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EC number: 944-550-8 | 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-22, study nr. 940305, is described in a summary study report on human Insulin 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 of effects on embryo-fetal development in the rabbit according to ICH 4.1.3 guideline.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: ICH 4.1.3 Study for Effects on Embryo-Fetal Development
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Reference substance name:
- Human Insulin
- Molecular formula:
- C257H383N65O77S6
- IUPAC Name:
- Human Insulin
- Test material form:
- solid: particulate/powder
- Remarks:
- White powder
- Details on test material:
- Molecular formula: C257H383N65O77S6
Molecular weight: 5807.66 g/mol
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- not specified
- Details on exposure:
- the daily dose was given as subcutaneous injections twice daily.
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- Animals were premated
- Duration of treatment / exposure:
- The pregnant rabbits in were dosed from GD6 to GD18
- Frequency of treatment:
- Daily
- Duration of test:
- 29 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.04 other: mg/kg/d
- Dose / conc.:
- 0.11 other: mg/kg/d
- Dose / conc.:
- 0.38 other: mg/kg/d
- No. of animals per sex per dose:
- 20
- Control animals:
- yes
- yes, concurrent vehicle
- Details on study design:
- Dose levels are based on a preliminary study.
Examinations
- Maternal examinations:
- Clinical signs, mortality, body weight, food consumption, toxicokinetics, and blood glucose levels
- Ovaries and uterine content:
- The ovaries and uteri were examined for number of corpora lutera, number og implantation sites, number and distribution of live young, number and distribution of embryofoetal deaths
- Fetal examinations:
- Offsprings were examined externally then sacrificed, weighed, sexed and dissected to examine for visceral abnormalities.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased weigt gain were seen at all doses.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Increased food and water intake were seen at all doses persisting to end of the study.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a dose related reduction in plasma glucose. After 4 hours the mid and low dose group had recovered after the first dose. For the high dosed group plasma glucose had returned (partial) to normal after 4 hours.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- A higher incidence of early embryonic deaths was seen at 0.38 mg/kg/d human insulin
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- not specified
- Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 0.38 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- A higher incidence of early embryonic deaths was seen at 0.38 mg/kg/d human insulin.
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- Litter size and weight were reduced due to a higher incidence of early embryonic deaths was seen at 0.38 mg/kg/d human insulin
- Changes in postnatal survival:
- no effects observed
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Dosage related increase of some characteristic skeletal abnormalities (absent/fused/misshapen vertebral elemennts and/or ribs with additional or connected sternebrae) for human insulin treated animals at 0.11 and 0.38 mg/kg/d.
- Visceral malformations:
- not specified
Effect levels (fetuses)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 0.11 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- skeletal malformations
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 0.11 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Applicant's summary and conclusion
- Conclusions:
- Effects of human insulin on embryo-fetal development in the rabbit was conducted according to ICH 4.1.3 guideline. Treatment with human insulin was associated at all dosages with increased maternal bodyweight gain and food intake and dose related reduction in plasma glucose levels. An increase in early embryonic deaths at 0.38 mg/kg/d was associated with a reduction in litter size and litter weight. Treatment at 0.11 mg/kg/d and 0.38 mg/kg/d was also associated with a higher proportion of foetuses with skeletal abnormalities affecting the vertebrae, ribs and sternum. Moreover, such effects on the foetus have been obtained in other studies after treatment with insulin and are considered most likely to be related to the reduction of maternal blood glucose.
- Executive summary:
Effects of human insulin on embryo-fetal development in the rabbit was conducted according to ICH 4.1.3 guideline. Treatment with human insulin was associated at all dosages with increased maternal bodyweight gain and food intake and dose related reduction in plasma glucose levels. In addition, one animal in the human insulin 0.11 mg/kg/d group was found dead on Day 7, one day after the first dose. An increase in early embryonic deaths at 0.38 mg/kg/d was associated with a reduction in litter size and litter weight. Treatment at 0.11 mg/kg/d and 0.38 mg/kg/d was also associated with a higher proportion of foetuses with skeletal abnormalities affecting the vertebrae, ribs and sternum. Moreover, such effects on the foetus have been obtained in other studies after treatment with insulin and are considered most likely to be related to the reduction of maternal blood glucose.
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