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Description of key information

Toxicity via the oral route is addressed by upper intake level (UL) for adults determined by the Scientific Committee on Food (SCF), being
UL = 250 mg/d, corresponding to 3.6 mg/kg bw/d (70 kg person) for magnesium (the report of SCF is attached on this summary; see below).
Data waiving is envisaged for repeated dose toxicity via dermal and inhalation route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Read across MgCl2 *6 H2O

The toxicity of magnesium chloride hexahydrate can reasonably be assumed to be determined by the availability of magnesium ions in solution. The water solubility of magnesium (6.7 mg/L at 21°C/pH 10.8) is 106orders of magnitude lower than the water solubility of magnesium chloride hexahydrate (1670 g/L at 20°C). Thus, read across to magnesium, based on worst case consideration, is justified and will likely lead to rather conservative no-effect levels. In conclusion, it was decided to waive repeated dose oral toxicity testing of magnesium and to read across from magnesium chloride for animal welfare reasons.

Read across to MgO

An acute inhalation study in human volunteers is available, in which the potential of MgO to cause symptoms similar to that of metal fume fever is investigated. Due to the fact that magnesium metal is passivated on its surface by the formation of an oxide layer, and since in the case of fine powders this oxide layer will form a substantial part of the particle mass, and also because magnesium oxide and magnesium metal are of similarly low solubility (interpreted as a measure of similar bioavailability), read across from data on magnesium oxide to magnesium metal is considered justified without restriction.

Repeated dose toxicity, oral

Guideline compliant repeated-dose toxicity studies in rodents with oral administration of magnesium (28-day study acc. to OECD TG 407 or 90-day study acc. OECD TG 408) are not available. Nevertheless, three animal studies on various magnesium salts could be made available by literature search (e.g. magnesium chloride hexahydrate and magnesium distearate) fulfilling the requirements under REACH.

 

However, the Scientific Committee on Food has determined an upper intake level (UL) of magnesium for adults of 250 mg/d, corresponding to 3.6 mg/kg bw/d, taking into account an average body weight of 70 kg/person.

Repeated dose toxicity, dermal

A dermal repeated-dose toxicity study for magnesium is considered to be scientifically unjustified for the following reasons:

(i) For magnesium, inhalation can be anticipated and thus, the provision (1) of Annex VIII, point 8.6.1 is not fulfilled.

(ii) Furthermore, following the HERAG guidance for metals and metal salts (see section 7.1.2), a dermal absorption rate in the range of max. 0.1-1.0 % can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Therefore, also the provision (3) of Annex VIII, point 8.6.1 is not fulfilled.

Testing of sub-chronic toxicity via the dermal route is therefore not required.

Repeated dose toxicity, inhalation

Read across MgSO4 for systemic effects

Systemic effects of magnesium and magnesium salts such as magnesium sulfate can reasonably assumed to be determined by the availability of magnesium ions in solution. Since magensium is poorly soluble in water (Mg: 6.7 mg/L at 21°C/pH 10.8) and MgSO4 is highly water soluble (710 g/L at 20°C) the effects occurred for magnesium sulfate will be higher than the effects expected for magnesium.

Therefore, read across is considered to be justified but is inherently very conservative.

Adequate long-term data on inhalation exposure are not available. However, according to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic inhalation toxicity is not considered to be required, for the following reasons:

(i) Although magnesium is poorly water soluble (6.7 mg/L at 21°C/pH 10.8), no pH-related effects need to be assumed upon contact with respiratory tract epithelia, and any lung overload associated with inert particles can be excluded. This is based on the following information:

- Two published animal studies (Hori 1994) for sub-chronic and chronic inhalation could be made available which provide tentative information on the health effects of magnesium. Inhalation exposure of rats to 2.3 mg/m3magnesium sulfate for 1 month or 1 year did not show any noticeable effects on growth curves and organ weights in the treatment group. The number of adenomas in the exposure groups was not significantly greater than that of the control group.

 

- Reichrtová & Taká (1992) conducted a study where Wistar rats were exposed by inhalation to a dust (particles smaler than 5µm) containing a high percentage of MgO (up to 1000 mg/m3). This dust was collected from environmental sample collection devices around Slovak magnesite factory. Several results were reported. Animals receiving repeated exposures totaling 200 hours showed a diminished ability to eliminate magnesium as compared to animals that received a single exposure. Repeated exposures caused increased levels of magnesium in the serum and urine, indicating that the inhaled dust was gradually dissolved in the body. The inhaled dust was eliminated by the lymphatic system as well, as evidenced by histological examination of the spleen, where particles were present in sinusoid macrophages. Even though significant amounts of magnesium were excreted, increased magnesium levels were observed in the liver, spleen, and lung 25 days after the last exposure. In the lung, dust particles were found in thickened interalveolar septa and macrophages, but no signs of pulmonary fibrosis were observed. the findings showed that MgO dust was eliminated by blood and lymph.”

