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THE POTENTIAL TOXICOKINETICS AND GENERAL SAFETY CONSIDERATIONS FOR CALCIUM SULFATE

Introduction

There are two forms of Calcium Sulfate : the anhydrite and dihydrate. Sulfates occur naturally in numerous minerals including gypsum (calcium sulfate dihydrate). Sulfates are used in a variety of industries and are discharged into water. Some of these salts are highly water soluble (sodium, potassium) whereas others are less so (calcium). Both calcium and sulfate ions are necessary nutritional elements for animals and they are derived from a variety of sources with an average daily intake of around 500 mg sulfate per day.

Kinetics of Calcium Sulfate Exposure

Oral ingestion is the primary route of exposure for sulfates, including calcium sulfate. This may be via food or drinking water. A study [3] examining bioavailability of calcium from milk or water showed no significant difference between the two. As with other calcium salts, solubility will affect absorption. In addition, for sulfates, dietary constituents will affect bioavailability. Approximately 19% and 17% of total body sulfate comes from diet and water/beverages. Inorganic sulfate can also be derived from degradation of food proteins such as methionine and cysteine. Two known methods of absorption of calcium ions from the diet are passive absorption across electrochemical gradients and active absorption against electrochemical gradients. For sulfate absorption, there is little evidence to indicate the mechanism of absorption. It is known that soluble sulfate salts in water will result in up to 80% absorption whereas insoluble salts will not be absorbed. Calcium sulfate is certainly less soluble than sodium or potassium. Calcium sulphate has, however been shown to be a highly available source of calcium for premenopausal women [6] and is used as a salt supplement in bread. Sulfate absorption is poor when given in large bolus doses [7]. As a source of calcium it has been shown that human utilisation of calcium from calcium sulfate in the drinking water of humans can be around 18%. This value is well below the figure reported for calcium sulfate absorption of 73% for wistar rats where this material was administered in the diet. There is an apparent dose dependency for absorption which does suggest passive uptake only occurs as it has been seen that excess sulfate is excreted in faeces. As with other calcium salts dermal and inhalation absorption are likely to be limited.

Distribution of sulfate is throughout the body, although it is not tightly bound to plasma proteins [5] as it is required for normal cellular function. The sulfate becomes incorporated into normal physiological turnover. The excretion of sulfate is primarily via the kidney and the glomerular filtration rate is dependant upon degree of reabsorption [5] which is itself capacity limited. It has been noted that a common feature of renal failure is increased serum sulfate levels and therefore a specific function for excretion of sulfate ions may exist. Calcium is also excreted via the kidney as a primary route.

Adverse Effects of Calcium Sulfate

A single skin irritation study with laboratory animals showed no irritation effects with the dihydrate form of calcium sulfate. Additionally, no skin sensitisation effects were seen in the guinea pig as a laboratory model.

The single dose acute toxicity of calcium sulfate dihydrate showed the LD50to be in excess of 2000 mg/kg.

A limited number of genotoxicity studies show calcium sulfate dihydrate to be non genotoxic in vivo or in vitro.

There is a limited repeated dose toxicity data in laboratory animals. One study with calcium sulfate dihydrate, a combined repeated dose and reproduction screening study in the rat showed no effects on reproduction or foetal development at a high dose of 1000 mg/kg/day. Effects on the adult animals was limited to one sex (male). These effects were alterations to blood chemistry parameters. A ‘No Observed Adverse Effect Level’ was 100 mg/kg/day.

In general the adverse effects associated with human exposure, (particularly infant exposure) at high levels of sulfate were gastro-intestinal problems such as diarrhoea [1]. These effects are considered to be due to osmotic effects. A further study also supported these findings [2] although a true dose response relationship was not established and small group size did not help the evaluation. A study in adults [4] failed to show a similar effect. The studies involved evaluating effects of high sulfate levels in drinking water. Although not considered in the references to sulfate over exposure, the effects of high dose calcium have been documented and are primarily associated with hypercalcaemia. The solubility of calcium sulfate salt does make it less likely to have a calcium overload when compared with calcium carbonate. Sulfate and undigested sulphur compounds have been implicated in the aetiology of ulcerative colitis.


Overview

In general there is limited information regarding the toxicokinetics of calcium sulfate. Absorption of sulfate is likely to be passive but the excretion, via the kidney is a specific process. The effects of excess sulfate exposure are compounded by the general turnover of sulfate as a normal physiological and biochemical process. The limited toxicity studies in laboratory animals with the dihydrate form of calcium sulfate show no major adverse effects.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

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