Dimethyl adipate

Endpoint summary

Description of key information

Neither classified as a skin or eye irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

January 09 to March 02, 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structurally related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these substances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

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
- Source: L'Abbaye de Bellefontaine, F-49122 Begrolles en Mauges, France
- Weight at study initiation: 2.5 ± 0.1 kg
- Housing: Individually in polystyrene cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ±3 °C
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

1h, 24h, 48 h, and 72 h after exposure termination;

Number of animals:

3 animals

Details on study design:

TEST SITE
- Area of exposure: right flank
- coverage: 6 cm²
- Type of wrap if used: gauze patch held in place with semi-occlusive dressing

SCORING SYSTEM:
Erythema score: 0-4
Edema score: 0-4

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Interpretation of results:

not irritating

Conclusions:

Under the conditions of this assay, the test article has no skin irritating potential.

Executive summary:

DBE has been tested for skin irritation on 3 New Zealand White rabbits according to OECD guideline n° 404 and EU guideline n° B.4 (Draize Method) in compliance with Good Laboratory Practice. The rabbits received a dermal dose of 0.5 ml of DBE on a gauze on intact and abraded skin sites under an semiocclusive dressing for a period of 24 hours. Scores for erythema and oedema were measured 1, 24, 48 and 72 hours after patch removal and primary cutaneous index was calculated (maximum possible index =12). No sign of dermal irritation (score = 0 for erythema and oedema) was observed for intact skin site of the 3 rabbits at any reading time. Primary Irritation Index was = 0.0. No other signs of intoxication were observed.

Based on these results DBE is not classified irritating to skin according to the criteria of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Study period:

April 2, 1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study did not evaluate irritation but limited its observation to corrosion over a period of 48 hours.

Justification for type of information:

This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structuraly related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these susbtances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.

Qualifier:

according to guideline

Guideline:

other: US Department of Transportation 49 CFR 173.240

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

Albino rabbits (n=6) weighing 2-3 kg

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 mL = 0.5 g (assuming density of 1).
Density of structurally similar substance, DBE (EC#906 -170 -0), is 1.0915.

Duration of treatment / exposure:

4 hours

Observation period:

48 hours

Number of animals:

6 rabbits

Details on study design:

Six albino rabbits, weighing between 2-3 kg, were shaved dorsally and placed into FDA-type stocks. The test material, 0.5 mL, was applied under a 1.5 x 1.5 inch, 12-ply cotton gauze pad and the trunk of each animal was loosely fitted with rubber sheeting. After 4 hours, the rabbits were removed from the stocks, the wrappings and gauze were removed and any skin reactions were evaluated. The test sites were washed and re-evaluated at 24 and 48 hours for corrosion.

Irritation parameter:

other: corrosion

Basis:

mean

Time point:

24/48 h

Score:

0

Max. score:

0

Reversibility:

other: no corrosion observed

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

0/6 animals exhibited corrosion.

Other effects:

Not evaluated

Conclusions:

The material is not corrosive to skin according to US Department of Transportation 49 CFR 173.240(a)(1).

Executive summary:

Six albino rabbits, weighing between 2-3 kg, were shaved dorsally and placed into FDA-type stocks. The test material, 0.5 mL, was applied under a 1.5 x 1.5 inch, 12-ply cotton gauze pad and the trunk of each animal was loosely fitted with rubber sheeting. After 4 hours, the rabbits were removed from the stocks, the wrappings and gauze were removed and any skin reactions were evaluated. The test sites were washed and re-evaluated at 24 and 48 hours for corrosion.

The material is not corrosive to skin according to US Department of Transportation 49 CFR 173.240(a)(1).

Reference 3

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4470 (Acute Dermal Irritation)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Duration of treatment / exposure:

4 hours

Observation period:

24, 48, 72 hours

Number of animals:

6 (3m/3f)

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Average Dermal Irritation Score (ADIS) was 0.0. No irritation was observed. This material would probably not be considered to produce dermal irritation as defined in EPA Guidelines.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Average Dermal Irritation Score (ADIS) was 0.0. No irritation was observed. This material would probably not be considered to produce dermal irritation as defined in EPA Guidelines.

