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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement based on available physical-chemical and toxicokinetics data
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement based on available physical-chemical and toxicokinetics data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium disilicate
EC Number:
237-623-4
EC Name:
Disodium disilicate
Cas Number:
13870-28-5
Molecular formula:
Na2Si2O5
IUPAC Name:
disodium disilicate
Details on test material:
- Name of test material (as cited in study report): disodium disilicate (delta-crystalline)
- Physical state: White crystalline powder
Radiolabelling:
no

Administration / exposure

Details on study design:
Expert statement based on available physical-chemical and toxicokinetics data

Results and discussion

Preliminary studies:
not applicable (expert statement)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, no absorption by the dermal and inhalation routes is expected, which is further supported by the inhalation acute toxicity studies results. Bioaccumulation is not likely to occur based on the physical-chemical properties and the information available from kinetic studies, demonstrating a fast urinary excretion. When ingested and transformed to silica gel, absorption is insignificant and excretion is expected mainly via the faeces. No metabolism, especially not a conversion to potential toxic metabolites is expected in the human body.

Any other information on results incl. tables

Toxicological profile of disodium disilicate (delta-crystalline)

An acute oral toxicity study with rats revealed a LD50-value of > 2000 mg/kg bw due to what appeared to be primary local effects (corrosive effects of the GI tract). An acute inhalation toxicity study with rats revealed a LC50-value of > 3500mg/m³ (the highest technically achievable concentration). An additional acute inhalation toxicity study showed that three consecutive exposures of rats to disodium disilicate (delta-crystalline) at 10.8 mg/m³ produced no significant biochemical or cytological changes in bronchoalveolar lavage fluid (BALF). In an eye irritation test in rabbits, disodium disilicate (delta-crystalline) showed irritation and corrosive effects towards the mucosal membranes that caused a serious damage to the eye but in a skin irritation study in rabbits, no irritation or corrosion effects were observed. A LLNA (Local Lymph Node Assay) did not reveal skin sensitising properties. Disodium disilicate (delta-crystalline) was not mutagenic in a bacterial mutagenicity test (a reverse mutation test - Ames test) in the presence and absence of metabolic activation, even if applied at toxic doses. A read across approach was applied to assess other genotoxicity tests in vitro and in vivo, using data from members of the soluble silicates group (sodium silicates and metasilicates) as these substances are chemically almost identical and differ from disodium disilicate (delta-crystalline) only in the crystal structure and the molar ratio of sodium and silicate. It was shown that sodium silicate is negative in an in vitro chromosome aberration and in an in vitro HPRT test both in V79 cells. In addition sodium metasilicate did not induce chromosome aberrations in an in vivo mouse bone marrow chromosome aberrations test. Thus, it was concluded that disodium disilicate (delta-crystalline) does not have a genotoxic potential. A read across approach was applied to assess oral repeated dose toxicity and toxicity to reproduction, using data from studies with sodium silicates and metasilicates. In the most appropriate study (representing for risk assessment the most conservative approach), a 180 days chronic study with rats, a NOAEL of 159 mg/kg bw/day (highest examined dosage) was determined for sodium silicate, as no significantly treatment related effects were found. In a 4-generation study, the effect of sodium silicate administered via drinking water to rats was assessed. Due to the limitations of the study only a NOAEL for parental toxicity (> 159 mg/kg bw/day) could be derived. In a develpmental toxicity study with mice, no developmental effects were observed up to and including 200 mg/kg bw/day of disodium metasilicate. The NOAEL for developmental toxicity was determined to be > 200 mg/kg bw/day. In another study that aimed to investigate effects on male fertility, it was shown that after a subcutaneously or intratesticularly administration of sodium silicate to male rats, no testicular effects were observed. In addition, in repeated dose toxicity studies with rats, mice and dogs the macrospcopic and microscopic examination of reproductive organs did not reveal treatment – related effects. Altogether, it was concluded that disodium disilicate (delta-crystalline) has no toxic effects in regard to reproduction toxicity (fertility and development).

