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EC number: 944-549-2 | 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- 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-21, study nr. 940304, 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.
The study is a study for effects on pre- and postnatal development, including maternal function, in the rat according to ICH 4.1.2 guideline.
Data source
Reference
- Reference Type:
- other company data
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: ICH 4.1.2 Study for Effects on Prenatal and Postnatal Development, Including Maternal Function
- GLP compliance:
- yes
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 with the acitve pharmaceutical ingredient Insulin aspart.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- not specified
- Details on exposure:
- A reference group received 7.9 mg/kg/bid human insulin.
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- Animals were premated
- Duration of treatment / exposure:
- The pregnant dams in F0 were dosed from GD6 until sacrifice on day 21 post partum.
- Frequency of treatment:
- The daily dose given as two daily subcutaneous injections
- Duration of test:
- 2 generation study
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 other: U/kg/bid
- Remarks:
- Control animals
- Dose / conc.:
- 0.38 mg/kg bw/day (actual dose received)
- Remarks:
- corresponding to 5 U/kg twice a day
- Dose / conc.:
- 1.9 mg/kg bw/day (actual dose received)
- Remarks:
- corresponding to 25 U/kg twice a day
- Dose / conc.:
- 7.6 mg/kg bw/day (actual dose received)
- Remarks:
- corresponding to 100 U/kg twice a day
- No. of animals per sex per dose:
- 28
- Control animals:
- yes
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- Clinical signs, mortality, body weight, food and water consumption, blood glucose levels, pregnancy rate, duration of pregnancy
- Ovaries and uterine content:
- The uteri were examined for implatation sites and numbers
- Fetal examinations:
- F1 pups were counted, sexed, weighed and examined for external abnormalities
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Three females receiving 1.9 mg/kg/d and 3 females receiving 7.9 mg/kg/d insulin aspart and 8 females receiving 7.9 mg/kg/d human insulin died or were sacrificed at or around the time of parturition (days 20-23 of gestation). This effetc was considered to be attributable to the pharmacological properties of the test substance.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased weigt gain were seen during gestation for the groups receiving 100 IU/kg/bid insulin aspart and 100 IU/kg/bid human insulin.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- increased food and water intake were seen during gestation for the groups receiving 7.9 mg/kg/d insulin aspart .
- Food efficiency:
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Plasma glucose profiles were determined on the first day of dosing (day 6 of gestation). Subsequent recovery times towards normoglycaemia showed some dosage dependency.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- effects observed, treatment-related
- Description (incidence and severity):
- Duration of pregnancy was slightly greater at 1.9 and 7.9 mg/kg/d insulin aspart
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Duration of pregnancy was slightly greater at 1.9 and 7.9 mg/kg/d insulin aspart - Changes in number of pregnant:
- not specified
- Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 1.9 mg/kg bw/day (actual dose received)
- Basis for effect level:
- mortality
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly increased pup growth to day 4 post partum, followed by reduced pup weight gain to day 16 post partum was observed at 1.9 and 7.9 mg/kg/d insulin aspart
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Slightly increased pup growth to day 4 post partum, followed by reduced pup weight gain to day 16 post partum was observed at 1.9 and 7.9 mg/kg/d insulin aspart - Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- no effects observed
- External malformations:
- not specified
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Details on embryotoxic / teratogenic effects:
- The growth, sexual maturation, behavioral characteristics and reproductive capacity of the selected untreated F1 generation were not adversely affected by treatment of F0 parent
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 7.6 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In conclusion, treatment with insulin aspart at 1.9 and 7.6 mg/kg/d insulin aspart was associated with major effects in adults (F0) females, which were considered to be attributable to the pharmacological properties of the test substance. However, there were no obvious adverse effects of treatment on the development, maturation or reproductive capacity of offspring at these dosages, other than minor changes in pup weight gain, which were propably secondary to the maternal pharmacological response.
No adverse effects of treatment were seen among adult females or offspring at 0.38 mg insulin aspart/kg/d.
(1 mg Insulin aspart is corresponding to 26.33 U i.e. the dose level used were approximately 0; 0.38; 1.9; 7.6 mg/kg/d) - Executive summary:
Treatment with insulin aspart at 1.9 and 7.6 mg/kg/d insulin aspart was associated with major effects in adults (F0) females, which were considered to be attributable to the pharmacological properties of the test substance. However, there were no obvious adverse effects of treatment on the development, maturation or reproductive capacity of offspring at these dosages, other than minor changes in pup weight gain, which were propably secondary to the maternal pharmacological response.
No adverse effects of treatment were seen among adult females or offspring at 0.38 mg insulin aspart/kg/d.
(1 mg Insulin aspart is corresponding to 26.33 U i.e. the dose level used were approximately 0; 0.38; 1.9; 7.6 mg/kg/d)
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