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Description of key information

Human data on local irritation/corrosion are not available. 
In a primary dermal irritation study according to OECD Guideline 404 and EU Method B.4 reversible irritation was observed.
The results of a study according to OECD Guideline 405 and EU Method B.5 give no evidence of an eye damaging or eye irritating potential of bis (2-ethylhexyl) carbonate.

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
Study period:
2002-01-08 to 2002-01-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
17 July 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
29 December 1992
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: no data
- Weight at study initiation: 3.41, 3.56 and 4.19 kg
- Housing: individual housing (100 x 45 x 40 cm, L x B x H) in a battery of cages, equipped with a paper roll disposal system
- Diet: ad libitum, standard laboratory rabbit diet Teklad Global Rabbit Diet (pelleted diet, batch no. H134) produced by Harlan Teklad, Shaw's farm, Blackthorn Bicester, Oxon, OX6 OTP, England
- Water: ad libitum, drinking water as for human consumption
- Acclimation period: about 6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 16
- Photoperiod: Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: Each animal served as its one control with adjacent area of untreated skin.
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 mL
- Concentration (if solution): undiluted
Duration of treatment / exposure:
4 h
Observation period:
8 days
Number of animals:
3
Details on study design:
PRE-EXPERIMENTAL PROCEDURE
The skin of the back of the animals was clipped 24 h before treatment and examined for potential lesions. Since the animals showed no evidence of abnormalities, it was allocated to the test.

ADMINISTRATION OF THE TEST ARTICLE
The test article was used as supplied by the sponsor. One of the animals (rabbit no. 1) was treated with 0.5 ml of the liquid test article, which was applied to the left side of the back, the untreated right side served as control. The test article was applied to a gauze patch and then applied to the skin. The closed patch exposure was effected by means of a semiocclusive bandage using Ypsiplast® (Holthaus Medical, Remscheid-Lüttringhausen), non-irritating tape Elastoplast® (Beiersdorf AG, Hamburg) and Stülpa® (P. Hartmann AG, Heidenheim-Brenz), which enveloped the whole of the animal's trunk. Exposure duration was 4 h. Since there were only a moderate response to the application of the test article, the further two animals were treated subsequently in the same manner.

SCORING SYSTEM: Draize scoring scheme as stipulated by OECD 404
Irritation parameter:
erythema score
Basis:
animal: 1
Time point:
other: Mean 24, 48 and 72 h
Score:
2.33
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal: 2
Time point:
other: Mean 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: slight eschar formation recorded on day 4 and 5
Irritation parameter:
erythema score
Basis:
animal: 3
Time point:
other: Mean 24, 48 and 72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal: 1
Time point:
other: Mean 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 4 days
Irritation parameter:
edema score
Basis:
animal: 2
Time point:
other: Mean 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
edema score
Basis:
animal: 3
Time point:
other: Mean 24, 48 and 72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritant / corrosive response data:
CLINICAL SKIN OBSERVATIONS
- Slight to well-defined erythema was observed in all animals 1 h after patch removal following the 4-hour exposure and was still apparent, unchanging or increasing in degree, up to day 4 or 5 after exposure. The score 3 was observed in one animal 24 and 48 h and in one animal 72 h after exposure. Subsequently, a decreased degree of erythema was observed until the reversibility on days 7 and 8 after exposure.
Very slight to slight oedema was seen in the animals between 1 h and day 5 after exposure. Additionally, slight eschar formation was observed in one animal on days 4 and 5 after exposure.

REVERSIBILITY
- The observed findings were fully reversible within 8 days after patch removal.
Other effects:
TOXIC EFFECTS OTHER THAN SKIN IRRITATION
- No other toxic effects were observed.

Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Time point

Erythema

Max score 4

Edema

Max score 4

1 hour

1/2/1

0/1/0

24 hours

2/2/3

1/1/2

48 hours

2/2/3

1/1/2

72 hours

3/2/2

1/1/1

4 days

2/2#/2

0/1/1

5 days

1/2#/2

0/1/1

6 days

1/1/1

0/0/0

7 days

1/0/1

0/0/0

8 days

0/-/0

0/-/0

Average

24, 48, 72 hours

2.33/2/2.67

1/1/1.67

Reversibility*)

c/c/c

c/c/c

Time for reversion

8/7/8 days

4/6/6 days

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

# Slight eschar formation

Interpretation of results:
Category 2 (irritant)
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
Judgement is based on erythema/eschar and oedema calculated as the mean scores following grading at 24, 48 and 72 hours after removal of the test material, in consideration of reversibility.
The test substance is considered to be a skin irritant Category 2 according to CLP, EU GHS (Regulation (EC) No 1272/2008).
Executive summary:

In a primary dermal irritation study according to OECD Guideline 404, 17 July 1992 and EU Method B.4, 29 December 1992, three White New Zealand rabbits were semi-occlusive dermaly exposed to 0.5 mL of Bis(2-ethylhexyl) carbonate (approx. 100 % a.i.) for 4 hours. Animals then were observed for 8 days. Irritation was scored by the method of Draize as stipulated by OECD Guideline 404.