- Kuschner (1997) reports that inhalation of fine and ultrafine MgO particles to humans (please refer to section 7.10.1 for more information) at concentrations up to 230 mg/m³ over 15 minutes or 143 mg/m³ over 45 minutes did not result in any adverse effects (inflammation markers, or subjective symptoms). This result suggests that inhalation of MgO dust does not produce adverse effects up to these concentrations. In consequence, local effects are not anticipated for this substance.

In conclusion it can be stated that no DNEL for long-term inhalation for local effects in workers or the general population must be derived.

 

(ii) In accordance with ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, a DNEL for systemic effects could be derived by route-to-route extrapolation from the UL of 250 mg/person and day which is based on the recommendation published by the Scientific Committee on Food (SCF/CS/NUT/UPPLEV/54 Final, 11 Oct 2001).


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic inhalation toxicity is not considered to be required, since (i) magnesium metal does not elicit any relevant local effects in lungs if inhaled and (ii) a DNEL for sub-chronic inhalation, systemic effects could be derived via route-to-route extrapolation from the NOAEL of 250 mg Mg/d, which was given by the Scientific Committee on Food, 2001. For detailed information please see below.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for sub-chronic inhalation toxicity is not considered to be required, since (i) magnesium metal does not elicit any relevant local effects in lungs if inhaled and (ii) a DNEL for sub-chronic inhalation, systemic effects could be derived via route-to-route extrapolation from the NOAEL of 250 mg Mg/d, which was given by the Scientific Committee on Food, 2001. For detailed information please see below.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
According to Annex VIII, point 8.6.1, column 2 of Regulation No 1907/2006, information on sub-chronic toxicity testing via the dermal route shall be provided if (1) inhalation of the substance is unlikely; and (2) skin contact in production and/or use is likely; and (3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.
For magnesium, inhalation can be anticipated. Therefore, provision (1) of Annex VIII, point 8.6.1 is not fulfilled. Furthermore, following the HERAG guidance for metals and metal salts (see section 7.1.2), a dermal absorption rate in the range of max. 0.1-1.0 % can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Therefore, also provision (3) of Annex VIII, point 8.6.1 is not fulfilled.
In conclusion, testing for sub-chronic dermal toxicity testing with magnesium is not considered to be required according the criteria laid down in Annex VIII, point 8.6.1. It can safely be anticipated that there will be no systemic risk in case of dermal long-term exposure to magnesium. Additional toxicity studies are not expected to provide further information, thus there is no need for any further repeated dose testing.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
According to Annex VIII, point 8.6.1, column 2 of Regulation No 1907/2006, information on sub-chronic toxicity testing via the dermal route shall be provided if (1) inhalation of the substance is unlikely; and (2) skin contact in production and/or use is likely; and (3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.
For magnesium, inhalation can be anticipated. Therefore, provision (1) of Annex VIII, point 8.6.1 is not fulfilled. Furthermore, following the HERAG guidance for metals and metal salts (see section 7.1.2), a dermal absorption rate in the range of max. 0.1-1.0 % can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Therefore, also provision (3) of Annex VIII, point 8.6.1 is not fulfilled.
In conclusion, testing for sub-chronic dermal toxicity testing with magnesium is not considered to be required according the criteria laid down in Annex VIII, point 8.6.1. It can safely be anticipated that there will be no systemic risk in case of dermal long-term exposure to magnesium. Additional toxicity studies are not expected to provide further information, thus there is no need for any further repeated dose testing.

Justification for classification or non-classification

The only effect observed is that magnesium causes diarrhoea if ingested in high doses. According to the scientific commitee on food, 2001 it can be assumed that the no-effect level of daily magnesium intake is 250 mg/day. It is explicitly note that this value does not include Mg normally present in foods and beverages. This effect could be regarded as non "significant" or "severe", and do not indicate functional disturbance or morphological changes of toxicological relevance.

For the reasons presented above, classification for repeated dose toxicity (oral, dermal and inhalation) and specific target organ toxicant (STOT) – repeated exposure, respectively is not required according to Regulation (EC) 1272/2008 and subsequent adaptations.

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