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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
distribution
Qualifier:
no guideline followed
Principles of method if other than guideline:
In this study the C14 tracer isotope has been administered by implantation of a pellet of CaC14O3 in the peritoneal cavity and by application of powdered CaC14O3 over the peritoneal viscera of the rat.
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 473 g (expt 1) and 422 g (expt 2)
Route of administration:
intraperitoneal
Vehicle:
other: Pellets of CaCO3 were prepared using gelatin (expt 1)
Details on exposure:
Experiment 1: The rat was given about 0.40 millicuries of C14 by implanting, through an abdominal incision, a pellet of the test material in each of the lower quadrants of the peritoneal cavity.

Experiment 2: About 145 mg of powdered CaC14O3 (0.065 millicurie or 1.3x10^6 counts per minute) was distributed over the peritoneal viscera of the rat.
Duration and frequency of treatment / exposure:
Experiment 1: 6 days

Experiment 2: 40 days
Remarks:
Doses / Concentrations:
Experiment 1: The rat was given about 0.40 millicuries of C14 (8.3 x 10^6 counts per minute).

Experiment 2: The rat was given about 0.065 millicuries of C14 (1.3 x 10^6 counts per minute).
No. of animals per sex per dose / concentration:
One animal was used
Control animals:
not specified
Details on dosing and sampling:
Experiment 1: Collections of excreta and expired air were made, beginning 2 hours after the operation, over the time intervals indicated in Table 1. Six days after the implantation of the pellets the animal was sacrificed by slitting its throat.

The tissues and body fluids sampled were blood, liver (for total C14 determination), muscle glycogen, body and mesenteric fat and proteins from visceral organs, the testes and the central nervous system. After skinning, the carcass was boiled in slightly alkaline water, permitting the bones and teeth and skeletal muscle to be isolated. The pelt was also analysed.

Experiment 2: Collections of expired air were made at intervals over a period of 40 days following the implantation of the CaC14O3. After sacrifice the carcass and pelt were analysed.
Details on absorption:
While dissecting the rat several small particles which apparently consisted of unabsorbed CaC14O3 were found. Their C14 content, present as inorganic carbon was found to be 12.9% of the total administered dose. The fat-free residue from the mesenteric fat depot contained an amount of C14, as inorganic carbon, which accounted for about 20% of the total dose of C14. Therefore, approximately 30% of the administered CaC14O3 remained unabsorbed.
Details on distribution in tissues:
See Table 2

Experiment 1: About 0.75% of the administered dose or about 1.0% of the absorbed dose was retained in the tissues. The C14 recovered in the tissues, excreta and expired air was 108% of the administered amount.

It is apparent that the greatest incorporation of C14 in bone and teeth took place in the inorganic carbonate fraction.
The radioautograph of the kidney shows that the C14 was concentrated in the cortical region.
The greater specific activity of C14 in the enamel of the incisor teeth than in the dentin is probably due to the presence in enamel of a greater amount of inorganic carbon, which has a high uptake of C14, than is present in dentin. No results as to the C14 content of the enamel of molar teeth were obtained because of the poor yields of enamel from these teeth.
In the fat the greater part of the activity resides in the glycerol fraction but a definite incorporation of C14 in the fatty acids took place.
Details on excretion:
See Table 1

Experiment 1: The administration of C14 as pellets of CaC14O3 prolonged the period of elimination of the labelled carbon and resulted in the body fluids having a high and constant C14 specific activity for the 48 hour period preceding the sacrifice.

Experiment 2: The largest amount of the administered C14 was present in the expired air of the rat on the 7th-8th day and no detectable C14 was present in the expired air on the 22nd day following implantation. The C14 retained 40 days after administration was 0.38 ± 0.05% of the total administered dos, 0.21 ± 0.03% being present in the pelt. These results indicate that a large fraction of C14 is excreted even when the isotope is present in the body as an insoluble inorganic compound.
Metabolites identified:
no

The weight of the animal just before being sacrificed was 474 g.

