EFSA GD on dermal absorption Industry feedback and considerations on bridging opportunities ECPA TEAM: Aggarwal M. 1, Fisher P. 3, Parr-Dobrzanski B. 5, Soufi M. 2, Strupp C. (Chair) 6 1 Dow AgroSciences; 2 DuPont de Nemours; 3 Bayer CropScience; 5 Syngenta; 6 ADAMA; Dr. Christiane Wiemann BASF
Overview Introduction: Dermal absorption (DA) for Plant Protection Products EFSA guidance on DA: New conservatism in dermal absorption Consequences for industry ECPA database ECPA database bridging opportunities and practical cases: Practical cases on bridging opportunities ECPA evaluation and conclusions drawn Revision of EFSA guidance on DA Current status and possible next steps Outlook: ECPA project DA of dried residues Slide 2
Introduction: Skin Structure and DA Penetration to dermis via: Passive diffusion Hair follicles between cells Skin multilayered Epidermis with Stratum corneum (SC) No blood supply Residue in SC cannot be absorbed Must reach dermis Major function barrier Slide 3
Why DA on pesticides? Integral part of non-dietary risk assessment Dermal exposure to Concentrated product (mixer/loader) Spray (applicator, bystander, resident) DA higher from spray than concentrate Dried residue (re-entry worker, resident partly) Currently DA from spray is used for re-entry worker RA DA converts external exposure to systemic exposure Systemic exposure compared to AOEL Exposure 100% of AOEL = acceptable risk AOEL = Acceptable Operator Exposure Level Slide 4
EFSA Guidance 2012: New Conservatism in DA 1. High default values 2. Limitation of read-across Unable to rely on existing data The ±25% rule Multi to one approach not taken into account (existing data for several products with a.i. used to conclude on DA of new product) No Expert judgement skin irritation and sensitization 3. Extrapolation to more dilute sprays Linear pro-rata assumed 4. Skin residues absorbed Not considering kinetics 5. More stringent criteria: recovery criteria (100 ± 5%) Replicate variability >25% of mean: Addition of S.D. 6. Same criteria applied to in vivo data, even though more kinetic information is available Industry-wide concern on impact of EFSA Guidance Document Slide 5
EFSA GD conservatism: Example A Mean (%) SD Receptor fluid 0.64 0.31 OECD TG Absorbed dose 0.64 Receptor compartment wash 0.19 0.10 Dermis 3.4 1.0 ECPA Absorbed dose 4.2 1.3 Tape strips (#3 last) 11.0 4.2 Epidermis 10.1 3.8 Absorption + skin residue 25.3 6.5 Total recovery 90.2 EFSA Absorbed dose 25.3+ 6.5+ 9.8= 42 10X Industry-wide concern on impact of EFSA GD Slide 6
Compounded, unrealistic conservatism AOEL LOAEL based on barely adverse effects LOAEL to NOAEL dose spacing 2x -10x Minimum 100x SF [10x inter-species & 10x intra-species] Correction method for oral absorption DA Study - in vitro vs. in vivo DA calculation (e.g., vs. reality) SC is absorbable Adjustment for recovery and SD DA from multiple days (in vivo studies) vs. AOEL per day Tier 1 exposure estimation models Conservatisms multiply to give irrelevant outcomes Substantially increase in study demands *ECPA database ~ 13/year (190 studies in 14 years, 1998 2012) ~ 85/year (170 studies in 2 years, 2012-2014) 5x increased demand Slide 7
ECPA database Analysis used worst-case definition of DA: 12 Notes on this definition: 1. Assumes all material in skin is absorbed (except upper layer of SC) It is always incorrect always overestimates absorption good correlation of absorption from in vitro to in vivo human when comparing absorption in receptor compartment without skin residues; Lehman et al 2011; Skin Pharmacol Physiol. 2011;24(4):224-30. http://www.karger.com/article/fulltext/324884) 2. Bioavailability from skin into bloodstream always <<100% Definition is highlyconservative Slide 8
Industry assessment: ECPA database All available studies until Feb. 2014 from each company homogenous database In vitro human skin studies only OECD TG- and GLP-compliant only Data rich and representative: 2 assessment phases 295 studies,749 DA values 173 actives, 19 formulation types Wide range for concentrations, MW and logpow Most conservative EFSA options used: DA calculation: OECD TG + whole skin - tape strips 1 & 2 DA 95 th percentile (to match worst-case EFSA exposure model) Slide 9
ECPA database Aggarwal et al., 2014 and 2015 Phase I: 190 studies Phase II: 295 studies Check reliability of conclusions from Phase I Increased number of formulation types improved read-across data Free to download at http://www.sciencedirect.com/science/article/pii/s0273230015000458 Slide 10
1. Default values: Concentrates 75% 5% a.s. EFSA GD No impact of a.s. content 25% >5% a.s. Percentile Dermal absorption Liquids Solids (n=250) (n=53) Median 0.6 0.3 75 th 1.3 0.7 95 th 5.2 1.7 Default values: 6% (liquids), 2% (solids) Slide 11
1. Default values: Sprays 75% EFSA GD Percentile Dermal Absorption All (n=446) Median 6.7 75 th 15.5 95 th 31.9 Default = 30% Slide 12
2. Read-across: Concentrates EFSA GD: No read-across Read-across is feasible: Solvent-based to others Water-based to solids Slide 13
2. Read-across: Sprays EFSA GD: No read-across Read-across is feasible: Impact of formulation type is limited Note: Spray dilute comprises of more than 99% water Slide 14
