Oxybis(2,1-ethanediyloxy-2,1-ethanediyl)diacrylate

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Three old rabbit study reports were available to evaluate the skin irritation/corrosion potential of tetraethyleneglycol diacrylate: two reliable studies with some restrictions (Hundingdon 1976, BASF 1978) and a not reliable study (IndBioTest 1977).
Industrial Biotest Laboratory was found to use fraudulent practices in some of their studies and reports. Since these studies were performed before the implementation of Good Laboratory Practices, it is not possible to verify the scientific credibility of most of these studies.
The two reliable studies (Hundingdon 1976, BASF 1978) were performed with 24-hours of exposure and showed contradictory results. The study of 1976 was performed on 3 rabbits and concluded that the substance is skin corrosive based on high individual erythema score (mean 24-72h). The study of 1978 was performed on 6 rabbits and concluded that the substance is slightly skin irritating but not classified into category 2 according to the GHS criteria (all the individual 24-72h scores for erythema and oedema below than 1.3 for 4/6 animals). The limitations of both studies are the longer exposure duration (24-hr instead of 4-h required to determine the skin irritation classification according to GHS) and the absence of information on substance purity.
Based on these contradictory conclusion, an in vitro skin irritation test was performed in order to determine the correct classification for human hazard assessment. The results of this OECD 439 test were negative with a viability score of 111%. With this result, no GHS classification is required.
The registrants are surprised of the non-classification for skin irritation and decided to perform a new in vivo study according to the OECD TG 404 in order to be sure that no classification of the substance is needed for skin irritation.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2020

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

2015

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Oxybis(2,1-ethanediyloxy-2,1-ethanediyl)diacrylate

EC Number:

241-789-3

EC Name:

Oxybis(2,1-ethanediyloxy-2,1-ethanediyl)diacrylate

Cas Number:

17831-71-9

Molecular formula:

C14H22O7

IUPAC Name:

2-(2-{2-[2-(prop-2-enoyloxy)ethoxy]ethoxy}ethoxy)ethyl prop-2-enoate

Test material form:

liquid

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo Global Services Inc., Denver, PA.
- Age at study initiation: Young adult (at least 12
- Weight at study initiation: 2.6 - 3.3 kg.
- Housing: individually housed in suspended wire-bottom cages.
- Diet (e.g. ad libitum): Fresh, Certified Rabbit LabDiet® (No. 5322) was provided daily
- Water (e.g. ad libitum): water was available ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): continuously recorded
- Humidity (%): continuously recorded
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

3 min, 1h and 4h

Observation period:

Exposure Site 1 of the initial animal was scored for dermal irritation immediately post-exposure and at one hour post-exposure.
Sites 2 (one-hour exposure) and 3 (four-hour exposure) were scored for dermal irritation at 1, 24, 48 and 72 hours and on Day 7 for all three animals and on Day 14 for two animals post-patch removal.

Number of animals:

one male - two females

Details on study design:

TEST SITE
Approximately 24 hours prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair.
The prepared site was approximately 10% of the body surface and remained intact.

Initially, one rabbit was dosed on Site 1. The test article was dosed by volume, 0.5 ml per site and placed onto a 2 x 3 cm gauze patch which was placed on the dose site. Gentle pressure was applied to aid in the distribution of the test article over the prepared site. The dose patch was secured with non-irritating tape and the rabbit was gently held in place. The dose patch was removed at 3 minutes post-exposure and the test site was gently washed with gauze saturated with corn oil and blotted dry with gauze following patch removal. The outline of the dose site was marked using an indelible marker.
Due to no observed corrosive or severely irritating effects in the initial animal, two additional animals were added to the study and dosed in the same manner. All three animals were dosed at Site 2 for an exposure period of one hour and Site 3 for an exposure period of four hours. The clipped area of the torso was covered with a piece of porous dressing large enough to cover all dose sites with at least 5 cm2 to spare on all sides of the gauze patch. Porous, non-irritating tape was used to encircle the trunk of the animal. After the exposure period, the wrappings and patches were removed and the sites gently washed with gauze saturated with corn oil and blotted dry with gauze. The outline of the dose site was marked using an indelible marker.

