Applications of Chemoinformatics in Predictive Toxicology for Regulatory Purposes, Especially in the Context of the EU REACH Legislation

Applications of Chemoinformatics in Predictive Toxicology for Regulatory Purposes, Especially in the Context of the EU REACH Legislation

Rafael Gozalbes, Jesús Vicente de Julián-Ortiz
DOI: 10.4018/IJQSPR.2018010101
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Chemoinformatics methodologies such as QSAR/QSPR have been used for decades in drug discovery projects, especially for the finding of new compounds with therapeutic properties and the optimization of ADME properties on chemical series. The application of computational techniques in predictive toxicology is much more recent, and they are experiencing an increasingly interest because of the new legal requirements imposed by national and international regulations. In the pharmaceutical field, the US Food and Drug Administration (FDA) support the use of predictive models for regulatory decision-making when assessing the genotoxic and carcinogenic potential of drug impurities. In Europe, the REACH legislation promotes the use of QSAR in order to reduce the huge amount of animal testing needed to demonstrate the safety of new chemical entities subjected to registration, provided they meet specific conditions to ensure their quality and predictive power. In this review, the authors summarize the state of art of in silico methods for regulatory purposes, with especial emphasis on QSAR models.
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The REACH Regulation

The European regulation 1907/2006 for Registration, Evaluation, Authorisation and Restriction of Chemicals (abbreviated as “REACH”) entered into force in 2007 (European Commission, 2006). The main objectives of REACH are the protection of human health and the environment from the risks that can be posed by chemicals, and the enhancement of the competitiveness of the EU chemicals industry. To achieve these objectives, REACH regulates both the production and use of chemicals when they are produced or imported into Europe in an amount greater than one tonne per year. According to this regulation, manufacturers and importers of chemicals in the European Union (EU) are required to register these substances and communicate the information necessary to ensure their safe use (as such, in mixtures or as part of the composition of items), by submitting a registration dossier to the European Chemicals Agency (ECHA, The degree of information required depends on the level of concern about the substance, being for example more complete for carcinogenic, mutagenic and/or toxic for reproduction (CMR) substances, or for highly toxic chemicals to aquatic organisms. Also, goods producers, distributors and downstream users should be rigorous in identifying these substances, and update and communicate information about them upon registration.

REACH has brought a revolution in the world of the regulation of chemicals, since for the first time the industry should take over the potential risk of the products generated and their potential impact on both human health and the ecosystem. Maintaining on the market requires the adoption of new obligations under REACH, since manufactured or imported substances that have not been previously submitted for registration to the ECHA cannot be commercialized, neither can be used for purposes other than those recorded. REACH is the paradigm of an international shift towards a responsible use of chemicals, and indeed other non-EU countries are studying/adopting similar legislations (Van Heerden, 2012).

Despite its importance and positive impact, the REACH regulation also raises strong criticism, especially from industrials that have to mandatorily adopt this legislation. The more controversial issues are:

  • 1.

    The registration process is very expensive, due to the high degree of experimental and administrative work required. These costs directly affect the competitiveness of companies that have to apply the regulation, and this is a particularly sensitive issue currently, due to the global economic crisis. Small and medium-sized enterprises are particularly exposed to this risk, to the extent that in some cases companies can be seen in the impediment to continue producing some of their products.

  • 2.

    At social level, REACH raises the ethical problem represented by the huge amount of animal testing necessary to meet the requirements of information (Rovida & Hartung, 2009). It is estimated that around twelve million vertebrate animals are used annually in the EU in experiments performed for different purposes (scientific, toxicological, and regulatory) (Scholz et al., 2013; Taylor & Rego, 2016) (Figure 1). Estimates of the large increase in the number of such experiments due to the REACH implementation have alerted and mobilized a high number of representative animal welfare organizations and broad social sectors.

Figure 1.

Animals used in experiments in the European Union in 2014 (Data not available from Portugal nor Sweden)


Thus, the need for alternative methods to reduce or replace animal testing is stronger than ever. In fact, the use of such methods instead of animal testing is clearly stimulated by the REACH regulation itself, which in its text states that “every effort must be made so that testing chemicals on animals is a last resort – when there is no other scientifically reliable way of showing the impact on humans or the environment”.This institutional encouragement of alternative methods is not new: the European Commission launched in 1991 the European Centre for the Validation of Alternative Methods (ECVAM), with the objective of validating techniques able to reduce, refine or replace animal testing of chemicals, biological products or vaccines. Also, the ECVAM was in charge of the promotion of the development and dissemination of alternative methods, their application to industrial level and its acceptance by the regulatory authorities. This centre is still in force, since 2011 under the name “European Union Reference Laboratory for Alternatives to Animal Testing” (EURL-ECVAM,

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