2. Read across: the ±25% rule Does the new formulation need to be tested for DA? Formulation Existing New Differences components (%) (%) (%) Active 20 20 0 Adjuvant 33 33 0 Emulsifier 3 3 0 Solvent 30 30 0 Anti-freeze 5 7.5 + 50% Water 9 6.5-28% Total 100 100 - Yes, according to EFSA GD Section 6.2, page 18 This is not sensible, and needs to be corrected EFSA agrees Slide 15
2. Read across: Multi to One: Example B 18 % absorption estimate EFSA worst-case definition 16 14 12 10 8 6 4 2 0 1000 EU endpoint 100 Study used for EU- agreed endpoints 10 1 0,1 0,01 Concentration [g/l] Study evaluation EFSA worst case definition BAS 1 - EC BAS 2 - EC BAS 3 - EC BAS 4 - EC BAS 5 - EC BAS 6 - EC BAS 7 - EC BAS 8 - EC BAS 9 - EC BAS 10 - EC BAS 11 - SC BAS 12 - SC BAS 13 - FS EFSA guidance: Composition differences force testing of different products. Expert judgement: considers EU-agreed endpoints to be reasonable worst-case Further testing of new products needed? EU endpoint for concentrate 8% nearly doubled due to addition of standard deviation: Is this sensible? Slide 16
2. Read-across: Case study C Same active substance DAS1 to DAS-4: EC or spray of EC DAS-5: EW or spray of EW Concentrate: y = -4.127ln(x) +22.896 (R 2 = 0.85) Read-across is also feasible within same group of formulation types on a case-by-case basis Spray Dilution: y = -3.22ln(x) +15.629 (R 2 = 0.80) Source: Corvaro M, Aggarwal M, Mehta J (2015). Applied In Vitro Toxicology (Accepted) Slide 17
2. Read across: Example D Bridging and dose response % of applied dose 8 7 6 5 4 3 2 EU agreed endpoint Non proportional dose response EFSA absorption estimates Skin residues in vitro can substantially exceed absorbance Expert judgement: EU agreed endpoints represent reasonable worst case 8 7 OECD Absorbed dose 1 0 BAS 1 - SC BAS 2 - SC BAS 24 - SC + Adjuvant Rat in vivo % of applied dose Human in vitro ADA 1 - SC BAS 3 - SE 2 Concentrate (100-125 g/l) Spray dilute 1:100-1:200 (0.5-1 g/l) Spray dilute 1:400 (0.376 g/l) 1 6 5 3 No proportional dose response over an up to 400 fold dilution range 0 BAS 1 - SC BAS 2 - SC BAS 2 - SC + Adjuvant ADA 1 - SC BAS 3 - SE Rat in vivo Human in vitro Concentrate (100-125 g/l) Spray dilute 1:100-1:200 (0.5-1 g/l) Spray dilute 1:400 (0.376 g/l) Slide 18
ECPA Database Results: 3. Extrapolation to more dilute sprays EFSA GD Absorption increases linearly with increasing dilution e.g., Increase dilution 10-fold = increase absorption 10-fold Assume linear increase up to 75% default Absorption is not proportional to concentration > 90% of times, increase in absorption was NOT linear ~ 25% of times it did NOT increase at all ECPA proposal If new concentration 2-fold the lowest tested: no Adjustment (BfR proposal) Assume linear from 2x to 5x up to 30% default Slide 19
ECPA Database Results: 4. Skin residues 90 80 70 Skin depotfactor= There is no correlation between DA and skin residues %Aborpttion of applied dose 60 50 40 30 20 Directly absorbed (receptor compartment) EFSA guidance DA Lehman et al 2011: good correlation DA in vivo and direct DA in vitro (receptor compartment) EFSA guidance largely overestimates compounds with high skin residues 10 0 0,01 0,1 1 10 100 1000 10000 Skin depot factor ~ 50% of the DA values have a skin depot factor >1 Only ~ 1% of those have direct DA > 10% Epidermis should not be considered as absorbed Slide 20
Revision of EFSA guidance document: Outline and expectations ECPA database provides an extensive state of the art scientific approach to evaluate DA Review of ECPA database should enable EFSA to reconsider DA evaluation criteria Options to reconsider Default values, Read-across approaches, Novel approach for non-tested dilutions Impact of skin residues Further aspects? Is revision of EFSA guidance document on DA in 2015 possible? Slide 21
Outlook ECPA: DA for surface deposits: EFSA guidance on the assessment of exposure of operators, workers, residents and bystanders: For the dermal absorption percentage to be used for the assessment of worker, resident and bystander exposure towards surface deposits, the higher of the values for the undiluted product and the in-use dilution should be used. The use of higher dermal absorption is based on the precautionary principle as no measured values for dried residues after application of dilutions are available In practice: thehighestvalueforthespray diluteisused Slide 22
Outlook ECPA: DA for re-entry workers: Calculate dose level to be tested: Potential dermal exposure (PDE) [µg a.s./day] = (DFR(0) [µg/cm 2 /kg a.s./ha] x AR [kg a.s./ha] x TC [cm 2 /h] x WD [h/day]) Convert µg/day to µg/cm 2 using relevant body surface area Air dry required volume of spray dilution to obtain calculated dose level on the septum Transfer the dose to the pre-wetted skin membrane in vitro and determine transfer efficiency If need adjust the dose volume to achieve targeted dose on the skin membrane Conduct the standard study Preliminary data shows Methodology works DA from dry residue is less than from spray Work is in progress with additional samples Slide 23
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