Silicon orthophosphate

Endpoint summary

Additional information

Silicon orthophosphate (molecular weight of 464 g/mol) is a solid, which is soluble in water (1085.4 mg/L at 20°C, pH=2). Since the substance is inorganic, no log Pow is derived. Due to a melting point above 300°C the vapour pressure is also not applicable.

Silicon orthophosphate is readily water soluble, dissociating completely into silicon and phosphate ions after systemic uptake (relevant pH ranges 2 -7). The tetravalent silicon ion and the phosphate ion will then react with the media to form different silicon and phosphate species depending on the pH and redox potential of the media. The dissociated silicon ion exists in water predominantly as H4SiO4/Si(OH)4, which is also the main species when silicon dioxide is dissolved in water. Therefore the silicon component of silicon orthophosphate can be covered by data from silicon dioxide, whereas the phosphate component will be covered by available data on phosphate compounds.

There are no studies on silicon orthophosphate available investigating toxicokinetic properties. Assessment of the toxicokinetic behavior was conducted mainly to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics of the substance and its dissociation products taking the "Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008)" into consideration.

Absorption

Taking the molecular weight and the good water solubility of silicon orthophosphate into consideration, oral and dermal absorption of the substance is in general possible. For the oral route, no data on absorption is available. Acute dermal toxicity of silicon orthophosphate in rats was investigated (Lütkenhaus 2012). No signs of systemic toxicity were observed in this study. Taking the particle size of 7.8 - 18.5 mm of the catalyst into consideration, into which silicon orthophosphate is included, respiratory absorption can be excluded.

However, an in vivo study investigating distribution of silicon dioxide is available: after oral application of synthetic amorphous silica (HDK V15) to rats (about 500 mg/kg bw), tissue values were apparently slightly increased in liver and kidney (Klosterkoetter 1969; see "Distribution" in the lower section), indicating absorption along the gastrointestinal tract in general. However, administration of silicon dioxide to humans did not result in an unequivocal increase of the substance in the kidney (Lang 1966; see "Excretion" in the lower section).

Phosphorus is most commonly found as the phosphate ion (sodium and potassium phosphates) in phosphate salts (monophosphate/orthophosphate), the latter being highly water soluble (EFSA 2005). Together with the small molecular weight (phosphorus: 31 g/mol; phosphate ion: 95 g/mol; sodium dihydrogenphosphate: 120 g/mol; disodium hydrogenorthophosphate: 142 g/mol) uptake of phosphorus compounds is favourable. In vivo, renal toxicity of phosphate compounds was investigated by Haut et al. (1980). Since a dose-dependent increase of phosphorus levels in urine samples and kidney tissues was observed, absorption after oral ingestion is likely. Indeed, net oral absorption has been reported to vary between 55 -90% (Leman 1996; Nordin 1986). Phosphate absorption is greatest in jejunum and takes place by a saturable, active transport meachanism, facilitated by 1,25 -dihydroxyvitamin D, as well as by passive diffusion (Chen 1974).

The water solubility of phosphate salts and the molecular weight of the phosphate ion suggest that crossing the lipid rich environment of the stratum corneum is negligible.

The physico-chemical parameters of phosphate compounds also suggest that absorption after inhalation via the respiratory tract epithelium is rather unlikely and that the substance therefore retains in the mucus. Particles deposited on the mucociliary blanket will be swallowed in the mouth, ingested and absorbed in the gastro-intestinal tract.

Metabolism

The water solubility of silicon orthophosphate suggests, that there is likely no significant metabolism. Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation. No effects with silicon orthophosphate were observed in a bacterial reverse mutation assay, indicating no reactivity of the substance or its metabolites under the test conditions.

In addition, the read-across substances silicon dioxide and phosphates are not subjected to any metabolism. Silicon dioxide revealed no genotoxic effects in a chromosmal assay and in a gene mutation assay in mammalian cells. The results of the in vitro studies showed, that genotoxicity was neither enhanced nor diminished in the presence of S9 metabolising system.

