2-methyl-m-phenylene 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: Data is from peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Dermal uptake and excretion of 14C-toluene diisocyante (TDI) and 14C-methylene diphenyl diisocyanate (MDI) in male rats. Clinical signs and histopathology following dermal exposure of male rats to TDI

Author:

H.D. Hoffmanna, E. Leiboldb, C. Ehnesb, E. Fabiana, R. Landsiedela, A.Gamera, A. Poolec

Year:

1999

Bibliographic source:

Toxicology Letters 199 (2010) 364–371

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as per mentioned below

Principles of method if other than guideline:

To evaluate the skin irritation effect of Toluene Diisocyanate in male Crl:WI (HAN) rats.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2, 4Toluene diisocyanate

IUPAC Name:

2, 4Toluene diisocyanate

Constituent 2

Reference substance name:

2-methyl-m-phenylene diisocyanate

EC Number:

202-039-0

EC Name:

2-methyl-m-phenylene diisocyanate

Cas Number:

91-08-7

Molecular formula:

C9H6N2O2

IUPAC Name:

1,3-diisocyanato-2-methylbenzene

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): 2,6-Toluene diisocyanate
- Molecular formula: C9H6N2O2
- Molecular weight: 174.1584 g/mol
- Smiles notation: c1(cccc(c1C)N=C=O)N=C=O
- InChl: 1S/C9H6N2O2/c1-7-8(10-5-12)3-2-4-9(7)11-6-13/h2-4H,1H3
- Substance type: Organic
- Physical state: Liquid

Test animals

Species:

rat

Strain:

other: Crl:WI (HAN)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Germany.
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: 300 to 350 g
- Fasting period before study: No data available
- Housing: They were housed individually,
in Macrolon cages or all glass metabolism cages
- Diet (e.g. ad libitum): Feed was Kliba lab diet was available for consumption ad libitum Water (e.g. ad libitum): Tap water was available for ad libitum
- Acclimation period: No data available.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

other: 24hours before dermal administration of the test material an area on the back of the animals was clipped free of hair (about 10 cm2) and washed with acetone.

Vehicle:

not specified

Controls:

other: Untreated skin areas of each animal served as control

Amount / concentration applied:

Preparation of test site (only for skin irritation):
24hours before dermal administration of the test material an area on the back of the animals was clipped free of hair (about 10 cm2) and washed with acetone. Prior to application a silicone ring spacer (2mm×34mm;
thickness×diameter) was glued on the skin (Histoacryl®; B. Braun, Germany). Test
material preparations were applied on the surface of the application site using a pipette
. Nylon mesh gauze was then glued on the surface of the silicone ring and a porous bandage was used to encircle the trunk of the animal.

Amount/concentration applied: 350 mg/kg

Duration of treatment / exposure:

8hour

Observation period:

48Hour

Number of animals:

6 male rats

Details on study design:

Details on study design
TEST SITE
- Area of exposure: The back of the animals.
- % coverage: 10 cm2
- Type of wrap if used: Nylon mesh gauze

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 8 hour

SCORING SYSTEM: Draize Method

Results and discussion

In vivo

Results

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 48

Max. score:

5

Reversibility:

no data

Remarks on result:

other: The local skin changes observed during visual assessment of skin reaction were irritation with prominent skin oedema and an increase in severity of signs during the post exposure period of two days

Irritant / corrosive response data:

The clinical observation of progressive irritation was verified by the histopathological changes which showed minimal to slight effects at 8 h which became more severe 48 h after treatment.

Other effects:

Due to the fact that dead animals in general do not show dermal erythema or dermal oedema no skin macroscopic changes were observed during necropsy. Histopathological examination of samples of skin from 6 non treated animals as control for the dermal exposure with 2,6 TDI revealed minimal focal serocellular crusts in 2 samples and in one sample a focally extensive sub- and intraepidermal and perifollicular micro abscesses with necroses.

