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EC number: 700-674-2 | CAS number: 147993-65-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Respiratory sensitisation
Administrative data
- Endpoint:
- respiratory sensitisation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Fully reported study, No guideline available
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 994
Materials and methods
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- No guideline for respiratory sensitisation is validated.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- 4,4'-methylenediphenyl diisocyanate
- EC Number:
- 202-966-0
- EC Name:
- 4,4'-methylenediphenyl diisocyanate
- Cas Number:
- 101-68-8
- Molecular formula:
- C15H10N2O2
- IUPAC Name:
- 1,1'-methylenebis(4-isocyanatobenzene)
- Reference substance name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- IUPAC Name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- Details on test material:
- SOURCE: ICI polyurethanes, Belgium
PURITY: monomeric 4,4'-MDI
HAPTEN-PROTEIN CONJUGATE: conjugate of 4,4'-MDI with guinea pig serum albumin (GPSA; Sigma
Chemical Co., St. Louis, MO)
Constituent 1
Constituent 2
Test animals
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Porcellus Animal Breeding, Sussex, UK
- Weight at study initiation: 250-300g
- Housing: individually
- Diet (e.g. ad libitum): ad libitum except during inhalation exposure periods
- Water (e.g. ad libitum):ad libitum except during inhalation exposure periods
- Acclimation period: at least 10 days
Test system
- Route of induction exposure:
- other: groups were exposed by intradermal injection, topical application, or inhalation exposure
- Route of challenge exposure:
- inhalation
- Vehicle:
- other: corn oil only in i.d. and topical exposures
- Concentration:
- Topical induction: Concentration in vehicle: 0, 10, 30, 100 %
Intradermal induction: Concentration in vehicle: 0, 0.0003, 0.003, 0.03, 0.3% of MDI
Inhalation induction: Concentration: between 19.4 and 23.7 mg/m³
Inhalation challenge concentration:
topical sensitisation: 25.9 to 36.4 mg/m³;
intradermal sens.: 27.6 to 36.5 mg/m³;
inhalation sens.: 34.6 to 44.1 mg/m³ - No. of animals per dose:
- topical: 4 groups, n=8;
intradermal: 5 groups, n=8;
inhalation: n=16 - Details on study design:
- MAIN STUDY
A. INDUCTION EXPOSURE
1. Topical induction
- No. of exposures: 1
- Exposure period: 6 hours under occlusion
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals untreated
- Site: shaved scapular region
- Concentrations: 400 μl of 0, 10, 30, 100 % MDI in corn oil
2. Intradermal induction
- No. of exposures: 1
- Test groups: 4 Groups of 8 animals
- Control group: 8 animals untreated
- Concentrations: 100 μl of 0, 0.0003, 0.003, 0.03, 0.3% of MDI in corn oil
3. Inhalation induction
- No. of exposures: 5
- Exposure period: 3 hours (nose only)
- Test groups: 3 Groups of 8 animals
- Control group: 8 animals exposed to dry air
- Frequency of applications: daily
- Duration: 5 days
- Concentrations: 19.4 and 23.7 mg/m³
B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 21
- Exposure period: 15 minutes
- Test groups: all induction groups
- Control group:
- Concentrations: topically induced: 25.9 to 36.4 mg/m³; intradermally induced.: 27.6 to 36.5 mg/m³; inhalation induction: 34.6 to 44.1 mg/m³
- Evaluation : 10 minute baseline monitoring after 15 minute settling period; Monitoring 15 minutes during exposure and 15 minutes after removal from the challenge atmosphere
EXPOSURE ATMOSPHERE:
pre-warmed air was passed over the surface of MDI maintained at 65°C to create a saturated vapour. The MDI vapour was condensed by cooling to form an aerosol, adjusted with air to provide the appropriate atmospheric concentration. Particle size: MMAD ± 1.5 μm
PARAMETERS ASSESSED DURING THE STUDY:
- pulmonary hypersensitivity: measured as changes in respiratory rate following inhalation challenge;
- contact hypersensitivity: measured by topical challenge (modified Magnusson and Kligman; 100 μl of 3% MDI on shaved flanks) and antibody responses: ELISA and Passive Cutaneous Anaphylaxis (PCA). Blood was drawn by cardiac puncture 18 days following the initiation of exposure - Challenge controls:
- control group n=7 received induction exposure to dry air and challenge expposure as treated animals
Results and discussion
- Results:
- Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful. No animals exhibited pulmonary responses following challenge with atmospheric MDI. In contrast, a proportion of animals exhibited pulmonary responses following inhalation challenge after induction by intradermal injection or topical application
Any other information on results incl. tables
GROUP |
% MDI |
PULMONARY RESPONSES |
PCA |
Topical 1 |
0 |
0/8 |
0/8 |
Topical 2 |
10 |
2/8 |
0/8 |
Topical 3 |
30 |
2/8 |
2/8 |
Topical 4 |
100 |
3/7 |
2/8 |
Intradermal 1 |
0 |
0/8 |
0/8 |
Intradermal 2 |
0.0003 |
0/6 |
0/8 |
Intradermal 3 |
0.003 |
1/8 |
0/8 |
Intradermal 4 |
0.03 |
5/8 |
1/8 |
Intradermal 5 |
0.3 |
5/8 |
3/8 |
Inhalation 1 |
0 mg/m3 |
1/7 |
0/8 |
Inhalation 2 |
19.4-23.7 mg/m3 |
0/16 |
0/16 |
Applicant's summary and conclusion
- Interpretation of results:
- sensitising
- Conclusions:
- The current study is a source key study used (Rattray et al. 1994) for read-across to MDI MT and indicates a potential of respiratory sensitization. Also no generally accepted and validated test system is available to investigate the sensitizing effects of substances on the respiratory tract, numerous animal studies are available to demonstrate the respiratory sensitizing potential. Groups of guinea pigs were exposed to 4,4’-MDI by intradermal injection, topical application, or inhalation exposure for induction and by inhalation to 25-44 mg/m3 MDI for the challenge exposure (Rattray et al. 1994). Attempts to sensitize guinea pigs by inhalation exposure to MDI were unsuccessful; no animals exhibited pulmonary responses following challenge with MDI. Intradermal injection or topical application of MDI induced specific antibody responses and pulmonary responses in 12-65 % of guinea pigs depending upon induction dose and route. The findings from the guinea pig study, indicating a potential for respiratory sensitization and are in line with findings from other animals studies and observations in humans. 4,4’-MDI is officially classified as respiratory sensitizer (Cat.1) EU GHS 1272/2008 CLP.
- Executive summary:
Numerous animal studies are available to demonstrate the respiratory sensitizing potential of MDI, which is supported by clinical observations in humans. For the endpoint respiratory sensitization all effects are consistent with the hypothesized MoA and direct electrophilic reactions of the NCO group on mMDI with biological nucleophiles. Reaction of NCO with a protein, marks antigen formation and the MIE of the sensitization process. Upon re-exposure via the respiratory route, protein-hapten complexes are recognized by the immune system, triggering an immunological response resulting in the induction of sensitization.
As the source substance 4,4’-MDI and the target substance MDI MT contain sufficient monomeric MDI, the driver of toxicity, similarities in reactions leading to respiratory sensitization are assumed. Accordingly, the CLP classification (Cat. 1, H334) for 4,4’-MDI is adopted to the target substance MDI MT.
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