Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

No reliable toxicokinetic data are available and therefore an assessment of the toxicokinetics of sodium metaphosphate has been performed using the available data.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

TEST MATERIAL: Sodium metaphosphate

 

Sodium metaphosphate, with formula H6O18P6.6Na or O18P6.6Na or (NaPO3)6, consists of a cyclic phosphate hexamere with sodium as counter ion. As the group is cyclic it does not contain any of the weakly acidic terminal hydroxyl groups, therefore corresponding acids possess only strongly acidic groups which in solution dissociate to approximately the same extent. Cyclic phosphates are known to react differently to the linear molecules and do not undergo the same rates and degrees of hydrolysis. In alkaline solutions cyclophosphates undergo ring fission to form linear polyphosphates with corresponding chain lengths. The resulting linear forms will follow the same hydrolysis/reaction processes as discussed for the polyphosphates.

Sodium metaphosphate is also known under the following synonyms: sodium polyphosphates; glassy; sodium polymetaphosphate; SHMP; hexasodium metaphosphate.

  

The test material is a powder.If dissolved in water sodium cations will dissociate from SHMP and therefore will be regarded individually if in watery solution.No low log oil/water partition coefficient value was determined for sodium metaphosphate as it is an inorganic phosphate, highly charged under ambient pH and highly water soluble.Solubility in fat or organic solvents is negligible. Therefore the passive passage across biological membranes will be negligible. However the passage across the biological membrane will be aided by its medium size (611.77 g/mol) and very highly water solubility (548 g/L at 20± 0.05°C).

 

 

Absorption

 

General:

Orthophosphate might be generated by hydrolysis of cyclic metaphosphate to polyphosphate and subsequent hydrolysis of the polyphosphates (see below). The ions sodium and orthophosphate are essential for cellular life. Therefore regulated uptake into cells will take place via the typical cellular uptake mechanisms specific for the respective ions. As a tightly regulated equilibrium of these ions is crucial for the functioning of normal cells (i.e. sodium: neuronal signal transduction, formation of the membrane potential of all living cells, etc.; phosphate: cell signalling, energy transfer (ATP), etc.) the amount of uptake is generally tightly regulated.

Oral:

Sodium ion fluxes in the intestine are complex and the key mechanism for the uptake of different substances like glucose, chorine or orthophosphate via specific co-transport trans-membrane proteins from the intestinal lumen into the brush-border epithelial cells. Na+/K+ ATPase then pumps sodium ions out again into the lumen while importing potassium ions under consumption of energy in form of ATP thereby keeping up a steep electrochemical gradient. In addition passive transport of Sodium occurs largely through tight junctions and the lateral spaces and is paracellular.

Intact metaphosphate is rather large for diffusion through pores (611.77 g/mol)and passive diffusion over lipid bilayers is negligible due to its very low lipophilicity. The size does not hinder pinocytosis and persorption, which might lead to absorption. Nevertheless the uptake via these routes is expected to be minimal.

Ivey & Shaver 1977 have shown that sodium hexametaphosphate was hydrolysed by 21.1% and 24.1% in rat and porcine small intestine after 1h, respectively (Ivey FJ & Shaver K, 1977, Enzymic hydrolysis of polyphosphate in the gastrointestinal tract. J. Agric. Food Chem., 25(1): 128–30). Therefore sodium hexametaphosphate might contribute to some extent to the total orthophosphate uptake if ingested. In hydrolysis studies by Gosselin the degradation of “sodium hexametaphosphate” in the rat blood is describe after intravenous injection, but it was stated that this name stands for the linear, open chain substance and are therefore not relevant for the here discussed substance.

Othophosphate if available is primarily taken up in the intestine by the sodium/phosphate cotransporter into the brush-border epithelial cells. Pinocytosis and other vesicle transport systems can also have an influence on sodium and phosphate homeostatis and fluxes. Transfer of sodium and phosphate to the blood circulation system and homeostatsis of these ions in other tissues are well regulated and similarly complex as the above stated uptake mechanisms and are broadly described in the general biochemical and medical literature.

