Progesterone

Endpoint summary

Additional information

Test system	Substance		Application			Test concentration		End point/Effect		Literature
In vitro
Salmonella Typhimurium TA97, 98, 100, 1535				With or without preincubation or metabolic activation: hamster or rat liver S-9, Aroclor 1254 (10 or 30%)	100-10000 µg/plate (test material solvent: DMSO)		Ames Negative			Zeiger, E., Anderson, B. Haworth, S., Lawlor, T.and Mortelmans, K.;Salmonell Mutagenicity Tests:IV. Result from the Testing of 300 Chemicals; Environ. Mol.Mutagen. 11(Suppl.12):1-158, 1988
E ColiWP2 UVRA				With or without Preincubation or Metabolic Activation: rat , hamster or mouse liver, S-9 or S-9, Aroclor 1254 (10 or 30%)	0.3-333.3 µg/plate (test material solvent: DMSO or acetone)		Ames Negative			Dunkel, V.C., Zeiger, E., Brusick, D., Mccoy, E., Mcgregor, D., Mortelmans, K., Rosenkranz, H.S. and Simmon,V.F.; Reproducibility of microbial mutagenicity assays:tests with Salmonella Typhimurium and Escherichia Coli using a standardized protocol; Environ. Mol. Mutagen. 6 (Suppl. 2): 1-254,1984
Escherichia coli polA (W3119 vs P3478)							Rec-assay, DNA effects (bacterial DNA repair) No conclusion			Mutat Res 87:211-297,1981
Human embryonicfibroblasts orrenal epithelia		Progesterone			1 µg/L		Two-fold increase the number of chromosomal aberrations			Serova, I.A. & Kerkis, Y.J. (1974)Cytogenetic effect of some steroidhormones and change in activity of lysosomal enzymes in vitro (Russ.) Genetica 10, 142-149)
Human lymphocytesfrom healthywoman		Progesterone			0.1-100 µg/mL		No chromosoma effects			Stenchever, M.A, Jarvis, J.A. &Kreger, N.K. (1969) Effect of selected estrogens and progestinson humanchromosomes in vitro.Obstet. Gynecol.34, 249-251.
Humankidney cells					100 µg/L		DNA Inhibition			Canadian Journal of Genetics and Cytology (National Research Council of, Publication Sales and Distribution,ON K1A OR6,) V.1-1959-, vol 10, pg 299,1968.
Mouse-embryo cells					1 mg/L		Cytogenetic analysis			Doklady Akademii Nauk SSSR.Proceedings of the Academy of Sciences of the. For English translation, see DBIOA and DKBSA (V/O)Mezhdunarodnaya Kniga 113095,) V.1 -1933-, vol 282, pg 173, 1985
Human lymphocytes					12 mg/L//22H		Cytogenetic analysis			Mutation Research. (Elsevier Science Pub. B.V., POB 211,1000 AE Amsterdam, Netherlands) V.1, 1964-, vol 651,pg 40, 2008
Rat hepatocytes,strain indicator:THY Incorp				No metabolicactivation	4-15 µg/ml,test materialsolvent DMSO		Unschedule DNA Synthesis Negative			Oshiro, Y, Bawierz, Ps and Piper,CE; absence of a genotoxic response from steroids in the rat primary hepatocyte unscheduled DNA synthesis assay; Environ.Mutagen. 8 (5):461-465, 1986]
Primary rathepatocytes (male)		Progesterone		Two experiments	0.00128 up to10 µg/ml		Highest concentration causedcytotoxicity. No unscheduled DNA synthesis or S-phase syntesis was induced			Schering Pharma Research ReportNo. A091. Study to evaluate the potential of Progesterone to induce unscheduled DNA synthesis in isolated rat hepatocytes in vitro, dated.
Primary rathepatocytes (female)		Progesterone		Two experiments according toGLP	Experiment 1:0.33, 1.0, 5.0,10.0 or 15.0µg/mlExperiment 2:1.0, 3.0, 5.0,7.0, 9.0 or11.0 µg/ml		Highest concentration causedcytotoxicity. No concentration dependent reproducible increase in the number of nuclear grain counts were observed			Schering Pharma Research Report No. A425.Evaluation of the Report: Unscheduled DNA synthesis in primary hepatocytes of rats in vitro with progesterone (Zk 4.981),dated 11 Jan 1993.
rat liver cells,female		Progesterone					No induction ofDNA repair		IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 139 (1974)
Human cells							Sister chromatid exchange SCE (No conclusion)		Mutat Res 297:101-180,1993
Human lymphocytes					20 mg/L		Sister chromatid exchange		Mutation Research. (Elsevier Science Pub. B.V.,POB 211, 1000 AE Amsterdam, Netherlands) V.1-1964-, vol 191, pg 121, 1987.
Human lymphocytes					8 mg/L/22H		In vitromicronucleolus test		Mutation Research. (Elsevier Science Pub. B.V.,POB 211, 1000 AEAmsterdam,Netherlands) V.1, 1964-, vol 651, pg 40, 2008
Human fibroblasts					12 mg/L		In vitromicronucleolus test		Mutation Research. (Elsevie Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands)V.1, 1964-, vol 651, pg 40, 2008
Mouse (BALB/c- 3T3) cells							Cell transformation Negative		Mutat Res 114:283-385,1983
Syrian hamster embryo (SHE) cells							Cell transformation,clonal assayNegative		Mutat Res 114:283-385,1983
Fischer rat embryo(RLV/1706)cells							Cell transformation,viral enhanced Positive		Mutat Res 114:283-385,1983
Rat embryo					2600 µg/L		Morphologicaltransformation		JNCI, Journal of the National Cancer Institute. (DC) V.61-79, 1978-87. For publisher information, see JNCIEQ., vol 67, pg 1303, 1981.
Mousefibroblasts					80 µg/L		Morphologicaltransformation		JNCI, Journal of the National Cancer Institute. (DC) V.61-79, 1978-87.For publisher information,see JNCIEQ., vol 67, pg 1303, 1981
Hamster-embryo					30 mg/L		Morphologicaltransformation		Carcinogenesis (). (Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford,) V.1- 1980 -, vol 16, pg 1329, 1995.
Syrian hamster embryo cells		Progesterone			Dose that did not induce chromosomalaberrations.		Induction of celltransformation		IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).,p. V6 139 (1974)
Baby rat kidney  cells infected with human papilloma virus -16 carrying the Ha-ras-1 oncogene		Progesterone					Induction of cell transformation		IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). p. V6 139 (1974)
Human sperm							Positive / sperm morphology		Mutat Res 115:73-148,1983
Mouse sperm							Negative / sperm morphology		Mutat Res 115:73-148,1983
Mouse fibroblasts				-S9, 20 days	0.01 mg/L		Morphological transformation		Environmental and Molecular Mutagenesis.(R.Liss, Inc., 41 E. 11th, New York, NY10003)V.10- 1987-, vol 37, pg 231, 2001

