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EC number: 219-799-4
CAS number: 2536-05-2
Description of Key information
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 and summarized below in Additional Informaiton. Data-gaps in this endpoint is satisfied by weight of evidence and read across from valid repeated dose toxicity studies for the inhalation route. Reliable repeated dose inhalation data in animals is available for the boundary substances (4,4’-MDI, pMDI and 4,4’-MDI/DPG/HMWP). The chronic repeated dose toxicity study (Reuzel et al. 1994, reliability 2) performed with pMDI is a guideline study (OECD 451). In addition, valid sub-chronic and sub-acute repeated dose toxicity studies are available for pMDI (Reuzel et al. 1994, Kilgour et al. 2002, reliability 2). For the 4,4’-MDI a valid chronic inhalation toxicity study is available (Hoymann et al. 1995, reliability 2) and a limited documented sub-chronic inhalation toxicity study (Heinrich et al. 1991, reliability 4). For the boundary substance 4,4’-MDI/DPG/HMWP a sub-acute toxicity study is available (Ma-Hock, 2021, reliability 1).
To support this weight of evidence and read across approach additional repeated dose toxicity testing is planned. It is considered to perform a sub-chronic inhalation toxicity study (OECD 413) with boundary substance 4,4’-MDI/DPG/HMWP. Additional, combined Repeated Dose Toxicity studies with Reproductive/ developmental Toxicity Screening tests (OECD 422) will be performed on 9 substances representing all sub-groups and key structural/chemical characteristics (see overview attached in Annex 27 in Chapter 13). These screening studies will confirm the proposed MoA on repeated dose toxicity or identify substances that may require additional testing.
Several sub-acute, sub-chronic and chronic studies have been performed on 4,4’-MDI, pMDI and 4,4’-MDI/DPG/HMWP and are described in Category justification document in Chapter 13 . A repeated dose dermal toxicity study was performed in rabbits with pMDI (Wazeter et al., 1964a) but since this only has fourteen days of treatment and only slight local skin irritants effects were observed this is omitted from this chapter, but rather described in chapter addressing skin irritation. As with the acute studies, in all repeated dose studies, toxic effects were limited to the site of contact with no systemic effects observed distant from the portal of entry. Key repeated dose studies days are described below:
The ‘Monomeric MDI’ subgroup
In a subchronic inhalation study with 4,4’-MDI, female Wistar rats were exposed to concentrations of MDI of 0, 0.3, 1 or 3 mg 4,4’-MDI/m3 for 18 hours a day on 5 days a week for 13-weeks. Reduced body weight gains and an increase in relative lung weights were found at 1 mg/m3 and above. At and above this concentration infiltration of mononuclear cells, goblet cell hyperplasia, erosion of the respiratory epithelium in the upper respiratory tract, hyperplasia of the bronchus-associated lymphatic tissue and inflammatory changes of the lung were additionally observed. At 3 mg/m3 there was an increase in the total cell count and proportion of granulocytes and lymphocytes, a decrease in the proportion of macrophages in the bronchoalveolar lavage fluid, an increase in protein, β-glucuronides and lactate dehydrogenase, and changes in lung function. No effects were observed at 0.3 mg/m3 (Heinrich et al., 1991).
A subsequent chronic inhalation study (Hoymann et al., 1995) was conducted with 4,4’-MDI. Female Wistar rats were exposed to 0.23, 0.70 or 2.05 mg 4,4’-MDI/m³ aerosols for 17 hours/day, 5 days /week for up to 24 months. Essentially, a dose-dependent impairment of the lung function in terms of an obstructive-restrictive malfunction with diffusion disorder, increased lung weights, an inflammatory reaction with increased appearance of lymphocytes in the lung in the high dose group as a sign of specific stimulation of the immune system by MDI, an intermediately 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, which was classified as preneoplastic, as well as a bronchiolo-alveolar adenoma were identified. The LOAEC for the female rat was identified as 0.23 mg/m3 based on minor histopathological pulmonary lesions after long-term inhalation of 4,4'-MDI aerosols.
