Inhalation Toxicological Properties of Low Soluble Particles and Their Relevance for C&L
Poorly soluble particulate substances of low toxicity are progressively coming under intense regulatory pressure culminating in unjustified additional testing (see the extensive data package required for various TiO2 forms) and/or classification & labelling requirements. Examples for this kind of substance group are TiO2, organic pigments and, more recently, different forms of amorphous silica particles.
In this context, it becomes increasingly evident that regulatory bodies (not only in Europe), including and especially RAC, intend to also take into consideration unspecific local effects like inflammatory pulmonary changes to justify very stringent C&L under CLP/GHS. Worthy of note, that for e.g. hydrophobic synthetic amorphous silica (SAS) it is argued that -although the effects are reversible and can be regarded to be not adverse but adaptive in nature- a CLH classification STOT RE 2 for inhalation will be required.
Considering the guidance values according CLP for STOT RE classification of particulates (up to 20 mg/m3 for STOT RE Cat 1; up to 200 mg/m3 for STOT RE Cat 2) it is obvious that under such exposure conditions almost all respirable low soluble particles will exhibit at least inflammatory changes in the respiratory tract. Resulting STOT RE classifications will have a significant impact on applications and use conditions. Depending on the tonnage band of the particle, numerous of these repeated dose animal studies will be performed for REACH registration purposes without gaining any new scientific insight or added value. The same unspecific “foreign material” or dust effect may be reproduced showing the same pathological feature.
Regarding animal welfare and unnecessary financial burden, there is no justification to reproduce these study results for a high number of particulate substances. The NOAECSs determined in these studies with rat may be in the single-digit scope (from ~ 0.5 mg/m³ upwards) and in significant cases below 20 mg/m ³. 200 mg/m³ is a far too high concentration to be tested for particles over a period of 90 days. Keeping this in mind, Assessment Factors normally used for Risk Assessment of data generated with rats, result in extremely ow Derived No Effect Levels which would be difficult to comply with at the workplace. Therefore, toxicological tools based on animal data should be used differently for proper Risk Assessment of particles.
As a result, there is a significant need to develop a new scientific approach to determine safe limit values for particles with more direct relevance for humans. In addition to toxicological data, especially epidemiological data could be the way forward to avoid C&L based on irrelevant and inappropriate exposure conditions.
Furthermore, in the Chemicals Strategy for Sustainability the EU Commission already published its ambition to ban substances classified as toxic for specific organs and respiratory sensitizers in consumer products and to prioritize such substances for (group)-restrictions under REACH. Instead of classifying and subsequently banning substances based on unspecific particles effects, another way to handle poorly soluble particulate substances of low toxicity is needed.
As a first step, data from inhalation studies in rodents with poorly soluble particulate substances of low toxicity will be collected. An inflammatory response is the first event observed in the lungs after exposure to this type of particles, therefore the methods used to characterise and quantify this inflammation are of specific interest. In addition to leukocyte counts, other methods (e.g. histopathology or cellular markers) will be assessed to identify the onset of true adverse effects. This may allow differentiation between adaptation and adversity and to identify a common NOAEC.
A human-based approach being valid for all low soluble particulate substances of low toxicity should be preferred, also for animal welfare reasons. Existing data on monitoring of inhalation associated with inflammatory markers in humans should be identified e.g. targeted human derived mechanistic cell- based assays.
Task Force objectives
- Develop a common understanding on the inflammatory response in rats and humans by taking into account epidemiological / occupational medicine expertise.
- Identification of potential biochemical marker (‘fingerprinting’) s to differentiate adverse from adaptive inflammatory responses.
- Identification of inflammatory markers for non-animal-based screening methods to avoid unnecessary animal testing.
- Define more realistic guidance values for hazard management measures by incorporating epidemiologically derived human data for inhalation exposure of poorly soluble particulates.
Task Force deliverables
First Step-Assessment of the inflammatory response:
- First Step-Assessment of the inflammatory response:
- Identification of different types of particle driven inflammation in the rat lung and evaluation regarding adverse chronic vs. adaptive nature.
- Identification of existing data on monitoring of inhalation associated with inflammatory markers in humans.
- Epidemiology evaluating the relevance of animal derived toxicological data for humans with focus on inflammation.
- Definition of a common threshold for inflammatory particle effects
Second Step-Development of regulatory guidance:
- Identification of existing NAMs (e.g. human based lung epithelial cell systems) for the identification of appropriate pulmonary inflammation markers with relevance for humans and develop strategies to avoid sub chronic studies as standard data requirement.
- Avoidance of using substance specific C&L criteria according to CLP for generic particle effects.
- Defining more realistic guidance on threshold values for C&L.
- OEL-value setting based on toxicological data supported by epidemiological knowledge.
It is foreseen that the Task Force will complete its work in 12 months, starting in early 2022.