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Assessment and methodological support
Scientific Opinion on the Science behind the Revision of the Guidance
Document on Dermal Absorption
This opinion provides the relevant data, evaluations and references that support the criteria proposed in the new draft guidance needed to facilitate assessment of dermal absorption of plant protection products (PPPs) under Directive 91/414/EEC and Regulation (EC) No 1107/2009. The new guidance will be finalised and published only after adoption and publication of this opinion. This opinion has been developed after a public consultation of EFSA on the current guidance document and an outsourced project carried out by the UK Chemicals Regulation Directorate (CRD, 2010). It is not intended to be an exhaustive review but builds on existing documents to which the reader is referred to, and addresses in more detail elements that are specifically relevant for the assessment of dermal absorption of plant protection products. It contains an overview on skin and substance properties and other determinants that have an impact on absorption, a description of important elements in the design of experimental studies and an analysis of available data on dermal absorption of PPPs. The PPR Panel concludes that assessment of dermal absorption in the absence of specific studies can be performed based on default values that the Panel derived from the analysis of the available databases. Elements for a tiered approach are described and commented on. The PPR Panel also concludes that in vitro human studies can be used as a stand alone test for assessment of dermal absorption. The Panel indicates some additional requirements to adapt existing OECD test guidelines to the special requirements of PPPs and their formulations. A harmonised reporting of the studies is also considered important. Some areas where further research could usefully be conducted have been identified.
© European Food Safety Authority, 2011
Following a request from EFSA, the Panel on Plant Protection Products and their Residues (PPR) was asked to deliver a scientific opinion on the science behind the revision of the guidance document on dermal absorption.
Experience has shown that interpretation of dermal absorption data lacks consistency even when the existing guidance document is used, leading to recurring issues that have provoked extensive debates during the evaluation of plant protection products (PPPs) under Directive 91/414/EEC. In addition to that there are also developments in scientific understanding of dermal absorption processes and new evaluations done in the field by national and supranational bodies (Holmgaard and Nielsen, 2009; WHO, 2006; OECD 2004a, b, c).
The starting point for the present opinion was a public consultation of EFSA on the current guidance document that was launched with the aim of involving stakeholders and to gain information about further issues to be addressed in the opinion. A report on the outcome of the consultation is available on the EFSA website (EFSA, 2009a).
The second preparatory step was an outsourced project carried out by the UK Chemicals Regulation Directorate (CRD) who was asked to provide a proposal for a revision of the guidance document based on literature review and analyses of data taking into account the outcome of the stakeholder consultation. The report from the outsourced project (CRD, 2010) is available on the EFSA website.
The present opinion provides the relevant data, evaluations and references that support the criteria proposed in the revised draft guidance document needed to facilitate evaluations of chemical PPPs under Directive 91/414/EEC and Regulation (EC) No 1107/2009.
It contains (i) an overview on skin and substance properties and other determinants that have an impact on absorption, (ii) a description of important elements in the design of experimental studies and (iii) an analysis of available data on dermal absorption of PPPs that together with (iv) an extensive literature review, constitute the basis for the different default assumptions and the decision criteria given in the draft guidance document.
The responses to the comments obtained in the public consultations are included as an appendix to this opinion. The Guidance constitutes a separate output of the PPR Panel.
The PPR Panel concludes that dermal absorption in the absence of specific studies that are not mandatory under the present regulation can be performed based on default values that the Panel derived from the analysis of the available databases. Depending on availability of studies, elements for a tiered approach have been described and are presented in the proposed guidance document. However, the PPR panel concludes that an in vitro human study can be used as a stand alone test to derive dermal absorption values for risk assessment. The Panel underlines the need for an adaptation of existing OECD test guidelines to the specificity of PPPs and their formulations. To this end some additional requirements have been indicated that would help in using the studies for this specific risk assessment.
Blood flow/vasodilatation has been considered to have a minor impact on dermal absorption since they only act after the compound has passed through the epidermis to the vascular dermis. Sweating/skin hydration have been reported to increase dermal absorption as have ambient temperature and high ethanol consumption, but the overall magnitude is reported to be only up to 2- fold. On this basis, the PPR Panel concludes that the influence of these parameters should not impact significantly on dermal absorption of pesticide formulations in normal use.
Mechanical lesions by either tape stripping or abrasion (e.g. by a rotating brush) cause up to >100 fold increase of absorption for compounds that have very low absorption, but this occurs only when the lesions reach the dermis. In individuals suffering from atopic dermatitis, skin areas not obviously affected by the disease showed about a 2-fold increase in permeability to sodium lauryl sulphate and polyethylene glycols (molecular weight (MW) 150-590). The PPR Panel considers it unlikely that individuals with extensive skin damage would leave the skin unprotected; in case of less extensive skin damage, it would in any case represent a minor fraction of the total exposed area. Based on these data, the PPR Panel concludes that the possible presence of skin damage to a limited skin area, or skin diseases such as atopic dermatitis, will not significantly impact on dermal absorption of pesticide formulations in normal use and that they are covered by the safety factors applied when deriving the acceptable operator exposure level (AOEL). Also minor differences in skin absorption due to age do not necessitate the establishment of different absorption values for children and adults.
Treatment of skin, in vivo and in vitro, with irritants such as sodium lauryl sulphate (SLS) has been shown to enhance dermal absorption/penetration, the magnitude of the enhancement varying with the compound, the experimental procedure and severity of irritation; in comparison to irritation, simple delipidisation (e.g. by acetone) may increase absorption by 2-fold. Other factors that determine dermal absorption of chemicals, include octanol/water partition coefficient, molecular weight/size, use of detergents/solvents and concentration of the substance. The PPR Panel also notes that there are no good predictors of absorption from pesticide formulations and therefore the PPR Panel is of the opinion that dermal absorption data on plant protection products should be generated on the formulated product, or a closely related product, and on concentrations representative of the spray dilutions as applied to the crop. It is proposed in line with the current regulation on classification ((EC) No 1272/2008) that formulations are considered similar when the content of each safener/synergist and other formulants is within 25% of the actual concentration of the tested formulation, although the Panel is not aware of any scientific evidence for this value. Available data were considered inadequate for any conclusion to be drawn regarding the potential to extrapolate between formulation types; in this case use of default values is suggested.
