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Eye irritation

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Administrative data

Endpoint:
eye 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: Eye irritation of the category substances is driven by the rapid reaction of NCO group on bioaccessible MDI with extracellular biological nucleophiles such as glutathione and protein, resulting in ocular irritation and an acute inflammatory response. All substances will be classified as Category 2 eye irritants according to the worst case substances (mMDI and pMDI).
Justification: Although eye irritation studies are not available for all substances of the MDI category, on the basis of a general consistency of effects in the data matrix and a common MoA, it can be assumed with high confidence that all MDI substance are eye irritants. For an overview of eye 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:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol
EC Number:
701-041-3
Molecular formula:
C14 H10 N O [C21 H24 N2 O5]n N C O with n=0, 1, 2, 3
IUPAC Name:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: Right eye (30 s exposure)
Irritation parameter:
iris score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0
Max. score:
2
Reversibility:
other: no effects
Remarks on result:
other: Right eye (30 s exposure)
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0.78
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: Right eye (30 s exposure)
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0.61
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: Right eye (30 s exposure)
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0.05
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: left eye
Irritation parameter:
iris score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0
Max. score:
2
Reversibility:
other: no effects
Remarks on result:
other: left eye
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
0.61
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: left eye
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
6 animals
Time point:
other: 24-48-72 h
Score:
0.56
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: left eye

Any other information on results incl. tables

Table 1: Individual draize scores in the left eye of rabbits (not rinsed)

Animal

No.

DRAIZE grade after

Mean

(24-48-72 h)

1h

24h

48h

72h

8days

Conj.

Che.

Conj.

Che.

Conj.

Che.

Conj.

Che.

Conj.

Che.

Conj.

Che.

1

2

2

1

1

1

1

1

1

0

0

1.0

1.0

2

2

1

1

1

1

1

1

1

0

0

1.0

1.0

3

2

1

0

1

0

0

0

0

0

0

0.0

0.33

4

2

1

0

0

0

0

0

0

0

0

0.0

0.0

5

2

1

1

1

1

1

1

1

1

1

1.0

1.0

6

2

1

1

0

1

0

0

0

0

0

0.67

0.0

Mean

2

1.16

0.67

0.67

0.67

0.5

0.5

0.5

0.16

0.16

Mean of 6 animals (24-48-72 h)

Conj. = 0.61

Che. = 0.56

Conj.: conjuctivae; Che.:Chemosis

Applicant's summary and conclusion

Interpretation of results:
other: slightly irritating
Conclusions:
Based on the available read-across data, the target substance 44MDI/DPG is considered to cause eye irritation. This is based on the hypothesis that the eye 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/DPG) are classified as Eye Irrit. Cat. 2.
Executive summary:

No eye irritation data exist for the target substance 44MDI/DPG. This endpoint is satisfied by weight of evidence and read across from six valid eye irritation studies performed with 4,4’-MDI, 2,2’-MDI, MDI mixed isomers, pMDI, 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 eye irritant category 2 (H319) for 4,4’-MDI is adopted for all category substances, including the target substance 44MDI/DPG.


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