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

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented publication which meets basic scientific principles.

Cross-reference

Reason / purpose for cross-reference:

other:

Remarks:

cited information

Reference

There is no skin sensitisation study available for Magnesium glucoheptonate. Since magnesium glucoheptonate is expected to dissociate to magnesium and glucoheptonate ions, medical and scientific literature data on skin sensitisation potential of glucoheptonate ion, its structurally related analogue gluconate, and organic and inorganic magnesium salts and compounds have been taken into account to evaluate skin sensitisation potential of Magnesium glucoheptonate. Additionally, toxicological profile of Calcium glucoheptonate can be considered. Calcium glucoheptonate is used for decades in both human and veterinary medicine for treatment of hypocalcaemia to correct calcium deficiency states (EMEA, 1998; Drop and Cullen, 1980). Similarly, Magnesium glucoheptonate is used as antihypomagnaesemic drug and as a nutritional supplement (Pharmacopoeia, 2015 on drugs.com). There is no maximum residue limit established for both Calcium and Magnesium glucoheptonate in foodstuff of animal origin (Commission Regulation, 2009, No. 37/2010). No cases of delayed contact hypersensitivity associated with glucoheptonates have been found in the literature (Dabeer & Chemservice SA, 2015). Glucoheptonates are widely used as imaging agents in nuclear medicine (please refer to read-across statement). No skin sensitisation or other types of allergic reactions due to the use of glucoheptonates are reported in the publically available scientific literature. Glucoheptonic acid is a structural sugar like analogue of an endogenous substance gluconic acid. Calcium gluconate and gluconic acid have been assessed for their safe use in cosmetics (CIR, 2014). "The 2014 Cosmetic Ingredient Review Expert Panel acknowledged that the group of monosaccharides, disaccharides, and their related Ingredients, including calcium gluconate and gluconic acid, are safe for humans at concentrations as used in cosmetics. Based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers.” Based on this information, no hypersensitivity reactions can be expected for glucoheptonate ion. Referring to skin sensitisation potential of magnesium ion, different organic and inorganic magnesium salts function as bulking agents, buffering agents and pH adjusters, antioxidants and skin conditioning agents in a wide variety of cosmetic formulations. “The Cosmetic Ingredient Review (CIR) Expert Panel reviewed the safety of magnesium sulfate, is being used at concentrations up to 11% and 25% in leave-on and rinse-off products, respectively. The CIR Expert Panel noted that the extensive clinical experience of the Panel, including the results of numerous patch tests, indicates that magnesium salts do not have the potential to induce sensitization. Anhydrous Magnesium sulfate was found to be non-sensitizer when tested up to a concentration of 50 % in the mouse local lymph node assay, according OECD Guideline 429 (CIR, 2014a). The Panel concluded that magnesium sulfate is safe in the present practices of use and concentration in cosmetics” (CIR, 2014a). Magnesium salts of ascorbic acid (Magnesium Ascorbate and Magnesium Ascorbyl Phosphate) (CIR, 2005), Magnesium aspartate (CIR, 2013) and Magnesium citrate (CIR, 2014b) are evaluated to be safe as used in cosmetic products. The Panel concluded that these magnesium salts are not sensitizing in human subjects. Based on this information, no skin sensitizing potential can be attributed to magnesium ion. As additional evidence on the absence of skin sensitising properties of magnesium ion can serve a skin sensitisation study with magnesium alloys used for implants for musculoskeletal surgery (Witte et al., 2008). The magnesium alloys tested as dissolved and solid materials in guinea pigs according to Magnusson-Kligman (OECD 406) test were all negative at challenge exposure. Based on this information no skin sensitisation potential can be expected for Magnesium glucoheptonate. The substance does not need to be classified and labelled as skin sensitizer.

Endpoint conclusion:

no adverse effect observed (not sensitising)

Based on negative results on skin sensitisation available for gluconates and organic and inorganic magnesium compounds, magnesium glucoheptonate does not meet criteria for classification and labelling as skin sensitiser according to European Regulation (EC) No. 1272/2008.

Data source

Reference

Reference Type:

publication

Title:

Comparative Effects of Calcium Chloride and Calcium Gluceptate

Author:

Drop, L.J., Cullen, D.J.

Year:

1980

Bibliographic source:

Br.J. Anaesth. (1980), 52, 501.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Effects of CaCl2 and Ca gluceptate injections on haemodynamic variables and on plasma ionized calcium concentrations were studied in ten patients following abdominal or vascular surgery.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Calcium glucoheptonate

EC Number:

241-203-6

EC Name:

Calcium glucoheptonate

Cas Number:

17140-60-2

Molecular formula:

C7H14O8.1/2Ca

IUPAC Name:

calcium bis(2,3,4,5,6,7-hexahydroxyheptanoate) (non-preferred name)

Test material form:

other: injections

Details on test material:

Name of test material (as cited in study report): Calcium gluceptate
- Molecular formula (if other than submission substance): C14H26CaO16•xH2O
- Molecular weight (if other than submission substance): 490.43 (anhydrous basis)
- Smiles notation (if other than submission substance): C(C(C(C(C(C(C(=O)[O-])O)O)O)O)O)O.C(C(C(C(C(C(C(=O)[O-])O)O)O)O)O)O.[Ca+2] (anhydrous basis)

Test animals

Species:

other: human

Sex:

male/female

Administration / exposure

Route of administration:

intravenous

Vehicle:

not specified

Details on exposure:

Ten patients who required artificial ventilation of the lungs following major abdominal or vascular surgery were studied. The age range was 27-90 yr body weight 48.6-76.9 kg. In each patient, surgery had been completed at least 12 h before the time of study; no blood or blood products had been administered in the preceding 4-h period. During the study period, i.v. fluids were restricted to 25 mL/h. Haemodynamic variables (mean arterial pressure (MAP), mean right atrial pressure (RAP) and heart rate (HR)) were monitored immediately before the calcium infusion and 5, 10, 20 and 30 min following completion
of the calcium infusion. Plasma ionized calcium concentration were measured as well.

Doses:

20 mL containing 18 mg elemental Ca /mL injection during 5 min.

Statistics:

Student's t test was used to test for statistical significance; values are given as mean± SEM.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

other: effective dose

Effect level:

18 other: mg elemental Ca /mL injection of Ca glucoheptonate

Based on:

element

Remarks:

Calcium

Remarks on result:

other: Calcium infusion resulted in a sustained increase in [Ca2+] plasma levels and in mean arterial pressure. No significant changes were recorded in mean right atrial pressure, heart rate or cardiac rhythm.

Any other information on results incl. tables

"Details of the patients are in table I. Mean initial [Ca2+] before each calcium infusion was less than normal (1.12 + 0.03 mmol litre-1) (Drop et al., 1978) and less than predicted by the McLean-Hastings nomogram (McLean and Hastings, 1935) (fig. 1). Calcium infusion resulted in a sustained increase in [Ca2+] (table II) and in mean arterial pressure (table III); changes in these variables were not materially influenced by the choice of calcium preparation. No significant changes were recorded in mean right atrial pressure, heart rate or cardiac rhythm. For the same increase in [Ca2+], [Ca] increased more following calcium gluceptate than after calcium chloride (table II). Other biochemical variables did not change during the periods of observation."

Applicant's summary and conclusion

Conclusions:

The availability of Ca ion is higher after Ca glucoheptonate injections than after CaCl2 injections. Ca plasma concentrations increased more following calcium gluceptate than after calcium chloride injections.

Executive summary:

Calcium chloride and calcium gluceptate were compared in their ability to increase plasma ionized calcium concentrations ([Ca2+]). 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).