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EC number: 202-966-0 | CAS number: 101-68-8
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study done according to Buehler protocol and reviewed by Quality Assurance Unit
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Deviations:
- yes
- Remarks:
- various induction and challenge doses were incorporated to determine dose-response; cross challenges were performed
- Principles of method if other than guideline:
- various induction and challenge doses were incorporated to determine dose-response; cross challenges were performed
- GLP compliance:
- no
- Remarks:
- prior to GLP, Quality Assurance review
- Type of study:
- Buehler test
- Justification for non-LLNA method:
- The Buehler test is a challenge assay and more appropriate for determining skin sensitization of highly reactive substances like diisocyanates. For this substance group the LLNA often provides over-predictive results
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): 4,4'-methylenediphenyl diisocyanate
- Molecular weight (if other than submission substance): 230
- Physical state: clear colorless liquid
- Storage condition of test material: room temperature, under nitrogen blanket
- Other: Supplier: American Cyanimid, Wayne, New Jersey, USA
Constituent 1
Constituent 2
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- male/female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Hazleton-Dutchland Laboratory Animals, Denver, PA
- Age at study initiation: 5-6 weeks
- Weight at study initiation: Males = 307 - 480 grams; Females = 299 - 462 grams
- Housing: Husbandry was according to current accepted guidelines of "Good Animal Husbandry": housed in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): (65 -75 degrees F)
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark
IN-LIFE DATES: From: To:
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: anhydrous acetone:olive oil (1:1)
- Concentration / amount:
- Induction: 10mM (0.25%), 30mM (0.75%), 100 mM (2.5%)
Challenge: 0.03mM (0.00075%), 0.3mM (0.0075%), 3mM (0.075%), 10mM (0.25%), 30mM (0.75%),
Challengeopen allclose all
- Route:
- epicutaneous, occlusive
- Vehicle:
- other: anhydrous acetone:olive oil (1:1)
- Concentration / amount:
- Induction: 10mM (0.25%), 30mM (0.75%), 100 mM (2.5%)
Challenge: 0.03mM (0.00075%), 0.3mM (0.0075%), 3mM (0.075%), 10mM (0.25%), 30mM (0.75%),
- No. of animals per dose:
- 15
- Details on study design:
- RANGE FINDING TESTS: Six animals were treated topically with concentrations of 1.0, 0.3, 0.1, 0.003 Molar material in 100% olive oil or in 1:1 mixture with olive oil and anhydrous acetone. The test material (30 ul) was applied directly to the skin under occlusion. After 6 hours, the patches were removed and the skin wiped free of excess material. Observations were made at 24 and 48 hours. Treated sites were scored according to Draize.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hours
- Test groups: 15 animals per group, approximately equal by sex, were administered 50 microliter test substance under occlusion
- Control group: 3 males and 3 females; no treatment
- Site: anterior portion of right flank
- Frequency of applications: 1 time a week
- Duration: 3 weeks
- Concentrations: 10mM (0.25%), 30mM (0.75%) 100 millimolar(2.5%) MDI
B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 14
- Exposure period: 6 hours
- Test groups: 25 microliters of five different concentrations under occlusion
- Control group: same challenge exposure as treated animals
- Site: opposite flank from site used for induction
- Concentrations: 0.03mM (0.00075%), 0.3mM (0.0075%), 3mM (0.075%), 10mM (0.25%), 30mM (0.75%) MDI
- Evaluation (hr after challenge): 24 and 48 hr
OTHER: - Challenge controls:
- 6 animals with no induction were challenged with: 0.03mM (0.00075%), 0.3mM (0.0075%), 3mM (0.075%), 10mM (0.25%), 30mM (0.75%) MDI
- Positive control substance(s):
- yes
- Remarks:
- m-TMI
Results and discussion
- Positive control results:
- m-TMI = 100%
In vivo (non-LLNA)
Resultsopen allclose all
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- low, 10mM (0.25%)
- No. with + reactions:
- 0
- Total no. in group:
- 15
- Clinical observations:
- no clinical findings
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: low, 10mM (0.25%). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: no clinical findings.
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- middle, 30mM (0.75%)
- No. with + reactions:
- 0
- Total no. in group:
- 15
- Clinical observations:
- no clinical findings
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: middle, 30mM (0.75%). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: no clinical findings.
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- high, 100mM (2.5%)
- No. with + reactions:
- 0
- Total no. in group:
- 15
- Clinical observations:
- no clinical findings
- Remarks on result:
- other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: high, 100mM (2.5%). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: no clinical findings.
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- low, 10 mM (0.25%)
- No. with + reactions:
- 1
- Total no. in group:
- 15
- Clinical observations:
- barely perceptible, non-confluent erythema (equivocal) in 2/15 animals
- Remarks on result:
- other: see Remark
- Remarks:
- Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: low, 10 mM (0.25%). No with. + reactions: 1.0. Total no. in groups: 15.0. Clinical observations: barely perceptible, non-confluent erythema (equivocal) in 2/15 animals.
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- middle, 30mM (0.75%)
- No. with + reactions:
- 0
- Total no. in group:
- 15
- Clinical observations:
- barely perceptible, non-confluent erythema (equivocal) in 4/15 animals
- Remarks on result:
- other: see Remark
- Remarks:
- Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: middle, 30mM (0.75%). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: barely perceptible, non-confluent erythema (equivocal) in 4/15 animals.
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- high, 100mM (2.5%)
- No. with + reactions:
- 0
- Total no. in group:
- 15
- Clinical observations:
- barely perceptible, non-confluent erythema (equivocal) in 5/15 animals
- Remarks on result:
- other: see Remark
- Remarks:
- Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: high, 100mM (2.5%). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: barely perceptible, non-confluent erythema (equivocal) in 5/15 animals.
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 500mM
- No. with + reactions:
- 15
- Total no. in group:
- 15
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 500mM. No with. + reactions: 15.0. Total no. in groups: 15.0.
- Group:
- negative control
- No. with + reactions:
- 0
- Remarks on result:
- no indication of skin sensitisation
Any other information on results incl. tables
Treated animals showed a very low degree of change in irrtation scores over the induction period.
Animals treated with low, mid or high induction concentrations exhibited equivocal responses to high challenge concentrations of the test material. Only one definitive response (score of 1) was seen at a low induction dose to the mid-high challenge concentration.
| Induction dose | Challenge dose | Responders |
| 10mM (0.25%) | 0.03mM (0.00075%) | 0/15 |
| 0.3mM (0.0075%) | 0/15 | |
| 3mM (0.075%) | 0/15 | |
| 10mM (0.25%) | 1/15 | |
| 30mM (0.75%) | 0/15 | |
| 30mM (0.75%) | 0.03mM (0.00075%) | 0/15 |
| 0.3mM (0.0075%) | 0/15 | |
| 3mM (0.075%) | 0/15 | |
| 10mM (0.25%) | 0/15 | |
| 30mM (0.75%) | 0/15 | |
| 100mM (2.5%) | 0.03mM (0.00075%) | 0/15 |
| 0.3mM (0.0075%) | 0/15 | |
| 3mM (0.075%) | 0/15 | |
| 10mM (0.25%) | 0/15 | |
| 30mM (0.75%) | 0/15 |
Applicant's summary and conclusion
- Interpretation of results:
- other: harmonized CLP classification as skin sensitizer category 1 (H317)
- Conclusions:
- All substances of the MDI category have a potential to be skin sensitizers due to the presence of reactive NCO groups. However, due to rapid reaction with superficial skin proteins (e.g. keratin) and moisture on the skin which leads to the formation of insoluble masses, dermal penetration is limited. This is consistent with the negative Buehler assay (in which the skin is intact as opposed to intradermal assays) and with the low prevalence of contact allergy reflected under documented human evidence. The Buehler test performed by Davis (1984) was performed similar to OECD Guideline 406 according to the Buehler method in guinea pigs. The study demonstrated that at epicutaneous occlusive induction doses of 0.25 %, 0.75 %, and 2.5 % 4’4-MDI, some animals exhibited marginal responses to high challenge concentrations of the test material (challenge concentrations: 0.00075 %, 0.0075 %, 0.075 %, 0.25 %, and 0.75 %). However, only one definitive response (score of 1) was seen at a low induction dose to the mid-high challenge concentration. Based on the lack of dose-response and the overall marginal and inconsistent results the no-effect level of this study was defined as 10 mM (2.5 %), which can be seen as a threshold under the test conditions used. Indication of a potential of skin sensitization was noted in additional animals tests and are supported by human clinical case reports (for more details see CJD document chapter 3.5.2.2.1 and 3.5.2.2.). Members of the MDI category are officially classified as skin sensitizer (Cat.1) EU GHS 1272/2008 CLP.
- Executive summary:
Numerous animal studies are available to demonstrate the skin sensitizing potential of MDI, which is supported by clinical observations in humans. For the endpoint skin 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 dermal route, protein-hapten complexes are recognized by the immune system, triggering an immunological response resulting in the induction of sensitization.
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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