Methylidynetri-p-phenylene triisocyanate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

(1992)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

Buehler test

Species:

guinea pig

Strain:

other: Crl:HA

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratory, Kißlegg, Germany
- Age at study initiation: approx. 3-4 weeeks
- Weight at study initiation: 268-344 g
- Diet and water: ad libitum
- Acclimation period: at least 7 days

Route:

epicutaneous, occlusive

Vehicle:

other: methyl ethyl ketone (MEK); dried with a molecular sieve

Concentration / amount:

1st to 3rd induction: 100% test substance (undiluted
Challenge: 50% test substance (in MEK)

Route:

epicutaneous, occlusive

Vehicle:

other: methyl ethyl ketone (MEK); dried with a molecular sieve

Concentration / amount:

1st to 3rd induction: 100% test substance (undiluted
Challenge: 50% test substance (in MEK)

No. of animals per dose:

experimental group: 20
control group: 10

Details on study design:

RANGE FINDING TESTS:
Range finding tests for induction were performed using 5 females.
- for induction: 0.5 ml of 0%, 25%, 50% and 100% of the test item in MEK were applied occlusively to the skin for 6 hours. 30 hours and 54 hours after the start of the application 3/5 and 2/5 animals showed skin reactions (grade 1).
Range finding tests for challenge were performed using 2 animals which were treated in the same manner als the control animals during induction.
- for challenge: 0.5 ml of 0%, 12%, 25% and 50% the test item in MEK were applied occlusively to the skin for 6 hours. No signs of irritation occured.

MAIN STUDY
A. INDUCTION EXPOSURE
- the animals were treated with the test item three times at intervals of seven days. The suitable areas of the body were shaved one day (24 hours) before each treatment. The volume applied per animal was 0.5 m on a hypoallergic patch and held in place on the skin with 'ORABAND' adhesive plaster. Six hours after treatment the patches were removed and any remaining test item was washed off the skin with physiological saline solution. Treatment areas were vusally assessed 30 hours after initiation of exposure.


B. CHALLENGE EXPOSURE
- Challenge: the animals were treated with the test item four weeks after the first (two weeks after the last) dermal induction. Backs and right flanks were shaved one day (24 hours) before challenge. The test item (50% in MEK) applied per animal was 0.5 m on a hypoallergic patch and held in place on the right flank with 'ORABAND' adhesive plaster. Six hours after treatment the patches were removed and any remaining test item was washed off the skin with physiological saline solution. 24 hours later the treatment areas were shorn.
Skin reactions were assessed 30 hours after initiation of the induction exposures, and 30 and 54 hours after the beginning of the challenge.

OTHER:
In addition to the skin reactions the following data were recorded: Mortality/ Clinical signs once daily; Body weights prior to start , on day 30 and at termination of the study.

Challenge controls:

As a control a patch loaded only with the vehicle was applied and fixed also to the right flank, cranial to the test item patch.

Positive control substance(s):

yes

Positive control results:

Reliability check of Buehler test with alpha-hexylcinnamicaldehyde revealed a sensitization rate of 100% (test substance concentration 30% for induction and 20% for challenge in polyethylene glycol 400). In the control group 0% of the animals reacted.

Reading:

other: first challenge

Hours after challenge:

24

Group:

test chemical

Dose level:

50%

No. with + reactions:

4

Total no. in group:

20

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50%. No with. + reactions: 4.0. Total no. in groups: 20.0.

Reading:

other: first challenge

Hours after challenge:

24

Group:

negative control

Dose level:

none

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 24.0. Group: negative control. Dose level: none. No with. + reactions: 0.0. Total no. in groups: 10.0.

Reading:

other: first challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

12

Total no. in group:

20

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50%. No with. + reactions: 12.0. Total no. in groups: 20.0.

Reading:

other: first challenge

Hours after challenge:

48

Group:

negative control

Dose level:

50%

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0.

