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Report on the Advisory list for selfclassification of dangerous substances

1. Background, contents, and use of the list

1.1 Background

When chemical substances are to be classified in terms of the danger they represent, their inherent properties are assessed on the basis of the knowledge and information available /1,57/. Such assessment is often carried out on the basis of results from animal testing. Assessment must be carried out individually for each property, which means that extensive animal testing may be required for a single substance. Thus, complete identification of all the properties that are classified at present can entail up to 30 animal studies on animals for just one substance.

Studies have shown that very little information is available on the danger posed to human beings and the environment by chemical substances in the European market. In 1999, the European Commission assessed the scope of available test data for substances which are available on the market in large quantities (more than 1,000 tonnes per manufacturer/importer per year in the EU). The Commission found that the minimum information on dangerous properties of substances required under EU regulations in order to carry out risk assessment of industrial chemicals was only available for 14 per cent of all the substances studied. For 21 per cent of all substances, no test data at all was available as regards their toxicity towards human beings or the environment /2/.

In 2000, the Danish EPA carried out a study to determine the extent of the data available on the danger, presented by the approximately 100,000 substances in the EU Inventory of Existing Substances^* /3/, in two of the world's largest sources of publicly available test data (RTECS, 2000^**; AQUIRE, 1994^***. This study showed that test data on selected types of effects were available for the following percentages of all Einecs substances /4/:

Table 1

Thus, in the assessment of the Danish EPA, information on the dangerous properties of chemical substances is at present incomplete or absent for approximately 90 per cent of all substances listed in the Einecs. This means that many chemical substances within the European market can have unknown dangerous properties even though they have been used for many years. Issues regarding animal ethics and financial considerations mean that it is unlikely that test data on the dangerous properties of these substances will be available within the foreseeable future.

The criteria on classification describe how available experimental test data (from animal testing, etc.) should be used in assessment and classification of the toxicity of substances for human beings and the environment. These criteria also describe how the danger presented by substances can be assessed by means of comparison to other, similar substances with known toxic properties (SARs, Structure-Activity Relationships). Finally, these criteria include the use of expert judgements, e.g. from practical experience of a given substance, as the basis for classification /1,57/.

In Denmark as well as internationally in the EU and the OECD the importance of developing alternative methods, which are not based on animal testing, are emphasized. Lower organisms such as algae and bacteria are already being used in tests for certain properties, and today good results have been achieved by means of alternative tests rather than tests on animals. A test method for skin irritation, which does not require the use of living animals, was recently added to the rules on classification /1,57/. As regards many dangerous properties, however, efforts made to discover suitable methods for testing which do not require use of laboratory animals have untill now not succeeded.

1.2 QSAR models - an alternative method for assessment of danger

Quantitative structure-activity relationships (QSAR models) can be used for assessment of dangerous properties as an alternative to animal testing. A QSAR model relates an effect with molecular descriptors found to be tied to this effect. Using information on the relevant molecular descriptors the models can predict effect for substances without test data. By using the ability of computers to go through large quantities of information, QSAR models have in this project been used to assess a big number of substances.

The principle behind structure-activity relationships is that substances with comparable structures possess similar properties. SARs and QSARs are well-known tools for assessment of chemical substances. These tools are used by authorities in the USA and the EU, as well as by industry, to assess physico-chemical, toxicological, and eco-toxicological properties and to predict the fate of substances in the environment.

The criteria for EU classification include the possibility of using expert judgements as well as conclusions based on structural analogies /1,57/. SARs and QSARs have been used for classification of effects on the aquatic environment in cases where no test data on toxicity or degradation in the aquatic environment were available. As regards classification for impacts on human health, SARs have been applied in specific cases, and this tool was recently used in a discussion of two special properties: Narcotic effect and defatting properties.

1.3 The Advisory list for selfclassification of dangerous substances

The Danish EPA has carried out work on QSAR models for several years, an area that continues to develop. At present, the Danish EPA has access to reliable models which are capable of predicting whether a substance possesses one or more of the dangerous properties selected in this context. The substances on this list have been assessed for the following dangerous properties: Acute oral toxicity, sensitization by skin contact, mutagenicity, carcinogenicity, and danger to the aquatic environment. According to validation results the models available to the Danish EPA identify the substances which possess these properties with a degree of accuracy of approximately 70 - 85 per cent, depending on the model used.

The basis for the list was the European Inventory of Existing Substances, Einecs. For technical reasons, the QSAR models can only assess chemical substances with unambiguous chemical structure, so-called discrete substances. The Danish EPA has used validated QSAR models to carry out a systematic assessment of the approximately 47,000 discrete organic substances in Einecs. Also, the approximately 7,000 chemical substances which have already been classified by EU authorities, have not been included in the assessment^****.

