Ethylene di(acetate)

Endpoint summary

Description of key information

Oral, rat: LD50 = 6860 mg/kg bw

Oral, guinea pig: LD50 = 4940 mg/kg bw

Inhalation (OECD 403), rat: LC50 = 0.845 mg/L air, corresponding to 129 ppm

Read across from structural analogue source substance propane-1,2-diyl diacetate (CAS 623-84-7).

Dermal (OECD 402), rabbit: LD50 > 2000 mg/kg bw

Read across from structural analogue source substance propane-1,2-diyl diacetate (CAS 623-84-7).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Lack of test material details and no individual data.

Principles of method if other than guideline:

Single oral administration by stomach tube in male rats.

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

other: albino Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 90 - 120 g
- Diet: Purina chows, supplemented by fresh vegetables
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: maximal concentration 500 mg/mL

DOSAGE PREPARATION (if unusual): The test material was insufficiently soluble to be fed in solution and was handled as temporary dispersion in 1% aqueous sodium sulfate of heptadecanol (trademarked "Tergitol" penetrant 7).

MAXIMUM DOSE VOLUME APPLIED: Individual dose levels were not reported for any of the substances tested including the test substance considered herein. According to the authors, the highest dose level which could safely be hold at one time by the animal was just over 10% of the animal’s bodyweight, corresponding to approx. 50 g/kg bw, when a substance was administered as a 50% solution. This is equivalent to a dose volume of 100 mL/kg bw.
Furthermore, it was reported that in most cases 10 animals were dosed to determine the toxicity of a particular dosage and enough dosages were given to include those at which no mortality occurred and those at which all tested animals died.
The test substance was administered as a 50% dispersion in 1% aqueous sodium sulfate of heptadecanol (trademarked "Tergitol" penetrant 7) and based on the information above and the resulting LD50 value, it appears unlikely that the test substance could have been administered at a dose volume > 100 mL/kg bw.
It is therefore assumed that the maximum dose volume applied was 100 mL/kg bw corresponding to a maximum dose level of 50000 mg/kg bw.

Doses:

Not specified (presumably up to 50000 mg/kg bw)

No. of animals per sex per dose:

ca. 10

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

The data were calculated by the method of probits, described by Bliss C.I. (1935. The calculation of the dosage-mortality curve. Ann. Appl. Biol. 22:134-167).

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

6 860 mg/kg bw

Based on:

test mat.

95% CL:

6 640 - 7 080

Remarks on result:

other: slope: 30.33

Mortality:

Mortality data were summarised for all substances tested. Therefore, no substance specific data were reported.
According to the authors, most deaths occurred within the first 48 h post-dose, but all deaths within 14 days post-administration were taken into account for calculation of LD50 values.

Clinical signs:

other: The test substance was tested along with other glycol esters. For this group, (near) fatal doses caused no narcosis but various degrees of sluggish depressed function.

Gross pathology:

Gross pathology findings were summarised for all substances tested. According to the authors, all doses caused some degree of irritation of the digestive tract. The primary target organ was the kidney; blood in urine and free blood beneath the capsule were seen at the highest dosages. The liver was less affected, but orange or reddish bile was often observed. Glycol esters were reported to produce livers of bright eosin colour.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Lack of test material details and no individual data.

Principles of method if other than guideline:

Single oral administration by stomach tube in guinea pigs.

GLP compliance:

no

Test type:

standard acute method

Species:

guinea pig

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 250 - 300 g
- Diet: Purina chows, supplemented by fresh vegetables
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: maximal concentration 50%

DOSAGE PREPARATION (if unusual): The test material was insufficiently soluble to be fed in solution and was handled as temporary dispersion in 1% aqueous sodium sulfate of heptadecanol (trademarked "Tergitol" penetrant 7).

MAXIMUM DOSE VOLUME APPLIED: Individual dose levels were not reported for any of the substances tested including the test substance considered herein. According to the authors, the highest dose level which could safely be hold at one time by the animal was just over 10% of the animal’s bodyweight, corresponding to approx. 50 g/kg bw, when a substance was administered as a 50% solution. This is equivalent to a dose volume of 100 mL/kg bw.
Furthermore, it was reported that in most cases 10 animals were dosed to determine the toxicity of a particular dosage and enough dosages were given to include those at which no mortality occurred and those at which all tested animals died.
The test substance was administered as a 50% dispersion in 1% aqueous sodium sulfate of heptadecanol (trademarked "Tergitol" penetrant 7) and based on the information above and the resulting LD50 value, it appears unlikely that the test substance could have been administered at a dose volume > 100 mL/kg bw.
It is therefore assumed that the maximum dose volume applied was 100 mL/kg bw corresponding to a maximum dose level of 50000 mg/kg bw.

Doses:

Not specified (presumably up to 50000 mg/kg bw)

No. of animals per sex per dose:

ca. 10

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

The data were calculated by the method of probits, described by Bliss C.I. (1935. The calculation of the dosage-mortality curve. Ann. Appl. Biol. 22:134-167).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 940 mg/kg bw

Based on:

test mat.

95% CL:

4 550 - 5 350

Remarks on result:

other: slope: 14.47

Mortality:

Mortality data were summarised for all substances tested. Therefore, no substance specific data were reported.
According to the authors, most deaths occurred within the first 48 h post-dose, but all deaths within 14 days post-administration were taken into account for calculation of LD50 values.

Clinical signs:

other: The test substance was tested along with other glycol esters. For this group, (near) fatal doses caused no narcosis but various degrees of sluggish depressed function.

Gross pathology:

Gross pathology findings were summarised for all substances tested. According to the authors, all doses caused some degree of irritation of the digestive tract. The primary target organ was the kidney; blood in urine and free blood beneath the capsule were seen at the highest dosages. The liver was less affected, but orange or reddish bile was often observed. Glycol esters were reported to produce livers of bright eosin colour.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

129 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Source: CAS 623-84-7

Remarks:

highest attainable concentration

Key result

Sex:

male

Dose descriptor:

LC0

Effect level:

0.845 mg/L air

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Source: CAS 623-84-7

Remarks:

corresponding to 129 ppm based on a molecular weight of 160.2 g/mol and a molar volume of 24.45 at 20 °C

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

0.845 mg/L air

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: Source: CAS 623-84-7

Remarks:

corresponding to 129 ppm based on a molecular weight of 160.2 g/mol and a molar volume of 24.45 at 20 °C

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Executive summary:

The acute inhalative toxicity of the target substance is estimated based on an adequate and reliable in vivo study of the structural analogue source substancepropane-1,2 -diyl diacetate (CAS 623-84-7). The determined LC50 value is 0.845 mg/L air (corresponding to 129 ppm). As explained in the analogue justification, the differences in molecular structure between the target and the source substance are unlikely to lead to differences in acute toxicity. Therefore, a LD50 value of 0.845 mg/L air for the target substance is considered for the hazard assessment and C&L purposes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) as the source and target substances are both esters of similar di-functional alcohols with acid acetic acid (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Source: CAS 623-84-7

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Executive summary:

The acute dermal toxicity of the target substance is estimated based on an adequate and reliable in vivo study of the structural analogue source substance propane-1,2 -diyl diacetate (CAS 623-84-7). The determined LD50 value is > 2000 mg/kg bw. As explained in the analogue justification, the differences in molecular structure between the target and the source substance are unlikely to lead to differences in acute toxicity. Therefore, a LD50 value of > 2000 mg/kg bw for the target substance is considered for the hazard assessment and C&L purposes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) as the source and target substances are both esters of similar di-functional alcohols with acetic acid (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Additional information

Acute oral toxicity

Two acute oral toxicity studies with ethylene diacetate in rats and guinea pigs are available (Smyth, 1941). Ethylene diacetate was administered as single oral dose by stomach tube in male rats and male and female guinea pigs. In rats and guinea pigs, groups of 10 animals received ethylene diacetate as 50% dispersion in water. The observation period following administration was 14 days. The data were calculated by the method of probits. The precision is indicated by the range of 95% probability.

Mortalities mostly occurred 48 hours post-dosing. Clinical signs comprised various degrees of sluggish depressed function. Gross necropsy revealed irritation of the digestive tract, primarily targeting the kidneys. Blood was found in urine and beneath the capsule at dosages of approximately 50000 mg/kg bw and orange or reddish bile was observed.

The resulting LD 50 value of the study in male rats was evaluated to be 6860 mg/kg bw and for guinea pigs 4940 mg/kg bw. For the purpose of hazard assessment, the oral LD50 of ethylene diacetate is considered to be greater than 2000 mg/kg bw.

 

Acute inhalation toxicity

There are no studies available investigating the acute toxicity via the inhalation route of ethylene diacetate. In order to fulfil the standard information requirement, read-across from the structurally related analogue substance propane-1,2-diyl diacetate (CAS 623-84-7) is conducted. In an acute inhalation toxicity study according to OECD guideline 403 with propane-1,2-diyl diacetate, a group of 6 male Fischer 344 rats was exposed whole body to the highest attainable vapour concentration of 129 ppm for 6 h. The animals were observed for a period of 14 days following administration. No mortality occurred and no clinical signs of toxicity were apparent and necropsy revealed no substance-related findings.

Therefore, the LC50 for male rats was greater than the highest attainable concentration of 129 ppm, corresponding to 0.845 mg/L.

 

Acute dermal toxicity

No studies are available investigating the acute toxicity via the dermal route of ethylene diacetate. In order to fulfil the standard information requirement, read-across from the structurally related analogue substance propane-1,2-diyl diacetate (CAS 623-84-7 is conducted. The acute dermal toxicity of propane-1,2-diyl diacetate was evaluated in a study according to OECD guideline 402 under GLP conditions (Dow, 1986). A group of 10 New Zealand White rabbits (5 males and 5 females) were treated with the undiluted test substance at the limit dose of 2000 mg/kg bw under semi-occlusive conditions for 24 h.

The animals were observed for a period of 14 days following administration. During the study period, no mortality and no clinical signs of toxicity occurred in any animal. Furthermore, no effects on body weight and no substance-related findings during necropsy were observed. Therefore, the LD50 value for males and females was estimated to exceed 2000 mg/kg bw.

 

Conclusion

In summary, studies from ethylene diacetate (CAS 111-55-7) investigating acute oral toxicity resulted in oral LD50 values greater than 2000 mg/kg bw.

For acute inhalation toxicity, a study with propane-1,2-diyl diacetate (CAS 623-84-7) is available. From the study, a LC50 value of 129 ppm (0.845 mg/L), the highest attainable vapour concentration, was obtained.

Furthermore, an acute dermal toxicity study conducted with propane-1,2-diyl diacetate (CAS 623-84-7) showed no effects at the limit dose of 2000 mg/kg bw.

Thus, the available data indicate a very low level of acute toxicity for the target and source substances and thus no hazard for acute oral, inhalative and dermal toxicity was identified.

Justification for classification or non-classification

Based on substance specific data and read-across from a structurally related substance following an analogue approach, the available data on acute oral, dermal and inhalation toxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008. The data are therefore conclusive but not sufficient for classification.