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EC number: 215-818-5 | CAS number: 1420-53-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- 1 996
- 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
- Reference substance name:
- Codeine
- EC Number:
- 200-969-1
- EC Name:
- Codeine
- Cas Number:
- 76-57-3
- Molecular formula:
- C18H21NO3
- IUPAC Name:
- Codeine
1
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 / concentrationsopen allclose all
- Remarks:
- Average daily doses of approximately 15, 30, and 70 mg test material /kg body weight to male rats
- Remarks:
- Average daily doses of approximately 15, 40, and 80 mg test material/kg bodyweight to female rats
- 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.
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