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EC number: 701-029-8
CAS number: -
Acute inhalation toxicity is a direct function of the toxicokinetic behavior of MDI substances at the extracellular/aqueous interface of the lung. As the NCO groups are highly reactive, nucleophiles (primarily GSH) at this extracellular interface play a key role in natural defense and detoxification mechanisms. The magnitude of the reaction of MDI substances with GSH is determined primarily by the NCO value and the rate of dissolution of the reacting MDI substance. In high dose animal studies, as the available NCO depletes the nucleophiles, the protective capacity is overwhelmed resulting in inflammation and cytotoxic effects ultimately leading to pulmonary edema and death within one to two days if concentration and duration of exposure is sufficient.
The rate of nucleophile depletion by MDI-based substances is driven by the availability of the NCO-group, which itself is a function of (1) the NCO value of the substance and (2) the molecular weight of its constituents (driving its reactive dissolution). Monomeric MDI isomers have been shown to become available at a similar rate in toxicokinetic studies (Wisnewski, 2018; Wisnewski et al., 2019a) which is consistent with the generally comparable LC50 values for all of the isomers. Conversely, higher molecular weight constituents have both a reduced NCO value and exhibit reduced water solubility, making them less accessible to react with GSH. Therefore, the substances with the highest available NCO value and bioaccessibility (mMDI and three-ring oligomers) are the most toxic, while those with increasing amounts constituents less able to react with GHS demonstrate reduced toxicity.
Tests also show that toxicity is limited to portal-of-entry effects. The absence of systemic toxicity is due to the extracellular reactions, combined with transcarbamoylation to proteins constitute a detoxification mechanism. Acute toxicity is only observed when this protective mechanism becomes overwhelmed and is limited to the lung.
This mode of action is supported with high confidence by reliable acute inhalation data available for multiple MDI isomers and modified MDI substances across the entire category.
Using the strict GHS LC50 cut-off for classification, the LC50 values obtained for members of the MDI category would trigger in most cases a Category 2 or 3. However, classification for these substances according to GHS legal text allows for the application of scientific judgement. It must be considered that the LC50 cut-off of 500 mg/m3 (approximately 50 ppm for pMDI), is over 2,500-fold above the saturated vapor concentration for pMDI.
Furthermore, the aerosols were generated using sophisticated techniques in the laboratory, whereby extremely small particles are generated in order to meet international guidelines for testing. This size and concentration of aerosol is not generated in the workplace even under foreseeable worst-case conditions (Ehnes et al., 2019). The particle size distribution of aerosols formed during actual spraying applications has virtually no overlap with that of the highly respirable aerosol generated in inhalation studies (see EC (2005)).
In addition, the EU legislation for classification and labelling of chemicals, the 67/548/EEC Substances Directive in Article 1(d) makes it clear that the object of classification is to approximate the laws of the Member States in relation to substances dangerous to man or the environment. In Article 4 in points 1 and 2 it is clearly stated that substances shall be classified based on their intrinsic properties according to the categories of danger as detailed in Article 2(2) and that the general principles of classification shall be applied as in Annex VI. Intrinsic properties are those inherent in the substance. Due to a very low vapor pressure (<0.01 Pa) MDI substances are not inherently toxic by inhalation since the saturated vapor concentration would be orders of magnitude below toxic concentration. It is only with modification and input (in terms of heat, cooling and size screening) that MDI substances become toxic after inhalation. The European Chemical Industry Council have discussed and given guidance for these situations, and on the classification of respective aerosols. Classification of MDI as “Harmful” is consistent with this guidance.
The acute inhalation data of pMDI and 4,4’-MDI data were considered by EU experts, and their conclusion that MDI be classified as “Harmful” and reported in the 25th Adaptation to Technical Progress (ATP) to the Dangerous Substances Directive (67/548/EEC). This was endorsed in the 28th ATP and both MDI substances remain as “Harmful” in the 30th ATP (adopted by Member States on 16 February 2007 and published 15th September 2008). The original decision was upheld in the EU Risk Assessment of MDI (Directive 793/93/EEC, 3rd Priority List) published in 2005, noting that considering “the exposure assessment, it is reasonable to consider MDI as harmful only and to apply the risk management phrase ‘harmful by inhalation’. This classification was also endorsed by the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE, now SCHER) in giving their opinion on the Risk Assessment (EC, 2008). With the enforcement of the CLP regulation (Regulation (EC) No 1272/2008) in 2009, the Dangerous Substance/Preparation Directive (DSD) was repealed and harmonized classifications were formally transferred to the CLP regulation; Members of the MDI category are officially classified with Acute Tox. 4 H332 (Annex VI Regulation (EC) No 1272/2008 (CLP regulation).
All substances of the MDI category share similar chemical features namely that they a) all contain a significant amount of mMDI, and b) contain at least two NCO functional groups per molecule which is bound to an aromatic ring and this ring is connected to a second aromatic ring by a methylene group. It is the NCO value (driven by the bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).
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