Isocyanic acid, polymethylenepolyphenylene ester, 2-ethyl-1-hexanol-blocked

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission, national OEL Germany

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Hazard evaluation of the target  substance MDI MT has been assessed according to the ECHA Read Across Assessment Framework (RAAF) and described in detail in attached analog approach Justification document in section 13.

In brief, the target substance MDI MT and the source substances 4,4-MDI and pMDI have in common their high reactivity and unique combination of physico-chemical properties which dictate a high degree of uniformity in their toxicological effects. Reactivity of the isocyanate, mainly the monomeric MDI content reacts with biological nucleophiles at the site of contact, which is the most important process affecting the hazard potential of the MDI substances in the body. Upon exposure, when MDI substances come into contact with aqueous matrix in the respiratory tract (or in the stomach or moisture on the skin), they do not dissolve readily, but form globules or solid masses, which react at their surface and in the organic phase (also called heterogeneous reaction). The particles or droplets of MDI substances will be readily transformed to particles of inert, insoluble, and non-toxic polyurea polymers. These polyurea are the main reaction product formed when the MDI substances contact water and serves as a detoxification reaction. The remaining unreacted isocyanate is the driver of toxicological effects. 

Due to the low solubilities of diisocyanates in the aqueous matrix of the lung fluid, the presence of MDI substances results in heterogeneous mixture (two distinct phases - diisocyanate and water). At this interface, one of the isocyanate groups will react with nucleophilic biomolecules (primarily thiol group on the glutathione) increasing the solubility of the MDI molecule, allowing the remaining isocyanate groups to be more available to react (for more detail, see Plehiers et al. (2019)). This ‘reactive dissolution’ defines the ‘bioaccessibility’ of the molecule (ability of contaminant to be solubilized in the lung medium) and plays a critical role in determining the toxic effects. 

It should be noted that the “reactive dissolution” is a heterogeneous transformation processes which occurs under physiologic conditions associated with their potential point-of-contact in humans (i.e. skin, lungs, gastrointestinal tract). Under these physiologic conditions, the presence of reactive biomolecules, such as glutathione and proteins, will far out-compete the reactivity of the aryl isocyanate group with water. These biomolecules possess the highly reactive primary aliphatic amine and sulfhydryl functional groups, the latter of which (in the physiologically relevant thiolate form) is estimated to be nine orders of magnitude more reactive with an aryl isocyanate group than is water. Under conditions where these highly reactive nucleophiles are present, the hydrolysis reaction and associated potential to form MDA are diminished and supplanted by reactions which form soluble (with mMDI) and insoluble (all other MDI constituents) adducts with these biomolecules. For this reason, the formation and biological formation of MDA can be disregarded with respect to human health hazards.

In mammalian systems, toxicity is consistent with the widely-recognized mode of action of inhaled chemical electrophiles, in this case through rapid conjugation of the bioaccessible NCO group with extracellular biological nucleophiles and their subsequent depletion resulting in site of exposure toxicity, including irritation and sensitization. Rapid reactivity of the MDI with the primary nucleophiles glutathione and proteins in the extracellular matrix also serves to detoxify the NCO group preventing not only systemic exposure but also electrophilic reactivity with distal tissue nucleophiles (systemic toxicity) or DNA (mutagenicity). The lack of systemic exposure negates any significant concern for reproductive toxicity.

 

As the source substance 4,4’-MDI and the target substance MDI MT contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions with extracellular nucleophilic biomolecules at the site of contact are assumed. As the higher molecular weight non-monomeric content of the UVCB substance MDI MT do not contains reactive centers and is consequently inert and thus do not contribute to the observed toxicity, it is reasonable to assume that using read across to the source substances 4,4’-MDI is warranted. Therefore  the source substances 4,4’-MDI and polymeric MDI (pMDI) are used for hazard evaluation and DNEL derivation for the target substance MDI MT.

Background:

According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8 (Version 2.1, Nov 2012), a national occupational exposure limit (OEL) can be used as a surrogate for a DNEL under certain circumstances (R.8.1.1). APPENDIX R. 8-13 is specifying the derivation of DNELs, when a community/national occupational exposure limit (OEL) is available. 

