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EC number: 944-548-7 | CAS number: -
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Justification for type of information:
- The present study, NDA report No. T-25, study nr. 940372, is described in a summary study report on Insulin aspart is based on GLP guideline studies prepared by Novo Nordisk. The summarised studies were performed as part of the non-clinical toxicity test regime for authorisation of Insulin aspart as human medicine and the studies are therefore in compliance with the guidelines for authorisation of human medicine.
Data source
Reference
- Reference Type:
- other company data
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- GLP compliance:
- yes
- Type of assay:
- other: micronuclei
Test material
- Reference substance name:
- Insulin aspart
- Molecular formula:
- C256H381N65O79S6
- IUPAC Name:
- Insulin aspart
- Test material form:
- solid: particulate/powder
- Details on test material:
- Molecular weight: 5793.6 Da
Constituent 1
- Specific details on test material used for the study:
- Study performed using the active pharmaceutical ingredient Insulin aspart as test substance
Test animals
- Species:
- mouse
- Strain:
- not specified
- Details on species / strain selection:
- Not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Not specified
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- Not specified
- Details on exposure:
- Administration of 200 U/ml on two occasions, 10 hours apart, at a dose volume of 5 ml/kg, allowed a total dose of 2000 U/kg/day to be administered. This corresponds to approximately 2000 times the therapeutic dose, and was selected as the maximum dose administered. In addtion two lower dose levels of 1000 and 500 U/kg/day were administered.
- Duration of treatment / exposure:
- Two subcutaneous injection, 10 hours apart, over 1 day.
- Frequency of treatment:
- Ones (two subcutaneous injection, 10 hours apart)
- Post exposure period:
- Animals were sacrificed 24 or 48 hours after the second treatment.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 other: U/kg/day
- Remarks:
- Administered over two injections
- Dose / conc.:
- 1 000 other: U/kg/day
- Remarks:
- Administered over two injections
- Dose / conc.:
- 2 000 other: U/kg/day
- Remarks:
- Administered over two injections
- No. of animals per sex per dose:
- Not specified
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Yes
Examinations
- Tissues and cell types examined:
- Polychromatic erythrocytes (PCE) from bone marrow
- Details of tissue and slide preparation:
- Not specified
- Evaluation criteria:
- Micronucleus frequency was estimate din 2000 PCE per animal
- Statistics:
- Not specified
Results and discussion
Test results
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- Slides from all dose groups were analysed and micronucleus frequency estimated in 2000 PCE per animal. All positive control animals exhibited increased numbers of micronucleated PCE such that the micronucleus frequency in the positive control group was significantly greater than in concurrent controls.
Negative (vehicle) control mice exhibited normal group mean ratios of PCE to NCE and normal frequencies of micronucleated PCE within historical negative control ranges. Mice treated with insulin aspart at all doses exhibited group mean ratios of PCE to NCE and frequencies of micronucelated PCE which were similar to the values for vehicle control groups a both sampling times. There were no instances of statistically significant increases in micornucleus frequency for any of the groups receiving the test article at either sampling time.
The maximum dose caused a marked drop in blood glucose levels in treated mice.
Applicant's summary and conclusion
- Conclusions:
- Insulin aspart did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of mice treated with subcutaneous injection using dose levels up to 2000 U/kg/day of inuslin aspart.
- Executive summary:
Insulin aspart was teset for its ability to induce micronuclei in the bone marrow of subcutaneously dosed male and female mice. Administration of 2000, 1000 or 500 U/kg/day (divided in two injections) were administered to the mice. Postive and negative (vehicle) control animals were also included. All animals were sacrificed 24 or 48 hours after the second injection.
Slides from all dose groups were analysed and micronucleus frequency estimated in 2000 PCE per animal. All positive control animals exhibited increased numbers of micronucleated PCE such that the micronucleus frequency in the positive control group was significantly greater than in concurrent controls.
Negative (vehicle) control mice exhibited normal group mean ratios of PCE to NCE and normal frequencies of micronucleated PCE within historical negative control ranges. Mice treated with insulin aspart at all doses exhibited group mean ratios of PCE to NCE and frequencies of micronucelated PCE which were similar to the values for vehicle control groups a both sampling times. There were no instances of statistically significant increases in micornucleus frequency for any of the groups receiving the test article at either sampling time.
It was concluded that insulin aspart did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of mice treated up to 2000 U/kg/day.
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