Read-across and alternative testing strategies for REACH 2018

Transcription

1 Read-across and alternative testing strategies for REACH 2018 Jeannette Paulussen, Ph.D. June 24, 2015 Content REACH & Alternative testing strategies In vitro testing and study waivers QSARs and Annex III Read across / grouping Practical considerations and case studies Take home message 1

2 REACH & Alternative testing strategies REACH and strategy To ensure REACH compliance - develop your REACH program timely Develop your REACH programme early Limited time to adjust registration strategy Include a clear planning Ensure uninterrupted business st June tonnes per year 2

3 REACH and strategy Market potential Lead registrant? Study waiving Alternative testing Assess and understand portfolio Evaluate regulatory opportunities Testing Dossier preparation and submission Alternative testing strategies Historical human data Annex XI Studies last resort In-vitro data Weight of evidence Literature data Annex III (Q)SAR Industry is Read across responsible Exposure based waiving 3

4 In vitro testing or study waivers Eye and Skin Irritation/Corrosion Bovine Corneal Opacity/Permeability assay (BCOP) Reconstructed Human Cornea-like Epithelium (EpiOcular) Hen s Egg Test ChorioAllantoic Membrane (HET-CAM) Skin irritation (Episkin and Epiderm) / corrosion (Epiderm) Corrositex (packing materials) 4

5 Eye Irritation REACH requirements Bovine Corneal Opacity and Permeability Test (BCOP; OECD 437) Inconclusive (IVIS > 3; 55) Negative (IVIS 3) Positive (IVIS>55) No classification for eye irritation; No further testing required UN GHS Category 1 (serious eye damage); No further testing required Further (in vivo) testing for classification EpiOcular (draft guideline) Positive (Tissue viability 60%) Negative (Tissue viability >60%) No classification for eye irritation; No further testing required Skin Irritation/Corrosion REACH requirements In vitro skin corrosion (OECD 431) Positive Assume corrosivity in vivo. No further testing required. Negative In vitro Corrositex (OECD 435) Subcategory 1A, 1B, 1C In vitro skin irritation (OECD 439) Positive Assume irritancy in vivo. No further testing required. Negative Substance is not an irritant (or corrosive) No further testing required. 5

6 In vitro skin sensitization Complex process that consisting out of various steps 1. Chemical absorption and binding with cellular proteins (haptenation) 2. Initiation of an inflammatory response in which the transcription factor Nrf2 plays an important role 3. Activation of dendritic cells that migrate to the lymph notes and activate T-cells (allergic reaction) In vitro skin sensitization A combination of three in vitro tests is required to mimic the physiological process Direct Peptide Reactivity Assay (DPRA) Determines the reactivity to proteins, via depletion of cysteine and lysine detected by HPLC/UV OECD 442C Keratinosens TM Determines Nrf2 activation in a cell line via induction of luciferase expression OECD 442D 6

7 In vitro skin sensitization Human Cell Line Activation Test (h-clat) Quantifying changes in expression of cell surface markers associated with DC activation ECVAM validated, draft guideline OR Myeloid U937 skin sensitization test (MUSST) Determines dendritic cell activation, via CD86 expression in U937 cells by flow cytometry ECVAM validation ongoing Possibility for in silico (QSAR) + 2 of the above tests? Not regulatory accepted yet, nor for C&L Study Waiver, e.g. - Acute dermal toxicity study: - Acute oral LD50 > 2000 mg/kg bw acute dermal may be waived - Agreed within Caracal (July 2014) - Until REACH update propose to waive acute dermal study when: 1. acute oral LD50 > 2000 mg/kg bw AND 2. physico-chemical properties do not suggest local effect 7

8 QSARs and Annex III (Q)SAR = prepare sound justification (Q)SAR should be justified for their validity, reliability, applicability, adequacy and their regulatory relevance (Q)SAR: Physchem: EPISuite, Pallas, Watson method How to use QSAR predictions Environmental fate: EPISuite, Canadian fugacity Ecotoxicity: EPISuite Toxicity: DEREK, Multicase, Skinperm OECD QSAR Toolbox 8

9 (Q)SAR = prepare sound justification (Q)SAR should be justified for their validity, reliability, applicability, adequacy and their regulatory relevance How to use QSAR predictions (Q)SAR generally not used as stand-alone methods the strongest is to use as Weight of Evidence combination with read across Mechanistic and metabolic domains are important Annex III: cost saving opportunity at a glance Opportunity to decrease Annex VII costs (phase-in substances) Valuable approach for well-defined substances Handle all (eco)tox and e-fate requirements with QSAR Only perform physico-chemical testing Expert report and IUCLID dossier preparation More than 50% cost savings compared to full Annex VII 9

10 Art 12.1 (b) and Annex III Read across / grouping Practical considerations 10

11 Read across = prepare sound justification How to use read-across For acceptance a strong scientific argument is needed: 1. Identify analogues with data 2. Assess structural similarity a. Same core/functional groups; same reactivity b. Same precursor or degradation product c. Constant pattern of properties across category d. Same Mode of Action/Adverse Outcome Pathway, Read across = prepare sound justification How to use read-across For acceptance a strong scientific argument is needed: 3. Determine composition Impurities/minor components present that could influence the hazard profile? 4. Gather physchem data: molecular weight, water solubility, partition coefficient, vapour pressure (consider also particle size) 5. Gather available hazard data 6. Confirm initial rationale 7. Decide on the need to gather additional data 11

12 Practical considerations Considerations SIEF status Substance identification Cost/ time Absorption/metabolism data Practical considerations SIEF status Are you the Lead Registrant? Are substances already registered? Use a trustee Data evaluation for SIEF acceptability Buy Data 12

13 Practical considerations Substance identification Has everyone substance identification data? Don t forget particle size distribution Impurities influencing C&L? Practical considerations Cost vs time May save money May save/cost time Depending on: - Endpoint - The level of detail provided to support the hypothesis 13

14 Practical considerations Absorption and metabolism May be important for your substance to reduce classification May save testing Depending on: - Endpoint Impurities can: 1. Influence the applicability of read across 2. Complicate the choice of the substance to be tested - The level of detail provided to support the hypothesis Read across = prepare sound justification Success Factors Interpolation within category members is very strong Extrapolation (e.g. edge of the category) is strong when a robust trend is present in the category/sound justification for analogue for that endpoint. A clear hypothesis based on the chemistry of the category that is supported by reliable and relevant hazard data (use QSAR and WoE). Good understanding of the kinetics of the substance 14

15 Read across / grouping Case studies Case Study different impurity profile Consortium: agreed to use a category approach to register inorganic salts having a common functional group A company had an impurity influencing the C&L of the substance leading to eye irritation C&L (H319) After evaluation of the data it was concluded: Two companies had this impurity One company had the impurity < C&L threshold One company had to classify the substance (H319) based on the conc. of the impurity The category showed some data gaps, e.g. Skin irritation vs impurity first tested the substance containing the impurity the result was negative we could therefore stop testing and avoid C&L 15

16 Case Study alkyl chains UVCBs with different alkyl chains; linear and/or branched (11 groups) Similar composition Ecotoxicity/fate: Costs Take home message Develop a strategic REACH program to help control costs Evaluate all regulatory opportunities (Annex XI and III) In vitro toxicity study possibilities Read across: Consider the presence of impurities Prepare a sound justification Realize that if analogue is classified your substance ditto Consider being a Lead registrant Influence decisions Use the generated data for GLOBAL use! 16

17 Thank you For more information: - Webinar Plan ahead with a clear REACH strategy : Articles: - REACH 2018, Specialty Chemicals Magazine, April Within Reach, EPC, p56-57, June