Table 1: Excretion of C14 by mature rat after implantation of CaC14O3in the peritoneal cavity

Time elapsed after administration

% injected dose excreted

Specific activity* x 106

Relative specific activity (long bones = 100)

Expired air

Urine

Faeces

Expired air

Urine

Expired air

Urine

2-21 h

1.09

0.0052

0.00

255

39.0

480

73

21-45 h

3.77

0.0156

0.0047

580

88.5

1100

170

45-69 h

9.42

0.0414

0.0052

1380

212

2600

400

69-93 h

15.4

0.0595

0.0150

2190

283

4100

530

93-117 h

20.8

0.0802

0.0253

2830

374

5300

700

117-141 h

20.9

0.0666

0.0165

2820

388

5300

730

141-142 h

0.80

-

-

2650

-

5000

-

* % of injected dose per mg carbon

 

 

Table 2: Distribution of C14 in tissues and their components after implantation of CaC14O3in the peritoneal cavity

Sample description

% of total administered dose x 103

Specific activity* (SA), x 106

Relative (SA) (long bones = 100)

Long bones (less marrow)

22.0

53.1 ± 0.72

100

Short bones

68.0

49.9 ± 0.54

94

Inorganic CO2(long bones)

-

428 ± 2.5

810

Inorganic CO2(short bones)

-

408 ± 2.4

770

Long bone protein

-

10.6 ± 0.64

20

Short bone protein

-

12.1 ± 0.21

23

Long bone marrow

-

52.0 ± 1.3

98

Molar teeth

0.37 ± 0.10

-

-

Incisor teeth

1.30 ± 0.032

-

-

Molar dentine

-

28.7 ± 0.81

54

Incisor dentine

-

28.1 ± 0.53

53

Inorganic CO2of incisor dentine

-

474 ± 12

890

Incisor enamel

-

54.2 ± 4.0

102

Whole blood**

11.2

16.8 ± 1.1

32

Haemin

-

3.1 ± 0.15

5.8

Red blood cell protein

-

4.06 ± 0.27

7.6

Plasma albumin

-

74.1 ± 0.48

140

Plasma globulin

-

60.6 ± 0.65

110

Liver (intact)

365

48.7 ± 0.54

92

Liver glycogen

-

24.9 ± 0.28

47

Liver fatty acids

-

9.54 ± 0.15

18

Muscle protein

62.9

6.93 ± 0.16

13

Muscle glycogen

-

6.8 ± 0.9

13

Myosin from muscle

-

5.47 ± 0.17

10

Body fat

30.5

1.73 ± 0.11

3.3

Fatty acids from body fat

-

1.27 ± 0.09

2.4

Glycerol from body fat

-

10.1 ± 0.2

19

Fat from viscera

-

2.13 ± 0.068

4.0

Fat from bones & teeth

-

1.70 ± 0.055

3.2

Protein – GI tract

25.3

37.1 ± 0.41

70

Protein – spleen

2.64

34.1 ± 0.34

64

Protein – testicles

3.97

27.5 ± 0.26

52

Protein - kidney

4.79

30.8 ±0.33

58

Protein – lungs

3.28

21.7 ± 0.17

41

Protein – heart

1.72

12.1 ± 0.39

23

Protein – brain & spinal cord

-

6.39 ± 0.17

12

Brain & spinal cord (intact)

