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Review Article

Guidance for the classification of carcinogens under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS)

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Pages 245-285 | Received 10 Aug 2009, Accepted 30 Sep 2009, Published online: 16 Dec 2009
 

Abstract

The United Nations Conference on Environment and Development (UNCED) has developed criteria for a globally harmonised system of classification and labelling of chemicals (GHS). With regard to carcinogenicity, GHS distinguishes between Category 1 (‘known or presumed human carcinogens’) and Category 2 (‘suspected human carcinogens’). Category 1 carcinogens are divided into Category 1A (‘known to have carcinogenic potential for humans’), based largely on human evidence, and 1B (‘presumed to have carcinogenic potential for humans’), based largely on experimental animal data. Concerns have been raised that the criteria for applying these carcinogenicity classifications are not sufficiently well defined and potentially allow different conclusions to be drawn. The current document describes an attempt to reduce the potential for diverse conclusions resulting from the GHS classification system through the application of a series of questions during the evaluation of data from experiments with rodents; epidemiological data, which could lead to Category 1A, have not been considered. Answers to each question can lead either to a classification decision or to the next question, but this process should only be implemented in an environment of informed scientific opinion. The scheme is illustrated with five case studies. These questions are: (1) Has a relevant form of the substance been tested? (2) Is the study design relevant to human exposure? (3) Is there a substance-related response? (4) Is the target tissue exposure relevant to humans? (5) Can a mode of action be established? (6) Is the mode of action relevant to humans? (7) What is the potency?

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Corrigendum

Acknowledgements

The authors thank Dr. John Doe (Syngenta), Dr. David Farrar (Ineos Chlor), and Professor Helmut Greim (Technical University Munich), who were the Stewards to this Task Force appointed by the ECETOC Scientific Committee, and Dr. Neil Carmichael (ECETOC) for their helpful comments. The authors also thank Christine Yannakas and Anita Jennings from the ECETOC Secretariat for their diligent support with the final editing of this paper.

Declaration of interest

This paper was prepared by a Task Force of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC). ECETOC is a scientific, non-profit making, non-commercial association with a mission to act as an independent, credible, peer-reviewed technical resource to all concerned with the assessment of health effects and environmental impact of chemicals. It is financed by its membership, which comprises some 50 of the leading companies with interests in the manufacture and use of chemicals. For this Task Force, ECETOC paid an honorarium to Prof. Alan Boobis and Dr. Douglas McGregor and reimbursed them for travel expenses related to participating in the Task Force. Dr. Mcgregor has previously published a mode of action for carcinogenicity of inhaled formaldehyde whilst a consultant to IPCS. All other authors participated in the Task Force during the normal course of their employment affiliation as shown on the first page. The employers that are commercial entities produce and market products that are subject to regulation by National and International authorities that may consider the Guidance proposed in this paper. The authors have sole responsibility for the writing and contents of the paper.

Notes

3Additional information on the work of the committee and its subcommittees as well as corrigenda, which would be issued after publication of this document, may be found on the UNECE Transport Division Web site at the following address: http://www.unece.org/trans/danger/publi/ghs/ghs_rev02/02files_e.html.

6EC Regulation 1272/2008 Article 9.5. When evaluating the available information for the purposes of classification, the manufacturers, importers, and downstream users shall consider the forms or physical states in which the substance or mixture is placed on the market and in which it can reasonably be expected to be used.

7This would be defined as the NOAEL for a non-genotoxic endpoint. Although the NOAEL is not used in the risk assessment of genotoxic carcinogens, this is partly because of concerns over communication and partly because of how the NOAEL is used normally to derive reference values (e.g., TDI). However, the NOAEL is simply an experimentally observed point on the dose-response curve at which the response is below a certain value determined by the power of the study. In general, the NOAEL corresponds numerically to the BMDL10, at least in the analyses to date that have focused on non-cancer endpoints (CitationBokkers and Slob, 2007). Hence, there is no a priori reason why it could not be used as described for the BMDL10 in this section.

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