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Description of key information

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
additional intradermal challenge to boost reactions, simultaneous challenge with several acrylates and methacrylates, potential repetition of induction procedure - deviations likely increased the number of positive reactions
Principles of method if other than guideline:
The guinea pig maximization (GPM)-test was performed in accordance with the original description by Magnusson and Kligman (J Invest Dermatol 1969: 52: 268-276 and Magnusson B, Kligman AM. Allergic contact dermatitis in the guinea pig. Identification of contact allergens. Springfield III: CC Thomas Publisher, 1970).

GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Older study available
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 300-400 g

Route:
intradermal and epicutaneous
Vehicle:
other: Induction: Mixture of olive oil and acetone (9:1); Challenge: Petrolatum
Concentration / amount:
Pretest:
The concentrations used for the pretest are not reported.

Main Test:
Intradermal induction: 1 % (w/w) test substance in olive oil/acetone (9:1)
Epicutaneous induction: 25 % in petrolatum
Intradermal Challenge: 1 % (w/w) in petrolatum
Epicutaneous Challenge: 0.2 % (w/w) in petrolatum

Route:
intradermal and epicutaneous
Vehicle:
other: Induction: Mixture of olive oil and acetone (9:1); Challenge: Petrolatum
Concentration / amount:
Pretest:
The concentrations used for the pretest are not reported.

Main Test:
Intradermal induction: 1 % (w/w) test substance in olive oil/acetone (9:1)
Epicutaneous induction: 25 % in petrolatum
Intradermal Challenge: 1 % (w/w) in petrolatum
Epicutaneous Challenge: 0.2 % (w/w) in petrolatum

No. of animals per dose:
30 animals: 15 animals in the test group and 15 animals in the control group
Details on study design:
PRETEST:
3 animals were used to evaluate the optimal concentration for intradermal and topical induction. The animals were not subsequently used in the sensitization experiments. No further data were given.

MAIN STUDY:
The details of the test design were as described in Björkner et al. 1984 (Contact Dermatitis, Vol 10: 286-304) and can be summarized as follows:
INDUCTION EXPOSURE
Intradermal application:
- No. of exposures: 3 pairs of injections are made simultaneously (2x 50 µl of Freund´s Complete Adjuvant (FCA) alone, 2x 50 µl of test substance alone and 2x 50 µl of the test agent emulsified in the adjuvant).
- Test groups: 15 animals
- Control group: 15 animals. The control animals were sensitized in the same way as the experimental group but without the test material.
- Site: Shoulder region
- Frequency of applications: One time

Epicutaneous application:
- Time of application: 1 week after the injections
- Exposure period: 48 hours
- Test groups: 15 animals
- Control group: 15 animals
- Site: Shoulder region; the same area which was used for injections
- Frequency of applications: One time

CHALLENGE EXPOSURE
- Two challenges were conducted.
- The amount of test material was approximately 0.015 g.
- The first challenge using 6 different (meth) acrylates including HDDA was 2 weeks after the epicutaneous induction.
- 48 h later, the animals additionally received a booster dose of HDDA intradermally in the same concentration and vehicle as used for the intradermal induction, but without FCA.
- The second challenge was one week after the first challenge and also consisted of 6 different (meth)acrylates: HDDA and 5 new substances (different from challenge 1)
- Control group: 15 animals. When the sensitized animals were challenged, the control animals were also patch-tested with the same chemicals and the same concentrations. As a booster dose, the control animals received olive oil intradermally.
- Site: clipped, shaved flank of the animal.
- Evaluation (hr after challenge): 24 hours after removal of the patch.

REMARK:
- If no animals or just a few showed positive reactions, the GPM test procedure was repeated once more.
- In all animals, challenge with hydroquinone (0.1 % w/w in alcohol), which is a possible additive in acrylate products, was performed. The authors reported that challenge with hydroquinone gave no response in any tested animal.
Positive control substance(s):
no
Reading:
rechallenge
Hours after challenge:
48
Group:
test group
Dose level:
0.2 % (w/w) in petrolatum
No. with + reactions:
9
Total no. in group:
15
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 0.2 % (w/w) in petrolatum. No with. + reactions: 9.0. Total no. in groups: 15.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0.2 % (w/w) in petrolatum
No. with + reactions:
0
Total no. in group:
15
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.2 % (w/w) in petrolatum. No with. + reactions: 0.0. Total no. in groups: 15.0.