1.50

5.24 ± 0.15

9.8

Pelt

130

2.20 ± 0.22

4.1

Debris & pelt remains

34600

-

-

* % of injected dose per mg carbon

** the haemoglobin concentration was 14.9%

Conclusions:
A significant incorporation of C14 was found in the inorganic carbonate fraction of bone and in bone protein, the dentin and enamel of teeth, fatty acids, glycerol, haemin, red cell protein, plasma proteins, central nervous system protein, liver and muscle glycogen, muscle protein and in the proteins of the testes and of the thoracic and abdominal viscera.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted to evaluate the ability of the large intestine to absorb calcium and magnesium from their sparingly water-soluble salts and also to determine whether fructooligosaccharides (FOS) stimulate the absorption of these minerals in rat large intestine in vivo. Rats were fed Ca- and Mg- free diets with and without 5% FOS. An aqueous suspension of CaCO3 and MgO was infused into the stomach via a gastric tube or into the caecum via an implanted catheter.
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Clea Japan, Tokyo, Japan
- Age at study initiation: 4 weeks
- Mean weight at study initiation: 221 - 227 g
- Housing: Individually housed in stainless steel wire mesh cages
- Diet: Stock diet (MF, Oriental Yeast, Tokyo, Japan) available ad libitum
- Water: Deionised water available ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 °C
- Humidity (%): 55 %
Route of administration:
other: Direct implantation into the caecum and the stomach
Details on exposure:
A polyethylene tube was implanted directly into the caecum of each rat.
All rats were fed the Ca and Mg free diet. Two groups were subsequently fed a fructooligosaccharide (FOS) free diet (control diet) and the other two groups were fed a FOS-containing diet (50 g/kg diet). In half of the rats from each diet group, 0.3 mL of the suspension of CaCO3 and MgO, which contained 930 µmol of Ca and 136 µmol of Mg, was infused into the caecum via the implanted tube. In the remaining rats from each group, the same suspension was infused into the stomach by intubation. The suspension was infused twice per day (9:00 and 18:00) for 10 days. For the last 7 days, the rats were subjected to a Ca and Mg balance study and all faeces and urine were collected.
No. of animals per sex per dose / concentration:
7 animals/group
Control animals:
yes
Details on dosing and sampling:
The amounts of Ca, Mg and P in the diet, infusion, faeces, urine and femur of each rat were determined.
Details on absorption:
Ca BALANCE:
The apparent absorption of Ca infused into the stomach was higher than that absorbed into the caecum. FOS feeding increased the apparent absorption and retention of Ca irrespective of the infusion route. The apparent absorption and retention of Ca increased in the case of infusion into the stomach in the FOS fed groups.

Mg BALANCE:
The apparent absorption of Mg into the caecum in rats was equivalent to the Ca and Mg infusion into the stomach for both the control and FOS-feeding groups. FOS feeding increased the apparent absorption of Mg irrespective of the infusion route. However, the retention of Mg did not significantly differ among all of the groups.

P BALANCE:
The apparent absorption of P was higher in rats with Ca and Mg infusion into the caecum than in rats with Ca and Mg infusion into the stomach. On the other hand, the retention of P was lower in rats with Ca and Mg infusion into the caecum than in rats with Ca and Mg infusion into the stomach. The apparent absorption of P was decreased by FOS feeding.

APPARENT ABSORPTION EFFICIENCY OF Ca, Mg AND P:
The apparent absorption ratio of Ca in FOS fed rats with Ca and Mg infusion into the stomach was higher than in the other 3 groups. The apparent absorption ratio of Ca did not differ among these 3 groups. Regardless of FOS feeding, the apparent absorption efficiency of Mg infused into the caecum was similar to that of Mg infused into the stomach. The apparent absorption efficiency of P was higher in the case of infusion in the caecum than in infusion in the stomach.

RETENTION EFFICIENCY OF Ca, Mg AND P:
The retention ratio of Ca in FOS fed rats with Ca and Mg infusion into the stomach was higher than in the other 3 groups. The retention efficiency of Ca did not differ among these 3 groups. The retention efficiency of Mg was similar among all of the 3 groups. The retention efficiency of P was decreased by FOS feeding, being lower in rats with Ca and Mg infusion into the caecum than in rats with Ca and Mg infusion into the stomach.

