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Interpretation on How to Properly Adopt Read-across Approach during Substance Registration and Matters Need Attention

from CIRS by

In-vitro,Read-across,Substance,Registration,EU,China

As one of the most frequently used alternative methods for hazard assessment, the read-across approach has been widely adopted in chemical registration in many counties and regions. Take new substance registration in China for example, read-across is widely used in serial registration. When carrying out serial registration, enterprises shall provide physicochemical data of each substance as well as a complete set of data that consists of health toxicological data and eco-toxicological data of new substances in the group. Besides, enterprises should submit at least one same health toxicological and ecotoxicological data for each new substance.

By adopting read-across, enterprises can reduce test burdens. Besides, the competent authority is available to identify the similarity of substances via the limited health toxicology and ecotoxicology data and to further determine the applicability of the read-across approach.

At present, read-across is mainly adopted in EU REACH registration. Under EU REACH, a large number of substances with structural similarities and homologues, such as petroleum cracking products and alkane homologous series, are registered via the read-across approach (including category). Meanwhile, additional tests may be required for certain substances that are confirmed lack of data during completeness check. In 2021, ECHA conducted 371 compliance checks covering more than 2,100 registration dossiers and addressing 341 substances. 300 of these checks were so called full compliance checks, addressing all relevant endpoints of substances of potential concern. They resulted in 280 draft decisions (about 93%) sent to companies, requesting more data to clarify long-term effects on human health or the environment. The absence of the above data is generally caused by the inapplicability of the exemption, QASR or read-across approach.

The read-across approach is generally adopted based on the hypothesis that structure similarity leads to property similarity or that substances may share the same metabolites. When one chooses to adopt this approach, the Read-across Assessment Framework issued by the ECHA can be referred to as a guidance document. If read-across is adopted based on structural similarity, enterprises shall assess the following information:

  • Information on substance identity, focusing on whether there is structural similarity and to what extent;
  • Information on the composition of target substances, such as purity. When UVCB substances are involved, compositions of the target substances shall be provided as much as possible to analyze the similarities;
  • Adequate information on physical and chemical properties, toxicology and ecotoxicology data, such as the data under Annex VII and VIII of the REACH Regulation;
  • A data matrix to fill data gaps, mainly for high tier toxicological data and eco-toxicological data;
  • An analysis of read-across predictions and the impact of structural dissimilarity on prediction result.

In practical cases, enterprises may adopt read-across to fill the data gaps based solely on structural similarities and there is no sufficient data to verify the hypothesis that structure similarity leads to property similarity. It is not likely to pass the expert review from ECHA. Similarities in key physicochemical data such as vapor pressure, octanol-water partition coefficient, and solubility are not sufficient to demonstrate similarities in toxicology and ecotoxicology data. If 28-day repeated dose toxicity data and ecotoxicological data of algae, daphnia and fish can demonstrate similarity in substances properties, it is possible to adopt the read-across approach to fill the data gaps.

It is worth mentioning that similarity in data of repeated dose toxicity (such as 28-day or 90-day) cannot support the similarity in developmental toxicity or reproductive toxicity. Therefore, enterprises may choose OECD Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. It not only saves the test cost but also verifies the similarity of repeated dose toxicity and reproductive/developmental toxicity at the same time.

In summary, the read-across approach is an excellent alternative method. However, it is necessary to collect data and assess similarities of substances as much as possible before adopting this approach. Moreover, attention shall be paid to the differences in its requirements in various countries to improve the acceptance rate.

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