Slight to well-defined erythema was observed in all animals 1 h after patch removal following the 4-hour exposure and was still apparent, unchanging or increasing in degree, up to day 4 or 5 after exposure. The score 3 was observed in one animal 24 and 48 h and in one animal 72 h after exposure. Subsequently, a decreased degree of erythema was observed until the reversibility on days 7 and 8 after exposure. Very slight to slight oedema was seen in the animals between 1 h and day 5 after exposure. Additionally, slight eschar formation was observed in one animal on days 4 and 5 after exposure. The observed findings were fully reversible within 8 days after patch removal.

Mean values of skin reactions at 24, 48 and 72 h were ≥ 2.3 ≤ 4.0 for erythema/eschar in 2 of 3 animals.

The test substance Bis(2-ethylhexyl) carbonate is considered to be a skin irritant Category 2 according to CLP, EU GHS (Regulation (EC) No 1272/2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002-01-28 to 2002-02-02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
17 July 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
29 December 1992
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: no data
- Weight at study initiation: 3.78, 4.32 and 4.80 kg
- Housing: individual housing (100 x 45 x 40 cm, L x B x H) in a battery of cages, equipped with a paper roll disposal system
- Diet: ad libitum, standard laboratory rabbit diet Teklad Global Rabbit Diet (pelleted diet, batch no. H134) produced by Harlan Teklad, Shaw's farm, Blackthorn Bicester, Oxon, OX6 OTP, England
- Water: ad libitum, drinking water as for human consumption
- Acclimation period: about 2 months

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 2O +/- 3
- Humidity (%): 30 - 70
- Air changes (per hr): 16
- Photoperiod: Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7.00 a.m.
Vehicle:
unchanged (no vehicle)
Controls:
other: Each animal served as its one control. The test article was introduced into the conjunctival sac of one eye, the untreated eye serving as a control.
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 mL
- Concentration: undiluted
Duration of treatment / exposure:
Eyes were not rinsed after treatment.
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3
Details on study design:
ADMINISTRATION OF THE TEST ARTICLE
- The liquid test article was used as supplied by the sponsor. One of the animals (rabbit no. 1) was treated in advance in order to assess ocular reactions to the test article. The animal was treated with 0.1 mL of the liquid test article, which was introduced into the conjunctival sac of the right eye after gently pulling the lower lid away from the eyeball. The lid was then gently held together for about 1 sec in order to limit loss of the test article. The untreated left eye served as control. Since there was no remarkable response to the instillation of the test article, the further two animals were treated subsequently in the same manner.

REMOVAL OF TEST SUBSTANCE
- Washing: no washing was done

SCORING SYSTEM: Draize scoring scheme as stipulated by OECD 405
In addition to the examination of the eyes, general clinical observation was conducted.

TOOL USED TO ASSESS SCORE: no tools mentioned
Irritation parameter:
conjunctivae score
Basis:
animal: #1, #2
Time point:
other: Mean 24, 48 and 72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: Mean 24, 48 and 72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2, #3
Time point:
other: Mean 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: #1, #2, #3
Time point:
other: Mean 24, 48 and 72 h
Score:
0
Max. score:
2
Irritation parameter:
chemosis score
Basis:
animal: #1, #2, #3
Time point:
other: Mean 24, 48 and 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
CLINICAL EYE OBSERVATION
- Slight or moderate redness and slight swelling of the conjunctivae were observed in all animals 1 h after instillation. Redness, slight or moderate in degree, was still apparent 24 h after instillation in the three rabbits and up to 72 h after instillation in rabbit no. 3. No ocular findings were seen on day 4 of the study.

REVERSIBILITY
- The observed findings were fully reversible within 4 days in all animals.
Other effects:
TOXIC EFFECTS OTHER THAN OCULAR IRRITATION/CORROSION
- No other toxic effects than slight ocular irritation were observed.

Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

60 min

0/0/0

0/0/0 

1/2/2

1/1/1

24 h

0/0/0

0/0/0

1/1/2 

 0/0/0 

48 h

0/0/0 

 0/0/0 

0/0/1

 0/0/0 

72 h

0/0/0 

0/0/0

0/0/1

 0/0/0 

4 days

0/0/0 

0/0/0

0/0/0

0/0/0

Average 24h, 48h, 72h

0/0/0 

0/0/0

0.33/0.33/1.33 

0/0/0 

Reversibility*)

 c/c/c

 c/c/c 

c/c/c

c/c/c

time for reversion

 

 

48h/ 48h/4d

 24h/24h/ 24h

 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
Judgement is based on effects on the cornea, iris and conjunctiva calculated as mean scores following grading at 24, 48 and 72 hours after instillation of the test material, in consideration of reversibility.
The test substance is considered to be neither a seriously eye damaging substance nor an eye irritant according to CLP, EU GHS (Regulation (EC) No 1272/2008).
Executive summary:

In a primary eye irritation study according to OECD Guideline 405, 17 July 1992 and EU Method B.5, 29 December 1992, 0.1 mL of Bis(2-ethylhexyl) carbonate (approx. 100 % a.i.) was instilled into the conjunctival sac of three White New Zealand rabbits. The eyes were not rinsed after substance application. Animals then were observed for 4 days. Irritation was scored by the method of Draize as stipulated by OECD Guideline 405.