Phosphates are routinely used in the nutrient broths that support cell cultures in the laboratory. They are part of metabolic activation mixtures (e.g. S9-mix) and therefore presumed to induce no genotoxic effects.

Distribution

Silicon dioxide is a small and slightly water soluble compound (60 g/mol; 76 -166 mg/L (Vogelsberger 2003)) and can therefore distribute within the body. The passage across biological membranes will be negligible and entering cells might only occur by diffusion through aqueous channels. After absorption, silicon is incorporated mostly in bone and connective tissue, including aorta, trachea, and skin (Elmadfa and Leitzmann 1998). An in vivo study investigating distribution of silicon dioxide is available (Klosterkoetter 1969). After oral application to 20 rats, which received 20 daily doses of 100 mg synthetic amorphous silica (HDK V15) per animal (corresponding to about 500 mg/kg bw) each, tissue values were apparently slightly increased in liver (4.2 µg vs. 1.8 µg in the controls) and in the kidney (14.2 µg vs. 7.28 g in the controls; spleen 5.5 µg vs. 7.2 µg in the controls).

Because of the high water solubility and the relatively small molecular weight of phosphorus compounds, they will be widely distributed within the body. The passage across biological membranes will be negligible and entering cells might only occur by diffusion through aqueous channels. A study with rats placed on dietary phosphorus intakes of 0.5, 1.0 and 2% (equivalent to 0.05, 0.1, and 0.2 g phosphorus/day, consisting of 80% sodium dihydrogenphosphate and 20% disodium hydrogenorthophosphate) for 18 weeks (Haut et al. 1980) is available. The aim of the study was to investigate the mechanism by which phosphates induces renal injury in uninephrectomized, partially nephrectomized and intact rats. Blood and urine samples were obtained and at the end of the study, kidney tissue was analyzed for calcium and phosphorus levels as well as for histological changes. At histopathology, phosphorus levels measured in kidney tissue were dose-dependently increased indicating an easily distribution of phosphorus compounds within the body. Further in vivo studies showed incorporation of phosphorus in the kidneys and also in the bone after repeated oral administration resulting in marked nephrocalcinosis affecting renal fuction (Matsuzaki et al. 2001, Schneider et al. 1980a+b, 1981, Hitchman et al. 1979, McFarlane 1941; Silverberg et al. 1986, Ritskes-Hoitinga et al. 1989).

Excretion

In 12 human volunteers, no significant increase in renal excretion of silicon dioxide was found following a single oral ingestion of 2500 mg Aerosil or FK700 (Lang 1966). Two groups consisting of 5 males and one female each (age 22 -28), received the test substances in two portions of 1250 mg suspended in 250 mL apple juice. Urine was collected daily and analysed for silicon dioxide prior and after treatment. For Aerosil, the individual baseline values of the six volunteers were very variable and individually different in the pre-test phase. Mean excretion rates ranged from 25 to 87 mg/d. After treatment, individual mean excretion ranged from 32 to 61 mg/d: in three volunteers excretion was constant or decreased rather than increased, while in the other three individuals excretion raised about 16 to 20 mg/d. For FK 700, the individual baseline of the pre-test phase also varied individually with mean excretion rates of 16 to 71 mg/d. In the post-treatment phase, individual mean excretion rates were 20 to 81 mg/d with constant or decreased excretion in two individuals and an increase of 10 to 20 mg/d in four persons. Overall, administration of two types of silica, renal excretion was not clearly detectable. The small apparent increases on the average of less than 0.5% of the total dose were in marked contrast to the high dose of 2500 mg administered. Silicon itself is suggested to be mainly excreted via urine (8.7 to 33.1 mg/24 hours after oral ingestion of 20 -50 mg/day, Reffitt et al. 1999; mean of 41%, Jugdaohsingh et al. 2002).

