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Diss Factsheets

Toxicological information

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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012
Reference Type:
study report
Title:
Unnamed
Year:
1977
Report date:
1977
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009
Reference Type:
study report
Title:
Unnamed
Year:
1964
Report date:
1964
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test material

Constituent 1
Reference substance name:
2,4'-methylenediphenyldiisocyanate
IUPAC Name:
2,4'-methylenediphenyldiisocyanate

Results and discussion

In vivo

Results
Irritation parameter:
other: summary assessment of irritation parameters from studies that are part of the WoE
Remarks on result:
other: 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) but gave no indication of corrosivity.

Applicant's summary and conclusion

Interpretation of results:
irritating
Conclusions:
Based on the available read-across data, the target substance 2,4’-MDI is 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 the target substance 2,4’-MDI) are classified as Skin Irrit. Cat. 2. This is in line with the current harmonized classification, with 2,4’-MDI classified as skin irritant category 2 (H315) CLP Annex VI Regulation (EC) No 1272/2008 (CLP regulation).
Executive summary:

No skin irritation data exist for the target substance 2,4’-MDI. 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 the target substance 2,4’-MDI. This is in line with the current harmonized classification, with 2,4’-MDI classified as skin irritant category 2 (H315) CLP Annex VI Regulation (EC) No 1272/2008 (CLP regulation).


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