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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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status not known, near guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acetic acid
EC Number:
200-580-7
EC Name:
Acetic acid
Cas Number:
64-19-7
Molecular formula:
C2H4O2
IUPAC Name:
acetic acid
Details on test material:
FDA 71-78 (Apple cider vinegar (acetic acid); table strength 5%)
Clear amber coloured liquid

Test animals

Species:
rabbit
Strain:
Dutch
Details on test animals or test system and environmental conditions:
Virgin, adult, Dutch-belted female rabbits were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The females were dosed with the indicated dosages by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose. The test material was prepared and doses calculated according to the following table:

Dosage Dose Concentration
(mg/kg) (ml/kg) (mg/ml)
250 1 250
251 - 500 2 125 - 250
501 - 750 3 133 - 250
751 - 1000 4 187 - 250
1001 - 1250 5 200 - 250
1251 - 1500 6 208 - 250
1501 - 1600 6.4 235 - 250
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 106 motile sperm.
Duration of treatment / exposure:
Days 6 - 18 of gestation
Frequency of treatment:
Daily
Duration of test:
Days 0-29 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
2.5 mg/kg bw/day (nominal)
Dose / conc.:
16 mg/kg bw/day (nominal)
Dose / conc.:
74.3 mg/kg bw/day (nominal)
Dose / conc.:
345 mg/kg bw/day (nominal)
Dose / conc.:
1 600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Approximately 12 pregnant females.
Control animals:
yes, sham-exposed
Details on study design:
An additional group of mated females was dosed with 2.5mg/kg 6-aminonicotinamide on day 9 and served as a positive control

Examinations

Maternal examinations:
Body weights were recorded on Days 0, 6, 12, 18, and 29 of gestation.
All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal
Ovaries and uterine content:
On Day 29 all does were subjected to Caesarean section under surgical anaesthesia, and the numbers of corpora lutea, implantation sites, resorption sites and live and dead foetuses were recorded. The urogenital tract of each animal was examined in detail for normality.
Fetal examinations:
The body weights of the live pups were recorded. all foetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live foetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection). All foetuses were then cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.

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):
Reduced bodyweight observed in dams treated with 1600 mg/kg/day.
Food consumption and compound intake (if feeding study):
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Abortions observed in all treated groups at incidences of: 0, 2, 1, 1, 2 for the 0, 16, 74.3, 345 and 1600 mg/kg/day treatment groups.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Reduction in the number of live litters from females treated with 345 and 1600 mg/kg/day.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Details on maternal toxic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal survival. Report of reduced body weight in dams at 1600 mg/kg bw/day. Some deaths or abortions occurred in all treated groups and some litter losses were reported at 345 and 1600 mg/kg/day. Maternal effects considered consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
16 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
dead fetuses
number of abortions
Remarks on result:
other:
Remarks:
Maternal effects considered consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits.

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Reduction in the number of live offspring observed at 16, 345 and 1600 mg/kg/day.
Changes in sex ratio:
no effects observed
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
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The administration of up to 1600 mg/kg (body weight) to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Executive summary:

In a developmental toxicity study in rabbits, apple cider vinegar, that contains 5% acetic acid, was administered by gavage at dose levels of 0, 16, 74.3, 345 and 1600 mg/kg/day for 13 consecutive days. The authors reported that administration of up to 1600 mg/kg bodyweight of the test material to dams for 13 days revealed no discernible effect on maternal or foetal survival, or on soft of skeletal tissues.

There was a reduction in pregnancy rate at the high dose and from 74.3 mg/kg/day, a dose-dependent decrease in maternal bodyweight gain in dams. Some deaths or abortions occurred in all treated groups and some litter losses were reported at 345 and 1600 mg/kg/day. Maternal effects were much more noticeable than effects on foetal development. It has been concluded that these findings are a consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits (EU, 2008). These effects are considered not to be a direct effect on embryonic implantation and development of acetic acid (EU, 2008). It is likely that this accounts for the apparent increased sensitivity of this species to oral administration of acetic acid.