Consultancy for Environmental and Human Toxicology and Risk Assessment Science Beyond Regulatory Compliance Cost Reduction in REACH Alternatives to Testing ChemicalWatch EXPO Berlin, April 2017 Peter Jenkinson CEHTRA
Contents REACH 2018 Data and Costs Main Drivers for Cost Reduction: Adaptations to standard information requirements Waivers Exposure-based adaptation Read-across QSARs Expert knowledge and experience OECD Study Design Managing adverse study data
Data in REACH - HH ES predominant for acute studies WE and RA very popular QSAR almost absent! Relative proportions of the principal options to fulfil information requirements for human health endpoints for the substances (phase-in, 100 tonnes & 1 000 TPA 3662 substances). 3
Data in REACH Env. Relative proportions of the principal options to fulfil information requirements for environmental endpoints for the substances (phase-in, 100 tonnes & 1 000 TPA 3662 substances). l 4
REACH 2018 Dossier Cost Total approximate cost of a REACH dossier: 350 K Annexes VII et VIII (10-100 TPA) 50 K Annex VII (1-10 TPA) Registration cost corresponds to: Studies: >80% of the total price (assuming no existing data) Technical dossier: RS, and compilation of study results & risk assessment ECHA submission fees (depends on tonnage) 5
Waivers 6
Waiver Variations Column 2 Waivers Mostly only available if classification is applied Quantitative = Simple: e.g. hydrolysis: not needed if readily biodegradable Qualitative = Less simple: e.g. fish study not needed if substance is highly insoluble, which is not clearly defined in REACH. If you waive then a long-term study is needed! Annex XI Adaptations Testing does not appear scientifically necessary Use of existing data Weight of evidence Testing is technically not possible Exposure-based adaptation 7
Use of Existing Data (1) REACH Annex XI, section 1.1.1 (physico-chemical properties) and 1.1.2 (data on human health and environmental properties) on the use of existing data enable the use of non-glp non-guideline information, under certain conditions. These include the demonstration that such information covers the essential elements of the internationally accepted test method, provided documentation is sufficient and the information is adequate for the purpose of C&L and/or risk assessment. Essentially, this means old study data on the substance itself. BUT, for many low tonnage substances there are likely to be little or no existing data 8
Use of Existing Data (2) Weight of Evidence If an individual study is of insufficient quality then a weight of evidence approach can be used to combine multiple studies of inadequate quality. There may be cases where data from sources other than tests specifically addressing an endpoint can provide valuable information The pooling of several of such studies concerning a specific endpoint could be a way for evidence-based analysis. BUT, for many low tonnage substances there are likely to be little or no existing data 9
Use of Existing Data (3) Section 1.1.3 of REACH Annex XI considers the opportunity of evaluating historical human data, such as epidemiological studies on exposed populations, accidental or occupational exposure data, and clinical studies. BUT, for most low tonnage substances the chance that such data exist, or is adequate to use for a data endpoint is remote, so this is only mentioned here for the sake of completeness. 10
Technically Not Possible REACH Annex XI section 2 states that testing for a specific endpoint may be omitted if it is technically not possible to conduct the study as a consequence of the properties of the substance, e.g. such properties include solubility, high volatility, colour, reactivity with water. This sounds good. In reality, it is rarely an option to avoid testing except for some of the PC tests, but rather it becomes a reason to use a modified or different test system. In fact it can be more expensive, because you not only have to use a non-standard method, but you have to justify it too! QSARs may be able to help in these cases. 11
Exposure-Based Adaptation (EBA) In situations where human or environmental exposure is absent or so low that additional effects information will not lead to improvement of risk management, exposure-based adaptation may be considered. This is included in step 2 of the general framework on generation of information (see Section B.2.2 and Chapter R.2). Adaption is based on the justification that: exposure is absent, not significant, or unlikely strictly controlled conditions apply for the whole life-cycle substances incorporated into an article and is not released 12
EBA (2) But, ECHA Chapter R.5 Guidance states: Exposure based adaptations may be appropriate under the following conditions: i) exposure is absent (= exposure excluded) or not significant throughout the whole life-cycle of the substance for manufacture and all identified uses or, ii) when strictly controlled conditions apply throughout the life cycle of the substance for manufacture and all uses and iii) no releases from the article life-cycle stage (and subsequent waste-life stage) is to be expected and consequently there is a negligible likelihood of exposure. Situation iii) only applies to substances incorporated into articles. 13
EBA Conclusions The reality is that EBA is extremely difficult to utilise The criteria for SCC are very demanding Some member state representatives do not believe that no exposure is possible EBA is an uphill battle! 14
Read-Across (RA) 15
RA Introduction Read-across entails the use of relevant information from analogous substance/s (the «source» information) to predict properties for the «target» substance(s) One of the most commonly used adaptations. By 25 January 2017, ECHA had received 50,748 registrations (including NONS updates); many are joint registrations. At the substance level, ECHA has identified 11,998 registered substances. Further analysis of the substance types, as declared by the registrants shows that about 69% of these are mono-constituent substances, 10 % are multi-constituent substances and 21 % are UVCBs. A read-across or category approach was used in up to 75% of analysed dossiers (8729 substances) for at least one endpoint (as of June 2014). ECHA Guidance: ECHA Guidance Chapter R.6, May 2008 Read-Across Assessment Framework (RAAF), May 2015 RAAF-Considerations on multi-constituent substances and UVCBs, March 2017 16
