Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Although there is no study in fertility available, an expert's statement (cf. Dekant) assessed that an extended one-generation reproductive and toxicity study was not required for zeolites since all relevant endpoints in this study design were already covered in the database on the zeolites' constituents Si(OH)₄ and Al³⁺.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

There are two key studies in developmental toxicity with type A zeolite available. No maternal or developmental toxicity was seen with oral doses up to 1600 mg/kg bw/d administered in both studies (NOAEL >= 1600 mg/kg bw/d).

There are also four oral supporting studies with the read-across substance sodium silicoaluminate in four different species. In none of these maternal or developmental toxicity was seen with doses up to 1600 mg/kg bw/d administered in all studies, too. Developmental toxicity was only assessed via the oral route.

Link to relevant study records

Reference

Reference 1

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

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

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

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.).

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

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.

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.

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.

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.

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day

Basis for effect level:

body weight and weight gain

mortality

necropsy findings

Abnormalities:

no effects observed

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.

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

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.

Developmental effects observed:

no

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.

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.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

experimental phase: Sep. 23 - Nov. 18, 1976; report dated: May 30, 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

orally administered from GD 6 to GD 18; 3 dose levels; examination of maternal mortality and weight gain as well as fetal malformations

GLP compliance:

not specified

Limit test:

no

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

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

108 virgin, New Zealand rabbit (5-6 monthe of age) and sixteen bucks were obtained from Pel-Freez Bio-animals, Inc. Rogers, Arkansas. Throughout the study, all animals were fed Purina Rabbit Chow and water ad libitum. The temperature was maintnined at approximately 23 °C and the humidity at approximately 50%. A light-dark cycle of 12 hours (7 AM 7 PM) was controlled by an automatic timing device.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled

Details on exposure:

The animnals received the doses daily from days 6 throuqh 18, inklusive, of gestation by intubation uring No. 8 French catheter attached to a combination 10 cc and 50 cc syringe.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The does were weighed on days 0, 6, 9, 12, 15, 18, 21, end 29 of gestation. These weights were used to determine the appropriate dose during the treatment period.

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 does were mintained for an 18-day orientation period before breeding to allow any preudo-pregnant animals to become sexually receptive. Then the doea were artificially lnseminated. The day of insemination was considered day 0 of gestation.

Duration of treatment / exposure:

GD 6-18

Frequency of treatment:

daily

Duration of test:

The dams were sacrificed on day 29 of gestation.

Dose / conc.:

74 mg/kg bw/day (nominal)

Dose / conc.:

345 mg/kg bw/day (nominal)

Dose / conc.:

1 600 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 females per dose group

Control animals:

yes, concurrent vehicle

other: positive: 2.5 mglkg of 6-amino nicotinamide on day 9 of gestation

Maternal examinations:

Does were weighed on days 0, 6, 9, 12, 15, 18, 21, end 29 of gestation. At sacrifice, a gross inspection of the viscera was performed.

Ovaries and uterine content:

The ovaries were removed and the numbers of corpora lutea of pregnancy were counted and recorded. The uterine horns were opened and the numbers of implantations, resorptions, and live or dead fetuses were recorded.

Fetal examinations:

The feituses were randomly selected for soft-tissue and skeletal examination; two-thirds for the former and one-third for the latter.

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

3 does died. One death occurred in the vehicle control group, one in the 345 mg/kg zeolite group, and one in the 1600 mglkg zeolite group.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Statiatical examination of maternal body weight gains showed no differences among the gains from day 0 to day 29; however, a statistical increase in the weight gain of the group
treated with 74 mglkg Zeolite during the treatment period (days 6 through 18) was noted. These data showed that these doses of Type A Zeolite caused no maternal toxicity.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Gross examination of the does at laporotomy revealed 2 does with 2 mammary growths in the 74 mg/kg group; one doe with a grainy liver in the 345 mg/kg group and one
doe with an ovarian cyst in the positive control group. These abnormalities and their numbers were not unusual and appeared not to be test-related.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Total litter losses by resorption:

effects observed, non-treatment-related

Early or late resorptions:

effects observed, non-treatment-related

Dead fetuses:

no effects observed

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

The conception rate in this study ranged from 90 to 95% which yielded sufficient numbers of fetuses for the teratogenic assessment of the zeolite in this species.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

The average number of corpora lutea and implantations were not significantly different among the groups, nor were there significant differences noted in the average numbers of resorptions.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

body weight and weight gain

changes in number of pregnant

dead fetuses

gross pathology

mortality

total litter losses by resorption

Key result

Abnormalities:

effects observed, non-treatment-related

Description (incidence and severity):

cf. gross pathological findings

Fetal body weight changes:

no effects observed

External malformations:

no effects observed

Description (incidence and severity):

cf. below (visceral malformations)

Skeletal malformations:

no effects observed

Description (incidence and severity):

No statistical differences were seen in the incidence of fetuses with skeletal defects or in the individual anomalies. Several individual defects were significantly increased in the 6-arnino-nicotinamide positive control group, although the number of fetuses with one or more abnormalities was not significantly increased.

Visceral malformations:

no effects observed

Description (incidence and severity):

Gross observation of the fetuses at laporotomy revealed several abnormalities in the positive-control group, but none in the Zeolite-treated-groups. Statistical analyses of the incidences of overall and individual soft-tissue defects showed no significant differentes between Zeolite-treated groups and the negative control.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

There was a statistically significant increase in the number of resorptions and decrease in the number of live fetuses noted in the 6-amino-nicotinamide positive control group compared to the negative controls. These data showed that no embryo toxicity, mortality or growth retardation was caused by the Zeolite at the levels tested.

Conclusions:

The data showed no increase in the incidences of soft-tissue or skeletal defects in rabbits treated with one of the tested levels of sodium aluminosilicate (Type A Zeolite). In addition, no maternal toxicity or mortality was seen that could be attributed to this material.

Executive summary:

Rabbits were dosed, by gavage, on days 6 -18 of gestation with levels of 74, 345, or 1600 mg/kg of body weight with Type A zeolite (called "sodium aluminosilicate" by the authors).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

other: rabbit, hamster, mouse, rat

Quality of whole database:

reliability 2

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

As no adverse effects were identified, there is no need for classification.