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Description of key information

No repeated dose toxicity study with magnesium 2-ethylhexanoate is available, thus the repeated dose toxicity will be addressed with existing data on the assessment entities magnesium and 2‑ethylhexanoic acid.

In relevant and reliable repeated dose toxicity studies for both assessment entities of magnesium 2‑ethylhexanoate, there were no toxicological findings reported that would justify a classification for specific target organ toxicity with repeated exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information


Magnesium, as one of the essential elements, is known for its U-shaped dose- response relationship. The U-shape dose-response describes a biphasic response to exposure to increasing amounts of a substance or condition. According to a recently published EFSA scientific opinion on dietary reference values for magnesium the daily recommendation for magnesium is between 300 and 350 mg/day. Variation in intake recommendations depends on age, sex and health. However, redistribution, reduced intake, reduced intestinal absorption, increased gastrointestinal loss or increased renal loss are causes of hypomagnesaemia. Magnesium deficiency entirely due to reduced dietary intake in otherwise healthy subjects is very uncommon. This kind of deficiency is mainly observed in patients with diseases. However, magnesium deficiency is linked to several severe health effects as described below.

Magnesium deficieny


“There is a substantial body of epidemiological and experimental evidence linking magnesium deficiency and atherosclerotic cardiovascular disease (Foxet al,2001). Experimental studies suggest that magnesium deficiency may play a role in the pathogenesis of atherosclerosis (Nadler & Rude, 1995). Magnesium deficiency may contribute to the progression of atherosclerosis by its effects on lipid metabolism, platelet aggregation and blood pressure” (Swaminathan, 2003).


“Magnesium deficiency has been implicated in osteoporosis. Magnesium content of trabecular bone is significantly lower in subjects with osteoporosis, and magnesium tolerance studies show increased retention of magnesium. Serum and red blood cell magnesium also appear to be lower in these subjects. Recent studies also suggest magnesium supplementation increases bone density or arrests bone loss in 80 % of osteoporotic subjects (Sojka & Weaver, 1995)” (Swaminathan, 2003).


“Magnesium has also been implicated in asthma. Ionised magnesium concentration was 20 % lower in asthmatics. In an epidemiological study a reduced magnesium intake, as determined by a dietary questionnaire, was associated with hyperreactivity of the airways to metacholine. The authors concluded that dietary magnesium intake was independently related to lung function, and low magnesium intake may therefore be involved in the aetiology of asthma (Brittonet al,1994)” (Swaminathan, 2003).

Hypertension and vascular tone

“There is an inverse relationship between magnesium intake and blood pressure and epidemiological studies show an increased incidence of hypertension in areas where the magnesium content of water is low (Nadler & Rude, 1995). Furthermore, magnesium supplementation was associated with a significant decrease in blood pressure in 10 out of 15 studies (Foxet al.,2001). In-vitro and in-vivo studies show that magnesium can influence vascular tone and reactivity. Magnesium deficiency increases angiotensin II induced plasma aldosterone concentration and production of thromboxane and vasoconstrictor prostaglandins (Nadleret al.,1993). Insulin resistance caused by magnesium deficiency also increases vascular tone. Changes in cytosolic free calcium produced by magnesium deficiency may increase vascular reactivity even further” (Swaminathan, 2003).


Magnesium excess

Compared to the above mentioned health issues due to magnesium deficiency, an excessive (long term) use or accidental overdose of magnesium is only linked to hypermagnesaemia or laxative effects.


Hypermagnesaemia is an electrolyte disturbance in which there is a high level of magnesium in the blood. It is defined as a level greater than 1.1 mmol/L. “The major cause of hypermagnesaemia is renal insufficiency associated with a significantly decreased ability to excrete magnesium. Increased intake of magnesium salts may cause a change in bowel habits (diarrhoea), but seldom causes hypermagnesaemia in persons with normal kidney function” (WHO report on vitamin and mineral requirements in human nutrition (Second edition, 2004)).

“In 6 healthy volunteers about 4 % of a 56.5 mmol oral dose of magnesium sulphate (ca. 1,400 mg) given in 4 hours was enterally absorbed without inducing hypermagnesaemia. In the literature, only few cases of toxic hypermagnesaemia (> 2.5 mmol/L) have been published, mostly owing to the (ab-) use of magnesium as laxatives or antacids in single doses of >2,500 mg magnesium” (Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Magnesium, 2001).