The good water solubility and the small molecular weight of phosphorus compounds are suggestive that the principal route of excretion will be via the kidney. In the study of Haut et al. (1980), urine phosphorus levels in rats were determined after 7 weeks of treatment. A dose-dependent increase in urine phosphorus levels was observed. Silverberg et al. (1986) administered tablets containing phosphate (113.6 mg/kg bw/day disodium hydrogenorthophosphate, 20.6 mg/kg bw/day potassium dihydrogenorthophosphate, and 17.4 mg/kg bw/day sodium dihydrogenorthophosphate) to humans. Urinary phosphorus excretion increased progressively after treatment. Furthermore, Elmadfa and Leitzmann (1998) estimate an excretion of about 60 to 80% via urine and 20 to 40 % via faeces. The latter being any test material that is not absorbed.

However, since silicon orthophosphate is included as extrudate into the matrix of a catalyst, oral, dermal and respiratory uptake can genreally be excluded.

* Chen TC, Castillo L, Korycka-Dahl M, De Luca HF (1974). Role of vitamin D metabolites in phosphate transport of rat intestine. J Nutr 104: 1056-1060. Council Directive 80/778/EEC relating to the quality of water intended for human consumption. Official Journal L 229, 30.08.1980, pp. 11-29.

* EFSA 2005, The EFSA Journal 233, 1-19: Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Phosphorus (Request N° EFSA-Q-2003-018)

* Elmadfa I and Leitzmann C (1998). Ernährung des Menschen. Verlag Eugen Ulmer Stuttgart, Germany

* Jugdaohsingh R, Anderson SH, Tucker KL, Elliott H, Kiel DP, Thompson RP, Powell JJ (2002). Dietary silicon intake and absorption, Am J Clin Nutr 75: 887-893.

* Lemann JR (1996). Calcium and phosphate metabolism: An overview in health and in calcium stone formers. In Coe FL et al.: kidney stones.

* McFarlane (1941). Experimental phosphate nephritis in the rat, J Pathol 52: 17-24

* Matsuzaki H, Masuyama R, Uehara M, Nakamura K, Suzuki K (2001). Greater effect of dietary potassium tripolyphosphate than of potassium dihydrogenphosphate on the nephrocalcinosis and proximal tubular function in female rats from the intake of a high-phosphorus diet, Biosci Biotechnol Biochem 65(4): 928 -34

* Nordin BEC (1976). Calcium, phosphate and magnesium metabolism. Edinburgh, Churchill Livingstone.

* Reffitt DM, Jugdaohsingh R, Thompson RP, Powell JJ (1999). Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion, J Inorg Biochem 76: 141-147

* Ritskes-Hoitinga J, Lemmens AG, Beynen AC (1989). Nutrition and kidney calcification in rats, Lab Anim 23(4): 313-8

* Schneider P, Pappritz G, Müller-Peddinghaus R, Bauer M, Lehmann H, Ueberberg H and Trautwein G (1980a). Die Kaliumhydrogenphosphat-induzierte Nephropathie des Hundes. I. Pathogenese der Tubulusatrophie. [Potassium Hydrogen Phosphate Induced Nephropathy in the dog. I Pathogenesis of Tubular Atrophy], Vet Pathol 17: 699 - 719

* Schneider P, Müller-Peddinghaus R, Pappritz G, Trieb G, Trautwein G and Ueberberg H (1980). Die Kaliumhydrogenphosphat-induzierte Nephropathie des Hundes. II. Glomeruläre Veränderungen. [Potassium Hydrogen Phosphate Induced Nephropathy in the dog II Glomerular alterations], Vet Pathol 17: 720 - 737

* Schneider P, Ober KM and Ueberberg H (1981). Contribution to the phosphate-induced nephropathy in the dog. Comparative light and electron microscopic investigations on the proximal tubule after oral appliction of K2HPO4, Na2HPO4, KCl and NaCl, Exp Path 19: 53 - 65

* Silverberg SJ, Shane E, Clemens TL, Dempster DW, Segre GV, Lindsay R, Bilezikian JP (1986). The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects, J Bone Miner Res1(4): 383-8

* Vogelsberger W (2003). Result of dissolution kinetics of amorphous silica in biological media. Unpublished report, Inst. Physikalische Chemie , Univ. Jena/Germany (CEFIC/ASAP report 2003)