Ibuprofen

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian cell study: DNA damage and/or repair

Type of information:

experimental study

Adequacy of study:

key study

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:

publication

Title:

Comparative mutagenic and genotoxic effects of three propionic acid derivatives ibuprofen, ketoprofen and naproxen

Author:

Philipose, B; Sing, R; Khan, KA; Giri, AK;

Year:

1997

Bibliographic source:

Mutation Research 393 (1997) 123-131

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

A sister chromatid exchange (SCE) assay was performed in Swiss mice. Paraffin-coated BrdU tablets were implanted subcutaneous, and the test substance was administered once intraperitoneal (25, 50, 100 mg/kg, 1h after tablet implantation) or once orally (gavage, 270 mg/kg, 0.5 h after tablet implantation) in 5 male mice per dose. Twenty-four hours after implantation, bone marrow slides were prepared and stained with fluorescence-plus-Giemsa technique. Per dose 150 cells were counted. 

GLP compliance:

no

Type of assay:

sister chromatid exchange assay

Test material

Test material information

Constituent 1

Reference substance name:

Ibuprofen

EC Number:

239-784-6

EC Name:

Ibuprofen

Cas Number:

15687-27-1

Molecular formula:

C13H18O2

IUPAC Name:

2-(4-isobutylphenyl)propanoic acid

Test material form:

solid

Specific details on test material used for the study:

Ibuprofen, purchased from the Sigma Chemical Company (St. Louis, MO).

Test animals

Species:

mouse

Strain:

Swiss

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Division of Laboratory Animals, Central Drug Research Institute, Lucknow.
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 30g
- Housing: 5 per cage with husk bedding
- Diet: standard rodent pellet diet (Gold Mohar, Lipton India Ltd., Chandigarh, India), ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 28 ± 2
- Humidity (%): 60 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: intraperitoneal and oral (gavage)

Vehicle:

VEHICLES
- Intraperitoneal: DMSO
- Oral: distilled water in 2% gum acacia

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Intraperitoneal: injection of 75 µL/mouse
- Oral: 0.3 mL/mouse

Duration of treatment / exposure:

24 hours

Frequency of treatment:

Single administration

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

25 mg/kg bw/day

Remarks:

intraperitoneal

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day

Remarks:

intraperitoneal

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day

Remarks:

intraperitoneal

Doses / concentrations 4

Dose / conc.:

270 mg/kg bw/day

Remarks:

oral

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control(s):

- Intraperitoneal: Mitomycin C, 1.5 mg/kg bw
- Oral: Cyclophosphamide in distlled water, 10 mg/kg

Examinations

Tissues and cell types examined:

Bone marrow

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION: The dose selected for the in vivo studies of three drugs (ibuprofen, naproxen, ketoprofen) was based on the LD50 dose of ibuprofen available in the literature. The highest dose selected in the i.p. study (100 mg/kg) was approximately one-third of the LD50 (320 mg/kg) of mice for ibuprofen reported earlier.

TREATMENT AND SAMPLING TIMES: BrdU tablets were implanted subcutaneously in the flank of mice under ether anesthesia. The substance was administered intraperitoneal (1h after implantation) and oral (0.5 hour after implantation).

DETAILS OF SLIDE PREPARATION:
- I.P. For SCE analysis, colchicine 4 mg/kg was injected i.p. 22 h after Brdu tablet implantation. Two hours later bone marrow was expelled with 0.075 M KCl at 37 °C for 20 min, cells were fixed three times with methanol/acetic acid (3:1). The slides were prepared and chromosomes were differentially stained with fluorescence-plus-Giemsa technique.
- ORAL: Twenty-two hours after the BrdU tablet implantation, colchicine was injected, and the rest of the procedure was the same as described above.

METHOD OF ANALYSIS: All the slides were coded and 30 second-division metaphase cells (40 ± 2 chromosomes) per animal were scored for SCE frequencies, i.e. a total of 150 cells were scored per dose tested.

Statistics:

- Dunnett’s multiple comparison for i.p. SCE results
- Student's t-test to compare the oral SCR results of each treated group

Results and discussion

Test results

Key result

Sex:

male

Genotoxicity:

positive

Remarks:

at 50- and 100- mg/kg doses (intraperitoneal) and at 270 mg/kg (oral)

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Additional information on results:

A significant increase in SCE was observed at 50- and 100-mg/kg doses. A single oral dose of ibuprofen (270 mg/kg) also gave a weak, but significant, increase in SCE when compared with control.
The SCE/cell after i.p. administration was 4.50, 5.04, 5.70, and 6.00 at 0, 25, 50, and 100 mg/kg bw.
The SCE/cell after oral administration was 4.68 and 6.16 at 0 and 270 mg/kg bw.