Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

excretion

Principles of method if other than guideline:

The rate of Zeolite Type A excretion was obtained from data on urinary excretion in rats after single oral administration.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): Zeolite Type A (sodium aluminosilicate)(Huber Corporation)
- Analytical purity: no data
- Analyses showed that it contained 14.7 % silicon and 16.4% aluminium.

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Sprague-Dawley Cox

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 240-260 g
- Diet (e.g. ad libitum): Purina Rat Chow (1500-2000 ppm silicon)
- Water (e.g. ad libitum): tap water; ad libitum
- Acclimation period: 4-5 days

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

quartz-distilled (QD) water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: All suspensions were prepared in quartz-distilled water which contained < 0.5 ppm silicon and aluminium. Concentrations (w/w) of dosing materials were adjusted so that all groups received the same dosage volume (10 mL/kg). The acutal weights administered were calculated by difference.

Duration and frequency of treatment / exposure:

once

Dose / conc.:

40 mg/kg bw (total dose)

Dose / conc.:

200 mg/kg bw (total dose)

Dose / conc.:

1 000 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

4

Control animals:

yes, concurrent vehicle

Details on study design:

For the determination of silicon in urine, the samples were dry-ashed, fluxed with Na2COJ, and then dissolved in hydrochloric acid. The concentrations of silicon in solution were measured by induction-coupled RF plasma optical emission spectrometry.

Details on dosing and sampling:

Rats were fasted for 17-18 hr, then dosed using a no. 10 French rubber feeding tube attached to a 3-ml plastic syringe. Concentrations (w/w) of dosing materials were adjusted so that all groups received the same dosage volume (10 ml/kg). The actual weights administered were calculated by difference. All suspensions were prepared in quartz-distilled (QD) water which contained <0.5 ppm silicon. Rats were dosed with 40, 200 or 1000 mg of test material/kg body weight. For each study a group of four or six control rats were given 10 ml QD water/kg body weight. Tail cups to collect faeces were used to prevent contamination of urine samples.

Statistics:

Group means were compared by Student’s t-test, except that when the values were not normally distributed a non-parametric test was used (Gibbons, 1971). The rates of excretion were fitted to zero-order and first-order kinetic equations (Barr, Goodnight, Sail, & Hellwig, 1976).

Details on excretion:

Zeolite Type A had an urinary excretion rate half-life time of 6-8 hr.

Particulare and total silicon in rat urine in the first 8 hours after the administration of Zeolite type A:
control group: 6.5 +/- 0.6 µg/ml urine (total); 2.2 +/- 1.1 µg/ml urine (particulate)
40 mg/kg group: 26.2 +/- 3.4 µg/ml urine (total); 1.4 +/- 0.3 µg/ml urine (particulate)
200 mg/kg group: 64.7 +/- 6.8 µg/ml urine (total); 1.6 +/- 1.3 µg/ml urine (particulate)
1000 mg/kg group: 80.9 +/- 13.5 µg/ml urine (total); 2.2 +/- 0.8 µg/ml urine (particulate)

It was of interest to find out whether particulate, or filterable, forms of silicon were produced during the time of maximum excretion in rats dosed with Zeolite Type A. While the total silicon concentration increased sharply with dose, the particulate silicon was not increased above control levels. The authors would, therefore, predict that toxic effects in the urinary tract would not result from single high doses of Zeolite type A.

Conclusions:

Zeolite Type A had an urinary excretion rate half-life time of 6-8 hr.

Executive summary:

The rate and extent of urinary excretion of silicon was determined in rats after oral administration of magnesium trisilicate, food-grade sodium aluminosilicate, sodium silicate or Zeolite type A. Only the results on the latter are documented here.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

absorption

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study was carried out to estimate the bioavailability of silicon and aluminum from Zeolite A administered as a capsule, oral suspension, and oral solution relative to an intravenous bolus infusion (i.v.) administered over a 1-1.5 min interval. Twelve dogs received single doses of Zeolite A after a 1 week control period in a randomized five-way crossover design. Plasma samples were drawn at time 0 and for 36 h after dosing. The concentrations of silicon and aluminum were determined by graphite furnace atomic absorption.

GLP compliance:

not specified

Specific details on test material used for the study:

Zeolite A (N-0974) raw material (Ethyl, lot no. 6)
Zeolite A suspension 10 mg/ml (MF no. 2705, Whitby, lot no. 908-11)

Radiolabelling:

no

Species:

dog

Strain:

Beagle

Sex:

female

Details on test animals or test system and environmental conditions:

Twelve female beagle dogs, 6-8 months of age at initiation of dosing, weighing from 7.3 to 8.7 kg were used in the study.
The dogs were individually housed in stainless-steel cages and maintained in an environmentally controlled room (72 +/- 1.4°F, humidity 42 +/- 7.9%) with a 12-h light/dark cycle. Water was available ad libitum. Diet was available for 2-3 h per day, and was provided at approximately 4 h after dosing for 3 h on the days of dosing.

