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Toxicological information

Carcinogenicity

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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

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

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)