For 4,4´-MDI and pMDI the German MAK Commission established a purely health based OEL (MAK-Value) of 0.05 mg/m³for inhalable aerosol referring to an 8-hour exposure period, that is the basis for the official national OEL in Germany (listed in TRGS 900). This OEL is used as a surrogate DNEL for long-term exposure. A ceiling limit value of 0.1 mg/m³was settled. This ceiling limit is used as a surrogate DNEL for short-term exposure. Since irritation to the respiratory tract is the most sensitive health effect these DNELs apply for local effect, in absence of any systemic toxicity no additional systemic DNELs need to be derived (see below for details). 

The justification of these OELs is given in the published 4,4´- MDI/pMDI evaluation of the German MAK Commission (MAK, 2008, 2015).

The German Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) is a group of renowned experts in the field of toxicology and occupational medicine from academia, but also from regulatory bodies and industry. The MAK Commission is independently organized within the German Research Association (DFG) and has a close liaison to the European Commission’s Scientific Committee for Occupational Exposure Limits (SCOEL). Amongst other duties, the group proposes maximum workplace concentrations (MAK values -maximum allowable concentration) for volatile chemicals and dusts.  Comprehensive justifications for these values and the charters of the group are made publicly available underhttp://onlinelibrary.wiley.com/book/10.1002/9783527694983.

As a basis for the evaluation for MDI, the MAK justification is referring to the EU Risk Assessment (2005) constituting an extensive peer reviewed data assessment and description.

 

Character of the general effect

In the evaluation of the German MAK Commission the justification of the OEL for 4,4´- MDI/pMDI is established based on the isocyanate (NCO) group which is common to the monomeric, oligomeric and the polymeric MDIs. This NCO group is highly reactive. Due to this high reactivity of the functional NCO group towards nucleophilic biomolecules the primary health effect of MDI is irritation at the point of contact, which can be demonstrated by the numerous acute, subacute and chronic bioassays, and sensitization.

After inhalation exposure, MDI reacts with nucleophilic low and higher-molecular components of the liquid films that cover the airways, glutathione (GSH) represents the most important nucleophile in quantitative terms. The low-molecular adducts or conjugates of MDI are absorbed and direct transcarbamoylation results in plasma protein adducts (albumin, hemoglobin). All observed health effects resulting from exposure to respirable aerosols in acute, subchronic or chronic bioassays and human studies can be allocated to primary alveolar reactivity (respiratory irritation and/or sensitization). No systemic effect other than secondary to primary irritation has been described. 

Acute toxicity:  

The acute oral and dermal toxicity data indicates very low toxicity in absence of any clinical signs. The key study acute for oral toxicity resulted in a LD50 >2000mg MDI MT (Schuengel 2007, pMDI Wazeter et al. 1964b), the key study for acute dermal toxicity resulted in a LD50 >9400 mg pMDI/kg bw (Wazeter, 1964a). In conclusion no acute systemic effect was identified which would require the derivation of acute DNELs. 

The most sensitive health effect resulting from acute inhalation exposure to respirable aerosols of MDI is irritation to predominately the bronchio-alveolar part of the respiratory tract. The key guideline acute inhalation study (OECD 403) was performed in rats at six exposure concentrations of highly respirable aerosols of pMDI (Pauluhn, 2008).The combined LC50 for both sexes was calculated as 310.2mg/m³. All observed clinical signs were indicative for a strong irritation of the respiratory tract. In the second key study, five groups of Wistar rats were nose-only exposed to liquid aerosol concentration of 300.0, 354.2, 399.2, 500.0 and 553.8 mg 4,4’-MDI/m³. The combined LC50 for both sexes was calculated as 431.2mg/m³. All observed clinical signs were indicative for a strong irritation of the respiratory tract.

Determination of protein and LDH in the BAL are known to be especially sensitive parameters for alveolar irritation. A detailed analysis on the early events of acute alveolar irritation was performed following an acute 6h exposure to highly respirable pMDI aerosols. An increased overall concentration of proteins as the earliest indication of a possible irritation of the alveoli in rats was observed starting at 0.7 mg/m³ (Pauluhn, 2000). Based on the rapid reversibility of the increased protein exudation, these effects are attributed to a temporary surfactant destabilization, and are considered as a homeostatic reaction and not to be adverse (NOAEC 0.7 mg/m³). Relevant changes to the bronchoalveolar lavage (BAL) are not observed until higher acute exposures of 2.4 mg pMDI/m³ and clinical symptoms of respiratory tract irritation are not observed until concentrations of 8 mg pMDI/m³. 

Acute irritating and direct local toxic effects well correlate with the associated subchronic and chronic endpoints (e.g. cell proliferation, see repeated dose toxicity). Therefore, there are no indications of cumulative or over additive effects, pointing towards a concentration rather than a dose dependent effect of MDI on the respiratory tract. As for the oral and dermal routes of exposure no acute systemic effect was identified which would require the derivation of an acute DNEL. 

Irritation 

Only slightly skin irritation was observed in a study performed in accordance to OECD Guideline 404 with MDI MT in rabbits (Gmelin, 2007a) and based on the available study data for MDI MT, CLP classification criteria were not met. Only mild irritation was observed in a skin irritation study performed with 4,4-MDI (Schreiber, 1981a). However, skin irritation was found in human occupation case reports (NIOSH, Jennison et al.1994) and 4,4’-MDI is officially classified as skin irritant (Cat.2) EU GHS 1272/2008 CLP. On a worst-case basis a read-across to 4,4’-MDI is considered for this endpoint. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin irritation.

In a valid guideline study Gmelin (2007a) observed transient slightly eye irritating effects in rabbits treated with MDI MT, CLP classification criteria were not met. Only mild irritation was observed in an eye irritation study performed with 4,4-MDI (Schreiber, 1981b) and moderate eye irritation in a study performed with pMDI (Wazeter (1964b). However, eye irritation was found in human occupation case reports (NIOSH, Jennison et al.1994) and 4,4’-MDI is officially classified as eye irritant (Cat.2) EU GHS 1272/2008 CLP. On a worst-case basis a read-across to 4,4'-MDI is considered for this endpoint. The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent eye irritation.

In acute and chronic animal inhalation bioassays MDI aerosols were demonstrated to be irritating to the respiratory tract. Effects were predominantly observed in the pulmonary region (see acute and repeated inhalation toxicity for more detailed description and quantification of observations). 

Skin sensitization 

Based on animal and human data MDI is a skin sensitizer. In consideration of human case reports and epidemiological studies the skin sensitizing potential of MDI cannot be regarded as strong. Though animal assays clearly indicate that MDI related skin sensitization is a threshold effect, induction and elicitation thresholds have been shown to not adequately correlate with human data. In absence of a reliable dose descriptor for skin sensitization a qualitative risk assessment in accordance to ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (Version 3.0, May 2016) is indicated.

Respiratory sensitization 

MDI is a respiratory sensitizer based on human evidence. It is known, that a specific sensitization of the respiratory tract may be induced by the inhalation or dermal route. For diisocyanates a potential relevance of dermal contact for the induction can be derived from animal experiments, although this has not yet been conclusively demonstrated based on human occupational case reports. A detailed presentation of the etiology of the diisocyanate specific respiratory hypersensitivity in humans is included in the justification of the MAK value: in principle exposure of humans to MDI aerosols can cause specific or nonspecific hyperreactivity of the airways. For the specific reactions, asthma (early type, late-phase reaction or dual type) is clearly more frequent as exogenic allergic alveolitis. Bronchial asthma is a known clinical picture triggered by diisocyanates such as MDI. 

