Coumarin

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference 1

Title:

Toxicology and Carcinogenesis studies of coumarin in F344/N rats and B6C3F1 mice

Author:

US Dept. of health and human services

Year:

1993

Bibliographic source:

National Toxicology Program TR 422

Reference 2

Title:

No information

Author:

IARC

Year:

2000

Bibliographic source:

IARC volume 77-9 (2000), monograph on coumarin

Materials and methods

Test guideline

Guideline:

other: see attached IARC monograph and NTP TR422 study on coumarin

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Coumarin

EC Number:

202-086-7

EC Name:

Coumarin

Cas Number:

91-64-5

Molecular formula:

C9H6O2

IUPAC Name:

2H-chromen-2-one

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 50 and 100 mg/kg/d
Basis:
nominal in diet

No. of animals per sex per dose:

60

Results and discussion

Effect levels

Key result

Dose descriptor:

T25

Effect level:

> 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no T25 identified. Effect type:carcinogenicity (migrated information)

Any other information on results incl. tables

Groups of 60 male and 60 female Fischer 344/N rats, six to seven weeks of age, were

administered coumarin (purity, > 97%) in corn oil by oral gavage at doses of 0, 25, 50

and 100 mg/kg bw daily for 103 weeks. Survival of low-, mid- and high-dose males

(9/50, 2/50 and 0/50 respectively) was significantly lower (p < 0.001) than that of

controls (28/50), as was body weight gain. In males, increased mortality was attributed

to increased severity of age-related spontaneous chronic progressive nephropathy. As

shown in Table 2, there was no increased incidence of renal tubule adenomas after

conventional single-section evaluation, but the incidence was increased based on the

results of step-sectioning of kidney tissue, although there was no dose–response

relationship. There was an increased severity of bile duct hyperplasia and renal tubule

hyperplasia in both sexes. An accompanying stop-exposure study was carried out in

which groups of 20 male rats received 100 mg/kg bw per day of coumarin by gavage in

corn oil for nine or 15 months followed by corn oil gavage only until the end of the study

at 103 weeks. Survival was 9/20 and 2/20 in the two groups, respectively. Whereas

hepatic lesions including bile duct hyperplasia were reversible and the incidence of renal

tubule adenomas, based on single sections, was not significantly increased, there was an

increase in the nine-month 100 mg/kg bw dose group after step-sectioning of the kidney

(National Toxicology Program, 1993). [The Working Group noted that the incidence of

renal tubule tumours was not increased after conventional examination of the kidney.]