in vivo
Female SD RatHepatocytes	Progesterone	Intragastric (gavage) Dose Regimen: partial hepatecto my after 3 days, rats killed 2 days later	100 mg/kg bw	In vivo micronucleolus Positive	Martelli, A, Mereto, E, Ghia, M, Orsi, P, Allavena, A, Depascalis, C.Rand Brambilla, G;Induction of micronuclei and ofenzyme-altered foc in the liver of female rats exposed to progesterone and three synthetic progestins; Mutat.Res. 419(1-3) 33-41, 1998
Male dog or femaleChinese hamster	Progesterone	Intramuscular orsubcutaneous	1-25 mg/animal, 7 daysa week for 6 weeks(intramuscular application) or 1 -100mg/animal, thriceweekly for 4 weeks	ChromosomalAbnormalities(stickness, clumping,condensation), aneuploidy,polyploidy in meiotic germcells.	Williams, D.L.,Runyan, J.W.& Hagen, A.A.(1968)Meiotic chromosomealterations produced by progesterone.Williams, D.L.,Hagen, A.A. &Runyan, J.W. Jr &(1971) Chromosomealterations producedin germ cells of dogs by progesterone. J.lab. clin. Med. 77, 417-429.Williams, D.L., Runyan,J.W. Jr. & Hagen, A.A.(1972) Progesterone-induced alteration of oogenesis in the Chinese hamsters. J. lab. clin. Med. 79, 972-977.
Han Wistar Rat, 3 male and 3 female	Progesterone	Daily administration for 14 d   Gavage	100 mg/kg/d	Slight to moderate apathy and atactic gait. No DNA adducts detected	Schering Research Report No. AG18,DNA adduct analysis in liver of male and female rats after daily intragastric administration of chlormadinine acetate, megestrol acetate, drospirenone, ethinylestradiol, norethisterone acetate, gestodene, estradiol orprogesterone over a period of 14 days, dated 23. Aug. 1996.
Dog		Intraarterial	100 µg/L	Cytogenetic Analysis	Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869-,vol 220, pg 1145,1968.
Mouse		Oral	1060 mg/kg	DNA damage	Medical ScienceResearch. (ElsevierApplied SciencePub. Ltd., Crown House,,Barking,Essex IG118JU, UK) V.15 -1987-, vol 15, pg 703, 1987.
Mouse		Subcutaneous	200 mg/kg	Unscheduled DNA synthesis	Journal of Endocrinology.(Biochemical Soc.Book Depot, POB 32,Colchester, CCO2 8HP,) V.1 -1939-, vol 60, pg 167, 1974
Mouse		Subcutaneous	200 mg/kg	DNA inhibition	Journal ofEndocrinology.(Biochemical Soc.Book Depot, POB 32,, Colchester, CO2 8HP,)V.1-1939-, vol 60, pg167, 1974
Rabbit		Intravenous	100 µg/L	DNA damage	Nippon Naibumpi Gakkai Zasshi.Journal of the Endocrine Society.(NaibumpiGakkai, c/oFuritsu Ika Daigaku, Kojinbashi Nishizume-Sagaru,Kamigyo-ku, Kyoto602, Japan)V.1-1925-, vol 51, pg1043, 1975.
Rhesus monkey, female	Progesterone	Daily treatment for 12 weeks. Subcutaneous	0.5, 5.0 or 50.0 µg/ml	No increase in Erythrocyte micronucleous formation	Schering Report No.3930, Testing of ZK9.471, ZK 5.931, ZK18.206 and ZK4.981 for mutageniceffects in a micronucleus test on female rhesus monkeysafter 12 weeks administration,dated 17 Jul. 1979.

Short description of key information:
A study in Wistar rats with application of 100 mg Progesterone per gavage showed no DNA adducts. Furthermore, no increase in erythrocyte micronucleous formation was detected in female rhesus monkeys. Further data is based on the result of a literature search (references are stated in the tables). There is a large amount of in vitro as well as in vivo studies reported in the literature for various endpoints with both, positive and negative results.

Endpoint Conclusion:

Justification for classification or non-classification

Various in vitro and in vivo test systems for investigation of genotoxic properties of progesterone have led to contradictive results.

Different publications show mutagenic effects in vivo and in vitro. A standard micronucleus assay in monkeys and DNA adduct analysis in rats from Schering AG did not indicate any genotoxic potential. Therefore, there are no sufficient evidences available to classify the endogenous substance progesterone as genotoxic.

Progesterone is not classified according to German legislation (TRGS-905).

Classification according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) is not required.