A comparison of the pulmonary effects described in female rats from the two chronic studies, one with 4,4’-MDI and the other with pMDI, was published by Feron et al. (2001). To assist the comparison and account for the lower proportion of mMDI in pMDI, the authors normalized the different MDI doses to total inhalation exposures calculated as 559; 1,972; 2,881; 6,001; 17,575 and 17,728 mg mMDI.h/m3. The major pulmonary effects in the two studies were characterized by hyperplasia, interstitial fibrosis and a low incidence of bronchiolo-alveolar adenoma, the latter occurring in the high exposure groups of both studies (i.e. total inhalation exposures of 17,728 and 17,575 mg.h/m3). Both studies also reported the presence of particle-laden macrophages predominantly in the alveoli close to the alveolar ducts which in some cases, particularly in high dose groups, were associated with areas of fibrosis. There was a clear quantitative dose response in both studies with the lowest dose of 559 mg mMDI.h/m3 from the study reported by Reuzel et al. (1994a) being described as the no-observed-adverse-effect-level (NOAEL) Feron et al. (2001) also suggested that the mild histopathological changes seen in the low exposure animals (0.23 mg/m3) in the Hoymann et al. (1995) study, would not have occurred if the exposure had been for six hours/day. An exposure of 0.2 mg/m3 over a six-hour period was judged to be the NOAEL in both studies. Overall, the analysis concluded that both studies showed similar qualitative responses to exposures to pMDI or 4,4’-MDI when compared on the basis of mMDI content..
The ‘Oligomeric MDI’ subgroup
In a subacute inhalation study by Kilgour et al. (2002), female Alpk:APfSD rats were exposed to pMDI aerosol at concentrations of 0, 1.0, 4.0 and 10 mg pMDI/m3, for 6 hours/day, 5 days/week, for 28 days, a 30-day recovery group was included. No clinical signs were noted during exposure and recovery phase. Body weights in all groups were comparable to controls throughout exposure and recovery periods. Lung weights were increased in animals exposed to 10 mg/m3 at the end of the exposure period, although this had returned to control values by day 30 post-exposure. Lung weights of all other treated groups were in the range of the control group. A dose-dependent influx of inflammatory cells, total protein levels and increase in enzyme activities indicated an inflammatory reaction. A statistically significant increase in both the total number of cells counted and alveolar macrophages in lavage fluid was noted at 10 mg/m3, and a slight (but not statistically significant) following exposure to 4 mg/m3. The polymorphonulear leukocytes (PMNs) and lymphocyte/other cells showed statistically significant, concentration-related increases in cell counts following exposure to 4 or 10 mg/m3 pMDI. At the end of the recovery phase, cell counts in exposed animals had returned to normal. Animals of the exposure groups 4 and 10 mg/m3 showed an increase of macrophages containing vacuoles (foamy macrophages), whereas the 1 mg/m3 group was in the range of the control animals. At the end of the recovery period few macrophages vacuoles were still discernable. In animal exposed to 10 mg/m3 pMDI a statistically significant increase in total protein and alkaline phosphatase activity was noted in lavage fluid at the end of exposure, whereas lactate dehydrogenase and N-acetyl glucosaminidase (NAG) activities were not increased. All other treated groups in the main study and all groups at the end of the recovery phase showed values similar to controls. A transient increase in phospholipids concentration was noted in the lavage fluid from animals exposed to 10 mg/m3 pMDI after exposure, no differences from control values were seen at the end of the recovery phase. In all exposure groups a statistically significant concentration-related increase in BrdU labelling index in terminal bronchioles were seen; a similar increase in centro-acinar alveoli were found in animals exposed to 4 and 10 mg/m3 pMDI. At the end of the recovery phase, labelling indices were similar to control values at all concentrations. No macroscopic