Calcium dihydroxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies are available.

Under physiological conditions, calcium oxide ultimately 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.

Effect on fertility: via oral route

Dose descriptor:

NOAEL

66.5 mg/kg bw/day

Species:

other: human

Quality of whole database:

No study is available for calcium dihydroxide. The NOAEL is based on the upper intake level for calcium of 36 mg/kg bw/day for humans established by the Scientific Committee on Food (2006) and converted to the calcium dihydroxide equivalent.

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 from studies investigating the effects of calcium compounds on the reproductive performance of male and female mice and rats.

In a calcium carbonate feeding study in mice [Richards and Greig, 1952] performed using a method similar to a one-generation reproductive toxicity study, the highest dose of 2% calcium carbonate (corresponding to 1.1% Ca) resulted in reduced number and total weight of litters and an increase in the number and proportion of litter deaths. This dose was considered as the LOAEL for reproductive performance. The dose level of 0.73 % Ca was established as the NOAEL, although there were some sporadic effects without statistical significance. However, the daily dose level in mg/kg bw could not be calculated as there were no 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.

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

i) The primary effect of calcium hydroxide is characterised by primary local irritating effects at the site of first contact, and

ii) Calcium cations and hydroxyl anions which are formed in aqueous media from calcium dihydroxide are physiologically essential elements and nutrients 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, 2006). 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. 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/day 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 (equivalent to 66.5 mg/kg bw/day for calcium dihydroxide) is recommended as a starting point for hazard assessment regarding reproductive toxicity and derivation of a corresponding DNEL.

iii) Supportive information is available in section 7.12 (s_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 (s_Han_2000) showing that calcium has a protective effect against lead accumulation in dams and their offspring, i.e. acts beneficially.

Effects on developmental toxicity

Description of key information

Three prenatal developmental toxicity studies are available for calcium salts and in addition an OECD TG 422 study is available for calcium carbonate. In each of these studies, no developmental, foetotoxic or teratogenic effects were noted at the highest dose tested. The NOAEL for developmental toxicity for calcium, derived from a study performed in mice using calcium oxide, was 315 mg Ca/kg bw/day, equivalent to 582 mg/kg bw/day for calcium dihydroxide.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well-documented study. The study allows the derivation of a NOAEL value for effects of Ca regarding developmental toxicity in rats and mice. In the current study, calcium was administered in the form of calcium oxide. Under physiological conditions, e.g. in the stomach upon oral administration, calcium oxide is converted into calcium hydroxide. The objective of the study was the evaluation of any effects of calcium. In view of the equivalence of calcium oxide and calcium hydroxide under physiological conditions, the results of the study can be used by read-across.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Limit test:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: Mice were housed in groups in disposable plastic cages.
- Diet: ad libitum
- Water: ad libitum; tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-27
- Humidity (%): 64-78

No further details are given.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

no detailed data given

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no detailed data given

Details on mating procedure:

The female mice were mated with young adult males.
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1; one male was not permitted to impregnate more than one female per group.
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
No further details are given.

Duration of treatment / exposure:

Day 6 to 15 of gestation.

Frequency of treatment:

Once daily.

Duration of test:

Until day 17 of pregnancy.

No. of animals per sex per dose:

mated: 25 to 26 mice
pregnant: 17 to 21 mice

Control animals:

yes

yes, sham-exposed

Details on study design:

no data available

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for appearance and behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: Average body weight was determined on days 0, 6, 11, 15 and 17

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes; however, compound intake occurred by gavage.
- Time schedule: All animals were observed daily with particular attention to food consumption and weight.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data; not applicable

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: The urogential tract of each dam was examined in detail for anatomical normality.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes

Statistics:

no data given

Indices:

no data given

Historical control data:

no data given

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Administration of up to 440 mg/kg bw/d of CaO to pregnant mice for 10 consecutive days had no clearly discernible effect on maternal survival.

Dose descriptor:

NOAEL

Effect level:

>= 440 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

>= 315 mg/kg bw/day

Based on:

element

Remarks:

Ca

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Administration of up to 440 mg/kg bw/d of CaO (= 315 mg Ca/kg bw/d) to pregnant mice for 10 consecutive days had no clearly discernible effect on foetal survival.
The number of abnormalities seen in either soft or skeletal tissues of test groups did not differ from the number occuring spontaneously in sham-treated controls.

Dose descriptor:

NOAEL

Effect level:

>= 440 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Dose descriptor:

NOAEL

Effect level:

>= 315 mg/kg bw/day

Based on:

element

Remarks:

Ca

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Developmental effects observed:

not specified

Conclusions:

Administration of up to 440 mg/kg bw/d of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of test groups did not differ from the number occuring spontaneously in sham-treated controls.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

582 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Quality of whole database:

Three reliable studies equivalent to OECD TG 414 are available. In addition, an OECD TG 422 study is available. These studies were perfomed using calcium oxide or calcium carbonate, but are applicable to calcium dihydroxide.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Three pre-natal developmental toxicity studies are available.

The design of all of these studies was comparable to OECD TG 414. In a study in which rats were dosed with calcium carbonate via feed [Shackelford et al., 1993] no adverse developmental, foetotoxic or teratogenic effects were noted at doses up to 1.25% Ca (equivalent to 938 mg Ca/kg bw/day) which was the highest dose tested. In a study in which rats were dosed with calcium oxide by gavage, the NOAEL for developmental effects and maternal toxicity was the high dose of 680 mg/kg bw/day (equivalent to 486 mg Ca/kg bw/day [Bailey and Morgareidge, 1974]. In a second study by the same authors, the highest calcium oxide dose of 440 mg/kg bw/day (equivalent to 315 mg Ca/kg bw/day) was established as the NOAEL for developmental effects and for maternal toxicity in mice.

In addition to these studies, an OECD TG 422 study in rats is available for calcium carbonate [Dunster, 2010]. No treatment-related effects were observed for reproduction/ developmental toxicity at the highest dose tested, therefore the NOEL for reproductive/ developmental toxicity was considered to be 1000 mg/kg bw/day from this study.

Lack of developmental/teratogenic effects or even beneficial effects of calcium supplementation on foetal development is further supported by human data (s_Villar_1990_calcium carbonate, s_Levine_1997_calcium carbonate, s_Koo_1999).

The lowest NOAEL for developmental toxicity of 315 mg Ca/kg bw/d is derived from the study on mice and is established as an NOAEL for risk assessment purposes. This is equivalent to an NOAEL for calcium dihydroxide of 582 mg/kg bw/day. This value is proposed for deriving the DNEL for developmental and teratogenic effects of calcium.

Toxicity to reproduction: other studies

Additional information

No other data available.

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 calcium dihydroxide and calcium carbonate, does not pose any hazard for reproduction and/or developmental toxicity. Classification for toxicity to reproduction is not warranted.