Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
A limited toxicokinetic assessment based on available physico/chemical properties of phosphoric acid (the final degradation product of polyphosphoric acid)indicates oral and dermal absorption factors of 50 to 100% and an inhalation absorption factor of 100%. Phosphoric acid is furthermore not considered to have bioaccumulative potential. Two supporting metabolism studies are available (Bonting, 1952 and 1956).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Polyphosphoric acid is a mixture of the corresponding acids to phosphate anion and its condensed phosphates as follows:

- orthophosphoric acid or phosphoric acid (17 -76%),

- pyrophosphoric acid (23 -50%),

- triphosphoric acid (1.5 -25%),

- tetraphosphoric acid (0 -12%)

- and pentaphosphoric acid (0 -7%).

 

A condensed phosphate anion M(n+2)PnO(3n+1) has one or several P-O-P bonds and has been obtained by heating (dehydration). When the substance polyphosphoric acid is in contact of excess of water, a rapid hydrolysis is observed with the longer chains (tri, tetra or penta) while a very slow hydrolysis is observed for the dimer form to ortho phosphate. The pyrophosphate ion is the simplest form of a condensed phosphate group. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependant upon the associated cations (if there are) and the ambient pH (if in solution).

No partition coefficient value was determined for these substances as they are inorganic phosphates that are highly ionic (depending on ambient pH). Because of this ionic nature the passive passage across biological membranes will be negligible. Pyrophosphate is an anion that occurs in all living cells and is formed mainly by the synthesis of DNA from Nucleotide triphosphates (DNAn + Deoxyribonucleotide triphosphate → DNAn+1 + pyrophosphate). Usually it is cleaved rapidly into two orthophosphate molecules by one of the different members of the alkaline phosphatase family which are present in all tissues. Pyrophosphate nevertheless is generally relatively stable against uncatalyzed hydrolysis (half life = 10 d in autoclaved Flat branch sediment (Blanchar RW and Riego DC, 1976, Tripolyphosphate and pyrophosphate hydrolysis in sediments, Soil sci. soc. Am. J 40: 225-229)).

 

 

Absorption

Oral

As stated above pyrophosphate is rapidly transferred into orthophosphate by intestinal alkaline phosphatase. So the majority of pyrophosphate is probably absorbed as orthophosphate. In addition direct uptake of pyrophosphate via diffusion or pinocytosis might add to the total uptake. Some recent publications seem to indicate that report that specific transmembranal transport proteins exist for pyrophosphate (Am J Hum Genet. 2002 Oct;71(4):985-91. Epub 2002 Sep 17. Autosomal dominant familial calcium diphosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH.) But whether comparable proteins are also involved in intestinal uptake of pyrophosphate is not clear at the moment.

The bioavailability of orthophosphate from pyrophosphate has also been shown by Feldheim et Al, 1985 (Feldheim W and Hesselbach C, 1985, Untersuchungen zum Calcium- und Phosphorstoffwechsel beim Mensche/Studies on Calcium and Phosphorous Metabolism in Man. 3rd Communication: Absorption Behaviour in Phosphates of different Chain Length in Miniature Pigs, Aktuelle Ernährungsmedizin 10(1); 30 - 33, 1985, Institut für Humanernährung der Universität Kiel). In this study supplementation of a basic diet with 1 – 3 g of either ortho- or pyrophosphate led to comparable uptake and excretion of orthophosphate.

Following the pKa of phosphoric acid (pKa1 = 2.1, pKa2 = 7.2, pKa3 = 12.3) the predominant forms in biological systems will be H2PO4(-) and HPO4(2-), including the human intestine with pH in the range of 5 to 8. Predominant mechanism for absorption of small well water soluble molecules and of ionic nature in the gastro-intestinal tract is passage through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Oral absorption might thus be as high as 100% if the inorganic phosphate intake is low, but will decrease with higher loads. Dietary compounds are also expected to influence the rate and extend of phosphate absorption via the GI tract. An oral absorption between 50 and 100% is therefore proposed.  

 

Respiratory tract:

Absorption of orthophosphoric acid or pyrophosphoric acid is unlikely via the inhalation route as the substances are hygroscopic and therefore small particles will not be present due to agglomeration. Although in general, hydrophilic substances are effectively removed from the air in the upper respiratory tract, the relevance of this mechanism for these compounds is difficult to predict as the octanol/water partition coefficient is not defined for inorganic substances. However as hydrophilic and hygroscopic substances, the 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 polyphosphoric acid that is inhaled. Although based on available physico/chemical data the systemic uptake of polyphosphoric acid might be limited, a worst-case absorption factor of 100% is proposed for inhalation.

