How ECHA decides whether “similar chemicals behave similarly” is good enough science.

One of the central goals of the EU’s REACH Regulation is to ensure the safe use of chemicals while minimizing animal testing. Anyone manufacturing or importing a substance in quantities above one tonne per year must generate sufficient information to demonstrate its safety. At the same time, Article 25(1) makes an important principle clear: testing on vertebrate animals must be used only as a last resort.

To achieve this, REACH Annex XI allows several alternative approaches for fulfilling information requirements. These include the use of existing data, weight of evidence, (Q)SAR models, in vitro methods, and one of the most widely used approaches of all: read-across.

On paper, the concept is remarkably simple. If two chemicals are sufficiently similar, perhaps the toxicity data from one can be used to predict the properties of the other. In reality, however, read-across is one of the most scientifically demanding and closely scrutinized approaches accepted by the European Chemicals Agency (ECHA).

Recent systematic studies now provide valuable insight into which read-across arguments succeed, which fail, and what this means for the future of non-animal chemical safety assessment.

The legal basis: What does REACH actually allow?

Section 1.5 of REACH Annex XI establishes the legal framework for grouping substances and applying read-across:

“Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint.”

In practical terms, this means that if a registrant can demonstrate that two or more substances are sufficiently similar, existing data from a well-characterized source substance may be used to predict the properties of another substance with limited data. The objective is straightforward: avoid unnecessary testing while maintaining a high level of protection for human health and the environment.

What exactly is read-across?

Read-across is a well-established in silico New Approach Methodology (NAM) used to fill toxicological data gaps for industrial chemicals. Rather than generating new experimental data, it uses existing information from one or more similar substances to predict the properties of another.

The underlying assumption is intuitive: substances that are sufficiently similar are expected to behave similarly.

Of course, the critical question immediately follows:

How similar is “similar enough”?

That is where the science becomes challenging.

Similarity is rarely based on chemical structure alone. ECHA expects registrants to justify why substances are expected to produce comparable biological effects, considering factors such as physicochemical properties, metabolism, toxicokinetics, toxicodynamics, and mechanistic evidence.

Ultimately, whether a read-across justification is scientifically acceptable is decided by ECHA.

Read-across is widely used, but acceptance is far from guaranteed

According to ECHA’s Sixth Report under Article 117(3) of REACH (2026), adaptations are now used more frequently than new experimental studies to satisfy REACH information requirements.

Among all adaptation strategies, read-across is the most common, accounting for 24.4% of all adaptations.

Popularity, however, should not be confused with regulatory success.

When ECHA concludes that a read-across justification is not sufficiently supported, it can require additional information through two different regulatory processes.

Testing Proposal Evaluation (TPE)

Before certain higher-tier studies, particularly vertebrate animal studies, are performed, ECHA evaluates whether the proposed testing is actually necessary.

Compliance Check (CCH)

ECHA also reviews submitted registration dossiers to determine whether the available information, including any read-across arguments, adequately fulfils the legal information requirements.

Two recent systematic reviews by Roe et al (2025, 2026) examined thousands of these regulatory decisions to understand what separates successful read-across submissions from unsuccessful ones.

What predicts success during Testing Proposal Evaluation?

Roe et al. (2025) reviewed 1,538 Testing Proposal Evaluation decisions published between 2008 and 2023.

Among the 304 decisions involving read-across, approximately 49% were accepted.

One finding stood out immediately.

Group-based read-across, where multiple substances belong to a defined category, had approximately 2.6 times higher odds of acceptance than traditional analogue-based read-across involving only one source and one target substance.

The authors also caution that this apparent advantage may be somewhat inflated. A single accepted category can generate multiple positive decisions, one for each member substance, even though all rely on the same scientific justification.

More revealing than the acceptance rate itself were the factors associated with ECHA’s decisions.

Factors that did not predict acceptance

Despite being included in many dossiers, the following arguments showed no association with regulatory success:

• Structural similarity alone
• Physicochemical similarity alone
• Bridging studies based on non-OECD assays

These arguments appear necessary, but clearly not sufficient.