Route of administration:

other: oral and intravenous (s. below)

Vehicle:

other: gelantin capsules and sterile water for oral administration, sodium chloride and water for injection

Details on exposure:

A 7 day control phase was initiated prior to the start of dosing. Each animal was then dosed with an oral capsule 30 mg/kg, oral solution 30 mg/kg (4 mg/ml), oral suspension 30 mg/kg (10 mg/ml) and i.v. solution 20 mg/kg (4 mg/ml) administered over 1-1.5 min. The oral solution and suspension were delivered via gavage, followed by oral gavage with deionized water to ensure that all of the test article was delivered. The i.v. dose was administered into a vein in either leg. The duration of each injection was generally 1-1.5 min.

Duration and frequency of treatment / exposure:

one time exposure

Dose / conc.:

110 mg/kg bw (total dose)

Remarks:

oral capsule 30 mg/kg, oral solution 30 mg/kg (4 mg/ml), oral suspension 30 mg/kg (10 mg/ml) and i.v. solution 20 mg/kg (4 mg/ml)

No. of animals per sex per dose / concentration:

12 (females only)

Control animals:

no

Details on dosing and sampling:

Blood was obtained via the jugular vein at 0 h (prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h after dosing. Plasma samples were stored frozen at -15°C until analysis.

The plasma samples were assayed for silicon and aluminum at the University of North Carolina School of Medicine Bioanalytical Laboratory
by graphite furnace atomic absorption spectrometry.

Statistics:

Pharmacokinetic parameter estimates for silicon were obtained using baseline corrected data. Baseline correction was carried out by subtracting
control data from treatment data for each dog. All negative values obtained by baseline subtraction were treated as zero. Non-baseline corrected
AUC silicon values were compared with the silicon AUC data obtained during the control period in order to establish that statistically significant
absorption of silicon from Zeolite A had occurred. Pharmacokinetic parameter estimates for aluminum were determined using non-baseline corrected data, due to the low aluminum concentrations achieved in the treatments and the irregular nature of the plasma aluminum data during the control period.

Details on absorption:

The mean extent of absorption of silicon from the oral capsule, oral solution and oral suspension of Zeolite A was 2.33%, 3.44% and 2.73%, respectively. The mean peak silicon concentrations for the oral dosage forms ranged from 1.28 to 2.95 mg/l and the mean time to reach maximum concentrations
ranged from 0.83 to 5.88 h, with most T'max values occurring within 2 h.

The absolute extent of aluminum absorption from Zeolite A observed after doses of the oral capsule, oral solution and oral suspension were 0.023%, 0.032% and 0.028% of the i.v. dose, respectively. There was no statistically significant absorption of aluminum from the oral capsule or suspension. Statistically significant absorption of aluminum occurred from the solution over control. Therefore, single-dose oral administration of Zeolite A results in low but appreciable absorption of silicon with little absorption of aluminum.

Details on excretion:

The mean elimination half-life and clearance of silicon from the i.v. dose of Zeolite A were 17.5 h and 0.221 +/- 0.0192 ml/min per kg.

The mean elimination halflife and clearance of aluminum were 91.2 h and 0.0495 ml/min per kg. The long half-life and slow clearance of aluminum after i.v. dosing was probably due to the high concentration of aluminum in plasma.

Conclusions:

The mean elimination half-life and clearance of silicon from the i.v. dose were 17.5 h and 0.221 +/- 0.0192 ml/min per kg. The mean extent of absorption of silicon from the oral capsule, oral solution and oral suspension was 2.33%, 3.44% and 2.73%, respectively, relative to the intravenous bolus. The mean elimination half-life and clearance of aluminum were 91.2 h and 0.0497 +/- 0.0082 ml/min per kg. The extent of absorption of aluminum from the oral dosage forms was less than 0.1%, relative to the intravenous infusion. The plasma aluminum AUC values from the oral capsule and suspension showed no statistical difference from those during the control period, but the aluminum AUC of the oral solution was statistically greater than the AUC of the corresponding control period.

Executive summary:

A study in beagle dogs was carried out to estimate the bioavailability of silicon and aluminum from Zeolite A administered as a capsule, oral suspension, and oral solution relative to an intravenous bolus infusion (i.v.) administered over a 1-1.5 min interval.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

absorption

Qualifier:

no guideline followed

Principles of method if other than guideline:

single administration by oral capsule, one dose level per substance, blood measurements up to 24 hours after dosing

GLP compliance:

not specified

Specific details on test material used for the study:

Zeolite A (N-0974) raw material (Ethyl, lot #07)
sodium aluminosilicate (lot #SR00002922)

Radiolabelling:

no

Species:

dog

Strain:

Beagle

Sex:

female

Details on test animals or test system and environmental conditions:

10-13 months of age at initiation of dosing, weighing from 7.3 to 11.6 kg
The dogs were individually housed in stainless steel cages and maintained in an environmentally controlled room. Water was available ad libitum. Diet was available for approximately 3 hours per day, and was provided at approx¬imately 4 hours after dosing for 3 hours on the days of dosing.

Route of administration:

oral: capsule

Vehicle:

other: Empty clear gelatin capsules (Jorgensen Lab¬oratories, lot #35, and J-104A) were used.

Duration and frequency of treatment / exposure:

single dose

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

Zeolite A

Dose / conc.:

16 mg/kg bw/day (nominal)

Remarks:

sodium aluminosilicate

No. of animals per sex per dose / concentration:

12 (females only)

Control animals:

no

Details on study design:

Blood was obtained via the jugular vein at 0 hour (prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. The plasma samples were assayed for silicon and aluminum by graphite furnace atomic absorption at the University of North Carolina School of Medicine, Bioanalytical Laboratory.

Type:

absorption

Results:

Zeolite A: AUC(silicon) = 9.5 ± 4.5 mg * hr/L, AUC(aluminium) = 342 ± 111 µg * hr/l

Type:

absorption

Results:

Sodium aluminosilicate: AUC = 7.7 ± 1.6 mg * hr/L, AUC(aluminium) = 338 ± 167 µg * hr/l

Details on absorption:

The mean AUC (± S.D.) for plasma silicon after dosing with Zeolite A and sodium aluminosilicate were 9.5 ± 4.5 and 7.7 ± 1.6 mg - hr/L respectively. These AUC values were compared by a one-way ANOVA. The ANOVA indicated that there was a significant difference between the means of the silicon AUC for the compounds (p = 0.041). A comparison using Tukey's standardized range test on the means only identified the value for Zeolite A as statistically greater than baseline (56% greater, p < 0.05).
The mean Cmax estimates (±S.D.) for plasma silicon from Zeolite A and sodium aluminosilicate were 1.07 ± 1.06 and 0.67 ± 0.27 mg/L respectively. There was no statistically significant difference between the maximum concentrations (p = 0.076). Although not statistically significant, the mean Cmax fbr Zeolite A was larger than that of any other treatment. The failure to reach statistical significance in this point estimate could be due to the variability in silicon absorption.
The mean Tmax estimates (±S.D.) for plasma silicon from Zeolite A and sodium aluminosilicate were 7.9 ± 6.4, 5.8 ± 4.6 hrs respectively silicon absorbed from the diet. The Tmax values were also compared using a one-way ANOVA. There was no significant difference between the Tmax values (p = 0.636).

The mean plasma aluminum AUC values for Zeolite A and sodium aluminosilicate (± S.D.) were 342 ±111 and 338 ± 167 µg * hr/L and the mean aluminum Cmax values (± S.D.) were 29 ± 9 and 27 ± 14 µg/L, respectively. The plasma aluminum Tmax values (± S.D.) were 3.5 ± 4.1 and 4.2 ± 4.3 hrs for Zeolite A and sodium aluminosilicat, respectively. There was no statistically significant absorption of aluminum from the aluminum containing treatments.

Metabolites identified:

no

Of the 12 dogs receiving Zeolite A none displayed emesis. Of the 12 dogs receiving sodium aluminosilicate, four displayed frothy or food like emesis. Of the 12 dogs receiving Zeolite A, four developed soft stool or diarrhea, one dog receiving so­dium aluminosilicate developed soft stool.

Conclusions:

In conclusion the mean silicon AUC values for Zeolite A and sodium aluminosilicate suggested that silicon is absorbed from the silicon containing products, only Zeolite A demonstrated a statistically greater absorption of silicon (56% increase) than any other treatment or baseline. The mean Tmax values of plasma silicon suggested similar rates of absorption. The aluminum data suggested that no statistically significant absorption of aluminum occurs after the single-dose administration of Zeolite A and sodium aluminosilicate.

Executive summary:

The purpose of this study was to compare the oral bioavailability of silicon and aluminum from Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide in dogs. Only the former two substances are documented here. Twelve female dogs received each com­pound as a single dose separated by one week in a randomized, 4-way, crossover design. Plasma samples were drawn at time 0 and for 24 hours after dosing.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

A structural analogue substance was used for assessment since the performed study is well documented, according to current guidelines and GLP compliant. Concerning animal welfare, there has been no need for the performance of an additional study in zeolites. The "Structural Analogues Substances Approach" is provided in chapter 13.2.

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

excretion

Principles of method if other than guideline:

The rate of Sodium aluminosilicate excretion was obtained from data on urinary excretion in rats after single oral administration.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): sodium aluminosilicate, tradename: Zeolex (Huber Corporation)
- Analytical purity: no data
- Other: Huber Corporation specified that this compound met all the purity and quality specifications of the Food Chemicals Codex; the analyses showed that it contained 30 % silicon and 5.4% aluminium.

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Sprague Dawley Cox

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 240-260 g
- Diet (e.g. ad libitum): Purina Rat Chow (1500-2000 ppm silicon)
- Water (e.g. ad libitum): tap water; ad libitum
- Acclimation period: 4-5 days

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

quartz-distilled (QD) water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: All suspensions were prepared in quartz-distilled water which contained < 0.5 ppm silicon and aluminium. Concentrations (w/w) of dosing materials were adjusted so that all groups received the same dosage volume (10 mL/kg). The acutal weights administered were calculated by difference.

Duration and frequency of treatment / exposure:

once

Dose / conc.:

40 mg/kg bw (total dose)

Dose / conc.:

200 mg/kg bw (total dose)

Dose / conc.:

1 000 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

4

Control animals:

yes, concurrent vehicle

Details on study design:

For the determination of silicon in urine, the samples were dry-ashed, fluxed with Na2COJ, and then dissolved in hydrochloric acid. The concentrations of silicon in solution were measured by induction-coupled RF plasma optical emission spectrometry.

Details on dosing and sampling:

Rats were fasted for 17-18 hr, then dosed using a no. 10 French rubber feeding tube attached to a 3-ml plastic syringe. Concentrations (w/w) of dosing materials were adjusted so that all groups received the same dosage volume (10 ml/kg). The actual weights administered were calculated by difference. All suspensions were prepared in quartz-distilled (QD) water which contained <0.5 ppm silicon. Rats were dosed with 40, 200 or 1000 mg of test material/kg body weight. For each study a group of four or six control rats were given 10 ml QD water/kg body weight. Tail cups to collect faeces were used to prevent contamination of urine samples.

Statistics:

Group means were compared by Student’s t-test, except that when the values were not normally distributed a non-parametric test was used (Gibbons, 1971). The rates of excretion were fitted to zero-order and first-order kinetic equations (Barr, Goodnight, Sail, & Hellwig, 1976).

Details on excretion:

The percentage of silicon that appeared in urine varied independently of the dose. The urinary excretion half-life for ingested sodium aluminosilicate was calculated to be 38 h.

Conclusions:

The urinary excretion half-life for ingested sodium aluminosilicate was calculated to be 38 h.

Executive summary:

The rate and extent of urinary excretion of silicon was determined in rats after oral administration of magnesium trisilicate, food-grade sodium aluminosilicate, sodium silicate or Zeolite type A. Only the results on sodium aluminosilicate are documented here.

Description of key information

Zeolite type A had an urinary excretion rate half-life time of 6-8 hr, that of ingested sodium aluminosilicate was considerably longer (38 h). Both substances were orally administered.

 

The mean elimination half-life and clearance of silicon from an i.v. dose of a type A zeolite were 17.5 h and 0.221 +/- 0.0192 ml/min per kg. The mean extents of absorption of silicon from an oral capsule, an oral solution and an oral suspension were 2.33%, 3.44% and 2.73%, respectively, relative to the intravenous bolus. The mean elimination half-life and clearance of aluminum were 91.2 h and 0.0497 +/- 0.0082 ml/min per kg. The extent of absorption of aluminum from the oral dosage forms was less than 0.1%, relative to the intravenous infusion. The plasma aluminum AUC values from the oral capsule and suspension showed no statistical difference from those during the control period, but the aluminum AUC of the oral solution was statistically greater than the AUC of the corresponding control period.

 

Similar rates of absorbtion were measured with a type A zeolite sodium aluminosilicate after oral administration:
Zeolite A: AUC(silicon) = 9.5 ± 4.5 mg * hr/L, AUC(aluminium) = 342 ± 111 µg * hr/l
Sodium aluminosilicate: AUC = 7.7 ± 1.6 mg * hr/L, AUC(aluminium) = 338 ± 167 µg * hr/l

 

 

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

3.44

Additional information

No dermal absorption is known. Because of their poor solubility in water, their high molecular weight and their ionic character, it can be assumed that zeolites cannot penetrate the intact skin.

Due to its inherent chemico-physical properties, the uptake of zeolite, cuboidal, crystalline, synthetic, non-fibrous is low and no potential risk for bioaccumulation is to be expected.