Ca, Mg and P CONTENTS IN SERUM AND FEMUR:
The serum concentration of Ca in the FOS fed groups was higher when Ca was infused into the stomach than when Ca was infused into the caecum. The dry and ash weights of femur samples and the serum concentrations of Mg and P did not differ among the groups. The P content of the femur samples in the FOS fed groups with Ca and Mg infusion into the caecum was lower than that in the other 3 groups.

pH AND WEIGHT OF CAECAL CONTENTS:
The pH of the caecal contents was decreased by FOS feeding while the weight of the caecal contents was increased by FOS feeding.

The initial and final body weights did not significantly differ between the groups. FOS feeding decreased food intake.

Conclusions:
The large intestine has the ability to absorb large amounts of Ca and Mg from CaCO3 and MgO, which are respectively very sparingly soluble in water and suggest that the stimulatory effect of FOS on the absorption of Mg takes place mainly in the large intestine.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
other: Bioavailability
Principles of method if other than guideline:
The study examined whether the bioavailability of calcium carbonate and calcium citrate could be improved by reducing the particle size. The study characterised the size distribution and morphology of nano calcium carbonate and nano calcium citrate. Because nanoscale supplements are novel formulas in health foods, the acute toxicity (see separate IUCLID entry), sub-chronic toxicity (see separate IUCLID entry) and bioavailability needs to be determined in both sexes of mice in advance. The anti-osteoporosis activity was demonstrated by an ovariectomised (OVX) mice model. A bilateral OVX ICR mouse model was utilised to mimic the condition in postmenopausal women. Bone mineral density (BMD) was examined after administering nano calcium carbonate and nano calcium citrate, respectively.
GLP compliance:
no
Radiolabelling:
no
Species:
mouse
Strain:
ICR
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: National Taiwan University Hospital, Taipei, Taiwan
- Age at study initiation: 8-10 weeks
- Diet: Pelleted mouse feed available ad libitum
- Water: Reverse osmosis water available ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25 °C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 h/12 h day/night cycle


Sham surgery (n = 6, SHAM) or bilateral ovariectomy (n = 30, OVX) was performed from a dorsal approach at 6 to 8 week old mice. Surgical removal of the ovaries is a well-represented approach to mimic the postmenopausal condition in mice. In the sham operation, ovaries were exteriorised and then replaced.
Route of administration:
oral: gavage
Duration and frequency of treatment / exposure:
Daily for 28 days
Remarks:
Doses / Concentrations:
Micro calcium carbonate: 1.3 g/kg bw
Nano calcium carbonate: 1.3 g/kg bw

Vitamin D3 was also administered by gavage along with the test materials at a concentration of 261 U/kg bw.
No. of animals per sex per dose / concentration:
At 2 months post ovariectomy, the OVX group of mice were randomly divided into groups of 6 animals.
Control animals:
yes, sham-exposed
Details on study design:
Biofunctionality of nano calcium carbonate on OVX ICR mice:
The test materials plus vitamin D3 were administered every day by gavage to the groups of mice for 28 days.

In vivo evaluation of serum calcium:
Female mice were randomly divided into groups of 24 animals (n = 6 in each group). Vitamin D3 (261 U/kg bw) plus micro calcium carbonate or nano calcium carbonate was administered by gavage to groups of mice at a dose of 1.3 g/kg bw.
Details on dosing and sampling:
Biofunctionality of nano calcium carbonate on OVX ICR mice:
The BMD of the whole body was analysed by dual-energy x-ray absorptiometry (pDEXA).

In vivo evaluation of serum calcium:
After 2, 6, 12 and 24 hours, blood sample were collected from the inferior vena cava of each mouse before autopsy. Serum calcium ion concentration was estimated using analysis kits.
Statistics:
Data were analysed statistically using ANOVA followed by the least-significant difference multiple comparison test to establish the significance of any differences. The level of statistical significance was set at p<0.05.

Serum calcium concentration:

Serum calcium concentrations were significantly higher in the nano calcium carbonate group than in the micro calcium carbonate group at 6 h post-administration and tended to be higher at 2 h post-administration. The nano calcium carbonate thus exhibited a higher efficacy than the microsized equivalent form.