In general, current mechanistic understanding of allergic responses such as respiratory allergy and allergic contact dermatitis is such, that it can be assumed that the development of sensitization (induction) and also the elicitation are threshold phenomena. This is acknowledged in the ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.8 (Version 2.1, Nov 2012) where it is indicated that (skin) sensitization is generally regarded as a threshold effect. A common initiating step in the induction of respiratory allergy and allergic contact dermatitis is e.g. the activation of dendritic cells. Furthermore, the ECHA Guidance Chapter R8 is indicating that “…as for skins sensitization, there is evidence that for respiratory sensitization dose-response relationships exist, although these are frequently less well defined (APPENDIX R. 8-11). This view in the ECHA guidance is in line with an extensive literature study which was performed to evaluate these dose-response relationships and related no-effect levels for sensitization and elicitation in skin and respiratory allergy in general. With respect to the respiratory tract, dose-response relationships and no-effect levels for induction were found in several human as well as animal studies (Arts et al., 2006, see respiratory sensitization for details). A more recent literature study with a specific focus on the sensitization of the respiratory tract confirmed the existence of such thresholds for chemical respiratory allergy in general (Cochrane et al., 2015). Besides an updated evaluation of animal experiments, this conclusion was derived from an extensive review of human studies of occupational asthma from various chemical substance classes. It is concluded, that even without a numerically defined threshold, or a complete understanding of the dose-response relationship, operational thresholds can be established to avoid induction of sensitization or elicitation of an allergic response. For diisocyanates in specific, the recent publication by Cochrane et al. (2015) also assessed the database for diisocyanates and concluded that the data suggests that there is a threshold for the acquisition of sensitization and that these threshold concentration are in the range of between 5 and 20 ppb. 

This conclusion is confirmed for MDI by the evaluation of large number of human occupational studies in larger cohorts by the MAK commission, concluding that “…if a pMDI concentration of less than 5 ppb (0.05 mg/m3) is maintained, no new cases of asthma attacks or asthmatic complaints were observed…” (e.g. Bernstein et al. 1993; in MAK 2008).

This practical experience indicates that induction and elicitation of an MDI specific chemical respiratory allergy would be covered by the existing OEL. However, rare case reports describe elicitation reactions well below the current OEL in sensitized individuals with symptoms, who were continued to be exposed.  Medical surveillance of lung function of exposed workers can effectively prevent the occurrence of severe acute asthma attacks (Tarlo, 2002 and 2005).

ECHA Guidance Chapter R8 further outlines that “…at present there are no validated or widely accepted animal or in vitro test protocols to detect respiratory sensitization or to determine the induction or elicitation thresholds.”

In recent years, an asthma model was developed in the BN rat in which dose response correlations and thresholds can be effectively identified. This model was validated with TMA and volatile (HDI and TDI) and non-volatile (MDI) diisocyanates (see respiratory sensitization for details). Asthma genic responses were demonstrated by means of lung inflammation identified in bronchoalveolar lavage fluid (BALF) and respiratory responses using whole body plethysmography. Both dermal and inhalation routes apply for induction and a single (TMA) or repeated mildly irritating challenges (diisocyanates) are required for elicitation. A no-effect level for induction with MDI was determined at about 5000 mg/m3 mins (i.e. 5 x 10-min/day to 97.1mg/m³and 5 x 360-min/day to 2.9 mg/m³), challenging at 41 mg/m³ (Pauluhn and Poole, 2011). For determining dose response correlations and thresholds for elicitation the last elicitation challenge is typically performed as group-wise dose escalation (5, 15, 40 mg/m³MDI). A no effect level of 5 mg/m³could be defined for the elicitation (Pauluhn, 2008). 

Summarized, for MDI the BN rat asthma model demonstrates the existence of thresholds for the induction by both the dermal and inhalation routes, and a threshold for elicitation of respiratory sensitization following induction and subsequent multiple challenges. The derived elicitation threshold C×t appears to be plausible relative to human evidence. The close association of C×t products triggering an elicitation response in asthmatic rats with the acute pulmonary irritation threshold C×t is intriguing and supports the view that for this class of chemicals portal of entry related allergic responses appear to be linked with pulmonary and/ or lower airway irritation. Accordingly, high concentrations delivered to the respiratory tract during short exposure periods appear to bear a higher sensitizing potency than equal C×t products during longer exposure periods (Pauluhn and Poole, 2011). Pauluhn (2008) examined if the results from this animal model could be applied to the human workplace experience and concluded that “Taking into account the current occupational exposure level of MDI (0.05 mg/m3), the conclusions derived from this bioassay of respiratory irritation and allergy are not at variance with existing human evidence and current occupational workplace standards.” 

