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Description of key information

Short description of key information on bioaccumulation potential result: 
No laboratory animal toxicokinetic studies exist; therefore, an assessment of basic toxicokinetics has been made based on the available data.

Key value for chemical safety assessment

Additional information

Magnesium levels in the body are regulated by homeostatic processes. These homeostatic processes are able to deal with moderate increases in magnesium intake: either by storage in bone or by excretion via urine, faeces or sweat. Therefore, magnesium and magnesium carbonate are not toxic to humans but are essential elements to life and serious disorders involving the cardiovascular, skeletal, gastrointestinal and central nervous systems may result from magnesium deficiency.

Discussion on bioaccumulation potential result:

Magnesium carbonate exists in nature as the mineral magnesite.

Magnesium is an essential element to all life forms and ecosystems and is naturally occurring in the environment and many foods. Magnesium carbonate has many different industrial and chemical uses, is used as a food additive (E504), is present in multi-vitamins and mineral supplements and has also been extensively used therapeutically as one form of gastric antacids.

Magnesium kinetics represent an open system consisting of several compartments (SCF, 2003): the intestinal tract (absorption compartment), blood (central compartment), cells, skeleton, central nervous system (deep compartments) and faeces, urine, sweat and milk during lactation (excretion). Magnesium balance is positive when the input is greater than the output in urine and faeces.

 

Essentiality

The body contains about 25 g of magnesium, making it the fourth most common mineral constituent in the body (Government of Canada, 1987). More than half the magnesium is in bone (67%); the remainder is found intracellularly in soft tissues (31%) and, to a lesser degree, in body fluids (approximately 1%).

Magnesium is an essential element in human metabolism and is required for over 300 enzyme reactions, including all reactions requiring adenosine triphosphate. Magnesium is required to regulate cell permeability, and inadequate levels of magnesium will severely affect cardiovascular, neuromuscular, and renal functions.

Under normal conditions, magnesium levels are carefully regulated, and short-term dietary deficiencies can be overcome by the large available pool of magnesium in bone. However, depletion can occur as a result of vomiting, diarrhoea, use of certain diuretics, alcoholism, and protein malnutrition. Deficiency produces weakness, mental disorder, lessening of muscle control, and gastrointestinal disorders. Because magnesium in the myocardium exchanges more readily than does the magnesium in skeletal muscles, it has been suggested that long-term magnesium deficiency may be a factor in cardiovascular disease.

Absorption

No partition coefficient value was determined for magnesium carbonate as it is an inorganic substance. Because of this ionic nature the passive passage across biological membranes will be negligible. However, as magnesium is a key element in various cellular processes its import and export through cell membranes is regulated via pore systems.

Approximately 40% to 50% of dietary magnesium is absorbed (McCarthy and Kumar, 1999). Magnesium is absorbed along the entire intestinal tract, but the sites of maximal magnesium absorption appear to be the distal jejunum and ileum (Expert Group on Vitamins and Minerals, 2002).

1,25-dihydroxy-vitamin D3 may mildly increase the intestinal absorption of magnesium; however, this effect may be an indirect result of increased calcium absorption induced by the vitamin.

Secretions of the upper intestinal tract contain approximately 1 mEq/L of magnesium, whereas secretions from the lower intestinal tract contain 15 mEq/L of magnesium. In states of nausea, vomiting, or nasogastric suction, mild to moderate losses of magnesium occur. In diarrhoeal states, magnesium depletion can occur rapidly owing to both high intestinal secretion and lack of magnesium absorption.

The concentration of magnesium in plasma is maintained between 1.9 and 2.6 mg/dL (1.6 to 2.1 meq/L), of which about 20% is bound to protein (Government of Canada, 1987). The magnesium content of soft tissues ranges from 15 to 22 mg/100 g (6 to 9 mmol/kg) and is mainly intracellular or membrane-bound.

Magnesium transport into or out of cells appears to require the presence of carrier mediated transport systems (Expert Group on Vitamins and Minerals, 2002). The efflux of magnesium from the cell is coupled to sodium transport and requires energy.

In an acute oral study with magnesium carbonate (Harlan Laboratories Ltd, 2010), no mortalities were observed in the observation periods and there were no clinical signs of systemic toxicity (with the exception of hunched posture noted in the initial treated animal during the day of dosing; however, no signs of systemic toxicity were noted in the additional four treated animals) or macroscopic effects noted at necropsy. The LD50 value was therefore >2000 mg/kg bw for oral exposure and demonstrates that magnesium carbonate is not acutely toxic via the oral route.

A 28-day repeat dose oral toxicity study combined with a reproduction/ developmental toxicity screening test was performed in the rat in accordance with OECD TG 422 (BSL, 2010). Magnesium chloride hexahydrate was administered daily by gavage to three groups of Wistar rats for 14 days pre-mating and 14 days mating in both male and females, during gestation period and up to post natal day 3 in females. Males were dosed for 28-29 days. Dose levels of 0, 250, 500 and 1000 mg/kg bodyweight/day were used. The repeated dose administration of magnesium chloride hexahydrate revealed no major toxicological findings. Based on the data generated from the study, the NOAEL for magnesium chloride hexahydrate is concluded to be 1000 mg/kg bw/day. This study is directly applicable to magnesium carbonate and hence the equivalent NOAEL for magnesium carbonate is 414 mg/kg bw/day. Therefore, magnesium carbonate is not considered to be toxic to rats following repeated exposure for up to 28 days.

