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Administrative data

Description of key information

No adverse effect found up to the highest dose 750 mg/kg/day in oral subacute toxicity study in rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study; well-performed and well-documented
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
once per day
Remarks:
Doses / Concentrations:
0, 100, 250, 750 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on results:
No Test Item related mortality occurred in this study.
Clinical symptoms observed during treatment and recovery period are related to local irritation of the Test Item. Dose-dependently moving of the bedding, salivation and piloerection were noted in the 250 and 750 mg/kg bw groups. No Test Item related findings were noted during weekly detailed clinical observation and in parameters of the functional observation battery. There were no biologically relevant differences in body temperature between the groups.
No Test Item related effect on body weight development and food consumption was observed during the treatment or recovery period of this study.
No Test Item related effect on haematological parameters and coagulation parameters were noted at the end of the treatment or recovery period.
No Test Item related effect on parameters of clinical biochemistry was noted at the end of the treatment or recovery period. A slightly lower serum level of Total Bile Acids in the 250 and 750 mg/kg bw groups at the end of the treatment period is not considered an adverse effect.
No Test Item related effect on urinary parameters was noted at the end of the treatment or recovery period.
There were no adverse Test Item related macroscopic findings in this study.
A higher liver weight in the 750 mg/kg bw group found at the end of the treatment period and associated with minimal centrilobular hepatocellular hypertrophy is considered an adaptive response to the Test Item and is not assumed to be adverse.
The premature death of one male rat treated at 250 mg/kg/day was considered to be due to gavage accident. All other animals survived until scheduled necropsy.
At terminal sacrifice, test item-related histopathological findings considered to be toxicologically relevant were seen in the liver and thyroid gland, in a low proportion of animals and at 750 mg/kg/day only. In the liver, minimal centrilobular hepatocellular hypertrophy was noted, corroborating the higher mean liver weight recorded in this group. In the thyroid gland, a minimal diffuse follicular cell hypertrophy was observed and considered to be secondary to the liver change. The liver and thyroid gland findings recovered completely during the recovery period.
Furthermore, in the nonglandular part of the stomach (at 750 mg/kg/day) and in the trachea (in all test item-treated groups, without clear dose-relationship), epithelial changes were seen which were considered to be indicative of a local irritant effect of the test item formulation, and therefore to be toxicologically irrelevant. They were no longer seen after the recovery period.
As a conclusion, histopathological liver and associated thyroid gland changes were minor in degree, restricted to the 750 mg/kg/day dose group and resolved during the recovery period. No other toxicologically relevant lesions were noted in pathology. Therefore, the dose of 750 mg/kg/day is considered to be the NOAEL (No Observed Adverse Effect Level) for pathology under the conditions of this study.
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Up to the highest applied dose of 750 mg/kg bw no signs of systemic toxicity were found.
Critical effects observed:
not specified

Table: Effects found in the provided study

            presented only if deviating values were obtained for controls and treated animals

At the time administration was concluded

At the time recovery was concluded

Vehicle control

(n = 5)

100 mg/kg bw

(n = 5)

250 mg/kg bw

(n = 4)

750 mg/kg bw

(n = 5)

Vehicle control

(n = 5)

750 mg/kg bw

(n = 5)

Clinical Chemistry

ALAT

[U/L]

Males

19.28

± 2.27

16.74

± 0.84

17.63

± 1.91

15.20**

± 1.03

16.50

± 1.43

14.20*

± 1.19

females

13.85

± 1.93

12.65

± 2.09

11.64

± 1.76

13.13

± 6.04

11.74

± 1.12

16.34

± 5.39

TBA

[µmol/L]

Males

63.75

± 48.64

61.34

± 67.12

45.83

± 15.14

21.20

± 9.67

36.28

± 15.08

47.94

± 30.90

females

33.87

± 13.88

35.19

± 30.76

15.43

± 12.58

11.57

± 7.72

26.72

± 14.86

14.17

± 10.05

Gluc

[mmol/L]

Males

6.86

± 1.98

9.81

± 0.79

8.32

± 1.77

11.65 **

± 2.61

8.85

± 2.24

8.82

± 0.53

females

5.19

± 0.86

5.80

± 0.64

5.73

± 0.21

5.89

± 0.34

6.91

± 1.14

7.54

± 2.46

Organ weight

Liver [g]

Males

8.04

± 0.35

8.52

± 0.47

8.54

± 0.81

9.86**

± 0.78

8.56

± 0.66

8.48

± 0.86

females

5.31

± 0.18

5.62

± 0.64

4.98

± 0.37

6.50 **

± 0.71

4.91

± 0.13

5.42

± 0.54

Mean ± SD

*: significantly different from vehicle control at p < 0.05

**: significantly different from vehicle control at p < 0.01

Conclusions:
The registration substance was investigated for its repeated dose toxicity according to the OECD Guideline 407. The rats were given the registration substance per gavage at doses of 0, 100, 250 and 750 mg/kg bw. The study comprised also the recovery groups for vehicle control and 750 mg/kg bw.
The NOAEL of 750 mg/kg bw was found.
Executive summary:

The registration substance was investigated for its repeated dose toxicity according to the OECD Guideline 407. The rats were given the registration substance per gavage at doses of 0, 100, 250 and 750 mg/kg bw. The study comprised also the recovery groups for vehicle control and 750 mg/kg bw.

No signs of treatment related systemic toxicity were observed with reference to mortality, clinical symptoms, body weight development, food consumption, haematology, clinical biochemistry, urinalysis, macroscopical examination. Increased liver weight at a dose level of 750 mg/kg/day was considered as an adaptive and reversible response. Histopathologically, liver and associated thyroid gland changes were minor in degree, restricted to the 750 mg/kg/day dose group and resolved during the recovery period. No other toxicologically relevant lesions were noted in pathology. Therefore, the dose of 750 mg/kg/day is considered to be the NOAEL (No Observed Adverse Effect Level) for pathology under the conditions of this study.

Slight clinical symptoms and epithelial changes in the nonglandular part of the stomach and in the trachea at 750 mg/kg/day indicate a local irritant effect.

Overall, the dose level of 750 mg/kg/day is considered to be the NOAEL (No Observed Adverse Effect Level) for this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One valid 28-day study in rats

Additional information

Justification for classification or non-classification

No classification assigned based on the results obtained in the oral 28 -day study in rats.