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Description of key information

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Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Due to their ubiquitous occurrence in the environment and their function as essential minerals for human nutrition (see also technical dossier section 7.10), calcium and magnesium are among the most extensively investigated elements with respect to physiological behaviour.

In the human body calcium serves as a structural element in bone. It is the fifth most abundant element by mass in the human body (1.5 %). Calcium is a common cellular ionic messenger with a broad range of functions. Further functions of calcium include, e.g., involvement in neurotransmitter release, and in muscle contraction. Also magnesium is involved in bone formation; its predominant function is as a cofactor in several hundred enzymatic reactions.

The focus of toxicokinetics, metabolism and distribution for calcium magnesium carbonate oxide (calcined dolomite) is on calcium and magnesium since in aqueous media calcined dolomite dissociates resulting in the formation of calcium and magnesium cations, and (hydrogen) carbonate and hydroxyl anions. Dissociation in water is accompanied by generation of heat.

Neither the alkaline reaction nor the generation of heat is of concern regarding systemic effects. Carbonate is either released as carbon dioxide (acid media, e.g. in the stomach). In neutral or basic media the solubility of calcined dolomite is very limited, so that free carbonate is quantitatively not available. Thus, only calcium (Ca2+) and magnesium (Mg2+) are considered in the current section. The key conclusion for this section is that both calcium and magnesium, as essential mineral nutrients underlie homoeostatic regulation and therefore cannot be considered as xenobiotics.

Absorption

Oral

Calcium
From dietary supplements such as calcium carbonate, calcium acetate, calcium lactate, calcium citrate, or calcium gluconate, net absorption amounts to 30 %. The oral absorption rate is independent of the solubility of the calcium salt and is therefore applicable to calcium contained in calcined dolomite.

Magnesium

Absorption is negatively correlated with luminal Mg concentration, varying between approximately 11 and 80 %. The typical intestinal absorption rate from dietary and soluble sources at magnesium balance is given as 30 - 40 %. Absorption of magnesium is - unlike calcium - dependent on the solubility of the substance. For calcined dolomite, containing magnesium as poorly soluble MgO, absorption of magnesium is proposed to amount to 15 %.

Dermal

Calcium and magnesium
Following an approach consistent with the methodology proposed in the HERAG guidance for metals (Anonymous, 2007: HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH, Hannover, Germany; August 2007), the following default dermal absorption factors for metal cations are proposed (reflective of full-shift exposure, i.e. 8 hours) for calcium present in calcined dolomite:

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %

In view of (1) the physiological role of calcium and magnesium as essential minerals and (2) the fact that any effects of calcined dolomite upon dermal exposure are characterised as local irritation (pH effect), dermal absorption of calcium and magnesium from calcined dolomite is proposed to be insignificant.

Dermal absorption of calcium from calcined dolomite is therefore considered to be negligible.

Dermal absorption of magnesium from calcined dolomite is therefore considered to be negligible.

Inhalation
Calcium and magnesium

Calcined dolomite technical material is supplied as a powder (or coarse grained material), from which airborne particles may be generated during handling.

The estimates for inhalation absorption are composed of 100 % absorption for material deposited in the pulmonary region, plus material deposited in the tracheobronchial and the head region (transported to the pharynx and swallowed), corrected for intestinal absorption (30 % for Ca, 15 % for Mg). As a result, total inhalation absorption is

 

Calcium

Magnesium

Calcium magnesium carbonate oxide (powder ≤ 2 mm)

13.6 %

6.81 %

Calcium magnesium carbonate oxide (coarse grained material)

17.5 %

8.95 %

Excretion

Calcium

Absorbed calcium is predominantly excreted via urine, and to a minor degree via faeces and sweat. Renal calcium excretion is the result of glomerular filtration (about 8 to 10 g calcium per day in adults) and tubular re-absorption (passive and active). Average 24 -hour excretion of calcium amounts to 40 mg in young children, 80 mg in prepubertal children and reaches about 150-200 mg in adults, largely independent of dietary calcium intake in healthy persons.

Magnesium

Absorbed magnesium is predominantly excreted via urine; the kidney plays an important role in homoeostatic regulation of the magnesium balance, by active re-absorption of magnesium taking place in Henle's loop. Renal excretion is the key mechanism for maintaining magnesium homoeostasis: the excretion rate varies according to magnesium supply and concentration in body fluids, thereby regulating systemic magnesium levels.

