Codeine sulphate

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to a guideline study conducted on a read-across material.

Justification for type of information:

The toxicological profile of the test material would not be different than that of codeine and the data are interchangeable. Codeine toxicology data is used to support the registered substance’s products in regulatory submissions. The test material is the sulfate salt form of codeine, a naturally occurring phenanthrene alkaloid and opioid agonist with analgesic, antidiarrheal, and antitussive activity.

Data source

Reference

Reference Type:

publication

Title:

NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF CODEINE (CAS NO. 76-57-3) IN F344/N RATS AND B6C3Fl MICE (FEED STUDIES)

Author:

NATIONAL TOXICOLOGY PROGRAM

Year:

1996

Bibliographic source:

NIH Publication No. 96-3360

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 400, 800, or 1 600 ppm test material for up to 106 weeks, with 9 or 10 rats per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 15, 30, and 70 mg test material /kg body weight to males and 15, 40, and 80 mg/kg to females.
Groups of 60 male and 60 female B6C3F, mice were fed diets containing 0, 750, 1 500, or 3 000 ppm test material for up to 106 weeks, with 9 or 10 mice per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 100, 200, or 400 mg test material /kg body weight to males and females.

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

Codeine

EC Number:

200-969-1

EC Name:

Codeine

Cas Number:

76-57-3

Molecular formula:

C18H21NO3

IUPAC Name:

Codeine

Test animals

Species:

other: Rats and mice

Strain:

other: F344/N rats and B6C3F mice

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Duration of treatment / exposure:

2 years

Frequency of treatment:

Daily in feed

Doses / concentrations

Doses / concentrations 1

Remarks:

Average daily doses of approximately 15, 30, and 70 mg test material /kg body weight to male rats

Doses / concentrations 2

Remarks:

Average daily doses of approximately 15, 40, and 80 mg test material/kg bodyweight to female rats

Doses / concentrations 3

Remarks:

Average daily doses of approximately 100, 200, or 400 mg test material /kg body weight to male and female mice

No. of animals per sex per dose:

9 or 10

Results and discussion

Results of examinations

Description (incidence and severity):

Rats: Chemical-related clinical findings were limited to ocular discharge in exposed males and females.

Description (incidence):

Rats: Survival of 400 ppm females was significantly greater than that of the controls; survival of all groups of exposed males and of 800 and 1 600 ppm females was similar to that of the controls.
Mice: Survival of exposed males and females was similar to that of the controls.

Description (incidence and severity):

Rats: There was an exposure-related decrease in mean body weights of males and females. The final mean bodyweight of 1 600 ppm males was 88 % that of the controls, and the final mean bodyweight of 1 600 ppm females was 89 % that of the controls.
Mice: Mean body weights of 750 and 1,500 ppm males and females were similar to those of the controls throughout most of the study. Mean body weights of 3,000 ppm males and females were less than those of the controls from about week 13, and the final mean bodyweights of these groups were 86 % and 82 % those of the respective controls.

Description (incidence and severity):

Rats: Feed consumption by exposed groups was similar to that by the controls.
Mice: Feed consumption by exposed groups was similar to that by the controls.

Description (incidence and severity):

Rats: Absolute and relative adrenal gland weights of 800 and 1 600 ppm males were significantly greater than those of the controls at 15 months.

Description (incidence and severity):

Rats: There were no increased incidences of neoplasms attributable to test material exposure at any site. At 2 years, there were exposure-related decreases in the incidences of adrenal medulla hyperplasia in males and females. There was an exposure-related decrease in the incidence of benign pheochromocytomas in males, and the incidences in exposed males were significantly lower than that in the controls. In 1 600 ppm females the incidences of mammary gland fibroadenomas and adenocarcinomas (combined) were significantly lower than those in controls. The decreased incidences of benign pheochromocytomas in males and mammary gland neoplasms in females were considered to be related to test material exposure.

