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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:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Reproduktionstoxikologische Studien mit Ascorbinsaure an Mäusen und Ratten
Author:
Frohberg H, Gleich J, and Kieser H
Year:
1973
Bibliographic source:
Arzneimittel-Forschung 23, Nr. 8 (1973)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
pre-guideline study; no differentiation of early or late resorptions
GLP compliance:
no
Remarks:
pre-GLP study

Test material

Constituent 1
Chemical structure
Reference substance name:
Ascorbic acid
EC Number:
200-066-2
EC Name:
Ascorbic acid
Cas Number:
50-81-7
Molecular formula:
C6H8O6
IUPAC Name:
5-(1,2-dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one (non-preferred name)

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/4
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
first trial: GD 6-15
second trial: GD 0 to day 21 p.p.
Frequency of treatment:
7/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Remarks:
Lowest dose group
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
low dose group
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
mid dose group
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
high dose group
No. of animals per sex per dose:
Historical controls: 760 dams
Concurrend control: 21 dams
Lowest dose group: 22 dams
Low dose group: 19 dams
Mid dose group: 21 dams
High dose group: 17 dams


Control animals:
yes, concurrent vehicle
yes, historical

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: at start and termination; body weight gain reported


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: No; sum of earla and late resorptions
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: two third per litter
- Head examinations: Yes: No data
Statistics:
means ± SD; statistical significance; method not specified
Indices:
no
Historical control data:
yes; from 760 dams

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:
no effects observed
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:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Abortions as percentage of implantations
Historical controls: 760 dams 2.2 %
Concurrend control: 21 dams 2.4 %
Lowest dose group: 22 dams 3.7 %
Low dose group: 19 dams 1.1 %
Mid dose group: 21 dams 0.9 %
High dose group: 17 dams 0.0 %


Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not specified
Other effects:
not examined
Details on maternal toxic effects:
no toxic effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: absence of adverse effects

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:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of adverse effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Ascorbic acid was not maternal toxic or reprotoxic in female Wistar rats up to 1000 mg/kg bw and day
Executive summary:

The developmental toxicity of ascorbic acid was investigated in female Wistar rats and NMRI mice in a series of pre-guideline studies.

In the first trial, the test substance dissolved in water was administered by oral gavage at dose levels of 0, 150, 250, 500 and 1000 mg/kg bw and day during GD 6-15. Caesarian section was performed at termination on GD 20. Uteri and fetuses were examined. Findings were subjected to statistical analysis. No maternal toxicity or developmental toxicity (including teratogenicity) was noted at any dose level including the top dose. Hence, the NOAEL was 1000 mg/kg bw and day in this study.

It should be noted that the same result was obtained with mice treated during GD 6-15 (data not reported in this endpoint study record).

Further, a second trial was conducted which is not reported here in full detail. Briefly, dams (24-27 per group at termination) received ascorbic acid (0, 250, 500, 1000 mg/kg bw and day) by oral gavage from GD 0 until day 21 post parturition. This treatment had no adverse effect on pregnancy, parturition, breeding instinct and lactation capacity of the mother animals, nor on the embryonic, foetal, and postpartum development of the progeny.

Overall, ascorbic acid at 1000 mg/bw and day was not maternal or developmental toxic in the rat. The studies were performed before the existence of a suitable test guideline, but generally meet the accepted methodology and are therefore considered to be valid and suitable for assessment.