Technical report 122

United Nation’s Globally Harmonized System (UN GHS) and its European implementation law EU regulation (EC) 1272/2008 (`CLP`)

An individual substance may be further distinguished:

• Category 1A: Known to have carcinogenic potential for humans;
• Category 1B: Presumed to have carcinogenic potential for humans;
• Category 2: Suspected human carcinogens

The placing of a substance in Category 1 is done on the basis of epidemiological (Category 1A) and/or animal data (Category 1B. Placement of substances in Category 2 is done on the basis of evidence from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1. Carcinogen classification under UN GHS or EU CLP is a one-step, criterion-based process that involves evaluation of the strength of evidence and consideration of all other relevant information to place a chemical with human cancer potential into the respective hazard category. The UN GHS as well as the EU CLP carcinogenicity classification schemes uses the terms ‘sufficient’ and ‘limited’ as defined by the International Agency for Research on Cancer (IARC).

Both, the UN GHS and the EU CLP system provide only little guidance on how to consider the tumourigenic effects of PSP in experimental animals upon inhalation under the conditions of lung overload in terms of carcinogenicity classification. Beyond the determination of the strength of evidence for carcinogenicity, the guidance documents indicate a number of generic factors that should be considered when determining the carcinogenicity hazard of a substance in humans. The full list of factors that influence this determination is very lengthy, but some factors that are of particular relevance when evaluating the tumorigenic effects of PSP in experimental animals upon inhalation, should be noted here:

Progression of lesion to malignancy;
The possibility of a confounding effect of excessive toxicity at test doses;
Mode of action and its relevance for humans, such as (secondary) mutagenicity, cytotoxicity with growth stimulation, mitogenesis, immunosuppression.

Beyond this generic identification of potential influencing factors to be considered in the classification decision, both regulations refer to the need to follow the IPCS “Conceptual Framework for Evaluating a Mode of Action for Chemical carcinogens’ as part of a weight of evidence analysis.

It is of note and direct relevance to the inhalation of PSP, however, that the UN GHS states that ‘if a mode of action of tumour development is conclusively determined not to be operative in humans, the carcinogenic evidence for that tumour may be discounted following expert review and weight of evidence analysis.’ Also, in a subsequent Chapter on confounding effects of excessive toxicity or localised effects, it states that tumours occurring only at excessive doses associated with severe toxicity or occurring only at sites of contact at excessive doses may have doubtful potential for carcinogenicity. In this context the EU CLP goes one step further as it states in Chapter on ‘Specific Target Organ Toxicity – Repeated Exposure’ that ‘lung overload’-induced effects in the rat require specific consideration as they may be species-specific with no relevance to humans.