Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

Subacute oral toxicity study in CD-1 mice (2 weeks)

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Materials and methods

Principles of method if other than guideline:

In a subacute toxicity study 15 male and 15 female mice per dose group were treated with 15 or 150 ppm of the test item in their drinking water for two weeks. 5 males and 5 females each served as control groups. The animals were observed for clinical signs and body weights, food and water consumption was measured. Blood for toxicokinetic investigation was collected at the end of the study.
The treatment resulted in the following mean daily test substance intake (in ascending dosages): 3.3 and 34.7 mg test item/kg body weight in males and 4.2 and 41.1 mg test item /kg body weight in females.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

EC Number:

875-892-5

Cas Number:

1375799-59-9

Molecular formula:

C13 H14 N8 O2 . Na

IUPAC Name:

Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Details on route of administration:

2 weeks (Animals received the test substance/tap water mixture until day of scheduled necropsy).

Vehicle:

unchanged (no vehicle)

Remarks:

The micronized test substance was administered in the tap water. The test substance was mixed into the drinking water at the appropriate concentrations at room temperature. The formulations were prepared once per week.

Analytical verification of doses or concentrations:

yes

Remarks:

The suitability of the proposed formulations was confirmed by the analyses of concentration and stability of dosage forms with concentrations of 0.001 mg/mLand 0.4 mg/mL. Analyses were carried out before the start of the study.

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

150 ppm

Doses / concentrations 2

Dose / conc.:

15 ppm

Doses / concentrations 3

Dose / conc.:

0 ppm

No. of animals per sex per dose:

5 in the negative control and 15 in the treatment groups

Control animals:

yes, concurrent no treatment

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

15 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

clinical signs

2

Dose descriptor:

NOAEL

Effect level:

150 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

water consumption and compound intake

Applicant's summary and conclusion

Conclusions:

In a subacute toxicity study 15 male and 15 female mice per dose group were treated with 15 or 150 ppm Molidustat in their drinking water for two weeks. 5 males and 5 females each served as control groups. Survival was not affected by the treatment. With the exception of reddened skin, no further treatment-related clinical findings were recorded. At 150 ppm the body weight development in females was slightly retarded. Food intake was not affected by the treatment. Water intake was in treated females groups and in 150 ppm males was slightly increased. The no-observed-adverse-effect level was 150 ppm in males and 15 ppm in female (due to a slight effect on body weight development).

Executive summary:

In a subacute toxicity study 15 male and 15 female mice per dose group were treated with 15 or 150 ppm of the test item in their drinking water for two weeks. 5 males and 5 females each served as control groups.
The animals were observed for clinical signs and body weights, food and water consumption was measured. The treatment resulted in the following mean daily test substance intake (in ascending dosages): 3.3 and 34.7 mg test item/kg body weight in males and 4.2 and 41.1 mg/kg body weight in females. Survival was not affected by the treatment. With the exception of reddened skin, no further treatment-related clinical findings were recorded.
In all male dose groups and in females at 15 ppm body weight development was comparable to that in the respective control group. At 150 ppm the body weight development in females was slightly retarded.
Food intake was not affected by the treatment. Water intake was in treated females groups and in 150 ppm males was slightly increased. The no-observed-adverse-effect level was 150 ppm in males and 15 ppm in female (due to a slight effect on body weight development).