abnormalities were noted. Histopathology of the lung showed in animals exposed to 10 mg/m3 pMDI an increase in bronchiolitis and thickening of the centro-acinar region, interstitial thickening at the acinar junctions, and accumulations of alveolar macrophages containing yellow pigment in the cytoplasm. In animals exposed to 4 mg/m3 pMDI 1/5 animals showed thickening of the centro-acinar region and bronchiolitis and 1/5 animals exposed to 1 mg/m3 pMDI showed bronchiolitis. After the recovery phase, alveolar macrophages containing a yellow pigment were present in the interstitium in all animals that had been exposed to 10 mg//m3 pMDI but were absent in animals exposed to 1 or 4 mg/m3 pMDI. In addition, 1/5 animals exposed to 10 mg/m3 pMDI still had bronchiolitis and centro-acinar thickening, but at a reduced severity and distribution to that seen in the main study. Ultrastructural findings suggest a perturbation of surfactant homeostasis by exposure to pMDI which is supported by the small increase in measured phospholipids and observation of foamy macrophages. Animals exposed to 10 mg/m3 pMDI showed a slight thickening of the interstitial alveolar wall in 3/5 animals. The thickening in the centro-acinar region was due to thickening of the interstitium, which partly attributable to the absorption of alveolar macrophages and partly due to excess collagen. Compound -related increases in the levels of surfactant were noted in the alveolar macrophages and lumina. In the alveolar macrophages, minimal to slight increases in lamellar surfactant were associated with minimal and moderate increases in amorphous surfactant in animals exposed to 10 mg/m3 pMDI. In the alveolar lumina, minimal to moderate increase in cell debris were noted in animals exposed to 10 or 4 mg/m3 pMDI. Associated with these increases in cell debris were increases in the amount of crystalline and lamellar surfactant. At 1 mg/m3 there was evidence of effect on surfactant homeostasis, with small increase in number and size of type II cell lamellar bodies and similar increases in amorphous, crystalline and lamellar surfactant in the alveolar lumina, which was seen as an adaptive response to exposure to low levels of irritant aerosol.
Based on findings of histopathology, bronchiolitis noted at 1 mg/m3 and evidence of effect on surfactant homeostasis at 1 mg/m3, NOAEC could not be defined and the LOAEC was set at 1 mg/m3 pMDI.
In a subchronic inhalation study (SC1) by Reuzel et al. (1994b) (original report Reuzel et al. (1985)) Wistar rats were exposed to pMDI aerosol at concentrations of 0, 0.35, 1.4 and 7.2 mg pMDI/m3, for 6 hours/day, 5 days/week over a period of 13 weeks. Transient slight growth retardation was observed in male rats exposed to 7.2 mg/m3 air. Haematology, blood chemistry and urinalysis did not show treatment-related effects. There were no significant differences in organ weights between the test and control groups. Gross examination at autopsy did not reveal changes which could be ascribed to the test substance. Histopathological examination revealed yellow material (possibly polyurea originated from test material) in the respiratory tract of rats exposed to 7.2 mg/m3. Under the conditions of this test no clear NOAEC was determined.
In an associated second subchronic study (SC2) by Reuzel et al. (1994b) (original report by (Reuzel et al., 1986)), Wistar rats were exposed to higher aerosol concentrations of 4.1, 8.4 and 12.3 mg pMDI /m3 air for 3-months. Severe respiratory distress was observed in rats exposed to 12.3 mg/m3 with 11 males and 4 females dying during the exposure period. Significantly less severe signs were seen in rats exposed to 8.4 mg/m3. This study demonstrated adverse effects in the lungs and nasal cavity at levels of 4.1 mg/m3 and above and included histological effects in the lungs (increase in alveolar macrophages and interstitial macrophage infiltration) and in the mediastinal lymph nodes (macrophages with yellowish inclusions). At 8.4 mg/m³ and above increased relative lung weights, partially reversible damage to the olfactory epithelium and basal cell hyperplasia were observed.
