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Description of key information

The test substance is covered by the category approach of methylenediphenyl diisocyanates (MDI).

Hence, data of the category substances can be used to cover this endpoint. The read-across category justification document is attached in IUCLID section 13. It is important to note that the MDI category approach for read-across of environmental and human hazards between the MDI substances belonging to the MDI category is work in progress under REACH. Therefore the document should be considered a draft.

The MDI is harmful by inhalation according to EU (H332; R20) and GHS (Cat. 4) classification.

The MDI is non toxic after single oral and dermal exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
431 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral exposure route:

The acute oral toxicity data is straightforward. A key study (reliabiltiy 1) using 4,4'MDI-homopolymer did not show toxicity via oral gavage up to 5000 mg/kg (Mallory, 2009). The animal studies demonstrated that the MDI has low acute oral toxicity. The key study describing the acute oral toxicity of generic-MDI conducted as a limit test according to EU guideline (84/449/EEC) with GLP(Reliability 1) did not find any mortality up to the maximum dose tested.The acute LD50 was found to be > 2000 mg/kg bw (Bomhard, 1990). The supporting study describing the acute oral toxicity of polymericMDI (pMDI) conducted similar to OECD 401 guideline (Reliability 2) also did not find any mortality up to the maximum dose tested, hence the LD50 is > 10000 mg/kg bw (Wazeter, 1964). Other studies on MDI are consistent with this.

Dermal exposure route:

Similar to acute oral toxicity data, the available animal studies demonstrated that the MDI has low acute dermal toxicity. Although it has to be mentioned that the scientific validity and the reporting of the listed studies is rather less than current standards. The key study describing the acute dermal toxicity of pMDI in rabbits did not find lethality up to the maximum dose tested and the LD50 was > 9400 mg/kg bw (Wazeter et al., 1964). Other studies on pMDI or 4,4’-MDI are consistent with this.

Inhalation exposure route:

The key guideline acute inhalation study (OECD 403) was performed in male and female rats at five exposure concentrations of 4,4-MDI (Pauluhn, 2008).The animals were nose-only exposed for 4 hours to liquid aerosol in concentrations of 0, 300, 354, 399, 500 and 554 mg/m3(analysed conc.), with a post exposure observation period of two weeks. Mass median aerodynamic diameter ranged between 2.1 and 3.5 µm across all groups.Male rats were apparently more susceptible than females.All MDI exposure groups exhibited clinical signs consistent with respiratory irritation, so the NO(A)EL was <300 mg/m3.Mortality occurred in a concentration related manner at 354 mg/m3and above.The LC50 for male rats was calculated as 368 mg/m3(95% confidence interval 296-458 mg/m3) and for females approximately 559 mg/m3.For both sexes combined, the LC50 was 431 mg/m3.

 

An acute inhalation study was performed in rats at only one concentration level of 2.24 mg/L/1h (Pauluhn 2003, 2004). This study was specifically designed to comply with NFPA 704, and also complied with the limit test of the OECD guideline 403 with deviations (only 1 hr exposure, concentration lower than limit test concentration) and is therefore reliable with restrictions. Exposure of 4,4’-MDI for 1 hr resulted in mortality shortly after exposure of one out of ten rats. Clinical signs were characterised by typical signs of respiratory tract irritation. Necropsy findings were unremarkable in surviving rats, whilst the rat that succumbed displayed signs of lung oedema which was considered to be the cause of death. The LC50 >2.24 mg/L/1h (analytical) in both males and females was determined.

 

For classification, there were two well conducted, guideline studies, with reliably generated aerosol atmospheres and analyzed concentrations taken into account (Appelman and de Jong , 1982a&b, Pauluhn, 2008). It was preferred to use these studies with reliable valid data rather than taking a mean of data reported in databases which do not critically assess the experimental set-up and analysis of the test-atmosphere. The GHS guidance has cut off values for Category 1 of 0.5 mg/L (500 mg/m3) for vapours and 0.05 mg/L for aerosols. GHS guidance section 3.1.2.1 note (d) states that where vapour and aerosol exist together the cut of value for Category 1 should be 100 ppmV. The result ofAppelman and de Jong (1982a, b) is an LC50 of 490 mg/m3 (0.49 mg/L), which falls just under the cut off for GHS Category 1 for vapours and mixed vapours/aerosols, but would be Category 2 for aerosols. Similarly the Pauluhn (2003,2004) study result of LC50>2.24 mg/L and Pauluhn (2008) study result of 431 mg/m3would also result in Category 2.

 

Classification of chemicals allows for the application of scientific judgement. It must be taken into account that the LC50 cut-off of 500 mg/m3 (approximately 50 ppm for pMDI), is over 2500-fold above the saturated vapour concentration for pMDI. At the saturated vapor concentration MDI has no effect on animals. Furthermore the aerosols were generated using sophisticated techniques in the laboratory, were of extremely small particle size only in order to meet international guidelines for testing of aerosols, and this sort and concentration of aerosol is not generated in the workplace (ISOPA, 2015). In spraying applications aerosols are formed where the particle size distribution has virtually no overlap with that of the highly respirable aerosol generated in inhalation studies (see EU Risk Assessment Report on methylene diphenyldiisocyanate, EINECS-No. 247-714-0, 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 on the basis of 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. MDI is not inherently toxic by inhalation, as evidenced by its lack of any effect at the saturated vapour concentration. It is only with modification and input (in terms of heat, cooling and size screening) that MDI becomes toxic after inhalation. The European Chemical Industry Council have discussed and given guidance for situations like that, and on the classification of respective aerosols (attached in 7.2.2 'Acute Toxicity Endpoint Summary Attached Documents'). Classification of MDI as “Harmful” is consistent with this guidance.

 

The Appelman and de Jong (1982a&b) data were considered by EU experts and their conclusion that MDI be classified as “Harmful” (Xn, R20) is 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 MDI remains 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.

This principle is considered to apply equally to theAppelman and de Jong (1982a&b) study and the Pauluhn (2008) results.

 

The classification as “Harmful”, is equivalent to GHS Category 4. For these reasons, the GHS proposal follows the EU Regulatory lead accepting that the animal data are inappropriate and classified pMDI as GHS acute toxicity category 4 (ISOPA 2007).

 

Assessment of the available acute toxicity data indicates that inhalation exposure to the aerosols of MDI results in toxicity confined predominantly to the respiratory tract. In terms of hazard characterization, MDI is harmful by inhalation according to EU (R20) and GHS (Cat. 4) classification. The MDI is non toxic after single oral and dermal exposure.


Justification for selection of acute toxicity – inhalation endpoint
GLP study conducted in line with OECD Guideline 403.

Justification for classification or non-classification

EU classification according to Annex I of Directive 67/548/EEC:

R20 GHS classification (GHS UN rev.2, 2007):

Inhalation route (vapour): Acute Category 4.

Not toxic by the dermal or oral routes.