1 Introduction to classification and (Q)SAR

The Advisory list for self-classification of dangerous substances

1.1 Background
1.2 Classification of chemicals
1.3 (Q)SARs and their use in chemical assessment

1.1 Background

When chemical substances are classified in terms of the danger they represent, their inherent properties are assessed on the basis of the knowledge and information available /2, 60/. Such assessments are often carried out on the basis of laboratory test results because the hazard classification criteria to a large extent refer to such results. Assessment must be carried out individually for each property, which means that often extensive animal testing may be required for a single substance. Thus, complete identification of all the properties for which hazard classification criteria exist, at present requires results from many animal studies for just one substance.

Given the extensive requirements for data from animal studies in chemical hazard and risk assessment, it is not surprising that lack of test data represents a major problem in the assessment of dangerous properties of chemicals. It is a well-known fact that there are currently few or no test data for a very large fraction of the 100,204 chemical substances on the European INventory of Existing Commercial chemical Substances (EINECS) /3, 4, e.g. 36/.This means that many chemical substances within the European market may have unknown dangerous properties even though they have been used for many years.

With the new chemicals legislation in EU, REACH, new information demands for chemicals have been imposed in the EU. However, especially for chemicals produced in volumes below 10 tpa per manufacturer or importer in the EU it is unlikely that test data on a broad spectrum of dangerous properties will be available within the foreseeable future.

With the aid of mathematical modelling, so-called (Quantitative) Structure-Activity Relationships, (Q)SARs, for prediction of properties of chemicals can be established. Classifications based on (Q)SARs predicted dangerous properties can save time and money if used as an alternative to animal testing, as well as increase the level of information for chemicals that will not undergo testing. The Danish EPA in 2001 published the first version of the advisory self-classification list of dangerous substances (denoted AL2001 in the current report) /5/ where 20.624 substances were assigned advisory classifications according to the following dangerous properties: Acute oral toxicity, sensitisation by skin contact, mutagenicity, carcinogenicity, and danger to the aquatic environment.

1.2 Classification of chemicals

Criteria for classification, packaging and labelling of dangerous substances and preparations is harmonised in order to protect public health and the environment and ensure the free movement of such products /6, 7, 60/. Harmonised hazard labelling allows consumers to recognize dangerous substances and preparations easily and to take adequate measures as regards risk avoidance and safe handling and disposal.

Existing regulation

The present regulation for classification and labelling involves an evaluation of the hazard of a substance or preparation in accordance to Council Reg. 1272/2008/EU /7/ and a communication of that hazard via the label.

Classification of a substance or preparation is considered in relation to several endpoints concerning physical-chemical properties, health effects or environmental properties. This evaluation must be made for any substance or preparation manufactured within or imported into the EU and placed on the EU market. Classification and labelling is therefore an essential element of risk management measures of chemicals.

All marketed substances and preparations must be evaluated for hazard classification and labelling, irrespective of the quantity placed on the market. The labelling is the first and in practice often the only information on the hazards of a chemical that reaches the user, which could be a consumer or a worker. In addition the hazard classification has a large number of downstream consequences within the EU legislation.

New regulation

By January 2009 the new CLP regulation on classification, labelling and packaging of substances and mixtures has had legal effect in the EU /7/. This regulation will gradually replace the present regulation for classification and labelling. The new regulation will come into force for single substances December 1^st 2010 and for mixtures June 1^st 2015 /7/. Until December 1^st 2010 substances and mixtures shall be classified labelled and packaged in accordance with the present legislation or they can be classified according to the CLP regulation.

The CLP regulation is based on the Globally Harmonised System of Classification and Labelling of Chemicals (GHS, UN 2007) /61/. The GHS classification criteria are in certain cases slightly different than those of the current legislation /7/.

1.3 (Q)SARs and their use in chemical assessment

Structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q)SARs, are theoretical models that can be used to predict the physico-chemical, biological (e.g. toxicological) and environmental fate properties of molecules based on the chemical structure.

(Q)SARs tools are used more and more by authorities e.g. in the US and the EU, as well as by industry, to assess physico-chemical, (eco-)toxicological, and fate properties of substances.

REACH

In the new EU chemicals legislation, REACH, all other options, including use of (Q)SARs, should be considered before performing (or requiring) vertebrate testing /1/. Annex XI of REACH contains the following wording regarding (Q)SARs:

Results obtained from valid qualitative or quantitative structure-activity relationship models ((Q)SARs) may indicate the presence or absence of a certain dangerous property. Results of (Q)SARs may be used instead of testing when the following conditions are met:

Results are derived from a (Q)SAR model whose scientific validity has been established,
The substance falls within the applicability domain of the (Q)SAR model,
Results are adequate for the purpose of classification and labelling and/or risk assessment, and,
Adequate and reliable documentation of the applied method is provided.

There will be no formal adoption process for (Q)SARs under REACH. QSAR Model Reporting Formats (QMRF’s) to compile information on endpoint, training set, validation results etc. for individual models will be gathered in a JRC QSAR Model Database. There will not be made fixed criteria for how the (Q)SARs should perform to receive regulatory acceptance, but rather a learning-by-doing process to gain experience and common understanding of use of (Q)SARs in chemical assessments /9/.

In the hazard and risk assessment process, (Q)SARs are already often used in combination with other sources of information on chemicals, either to prioritise chemicals for further assessment, to supplement or to replace testing.

With the implementation of REACH it is expected that (Q)SARs will be used increasingly for the direct replacement of test data as their use, when available and adequate, is in fact an obligation /9/. The goal of assessing many thousands of chemicals under REACH may not be achievable without the use of (Q)SARs and other non-test methods. Especially for low tonnage chemicals, (Q)SARs and other non-test methods may also give further information beyond the standard information requirements of regulations such as REACH.