Magnesium

Endpoint summary

Description of key information

Magnesium is an essential mineral nutrient. The human adult body contains approximately 25 g magnesium, 50-60 % of which are located in the bones. Thirty to forty percent of the Mg in the body is found in the soft tissues, functioning as a cofactor in hundreds of enzymatic reactions particularly in energy metabolism. Beyond this, it is involved into protein and nucleic acid synthesis, maintenance of the electrical potential of nervous tissues and cell membranes, hormone and neurotransmitter release, muscle contraction, cellular differentiation and many others. Intestinal absorption and excretion (mostly via urine), intra- and extracellular levels of dissolved Mg2+ are tightly regulated, constituting homoeostasis, depending on the body's needs and dietary supply.
Short description of key information on absorption rate: 
Following the HERAG guidance for metals and inorganic metal compounds, the following conservative default values for dermal absorption are proposed:
0.1 % for dry (dust) exposure
1.0 % for exposure to liquid/wet media

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

15

Absorption rate - dermal (%):

0.1

Absorption rate - inhalation (%):

8.1

Additional information

Due to their ubiquitous occurrence in the environment and the function as essential mineral for human nutrition (also see section 7.10 of the technical dossier), magnesium are among the most extensively investigated elements with respect to physiological behaviour.The key conclusion for this section is that magnesium, as essential mineral nutrient underlie homoeostatic regulation and therefore cannot be considered as xenobiotics.

 

Magnesium is involved in bone formation; its predominant function is as a cofactor in several hundred enzymatic reactions.

Absorption

Oral

Absorption is negatively correlated with luminal Mg concentration, varying between approximately 11 and 80 %. The typical intestinal absorption rate from dietary and soluble sources at magnesium balance is given as 30 - 40 %. Absorption of magnesium is - unlike calcium - dependent on the solubility of the substance. For calcium magnesium oxide, containing magnesium as poorly soluble MgO, absorption of magnesium is proposed to amount to 15 %.

Dermal

Following an approach consistent with the methodology proposed in the HERAG guidance for metals (Anonymous, 2007: HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH, Hannover, Germany; August 2007), the following default dermal absorption factors for metal cations are proposed (reflective of full-shift exposure, i.e. 8 hours) for magnesium:

 

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %

 

 

Inhalation

Magnesium as technical material is supplied as a powder (or coarse grained material), from which airborne particles may be generated during handling.

The estimates for inhalation absorption are composed of 100 % absorption for material deposited in the pulmonary region, plus material deposited in the tracheobronchial and the head region (transported to the pharynx and swallowed), corrected for intestinal absorption (15 % for Mg). As a result, total inhalation absorption is

 

		Magnesium
Magnesium powder		8.1 %

 

Excretion

Absorbed magnesium is predominantly excreted via urine; the kidney plays an important role in homoeostatic regulation of the magnesium balance, by active re-absorption of magnesium taking place in Henle's loop. Renal excretion is the key mechanism for maintaining magnesium homoeostasis: the excretion rate varies according to magnesium supply and concentration in body fluids, thereby regulating systemic magnesium levels.

Distribution

An extensive evaluation by the SCF is also available for magnesium, upon which the following conclusion is primarily based:

Magnesium is an essential mineral nutrient. The adult human body contains approximately 25 g magnesium. Thirty to forty per cent of the body's magnesium stores are found in muscles and soft tissues, 1 % in extracellular fluid, and the remainder in the skeleton, making up approximately 1 % of bone ash. In soft tissues magnesium functions as a co-factor of many enzymes involved in energy metabolism, protein synthesis, RNA and DNA synthesis, and maintenance of the electrical potential of nervous tissues and cell membranes. Magnesium levels in the body are subject to homoeostasis, regulated via the rate of renal excretion.

 

Discussion on bioaccumulation potential result:

Toxicokinetic behaviour of magnesium is assessed utilising mostly publications focusing on the nutritional and physiological role of magnesium. First and foremost, however, secondary literature in the form of official evaluation documents by EU bodies (e.g. EFSA) is extensively referred to. Much of this information consists of human data. This approach therefore follows the provisions of Annex XI, points 1.1.3 and 1.2 of Commission Regulation No 1907/2006, specifying general rules for adaptation of the standard testing regime.

 

Biological function and essentiality of magnesium:

Magnesium is an essential mineral nutrient; however, definitive recommendations for daily requirements have not yet been established by the Scientific Committee on Food. Magnesium is included in bone where it serves as a structural element, mainly as a surface constituent of hydroxyapatite. Most importantly, it is functioning as a cofactor in hundreds of enzymatic reactions particularly in energy metabolism, and beyond this, it is involved with protein and nucleic acid synthesis, maintenance of the electrical potential of the nervous system and cell membranes, hormone and neurotransmitter release, muscle contraction, cellular differentiation and many others.

