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Key value for chemical safety assessment

Additional information

ZK 5191 was tested to be a weak mutagen in absence of metabolic activation in a bacterial reverse mutation assay with the S. typhimurium strain TA100. The study was conducted with substance concentration from 0.1 to 6 mg/plate in the absense or presense of extrinsic metabolic activation (liver S9 mix form Aroclor 1254 -treated rats). [Schering AG, Report No. 6665/I; 1985 -06 -26]

ZK5191 was tested in a bacterial reverse mutation assay (Ames test) with different S typhimurium strains in presence and absence of metabolic activation. The test substance was weak positive in strain TA100 (-S9) [Schering AG, Report No. 6271; 1984-10-04]

Mice (10/sex/group) were treated intraperitoneally with 250, 500 and 1000 mg/kg of ZK 5191. After 24 and 48 h 5 animals /sex were sacrificed. ZK 5191did not induce chromosome breakage and mis-distribution of chromosomes in erythrocytes of bone marrow of mice. [Schering AG, Report No. Al38; 1997-02-10]

ZK 5191 did not show any mutagenic potential in HPRT-test with Chinese hamster cell line V79 up to the highest tested concentration of 2 mg/ml (cytotoxicity without S9-mix at 1.3 mg/ml and with S9 -mix at 1.15 mg/ml). [Schering AG, Report No. Al12; 1997-01-27]

ZK 5191did induce weak chromosomal aberration in human lymphocytes in presence of metabolic activation. The cells were treated with substance up to the concentration of 2 mg/ml (solubility and cytotoxicity as dose limiting factor) [Schering AG, Report No. AN65; 2000-03-29]

Primary female rat hepatocytes were incubated with ZK 5191 up to 0.5 mg/ml (reduced viability as limiting factor). ZK 5191 was not able to induce repairable DNA damage. [Schering AG, Report No. AM79; 1999-05-14]

Primary rat hepatocytes were incubated with ZK5191 up to a concentration of 0.6 mg/ml (limiting factor cytotoxicity). Hyrocortisone did not induce repairable DNA. [Schering AG, Report No. A02685; 2001 -05 -21]

Additionally, results of genotoxicity with hydrocortisone are cited in RTECS database (Feb 2010):

DNA inhibiton was found in rat mammary gland cells at 1 mg/L [Acta Pathologica et Microbiologica Scandinavica, Section A: Pathology. (Copenhagen, Denmark) V.78-89, 1970-81. For publisher information, see ACPADQ. v. 85, p. 57, 1977 (AMBPBZ)]

Cytogenetic analysis after intraperitoneal application of hydrocortisone to mice at 50 mg/kg [Acta Pathologica et Microbiologica Scandinavica, Section C: Immunology. (Copenhagen, Denmark) V.83-89, 1975-81. For publisher information, see ACPADQ. v. 84, p. 185, 1976 (APSCD2)]

DNA inhibition in mouse cells was seen at 100 nmol/L [Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 36, p. 1782, 1986 (ARZNAD)]

DNA inhibition after intraperitoneal application of guinea pigs at 50 mg/kg [Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 78, p. 1417, 1974 (BEXBAN)]

After intraperitoneal application of hydrocortisone to rats DNA inhibition appeared at 100 mg/kg [Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 81, p. 90, 1976 (BEXBAN)]

After intraperitoneal application to rats unscheduled DNA synthesis was found at 20 mg/kg [Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. [Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 94, p. 1511, 1982 (BEXBAN)]

In human liver cells DNA adducts were reported after exposure to 2 mmol/L and 2 mmol/L/1H and 2 mmol/plate/1H [Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 370, p. 49, 1996 (MUREAV)]

Guinea pig lung cells unscheduled DNA synthesis was found 1 mg/L [Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 171, p. 109, 1982 (PSEBAA)]

Guinea pig lung cells developed DNA inhibition after exposure to 1 mg/L [Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 171, p. 109, 1982 (PSEBAA)]


Short description of key information:
Gene mutation (bacterial reverse mutation assay): weak positive in strain TA100 (-S9)
(Schering AG, Report No. 6665/I; 1985-06-26)

Gene mutation (bacterial reverse mutation assay/ Ames test): weak positive in strain TA100 (-S9)
(Schering AG, Report No. 6271; 1984-10-04)

Micronucleus test (mouse, GLP): negative for mutagenic potential
(Schering AG, Report No. Al38; 1997-02-10)

HPRT test (Chinese hamster cell line V79, GLP): negative with and without metabolic activation
(Schering AG, Report No. Al12; 1997-01-27)

Clastogenicity test (human lymphocytes, GLP): weak clastogenic with metabolic activation
(Schering AG, Report No. AN65; 2000-03-29)

UDS test (primary female rat hepatocytes, GLP): negative
(Schering AG, Report No. AM79; 1999-05-14)

UDS test (primary rat hepatocytes, GLP): negative
(Schering AG, Report No. A02685; 2001-05-21)


Additionally, results of in vitro and in vivo genotoxicity studies with hydrocortisone (ZK 5191) are cited in RTECS database (Feb 2010). Tests and results are further described in chapter DISCUSSION.

Endpoint Conclusion:

Justification for classification or non-classification

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

In RTECS database some publications with positive results have been cited. Available GLP-studies from Schering AG indicated weak clastogenicity in human lymphocytes and a weak positive result in an AMES test. However, an in vivo mouse micronucleus test as well as other in vitro tests were negative. Hydrocortisone as an endogenous substance does not have to be labelled with regard to mutagenicity.

Hydrocortisone 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.