Silicic acid, aluminum magnesium sodium salt

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

excretion

Principles of method if other than guideline:

The rate of sodium silicate excretion was obtained from data on urinary excretion in rats after single oral administration of sodium aluminosilicate, Zeolite A, sodium silicate and magnesium trisilicate. Only data for sodium aluminosilicate were described in this entry.

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:

other: 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:

not specified

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:

no data

Remarks:

Doses / Concentrations:
40, 200 and 1000 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

yes, plain diet

Positive control reference chemical:

yes, 4 control animals received 10 mL of quartz-distilled water.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine

- Other:

Details on excretion:

At the 40 mg/kg level 12.4 % of administered sodium aluminosilicate was excreted in the urine, elevated levels of Si in the urine were observed only in the first 24 h after oral dosing. At the 200 and the 1000 mg/kg level 5.2 % and 1.3 % of the total administered test substance was excreted in the urine. The urinary excretion half-life for ingested sodium aluminosilicate was calculated to be 38 h. No significant increase in urinary aluminium was detected. Daily urinary aluminium excretion averaged 17.7 ± 3.2 µg for control rats and 15.1 ± 4.3 µg for sodium aluminosilicate treated rats. The excretion rate was independent of the doses applied indicating that the limiting factor is the rate of production of soluble or absorbable silicon in the gastrointestinal tract.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The half life time was 38 h.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The purpose of the study was to comparable the bioavailabilty of silicon and aluminium from sodium aluminosilicate, Zeolite A, magnesium trisilicate and aluminium hydroxide. Only data for sodium aluminosilicate were described in this entry.

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): magnesium trisilicate
- Analytical purity: no data

Species:

dog

Strain:

Beagle

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10-13 months
- Weight at study initiation: 7.3-11.6 kg
- Housing: The dogs were individually housed in stainless steel cages and maintained in an environmentally controlled room.
- Diet (e.g. ad libitum): Diet was available for approx. 3 hours per day and was provided at approximately 4 hours after dosing for 3 hours on the days of dosing.
- Water (e.g. ad libitum): water, ad libitum

Route of administration:

oral: capsule

Vehicle:

other: empty clear gelatin capsules

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing was equimolar based upon silicon content and adjusted to each dog´s body weight. Empty clear gelatin capsules were used.

Duration and frequency of treatment / exposure:

single administration

Remarks:

Doses / Concentrations:
20 mg/kg

No. of animals per sex per dose / concentration:

3

Control animals:

no

Positive control reference chemical:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 0 (prior to dosing), 0.5, 1, 1.5; 2, 3, 4, 6, 8, 12 and 24 hours after dosing

Details on absorption:

The mean plasma silicon AUC value was 8.8 ± 3.0 mg*h/L, the mean plasma silicon Cmax value was 0.75 ± 0.31 mg/L and the mean Tmax estimates for plasma silicon was 6.9 ± 6.3 hours.
The mean plasma aluminum AUC value was 315 ± 69 µg*h/L, the mean plasma silicon Cmax value was 24 ± 5 µg/L and the mean Tmax estimates for plasma aluminium was 5.7 ± 7.3 hours.

The results suggest that single oral administration of magnesium trisilicate yields to low absorption of silicon.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Reference 3

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

study initiation date: 23rd March 2016, experimental phase: 11th April - 23rd May 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

2004

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Sylodent VP5 (SAS)

Supplier: Grace GmbH & Co. KG
Appearance: white paste
SAS content: 10% w/w

Radiolabelling:

no

Species:

pig

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Back/flank skin from suckling pigs (aged 6 - 8 weeks) was obtained from a food source abattoir. Prior to them being scalded, samples of whole skin were excised from the trunk area of each animal and the samples clipped to remove excess hair. Skin membranes were cut from the clipped samples at a thickness setting of 400 µm using an electric dermatome.
Each membrane was given an identifying number and stored frozen, at approximately -20°C, on aluminium foil until required for use.

Type of coverage:

open

Vehicle:

other: oil in water emulsion (formula no. 659/001/003)

Duration of exposure:

24 h

Doses:

2 mg / cm² (= 200 µg SAS/cm²)

No. of animals per group:

6 skin membrances per test substance (from at least four different animals)

Control animals:

yes

Details on study design:

The application rates (2 mg/cm²) and exposure conditions (24 hour) used in this study were designed to simulate predicted normal human exposure to the test material.

Signs and symptoms of toxicity:

no effects

Dermal irritation:

not examined

Absorption in different matrices:

There was no detectable penetration of SAS through dermatomed pig skin using both AF4 and ICP methods.

According to the analytical laboratory, due to the contamination of the receptor fluid with very small skin debris and very small oil aerosols that have diffused from the skin samples into the receptor medium, a clear signal for silica particles could not be obtained. The situation was not improved by washing the receptor fluid with organic solvents to remove the oil aerosols due to the fact that the contamination was much higher than expected. The pre-testing with a pure receptor fluid spiked with a very low concentration of nano SAS particles (Colloidal Silica) demonstrated that the method was capable of detecting extremely low mass concentrations of SAS. Even using the blind sample to define the background and subtract the background of skin debris and oil aerosols from the test results did not provide any meaningful results.

ICP data did not present any evidence that silica was present in the receptor fluid samples and there was no indication that SAS was present in the noise scattering.

Asymmetric flow field-flow fraction (AF4) and multi angle light scattering is a viable option for analysing SAS particles in liquid media such as skin penetration receptor fluids. This was demonstrated by the Fraunhofer Institute using spiked receptor fluids. Contamination by skin debris and oil aerosols from the test materials and the test skin appeared to be very high in concentration and no meaningful results using the AF4 method could be obtained without removing the contaminants e.g. by washing or filtering. Analysis by ICP did not provide any evidence for penetration of SAS through dermatomed pig skin.

There was no detectable penetration of SAS through dermatomed pig skin using both AF4 and ICP methods. Quantification of SAS by either method was not possible in the presence of the contaminants that were already present in the test system.

Conclusions:

There was no detectable penetration of Syloid VP 5 (a SAS) through dermatomed pig skin using both AF4 and ICP methods. Quantification of SAS by either method was not possible in the presence of the contaminants that were already present in the test system.

Executive summary:

The purpose of this study was to investigate the in vitro percutaneous penetration of four synthetic amorphous silica (SAS) formulations prepared as ‘oil in water' (O/W) emulsions through pig dermatomed skin following a 24 hour exposure. Only the results of the examinations in Syloid VP 5 are documented here. An untreated control group and a group of skin samples treated with the ‘oil in water' emulsion were also included.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

excretion

Principles of method if other than guideline:

The rate of sodium silicate excretion was obtained from data on urinary excretion in rats after single oral administration of sodium aluminosilicate, Zeolite A, sodium silicate and magnesium trisilicate. Only data for sodium aluminosilicate were described in this entry.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): magnesium trisilicate
- Origin: Mallinkrodt Chemical Company (St. Louis, USA)
- Analytical purity: no data
- Other: analysis showed that it contained 20.2 % silicon.

Radiolabelling:

no

Species:

rat

Strain:

other: 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:

not specified

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:

no data

Remarks:

Doses / Concentrations:
40, 200 and 1000 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

yes, plain diet

Positive control reference chemical:

yes, 4 control animals received 10 mL of quartz-distilled water.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine

- Other:

Details on excretion:

The urinary silicon excretion half life times, determined by the method of Barr et al. (1976), were 16-20 hours. They were independent of dose within the 40 to 1000 mg/kg bw dosage range.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The half life time was 16-20 h.

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

toxicokinetics

Principles of method if other than guideline:

The purpose of the study was to comparable the bioavailabilty of silicon and aluminium from sodium aluminosilicate, Zeolite A, magnesium trisilicate and aluminium hydroxide. Only data for sodium aluminosilicate were described in this entry.

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): sodium aluminosilicate
- Analytical purity: no data

Species:

dog

Strain:

Beagle

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10-13 months
- Weight at study initiation: 7.3-11.6 kg
- Housing: The dogs were individually housed in stainless steel cages and maintained in an environmentally controlled room.
- Diet (e.g. ad libitum): Diet was available for approx. 3 hours per day and was provided at approximately 4 hours after dosing for 3 hours on the days of dosing.
- Water (e.g. ad libitum): water, ad libitum

Route of administration:

oral: capsule

Vehicle:

other: empty clear gelatin capsules

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing was equimolar based upon silicon content and adjusted to each dog´s body weight. Empty clear gelatin capsules were used.

Duration and frequency of treatment / exposure:

single administration

Remarks:

Doses / Concentrations:
16 mg/kg

No. of animals per sex per dose / concentration:

3

Control animals:

no

Positive control reference chemical:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 0 (prior to dosing), 0.5, 1, 1.5; 2, 3, 4, 6, 8, 12 and 24 hours after dosing

Details on absorption:

The mean plasma silicon AUC value was 7.7 ± 1.6 mg*h/L, the mean plasma silicon Cmax value was 0.67 ± 0.27 mg/L and the mean Tmax estimates for plasma silicon was 5.8 ± 4.6 hours.
The mean plasma aluminum AUC value was 338 ± 167 µg*h/L, the mean plasma silicon Cmax value was 27 ± 14 µg/L and the mean Tmax estimates for plasma aluminium was 4.2 ± 4.3 hours.

