HDI oligomers, uretdione

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)

GLP compliance:

yes (incl. QA statement)

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

Himalayan

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Strain: Himalayan strain, albino guinea pig (SPF)
- Source: BRL Ltd. Basel Switzerland
- Age at study initiation: approx. 6 weeeks
- Weight at study initiation: 268-400 g
- Housing: group housing of 2 animals per labelled metal cage with wire-floors
- Diet and water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 21°C
- Humidity (%): approx. 50%
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12

Route:

intradermal and epicutaneous

Vehicle:

other: corn oil for intradermal injections, acetone for epidermal applications

Concentration / amount:

intradermal induction: 5% test substance
epidermal induction: undiluted test substance
challenge: 50, 25, and 10% (w/w) test substance

Route:

epicutaneous, occlusive

Vehicle:

other: corn oil for intradermal injections, acetone for epidermal applications

Concentration / amount:

intradermal induction: 5% test substance
epidermal induction: undiluted test substance
challenge: 50, 25, and 10% (w/w) test substance

No. of animals per dose:

10 test animals/5 controls

Details on study design:

RANGE FINDING TESTS: Range finding tests were performed using 5 females.
- for intradermal induction: A %1 and 5% (w/w) test substance concentration in corn oil were injected into two sites (0.1 ml each).
- for epidermal induction: The undiluted test substance (0.5 ml) was applied epidermally on a shaved flank for 24 hours, using a non-woven patch (2.5 x 2.2. cm) and occlusive dressings.
- for challenge: Four concentrations of the test substance in acetone (100, 50, 25 and 10 % w/w, 0.05 ml each) were applied occlusively on a shaved flank of each of the four animals for 24 hours.

MAIN STUDY
A. INDUCTION EXPOSURE
- for intradermal induction: On Day 1 animals received three pairs of injections (0.1 ml/site), which are a) FCA/water 1/1, b) test substance 5% in vehicle, c) test substance 5% in FCA/vehicle 1/1
- for epidermal induction: On Day 7 the clipped area was rubbed with 10% sodium-dodecyl-sulfate in petrolateum using a spatula. On Day 8 the clipped area between the injection sites was treated with0.5 ml of the undiluted test substance using a Scotchpak-non-woven patch (2x4 cm) mouted on Micropore tape and secured with Coban elastic bandage. After 48 hours, the dressing was removed and residual test substance removed using a tissue moistened with tap water.

B. CHALLENGE EXPOSURE
- On Day 22 animals were treated epidermally with 0.05 ml of each of the following test substance concentrations 50, 25 and 10 % (w/w) in acetone on the clipped and shaved flank. For negative control solely vehicle was applied. After 24 hours, the dressing was removed and residual test substance removed using a tissue moisted with tap water.

OTHER:
In addition to the skin reactions the following data were recorded: Mortality/ Viability/ Toxicity twice daily; Body weights prior to start and at termination of the study.

Positive control substance(s):

yes

Remarks:

alpha-hexylcinnamicaldehyde

Positive control results:

The most recent control experiment with alpha-hexylcinnamicaldehyde, performed in July 1994, revealed a sensitization rate of 100% (test substance concentrations 10, 5, 2, 0%).

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50%. No with. + reactions: 9.0. Total no. in groups: 10.0.

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

25%

No. with + reactions:

7

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25%. No with. + reactions: 7.0. Total no. in groups: 10.0.

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

10%

No. with + reactions:

4

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 4.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

50%

No. with + reactions:

9

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 50%. No with. + reactions: 9.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

25%

No. with + reactions:

8

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 25%. No with. + reactions: 8.0. Total no. in groups: 10.0.

Reading:

2nd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

10%

No. with + reactions:

2

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 10%. No with. + reactions: 2.0. Total no. in groups: 10.0.

Reading:

other: 1st and 2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

0%

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

other: Reading: other: 1st and 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 5.0.

Induction - experimental group: All animals showed slight or well-defined erythema after the 48 hours occluded epidermal induction exposure. The control animals showed no skin reaction after the induction application.

Challenge -control group: No skin reactions were evident after the challenge exposure.

Challenge - experimental group: Nine, eight and five animals showed a skin reaction in response to the 50, 25 and 10 % test substance concentrations, respectively. These lead to a sensitisation rate of 90%. The reactions were characterised by discrete/ patchy erythemy, moderate and confluent redness and scaliness.

No mortality occures and no symptoms of systemic toxicity were observed in the animals in the main study during the study period. The average body weight gain of experimental and control animals was similar.

Executive summary:

A skin sensitization test (GPMT) was conducted according to OECD TG 406 on female guinea pigs (10 test animals and 5 controls). In this test the following concentrations were used based on a prior conducted range finding test: 5 % for intradermal induction (vehicle corn oil), 100 % for topical induction (vehicle acetone) and 50, 25, and 10 % for challenge (vehicle acetone). Before topical induction the skin was rubbed with 10 % sodium dodecyl sulfate in petrolateum. 48 and 72 hours after challenge exposure the treated sites were assessed.