Distribution

Calcium

The physiological importance of calcium has been extensively evaluated by the Scientific Committee on Food (SCF) as follows:

Over 99 % of the total calcium of the body is located in the bones, where it accounts for 39 % of the total body bone mineral content, and in the teeth, mostly as hydroxyapatite. Bone mineral provides structure and strength to the body and, very important, a reservoir of calcium that helps to maintain a constant concentration of blood calcium. Less than 1 % of total body calcium is found in soft tissues (~7 g) and body fluids (~1 g). Calcium in the extracellular fluid and the blood are kept constant at 2.5 mmol/L (10 mg/dL) (between 2.25 and 2.75 mmol/L) via cell surface calcium-sensing receptors in parathyroid, kidney, intestine, lung, brain, skin, bone marrow, osteoblasts and other organs. Calcium is present in blood in three different forms: as free Ca2+ ions, bound to protein (about 45 %), and complexed to citrate, phosphate, sulphate and carbonate (about 10 %). Ionised calcium is kept within narrow limits by the action of three hormones, parathyroid hormone, 1,25-dihydroxycholecalciferol, and calcitonin. Extracellular calcium serves as a source for the skeleton and participates in blood clotting and intercellular adhesion. Intracellular calcium varies widely between tissues and is predominantly bound to intracellular membrane structures of the nucleus, mitochondria, endoplasmatic reticulum or contained in special storage vesicles. Free Ca2+is only 0.1 μmol/L in the cytosol, which is 25,000 times lower than in the extracellular fluid (2.5 mmol/L). Intracellular calcium rises in response to stimuli interacting with the cell surface receptor. The increase of intracellular calcium comes from influx of extracellular calcium or from release of intracellular calcium stores. This activates specific responses like hormone or neurotransmitter release, muscle contraction, cellular differentiation and many others.

Therefore, due to its function as an essential element, distribution of calcium is actively regulated according to the body's requirements. Calcium levels in the body are subject to homoeostasis.

Magnesium

An extensive evaluation by the SCF is also available for magnesium, upon which the following conclusion is primarily based:

Magnesium is an essential mineral nutrient. The adult human body contains approximately 25 g magnesium. Thirty to forty per cent of the body's magnesium stores are found in muscles and soft tissues, 1 % in extracellular fluid, and the remainder in the skeleton, making up approximately 1 % of bone ash. In soft tissues magnesium functions as a co-factor of many enzymes involved in energy metabolism, protein synthesis, RNA and DNA synthesis, and maintenance of the electrical potential of nervous tissues and cell membranes. Magnesium levels in the body are subject to homoeostasis, regulated via the rate of renal excretion (see above).

Discussion on bioaccumulation potential result:

Toxicokinetic behaviour of calcium and magnesium is assessed utilising mostly publications focusing on the nutritional and physiological role of calcium and magnesium. First and foremost, however, secondary literature in the form of official evaluation documents by EU bodies (e.g. EFSA) is extensively referred to. Much of this information consists of human data. This approach therefore follows the provisions of Annex XI, points 1.1.3 and 1.2 of Commission Regulation No 1907/2006, specifying general rules for adaptation of the standard testing regime.

Biological function and essentiality of calcium:

In humans, calcium is an essential mineral nutrient, with daily requirements ranging between 400 mg for infants, up to 1200 mg for pregnant women, as assessed by the Scientific Committee on Food. Calcium serves as a structural element in bone and tooth formation (mainly as hydroxyapatite) and is furthermore involved in a broad range of physiological processes: It plays a central role in blood coagulation, is involved in cell adhesion, hormone and neurotransmitter release, muscle contraction, cellular differentiation, several intracellular signalling pathways, and many others.

Biological function and essentiality of magnesium:

Magnesium is an essential mineral nutrient; however, definitive recommendations for daily requirements have not yet been established by the Scientific Committee on Food. Magnesium is included in bone where it serves as a structural element, mainly as a surface constituent of hydroxyapatite together with calcium. Most importantly, it is functioning as a cofactor in hundreds of enzymatic reactions particularly in energy metabolism, and beyond this, it is involved with protein and nucleic acid synthesis, maintenance of the electrical potential of the nervous system and cell membranes, hormone and neurotransmitter release, muscle contraction, cellular differentiation and many others.

