TY - JOUR

T1 - Practical guidance to evaluate in vitro dermal absorption studies for pesticide registration

T2 - An industry perspective

AU - Kluxen, Felix M

AU - Felkers, Edgars

AU - Jensen, Signe M

AU - Domoradzki, JeanneY

AU - Lorez, Christine

AU - Fisher, Philip

AU - Wiemann, Christiane

N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2023

Y1 - 2023

N2 - While there are some regulatory assessment criteria available on how to generally evaluate dermal absorption (DA) studies for risk assessment purposes, practical guidance and examples are lacking. The current manuscript highlights the challenges in interpretating data from in vitro assays and proposes holistic data-based assessment strategies from an industry perspective. Inflexible decision criteria may be inadequate for real data and may lead to irrelevant DA estimates. We recommend the use of mean values for reasonably conservative DA estimates from in vitro studies. In cases where additional conservatism is needed, e.g., due to non-robust data and acute exposure scenarios, the upper 95% confidence interval of the mean may be appropriate. It is critical to review the data for potential outliers and we provide some example cases and strategies to identify aberrant responses. Some regional regulatory authorities require the evaluation of stratum corneum (SC) residue, but here, as a very simple pro-rata approach, we propose to review whether the predicted post 24-h absorption flux exceeds the predicted elimination flux by desquamation because otherwise it is not possible for the SC residue to contribute to systemic dose. Overall, the adjustment of DA estimates due to mass balance (normalization) is not recommended.

AB - While there are some regulatory assessment criteria available on how to generally evaluate dermal absorption (DA) studies for risk assessment purposes, practical guidance and examples are lacking. The current manuscript highlights the challenges in interpretating data from in vitro assays and proposes holistic data-based assessment strategies from an industry perspective. Inflexible decision criteria may be inadequate for real data and may lead to irrelevant DA estimates. We recommend the use of mean values for reasonably conservative DA estimates from in vitro studies. In cases where additional conservatism is needed, e.g., due to non-robust data and acute exposure scenarios, the upper 95% confidence interval of the mean may be appropriate. It is critical to review the data for potential outliers and we provide some example cases and strategies to identify aberrant responses. Some regional regulatory authorities require the evaluation of stratum corneum (SC) residue, but here, as a very simple pro-rata approach, we propose to review whether the predicted post 24-h absorption flux exceeds the predicted elimination flux by desquamation because otherwise it is not possible for the SC residue to contribute to systemic dose. Overall, the adjustment of DA estimates due to mass balance (normalization) is not recommended.

U2 - 10.1016/j.yrtph.2023.105432

DO - 10.1016/j.yrtph.2023.105432

M3 - Review

C2 - 37302560

VL - 142

JO - Regulatory Toxicology and Pharmacology

JF - Regulatory Toxicology and Pharmacology

SN - 0273-2300

M1 - 105432

ER -