Disodium fluorophosphate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
No key data exist. The available supporting data has been reviewed and an assessment of the toxicokinetics has been made.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

TEST MATERIAL: Disodium fluorophosphate

 

Disodium fluorophosphate, with formula Na2PO3F, can be regarded as the sodium salt of monofluorophosphoric acid. As compared to orthophosphate in the monofluorophosphate ion one of the ionisable OH groups is replaced by an isosteric fluorine atom. Monofluorophosphoric acid can undergo ionisation with loss of H⁺from each of the two –OH groups and therefore can occur in the -1 or -2 state. The degree of ionisation is dependent upon the associated cation and the ambient pH (if in solution).

Disodium fluorophosphate is also known under the following synonyms: disodium monofluorophosphate, phosphorofluoridic acid disodium salt, SMFP, sodium monofluorophosphate, fluoridophosphoric acid disodium salt. Two CAS numbers describe the same chemical entity: 10163-15-2 and 7631-97-2

 The test material is a colourless crystalline powder. If dissolved in water sodium cations will dissociate from SMFP and therefore will be regarded individually if in watery solution. Abiotic hydrolysis of the monofluorophosphate ion to orthophosphate and fluoride in watery solution is undetectable at room temperature. Nevertheless Rigalli (1995) report half-lives of 1.4 – 114 months for SMFP in different formulations. Stability seems to be dependent on the production process of these formulations. No low log oil/water partition coefficient value was determined for disodium fluorophosphate as it is an inorganic salt, 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 through pores will be aided by its low size (143.95 g/mol) and very highly water solubility (250 g/L).

General:

As some of the monofluorophosphate might be hydrolysed to orthophosphate and fluoride in watery solutions by phosphatase activity or at extreme temperatures or extreme pH (production process) all three species have to be regarded. 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. Fluoride though also essential for life of higher organisms is probably absorbed only by passive diffusion processes (see below). Monofluorophosphate might be transferred across biological membranes by phosphate or sulphate specific pores or transporters, though there is evidence that it is not absorbed in the intestine (see below).

Oral:

Sodium ion fluxes in the intestine are complex and the key mechanism for the uptake of different substances like glucose, chlorine 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.

Rigalli and co-workers (for references see below) have shown with a series of experiments in vitro, in rat and in humans that the monofluorophosphate ion is absorbed to some extent from the stomach to the blood circulation (Rigalli 1994). Absorption rates were determined to be k_g= 0.0078 ± 0.0014 min^-1when 2 mL of a 80 mmol/L solution of SMFP was introduced into the stomach of rats, which was isolated from the intestine by ligature of the pylorus. Based on the further experiments in the rat intestine it was found that monofluorophosphate ions that reach the intestine are hydrolysed to orthophosphate and fluoride by alkaline phosphatase in the duodenum and only these products of the hydrolysis are absorbed in the gut. Intestinal absorption of the unaltered monofluorophosphate is negligible to zero.

Orthophosphate if available is primarily taken up in the intestine by the sodium/phosphate co-transporter 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 homeostasis 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.

Fluoride available from non-enzymatic hydrolysis of SMFP is absorbed readily in the stomach after protonation to hydrofluoric acid by passive diffusion. The rate of absorption is inversely related to the gastric pH (ATSDR 2003). In the intestine fluoride hydrolysed from monofluorophosphate is readily taken up, probably by passive diffusion.

Dietary factors can influence the amount of absorption. For example, calcium forms insoluble calcium fluoride (fluorspar) at higher pH or aluminium forms non-absorbable aluminium hexafluoride ions in the presence of fluoride ions.

Respiratory tract:

The following particle size distribution data is available: > 96.5 % of the particles are < 100 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. Absorption of fluoride takes place in the upper respiratory tract and is quantitative (ATSDR 2003). Uptake of soluble monofluorophosphate ions either through pores or through paracellular diffusion might be possible but is expected to be low regarding the findings of Rigalli (1994) for the stomach. As for oral absorption passive diffusion across the lipid bilayer is negligible due to the extremely low lipophilicity of monofluorophosphate.

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 than via the oral route. The monofluorophosphate ion is, depending on the pH, likely to very highly ionised which reduces strongly the potential to penetrate the lipid rich environment of the striatum corneum. Therefore the absorption through the skin is expected to be low. The same argument goes for the potential hydrolysis product orthophosphate. For the absorption of fluoride through the skin no data is available, while the corresponding acid (hydrofluoric acid) is readily absorbed through the skin by passive diffusion (ATSDR 2003).

