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Diss Factsheets

Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
03.4.2012 to 27.07.2012
Reliability:
1 (reliable without restriction)
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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
observation period only 10 days
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
PIR modified MDI
Cas Number:
109331-54-6
IUPAC Name:
PIR modified MDI

Test animals / tissue source

Species:
rabbit
Strain:
Himalayan

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: The left eye, which remained untreated, served as a control.
Amount / concentration applied:
0.1 ml undiluted test item
Duration of treatment / exposure:
24 h
Observation period (in vivo):
up to 10 days
Number of animals or in vitro replicates:
3
Details on study design:
- Washing (if done): yes
- Time after start of exposure: 24 h after instillation

SCORING SYSTEM: yes

TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein (yes)

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 10 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
>= 0 - <= 2
Max. score:
4
Reversibility:
fully reversible within: 10 days
Other effects:
White deposits were observed in animal no. three 72 hours to 9 days, loss of hair on upper and lower eyelid 4 to 10 days after instillation. There were no systemic intolerance reactions.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the study data, the test substance is considered as non-irritating to eyes according to EC regulation 1272/2008.
However, 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. 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 (for more details see Category Justification Document IUCLID section 13).
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 substance MDI-PIR.
Executive summary:

The test substance was slightly irritating to the eyes of rabbits according to OECD TG 405 (Leuschner, 2012). The mean irritation index for redness conjunctivae was 1.0 of max. 3. Signs were fully reversible in all animals within 10 days. Chemosis was observed in one animal (mean irritation index = 1.3 of max. 4) 48 hours to 5 days after instillation. No irritation effects were seen at cornea or iris 24 hours after instillation. No systemic intolerance reactions were observed.


Even the test results indicate only a slight irritating effect, reversible within 10 days, the MDI group approach is followed and 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 substance MDI-PIR.