The primary site of calcium absorption is the small intestine, where some 90% of calcium is absorbed. Serum calcium concentration is up-regulated following administration of nano calcium carbonate, especially at 6 and 12 h post-administration.

BMD of the whole body:

The BMD of the whole body in OVX mice was significantly lower than in SHAM mice.

The BMD value of the whole body in the micro and nano calcium carbonate treated OVX mice was greater than in the placebo treated OVX mice.

The BMD of the nano calcium carbonate treated OVX mice was significantly higher than in the micro calcium carbonate treated OVX mice.

Oestrogen enhances active calcium absorption; therefore, the BMD of OVX mice was significantly attenuated compared to the SHAM mice.

Conclusions:
Administration of nano calcium carbonate to OVX mice was more effective at inducing calcium uptake (as shown by increased serum calcium concentrations) and maintained their BMD. These data suggest that nano calcium carbonate is more bioavailable than the micro form.
Thus, nano calcium carbonate is a potential and convenient calcium supplement.

Description of key information

No toxicokinetic studies exist, therefore an assessment of basic toxicokinetics has been made based on the available data.

Key value for chemical safety assessment

Additional information

Calcium levels in the body are regulated by homeostatic processes. These homeostatic processes are able to deal with moderate increases in calcium intake: either by storage in bone or by excretion via urine, faeces or sweat. Therefore, calcium and calcium carbonate are not toxic to humans but are essential elements to life and serious disorders, such as retarded skeletal growth may result from calcium deficiency.

Discussion on bioaccumulation potential result:

Calcium carbonate is an odourless, tasteless solid. It exists in nature as the minerals aragonite and calcite.

Calcium is an essential element to all life forms and ecosystems and is naturally occurring in the environment and many foods. Calcium carbonate has many different industrial and chemical uses, is used as a food additive (E170) and has also been extensively used therapeutically as one form of gastric antacids.

 

Absorption

No partition coefficient value was determined for calcium carbonate as it is an inorganic substance. Because of this ionic nature the passive passage across biological membranes will be negligible. However, as calcium is a key element in various cellular processes their import and export over cell membranes is regulated via pore systems.

The balance of calcium carbonate metabolism is tightly regulated by the hormones parathormone, calcitriol (vitamin D) and calcitonin. Uptake of calcium in the intestine is mediated mainly by specific transmembrane transport proteins. Nevertheless other mechanisms like passive diffusion or pinocytosis may also contribute to some extent to absorption of the ion.

Typical intestinal uptakes for calcium from the diet are approximately 800 mg/person/day (European Commission Scientific Committee on Food, 2003).

Absorption of calcium from the gut is generally thought to occur by two processes:

1.        Active Transport: In the duodenum and upper jejunum where soluble calcium is absorbed against an electrochemical gradient. The process is saturable and regulated by dietary intake and the needs of the body. Active transport involves three stages, namely entry across the brush border of the enterocyte via calcium channels and membrane-binding transport proteins, diffusion across the cytoplasm attached to calcium binding protein calbindin-D9K, and secretion across the basolateral membrane into the extracellular fluid against an electrochemical gradient either in exchange for sodium or via a calcium pump. Active transport is negatively correlated with dietary calcium intake and is mediated via parathyroid hormone.

2.        Passive Diffusion: Diffusion takes place down an electrochemical gradient together with water, sodium and glucosevia intercellular junctions or spaces, occurs in all parts of the gut and is predominantly dependent on the calcium concentration in the gut lumen. The calcium needs to be in a soluble form for this to happen. Increases in the osmolarity of the luminal contents of the intestine stimulate passive diffusion. Except in premature infants passive calcium absorption accounts for not more than 8 to 23% of the total calcium absorbed.

Calcium carbonate has been widely used as an antacid and therefore there is sufficient data in animals and man to show the toxicokinetic profile and potential hazards.

