Magnesium 2,3,4,5,6,7-Hexahydroxyheptanoate

Endpoint summary

Description of key information

Magnesium glucoheptonate is a medicine used against antihypomagnaesemia and can be administered to patients orally at dose levels of 158-396 mg/kg bw. In old animal studies, LD50 of 21,260 and 18,170 mg/kg bw were reported for white mouse and rat, respectively. To prove the reliability of these values, data on structurally similar calcium and magnesium gluconates were taken into account. Additionally, acute hazard profile of several organic and inorganic magnesium salts and compounds was considered. Calcium glucoheptonate, similarly to magnesium glucoheptonate, is a therapeutic drug against hypocalcaemia in animals and humans and is used as an imaging agent in nuclear medicine. Acute toxicity of gluconates is very low (LD50 > 5000 mg/kg bw) in different species. Moreover, calcium and magnesium gluconates are recognised as safe (GRAS) and are notified as dietary supplements. Thus, no acute toxicity by oral route can be attributed to sugar-like glucoheptonate ion. Acute oral toxicity of elemental magnesium is low. LD50 of greater than 2000 mg/kg bw were reported for several magnesium salts and compounds in various species. Considering the reported rat LD50 of 660 mg/kg bw for element magnesium obtained in an acute study with MAH, and providing that toxicity would depend on excess of magnesium, the corresponding dose of 7238 mg/kg bw could be calculated for magnesium glucoheptonate. In conclusion, LD50 of 21,260 and 18,170 mg/kg bw for mice and rats, respectively, have been considered to be reliable and can be used as key values in this dossier.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented publication.

Principles of method if other than guideline:

Acute toxicity data on magnesium glucoheptonate are presented in the US patent relating to its use as pharmaceutical and for clinical employment in compositions and as a pharmaceutical carrier.

GLP compliance:

no

Species:

other: mouse and rat.

Strain:

not specified

Sex:

not specified

Route of administration:

other: various routes of administration

Vehicle:

not specified

Doses:

No data

No. of animals per sex per dose:

No data

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

21 260 mg/kg bw

Based on:

test mat.

Remarks on result:

other: for white mouse

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

18 170 mg/kg bw

Based on:

test mat.

Remarks on result:

other: for rats

Acute toxicity was studied in the white mouse, the rat, guinea pig, and rabbit. The LD50 was determined for various routes of administration. Since magnesium glucoheptonate was administered also by iv and ip routes to guinea pigs and rabbits, the results are not shown here as these routes of exposure are not relevant.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 values established for mice and rats exceed even 5000 mg/kg bw.
The conclusion on toxicity effects by the author: "Magnesium glucoheptonate has a very low acute tox icity. The chronic toxicity is also remarkably low and, indeed, with prolonged treatment, there is no noticeable toxic effect. Histological examination of animals after prolonged treatment shows normal internal organs. In traperitoneal treatment of pregnant rats during gestation has no effect on the normal birth of normal offspring".

Executive summary:

Acute toxicity data on magnesium glucoheptonate are presented in the US patent relating to its use as a new pharmaceutical. Acute oral toxicity is very low (LD50 of 21,260 and 18, 170 mg/kg bw were determined for white mouse and rat, respectively).

The invention of the patent also relates to a clinical employment of magnesioum glucoheptonate in compositions and as a pharmaceutical carrier. The invention relates also to a method of treating mammalian digestive tracts which comprises administering to said mammal at least 4.0 g. of magnesium glucoheptonate. This magnesium salt can be used as a cholecystokinetic and as a choleretic, as a laxative or purgative or for prophylactic treatment of dyspeptic con ditions tending toward constipation safely without side effects and with a great deal more acceptance by the patients than previous treatments heretofore known.

Magnesium glucoheptonate is now found to be a much more effective material in X-ray examination of gall bladders because it is much more acceptable to patients and is much more easily tolerated by the patient. Magnesium glucoheptonate induces increased bile flow by physiological means alone: contractions of the gall bladder indeed are accompanied by relaxation of the sphincter of Oddi. Further advantage of magnesium glucoheptonate is that it is a pleasant tasting material which, surprisingly, is usable as a laxative or as a purgative, since the drug is endowed with peristaltic exciting activity in proportion to the dose ad ministered. Only at the most severe doses and only occasionally does magnesium glucoheptonate cause any discomfort and then it is only very minor. Magne sium glucoheptonate also brings about an improvement in appetite ‘and a lessening of digestive dif?culties and feel ings of abdominal tension after meals.

