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Diss Factsheets

Administrative data

Description of key information

Skin Irritation:

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.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.

Eye Irritation:

30 minutes of exposure to 2,6- Toluene diisocyanate caused severe conjunctival irritation to eyes.

Hence 2,6- Toluene diisocyanate was evaluated as irritating to human eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
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
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
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.
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
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.

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.

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

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: data is from safety assessment reports
Qualifier:
equivalent or similar to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
To determine the threshold value for the irritation in humans when exposed to 2,6- Toluene diisocyanate for short duration.
GLP compliance:
not specified
Species:
human
Strain:
not specified
Details on test animals or tissues and environmental conditions:
no data
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.05 – 0.2 ml/m3 of 2,6-Toluenediisocyanate vapours
Duration of treatment / exposure:
30 minutes
Observation period (in vivo):
no data
Number of animals or in vitro replicates:
no data
Details on study design:
no data
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 30 minutes
Remarks on result:
other: Severe conjunctival Irritation was observed
Irritant / corrosive response data:
30 minutes of exposure to 2,6- Toluene diisocyanate caused severe conjunctival irritation to eyes.

Table 1:Effects of experimental exposure of persons to defined constant concentrations of TDI

Concentration (ml/m3)

TDI

Exposure duration (in minutes)

Symptoms

0.05

2,6 –TDI

30

Odour and eye irritation was observed

0.08 

2,6 – TDI

30

Slight conjunctival irritation, prickling in the nose

0.1

2,6 –TDI

30

Severe irritation of the eyes and nose

0.2

2,6- TDI

30

Severe irritation of the eyes and nose.

 where TDI - Toluene diisocyanate

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A study was conducted to determine the threshold value for the irritation in humans when exposed to 2,6- Toluene diisocyanate for short duration.
30 minutes of exposure to 2,6- Toluene diisocyanate caused severe conjunctival irritation to eyes.
Hence 2 ,6- Toluene diisocyanate was evaluated as irritating to human eyes.
Executive summary:

A study was conducted to determine the threshold value for the irritation in humans when exposed to 2,6- Toluene diisocyanate for short duration.

Human volunteers were exposed to 0.05 – 0.2 ml/m3 vapours of 2,6- Toluene diisocyanate for 30 minutes. It was seen that the irritation potential of 2,6 -Toluene diisocyanate increased gradually with the increase in concentration of the test chemical.30 minutes of exposure to 2, 6- Toluene diisocyanate caused severe conjunctival irritation to eyes.

Hence 2,6- Toluene diisocyanate was evaluated as irritating to human eyes.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation:

Various studies for target as well as its read across were summarized as follows:

The skin irritation study (Toxicology Letters; 199 (2010) 364–371) for 2,6-Toluenediisocyanate was conducted in male 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.

Skin irritation study was carried out (HUMAN HEALTH TIER II ASSESSMENT FOR Toluene diisocyanates- INVENTORY MULTITIERED ASSESSMENT AND PRIORITISATION (IMAP) NICNAS- 2017) in rabbits for test chemical (91 -08 -7). The test sample was applied on unabraded rabbit skin for 4 hour exposure period and under semi-occlusion and the mean erythema and oedema was scored after 24, 28 and 72 hours. The effects were observed till 13 days to check for recovery.

 Since the rabbits produced erythema and oedema scores over the reading times were 2.66 and 1.55, the test chemical 2, 6-Toluene diisocyanate (CAS No: 91-08-7) was considered as irritating to rabbit skin.

The skin irritation study for the similar substance 584-84-9 (2,4-Toluene diisocyanate)was conducted (Toxicology Letters; 199 (2010) 364–371)in male 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, 4-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, 4-TDI were sacrificed. Without prior washing treated and untreated skin (control) was excised and processed for histo-pathological examination. Two groups of 3 animals dosed with 2, 4-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, 4-Toluene diisocyanate (CAS No: 584-84-9) was considered as irritant to the skin of rats.

Based on the available studies for the target as well as its isomer (read across substance), 2,6- Toluene diisocyanate can be considered as skin irritant.

 

Eye Irritation:

Various studies were summarized in The MAK Collection for Occupational Health and Safety. 292–338, 2012 to assess the ocular irritation of 2,6- Toluene diisocyanate in humans.

A study was conducted to determine the threshold value for the irritation in humans when exposed to 2,6- Toluene diisocyanate for short duration.

Human volunteers were exposed to 0.05 – 0.2 ml/m3 vapours of 2,6- Toluene diisocyanate for 30 minutes. It was seen that the irritation potential of 2,6 -Toluene diisocyanate increased gradually with the increase in concentration of the test chemical. 30 minutes of exposure to 2, 6- Toluene diisocyanate caused severe conjunctival irritation to eyes.

Hence 2,6- Toluene diisocyanate was evaluated as irritating to human eyes.

Various studies were summarized in GESTIS, 2016 to evaluate the irritation potential of 2,6-Toluene diisiocyanate in humans and rabbits.

The eye irritation potential of 2,6 -Toluene diisocyanate was assessed in humans. Concentration of vapours of 2,6 –Toluene diisocyanate approx. 50 ppb and upwards caused subjective and objective eye irritation in humans.

Hence 2,6- Toluene diisocyanate was considered severely irritating to human eyes.

In an another eye irritation study was conducted in rabbit according to OECD 405 to assess the irritation tendency of 2,6- Toluene diisocyanate. A one-hour semi-occlusive application of 2,6- Toluene diisocyanate to rabbit eyes (according to OECD directive 405) caused chemical burns with a considerably delayed healing tendency.

Necroses with subsequent corrosion scabs accompanied by granuloma formation could be evidenced after 24-hour contact with eyes. Hence 2,6- Toluene diisocyanate was considered severely irritating to rabbit eyes.

In an another eye irritation potential of 2,6 -Toluene diisocyanate was assessed in rabbits.50- 100 µl of 2,6- Toluene diisocyanate was instilled into rabbit eyes and effects were observed. 2,6 – Toluene diisocyanate caused extreme irritation and, within a period of 30 days, irreversible effects on rabbit eyes were observed.

Hence 2,6- Toluene diisocyanate was considered severely irritating to human eyes.

Based on the available studies for target substance and applying the weight of evidence approach, 2,6-Toluene diisocyanate can be considered as irritating to eyes.

Justification for selection of skin irritation / corrosion endpoint:

data is from peer reviewed journals having Klimisch rating 2

Justification for selection of eye irritation endpoint:

data is from peer reviewed journals having Klimisch rating 2

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Available data for 2,6-Toluene diisocyanate indicate that it is likely to cause irritation to skin and eyes.

Hence, 2,6- Toluene diisocyanate can be evaluated as an “Irritant” to eyes and skin.