Tris(p-isocyanatophenyl) thiophosphate

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. 4-5 weeeks
- Weight at study initiation: 275-371 g
- Diet and water: ad libitum
- Acclimation period: at least 5 days

Route:

epicutaneous, occlusive

Vehicle:

other: methyl ethyl ketone (MEK)

Concentration / amount:

1st to 3rd induction: 100% test substance (undiluted)
1st challenge: 50% test substance (in MEK)
2nd challenge: 25% (in MEK)

Route:

epicutaneous, occlusive

Vehicle:

other: methyl ethyl ketone (MEK)

Concentration / amount:

1st to 3rd induction: 100% test substance (undiluted)
1st challenge: 50% test substance (in MEK)
2nd challenge: 25% (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. No signs of irritation occured.
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%, 25%, 50% and 100% of 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
- First 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.
- Second challenge: the second challenge was performed one week after the 1st challenge with 0.5 ml of a 25% test item formulation in MEK in the same way with the exception that the left flank of the animals were shorn and the patches were applied to the left flank.
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

Remarks:

Reliability check of Buehler test with alpha-hexylcinnamicaldehyde revealed a sensitization rate of 100% (test substance concentration 40% for induction and 20% for challenge).

Reading:

other: first challenge

Hours after challenge:

24

Group:

test chemical

Dose level:

50%

No. with + reactions:

6

Total no. in group:

17

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50%. No with. + reactions: 6.0. Total no. in groups: 17.0.

Reading:

other: first challenge

Hours after challenge:

24

Group:

negative control

Dose level:

50%

No. with + reactions:

7

Total no. in group:

10

Remarks on result:

other: Reading: other: first challenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 50%. No with. + reactions: 7.0. Total no. in groups: 10.0.

Reading:

other: second challenge

Hours after challenge:

24

Group:

test chemical

Dose level:

25%

No. with + reactions:

0

Total no. in group:

17

Remarks on result:

other: Reading: other: second challenge. . Hours after challenge: 24.0. Group: test group. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 17.0.

Reading:

other: second challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

25%

No. with + reactions:

0

Total no. in group:

17

Remarks on result:

other: Reading: other: second challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 17.0.

Reading:

other: second challenge

Hours after challenge:

24

Group:

negative control

Dose level:

25%

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: other: second challenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 10.0.

The animals in the test item group and in the control group showed no clinical signs of toxicity. Three animals of the test item group died (two on day 11 and one on day 12).

Interpretation of results:

not sensitising

Remarks:

Migrated information

Executive summary:

A skin sensitization test according to OECD guideline 406 (Buehler Patch Test) was conducted on female guinea pigs with the neat test substance (27% of tris(p-isocyanatophenyl) thiophosphate in ethyl acetate) for dermal induction. For challenge test concentrations of 50% (1st challenge) and 25% (2nd challenge) formulated in methyl ethyl ketone were applied. 24 and 48 hours after challenge exposure the treated sites were assessed. The first challenge let to skin effects (grade 1) in 6 of 17 animals (35%) in the test item group and in 7 of 10 animals (70%) of the control group. The second challenge with 25% test item did not induce skin effects at all. Under the conditions tested the test item exhibits no skin sensitization potential.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Tris(p-isocyanatophenyl) thiophosphate is marketed and handled as solution in ethyl acetate containing approximately 27% of tris(p-isocyanatophenyl) thiophosphate. Removal of the solvent from a solution of 27% of tris(p-isocyanatophenyl) thiophosphate in ethyl acetate does invariably lead to generation of higher molecular weight species. This is due to the inherent reactivity of the isocyanate moieties and the process can thus be monitored via the decrease of the isocyanate content (see IUCLID section 1.4: analytical material balances before/after solvent removal). Therefore, a solution of 27% of tris(p-isocyanatophenyl) thiophosphate in ethyl acetate was employed as test substance for all toxicological tests as this was believed to best represent the substance to be registered.

Skin sensitisation

A skin sensitization test according to OECD guideline 406 (Buehler Patch Test) was conducted on female guinea pigs with the neat Desmodur RFE (27% of tris(p-isocyanatophenyl) thiophosphate in ethyl acetate) for dermal induction. In the test item group slight skin irritation (grade 1) was observed after induction. For challenge test concentrations of 50% (1st challenge) and 25% (2nd challenge) formulated in methyl ethyl ketone were applied. 24 and 48 hours after challenge exposure the treated sites were assessed. The first challenge let to skin effects (grade 1) in 6 of 17 animals (35%) in the test item group and in 7 of 10 animals (70%) of the control group. The second challenge with 25% test item did not induce skin effects at all. Under the conditions tested the test item exhibits no skin sensitization potential.

Migrated from Short description of key information:
The test item did not show skin sensitizing effects in the Guinea pig Buehler Patch Test.

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

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Although the substance is a triisocyanate and as such the molecular structure shows free N=C=O groups, it does not show the typical (local) reactivity of monomeric isocyanates in toxicological tests, which can be described as moderate to strong skin, eye and respiratory tract irritation, and sensitization. Rather, the substance in ethyl acetate was shown to be only slightly irritating to the skin and not irritating to the eyes of rabbits. It also did not exhibit sensitizing effects to the skin of Guinea pigs. A 4 week inhalation toxicity study in rats did not reveal robust evidence of pulmonary irritation and injury, rather changes suggestive of increased accumulation of polymeric material engulfed by alveolar macrophages were observed which appear to follow a particle-overload-like phenomenon. Overall, no isocyanate-typical toxicological effect and no skin sensitization was induced by the substance and thus, hypersensitivity of the respiratory tract cannot be expected.

Justification for classification or non-classification

According to EU Regulation 1272/2008 no classification is required with regard to sensitization.