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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions.

Data source

Reference Type:
Evaluation of the maternal and developmental toxicity of aluminium from high doses of aluminium hydroxide in rats.
Gomez et al.
Bibliographic source:
Vet. Hum. Toxicol. , 32: 545-548.

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
: lack of details on test substance
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Reference substance name:
Aluminium hydroxide
EC Number:
EC Name:
Aluminium hydroxide
Cas Number:
aluminum trihydroxide
Details on test material:
- Name of test material (as cited in study report): Aluminium hydroxide
- Analytical purity: analytical grade was obtained from E. Merck (Darmstadt, FRG). No further information.

Test animals

Details on test animals or test system and environmental conditions:
- Source: Interfauna Iberica (Barcelona, Spain)
- Weight at study initiation: 225-240 g
- Diet: Food (commercial chow, Panlab , Barcelona, Spain), ad libitum
- Water: tap water: ad libitum
- Acclimation period: 10 days

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

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
Details on the preparation of dosing solutions and on administration of the test substance are not provided.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Details on mating procedure:
Females were housed with males (2:1) until copulation was detected.
Finding of sperm indicated copulation and the day of detection was designated day 0 of gestation.
Duration of treatment / exposure:
10 days (GD 6-15).
Frequency of treatment:
Daily (twice).
Duration of test:
20 days (GD 0-20).
Doses / concentrations
Doses / Concentrations:
0, 192, 384, 768 mg/kg/bw/day equivalent to 66.5, 133.0, 266.0 mg Al/kg bw/day
actual ingested
No. of animals per sex per dose:
Twenty females for each dose group, 18-19 pregnant rats at termination.
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were randomly assigned to each experimental/control group.

Maternal-placental-fetal Al contents following gestational exposure have been examined. Al concentrations (µg/g wet weight) in maternal liver, brain, bone, placenta; and whole fetus (detection limit 0.05 µg/g).


Maternal examinations:
Clinical signs of toxicity, appearance, behavior changes were observed daily within 3 day intervals during pre-treatment, treatment and post-treatment period.
Hematological and serum biochemical analyses were performed on day 20 of gestation after euthanazy; blood was obtained by cardiac puncture.

Maternal body weight and food consumption:
Food consumption, maternal body weight and absolute/relative organ weight (kidney, liver, gravid uterine weight).

Post-mortem examination:
Animals sacrificed of GD 20.
Ovaries and uterine content:
Uterine content:
• Number of litters;
• corpora lutea;
• implantations/litter;
• preimplantation loss/litter;
• viable implants/litter;
• early resorption;
• late resorption;
• dead fetuses;
• postimplantation loss/litter.

Fetal examinations:
• Sex ratio;
• fetal body weight.
• Fetal examination for external and visceral abnormalities and skeletal malformations and variations performed.
• The unit of comparison was the pregnant female or the litter.
• Results of the quantitative continuous variables (e.g., maternal body weights, organ weights, fetal 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 evaluated using the Kruskal-Wallis test when appropriate. The incidence of developmental abnormalities was not analyzed statistically because no differences were evident between treated and control groups.
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:
No signs of toxicity, changes in body weight gain, absolute and relative internal organ weights (liver, kidney, gravid uterine) were observed in any group during the test (GD 0-20).

Group I
• increased number of early resorption (statistically non-significant).

Group II:
• >number of post-implantation loss (2.2 times);
• increased number of early resorption(not statistically significant).

Group III:
increased number of early resorption (statistically non-significant).

Statistically significant dose- and time-dependent decreased maternal food consumption during the treatment periods (6-15) was observed in Al treated animals compared to control group rats. However, food consumption recovered during the post-treatment period on GD 15-20.

No significant treatment-related differences were observed after exposure to Al hydroxide at any dose levels in:
• the number of corpora lutea;
• in percentage of pre-implantation loss ;
• in the number of total implants and viable; or nonviable implants per litter.
• > percentage of post-implantation loss – at 133 mg Al/kg bw/day (12.48± 11.56 vs 0.55 ± 0.90 in control group).

No dose-response observed for post-implantation losses. High variability was evident in all Al treated and control groups.

No Al related treatment effects were observed on maternal hematology and biochemical parameters at termination (GD 20) (data not shown).

No increased Al levels in maternal liver, bone, brain and placenta in Al treated animals compared to the control group was detected.

The maternal/placental Al concentrations were not statistically different between control and treated rats (high variability is evident in all groups).

Effect levels (maternal animals)

Dose descriptor:
Effect level:
266 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No differences were observed between control and Al treated groups in the incidence of individual malformations (external, visceral, or skeletal), or in the number of total malformations.

No significant changes in the incidence of any developmental variations were reported.

No increased Al levels in whole fetuses in any Al treated group (limit of detection – 0.05 μg/g.

Embryotoxic /teratogenic effects:
No Al treatment-related differences in number of live fetuses per litter, gender ratio, fetal body weight were detected.

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

The goal of study is to assess the developmental toxicity and embryotoxic/teratogenic potential of high doses of target compound - AI(OH)3orally administered to rats during the period of active organogenesis.

No significant general/maternal toxicity was observed in any Al treated groups that were orally exposed to Al hydroxide at doses 66.5, 133 and 266 mg Al/kg bw/day.

The results have contributed to the weight of evidence on the lack of pre-natal developmental toxicity of Al hydroxide administered orally to rats at high doses (66.6; 133 and 266 mg Al/kg bw/day). Toxicokinetic studies support the reported negative developmental outcomes.

Well designed and conducted study with many studied endpoints comparable to guideline OECD TG 414 with acceptable deviations.

However, particular test data/relevant information are absent (physiochemical properties, identification including CAS number, details on food and water quality (Al content in diet, water); details on test substance formulations (preparation, pH, stability and homogeneity of the preparation), details on reported negative teratogenic effects are not provided.