Codeine sulphate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: 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 five male and five female F344/N rats were given 0, 1 562, 3 125, 6 250, 12 500, or 25 000 ppm test material in feed for 14 days, which resulted in daily doses of approximately 125, 250, 450, 650, or 750 mg test material/kg bodyweight to males and 125, 250, 500, 700, or 300 mg/kg to females.
Groups of five male and five female B6C3Fl mice were given 0, 781, 1 562, 3 125, 6 250, or 12 500 ppm test material in feed for 14 days, which resulted in daily doses of approximately 150, 300, 600, 1 300, or 3 000 mg test material/kg body weight to males and 200, 400, 750, 1 500, or 3 000 mg/kg to females.

GLP compliance:

no

Limit test:

no

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 B6C3Fl mice

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Duration of treatment / exposure:

14 days

Frequency of treatment:

Daily in feed

Doses / concentrations

Doses / concentrations 1

Remarks:

125, 250, 450, 650, or 750 mg/kg male rats

Doses / concentrations 2

Remarks:

125, 250, 500, 700, or 300 mg/kg female rats

Doses / concentrations 3

Remarks:

150, 300, 600, 1 300, or 3 000 mg/kg male mice

Doses / concentrations 4

Remarks:

200, 400, 750, 1 500, or 3 000 mg/kg female mice

No. of animals per sex per dose:

5

Results and discussion

Results of examinations

Description (incidence):

Rats: One female exposed to 6 250 ppm, one male and three females exposed to 12 500 ppm, and all males and females exposed to 25 000 ppm died during the study.
Mice: All mice survived to the end of the study.

Description (incidence and severity):

Rats: Final mean body weights and mean bodyweight gains of all exposed groups except 1 562 ppm females were significantly lower than those of the controls.
Mice: The final mean body weight of 3 125 ppm females was significantly greater than that of the controls; the final mean body weight of 12 500 ppm females and the mean bodyweight gains of 12 500 ppm males and females were significantly lower than those of the controls.

Description (incidence and severity):

Mice: Absolute and relative liver weights of 3,125, 6 250, and 12 500 ppm males and of 12 500 ppm females and the absolute and relative right kidney weights of 12 500 ppm males were significantly lower than those of the controls.

Description (incidence and severity):

Rats: No chemical-related gross lesions were observed in rats at necropsy. Thickening of the forestomach mucosa (hyperplasia and hyperkertosis) and lymphoid depletion of the thymus in exposed males and females and testicular degeneration in exposed males, observed primarily in the 12 500 and 25 000 ppm groups, were associated with decreased survival and increased morbidity in these groups.

Mice: No gross lesions were attributed to test material exposure.

Description (incidence and severity):

Mice: No histopathologic lesions were attributed to test material exposure.

Effect levels

Remarks on result:

not measured/tested

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test all rats receiving 25 000 ppm died and final mean bodyweights of 12 500 ppm males and females were 62 % and 80 % those of the controls, respectively.
There were no chemical-related deaths or histopathologic lesions in mice in the 14-day study; however, final mean body weights of 12 500 ppm males and females were 90 % those of the controls.

Executive summary:

The repeated dose toxicity of the test material was assessed in rats and mice in a 14-day study.

Rats: Groups of five male and five female F344/N rats were given 0,1 562, 3 125, 6250, 12500, or 25000 ppm test material in feed for 14 days, which resulted in daily doses of approximately 125, 250, 450, 650, or 750 mg test material/kg bodyweight to males and 125, 250, 500, 700,or 300 mg/kg to females. One female exposed to 6250 ppm, one male and three females exposed to 12500 ppm, and all males and females exposed to 25000 ppm died during the study. Final mean body weights and mean bodyweight gains of all exposed groups except 1562 ppm females were significantly lower than those of the controls.

No chemical-related gross lesions were observed in rats at necropsy. Thickening of the forestomach mucosa (hyperplasia and hyperkertosis) and lymphoid depletion of the thymus in exposed males and females and testicular degeneration in exposed males, observed primarily in the 12 500 and 25 000 ppm groups, were associated with decreased survival and increased morbidity in these groups.

Mice: Groups of five male and five female B6C3Fl mice were given 0,781, 1 562, 3125, 6250, or 12500 ppm test material in feed for 14 days, which resulted in daily doses of approximately 150,300, 600, 1300, or 3000 mg test material/kg body weight to males and 200, 400, 750, 1500, or 3000 mg/kg to females. All mice survived to the end of the study. The final mean body weight of 3125 ppm females was significantly greater than that of the controls; the final mean body weight of 12500 ppm females and the mean bodyweight gains of 12500 ppm males and females were significantly lower than those of the controls.

Absolute and relative liver weights of 3, 125, 6250, and 12500 ppm males and of 12500 ppm females and the absolute and relative right kidney weights of 12500 ppm males were significantly lower than those of the controls. No gross or histopathologic lesions were attributed to test material exposure.