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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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / 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-20, study nr. 940303, 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 fertility and Embryofoetal developmental toxicity study in the Rat performed in accordance with ICH test guidelines 4.1.1 + 4.1.3 (comparable to OECD 421/422).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1996
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- Subcutaneous administration used instead of oral administration.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- Subcutaneous administration used instead of oral administration.
- 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
- Specific details on test material used for the study:
- Study performed with the active pharmaceutical ingredient Human Insulin (Actrapid)
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- not specified
- Details on exposure:
- NA
- Details on mating procedure:
- NA
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Female rats were treated for 2 weeks prior mating and dosing continued up to and including day 15 of pregnancy (total of 29 days).
Male rats were treated for 4 weeks prior mating and dosing continued up to day 20 of pregnancy (total of 48 days). - Frequency of treatment:
- Twice daily. S.C administration.
- Details on study schedule:
- NA
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Vehicle control group
- Dose / conc.:
- 7.6 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on results of a previous study
the daily dose level was distrubuted into subcutaneous injections twice daily - Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not specified
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: NA
BODY WEIGHT: Yes
- Time schedule for examinations: NA
-Other:
- Food and water consumption was recorded, although not a feeding or water study. - Sperm parameters (parental animals):
- Parameters examined in [all] male rats:
[testis weight, sperm count, sperm motility, sperm morphology] - Litter observations:
- STANDARDISATION OF LITTERS
- not specified
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
[number and distrubution, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain].
Live young were examined externally and weighted. Half the fetuses were examined for viceral abnormalities and half were examined for skeletal abnormalities.
GROSS EXAMINATION OF DEAD PUPS:
[ yes, for external and internal abnormalities] - Postmortem examinations (parental animals):
- SACRIFICE
- Female and Male animals killed at Day 20 of pregnancy.
GROSS NECROPSY
- Yes, not specified
HISTOPATHOLOGY / ORGAN WEIGHTS
- Congenital abnormalities and number of corpora lutea (maternal animals)
- male reproductive system including, testes and sperm (parental animals) - Postmortem examinations (offspring):
- SACRIFICE
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera, Skeletal morphology and Orbital socklet morphology.]
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively. - Statistics:
- not specified
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Death of one male animal 7.60 mg/kg/day. This effect was most likely related to the pharmacological action of human insulin (Actrapid) causing severe hypoglycemia.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Weight gain (and increased food and water intake) observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A dosage related increase in food and water intake was seen, although the study is not a feeding study.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Plasma glucose was reduced from about 10 mmol/l to 4-6 mmol/l at one hour after dosing with 7.60 mg/kg/day, rate of recovery showing some dosage-dependency.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly reduced pre- and post implantation losses were observed at 7.60 mg/kg/day.
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- Slightly reduced sperm counts and motility and focal seminiferous epithelial atrophy with vacuolation of Sertoli cells in testes at 7.60 mg/kg/day.
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 7.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- reproductive function (oestrous cycle)
- reproductive function (sperm measures)
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 7.6 mg/kg bw/day (actual dose received)
- System:
- male reproductive system
- Organ:
- testes
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not examined
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Detailed foetal examination revealed a slight dosage related increase in the incidence of fetuses with absent or small orbital sockets at 7.60 mg/kg/day.
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not specified
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- ca. 7.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- ophthalmological examination
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 7.6 mg/kg bw/day (actual dose received)
- System:
- other:
- Organ:
- other: ophthalmological abnormalities
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 7.6 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects in the absence of other toxic effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- A fertility and embryofoetal developmental toxicity study in the Rat performed in accordance with ICH test guidelines 4.1.1 + 4.1.3 (comparable to OECD 421/422). 24 male and 24 female rats were daily dosed subcutaneously with Human Insulin (0, 7.6 mg/kg/ bw/day) for 4-7 weeks. Mortality was observed in one male at highest dose level, an effect of the pharmacological action of severe insulin-induced hypoglycemia. However, terminal studies on male rats also revealed a slightly reduced sperm count and and motility and histopathology showed focal seminiferous epithelial atrophy with vacuolation of Sertoli cells in testes of male rats dosed 7.6 mg/kg/day. Detailed foetal examination revealed a slight dosage related increase in fetuses with absent or small orbital socket. No other toxicity was observed in parental or foetal animals.
- Executive summary:
A fertility and embryofoetal developmental toxicity study in the Rat performed in accordance with ICH test guidelines 4.1.1 + 4.1.3 (comparable to OECD 421/422). 24 male and 24 female rats were daily dosed subcutaneously with Human Insulin (0, 7.6 mg/kg/ bw/day) for 4-7 weeks. Mortality was observed in one male at highest dose level, an effect of the pharmacological action of severe insulin-induced hypoglycemia. However, terminal studies on male rats also revealed a slightly reduced sperm count and and motility and histopathology showed focal seminiferous epithelial atrophy with vacuolation of Sertoli cells in testes of male rats dosed 7.6 mg/kg/day. Detailed foetal examination revealed a slight dosage related increase in fetuses with absent or small orbital socket. No other toxicity was observed in parental or foetal animals.
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