In a combined chronic toxicity and carcinogenicity key study (Reuzel et al., 1990; Reuzel et al., 1994a) conducted according to OECD Guideline 453 rats were exposed for 6 hours/day, 5 days/week for one year (satellite groups) or two years (main groups) to aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg pMDI /m3 (analytical concentrations: 0, 0.19, 0.98, 6.03 mg/m3). The effect of chronic exposure of rats to respirable pMDI aerosol was confined to the respiratory tract. The compound-related changes were found in the nasal cavity, the lungs and the mediastinal lymph nodes, and to some degree they were already present after one year of exposure. Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m3 over two years was related to the occurrence of pulmonary tumors in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). In this two-year rat study, the NOAEC was 0.2 mg/m3 for the repeated dose toxicity of pMDI. The LOAEC was set at 1.0 mg/m3.
The ‘MDI and its reaction products with glycols’ subgroup
Pre-liminary results are available for a subacute inhalation study (Ma-Hock, 2021) which was conducted according to OECD 412 on 4,4’-MDI/DPG/HMWP. This study was designed as closely as possible to the study described above by Kilgour et al. (2002) on pMDI to generated comparable data on 2 category boundary substances. A qualitative and quantitative comparison between these studies will be described in more detail in the category justification document attached to this dossier.
Male and female Wistar rats (7 animals per sex and exposure group) were exposed to 4,4’-MDI/DPG/HMWP liquid aerosol at concentrations of 0, 1.0, 4.0 and 10 mg/m3 (analytical conc.: 0, 1.0, 3.9 and 9.8 mg/m3), for 6 hours/day, 5 days/week, for 4 weeks (main study). To evaluate the reversibility of effects, 28-day recovery groups were included (recovery control group and 10 mg/m3 exposure group). No mortality was observed throughout the study. During the exposure period clinical signs like respiration sound and piloerection were noted in animals exposed to 10 mg/m3 and one animal exposed to 4 mg/m3. In all other animals, no clinical signs were observed during the exposure period. No clinical signs were observed during the recovery period. Body weights of males exposed to 10 mg/m3 was slightly lower throughout the exposure period but were in the range of the concurrent control at the end of the recovery period. All other groups were comparable throughout exposure and recovery period. A significant increase in mean relative lung weights was observed in males and females of the 10 mg/m3 exposure group, although this had returned to control values at the end of the recovery period. Regarding clinical chemistry, one female of exposure group 4 mg/m3 and 2 females of exposure group 10 mg/m3 (main study) showed an increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. These effects were regarded as caused by the implant of Alzet osmotic minipumps, thus regarded as treatment related but not substance related effect. All other changes in clinical chemistry observed in exposed animals were regarded as incidental and not treatment related. In animals exposed to 10 mg/m3 a lymphocytic-monocytic inflammation was observed indicated by increased total cell counts as well as absolute and relative lymphocyte and monocyte counts. This type of inflammation was confirmed by marginal, non-relevant increases of lactate dehydrogenase (LDH BAL) and alkaline phosphatase (ALP BAL) activities, but relevantly, slight increases of γ-glutamyl transferase (GGT BAL) activities among these individuals. In BAL of rats exposed to 10 mg/m3 increases of high total protein levels were observed. At the end of the recovery period total protein levels and enzyme activities and cell counts had returned to control levels. Treatment-related histopathological findings were observed in lungs, trachea, larynx, tracheobronchial lymph nodes and mediastinal lymph nodes in male and female animals. Interstitial inflammation of the terminal bronchi was observed in animals exposed to 4 mg/m3 and 10 mg/m3. Hypertrophy/hyperplasia of large, medium and terminal bronchi were observed in animals exposed to 4 mg/m3 and 10 mg/m3, which was associated with an increase in cell proliferation, indicated as a significant increase in BrdU labeling indices. A statistically significantly increased cell proliferation was also observed in animals exposed to 1 mg/m3 in large, medium and terminal bronchi. In alveoli there was a trend towards increased cell proliferation, however there was no dose-response relationship, statistically significance was only seen in males exposed to 10 mg/m3. Pneumocytes type II cells showed minimal proliferation in few animals of the 4 mg/m3 and 10 mg/m3 exposure group. Interstitial inflammation