Technical report 122

Conclusions on the rat lung overload issue from a regulatory perspective

Various chemical hazard classification systems that aim identifying the potential hazard associated with the inhalation effects of poorly soluble particles of low toxicity (PSP) exist. While some of them, like the United Nations globally harmonised system of classification and labelling of chemicals (UN GHS) or its EU implementation law CLP have direct regulatory consequences, others such as the IARC or the German MAK cancer classification schemes may not have such direct consequences, but inform regulators for classification and labelling decisions or the setting of occupational exposure limits. All these systems have in common that they are hazard and not risk-based. It is noteworthy, however, that the German MAK cancer classification system allows recognition of threshold effects as a pragmatic way to manage risks associated with exposure to PSP and nuisance dusts in general.

The classification systems typically foresee that hazards are established on the basis of animal studies, most often in rats. While this is also possible on the basis of human data, the burden on data quality is high. Good quality human data allowing hazard identification or to eventually question the relevance of hazards identified in animal studies, are rarely available. As has been shown in the previous chapters, the rat is more sensitive than humans, primates or other rodents to the effects of inhaled particles predominantly because of their tendency to impair lung clearance mechanisms leading to an overloading of the rat lungs at high particulate exposure conditions. Such overload conditions induce lung inflammation and histopathological changes which can ultimately lead to fibrosis and in some cases also lung tumours.

The existing regulatory frameworks only provide little considerations of these very rat specific responses to PSP under the conditions of overload. Only the EU CLP Regulations identifies for the hazard of ‘specific target organ toxicity following repeated exposure’ (STOT-RE) the condition of rat lung overload as a mechanism which may not be relevant to humans. While the EU CLP guidance states that the relevance of lung overload in animals to humans is not clear and subject to continued scientific debate, it is recommended to consider at the minimum the UN GHS/EU CLP guideline values for STOT classifications as human equivalent concentrations (HECs) and not NOAELs stemming from the animal inhalation studies. With regard to the carcinogenicity classification, neither the UN GHS nor the EU CLP Regulation identify or at least recognise the lung overload condition as a rat-specific mechanism of toxicity. Specific recognition and clarification of the issue in a chemical hazard classification context is necessary.