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EC number: 219-799-4
CAS number: 2536-05-2
The test substance is part of a category approach of methylenediphenyl diisocyanates (MDI) with existing data gaps filled according to ECHA guidance on Read Across (ECHA, 2017). The read-across category justification document is attached in IUCLID section 13. In this category Substances of the MDI category all share similar chemical features namely that they a) all contain high levels of mMDI, and b) contain have at least two aromatic NCO groups that are electronically separated from other aromatic rings by at least a methylene bridge. It is the NCO value (driven by the bioaccessible NCO groups on relatively soluble mMDI and low molecular weight species (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. The substances 4,4’-MDI, 4,4’-MDI/DPG/HMWP and pMDI are identified as the boundary substances within this MDI category. These three substances represent the of key parameters (i.e. mMDI content and NCO value) within the MDI category that determine the hypothesized Mode of Action (MoA). Although NCO groups are present on the higher molecular weight constituents, they do not contribute to the toxicity profile because they are hindered due to their increased size and hydrophobicity.
The chronic toxicity and the carcinogenicity of 4,4’-MDI was investigated by Hoymann et al. (1995) in a long-term inhalation study over a maximum of 24 months including satellite groups with 3, 12, and 20 months exposure. Female Wistar rats in groups of 80 animals were exposed for 17 hours/day, 5 days/week to 0, 0.23, 0.70, and 2.05 mg/m3 4,4’-MDI in aerosol form. A dose-dependent impairment of the lung function in the sense of an obstructive-restrictive malfunction with diffusion disorder, increased lung weights, an inflammatory reaction with increased appearance of lymphocytes (but not of granulocytes) in the lung in the high dose group as a sign of specific stimulation of the immune system by 4,4’-MDI, a moderately retarded lung clearance in the high dose group as well as dose-dependent interstitial and peribronchiolar fibrosis, alveolar bronchiolisations and a proliferation of the alveolar epithelium as well as a bronchiolo-alveolar adenoma (at 2.05 mg/m3) were reported. There was no 4,4’-MDI-related increase in the organ-specific tumor rate. The number of tumor bearing rats was identical, and the total number of tumors did not significantly differ between the control and the high dose group.
In a combined chronic toxicity and carcinogenicity study, rats were exposed for 6 hours/day, 5 days/week for 2 years to pMDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m3 (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m3) (Reuzel et al., 1994a). This GLP reliability 2 key study was conducted according to OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies). Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m3 was related to the occurrence of pulmonary tumors in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). Therefore, pMDI was carcinogenic in rats after long-term inhalation to aerosol concentrations of 6.0 mg/m3. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumors.
The two carcinogenicity studies (Reuzel et al., 1994a; Hoymann et al., 1995) have been compared by Feron et al. (2001), with the aim of providing a definitive overview of the chronic pulmonary toxicity/carcinogenicity of MDI substances. In this study, the test materials and study designs were compared, and an in-depth review of observed histopathological lesions was provided (with many lung slides re-examined). The extensive comparative analysis of both carcinogenicity studies showed that qualitatively, the results were comparable. In addition, Feron et al. (2001) concluded that the major pulmonary effects, increased lung weights, bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicate a very similar quantitative response of the lungs to pMDI and mMDI. In summary, by performing a comparison and normalization of inhalation parameter of both carcinogenicity studies, Feron et al. (2001) revealed that both studies were interrelated and that qualitative and the quantitative similarity for major lung lesions was driven by the unreacted mMDI content of both substances.
Three cancer mortality studies have been conducted that focused on assessing the potential long-term health effects of diisocyanate exposure. These studies were conducted in polyurethane foam production facilities in the US, Sweden and the UK, respectively Schnorr et al. (1996), and Hagmar (1993a; 1993b) (updated by Mikoczy et al. (2004)), and Sorahan and Pope (1993) updated by Sorahan and Nichols (2002). In summary, cohorts of workers with potential exposure to TDI, MDI and other chemicals from these three studies when combined represent the long-term mortality experience of over 17,000 polyurethane foam production workers. In two of the cohorts, cancer incidence as well as mortality incidence was studied. Among the various cancer sites examined, suggestive findings across studies were reported only in regard to lung cancer among women employees.
