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Key value for chemical safety assessment

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Urea phosphate is directly dissociated into urea and phosphoric acid in aqueous environment. Therefore, all data are based on studies of urea and phosphoric acid individually as intrinsic properties can be mostly read across from urea and phosphoric acid. Apart from pH effects, direct phosphate effects may also occur, therefore these data can be supported by e.g. data on calcium dihydrogenorthophosphate.

Based on all data available, for urea phospate 50% for oral absorption, 10 -50% for dermal absorption (higher due to skin corrosion), and 100% worst case assumption for inhalation absorption is used for risk assessment purposes.

Urea

Urea is produced in the body of mammals as a consequence of normal physiological processes, primarily by the detoxification of ammonia resulting from protein catabolism, via the urea cycle. The quantity of urea produced by an adult human is influenced by dietary protein intake but is reported to be typically between 20 -50 g/day. Urea is generated in the liver by the urea (ornithine) cycle by the action of the terminal enzyme arginase I on L-arginine. Reference ranges for urea in human blood are 70 -210 mg/L (7 -21 mg/dL). Therefore assuming a blood volume of 5L (for an adult) and serum proportion of 55%, the quantity of urea present in the blood at any one time is 192.5 -577.5 mg or (assuming a bodyweight of 70 kg), 2.75 -8.25 mg/kg bw.

The urea produced by the urea cycle is removed from the blood by glomerular filtration (as a small, water-soluble molecule), but is largely reabsorbed by the renal tubules. Some urea is transported by specific transport systems back into the urine. The clearance of urea is estimated to be 75 mL/minute, equivalent to approximately 1.5% of the total blood volume/minute. Urea also plays a physiological role in renal countercurrent exchange. Urea is present in saliva in appreciable concentrations (approximately 200 mg/L) and is also present in the epidermis at high levels, where it plays a role in skin hydration.

Urea is present at appreciable levels in the human epidermis, where it may play a role as a humectant, maintaining hydration of the stratum corneum. At very high levels of exposure, urea may act as a denaturant and may enhance the dermal absorption of other compounds. Bronaughetal(1982), report a dermal absorption value of 7.2%, based on the results of a study in the ratin vivoand comparable resultsin vitro. Urea also has a low logP value indicating a low dermal absorption.

Phosphoric acid

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 in the GI 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.

Respiratory absorption: although phosphoric acid is a solid at room temperature, the substance is hygroscopic and no airborne particles are to be expected. Although in general, hydrophilic substances are effectively removed from the air in the upper respiratory tract, the relevance of this mechanism for phosphoric acid is difficult to predict as the octanol/water partition coefficient is not defined for inorganic substances. Hydrophilic substances also have the tendency to be retained in the aqueous fluids (mucus) lining of the respiratory tract, limiting the systemic uptake.

Dermal absorption will be significant as the substance has a low molecular weight and is very well water soluble. It may however be too hydrophilic to cross the lipid rich environment of the stratum corneum, also as the assumed octanol/water partition coefficient is expected to be low. As phosphoric acid is corrosive to skin, 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.

Wide distribution throughout the body is to be expected 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.

Excretion will be via urine as characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine.