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Toxicological information

Developmental toxicity / teratogenicity

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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:
study report
Title:
Unnamed
Year:
1996
Report date:
1996

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

Constituent 1
Chemical structure
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
Specific details on test material used for the study:
Study performed with the acitve pharmaceutical ingredient Human insulin.

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
not specified
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
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: U/kg/bid
Remarks:
Control animals
Dose / conc.:
7.6 mg/kg bw/day (actual dose received)
Remarks:
corresponding to 100 IU/kg/bid
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):
8 females receiving 7.6 mg/kg/d human insulin died or were sacrificed at or around the time of parturition (days 20-23 of gestation). This effect 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 rats receiving 7.6 mg/kg/bid human insulin.
Food consumption and compound intake (if feeding study):
no effects observed
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 7.6 mg/kg/d human insulin
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 7.6 mg/kg/d human insulin
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Key result
Dose descriptor:
LOAEL
Effect level:
7.6 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
effects on pregnancy duration
mortality

Maternal abnormalities

Key result
Abnormalities:
no effects observed

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 7.6 mg/kg/day
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 7.6 mg/kg/day
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
Lowest effective dose / conc.:
7.6 mg/kg bw/day (nominal)
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
In conclusion, treatment with human insulin at 0 and 7.6 mg/kg/d. Human insulin 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.
Executive summary:

The effect of Human Insulin on pre and postnatal development including maternal function, was investigated in a study in pre-mated Sprague Dawley rats exposed to human insulin at 0 or 7.6 mg/kg/d by subcutaneous injection from 6 of pregnancy to day 21 post partum.

Treatment with human insulin at 0 and 7.6 mg/kg/d. Human insulin 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.  

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