Magnesium carbonate

Endpoint summary

Description of key information

Repeat dose oral toxicity: A 28-day and a 90-day repeat dose oral toxicity study in rats are available that have evaluated the repeated dose toxicity of magnesium chloride hexahydrate. These results are directly applicable to magnesium carbonate. A 13-week study in the mouse and a number of human studies are also available. No severe or adverse toxicological effects were reported following oral administration of the test material for 28 days. The main effects observed in the 90-day study in rats and some of the long-term human studies were transient soft stools and diarrhoea.  Based on the human data, the EC SCF has concluded a NOAEL equivalent to 14.5 mg MgCO3/kg bw/day.
Repeat dose dermal toxicity: No studies on the repeated dose dermal toxicity of magnesium carbonate are available.
Repeat dose inhalation toxicity: No studies on the repeated dose inhalation toxicity of magnesium carbonate are available. 

Additional information

Justification for read-across

Read-across from magnesium chloride and magnesium chloride hexahydrate to magnesium carbonate is justified on the following basis.

 

Due to the presence of acid, mainly in the form of hydrochloric acid, in the stomach, magnesium carbonate will be converted into magnesium chloride when orally ingested. Furthermore, magnesium chloride is significantly more soluble than the carbonate salt and therefore represents the worst case in terms of its bioavailability for systemic absorption.

In addition, both salts have been shown to have no acute toxicity and do not exhibit evidence of systemic toxicity when tested at a concentration of 2000 mg/kg bw in acute oral studies.

Magnesium carbonate and magnesium chloride also occur in the natural environment and humans are widely exposed to naturally occurring magnesium carbonate and chloride, e.g. via drinking water and food on a day to day basis. Ingested magnesium, carbonate and chloride ions are actively regulated by the body. Any systemic toxicity is likely to be caused by absorption of the magnesium ion rather than either the carbonate or chloride counterions and hence studies on magnesium salts can be read across from one to the other.

These data are therefore deemed reliable for read across to magnesium carbonate as they represent the worst case for potential repeated dose toxicity via the oral route.

 

 

Repeat dose oral toxicity:

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. Clinical signs, mortality, clinical observations, bodyweight and food consumption were monitored during the study. Haematology and clinical biochemistry were evaluated prior to termination on randomly selected males and females from each dose group. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

The repeated dose administration of magnesium chloride hexahydrate revealed no major toxicological findings. Based on the data generated from the study, the NOAEL is believed to be 1000 mg/kg bw/day for magnesium chloride hexahydrate. This study is directly applicable to magnesium carbonate and hence the equivalent NOAEL for magnesium carbonate is 414 mg/kg bw/day.

A 90 day repeated dose oral toxicity study in rats was performed (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. There were no toxic changes in food consumption, organ weights, haematology and biochemistry and histopathological examinations in any treated group. The NOAEL was estimated to be 308 mg MgCl2/kg bw/day for males and 299 mg MgCl2/kg bw/day for females. 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 occurs in the natural environment and humans are widely exposed to naturally occurring magnesium carbonate, e.g. via drinking water on a day to day basis. Magnesium carbonate is also a food additive approved by the Council Directive 95/2/EC on food additives (approved as E504). Ingested magnesium and carbonate ions are actively regulated by the body.

The European Commission Scientific Committee on Food has produced a report on the Tolerable Upper Intake Level of Magnesium (SFC, 2001). The report describes the results obtained in a number of studies on magnesium salts and concludes that the derivation of an upper intake level (UL) for magnesium can be based on the evidence of a number of different clinical studies of varying durations. Data include studies on children, pregnant women, hypertensive and cardiac patients as well as adult volunteers. According to the SCF Opinion, 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 only seen at oral Mg doses greater than 2500 mg Mg (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, 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, for NOAEL and LOAEL.

 

Repeat dose dermal toxicity:

Currently, no studies are available that have evaluated the repeated dose dermal toxicity of magnesium carbonate. Magnesium carbonate is an inorganic ionic solid. It is expected to partition strongly to water rather than organic media. While it is not possible to measure or accurately predict an octanol/water partition coefficient for inorganic ionic substances, such a value would be expected to be very low. Electrolytes are also known not to penetrate the skin in any significant quantity. Given the physico-chemical properties of magnesium carbonate, it is not expected that the substance would penetrate the skin in any significant quantity and so would therefore not cause any toxic effects following repeated dermal exposure.

 

Repeat dose inhalation toxicity:

Currently, no studies are available that have evaluated the repeated dose inhalation toxicity of magnesium carbonate. 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.

Justification for classification or non-classification

No systemic toxicological findings could be detected in rats after repeated administration of magnesium chloride hexahydrate by the oral route for a period of 28 days (the study is directly applicable to magnesium carbonate). In a 90 day repeated dose oral feed study in rats, there were no toxic changes in food consumption, organ weights, haematology and biochemistry and histopathological examinations in any treated group. However, 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. According to the SCF Opinion, the most sensitive adverse effect in human studies was diarrhoea but is completely reversible within 1 to 2 days and does not represent a significant health risk in subjects with intact renal function. Therefore, a classification as STOT RE is not justified and no classification is proposed.