Magnesium 2-ethylhexanoate

Endpoint summary

Additional information

1.  Introduction

Unless otherwise stated, the information provided in this section was taken from the EFSA Scientific Opinion on Dietary Reference Values for magnesium, 2015.

1.1.        Chemistry

According to the EFSA scientific opinion on dietary reference values for magnesium, published in 2015, magnesium (atomic number 12, atomic mass 24.30 Da) is an alkaline earth. It is the eighth most abundant element in the earth’s crust and the eleventh most abundant element in the human body. Like calcium, its oxidation state is +2 and, it does not occur in the native metallic state, but rather as the free cation Mg2+ in aqueous solution or as the mineral part of a large variety of compounds, including chlorides, carbonates and hydroxides.

1.2.        Biochemical functions

Magnesium is an essential element in biological systems and present in every cell type in every organism. It acts as a cofactor for more than 300 enzymatic reactions that require the presence of magnesium ions for their catalytic action. For example the activity of ATP (adenosine triphosphate), which is the main source of energy in every cell, is dependent on magnesium. Magnesium is binding to the nucleotide, which induces an adequate conformation and helps to weaken the terminal O–P bond of ATP, thereby facilitating the transfer of phosphate (Sanders et al., 1999; Rude and Gruber, 2004)). As ATP utilization is involved in many metabolic pathways, magnesium is essential in the intermediary metabolism for the synthesis of carbohydrates, lipids, nucleic acids and proteins, as well as for specific actions in various organs such as the neuromuscular or cardiovascular system. Magnesium can interfere with calcium at the membrane level or bind to membrane phospholipids, thus modulating membrane permeability and electrical characteristics. Magnesium has an impact on bone health through its role in the structure of hydroxyapatite crystals in bone (Blumentahl et al. 1977; Bigi et al. 1992; Bachra et al. 1965, Manicourt et al. 1981; Cohen & Kitzes 1981)

1.3.        Dietary sources and intake data

1.3.1.     Dietary sources

According to the WHO report on vitamin and mineral requirements in human nutrition (Second edition, 2004) “magnesium is widely distributed in plant and animal foods, and geochemical and other environmental variables rarely have a major influence on its content in foods. Most green vegetables, legume seeds, beans, and nuts are rich in magnesium, as are some shellfish, spices, and soya flour, all of which usually contain more than 500 mg/kg fresh weight. Although most unrefined cereal grains are reasonable sources, many highly-refined flours, tubers, fruits, fungi, and most oils and fats contribute little dietary magnesium (<100 mg/kg fresh weight) (Koivistoinen P., 1980; Paul AA., 1978; Tanet al.,1985)”.

According to the Regulation No 1925/2006 and Directive 2002/46/EC magnesium as for example magnesium acetate, magnesium chloride or magnesium oxide may be added to both foods and food supplements, whereas several magnesium formulations like magnesium malate, magnesium pyruvate and magnesium succinate may be added to food supplements only . The magnesium content of infant and follow-on formulae and the maximum magnesium content of processed cereal-based foods and baby foods for infants and young children is regulated by Commission Directive 2006/141/EC and Commission Directive 2006/125/EC. According to tolerance values for minerals in food and food supplements the upper tolerance value for minerals in food is 45 %, in food supplements 50 % (Guidance document for competent authorities, tolerances for the control of compliance of nutrient values declared on a label with EU legislation, published in 2012).

1.3.2.     Recommended dietary intake

An overview of dietary reference values for magnesium in newborn, children and adults are shown below. These data were reported in the WHO report on vitamin and mineral requirements in human nutrition- Second edition, 2004. More recent recommendations about magnesium intake in German-speaking countries (D-A-CH, 2015) and from Nordic Council of Ministers (NCM, 2014) are similar.

Group	Assumed body weight (kg)	Recommended magnesium intake (mg/day)
Infants and children
0-6 months
Human milk fed	6	26
Formula fed	6	36
7-12 month	9	54
1-3 years	12	60
4-6 years	19	76
7-9 years	25	100
Adolescents
Females,             10-18 years	49	220
Males, 10-18 years	51	230
Adults
Females
19-65 years	55	220
65+ years	54	190
Males
19-65 years	65	260
65+ years	64	224

 

 

2.  Toxicokinetics

2.1.        Absorption

Magnesium absorption takes place in the distal small intestine through a paracellular process via tight junctions and is driven by electrochemical gradients and solvent drag. Saturable transcellular absorption seems to be significant only at low dietary intakes. At usual intakes, magnesium absorption is only loosely regulated; relative absorption is generally considered to be 40–50 %, but figures from 10 to 70 % have also been reported. The fractional absorption of magnesium decreases with increasing magnesium intake, which makes the comparison between studies difficult (Sabatier et al., 2003a). Magnesium absorption can be inhibited by phytic acid and phosphate and enhanced by the fermentation of soluble dietary fibre, although the physiological relevance of these interactions at intakes considered to be adequate remains to be established.

2.2.        Distribution

Approximately 0.3 % of body magnesium circulates in the serum (Elin, 1987):

·        54 % as free cations, which is the bioactive form,

·        33 % in a protein-bound form (mainly to albumin 75 %)

·        13 % as anion complexes.