 

The acute oral toxicity of SMFP is moderate with a derived LD50 of 710 mg/Kg bw for mice and 570 mg/Kg bw for rats. Data from sub-acute repeated dose studies show that at 0.17 % (w/w) SMFP in the diet for 28 days, rats develop renal lesions (inflammation and fibrotic change in the Henle loops) that are comparable to fluoride intoxication. These findings support the above mentioned uptake mechanisms with the hydrolysis of fluoride from the monofluorophosphate ions in the duodenum. The inhalation toxicity is low, the LD50 rat is > 2.1 mg/L air. Regarding the low toxicity after inhalation, a significant absorption of SMFP via this route is unlikely. SMFP showed no skin irritation potential inin vitrotests and only very mild eye irritation potential which does not trigger a classification according to CLP. In the local lymph node assay (skin sensitization) a dose dependent increase of the stimulation index was seen which was nevertheless not sufficient to trigger classification. This data is indicative for a low but relevant absorption through the skin.

Distribution

Sodium and Phosphate are natural components of blood as free ions and their distribution and circulations is as precisely regulated as their uptake.

Un-metabolised monofluorophosphate ions absorbed in the stomach reach the circulation and bind covalently to plasma globuline proteins (a2-macroglobulin and C3) as shown by Rigalli 1997 and 1996 for rats and humans. Fluoride is rapidly distributed via the blood circulation as free ion to all organs and tissues and is able to penetrate the blood placenta barrier, while the blood brain barrier is relative effective (in rats and ewes, ATSDR 2003) reducing the brain fluoride levels to about 10 % of the plasma levels. Fluoride blood cell levels are ca. 50 % of the plasma levels.

Soft tissues are in equilibrium with plasma concerning fluoride levels with a ratio of 0.4:0.9. Since all ions are inorganic and charged, their accumulation in body fat is not favourable. Bioaccumulation is not to be expected in fat. Nevertheless fluoride is introduced readily into the crystalline matrix of bones and teeth replacing hydroxyl ions in the crystal lattice of hydroxyl apatite. Thereby in a normal physiological situation approximately 99 % of the total fluoride body burden is retained in bones and teeth (EHC 227, 2002).

The terminal half-life of free fluoride is 2 to 9 hours in humans, while the plasma clearance in pigs was determined to be 0.88 hours (ATSDR 2003). As fluoride is incorporated and also freed during rearrangement of bone tissues the biological half-life of fluoride was estimated to be 58.5 days in pigs (oral exposure, 2 mg fluoride/kg/day as sodium fluoride for 6 months) (ATSDR 2003).

 Metabolism

As stated above the monofluorophosphate ion is hydrolysed by alkaline phosphatase into orthophosphate and fluoride in the intestine. Monofluorophosphate transferred to blood binds (covalently) to the plasma globuline proteinsa2-macroglobulin and C3. From these protein fluoride (and orthophosphate) is freed obviously by alkaline phosphatise activity and/or by protein degradation processes. The underlying mechanisms are still under investigation. All ions (sodium, monofluorophosphate, fluoride 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. As already stated above fluoride is introduced into hydroxyl apatite of bones and teeth.

 Excretion

The excretion of unaltered monofluorophosphate in the urine is not described by Rigalli et al. From their experiments it is likely that all absorbed monofluorophosphate is metabolised to orthophosphate and fluoride. Tissue fluoride levels are not homeostatically regulated but based on the equilibrium with the plasma by passive diffusion. Accordingly urine fluoride levels are directly related to the intake (EHC 227, 2002).

Any SMFP 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.

 Literature:

ATSDR 2003: TOXICOLOGICAL PROFILE FOR FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE, U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service, Agency for Toxic Substances and Disease Registry, September 2003, http: //www. atsdr. cdc. gov/ToxProfiles/TP. asp?id=212&tid=38

 

EHC 227: WHO Library Cataloguing-in-Publication Data - Fluorides. Environmental health criteria 227, 2002, ISBN 92 4 157227 2, ISSN 0250-863X, NLM classification: QV 282, http: //www. inchem. org/documents/ehc/ehc/ehc227. htm

 

 

Rigalli and co-workers:

 Gastric and intestinal absorption of monofluorophosphate and fluoride in the rat. Rigalli A, Cabrerizo MA, Beinlich AD, Puche RC. Arzneimittelforschung. 1994 May;44(5):651-5. PMID: 8024641

 Long Term Stability of Sodium Monofluorophosphate. Rigalli A, Iglesias AM, Puche RC. Drug Development and Industrial Pharmacy Jan 1995, Vol. 21, No. 4: 517–521. [Cited in literature but not available for purchase].

 Bioavailability of fluoride administered as sodium fluoride or sodium monofluorophosphate to human volunteers. Rigalli A, Morosano M, Puche RC. Arzneimittelforschung. 1996 May;46(5):531-3. PMID: 8737641

 Binding of monofluorophosphate to alpha2-macroglobulin and C3. Rigalli A, Esteban L, Pera L, Puche RC. Calcif Tissue Int. 1997 Jan;60(1):86-9. PMID: 9030485

 In postmenopausal osteoporosis the bone increasing effect of monofluorophosphate is not dependent on serum fluoride. Rigalli A, Pera L, Morosano M, Masoni A, Bocanera R, Tozzini R, Puche RC. Medicina (B Aires). 1999;59(2):157-61. PMID: 10413893