4,4'-methylenediphenyl diisocyanate

Skin irritation / corrosion

Administrative data

Endpoint:

skin 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, scoring for erythema were not performed due to coloration of skin with the test substance)

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 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

analytical purity of the test substance not reported, only 8 days observation, scoring for erythema were not performed due to coloration of skin with the test substance

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'-diisocyanat
- Analytical purity: not reported

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

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


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

Test system

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

Duration of treatment / exposure:

4 h

Observation period:

8 days

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: 2.5x2.5 cm on both sides of the body (left and right)


REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water
- Time after start of exposure: 4 h


SCORING SYSTEM: Draize score

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24-48-72 h

Score:

0.61

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: left skin side

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24-48-72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 3

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 24-48-72 h

Score:

1.33

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 24-48-72 h

Score:

1.33

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 5

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 24-48-72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 6

Irritation parameter:

edema score

Basis:

animal #4

Time point:

other: 24-48-72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 7

Irritation parameter:

edema score

Basis:

animal #5

Time point:

other: 24-48-72 h

Score:

1.33

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: right skin side

Results 8

Irritation parameter:

edema score

Basis:

animal #6

Time point:

other: 24-48-72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 8 days

Remarks on result:

other: right skin side

Irritant / corrosive response data:

The scoring for erythema was not possible due to coloration of skin with the test substance.

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

The current study is a source key study used for read-across to MDI category and indicates only mild irritation, an older but well conducted non GLP-study with the 4,4’-MDI applied under occlusive dressings (Schreiber, 1981). Very slight (barely perceptible) to slight (clearly perceptible) oedema was observed during the first 72 hours after removal of the dressings. By day eight, only very slight oedema was visible in three of six animals. Unfortunately the skin responses were not observed till 14 days post exposure. Erythema formation could not be evaluated due to substance-related discoloration of the skin. Similar to other point of contact toxicological effects, the hypothesized MoA by which irritation is produced is reactivity of the NCO group with biological nucleophiles at the site of contact (skin, mucous membranes and respiratory tract) (DFG, 2008). With all tested MDI category members, signs of skin irritation were observed, which supports the official classification as skin irritant (Cat.2) EU GHS 1272/2008 CLP.

Executive summary:

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. No other toxicities that are inconsistent with this MoA are observed. Although skin irritation studies are not available for all category substances, the common consistency of effects in the data matrix can be assumed with high confidence as representatives from all subgroups show irritation in studies with sufficient quality. 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 as opposed to category 1. For this endpoint, all effects are consistent with the hypothesized MoA of direct electrophilic reactions of the NCO group on available MDI substances (i.e. most soluble) with biological nucleophiles.

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).