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Diss Factsheets

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-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:
1996
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

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

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.