Guidance on Dermal Absorption 1 EFSA Panel on Plant Protection Products and their Residues

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 chemical plant protection products. It is based on the opinion on the science behind the revision of the guidance document on dermal absorption (EFSA, 2011) to which the guidance refers to in many instances. Basic details of experimental design, available elsewhere, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with plant protection products 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, 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 Draft Assessment Reports and Registration Reports is also provided. The issue of nanoparticles in plant protection products is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of plant protection products. © European Food Safety Authority, 2012 1 On request from EFSA, Question No EFSA-Q-2010-01324, adopted on 18 April 2012. 2 Panel members: Jos Boesten, Claudia Bolognesi, Theo Brock, Ettore Capri, Anthony Hardy, Andrew Hart, Karen Ildico Hirsch-Ernst, Susanne Hougaard Bennekou, Michael Klein, Robert Luttik, Kyriaki Machera, Angelo Moretto (until January 2011), Bernadette Ossendorp, Annette Petersen, Yolanda Pico, Andreas Schäffer, Paulo Sousa, Walter Steurbaut, Anita Strömberg, Maria Tasheva, Ton van der Linden, Christiane Vleminckx. Correspondence: [email protected] 3 Acknowledgement: EFSA wishes to thank the members of the Working Group on Toxicology of Pesticides Claudia Bolognesi, Karen Ildico Hirsch-Ernst, Susanne Hougaard Bennekou, Angelo Moretto (until January 2011), Yolanda Pico, Maria Tasheva and Christiane Vleminckx, the hearing experts Ingrid Becks-Vermeer and Ian Dewhurst and the EFSA staff Juan Parra Morte, Judith Ricketts, István Sebestyén, Hans Steinkellner and Manuela Tiramani for the support provided to this scientific output. Guidance on Dermal Absorption EFSA Journal 2012;10(4):2665 2 TABLE OF CONTENTS Abstract .................................................................................................................................................... 1 Table of contents ...................................................................................................................................... 2 Background as provided by EFSA ........................................................................................................... 3 Terms of reference as provided by EFSA ................................................................................................ 3 1. Introduction ................................................................................................................................. 4 2. The skin and properties affecting dermal absorption .................................................................. 5 3. Elements for a tiered approach .................................................................................................... 6 4. Elements of a study design and reporting that reduce experimental variation and aid consistent interpretation ............................................................................................................................... 7 5. Interpretation of studies ............................................................................................................... 9 5.1. Tape stripping ......................................................................................................................... 9 5.2. Recovery ............................................................................................................................... 10 5.3. Rounding of values ............................................................................................................... 10 5.4. Variability within the results and outliers ............................................................................. 11 5.5. Dilution rates (tested concentrations) ................................................................................... 11 5.6. In vitro studies with mammalian skin ................................................................................... 12 5.7. Non-human primates in vivo ................................................................................................. 13 5.8. Rat in vivo ............................................................................................................................. 14 5.9. Integration of in vivo and in vitro data .................................................................................. 15 5.10. Choice of dermal absorption values for worker/resident exposure ....................................... 16 5.11. Use of data from field studies ............................................................................................... 16 6. How to proceed when there are no data on the formulation under consideration ..................... 17 6.1. Default values ....................................................................................................................... 17 6.1.1. Consideration of the oral absorption value when setting a default value .......................... 17 6.2. Use of data on similar formulations ...................................................................................... 17 6.3. Data on the active substance ................................................................................................. 18 6.4. Microencapsulated formulations ........................................................................................... 18 6.5. Formulations containing more than 1 active substance ........................................................ 18 6.6. Use of other information ....................................................................................................... 18 6.6.1. (Q)SAR .............................................................................................................................. 18 6.6.2. Information on related active substances ........................................................................... 19 6.6.3. Comparison of oral and dermal toxicity data ..................................................................... 19 7. Data presentation in Draft Assessment Reports and Registration Reports ............................... 20 8. Flow charts ................................................................................................................................ 21 References .............................................................................................................................................. 29 Glossary .................................................................................................................................................. 30 Guidance on Dermal Absorption EFSA Journal 2012;10(4):2665 3 BACKGROUND AS PROVIDED BY EFSA The preparation and revision of the EU Guidance Documents to assist the implementation of Council Directive 91/414/EEC was originally the responsibility of the European Commission; this remit has been transferred to EFSA regarding risk assessment Guidance Documents. In 2006, EFSA has consulted Member States on their priorities for development and revision of such Guidance Documents. In response some Member States expressed a wish for an update/revision of the Guidance Document on Dermal Absorption (SANCO/222/2000 rev.7, 19 March 2004). In the practical use of this Guidance Document during the peer review under Directive 91/414/EEC several issues are recurring since they are not or only insufficiently covered by the current Guidance Document. Moreover re-evaluations (OECD, 2011; Environmental Health Criteria 235; Dermal Absorption, 2006), have been carried out in which refined or alternative approaches to the assessment of dermal absorption were presented. The report from the 2009 public consultation carried out by EFSA on the current Guidance Document suggests clearly that there is a need for substantial changes. In an EFSA outsourced project published in 2010 these comments were analysed, databases on dermal absorption were also analyzed and relevant literature was reviewed. In the report thereof further needs for updates and recommendations for a revised Guidance Document have been presented. After delivery of the report the PPR Panel started working on an Opinion on the Science behind the Revision of the Guidance Document on Dermal Absorption, which is in an advanced stage. The current evaluations and recommendations given in it show clearly that such a revision is highly desirable. TERMS OF REFERENCE AS PROVIDED BY EFSA The Scientific Panel on Plant Protection Products and their Residues is asked to prepare a revision of the Guidance Document on Dermal Absorption (SANCO/222/2000 rev.7, 19 March 2004). As this Guidance Document has been initially prepared by Commission and includes Management options, Commission and Member States will be consulted as provided by Article 22 of Regulation (EC) No 178/2002 to promote the effective coherence between risk assessment, risk management and risk communication functions. The revision will be based on: the comments received in 2009 within an EFSA stakeholder public consultation on the current guidance document SANCO/222/2000 rev.7, the evaluations provided in the final report from an EFSA outsourced project “Proposal for a Revision of the Guidance Document on Dermal Absorption” and the results and recommendations already given in a draft “Scientific Opinion on the Science behind the Revision of the Guidance Document on Dermal Absorption” which is already at an advanced stage. on a possible additional public consultation on this final draft opinion. recommendations of Commission and Member States regarding issues related to Risk Management. 4 http://www.efsa.europa.eu/en/scdocs/scdoc/282r.htm 5 http://www.efsa.europa.eu/en/scdocs/scdoc/52e.htm Guidance on Dermal Absorption EFSA Journal 2012;10(4):2665 4