Factors associated with successful read-across

Successful submissions were more likely to include:

• Group-based rather than analogue-based approaches
• Bridging studies performed according to OECD Test Guidelines
• Well-characterized constituents, particularly for UVCB substances
• Evidence supporting a common biological target, even when common metabolites were not identified

Factors associated with rejection

Perhaps the most surprising finding was that dossiers attempting to identify metabolites for both source and target substances were more likely to be rejected, especially for UVCB substances.

At first glance, this seems counterintuitive. One might reasonably expect that additional mechanistic evidence would strengthen the scientific case.

Instead, the results demonstrate an important lesson in regulatory science: more information does not automatically produce a stronger argument. The relevance and quality of the evidence matter far more than its quantity.

Compliance Checks paint an even tougher picture

Roe et al. (2026) extended their analysis by reviewing 2,386 Compliance Check decisions published before April 2024.

The outcome was considerably more demanding.

Only about 7.5% of read-across adaptation proposals were considered satisfactory.

Successful dossiers consistently demonstrated two key characteristics.

First, they established clear toxicokinetic similarity, showing that the registered substance and its analogues were processed similarly within the body.

Second, they demonstrated clear toxicodynamic similarity, supported by appropriate bridging studies.

These arguments were often reinforced by complementary in vitro data and QSAR predictions.

The message is clear.

Showing that two molecules look alike is rarely enough.

Successful read-across demonstrates that substances behave similarly inside the body and ultimately produce similar biological effects.

Where is read-across heading?

According to Cronin and Schultz (2026), several scientific challenges remain before read-across reaches its full potential.

Among the most important are:

• defining acceptable levels of uncertainty;
• evaluating similarity beyond simple structural resemblance while avoiding activity cliffs;
• improving the assessment of metabolites and degradation products;
• increasing the quality of source data; and
• understanding how artificial intelligence can support regulatory decision-making.

The future of read-across is likely to become increasingly mechanistic.

Rather than relying primarily on structural similarity, future assessments are expected to integrate biological, computational, and mechanistic evidence while making uncertainty more transparent and scientifically defensible.

Read-across is also expanding into new application areas, including nanomaterials, PFAS, UVCB substances, botanical mixtures, endocrine disruptors, N-nitrosamine impurities, and broader One Health assessments.

Key takeaways

Read-across is not a shortcut.

It is a scientifically structured argument that must convincingly demonstrate why data from one substance can predict the properties of another.

Recent evidence from thousands of ECHA decisions shows that successful read-across depends far less on simply demonstrating structural similarity than on building a coherent biological case supported by toxicokinetic evidence, toxicodynamic evidence, high-quality bridging studies, and robust supporting data.

As regulatory science continues to evolve, read-across is likely to become an even more important component of New Approach Methodologies. The challenge will not be using more evidence, but using the right evidence to reduce uncertainty while maintaining confidence in chemical safety decisions.

References

Cronin, M.T.D. & Schultz, T.W. (2026). Read-Across for Toxicological Data Gap Filling: State-of-the-Art, Challenges and Future Needs. Current Opinion in Toxicology. https://doi.org/10.1016/j.cotox.2026.100602

Roe, H.M., Tsai, H.D., Ball, N., Wright, F.A., Chiu, W.A. & Rusyn, I. (2025). A Systematic Analysis of Read-Across Adaptations in Testing Proposal Evaluations by the European Chemicals Agency. ALTEX, 42(1), 22–38. https://doi.org/10.14573/altex.2408292

Roe, H.M., Tsai, H.D., Ball, N., Oware, K.D., Han, G., Chiu, W.A. & Rusyn, I. (2026). What Does “Success” Look Like in Compliance Check Decisions by the European Chemicals Agency? The Curious Cases of Accepted Read-Across Adaptations. ALTEX, 43(1). https://doi.org/10.14573/altex.2505191

European Chemicals Agency (ECHA) (2026). The Use of Alternatives to Testing on Animals for the REACH Regulation. Sixth report under Article 117(3) of the REACH Regulation. Available here. Accessed 04.08.2026.