July 8, 2020 by Rhiannon Smith
In June, ECHA issued a report to the European Commission on progress under the REACH regulation on the reduction of in vivo testing. The report discusses aspects which have been implemented by ECHA and reviews the effectiveness and shortcomings of approaches followed by registrants. ECHA note that registrants use a range of approaches to reduce animal testing, including read across, weight of evidence and the use of QSAR. However, many dossiers are not fully compliant and the adaptations applied are not always scientifically robust. ECHA highlight the need for dossiers to be updated and propose potential ways to address the shortcomings.
The most common issues identified for read across are:
- Insufficient substance identity information
- Poor documentation, including read across assessments/category justifications
- Deficiencies in the hypothesis and justification for predicting effects in the target substance(s)/category members
- Deficiencies in the arguments and evidence to justify read across, such as toxicokinetics
- Deficiencies in the evidence to support the read across, such as bridging studies
- Deficiencies in the quality of the data which are being read across
ECHA highlight the need for further data, particularly on toxicological mechanisms and toxicokinetics, as well as bridging data from lower tier/screening studies, such as OECD 422 combined repeat dose and reproductive toxicity screening studies. ECHA note the potential for new approaches, such as in vitro screening using human cells, but counter this with the need to integrate these specific pieces of evidence within the complexity of vertebrate toxicokinetics and toxicology.
ECHA propose that registrants proactively update and improve existing read across approaches, citing the availability of the Read Across Assessment Framework for self-assessment by registrants of read across and category approaches.
Weight of evidence and data waiving
ECHA note that registrations often lack sufficient reliable data and justification to support their weight of evidence and data waiving approaches, highlighting the need for reliable sources of information and sufficient documentation, including discussions on the relevance of each line of evidence provided and justification that the available lines of evidence robustly address each element of the information requirement.
ECHA propose that registrants follow the weight of evidence templates which were published in 2017.
During the preparation of the report, ECHA undertook a spot check on QSAR prediction records and found that a substantial number of these were not adequate. ECHA screened the records on the “adequacy of the input structure, applicability domain and the coverage of the specific chemical space” and found the most common issues were:
- Inconsistencies between the registered substance and the modelled structure
- Insufficient data points in the model training set
- Insufficient coverage of structural fragments for the modelled structure/registered substance in the training set
- Insufficient justification for the prediction on the reliability to complete the endpoint and relevance to the substance
- Substance properties outside the applicability domain
- Assessment of the impact of other factors in assessment of the endpoint and selection of the prediction, such as biotransformation rates
ECHA highlight the need for QSAR predictions to be accompanied by appropriate QMRF and QPRF documents (QSAR method and prediction reports) and propose that registrants follow the practical guide on how to use and report QSARs, which was published in 2017.
Looking forward, ECHA highlight that a balance needs to be struck between avoiding unnecessary testing on animals and ensuring that there is sufficient data on the hazards of chemicals in order to protect the environment and human health. ECHA aim to use the data from REACH registrations to develop its EU chemicals knowledge database and to use this as a resource in its wider plans for the European Green Deal and other initiatives.
wca recommend that registrants regularly review their dossiers to ensure that they remain compliant and address any changes in the expectations for REACH registrations. These include ensuring that dossiers contain sufficient evidence to address information requirements and including robust evidence and justifications where non-test methods have been used.
wca have a wealth of experience in preparing, reviewing and updating REACH dossiers, if you would like to discuss how we can assist with your substances, please contact us.
Photo credit: Zforgacs / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)
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