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

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

May 1981

GLP compliance:

yes (incl. QA statement)

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

Remarks:

Crl:CD-1(ICR)BR

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

other: 100 mM Sodium hydrogen carbonate/ L demineralized water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The formulations were prepared once weekly taking into account the analytically determined stability. For the preparation of the formulations the content of test item was calculated based on the purity of 100 %. Preparation of the test formulations was performed based on weight, not taking into account the actual density of the vehicle.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to the start of treatment, the test formulation was checked with regard to accuracy of concentration and stability of dosage forms prepared in the same way as it was done in the study. Analyses were carried out before the start of the study. Stability: Prior to the start of treatment the dosage forms were analyzed shortly after preparation, 4, 8, and 14 days thereafter. After termination of the study the dosage forms were analyzed shortly after preparation, 7, and 14 days thereafter.

Duration of treatment / exposure:

At all dose levels, 60 animals per dose and sex were used as main groups treated over a period
of 728-736 days.

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: mg/kg via drinking water

Doses / concentrations 2

Dose / conc.:

0.54 other: mg/kg via drinking water

Doses / concentrations 3

Dose / conc.:

1.61 other: mg/kg via drinking water

Doses / concentrations 4

Dose / conc.:

5.35 other: mg/kg via drinking water

No. of animals per sex per dose:

60

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Key result

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In conclusion, in a 2-year oncogenicity study in mice, Molidustat is non-carcinogenic.
Minor mode of action-related effects on hematopoiesis were observed at 5 mg/kg.

Executive summary:

In a study conducted according to OECD guideline 451 (1981) the carcinogenic potetial of Molidustat was investigated by daily oral administration in drinking water of 0, 0.54, 1.61, and 5.35 mg/kg of the substance over a period of up to 2 years to female and male CD-1 mice. The treatment of mice with the test item was well tolerated.
No test item-related mortality or toxicologically relevant test-item-related signs of systemic toxicity were observed up to the high dose of 5 mg/kg. Histopathological investigation did not show any treatment-related increase in neoplastic and non-neoplastic lesions up to and including 5 mg/kg. Thus, Molidustat, is non-carcinogenic in mice. Based on the pharmacological mode of action of the test item, erythrocyte count, hemoglobin concentration and hematocrit value were significantly increased in both sexed dosed at 5.0 mg/kg which was also reflected in a slight increase in medullary and splenic erythropoiesis. In conclusion, in a 2-year oncogenicity study in mice, Molidustat is non-carcinogenic. Minor mode of action-related effects on hematopoiesis were observed at 5 mg/kg.