Reference 5

Endpoint:

skin irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Study period:

January 31 to February 02, 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structurally related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these substances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

24-hour occlusive application (more stringent exposure conditions)

GLP compliance:

yes

Remarks:

quality assurance documentation provided

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Young adult male and female New Zealand White rabbits were received from Hare Marland, Hewitt; New Jersey. The rabbits were housed singly in
suspended, stainless steel, wire-mesh cages. Each rabbit was assigned a unique identification number which was recorded on a card affixed to the
cage. Purina Certified High Fiber Rabbit Chowand water were available ad libidum except as noted under Protocol. Rabbits were quarantined, weighed and observed for general health for approximately 2 weeks. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 20°C +/- 2°C and relative humidity of 50% +/- 10%. Any excursions outside these ranges were of small magnitude and/or brief duration and did not adversely affect the validity of the study.

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.5 mL
- Concentration (if solution): not specified

Duration of treatment / exposure:

24 hours

Observation period:

24 h, 48 h, 72 h after the end of application

Number of animals:

6 animals per group

Details on study design:

TEST SITE
- Area of exposure: scapular to lumbar region of back
- % coverage: not specified
- Type of wrap if used: rubber sheeting
REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes,
- Time after start of exposure: 24 hours

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 24 h

Score:

2

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 24 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 24 h

Score:

0

Max. score:

0

Reversibility:

other: no irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: 24 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: 24 h

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: 24 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 48 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 48 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 48 h

Score:

0

Max. score:

0

Reversibility:

other: no irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: 48 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: 48 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: 48 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: 72 h

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: 72 h

Score:

0

Max. score:

0

Reversibility:

other: no irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: 72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: 72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: 72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Other effects:

No edema was observed exept for animal No. 6, which showed slight (score 1) edema 48 hours and 72 hours after exposure.

DBE produced moderate erythema in one rabbit; mild erythema in 4 rabbits and no erythema in one rabbit 24 hours after treatment. No edema was present. By 48 hours after treatment; 2 rabbits exhibited moderate erythema and 4 rabbits exhibited no to mild erythema; one rabbit had slight edema. By 72 hours, one rabbit exhibited severe erythema with fissuring and slight edema. No to mild erythema and no edema were observed in the other 5 rabbits. One rabbit exhibited no dermal irritation throughout the study. All rabbits exhibited red swollen nictitating membranes and a milky-white

ocular discharge during the study. Since 3 other test materials were tested concurrently with DBE (each material applied to a separate test site); these clinical signs cannot be specifically attributed to DBE. A summary of responses is presented in the following table.

	Summary of Skin Responses to DBE
	Erythema			Edema
Response	24 hr	48 hr	72 hr	24 hr	48 hr	72 hr
No Response	1/6	1/6	2/6	6/6	5/6	5/6
Slight	0/6	1/6	1/6	0/6	1/6	1/6
Mild	4/6	2/6	2/6	0/6	0/6	0/6
Moderate	1/6	2/6	0/6	0/6	0/6	0/6
Severe	0/6	0/6	1/6	0/6	0/6	0/6

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Remarks:

Migrated information

Conclusions:

Under the conditions of this study, DBE was considered as highly irritant based on its capacity to induce moderate to severe erythema.

Executive summary:

A skin irritation test was performed similar to OECD Guideline 404 and EPA GLP conditions. Approximately 0.5 mL aliquots of DBE were applied directly on the test sites of 3 male and 3 female New Zealand White rabbits closely clipped to expose the skin. Wrapping was used to retard evaporation and to keep the test material in contact with the skin without undue pressure.

 

Approximately 24, 48 and 72 hours after application of the test material, the test sites were evaluated for erythema, edema and other evidence of dermal effects and were scored according to the Draize Scale. The adjacent areas of the untreated skin were used for comparison.

DBE produced moderate erythema in one rabbit; mild erythema in 4 rabbits and no erythema in one rabbit 24 hours after treatment. No edema was present. By 48 hours after treatment; 2 rabbits exhibited moderate erythema  and 4 rabbits exhibited no to mild erythema; one rabbit had slight edema. By 72 hours, one rabbit exhibited severe erythema with fissuring and slight edema. No to mild erythema and no edema were observed in the other 5 rabbits. One rabbit exhibited no dermal irritation throughout the study.