REMOVAL OF TEST SUBSTANCE
- Washing : no

SCORING SYSTEM:
- Method of calculation:
Erythema and edema were scored according to the numerical Draize1 scale. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Additional
signs were described.

ERYTHEMA
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4

EDEMA
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-defined by definite raising) 2
Moderate edema (raised approximately 1 millimeter) 3
Severe edema (raised > 1 mm & extending beyond the area of exposure) 4

Body weights were recorded pre-test and at study termination.
Animals were observed for mortality, toxicological and pharmacological effects at least once daily.
All animals were humanely euthanized with a 1 ml intravenous injection (via the marginal ear vein) of Fatal-Plus® following study termination

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Remarks:

1-hour exposure

Basis:

mean

Remarks:

3 rabbits

Time point:

24/48/72 h

Score:

1.9

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: Mean Individual data = 2 - 1.67 - 2

Results 2

Irritation parameter:

edema score

Remarks:

1-h exposure

Basis:

mean

Remarks:

3 rabbits

Time point:

24/48/72 h

Score:

1.22

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Mean individual data : 1 - 1 - 1,67

Results 3

Irritation parameter:

erythema score

Remarks:

4-h exposure

Basis:

mean

Remarks:

3 rabbits

Time point:

24/48/72 h

Score:

2.4

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Mean individual score = 2 - 2.3 - 3

Results 4

Irritation parameter:

edema score

Remarks:

4-h exposure

Basis:

mean

Remarks:

3 rabbits

Time point:

24/48/72 h

Score:

1.9

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: Mean individual scores = 2 - 1.3 - 2.3

Irritant / corrosive response data:

3-minute exposure : no edema observed after 1 hour. Erythema of 2 observed after 1 hour. Based on these results, the test item is not considered as corrosive.
1-hour exposure : moderate erythema and slight edema were observed in the 3 rabbits exposed. Based on these results, the test item is not considered as corrosive.
4-hour exposure : moderate erythema and edema observed in the 3 rabbits exposed. Based on these results, the test item is considered as irritating to the skin.

Other effects:

Abnormal physical signs including diminished food consumption, wetness, soiling and yellow staining of the anogenital area were observed.
Body weight : Two animals gained weight and one animal’s weight remained the same by study termination.

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Under the experimental conditions of this study, the test item was considered as irritating to skin when applied topically to rabbits after 4 -hour exposure according to the Regulation EC 1272/2008 (CLP) and GHS criteria.

Executive summary:

The purpose of this study was to determine the irritant or corrosive effects, if any, of a test article when applied to the skin of a rabbit.

Initially, one healthy male New Zealand White rabbit was dosed dermally with 2-Propenoic acid, oxybis(2,1-ethanediyloxy-2,1-ethanediyl) ester.The test article (0.5 ml) was applied dermally to Site 1 for an exposure period of 3 minutes. Erythema and edema were scored immediately post-exposure and at one hour post-exposure. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Due to no observed corrosive or severely irritating effects in the initial animal, two additional animals (females) were added to the study.

All three animals were dosed at Site 2 for an exposure period of one hour and Site 3 for an exposure period of four hours. Erythema and edema were scored at 1, 24, 48 and 72 hours and on Day 7 for all three animals and on Day 14 for two animals for the one and four-hour exposures. Animals were observed for mortality, toxicological and pharmacological effects at least once daily. Body weights were recorded pre-test and at termination.

 

No unscheduled deaths occurred during the study. and no clinical signs were noted in any animals.

Abnormal physical signs including diminished food consumption, wetness, soiling and yellow staining of the anogenital area were observed.

Two animals gained weight and one animal’s weight remained the same by study termination.

After 3 -minute exposure (one animal), erthema score was of 2, and edema score of 0 : no sign of corrosion.

After a 1-hour exposure (three animals), mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.            erythema: 2 - 1.67 - 2

.            edema: 1 - 1 - 1,67

 

After a 4-hour exposure (three animals), mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.            erythema: 2 - 2.3 - 3

.            edema: 2 - 1.3 - 2.3

 

Under the experimental conditions of this study, the test item was considered as irritating to skin when applied topically to rabbits after 4 -hour exposure according to the Regulation EC 1272/2008 (CLP) and GHS criteria.