Appearance and behaviour of the test item group were not different from the control group. One animal of the control group (animal no. 1) showed following clinical signs: from day 11 - 24 : difficulty in breathing from day 13 to 15: piloerection, pale One animal of the test item group (animal no. 30) showed following clinical signs: from day 12 - 26: difficulty in breathing from day 13 to 24: piloerection, pale By the end of the study the mean body weight of the treatment group animals was in the same range than that of the control group

Executive summary:

A skin sensitization test according to OECD guideline 406 (Buehler Patch Test) was conducted on female guinea pigs with

Triphenylmethane-4,4',4''-triisocyanate (tested as a 27% solution in ethyl acetate)

The challenge with 50% test item formulation led to skin effects (grade 1 -2) in 12 of 20 animals (60%) in the test item group and to no skin effects in the control group. Under the conditions tested the test item exhibits a skin sensitization potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Triphenylmethane-4,4',4''-triisocyanate obtained in a solvent-based manufacturing process and is not isolated throughout the process. A solvent-freeTriphenylmethane-4,4',4''-triisocyanate is a solid which would significantly complicate the manufacturing process. Beyond that Triphenylmethane-4,4',4''-triisocyanate is not marketed as such but as a solution to facilitate handling of the substance by downstream users. A solution of 27% Triphenylmethane-4,4',4''-triisocyanate in ethyl acetate (w/w) represents the trade product for which a base set of toxicological information was already available. On the other hand, as displayed in IUCLID section 1.4, removal of the solvent from the trade product invariably leads to the formation of higher molecular weight species, due to the inherent reactivity of the isocyanate moieties. Further, analysis of the toxicity profile of the solvent in the trade product (= ethyl acetate: no skin sensitization) demonstrates that the available study with the trade product reflect the hazard of Triphenylmethane-4,4',4''-triisocyanate (= active ingredient in the trade product). In addition the results of the dose range-finding study for induction treatment showed that the requirement of the OECD TG, that the concentration of Triphenylmethane-4,4',4''-triisocyanate should be the highest to cause mild irritation, is fulfilled because 3/5 (30 hrs after the start of the application) and 2/5 (50 hrs after the start of the application) animals showed skin reactions when applying the trade product. In view of this and the need to consider animal welfare, no further testing was done for skin sensitization.

A skin sensitization test according to OECD guideline 406 (Buehler Patch Test) was conducted on female guinea pigs with

Triphenylmethane-4,4',4''-triisocyanate (tested as a 27% solution in ethyl acetate)

The challenge with 50% test item formulation led to skin effects (grade 1 -2) in 12 of 20 animals (60%) in the test item group and to no skin effects in the control group. Under the conditions tested the test item exhibits a skin sensitization potential.

Justification for selection of skin sensitisation endpoint:
Only one study available

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No validated animal model is available to assess the potential for respiratory sensitization or asthma in humans. Only one case report describes physiological abnormalities consistent with both asthma and alveolitis in a pulmonary function test of a male worker who had contact with various chemicals used in processing, one of which was later identified as triphenylmethane triisocyanate. However, due to the chemical structure with three isocyanate functional groups and the well known reactivity of diisocyanates, respiratory sensitization is likely to occur.

Justification for selection of respiratory sensitisation endpoint:
Only one case report describes physiological abnormalities in pulmonary function tests after occupational exposure which are consistent with both asthma and alveolitis.

Justification for classification or non-classification

Skin sensitisation

60% of the animals responding in a buehler assay at 27% topical induction dose of Triphenylmethane-4,4',4''-triisocyanate (= 100%

trade product).

According to EU-Directive 67/548/EEC, Annex VI Triphenylmethane-4,4',4''-triisocyanate shall be classified as sensitising.

According to Regulation (EC) No 286/2011 of 10 March 2011 amending Regulation (EC) No 1272/2008 Triphenylmethane-4,4',4''-triisocyanate shall be allocated to Sub-category 1B.

Respiratory sensitisation

A chemical structure related to substances (diisocyanates) known to cause respiratory hypersensitivity is given.

According to EU-Directive 67/548/EEC, Annex VI Triphenylmethane-4,4',4''-triisocyanate shall be classified as sensitising.

According toRegulation (EC) No 1272/2008 Triphenylmethane-4,4',4''-triisocyanate shall be allocated to Category 1.