Registration Dossier

Administrative data

Description of key information

No acute toxicity studies with magnesium 2-ethylhexanoate are available, thus the acute toxicity will be addressed with existing data on the assessment entities magnesium and 2-ethylhexanoic acid.

Signs of acute oral or acute dermal toxicity are not expected for magnesium 2-ethylhexanoate, since the two moieties magnesium and 2-ethylhexanoic acid have not shown signs of acute oral or acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Additional information

No acute toxicity studies with magnesium 2-ethylhexanoate are available, thus the acute toxicity will be addressed with existing data on the individual moieties magnesium and 2-ethylhexanoic acid.

 

Magnesium

Acute oral toxicity

Humans must consume magnesium at regular intervals via diet or supplementation, mainly via oral application. “The daily recommendation for magnesium is controversial, as the literature is conflicting and varies between countries, although values of >300 mg/day are usually reported for healthy adults with adjustment for age, sex and nutritional status” (Kass et al., 2017). However, an excessive use can lead to mild side effects. When unabsorbed magnesium reaches the intestine or colon it can attract water from nearby tissue through osmosis. Therefore excessive use of magnesium and high amounts of unabsorbed magnesium in the intestine lead to diarrhoea. Side effects like diarrhoea or hypoventilation are known but mostly owing to the abuse of magnesium. For instance, Fung et al.(1995) reported the case of a 69 years old multimorbid woman who took about ca. 24 000 mg magnesium daily as an antacid. The observed serum levels increased up to 6.7 mmol/L and caused hypoventilation, but the patient recovered.

“Magnesium in foods derived from plant or animal sources has not been demonstrated to induce diarrhoea nor other adverse effects in healthy persons, probably as magnesium is bound to matrices and hence is mostly not easily bioavailable. On the other hand, easily dissociable magnesium salts (e.g. chloride or sulphate; included are compounds like magnesium oxide becoming readily dissociable after the reaction with gastric hydrochloric acid) which are present in water, many supplements and drugs, exert dose-dependent laxative effects” (EFSA scientific opinion on dietary reference values for magnesium).

Diarrhoea induced by easily dissociable magnesium salts or compounds like magnesium oxide 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.

Acute dermal toxicity

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10 % or 100 % default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals yields substantially lower figures, which can be summarised briefly as follows:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn) and current metal risk assessments under REACH, which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than its mass. The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours): From exposure to liquid/wet media: 1.0 %; From dry (dust) exposure: 0.1 %. This approach is consistent with the methodology proposed in 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).

For reference list please refer to endpoint summary of the moieties.

 

2-ethylhexanoic acid

Acute oral toxicity

In an acute oral toxicity study 4 rats/sex/dose were dosed with 90, 722, 1445 or 2890 mg/kg bw. No mortality was observed in the 90, 722 and 1445 mg/kg bw dose groups. The test material caused mortality in rats administered a dose of 2890 mg/kg bw (4/4), and transitory weakness at lower doses in a dose-dependent manner. The LD50 was calculated to 2043 mg/kg bw.

 

In another acute oral toxicity study 5 rats/sex/dose have been administered 0.2, 1.6, 3.2 and 4.0 ml 2-ethylhexanoic acid/ kg bw. No substance related clinical signs nor mortality was observed at 0.2 and 1.6 ml/kg. However, 1/10 animals died. After administration of 3.2 ml/kg and 4 ml/kg apathy dyspnea abdominal position and re crusted eyes and snouts were observed. Mortality in these dose groups was 3/10, 5/10, respectively. LD 50 was estimated to be 4 mL/kg bw, being equivalent to 3640 mg/kg bw (density 0.91 g/ml). This result is supported by another study which however was poorly documented.

 

Acute dermal toxicity

Dermal toxicity of 2-ethylhexanoic acid was tested in an OECD 402 guideline study. Five Wistar rats/sex/dose have been exposed dermally (semi-occlusive to a limit dose of 2000 mg/kg bw 2‑ethylhexanoic acid. No mortality and no clinical symptoms beside eschar formation have been observed. LD50 dermal therefore is > 2000 mg/kg bw.

Magnesium 2-ethylhexanoate

Signs of acute oral or acute dermal toxicity are not expected for magnesium 2-ethylhexanoate, since the two moieties magnesium and 2-ethylhexanoic acid have not shown signs of acute oral or acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg). Under the assumption that the constituents of magnesium 2-ethylhexanoate show their toxicological profile individually upon dissolution, the acute oral and dermal (systemic) toxicity of magnesium decanoate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1.

A study for acute toxicity via inhalation was not conducted with magnesium 2-ethylhexanoate, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

The calculated oral and dermal LD50 for magnesium 2-ethylhexanoate is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Justification for classification or non-classification

Based on in vivo oral and dermal LD50 data for the assessment entities magnesium and 2 -ethylhexanoic acid, acute toxicity estimates for magnesium 2-ethylhexanoate have been calculated resulting in LD50 values > 2000 mg/kg bw.

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 acute oral or dermal toxicity nor for specific target organ toxicity after single exposure (STOT SE).