This covers both the elicitation and induction phase since in accordance to ECHA Guidance Chapter R.8 “…the dose required to induce sensitization in a non-sensitized subject is usually greater than that required to elicit a reaction in a previously sensitized subject”. 

Repeated dose toxicity / carcinogenicity 

Chronic studies have demonstrated that for repeated inhalation exposure the toxicity of 4,4’-MDI and pMDI is determined by the local irritating effects on the bronchioalveolar region of the respiratory tract. For chronic daily 6-hour exposure (5 days/week) of rats to respirable aerosols, the first indications of irritating effects, e.g. histological effects, are observed from 1 mg pMDI/m³. In comparison to subchronic studies a longer duration of the exposure did not result in a reduction of the effect concentration (NOAEC 0.2 mg pMDI/m³; Reuzel et al., 1990). Concentrations of 6 mg/m³resulted in chronic-inflammatory changes with an increased incidence of bronchoalveolar adenoma and one carcinoma, mainly in the lower respiratory tract. During a long-term inhalation experiment with MDI aerosol with a daily 17-hour exposure (7 days/week), a pulmonary adenoma developed in addition to chronic-inflammatory changes to the respiratory tract at 2 mg/m³(Hoymann et al. 1997). These findings were assessed as typical subsequent reactions of rat’s lungs to a direct irritating effect on the alveoli and the chronic inflammation (regenerative cell proliferation) associated with this. Fibrotic effects may occur secondary to chronic plasma exudation in the alveolar region. Similar findings have also been described for substances with similar effect profiles (alveolar irritation) (Pauluhn et al. 2007). There are no indications of systemic toxicity. 

According to the MAK justification human case studies are of relatively low quality (e.g due to co-exposure to toluene diisocyanate and inaccurate exposure specifications). Impairment of the lung function due to long-term exposure was observed with pMDI up to 87 ppb (0.9 mg/m³), whilst for a predominantly observed maximum concentration of 20 ppb (0.2 mg/m³) no significant changes in the lung spirometry were found. However, a few people were found to have airway-related complaints although airway-related complaints were not significantly more frequent for exposures below 10 ppb pMDI (0.1 mg/m³). 

For MDI, no repeated dose dermal toxicity studies are available. In a dermal penetration study of 4,4’-MDI in rats only 0.9% of the applied radioactivity was absorbed at the most (Leibold et al.,1999) and systemic effects were not identified in repeated dose inhalation toxicity studies. Therefore is can be anticipated that as for inhalation exposure the local irritative effect and the sensitizing potential is the most sensitive effect for repeated dermal contact to MDI. These effects are covered by the qualitative risk assessment preventing from dermal contact by the appropriate risk management measures. 

Reproductive toxicity:

In the absence of maternal toxicity identified by respiratory tract irritation no embryotoxic effects occurred in rat developmental toxicity studies (NOAEC developmental toxicity 3 mg 4,4’-MDI/m³, 4 mg pMDI/m³). No systemic toxicity to reproductive organs was identified in sub-chronic and chronic toxicity studies. 

No fertility study including functional parameters is available. But due to the strong irritating properties and the absence of any systemic toxicity in repeated dose studies, there are no exposures to be expected at which there is a realistic possibility of toxicity to fertility. 

Conclusion for workers: 

The primary health effect of the source substances 4,4’-MDI and pMDI is irritation at the point of contact and sensitization. In rats effect levels for lower respiratory tract irritation from short-term inhalation studies with corresponding biochemical and cellular changes in the bronchoalveolar lavage and cell proliferation of the bronchoalveolar epithelial cells (NOAEC 0.7 mg/m³, LOAEC 1 mg/m³) correlate with histopathological findings from studies with chronic lifetime exposure (NOAEC 0.2 mg/m³, LOAEC 1 mg/m³). As shown by this comparison of the acute and long term thresholds the effect of 4,4’-MDI and pMDI on the respiratory tract mainly depends on the concentration level, which is in line with the direct irritation mechanism of toxicity. 