Any other information on results incl. tables

TABLE 1:The assessment of skin reactions according to Draize and definition of gradings used for histopathology
Grading	Erythema	Oedema	Histopathology
0	No erythema	No oedema	-
1	Very slight; barely perceptible	Very slight; barely perceptible	Minimal
2	Well defined	Slight; edges well defined by raising	slight
3	Moderate to severe	Moderate raised approximately 1mm	Moderate
4	Severe (beet redness) eschar formation preventing grading of E	Severe raised more than 1 mm; extending beyond area of exposure	Marked, severe
5	-	-	Massive. extreme

 

Table 2 Clinical skin findings and histopathological findings following treatment with 2, 6 TDI at a dose level of about 350 mg/kg body weight; 12mg/cm2.
	Exposure time (dermal) 8 h (2,6 TDI)
Clinical observation (hours after start of exposure	8	24	48
Number of animals clinical observation	6	3	3
Number of animals sacrificed + histopathology	3	-	3
Clinical findings
Erythrema (number of animals/grading)	6/none	2/none 1/1	1/1 2/2
Oedema (number of animals/grading)	1/12/23/3	2/1 1/2	1/1 2/2
Dryness of skin (number of animals)	6	3	3
Intensified sensitivity to touch at application site (number of animals)	None	None	3
Histopathological findings Minimal to slight multifocal to coalescing subepidermal edema//minimal to slight multifocal hydropic degeneration of basal cell layer with cleft formation//slight diffuse spongiosis//multifocal full thickness necrosis of epidermis//minimal diffuse and perivascular lymphoplasmacytic infiltration//foreign material (yellow-brownish) with keratin scales (number of animals/grading)
	1/1-2 2/2	-	-
Multifocal serocellular crusts//moderate to severe multifocal to coalescing epidermal full thickness necrosis with sub- and intraepidermal as well as follicular and perifollicular micro-abscesses, exocytosis and numerous degenerated neutrophilic granulocytes with erosion and ulceration//slight to moderate perivascular lymphoplasma-histiocytic and neutrophilic infiltration//Slight to moderate diffuse spongiosis, acanthosis and hydropic degeneration of basal cell layer (number of animals/grading)	-	-	1/2-3 1/3 1/3-4
Note: No macropathologic abnormalities of the treated skin were observed in the dead animals prior to skin sampling for histopathology.

Applicant's summary and conclusion

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test chemical 2, 6-Toluene diisocyanate (CAS No: 91-08-7) was considered to be an irritant in male Crl: WI (HAN) rats.

Executive summary:

The skin irritation study for 2,6Toluenediisocyanate was conducted inmale Crl: WI (HAN) rats for observation period of 48 hour period.

 

For this experiment 4 groups of 3 animals were treated with test chemical on clipped area on the back of the animals which was carefully checked for pre-existing signs of skin irritation or dense patches of hair. Only animals with intact healthy skin were used. From the selected animals 6 were dosed with pure liquid 2,6-TDI (nominal 350 mg/kg body weight; 12mg/cm2) and placed in Macrolon cages (single caging). After the exposure period of 8 h the protective cover was removed from all animals and the treated skin was examined clinically. Afterwards 3 animals dosed with 2, 6-TDI were sacrificed. Without prior washing treated and untreated skin (control) was excised and processed for histopathological examination. Two groups of 3 animals dosed with 2,6-TDI were kept for further clinical observation. After washing of the exposed skin with Lutrol E 400. These animals were kept in Macrolon cages (single housing) until sacrifice about 48 h post exposure. Subsequently treated and untreated skin (control) was excised and processed for histopathological examination.Grading of skin reactions used according to Draize and grading used for histopathology show that the chemical is slightly irritant to skin.

 

At 8 h the findings were characterized by minimal to slight multifocal to coalescing subepidermal oedema, minimal to slight multifocal hydropic degeneration of basal cell layer, slight diffuse spongiosis and multifocal full thickness necrosis of epidermis. At 48 h the effects were more severe with findings of multifocal serocellular crusts, moderate to severe multifocal to coalescing epidermal full thickness necrosis with sub- and intra-epidermal as well as follicular and perifollicular micro-abscesses, exocytosis and numerous degenerated neutrophilic granulocytes with erosion, slight to moderate perivascular lymphoplasma-histiocytic and neutrophilic infiltration, slight to moderate diffuse spongiosis, acanthosis and hydropic degeneration of basal cell layer. No mortality and no signs of systemic toxicity occurred in any animal during the observation periods up to 48 h

 

On the basis of observed skin effects, the test material 2, 6-Toluene diisocyanate (CAS No: 91-08-7) was considered as irritant to the skin of rats