Codeine sulphate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

review article or handbook

Title:

PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION

Author:

Delatte MS

Year:

2010

Bibliographic source:

NDA 202245, DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

Materials and methods

GLP compliance:

yes

Type of assay:

mammalian erythrocyte micronucleus test

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:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

- Vehicle(s)/solvent(s) used: Methylcellulose USP and Reverse Osmosis/Deionised Water

Duration of treatment / exposure:

three consecutive days

Frequency of treatment:

daily

Post exposure period:

bone marrow harvest occurred ca. 3 hours after the last dose administration (test material treated rats)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 other: mg/kg

Doses / concentrations 2

Dose / conc.:

100 other: mg/kg

Doses / concentrations 3

Dose / conc.:

200 other: mg/kg

Doses / concentrations 4

Dose / conc.:

400 other: mg/kg

No. of animals per sex per dose:

5 with the exception of the 50 mg/kg dose level (only 5 females) and the 400 mg/kg dose level (only 5 males)

Control animals:

yes, concurrent vehicle

Positive control(s):

yes: cyclophosphamide; ethylmethanesulphonate

Results and discussion

Test results

Sex:

male/female

Genotoxicity:

negative

Toxicity:

yes

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Any other information on results incl. tables

- Mortality: Mortalities were reported in males at 400 mg/kg/day (n=3/5) and in females at 200 mg/kg (n=6/8). Note that three males and five females from these dose groups were found dead prior to the scheduled sacrifice. On day 2, the male animals were found dead either immediately after treatment (n=1) or one hour after treatment (n=2). The five females were found dead one hour after treatment on day 2. A single female from the 200 mg/kg/day group was euthanised prior to the scheduled sacrifice during the morning of day 2 (prior to

treatment).

- Clinical observations: A variety of clinical signs were observed in treated animals. These signs varied in regard to the incidence in which they were reported and the treatment days on which they were observed. The clniical signs were generally produced in a dose-related manner in treated animals. Acorss sexes, the clinical signs included convulsions, yellow harircoat-perineal area, protruding eyes, hypoactivity, and swollen nose. In females, clear oral discharge, red hair coat-nose, recumbant-sternal, lacrimation, rough hair coats, hunched posture, irregular respiration, cold t touch, and hyperactivity were also observed.

- Micronucleus assay: The test material did not produce a statistically significant increase in the averaged % micronucleated polychromatic erythrocytes and ratio of PCE:NCE when compared to control.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test the test material was negative for genotoxicity. The test material did not produce statistically significant increases in the averaged % micronucleated polychromatic erythrocytes and the ratio of PCE:NCE when compared to the control.