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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose 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. Original reference in Japanese, study summary and tables in English.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: guidelines for 28-Day Repeat Dose Toxicity Test of Chemicals (Japan)
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-aminoethylamino)ethanol
EC Number:
203-867-5
EC Name:
2-(2-aminoethylamino)ethanol
Cas Number:
111-41-1
Molecular formula:
C4H12N2O
IUPAC Name:
2-[(2-aminoethyl)amino]ethan-1-ol
Details on test material:
2-(2-aminoethylamino)ethanol, purity 99.9 %

Test animals

Species:
rat
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 358-440 g ; females 221-275 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 60; 250; 1000 mg/kg bw / day
Basis:
nominal in water
No. of animals per sex per dose:
6 rats
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 days in a recovery group (6/sex) in dosis groups 0, 250 and 1000 mg/kg bw / day

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: every 3 days

FOOD CONSUMPTION AND COMPOUND INTAKE
- food consumption was recorded

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once during the treatment and recovery periods
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: not further described
- Animals fasted: No data
- How many animals: all animals

URINALYSIS: Yes
- Time schedule for collection of urine: not further described
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
- Animals were sacrificed at day 29  and day 43 after a 14-day recovery period.
- GROSS PATHOLOGY: Yes
- HISTOPATHOLOGY: Yes
Statistics:
The data were subjected to statistical analysis. However, it is not clear which method was used because this is not described in the English language sections of the paper.

Results and discussion

Results of examinations

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):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
(1) 28-day treatment groups

BODY WEIGHT AND WEIGHT GAIN
Body weight development was very similar in all treated groups and not influenced by the treatment.

FOOD CONSUMPTION
A temporary decrease in the food consumption was noted in females given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day duringthe early administration period

HAEMATOLOGY
Hematology revealed a decrease in hemoglobin concentration in both sexes given 1000 mg/kg bw / day (p<0.01 in males, p<0.05 in females).

CLINICAL CHEMISTRY
Blood chemistry revealed an increase in GOT activity in males given 250 and 1000 mg/kg bw / day (both p<0.05), a decrease in total cholesterol in females given 1000 mg/kg bw / day (p<0.05) and a decrease in chloride concentration in males given 1000 mg/kg bw / day (p<0.05). 

URINALYSIS
Urinalysis revealed an increase in protein concentration in females given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day, an increase in the specific gravity in females given 250 and 1000 mg/kg bw / day (p<0.05 and p<0.01, resp.), and a decrease in urinary volume in females given 1000mg/kg bw / day (p<0.05). 

ORGAN WEIGHTS
Kidneys: increased absolute and relative kidney weights were noted in males and increased relative kidney weights in females p<0.01) given 1000mg/kg bw / day. The relative adrenal weights were decreased in males given 1000 mg/kg (p<0.05) but no associated histopathological lesions were found. 

HISTOPATHOLOGY:
Histopathologically, deposition of amphophilic bodies and swelling in the renal proximal tubules in the cortico-medullary junction were noted in males given 250 mg/kg bw / day and in both sexes given 1000 mg/kg bw / day. Mucosal thickening of the stomach at the limiting ridge was noted in both sexes given 250 and 1000 mg/kg bw / day. 


(2) 14-day recovery groups

Compound-related changes were reversible except for those in the kidney and stomach after a 14-day recovery period, without gaining a level of statistical significance.

Effect levels

Dose descriptor:
NOEL
Effect level:
60 other: mg/kg bw / day
Sex:
male/female
Basis for effect level:
other: urinalysis; kidney weight and kidney histopathology at 250 mg/kg bw/d

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 

Dose [mg/kg bw / d]

Endpoint

Males

Females

 

0

60

250

1000

0

60

250

1000

 

 

 

 

 

 

 

 

 

Weight data at day 28

 

 

 

 

 

 

 

 

Body weight [g]

389

412

386

394

237

248

238

234

Kidneys [g]

2.8

2.95

2.97

3.19**

1.87

1.90

1.94

2.12

Kidneys [%]

0.72

0.72

0.78

0.81**

0.79

0.77

0.82

0.91**

Adrenals [mg]

69

65

64

58

75

75

80

75

Adrenals [%]

18

16

17

15*

32

31

34

32

 

 

 

 

 

 

 

 

 

Clinical chemistry

 

 

 

 

 

 

 

 

Hemoglobin [g/l]

15.8

15.7

16.0

14.9**

15.9

15.5

15.2

14.8*

GOT [IU/l]

65

61

76*

76*

67

70

70

69

Chloride [mEq/l]

110

108

110

107*

111

111

112

110

Cholesterol [mg/dl]

66

64

51*

55

85

72

78

57*

 

 

 

 

 

 

 

 

 

Urinalysis

 

 

 

 

 

 

 

 

Volume [ml]

14.8

17

14.7

13.4

11.4

9.6

7.8

4.5*

Gravity [g/ml]

1.062

1.06

1.069

1.07

1.053

1.073

1.081*

1.1**


Values expressed as means; * = p<0.05; ** = <0.01

Applicant's summary and conclusion

Executive summary:

Repeated Dose 28 - Day Oral Toxicity:

In a subacute toxicity study AEEA (99,9 % a.i.) was administered to six Crj:CD (SD) rats per sex per dose by gavage at dose levels of 0, 60, 250 or 1000 mg/kg bw/day for a period of 28 days (Okazaki, 1996). The NOEL was considered to be 60 mg/kg bw/day for both males and females.

In the 28-day treatment a temporary decrease in the food consumption was noted in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day during the early administration period. Hematology revealed a decrease in hemoglobin in both sexes given 1000 mg/kg bw/day. Blood chemistry revealed an increase in GOT in males given 250 and 1000 mg/kg bw/day, a decrease in total cholesterol concentration in females given 1000 mg/kg bw/day and a decrease in chloride concentration in males given 1000 mg/kg bw/day. Urinalysis revealed an increase in protein concentration in females given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day, an increase in the specific gravity in females given 250 and 1000 mg/kg bw/day and a decrease in urinary volume in females given 1000 mg/kg bw/day. Increased absolute and relative kidney weights were noted in males and increased relative kidney weights in females given 1000 mg/kg bw/day. The relative adrenal weights were decreased in males given 1000 mg/kg bw/day but no associated histopathological lesions were found. Histopathologically, deposition of amphophilic bodies and swelling in the renal proximal tubules in the corticomedullary junction were noted in males given 250 mg/kg bw/day and in both sexes given 1000 mg/kg bw/day. Mucosal thickening of the stomach at the limiting ridge was noted in both sexes given 250 and 1000 mg/kg bw/day. In the 14 -day recovery groups compound-related changes were reversible. After the 14 -day recovery period minimal (grade 1) focal basophilic changes in the proximal tubule was noted in 2/6 and 5/6 males at 250 and 1000 mg/kg bw/d, respectively. The relevance of this finding is questionable since this effect was observed in males of the recovery group, but neither in males of the 1000 mg/kg bw/d group nor in the 1000 mg/kg bw/d females dosing and recovery group and was also present in 1/6 control females.

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a repeated dose oral toxicity study in rodents (OECD guideline 407).