Airway-related complaints in workers were not significantly more frequent for exposures below 10 ppb pMDI (0.1 mg/m³). For the development of a specific hypersensitivity of the airways, exposures of over 0.2 mg/m³or intensive skin contact are important. This is why higher peak concentrations should be avoided. 

Based on this human experience the MAK value was set to 0.05 mg/m³(MAK 1992). Higher peak concentrations should be avoided to momentary values of 0.1 mg/m³. 

Since both MDI and pMDI have equal amount of reactive NCO groups and have only minor differences between the biological effects of both substances, the MAK value of 0.05 mg/m³now also applies for both MDI and pMDI, representing the official legally binding OEL (TRGS 900, 2006). 

Literature: 

 All cited studies are reported in the respective end points or read across justification

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

As with workers, hazard evaluation and DNEL derivation for the target substance MDI MT for the general population is based on the hazards associated with the source substances (4,4’-MDI and pMDI).  For a detailed description of the data along with the detailed justification, see the Analog Read Across Justification Document attached in section 13.   

The primary health effect of MDI and pMDI is irritation and sensitization at the point of contact. No reliable dose descriptors can be derived for dermal and ocular irritation and for sensitization via the skin. Therefore a qualitative approach is indicated to appropriately minimize the risk for exposure. 

For exposure to respirable aerosols to rats, effect levels for lower respiratory tract irritation from short-term inhalation studies with corresponding biochemical and cellular changes in the bronchoalveolar lavage and cell proliferation of the bronchoalveolar epithelial cells correlate with histopathological findings from studies with chronic lifetime exposure. As shown by this comparison of the acute and long term thresholds the effect of 4,4’-MDI and pMDI on the respiratory tract mainly depends on the concentration level, which is in line with the direct local irritation mechanism of toxicity. 

For MDI, airway-related complaints in workers were not significantly more frequent for exposures below 10 ppb pMDI (0.1 mg/m³). For the development of a specific hypersensitivity of the airways, exposures of over 0.2 mg/m³ or intensive skin contact are important. This is why higher peak concentrations should be avoided. 

Based on this human experience the MAK value was set to 0.05 mg/m³ (MAK 1992). Higher peak concentrations should be avoided to momentary values of 0.1 mg/m³. 

 Extrapolation to the general population should take into account the potential higher susceptibility of sensitive individuals towards local effects at the respiratory tract as the most sensitive health effect as well as the different exposure situation. For differences in susceptibility between workers compared to the general population ECHA guidance Chapter R.8 is proposing to apply the quotient of 2 (Table R.8-6). 

As mentioned earlier mechanistic studies suggest a close association of C×t products triggering asthmatic responses with the acute pulmonary irritation threshold C×t. This observation supports the view that for this class of chemicals portal of entry related allergic responses appear to be linked with pulmonary and/ or lower airway irritation. The DNELs for local effects for the general population would then sufficiently cover decrements in lung function due to respiratory sensitization of the general population(see respiratory sensitization for details). 

Based on the MAK value for workers and a factor of 2 to extrapolate to the general population, the DNEL for local effects is therefore derived to be 0.025 mg/m³ for long term exposure and 0.05 mg/m³ for short term exposure, which would sufficiently cover respiratory sensitization. 

As the source substances 4,4’-MDI, pMDI and the target substance MDI MT contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions leading to inflammation and irritation to the respiratory tract is predicted. In addition, as the higher molecular weight non-monomeric content of the UVCB substance MDI MT do not contains reactive centers and is consequently inert and thus do not contribute to the expected toxicity, it is reasonable to assume that using read across to the source substances 4,4’-MDI and pMDI is warranted, thus the DNELs calculated from the source substances applies also for the target substance MDI MT.