Liraglutide precursor

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2014

Report date:

2003

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes

Type of assay:

other: micronuclei in erythrocytes of the bone marrow

Test material

Specific details on test material used for the study:

Study performed using the active pharmaceutical ingredient Liraglutide as test substance

Test animals

Species:

rat

Strain:

other: Crl:CD BR(CD)

Details on species / strain selection:

Not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not specified

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

Phosphate buffer

Details on exposure:

Four groups, each of seven male rats were administered 0, 7.5, 15 and 30 mg liraglutide/kg/day on four consecutive days. Additionally, one vehicle, one untreated, and one positive control (Cyclophoschamide 40mg/kg single dose) group were administrated.

Duration of treatment / exposure:

-One daily administration for four consecutive days for the treated, untreated, and vehicle control group.
-The positive control group was given a subcutaneous injection of Cyclophoschamide.

Frequency of treatment:

Four (one subcutaneous injection per day)

Post exposure period:

Animals were sacrificed 24 hours after the last treatment.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

7.5 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

30 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

7 male rats per dose

Control animals:

yes, concurrent vehicle

Positive control(s):

Yes, Cyclophoschamide.

Examinations

Tissues and cell types examined:

Polychromatic erythrocytes (PCE) from bone marrow

Details of tissue and slide preparation:

Not specified

Evaluation criteria:

Micronucleus frequency was estimate din 1000 PCE per animal

Statistics:

Not specified

Results and discussion

Test results

Key result

Sex:

male

Genotoxicity:

negative

Toxicity:

yes

Remarks:

reduction in weight gain and in the ratio between polychromatic and normochromatic erythrocytes compared to controls.

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

Slides from all dose groups were analysed and micronucleus frequency estimated in 1000 PCE per animal. All positive control animals exhibited increased numbers of micronucleated PCE such that the micronucleus frequency in the positive control group was significantly greater than in concurrent controls.

Mice treated with all three doses levels of Liraglutide showed a reduction in weight gain relative to control, and a reduction in group mean ratios of PCE to NCE compared to control group. Furthermore, the group mean frequencies of micronucleated erythrocytes were similar to those of the controls at all dose levels.

Liraglutide did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of treated rats up to 30 mg/kg, a dose at which bone marrow toxicity was seen.

Applicant's summary and conclusion

Conclusions:

Determination of micronuclei in the bone marrow of Liraglutide treated rats was conducted in accordance to OECD Test Guideline 474. The test compound did not induce micronuclei in polychromatic erythrocytes of the bone marrow of rats treated up to 30 mg/kg/day, a dose at which bone marrow toxicity were seen.

Executive summary:

Determination of micronuclei in the bone marrow of Liraglutide treated rats was conducted in accordance to OECD Test Guideline 474. Liraglutide was assayed for its potential to induce micronuclei in the bone marrow of polychromatic erythrocytes (PCE) of male Crl:CD®BR(CD) rats after s.c. injection. Four groups, each of seven male rats were administered 0, 7.5, 15 and 30 mg liraglutide/kg/day on four consecutive days. The rats were killed 24 hours after the final administration and bone marrow was sampled. All three dose levels caused a reduction in weight gain relative to controls and a reduction in the ratio between polychromatic and normochromatic erythrocytes. The group mean frequencies of micronucleated erythrocytes were similar to those of the controls at all dose levels. Liraglutide did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of treated rats up to 30 mg/kg, a dose at which bone marrow toxicity was seen.