Registration Dossier

Administrative data

Description of key information

Oral: NOAEL (rat) ≥ 796 (m) and 1195 (f) mg/kg bw/day (subchronic)
Inhalation: NOAEC (rat) ≥ 227 mg/m³ (subacute)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. Lack of test material details and no clinical biochemistry.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
lack of test material details and no clinical biochemistry
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 53 - 54 g
- Housing: 5 animals of the same sex per cage
- Diet: basal diet of ground Purina Laboratory Chow
- Water: ad libitum
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with: basal diet of ground Purina Laboratory chow
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 7 days/week
Remarks:
Doses / Concentrations:
0.1, 1 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
25, 250 mg/rat/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
79.6, 796 mg/kg bw/day (males)
Basis:
other: mean dose value as calculated from the reported body weight and mean value per rat
Remarks:
Doses / Concentrations:
119.5, 1195 mg/kg bw/day (females)
Basis:
other: mean dose value as calculated from the reported body weight and mean value per rat
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each group was recorded at approximately weekly intervals

DIET EFFICIENCY: Yes
- Body weight gain in g/food consumption in g per unit time (Day 0- 27; Day 28-60; Day 61-89 and Day 0-89) X 100 calculated as time-weighted averages from the consumption and body weight gain data were determined.

FEED EFFICIENCY: Yes
- Diet efficiency (Body weight gain in g/food consumption in g per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain) x 1.01 or x 1.001, respectively

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 47 and Day 89
- How many animals: 10 animals per sex from the high dose group and the control group were examined.
- Parameters checked: hematocrit, hemoglobin, white blood cell value and differential blood values

URINALYSIS: Yes
- Time schedule for collection of urine: Day 47 and Day 89
- How many animals: 5 animals per sex from the high dose group and the control group were examined.
- Parameters checked: pH value, specific gravity, albumin, sugar, occult blood, ketones and physical characteristics were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, kidneys, spleen, heart, brain, lungs and testes.
HISTOPATHOLOGY: Yes. Trachea, lung, heart, tongue, oesophagus, stomach, small and large intestine, liver, kidney, urinary bladder, pituitary, adrenal, pancreas, thyroid, parathyroid, testes, ovary and uterus, spleen, femoral bone marrow, cerebrum, cerebellum and eye.
Statistics:
Mean values were calculated and the Students´s t-test was applied.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
High dose group (males): reduced white blood cell value (non adverse)
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
One animal in low dose group was found dead on Day 85, no treatment related effect.

BODY WEIGHT AND WEIGHT GAIN
No effects were observed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No effects were observed.

FOOD EFFICIENCY
No effects were observed.

HAEMATOLOGY
No treatment related effects were observed. White blood cell counts of the control and high dose males were within the normal range. However, at the 5% significance level (Student t-test) the average white blood cell count of the treated group was significantly lower than the control at Day 47 and 89. According to the author, it appeared that the control average white blood cell count was probably high (see Table 2 under "Any other information on results incl. tables").

URINALYSIS
No effects were observed.

ORGAN WEIGHTS
No effects were observed.

GROSS PATHOLOGY
No effects were observed. One high-dose male had multiple, yellowish nodules characteristic of chronic murine pneumonia in all lobes of the lungs.

HISTOPATHOLOGY: NON-NEOPLASTIC
No adverse effects were observed.
Dose descriptor:
NOAEL
Effect level:
>= 250 other: mg/rat/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Effect level:
>= 796 mg/kg bw/day (nominal)
Based on:
other: mean dose value as calculated from the reported body weight and mean value per rat
Sex:
male
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Effect level:
>= 1 195 mg/kg bw/day (nominal)
Based on:
other: mean dose value as calculated from the reported body weight and mean value per rat
Sex:
female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

All animals exhibited varying, generally mild degree of chronic murine pneumonitis, with no discernable pattern of involment in different groups. Minimal focal chronic pyelonephritis was present in 2 animals in the high dose group and in one control animal one low dose group. There was no oxalate crystal precipitation in the kidneys of the test group animals or other evidence of nephrosis. Minimal focal chronic myocarditis was present in one animal each in the high dose and the control group. Squamous metaplasia of the epithelium of rare thyroid follicles was seen in two animas in each group. A parasitic worm was found within the colon of one control animal.

The abnormalities seen are typical of natural disease processes commonly found in laboratory rats. There is no morphologic evidence in the tissues examined of abnormality due to the experimental feeding program.

Table 1. Average Body Weights.

 

Group [% diet]

Days on
Diet

1

0.1

control

1

0.1

control

 

Males

Females

0

56

50

54

53

53

55

7

99

86

96

92

88

93

14

150

138

147

130

127

129

20

200

187

202

166

158

163

27

250

235

251

184

176

185

34

303

280

292

209

202

210

40

343

320

332

226

217

225

47

361

345

342

235

228

233

53

400

377

382

244

241

242

60

408

394

386

258

253

260

64

427

404

414

257

254

261

70

432

419

428

263

263

268

76

462

440

454

273

271

279

82

472

442

464

279

284

284

89

476

462

465

280

280

284

Mean

322.6

305.3

313.9

209.9

206.3

211.4

Mean over all Males/Females 

 

313.9

 

 

209.2

Table 2. Results of Hematology.

 White blood cell value

x 103 

Group [% diet]

1

control

1

control

Males

Females

Day 47

17.9

23.1

19.1

18.6

Day 89

16.4

21

15.4

12.9

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 VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles. Lack of details on study design and test material.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
lack of details on study design and test material
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: A&E Farms, Altamont, USA
- Diet: Purina Laboratory Chow, either ground or pelleted
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical glass inhalation chambers
- Source and rate of air: filtered air at 1 L/min through a 125 mL gas washing bottle fitted with a fritted cylinder and partially filled with the compound.
- System of generating vapour: The fritted cylinder broke up the air stream into small bubbles which rose through the column of the test material and assisted in vaporising the compound into the air stream. The gas washing bottle was placed in a water bath heated to 100 °C. The effluent air from the gas washing bottle was passed directly into the inhalation chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Samples were taken in methanol each day and analyzed by gas chromatography.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were calculated on the basis of air flow and weight loss of compound and gas chromatography of air samples.
Duration of treatment / exposure:
29 days
Frequency of treatment:
6 h/day, 5 days/week
Remarks:
Doses / Concentrations:
saturated atmosphere range 97.7 - 183.9 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
saturated atmosphere range 877 - 1759 mg/m³
Basis:
other: nominal conc. as calculated from range 0.877 - 1.759 mg/L
Remarks:
Doses / Concentrations:
saturated atmosphere range 8.8 - 23.7 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
saturated atmosphere range 80 - 227 mg/m³
Basis:
other: analytical conc. as calculated from range 0.08 - 0.227 mg/L
No. of animals per sex per dose:
6
Control animals:
yes
Observations and examinations performed and frequency:
BODY WEIGHT: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to the first exposure and following the 20th exposure
- Parameters checked: haemoglobin, cell volume, white cell count and differential

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, kidneys, spleen, heart, brain, lungs and testes.
HISTOPATHOLOGY: Yes. Trachea, lung, heart, tongue, oesophagus, stomach, small and large intestine, liver, kidney, urinary bladder, pituitary, adrenal, pancreas, thyroid, parathyroid, testes, ovary and uterus, spleen, femoral bone marrow, cerebrum, cerebellum and eye.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
slight lacrimation and yellow tinged fur (non adverse)
Mortality:
mortality observed, treatment-related
Description (incidence):
slight lacrimation and yellow tinged fur (non adverse)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
treatment group: slighlty impaired BW gain
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
No animals died during the study period. Slight lacrimation in the treatment and control group was observed throughout each exposure and on the seventh exposure it was noted that the experimental animals´ fur was becoming tinged with yellow.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain in the treatment group was slightly reduced in comparison to the control group.

HAEMATOLOGY
No effects on haematological parameter observed.

GROSS PATHOLOGY
No gross lesions at necropsy in all animals. No evidence was seen of irritant effects on the upper respiratory tract, eyes or nose.

HISTOPATHOLOGY
The experimental and control groups showed the common chronic murine pneumonitis and both groups seemed to be equally affected. There was no evidence of chemical pneumonitis nor of the presence of any unabsorbed foreign substance in the alveoli.

OTHER FINDINGS
The analytical concentrations were about ten times lower than the calculated concentrations. Therefore, 26 g of hair of the test animals was analysed and 23.8 mg of the test compound could be extracted.
Dose descriptor:
NOEC
Effect level:
>= 227 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects
Dose descriptor:
NOEC
Effect level:
>= 23.7 ppm (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Table 1. Results of haematology (mean out of 6 animals).

 

Haemoglobin

Cell volume

White blood cell count

Pre-exposure

 

Treatment group

15.8

49.3

18.48

Control group

15.4

49.3

23.97

Post-exposure

 

Treatment group

19.2

49.2

21.92

Control group

19.5

50.2

24.53

Table 2. Chamber concentrations.

Method

Range

[ppm]

Mean

[ppm]

Standard

deviation

Number of observations

Calculated weight
loss and air flow

91.7-183.9

137.7

26.4

22

Gas chromatography
of air samples

8.8-23.7

*

3.6

27

*: unreadable in study report

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles. Lack of details on study design and test material.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
lack of details on study design and test material
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: A&E Farms, Altamont, USA
- Diet: Purina Laboratory Chow, either ground or pelleted
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical glass inhalation chambers
- Source and rate of air: filtered air at 1 L/min through a 125 mL gas washing bottle fitted with a fritted cylinder and partially filled with the compound.
- System of generating vapour: The fritted cylinder broke up the air stream into small bubbles which rose through the column of the test material and assisted in vaporising the compound into the air stream. The gas washing bottle was placed in a water bath heated to 100 °C. The effluent air from the gas washing bottle was passed directly into the inhalation chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Samples were taken in methanol each day and analyzed by gas chromatography.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were calculated on the basis of air flow and weight loss of compound and gas chromatography of air samples.
Duration of treatment / exposure:
29 days
Frequency of treatment:
6 h/day, 5 days/week
Remarks:
Doses / Concentrations:
saturated atmosphere range 97.7 - 183.9 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
saturated atmosphere range 877 - 1759 mg/m³
Basis:
other: nominal conc. as calculated from range 0.877 - 1.759 mg/L
Remarks:
Doses / Concentrations:
saturated atmosphere range 8.8 - 23.7 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
saturated atmosphere range 80 - 227 mg/m³
Basis:
other: analytical conc. as calculated from range 0.08 - 0.227 mg/L
No. of animals per sex per dose:
6
Control animals:
yes
Observations and examinations performed and frequency:
BODY WEIGHT: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to the first exposure and following the 20th exposure
- Parameters checked: haemoglobin, cell volume, white cell count and differential

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, kidneys, spleen, heart, brain, lungs and testes.
HISTOPATHOLOGY: Yes. Trachea, lung, heart, tongue, oesophagus, stomach, small and large intestine, liver, kidney, urinary bladder, pituitary, adrenal, pancreas, thyroid, parathyroid, testes, ovary and uterus, spleen, femoral bone marrow, cerebrum, cerebellum and eye.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
slight lacrimation and yellow tinged fur (non adverse)
Mortality:
mortality observed, treatment-related
Description (incidence):
slight lacrimation and yellow tinged fur (non adverse)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
treatment group: slighlty impaired BW gain
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
No animals died during the study period. Slight lacrimation in the treatment and control group was observed throughout each exposure and on the seventh exposure it was noted that the experimental animals´ fur was becoming tinged with yellow.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain in the treatment group was slightly reduced in comparison to the control group.

HAEMATOLOGY
No effects on haematological parameter observed.

GROSS PATHOLOGY
No gross lesions at necropsy in all animals. No evidence was seen of irritant effects on the upper respiratory tract, eyes or nose.

HISTOPATHOLOGY
The experimental and control groups showed the common chronic murine pneumonitis and both groups seemed to be equally affected. There was no evidence of chemical pneumonitis nor of the presence of any unabsorbed foreign substance in the alveoli.

OTHER FINDINGS
The analytical concentrations were about ten times lower than the calculated concentrations. Therefore, 26 g of hair of the test animals was analysed and 23.8 mg of the test compound could be extracted.
Dose descriptor:
NOEC
Effect level:
>= 227 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects
Dose descriptor:
NOEC
Effect level:
>= 23.7 ppm (analytical)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Table 1. Results of haematology (mean out of 6 animals).

 

Haemoglobin

Cell volume

White blood cell count

Pre-exposure

 

Treatment group

15.8

49.3

18.48

Control group

15.4

49.3

23.97

Post-exposure

 

Treatment group

19.2

49.2

21.92

Control group

19.5

50.2

24.53

Table 2. Chamber concentrations.

Method

Range

[ppm]

Mean

[ppm]

Standard

deviation

Number of observations

Calculated weight
loss and air flow

91.7-183.9

137.7

26.4

22

Gas chromatography
of air samples

8.8-23.7

*

3.6

27

*: unreadable in study report

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Subacute toxicity: oral

A subacute study was performed as a limit test, administrating 7232 mg/kg bw/day 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate to a group of 10 rats via gavage, 5 days/week within 23 days (Raleigh, 1984b).

In the study, 3/10 animals were killed by mechanical intubation accidents and 2/10 animals died after the 7th and 1/10 died following the 13th administration. No marked consistent changes in the blood values were reported. During gross pathology and histopathological examination, there were signs of minimal chronic murine pneumonitis in the 3 rats that succumbed. The 4 animals that were sacrificed at the end of the study showed mild to moderate hydropic degeneration of the liver. No evidence of “Glycol toxicity” in the form of nephrosis or calcium oxalate crystal deposition in the kidney tubules was observed in the test animals.

Subchronic toxicity: oral

A subchronic study with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate similar to OECD guideline 408 is available (Raleigh, 1984a). 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate was administered to groups of 15 Sprague-Dawley rats at doses of 0.1, 1 % in the diet (corresponding to calculated concentrations of 79.6, 796 mg/kg bw/day (m) and 119.5, 1195 mg/kg bw/day (f)), 7 days/week for 13 weeks. A concurrent negative control group receiving the diet only was included in the testing.

In the study, no test substance related mortality occurred and no signs of systemic toxicity were observed. In addition, no effects on body weight gain, food consumption, organ weights, haematological parameters and urinalysis were observed. During gross pathology and histopathological examination, no test substance related changes were apparent. There was no oxalate crystal precipitation in the kidneys of the test group animals or other evidence of nephrosis.

Thus, the resulting NOAEL for repeated dose toxicity is greater than the highest applied dose of 1% in the diet corresponding to 796 mg/kg bw/day (m) and 1195 mg/kg bw/day (f).

Subacute toxicity: inhalation

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate was tested in a subacute toxicity study via the inhalation route (Raleigh, 1984c). The study was performed as a limit test, at a saturated atmosphere ranging from 80 - 227 mg/m³ to a group of 6 male rats, 6 h/day, 5 days/week for 29 days.

No mortality was observed during the study period. Slight lacrimation in the treatment and control group was observed throughout each exposure and on the 7th exposure it was noted that the experimental animals´ fur was becoming tinged with yellow. Body weight gain in the treatment group was slightly reduced in comparison to the control group. No effects on haematological parameter and no changes during gross pathology were observed. No evidence was seen of irritant effects on the upper respiratory tract, eyes or nose. Histopathology showed no evidence of chemical pneumonitis or of the presence of any unabsorbed foreign substance in the alveoli.

Thus, the resulting NOEC for repeated dose toxicity via inhalation is greater than the highest administered dose of 277 mg/m³ air.

Conclusions for repeated dose toxicity

In summary, one subchronic repeated dose toxicity study via the oral route showed no adverse systemic effects resulting in a NOAEL greater than the highest applied dose of NOAEL of 796 mg/kg bw/day (m) and 1195 mg/kg bw/day (f) in rats.

One subacute repeated dose toxicity study via the inhalation route showed no adverse systemic effects resulting in a NOEC greater than the highest applied dose of 277 mg/m³ air in male rats.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected study is the most adequate and reliable study with the longest duration and the lowest dose descriptor.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
There is only one study available.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
There is only one study available.

Justification for classification or non-classification

The available data on the repeated dose 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.