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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
Study period:
May 12 - Jun. 20, 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
orally administered from GD 6 to GD 15; 2 dose levels; examination of maternal mortality and weight gain as well as fetal malformations
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Zeolite, cuboidal, crystalline, synthetic, non-fibrous
EC Number:
930-915-9
Cas Number:
1318-02-1
Molecular formula:
M2/nO • Al2O3 • ySiO2 • wH2O (n is the valency of the cation M, predominantly Na, y can range from 0.64 to 8.8, and w is the number of water molecules (general formula) Na: 1.34 - 24.02%, Al: 2.20 - 39.51%, Si: 15.52 - 68.64% (general composition); additionally, depending on the water quality: Ca, Mg and K might be present below 6%
IUPAC Name:
Zeolite, cuboidal, crystalline, synthetic, non-fibrous
Test material form:
solid: particulate/powder
Remarks:
no surface treatment
Specific details on test material used for the study:
Type A Zeolite (called "Sodium Aluminosilicate" by the authors)
The formulation of the zeolite used in this test was: 16.0% Sodium, 20.1% Aluminum, 40.6% Silicone dioxide, and 21.0% moisture.
Simple No.: UDX-8709

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
103 sexually nature male and virgin female rats, derived from the Sprague-Dawley strain, were obtained from Charles River Breeding Laboretories. Upon arrival, the rats were placed in individual, stainless steel cagea with raised wire-mesh floors. Throughout the experiment, water and Purin Chow were available ad libitum. The room temperature was maintained at approximately 23 °C and the humidity at approximately 50%. The lighting was controlled to provide 12 hours of dark and 12 hours of light (7:00 a.m. - 7:00 p.m.).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dosing solutions were adjusted on days 9 and 12 of gestation to allow for changes in body weight.
The dosing solutions were prepared by mixing with a magnetic stirrer 15 minutes before and during the dosing procedure. Ten ml samples of each solution were retained for analysis; however, the samples were inadvertently placed in storage where they pracipitated and could no longer be solubilized for analysis.
Details on mating procedure:
The females were maintained for two weeks before exposure to males, to allow any pseudo-pregnant animals to become sexually receptive. At the end of the two-week period, the females were paired with the males and vaginal smears and observation for plugs were commenced. The day the vaginal smear showed the presence of sperm was designated day 0 of pregnancy and the male was removed.
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily
Duration of test:
until GD 20
Doses / concentrationsopen allclose all
Dose / conc.:
74 mg/kg bw/day
Dose / conc.:
1 600 mg/kg bw/day
No. of animals per sex per dose:
20 (females)
Control animals:
yes, concurrent vehicle
other: positve control (asperine)
Details on study design:
After a three-day accllmation period, the female rats were weighted and randomly distributed into four groups of twenty rats on the basis of body weight. The mean body weights of the groups were as similar as possible and each group contained similar numbers of rats with light, medium or heavy body weights. The male rats in this study were utilized as breeders only; therefore, no records were maintained on them.
The dams received the appropriate treatment by gavage on days 6 through 15 of gestation inclusive. Each animal received 10 ml/kg of body weight of the appropriate Zeolite solution or vehicle (water) as follows: Group 1 - 10 ml/kg distilled water, (negative vehicle control); Group 2 - 74 mg/kg Zeolite; Group 3 - 1600 mg/kg Zeolite; Group 4 - 250 mg/kg aspirin (positive control). The dosing solutions were adjusted on days 9 and 12 of gestation to allow for changes in body weight.

Examinations

Maternal examinations:
The females were weighed on days 0, 6, 9, 12, 15, 18 and 20 of gestation.
Ovaries and uterine content:
On day 20 of gestation, the dams were sacrificed. The numbers of corpora lutea of pregnancy were recorded. Then, the uterine horns were excised, and the numbers of implantations, resorptions, live or dead fetuses and their positions in the horns were recorded. The fetuses were drled of amniotic fluid, weighed, and inspected for gross malformations. One-third of each litter were eviscerated and cleared with alcoholic KOH, stained with Alizarin Red and examined for skeletal defects. The remaining fetuses were fixed whole in Bouin's solution, razor-blade sectloned and examined for soft-tissue defects by the Wilson method.
Fetal examinations:
s. above
Statistics:
The conception rate in this study ranged from 80 to 90%, thus assuring a sufficient number of fetuses to assess the teratogenic potential of sodium aluminosilicate.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no maternal deaths in the Zeolite treated group, although there were three deaths in the positive control group. Two of those deaths were attrlbuted to the pulmonary aspiration of the aspirin.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no statistically significant differences in maternal weight gain, which further indicated the lack of maternal toxicity or mortality from the Zeolite.

Maternal developmental toxicity

Other effects:
no effects observed
Description (incidence and severity):
Statistical examination of the numbers of corpora lutea, implantations and resorptions revealed no significant differences due to Zeolite treatment.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day
Basis for effect level:
body weight and weight gain
mortality
necropsy findings

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no statistical differences in the weight of the fetuses.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no statistical differences in the number of live or dead fetuses. or in the weight of the fetuses.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
s. below (visceral malformations)
Skeletal malformations:
no effects observed
Description (incidence and severity):
No statistical differences were noted in the incidence of skeletal defects in treated groups, although a significant increase in the overall incidence of skeletal abnomallties occurred in the positive control (aspirin) group.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
There were no signifcant differences seen in the incidence of gross or soft-tissue malformations. One fetus in the 74 mg/kg group had multi-malformations. Hydronephrosis, often times classified as a variation, occurred in a low percentage in the Zeolite treated groups.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
visceral/soft tissue: urinary
Description (incidence and severity):
Hydronephrosis occurred in a low percentage (c. 1%) in the Zeolite treated groups.

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

These data showed that sodium aluminosilicate (Type A Zeolite) was not teratogenic in rats at the levels treated. As hydronephrosis only occured in one percent of treated animals (two animals each of the 74 and 1600 mg/kg bw/d groups), it was not statistically relevant.

Applicant's summary and conclusion

Conclusions:
No deleterious, uternal, embryo, or fetal toxic effects were seen in Charles River rats administered levels of 74 or 1600 mgikg of body weight of sodium aluminosilicate (Type A Zeolite) on days 6 through 15 of gestation. Also, no test-induced teratogenicity was noted when compared to the control.
Executive summary:

A teratological study of Type A zeolite (called "sodium aluminosilicate" by the authors) was performed in rats.