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Description of key information

Calcium glucoheptonate is a veterinary and human medicine to correct calcium defficiency conditions.

Calcium glucoheptonate is a veterinary and human medicine to correct calcium defficiency conditions. It is also used as a dietary supplement. The acute oral toxicity of a structurally similar analogue calcium gluconate and its derivatives is very low. Calcium gluconate is generally recognized as safe (GRAS) for a number of food uses and as a nutrient supplement. Another salt of glucoheptonic acid magnesium glucoheptonate was practically non-toxic in rats in mice with LD50 values of 18,170 and 21,260 mg/kg bw, respectively. Oral LD50 values of ca. 2000 mg/kg bw and greater were established for rats and mice in acute oral studies with different types of calcium chloride and calcium sulphate, dyhydrate. Rabbit was the most sensitive specie with LD50 of 500 mg/kg bw established for anhydrous calcium chloride. The toxicity effects were attributed to highly irritating properties of calcium chloride, while LD50 of 500 mg/kg bw was rather due to severe irritation symptoms of stomach, and a systemic LD50 could not be reached. An oral LD50 of 3061 mg/kg bw was calculated for calcium glucoheptonate based on the lowest LD50 of 500 mg/kg bw and 5.9 % total calcium content in the product. In conclusion, no acute hazard by oral route of exposure exists for calcium glucoheptonate.

It is also used as a dietary supplement. The acute oral toxicity of a structurally similar analogue calcium gluconate and its derivatives is very low. Calcium gluconate is generally recognized as safe (GRAS) for a number of food uses and as a nutrient supplement. Another salt of glucoheptonic acid magnesium glucoheptonate was practically non-toxic in rats in mice with LD50 values of 18,170 and 21,260 mg/kg bw, respectively. Oral LD50 values of ca. 2000 mg/kg bw and greater were established for rats and mice in acute oral studies with different types of calcium chloride and calcium sulphate, dyhydrate. Rabbit was the most sensitive specie with LD50 of 500 mg/kg bw established for anhydrous calcium chloride. The toxicity effects were attributed to highly irritating properties of calcium chloride, while LD50 of 500 mg/kg bw was rather due to severe irritation symptoms of stomach, and a systemic LD50 could not be reached. An oral LD50 of 3061 mg/kg bw was calculated for calcium glucoheptonate based on the lowest LD50 of 500 mg/kg bw and 5.9 % total calcium content in the product. In conclusion, no acute hazard by oral route of exposure exists for calcium glucoheptonate.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 061 mg/kg bw
Quality of whole database:
The quality of the whole database is high since numerous studies are available for structurally similar gluconates (Ca and Mg) and their derivatives.

Additional information

There are no animal acute toxicity studies available for calcium glucoheptonate. Since Calcium glucoheptonate is a human and veterinary medicine used to treat hypocalcaemia in humans and animal species, no classical toxicity studies were carried out with calcium glucoheptonate in laboratory animals (EMEA, 1998). Calcium glucoheptonate is of low toxicity in both humans and the target species (EMEA, 1998).

In the following the results of clinical-pharmacological investigations with calcium glucoheptonate in patients with hypocalcaemia are presented. The acute toxicity result of another salt of glucoheptonic acid, magnesium glucoheptonate, have been taken into account since magnesium like calcium is a macroelement and therefore its toxicity range is believed to give a certain indication on the acute oral toxicity of Calcium glucoheptonate. Calcium glucoheptonate is a structurally similar analogue of Calcium gluconate (please refer to read-across statement). Therefore, toxicity studies with gluconates and their derivatives have also been included to the endpoint as well. Since all studies have certain defficiencies (no GLP, no guideline followed, no clear study protocol or data belong to secondary sources), weight-of-evidence approach is considered to be more appropriate.

Acute oral toxicity of glucoheptonates

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).

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.

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.

Acute oral toxicity of magnesium glucoheptonate is reported in a US patent (1962) dealing with methods employing this pharmaceutical. LD50 of 21,260 and 18,170 mg/kg bw were determined for white mouse and rat, respectively.

Acute oral toxicity of gluconates and its derivatives

Gluconate ion differs from glucoheptonate by one carbon increment (HC-OH) and therefore the substances 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).