Cross reactivity for 1,6 -Hexandioldiacrylate was checked by challenge reactions with 1,4 -butandioldiacrylate (BUDA), diethyleneglycoldiacrylate (DEGDA), tetraethyleneglycoldiacrylate (TEGDA), tripropyleneglycoldiacrylate (TPGDA), neopentylglycoldiacrylate (NPGDA).

Positive reaction was seen with BUDA (1/15), DEGDA (4/15) and TEGDA (4/15).

Interpretation of results:
sensitising
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Skin sensitization

There are valid in vivo data available for the assessment of the skin sensitization potential of 1,6-hexanedioldiacrylate (HDDA).

 

In an in vivo study according to the method described by Magnusson and Kligman, 30 female Dunkin-Hartley guinea pigs were used (15 animals as test group, and 15 animals as control group) (Björkner 1984). Sensitization was induced intradermally (1 % in olive oil/acetone using FCA) as well as epicutaneously (25 % in petrolatum) one week later. The animals were challenged epicutaneously two weeks later with 0.2% of the test material in petrolatum and 5 further structurally similar substances to assess cross reactivity. After an intradermal booster reaction (1%), animals were challenged again with 0.2% of the test material in petrolatum and 5 other structurally related substances. The authors mentioned the possibility that the induction procedure was repeated (depending on the number of positive reaction after the first round), but did not specify, if this was the case for HDDA. Despite these deviations (booster induction, possible repetition) only 9 of 15 animals showed positive reaction to HDDA.

In a second study by Clemmensen (1985), sensitisation was intradermally induced with 1% HDDA in soy bean oil in guinea pigs following a protocol similar to the GPMT described in the OECD 406 guideline. 25% HDDA were used for the epicutaneous induction. The challenge concentration was determined in a pre-test, but was increased in a second experiment. Dependent on the concentration used, 9/20 (0.3%) or 14 of 16 (0.5%) of the animals showed positive reactions. No control animals reacted to HDDA.

In another GPMT performed according to the Magnusson and Klingman method (Nethercott 1983), several induction concentrations were evaluated. The same concentration were used per animal for intradermal and epicutaneous induction: 0.83 , 2.5, 5.0 and 7.5 %. The positive reactions after challenge with a non-irritant concentration were 1/10, 3/10, 5/10 and 6/10, respectively. A clear dose response was observed. No negative control was used, but because of only one positive reaction in the lowest dose group, all reactions are assumed to be test substance related.

Van der Walle (1982) performed three different assays, one GPMT and 2 FCATs. Intradermal induction with app. 11% HDDA was compartively high in all assays, followed in the case of the GPMT by an epicutaneous induction with 22%. While a single intradermal induction was used for the GPMT, 5 injections were performed for the FCATs. Two challenges were performed with 0.2% (GPMT) and 0.6% (FCAT). No positive reactions were observed in the GPMT. In the first FCAT three of eight animals reacted to HDDA, while in the second test only one out of ten showed a positive reaction. The authors conclude that HDDA, though a strong irritant to guinea pigs, is only a moderate sensitizer.

In an unpublished optimisation test (Ciba Geigi, 1978), all 20 animals reacted to an epicutaneous challenge of 0.1% HDDA in vaseline.The high number of positive reaction can be explained by the harsh conditions of induction. 0.1% HDDA in propylene glycol was injected 10 times in the course of three weeks, mixed with complete Freund's adjuvance in the latter two weeks.

A further guinea pig study by Paker et al. (1983) as well as several reports in humans (see IUCLID section 7.10.4) confirm the sensitizing potential of HDDA.

 

Respiratory sensitization

No information is available.

 


Migrated from Short description of key information:
Though no GLP guideline studies exist and all publication deviate from standard procedures, all support a skin sensitizing potential of 1,6-hexanedioldiacrylate.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

1,6-hexanedioldiacrylate was demonstrated to be a skin sensitizer. No conclusion regarding the potency can be drawn. Most studies showed a moderate rather than strong sensitisation potential. Despite additional intradermal inductions, the GPMT by Björkner et al. does only just miss the criteria for subcategory 1B (60% react at 1% induction). In the study by Clemmensen, subcategorisation would be dependent on the challenge concentration, but only limited information is provided, how and why the different concentrations were selected. Further assays (Nethercott, Van der Walle) support at most a moderate potential, but lack certain information on dose selection.

All in all, the available data is considered insufficient to assign a subcategory. The substance is therefore classified as a sensitizer category 1 according to GHS criteria.

 

There are no data available to classify 1,6-hexanedioldiacrylate as a sensitizer of the respiratory tract.