ECHA - RAAF RAAF = Read-Across Assessment Framework RAAF document 2015 Primarily designed for use by experts within ECHA to facilitate consistent assessment of RA arguments for mono-constituents, encountered during dossier evaluation. Also made publicly available to facilitate improvements in the use of RA by registrants. RAAF document 2017 Not guidance, just serves to highlight the difficulties of RA for multi-constituents and UVCBs. Principles of a RA approach under REACH Structural similarity (a pre-requisite) Read-across hypothesis Comprehensive justification 17
Description and selection of the scenarios Target Source 1 Source 2 Analogue approach RAAF - Scenarios Source Source Target Source Source Source Source Category approach 18
RAAF - Assessment Scientific assessment Each scenario consists of a pre-defined set of Assessment Elements (AEs) that, when taken together, cover all of the essential scientific aspects that need to be addressed in the read-across approach for a particular scenario Full set of AEs in annexes A to F Conclusion on the adequacy and scientific robustness of the information provided in the dossier for the AE is reflected by the selection of one Assessment Option (AO) 19
RAAF Acceptance Tree 20
RA Conclusions RA has been very popular in REACH But, with the RAAF, ECHA has set a high threshold of acceptance for mono-constituents For multi-constituents and UVCBs, we can infer from the RAAF 2017 document, that it will be almost impossible to achieve acceptance What about RA in dossiers submitted before RAAF?? In practice RA is difficult and time-consuming, especially for multis and UVCBs 21
QSAR 22
QSAR in REACH Surprisingly QSAR has hardly been used in 2010/13 dossiers For sensitisation, which is well covered by the available QSAR systems, used for only 1.5% of substances Why? Lack of in-house QSAR expertise Lack of confidence in acceptance by ECHA No need, sufficient data available RA and/or WoE seen as easier options Accurate QSARs not available before ~2013 Results not palatable.. More information on QSAR models and their use in the next presentation. 23
Intelligent Study Design When Alternatives are Not Possible 24
Standard Requirements - Studies Generally, the amount of existing data decreases in parallel with the tonnage That is, 2010 data > 2013 data > 2018 data Fortunately the data requirements also decrease with tonnage But many 2018 substances are data poor Consequently, WoE will be difficult EBA is not so simple RA is not so simple QSAR tools have improved, so may be used more than before However, most standard requirements will be met by doing OECD studies 25
SMEs and 2018 2018 will be the deadline for SMEs, because: Low tonnage substances often associated with smaller companies Large companies may believe that they have done their share in 2010/2013 Profit too small to make them a priority for large companies Large companies may have taken role of downstream user and forced their suppliers to register SMEs reducing their portfolio of substances, and/or reducing tonnage to avoid Annex VIII 26
SMEs and OECD Studies Most SMEs will have little experience at placing studies at CROs Must either trust the CRO to provide unbiased advice, or Seek support from a consultant But difficult to be expert in everything and easy to take the wrong decision, or to know when a cheaper/better option is available 27
Reducing Study Costs - Choosing the CRO Example - Genetic toxicology At >10 TPA, 3 in vitro genetox tests are required The selection of the assay design and the CRO can make a huge difference to the total cost. Study OECD CRO 1 CRO 2 CRO 3 Ames 471 2000 3300 5800 MN or CA 487/473 14600 22000 25000 HPRT/MLA 476/490 10000 22000 22000 Total Euro 26600 47300 51000 OECD often requires a single experiment, CRO may perform duplicates because of habit Different cell lines may permit cheaper procedure CRO may specialise in pharma. 28
Reducing Study Costs - CRO Recommendations Repeat Dose toxicology It is rare to perform an Annex VIII OECD 407 28-day repeat dose toxicity study, or OECD 422 combined repeat dose and reproductive toxicity study, and observe no effects. Initially, histopathology is performed on control and high dose. When effects are observed by the pathologist at the high dose then a track-down to the mid and low dose groups is recommended at extra cost! But often the effects may be concluded to be non-adverse (e.g. liver hypertrophy). The histopathology results of the mid and low dose groups may have little impact on this conclusion, so this extra cost (could be several thousands of Euros) may be avoided. 29
Reducing Study Costs - When to do In Vitro Skin sensitisation is a standard requirement in Annex VII to X A battery of 3 in vitro tests is the new default The cost of the three tests is ~ 15K vs 5K for the previous default of LLNA (mouse study) If the battery is positive (that s another story) then an LLNA is needed for potency (CLP), total now ~20K There are circumstances where the in vitro tests are not valid and the LLNA may be selected instead Who will give you the best advice? CROs wish to develop their historical database ECHA wants to see more data to know how the tests perform in reallife (allegedly!) The reality is that the tests are hardly validated and no one knows how to interpret them, guidance is notable by its absence. 30
Reducing Study Costs - Managing Adverse Results Studies do not always provide the expected (hoped for) result. Adverse study results are generally followed by a recommendation from the CRO, or ECHA strategy, to perform more studies. Example, false-positive in mammalian cell genotoxicity test, CRO may take precautionary position Ames positive may lead to recommendation to do transgenic assay (>100K!), Comet assay is the much cheaper alternative (~30K) 31
Reducing Study Costs - Doing Just What is Needed Example hydrolysis study A full hydrolysis study is ~ 30K But, if all you need is to demonstrate that the hydrolysis half-life is <12 hours, (so that the environmental studies may be done on the degradation products), then Do a modified protocol for ~ 10K 32
Thank you for your attention 33