Upon oral ingestion, calcium carbonate dissolves slowly in the stomach. It reacts with gastric hydrochloric acid to produce calcium chloride, carbon dioxide and water (Committee on Updating of Occupational Exposure Limits, 2003). The calcium chloride (90%) is converted into insoluble calcium salts and is not absorbed. The remaining soluble fraction is available for absorption from the intestines via the two mechanisms described above.

In acute oral (Bradshaw, 2008), dermal (Bradshaw, 2010) and inhalation (Schuler D, 2010) studies with calcium carbonate, no mortalities were observed in the observation periods and there were no clinical signs of systemic toxicity (with the exception of ruffled fur observed in all animals from the end of inhalation exposure up to test day 4) or macroscopic effects noted at necropsy. The LD50 values were therefore >2000 mg/kg bw, >2000 mg/kg bw and >3 mg/L air (the highest technically achievable concentration), for oral, dermal and inhalation exposures, respectively and demonstrate that calcium carbonate is not acutely toxic.

A sub-acute repeat dose oral toxicity study combined with a reproduction/ developmental toxicity screening test was performed in the rat in accordance with OECD TG 422 (Dunster, 2010). Calcium carbonate (nano) was administered by gavage to male and female Wistar rats, for up to forty-eight consecutive days (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 0, 100, 300 and 1000 mg/kg bodyweight/day. Although administration of the test material resulted in treatment-related effects at all dose levels, these effects were considered not to represent an adverse effect of treatment. Hence, the NOAEL for systemic toxicity was considered to be 1000 mg/kg bodyweight/day (the highest dose tested) and calcium carbonate is not considered to be toxic to rats following repeated exposure for up to 48 days.A 90 day repeat dose oral toxicity study was performed in the rat in accordance with OECD TG 408 (Sung et al, 2014). Nanocalcium carbonate was administered by gavage to male and female Sprague-Dawley rats, for 90 consecutive days, at dose levels of 0, 250, 500 and 1000 mg/kg bodyweight/day. Administration of the test material resulted in no treatment-related effects at all dose levels and no changes in blood calcium levels. Hence, the NOAEL for systemic toxicity was considered to be 1000 mg/kg bodyweight/day (the highest dose tested) and nanocalcium carbonate is not considered to be toxic to rats following repeated exposure for up to 90 days. Oral dosing of nanocalcium carbonate at 1000 mg/kg bw/day for 90 -days is considered not to affect measured levels of calcium in the blood.

Although calcium carbonate has the potential to be inhaled due to its particle size distribution it doesn’t exhibit acute inhalation toxicity in the rat. However, its nature as a physiological substance will probably lead to some absorption via the respiratory tract. Non-resorbed particles in the oral cavity, the thorax and the lungs will be transferred to the gastro-intestinal tract with the mucus and absorbed there. Therefore, absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled. A 90-day inhalation study on calcium carbonate (nano) using dose levels of 0.26, 0.123, 0.212 and 0.399 mg/L provided a NOAEC of 0.212 mg/L. However, systemic toxicity effects were not observed and the effects on the animals were limited to local irritation and organ weight changes in the lungs. There was no evidence in the clinical chemistry parameters of a significant absorbtion of calcium carbonate (nano).

Absorption via the dermal route is expected to be very low based on the inorganic nature of calcium carbonate; hence, the lack of dermal toxicity seen in the study.

Furthermore, there was no systemic toxicity observed in the skin and eye irritation studies performed with calcium carbonate (Sanders, 2004) indicating that either the systemic absorption and/or the toxicity of calcium carbonate are low.

Because of the increased levels of unabsorbed insoluble calcium salts in the gut following high dose calcium carbonate administration, side effects include constipation. In addition, the breakdown of carbonate to carbon dioxide can result in flatulence.

It is generally the elevation of calcium levels that can be of concern if high doses are given over a prolonged period. Supplementation of animal diets with up to five times the daily requirement of calcium may not necessarily increase calcium concentrations in tissues and plasma in animals. This suggests that the body is capable of dealing with moderate increases. It is apparent that it is the overload of calcium via calcium carbonate as a therapeutic agent that may induce effects as a consequence of hypercalcaemia. However, these effects are more prevalent in those people suffering from renal insufficiency.

