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Description of key information

Short description of key information on bioaccumulation potential result: 
Calcium is an essential mineral nutrient. In the human body it serves as a structural element in bone (99 % of the body's Ca stores are located in bone and teeth). It is the fifth most abundant element by mass (1.5 %). Calcium is a common cellular ionic messenger with many functions. Further, calcium plays an important role in neurotransmitter release, muscle contraction, and many other physiological processes. Intestinal absorption and excretion (mostly via urine), intra- and extracellular levels of dissolved Ca2+ are tightly regulated, constituting homoeostasis, depending on the body's needs and dietary supply.
Short description of key information on absorption rate:
Following the HERAG guidance for metals and inorganic metal compounds, the following conservative default values for dermal absorption are proposed:
0.1 % for dry (dust) exposure
1.0 % for exposure to liquid/wet media
These absorption rates are applicable to calcium present in calcium oxide.
However, since calcium oxide is irritating to skin, dermal exposure has to be minimised as far as technically feasible. Thus, an absorption rate for dermal exposure is not considered for the chemical safety assessment.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Due to its ubiquitous occurrence in the environment and its function as an essential mineral for human nutrition (see also technical dossier section 7.10), calcium is 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.

The focus of toxicokinetics, metabolism and distribution for calcium oxide is on calcium since in aqueous media calcium oxide dissociates forming calcium cations 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. Thus, only calcium (Ca2+) is considered in the current section. The key conclusion for this section is that calcium, as essential mineral nutrients underlie homoeostatic regulation and therefore cannot be considered as xenobiotics.

Absorption

Oral

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 calcium oxide.

Dermal

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 calcium oxide:

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %

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

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

Inhalation

Calcium oxide 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). As a result, total inhalation absorption is

 

Calcium

Calcium oxide (powder ≤ 0.2 mm)

19.0 %

Calcium oxide (coarse grained material > 10 mm)

18.1 %

 

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.

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 importantly, 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 maintained 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. The concentration of 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.

Discussion on bioaccumulation potential result:

Toxicokinetic behaviour of calcium is assessed utilising mostly publications focusing on the nutritional and physiological role of calcium. 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 significance of the hydroxyl ion:

The anionic counter ion released from calcium oxide, irrespective of being present as oxide or hydroxide, is the hydroxyl ion. As an element of the acid-base system hydroxyl ions are not relevant in terms of toxicokinetics: If calcium oxide is ingested, hydroxyl ions will be neutralised by gastric juice. Upon either inhalation exposure or deposition on the skin, hydroxyl ions released from calcium oxide 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 abosorbed 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.

Inhalation absorption:

Systemic availability of calcium from calcium oxide 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 calcium oxide 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 to be (also see section 4.5 of the technical dossier):

Calcium oxide (powder ≤ 0.2 mm): 17.34 µm

Calcium oxide (coarse grained material > 10 mm): 18.26 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 oxide

55.7 - 59.2 %

0.8 %

1.1 %

57.6 - 61.1 %

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, calcium underlies intestinal absorption kinetics, hence contributes to systemic availability according to its oral absorption factor of 30% (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

Calcium oxide (powder ≤ 0.2 mm)

19.1%

Calcium oxide (coarse grained material > 10 mm)

18.1 %

Distribution and elimination:

The main focus of toxicokinetics, metabolism and distribution for the substance of interest is on calcium since in aqueous media calcium oxide dissociates under formation of calcium 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 +, where it accounts for approximately 45 %, the remainder 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.

Calcium is an essential mineral nutrient for humans and therefore cannot be considered as a xenobiotic substance. Calcium is homoeostatically regulated, with the skeleton serving as a reservoir to compensate for short-term fluctuations in dietary supply of this mineral. In view of its essential role in human nutrition, the existing information on calcium is considered as sufficient for assessment of its physiological behaviour, and for hazard assessment of calcium oxide.

Discussion on absorption rate:

A published in vitro study on dermal absorption of calcium 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 calcium present in calcium oxide:

For exposure to liquid/wet media: 1.0 %

For dry (dust) exposure: 0.1 %

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