1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 Jan 2010-10 Feb 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

EC Number:

701-173-1

Molecular formula:

C14 H10 NO (C15 H12 N2 O2 R)n NCO where R = C4 H8 O2 and C4 H8 O3 and C3 H6 O2, n=0-2

IUPAC Name:

1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol

Details on test material:

Test Article 3
Identification of
Product Formulation:Suprasec 2015 (Suprasec 2015 PPF)
Lot/Batch No.: RZBX 354
Physical Description:Light yellow viscous liquid
Composition/Purity: 4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with butane- 1,3-diol, 2,4'-diisocyanatodiphenylmethane, 2,2'-oxydiethanol and propane-1,2-diol
Stability: The test substance was expected to be stable under standard laboratory conditions, under nitrogen blanket for the duration of testing.
Storage Conditions:Room temperature (10-30°C), under nitrogen

Dose Preparation
Suprasec 2015 were heated in a hot water bath at 75°C for 30 minutes to achieve liquid states. All three were then described as clear yellow liquids.

Formulated Test Article Analysis
The test articles were dosed as received and therefore no sample analysis were performed.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Total 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.

IN-LIFE DATES: From: 27 Jan 2010 To: 10 Feb 2010

Test system

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

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:

4 hours

Observation period:

14 days

Number of animals:

Three

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.

Test Article----------pH meter----------pH (litmus) paper
Test article 1-----------4.75--------------5
Test article 2-----------5.88--------------5
MDI/PD/DEG/PG-----------6.02--------------5
Test article 4-----------5.55--------------5
Test article 5-----------6.35--------------5

Within 24 hours before initiation of the test, fur was removed from the dorsal trunk of each animal by clipping. Care was taken to avoid abrading the skin. Only animals with healthy intact skin were used.

Each test article was applied to an area (~5cm x 5cm) on the dorsal trunk of each animal and covered with a gauze patch. In the case of liquids or some pastes, it may be necessary to apply the test article to the gauze patch and then apply that to the skin. Each patch was loosely held in contact with the skin with a sheet of rubber dam. The trunk of the animal was wrapped with an elastic bandage dressing, which was held in place with non-irritating tape for a four-hour exposure period. At the end of the exposure period, residual test article was removed using corn oil, without altering the existing response or the integrity of the epidermis. The corn oil was placed on the gauze, saturated and allowed to soak into the skin for ~15 minutes or until the gauze could easily be removed before being wiped with gauze. The degree of erythema and edema was evaluated at each site according to the Draize. Photographs were taken of the sites at every observation period for each animal.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 0 - <= 2

Max. score:

2

Remarks on result:

other: Severe erythema and severe edema, sloughing, flaking and fissuring of the skin observed

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

1

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

1

Results 4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

>= 0 - <= 2

Max. score:

2

Results 5

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 6

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritant / corrosive response data:

Dermal Irritation and Corrosivity:

The following is a summary of the most severe dermal responses observed:

Test Article-------------Dermal Responses----------------------------------Comments
Test article 1---Severe erythema and severe edema-------------------Necrosis, sloughing, flaking and fissuring of the skin observed
Test article 2---Severe erythema and severe edema-------------------Necrosis, sloughing, flaking and fissuring of the skin observed
Test article 3---Severe erythema and severe edema--------------------Sloughing, flaking and fissuring of the skin observed
Test article 4---Moderate to severe erythema and moderate edema----Sloughing and flaking of the skin observed
Test article 5---Moderate to severe erythema and moderate edema---Flaking of the skin observed

Other effects:

No mortality was observed during the study. No clinical signs were recorded during the course of the study.