 

Oral absorption of magnesium:

From dietary sources, magnesium is absorbed in the intestine by, on average, 30–40 % (SCF opinion). However, absorption rates of magnesium from soluble sources are highly variable, ranging between 11 and 80 %, depending on the dose (Fine, 1991; Danielson, 1979; Spencer, 1980; Roth, 1979; Graham, 1960; Schwartz, 1978). Overall, an absorption rate of approximately 50 % from soluble magnesium salts is proposed as a reliable estimate. The mechanism appears to involve both passive diffusion and either an active transport system or facilitated diffusion (SCF opinion; Roth, 1979). Magnesium turnover varies by age, growth status, physical activity, pregancy-lactation, fluid consumption, stress exposure, drugs and diseases. The magnesium balance is regulated by homoeostasis, allowing adaptation to a wide range of magnesium intakes.

 

However, intestinal absorption of magnesium from MgO has been investigated in comparison to more soluble salts by Firoz and Graber (2001). Fractional absorption of magnesium from MgO was estimated at 4 %. However, this appears to be a biased estimate in view of (1) the high variation among individual values and (2) the finding of only 9-11 % absorption from the soluble salts magnesium chloride, acetate, and aspartate, at physiological doses. However, the 4 % figure for MgO represents approximately 30-40 % of those for the more soluble salts, which appears plausible. For assessment of magnesium a value of 15 % is therefore proposed, corresponding to approximately 1/3 of the 50 % figure for dietary and soluble magnesium.

 

Inhalation absorption

Systemic availability of Magnesium powder is a function of regional deposition in the respiratory tract, which in turn depends foremost on particle size. However, product specific physical particle size distributions do not necessarily reflect the particle size of aerosols that may be formed under practically relevant workplace conditions, for example during manual operations such as filling and emptying of bags, or under mechanical agitation as in mixing and weighing operation.

 

Therefore, physical particle size distribution and the median (D50) physical particle size were determined for the airborne fraction of Magnesium powder, representing the range of commercially available particle sizes (see IUCLID section 4.5 “particle size distribution (granulometry)).

 

The airborne fraction was generated during mechanical agitation in a rotating drum according to the modified method of Heubach (1991) and the particle size distribution was determined by laser diffraction by the Sponsor himself.

 

The relative density of Magnesium powder was measured by Siemens AG according to OECD 109 (gas pycnometer method). Data on particle size, relative density and calculated mass median aerodynamic diameter (MMAD) as well as the relevant parameter for predicting airway deposition of particulate matter, is presented in the following table:

 

Sample	relative density	D50* (mm)	MMAD of airborne particles (mm)	Geometric standard deviation of MMAD
Magnesium powder	1.76 at 23°C	52.70	25.60	1.72

*D50 = median physical particle size

#MMAD = mass median aerodynamic diameter

 

A physical particle size of 52.70 µm, corresponding to a MMAD of 25.60 µm was measured for Magnesium powder. This value can be selected as a reasonable worst case for occupational inhalation exposure.

 

In order to estimate the deposition in the respiratory tract (head, tracheobronchial and pulmonary region) of particles the Multiple Path Particle Deposition (MPPD) model (CIIT, 2002-2006) was used with the following input data; The human–five lobular lung model, a polydisperse particle distribution, oronasal (normal augmenter) mode, a full shift breathing rate of- corresponding to a tidal volume of 1100 ml and a breathing frequency of 20/min, and an aerosol concentration of 500 µg/m3.

 

Calculated deposition fractions of Magnesium powder (see IUCLID section 4.5 “particle size distribution (granulometry)).

Sample	Head [%]	TB [%]	PU [%]
Magnesium powder	53.25	0.13	0.06

 

The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.

 

In consequence, the material deposited in the head and tracheobronchial regions would be translocated to the gastrointestinal tract without any relevant dissolution in view of the low water solubility of barium carbonate, where it would be subject to gastrointestinal uptake at a ratio of 2.8%. The material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice. Thus total predicted inhalation absorption is given in the appendix for each respective substance.

 

 

Absorption factor, magnesium	absorption factors* via inhalation [%]
Test item
Magnesium powder	8.1

 

 

Distribution and elimination:

The human body contains approximately 25 g magnesium. Approximately two-thirds of the body stores are located in the bones, 1 % is found in extracellular fluids, and approximately one third (30-40 % acc. to FAO/WHO) intracellularly in muscles and soft tissues. Absorbed magnesium is predominantly excreted via urine; the kidney plays an important role in homoeostatic regulation of the magnesium balance, by active re-absorption of magnesium taking place in Henle's loop.

Magnesium is an essential mineral nutrient for humans and therefore cannot be considered as xenobiotic substances. Magnesium is homoeostatically regulated, with the skeleton serving as a reservoir to compensate for short-term fluctuations in dietary supply of these minerals. In view of their essentiality for human nutrition, the existing information on magnesium is considered as sufficient for assessment of their physiological behavior.

 

Discussion on absorption rate:

A published in vitro study on dermal absorption of magnesium constituting academic research is available. However, this study does not provide endpoint information suitable for derivation of an absorption rate that could be of use in a regulatory context. The study by Laudanska et al. (2002) is therefore considered as supportive data but will not be used for derivation of dermal absorption rates.

Nevertheless, following an approach consistent with the methodology proposed in the HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH, Hannover, Germany; August 2007), the following default dermal absorption factors for metal cations are proposed (reflective of full-shift exposure, i.e. 8 hours) for magnesium.

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %