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Administrative data

Description of key information

Skin
In vivo
- Rabbit, 4 h, semiocclussive: irritating to skin (Draize; HRC 1987, acc. OECD 404, Val. 1)
- Rabbit, 20 h, occlussive: irritating to skin (comp. OECD 404; BASF AG 1974)
Eye
In vivo
- Rabbit, 24 h, substance was not washed out: not irritating (Draize, BASF AG 1971, comp. OECD 405)
- Rabbit, 24 h, substance was not washed out: not irritating (Draize, TNO 1978, Val. 2)
- Rabbit, 24 h, substance was not washed out: not irritating (Draize, Litton Bionetics 1972, Val. 2)
- Rabbit, 24 h, substance was not washed out: Risk of serious damage to eyes (effects were seen for cornea, iris, conjunctivae redness and -chemosis and were not fully reversible in at least one out of six animals within 7 days; Draize, Fraunhofer Gesellschaft 1979, Val. 2)
- Rabbit, 24 h, substance was not washed out: Risk of serious damage to eyes (effects were seen for cornea, iris, conjunctivae redness and -chemosis and were not fully reversible in at least one out of six animals within 7 days; Draize, TNO 1978, Val. 2)

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Buckmasters, Henham, GB
- Age at study initiation: 11-13 weeks
- Weight at study initiation: 2.4 - 2.9 kg
- Housing: individually in metal cages with perforated floors
- Diet: SDS Standard Rabbit Diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: yes (not further specified)

ENVIRONMENTAL CONDITIONS
- Temperature: 19 °C
- Humidity: 30 - 70 %
- Air changes: approx. 19 per hour
- Photoperiod: 12 hrs dark / 12 hrs light
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated sites of the same animal served as control.
Amount / concentration applied:
0.5 ml undiluted test material
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3 animals
Details on study design:
Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers from the dorso-lumbar region of each rabbit exposing an area of skin approximately 10 cm square.
A 0.5 ml aliquot of HDDA was applied under a 2.5 cm square gauze pad to one intact skin site on each animal.
Each treatment site was occluded with "Elastoplast" elastic adhesive dressing for a four hour period. The animals were not restrained during the exposure period and were returned to their cages.
At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the treatment site was washed using water to remove any residual test substance.

Examination of the treated skin was made on Day 1 (i.e. approximately 30 minutes after removal of the patches) and on Days 2, 3 and 4. Additional observations were made on Days 5 through 14.

Grading and scoring of the dermal reactions were performed using the prescribed numerical scoring system according to Draize.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24-48-72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation was seen on days 9 through 14
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24-48-72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation was seen on days 9 through 14
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24-48-72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: desquamation was seen on days 9 through 14
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24-48-72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24-48-72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24-48-72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritant / corrosive response data:
The single semi-occlusive application of HDDA to intact rabbit skin for four hours elicited persistent well-defined to moderate dermal irritation.

Table 1: Erythema and edema scores of the individual animals from day 1 to day 14

 

Animal 1

Animal 2

Animal 3

Day

Erythema

Edema

Erythema

Edema

Erythema

Edema

1

2

3

2

3

2

3

2

2

3

2

3

2

3

3

2

2

2

2

2

2

4

2

3

2

2

2

2

5

2

2

2

2

2

2

6

2

2

2

2

2

2

7

2

1

2

1

2

2

8

2

1

2

1

2

2

9

2

2

2

2

2

2

10

2

2

2

2

2

2

11

2

1

2

2

2

2

12

2

1

2

1

2

1

13

1

1

2

1

1

1

14

1

0

1

1

1

1

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are valid in vivo data available for the assessment of the skin and eye irritation potential of 1,6-hexanedioldiacrylate.

 

Skin

In a skin irritation test, according to OECD guideline 404, a 0.5 ml aliquot of HDDA was applied under a 2.5 cm square gauze pad to one intact skin site on each of three animals (HRC1987, Val. 1). The test material was applied under semiocclusive conditions for 4 hours. Grading and scoring of the dermal reactions were performed using the scoring system according to Draize. The single semi-occlusive application of HDDA to intact rabbit skin for four hours elicited persistent well-defined to moderate dermal irritation. Very slight to well-defined erythema with or without very slight to moderate edema was seen in all three animals throughout the study. Desquamation was seen in all animals from days 9 through 14.

A further skin irritation test was performed with two White Vienna rabbits (BASF AG 1974, comp. OECD 404). A 20-hour occlusive exposure to ca. 1 ml of the undiluted test substance produced a moderate erythema exceeding application area and edema (in some cases brownish) during day 1 to day 4 in both treated animals. The mean score for the 24, 48 and 72 h reading for erythema was 2.5, for edema it was 2.83, respectively. At the end of the observation period (day 8), erythema (grade 2) was still observed in one animal and scaling was seen in two animals.

In several further studies which were predominantly conducted within the framework of a ring study, rabbits were exposed to the unchanged test substance for 24 h under occlusive conditions, according to the method of Draize. The results, determined by different testing laboratories, showed a broad variation of the individual irritating scores obtained. No differences in skin irritation were seen, when different technical products were tested in comparison with distilled hexanedioldiacrylate in the same species under the same experimental conditions. Despite of the varying irritating scores obtained in the individual studies, a clear skin irritation potential for 1,6-hexanedioldiacrylate was demonstrated in all studies (BASF AG 1974; Hazleton Laboratories 1979; IFREB 1979; BASF AG 1979; IFREB 1979; INBIFO 1979; Fraunhofer Gesellschaft 1979; TNO 1979; LPT 1979; IBR 1979; Covance 1997 and 1999; Gelbke 1979: all Val. 2).