Magnesium concentrations in blood cells are higher than in the serum: eight times in reticulocytes, three times in red blood cells.

Magnesium is approximately equally distributed in bone and soft tissues, less than 1 % being present in blood compartments. Cellular magnesium concentrations are constantly in the range of 17–20 mmol/L (Swaminathan, 2003), despite rapid movements across cell membranes through multiple carriers and channels. Intracellular concentrations have been observed to decrease linearly with increasing age, without parallel changes in plasma magnesium concentration (Barbagallo et al., 2000; Barbagallo et al., 2009).

The most important transport system to tissues appears to be the transient receptor potential melastatin 7 (TRPM7), associated with cell proliferation or apoptosis; TRPM7, which is also permeable to calcium, is negatively regulated by intracellular magnesium and magnesium–nucleotide complexes (Romani, 2011; Park et al., 2014). TRPM6, functioning with TRPM7 or independently, is specifically expressed in the colon and distal renal tubule, where it plays a role in the reabsorption of magnesium (Woudenberg-Vrenken et al., 2009; Romani, 2011).

 

Total body magnesium content in a healthy adult is around 20–28 g (Rude, 2014). According to a review published by Swaminathan (2003)

·        52,9 % of magnesium is present in bone, of which 30 % is exchangeable present on cortical bone and functions as a reservoir to stabilize the serum concentration (Alfrey & Miller, 1973; Laireset al., 2004)

·        27 % in muscle, where mitochondria are considered to be the intracellular storage site (Kubota et al., 2005; Wolf and Trapani, 2008)

·        19,3 % in soft tissue

·        0.5 % in red blood cells

·        0.3 % in serum

2.3.        Metabolism

Magnesium as cation is used as a cofactor for essential enzymatic processes. However, it is absorbed, stored and eliminated but no further metabolism is known to occur.

2.4.        Elimination

2.4.1.     Urine

The kidney plays a major role in magnesium homeostasis and maintenance of serum concentrations. Around 80 % of serum magnesium is ultrafiltrable through the glomerulus, but only around 3 % of the filtered fraction appears in the urine, owing to an efficient reabsorption taking place mainly (60–70 %) in the thick ascending loop of Henle. This transport is directly related to sodium chloride reabsorption and the positive luminal voltage in this segment. The main stimuli that increase urinary magnesium excretion are high natriuresis, osmotic load and metabolic acidosis; those that reduce it are metabolic alkalosis, parathyroid hormone and, possibly, calcitonin (Musso, 2009). The remaining part of the reabsorption takes place in the distal convoluted tubule via an active transcellular mechanism that finally controls the amount excreted in the urine (Daiet al., 2001).

2.4.2.     Faeces

A large proportion of the magnesium content of faeces stems from unabsorbed magnesium (Lakshmananet al., 1984). The endogenous routes of elimination of absorbed magnesium through the digestive tract are bile, pancreatic and intestinal juices, and intestinal cells; part of these endogenous losses can be reabsorbed (Swaminathan, 2003). Using stable isotopes, endogenous faecal excretion has been determined to be 49 ± 11 mg/day in six healthy men aged 26–41 years (Sabatieret al., 2003b), around 15 mg/day in 9- to 14-year-old boys and girls (Abramset al., 1997) and from 4.7 to 21.7 mg/day in five girls aged 12–14 years, without influence of calcium intake (Sojkaet al., 1997).

In a meta-analysis of balance studies in adults, Hunt and Johnson (2006) estimated a basal urinary and faecal loss at zero intake, which amounts to approximately 20 mg/day.

2.4.3.     Skin and sweat

Reported sweat magnesium concentrations are very variable, ranging from 3 to 60 mg/L depending on the environment, with a hot and humid environment associated with the highest losses (Nielsen and Lukaski, 2006). After 24-hour exposure to 37 °C, sweat losses amounted to 25 % of the total daily magnesium loss (Consolazioet al., 1963).

Very different figures have been reported for magnesium sweat losses, which can be at least partially explained by different techniques for sweat collection; the highest values are reported after intense exercise and/or in a hot environment. At moderate physical activity performed around thermoneutrality, it is considered that magnesium losses through sweat are likely to be modest, in the range of 1–5 mg/day, on the basis of a daily sweat volume of around 0.5 L/day (Shirreffs and Maughan, 2005; Subudhiet al., 2005).

2.4.4.     Menses

Hunt and Schofield (1969) measured menstrual magnesium losses in five women (20–40 years of age); for the whole menstrual period, these varied from 2 ± 1 mg to 7 ± 5 mg in different experimental settings. On a daily basis, this loss appears to be marginal. Hunt and Johnson (2006) reported on menstrual magnesium losses amounting to 2.3 mg/day, with a range of 0.3–6.5 mg/day, although the source of these data is unclear. Considering a magnesium concentration in whole blood of around 35–40 mg/L in healthy women in the control group (Abdulsahib, 2011) and the volume of blood loss (median 18–30 mL per menstrual period (Hallberget al., 1966; Harveyet al., 2005)), a median magnesium loss of around 0.6–1.2 mg/menstrual period can be calculated. The EFSA Panel considers that magnesium losses through menstruation in women are negligible.

 

 

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