Trimagnesium bis(orthophosphate)

Endpoint summary

Description of key information

In the absence of specific data on the ADME of trimagnesium bis(orthophosphate), its physicochemical properties and relevant toxicity data

(where available) were assessed for insights into likely ADME characteristics. Although trimagnesium bis(orthophosphate) has a MW >100 g/mol (262 g/mol) and is slightly soluble in water it is considered that absorption via the oral route is likely to be moderate due to its nature to ionize into phosphate and magnesium. Phosphate and magnesium are important biological molecules which are tightly regulated systemically as well as intra-cellular. Absorption of trimagnesium bis(orthophosphate) 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 trimagnesium bis(orthophosphate) itself is not expected but the ionic forms of phosphate and magnesium are widely distributed due to the indispensable character of phosphate and magnesium. The suggested metabolism involves hydrolysis to the more soluble and polar products, magnesium 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

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

There are no studies available in which the toxicokinetic behaviour of trimagnesium bis(orthophosphate) (CAS 7757-87-1) 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 trimagnesium bis(orthophosphate) 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).

Trimagnesium bis(orthophosphate) is a solid at 20°C with a molecular weight of 262 g/mol and a water solubility of 48 mg/L at 20°C and pH8-9.

 

ABSORPTION

Oral

No specific data regarding oral absorption of trimagnesium bis(orthophosphate) were found. ECHA guidance suggests that absorption is considered favourable for substances with a molecular weight (MW) below 500 Daltons (ECHA, 2014). Therefore, the MW (262 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 trimagnesium bis(orthophosphate) to be 48 mg/L at pH 8-9 whereas at neutral pH the water solubility increased dramatically (928 mg/L at pH7.2). It could be assumed that trimagnesium bis(orthophosphate) dissolves in the gastrointestinal fluids and the substance may (since the MW is below 500) pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (ECHA, 2014). However, as magnesium and phosphate are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. No clinical signs or pathological findings were observed following a single oral dose of trimagnesium bis(orthophosphate). So no conclusion regarding absorption can be drawn from this observation. In the absence of specific data to the contrary, a default value of 100% is suggested.

 Inhalation

According to ECHA (2014) guidance, particles with aerodynamic diameters below 100 µm have the potential to be inhaled.

The granulometry study shows that trimagnesium bis(orthophosphate) consists of at least 95% of particles with a particle size of <100 µm (considered to be respirable). As such the particle size distribution indicates substance is an inhalation risk (a significant proportion of the particles are present at < 100 µm).

Therefore trimagnesium bis(orthophosphate) particles can be inhaled (ECHA, 2014). Besides, 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 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.

Dermal

ECHA guidance suggests that absorption is considered favourable for substances with a MW below 100 g/mol (ECHA, 2014). Therefore, the MW (262 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 trimagnesium bis(orthophosphate) (48 mg/L) indicates that dermal absorption will be low to moderate (ECHA, 2014). No logP value could be determined for trimagnesium bis(orthophosphate) 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). QSAR analysis of trimagnesium bis(orthophosphate) suggests a very low dermal absorption rate with an absorption potential of 10%. Due to the slight soluble character of trimagnesium bis(orthophosphate) a conservative approach of a moderate skin absorption of 50% is recommended.

 

DISTRIBUTION/METABOLISM

No data were found regarding the distribution and metabolism for trimagnesium bis(orthophosphate). Looking at the physical/chemical parameters of trimagnesium bis(orthophosphate) (MW=262 g/mol, inorganic, slightly soluble) a wide tissue distribution is not assumed (ECHA, 2014). But the structure suggests trimagnesium bis(orthophosphate) will slowly ionise to phosphate anions and magnesium species. Phosphate is dissolved as ions in blood. Magnesium 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). Magnesium is complexed to important biological molecules (e. g. DNA, ATP, etc.).

 

EXCRETION

Assuming homeostasis of these indispensable nutrients the same amount is excreted as taken up. Magnesium 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.