The dosage of magnesium glucoheptonate must exceed 4 g. in order to obtain the beneficial therapeutic etfects. Normally, dosages of approximately 7.5 g., twice a day, are used in acute and chronic a?ection of the liver and biliary tracts, in hepatopancreatic dyspepsia and habitual or occasional constipation. The dosage of about 12.5 g. has a laxative effect, whereas a dosage of about 25 g. has a purgative one; in serial X-ray examination of the gall bladder are normally employed about 17.5 to 20 g. of magnesium glucoheptonate. The salt is usually ad ministered as a 50% solution in water. Thus, the usual dosage is either 15 or 50 cc. of a 50% solution.

In summary, the magnesium glucoheptonate has these pharmacological activities: - It induces an emptying of the gall bladder; - It increases the secretion of bile without changing its glycotamocholate concentration; - It relaxes the Oddi’s sphincter; - It increases the enterical peristalsis; - Magnesium glucoheptonate has a very low acute tox icity. The chronic toxicity is also remarkably low and, indeed, with prolonged treatment, there is no noticeable toxic effect. Histological examination of animals after prolonged treatment shows normal internal organs. In traperitoneal treatment of pregnant rats during gestation has no effect on the normal birth of normal offspring.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

18 170 mg/kg bw

Quality of whole database:

The quality of the whole database is high since one literature source on acute oral toxicity of magnesium glucoheptonateare is available and numerous publications are available for structurally similar gluconates (Ca and Mg), their derivatives as well as for magnesium salts and compounds.

Additional information

There is one literature source available for acute oral toxicity of magnesium glucoheptonate which is chosen as key study. The study results are reported in a US Patent (1962) dealing with methods employing magnesium glucoheptonate as pharmaceutical for treating patients with hypomagnesemia. LD50 of 21,260 and 18,170 mg/kg bw were determined for white mouse and rat, respectively. Since the study results are brief and without sufficient details on study conditions, animal state and exposure conditions, information on the acute oral toxicity has been retrieved from supporting studies on calcium glucoheptonate, calcium and magnesium gluconates (structurally similar substances to glucoheptonate; please refer to read-across statement) as well as studies with magnesium salts and compounds. Additionally, information on therapeutic doses of these classes of compounds is considered to prove the reliability of reported LD50 values for magnesium glucoheptonate in the US patent.

Data on therapeutic dosages for magnesium glucoheptonate

Magnesium glucoheptonate is used as antihypomagnaesemic drug and as a nutritional supplement (Pharmacopoeia, 2015 on drugs.com). Tablets containing 500 mg magnesium glucoheptonates (providing 25 mg elemental magnesium) can be taken for prophylaxis. Magnesium glucoheptonate (20 -50 mmol/day equivalent to 9490 -23735 mg/day or 158-396 mg/kg bw, based on molecular weight of 474.7 g/mol (Pharmacopoeia, 2015) and body weight of 60 kg) in divided doses is used by patients when magnesium losses are continuous (Gambling et al., 1988).

Acute oral toxicity of calcium glucoheptonate

Calcium glucoheptonate is reported to be human and veterinary medicine to treat hypocalcaemia in humans and animals species. Therefore no classical toxicity studies were carried out with calcium glucoheptonate in laboratory animals (EMEA, 1998). Calcium salts have been widely used in human pregnancy by way of oral calcium supplementation and no association has been observed between calcium exposure and adverse effects on human reproduction (EMEA, 1998). In humans, the absorption of calcium is increased during pregnancy and lactation. Calcium glucoheptonate is used for decades in both human and veterinary medicine for treatment of hypocalcaemia to correct calcium deficiency states (EMEA, 1998; Martindale, 1982b, cited in Suryanarayanan, 1985; Drop and Cullen, 1980, Mostbeck, 1954). Therefore, no classical toxicity studies were carried out with calcium glucoheptonate in laboratory animals. In human medicine, the normal dose is intended to provide 50 mmol of calcium daily (equivalent to 25 g/day of calcium glucoheptonate). In cases of hypocalcaemia, parenteral administration of 2.25 to 4.5 nmol calcium (equivalent to 1.125 to 2.25 g/day of calcium glucoheptonate) may be given and repeated as necessary (EMEA, 1998). Calcium gluceptate is also used as an antihypermagnesemic drug, as an electrolyte replenisher, and as a nutritional supplement (drugs.com, 2015). Additionally, there is no maximum residue limit established for calcium glucoheptonate in foodstuff of animal origin (Commission Regulation, 2009, No. 37/2010).

