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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:
other: Well documented publication giving sufficient detail for evaluation.
Objective of study:
excretion
Principles of method if other than guideline:
Measurement of urinary excretion after single oral application
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Route of administration:
oral: unspecified
Vehicle:
not specified
Remarks:
Doses / Concentrations:
two trials with 40 and 1000 mg/kg, respectively
Details on excretion:
At the 40 mg/kg level 18.9% of administered silicate was excreted in the urine, elevated levels of Si in the urine were observed only in the first 24 hrs after oral dosing.  At the 1000 mg/kg level 2.8% of the total administered silicate was excreted in the urine. The urinary excretion half-life for ingested sodium silicate was calculated to be 24 hours. 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.
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:
other: Well documented publication giving sufficient detail for evaluation.
Objective of study:
excretion
Principles of method if other than guideline:
Measuremant of urinary concentration after oral application.
GLP compliance:
no
Species:
dog
Route of administration:
other: oral:gavage and intravenous
Details on excretion:
The output of silica (SiO2) in the urine markedly increased without corresponding increase in the blood and returned to normal after some hours. Moderate increases in the concentration of silica in the blood and enormous increases in the urine were observed following intravenous injection. As upon oral ingestion, silica levels in  the urine returned to normal after the end of injection.

Description of key information

Key value for chemical safety assessment

Additional information

There are only limited experimental studies available in which the toxicokinetic properties of silicic acid, sodium salt were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of sodium silicate according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012)”.

Silicic acid, sodium salt (= sodium silicate; CAS 1344-09-8) is composed of oligomers of the tetrahedral orthosilicate anion SiO4 with sodium cations as counter ion. The connectivity of silicon atoms in terms of Si-O-Si bonds varies depending on the concentration of sodium cations: the more Na+, the less Si-O-Si bonds are formed and vice versa. Therefore, the connectivity of silicon atoms in sodium silicate varies depending on the mixing ratio of the silicon source (quartz sand) and the sodium source (soda ash or NaOH). The resulting molecular structures are described in terms of molar ratios (SiO2:Na2O). Molar ratios (MR) of commercial sodium silicate typically vary between 1.5 and 4. The higher the molar ratio, the less sodium ions are present in the silica network and consequently the less alkaline the silicates are.

Sodium silicate is manufactured in various molar ratios as lumps, powders or aqueous solutions. Solid sodium silicate glass (lumps) is produced by the direct fusion of precisely measured portions of pure silica sand (SiO2) and soda ash (Na2CO3) at temperatures above 1000 °C. Solutions of soluble silicates ("waterglass") may be produced either by dissolving the soluble silicate lumps in water at elevated temperatures (and partly at elevated pressure) or by hydrothermally dissolving a reactive silica source (mainly silica sand) in sodium hydroxide solution.

Sodium silicate is an amorphous glass melt (lumps) with a three-dimensional structure. Following further processing it can be used as aqueous solution or spray-dried powder with ca. 20% of residual water. The anhydrous solid dissolves extremely slowly at ambient conditions. The lumps can be solubilised only at elevated temperature and pressure, whereas spray-dried solutions readily dissolve in water. Aqueous solutions are infinitely miscible with water. However, since the aqueous solution is characterised by dynamic polymerisation/hydrolysis equilibrium of monomeric SiO2 (aq.), oligomeric silicate ions and polysilicate ions, determination of quantitative water solubility is strongly pH-dependent. The vapour pressure of sodium silicate has been determined for two solid sodium silicates with different molar ratios: 0.31 Pa at 1165 °C (MR 2.0) and 0.16 Pa at 1172 °C (MR 3.0). As a consequence the vapour pressure at ambient temperatures is negligibly low and thus not relevant. The partition coefficient n-octanol/water is also not relevant, as alkali silicates are ionisable inorganic compounds which are not soluble in alcohol.

Sodium silicate is member of the soluble silicates category. In general, the category members are structurally very similar and the biological properties are mainly governed by their intrinsic alkalinity. As the members of the soluble silicates category exhibit a similar toxicological profile, data on disodium metasilicate (CAS 6834-92-0) and silicic acid, potassium salt (= potassium silicate; CAS 1312-76-1) can be used when no data are available for sodium silicate.

Absorption and distribution

Acute oral toxicity studies with sodium silicate have been conducted in rats using molar ratios of 2.0 (Spanjers and Til, 1981) and 3.27 (Spanjers and Til, 1980). In both studies only limited details were reported. In the key study referred to by Spanjers and Til (1981), male and female rats were administered sodium silicate (MR 2.0) at the dose levels of 3300 – 6860 mg/kg bw. Clinical symptoms observed in a dose-dependent manner consisted of sedation, abdominal discomfort, sluggishness and unconsciousness. No treatment-related gross alterations were found. The LD50 value was determined to be 3400 mg/kg bw for both sexes. In another study of Spanjers and Til (1980), male and female rats were administered sodium silicate (MR 3.27) in dose levels of 3430 – 8490 mg/kg bw. In a dose-dependent manner, animals showed sedation, abdominal discomfort, sluggishness and unconsciousness. Survivors recovered at the end of the 14-day observation period. No treatment-related gross alterations were found. The LD50 was calculated to be 5150 mg/kg bw for male and female rats.

