About Read-across

Chemical Read-across is regarded as a non-testing technique in which endpoint information for one substance (the source substance) is used to predict the same endpoint for another substance (the target substance), which is considered to be “similar” in some way (usually on the basis of structural similarity or on the basis of the same mode or mechanisms of action).

Both source and target substances have physicochemical, toxicological and ecotoxicological properties that are likely to be similar or follow a regular pattern as a result of structural similarity.

These similarities may be based on the following:

  • Common functional group (i.e. chemical similarity).
  • Common precursors and/or likelihood of common breakdown products through physical and/or biological processes which result in structurally-similar degradation products (i.e. similarity through (bio)transformation).
  • A constant pattern in the changing of the potency of the properties across the group (i.e. of physicochemical and/or biological properties).

Applying this concept means that information requirements for physicochemical, human health and/or environmental properties may be predicted from information from tests conducted on the source substance(s) by interpolation to the target substance(s), thus filling existing data gaps. For any of these endpoints, it may be performed in a qualitative or quantitative manner. In any case, expert judgement is needed and a robust justification should be provided.

Qualitative read-across, which main application is in hazard identification, involves:

  • The identification of a chemical substructure or mode or mechanism of action that is common to the substances (which are considered to be analogues); and
  • The assumption that the presence (or absence) of a property/activity for a substance can be inferred from the presence (or absence) of the same property/activity for the analogous substance(s).

Quantitative read-across involves:

  • The identification of a chemical substructure or mode or mechanism of action that is common to the substances (which are considered to be analogues); and
  • The assumption that the known value of a property for (one) substance(s) can be used to estimate the unknown value of the same property for another substance.

Chemical Read-across has gained much attention in recent years in particular for the way in which it can be used as a means of fulfilling data gaps under the European Union’s Registration, Evaluation, Authorization and Restriction of Chemicals regulation (EU REACH), which aims to fill data gaps for thousands of chemicals under short deadlines. In fact, while the read-across concept has been utilized for many years in the High Production Volume (HPV) program under the Organization for Economic Co-operation and Development (OECD) or the United States Environmental Protection Agency (US EPA), EU REACH has really provided the impetus to both update and harmonize the available technical guidance.

Technical Guidance

Guidance documents provide clear definitions of what is meant by analogue, category, and read-across approaches, highlight the interrelationship between these and (Quantitative) Structure–Activity Relationships ((Q)SARs), and provide specific guidance on special types of categories. It is worth noting that the drafting group responsible for developing the OECD and EU REACH guidance was one and the same; the OECD guidance was merely published a few months earlier.

OECD’s guidance on how to approach chemical categories and read-across provides a scientific and methodological background to the analogue and category approaches, outlining general aspects of grouping chemicals such as the identification of analogues/members of categories, the mechanistic basis for using analogues or chemical categories, and the robustness of both approaches. It also focuses on practical aspects for forming and documenting analogue and chemical category approaches, proposing analogue/category reporting formats (ARF, CRF) for structured and harmonized reports. There are also case studies published on their Series on Testing and Assessment, providing illustrative examples for read-across approaches.

Similarly, the European Chemicals Agency (ECHA) published their own guidance on QSARs and grouping of chemicals, to fulfil information requirements under the EU REACH regulation. An illustrative example of a grouping of substances and read-across approach was developed to support companies in complying with their obligations.

Under EU REACH, animal testing should be used as a last resort, after all approaches have been considered. This makes chemical read-across a powerful tool to fulfil this requirement. Indeed, read-across is the most commonly used alternative approach for data gap filling in registrations submitted under the EU REACH regulation, after experimental studies (ECHA, 2017).

To assist applicants in increasing the robustness of their approaches, ECHA has published the Read-across assessment framework (RAAF). The RAAF is primarily designed for use by experts in ECHA to help consistently assess the read-across studies encountered during dossier evaluation, but by making it publicly available ECHA has increased transparency and applicants can compare their read-across studies against the criteria by which they will be assessed. The RAAF provides a framework and guidance for consistent evaluation of the scientific aspects of a proposed read-across case, resulting in an output which is suitable for subsequent regulatory consideration of the read-across case, and reflects the experience gained from dossier evaluation in the context of the EU REACH information requirements.

While there is a need to exploit chemical read-across, there are still many hurdles in terms of characterizing what an acceptable and credible read-across represents. In recent years, more attention has been given to how New Approach Methodologies (NAMs) can support a read-across hypothesis. An example of such a project is the EU-ToxRisk (An Integrated European ‘Flagship’ Programme Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century), a platform for industry, regulatory and academic stakeholders on practical issues related to the submission of read-across justifications in risk assessment. An EU-ToxRisk Advisory Document on NAM-enhanced read-across is under preparation and several case studies are currently ongoing.


A number of tools and projects have been undertaken to help facilitate chemical read-across approaches. The OECD, in particular, has made significant efforts to promote regulatory applications of non-testing approaches such as (Q)SARs and Read-across. Under its (Q)SAR program, OECD initiated the development of the OECD QSAR Toolbox to make Read-across and (Q)SAR technology readily accessible, transparent, and less demanding in terms of infrastructure costs. The QSAR Toolbox assists in the development, evaluation, justification, and documentation of read-across within analogue and category approaches. A different conceptual framework of Adverse Outcome Pathways (AOPs) is being exploited to assist in the development of read-across for more complex endpoints such as repeated dose toxicity or reproductive/developmental toxicity.


Guidance on Grouping of Chemicals, Second Edition, OECD Series on Testing and Assessment, No. 194. OECD Publishing, Paris (2017) https://doi.org/10.1787/9789264274679-en.

Guidance on information requirements and chemical safety assessment, Chapter R.6: QSARs and grouping of chemicals. European Chemicals Agency (2008) https://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf/77f49f81-b76d-40ab-8513-4f3a533b6ac9

ECHA-17-R-01-EN Read-Across Assessment Framework (RAAF). European Chemicals Agency (2017). DOI 10.2823/619212 https://echa.europa.eu/documents/10162/13628/raaf_en.pdf/614e5d61-891d-4154-8a47-87efebd1851a

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