Slight or moderate redness and slight swelling of the conjunctivae were observed in all animals 1 h after instillation. Redness, slight or moderate in degree, was still apparent 24 h after instillation in the three rabbits and up to 72 h after instillation in rabbit no. 3. No ocular findings were seen on day 4 of the study. The observed findings were fully reversible within 4 days in all animals.

Calculated mean scores following grading at 24, 48 and 72 hours after installation of the test material for effects on the conjunctiva are 0.33 for two animals and 1.33 for the third animals. Mean scores for effects on the cornea as well as for effects on the iris were 0.0 for all animals.

The test substance Bis(2-ethylhexyl) carbonate is considered to be neither a seriously eye damaging substance nor an eye irritant according to CLP, EU GHS (Regulation (EC) No 1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In a primary dermal irritation study according to OECD Guideline 404, 17 July 1992 and EU Method B.4, 29 December 1992, three White New Zealand rabbits were semi-occlusive dermaly exposed to 0.5 mL of Bis(2-ethylhexyl) carbonate (approx. 100 % a.i.) for 4 hours. Animals then were observed for 8 days. Irritation was scored by the method of Draize as stipulated by OECD Guideline 404.

Slight to well-defined erythema was observed in all animals 1 h after patch removal following the 4-hour exposure and was still apparent, unchanging or increasing in degree, up to day 4 or 5 after exposure. The score 3 was observed in one animal 24 and 48 h and in one animal 72 h after exposure. Subsequently, a decreased degree of erythema was observed until the reversibility on days 7 and 8 after exposure. Very slight to slight oedema was seen in the animals between 1 h and day 5 after exposure. Additionally, slight eschar formation was observed in one animal on days 4 and 5 after exposure. The observed findings were fully reversible within 8 days after patch removal.

Mean values of skin reactions at 24, 48 and 72 h were ≥ 2.3 ≤ 4.0 for erythema/eschar in 2 of 3 animals.

The test substance Bis(2-ethylhexyl) carbonate is considered to be a skin irritant Category 2 according to CLP, EU GHS (Regulation (EC) No 1272/2008).

Eye irritation

In a primary eye irritation study according to OECD Guideline 405, 17 July 1992 and EU Method B.5, 29 December 1992, 0.1 ml of Bis(2-ethylhexyl) carbonate (approx. 100 % a.i.) was instilled into the conjunctival sac of three White New Zealand rabbits. The eyes were not rinsed after substance application. Animals then were observed for 4 days. Irritation was scored by the method of Draize as stipulated by OECD Guideline 405.

Slight or moderate redness and slight swelling of the conjunctivae were observed in all animals 1 h after instillation. Redness, slight or moderate in degree, was still apparent 24 h after instillation in the three rabbits and up to 72 h after instillation in rabbit no. 3. No ocular findings were seen on day 4 of the study. The observed findings were fully reversible within 4 days in all animals.

Calculated mean scores following grading at 24, 48 and 72 hours after installation of the test material for effects on the conjunctiva are 0.33 for two animals and 1.33 for the third animals. Mean scores for effects on the cornea as well as for effects on the iris were 0.0 for all animals.

The test substance Bis(2-ethylhexyl) carbonate is considered to be neither a seriously eye damaging substance nor an eye irritant according to CLP, EU GHS (Regulation (EC) No 1272/2008).

Respiratory irritation

No data on the respiratory irritation are available.

 

There are no data gaps for the endpoint irritation/corrosion. No human information is available for this endpoint. However, there is no reason to believe that these results from laboratory animals would not be applicable to humans.


Justification for selection of skin irritation / corrosion endpoint:
study according to OECD and EU guidelines, no deviations, GLP

Justification for selection of eye irritation endpoint:
study according to OECD and EU guidelines, no deviations, GLP

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

A classification of Bis(2-ethylhexyl) carbonate is not justified for eye damaging or eye irritating effects according to CLP, EU GHS (Regulation (EC) No 1272/2008) as well as the former European directive on classification and labelling Directive 67/548/EEC.

Classification of eye effects is based on diagnosis of cornea, iris and conjunctiva, calculated as mean scores following grading at 24, 48 and 72 hours after treatment, in consideration of reversibility. Results were taken from the key study on eye irritation,

performed according OECD Guideline 405 and EU Method B.5.

A classification of Bis(2-ethylhexyl) carbonate is justified for skin irritation according to CLP, EU GHS (Regulation (EC) No 1272/2008 as well as the former European directive on classification and labelling Directive 67/548/EEC. In a study performed according to OECD Guideline 404 and EU Method B.4 reversible irritation was observed. Mean scores of skin reactions at 24, 48 and 72 h were ≥ 2.3 ≤ 4.0 for erythema/eschar in 2 of 3 animals.Therefore, it is justified to classify Bis(2-ethylhexyl) carbonate as skin irritant Category 2 according to CLP, EU GHS (Regulation (EC) No 1272/2008) and with R38 according to the former European directive on classification and labeling Directive 67/548/EEC.

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