Guidance on dermal absorption

Abstract

This guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of active substances in Plant Protection Products (PPPs). It is based on the 'scientific opinion on the science behind the revision of the guidance document on dermal absorption' issued in 2011 by the EFSA Panel on Plant Protection Products and their Residues (PPR). The guidance refers to the EFSA PPR opinion in many instances. In addition, the first version of this guidance, issued in 2012 by the EFSA PPR Panel, has been revised in 2017 on the basis of new available data on human in vitro dermal absorption for PPPs and wherever clarifications were needed. Basic details of experimental design, available in the respective test guidelines and accompanying guidance for the conduct of studies, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with PPPs are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin (regarded to provide the best estimate), data from experimental animals (rats) in vitro and in vivo, and the so called 'triple pack' approach. Various elements of study design and reporting that reduce experimental variation and aid consistent interpretation are presented. A proposal for reporting data for assessment reports is also provided. The issue of nanoparticles in PPPs is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of PPPs.

Keywords: default values; dermal absorption; in vitro; in vivo; plant protection products; triple pack.

Flow chart 1a

Procedure to select default absorption values

Flow chart 1b

Procedures to follow when there are no dermal absorption data on the actual formulation under evaluation

Flow chart 2

General procedure for decision of dermal absorption value of plant protection products

Flow chart 3

Procedures to follow when using dermal absorption data generated at dilutions different to those representing ‘in use’ conditions

Flow chart 4a

Consideration of stratum corneum and application site residues in vitro

Flow chart 4b

Consideration of stratum corneum and application site residues in vivo

Flow chart 5

Procedures to follow when reading across dermal absorption data between formulation types

Flow chart 6

Procedures to follow when extrapolating dermal absorption data on an active substance to a formulated product

Figure B.1

Box plots, by sample size n, of the ratio of logit‐transform based upper confidence limit to raw data upper confidence limit. Red line highlights where the limits are equal and blue lines where the ratio is between 0.9 and 1.1

Figure B.2

Box plots, by sample size n, of the ratio of raw data upper confidence limit to the sample maximum. Red line highlights where the limits are equal

Figure B.3

Exploration of pro‐rata extrapolation for dilutions. Each point corresponds to a study with more than one dilution of the same active substance. The horizontal axis shows the ratio of the concentrations for the two dilutions. The vertical axis shows the ratio of the fraction absorbed (average of replicates) for the lower concentration to the fraction absorbed at the higher concentration (average of replicates). Both axes are logarithmic. The thick red line corresponds to pro‐rata extrapolation and the thick blue line corresponds to Aggarwal et al. (2014, 2015); points coloured light blue are cases where pro‐rata extrapolation would predict absorption in excess of 30%, i.e. where step 3 in the extrapolation scheme proposed in section 4.7 of Aggarwal et al. (2014) would apply

Figure B.4

Dependence of fraction absorbed (logit scale) on concentration (logarithmic scale)

Figure B.5

Dependence of fraction absorbed (logit scale) on formulation category and on concentration status (dilution/concentrate)

Figure B.6

Scatter plot of dermal absorption vs log P_ow. Vertical green lines depict cut off at log P_ow < −1 and > 4. Horizontal black line depicts the 10% value. Red crosses denote records for which log P_ow < −1 or > 4 and MW > 500

Figure B.7

Scatter plot of dermal absorption vs molecular weight. Vertical green line depicts cut off at MW > 500. Horizontal black line depicts the 10% value. Red crosses denote records for which log P_ow < −1 or > 4 and MW > 500