Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: performed according to GLP and OECD guideline 474

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dapsone, batch no. 70522014, white powder, purity 99.69%, stored at 1-10 degrees C in the dark.

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River-UK Ltd
- Age at study initiation: 7 weeks
- Weight at study initiation: 26-33g
- Diet (e.g. ad libitum): availabe ad-libitum
- Water (e.g. ad libitum): availabe ad-libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 deg C
- Humidity (%): 52-61%
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
1% methylcellulose in water
Details on exposure:
Groups of 8 males mice (as there was no evidence of sex-related differences in toxicity in the range finding test) were used for each dose groups and one control group. Dose levels were 0, 43.75, 87.5, 175 mg/kg bw/day in the main experiment. A positive control group of 8 male mice received 40 mg/kg cyclophosphamide once on day 2 of the experiment.
Duration of treatment / exposure:
2 consecutive days
Frequency of treatment:
daily once
Post exposure period:
none
No. of animals per sex per dose:
8 males per dose (as no evidence of sex-related differences in toxicity was revealed in the range finding test)
Control animals:
yes, concurrent no treatment
Positive control(s):
cyclophosphamide, 40 mg/kg bw once on day 2

Examinations

Tissues and cell types examined:
Bone marrow were analysed for numbers of micronucleated polychromatic erythrocytes.
Details of tissue and slide preparation:
femours were excised and the content washed out with a syringe into 1% fetal bovine serum in RPMI medium
Evaluation criteria:
Slides had to have at least 1000 scorable cells (PCE and NCE).
A statistical increase in CE is necessary,
the frequency of PCE is higher than the historical control range.
Statistics:
Statistics was applied

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Positive controls validity:
valid
Additional information on results:
A significant increase in PCE was found with Dapsone as compared to the control group, but a significant increase with the positive control was observed, thus validating the study.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Based on the available Mouse micronucleus test (bone-marrow) it can be concluded that Dapsone is not mutagenic in-vivo.
Executive summary:

In the present mouse micronucleus study, no increase in PCE was observed with Dapsone, while the positive control Cyclophosphamide showed a significant increase in PCE. With Dapsone the mice were treated up to the highest dose not causing mortality as shown in the pre-experiment.

Based on the absence of any increase of PCE with Dapsone at any dose level tested, it is concluded that Dapsone has no mutagenic potential in-vivo.