‘How to use and report (Q)SARs’ for the assessment of substances under BPR

ECHA recently published a guidance document on How to apply ECHA’s practical guide ‘How to use and report (Q)SARs’ for the assessment of substances under BPR1 (May 2019). This document discusses the applicability of ECHA’s practical guide ‘How to use and report (Q)SARs’2, which only refers to REACH, to the hazard assessment of biocidal active substances.

Procedures for using (Q)SAR as an alternative method to testing are very close under REACH and BPR. Therefore, ECHA’s practical guide ‘How to use and report (Q)SARs’2 and ECHA’s Guidance On Information Requirements And Chemical Safety Assessment [R.6]3 are in principle applicable to hazard assessment of biocidal active substances.

An short overview of how to use and report (Q)SARs for the assessment of biocidal active substances according to ECHA is provided below, based on ECHA’s practical guide ‘How to use and report (Q)SARs’2 and also including the biocide specific issues as discussed in the new (Q)SAR guidance document1.

How to use and report (Q)SARs

ECHA’s practical guide ‘How to use and report (Q)SARs’2 presents the definitions of (Q)SAR, as being ‘a SAR is a qualitative relationship that relates a (sub)structure to the presence or absence of a property or activity of interest’ and ‘a QSAR is a mathematical model relating one or more quantitative parameters, which are derived from the chemical structure, to a quantitative measure of a property or activity’.

Before using (Q)SARs it is essential to first collect all available (experimental) information. Other issues important when starting with (Q)SARs are that the chemical structure needs to be well defined and that reliable and adequate experimental (measured) results prevail over estimated values. In addition, the recommended strategy for using (Q)SAR results is that these should be part of a weight of evidence (WoE) approach or as supporting information and that all (Q)SAR models available to the applicant for the endpoint to be fulfilled should be run, especially when models are independent from each other. Also, it is recommended that the closer to a regulatory threshold the predicted result is, the more accurate the prediction needs to be.

The conditions for using (Q)SAR results specifically for biocidal active substances1,4 are:

  1. The results are derived from a (Q)SAR model whose scientific validity has been established. ECHA follows the OECD principles for validating (Q)SAR models5, which states that a (Q)SAR model should be associated with (a) a defined endpoint; (b) an unambiguous algorithm; (c) a defined domain of applicability; (d) appropriate measures of goodness-of-fit, robustness and predictivity; and (e) a mechanistic interpretation, if possible.
  2. The substance falls within the applicability domain of the (Q)SAR model. A practical approach is presented in ECHA’s practical guide ‘How to use and report (Q)SARs’2, which includes that the following elements are checked: (a) descriptor domain; (b) structural fragment domain; (c) mechanistic and metabolic domains, if possible; (d) analogues in the training set; (e) accuracy of model predictions for analogues; and (f) considerations for specific substances.
  3. The results are adequate for the purpose of classification and labelling and risk assessment. The (Q)SAR prediction should be not only reliable, but also relevant for regulatory decision.
  4. Adequate and reliable documentation of the applied method is provided. Detailed information is provided in the new QSAR guidance document1. The date of submission is important, because the BPR only prescribes IUCLID as format for submissions from 1 September 2013 onwards, but Document IIIA is the corresponding format for reporting (Q)SARs for the dossiers submitted before 1 September 2013. If IUCLID is used, a detailed approach is included in ECHA’s practical guide ‘How to use and report (Q)SARs’2. If IUCLID is not used, a template is provided in Annex 2 of the new (Q)SAR guidance document1, which should be completed and included as a Doc IIA document to the CAR.

In addition, ECHA’s practical guide ‘How to use and report (Q)SARs’2 also describes some practical examples how to assess the reliability of QSAR predictions and QSAR models related to REACH and a number of BPR endpoints.

References

  • How to apply ECHA’s practical guide ‘How to use and report (Q)SARs’ for the assessment of substances under BPR, European Chemicals Agency, 2019, https://echa.europa.eu/documents/10162/13655/how-to-apply-echas-practical-guide_bpr_en.pdf/98fce7a8-046f-f488-422d-a03a075fb1bc
  • Practical Guide – How to use and report (Q)SARs, European Chemicals Agency, 2016, http://echa.europa.eu/documents/10162/13655/pg_report_qsars_en.pdf
  • REACH Guidance On Information Requirements And Chemical Safety Assessment, https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment
  • Annex IV of Regulation (EU) No 528/2012 of the European parliament and of the council of May 2012 concerning the making available on the market and use of biocidal products.
  • Guidance document on the validity of (quantitative)structure-activity relationships [(Q)SAR] models, OECD No.69, 2007, http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?doclanguage=en&cote=env/jm/mono(2007)2