Respiratory tract:

The following particle size distribution data is available: > 85% of the particles are < 100 µm; 0.8 to 12.2 % are < 1 µm, 78.9 to 86.4% are < 10 µm.This indicates that absorption via inhalation of the substance is well possible as particles at the size of < 10 µm are respirable and at the size of < 4 µm are able to reach the alveoli. The absorption of sodium and phosphate through specified pore systems is possible, nevertheless expected to be low as compared to oral absorption. Uptake of soluble metaphosphate ions might be possible through paracellular passive diffusion but is expected to be minimal. As for oral absorption passive diffusion across the lipid bilayer is negligible due to the extremely low lipophilicity of metaphosphate.

Non-resorbed particles in the oral cavity, the thorax and the lungs will be transferred to the gastro-intestinal tract with the mucus and absorbed there. Therefore absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled.

Dermal:

Sodium ions can penetrate the skin to some extent but the absorption is much lower then via the oral route. The metaphosphate is, depending on the pH, highly to very highly ionised which reduces drastically the potential to penetrate the lipid rich environment of the striatum corneum. The same argument goes for the potential hydrolysis products which are linear polyphosphates and orthophosphate. Therefore dermal uptake of phosphates will probably be minimal.

 

The acute oral toxicity is low (an acute oral study in rats determined the LD50to be >2000 mg/kg bw). The acute inhalation toxicity is even lower as no fatalities occurred in rats after exposure to the highest attainable concentration of 3.69 mg/L for 4 h. This supports the assumption that sodium metaphosphate is hardly absorbed via the respiratory tract. Data from a chronic repeated dose study shows that at 5 % (w/w) sodium metaphosphate in the diet for 2 years, rats develop renal lesions (tubular necrosis, chronic pyelonenephritis), while with 0.5 % in the diet no effects were seen. These lesions are typical for excessive orthophosphate uptake and this result supports the above stated theory that the metaphosphate is partly hydrolysed and taken up as orthophosphate.

The abiotic degradation, hydrolysis as a function of pH data has shown sodium metaphosphate does undergo hydrolysis, with the formation of orthophosphates. However, it was not possible to obtain a definitive result for hydrolytic stability since the hydrolysis product of sodium metaphosphate is a complex mixture of phosphates and the concentration of any individual component monitored may be influenced by the hydrolysis of larger complex phosphates.

 

 

Distribution

 

Sodium and Phosphate are natural components of blood as free ions and their distribution and circulations is as precisely regulated as their uptake. Should unhydrolised metaphosphate reach the circulation it would be distributed via the circulation to all tissues, but both passive or active distribution in the tissues is very unlikely given the absence of specific trans-membrane transporters and the ionic nature of the substance which hinders passive diffusion across lipid bilayers.

Since the ions are inorganic and charged their accumulation in body fat is not favourable. Bioaccumulation is not to be expected.

 

 

Metabolism

 

Metaphosphate is obviously hydrolysed to linear polyphosphates and finally orthophosphate in the intestine (see above). All sodium, polyphosphates and orthophosphate are in their most stable electronic state and therefore cannot be expected to be reduced or oxidised. Accordingly no further metabolism is to be expected except for orthophosphate which might be used in catabolic processes where physiological organic phosphate esters like phosphatidyl inositol, adenosine triphosphate, etc are formed.

 

 

Excretion

 

Should unhydrolysed metaphosphatethe circulationthe very high water solubility and the relatively low molecular weight make it likely that the principal route of excretion will be via the kidneys. Any test material that is not absorbed, following oral ingestion is likely to be excreted via the faeces.

Assuming homeostasis of sodium and orthophosphate (formed by hydrolysis of the test compound) as indispensable nutrients in a healthy organism the same amount of the ions is excreted as taken up. Sodium and orthophosphate are generally excreted mainly via kidneys but also via faeces and sweat.