1,1'-Methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with [(methylethylene)bis(oxy)]dipropanol

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: Meets generally accepted scientific standards; sufficiently documented and acceptable for assessment.

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:

1977

Report date:

1977

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

0.5 ml of undiluted compound was applied to the clipped, intact abd abraded skin of six albino male and female rabbits under a one inch by one inch square patch, two single layers thick. The patches were held in place with adhesive tape. The trunk of each animal was wrapped with plastic strips, to retard evaporation and avoid contamination, for the 24-hr exposure period. Observations were made over a period of seven days. 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

Test material information

Constituent 1

Reference substance name:

75880-28-3

Cas Number:

75880-28-3

IUPAC Name:

75880-28-3

Test animals

Species:

rabbit

Strain:

other: albino

Details on test animals or test system and environmental conditions:

no data

Test system

Type of coverage:

occlusive

Preparation of test site:

other: shaved (intact) and abraded

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

Amount(s) applied: 0.5 ml/animal

Duration of treatment / exposure:

24 hours

Observation period:

1, 24, 48, 72 hours and 5, 7 days after removal of patches

Number of animals:

intact skin: 3 males and 3 femals,
abraded skin: 3 males and 3 femals

Details on study design:

see "Principles of method"

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

other: erythema score (intact skin)

Basis:

animal: #1, 2, 3, 4, 5, 6

Time point:

other: 24, 48, 72 hours

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 24, 48 and 72 hours: 2.0

Results 2

Irritation parameter:

other: edema score (intact skin)

Basis:

animal: #1, 2, 3, 4, 5, 6

Time point:

other: 24, 48, 72 hours

Score:

1 - 2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 24, 48 and 72 hours: 1.1

Results 3

Irritation parameter:

other: erythema score (abraded skin)

Basis:

animal: #1, 2, 3, 4, 5, 6

Time point:

other: 24, 48, 72 hours

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 24, 48 and 72 hours: 2.0

Results 4

Irritation parameter:

other: edema score (abraded skin)

Basis:

animal: #1, 2, 3, 4, 5, 6

Time point:

other: 24, 48, 72 hours

Score:

1 - 2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: mean score after 24, 48 and 72 hours: 1.4

Irritant / corrosive response data:

Observations following application (intact and abraded skin):
1 hour: no erythema or edema (zero readings)
24 hours: slight erythema, very slight to slight edema
48-120 hours: gradual improvement
168 hours: all scored zero

Other effects:

none

Any other information on results incl. tables

The author specified a Primary Irritation Score (together for erythema and edema, intact and abraded skin, 24 and 72 hour readings) of 3.1. Note: The term 'primary irritant' is given to a substance which produced an empirical score ( Primary Irritation Score) of 5 or more when tested by the method described.

Applicant's summary and conclusion

Interpretation of results:

other: slightly irritating

Conclusions:

The test substance 4,4'-MDI/TPG was slightly irritating when tested on male and female rabbits. 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 skin irritant category 2 (H315) 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 irritating when tested on male and female rabbits under occlusive conditions. 24 hours after application slight erythema and very slight to slight edema were observed. All effects were 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 skin irritant category 2 (H315) for 4,4’-MDI is adopted for all category substances, including the substance 4,4’-MDI-TPG.