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Dermal Absorption

A key element to risk in the European non-dietary assessment approach is dermal absorption. To estimate exposure via the dermal route one may either use default values or derive compound and product-specific study-based estimates. This is a topic where the European Union has successfully introduced and accepted NAMs in the regulatory context by accepting studies conducted according to OECD TG 428 (OECD, 2004), to determine the fraction of the external dose that may be available to exhaust the systemic health-based guidance value. To support regulatory trust and acceptance, CropLife Europe has initiated multiple projects with respect to dermal absorption, for example, data collection (Aggarwal 2014, 2015) that resulted in revised default values for Europe based on updated databases. However, the relevance and applicability of aspects of the current guidance were questioned by conducting thorough data analyses. For example, how or if mass balance affects dermal absorption (Kluxen et al. 2019). Alternative data-based assessment strategies were proposed for evaluating in vitro studies (Kluxen et al. 2023), which may result in more appropriate dermal absorption values. To facilitate method robustness CLE has initiated an interlaboratory ring-trial (Kluxen et al 2022).

A key exposure-related problem for pesticidal non-dietary risk assessment is how to estimate dermal absorption for dried residues as compared to liquid sprays. Thus, CLE developed a method to directly test dried residues (Aggarwal et al. 2019) and proposed an approach for dose selection (Morgan et al. 2021). However, it was discussed that there is generally a substantial source of bias in the extrapolation from results of cells with very small diameters to larger body or extremity exposure scenarios and the use of relative absorption values, thus, new evaluation strategies were proposed (Kluxen et al. 2022) that align more with the exposure scenarios and model framework.

CLE is continuing its activities to gain improved understanding on dermal absorption and how to appropriately integrate this into the risk assessment equations. The data generation and data driven analyses have significantly increased the state-of-the-art knowledge and might facilitate re-consideration of some postulated overarching conservatism contributing to the compounded conservatism in non-dietary risk assessment (Cochran & Ross, 2017; Kluxen et al., 2021).

CropLife Contributions

Aggarwal, M., Battalora, M., Fisher, P., Hueser, A., Parr-Dobrzanski, R., Soufi, M., Mostert, V., Strupp, C., Whalley, P., Wiemann, C., & Billington, R. (2014). Assessment of in vitro human dermal absorption studies on pesticides to determine default values, opportunities for read-across and influence of dilution on absorption. Regulatory Toxicology and Pharmacology, 68(3), 412-423. DOI: 10.1016/j.yrtph.2014.01.012

Aggarwal, M., Fisher, P., Hueser, A., Kluxen, F. M., Parr-Dobrzanski, R., Soufi, M., Strupp, C., Wiemann, C., & Billington, R. (2015). Assessment of an extended dataset of in vitro human dermal absorption studies on pesticides to determine default values, opportunities for read-across and influence of dilution on absorption. Regulatory Toxicology and Pharmacology, 72(1), 58-70. DOI: 10.1016/j.yrtph.2015.02.017

Aggarwal, M., Fisher, P., Kluxen, F. M., Maas, W., Morgan, N., Parr-Dobrzanski, R., Strupp, C., & Wiemann, C. (2019). Assessing in vitro dermal absorption of dry residues of agrochemical sprays using human skin within OECD TG 428. Regulatory Toxicology and Pharmacology, 106, 55-67. https://doi.org/10.1016/j.yrtph.2019.04.016

Kluxen, F. M., Felkers, E., Baumann, J., Morgan, N., Wiemann, C., Stauber, F., Strupp, C., Adham, S., & Kuster, C. J. (2021). Compounded conservatism in European re-entry worker risk assessment of pesticides. Regulatory Toxicology and Pharmacology, 104864. https://doi.org/https://doi.org/10.1016/j.yrtph.2021.104864

Kluxen, F. M., Felkers, E., Jensen, S. M., Domoradzki, J., Lorez, C., Fisher, P., & Wiemann, C. (2023). Practical guidance to evaluate in vitro dermal absorption studies for pesticide registration: An industry perspective. Regulatory Toxicology and Pharmacology, 142, 105432. https://doi.org/https://doi.org/10.1016/j.yrtph.2023.105432

Kluxen, F. M., Felkers, E., McEuen, S., Fisher, P., Strupp, C., Lorez, C., Domoradzki, J. Y. & Wiemann, C. (2022). A new conceptional model for deriving average dermal absorption estimates from studies with multiple tested concentrations for non-dietary risk assessment of pesticides. Arch Toxicol, 96(9), 2429-2445. https://doi.org/10.1007/s00204-022-03320-3

Kluxen, F. M., Gregoire, S., Schepky, A., Hewitt, N. J., Klaric, M., Domoradzki, J. Y., Felkers, E., Fernandes, J., Fisher, P., McEuen, S. F., Parr-Dobrzanski, R., & Wiemann, C. (2019). Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database. Regulatory Toxicology and Pharmacology, 108, 104475. https://doi.org/10.1016/j.yrtph.2019.104475

Kluxen, F. M., Totti, S., Maas, W., Toner, F., Page, L., Webbley, K., Nagane, R., Mingoia, R., Whitfield, C., Kendrick, J., Valentine, C., Dorange, J. B., Egron, C., Imart, C., Domoradzki, J. Y., Fisher, P., Lorez, C., McEuen, S., Felkers, E., . . . Wiemann, C. (2022). An OECD TG 428 study ring trial with (14)C-Caffeine demonstrating repeatability and robustness of the dermal absorption in vitro method. Regulatory Toxicology and Pharmacology, 132, 105184. https://doi.org/10.1016/j.yrtph.2022.105184

Morgan, N., Hewitt, N., Felkers, E., Wiemann, C., Kluxen, F. M., & Kuster, C. J. (2021). Dose setting for dermal absorption studies on dried foliar residues. Ann Work Expo Health, 65(4):397-405. DOI: 10.1093/annweh/wxaa139

References

OECD, 2004. OECD Guideline for the Testing Chemicals. Skin Absorption: in vitro Method. https://doi.org/10.1787/9789264071087-en

Cochran, R. C., & Ross, J. H. (2017). A method for quantitative risk appraisal for pesticide risk assessments [Article]. Journal of Toxicology and Environmental Health – Part A: Current Issues, 80(1), 1-17. https://doi.org/10.1080/15287394.2016.1224747