Testosterone

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

An UDS-test conducted in vitro with primary hepatocytes showed no increased DNA-repair after treatment. In addition, an assay for DNA-adducts in human liver slices was negative. These findings are substantiated by data taken from the IARC Supplement 6 indicating no induction of sperm abnormalities, no micronuclei in vivo and negative results in a bacterial mutagenic assay.

Link to relevant study records

Reference

Endpoint:

in vitro DNA damage and/or repair study

Remarks:

Type of genotoxicity: DNA damage and/or repair

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Aug to Nov 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 482 (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of assay:

DNA damage and repair assay, unscheduled DNA synthesis in mammalian cells in vitro

Target gene:

unspecified

Species / strain / cell type:

hepatocytes: female rat, primary cells

Additional strain / cell type characteristics:

not applicable

Metabolic activation:

without

Test concentrations with justification for top dose:

Pre-test: 0.5 to 500 µg/ml

Main tests: 1. + 2. Experiment: 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 µg/ml

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

True negative controls:

no

Positive controls:

yes

Positive control substance:

2-acetylaminofluorene

Species / strain:

hepatocytes: female rat, primary cells

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Positive controls validity:

valid

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

In both main experiments cytotoxicity at a concentration of 35 µg/ml could be observed.

Precipitation was seen at concentrations higher that 50 µg/ml (pre-test).

Conclusions:

Interpretation of results (migrated information):
negative

Testosterone is non-effective in the UDS test (non-genotoxic).

Executive summary:

Primary rat hepatocytes were exposed in two independent tests to testosterone (5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 µg/ml) for 18 h in the presence of methyl-³H-thymidine. The following concentrations were selected  for evaluation of the nuclear grain: 20, 25, 30, 35 or 40 µg/ml. No reproducible concentration dependent increase of DNA repair was observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

Read-across justification summary is attached to this endpoint summary.

Mutagenicity

 

Test system	Application	Effect	Study Reference
Rat, female, freshly isolated primary hepatocytes	UDS-Test under GLP conditions  Testosterone exposure for 18 h in the presence of methyl-^3H-thymidine 20 µg/ml, 25 µg/ml, 30 µg/ml, 35 µg/ml or 40 µg/ml	No reproducible concentration dependent increase of DNA repair.	Anonymous.1994.nscheduled DNA synthesis in primary hepatocytes of female rats in vitro with testosteron (ZK 5040) . Cytotest Cell Reserarch GmbH, Germany.AE82 Bayer Schering Pharma AG ; TX94191;1994-12-19
Rat	Ames Test with S. typhimurium TA 1535, TA 1537, TA 98, TA 102 and TA 100	ZK 5155 did not show a mutagenic potential in a bacterial reverse mutation assay (Ames test in S. typhimurim strains TA98, TA1537, TA100, TA102, TA1535) when tested up to the highest recommended dose level of 5.0 mg/plate in theabsenceor presence of extrinsic metabolic activation (liver S9 mix from Aroclor 1254 -treated rats).	Reimann, R. 1996. Salmonella typhymurium reverse mutation assay with ZK 5155 Cytotest Cell Research GmbH   AN15; CCR No 519000; Bayer Schering Pharma; TX 95140; 1996-03-24

Mutagenicity - Human 

 

Test system	Application	Effect	Study Referenc
Human liver slices	DNA adduct sampling by^32P-postlabeling 8 male and 7 female donors 5 µg/ml Incubation at 37°C for 6 h	No DNA adducts detected	Feser-Zügner, W. 1996.Use of human liver slides for the detection of drug induced DNA-adducts in vitro by means of the 32P-postlabeling technique. Experimental Toxicology, Schering AG, AN95 Bayer Schering Pharma AG; KI 94083; 1996-07-10

Other results from open literature

Test System	Application	Effect	Literature
Mouse	Testosterone	No induction of sperm abnormalities	Topham 379, 1980 as cited by IARC Suppl 6 506-507 1987.
Mouse	Testosterone	No micronuclei in vivo	Van Buul&Van Buul 237, 1982 as cited by IARC Suppl 6 506-507 1987.
S. typhimurium TA1535, TA1537, TA1538	Testosterone	Not reverse mutation	Ingerowski et al., 93, 1981 as cited by IARC Suppl 6 506-507 1987.
Hamster	Testosterone or testosterone propionate.Syrian hamster embryo cells were reduced by incubation with testosterone or testosterone propionate at 10-30 μg/ml in a dose-dependent manner	The propionate induced dose-dependent cell transformation at concentrations of 1-30 μg/ml, while testosterone was effective only at 30 μg/ml. At that concentration, the transformation frequency induced by testosterone and the propionate was one-half that induced by 1 μg/ml benzo[a]pyrene. Neither steroid significantly increased the frequency of chromosomal aberrations or aneuploidy. Testosterone did not induce gene mutations at the hprt or Na+/K+ ATPase locus	Tsutsui, T., Konine, A., Huff, J. & Barrett, J.C. (1995) Effects of testosterone, testosterone propionate, 17beta-trenbolone and progesterone on cell transformation and mutagenesis in Syrian hamster embryo cells. Carcinogenesis, 16, 1329-1333.

Justification for selection of genetic toxicity endpoint

Test substance is the same as registration substance (Testosterone).  Reliable test (Guideline and GLP) test data indicate that testosterone is not genotoxic.

Justification for classification or non-classification

Taking into account all data, it is not expected that testosterone exhibits any genotoxic/mutagenic potential.

Based on the results there is no classification required according to Directive 67/548/EEC and Regulation (EC) 1272/2008 (CLP).