From the methodological point of view the PPR Panel considers that:
- The use of data generated following exposures of human torso/breast and upper leg skin in vitro will provide realistic dermal absorption values for use in exposure modelling.
- The use of dermatomed (split-thickness) skin is recommended because both flux and % absorption can be calculated and used for risk assessment, whereas with full-thickness skin only % absorbed can be used.
- Solid material should be moistened with a minimal volume of vehicle (e.g. water or physiological saline, no organic solvents) to make a paste.
- In in vitro studies the receptor fluid should not be a rate-limiting element in absorption because of an insufficient solubility of the material under test. In current practice, the expected concentration of the active substance in the receptor fluid should not be higher than 10% of the maximal solubility of the product in the given receptor fluid. Moreover, the receptor fluid should not affect the integrity of the barrier function of the skin.
- The total amount of a chemical penetrating during a certain time period is not very informative on its own unless most of the compound has been already absorbed. This is defined as 75% absorption taking place in 50% or less of the sampling time.
- In order to mimic operator/worker in use conditions, exposure time should be 6 - 10 hours, after which the compound should be swabbed.
- Sampling time should last 24 hours and over 75% of the absorption should occur within half of the duration of the total sampling period: in such a case indication of the basis for calculation of absorption, including considerations of the amount of substance present in the stratum corneum, are provided.
- The PPR Panel is of the opinion that both % absorbed and maximum flux are parameters that can be used to compare dermal absorption for instance between species of skin areas, the flux being independent from the recovery of the substance. The maximum flux can be calculated during the first hours, i.e. the first 2 hours (or less if absorption is very rapid) of the linear part of the curve correlating amount absorbed with time.
- Tape strips should be analysed separately. The PPR Panel follows the general approach used within EFSA Pesticide Risk Assessment and Peer Review (PRAPeR) whereby the first 2 tape strips are assumed to represent material that will not become bioavailable. The Panel notes that it is very difficult to standardise the tape stripping technique and is not aware of any scientific evidence for the notion that specifically the outer two tape strips can be regarded as non-bioavaliable. Accordingly, this number of two is applied in the guidance only on the basis that it is established practice in current risk assessment of PPP’s within in the EU. Only if absorption is essentially complete at the end of the study (75% occurring within half of the study duration) all tape stripped material can be excluded.
- The substance remaining in the skin at the end of exposure should be considered as absorbed/absorbable after removal by washing that should be representative of normal hygiene practices e.g. an aqueous soap solution.
The PPR Panel considers that skin metabolism will not alter the calculated absorption significantly as the metabolically active cells are below the stratum corneum and therefore the main barrier to absorption has to be passed before any metabolism can occur. In addition, the determination of skin absorption for risk assessment usually considers the total percentage penetration of a compound into and across the skin.
Since according to EU Regulation (EC) No 1107/2009 data from human volunteer studies cannot be used to perform risk assessment, only issues related to studies in non-human primates are discussed although most of the considerations will also apply to studies in humans. There are difficulties in such studies relating to the determination of the overall mass balance (e.g. recoveries and carcass and application site residues). It is important to underline the need to cover possible metabolites or marker compound (or compounds) if non-radiolabelled compounds are used that allow back extrapolation to absorbed material based on the amount in urine, faeces and exhaled air.
The PPR Panel is of the opinion that in any case, experiments with non-human primates are difficult to carry out and to be interpreted. Therefore, their use is discouraged, and the recommendations provided in the guidance solely refer to already existing studies.
Techniques used to determine the relationship between excreted and absorbed material generally involve comparison of excreted material following oral, intravenous or dermal dosing. The dermal study should include a sampling duration long enough to confirm that excretion is essentially complete. Indications for calculations are provided indicating the issues related to first-pass effect, incomplete absorption or extensive biliary excretion when the oral route is used for comparison. The alternative approach of determining the ratio of the area under the curve (AUC) from intravenous or oral dosing with that from an equivalent dermal dose is also presented. In any case, it is the responsibility of the notifier to present a justification for the analytical method used and how the recovered material relates to the amount actually absorbed.
The Panel also identified the need for a harmonised reporting of the studies that will help in taking decisions that are consistent across time and MS.
In summary, the approaches recommended in this opinion are based on a combination of methods and default values. Some of these are based on evaluation of data but others are based on recommendations in other regulations/guidance for which the Panel could not find clear scientific support. Overall, taking account of the uncertainties involved, it is the Panels opinion that the dermal absorption estimate will be sufficiently protective.
The PPR Panel recommends that a new guidance document on dermal absorption should be adopted along the lines of that set out in a separate document.
The new guidance will be finalised and published only after adoption and publication of this opinion.
The guidance should be reviewed periodically and if appropriate revised as well as when relevant new data becomes available.
Further research could usefully be conducted on: (i) default values, (ii) (Q)SAR and read-across, (iii) skin lesions and diseases (relevance and occurrence), (iv) evaluation of the proper experimental conditions to mimic use of PPE, (v) extrapolation between formulation types, (vi) identification of the most appropriate approach to define dermal absorption values for re-entry workers (dilution versus concentrate) and (vii) studies on dermal absorption of nanoformulations.
Dermal Absorption, Pesticides, Guidance