Although the following two studies are not classical acute oral toxicity studies in animals, but clinical i.v. studies in patients with hypocalcaemia, they do provide support that the use of calcium glucoheptonate is safe for therapeutic use.

Calcium chloride and calcium gluceptate were compared in their ability to increase plasma ionized calcium concentrations ([Ca2+]) (Drop and Cullen, 1980). To correct a low ionized calcium concentration, each of 10 critically ill patients received both calcium chloride (10 ml of a 10% solution, containing elemental calcium 27 mg/mL) and calcium gluceptate (20 ml, containing elemental calcium 18 mg/mL) over a 5-min period in randomized order approximately 6 h apart. [Ca2+] and haemodynamic variables (mean arterial pressure (MAP), mean right atrial pressure (RAP) and heart rate (HR)) were monitored for a 30-min period following completion of calcium infusion. Infusion of either calcium preparation was associated with similar increases in [Ca2+] (5 min after infusion of calcium chloride: 33 ± 3.1%; calcium gluceptate: 32 + 4.3% (mean + SEM)) and the effects on MAP were similar for each solution (11.1 ± 1.8% and 9.7 + 2.4%, respectively). The availability of Ca ion was however higher after Ca glucoheptonate injections than after CaCl2 injections. Ca plasma concentrations increased more following calcium gluceptate than after calcium chloride injections.

Calcium glucoheptonate (ampoules of 10 mL as 10 % and 20 % solution) was tested in patients for its tolerance, harmlessness of paravenous injection, the monitoring of serum calcium levels and clinical therapeutic success (Mostbeck, 1954). The reason for the testing were several deficiencies known for another calcium salts (calcium chloride, calcium lactobionate, calcium gluconate and calcium lactate) used in therapy of hypocalcaemia. The shortcomings of parenteral injections of the calcium salts used were either poor solubility and stability in water or local irritation (or necrotic reactions). Also, a dynamic of increase and decrease in serum calcium level could be much to be desired. Calcium glucoheptonate has a sufficient calcium content (8 -17 %) and is well soluble (until 75 %) in water. Its stability even at low temperatures is well suitable for injection preparations.

Calcium glucoheptonate was well tolerated in 150 cases of intravenous injections. The injections were accompanied with flushing which were characteristically for all calcium salts and which were more pronounced by 20 % solution than by 10 % solution. By slow injection regime, 2 -3 ampoules coul be injected to a patient without side effects. Chills, increases in body temperature or other pyrogenic reactions were not observed. In contrast to calcium gluconate, which injections were accompanied with a sudden increase and decrease of serum calcium levels, calcium glucoheptonate caused a rapid increase (within 10 min) followed by a slow decrease of serum calcium levels, which did not reach the baseline even 24 hours later. Due to this benefit, to hold a high and long lasting serum calcium levels, a well clinical effect is guaranteed for calcium glucoheptonate.

Similarly to calcium gluconate, calcium glucoheptonate 20 % (0.2 -0.5 cm³) did not produced inflammation reactions when it was injected subcutaneously under the ears of rabbits. Even with random paravenous infiltration on patients, there was no inflammation but only slightly rash decreasing burning.

Calcium glucoheptonate complexed with technetium is used in nuclear medicine as an organ scanning agent (Chi et al., 1978, cited in Suryanarayanan, 1985; please refer also to read-across statement for further references). It is very soluble in water ( Suryanarayanan and Mitchell, 1984) and is particularly useful in the preparation of veterinary products containing a high calcium concentration.

In conclusion, based on these data no acute oral toxicity can be attributed to glucoheptonate anion.

Acute oral toxicity of magnesium and calcium gluconates and its derivatives

Gluconate ion differs from glucoheptonate by one carbon increment (HC-OH) and therefore gluconates and glucoheptonates are believed to be involved in similar metabolic carbohydrate pathways in mammals (please refer to read-across statement). For this reason, acute toxicity data on gluconic acid and its derivatives have been taken into account to assess acute toxicity data of glucoheptonate anion.

