Hexacalcium hexaoxotris[sulphato(2-)]dialuminate(12-)

Endpoint summary

Description of key information

Data and assessment from CaSO4 according to justification for read across (see separate document in iuclid chapter 13). Repeated dose oral: Currently, seven different animal studies are available that have evaluated the repeated dose toxicity of (calcium) sulfate. None of the studies describes any severe toxicological effects after oral administration of (calcium) sulfate.
Repeated dose inhalation: Currently, four different animal studies are available that have evaluated the repeated dose inhalation toxicity of (calcium) sulfate. Besides the animal studies, several health surveillance data, mainly from gypsum miners are also available. 
Repeated dose dermal: No studies on dermal toxicity of calcium sulphate are available

Additional information

Repeated dose toxicity: oral

Currently, seven different animal studies are available that have evaluated the repeated dose toxicity of (calcium) sulfate. None of the studies describes any severe toxicological effects after oral administration of (calcium) sulfate. NIER 2002 reported decreased haematological parameters (e.g. BUN, AST, ALT, protein, cholesterol, and creatinine). The haematological findings were not confirmed by other studies; Wurzner 1979, Takaagi 1999 and Ota 2006 explicitly state that no changes on haematological parameters or blood chemistry were observed. Alterations in liver weight were observed in different studies but were not consistent, reporting increase (Ota 2006) as well as decrease in liver weights (NIER 2002, Takaagi 1999). In all cases, no treatment-related histopathologic changes were observed after oral administration of sulfate. Only one study (Takaagi 1999) observed diarrhoea as consequence of ammonium sulfate administration whereas another (Ota 2006) explicitly state that no diarrhoea was noticed using the same substance and concentration.

 

Besides the animal studies, Heizer et al. (1997) found that in normal adult subjects, sulfate in drinking water at a concentration of 1200 mg/L caused a measureable but clinically insignificant increase in stool mass and decrease in stool consistency and appearance time, but no change in stool frequency and no complaint of diarrhoea.

 

European Food Safety Authority EFSA evaluated the use of calcium sulfate as food ingredient in detail. Calcium sulphate is an approved food additive (E 516). It was evaluated by the Scientific Committee on Food in 1990 and was allocated an Acceptable Daily Intake (ADI) not specified (SCF 1991). In 2003, 2004, and 2008 the Panel evaluated the use of calcium sulphate added for specific nutritional purposes in foods and concluded that this use is not of concern from the safety point of view (EFSA 2003, 2004, and 2008). Also the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has evaluated calcium sulphate and has allocated an ADI not specified. Furthermore, ADIs not specified were also allocated to the single calcium and sulphate ions and to sodium sulphate (JECFA 1986, 2000, 2002).

The Panel concluded that use of calcium sulphate as a mineral substance in foods intended for the general population is not of safety concern.

 

Taken together, at best slight effects were observed after oral administration of calcium sulphate to animals. These included (unspecified) alterations in liver weight and blood chemistry/haematology. It is likely that these alterations may be caused by a disturbance of water balance rather than by toxic effects. As calcium sulphate is furthermore used as food additive with an ADI not allocated, it can be concluded intake of calcium sulphate should not pose a need for concern regarding its toxicity via the oral route.

 

References:

 

EFSA, 2003: Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to Calicum Sulphate for use in foods for particular nutritional uses. Adopted on 10 December 2003. The EFSA Journal, 20, 1-6

 

EFSA, 2004: Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to Calicum Sulphate as a mineral substance in foods intended for the general population. Adopted on 7 October 2004.The EFSA Journal, 112, 1-10

 

EFSA, 2008: Calcium sulphate for use as a source of calcium in food supplements; Scientific Panel on Food Additives and Nutrient Sources added to food. Adopted on 24 September 2008. The EFSA Journal, 814, 1-9

 

JECFA, 1986 Evaluation of certain food additives and contaminants. Twenty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series, No. 733, 1986, and corringendum.

