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Diss Factsheets
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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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- 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:
- The test material toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with test material concentrations at 0, 400, 800, and 1 600 ppm. Blood samples were collected from individual rats on days 7, 21, and 90 at 2:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00 - 8:00 a.m. Plasma concentrations of test material and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free test material and morphine released after samples were treated with β-glucuronidase.
- 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
- Radiolabelling:
- yes
- Remarks:
- [I-’H] test material (specific activity, 20 Ci/mmol)
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
Doses / concentrations
- Remarks:
- 0, 400, 800 and 1 600 ppm
Results and discussion
Any other information on results incl. tables
Plasma concentrations of unconjugated test material increased with the daily amount of test material consumed and fluctuated over the course of the study. The peak plasma concentrations of the test material occurred at 11:00 p.m. on day 7. Overall, plasma concentration profiles of unconjugated test material were similar in both sexes. ANOVA analysis indicated that test material plasma concentrations were dose dependent (p < 0.01). In most cases, female rats had higher plasma concentrations of the test material and its metabolites than males. Plasma concentrations of unconjugated codeine consistently decreased from day 7 to day 90 (ANOVA, p < 0.01),which may be related to the decrease of test material intake over the course of the study. However, because the intake on day 7 and day 21 were comparable, the reduction in plasma test material concentrations may also have resulted from enzyme induction.
AUC values increased with dose (F-test, p < 0.01) and varied considerably throughout the study. However, the calculated AUC values generally decreased as the study progressed, which indicated that the test material did not accumulate during the study.
Plasma concentrations of conjugated test material were also determined. Results indicated that most test material was present in plasma as the unconjugated form, and the concentrations of conjugated test material were very low. Plasma concentrations of total test material (unconjugated and conjugated) were generally higher in females than in males, but the difference was less consistent than for free codeine. As expected, the estimated AUC values of total test material were slightly higher than the AUC values of unconjugated test material and also increased with dose (F-test, p < 0.01).
The distribution of test material and test material-derived metabolites in plasma (mean ± SE, N = 360) based on data from day 7 to day 90 was as follows: Free test material (11.8 ± 0.47 %) and conjugated test material (1.42 ± 0.l6 %).
Plasma concentrations of test material and total test material steadily decreased from day 7 to 16 months and then rebounded at 24 months.
In most cases, female rats showed higher plasma concentrations of the test material and its metabolites than males.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test plasma concentrations of both the test material and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both the test material and morphine correlated well with the amounts of test material added to the feed.
Bioavailability of the test material using the dosed feed route increased with dose, varying from 10 % to 25 %. Concentrations of conjugated test material were very low. The results suggested that demethylation of the test material in rats is the main metabolic pathway and was maintained over the course of the study. - Executive summary:
The test material toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with test material concentrations at 0, 400, 800, and 1 600 ppm. Blood samples were collected from individual rats on days 7, 21, and 90 at 2:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00 - 8:00 a.m. Plasma concentrations of test material and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free test material and morphine released after samples were treated with β-glucuronidase.
Results indicated that plasma concentrations of both the test material and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both the test material and morphine correlated well with the amounts of test material added to the feed.
Bioavailability of the test material using the dosed feed route increased with dose, varying from 10 % to 25 %. Concentrations of conjugated test material were very low. The results suggested that demethylation of the test material in rats is the main metabolic pathway and was maintained over the course of the study.
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