Toxicokinetic analysis of disodium disilicate (delta-crystalline)

Disodium disilicate (delta-crystalline)is a crystalline powder at room temperature with a molecular weight of 198.148 g/mol. The substance water solubility was determined to be very high, > 700 g/L.Disodium disilicate (delta-crystalline)is degraded hydrolytically to monosilicate ions (water glass) that are identical to naturally occurring silicate which is widespread in nature. As the substance is solid and its boiling point is above 300°C the vapour pressure ofdisodium disilicate (delta-crystalline)is expected to be very low, therefore little exposure via inhalation is expected. In addition the logPow is expected to be very low as the substance is an inorganic compound that does not dissolve in n-octanol, therefore it can be assumed that very little direct absorption across the respiratory tract epithelium will occur. Further,disodium disilicate (delta-crystalline)showed no toxicity after inhalation administration, in an acute inhalation toxicity study (nose only) and in a BALF test (whole body). Together, this indicates low systemic availability after inhalation and if bioavialable, no toxicity effects via this route of administration. Similarly, based on physical – chemical properties ofdisodium disilicate (delta-crystalline)the substance is not likely to penetrate skin as the logPow – value and high water solubility do not favour dermal penetration. Furthermore, application ofdisodium disilicate (delta-crystalline)to skin of rabbits did not cause irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study. Applied to the skin of guinea pigs, no sensitising effects were observed.

Administered orally,disodium disilicate (delta-crystalline)is likely to dissolve in the stomach, due to its high water solubility if administered as solution. Since concentrated silicate solutions are only stable at pH values above 11.5 and lowering the pH below 11.5 leads to the formation of an insoluble silica gel, it can be reasonably assumed that after ingestion gel formation will be induced by the hydrochloric acid of the stomach. The degree of gel formation will depend on the (concentration of the solution) amount of ingested silicate solution and the neutralising and buffering capacity of the gastrointestinal tract. Gastrointestinal absorption of insoluble silica will be insignificant and the substance is expected to be excreted mainly via faeces without becoming bioavailable. The small amounts ofdisodium disilicate (delta-crystalline)absorbed via the GI tract are mostly excreted via urine due to its molecular weight and to a lesser extent via the faeces. Markedly increased and rapid urinary excretion of silica was observed when soluble sodium silicates were administered by various routes to rats (oral, Benke and Osborn 1979), dogs (oral and intravenous, King et al. 1933), cats (oral, intraperitoneal and inhalative, King and McGeorge 1938) and guinea pigs (oral and intraperitoneal, Sauer et al. 1959). The urinary silica excretion half-life after administration of sodium silicate to rats via stomach tube was 24 h (Benke and Osborn 1979). The excretion rate was independent of the doses applied indicating that the limiting factor is the rate of production of soluble or absorbable silica in the gastrointestinal tract. The same observation was made with sodium metasilicate, pentahydrate in guinea pigs (Sauer et al. 1959).

In any case when absorbable and bioavailable (after, e.g. ingestion), toxicity to orally administereddisodium disilicate (delta-crystalline)or sodium metasilicate is low as was shown in acute and chronic toxicity studies. Additionally the compounds are expected to have a very low BCF-value (a very low logPow is expected) therefore the compound when distributed in the body is not likely to be bioaccumulated. This is supported by the toxicokinetic results mentioned above, showing that excretion of silicon with the urine was markedly increased after ingestion of silicate.

Silica is an essential trace element participating in the normal metabolism of higher animals. It is required in bone, cartilage and connective tissue formation as well as participating in other important metabolic processes. The silica is present almost entirely as free soluble monosilicic acid (1986). Thus, obviously no toxic effects are expected from the hydrolysed products ofdisodium disilicate (delta-crystalline).

Based on the structure of the molecule and its nature, no metabolism is expected in the human body. This is in compliance with the results obtained in the Ames test showing no mutagenicity effect with and without S9 activating metabolising system.

Summary

Based on physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, no absorption by the dermal and inhalation routes is expected, which is further supported by the inhalation acute toxicity studies results. Bioaccumulation is not likely to occur based on the physical-chemical properties and the information available from kinetic studies, demonstrating a fast urinary excretion. When ingested and transformed to silica gel, absorption is insignificant and excretion is expected mainly via the faeces. No metabolism, especially not a conversion to potential toxic metabolites is expected in the human body.