Gastrointestinal function

“Drinking-water in which both magnesium and sulphate are present in high concentrations can have a laxative effect, although data suggest that consumers adapt to these levels as exposures continue. Laxative effects have also been associated with excess intake of magnesium taken in the form of supplements, but not with magnesium in diet” (WHO report on vitamin and mineral requirements in human nutrition (Second edition, 2004)).

These mild and reversible effects of magnesium overdoses appear to be linked to the relative low absorption rates of magnesium.


Taken together, magnesium deficiency has severe effects on human health, due to its biological role, e.g. as essential cofactor in enzymatic processes. Excessive use of magnesium as laxatives, antacids or daily magnesium supplementation has only mild and reversible effects on human health. However, the above mentioned examples for health issues in magnesium deficiency and excess use clearly demonstrate that magnesium deficiency is more relevant to human health than magnesium overdoses.


Britton J, Pavord I, Richards K, Wisniewski A, Knox A, Lewis S, Tattersfield A, Weiss S. Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample.Lancet.1994;344:357–362

Durlach, J., Bara, M. and Guiet-Bara, A. (1985) Magnesium level in drinking water and cardiovascular risk factor: a hypothesis. Magnesium 4, 5–15.

Ferrier, C. (2001) Bottled Water: Understanding a Social Phenomenon. World Wildlife Fund, Washington, DC, April, p. 13.

Fox C, Ramsoomair D, Carter C. Magnesium: its proven and potential clinical significance. South Med J. 2001; 94:1195–1201

Garzon, P. and Eisenberg, M.J. (1998) Variation in the mineral content of commercially available bottled waters: implications for health and disease. Am. J. Med. 105, 125– 130.

Hunt CD and Johnson LK, 2006. Magnesium requirements: new estimations for men and women by cross-sectional statistical analyses of metabolic magnesium balance data. American Journal of Clinical Nutrition, 84, 843-852.

Nadler JL, Rude RK. Disorders of magnesium metabolism. Endocrinol Metab Clin North Am. 1995; 24:623–641.

Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 1993; 21:1024–1029

Sabatier, M., Arnaud, M.J., Kastenmayer, P., Rytz, A. and Barclay, D.V. (2002) Meal effect on magnesium bioavailability from mineral water in healthy women. Am. J. Clin. Nutr. 75, 65–71.

Sojka JE, Weaver CM. Magnesium supplementation and osteoporosis.Nutr Rev.1995;53:71–74

Swaminathan R, 2003. Magnesium metabolism and its disorders. Clinical Biochemical Review, 24, 47-66.

Verhas, M., de la Gueronniere, V., Grognet, J.-M., Paternot, J., Hermanne, A., Van den Winkel, P., Gheldof, R., Martin, P., Fantino, M. and Rayssiguier, Y. (2002) Magnesium bioavailability from mineral water. A study in adult men. Eur. J. Clin. Nutr. 56, 442–447.


2-ethylhexanoic acid

Repeated dose toxicity: oral

Several repeated oral dose studies for 2-ethylhexanoic acid were available for assessment. A diet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups. In both studies, all toxicity observed at higher concentrations (changes in clinical chemistry, absolute and relative organ weights, microscopic changes in kidney liver and fore stomach) was reversible within 28 days after exposure ceased.



Magnesium 2-ethylhexanoate

As the two assessment entities of magnesium 2-ethylhexanoate do not induce adverse effects in any relevant and reliable repeated dose toxicity study, magnesium 2-ethylhexanoate in all probability has also no potential to induce adverse effects after repeated exposure.

For the purpose of hazard assessment of magnesium 2-ethylhexanoate, the point of departure for the most sensitive endpoint of each assessment entity will be used for the DNEL derivation. In case of 2‑ethylhexanoic acid in magnesium 2-ethylhexanoate, the NOAEL of 100 mg/kg bw/day for the developmental toxicity will be used.

Justification for classification or non-classification

According to the criteria of REGULATION (EC) No 1272/2008, magnesium 2-ethylhexanoate does neither have to be classified and has no obligatory labelling requirement for repeated oral toxicity nor for specific target organ toxicity after repeated exposure (STOT RE).