Mice: There were no increased incidences of neoplasms attributable to test material exposure at any site. At 15 months, the incidence of thyroid gland follicular cell hyperplasia in 3 000 ppm males was significantly greater than that of the controls, and this lesion was observed in 1 500 and 3 000 ppm females. At 2 years, the incidences of follicular cell hyperplasia in all exposed groups of mice were significantly greater than those in the controls, but there were no increases in thyroid gland follicular cell neoplasms. The incidence of centrilobular fatty change in the liver of 3 000 ppm males was significantly lower than that in the controls at 15 months, and the decreased incidence appeared to be related to exposure level. At 2 years, the incidences of eosinophilic foci, foci of fatty change, centrilobular cytomegaly, and centrilobular fatty change in 3 000 ppm males were lower than those in the controls. The incidence of hepatocellular adenomas and the incidence of hepatocellular adenomas or carcinomas (combined) in 3 000 ppm males and females were significantly lower than those in the controls; this was considered to be related to lower body weights in these groups.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the 2-year feed study, there was no evidence of carcinogenic activity of the test material in male or female F344/N rats exposed to 400, 800, or 1 600 ppm. There was no evidence of carcinogenic activity of the test material in male or female B6C3F, mice exposed to 750, 1 500, or 3 000 ppm.

Executive summary:

The carcinogenicity of the test material was assessed in rats and mice in a 2-year study.

Rats: Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 400, 800, or 1 600 ppm test material for up to 106 weeks, with 9 or 10 rats per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 15, 30, and 70 mg test material/kg body weight to males and 15, 40, and 80 mg/kg to females.

Survival of 400 ppm females was significantly greater than that of the controls; survival of all groups of exposed males and of 800 and 1 600 ppm females was similar to that of the controls. There was an exposure-related decrease in mean body weights of males and females. The final mean bodyweight of 1 600 ppm males was 88 % that of the controls, and the final mean bodyweight of 1 600 ppm females was 89 % that of the controls. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings were limited to ocular discharge in exposed males and females.

Absolute and relative adrenal gland weights of 800 and 1 600 ppm males were significantly greater than those of the controls at 15 months. There were no increased incidences of neoplasms attributable to test material exposure at any site. At 2 years, there were exposure-related decreases in the incidences of adrenal medulla hyperplasia in males and females. There was an exposure-related decrease in the incidence of benign pheochromocytomas in males, and the incidences in exposed males were significantly lower than that in the controls. In 1 600 ppm females the incidences of mammary gland fibroadenomas and adenocarcinomas (combined) were significantly lower than those in controls. The decreased incidences of benign pheochromocytomas in males and mammary gland neoplasms in females were considered to be related to test material exposure

Mice: Groups of 60 male and 60 female B6C3F, mice were fed diets containing 0, 750, 1 500, or 3 000 ppm test material for up to 106 weeks, with 9 or 10 mice per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 100, 200, or 400 mg test material/kg body weight to males and females.

Survival of exposed males and females was similar to that of the controls. Mean body weights of 750 and 1,500 ppm males and females were similar to those of the controls throughout most of the study. Mean body weights of 3,000 ppm males and females were less than those of the controls from about week 13, and the final mean bodyweights of these groups were 86 % and 82 % those of the respective controls. Feed consumption by exposed groups was similar to that by the controls.

There were no increased incidences of neoplasms attributable to test material exposure at any site. At 15 months, the incidence of thyroid gland follicular cell hyperplasia in 3 000 ppm males was significantly greater than that of the controls, and this lesion was observed in 1 500 and 3 000 ppm females. At 2 years, the incidences of follicular cell hyperplasia in all exposed groups of mice were significantly greater than those in the controls, but there were no increases in thyroid gland follicular cell neoplasms. The incidence of centrilobular fatty change in the liver of 3 000 ppm males was significantly lower than that in the controls at 15 months, and the decreased incidence appeared to be related to exposure level. At 2 years, the incidences of eosinophilic foci, foci of fatty change, centrilobular cytomegaly, and centrilobular fatty change in 3 000 ppm males were lower than those in the controls. The incidence of hepatocellular adenomas and the incidence of hepatocellular adenomas or carcinomas (combined) in 3 000 ppm males and females were significantly lower than those in the controls; this was considered to be related to lower body weights in these groups.

In conclusion, under the conditions of the 2-year feed studies, there was no evidence of carcinogenic activity of the test material in male or female F344/N rats exposed to 400, 800, or 1 600 ppm. There was no evidence of carcinogenic activity of the test material in male or female B6C3F, mice exposed to 750, 1 500, or 3 000 ppm. Thyroid gland follicular hyperplasia was increased in exposed male and female mice. Decreased incidences of benign pheochromocytomas of the adrenal medulla in male rats and mammary gland fibroadenomas and fibroadenomas or adenocarcinomas (combined) in female rats were related to test material exposure.