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Description of key information

In section 7.10.5 (Exposure related observations in humans: other data), a number of different clinical studies are presented. All of these deal with the effects of magnesium salts on different aspects of human health. Data include studies on children, pregnant women, hypertensive and cardiac patients as well as adult volunteers. Publications were only considered when the presence or absence of “mild diarrhoea” was stated, as this is considered to be the most sensitive non-desired or adverse effect. 
Attention was paid on the form of magnesium salts administered. Only studies with orally administered easily dissociable magnesium salts (e.g. chloride or aspartate; as well as compounds like MgO becoming readily dissociable after the reaction with gastric hydrochloric acid) were included; Mg contained in food derived from plant or animal sources (e.g. phytates) being known to be poorly dissociable and considered to have a lower, if any, potential to induce diarrhoea, were not included in the assessment.
These data are all included in the Opinion of the Scientific Committee on Food of the European Commission (SCF, 2001) which therefore serves as the key study for repeated-dose oral toxicity.

Additional information

Applicability of the read-across

All studies presented in section 7.10.5 and summarized in the SCF Opinion on Derivation of a Tolerable Upper Intake Level of Magnesium Compounds (SCF, 2001) used magnesium compounds which are soluble either in water or in acidic solutions (such as gastric acid). Magnesium from plant or animal sources (i.e. dietary magnesium) was not considered in the studies as this is known to be poorly dissociable and the bioavailability of magnesium from magnesium salts appears to be dependent on their water solubility.

Organic salts of magnesium such as magnesium-L-aspartate have the greatest water solubility and demonstrate a greater oral absorption and bioavailability compared to less soluble magnesium preparations such as magnesium oxide, magnesium hydroxide, magnesium carbonate and magnesium sulphate (EFSA Journal 2005 167: 1-6). It can therefore be stated without reasonable doubt that oral bioavailability of magnesium from magnesium carbonate is at best equal to the absorption from magnesium-L-aspartate, the compound used for most of the cited studies.

In acidic solutions, magnesium carbonate will dissociate into magnesium and carbonate ions the latter of which in part react to form water and carbon dioxide. Taking this information as a basis, the oral availability of magnesium carbonate can sufficiently be described with the examination of the magnesium cation, taking into account the effects of the respective anion. The only restriction may be that the source of magnesium (i.e. the magnesium salt) shall be of at least equal bioavailability. It is therefore considered justified to use the data derived with other easily bioavailable magnesium salts to describe effects after oral uptake of magnesium carbonate.

 

Toxicological properties

The toxicological effects of oral magnesium intake are described in detail in the SCF Opinion cited above.

Magnesium in foods derived from plant or animal sources has not been demonstrated to induce adverse effects in healthy persons, probably as Mg is bound to matrices (e.g. phytic acid, phosphates, chlorophylls, biological apatites) and hence is mostly not easily dissociable. On the other hand, easily dissociable magnesium salts (e.g. chloride, sulphate, aspartate, and compounds like MgO becoming readily dissociable in gastric hydrochloric acid) exert dose-dependent effects.

Animal experiments have proven a significant cubic relation between the logarithm of orally administered Mg and the Mg concentrations in plasma and bone. In other words, oral Mg supply has to be considerably increased to increase plasma Mg. This is partially based on the fact that renal magnesium clearance is significantly increased upon administration of higher magnesium doses (adaption). Also, the magnesium uptake in the intestine is self-regulating as higher intestinal doses induce laxative effects, leading to increased fecal excretion of magnesium.

In the literature, only few cases of toxic hypermagnesaemia (serum Mg >2.5 mmol/L, resulting in decreased neuromuscular transmission up to muscle relaxant effects) have been published, mostly owing to the (ab-)use of Mg as laxatives or antacids in single doses of >100 mmol Mg (ca. 2500 mg magnesium). These doses exceed the NOAEL by a factor of more than 10 and could be achieved by oral intake of more than 8.4 g magnesium carbonate.

The most sensitive non-desirable effect of orally administered easily dissociable magnesium salts is mild diarrhoea. From the data presented one can conclude that this occurs in adult subjects at oral doses of about 365 mg Mg per day, hence presenting the LOAEL. No laxative effects have been observed in adult men and women – including during pregnancy and lactation – at doses up to 250 mg Mg per day. Therefore, this dose is considered as being the no-observed-adverse-effect level (NOAEL).

Using the molecular masses of magnesium (24.3 g/mol) and magnesium carbonate (84.314 g/mol), the N(L)OAELs for magnesium can be converted into their respective values for magnesium carbonate: NOAEL = 867 mg/day; LOAEL = 1265 mg/day. Based on the ECHA default adult human body weight of 60 kg, the NOAEL and LOAEL are equivalent to bodyweight doses of 14.5 and 21.1 mg/kg bw/day, respectively.

 

Summary

Diarrhoea induced by easily dissociable Mg 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 Mg salts (e.g. phytates) have a lower, if any, potential to induce diarrhoea.

Toxic hypermagnesaemia, presenting e.g. with hypotension or muscular weakness, is seen only at oral Mg doses greater than 2500 mg Mg (equivalent to 8.4 g magnesium carbonate). The NOAEL and LOAEL for oral magnesium supplementation (on top of its presence in food and beverages) are derived to be 250 and 365 mg Mg/day, based on the occurrence of mild diarrhoea. These values correspond to magnesium carbonate doses of 14.5 and 21.1 mg/kg bw/day, respectively.