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

It is widely accepted that substances that cannot penetrate through the skin will not be sensitizers. LogKow and molecular weight (MW) have been used to set thresholds for sensitization potential. Highly hydrophilic substances e.g. LogKow ≤ 1 are expected not to penetrate effectively to induce sensitization. To investigate whether LogKow >1 is a true requirement for sensitization, a large dataset of substances that had been evaluated for their skin sensitization potential under Registration, Evaluation, Authorisation and restriction of CHemicals (REACH), together with available measured LogKow values was compiled using the OECD eChemPortal. The incidence of sensitizers relative to non-sensitizers above and below a LogKow of 1 was explored. Reaction chemistry principles were used to explain the sensitization observed for the subset of substances with a LogKow ≤0. 1482 substances were identified with skin sensitization data and measured LogKow values. 525 substances had a measured LogKow ≤ 1, 100 of those were sensitizers. There was no significant difference in the incidence of sensitizers above and below a LogKow of 1. Reaction chemistry principles that had been established for lower MW and more hydrophobic substances were found to be still valid in rationalizing the skin sensitizers with a LogKow ≤ 0. The LogKow threshold arises from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potential and potency.