Dolomite (CaMg(CO3)2), calcined

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

21 mg/kg bw/day

Additional information

Only limited data are available on effects of calcium carbonate and magnesium sulphate on the reproductive performance of male and female mice and rats, respectively. A preliminary NOAEL for calcium effects on reproduction and development of offspring may be derived from a CaCO3 feeding study in mice (Richards and Greig, 1952).The study design was similar to that of a one-generation reproductive toxicity study. The highest dose of 2 % CaCO3 (corresponding to 1.1 % Ca) resulted in reduced numbers and total weight of litters, and increased both the number and proportion of litter deaths, hence being considered as LOAEL for effects on reproductive performance. The dose level of 0.73 % Ca may be established as NOAEL although there were some sporadic effects without statistical significance. However, no daily dose levels could be calculated due to lack of data on daily food intake.

However, with respect to potential hazards of calcium for reproduction the following aspects have to be taken into account:

i) The primary effect of calcined dolomite, extrapolated from calcium oxide, magnesium oxide and the corresponding hydroxides by read-across, is characterised by primary local irritating effects at the site of first contact, and

ii) Calcium and magnesium cations and carbonate and hydroxyl anions which are formed in aqueous media from calcined dolomitic lime are physiologically essential elements and serve as nutrients or otherwise as physiologically functional compounds (e.g. carbonate as an integral part of the blood buffering system) for all mammals including humans. Comprehensive evaluations of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements have been presented in the scientific opinions of the Scientific Committee on Food (SCF), also see 7.1.1 of the technical dossier (basic toxicokinetics). Where possible, tolerable upper intake levels (UL) for different human populations have been established. The UL is an estimate of the highest level of intake entailing no appreciable risk of adverse health effects. Opinions of the Scientific Committee on Food including tolerable upper intake levels for calcium and magnesium have been published (Anonymous, 2006). In the opinion on calcium, the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, corresponding to a dose of about 36 mg calcium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.

In the opinion on magnesium, the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for magnesium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily magnesium intakes of 250 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 250 mg of magnesium per day for magnesium intake from all sources is proposed for adults, corresponding to a dose of about 3.6 mg magnesium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.

Therefore, the tolerable upper intake level of 36 mg Ca/kg bw/day or 3.6 mg Mg/kg bw/d is recommended as a starting point for hazard assessment regarding reproductive toxicity.

iii) Supportive information is available in section 7.12 of the technical dossier (Mortimer, 1988) showing that calcium is essential for the function of human spermatozoa (acrosome reaction), i.e. calcium has a beneficial effect on reproductive performance.

iv) Supportive information is available in section 7.12 of the technical dossier (Han, 2000) showing that calcium has a protective effect against lead accumulation in dams and their offspring, i.e. acts beneficially.

The NOAEL for CaCO3.MgO is obtained by converting the UL for magnesium, considering the molecular weight of magnesium and CaCO3.MgO.

Short description of key information:
Calcium, as an essential and abundantly available mineral nutrient, is not toxic to reproduction/fertility.
Magnesium, as an essential and abundantly available mineral nutrient, is not toxic to reproduction/fertility.
OH- is neutralised in body fluids, hence not relevant in terms of toxicity to reproduction/fertility. Also carbonate is not relevant in terms of toxicity to reproduction/fertility.
The NOAEL for fertility of CaCO3.MgO, converted from Mg taking into account the respective molecular weights, has been determined at 21 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

Calcium is not teratogenic. The NOAEL for calcium, derived from the key study on CaO, was determined at 315 mg Ca/kg bw.
Magnesium is not teratogenic. The NOAEL for magnesium, derived from the key study on MgCl2*6H20, was determined at 96 mg Mg/kg bw.
The NOAEL for teratogenicity of CaCO3.MgO, converted from Mg taking into account the respective molecular weights, has been determined at 554.5 mg/kg bw/d.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

554.5 mg/kg bw/day

Additional information

Three pre-natal developmental toxicity studies establishing a dose-response relationship of potential adverse effects of calcium after oral administration of calcium oxide and calcium carbonate to rats and mice were identified (Shackelford et al., 1993; Bailey and Morgareidge, 1974). The design of these three studies was comparable to the OECD guideline 414. In all studies no adverse developmental, foetotoxic or teratogenic effects were noticed up to and including the highest dose levels tested. These studies allow the derivation of a NOAEL value for developmental effects of calcium.

From the study on rats given CaCO3 in feed (Shackelford et al., 1993) the highest dose of 1.25 % Ca is established as the NOAEL for developmental effects, corresponding to a daily dose of 938 mg Ca/kg bw/d. In a gavage study on rats (Bailey and Morgareidge, 1974) the highest CaO dose of 680 mg/kg bw/d was established as the NOAEL for developmental effects and for maternal toxicity, corresponding to a calcium dose of 486 mg/kg bw/d. In a gavage study on mice by the same authors (Bailey and Morgareidge, 1974) the highest CaO dose of 440 mg/kg bw/d was established as the NOAEL for developmental effects and for maternal toxicity, corresponding to a calcium dose of 315 mg/kg bw/d.

Lack of developmental/teratogenic effects or even beneficial effects of calcium supplementation on foetal development is further supported by human data (please refer to section 7.10.1 of the technical dossier: Villar, 1990; Levine, 1997, Koo, 1999).

The lowest NOAEL for developmental toxicity of 315 mg calcium/kg bw/d is derived from the study on mice and is established as an NOAEL for risk assessment purposes.

Pre-natal developmental toxicity of magnesium was studied in rats administered magnesium chloride hexahydrate orally by gavage (Usami et al., 1996). A dose- response relationship was investigated. No adverse developmental, foetotoxic or teratogenic effects were observed up to and including the highest dose level of 800 mg/kg bw/d. Thus, the NOAEL was estimated to be higher than 800 mg/kg bw/d for both the dams and the foetuses. This dose corresponds to a magnesium dose of 96 mg/kg bw/d.

The NOAEL of 96 mg Mg/kg bw/d is established as an NOAEL for risk assessment purposes of compounds containing magnesium.

The NOAEL for developmental toxicity/teratogenicity of CaCO3.MgO is established based on the lowest relevant NOAEL for Mg, converted into a CaCO3.MgO- related figure taking into account the molecular weight of magnesium and CaCO3MgO.

Justification for classification or non-classification

Both calcium and magnesium are essential mineral nutrients for mammals including humans. Based on evaluation of a wealth of human medical and nutritional data (Anonymous, 2001 [FAO/WHO report]; Anonymous, 2006 [SCF opinion]), it is concluded that calcium and magnesium, therefore also CaCO3.MgO, does not pose any hazard for reproduction and/or developmental toxicity. Classification for toxicity to reproduction is not warranted.