Registration Dossier

Administrative data

Description of key information

Based on substance specific data and read-across from Propane-1,2-diyl diacetate (CAS 623-84-7):
Oral: LD50 = 15594 mg/kg bw (lowest dose descriptor available)
Inhalation: LC0 = 0.845 mg/L (vapour, max. att. conc.)
Dermal: LD50 = 9040 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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 individual data.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
lack of test material details and individual data
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Fasting period before study: 18 h
- Diet: Purina Laboratory Chow, ad libitum
- Water: ad libitum
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 22 mL/kg bw
Doses:
six dose levels from 9.0 - 22.0 mL/kg bw
No. of animals per sex per dose:
6
Control animals:
no
Statistics:
The LD50 was calculated by the method of Lichtfield and Wilcoxon (1949).
Sex:
male
Dose descriptor:
LD50
Effect level:
13.8 mL/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
15 594 mg/kg bw
Based on:
test mat.
Remarks on result:
other: mean dose value as calculated from relative density 1.13 (Esterchem, 2011)
Mortality:
The animals that died usually died within 10-60 min following administration.
Clinical signs:
Prior to death animals showed vasodilation, gasping, cyanosis and prostration.
Gross pathology:
6 rats of the 14.1 mL/kg bw group were necropsied and examined microscopically. 4 of the rats had died 1 h after administration. Examination of the tissue showed that the animals died of shock. The remaining 2 rats survived 12 days and had no gross or microscopic lesions in any organs examined except that the liver showed a slight increase in hepatocytic mitosis.
Other findings:
None of the rats observed in the gross pathology showed any evidence of glycol toxicity. Nephrosis or calcium oxalate crystal deposition in the tubules of the kidney did not occur.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from the target substance and studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional groups, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given.
Principles of method if other than guideline:
The test material was administered to rabbits under an occlusive dressing for 24 h.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.5 - 3.5 kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: The fur was removed from the entire trunk by clipping.
- Type of wrap if used: The test material was retained beneath an impervious plastic film.
Duration of exposure:
24 h
Doses:
First experiment
2, 4, 8 and 16 mL/kg bw
Second experiment
8 and 16 mL/kg bw
No. of animals per sex per dose:
4
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- The animals were immobilized during the contact period
Statistics:
Based upon mortalities the most probable LD50 value and its fiducial range are estimated by the method of Thompson W.R. (1947) using the tables of Weil G.S. (1952). Where possible, in parentheses limits of ± 1.96 standard deviations are given while the absence of parentheses indicates that no range is calculable because no dosage resulted in fractional mortality.
Sex:
male
Dose descriptor:
LD50
Effect level:
8 mL/kg bw
Based on:
test mat.
95% CL:
1.91 - 33.5
Sex:
male
Dose descriptor:
LD50
Effect level:
9 040 mg/kg bw
Based on:
test mat.
Remarks on result:
other: dose value as calculated from relative density of 1.13
Mortality:
First experiment:
16 mg/kg bw: 3/4 animals died 4 days after treatment
Second experiment:
No mortality occurred during the study period.
Clinical signs:
First and second experiment:
No clinical signs of toxicity were observed up to the end of the observation period (no information about length, at least 8 days).
Body weight:
First experiment:
16 mL/kg bw: the surviving animal showed an increase in body weight
8 mL/kg bw: one surviving animal showed an increase in body weight, the other surviving animal showed a decrease in body weight
Second experiment:
All animals had depressed body weight (no further information).
4 mL/kg bw: one surviving animal showed an increase in body weight, two surviving animals showed a decrease in body weight
2 mL/kg bw: one surviving animal showed an increase in body weight, two surviving animals showed a decrease in body weight
Gross pathology:
First experiment:
Congestion of the liver and kidneys (no further information). Effect of the lungs in one animal (no further information).
Second experiment:
Pathology revealed no substance-related findings.
Other findings:
First experiment:
Skin irritation was obvious in the high dose group and described as marked erythema (no further information).
Second experiment:
No skin irritation or other findings are reported.

Table 1. Results of the first acute dermal toxicity experiment.

Dose
[mL/kg bw]
Toxicological results* Time of death Mortality (%)
16 3/0/4 Day 4 75
8 2/0/4 Day 4 and Day 8 50
4 1/0/4 Day 4 25
2 1/0/4 Day 4 25

Table 2. Results of the second acute dermal toxicity experiment.

