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Toxicological information

Genetic toxicity: in vivo

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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (supervised by NTP); published data without detailed documentation

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
2010
Report Date:
2010
Reference Type:
publication
Title:
Toxicity and carcinogenicity of androstendione in F344/N rats and B6C3F1 mice
Author:
Blystone CR et.al.
Year:
2011
Bibliographic source:
Food and Chemical Toxicology 49, 2116-2124

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: NTP laboratory health and safety guidelines
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Principles of method if other than guideline:
The study was performed according to standard three-exposure protocol as described by Shelby et al., Environ. Mol. Mutagen. 21, 1993, 160-179.

Cited from report: "These are the basic guidelines for arriving at an overall assay result for assays performed by the National Toxicology Program. Statistical as well as biological factors are considered. For an individual assay, the statistical procedures for data analysis have been described in the preceding protocols. There have been instances, however, in which multiple aliquots of a chemical were tested in the same assay, and different results were obtained among aliquots and/or among laboratories. Results from more than one aliquot or from more than one laboratory are not simply combined into an overall result. Rather, all the data are critically evaluated, particularly with regard to pertinent protocol variations, in determining the weight of evidence for an overall conclusion of chemical activity in an assay. In addition to multiple aliquots, the in vitro assays have another variable that must be considered in arriving at an overall test result. In vitro assays are conducted with and without exogenous metabolic activation. Results obtained in the absence of activation are not combined with results obtained in the presence of activation; each testing condition is evaluated separately." The summary table in the Abstract of the Technical Report presents a result that represents a scientific judgement of the overall evidence for activity of the chemical in an assay.
GLP compliance:
not specified
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no data in NTP TR 560

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: F344/N
no further data in NTP TR 560

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil
Details on exposure:
Preliminary range-finding studies were performed. Factors affecting dose selection included chemical solubility and toxicity and the extent of cell cycle delay induced by androstenedione exposure.
Duration of treatment / exposure:
3 days; The animals were killed 24 hours after the third dosing and bone marrow samples prepared.
Frequency of treatment:
three times at 24-hour interval
Post exposure period:
24 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
312.5 and 625 mg/kg bw
Basis:
actual ingested
exposure: 3 days
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
The positive control animals received injections of cyclophosphamide (15 or 25 mg/kg).

Examinations

Tissues and cell types examined:
The animals were killed 24 hours after the third dosing, and blood smears were prepared from bone marrow cells obtained from the femurs. Air-dried smears were fixed and stained. 2000 polychromatic erythrocytes (PCEs; reticulocytes) were scored for the frequency of micronucleated cells in each of up to five animals per dose group. In addition, the percentage of PCEs among the total erythrocyte population in the bone marrow was scored for each dose group as a measure of toxicity.
Evaluation criteria:
In the micronucleus test, an individual trial is considered positive if the trend test P value is less than or equal to 0.025 or if the P value for any single dosed group is less than or equal to 0.025 divided by the number of dosed groups. A final call of positive for micronucleus induction is preferably based on reproducibly positive trials. Ultimately, the final call is determined by the scientific staff after considering the results of statistical analyses, the reproducibility of any effects observed, and the magnitudes of those effects.
Statistics:
The frequency of micronucleated cells among PCEs was analyzed by a statistical software package that tested for increasing trend over dose groups with a one-tailed Cochran-Armitage trend test, followed by pairwise comparisons between each dosed group and the control group (Integrated Laboratory Systems (ILS), Micronucleus Data Management and Statistical Analysis Software, Version 1.4. ILS, Inc., P.O. Box 13501, Research Triangle Park, NC 277071990, 1990). In the presence of excess binomial variation, as detected by a binomial dispersion test, the binomial variance of the Cochran-Armitage test was adjusted upward in proportion to the excess variation.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
In vivo, no significant increases in the frequencies of micronucleated PCEs (reticulocytes) were observed in bone marrow of male F344/N rats administered androstenedione (312.5 or 625 mg/kg) by gavage once daily for 3 days. No significant changes in the percentages of PCEs among total erythrocytes were seen in the rats, suggesting no androstenedione-associated toxicity in the bone marrow.

Applicant's summary and conclusion

Conclusions:
negative
Executive summary:

Cited from NTP-report:

"No significant increases in the frequencies of micronucleated polychromatic erythrocytes, indicators of chromosomal damage, were observed in bone marrow of male rats administered androstenedione by gavage once daily for 3 consecutive days."