The primary effects of excess calcium are:

1.        Milk-alkali Syndrome: Characterised by metabolic alkalosis and hypercalcaemia. The effects seen include weight loss, nausea, polyuria, dehydration and eventually renal failure.

2.        Nephrocalcinosis:calcium excretion via the kidney involves glomerular filtration and tubular reabsorption: both passive and active. In situations of hypercalcaemia, the presence of excess calcium in the kidney upsets the normal homeostatic processes. There is an impairment in normal renal function including normal clearance of materials such as creatinine. As a further consequence, phosphate retention increases resulting in the precipitation of both calcium and phosphate in renal tubules.

3.        Interactions with other minerals: Elevations in calcium levels are known to interfere with other minerals including iron, phosphorus, magnesium and zinc. It has been noted that these negative interactions (including inhibition of absorption) only present a problem when there is a dietary insufficiency.

 

Distribution

Following absorption, the calcium ions are distributed in the serum and then throughout the body. The majority of calcium is stored in the skeleton.

Calcium, as a bulk metal is found in a variety of proteins and enzymes and is important in the transmission of signals in nerves. At the cellular level, metal ions, such as calcium are used in biology in communication roles to trigger cellular responses.

At the macroscopic level, solid calcium compounds also play a structural role as a major component of bones, teeth and shells.

As calcium ions are indispensable to life their distribution is tightly regulated systemically as well as intra-cellular.

 

Metabolism

Calcium ions are inorganic and stable to reduction or oxidation in biological systems. Calcium carbonate plays a wide variety of roles in biological processes, for example acting as a catalytic site for reactions and or transferring atoms or groups to catalytic sites. Calcium is also complexed to important biological molecules such as calmodulin, calbindin.

 

Excretion

Assuming homeostasis of this indispensable nutrient, the same amount is excreted as taken up. Calcium is generally excreted mainly via kidneys but also via faeces and sweat. 

 

Overview

In general, calcium levels in the body are regulated by homeostatic processes. These homeostatic processes are able to deal with moderate increases in calcium intake: either by storage in bone or by excretion via urine, faeces or sweat. Therefore, calcium and calcium carbonate are not toxic to humans but are essential elements to life and serious disorders, such as retarded skeletal growth may result from calcium deficiency.

 

References:

European Commission Scientific Committee on Food (2003), Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Calcium, SCF/CS/NUT/UPPLEV/64 Final, 23 April 2003.

Committee on Updating of Occupational Exposure Limits, a committee of the Health Council of the(2003), Calcium Carbonate (CAS No.: 471-34-1): Health Based Reassessment of Administrative Occupational Exposure Limits, No. 2000/15OSH/061, The Hague, 3 March 2003

Bradshaw J (2008), Calcium carbonate: Acute oral toxicity in the rat - fixed dose method, Harlan Laboratories Ltd, Report No. 1992/0009

Bradshaw J (2010), Calcium carbonate (nano): Acute Dermal Toxicity (Limit Test) in the Rat, Harlan Laboratories Ltd, Report No. 2974/0004

Schuler D (2010), Calcium carbonate (CAS: 471-34-1): 4-Hour Acute Inhalation Toxicity Study in the Rat, Harlan Laboratories Ltd., Report No. C73872

Dunster J (2010), Calcium carbonate (nano): Oral Gavage Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat,Harlan Laboratories Ltd., Report No. 2974/0010

van Triel JJ (2015), Sub-chronic (13 -week) inhalation (nose-only) toxicity study with Calcium carbonate (nano) in rats, TNO Triskelion, Report No. V20497/02

Sanders A (2004), PCC: Acute Dermal Irritation in the Rabbit, Safepharm Laboratories Ltd, Report No. 1992/005

Sanders A (2004), PCC: Acute Eye Irritation in the Rabbit, Safepharm Laboratories Ltd, Report No. 1992/006