In total, nine, eight and five animals showed a skin reaction in response to the 50, 25 and 10 % challenge concentrations, respectively (sensitisation rate up to 90%). No challenge skin reactions were observed in the control animals in response to all test substance concentrations. Thus, under the conditions of this study a skin sensitisation property was concluded for the substance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The substance proved to have askin sensitizing property in a Guinea Pig Maximization Test according to OECD TG 406. Female guinea pigs were exposed to test substance concentrations at 5 % for intradermal induction, 100 % for topical induction and 50, 25, and 10 % for challenge. Before topical induction the treated skin area was rubbed with 10 % sodium dodecyl sulfate. 48 and 72 hours after challenge exposure the treated sites were assessed.

In total, nine, eight and five animals showed a skin reaction in response to the 50, 25 and 10 % challenge concentrations, respectively (sensitisation rate up to 90 %). No challenge skin reactions were observed in the control animals in response to all test substance concentrations. Thus, under the conditions of this study a skin sensitisation property was concluded for the substance.

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

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No animal study investigating the respiratory sensitisation potential is available for the substance.

Diisocyanates in general are known respiratory sensitizers in humans. For HDI oligomers, uretdione in particular no respective human data are available.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, classification as Skin Sensitising Cat.1 (H317: May cause an allergic skin reaction) is warranted.

Regulation (EU) No 286/2011 amending Regulation (EC) No 1272/2008 states that, where data are sufficient, a refined evaluation allows the allocation of skin sensitizers into sub-category 1A (strong sensitizers) or sub-category 1B (other skin sensitizers). Where data are not sufficient a classification as Skin Sensitisation Category 1 without sub-categorisation applies.

 

HDI derived homopolymers (in short HDI homopolymers), like HDI oligomerisation products, uretdione type, isocyanurate type, iminooxadiazindione type and biuret type (all CAS no 28182 -81 -2), that are composed solely by different oligomerisation products of 1,6-hexamethylene diisocyanate monomer, were considered to have a similar skin sensitisation potential. This is based on structural analogy, on similar physico-chemical properties (vapour pressure, viscosity, hydrolytically unstable, reactive with nucleophiles) and on results of in vivo skin sensitisation assays of the substances. Consequently, all of these substances should be allocated to the same category/sub-category for skin-sensitisation.

Here in brief is the rationale for the categorization of HDI homopolymers for skin sensitisation:

With regard to sub-categorisation, studies of HDI homopolymers give an inconsistent picture. From the majority of studies it could be seen, that application of the formal criteria for sub-categorisation according to Regulation (EU) No 286/2011 leads to category 1B, but some studies does also point to a strong sensitisation potential (category 1A), and in some cases a discrimination between sub-categories 1A and 1B is not possible based on the test results.

The classification criteria of Regulation (EU) No 286/2011 cover human as well as animal data. For HDI homopolymers conclusive human data on skin sensitisation are not available (Abschlussbericht zum Forschungsvorhaben FP 272, IVDK, Goettingen, September 2011), which could be partly ascribed to the instability of the test preparations (Frick et. al., Contact Dermatitis 51, 73-78, 2004). Few publications point to human experience with positive patch test reactions indicating skin sensitization (Aalto-Korte et. al., Contact Dermatitis 63, 357-363, 2010), but this seems not to be a very frequent observation.

For HDI monomer, the precursor of HDI homopolymer, no sub-categorisation is currently concluded, since limited data on potency and inconsistent human and animal data does not allow a clear discrimination. Taking into account the database on HDI monomer a sub-categorisation of HDI homopolymers as 1A (strong sensitizer) based on worst case conclusion from the animal data with (some) HDI homopolymers seems not to be adequate and proportionate, since the less reactive HDI homopolymers are not assumed to be the more potent skin sensitizers than the respective monomer. Indeed, scientific evidence exists for some time that chemical reactivity or, more precisely, protein reactivity is linked to the potency of skin sensitisation (Lepoittevin et. al., Allergic Contact Dermatitis: The Molecular Basis. Springer, Berlin, 1998).

Overall, in a weight of evidence approach based on limited data on human experiences and inconsistent animal data as well as based on a comparison of the available data with HDI monomer it is concluded that the available data for HDI homopolymers currently do not allow a solid assessment of the potency. Therefore according to Regulation (EU) No 286/2011, 3.4.2.2.1.1 (“Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation") HDI homopolymers, and also HDI oligomers, uretdione type, should be currently classified in Category 1, without further sub-categorization.

 

A full and detailed justification concerning the classification of these HDI homopolymers is available and attached to this endpoint summary.