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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:
supporting study
Study period:
not specified
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
period of exposure was too short (5 days only and only a portion of the period of major organogensis was covered (gestation days 8 to 12); acc. to guidline treatment should cover the period of major organogensis, which may taken as days 6 - 15 of gestation); clinical examination and food consumption of the dams were not measured/reported; body weight of dams was measured, but interval of measurement was not given; dams were not sacrifced before birth, but were allowed to give birth; dams were not examined macroscopically; uterine content not examined for foetal deaths; sex of offspring was not determined; offspring were not examined externally or for skeletal and soft tissue anomalies; time of maternal death was not reported

Data source

Reference
Reference Type:
publication
Title:
Further evaluation of an in vivo teratology screen
Author:
Kavlock, R. J. et al.
Year:
1987
Bibliographic source:
Teratogenesis, Carcinogenesis, and Mutagenesis 7: 7 - 16.

Materials and methods

GLP compliance:
not specified
Remarks:
GLP was not compulsory at time of study conduct
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Sodium acetate
EC Number:
204-823-8
EC Name:
Sodium acetate
Cas Number:
127-09-3
Molecular formula:
C2H4O2.Na
Test material form:
not specified
Details on test material:
not specified
Specific details on test material used for the study:
not specified

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory (Wilmington, MA)
- Age at study initiation: approx. 60 days old
- Diet (ad libitum): rodent chow (Wayne Lab Blox)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C
- Relative humidity: 40 to 60 %
- Photoperiod (hrs dark / hrs light): 12 /12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: either distilled water or corn oil depending on the solubility of the test item
Details on exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: timed pregnant
- Proof of pregnancy: day of sperm plug identification was considered day 1 of pregnancy
Duration of treatment / exposure:
days 8 to 12 of gestation
Frequency of treatment:
daily
Duration of test:
22 days (day 1 of pregnancy until 2 days after birth)
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30 animals
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the dose was selected either from a preliminary toxicity study in nonpregnant mice or from information in the literature.
Pregnant females were dosed at 1) a level predicted to induce a mild degree of maternal toxicity [a slight (approximately 10%) deficit in weight gain but not more than 10% lethality] or 2) a level stated to be teratogenic in the literature.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, mortality was reported

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes, body weight change was recorded

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: No data

OTHER:
- Percentage of pregnant animals was recorded.
Ovaries and uterine content:
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: No data
- Percentage of resorptions: Yes
Fetal examinations:
NOTE: day 20 of gestation was considered postnatal day 1

- External examinations: No data
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

- On postnatal day 1 and 3, the litters were counted and weighed as a unit.
Statistics:
Data analysis was performed using the General Linear Models procedure on SAS (SAS Institute Inc.)*. When a significant treatment effect was detected by analysis of variance, individual group means were compared using Student’s t-test on least-squares means. Since our a priori hypothesis was that treatments could only reduce litter size, a one-tailed test was used for that variable. The number of live pups on postnatal day 1 was used as a covariate in the analysis of pup weights.

*Reference:
- SAS Institute Inc.: “SAS User Guide: Statistics, 1982 Edition.” Cary, NC: SAS Institute, Inc., 1982.
Indices:
not specified
Historical control data:
not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
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
Details on results:
MORTALITY
- 1000 mg/kg bw/day: 3/30 animals died after treatment with the test item
- control group: none of the animals died

BODY WEIGHT AND WEIGHT CHANGES
- 1000 mg/kg bw/day: the mean weight change of the animals of the treatment group was 7.44 g ± 0.29 g (not statistically different from control value)
- control group: the mean weight change of the animals of the control group was 6.73 g ± 0.31 g

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:
no effects observed
Dead fetuses:
not specified
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:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
EARLY OR LATE RESORPTIONS
- 1000 mg/kg bw/day: no resorptions were observed after treatment with the test item.
- control group: 3% resorptions were observed.

CHANGES IN NUMBER OF PREGNANT
- 1000 mg/kg bw/day: 83 % of the animals were pregnant (25 /30 animals).
- control group: 80 % of the animals were pregnant (32/40 animals).

Effect levels (maternal animals)

Remarks on result:
other: see "Remarks"
Remarks:
Acc. to the results presented by the authors, 3/30 females of the treatment group died, but none of the control group females died (0/40). The mean weight change of the animals of the treatment group was not statistically different from the control value. No resorptions were observed after the treatment with the test item. 83 % of the females of the treatment group were pregnant (25/30 females) compared to 80 % of the females of the control group (32/40).

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
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 specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
no effects observed
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
FOETAL/PUP BODY WEIGHT CHANGES
- 1000 mg/kg bw/day: the mean weights of the offspring of the treatment group were 1.55 g ± 0.02 g and 2.03 g ± 0.06 g for postnatal day 1 and 3, respectively (not statistically different from control value)
- control group: the mean weights of the animals of the control group were 1.56 g ± 0.02 g and 2.06 g ± 0.04 g for postnatal day 1 and 3, respectively.

CHANGES IN POSTNATAL SURVIVAL/REDUCTION IN OFFSPRING ALIVE
- 1000 mg/kg bw/day: no statistically significant changes in average litter size at birth (postnatal day 1) were observed compared to the control group after treatment with the test item (treatment group: 10.48 ± 0.68; control group: 9.94 ± 0.53). Furthermore, no statistically significant changes in average litter size at postnatal day 3 were observed compared to the control group after treatment with the test item (treatment group: 10.40 ± 0.67; control group: 9.88 ± 0.52).
More than 99 % of the pups of the treatment group survived until postnatal day 3.

Effect levels (fetuses)

Remarks on result:
other: Acc. to the authors, there were no statistically significant differences between the mean weight & average litter size at birth of offspring of the treatment group vs. the control. > 99 % of the pups of the treatment group survived until postnatal day 3.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Acc. to the results presented by the authors, 3/30 females of the treatment group died, but none of the control females died (0/40). The mean weight change of the females of the treatment group was not statistically different from the control value. No resorptions were observed after the treatment with the test item. 83 % of the females of the treatment group were pregnant (25/30 females) compared to 80 % of the females of the control group (32/40). Furthermore, there were no statistically significant differences between the mean weight and the average litter size at birth of the offspring of the treatment group compared to the control group. More than 99 % of the pups of the treatment group survived until postnatal day 3.

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