Canrenone

Carcinogenicity

Description of key information

Long-term (104-week) rat study with potassium canrenoate: Increased incidence of myelocytic leukaemia at 50 mg/kg bw/day and above; NOAEL = 20 mg/kg bw/day [Wagner 1987]

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: short abstract of results on long-term studies with potassium canrenoate

Principles of method if other than guideline:

no data

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on exposure:

no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

52 and 104 weeks

Frequency of treatment:

daily

Post exposure period:

13 weeks (52-week study)

Remarks:

Doses / Concentrations:
30, 90, 270 mg/kg (52-week study) and 20, 50, 125, 270 mg/kg (104-week study)
Basis:
nominal conc.

No. of animals per sex per dose:

no data ((52-week study)
50 animals per sex per dose (104-week study)

Control animals:

yes

Details on study design:

no data

Positive control:

no data

Observations and examinations performed and frequency:

no data

Sacrifice and pathology:

no data

Other examinations:

no data

Statistics:

no data

52-week study

There was an increased incidence of myelocytic leukaemia at the 90 and 270 mg/kg doses. Leukaemia was observed in the high-dose group after 28 weeks of treatment. There were significant increases in mammary tumours (adenomas, fibroadenomas and adenocarcinomas) and no significant increase of hepatocellular carcinoma, jejunal adenocarcinoma, follicular and medullary adenomas of the thyroid and adenomas of the kidney, pancreas, lung and ear duct. Cellular hypertrophy in the liver, thyroid and adrenal gland were seen after 52 weeks of dosing with potassium canrenoate. However, after 13 weeks of recovery, most of these changes were reversible.

104-week study

A dose-related incidence of myelocytic leukaemia, more frequent in males than females, was seen. Leukaemia was observed at dosages of 50 mg/kg/day and above, reaching statistical significance at 125 and 270 mg/kg/day. The first observation of leukaemia was at 32 weeks, eight were diagnosed at post-mortem examination at 52 weeks and there was a total of 30 cases by the end of two years. A statistically significant increase in the incidence of hepatic, thyroid, testicular, skin, brain, histiocytic and mammary tumours was noted. However, the tumour incidence in all organs at 20 mg/kg/day was similar to controls.

Executive summary:

Canrenone is a metabolite of potassium canrenoate, a drug formerly used for therapy of hypertension.

A 52-week study of potassium canrenoate in the rat was conducted. Animals were given oral doses of 30, 90 and 270 mg/kg/day. There was an increased incidence of myelocytic leukaemia at the 90 and 270 mg/kg doses. Leukaemia was observed in the high-dose group after 28 weeks of treatment. There were significant increases in mammary tumours (adenomas, fibroadenomas and adenocarcinomas) and no significant increase of hepatocellular carcinoma, jejunal adenocarcinoma, follicular and medullary adenomas of the thyroid and adenomas of the kidney, pancreas, lung and ear duct. Cellular hypertrophy in the liver, thyroid and adrenal gland were seen after 52 weeks of dosing with potassium canrenoate. However, after 13 weeks of recovery, most of these changes were reversible.

These findings prompted a two-year study of potassium canrenoate in rats. Animals were given doses of 20, 50, 125 and 270 mg/kg/day, with 50 rats of each sex per dose.A dose-related incidence of myelocytic leukaemia, more frequent in males than females, was seen. Leukaemia was observed at dosages of 50 mg/kg/day and above, reaching statistical significance at 125 and 270 mg/kg/day. The first observation of leukaemia was at 32 weeks, eight were diagnosed at post-mortem examination at 52 weeks and there was a total of 30 cases by the end of two years. A statistically significant increase in the incidence of hepatic, thyroid, testicular, skin, brain, histiocytic and mammary tumours was noted. However, the tumour incidence in all organs at 20 mg/kg/day was similar to controls.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the results of two long-term studies in rats (increased incidence of myelocytic leukemia) a self classification of the substance according to Directive 67/548/EEC or Regulation (EC) No. 1272/2008 (CLP) is recommended as follows:

DSD: R40, Carc. Cat. 3 (Limited evidence of a carcinogenic effect)

GHS: Carc. 2 (H351: Suspected of causing cancer)

Additional information

Canrenone is a metabolite of potassium canrenoate, a drug formerly used for therapy of hypertension.

A 52-week study of potassium canrenoate in the rat was conducted. Animals were given oral doses of 30, 90 and 270 mg/kg/day. There was an increased incidence of myelocytic leukaemia at the 90 and 270 mg/kg doses. Leukaemia was observed in the high-dose group after 28 weeks of treatment. There were significant increases in mammary tumours (adenomas, fibroadenomas and adenocarcinomas) and no significant increase of hepatocellular carcinoma, jejunal adenocarcinoma, follicular and medullary adenomas of the thyroid and adenomas of the kidney, pancreas, lung and ear duct. Cellular hypertrophy in the liver, thyroid and adrenal gland were seen after 52 weeks of dosing with potassium canrenoate. However, after 13 weeks of recovery, most of these changes were reversible.

These findings prompted a two-year study of potassium canrenoate in rats. Animals were given doses of 20, 50, 125 and 270 mg/kg/day, with 50 rats of each sex per dose. A dose-related incidence of myelocytic leukaemia, more frequent in males than females, was seen. Leukaemia was observed at dosages of 50 mg/kg/day and above, reaching statistical significance at 125 and 270 mg/kg/day. The first observation of leukaemia was at 32 weeks, eight were diagnosed at post-mortem examination at 52 weeks and there was a total of 30 cases by the end of two years. A statistically significant increase in the incidence of hepatic, thyroid, testicular, skin, brain, histiocytic and mammary tumours was noted. However, the tumour incidence in all organs at 20 mg/kg/day was similar to controls.

Justification for selection of carcinogenicity via oral route endpoint:
Only one publication with 52- and 104-week studies available

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: other