The results obtained under occlusive conditions should all be considered as overpredictive due to the harsh test conditions if compared to actual guideline recommendations (4 h under semiocclusive conditions).

 

Eye

No signs of eye irritation were seen in a Draize test, which was performed with two White Vienna rabbits (BASF AG 1974, comp. OECD 405). Eyes were left unwashed after application of 0.05 ml 1,6-hexanedioldiacrylate and the animals were observed for 8 days. The mean score for conjunctivae redness for the 24, 48 and 72 h reading was 1.0 and was fully reversible in 2/2 animals within 7 days. Scores for iritis, cornea opacity and conjunctivae chemosis were 0 at any time point.

This non-irritating result was confirmed in two further Draize tests, which were conducted with 0.1 ml of 1,6-hexanedioldiacrylate: Also here, no signs of eye irritation were seen after application of the test substance into one eye of 6 New Zealand White rabbits in each study (TNO 1978; Litton Bionetics 1972; both Val. 2). The eyes were left unwashed after application of the substance and the animals were observed for 7 days. Until 24 hours after instillation of the test material, slight redness and chemosis of the conjunctivae was observed, but all effects were fully reversible in all animals at the latest of 7 days.

There are two further studies available which clearly provided signs of serious eye irritation. However, these results should be considered as overpredictive due to the harsh test conditions if compared to actual guideline recommendations (substance was not washed out after 24 hours, observation period was completed after 8 days). Additionally, no information was available in terms of the amount and definition of impurities within the test material. Nevertheless, the test substance was legally classified as R36 according to EU-criteria (67/548/EEC) and as Category 2 according to GHS-criteria (1272/2008/EC) as a precautionary measurement:

The first study, clearly showing signs of serious eye irritation, was conducted with 6 New Zealand White rabbits; the eyes were left unwashed after application of 0.1 ml 1,6-hexanedioldiacrylate and the animals were observed for 8 days (Fraunhofer Gesellschaft 1979, Val. 2). During the first day after instillation slight corneal opacity was observed in three out of six rabbits, slight iritis was seen in one and lesions of the conjunctivae were seen in four rabbits. In 4 animals corneal opacity, iritis, conjunctival redness, chemosis and sometimes secretion were reported during the study period. Effects were seen to be reversible only in part within 8 days. The remaining 2 rabbits were free of symptoms during the whole observation period.

The result of the second study also clearly indicates a severe eye irritating potential of 1,6-hexanedioldiacrylate (TNO 1978, Val. 2). 0.1 ml 1,6-Hexanedioldiacrylate was applied to one eye of each of 6 New Zealand White rabbits, the eyes were also left unwashed after application and the animals were observed for 7 days. During the first day after instillation slight corneal opacity was observed in 4/6 rabbits, slight iritis 2/6 rabbits and slight or moderate redness/chemosis of the conjunctivae in all six rabbits. In the course of the seven-day observation period some recovery occurred. At the end of this period slight or moderate corneal opacity was still observed in two rabbits, slight iritis in one rabbit and slight or moderate redness/chemosis of the conjunctivae in two rabbits. In addition, increased eye discharge, in some cases with moistening of the lids and hairs just adjacent to lids was seen in all animals. In one case discharge lasted up to day 7. 


Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin

Due to the skin irritation effects observed, 1,6-hexanedioldiacrylate fulfills the requirements to be classified as skin irritant according to EU-criteria (67/548/EEC) as R38 and according to GHS-criteria (1272/2008/EC) as Category 2.

 

Eye

For the eye, the data currently available present an unequivocal result:

On the one hand, in three studies no or only slight effects were observed in the eyes of the tested animals, which were all fully reversible after an observation period of 7 or, in one case, 8 days.

On the other hand, severe eye irritation effects were observed on corneal opacity, iritis, conjunctival redness and chemosis in two studies, which would -at first glance- justify a R41/category 1 classification. However, due to the harsh test conditions applied, compared to actual guideline recommendations, the results obtained are considered to be overpredictive, as the substance was not washed out after 24 hours and the observation periods were completed after only 8 days. Additionally, no information was available in terms of the amount and definition of impurities within the test material.

Considering the whole observation period from the moment of application until observation day 8, a tendency of decreasing effects in the eyes of the animals can be seen with preceding time (which presumably would have been fully reversible after an observation period of 21 days). Additionally, the effects observed would presumably have been less severe if 1,6-hexanedioldiacrylate had been washed out after 24 hours. Nevertheless it was demonstrated in these studies that 1,6-hexanedioldiacrylate holds a distinct irritating potential to the eye.

Therefore, taken the results together, on the basis of an weight of evidence approach and as a precautionary measure, 1,6-hexanedioldiacrylate has to be classified as eye irritant according to EU-criteria (67/548/EEC) as R36 and according to GHS-criteria (1272/2008/EC) as Category 2.

 

Respiratory system

Actually, there are no data available for a classification according to this endpoint.