Two of the three studies reported a statistically significant increased standardized mortality ratio (SMR) for lung cancer for female workers (SMR 1.81 Sorahan and Nichols (2002), SMR 3.52 Mikoczy et al. (2004)), and the third reported a non-statistically significant increased SMR (1.73 (Schnorr et al. (1996)) for female and a non- statistically significant decreased SMR (0.79 (Schnorr et al. (1996)) for male workers. However, no dose-response relation was found in either study and the authors of both studies with statistical findings concluded that the excess rates were unlikely to be attributable to the occupational exposures present in the plants under investigation. Evidence was presented from other epidemiologic research that the percentage of smokers in female polyurethane foam production workers in the UK was higher than in non-exposed controls and also higher than in women of the general UK population. The excess of pancreatic cancers reported by Sorahan and Nichols (2002) was interpreted by him not to be related to the working conditions in the factories. This interpretation is further supported by the fact that in the other two cohort studies no excess was found. On the contrary, Mikoczy et al. (2004) reported a deficit in pancreatic cancer in the Swedish cohort.
Classified by CLP as Carc Cat 2 (H351): Suspected of causing cancer by inhalation.
Detailed information on the Mode of Action is available in Category Justification Document.
4,4’-MDI has been classified as a category 2 carcinogen in Europe according to CLP. The hypothesized MoA of carcinogenicity of MDI, and indeed all MDI category substances, is based the high reactivity of the NCO group. Upon exposure, the bioaccessible NCO rapidly reacts with extracellular nucleophilic scavenger biomolecules at the site of contact. Since the majority of biologically accessible NCO groups are present in the form of a high residual concentration of mMDI isomers (and to a somewhat lesser extent oligomeric 3-ring constituents in pMDI), inhalation of these is considered the worst case and most relevant source of information for human health hazards.
Reliable carcinogenicity data after inhalation exposure is available for the source substances 4,4’-MDI and pMDI and supports the proposed mechanism of action. Carcinogenic effects after long-term inhalation exposure to 4,4’-MDI or pMDI in rats are limited to the respiratory tract (mainly benign lung adenomas).
The mode of action for carcinogenicity of MDI substances was reviewed in detail by Greim, in the report from the MAK Collection for Occupational Health and Safety (DFG, 2008). Greim (2008) considered that based on all available data, a mechanism related to the local lung-irritating effect of MDI to be relevant. The initiating event is reaction of bioaccessible NCO groups on MDI substances which react with nucleophilic biomolecules at the MDI/lung fluid interface to form MDI conjugates. This depletion of nucleophilic scavenger molecules (i.e. glutathione) allows reaction with alveolar surfactants and destabilisation of the protective surfactant systems of the lungs. Precipitated MDI and surfactant complexes are subsequently phagocytosed by alveolar macrophages or eliminated from the deposition site via mucociliary clearance (Pauluhn, 2000a; Pauluhn and Lewalter, 2002). Concomitant to the initiating event is alveolar protein exudation, allowing protein content of alveolar lavage fluids to serve as a measure of acute alveolar irritation (Pauluhn et al., 1999b; Pauluhn, 2000a; Kilgour et al., 2002).
There exist other possible MoA for the carcinogenic action of 4,4’-MDI and pMDI that warrant consideration.
A MoA involving hypertrophy or hyperplasia of the type-II pneumocytes as a result of reactions of MDI substances with the surfactant and/or with glutathione or due to cytotoxicity of type-I pneumocytes is plausible. This aetiopathology would not contradict the above hypothesis that toxicity is a function of the reactivity of the NCO on MDI substance with biological nucleophiles at the site of contact. The increased regenerative proliferation of type-II cells, regardless of whether this is the result of irritating damage to type-I pneumocytes or a chronically increased surfactant synthesis capacity (compensation for the fraction of surfactant removed by MDI substance), is therefore considered to be the cause of the preneoplastic changes in rats, which is a known chronic reaction of rat lung to irritating substances (Friemann et al., 1999). The documentation of the MAK values summarises thus: “On the basis of all available data, a mechanism via the local irritating effects of MDI in the lungs is considered relevant (Reuzel et al., 1994a; Pauluhn et al., 1999b; BAuA, 2000; Kilgour et al., 2002; Gledhill, 2003b; Gledhill, 2003a; EC, 2005)”. The EU Risk Assessment (2005) agreed on a likely relevance of secondary local toxicity in pulmonary tumor formation by pMDI aerosol. Consistent with this assumption is the observation that hyperplasia of type II alveolar cells in rats is a common non-specific reaction to many forms of toxic lung injury (Friemann et al., 1999). It is commonly accepted (though not proven for the lung) that such processes can produce tumors through non-genotoxic (epigenetic) mechanisms.
Other possible hypotheses for the carcinogenicity of 4,4’-MDI and pMDI might involve genotoxicity. A direct genotoxicity and mutagenicity MoA due to reactive NCO groups on 4,4’-MDI and pMDI is not supported by the available genotoxicity data (see IUCLID chapter 7.6) or by the observed absence of tumors outside the lungs in the two year animal inhalation study in rats by Reuzel et al. (1994a).
