincing case that the MW > 500 cut-off was not a true requirement for sensitization, the number of counter examples identified were too few to draw any statistical conclusions. This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW> 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings. The study also assessed whether the same reaction chemistry principles established for low MW sensitizers applied to chemicals with a MW > 500. The existing reaction chemistry considerations were found appropriate to rationalize the sensitization behaviour of the 14 sensitizers with a MW > 500. The existence of the MW 500 threshold, based on the widespread misconception that the ability to penetrate efficiently the stratum corneum is a key determinant of skin sensitization potential and potency, was refuted. Copyright © 2016 John Wiley & Sons, Ltd.

The GARD platform for potency assessment of skin sensitizing chemicals

“…Once more chemicals receive human potency classifications, it should be possible to smoothly develop a human potency model based on the GARD platform. capacity and potency has recently been proven wrong (Fitzpatrick et al, 2017). Furthermore, access to lower skin layers may in reality be greatly facilitated by impaired skin barrier function, due to, e.g., wet work and small wounds.…”

Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for skin sensitization

“…Their investigation was based on the training set of the TIssue Metabolism Simulator for Skin Sensitization (TIMES‐SS) expert system (Patlewicz et al ., ) and they identified 13 substances with a MW> 500, of which 5 were sensitizers. We have found similar results based on a larger dataset that is discussed in a companion manuscript (Fitzpatrick et al ., ). Here, we tested the hypothesis that a LogKow threshold ≤ 1, as discussed in Roberts et al .…”

Computational approaches for skin sensitization prediction

“…Although some substances bind to skin proteins directly, others need to undergo activation through autoxidation (pre-haptens) or enzymatic reactions (pro-haptens) (Karlberg et al 2008). The relevance of skin permeability in skin sensitization is a field of active research and is not yet fully understood (Alves et al 2015a;Fitzpatrick et al 2017aFitzpatrick et al , 2017b.…”