Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study similar to OECD 414 conducted with the read across partner aluminium hydroxide.

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the Maternal and Developmental Toxicity of Aluminum from High doses of Aluminum Hydroxide in Rats
Author:
Gomez, M.
Year:
1990
Bibliographic source:
Vet Hum Toxicol 32 (6) December 1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
test substance was applied from gestational day 6 to 15
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Aluminum hydroxide (analytical grade), was purchased from E. Merck (Darmstadt, Germany)

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Interfauna Iberica, Barcelona, Spain
- Weight at study initiation: 225-240 g
- Housing: 2:1 (females:males)
- Diet (e.g. ad libitum): commercial show (Panlab, Barcelona, Spain), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 10d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23°C
- Humidity (%): 45 ± 5%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
dissolved in water

VEHICLE
- Concentration in vehicle: 192, 384, and 768 mg/kg/d
- Amount of vehicle (if gavage): 2 equal administrations
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:2
- Length of cohabitation: until copulation was detected
- Proof of pregnancy: Findings of sperm indicated copulation and the day of detection was designated day 0
Duration of treatment / exposure:
gestational days 6-15
Frequency of treatment:
twice a day
Duration of test:
20 days
No. of animals per sex per dose:
20 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The highest dose of 768 mg Al(OH)3 /kg/d would be equivalent to a 60 kg person ingesting 16 g of Aluminum/day, which is by far more than the average amount of ingested Aluminum and also extents the dose of Aluminum taken upon medication using antacides.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: daily during pre-treatment, treatment and post-treatment

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: liver and kidney weights, gravid uterine weight number of ovarian corpora lutea and pregnancy, status of uterine implantation sites

OTHER:
Hematologic determinations amd serum biochemical analyses were conducted after sacrification
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes:1/3 per litter
- Skeletal examinations: Yes: remaining

- Other: 3 fetuses from each dam were used for whole body analyses of Aluminum
Statistics:
Results of the quantitative continous variables (eg. maternal body weight gain, maternal food consumption, maternal organ weights, etc) were compared using analysis of variance (ANOVA) with significant F values further analyzed using Student´s t-test or Mann-Whitney U-test.
Nonparametric data were statistically treated using the Kruskal-Wallis test when appropriate.
The incidence of developmental anomalies was not analyzed statistically, because of inspection it was obvious that none of the treated groups differed from the controls.
Indices:
N.A.
Historical control data:
Not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
No maternal deaths or signs of toxicity were observed during the study.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
768 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:
No embryotoxic effects were observed during the study.

Effect levels (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Statistically significant decreases in maternal food consumption were found during the treatment period and during the total study period and were not considered treatment-related toxic effects since those differences were sporadic and not dose related. Maternal stress during the gavage administration (twice a day) may have been responsible for the decreases in food consumption. The concentrations of Al in maternal liver, maternal brain, maternal bone and placenta as well as in whole-body fetuses did not differ significantly between the control and Al(OH)3-treated groups.

Applicant's summary and conclusion

Conclusions:
Administration of Aluminum hydroxide (twice a day by gavage) from day 6 to 15 of gestation resulted in a NOAEL of 768 mg/kg/day for Al(OH)3, which corresponds to a Aluminum dose of 207 mg/kg/day.
Executive summary:

In a developmental toxicity study (similar to OECD 414), Aluminum hydroxide was administered to 20 pregnant female Wistar rats per dose group. The dosages were split into 2 gavages per day resulting in dose levels of 0,192, 378 and 768 mg/kg body weight from days 6 to 15 of gestation.

No treatment-related maternal and developmental signs of toxicity were observed at any dose level. Thus, the maternal and the developmental NOAEL is 768 mg/kg/day.

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rat, with deviation in the exposure period.