Potency in carcinogenicity and reproductive toxicity classification

Potency in carcinogenicity and reproductive toxicity classification [Completed]

Classification should give guidance on the potential hazards of chemicals. Once the nature of the hazard is known, potency is the most important indicator of the degree of the hazard. Classification for carcinogenicity and reproductive toxicity does not distinguish between chemicals with up to 7 orders of magnitude difference in potency. This can cause problems in communication and has downstream consequences for the use of chemicals which may be inappropriate. There is methodology in the EU guidelines for assessing potency which is scientifically valid and should be used more widely. Classification schemes which incorporate potency have been developed. These would promote clarity of communication and more relevant downstream risk management for chemicals. It is hoped this work will start a discussion on changing the GHS criteria.

Hennes C, Batke M, Bomann W, DuHayon S, Kosemund K, Politano V, Stinchcombe S, Doe J. 2014. Incorporating potency into EU classification for carcinogenicity and reproductive toxicity.
Regulatory Toxicology & Pharmacology 70(2):457-467
Doi: 10.1016/j.yrtph.2014.07.022 (Open Access) [Footnote: Deceased]

This Open Access article is available via http://bit.ly/ecetoc-art2014-Hennes-et-al

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Background

The Classification of Chemicals in Europe has reached a tipping point with the real possibility of exclusion and non-listing of chemicals automatically following classification as a Category 1 CMR. Moreover the criteria which are now used to classify a chemical are changing so that many effects which would not have led to classification a few years ago now do so. These changes have followed the introduction of the GHS criteria into the new Classification, Labelling and Packaging Directive which has replaced the Dangerous Substances Directive and the Dangerous Preparations Directive. The drivers for these changes appear to be a desire to simplify the process and codify certain elements of professional judgement which were within the previous systems.

The scientific basis for the changes in the system is not sound. It is based on the premise that certain types of toxic effect, namely carcinogenicity and reproductive toxicity, have dose-response curves which do not have a threshold. If a hazard is identified at high doses the assumption is made that the effect will be seen at a reduced incidence even at dose levels where no biological changes can be discerned in toxicological studies. While there is a theoretical possibility of this happening with some modes of action, such as genotoxicity, research over the last 20 years has shown that this is not the case in the majority of cases.

ECETOC has identified an approach to address this situation through the application of the criteria for classification for Specific Target Organ Toxicity (STOT) to effects which have a theoretical threshold. The argument is that the primary effect is in essence specific target organ toxicity and should be classified as such. The adoption of the STOT criteria for the classification of carcinogenicity and reproductive toxicity would have the following benefits:

  • It would allow effects seen only after excessively high doses to be discounted.
  • It would make the decisions about classification more objective, and therefore easier for regulatory authorities to make and justify, leading to fewer disputes.
  • Outcomes of classification decisions would be easier for industry to predict.
  • It would identify those chemicals which really need special risk management procedures without devaluing the system.

Incorporation of the concept of potency into guidance for classification was also considered in the May 2011 workshop organised by the Endocrine Disruption Task Force, with participation of representatives of regulatory authorities. While a change in GHS criteria would take many years to achieve, the STOT criteria could be incorporated in the CLP guidelines much faster. ECETOC could facilitate the adoption of the STOT criteria by testing the science which underpins the concept for carcinogens and reproductive toxicants and by bringing other stakeholders into the debate.

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