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Description of key information

Short description of key information on bioaccumulation potential result: 
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

SFL is primarily composed of inorganic substances. The major constituent is calcium carbonate (61.8 - 95.6 %w/w) along with silicon dioxide and a small amount of other inorganic salts (including calcium salts) and the remainder is composed of organic plant material. SFL is not classified for human health, based on studies performed on the substance itself. Of its components, only calcium oxalate is classified as acutely toxic via the oral and dermal routes (category 4).. As a result, it is considered that the properties of SFL are governed by those of calcium and calcium carbonate and hence the toxicokinetics assessment of SFL has been based mainly on calcium/ calcium carbonate.

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:

SFL is primarily composed of inorganic substances. The major constituent is calcium carbonate (61.8 - 95.6 %w/w) along with silicon dioxide and a small amount of other inorganic salts (including calcium salts) and the remainder is composed of organic plant material. SFL is not classified for human health. Of its components, only calcium oxalate is classified as acutely toxic via the oral and dermal routes. As a result, it is considered that the properties of SFL are governed by those of calcium carbonate and hence the toxicokinetics assessment of SFL has been based mainly on calcium/ calcium carbonate.

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 its 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 glucose via intercellular junctions or spaces and 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 [Harlan Laboratories Ltd (2013a)] and dermal [Harlan Laboratories Ltd (2013d)] toxicity studies on SFL no mortalities were seen in the observation periods and there were no clinical signs of systemic toxicity or macroscopic effects noted at necropsy. The LD50 value was therefore >2000 mg/kg bw for oral and dermal exposure and demonstrates that SFL is not acutely toxic via the oral or dermal routes. Similarly, in acute oral [Bradshaw (2008)] and dermal [Bradshaw (2010a)] toxicity studies with calcium carbonate no mortalities were seen in the observation periods and there were no clinical signs of systemic toxicity or macroscopic effects noted at necropsy. The LD50 value was therefore >2000 mg/kg bw for oral and dermal exposures and demonstrates that calcium carbonate is not acutely toxic via the oral or dermal routes.

SFL as manufactured and supplied contains approximately 30 %w/w of water. Although it remains as a powder in this form, it is damp and non-free-flowing and it was found to be impossible to generate a stable dust atmosphere for inhalation testing in this form. However, in order to investigate the intrinsic properties of the substance, testing was performed on a sample of SFL which had been dried until the water content was approximately 2.14 % w/w [Harlan Laboratories Ltd (2013b)]. No mortalities were seen in the observation period. Clinical signs were limited to increased respiratory rate, hunched posture, pilo-erection and wet fur. Occasional instances of red/brown staining around the snout were also noted. Animals appeared normal from days 7 to 9 post-exposure. There were some effects on bodyweight with all animals showing reasonable body weight gains by the second week of the observation period. No macroscopic effects were noted at necropsy. The inhalation LC50 was > 5.09 mg/L air, demonstrating that SFL is not acutely toxic via the inhalation route. Similarly in a study performed with calcium carbonate [Schuler D (2010)] no mortalities were seen in the observation period 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 LC50 value in this study was >3 mg/L air (the highest technically achievable concentration)demonstrating that calcium carbonate is not acutely toxic via the inhalation route.

A 28 day 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 28 days.This result is considered to be relevant to SFL based on the fact that SFL is primarily composed of calcium carbonate and other calcium salts. Other repeat dose toxicology studies on constituents of SFL in both rats and mice resulted in NOAEL values ≥1000 mg/kg bodyweight/day (except for magnesium chloride hexahydrate given in the diet, which caused soft stool at the maximum dose level), and therefore support the conclusion that SFL is non-toxic via the oral route (section 5.6.1.1).

Although calcium carbonate has the potential to be inhaled due to its particle size distribution it does not exhibit acute inhalation toxicity in the rat (see above). 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.

Absorption via the dermal route is expected to be very low based on the inorganic nature of SFL and calcium carbonate; hence, the lack of dermal toxicity seen in the studies. In addition a mouse lymph node sensitisation assay on SFL [Harlan Laboratories Ltd (2013f)] showed no evidence of clinical signs, skin irritation or sensitisation.

Furthermore, there was no systemic toxicity observed in the skin and eye irritation studies performed with calcium carbonate [Sanders (2004)] or in the eye irritation study performed with SFL [Harlan Laboratories Ltd (2013e)] indicating that either the systemic absorption and/or the toxicity of calcium carbonate and SFL 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.

The elevation of calcium levels may 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. Consequently, normal and moderate excess exposure to SFL will not cause any significant adverse toxic effects.

 

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

Harlan Laboratories Ltd (2013a). Sugar Factory Lime (Wet): Acute Oral Toxicity Study in the Rat - Fixed Dose Method.. Report No.: 41300331

Harlan Laboratories Ltd (2013b). Sugar Factory Lime (Dry): Acute Inhalation Toxicity (Nose Only) Study in the Rat. Report No.: 41300335

Harlan Laboratories Ltd (2013d). Sugar Factory Lime (Wet): Acute Dermal Toxicity (Limit Test) in the Rat. Report No.: 41300380

Harlan Laboratories Ltd (2013e). Sugar Factory Lime (Wet): Acute Eye Irritation in the Rabbit. Report No.: 41300333

Harlan Laboratories Ltd (2013f). Sugar Factory Lime (Wet): Local Lymph Node Assay in the Mouse. Report No.: 41300334

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

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