A 90-day repeated dose oral toxicity study in rats is also available (Takizawa, 2000). Magnesium chloride hexahydrate was administered to Fischer 344 rats in the diet at concentrations of 0, 62, 308 and 1600 mg MgCl2/kg bw/day in males and 0, 59, 299 and 1531 mg MgCl2/kg bw/day in females. No treatment related deaths were observed during the study. Transient soft stool and a sustained increase in water consumption were observed both in males and females of the high dose group and a slight reduction in body weight gain was noted in the high dose males. The NOAEL was concluded to be 308 and 299 mg MgCl2/kg bw/day in males and females respectively. There were no toxic changes in food consumption, organ weights, haematology and biochemistry and histopathological examinations in any treated group. This study is directly applicable to magnesium carbonate and hence the equivalent NOAELs for magnesium carbonate are 127 mg/kg bw/day for males and 124 mg/kg bw/day for females.

Magnesium carbonate is always prepared and used as a suspension and is never isolated in its solid or powder form. Therefore, exposure to aerosols, particles or droplets of magnesium carbonate of an inhalable size will not occur.

Absorption via the dermal route is expected to be very low based on the inorganic nature of magnesium carbonate; hence, systemic absorption and dermal toxicity are not expected.

Furthermore, there was no systemic toxicity observed in the skin and eye irritation studies performed with magnesium carbonate (Harlan Laboratories Ltd, 2010) indicating that the systemic absorption and/or the toxicity of magnesium carbonate are low.

The primary effect of excess oral magnesium is a laxative effect. However, the human body can adapt to this laxative effect over time. According to the SCF Opinion (SCF, 2001), diarrhoea induced by easily dissociable magnesium salts (including magnesium carbonate) is considered to be the most sensitive adverse effect but is completely reversible within 1 to 2 days and does not represent a significant health risk in subjects with intact renal function. Poorly dissociable magnesium salts (e.g. phytates) have a lower, if any, potential to induce diarrhoea. Toxic hypermagnesaemia, presenting e.g. with hypotension or muscular weakness, is only seen at oral magnesium doses greater than 2500 mg magnesium (equivalent to 8.4 g magnesium carbonate). The NOAEL and LOAEL for oral magnesium uptake are derived to be 250 and 365 mg Mg/day, respectively, based on the occurrence of mild diarrhoea. These values correspond to a NOAEL and LOAEL for magnesium carbonate of 14.5 and 21.1 mg/kg bw/day, respectively.

Distribution

The administration of radiolabelled magnesium to rats and dogs revealed that the isotope was incorporated in all organs (Expert Group on Vitamins and Minerals, 2002). The highest amounts are found in the heart and skeletal muscle and approximately one half of the magnesium content of the body is located in the bones. As magnesium ions are indispensable to life their distribution is tightly regulated.

Metabolism

Magnesium ions are inorganic and stable to reduction or oxidation in biological systems. Magnesium is a critical cation and cofactor in numerous intracellular processes (McCarthy and Kumar, 1999). It is a cofactor for adenosine triphosphate; an important membrane stabilizing agent; required for the structural integrity of numerous intracellular proteins and nucleic acids; a substrate or cofactor for important enzymes such as adenosine triphosphatase, guanosine triphosphatase, phospholipase C, adenylate cyclase, and guanylate cyclase; a required cofactor for the activity of over 300 other enzymes; a regulator of ion channels; an important intracellular signaling molecule; and a modulator of oxidative phosphorylation. Finally, magnesium is intimately involved in nerve conduction, muscle contraction, potassium transport, and calcium channels. 

Excretion

Magnesium levels in the body are primarily controlled by the kidney, with as little as 2% of endogenous magnesium excreted in the faeces (Government of Canada, 1987). Normal renal regulation of magnesium usually consists of glomerular filtration and tubular reabsorption, which are hormonally controlled. Because the renal threshold for magnesium (between 1.3 and 1.7 meq/L) is near normal serum values, a portion of dietary magnesium will appear in the urine, regardless of magnesium status. The maximum renal capacity is over 2.0 g/day.

Overview

In general, magnesium levels in the body are regulated by homeostatic processes. These homeostatic processes are able to deal with moderate increases in magnesium intake: either by storage in bone or by excretion via urine, faeces or sweat. Therefore, magnesium and magnesium carbonate are not toxic to humans but are essential elements to life and serious disorders involving the cardiovascular, skeletal, gastrointestinal and central nervous systems may result from magnesium deficiency.

References:

Expert Group on Vitamins and Minerals (2002), Review of Magnesium, August 2002, EVM/01/13.RevisedAug2002

SCF (2001), Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Magnesium, SCF/CS/NUT/UPPLEV/54 Final, 11 October 2001.

Government of Canada (1987), Magnesium, Magnesium (11/87), September 1978 (Updated November 1987),http://dsp-psd.pwgsc.gc.ca/Collection/H48-10-1-52-1987E.pdf

McCarthy JT and Kumar R (1999), Divalent Cation Metabolism: Magnesium, In Atlas of Diseases of the Kidney, Volume , Chapter 4, Edited by Tomas Berl and Joseph V. Bonventre

 

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