References

Benke G.M., et al., (1979). Urinary silicon excretion by rats following oral administration of silicon compounds. Fd. Cosmet. Toxicol. 17, 123-127.

Carlisle E.M., (1986). Silicon as an essential trace element in animal nutrition. Ciba Found symp. 121:123-39

Hawkins D.R., (1988). The importance of bioavailability in toxicity testing. HRC (eds.) Newer Methods in Toxicity Testing: Kinetic Monitoring. Bartham Press Ltd. London

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

King E.J., et al., (1993). The excretion of administered silica. Biochem. J. 27, 1007-1014.

Marquardt H., et al., (1999). Toxicology. Academic Press, San Diego, USA, 1999

Mutschler E., et al., (2001). Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2001

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

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient, no absorption by the dermal and inhalation routes is expected, which is further supported by the inhalation acute toxicity studies results. Bioaccumulation is not likely to occur based on the physical-chemical properties and the information available from kinetic studies, demonstrating a fast urinary excretion. When ingested and transformed to silica gel, absorption is insignificant and excretion is expected mainly via the faeces. No metabolism, especially not a conversion to potential toxic metabolites is expected in the human body.
Executive summary:

Toxicological profile of disodium disilicate (delta-crystalline)

An acute oral toxicity study with rats revealed a LD50-value of > 2000 mg/kg bw due to what appeared to be primary local effects (corrosive effects of the GI tract). An acute inhalation toxicity study with rats revealed a LC50-value of > 3500mg/m³ (the highest technically achievable concentration). An additional acute inhalation toxicity study showed that three consecutive exposures of rats to disodium disilicate (delta-crystalline) at 10.8 mg/m³ produced no significant biochemical or cytological changes in bronchoalveolar lavage fluid (BALF). In an eye irritation test in rabbits, disodium disilicate (delta-crystalline) showed irritation and corrosive effects towards the mucosal membranes that caused a serious damage to the eye but in a skin irritation study in rabbits, no irritation or corrosion effects were observed. A LLNA (Local Lymph Node Assay) did not reveal skin sensitising properties. Disodium disilicate (delta-crystalline) was not mutagenic in a bacterial mutagenicity test (a reverse mutation test - Ames test) in the presence and absence of metabolic activation, even if applied at toxic doses. A read across approach was applied to assess other genotoxicity tests in vitro and in vivo, using data from members of the soluble silicates group (sodium silicates and metasilicates) as these substances are chemically almost identical and differ from disodium disilicate (delta-crystalline) only in the crystal structure and the molar ratio of sodium and silicate. It was shown that sodium silicate is negative in an in vitro chromosome aberration and in an in vitro HPRT test both in V79 cells. In addition sodium metasilicate did not induce chromosome aberrations in an in vivo mouse bone marrow chromosome aberrations test. Thus, it was concluded that disodium disilicate (delta-crystalline) does not have a genotoxic potential. A read across approach was applied to assess oral repeated dose toxicity and toxicity to reproduction, using data from studies with sodium silicates and metasilicates. In the most appropriate study (representing for risk assessment the most conservative approach), a 180 days chronic study with rats, a NOAEL of 159 mg/kg bw/day (highest examined dosage) was determined for sodium silicate, as no significantly treatment related effects were found. In a 4-generation study, the effect of sodium silicate administered via drinking water to rats was assessed. Due to the limitations of the study only a NOAEL for parental toxicity (> 159 mg/kg bw/day) could be derived. In a develpmental toxicity study with mice, no developmental effects were observed up to and including 200 mg/kg bw/day of disodium metasilicate. The NOAEL for developmental toxicity was determined to be > 200 mg/kg bw/day. In another study that aimed to investigate effects on male fertility, it was shown that after a subcutaneously or intratesticularly administration of sodium silicate to male rats, no testicular effects were observed. In addition, in repeated dose toxicity studies with rats, mice and dogs the macrospcopic and microscopic examination of reproductive organs did not reveal treatment – related effects. Altogether, it was concluded that disodium disilicate (delta-crystalline) has no toxic effects in regard to reproduction toxicity (fertility and development).