A case report showed that ingestion of 100 mL of a sodium silicate egg preserving solution with a molar ratio of 3.2 (but unspecified concentration) caused severe vomiting, diarrhea and bleeding, elevated blood pressure and renal damage, but was not fatal (Schleyer and Blumeberg, 1982).

Taking into account all available data, the findings of the acute oral toxicity studies of soluble silicates indicate that the main cause of acute toxicity was most probably local irritation due to the highly alkaline soluble silicates. Moreover, the acute oral toxicity of sodium silicate is generally inversely correlated to the molar ratio of SiO2/Na2O, as the toxicity potential decreases in rats with increasing molar ratio.

With regard to the dose administered and the effects observed, systemic bioavailability of sodium silicate is considered to play only a minor role. This is confirmed by oral repeated dose toxicity studies with sodium silicate performed in rats and dogs which showed no treatment-related effects on gross pathology and histopathology.

Sodium silicate with a molar ratio of 3.2 has been tested in male and female rats for an exposure period of 180 days (Smith et al., 1973). No adverse effects were observed in rats of both sexes administered the test substance via the drinking water. The NOAEL was determined to be > 159 mg/kg bw/day (highest tested dose). Newberne and Wilson (1970) investigated the oral repeated dose toxicity of 2400 mg sodium silicate/kg bw/day in rats and dogs for an exposure period of 28 days. The only treatment-related effects observed in rats were polydipsia, polyuria and soft stools at 2400 mg/kg bw/day. Dogs exhibited gross renal cortical lesions, polydipsia, polyuria and soft stools at 2400 mg/kg bw/day (Newberne and Wilson, 1970).

No data on acute inhalation toxicity are available on sodium silicate. As a consequence of the low vapour pressures of sodium silicates, inhalation is not considered to be a significant route of exposure. The mean particle size for granules (MR 2.0 and MR 2.65) is 700 µm (PQ Corporation, 2009, unpublished data). Furthermore, in commercial granular products, 96-98% of the particles are > 200 µm and therefore sodium silicate is essentially non inhalable. Due to the hygroscopic properties and the ready solubility in water, the majority of particles, if inhaled, will be retained and dissolved by mucus in the upper respiratory tract. Thus, effects would be restricted to local corrosive/irritant effects, due to the intrinsic alkalinity of sodium silicate. Also based on the hygroscopic properties, anhydrous sodium silicate tends to aggregate in the presence of moisture.

An acute inhalation toxicity study is available for potassium silicate (30%, MR 2.47), which only differs from the sodium silicate by the counter ion. In a limit test with 2.06±0.19 mg/L, no deaths occurred in rats (Durando, 2004). Only clinical signs caused by irritation (hunched posture and hypoactivity), which all were reversible, were observed. A case report demonstrated that after ingestion of 500 mL of an egg-preserving solution containing sodium silicate in suicidal intention a 68 year old woman died within 1 h by suffocation (Schleyer and Blumberg, 1982; Sigrist and Flury, 1985). Aspiration of the vomited silicate solution caused obstruction of the lungs by precipitation of amorphous silica. The transformation of sodium silicate from liquid to solid occurred in the lungs by means of the carbonic acid of expiration air.

Taking into account all available information, inhalation is not considered to be a significant route of exposure which is in line with the low vapour pressures for sodium silicates.

No data on acute dermal toxicity are available on sodium silicate. However, with respect to the intrinsic alkalinity of silicic acid, sodium salt it is predicted that the primary effect after dermal exposure will be local skin irritation to corrosion at the site of contact. Moreover, it can be assumed that dermal bioavailability is rather limited due to the relative high water solubility, the very low lipophilicity and the molecule size of sodium silicate. However, it should be mentioned that damage to the skin surface due to corrosivity may enhance dermal penetration.

A limit test was performed with 5000 mg/kg bw potassium silicate (30%, MR = 2.47) for the dermal exposure route in rats (Durando, 2004). No deaths occurred. Only clinical signs caused by irritation (erythema and alopecia) were observed.

In addition, a case report demonstrated that a fifty-seven year old dyer was regularly exposed at work to 20% sodium silicate solution (CAS 1344-09-8) of unknown molar ratio. The man had recurrent ulcerative lesions on his left hand over a period of two years. The ulcers were associated with chronic eczematous changes resulting from primary irritant contact dermatitis to sodium silicate, as indicated by a positive patch test. The man also had another type of cutaneous reaction to sodium silicate, contact urticaria. An immediate wheal and flare reaction was seen fifteen minutes after the application of sodium silicate to a scratch test site. Such a response was not seen in healthy control subjects.

As also demonstrated for the section “irritation/corrosion”, sodium silicate can be irritating to corrosive to the skin depending on the molar ratio and the concentration. Therefore, effects would predominantly occur if not be restricted to local corrosive/irritant effects, due to the intrinsic alkalinity of sodium silicate. In general, dermal absorption is considered to be low. However, damage to the skin surface due to corrosivity may enhance dermal penetration.

