Registration Dossier

Administrative data

Description of key information

MDI is harmful by inhalation according to EU (R20) and GHS (Cat. 4) classification. MDI-TPG 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
Dose descriptor:
discriminating dose
Value:
15 800 mg/kg bw
Quality of whole database:
The study is of sufficient quality (Klimisch score=2)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
310 mg/m³
Quality of whole database:
The study is GLP compliant and is of high quality (Klimisch score=1)

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
7 940 mg/kg bw
Quality of whole database:
The study is of sufficient quality (Klimisch score=2)

Additional information

Oral exposure route

The acute oral toxicity of Mondur PF (MDI-TPG) was low with an LD50 value > 15800 mg/kg bw for male and female rats. Single administration of 15800 mg/kg bw was tolerated without mortality, but transient signs of reduced activity were observed (Birch, 1977).

Dermal exposure route

The acute dermal toxicity of Mondur PF (MDI-TPG) was low with an LD50 value > 7940 mg/kg bw for male and female rabbits. Single administration of 7940 mg/kg bw over 24 hours was tolerated without mortality, but transient signs of reduced activity were observed (Birch, 1977).

Inhalation exposure route

The acute inhalation toxicity of Mondur PF (MDI-TPG) vapor revealed an LC50 value > 480 mg/m3 for male rats. An 6-hr vapor exposure of 480 mg/m3 was tolerated without mortality and without signs of intoxication by all animals. Body weight development was not affected (Birch, 1977). Due to the low test concentration of 480 mg/m3 Mondur PF vapor this study is considered to be of limited value for classification. Therefore, acute inhalation toxicity of MDI-TPG was evaluated by read-across with other MDI substances.

Considerations on classification - read-across with other MDI substances

For classification, there were two well conducted, guideline studies, with reliably generated aerosol atmospheres and analyzed concentrations (Appelman and De Jong, 1982a,b; Pauluhn, 2008b). It is 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-off value for Category 1 should be 100ppmV. The result of the Appelman and De Jong study (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 (2008b) study result of 310 mg/m3 would 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 this 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. 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 diphenyl diisocyanate, 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. The European Chemical Industry Council have discussed and given guidance on both the concept of intrinsic toxicity and normal handling and use in classification, and on the classification of aerosols (attached in 7.2.2 'Acute Toxicity Endpoint Summary Attached Documents'). Classification of MDI as “Harmful” is consistent with this guidance.

The data of Appelman and De Jong (1982a,b) 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 the Appelman and De Jong (1982a,b) study and the Pauluhn (2008b) 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.

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 – oral endpoint
Only one key study available

Justification for selection of acute toxicity – inhalation endpoint
Lowest LC50 value of both available key studies (see also "Discussion")

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

Based on the classification of monomeric MDI according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) the following classification or non-classification is recommended for MDI-TPG (read-across based on grouping of substances - category approach):

Acute oral and dermal toxicity

Based on the results of the available acute toxicity studies with other MDI substances, classification of acute toxicity for the oral or dermal route is not warranted according to Directive 67/548/EEC or Regulation (EC) No.1272/2008 (CLP).

Acute inhalation toxicity

With regard to acute inhalation toxicity MDI was classified with R20 (harmful by inhalation) according to Directive 67/548/EEC and with Acute Tox. Cat 4 (H332: harmful if inhaled as vapour) according to Regulation (EC) No.1272/2008 (CLP).