A second indirect mechanism for the carcinogenicity of 4,4’-MDI and pMDI might be postulated involving genotoxicity and the hydrolysis of MDI substance to the mutagenic/carcinogenic MDA. In the MAK review of 2008 (DFG, 2008), this was discussed and it was concluded that while the formation of MDA could not be fully excluded, the available toxicological data provide no indication for a relevant contribution of MDA to the toxicity of MDI substances after inhalation exposure. Consistent with this viewpoint is the observation that only MDA-GSH conjugates and acetylised MDA-GSH conjugates, but not free MDA, have been found in the urine or blood of humans (Sennbro et al., 2003) and animals (Gledhill et al., 2005) following exposure to MDI substances. Furthermore, while MDA resulted in DNA adducts in the liver after oral administration of MDA (EC, 2001), neither MDI-DNA nor MDA-DNA adducts were detected in the tumor target tissue (lung) after chronic 4,4’-MDIMDI exposure via inhalation (Vock et al., 1996).
Finally, a non-genotoxic MoA for the carcinogenicity of 4,4’-MDI and pMDI not linked to NCO reactivity with biological nucleophiles is plausible. This would involve lung overload-like effects due to formation of insoluble MDI adduct particles leading to lung tumor development. In this MoA inhaled 4,4’-MDI substances react with nucleophiles and converted into partially soluble adducts or self-polymerize into an insoluble, non-reactive, non-toxic urea particle. Impaired or ineffective clearance of these particles leading to accumulation of insoluble inert polymerized particles within the lungs may lead to “lung-overload-like” effects and lung cancer. This is often referred to as excessive particulate lung burden of poorly soluble low toxic particles (PSP). The hallmark of lung particle-overload is an impairment of alveolar macrophage-based clearance. The effects seen mainly in rats involve a sequence of inflammatory responses, altered particle kinetics, altered morphology, and finally chronic disease states including fibrosis and the induction of benign and malignant lung tumors (Oberdörster, 1995). Already Oberdörster (1995) questioned the relevance for humans of lung tumors formed by lung-overload effects with poorly soluble low toxic particles (PSP) like seen in chronic rat inhalation studies. This is in line with more recent publications which indicated no evidence that humans develop lung tumors following exposure to poorly soluble particle (ECETOC, 2013; Bevan et al., 2018) Beside the questionable relevance of PSP lung overload-like effects for humans, evaluations by Pauluhn (2014b) with high molecular weight anionic polyurethane-polyurea in rats (see chapter on repeated dose, 220.127.116.11) indicated that possible lung overload-like effect should be covered by the NOAELs for pulmonary irritation and thus should be disregarded as leading cause of 4,4’-MDI carcinogenicity.
Overall, the available evidence supports a hypothesized MoA for formation of lung tumors in rats by MDI substances through chronic regenerative cell proliferation and not genotoxicity. It would therefore follow that this MoA should be threshold-based and since the NO(A)ECs and LO(A)ECs from the short-term and chronic inhalation studies are remarkably consistent there is no indication of a lowering of this threshold with increasing exposure duration.
Since all substances of the MDI category contain high levels of mMDI (mostly 4,4’-MDI), and the non-monomeric MDI constituents do not modulate or contribute to toxic mode of action, data gaps on other MDI substances is filled by read-across to 4,4’-MDI.
Finally, it needs to be appreciated that the test material in the rodent bioassays was delivered as respirable aerosols. Such atmospheres are technically very difficult to achieve and maintain, and in practice are not formed outside of the laboratory. For instance, in inhalation toxicity tests, the test substance often needs to be heated to allow for nebulization so that aerosols are formed. As a general rule particles are described as inhalable or respirable depending on size. Inhalable particles can enter the nose but because of the relatively large size deposit entirely in this region. Finer, respirable particles, (10 µm MMAD or less), can penetrate to lower regions of the respiratory tract and deposit in terminal alveolar regions. As respirable particles are deposited throughout the lung, but the tumours were only seen in the bronchiole-alveolar region, the regional deposition of respirable particles in the lower regions of the lung is a key event in tumour development. For MDI to be present in the workplace atmosphere in respirable form for prolonged durations seems inconceivable. It is also to be noted that epidemiological data do not demonstrate any carcinogenic risk for workers in the MDI using (polyurethane) industry (). Evaporation of MDI can occur, but only to a very low extent because of its very low vapour pressure of <0.000002 kPa at room temperature. If the workplace atmosphere would be completely saturated with the test substance, it would contain around 0.1-0.2 mg/m3 MDI, which is close to the 8h-TWA occupational exposure limit of 0.05 mg/m3.
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