Under the conditions of this study, DBE was considered as highly irritant based on its capacity to induce moderate to severe erythema.

Reference 6

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to Department of Transportation Skin Corrosion Test on rabbit skin and limited information is available.

Justification for type of information:

This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structuraly related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these susbtances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: Department of Transportation, Hazardous Materials Regulations, title 49 CFR, Section 173.240(a)(1), December 31, 1973

Deviations:

not specified

Principles of method if other than guideline:

equivalent or similar to OECD TG 404

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young adults
- Weight at study initiation: 2-3 kg

Type of coverage:

occlusive

Preparation of test site:

other: test sites were clipped free of fur

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

4 hours after application, 24 and 48 hours after the application

Number of animals:

six

Details on study design:

Six albino rabbits weighing between 2-3 kg were clipped free of hair on the back and placed in FDA-type stocks. 0.5 ml of the test material (as supplied) was applied under 1.5 x 1.5 inch, 12-ply cotton gauze pads and the trunk of each rabbit was then loosely wrapped with rubber sheeting. After 4 hours, the rabbits were removed from the stocks, the wrapping and gauze pads were removed and any skin reactions were evaluated. The test sites were then washed. Readings were again made at 24 and 48 hours afte the initial application

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 4, 24 and 48 hours after application

Score:

0

Irritant / corrosive response data:

None of the animals exposed to adipic acid, dimethyl ester exhibited any signs of corrosion.

Other effects:

none

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: Department of Transportation, Hazardous Materials Regulations, title 49 CFR, Section 173.240(a)(1), December 31, 1973

Conclusions:

When tested and classified according to the regulations of the Department of Transportation, adipic acid, dimethyl ester was not found to be corrosive to rabbit skin.

Executive summary:

This skin corrosion study on rabbits was conducted according to Department of Transportation, Hazardous Materials Regulations, title 49 CFR, Section 173.240(a)(1), December 31, 1973. Six albino rabbits weighing between 2-3 kg were clipped free of hair on the back and placed in FDA-type stocks. 0.5 ml of the test material (as supplied) was applied under 1.5 x 1.5 inch, 12-ply cotton gauze pads and the trunk of each rabbit was then loosely wrapped with rubber sheeting. After 4 hours, the rabbits were removed from the stocks, the wrapping and gauze pads were removed and any skin reactions were evaluated. The test sites were then washed. Readings were again made at 24 and 48 hours afte the initial application.

When tested and classified according to the regulations of the Department of Transportation, adipic acid, dimethyl ester was not found to be corrosive to rabbit skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

The available skin irritation studies for DMA, DMG and the mix of dibasic esters show that this substance is not irritating to the skin.

 

Eye irritation:

The available Eye irritation data on DMA are inconsistent and unfortunately there is either minimum information available in the report or the study is only reported in summary form on the EPA website. However it does appear that DMA can be irritating to some extent to the eyes, albeit reversible irritation.

Looking at the more comprehensive studies available for the Dibasic esters it appears that these arr also irritating to some degree but do not meet the criteria for classification in the EU as irritating to the eyes.

Given the larger number of studies (reported in more detail) for the DBE, and given that DMA is a component of DBE, it is considered that DMA would be mildly irritating, but not classified as irritating to the eyes.

Respiratory irritation:

No studies are available that assess respiratory irritation specifically. However in a 90-day repeated dose inhalation study with DMA there was evidence of local cyctotoxicity in the upper respiratory tract at 400 ppm.

Justification for selection of skin irritation / corrosion endpoint:

Study according to OECD Guideline 404 under GLP .

Justification for selection of eye irritation endpoint:

Study according to OECD Guideline 405 under GLP .

Justification for classification or non-classification

The incidence and severity of the signs of irritation observed among those different studies were below the criteria of Annex VI Directive 67/548/EEC or EU Regulation 1272/2008 (CLP), therefore warranting no classification for respiratory, skin or eye irritation.