2,2'-methylenediphenyl diisocyanate

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 4th 2010 - December 10st 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Justification for type of information:

Hypothesis: 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, which results in tissue damage and acute inflammation with the release of inflammatory mediators and cytokines.

Justification: 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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-methylenediphenyl diisocyanate

EC Number:

219-799-4

EC Name:

2,2'-methylenediphenyl diisocyanate

Cas Number:

2536-05-2

Molecular formula:

C15H10N2O2

IUPAC Name:

1,1'-methylenebis(2-isocyanatobenzene)

Details on test material:

- Name of test material (as cited in study report): MDI 22
- Physical state: solid
- Purity: approx. 100 % (as indicated by the sponsor)
- Lot/batch No.: WRS 3792
- Storage condition of test material: room temperature

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crl:KBL(NZW)BR
- Sex: female
- Source: Charles River, Kißlegg, Germany
- Age at study initiation: adult
- Weight at study initiation: 2.9-3.1 kg
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3
- Humidity (%): 50 +/- 25
- Photoperiod (hrs dark / hrs light): 12 / 12

Test system

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: moistened with corn oil

Controls:

other: 0.5 ml corn oil was applied as control on the conlateral skin area

Amount / concentration applied:

Amount: 0.5 g

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48, 72 hours as well as 7 and 14 days after patch removal

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: approx. 2.5 x 2.5 cm
- Type of wrap if used: gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing: treated skin area carefully washed with corn oil
- Time after start of exposure: 4 hours

SCORING SYSTEM: according to DRAIZE

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 24, 48, 72 hours

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score after 72 hours: 0.3

Results 2

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 24, 48, 72 hours

Score:

0 - 1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 72 hours: 0.3

Results 3

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 24, 48, 72 hours

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score after 72 hours: 2.0

Results 4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 24, 48, 72 hours

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 72 hours: 1.0

Results 5

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 24, 48, 72 hours

Score:

1 - 3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score after 72 hours: 2.0

Results 6

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 24, 48, 72 hours

Score:

0 - 2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 72 hours: 1.0

Other effects:

No systemic intolerance reactions were observed.

Any other information on results incl. tables

Table 1: Summary of irritant effects on the skin (Exposure: 4 hours)

Observation time               1h  24h 48h 72h day7 day14

(after patch removal)
Animal 1
Erythema (redness)
 and eschar formation           0   0   0   1    1    0
Oedema formation                0   0   0   1    0    0

Animal 2
Erythema (redness)
 and eschar formation           0   2   2   2    1    0
Oedema formation                0   1   1   1    0    0

Animal 3
Erythema (redness)
 and eschar formation           0   1   2   3    1    0
Oedema formation                0   0   1   2    0    0

Animal 1, 2 and 3: desquamation on day 7 after patch removal

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the test results, GHS criteria for classification are not met.

Executive summary:

In a dermal irritation/corrosion study according to OECD TG 404 the test substance was applied under semiocclusive dressings for 4 hours to the shaved skin of 3 female rabbits. Skin irritation was assessed after 1, 24, 48, 72 hours and 7 days using the Draize scale. The mean irritation index for erythema was 1.4 of max. 4 (0.3-2.0), the mean irritation index for edema was 0.8 of max. 4 (0.3 -1.0). Signs were fully reversible in all animals within two weeks. The weight of these evidences indicates that the test substance may be considered as "slightly irritating to the skin". No relevant systemic intolerance reactions were observed.

Based on the test results, GHS criteria for classification are not met. However, 2,2’-MDI is harmonized classified in the European Union with H315 CLP Annex VI Regulation (EC) No 1272/2008 (CLP regulation).