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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Aluminium hydroxide
EC Number:
244-492-7
EC Name:
Aluminium hydroxide
Cas Number:
21645-51-2
Molecular formula:
AlH3O3
IUPAC Name:
aluminum trihydroxide
Specific details on test material used for the study:
Aluminum hydroxide, analytical grade, was provided by the Merck Company (Darmstadt, FRG).

Test animals

Species:
mouse
Strain:
Swiss
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Panlab, Barcelona, Spain
- Age at study initiation: sexually mature
- Weight at study initiation: 28-32 g
- Fasting period before study: no
- Housing: Mice were individually housed in environmentally controlled rooms
- Diet: ad libitum, Panlab certified chow (Barcelona, Spain).
- Water: ad libitum, demineralized water
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2° C
- Humidity (%): 50±10%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hour light-dark-photocycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Pregnant mice were given by gavage a daily dose of aluminum hydroxide dissolved in distilled water
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Five females were placed with two males in separated cages until copulation was detected. Finding of sperm indicated copulation and the day of detection was designated day 0 of pregnancy.
- M/F ratio per cage: 2/5
- Proof of pregnancy: Finding of sperm referred to as day 0 of pregnancy
Duration of treatment / exposure:
Gestational days (GD) 6-15
Frequency of treatment:
daily
Duration of test:
Up to GD 18
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
66.5 mg/kg bw/day
Remarks:
corresponding to 23 mg aluminium/kg bw/day.
Dose / conc.:
133 mg/kg bw/day
Remarks:
corresponding to 46 mg aluminium/kg bw/day.
Dose / conc.:
266 mg/kg bw/day
Remarks:
corresponding to 92 mg aluminium/kg bw/day.
No. of animals per sex per dose:
20 mated females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: The mated females were distributed randomly in four groups

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for appearance and behavior.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were computed for the pretreatment, treatment, and posttreatment periods from daily records.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption was computed for the pretreatment, treatment, and posttreatment periods from daily records.

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18
- Organs examined: The heart, lungs, spleen, liver, kidneys, and brain were weighed for organ/body weight comparisons.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included: Uteri were removed, and the number of total implantations and live, dead and resorbed fetuses were recorded.
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Blood sampling:
- Plasma: No
- Serum: No
Fetal examinations:
- External examinations: Yes, Following body weight, body length and sex determinations, each fetus was externally examined for gross abnormalities.
- Soft tissue examinations: Yes, More than half of viable fetuses evaluated for skeletal abnormalities, the remainder were fixed in Bouin's fluid and examined for visceral anomalies
- Skeletal examinations: Yes, More than half of the viable fetuses were assigned for the evaluation of skeletal abnormalities after staining with Alizarin Red S
- Head examinations: No data
Statistics:
The litter was considered the basic unit for statistical analysis. Maternal body weight gain and food consumption were evaluated by analysis of variance with differences among groups determined by Student's t test or Mann-Whitney U test. Nonparametric data were analyzed by the Kruskal-Wallis test.
Because of the very few number of malformations or developmental variations, the incidence was not analyzed statistically. The level of significance for all analysis was P<0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No aluminum hydroxide-related clinical signs of toxicity were observed in the pregnant mice of any group.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No aluminum hydroxide-related deaths were observed in the pregnant mice of any group.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Maternal toxicity was also assessed by examining the changes in maternal weight gain and food consumption. No significant differences between the aluminum hydroxide-treated groups and the control group were noted.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Upon sacrifice, the absolute and relative weights of heart, lungs, spleen, liver, kidneys and brain were similar between treated and control groups.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross postmortem effects attributed to the treatment were recorded.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the number of implantations and number of resorptions.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the number of resorptions.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the number of resorptions.
Dead fetuses:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the number of live and dead fetuses.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
> 266 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 92 mg/kg bw/day
Based on:
other: Aluminum content
Basis for effect level:
other: No adverse effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Body weights of fetuses removed on day 18 of gestation were not affected by any dose of aluminium hydroxide.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the number of live and dead fetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The administration of aluminum hydroxide by oral gavage daily from day 6 to 15 of gestation had no recognizable adverse effects on the fetal sex ratio.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Body weights and body lengths of fetuses removed on day 18 of gestation were not affected by any dose of aluminium hydroxide.
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No remarkable external malformations were found in any group.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No remarkable skeletal abnormalities were found in any group.
Visceral malformations:
no effects observed
Description (incidence and severity):
No remarkable internal soft-tissue defects were found in any group.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
> 266 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 92 mg/kg bw/day
Based on:
other: Aluminum content
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Maternal Relative Organ Weights of Mice Receiving Aluminum Hydroxide on Days 6 Through 15 of Gestation

Dose (mg/kg/day)
0 66.5 133 266
mean  SE mean  SE mean  SE mean  SE
Heart 0.31 0.01 0.35 0.03 0.34 0.03 0.35 0.02
Lungs 0.56 0.04 0.61 0.05 0.46 0.04 0.52 0.07
Spleen 0.23 0.02 0.25 0.03 0.20 0.01 0.27 0.04
Liver 4.39 0.16 4.82 0.17 4.25 0.27 4.26 0.28
Kidneys 0.81 0.03 0.89 0.07 0.88 0.06 0.89 0.09
Brain 0.79 0.03 0.77 0.09 0.87 0.07 0.87 0.10

Table 2: Effects of Aluminum Hydroxide Administered to Mice on Days 6 Through 15 of Gestation

Dose (mg/kg/day)
0 66.5 133 266
mean  SE mean  SE mean  SE mean  SE
No. of litters 20 - 18 - 19 - 18 -
No. of total implants/litter 11.50 0.70 12.40 0.70 11.80 0.70 11.10 1.00
No. of resorptions/litter
early 0.40 0.20 3.00 1.70 2.40 1.10 1.30 1.10
late 0.00 0.00 0.10 0.20 0.10 0.30 0.10 0.30
No. of live fetuses/litter 11.10 0.70 9.40 1.10 9.20 1.10 9.80 1.20
No. of dead fetuses/litter 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
Sex ratio (M:F)/litter 1.34 0.25 0.96 0.07 1.02 0.17 1.13 0.25
Fetal body weight (g) 1.40 0.02 1.41 0.03 1.43 0.02 1.42 0.03
Fetal body length (cm) 3.11 0.02 3.11 0.03 3.24 0.03 3.10 0.03

Applicant's summary and conclusion

Conclusions:
In a prenatal developmental toxicity study in Swiss mice, aluminum hydroxide did not induce maternal toxicity up to 266 mg/kg bw/day. Neither embryotoxicity nor teratogenicity was detected in any treatment group. The no observed adverse effect level (NOAEL) for maternal and developmental effects is therefore >266 mg/kg bw/day (corresponding to 92.01 mg Al/kg bw/day).
Executive summary:

In a developmental toxicity study (similar to OECD TG 414), aluminum hydroxide was orally administered to groups of 20 pregnant female Swiss mice/dose by gavage at dose levels of 0, 66.5, 133 and 266 mg/kg bw/day in distilled water from days 6 through 15 of gestation.

There were no treatment-related effects in mortality, clinical signs, body weight or maternal developmental parameters observed. The maternal NOAEL is therefore considered to be >266 mg/kg bw/day (corresponding to 92.01 mg Al/kg bw/day).

In addition, there were no treatment-related effects in developmental parameters in offspring. The developmental NOAEL is therefore considered to be >266 mg/kg bw/day (corresponding to 92.01 mg Al/kg bw/day).