Calcium bis(dihydrogenorthophosphate)

Endpoint summary

Description of key information

In the absence of specific data on the ADME of calcium bis (dihydrogenorthophosphate) (MCP), its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. MCP has a MW < 500 g/mol (235 g/mol) and is soluble in water. It is considered that absorption via oral route is likely to be moderate due to its nature to ionise into phosphate and calcium. Phosphate and calcium are important biological molecules which are tightly regulated systemically as well as intra-cellular. Absorption of MCP itself via inhalation route will be low due to its molecular weight. 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 MCP 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 calcium bis (dihydrogenorthophosphate) (CAS 7758-23-8) 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 calcium bis (dihydrogenorthophosphate) (MCP) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the physicochemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014).

Calcium bis (dihydrogenorthophosphate) is a solid at 20°C with a molecular weight of 235 g/mol and a water solubility of 93900 mg/L.

ABSORPTION

Oral

No specific data regarding oral absorption of calcium bis (dihydrogenorthophosphate) (MCP) 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 MW (235 g/mol) might 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 MCP to be 93900 mg/L at neutral conditions, which shows it is soluble in water. No log oil/water partition coefficient (logP) value was determined as MCP is an inorganic phosphate, therefore the passive passage across biological membranes will be negligible. However as calcium and phosphate are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and ion transporters and are usually tightly regulated. Looking at the acute oral toxicity study, mortality at high dosage and piloerection, diarrhea and moderate depression were the clinical signs observed in rats following a single oral dose of MCP. Taking together, MCP is absorbed to a certain extent via the oral 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 (235 g/mol) suggests dermal absorption is possible. 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 MCP (93900 mg/L) indicates that dermal absorption will be moderate to high (ECHA, 2014). 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). Moreover, the in vitro skin irritation studies performed with MCP showed no irritating effects. Overall, taking into account the physicochemical properties of MCP and available toxicological data the dermal absorption potential of the substance is anticipated to be low. QSAR analysis of MCP suggest a moderate dermal absorption rate with an absorption potential of 50% which is also recommended.

Inhalation

According to ECHA guidance (ECHA 2014), 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 MCP was measured up to 3.03 µm. Therefore, MCP particles can be inhaled and, since they are below 15 µm, may reach the alveolar region of the respiratory tract (ECHA, 2014). Also, the substance is not lipophilic therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. However, its nature as physiological substance (calcium cations and phosphate anions) 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 gastrointestinal 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 MCP. Looking at the physicochemical parameters of MCP (MW > 100 g/mol, inorganic, soluble) a wide tissue distribution is not assumed (ECHA, 2014). But the structure suggests MCP will ionise to phosphate anions and calcium species. Phosphate is dissolved as ions in blood. Calcium is partly dissolved as ions 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. Ca: 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.