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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reasonably well documented study meeting generally accepted scientific principles but not conducted in compliance with GLP. Study acceptable for assessment. This result was obtained by valid read-across.

Data source

Reference
Reference Type:
other: summary report
Title:
Unnamed
Year:
1973

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not applicable
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): citric acid, FDA 71 54
- Physical state:Fine white crystalline material

Test animals

Species:
hamster
Strain:
other: outbred strain of golden hamster
Details on test animals and environmental conditions:
outbred strain of golden hamster

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Yes, but no details provided
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 1-2 ml/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused.
- The females were mated (1 to 1) with mature males.
- The appearance of motile sperm in the vaginal smear was considered Day 0 of gestation.
Duration of treatment / exposure:
Days 6 to day 10 of gestation
Frequency of treatment:
Daily
Duration of test:
Day 0 - Day 14
No. of animals per sex per dose:
24-29 females
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg body weight of Aspirin

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for appearance and behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: recorded on days 0, 8, 10 and 14 of gestation.

FOOD CONSUMPTION: Yes
- Time schedule: all animals were observed daily for food consumption.

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: all does were subjected to Caesaren section under surgical anesthesia.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number and sex of live and dead fetuses: Yes
Fetal examinations:
External examinations: Yes
- Body weights of the live pups were recoded.
- All fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. .

Soft tissue examinations: Yes
- One-third of the fetuses of each litter underwent detailed visceral examinations employing 10x magnification.

Skeletal examinations: Yes
- Two-third of the fetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects (Sternebrae, Ribs, Vertebrae, Skull, Extremities and Miscellaneous)

Head examinations: No data
Statistics:
No data
Indices:
No data
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- The pregnancy rates was comparable among groups and survival of pregnant females was not affected by treatment with the test substance.
- Maternal body weights and weight gains were comparable among groups.
- There were no treatment-related effects on the number of abortions, corpora lutea, implantation sites, live litters and resorptions.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 272 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- The number of live and dead fetuses, sex ratio and average fetal weight was not affected by treatment of dams with the test substance.
- 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:
> 272 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Maternal toxicity:

-Survival of dams: death at control; 2.72; 12.6; 58.7 and 272 mg/kg: 1, 0, 0, 0 and 1

-Body weight of dams: no compound-related changes compared to control

Fetotoxicity:

-Death:dead fetuses at control; 2.72; 12.6; 58.7 and 272 mg/kg: 0, 0, 7, 1 and 0

- Average fetus weight: no change in treated groups compared to controls

-Skeletal findings and Soft tissue abnormalities:

Pos. controls (no. of fetuses affected/no. of litters affected): sternebrae (incomplete oss.) in 96/18, sternebrae (missing) in 33/10, ribs more than 13in 65/16, extremities (incomplete oss.) in 2/2

-Skeletal findings:(no. of fetuses affected/no. of litters affected) in control, pos. control, 2.72; 12.6; 58.7 and 272 mg/kg

sternebrae (incomplete oss.): 95/21, 93/21, 66/18, 104/22 and 72/19

sternebrae (missing): 30/12, 27/15, 15/7, 21/8 and 15/9

ribs more than 13: 41/15, 59/18, 57/21, 61/17 and 43/19

extremities (incomplete oss.): 5/4, 6/4, 1/1, 1/1 and 2/2

-Soft tissue abnormalities: no compound related changes

58.7 mg/kg: 1 pup with meningoencephalocele

All other findings were completely in the range of spontaneous abnormalities found in negative controls.

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):

- Organ weights P and F1: no

- Histopathology P and F1:

P: urogenital tract, number of implantation and resorption sites

F1: All fetuses were examined grossly, one-third of fetuses of each litter underwent detailed visceral examinations employing 10x magnification, two-third were examined for skeletal defects

 

Applicant's summary and conclusion

Conclusions:
The administration of up to 272 mg/kg bw of citric acid to pregnant hamsters for 5 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:

Female hamsters (24-29 animals/group; outbred strain of golden hamster) received daily doses of 2.72, 12.6, 58.7 and 272 mg/kg bw citric acid by gavage during days 6-10 of gestation. A control group was included. All animals were observed daily for appearance and behaviour with particular attention to food consumption and body weight. Body weights were recorded on day 0, 8, 10 and 14 of gestation. The females were sacrificed at day 14. The urogenital tract of each animal was examined in detail. Between 19 and 23 females were pregnant at term in all groups.

No clearly discernible effects on maternal survival, body weight gains, number of corpora lutea, implantations and resorptions were observed. The number of live litters, live and dead foetuses, the foetus weights and sex ratio were not affected by treatment. No difference in number or kind of abnormalities (in either soft or skeletal tissues) was found between exposed and control groups.

Under the conditions of the test, administration of up to 272 mg/kg bw of citric acid had no adverse effects on adult hamsters and their foetuses.