Calcium gluconate is generally recognized as safe (GRAS) for a number of food uses and as a nutrient supplement to provide a portion of the dietary reference value for calcium (FDA, 2003). 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.

Calcium gluconate is listed in an essential medicine by WHO (2015).

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).

In a most recent acute oral toxicity study, Polycalcium, a mixed composition of Polycan and Calcium lactate-gluconate 1:9 (g/g), was tested in Sprague-Dawely (SD) rats (Kim et al., 2013). Polycan is a purified β-glucan from Aureobasidium pullulans SM-2001, and comprises mostly β-1,3/1,6-glucan and other organic materials, such as amino acids, mono- or di-unsaturated fatty acids (linoleic and linolenic acids), and fibrous polysaccharide. Polycan is known to safe (Lee, 2005, cited in Kim et al., 2013) and authorized functional food material in Korea (No. 2011-02) for bone health and approved Generally Recognized As Safe in USA (GRAS notice No. GRN 000309). But Polycalcium, a mixture of Polycan and calcium lactate-gluconate has not been investigated in the view of toxicology.In order to investigate the toxicity and identify target organs, Polycalcium were once orally administered to female and male SD rats at dose levels of 2000, 1000, 500 and 0 (control) mg/kg body weights. The mortality, changes on body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs and treatment sites based on the recommendation of KFDA Guidelines [2009-116, 2009]. As the results of single oral treatment of Polycalcium, no treatment related mortalities were observed within 14 days after end of treatment up to 2000 mg/kg, the limited dosage of rodents in the both genders. In addition, no Polycalcium treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected. In addition, no specific target or clinical sings were detected in this study.The results obtained in this study suggest that the Polycalcium is non-toxic in rats. The LD50 and approximate LD in rats after single oral dose of Polycalcium were considered over 2000 mg/kg in both female and male, respectively.

Acute oral toxicity of elemental calcium.

Human data

Calcium is an essential nutrient that must be provided by the diet. In 1993, the Scientific Committee for Food (SCF) adopted an opinion on the nutrient and energy intakes for the European Community, in which Population Reference Intakes (PRIs) for calcium for all age groups from 6 months upwards were derived (EFSA, 2015). The SCF (2003, cited in EFSA, 2015) set a Tolerable Upper Intake Level (UL) for calcium based on the evidence of different intervention studies of long duration, some of which were placebo controlled, in which total daily calcium intakes of 2 500 mg from both diet and supplements were tolerated without adverse effects. The UL of 2500 mg/day is valid for calcium from all sources (diet and supplements) for adults, and for pregnant and lactating women.

EFSA estimated dietary intake of calcium from food consumption data from the EFSA Comprehensive European Food Consumption Database (EFSA, 2011b), classified according to the food classification and description system FoodEx2 (EFSA, 2011a). Data from 13 dietary surveys in nine European Union (EU) countries were used. The countries included Finland, France, Germany, Ireland, Italy, Latvia, the Netherlands, Sweden and the UK. The data covered all age groups from infants to adults aged 75 years and older. Based on these data, Population Reference Intake (PRI) of 950 mg/day is established for adults.

Animal data

LD50 values of calcium chloride for mice and rats were determined by administering the substance orally to groups of 15 animals (SIDS, 2002). The LD50 values were determined by the up and down method after 3-day observation period. Although necropsy was not described, the oral LD50 ranged from 3798 (male) and 4179 mg/kg bw (female) in rats to 2045 (male) and 1940 mg/kg bw (female) in mice. The studies on acute oral toxicity in male rabbits were carried out by the method similar to OECD Test Guideline 401 under GLP. Several forms of calcium chloride (anhydrous, di- and hexahydrate powder) were administered orally by gavage to groups of 1 to 5 rabbits at doses of 250 to 2000 mg/kg bw to determine LD50 values. Weight loss in the surviving animals was observed in the first two days after dosing, which was then recovered. Gross post-mortem examination revealed perforation and severe ulceration of the stomach in the dead animals. Old ulcers were also detected in the stomach of some of the surviving animals. In these studies, the acute oral toxicity is attributed to the severe irritating property of the original substance or its high-concentration solutions to the gastrointestinal tract. In humans, however, acute oral toxicity is rare because large single doses induce nausea and vomiting. Hypercalcemia may occur only when there exists other factors that alter calcium homeostasis, such as renal inefficiency and primary hyperthyroidism.