Body weight data are presented in the table below:

Body Weights (kg)
Animal No.----------Sex---------Initial-------Final
2707---------------M-----------2.5---------2.7
2708---------------M-----------2.5---------2.9
2709---------------F------------2.3--------2.5

Any other information on results incl. tables

Table 1: Dermal Observations/Post Treatment (Site 3 - Test article 3: 44MDI/14BD/DEG/PG)

	30-60 minutes post-dose					24 hours (Day 2)
Rabbit No	Erythema	Edema	Necrosis	Fissuring	Sloughing	Erythema	Edema	Necrosis	Fissuring	Sloughing
2707M	1	2	-	-	-	1	0	-	-	-
2708M	1	1	-	-	-	1	0	-	-	-
2709F	1	0	-	-	-	1	0	-	-	-
	48 hours (Day 3)					72 hours (Day 4)
2707M	1	0	-	-	-	2	2	-	-	-
2708M	0	0	-	-	-	1	0	-	-	-
2709F	1	0	-	-	-	1	0	-	-	-
	Day 5					Day 6
2707M	3	2	-	-	-	3	2	-	-	-
2708M	2	1	-	-	-	2	1	-	-	-
2709F	1	0	-	-	-	2FL	1	-	-	-
	Day 7					Day 8
2707M	3	3	-	-	-	4FL	4	-	+	-
2708M	2	2	-	-	-	3FL	3	-	-	-
2709F	2FL	2	-	-	-	3FL	3	-	-	-
	Day 9					Day 10
2707M	4FL	4	-	+	-	4FL	4	-	+	-
2708M	4FL	4	-	-	-	4FL	4	-	-	-
2709F	3FL	3	-	-	-	3FL	3	-	-	-
	Day 11					Day 12
2707M	4FL	4	-	-	+	4FL	4	-	-	+
2708M	4FL	4	-	-	+	4FL	4	-	-	+
2709F	4FL	4	-	-	-	4FL	4	-	-	-
	Day 13					Day 14
2707M	3FL	2	-	-	+	3FL	2	-	-	+
2708M	3FL	3	-	-	-	3FL	2	-	-	-
2709F	3FL	3	-	-	-	3FL	2	-	-	-

- = Not observed

+ = Observed

FL = Flaking

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Based on the results of this Comparative Primary Dermal Irritation Study in Rabbits, the following are the classifications of the test articles when applied for four hours to the skin of rabbits and removed according to the methodology utilized in this assay ;

Test Article -----------EEC Irritation Rating------GHS Classification-------Corrosivity
TA1 ------Corrosive---------------Category 1 C------------Corrosive
TA 2 -------Corrosive---------------Category 1 C------------Corrosive
TA 3 (MDI/1,4BD/DEG/PG) -------Irritant-------------------Irritant-Category 2------Non – Corrosive
TA 4 ------Irritant-------------------Irritant – Category 2-----Non – Corrosive
TA 5 -------Irritant-------------------Irritant – Category 2-----Non – Corrosive

Executive summary:

The purpose of this study was to determine and compare the potential irritant and/or corrosive effects of five test articles on the skin of rabbits when the materials were removed in a prescribed method to insure that removal had no effect on the integrity of the skin sites.

The test articles were initially applied to five sites on the clipped dorsal trunk of three New Zealand White rabbit for a four-hour exposure period at 0.5 mL per site. As per design of this comparative assay, the patches were saturated with corn oil for a minimum of 15 minutes prior to removal in order to reduce / eliminate the possibility of mechanical damage to the skin. Observations for dermal irritation were recorded for the rabbits 30-60 minutes after patch removal, and then 24, 48 and 72 hours (±1 hour) and daily through Day 14. Grading of irritation was according to the method of Draize. Photographs were taken of the sites at every observation period for each animal.

The following is a summary of the most severe dermal responses observed:

Test Article	Dermal Responses	Comments
Test article 1	Severe erythema and severe edema	Necrosis, sloughing, flaking and fissuring of the skin observed
Test article 2	Severe erythema and severe edema	Necrosis, sloughing, flaking and fissuring of the skin observed
MDI/1,4BD/DEG/PG	Severe erythema and severe edema	Sloughing, flaking and fissuring of the skin observed
Test article 4	Moderate to severe erythema and moderate edema	Sloughing and flaking of the skin observed
Test article 5	Moderate to severe erythema and moderate edema	Flaking of the skin observed

Based on the results of this Comparative Primary Dermal Irritation Study in Rabbits, 4,4 -MDI/1,4BD/DEG/PG is classified as an Irritant Category 2.