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Toxicological information

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Key value for chemical safety assessment

Effects on fertility

Description of key information

Under physiological conditions, lime (chemical) hydraulic, mainly consisting of calcium hydroxide, dissociates into Ca2+ and OH-.
Calcium, 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.
The other main constituents calcium carbonate and calcium silicate remain largely undissolved or release CO2, are not classified for dangerous properties, and are therefore of limited toxicological relevance.
The NOAEL for fertility of lime (chemical), hydraulic, converted from Ca taking into account the respective molecular weights, has been determined at 120 mg/kg bw/day.

Effect on fertility: via oral route
Dose descriptor:
120 mg/kg bw/day
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Only limited data are available on effects of calcium compounds 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.

Data are available from an OECD TG 422 study in rats performed using calcium carbonate [Dunster, 2010]. There were no treatment related effects observed on mating, fertility or gestation length at any dose level. The offspring litter size, viability, growth and development were all comparable to controls and no adverse effects were noted. Since no treatment-related effects were observed for reproduction, a NOEL for reproductive toxicity was considered to be 1000 mg/kg bw/day, equivalent to 400 mg Ca/kg bw/day.

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

i) The primary effect of lime (chemical) hydraulic is characterised by primary local irritating effects at the site of first contact, mainly due to the dominant main constituent calcium hydroxide;

ii) Calcium, released as calcium cations in aqueous media from hydraulic lime is a physiologically essential element and nutrient for all mammals including humans. Hydroxyl anions are causative for local irritating effects, but not relevant regarding systemic exposure. 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. In the opinion on calcium (Anonymous, 2006), 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.

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.

v) The remaining main constituents (except calcium hydroxide) and major impurities of hydraulic lime are not classified for dangerous properties and therefore considered to be toxicologically non-relevant.

According to the specification, lime (chemical) hydraulic contains 66 % calcium, expressed as oxide equivalents (CaO). Considering the molecular weight of calcium (40.08 g/mol), the content of calcium in hydraulic lime (chemical), is 47.17 % Ca.

The NOAEL for lime is obtained by converting the UL for calcium, considering the content and molecular weight of calcium and lime (chemical), hydraulic. Thus the NOAEL for lime (chemical) hydraulic is 120 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.

The NOAEL for teratogenicity of lime (chemical), hydraulic, converted from calcium taking into account the molecular weights, has been determined at 668 mg/kg bw/d considering the effects of calcium, as lime (chemical), hydraulic contains 66 % Ca in term of oxide equivalents (or 41.17 % Ca).

Effect on developmental toxicity: via oral route
Dose descriptor:
668 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

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 in 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 in 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.

The NOAEL for developmental toxicity/teratogenicity of lime (chemical), hydraulic is established based on the lowest relevant NOAEL for Ca, converted into a lime (chemical) hydraulic-related figure taking into account the content of Ca (66 % in terms of oxide equivalents, absolute 47.17 % Ca). The NOAEL for lime (chemical) hydraulic therefore is 668 mg/kg bw/d.

Justification for classification or non-classification

Calcium is an essential mineral nutrient 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, therefore also lime (chemical) hydraulic, does not pose any hazard for reproduction and/or developmental toxicity. Classification for toxicity to reproduction is not warranted.

Additional information