After single oral administration of 2,000 mg /kg bw of calcium sulphate dihydrate to 4 female animals by gavage, the LD50 for rats was determined in accordance with an OECD TG 420, Acute Oral Toxicity-Fixed dose procedure (SIDS, 2003). No dead animals were observed at the limit test exposed to 2,000 mg/kg, so oral LD50 for rats was greater than 2,000 mg/kg bw. There were no specific clinical signs during test period. No abnormal necropsy opinions in relation to administration of calcium sulfate, dihydrate. Rats showed normal body weight gain during test period.

Assessment of acute oral toxicity for Calcium glucoheptonate

If Calcium glucoheptonate were tested in an acute oral toxicity study, administered Calcium glucoheptonate would be dissociated into calcium and glucoheptonate ions in stomach. The absorption, the distribution and the excretion of the ions in animals is regulated separately. Similarly to ADME parameters of gluconates (SIDS, 2004), glucoheptonate ion is expected to be absorbed rapidly, completely metabolised and excreted in the urine (please refer to read-across statement). Based on LD50 of of 21,260 and 18,170 mg/kg bw for mice and rats, respectively, no acute oral toxicity can be attributed to glucoheptonate ion.

Referring to calcium ion, calcium is the most abundant inorganic constituent of all animal species and has an important role in the nutrition of animals and humans (SIDS, 2002). The homeostasis and mechanisms of action of calcium ions are well reviewed in standard textbooks on pharmacology, physiology, biochemistry and nutritional science (SIDS, 2002). In adult humans, the total calcium in the body is approx. 830-1100 g. Ninety-nine percent of the calcium is retained in skeletons. Hormonal systems maintain a relatively constant calcium concentration of about 100 µg/mL in the plasma by controlling the intestinal absorption of dietary calcium, the release of calcium from bones, and renal absorption/excretion. Excess calcium is excreted in the urine via glomerulal filtration. The renal tubules are able to excrete as well as reabsorb calcium. Thus the tubules are able to produce efficiently a net excretion of calcium to achieve homeostasis when abnormally high levels of calcium are ingested. A significant increase in the calcium concentration in plasma will only occur after high calcium intake in conjunction with other disorders that alter calcium homeostasis, such as renal insufficiency and primary hyperthyroidism (SIDS, 2002). Based on animal acute oral toxicity data available for Calcium chloride (SIDS, 2002) and calcium sulphate (SIDS, 2003), the acute toxicity originating from calcium ion is low (average aproximates to around 2000 mg/kg bw). Deaths and other acute toxicity effects observed in animals treated with calcium chloride were attributed to highly irritating properties of different calcium chloride salts, while systemic effects could not be reached. In contrast, no deaths, clinical signs and findings by necropsy were observed in animals treated with 2000 mg/kg bw calcium sulphate dihydrate in an acute oral toxicity study (SIDS, 2003). Since calcium sulphate does not possess irritating properties, it explains such a difference in the effects observed in these studies.

Taking into account the lowest LD50 of 500 mg/kg bw established for anhydrous calcium chloride in a rabbit' study, a corresponding LD50 for calcium glucoheptonate can be calculated:

Molecular weight (MW) of:

- anhydrous calcium chloride is 110.98 g/mol;

- Calcium is 40.08 g/mol;

- Total calcium content in Calcium glucoheptonate: 5.9 %.

Based on molecular weights, 500 mg anhydrous calcium chloride contains 180.6 mg Calcium: (500 x 40.08) / 110.98. If 180.6 mg Calcium were 5.9 %, then the corresponding quantity of Calcium glucoheptonate would be equal to 3061 mg of calcium glucoheptonate: ((180.6 x 100 %) / 5.9 %).

The calculated LD50 of 3061 mg/kg bw for calcium glucoheptonate shows that no risk of acute oral toxicity exists for calcium glucoheptonate.


Justification for selection of acute toxicity – oral endpoint
No study is selected since evaluation of acute oral toxicity of Calcium glucoheptonate is based on weight-of-evidence approach.

Justification for classification or non-classification

Based on the estimated oral LD50 of 3061 mg/kg bw, calcium 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.