Gluconic acid and its derivatives are naturally occurring substances. In mammalian organisms both D-gluconic acid and its 1,5-lactone are important intermediates in the carbohydrate metabolism. Gluconate is a metabolite of glucose oxidation. The daily production of gluconate from endogenous sources is about 450 mg/kg for a 60 kg person (SIDS, 2004; FDA, 2003).

Magnesium gluconate is generally recognized as safe (GRAS) (FDA, 2003a) and notified as a dietary ingredient (supplement) (FDA, 2004).

Calcium gluconate is also GRAS for a number of food uses and as a nutrient supplement to provide a portion of the dietary reference value for calcium (FDA, 2003b). Foods that are intended to be fortified with calcium gluconate may include, but are not limited to, milk, soft drinks, juices, (near) waters, dairy products, soy products, baked goods, and confectionery.

There is also considerable experience with the comparatively low toxicity of gluconate to man and animals. Glucono-delta-lactone and gluconic acid were not toxic to animals and humans when given at very high dose levels (> 2000 mg/kg bw). When three men were given 10 g (167 mg/kg) of glucono-delta-lactone orally as a 10 per cent. solution, the amounts recovered in the urine in 7 hours represented 7.7-15 per cent. of the dose. No pathological urine constituents were noted. When 5 g (84 mg/kg) was given orally none was recovered in the urine. The largest dose given to man was 30 g (500 mg/kg) (Chenoweth et al., 1941, cited in WHO, 1966).The administration for 3-6 days of large oral doses (5-10 g/day) of gluconic acid to five normal humans did not produce any renal changes, as by the absence of blood, protein, casts and sugar in the urine (Chenoweth et al., 1941, cited in WHO, 1966 and WHO, 1999). Oral LD50 for animal species are reported for gluconic acid and its isomer glucono-delta-lactone: 5940, 6800, 7850 and 5600 in rats, mice, rabbits and hamsters, respectively (WHO, 1966; WHO, 1999). In several further acute oral toxicity studies with sodium gluconate, no deaths were observed at any dose level tested in rats and dogs, therefore LD50 values of greater than 2000 were reported for both species (Mochizuki, 1995; Okamoto, 1995; SIDS, 2004). A gavage study with potassium gluconate and rats reported a LD50 of 6060 mg/kg bw (TNO, 1978, cited in SIDS, 2004). LDL0 of 10,000 mg/kg bw is reported for calcium gluconate in rats (RTECS, 1978; Sarabia et al., 1999).

Based on these data, no acute toxicity by oral route of exposure can be associated with glucoheptonate anion.

Acute oral toxicity of elemental magnesium, its salts and compounds.

Since magnesium salts and compounds are believed to dissociate in aquatic environment including gastrointestinal fluid in case of oral ingestion, data on oral toxicity of released magnesium ion can be taken into account to assess acute toxicity hazard.

Human data

Magnesium is an essential nutrient for all living organisms. As a cofactor in numerous enzymatic reactions, magnesium fulfils various intracellular physiological functions (Jahnen-Dechent and Ketteler, 2012, cited in read-across statement). Along with calcium, magnesium is considered a major element in human nutrition, and is one of the four electrolytes along with calcium (Ca), sodium (Na), and potassium (K). Thus, imbalance in magnesium status—primarily hypomagnesaemia as it is seen more often than hypermagnesaemia—might result in unwanted neuromuscular, cardiac or nervous disorders.

Cases of hypermagnesaemia are however more relevant for this REACH dossier. Therefore, information on clinical cases, poisoning incidents, NOAEL, and Upper Tolerated Level have been summarised here.

One of the first cases of accidental poisoning with Mg sulphate was published by Sang in 1891: a 35 years old woman died 75 minutes after drinking 4 ounces of ordinary Epsom salt (about 120 g) dissolved in a tumbler of hot water. This quantity corresponds to 11.8 g elemental magnesium based on Molecular weight of 246.5 g/mol for Epsom salt (magnesium hepathydrate: MgSO4 x 7 H2O). The dose corresponds to 197 mg elemental magnesium /kg bw based on body weight of 60 kg for general population.