The results suggest that single oral administration of sodium aluminosilicate yields to low absorption of silicon and only poorly absorption of aluminium.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Jan, 20 - Oct. 13, 2011; experimental phase: Jan. 26 - May 3, 2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study is a further investigation of an OECD-guideline (407) repated dose oral one. It was performed for the chemical analysis of
silicon concentration (blood analysis) and the transmission of silicon particles in organ samples examined by electron microscopy.

GLP compliance:

no

Remarks:

The main study was performed under GLP conditions except for the chemical analysis of silicon concentration and the transmission electron microscopy of silicon particles in organ samples documented in this endpoint.

Specific details on test material used for the study:

supplied by JRC, Ispra, on behalf of the sponsor, CEFIC, The European Chemical Industry Council

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

purchased from: Charles River Deutschland, Sulzfeld, Germany

Sex:

male

Details on test animals or test system and environmental conditions:

Animals were housed in groups of 5 per cage in Makrolon Type IV cages in animal room T1.044 in the conventional area. Absorbent softwood was used as bedding material in the cages (Lignocel BK 8-15, ssniff GmbH, Soest, Germany). Drinking water from the Hannover city water supplier was offered fresh weekly, in Makrolon bottles (approximately 300 ml), ad libitum. Food was offered ad libitum fresh weekly. The diet used (ssniff R/M-H) was supplied by ssniff GmbH, Soest, Germany. The temperature in the animal room was set at 22 ± 2oC and the rel. humidity at 30 - 70%. The animal room lighting was a 12-hour light/dark cycle controlled by an automatic timing device.

Route of administration:

oral: gavage

Vehicle:

other:

Duration and frequency of treatment / exposure:

28 d, daily exposure

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent vehicle

Details on study design:

s. below

Statistics:

Differences between groups were considered case by case as statistically significant for p<0.05. Data were analyzed using analysis of variance. If the group means differed significantly according to the analysis of variance, the means of the treatment groups were compared with the means of the control group, using DUNNETT's modification of the t-test. Kruskal-Wallis ANOVA and Mann-Whitney U-test were applied in the case of non-homogeneous data. The statistical evaluation of the histopathological findings was done with the two-tailed FISHER test using the PROVANTIS system. For comparisons of semiquantitative data, the Chi-square test was used.

Details on absorption:

Transmission electron microscopy (non-GLP) found electron dense structures composed of irregular homogenous to fine granular material in the cytoplasm of mesenteric lymph nodes cells, liver cells and kidney cells of all animals from the control and from the high dose group. The granular structures measured only few nanometer. However, these structures did not have the shape or appearance of amorphous material such as amorphous silica.

Details on distribution in tissues:

Determination of Silicon Ion Concentration
The results of the chemical analysis of silicon ion concentration are presented in Table 19. In summary, the ion concentrations in kidney, liver and blood were comparable in control animals (group 1) and high dose animals (group 4) and no treatment related changes were observed.

Determination of Silicon Particles
For electron microscopical investigation two samples per organ of the mesenteric lymph nodes, kidney as well as liver of all high dose group animals (group 4) were used. Vehicle treated animals served as controls (group 1).
To achieve better visibility of possible nanoparticles in comparison to the biological background composed of the organic structure, ultrathin sections have not been contrasted using uranyl acetate and lead citrate.

Mesenteric lymph node: Occasionally, cells of the mesenteric lymph node of all animals of the untreated group (group 1) and of the amorphous silica treated group (group 4) showed electron dense structures. Theses electron dense structures were found intracytoplasmatically in vacuoles and were characterized by irregular homogenous to fine granular material.
Liver: Occasionally, liver cells of all animals of the untreated group (group 1) and of all animals of the amorphous silica treated group (group 4) showed electron dense structures. Theses electron dense structures were found intracytoplasmatically in vacuoles and were characterized by irregular homogenous to fine granular material.
Kidney: Occasionally, kidney cells of all animals of the untreated group (group 1) and of all animals of the amorphous silica treated group (group 4) showed electron dense structures. Theses electron dense structures were found intracytoplasmatically in vacuoles and were characterized by irregular homogenous to fine granular material.

Conclusions:

Toxicological analysis of silica ion concentrations in blood, kidney and liver tissue did not reveal differences between the control and the dose group. This result is most likely due to the naturally occurring high background values of silica.

Executive summary:

This is a toxicokinetic examination of an oral 28-day study in rats. It showed, that silicon is naturally absorbed by the body, as shown by its presence in blood, kidneys and liver of treated as well as untreated animals.

Description of key information

Referring to the toxicokinetic properties of structurally related compounds, no risk potential is expected for SMAS.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

See basic toxicokinetics.