 

JECFA, 2000, Sodium Sulphate. WHO Food Additives Series ; 44 Prepared by the fifty third meeting of the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) IPCS – International Programme on Chemical Safety, World Health Organization, Geneva

 

JECFA, 2002, Evaluation of certain food additives and contaminants. Fifty-seventh report f the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series, No 909

 

SCF 1991: Report of the Scientific Committee for Food on a First Series of Food Additives of Various Technological Functions. Opinion expressed on 18 May 1990

 

 

Repeated dose toxicity: dermal

Currently, no studies are available that have evaluated the repeated dose inhalation toxicity of (calcium) sulfate.Calcium sulfate is an inorganic ionic solid and therefore expected to partition strongly to water rather than organic media. While it is not possible to measure or accurately predict an octanol/water partition coefficient for inorganic ionic substance, such a value would be expected to be very low. Electrolytes are also known not to penetrate the skin in any significant quantity. Given the physico-chemical properties of calcium sulfate, it is not expected that the substance would penetrate the skin in any significant quantity and so would therefore not cause any toxic effects following acute dermal exposure.

 

Furthermore, plaster of Paris, containing mainly the hemihydrous calcium sulfate, has been used in the immobilization of broken bones and is not known to have been associated with any toxic effects, despite intimate skin contact, for longer periods of time, over considerable areas of skin. As this use simulates dermal toxicity, it can safely be inferred that an dermal exposure test would be unlikely to cause any toxic effects.

 

 

Repeated dose toxicity: inhalation

Currently, four different animal studies are available that have evaluated the repeated dose inhalation toxicity of (calcium) sulfate. In none of these studies, using calcium sulfate concentrations ranging from 10-100 mg/m³ any mortality was observed. The only concern was a decrease in glutathione concentrations observed by Clouter 1997 and 1998. No other study was available that could affirm this observation. Mild indications for inflammation were also observed but it is not clear if this was calcium sulphate-specific or caused by the general dust burden.

 

Besides the animal studies, several health surveillance data, mainly from gypsum miners were assessed. None of these five studies, conducted on 4 to 241 subjects which were exposed to (calcium) sulfate dust for up to 30+ years has detected any signs of systemic toxicity caused by repeated exposure to calcium sulfate dust (Riddell 1934, Schepers 1955, Kelada 1978, Oakes 1982, Burilkov 1990). The exposure concentrations were only reported in 3 studies, ranging from 2.8-6 mg/m³ (Oakes 1982) over 16-40 mg/m³ (Burilkov 1990) to <5-150 mg/m³. It was also found that calcium sulfate per se causes no pneumoconiosis (Riddell 1934, Schepers 1955, Burilkov 1990); if such an indication is given, it was mainly attributed to the quartz (silica) content, which is a current impurity in raw gypsum (Oakes 1982) and known to cause pneumoconiosis (“silicosis”). Nevertheless, it must be admitted that in one study (Schepers 1955) appearance of pneumonia was found after necropsy of four gypsum plant workers. None of the other four publications (all with significantly higher numbers of participants) has given any indication for gypsum-induced pneumonia. Furthermore, the publication of Schepers (1955) provides no information on composition of the gypsum dust (e.g. silica content), exposure concentrations, or other confounding factors such as smoking. Therefore study is deemed not reliable.

Other clinical signs reported, such as running nose, dyspnoea, coughing, or altered breath sounds may predominantly be attributed to effects of dust in general and pose no substance-specific symptom.

 

Taken together, the inhalation exposure to calcium sulphate is highly likely to pose no hazard to human health. The most severe observations after inhalation exposure included slight inflammation in some but not all individuals. It is not proven that this is a calcium sulphate specific effect or just caused by general dust overload. No indication for calcium sulphate-induced pneumoconiosis was found.

Justification for classification or non-classification

No systemic toxicological findings could be detected after repeated administration of calcium sulphate by either oral or inhalation route. The only concern that was found after oral uptake could be the occurrence of loose stool or diarrhoea which is caused by osmotic effect in the gastrointestinal lumen but forces no classification as STOT RE. Also the observed slight signs of inflammation observed after inhalation exposure cannot clearly be attributed to calcium sulphate as in different studies no increase of lung macrophages was observed. Therefore, a classification as STOT RE is not justified.

Classification of Ettringite according to Regulation (EC) No 1272/2008 (CLP) and Directive 67/548/EEC and subsequent regulations

- No classification needed: the data are conclusive but not sufficient for classification.