4,4'-methylenediphenyl diisocyanate

Eye irritation

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: Guideline study with acceptable restrictions (analytical purity of the test substance not reported, only 8 days observation)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

analytical purity of the test substance not reported, only 8 days observation

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-methylenediphenyl diisocyanate

EC Number:

202-966-0

EC Name:

4,4'-methylenediphenyl diisocyanate

Cas Number:

101-68-8

Molecular formula:

C15H10N2O2

IUPAC Name:

1-isocyanato-4-[(4-isocyanatophenyl)methyl]benzene

Constituent 2

Reference substance name:

benzene, 1,1'- methylenebis[4-isocyanato-

IUPAC Name:

benzene, 1,1'- methylenebis[4-isocyanato-

Details on test material:

- Name of test material (as cited in study report): Diphenylmethan-4,4'-diisocyanate
- Analytical purity: not reported

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Mean weight at study initiation: 2.3 Kg
- Housing: single
- Diet (e.g. ad libitum): ssniff (Seoest)
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-18
- Humidity (%): 40
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml in both eyes.

Duration of treatment / exposure:

The right eye was wahed 30 s after application. The left eyes was kept unwashed

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The right eye was wahed 30 s after application. The left eyes was kept unwashed
- Time after start of exposure:


SCORING SYSTEM: Draize score

Fluorescein-testing was performed a tthe right eye 24h after instillation.

Results and discussion

In vivo

Results

Results 1

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)

Results 2

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)

Results 3

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)

Results 4

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)

Results 5

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

Results 6

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

Results 7

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

Results 8

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: harmonized CLP classification as eye irritant category 2 (H319)

Conclusions:

The current study is used as key source study used (Schneider 1981) for read-across to MDI category and indicates only slightly eye irritating effect after instillation of 4,4’-MDI. Only minimal cornea opacity was observed. Conjunctivae redness and chemosis up to grade 2 were observed in all animals 1 hour after substance instillation, but the severity decreased within 72 hours. Both effects were not fully reversible within 8 days of observation continued to subside so that on day 8, only one animal showed grade 1 redness and chemosis. No lesions of the iris were observed. The results of this study cannot be exactly compared to the CLP classification criteria as a reading on day 21 was not included. Given the low initial severity and the observed decrease of the effects over 8 days, it is likely that the results would not trigger a CLP classification as irritating to the eyes. However, five of the six tested MDI category substances did show signs of eye irritation. There is limited human information on mMDI (not further specified) which has been reported to cause eye irritation in exposed workers (Jennison et al., 1994). Members of the MDI category are officially classified as eye irritant (Cat.2) EU GHS 1272/2008 CLP.

Executive summary:

In the eyes, the NCO functional group on MDI substances reacts with biological nucleophiles including glutathione and proteins (e.g. in the tear film, the conjunctival epithelium, or the corneal epithelium) leading to inflammatory irritation. Reliable eye irritation data from animal studies are available for only representative substances of the MDI category. With five of the six tested substances, signs of eye irritation, but not of corrosion, were observed. The onset of irritating properties observed in the available studies is consistent with the hypothesized MoA and that local toxicity of the category substances is driven by the rapid reaction of the bioaccessible NCO group on mMDI with extracellular biological nucleophiles such as glutathione and protein, resulting in ocular irritation and an acute inflammatory response.

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 is 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 bioaccessible groups on monomeric MDI and low molecular weight constituents (e.g. three-ring oligomer) which is responsible for chemical and physiological reactivity and subsequent toxicological profile. As reactive NCO groups are a common feature of all substances of the MDI category, it is predicted that these have a similar reactivity profile and a read across within the category is warranted (detailed information on the Mode of Action is available in Category Justification Document).