The criteria for computer-model selection of substances for a given property have been defined to match the criteria for classification of chemical substances as closely as possible. /1/. For properties, where the criteria are open to interpretation, such definitions have been specified in accordance with the Danish EPA’s best judgement with a view to providing the public with an operative list. The preparation of this list is described in more detail in Part II.

The result of the computer-based assessment is this Advisory list for selfclassification of dangerous substances, which comprises 20,624 chemical substances with suggested classifications for one or more of the dangerous properties selected.

By making this Advisory list for selfclassification of dangerous substances available to the public, the Danish EPA wishes to offer manufacturers / importers a tool which can be used when carrying out selfclassification of chemical substances for those dangerous properties which are included in the list. Enterprises are encouraged to include the advisory classifications provided in this list in their assessment of chemical substances where no results from animal testing or other reliable data on the relevant dangerous properties are available.

The selected dangerous properties and classifications are listed in Table 2.

Table 2

For each substance on the list, the following information is included in addition to the advisory classifications: Einecs name in Danish and English, Einecs number, and CAS number.

Figure 1 shows how many of the 20,624 substances in this list have been included with advisory classifications for each dangerous property.

Figure 1:

It should be noted that the Advisory list for selfclassification of dangerous substances is not an exhaustive list of all the dangerous substances in the EU Inventory of Existing Substances (Einecs). As was mentioned above, the substances assessed here comprise only approximately half of all substances in Einecs.

At the same time, the list cover only those selected dangerous properties which feature the most reliable computer-generated predictions. Therefore these substances may well possess other dangerous properties.

Finally, for each of the selected dangerous properties, only the substances for which the model predictions are most reliable, have been included in the list. As a result, substances that were assessed but not included in this list may well possess one or more of the dangerous properties selected.

Similarly, if a substance is included in this list and does not have an advisory classification for e.g. carcinogenicity, the substance can nevertheless have this property. The reason for this could be that the models for carcinogenicity applied do not have good coverage for this specific chemical substance.

If a substance is not included in the list, or it is on the list but without one or more advisory classifications, this can then be due to the models predicting that the substance does not possess these dangerous properties, or it can be because the models are not able to give a good prediction in these cases.

Finally, out of the substances that a model cover, it can sometimes erroneously estimate substances as not having a property which they in fact do have (false negatives). With other substances, the models will attribute a specific property to a substance, which actually does not possess that property (false positive). The Advisory list for selfclassification of dangerous substances can be used to identify substances that do possess dangerous properties, well knowing that that some predictions will be false positives. If the list had contained negative predictions, a part of these would also be incorrect (false negatives). By this, substances which in reality possess dangerous properties would be advised not to be classified for this.

This list, only containing positive predictions, can not be used to "acquit" substances of dangerous properties.

1.4 The duty of manufacturers and importers to carry out selfclassification

Manufacturers or importers are responsible for investigating the properties of chemical substances and for classifying them in accordance with their inherent dangerous properties before marketing them. Such selfclassification must be carried out on the basis of available information on substances in accordance with the criteria of the Statutory Order on Classification /1,57/.

As regards the approximately 7,000 substances for which harmonised classification has been adopted, the classification of the List of dangerous substances shall be applied /5/. For the remaining approximately 93,000 of the 100,000 substances in the EU Inventory of Existing Substances /2/, importers/manufacturers are obliged to assess whether such a substance should be classified as dangerous (selfclassification). Selfclassification must be carried out in accordance with the criteria in Appendix 1 of the Statutory Order on Classification.

The Advisory list for selfclassification of dangerous substances is intended as a tool to help manufacturers / importers fulfil their duty to carry out correct classification in those cases where no other information is available on a given substance. When preparing this list, the Danish EPA has not examined whether data on individual substances is available in literature. The duty to map available information on substances for selfclassified lies with manufacturers / importers. Reliable test results or relevant specialist knowledge on specific substances should always be used in preference to computer predictions. This is to say that where such information - which runs contrary to the recommendations of this list - is available, it should be used instead of the classifications featured in this advisory list. At the same time, it should be emphasised that this advisory list includes only some of the dangerous properties which must be considered by manufacturers / importers in their assessment of substances. Manufacturers / importers should also carry out assessment of other properties regarding flammability, explosivity, and danger to human health and the environment.

Use of the list

It is recommended that the list be used for selfclassification in the following way:

1. Examine if the substance is on the List of dangerous substances /5/. If so it should be classified accordingly.
2. If the substance is not on the List of dangerous substances, it should be classified according to the criteria in the Statutory Order on Classification /1/.
3. In cases of an otherwise unsufficient data basis for selfclassification, it is recommended to use the Advisory list for selfclassification of dangerous substances.