of alveoli was noted in males of the 4 mg/m3 and 10 mg/m3 exposure groups. In the alveolar lumina, neutrophilic infiltration was found occasionally. Debris was seen in one male of the 4 mg/m3 exposure group in alveolar lumina consisting of fragments of cells. Alveolar macrophage accumulation was seen with increased severity in males and females exposed to 10 mg/m3. A minimal increase in alveolar macrophages was still present in females at the end of the recovery period. Macrophages with foamy cytoplasm (foamy macrophages) were observed in males of the 4 mg/m3 and 10 mg/m3 exposure groups and in females exposed to 10 mg/m3. Epithelial alteration in the larynx was noted with increased incidence and severity in treated animals and was characterized by a focal, ventrally located change of the epithelium from cuboidal to focally flattened cells and was noted with increased incidence and severity in treated animals. Lymphocyte infiltration was seen in the submucosa in treated animals. The trachea epithelium on the tip of the carina was changed from its normal cuboidal, ciliated appearance to a single layer of flattened cells with loss of cilia in treated animals. Hyperplasia of the trachea epithelium was seen in males exposed to 4 mg/m3 and 10 mg/m3 and females exposed to 10 mg/m3. Beneath the epithelium, there was an increased infiltration of lymphocytes in single animals. A diffuse enlargement of mediastinal and tracheobronchial lymph nodes was seen in treated animals. The histopathological changes noted after termination of exposure were mostly reversible. An increased incidence of minimal alveolar macrophage accumulation was still observed at the end of the recovery period in treated females. Increased cell proliferation in alveoli was still observed in treated males. No other treatment related findings were observed at the end of the recovery period.
In summary, substance-related systemic effect was not observed. Under the current study conditions, the no observed adverse effect level (NOAEL) for systemic toxicity was 10 mg/m³. The NOAEL for local toxicity could not be established due to the slight changes in labeling indices present at 1 mg/m³ (Ma-Hock, 2021).
A large dataset is available in human epidemiological and case studies for chronic exposure to diisocyanates in the workplace and reported effects are limited to respiratory system. Effects associated with respiratory sensitization are described in chapter sensitization and potential carcinogenicity is described in carcinogenicity chapter. In general, long term exposure to MDI substances can result in non-immunological decreases in lung function and other respiratory symptoms associated with chronic irritation. Interpretation of many of these studies is confounded by simultaneous exposure to TDI and inaccurate exposure data. Despite these limitations, pMDI concentrations as low as 87 ppb (0.9 mg/m3) were shown to correlate with deterioration in lung function whereas when exposures were below a maximum concentration of 20 ppb (0.2 mg/m3), no significant changes in lung spirometry was generally observed (DFG, 2008). The frequency of respiratory complaints was not significantly increased when exposure levels were below 10 ppb (0.1 mg/m3) (DFG, 2008).
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint: No system toxicity up to the highest dose group tested
Inhalation is the most appropriate route of exposure for assessing occupational risk of substances of the MDI category in humans. Repeated dose studies are available for the three boundary substances , GLP compliant study on both 4,4’-MDI and pMDI with reliability 2, conducted according to OECD Guideline 453 (combined chronic toxicity/carcinogenicity studies) and two 28 day studies on pMDI and 4,4’-MDI/DEG/HMWP. In all repeated dose studies, toxic effects were limited to the site of contact with no systemic effects observed distant from the portal of entry, which is in line with the discussed MoA of MDI toxicity (see category justification document).
Repeated dose toxicity: inhalation - local effects (target organ) respiratory: respiratory tract
Inhalation is the most appropriate route of exposure for assessing occupational risk of substances of the MDI category in humans. Repeated dose studies are available for the three boundary substances, GLP compliant study on both 4,4’-MDI and pMDI with reliability 2, conducted according to OECD Guideline 453 (combined chronic toxicity/carcinogenicity studies) and two 28 day studies on pMDI and 4,4’-MDI/DEG/HMWP. Consistent with the hypothesized MoA proposed (see category justification document) for these substances the primary health effect following inhalation exposure is local irritation within the respiratory tract without significant systemic exposure or toxicity.
ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7a: Endpoint Specific Guidance (Version 3.0, August 2014; page 20 “Selection of the appropriate route of exposure for toxicity testing“) is indicating that “the overall objective of toxicity testing is to determine the potential hazard of the test substance to human beings”. It is stressed that “toxicity data obtained using the appropriate route of exposure are preferred” and that “route-to-route extrapolation should be considered on a case-by-case basis and may introduce additional uncertainties”. The evaluation of toxicokinetic information should be taken into account to address such uncertainties. For reactive substances like diisocyanates significant toxicokinetic differences can be demonstrated, e.g. with respect to primary reaction products at the portal of entry (oral, dermal, inhalation). Since the most relevant route of exposure is inhalation hazard characterization shall preferably be performed via inhalation.
This endpoint is satisfied by weight of evidence and read across from valid repeated dose toxicity studies for the inhalation route. This is justified since all category 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 extremes 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.
As described in the Toxicokinetics (IUCLID 7.1.), the hypothesized MoA of toxicity for all substances of the MDI category is the reaction of the electrophilic NCO group with extracellular biological nucleophiles such as cellular proteins and is limited to point of contact effects without subsequent systemic toxicity. Reliable inhalation data is available for the source boundary substances 4,4’-MDI, pMDI (representative of the worst-case most available NCO) and 4,4’-MDI/DPG/HMWP (as a typical representative of the ‘MDI and its reaction products with glycols’ subgroup with the highest average molecular weight and least amount of bioaccessible NCO). Results from these studies are consistent with the hypothesized MoA and assertion that MDI substance toxicity after repeated inhalation exposure in animals is limited to local effects caused by inflammation and irritation to the respiratory tract without subsequent systemic toxicity. In regard to these local effects after inhalation, the lungs are the primary organ affected since olfactory lesions were only observed at higher concentrations/doses.
As an MDI substance enters the lung, NCO groups react with biological nucleophiles at the MDI/lung fluid interface to form MDI-conjugates. Formation of these MDI-adducts depletes protective nucleophiles in the lung and results in pulmonary irritation and inflammatory cell influx. MDI only enters the systemic circulation in the form of MDI-GSH or protein adducts. Consequently, there is no systemic exposure to the toxic NCO functional group which is consistent with the lack of distal toxicity in any study conducted. As described above, due to its role in further reducing the solubility (and hence subsequent bioaccessibility), the non-monomeric MDI constituents of the substances do not add to toxicity profile.
Read-across is used to predict the outcome on other MDI substances on the basis of the hypothesized MoA common to all substances of the MDI category and that they contain high levels of mMDI with bioaccessible NCO groups. As the non-monomeric MDI constituents do not contribute to the observed toxicity, the level of NCO in the substances can predict toxic effects for all endpoints with high confidence. The available repeated dose inhalation data on 4,4-MDI, pMDI and 4,4’-MDI/DPG/HMWP, demonstrate that the toxicity expressed by the category substances containing non-monomeric MDI constituents (e.g. three-ring and glycol adducts) are comparable to that expressed by the substances of the ‘Monomeric MDI’ subgroup due to them containing significant levels of free mMDI and the fact that non-monomeric MDI constituents present no additional hazards.
All substances of the MDI category are classified with STOT Repeated Exposure Cat 2 according to CLP. Therefore, based on the described MoA and the addressed RAAF Assessment Elements, the available data on the endpoint Repeated Dose Toxicity are considered adequate and sufficient for classification and labelling and read-across without the need for additional toxicity testing.
. Classified as STOT RE 2 according to CLP: May cause damage to the respiratory system through prolonged or repeated exposures.
Detailed information on the Mode of Action is available in the Category Justification Document.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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