Frequently Asked Questions

What is REACH?

REACH is the legislation that regulates the market of chemical substances, produced and imported. All chemical substances require characterization of their environmental and toxicological properties, before their use in Europe. This is a huge effort which requires chemical industry to notify the properties of their chemicals.

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What are in silico methods?

In silico methods means computer-based methods.  In our context, they are computer-based methods for assessing the toxicity of chemicals. In silico methods refer to databases of existing experimental data on the toxicity of chemicals used to build upthe models. For detailed information view the ebook Theory, guidance and applications on QSAR and REACH. The advantage of in silico methods is that they make it possible to assess the toxicity of large numbers of chemicals quickly using software on a desktop computer, instead of long and expensive tests in laboratories. They are also used in addition to available laboratory data to generate a stronger ‘weight of evidence’.  In silico methods include QSAR models, Read across and Virtual Screening. The term in silico contrasts with in vivo and in vitro.  In vivo methods involve testing chemicals on living organisms, including invertebrates, fish and animals.  In vitro methods involve test-tube research. Both in silico and in vitro methods are known as “alternative methods”.  In silico methods make use of existing data from in vivo and in vitro tests.

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What is QSAR?

The methods called quantitative structure-activity relationship(QSAR) are based on the assumption that the activity of a certain chemical, for instance the toxic effect, is related to its chemical structure through a certain mathematical algorithm, or rule. QSAR models are also called in silico methods, which actually refer to a somehow broader set of methods. Sometimes the expression SAR is used, which refers to methods which are non quantitative. For instance, this applies to models where the toxicity, not expressed in a quantitative way, but only as category (such as toxic or not toxic) is linked to the occurrence of a given fragment in the molecule.

For detailed information view the ebook Theory, guidance and applications on QSAR and REACH

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What is read-across?

Read-across is a non-testing method, like QSAR models. In case of read-across, the evaluation is done considering one or few chemicals, similar to the target compound. The assumption is that the property of the target chemical to be evaluated is similar to the properties of the similar compound(s). ToxRead is a program for read-across.

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How to evaluate QSAR models?

Results of the QSAR models depend on the property to be evaluated, on the individual QSAR model, on the chemical to be evaluated and in some cases on the user, for the models where parameters have to be fixed by the user, or decisions have to be taken on the result validity. The general evaluation of a model is typically done using a set of chemicals, using statistical methods, such as internal and external validation. This provides an evaluation on the general performance of the model. In addition, a careful evaluation on the specific use for the target chemical should be done. If the user has no experience, it is advisable to ask for advice.

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What makes a good QSAR model?

According to REACH regulation (Annex XI) an assessment using a QSAR model is valid if:

  • the model is recognised as scientifically valid;
  • the substance is included in the applicability domain of the model;
  • results are adequate for classification and labelling and for risk assessment;
  • adequate documentation of the methods is provided.

These four ‘conditions’ are specific to the regulatory context, and address important scientific and practical aspects of the use of in silico models. The four conditions are not just about the model, but also the chemical used for an assessment, the particular regulatory function it is used for, and how well the model and its use are documented.  

A QSAR model is built on a set of experimental data for particular chemicals (a “training set”) and it is trialed by testing other chemicals for which there is also experimental data available (the “test set”).  Thus, a QSAR model is designed to evaluate a particular set of chemicals in relation to a particular endpoint. While it can be used for other chemicals outside this “applicability domain”, the evaluation of those chemicals will have a higher level of uncertainty. For this reason, REACH and ECHA do not provide approval for models: each use of QSAR models has to be evaluated on its own merit, on a case-by-case basis.

The REACH demand to provide “adequate documentation of the models” and their use, to ensure the quality of models and their use.

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Is it possible to use QSAR for REACH?

REACH promotes innovation and mentions that new, alternative methods should be searched to improve the evaluation of the chemicals. QSAR methods are included in the alternative methods. Annex XI of REACH defines the conditions to use QSAR models. Within these conditions, the use should evaluate the following points: The QSAR model should be scientifically valid. The evaluation has to be done on the use of the model for a defined chemical (check of the applicability domain). Indeed, it may be that a model is appropriate for a chemical, but not for another. The model should be suitable for risk assessment or classification and labeling. Thus, the model has to adhere to the requirement of REACH for the particular data which are defined by the regulation. It is important to provide suitabledocumentation. Thus, copying the value obtained by a certain model without proper evaluation of the results may be not sufficient.

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Which models can be used for REACH?

REACH regulates the chemical substances. REACH and ECHA (the European Chemicals Agency) do no provide a list of suitable QSAR models. Within Annex XI REACH clearly states that appropriate evaluation of the applicability domain has to be done. Indeed, it may be that a model is appropriate for a chemical, but not for another. Thus, the issue is more complex than simply listing good or bad models. The reliability of the QSAR models strongly depends on the property. In case of physico-chemical properties, mainly in cases where there are thousands of data, good models exist. For this kind of endpoint, the uncertainty of the experimental data is limited. In case of more complex endpoints, in particular for chronic endpoints for human toxicity, the number of data is more limited, and the uncertainty of the experimental values is much higher. CALEIDOS follows ANTARES project. ANTARES evaluated QSAR models for REACH and provided a list of tens of QSAR models that perform better than others. CALEIDOS evaluates if these models provide predictions that could have been used instead of experimental data within REACH regulation.

See the overall evaluation of QSAR models for specific endpoints.

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Are QSAR models available for all endpoints?

QSAR models are available and in use for some endpoints, while being limited for others (e.g. long term mammalian toxicity).  There are several reasons, including:

  • the limited amount of high quality experimental data currently available (and released by industry) for some endpoints,
  • the higher complexity of the chemical and biological processes involved in generating the toxicity for some endpoints, and
  • the lower regulatory acceptance for certain endpoints.  

In general, for physico-chemical properties, QSAR models are more reliable, because the phenomenon to be modelled is less complex, and thousands of experimental results are available in the databases, whereas for models to predict chronic effects, the data are much more limited, and the phenomenon is much more complex. The EC funded ANTARES project evaluated the best existing models for several endpoints and CALEIDOS if these models can be used for REACH.

See the overall evaluation of QSAR models for specific endpoints.

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Is there an independent review of QSAR models?

ECHA does not intend to produce a list of approved models, because the value of a model depends on how it is used. Every user of QSARs needs to be aware that QSAR models are only appropriate and reliable for specific sets of chemicals. A highly reliable model will not produce reliable results for chemicals that lie outside the domain of applicability.  In addition, models may be suitable for different regulatory functions: risk assessment, classification and labelling or prioritization, because each makes different demands on the model. In terms of the form of the outputs, the QSAR Model Reporting Format (QMRF) checks that a certain number of pieces of information are given.  However, such an assessment is carried out on the basis of the values provided by the developer of the model, and these are not checked independently.

The EC funded ANTARES projectevaluated the existing models which could be used for REACH. Hundreds of possible models were identified and listed, which theoretically could be used for tens of REACH endpoints.

Further evaluation of the models has been done by the project CALEIDOS.

See the overall evaluation of QSAR models for specific endpoints.

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