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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards; sufficiently documented and acceptable for assessment.
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:
1977
Report date:
1977

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
0.1 ml of undiluted compound was placed in the conjunctival sac of the right eye of each of six albino male and female rabbits and observations made over a period of seven days for inflammation. The treated eyes were washed with sodium chloride solution USP after the 24-hour reading. The left eye served as control. The data were scored according to the method of Draize, Woodard and Calvery (Journal of Pharm. and Exp. Therapeutics, Vol. 82, Dec. 1944).
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
75880-28-3
Cas Number:
75880-28-3
IUPAC Name:
75880-28-3

Test animals / tissue source

Species:
rabbit
Strain:
other: albino
Details on test animals or tissues and environmental conditions:
no data

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye served as control
Amount / concentration applied:
Amount(s) applied: 0.1 ml/animal
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
1, 24, 48, 72 hours and 5, 7 days after instillation
Number of animals or in vitro replicates:
3 males and 3 females
Details on study design:
see "Principles of method"

Results and discussion

In vivo

Results
Irritation parameter:
overall irritation score
Basis:
animal: #1, 2, 3, 4, 5, 6
Time point:
other: 24, 48, 72 hours
Score:
8.4
Max. score:
110
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Observations following application:
Immediate: discomfort was slight
10 min and 1 hour: slight erythema, copius discharge
24 hours: areas of barely perceptible corneal dullness in four animals, slight to moderate erythema, copius discharge
48-120 hours: gradual improvement
168 hours: all scored zero
Other effects:
none

Applicant's summary and conclusion

Interpretation of results:
other: The test substance was not classed as an eye irritant using the grading system outlined by Draize et al. 1944
Conclusions:
The test substance 4,4'-MDI/TPG was slightly eye irritating when tested on male and female rabbits. Slight to moderate erythema was observed 24 hours after instillation, which was fully reversible within 7 days. The test substance was not classed as an eye irritant according to the authors using the grading system outlined by Draize et al. 1944. 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 4,4'-MDI/TPG.
Executive summary:

The test substance 4,4'-MDI/TPG was slightly eye irritating when tested on male and female rabbits and was not classed as an eye irritant by the authors using  the grading system outlined by Draize et al (1944). Slight to moderate erythema was observed 24 hours after instillation, which was fully reversible within 7 days.


Even the test results indicate only a slightly irritating effect, reversible within 7 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 4,4’-MDI-TPG.