Biological significance of the hydroxyl and carbonate ions:

The anionic counter ions released from calcium magnesium carbonate oxide (calcined dolomite) are the carbonate and the hydroxyl ion. Both ions are elements of the body's acid-base system. Carbonate is involved in the buffering system of body fluids, first and foremost the blood. However, any systemic uptake of carbonate from calcined dolomite is not foreseen: If ingested, carbonate will be released as carbon dioxide in the acid environment of the stomach; in neutral and basic media, however, calcined dolomite is only poorly soluble; systemic uptake via the skin or if inhaled is therefore not relevant for carbonate. Also hydroxyl ions are not relevant in terms of toxicokinetics: If calcined dolomite is ingested, hydroxyl ions will be neutralised by gastric juice. Upon either inhalation exposure or deposition on the skin, hydroxyl ions released from calcined dolomite may lead to irritation of the skin or the respiratory tract, depending on the amount of substance dissolved, due to a pH effect. This is a local effect and therefore need not be considered further in the assessment of toxicokinetics and metabolism.

Oral absorption of calcium:

Calcium must be present in a soluble form, generally ionised, at least in the upper small intestine or bound to or complexed by a soluble organic molecule before it can cross the wall of the intestine. Absorption in the intestine is the result of two processes: (1) Active transport across membranes in the duodenum and the upper jejunum, which is regulated depending on 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-bound transport proteins, diffusion across the cytoplasma attached to the 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, a Ca-ATPase activated by calbindin, calcium and calmodulin. Active transport is negatively correlated with dietary calcium intake. This control is mediated via parathyroid hormone and 1,25(OH)2D. The renal production of 1,25(OH)2D is stimulated by increased parathyroid hormone secretion in response to a decrease of Ca2+in blood. Furthermore, it stimulates the expression of the gene encoding calbindin, thereby enhancing calcium absorption in the intestine. Both parathyroid hormone and 1,25(OH)2D also increase renal re-absorption of calcium and bone resorption. (2) Passive diffusion occurs throughout the small intestine, but mainly in the ileum and very little in the large intestine. On average, calcium is absorbed in the intestine by approximately 30 %.

Most retained calcium is stored in the skeleton (99 % of the body’s calcium), depending on its needs. The main factors affecting the efficiency of calcium storage in bone are not dietary; they are physiological, related to growth, pregnancy and lactation, for example. Deposition and resorption of bone are regulated by several hormones.

Oral absorption of magnesium:

From dietary sources, magnesium is absorbed in the intestine by, on average, 30–40 % (SCF opinion). However, absorption rates of magnesium from soluble sources are highly variable, ranging between 11 and 80 %, depending on the dose (Fine, 1991; Danielson, 1979; Spencer, 1980; Roth, 1979; Graham, 1960; Schwartz, 1978). Overall, an absorption rate of approximately 50 % from soluble magnesium salts is proposed as a reliable estimate. The mechanism appears to involve both passive diffusion and either an active transport system or facilitated diffusion (SCF opinion; Roth, 1979). Magnesium turnover varies by age, growth status, physical activity, pregnancy-lactation, fluid consumption, stress exposure, drugs and diseases. The magnesium balance is regulated by homoeostasis, allowing adaptation to a wide range of magnesium intakes. In calcined dolomite, magnesium is present as the oxide, which is only poorly soluble.

For assessment of oral absorption from calcined dolomite, the information referred to above is therefore less relevant. Intestinal absorption of magnesium from MgO has been investigated in comparison to more soluble salts by Firoz and Graber (2001). Fractional absorption of magnesium from MgO was estimated at 4 %. However, this appears to be a biased estimate in view of (1) the high variation among individual values and (2) the finding of only 9-11 % absorption from the soluble salts magnesium chloride, acetate, and aspartate, at physiological doses. However, the 4 % figure for MgO represents approximately 30-40 % of those for the more soluble salts, which appears plausible. For assessment of magnesium of absorption from calcined dolomite, a value of 15 % is therefore proposed, corresponding to approximately 1/3 of the 50 % figure for dietary and soluble magnesium.

Inhalation absorption:

Systemic availability of calcium and magnesium from calcined dolomite is a function of regional deposition in the respiratory tract, depending on the particle size of airborne dust. Dust may be released to air under practically relevant workplace conditions, for example during manual operations such as filling and emptying of bags, or during mechanical agitation as in mixing and weighing operations.

