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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: subacute and subchronic
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no official method, no GLP, decent documentation about methodology, basic/limited info about processing of results data and results; however this publication is key data since the lowest NOEL has been determined here.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
german title [Zur Toxikologie des Äthylenglykol-Monoäthyläthers], english translation [On the toxicology of Ethyleneglycol-monethylether]
Author:
Stenger EG, Aeppli L, Müller D, Peheim E, Thomann P
Year:
1971
Bibliographic source:
Arzneimittel-Forschung (Drug Research) 6, 880-885
Reference Type:
publication
Title:
No information
Author:
Gross, E., cited in: Patty, F.A., Industrial Hygiene and Toxicology, Interscience Publishers, Vol. II, 2nd Ed., 1963
Year:
1963
Bibliographic source:
Industrial Hygiene and Toxicology, Interscience Publishers, Vol. II, 2nd Ed.

Materials and methods

Principles of method if other than guideline:
Subacute and subchronic oral toxicity and toxicity to reproduction
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethoxyethanol
EC Number:
203-804-1
EC Name:
2-ethoxyethanol
Cas Number:
110-80-5
Molecular formula:
C4H10O2
IUPAC Name:
2-ethoxyethanol
Details on test material:
Test substance as stated in publication (German language): Äthylenglykol-Monoäthylether, english translation [Ethylene glycol monoethyl ether];
Specific weight as stated in publication: 0.929
Dilutions of the substance: prepared with physiological saline solution

Test animals

Species:
other: rabbit (Gross E); rat; dog
Strain:
other: no data - rabbit (Gross E); Wistar, "CF-Mehrzweck" (rat); Beagle (dog)
Sex:
male/female
Details on test animals or test system and environmental conditions:
rabbit (Gross): no further details

rat:
supplier: Carworh Europe
health status: SPF
weight: 120-140 g
feed: Tierfutter Nafag Futterwürfel Nr. 185 (English, translated: Animal feed Nafag feed cubes Nr. 185)
housing: Makrolon cage, 5 animals/cage
lighting: daylight
temperature: 23 +/- 2 °C
relative humidity: 55+/- 10 °C

dog:
supplier: directly from breeder, England
health status: conventional
weight: 7.0 - 14.0 kg
feed: Tierfutter Nafag Futterwürfel Nr. 164 (English, translated: Animal feed Nafag feed cubes Nr. 164)
housing: metal cage, 1 animal/cage
lighting: daylight
temperature: 21 +/- 2 °C
relative humidity: 55 +/- 10 %

Administration / exposure

Route of administration:
other: per os/oral gavage (rabbit, Gross E);
Details on oral exposure:
rat study, per os: substance dosed in 10 ml/kg/d physiological saline solution for 13 weeks
dog study, per os, 11 d: dosed in 5 ml/kg/d physiological saline solution
dog study, per os, 13 wk: dosed as 1 gelatine capsule/d
Analytical verification of doses or concentrations:
not specified
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.1 - 1 ml/kg/d
Basis:
other: 7 applications (rabbit, Gross E)
Remarks:
Doses / Concentrations:
0, 50, 100, 200 µl/kg/d (0, 46, 93, 186 mg/kg/d); 100 µl/kg/d (93 mg/kg/d) for 8 weeks (until d 59) followed by 400 µl/kg/d (370 mg/kg/d) for 5 weeks; 200 µl/kg/d (186 mg/kg/d) for 8 weeks (until d 59) followed by 800 µl/kg/d (741 mg/kg/d) for 5 wk.
Basis:
other: rat, per os, 7 times/wk, 13 wk
Remarks:
Doses / Concentrations:
500, 1000 µl/kg bw/d
Basis:
other: dog, per os, 5 times/wk, 11 d (diluted with 50 ml water)
Remarks:
Doses / Concentrations:
0, 50, 100, 200 µl/kg bw/d
Basis:
other: dog, per os, 7 times/wk, 13 wk
No. of animals per sex per dose:
no data (rabbit, Gross E)
5 male and 5 female (rat, per os, 13 wk study)
1 male and 1 female (dog, per os, 11 d study)
3 male and 3 female (dog, per os, 13 wk study)
Control animals:
other: no data: (rabbit, Gross, E); yes, for other studies
Details on study design:
Post-exposure period: no data for rabbit study (rabbit, Gross E) and other studies

Results and discussion

Effect levels

Dose descriptor:
NOEL
Effect level:
25 other: µL/kg/day
Based on:
test mat.
Basis for effect level:
other: result from developmental toxicity evaluation; the effect level corresponds to 23 mg/kg (with a density of 0.919 g/mL at 25 °C)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

rabbit (Gross E): albuminuria, hematuria (see also more details in publication: Gross E., cited in Patty F.A., 1963)

Results subchronic oral gavage rat (13 weeks):

At doses of 50, 100 and 100/400 µL/kg/day (increased dosage from 100 to 400 µL/kg at day 59 of the study period) no treatment related systemic changes in the analysed organs were observed. The administration of 200 µL/kg/day resulted in all 5 male rats in obvious changes in the testes (interstitium loosened oedematously). In the tubuli there was a lack of the last ripening step from the normally arranged germinal epithelium to the spermatocytes. In the spleens of all animals haemosiderin deposits were observed. Nearly same results were observed in the dose group 200/800 µL/kg/day (increased dosage from 200 to 800 µL/kg at day 59 of the study period).

Results subchronic oral gavage (gelatine capsules) dog (13 weeks):

At doses of 50 and 100 µL/kg/day no macroscopic nor histological treatment related systemic changes in the analysed organs were observed. At 200 µL/kg/day changes of the testes in the 3 male dogs were seen. In 2 male and one female slight changes were observed at the kidneys.

Summarised results (rat and dog):

Mortalities: none (13 wk rat study; 11d dog study; 13 wk dog study)

Symptoms: none (13 wk rat study; 11 d dog study; 13 wk dog study)

Body weight development: at dosage including level 800 µl/kg/d from day 60 on slightly retarded for males (13 wk rat study); 1 and 3 kg, 2 and 2.6 kg (11 d dog study); no effect (13 wk dog study)

Feed consumption: at dosage including level 800 µl/kg/d from day 60 on reduced (13 wk rat study); not measured (11 d dog study); no effects (13 wk dog study)

Hemoglobin and hematocrite:

no effect (11 d dog study)

13 wk rat study:

       Hemoglobin g% (group mean values)
dose (µl/kg/d)  wk 0 wk 4   wk 5  wk 9  wk 13
 0  -  -  14.1  15.3  15.6
 50  -  -  -  -  -
 100  -  -  -  -  14.4
 200  -  -  13.7  14.5  14.2
 100/400  -  -  -  -  12.6
 200/800  -  -  -  -  11.0

13 wk rat study:

               Hematocrite % (group mean values)
 dose (µl/kg/d)  wk 0  wk 4  wk 5  wk 9  wk 13
 0  -  -  47  47  49
 50  -  -  -  -  -
 100  -  -  -  -  47
 200  -  -  45  47  47
 100/400  -  -  -  -  42
 200/800  -  -  -  -  39

13 wk dog study:

               Hematocrite % (group mean values)
 dose (µl/kg/d)  wk 0  wk 4  wk 5  wk 9  wk 13
 0  47  -  46  48  50
 50  47  -  47  45  47
 100  48  -  42  44  43
 200  45  -  37  38  38

13 wk dog study:

               Hemoglobin g% (group mean values)
 dose (µl/kg bw/d)  wk 0  wk 4  wk 5  wk 9  wk 13
 0  15.6  -  15.5  15.6  16.9
 50  15.6  - 15.8  14.7  15.7
 100  15.7  -  14.4  14.1  14.9
 200  15.1  -  12.4  12.1  13.2

Results on developmental toxicity:

The administration of 0, 12.5, 25, 50, 100, 200, or 400 µL/kg/day during gestation (day1 to day 21) resulted in a NOEL for the rat of 25 µL/kg/day. As this value was the lowest according to the complete study results of Stenger et al. (1971), the author of this IUCLID dossier considered this low value also as the overall NOEL for this endpoint.

Applicant's summary and conclusion

Conclusions:
The test substance 2-ethoxyethanol was administered during 13 weeks (subchronic) to rats and dogs. According to these results NOELs for the rat and the dog were determined to be 100 µL/kg/day and 50 µL/kg/day. Additionally the developmental toxicity of the test substance was evaluated. Female rats were administered different concentrations of the test substance orally during gestation (day 1 to 21). The derived NOEL from this experiment was 25 µL/kg/day for the rat. The author of the publication mentioned that according to this developmental toxicity result, the overall NOEL for the rat should be reduced to 50 µL/kg/day. In the opinion of the author of IUCLID dossier the overall NOEL should correspond to the lowest value, thus 25 µL/kg/day.