Assessment of in vitro human dermal absorption studies on pesticides to determine default values, opportunities for read-across and influence of dilution on absorption

• Published in: Regulatory toxicology and pharmacology Vol. 68; no. 3; pp. 412 - 423
• Main Authors: Aggarwal, M., Battalora, M., Fisher, P., Hüser, A., Parr-Dobrzanski, R., Soufi, M., Mostert, V., Strupp, C., Whalley, P., Wiemann, C., Billington, R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-04-2014
• Subjects: Agrochemicals; Animals; Dermal absorption; Human skin; Humans; In vitro; In Vitro Techniques; Pesticides; Pesticides - pharmacokinetics; Plant protection products; Risk Assessment; Skin - metabolism; Skin Absorption; Human skin; Agrochemicals; In vitro; Plant protection products; Pesticides; Dermal absorption
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2014.01.012

•A robust data set from 190 in vitro human dermal absorption studies is evaluated.•Defaults of 6% for liquids, 2% for solids and 30% for spray dilutions are proposed.•Read-across strategy between formulation types is presented.•Dermal absorption of sprays does not increase linearly with increasing dilution.•Novel science-based extrapolation option for sprays from existing data is presented.
Dermal absorption is an integral part of non-dietary human safety risk assessments for agrochemicals. Typically, dermal absorption data for agrochemical active substances are generated from the undiluted formulation concentrate and its spray dilutions. European Food Safety Authority (EFSA) guidance, which combines highly conservative default values, very limited opportunities for read-across from existing data and other overly conservative conclusions, was the driver for this assessment. To investigate the reliability of the EFSA guidance, a homogeneous data-set of 190 GLP and OECD guideline compliant in vitro human skin studies, chosen to match the test method preferred by EU data requirements, was evaluated. These studies represented a wide range of active substances, formulation types, and concentrations. In alignment with EFSA guidance on human exposure assessment, a conservative estimate of absorption (95th percentile) was chosen to define defaults, which were also based on the EFSA worst-case assumption that all material in skin, excluding the first two tape strips, is absorbed. The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. Relatively high dermal absorption values for organic solvent-based formulations, compared to water-based or solid concentrates, support their use as worst-case surrogate data for read-across to other formulation types. The current review also shows that dermal absorption of sprays does not increase linearly with increasing dilution, and provides a novel, science-based option for extrapolation from existing data.