Ammonium magnesium orthophosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Adequacy of study:

key study

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Guideline:

other: expert statement

Deviations:

not applicable

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium magnesium orthophosphate

EC Number:

232-075-2

EC Name:

Ammonium magnesium orthophosphate

Cas Number:

7785-21-9

Molecular formula:

H3-N.H3-O4-P.Mg

IUPAC Name:

ammonium magnesium orthophosphate

Test material form:

solid: crystalline

Radiolabelling:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

As the magnesium ammonium phosphate dissociates to its respective ammonium, magnesium and phosphate ions, it is considered acceptable to approach the assessment of magnesium ammonium phosphate based on the individual components.
Since Numerous data is available for the evaluation of ammonia, phosphate and magnesium as food additivesn

Applicant's summary and conclusion

Executive summary:

It is well established that ammonia, magnesium and phosphate are essential for humans and animals, which are found ubiquitously in the environment, being released from both natural and anthropogenic sources.

As the magnesium ammonium phosphate dissociates to its respective ammonium, magnesium and phosphate ions, it is considered acceptable to approach the assessment of magnesium ammonium phosphate based on the individual components. Since numerous data is available for the evaluation of ammonia, phosphate and magnesium as food additives, following toxicokinetic summary was extracted from an evaluation of toxicokinetic information performed by renowned scientific bodies (ATSDR: "TOXICOLOGICAL PROFILE FOR AMMONIA", 2004; BfR ( Federal Institute for Risk Assessment): "Use of Minerals in Foods", 2005).

Magnesium:

"Magnesium is taken up by means of a carrier-induced process and passive diffusion in the small intestine.

Between 20 and 50% are available from a mixed diet when adults take up on average around 90 mg magnesium per meal. The intestinal absorption rate is higher when magnesium intake is lower or there is a deficiency condition (Rude, 2000; Sabatier et al., 2003). For instance, Fine et al. (1991a) established that 65% of magnesium was absorbed at an intake of 36 mg per day whereas only 11% could be taken up from food with an intake of 973 mg magnesium per day. Magnesium citrate, chloride, lactate and aspartate are more readily available than the poorly absorbable magnesium oxide and magnesium sulphate.

Magnesium is mainly excreted through the kidneys. Around 90% of the glomerularly filtered amount is reabsorbed. Only 3-5% of the glomerularly filtered Mg2+ is excreted in urine (5-8.5 mmol magnesium per day). Renal excretion is influenced by calcium, parathormone and calcitonin. In the event of a deficiency, excretion is markedly reduced whereby excretion of less than 4 mmol per day is an indication of a magnesium deficiency.

Requirements: The exact requirements of magnesium in human beings are not known. More recent balance studies assume a physiological requirement of 3.0-4.5 mg/kg body weight and day. This means that 350 and 280 mg/day respectively are probably adequate for adult men and women. In the case of children aged between 9-14 a positive Mg balance was measured after an intake amount of 6.0 mg/kg body weight and day (Abrams et al., 1997)."

Phosphate:

"Adults absorb between 55 and 70% of inorganic phosphate from a mixed diet (FNB, 1997). High calcium intake may lead to complex formation which can inhibit the resorption of phosphorus.

The kidneys are the most important organ system for phosphorus homoeostasis. Phosphorous is filtered glomerularly and around 80% is resorbed in the proximal tubule by means of sodium co-transport. The calcium concentration in plasma falls when the glomerular filtration rate sinks whereas the phosphate concentration increases as, in this case, the kidneys do not excrete phosphate nor can calcium be sufficiently reabsorbed. Renal phosphate excretion is increased through parathormone, calcitonin, calcium intake, oestrogens, thyroxin and acidosis and reduced by insulin, growth hormone and cortisol (Löffler and Petrides, 2003). The metabolism of inorganic insulin, phosphate is closely linked to that of calcium.

In hydroxylapatite phosphorus helps to strengthen bone structure. In the hydroxylapatite compounds, calcium and phosphorus are in a steady ratio of around 2:1 (Bowman and Russel, 2001). Together with calcium, phosphate is the main component of the inorganic part of the skeleton. Organophosphorus compounds are important building blocks of nucleic acids which occur in all living cells. Phospholipids, like for instance lecithins, are important structural elements of cell membranes. Numerous metabolic processes of the cell are regulated by phosphorylation reactions. As a component of adenosine triphosphate (ATP), phosphorus plays a key role in cellular energy supply and conversion. In muscle tissue creaBfR- Wissenschaft 111 tine phosphate, the phosphorylated form of creatine, is the main source of energy besides ATP. As the dihydrogen phosphate-hydrogen phosphate system, phosphate acts as a buffer in the intracellular space and blood plasma in conjunction with acid-base status (D-A-CH, 2000; Garg and Anderson, 2003; Grimm and Jahreis, 2000; Löffler and Petrides, 2003).

Requirements: The average requirements of adults are given as 580 mg/day (FNB, 1997)."

Ammonia:

"Ammonium ion is endogenously produced in the human digestive tract, much of it arising from the bacterial degradation of nitrogenous compounds from ingested food. About 4,200 mg/day are produced, greater than 70% of which is synthesized or liberated within the colon and its fecal contents. The total amount absorbed is about 4,150 mg/day, or 99% of the amount produced (Summerskill and Wolpert 1970); absorption after oral loading of NH4 + is similarly complete (Fürst et al. 1969). Evidence from Castell and Moore (1971) and Mossberg and Ross (1967) suggests that absorption of NH4 + increases as the pH of the contents of the lumen increases, and that the ammonium ion is actively transported at the lower pH levels (pH 5 was lowest detected absorption). Ammonium ion absorbed from the gastrointestinal tract travels via the hepatic portal vein directly to the liver, where in healthy individuals, most of it is converted to urea and glutamine. Human and animal data show that little of it reaches the systemic circulation as ammonia or ammonium compounds, but that it is a normal constituent of plasma at low levels (Brown et al. 1957; Pitts 1971; Salvatore et al. 1963; Summerskill and Wolpert 1970).

Human oral exposure data for NH4 + clearly indicate that it readily enters the portal circulation and is delivered to the liver (Conn 1972; Fürst et al. 1969), as has been shown to be the case for endogenously produced NH4 + (Pitts 1971; Summerskill and Wolpert 1970).

Un-ionized ammonia is freely diffusible, whereas the ammonium ion is less so and is relatively confined to the extracellular compartment (Stabenau et al. 1958). However, ammonium ion is in dynamic equilibrium with dissolved ammonia. Therefore, ammonium compounds that enter the circulatory system or other body fluids can thus freely penetrate tissue cells as ammonia.

Ammonia and ammonium ion are metabolized to urea and glutamine mainly in the liver by the process diagrammed in Figures 3-3 and 3-4 and described by Fürst et al. (1969) and Pitts (1971). However, it can be rapidly converted to glutamine in the brain and other tissues as well (Takagaki et al. 1961; Warren and Schenker 1964). The nitrogen is released from glutamine within tissue cells and used for protein synthesis as needed (Duda and Handler 1958; Fürst et al. 1969; Richards et al. 1975; Vitti et al. 1964). Ingestion of ammonium salts leads to almost complete conversion of ammonium ion into urea in the liver, whereas exposure by other routes may lead to its metabolism in body tissues to glutamine or tissue protein (Fürst et al. 1969; Vitti et al. 1964)."