Metabolism

From the chemical structure of silicic acid, sodium salt, it can be deduced that silicic acid, sodium salt is not metabolised in-vivo. By calculating potential metabolites via OECD QSAR toolbox v.3.2 (2013), this assumption is confirmed: metabolites were generated neither by the liver metabolism simulator nor by the skin metabolism simulator nor by the microbial metabolism simulator. Based on this information, it is considered to be very unlikely that silicic acid, sodium salt will be metabolised in-vivo. Repeated dose toxicity studies via the oral route performed in rats, mice and dogs also support the hypothesis that there are no toxic metabolites of silicic acid, sodium salt in-vivo.

In addition, studies with disodium metasilicate in mice did not induce chromosome aberrations in the bone marrow and did not alter cell proliferation in the auricular lymph nodes using the local lymph node assay (Ito et al, 1986; Saiwai et al., 1980; Karrow et al., 2002). No indication has therefore been found that toxic metabolites are formed in-vivo.

Moreover, studies on genetic toxicity in-vitro were all negative with disodium metasilicate (Ames test) or with silicic acid, sodium salt (MR=3.3; 36% active ingredient; gene mutation and chromosome aberration in V79 cells), indicating that there is also no evidence of reactivity under the in-vitro test conditions (BASF SE 2012; Schulz, 2006; Wollny 2009).

Excretion

The limited toxicokinetic studies on rats, guinea pigs, cats and dogs showed that the excretion of silicon dioxide with the urine was markedly increased after exposure (oral, inhalation or intravenous injection) to silicates. The excretion rate was independent of the doses applied indicating that the limiting factor is the rate of production of soluble or absorbable silicon dioxide in the gastrointestinal tract.

Since silicic acid, sodium salt is a polar substance and water soluble, its elimination mainly occurs by the kidneys. In the excretion study of Sauer et al. (1959), sodium metasilicate pentahydrate was administered to guinea pigs by the oral route. Urinary silicon levels were measured after a single dose or after repeated doses (4 doses) of sodium metasilicate pentahydrate (equivalent to 80 mg SiO2). The excretion rates were neither precisely determined nor were detailed dose-response data obtained. Within 8 days, 60% of the silica administered as a single dose and 96% of the silica administered as repeated doses was excreted. The urinary excretion was apparently limited by restricted absorption from the gastrointestinal tract.

Therefore, the excretion rate was independent of the doses applied. The limiting factor is the rate of production of soluble or absorbable silicon in the gastrointestinal tract.

Markedly increased and rapid urinary excretion of silica was also observed when various “soluble silicates” were administered to rats (oral, Benke and Osborn, 1979), dogs (oral and intravenous, King et al., 1933) and cats (oral, intraperitoneal and inhalative, King and McGeorge, 1938). Benke and Osborne (1979) determined urinary excretion levels of silicon after single oral administration of sodium silicate (analytical amount of silicon: 25.9%). The dose levels were 40 and 1000 mg/kg bw. Urine was collected in periods of 0 – 24, 24 – 48, 48 – 72 and 72 – 96 hours after dosing. The rats excreted urinary silicon in excess of background levels. The urinary silicon excretion increased rapidly after dosing and the majority of silicon was excreted during the first 24 hours. For sodium silicate, a half-life of 24 hours was determined with a first-order excretion kinetic. The amount of silicon excreted in urine increased with the dose level, but when expressed as percentage of dose, the urinary silicon excretion decreased with increasing dose (18.9% of silicon dose recovered in urine at the low dose and 2.8% at the high dose). The fact that the increase in urinary excretion was not in direct proportion to the increase in dose may have been due to the saturation of some processes, related either to the absorption or to the excretion of silicon. Similar findings were reported by King et al. (1933), who administered silicic acid to dogs and found that increasing the dose caused a smaller fraction of the silicon to be excreted in urine. Benke and Osborne (1979) proposed that an acid mediated hydrolysis in the gastrointestinal tract is responsible for forming soluble or absorbable forms of silicon and that, therefore, lower silicon doses are not excreted more rapidly.

Silicon is an essential ultratrace element participating in the normal metabolism of the mammalian body. It is required in bone, cartilage and connective tissue formation as well as participating in other important metabolic processes. Also, sodium is an essential element of the mammalian body. The salt of the metal ion is a natural constituent of the regular human diet.

Taking into account all available data, the biological properties of silicic acid, sodium salt are mainly governed by its intrinsic alkalinity. Silicic acid, sodium salt was shown to possess a low systemic toxicity and is therefore expected to have only a low potential to accumulate in biological systems.  

 

Literature (not cited in IUCLID):

ECHA (2012) Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

Sauer et al. (1959) Silica metabolism in guinea pigs. Can. J. Biochem. Physiol. 37, 183-191

King and McGeorge (1938) The solution and excretion of silica. Biochem. J. 32, 426-433