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Description of key information

In the absence of specific data on ADME of pentacalcium hydroxide tris( orthophosphate) (TCP), its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. Although TCP has a MW >500 g/mol (502.0 g/mol) and is slightly soluble in water it is considered that absorption via oral route is likely to be moderate due to its nature to ionize into phosphate and calcium. Phosphate and calcium are important biological molecules which are tightly regulated systemically as well as intra-cellular. Absorption of TCP itself via inhalation route will be low due to its molecular weight and low solubility. Non-resorbed particles in the oral-nasal cavity, airways and lungs will be transferred to the gastrointestinal tract with the mucus and absorbed there. Therefore, the absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled. Low dermal absorption is expected. Based on a precautionary approach, an absorption default value of 100% is considered appropriate for oral and inhalation route and 50% for the dermal route. Wide tissue distribution of absorbed TCP itself is not expected, but the ionic forms of phosphate and calcium are widely distributed due to the indispensable character of phosphate and calcium. The suggested metabolism involves hydrolysis to the more soluble and polar products, calcium and phosphate ions. Due to these factors, urinary excretion as well as via faeces and sweat is the most probable route of elimination and bioaccumulation is unlikely.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of pentacalcium hydroxide tris(orthophosphate) (CAS 12167-74-7) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of pentacalcium hydroxide tris(orthophosphate) (TCP) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014).

Pentacalcium hydroxide tris(orthophosphate) is a solid at 20°C with a molecular weight of 502 g/mol and a water solubility of 6.57 mg/L.

ABSORPTION

Oral

No specific data regarding oral absorption of pentacalcium hydroxide tris(orthophosphate) (TCP) were found. ECHA guidance suggests that absorption is considered favourable for substances with a molecular weight (MW) below 500 g/mol (ECHA, 2014). Thus, the molecular weight of TCP with 502 g/mol might not be indicative of absorption. For a substance to be absorbed efficiently from the gastrointestinal tract it must be in solution. A recent study report determined the water solubility of TCP to be 6.57 mg/L at neutral conditions, whereas it was moderately soluble in more acidic conditions (483 mg/L at pH 5.5). It could be assumed that TCP dissolves in the gastrointestinal fluids but the substance itself may not easily (since the MW is above 500) pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (ECHA, 2014). However, TCP might ionise into its ions calcium and phosphate. Calcium and phosphate are key elements in various cellular processes their import and export over cell membranes is regulated via ion transporters and are usually tightly regulated. Looking at the acute oral toxicity study, piloerection was the only clinical sign observed in rats following a single oral dose of TCP. This could be an indicator of absorption via this route. In the absence of specific data to the contrary, a default value of 100% is suggested.

 

Dermal

ECHA guidance suggests that absorption is considered favourable for substances with a MW below 100 g/mol (ECHA, 2014). Therefore, the MW (502 g/mol) suggests dermal absorption is not likely. For a compound to penetrate the stratum corneum, it must be sufficiently water soluble i. e. above 1 mg/L (ECHA, 2014). The aqueous solubility of TCP (6.57 mg/L) indicates that dermal absorption will be low to moderate (ECHA, 2014). No logP value could be determined for TCP as it is an inorganic substance, therefore the passive passage across biological membranes will be negligible. In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake via the skin is possible (ECHA, 2014). Neither in an acute dermal toxicity study nor in a skin irritation study any systemic or irritating effects were observed indicating a low dermal absorption. QSAR analysis of TCP suggests a very low dermal absorption rate with an absorption potential of 10%. Due to the slight soluble character of TCP a conservative approach of a moderate skin absorption of 50% is recommended.

 

Inhalation

According to ECHA (2014) guidance, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. In a recent study report, the mean mass median aerodynamic diameter of TCP was measured at 3.08 µm. Therefore TCP particles can be inhaled and, since they are below 15 µm, may reach the alveolar region of the respiratory tract (ECHA, 2014). Besides, the substance is not lipophilic therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. However, since TCP might ionize calcium and phosphate ions will probably lead to some absorption via the respiratory tract. Non-resorbed particles in the oral-nasal cavity, the airways 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. On this basis, a default of 100% is proposed.

 

DISTRIBUTION/METABOLISM

No data were found regarding the distribution and metabolism for TCP. Looking at the physical/chemical parameters of TCP (MW >500 g/mol, inorganic, slightly soluble) a wide tissue distribution is not assumed (ECHA, 2014). But the structure suggests TCP will slowly ionise to phosphate anions and calcium cations. Phosphate is dissolved as ions in blood. Calcium is partly dissolved as an ion while about 50% is bound to albumin in blood. As both ions are indispensable to life their distribution is tightly regulated systemically as well as intra-cellular. Both ions are inorganic and stable to reduction or oxidation in biological systems. Phosphate is condensed to di- and triphosphates (e. g. AMP, ADT, ATP). Calcium is complexed to important biological molecules (e. g. calmodulin, calbindin, etc.).

 

EXCRETION

Assuming homeostasis of these indispensable nutrients the same amount is excreted as taken up. Calcium and phosphate are generally excreted mainly via kidneys but also via faeces and sweat (varying for the specific ion).

 

References:

ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014.