Registration Dossier

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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Documentation insufficient for assessment but available information suggests the work is probably valid. This result was obtained by valid read-across.

Data source

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

Materials and methods

GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): citric acid, FDA 71 54

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No info
- Age at study initiation: No info
- Weight at study initiation: No info
- Fasting period before study: No info
- Housing: Females singly after mating
- Diet (e.g. ad libitum): No info
- Water (e.g. ad libitum): No info
- Acclimation period: No info

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No info
- Humidity (%):No info
- Air changes (per hr): No info
- Photoperiod (hrs dark / hrs light): No info

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Yes, but no details provided
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: no info

DIET PREPARATION
- Rate of preparation of diet (frequency): No info
- Mixing appropriate amounts with (Type of food): No info
- Storage temperature of food: No info

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: No info
- Amount of vehicle (if gavage): No info
- Lot/batch no. (if required): No info
- Purity: No info
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: no information
- M/F ratio per cage: no info
- Length of cohabitation: no info
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. ,,NO INFO
- Further matings after two unsuccessful attempts: [NO INFO
- Verification of same strain and source of both sexes: [NO INFO
- Proof of pregnancy: [vaginal plug
- Any other deviations from standard protocol: NO INFO
Duration of treatment / exposure:
Days 6 to 15 of gestation
Frequency of treatment:
Daily, by gavage
Duration of test:
Exposure period days 0 – 15 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.95, 13.7, 63.6, 295 mg/kg/bw/day
Basis:
no data
No. of animals per sex per dose:
25 females
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Not stated
- Rationale for animal assignment (if not random): Not stated

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included. No, but report noted that these were done on a daily basis

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: On days 0, 8, 10,14

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - NA
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: -
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: - na

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NA
- Time schedule for examinations: YES

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day On day 20
- Organs examined: No
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes: [all per litter / half per litter / #? per litter ]
- Skeletal examinations: Yes: [2/3 per litter ]
- Head examinations: Yes
Statistics:
no
Indices:
no
Historical control data:
no

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
None noted

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No indication

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 295 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The administration of up to 295 mg/kg (body weight) of the test material to pregnant rats for 10 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 ccntrols."
Therefore the NOAEL is greater than 295 mg/kg