Toxicokinetic analysis of disodium disilicate (delta-crystalline)

Disodium disilicate (delta-crystalline)is a crystalline powder at room temperature with a molecular weight of 198.148 g/mol. The substance water solubility was determined to be very high, > 700 g/L.Disodium disilicate (delta-crystalline)is degraded hydrolytically to monosilicate ions (water glass) that are identical to naturally occurring silicate which is widespread in nature. As the substance is solid and its boiling point is above 300°C the vapour pressure ofdisodium disilicate (delta-crystalline)is expected to be very low, therefore little exposure via inhalation is expected. In addition the logPow is expected to be very low as the substance is an inorganic compound that does not dissolve in n-octanol, therefore it can be assumed that very little direct absorption across the respiratory tract epithelium will occur. Further,disodium disilicate (delta-crystalline)showed no toxicity after inhalation administration, in an acute inhalation toxicity study (nose only) and in a BALF test (whole body). Together, this indicates low systemic availability after inhalation and if bioavialable, no toxicity effects via this route of administration. Similarly, based on physical – chemical properties ofdisodium disilicate (delta-crystalline)the substance is not likely to penetrate skin as the logPow – value and high water solubility do not favour dermal penetration. Furthermore, application ofdisodium disilicate (delta-crystalline)to skin of rabbits did not cause irritation or corrosion nor systemic effects (mortality) in a skin irritation/corrosion study. Applied to the skin of guinea pigs, no sensitising effects were observed.

Administered orally,disodium disilicate (delta-crystalline)is likely to dissolve in the stomach, due to its high water solubility if administered as solution. Since concentrated silicate solutions are only stable at pH values above 11.5 and lowering the pH below 11.5 leads to the formation of an insoluble silica gel, it can be reasonably assumed that after ingestion gel formation will be induced by the hydrochloric acid of the stomach. The degree of gel formation will depend on the (concentration of the solution) amount of ingested silicate solution and the neutralising and buffering capacity of the gastrointestinal tract. Gastrointestinal absorption of insoluble silica will be insignificant and the substance is expected to be excreted mainly via faeces without becoming bioavailable. The small amounts ofdisodium disilicate (delta-crystalline)absorbed via the GI tract are mostly excreted via urine due to its molecular weight and to a lesser extent via the faeces. Markedly increased and rapid urinary excretion of silica was observed when soluble sodium silicates were administered by various routes to rats (oral, Benke and Osborn 1979), dogs (oral and intravenous, King et al. 1933), cats (oral, intraperitoneal and inhalative, King and McGeorge 1938) and guinea pigs (oral and intraperitoneal, Sauer et al. 1959). The urinary silica excretion half-life after administration of sodium silicate to rats via stomach tube was 24 h (Benke and Osborn 1979). The excretion rate was independent of the doses applied indicating that the limiting factor is the rate of production of soluble or absorbable silica in the gastrointestinal tract. The same observation was made with sodium metasilicate, pentahydrate in guinea pigs (Sauer et al. 1959).

In any case when absorbable and bioavailable (after, e.g. ingestion), toxicity to orally administereddisodium disilicate (delta-crystalline)or sodium metasilicate is low as was shown in acute and chronic toxicity studies. Additionally the compounds are expected to have a very low BCF-value (a very low logPow is expected) therefore the compound when distributed in the body is not likely to be bioaccumulated. This is supported by the toxicokinetic results mentioned above, showing that excretion of silicon with the urine was markedly increased after ingestion of silicate.

Silica is an essential trace element participating in the normal metabolism of higher animals. It is required in bone, cartilage and connective tissue formation as well as participating in other important metabolic processes. The silica is present almost entirely as free soluble monosilicic acid (1986). Thus, obviously no toxic effects are expected from the hydrolysed products ofdisodium disilicate (delta-crystalline).

Based on the structure of the molecule and its nature, no metabolism is expected in the human body. This is in compliance with the results obtained in the Ames test showing no mutagenicity effect with and without S9 activating metabolising system.

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