4,4'-Methylenediphenyl diisocyanate, oligomers

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-Methylenediphenyl diisocyanate, oligomers

EC Number:

500-040-3

EC Name:

4,4'-Methylenediphenyl diisocyanate, oligomers

Cas Number:

25686-28-6

Molecular formula:

C14 H10 N O [C29 H20 N4 O2]n NCO, n= 0-2

IUPAC Name:

1,1'-methylenebis(4-isocyanatobenzene) homopolymer

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

ThTotal Number: Three
Gender:Male and Female
Age Range:12 weeks at start of dosing; records of dates of birth for animals used in this study are retained in the Calvert archives.
Body Weight Range:2.3 to 2.5 kilograms at the outset (Day 1) of the study.
Animal Source:Harlan, Oxford, MI
Experimental History:Purpose-bred and experimentally naïve at the outset of the study.
Identification:Ear tag and cage card
Housing:Animals were individually housed in compliance with USDA Guidelines. The room in which the animals were kept was documented in the study records. No other species were kept in the same room.
Lighting:12 hours light/12 hours dark
Room Temperature:18 to 22°C
Relative Humidity:14 to 62%
Food:All animals had access to PMI Certified Hi-Fiber Rabbit Diet as per Calvert SOP. The lot number(s) and specifications of each lot used are archived at Calvert. No contaminants were known to be present in the certified diet at levels that would be expected to interfere with the results of this study. Analysis of the diet was limited to that performed by the manufacturer, records of which are maintained in the Calvert archives.
Water:Tap water was available ad libitum, to each animal via an automatic watering device. The water is routinely analyzed for contaminants as per Calvert SOP’s. No contaminants were known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis are maintained in the Calvert archives.
Acclimation:Study animals were acclimated to their housing for a minimum of 5 days prior to dosing.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

A dose of 0.5 ml of the liquid test article was applied to each of the test sites. The test article was applied directly on the intact skin sites. Five sites per rabbit (one for each test article) were utilized.

Duration of treatment / exposure:

4hr

Observation period:

14days

Number of animals:

3

Details on study design:

The pH of the article was determined by the testing facility prior to experimental start (pH meter) and after in-life termination (litmus paper). The methods of pH determinations were pH Testr 3+ Oakion and pH (litmus) paper.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not fully reversible within: 14 days

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

2

Reversibility:

not fully reversible within: 14 days

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

2

Reversibility:

not fully reversible within: 14 days

Results 4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 2 - <= 3

Max. score:

3

Reversibility:

not fully reversible within: 14 days

Results 5

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not fully reversible within: 14 days

Results 6

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

not fully reversible within: 14 days

Irritant / corrosive response data:

Not corrosive

Any other information on results incl. tables

	30-60 minutes post-dose					24 hours (Day 2)
Rabbit No	Erythema	Edema	Necrosis	Fissuring	Sloughing	Erythema	Edema	Necrosis	Fissuring	Sloughing
2526F	0	0	-	-	-	2	2	-	-	-
2527F	0	1	-	-	-	2	1	-	-	-
2528F	1	1	-	-	-	1	0	-	-	-
	48 hours (Day 3)					72 hours (Day 4)
2526F	2	3	-	-	-	3	3	-	-	-
2527F	2	3	-	-	-	2	3	-	-	-
2528F	2	3	-	-	-	2	3	-	-	-
	Day 5					Day 6
2526F	3	3	-	-	-	3	3	-	-	-
2527F	2	3	-	-	-	3	3	-	-	-
2528F	3	2	-	-	-	3	2	-	-	-
	Day 7					Day 8
2526F	3	3	-	-	-	3	3	-	-	-
2527F	2	2	-	-	-	2	2	-	-	-
2528F	3	2	-	-	-	2	2	-	-	-
	Day 9					Day 10
2526F	3	2	-	-	-	3	2	-	-	-
2527F	2	2	-	-	-	2	1	-	-	-
2528F	2	2	-	-	-	2	2	-	-	-
	Day 11					Day 12
2526F	3	2	-	-	-	2	2	-	-	-
2527F	2	1	-	-	-	2	1	-	-	-
2528F	2	1	-	-	-	2	1	-	-	-
	Day 13					Day 14
2526F	2	2	-	-	-	2	2	-	-	-
2527F	1	1	-	-	-	1	0	-	-	-
2528F	1	1	-	-	+	1	1	-	-	+

- = Not observed

+ = Observed

FL = Flaking

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

The test material was found to be non corrosive although irritating to the skin of rabbits according to the EEC Irritation Rating and the GHS Classification was irritating (category 2).

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).