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EC number: 202-966-0 | CAS number: 101-68-8
- 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
Skin irritation / corrosion
Administrative data
- Endpoint:
- skin irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline study with acceptable restrictions (analytical purity of the test substance not reported, only 8 days observation, scoring for erythema were not performed due to coloration of skin with the test substance)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 981
- Report date:
- 1981
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Deviations:
- yes
- Remarks:
- analytical purity of the test substance not reported, only 8 days observation, scoring for erythema were not performed due to coloration of skin with the test substance
- GLP compliance:
- no
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-isocyanato-4-[(4-isocyanatophenyl)methyl]benzene
- Reference substance name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- IUPAC Name:
- benzene, 1,1'- methylenebis[4-isocyanato-
- Details on test material:
- - Name of test material (as cited in study report): Diphenylmethan-4,4'-diisocyanat
- Analytical purity: not reported
Constituent 1
Constituent 2
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Mean weight at study initiation: 2.3 Kg
- Housing: single
- Diet (e.g. ad libitum): ssniff (Soest)
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-18
- Humidity (%): 40
- Photoperiod (hrs dark / hrs light): 12/12
Test system
- Type of coverage:
- occlusive
- Preparation of test site:
- shaved
- Vehicle:
- unchanged (no vehicle)
- Controls:
- no
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml - Duration of treatment / exposure:
- 4 h
- Observation period:
- 8 days
- Number of animals:
- 6
- Details on study design:
- TEST SITE
- Area of exposure: 2.5x2.5 cm on both sides of the body (left and right)
REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 4 h
SCORING SYSTEM: Draize score
Results and discussion
In vivo
Resultsopen allclose all
- Irritation parameter:
- edema score
- Basis:
- mean
- Time point:
- other: 24-48-72 h
- Score:
- 0.61
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 8 days
- Remarks on result:
- other: left skin side
- Irritation parameter:
- edema score
- Basis:
- mean
- Time point:
- other: 24-48-72 h
- Score:
- 1
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #1
- Time point:
- other: 24-48-72 h
- Score:
- 1.33
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #2
- Time point:
- other: 24-48-72 h
- Score:
- 1.33
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #3
- Time point:
- other: 24-48-72 h
- Score:
- 1
- Max. score:
- 4
- Reversibility:
- fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #4
- Time point:
- other: 24-48-72 h
- Score:
- 0.33
- Max. score:
- 4
- Reversibility:
- fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #5
- Time point:
- other: 24-48-72 h
- Score:
- 1.33
- Max. score:
- 4
- Reversibility:
- not fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritation parameter:
- edema score
- Basis:
- animal #6
- Time point:
- other: 24-48-72 h
- Score:
- 0.67
- Max. score:
- 4
- Reversibility:
- fully reversible within: 8 days
- Remarks on result:
- other: right skin side
- Irritant / corrosive response data:
- The scoring for erythema was not possible due to coloration of skin with the test substance.
Applicant's summary and conclusion
- Interpretation of results:
- Category 2 (irritant) based on GHS criteria
- Conclusions:
- The current study is a source key study used for read-across to MDI category and indicates only mild irritation, an older but well conducted non GLP-study with the 4,4’-MDI applied under occlusive dressings (Schreiber, 1981). Very slight (barely perceptible) to slight (clearly perceptible) oedema was observed during the first 72 hours after removal of the dressings. By day eight, only very slight oedema was visible in three of six animals. Unfortunately the skin responses were not observed till 14 days post exposure. Erythema formation could not be evaluated due to substance-related discoloration of the skin. Similar to other point of contact toxicological effects, the hypothesized MoA by which irritation is produced is reactivity of the NCO group with biological nucleophiles at the site of contact (skin, mucous membranes and respiratory tract) (DFG, 2008). With all tested MDI category members, signs of skin irritation were observed, which supports the official classification as skin irritant (Cat.2) EU GHS 1272/2008 CLP.
- Executive summary:
By dermal contact, the majority of the available NCO groups react with proteins and moisture on the skin, leading to the formation of an insoluble polymerized mass limiting absorption such that only a small fraction is available to penetrate into the viable skin layers. Residual toxicity, as demonstrated by mild irritation potential, is consistent with the hypothesized MoA that effects are driven by the rapid MDI-adduct formation with extracellular biological nucleophiles. No other toxicities that are inconsistent with this MoA are observed. Although skin irritation studies are not available for all category substances, the common consistency of effects in the data matrix can be assumed with high confidence as representatives from all subgroups show irritation in studies with sufficient quality. All tested substances caused signs of skin irritation including inflammation (erythema and oedema) and additionally in some cases hyperplasia (thickening (coriaceousness), scaling, flaking or fissuring). Although not all studies demonstrated full reversibility of these signs, their severity decreased towards the end of the studies, such that only mild symptoms remained by the end of the observation periods. Furthermore, no signs of irreversible skin damage (i.e. ulcers, bleeding, bloody scabs, skin blanching, alopecia, scars or other signs indicative of necrosis into the dermis) were reported in any of the available studies, justifying all substances of the MDI category being regarded as skin irritants of category 2 as opposed to category 1. For this endpoint, all effects are consistent with the hypothesized MoA of direct electrophilic reactions of the NCO group on available MDI substances (i.e. most soluble) with biological nucleophiles.
All substances of the MDI category share similar chemical features namely that they a) all contain a significant amount of mMDI, and b) contain at least two NCO functional groups per molecule which is bound to an aromatic ring and this ring is connected to a second aromatic ring by a methylene group. It is the NCO value (driven by the bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).
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