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Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Hypothesis: The molecular initiating event (MIE) for skin sensitization has been identified as reaction of bioaccessible NCO with glutathione. Since all MDI substances contain significant amounts of bioaccessible NCO, all substances of the MDI category are considered sensitizers.
Justification: The AOP for the acquisition of skin sensitization is well recognized. In the case of substances of the MDI category, the MIE of the sensitization process is the reaction of bioaccessible NCO on MDI with biological nucleophiles and particularly glutathione. All data including research and animal test data are consistent with this hypothesized MoA. All substances of the MDI category contain sufficient bioaccessible NCO to elicit the MIE of dermal sensitization. For an overview of skin sensitization data across the category members, see attached table under "overall remarks, attachments".
For more details see category justification document attached in IUCLID section 13 and field “Executive Summary” below.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

Test material

Constituent 1
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with butane-1,3-diol, 2,4'-diisocyanatodiphenylmethane, [(methylethylene)bis(oxy)]dipropanol and propane-1,2-diol
EC Number:
500-312-1
EC Name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with butane-1,3-diol, 2,4'-diisocyanatodiphenylmethane, [(methylethylene)bis(oxy)]dipropanol and propane-1,2-diol
Cas Number:
123714-19-2
Test material form:
liquid: viscous
Details on test material:
Batch # 290832

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:
Based on the available read-across data, the target substance 44MDI/1,3-BD/TPG/PGis considered a skin sensitizer. This is based on the hypothesis that the skin sensitization potential of all MDI category members results from highly reactive NCO groups that react with extracellular biological nucleophiles and cellular proteins. These reactive NCO groups are present in all category substances to significant percentages. Therefore, for all category members for which no substance-specific data is available (including 44MDI/1,3-BD/TPG/PG), the harmonized EU classification of 4,4’-MDI as Skin Sens. Cat. 1 (H317) is adopted.
Executive summary:

No skin sensitization data exist for the target substance 44MDI/1,3-BD/TPG/PG. This endpoint is satisfied by weight of evidence and read across from six valid skin sensitization studies performed with 4,4’-MDI, 2,2’-MDI, 4,4’-MDI homopolymer, and 4,4’-MDI/DPG, all belonging to the MDI category. All of the available studies are assigned Klimisch ratings of either 1 or 2.


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 are 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 low molecular weight bioaccessible groups on monomeric MDI and three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As mentioned above, all substances of the MDI category contain a high content of monomeric MDI. This is key to the hypothesised MoA for all substances of the MDI category.


Since it has been demonstrated that NCO value (as attenuated by solubility) is responsible for toxicity and the higher molecular weight, low solubility components do not contribute to the observed toxicity, it is reasonable to assume that their presence in these mixtures diminishes the overall toxicity causing variation in effect. However, as all substances contain sufficient bioaccessible MDI constituents to elicit effects, a worst-case approach is adopted in which the most bioaccessible substances are read across to all substances of the MDI category. Accordingly, the harmonized CLP classification (Category 1, H317) for 4,4’-MDI is adopted for all substances of the MDI category, including 44MDI/1,3-BD/TPG/PG.


For more details see category justification document attached in IUCLID section 13.