Dose
[mL/kg bw]
Toxicological results* Time of death Mortality (%)
16 0/0/4 - -
8 0/0/4 - -

* first number = number of dead animals

second number = number of animals with clinical signs

third number = number of animals used

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
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.

Additional information

Acute oral toxicity

Justification for grouping of substances and read-across

There is only limited data available on the acute toxicity via inhalation of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7). In order 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, read-across from a structurally related substance is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, Propane-1,2-diyl diacetate (CAS 623-84-7) is selected as reference substances for assessment of acute toxicity by inhalation.

The read-across is based on the structural similarity between the source and target substances which are both esters of similar di-functional alcohols with the carboxylic acid acetic acid. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of Acute toxicity

CAS#

111-21-7 (a)

623-84-7 (b)

Chemical name

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

Propane-1,2-diyl diacetate

Molecular weight (g/mol)

234.25

160.17

Acute toxicity, oral

Experimental result:
LD50 = 15594 mg/kg bw

--

Acute toxicity, inhalation

RA CAS 623-84-7

Experimental result:
LC0 > 0.845 mg/L

Acute toxicity, dermal

Experimental result:
LD50 9040 mg/kg bw

Experimental result:
LD50 > 2000 mg/kg bw

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

Acute oral toxicity

CAS 111-21-7

A study similar to OECD guideline 402 was conducted in Sprague-Dawley rats (Raleigh, 1984). Groups of 6 animals were dosed at concentrations from 9-22 mL/kg bw 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate by gavage. In the study, mortality occurred in animals of the 14.1 mL/kg bw group. The animals died within 10-60 min following administration showing vasodilation, gasping, cyanosis and prostration prior to death. Necropsy and histopathological examination was performed in 6 rats of the 14.1 mL/kg bw group. Examination of the tissue showed that the animals died of shock (no further information). The surviving 2 animals of the group were necropsied and showed no gross or microscopical lesions in any organs examined with the exception of the liver showing a slight increase in hepatocytic mitosis. None of the rats observed in the gross pathology showed any evidence of “Glycol toxicity”. Nephrosis or calcium oxalate crystal deposition in the tubules of the kidney did not occur. Thus, the LD50 value was estimated to be 13.8 mL/kg bw (corresponding to 15594 mg/kg bw as calculated from relative density).

In another study, undiluted 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate was administered to rats by gavage (Union Carbide, 1967). Groups of 5 animals were dosed at concentrations of 8, 16 and 32 mL/kg bw 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate by gavage. All animals of the high-dose group died on the day of application. At 16 and 8 mL/kg bw, no animals died and no clinical signs of toxicity were observed. An increase in body weight of all animals in the low- and mid-dose groups were observed. In the study, a LD50 value of 22.63 mL/kg bw was calculated, corresponding to 25572 mg/kg bw.

Acute inhalation toxicity

One publication is available providing basic data on the acute toxicity by inhalation route of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7). In order to fulfil the standard information requirements set out in Annex VIII, 8.5.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 an additional read-across from the structurally related analogue substance Propane-1,2-diyl diacetate (CAS 623-84-7) is conducted.

CAS 111-21-7

In the study with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, 6 rats were exposed for 8 h to substantially saturated vapour (Union Carbide, 1967). Based molecular weight (234.25 g/mol) and estimated vapour pressure (0.0394 Pa at 20°C; Nagel, 2011), the saturated vapour concentration of the substance is estimated to be ca. 0.004 mg/L. No mortality and no clinical signs of toxicity were observed. All animals showed increased body weight. One rat had an abscess on the right diaphragmatic lobe of the lungs. The authors concluded that this effect was not caused by the test material. No effects were observed in the remaining animals. Thus, in the present study the LC0 for rats was the saturated vapour concentration of 0.004 mg/L.

CAS 623-84-7

The acute inhalation toxicity of Propane-1,2-diyl diacetate was evaluated in a study equivalent to OECD guideline 403 (Dow, 1986). A group of 6 male Fischer 344 rats were exposed whole body to the highest attainable 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 LC0 for male rats was the highest attainable concentration of 129 ppm, corresponding to 0.845 mg/L.

Inhalation tests with a saturated vapour atmosphere represent a worst case situation, because it is assumed that the undiluted vapour will be 100% bioavailable after inhalation. Contrary to that, for an aerosol it cannot be ensured that the particles will reach the alveolar region in many cases, and, in addition, it is anticipated that the substance will always be sprayed as a constituent within a preparation (i.e. diluted). In addition, an EBA approach was conducted in accordance with Annex XI, Section 3 of Regulation (EC) 1907/2006, and all exposure scenarios are considered to be safe. It is not assumed that any peak exposures of aerosols with the pure substance will occur; if there would be a peak exposure with vapour, experimental data are available indicating that no adverse effects occur.

Acute dermal toxicity

CAS 111-21-7

Two studies investigating the acute dermal toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate are available (Smyth, 1969; Union Carbide, 1984).

The acute dermal toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate was evaluated in rabbits using a 24 h occlusive treatment comparable to the "one-day cuff method" of Draize (Smyth, 1969). A group of 4 New Zealand White rabbits was treated with the undiluted test substance under occlusive conditions for 24 h. The animals were observed for a period of 14 days following administration. Based upon mortalities the most probable LD50 value and its fiducial range were estimated by the method of Thompson W.R. (1947) using the tables of Weil G.S. (1952). In the study, no dosage resulted in fractional mortality and the LD50 was estimated to be 8 mL/kg bw (9040 mg/kg bw as calculated from relative density).

In the second study, 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) was administered to rabbits under an occlusive dressing (Union Carbide, 1984). Groups of 4 rabbits were treated with the undiluted test material under occlusive conditions at concentrations of 2, 4, 8 and 16 mL/kg bw in the first experiment and at concentrations of 8 and 16 mL/kg bw in a second experiment. In the first experiment, 3/4 animals of the high-dose group died 4 days after treatment whereas in the second experiment no mortality was observed. Besides the mortality in the first experiment, no clinical signs of toxicity were observed in both experiments up to the end of the observation period (at least 8 days, no further information). In both experiments, animals showed increased as well as depressed body weights in the different groups without a dose-response relationship. Gross pathology of animals of the first experiment showed congestion of the liver and kidneys and effects of the lungs in one animal (no further information). In the second experiment, gross pathology revealed no substance-related findings. Local effects of skin irritation were obvious in the high-dose group and described as marked erythema (no further information). In the second experiment, no skin irritation or other findings were reported. Based on the result of the study, a LD50 value of 8 mL/kg bw was estimated (9040 mg/kg bw as calculated from relative density).

Acute toxicity, other routes

CAS 111-21-7

One study is available investigating the acute toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate after single intratracheal instillation of the test material in six rats (Raleigh, 1984). A bent needle was inserted into the trachea and 0.1 mL of the undiluted test material was injected. After closure of the incision, the animals were held, head up, for a moment to facilitate flow into the lungs. The animals were observed for a period of 14 days following administration.

In the study, 1/6 animals died at Day 11 (animal #590) and clinical signs were seen in 2/6 animals including weakness, rough coats and laboured respiration (animal #590 and #586). These two animals avoided food, developed diarrhoea and one animal lost body weight. Body weights in survivors were normal. In animal #590, mottled lung was observed during gross pathology. Histopathological examinations showed that the tracheas of two animals had massive aspiration pneumonia (animal #590 and 596). Of the four rats that survived, one had no inflammatory pulmonary lesions, two had mild to moderate chronic murine pneumonitis and one had patchy pulmonary edema and localised interstitial suppurative pneumonitis. The tracheal lesions were those that occur routinely in rats and are not treatment-related. The pulmonary lesions could be related to the introduction of foreign material into the airway and did not represent specific toxicological effects.

Conclusion for acute toxicity

In summary, acute oral toxicity studies from 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) resulted in oral LD50 values in rats of 15594 and 25572 mg/kg bw, and thus well above the currently applied limit value of 2000 mg/kg bw.

For acute inhalation toxicity, studies with Propane-1,2-diyl diacetate (CAS 623-84-7) and with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) are available. From the study conducted with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate, saturated vapour (0.004 mg/L) resulted in no mortality. In addition, the highest attainable concentration of Propane-1,2-diyl diacetate (CAS 623-84-7) resulted in the LC0 value of 0.845 mg/L.

Acute dermal toxicity studies conducted with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) resulted in an LD50 value in rats of 9040 mg/kg bw, and thus well above the currently applied limit value of 2000 mg/kg bw.

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 selection of acute toxicity – oral endpoint
The selected study is the most adequate and reliable study with the lowest dose descriptor.

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from a structural analogue and from substance-specific data and based on the weight of evidence from all available studies.

Justification for selection of acute toxicity – dermal endpoint
The selected study is the most adequate and reliable study based on overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on substance specific data and read-across from the source substance Propane-1,2-diyl diacetate (CAS 623-84-7), the available data on the acute toxicity of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.