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Skin irritation / corrosion

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Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Justification for type of information:
Hypothesis: 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, which results in tissue damage and acute inflammation with the release of inflammatory mediators and cytokines.
Justification: 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. For an overview of skin irritation 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:
1981
Report date:
1981

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

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:
other: mildly irritating
Conclusions:
Based on the available read-across data, the target substance 44MDI/1,3-BD/TPG/PGis considered to cause skin irritation. This is based on the hypothesis that the skin irritation 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, all category members for which no substance-specific data is available (including 44MDI/1,3-BD/TPG/PG) are classified as Skin Irrit. Cat. 2.
Executive summary:

No skin irritation data exist for the target substance 44MDI/1,3-BD/TPG/PG. This endpoint is satisfied by weight of evidence and read across from nine valid skin irritation studies performed with 4,4’-MDI, MDI mixed isomers, pMDI, 4,4’-MDI homopolymer, 4,4’-MDI/4,4’-MDI homopolymer/1,3-BD/TPG/PG, 4,4’-MDI/DPG, MDI Mixed Isomers/PIR and 4,4’-MDI/TPG, 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. Therefore, the harmonized CLP classification as skin irritant category 2 (H315) for 4,4’-MDI is adopted for all category substances, including 44MDI/1,3-BD/TPG/PG.


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