The SCF (31st Series, 1993) determined an Acceptable Range of Intake for Adults of 150-500 mg/day (EFSA, 2006).

High doses of magnesium compounds induce laxative effects in humans. 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 Mg is bound to matrices (chelated e.g. to phytic acid, phosphates, chlorophylls or it is included in biological apatities (skeleton) and hence is mostly not easily dissociable. In aqueous solutions, Mg salts (e.g., sulphate, chloride, phosphate, citrate, and carbonate) are mostly dissociated depending on the concentration, pH and temperature. They become also readily dissociable after the reaction with gastric hydrochloric acid. Many magnesium supplements and drugs exert dose-dependent laxative effects. No laxative effects have been observed in adult men and women -also 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).

Except diarrhoea are hypotension, nausea and vomiting, hypoventilation and respiratory depression have been reported at dose levels > 2500 mg/person/day. Tolerable Upper Intake Level of 250 mg/day is derived for humans for readily dissociable magnesium salts and compounds, excluding magnesium from foods and beverages.

Similarly, the United States Institute of Medicine concluded that the tolerable upper level of magnesium to avoid the laxative effects of magnesium in pharmacological agents was 350 mg/day. It stressed that this does not include magnesium in food or water (Institute of Medicine, 1997, cited in WHO, 2012).

Magnesium is naturally occurring constituent of man, animals and plants and it is therefore occur in foodstuffs. It constitutes one of the major electrolytes present in all biological materials. The Committee therefore established a group ADI not specified for those cations (SCF, 1990). No safety problems are likely to arise, provided the contributions from food intake do not disturb the homoeostatic mechanisms controlling the electrolyte balance of the body. Large single doses of magnesium taken in bulk are known to produce diarrhoea particularly in children, and should be avoided. Later, ADIs “not specified” were allocated for majority of magnesium salts and compounds including the group of gluconates (WHO, 2000; WHO, 2007). Additionally, there is no maximum residue limit established for all magnesium compounds listed in foodstuff of animal origin (Commission Regulation, 2009, No. 37/2010).

Animal data

Extensive regulatory toxicology tests on Magnesium-L-Aspartate Hydrochloride (MAH) have proven a high degree of safety (unpublished data): single dose toxicity following oral administration revealed LD50 doses of 6.8, 6.9 and 4.5 g MAH/kg b.w. in rats, mice and dogs, corresponding to (rounded) 660, 670 and 440 mg Mg2+/kg b.w. Mortality was induced by respiratory paralysis due to neuromuscular blockade, as known from other Mg salts (Classen, 2002).

An acute oral toxicity test has been performed with magnesium dihydrogen diphosphate (purity 97.5%), conducted in accordance with good laboratory practice (GLP) according to Organisation for Economic Co-operation and Development (OECD) Test Guideline 423. Three female Balb/c mice were dosed by gavage at the limit dose of 2000 mg/kg bw. There were no deaths and no abnormal clinical signs. Therefore, the oral median lethal dose (LD50) exceeds 2000 mg/kg bw (WHO, 2012).

Assessment of acute oral toxicity for Magnesium glucoheptonate

If acute oral toxicity were due to excess of magnesium, the reported rat LD50 of 660 mg Mg2 +/kg bw (Classen, 2002) would correspond to 7238 mg magnesium glucoheptonate /kg bw (based on molecular weights of 266.6 g/mol and 24.31 g/mol for magnesium glucoheptonate and magnesium, respectively). This value is of the same order of magnitude as reported in an old acute toxicity study for rats (18,170 mg/kg bw) in the abovementioned US patent (1962). As reported by Scientific Committee for Food (SCF, 1991) magnesium originating from foods derived from plant or animal sources does not produce adverse effects in such a range as magnesium from easily dissociable salts and compounds. It is probably due to the binding of magnesium to natural substances in form of chelates.

Providing that magnesium glucoheptonate is a less dissociable substance than inorganic magnesium salts, a lower acute toxicity level reported in the old US patent is explainable.

Justification for classification or non-classification

Based on the oral LD50 of 18,170 mg/kg bw reported for rats, magnesium glucoheptonate does not meet criteria for classification and labelling as acute toxic substance by oral route of exposure according to European Regulation (EC) No. 1272/2008.