 

Dermal:

Dermal absorption could be significant as orthophosphate acid or pyrophosphate have low to moderate molecular weight and are very well water soluble. They may however be too hydrophilic (as highly ionised) to cross the lipid rich environment of the stratum corneum but due to the absence of the octanol/water partition coefficient, this is difficult to predict.

However, orthophosphate acid and polyphosphoric acid are classified corrosive Cat 1B and dermal route is not considered as appropriate for testing. Although, available data indicates that dermal uptake will probably be minimal, it should be considered that any skin damage might enhance penetration of the substance. It is generally accepted that the dermal absorption will not be higher compared to the oral absorption. As a default value of 100% skin absorption should be used for substances with molecular mass below 500, the dermal absorption factor for polyphosphoric acid is set at 50 - 100% as for the oral absorption.

Distribution

Pyrophosphate is not expected to reach the blood circulation but will be cleaved either by extracellular or intracellular alkaline phosphatases after uptake in the intestine (or in the lung) even if recent research revealed a transporter protein responsible for export of pyrophosphate from cell lumen to the extracellular matrix in joints and in kidneys probably in order to complex free calcium ions thereby inhibiting crystallisation of calcium apatite (growth regulation of bones) and calcium phosphate / calcium oxalate (inhibition of kidney stone formation) respectively (Cell Physiol Biochem. 2009;24(5-6):595-604. Epub 2009 Nov 4. The pyrophosphate transporter ANKH is expressed in kidney and bone cells and co-localises to the primary cilium/basal body complex.) Whether pyrophosphate is produced exclusively by pyrophosphate excreting cells or whether pyrophosphate is actively transported to these cells is not clear to date.

Wide distribution throughout the body is to be expected for orthophosphate as small water-soluble molecules and ions will diffuse through aqueous channels and pores. Depending on the structure in which the phosphate is covered, the uptake by cells might either be via active or passive transport. The phosphate levels are regulated via homeostasis.

 

Metabolism

Pyrophosphate is hydrolysed to orthophosphate by ubiquitous alkaline phosphate activity (different iso-enzymes in different tissues). Orthophosphate then takes part in various physiological processes including formation of Deoxyribonucleotide phosphates (e.g. AMP, cAMP, ADT, ATP). Phosphoric acid is also an essential constituent of the human organism, not only in the bones and teeth, but also in many enzyme systems. Phosphorus plays an important role in carbohydrate, fat and protein metabolism.

 

Excretion

Phosphate formed from pyrophosphate are generally excreted mainly via kidneys but also via faeces and sweat (varying for the specific ion).

As stated above pyrophosphate is also excreted via specialized cell in the kidneys into the urine, probably in order to inhibit kidney stone formation from high urinary calcium concentrations. O’Brien et al reports a dose dependent rise of pyrophosphate excretion after feeding healthy and kidney stone forming human volunteers with defined diets that provided 1.5, 3.0 or 4.5 g/d/person orthophosphate in three successive weeks. Pyrophosphate excretion was comparable in the two groups and ranged from 3.5 - 13 mg/24 h in the 1.5 g diet phase to 15 – 40 mg/24 h in the 4.5 g diet phase (Urinary pyrophosphate in normal subjects and in stone formers. O'Brien MM, Uhlemann I, McIntosh HW. Can Med Assoc J. 1967 Jan 14;96(2):100-3.).

Toxicological data

 

Acute toxicity

The oral LD50 in rats is greater than 1000 mg/kg bw. Phosphoric acid is corrosive and mildly irritating to the skin and eyes.

 

Subacute, subchronic and chronic toxicity studies

Studies with phosphate salts showed that at high levels of phosphate, adverse effects were observed in parathyroids, kidneys and bones. The critical effect observed in these studies which were performed in rats, was renal calcification (nephrocalcinosis), due to precipitation of calcium phosphate, as the levels of phosphate at the doses used were such that phosphate homeostasis was dysregulated. It was difficult to identify no-observed-adverse-effect levels (NOAELs) in these studies, because there is a background incidence of nephrocalcinosis, determined by dietary intake of calcium and vitamin D.

The 90-day oral administration of KASAL (sodium aluminium phosphate) to purebred beagle dogs at dietary levels of 0.3, 1.0 and 3.0% revealed in three of the Group animals renal. No significant other changes were noted. Thus the dietary level of 1% can be considered as NOAEL (this is equivalent to 322.88 mg/kg bw/day without consideration of the cations’part).