The particle size distribution of the airborne fraction during mechanical agitation in a rotating drum was determined according to the modified Heubach method (see section 4.5 of the technical dossier). The relative density of calcined dolomite powder was measured according to OECD 109 (gas pycnometer method; section 4.4 of the technical dossier). From these data, the mass median aerodynamic diameter (MMAD) as well as the relevant parameter for predicting airway deposition of particulate matter was estimated as follows (also see section 4.5 of the technical dossier):

Calcium magnesium carbonate oxide (powder ≤ 2 mm): 30.31 µm

Calcium magnesium carbonate oxide (coarse grained material): 44.39 µm

Therefore, airborne particles may partly be deposited in the respiratory tract. From the particle size distribution, the proportions of airborne dust deposited in the extra-thoracic (head), tracheo-bronchial (TB) and alveolar (PU) region, respectively, have been estimated by the MPPD model (see section 4.5 of the technical dossier) as:

 

Head

TB

PU

Total

Calcium magnesium carbonate oxide

45.3 - 56.8 %

0.1 - 0.2 %

0.0 - 0.4 %

45.4 - 57.4 %

Only particles deposited on mucous membranes are available for absorption. For material deposited in the alveolar (PU) region a default absorption factor of 100 % is assumed in absence of specific data. Particles deposited in the head and the TB region are transported to the pharynx by mucociliary excitation, and subsequently swallowed. In the GI tract, both calcium and magnesium underlie intestinal absorption kinetics, hence contribute to systemic availability according to their oral absorption factors of 30 and 15 %, respectively (see above). Total inhalation absorption is therefore obtained by summing up the fraction deposited in the pulmonary region (100 % absorption) and the TB and head fractions corrected for intestinal absorption. As a result, total inhalation absorption is

 

Calcium

Magnesium

Calcium magnesium carbonate oxide (powder ≤ 2 mm)

13.6 %

6.81 %

Calcium magnesium carbonate oxide (coarse grained material)

17.5 %

8.95 %

Distribution and elimination:

The main focus of toxicokinetics, metabolism and distribution for the substances of interest is on calcium and magnesium since in aqueous media calcined dolomite dissociates under formation of calcium and magnesium cations and hydroxyl ions. Dissociation in water is accompanied by generation of heat. Neither the alkaline reaction nor the generation of heat is of concern regarding systemic effects. Thus, further evaluation of hydroxyl ions is not considered to be necessary.

Calcium:

More than 99 % of the calcium stores in the body are located in the bones and teeth. The soft tissues accordingly contain less than 1 % of total body calcium. In extracellular fluids calcium is tightly regulated at a concentration of approximately 2.5 mmol/L (10 mg/dL). In blood, calcium is available as free Ca2 + by approximately 45 %, the rest being complexed to citrate, phosphate, sulphate, and carbonate (ca. 10 %). Regulation of Ca levels is effected via three hormones, parathyroid hormone, 1,25-dihydroxycholecalciferol, and calcitonin. The extracellular calcium is involved in blood coagulation and cell adhesion, and serves as a source for bone metabolism. Intracellular calcium is primarily bound to membrane structures of the nucleus, mitochondria, endoplasmatic reticulum, or stored in special vesicles. The intracellular concentration of free Ca2+ is only 0.1 µmol/L, i.e. approximately 25,000 times below the extracellular level.

Magnesium:

The human body contains approximately 25 g magnesium. Approximately two-thirds of the body stores are located in the bones, 1 % is found in extracellular fluids, and approximately one third (30-40 % acc. to FAO/WHO) intracellularly in muscles and soft tissues. Absorbed magnesium is predominantly excreted via urine; the kidney plays an important role in homoeostatic regulation of the magnesium balance, by active re-absorption of magnesium taking place in Henle's loop.

Both calcium and magnesium are essential mineral nutrients for humans and therefore cannot be considered as xenobiotic substances. Calcium and magnesium are homoeostatically regulated, with the skeleton serving as a reservoir to compensate for short-term fluctuations in dietary supply of these minerals. In view of their essentiality for human nutrition, the existing information on both calcium and magnesium is considered as sufficient for assessment of their physiological behaviour, and for hazard assessment of calcined dolomite.

Discussion on absorption rate:

A published in vitro study on dermal absorption of calcium and magnesium constituting academic research is available. However, this study does not provide endpoint information suitable for derivation of an absorption rate that could be of use in a regulatory context. The study by Laudanska et al. (2002) is therefore considered as supportive data but will not be used for derivation of dermal absorption rates.

Nevertheless, following an approach consistent with the methodology proposed in the HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH, Hannover, Germany; August 2007), the following default dermal absorption factors for metal cations are proposed (reflective of full-shift exposure, i.e. 8 hours) for both calcium and magnesium present in calcium magnesium carbonate oxide (calcined dolomite):

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %