Technical Report 122

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

Under both classification systems, the UN GHS and the EU CLP, non-tumourigenic longer term effects associated with inhalation exposure to PSP are addressed under the so-called ‘STOT-RE' classification. Definitions, criteria and guidance to classify substances that produce specific target organ toxicity arising from repeated exposure (‘STOT-RE'), including inhalation exposure to particles are provided. Final classification depends upon the availability of reliable evidence that a repeated exposure to the substance has produced a consistent and identifiable toxic effect in humans or, that toxic effect which have been observed in experimental animals are relevant for human health. In both schemes, two STOT-RE hazard categories exist: Category 1 for substances that have produced significant toxicity in humans or experimental animals following repeated exposures or Category 2 for substances that on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

The following guidance values assist with classification based on the results obtained from 90-day dust inhalation studies in experimental animals:


The above values are not intended as strict demarcation values but should be used as guidance as part of a weight of evidence approach. If a specific toxicity profile is seen in animal studies below the guidance values and the nature of the effect is such that it appears only in a single species that is particularly susceptible to this effect, then a classification may not be warranted. Likewise, a specific toxicity profile may be seen in animal studies occurring above the guideline values, but there is supplementary information from other sources (e.g., human case experience) which support a conclusion that in view of the weight of evidence, classification would be the prudent action to take.

While the UN GHS does not specifically recognise the phenomenon of "lung overload” in rats for the inhalation toxicity of poorly soluble particles of low toxicity (‘PSP') within its classification schemes, it is considered as a rat specific mechanism which may not be relevant to humans.

Adverse effects considered supporting STOT-RE classification

The UN GHS as well as the EU CLP regulation, here specifically the ECHA guidance document to EU CLP, describes the evidence required to associate repeated exposure to a substance with a consistent and identifiable toxic effect triggering a STOT-RE classification. It is recognised that evidence from human experience/incidents is usually restricted to reports of adverse health consequences, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

Evidence from appropriate studies in experimental animals can provide much more detailed information such as clinical observations, haematology, clinical chemistry, macroscopic and microscopic pathological examination. This can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, must be taken into consideration in the classification process. Examples of relevant toxic effects in humans and/or animals that are of particular relevance to inhaled PSP are provided below:

• Morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, or due to an overwhelming of the de-toxification process by repeated exposure;
• Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed at microscopic examination;
• Multifocal or diffuse necrosis, fibrosis or granuloma formulation in vital organs with regenerative capacity;
• Evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.
• However, the UN GHS also recognises that a number of effects may be seen that would not justify classification as STOT-RE. The ones of relevance to the rat PSP inhalation studies, are
• Adaptive responses that are not considered toxicologically relevant;
• Substance-induced species-specific mechanisms of toxicity that have been demonstrated with reasonable certainty to not be relevant for human health.

While the criteria and classification guidance values as well as the described effects considered to support or not to support a STOT-RE classification are the same as those presented in the UN GHS, ECHA has developed a substantial guidance document assisting in deciding whether inhalation exposure to particles warrants a STOT-RE hazard classification.

As stated before, of particular relevance for the classification of particles causing effects by inhalation is the specific recognition of the phenomenon of ‘lung overload' in Section 3.9 as a mechanism not relevant to humans Here, the ECHA guidance for the EU CLP Regulation states that ‘The relevance of lung overload in animals to humans is currently not clear and is subject to continued scientific debate.' (ECHA, 2012b). While this statement is inconclusive with regard to the dealing with effects observed under the conditions of lung overload from a classification standpoint, it at least recognises the issue suggesting the need for applying weight of evidence and expert judgment in the final classification decision.

Lastly, it should be noted that numerous sub-chronic or chronic experimental rat inhalation studies with PSPs such as titanium dioxide, coal dust or talc revealed that at typical particle exposure concentrations of 1 to 30 mg/m3, the conditions of lung overload were achieved and pulmonary inflammatory responses, altered morphology, epithelial hyperplasia and finally chronic disease including fibrosis observed (ILSI, 2000). Applying strictly above UN GHS/EU CLP guideline values to those data without taking into account dose-response differences between rat and humans, also with regard to particle size distribution differences would basically lead to a STOT-RE classification for virtually any poorly soluble particle. Hence, similarly to the need of adjusting the NOAELs from animal experiments by dosimetric modelling (e.g., MPPD) for setting health based exposure limits for PSP (Section 8.3), it is recommended to consider at the minimum the UN GHS/EU CLP guideline values for STOT classifications as human equivalent concentrations (HECs).