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The Advisory list for self-classification of dangerous substances

4 Discussion & Conclusions

• 4.1 Chemicals on AL2009 that were not on AL2001
• 4.2 Chemicals on AL2001 that are not on AL2009
• 4.3 Conclusion

The 2009 update of the advisory classification list has been made using entirely new models for the CMR advisory classifications; i.e. none of the models used to make the advisory classifications for mutagenicity and carcinogenicity on AL2001 were used in this update.

Annex 2 contains examples of how further structural analyses of substances belonging to various chemical classes can be made on top of the predicted properties from this project to visualize and gain further insight into relations between sub-structures and, in this case, the carcinogenicity properties of chemicals.

For the environmental advisory classifications some of the models used for AL2001 were used again (BCFWIN and model for aquatic toxicity to Fathead minnow), and new models were applied for biodegradation and aquatic toxicity to Dahpnia and Algae.

The total numbers of chemicals on AL2001 compared to AL2009 cannot be directly compared because AL2001 contained advisory classifications for skin sensitization and acute oral toxicity and these endpoints are not updated in AL2009, whereas advisory classification for reproductive toxicity is included on AL2009 but not on AL2001.

However, comparisons between AL2001 and AL2009 are made in the following for the individual advisory classifications represented in both lists, i.e. advisory classifications for mutagenicity, carcinogenicity and danger to the aquatic environment.

4.1 Chemicals on AL2009 that were not on AL2001

As shown in figure 5 a larger number of chemicals have been assigned advisory classifications for the individual advisory classifications in the current advisory list than in the former. This is due primarily to the application of entirely different models with in many cases larger chemical domains than the models applied for AL2001. Also, a little more substances were included in the start list for AL2009 than for AL2001 (49,292 for AL2009 and approximately 47,000 for AL2001)

For the advisory classifications for danger to the aquatic environment the reasons for the differences more specifically relate to the addition of aquatic toxicity models for Daphnia and Algae, plus the use of the non-linear BIOWIN 2 model instead of the linear BIOWIN 1 model, which was used for AL2001. BIOWIN 1 has a lower sensitivity than BIOWIN 2.

For the carcinogenicity and mutagenicity endpoints the increased number of predictions on AL2009 as compared with AL2001 is generally due to the use of new and improved (Q)SAR-models with larger applicability domains.

Figure 5 presents an overview of the number of advisory classifications for individual endpoints on AL2001 and AL2009. Reproduction is included although this endpoint was not addressed in AL2001.

Figure 5: Overview of the number of substances for each advisory classification in the new and the previous version of the advisory self-classification list. The exact number of advisory classifications is shown for each bar. (Note: Reproductive toxiticity was not included in AL2001. Also, the advisory classifications for acute oral toxicity Xn, R22 and sensitisation by skin contact, R43 have not been updated in the current list and are therefore not included.)

* AL2001 Total: This number refers only to number of chemicals with advisory classifications for mutagenicity, carcinogenicity and danger to the aquatic environment. The total number of chemicals on AL2001 is 20,624.

4.2 Chemicals on AL2001 that are not on AL2009

There are also substances that were assigned advisory classifications on AL2001 that are not on AL2009. It is for the individual endpoints seen that between 11 and 14% of the advisory classifications from AL2001 are not on AL2009. Again, the differences are primarily due to the use of new models for AL2009.

Chemicals on AL2001 may not have been included in AL2009 for one or more of the following reasons:

• they have been formally classified in the EU
• they were not included on the new starting list for technical reasons (e.g. errors in the structural information or structure information not accepted by the (Q)SAR software)
• they were not within the applicability domain of some or all of the models applied for AL2009
• they do not fulfil the new (Q)SAR model algorithms established for advisory classifications in AL2009

For the mutagenicity endpoint, for example, where five models were used, many of the chemicals that fell out did not have robust predictions (within applicability domain) in two or three models, but often with flags in one or more of these models showing that a possible active fragment was identified. Additionally, many have positive predictions in models for in vitro genotoxicity endpoints (which were not included in the evaluation). In total, the majority of the chemicals that were not identified this time appear to be borderline mutagens.

As there were mixed results (negative / out-of-domain / positive) from the battery of models applied within an endpoint, it is not possible to divide the chemicals strictly into groups of chemicals that were not identified this time because they could not be predicted (i.e. outside domain) or because the models applied in the new selection algorithm for AL09 predict them to be negative for the effect.

A detailed comparison between numbers of chemicals with advisory classifications for carcinogenicity, mutagenicity and danger to the aquatic environment on AL2001 and AL2009 is given in table 7.

* Due to overlap; some chemicals have advisory classifications for more than one CMR endpoint
** with one of the classifications for danger to the aquatic environment

Table 7. Overview of the occurrence of substances on AL2001 and AL2009

4.3 Conclusion

Due primarily to the application of combinations of new (Q)SAR models, in many cases with larger applicability domains, the number of substances with advisory classifications for carcinogenicity, mutagenicity and danger to the aquatic environment has increased considerably for individual classifications as compared to AL01. Moreover, reproductive toxicity (possible harm to the unborn child) was included for the first time.

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Version 1.0 September 2009, © Danish Environmental Protection Agency