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Toxicological information

Carcinogenicity

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Description of key information

Calcium (when administered orally in feed as Ca-lactate) is not carcinogenic. Neither toxicity nor carcinogenic activity was observed in rats.
The NOAEL of calcium oxide, converted from Ca taking into account the respective molecular weights, has been determined at 391 mg/kg bw/d.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
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:
Under physiological conditions, the hydroxyl-ions released from burnt dolomitic lime following oral adminstration have been neutralised in the GI tract and are therefore not relevant for consideration of systemic toxicity. Therefore for assessment of any systemic effects of burnt dolomitic lime following administration via the oral route, the calcium ion Ca2+ is the chemical species of interest. In the current study, calcium was administered in the form of calcium lactate, the lactate ion being an integral component of mammalian energy metabolism and therefore toxicologically not relevant. The objective of the study was the evaluation of any effects of calcium. In view of the the limited relevance of the anionic counter-ions discussed here, calcium released both from calcium magnesium oxide and calcium lacatate can be considered as structurally equivalent, and the results of the study can be used by read-across.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The long-term toxicity/carcinogenicity of calcium lactate, a food additive, was examined in F344 rats. Calcium lactate was given ad lib. in the drinking water at levels of 0, 2.5 or 5 % to groups of 50 male and 50 female rats for two years.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc. (Kanagawa, Japan)
- Age at study initiation: 6 weeks old
- Housing: Rats were housed three (or four) males or five females per plastic cage
- Diet (ad libitum): Basal diet (CRF-1; Oriental Yeast Inc., Tokyo, Japan)
- Water (ad libitum): Distilled water containg calcium lactate

ENVIRONMENTAL CONDITIONS
- Temperature: 24 +/- 1 °C
- Relative humidity: 55 +/- 5 %
No further information on the test animals was stated.
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Calcium lactate was dissolved in distilled water at levels of 0 (control), 2.5 or 5 %.
No further information on the exposure was stated.


Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
ad libitum
Post exposure period:
9 weeks
Remarks:
Doses / Concentrations:
0, 2.5 or 5 % calcium lactate in distilled water
Basis:
nominal in water
No. of animals per sex per dose:
50 males / 50 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: These dose levels were selected based on a 13-week subchronic toxicity study conducted prior to the present study (Matsushima et al., 1989)
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included: Clinical signs and deaths were recorded

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured once a week for the first 13 week of the study, and every 4 weeks thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: The calcium lactate solutions were replaced with freshly prepared solutions three times a week, on which occassions the amount of solution consumed was measured in order to calculate the intake of calcium lactate.

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At week 113

CLINICAL CHEMISTRY: Yes

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

No further information on observations and examinations performed and frequency was stated.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At week 113, all survivng animals were killed and autopsied. An autopsy was immediatley performed on rats that died (or were killed when moribund) during the study and those killed at the end of the study. The animals were then examined macro- and mircoscopically for the presence of non-neoplastic and neoplastic lesions. All organs and / or tissues were routinely fixed in 10 % buffered formalin, sectioned and stained with haematoxylin and eosin.
No further information on sacrifice and pathology was stated.
Statistics:
Statistical analyses were performed using Fisher's exact probability test and/or the chi-square test, and also the age-adjusted statistical test recommended by Peto et al. (1980).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
The mortality rate in high-dosed females was slightly higher than those in the two other groups. This difference, however, was not significant.

BODY WEIGHT AND WEIGHT GAIN
Calcium lactate inhibited the growth of rats of both sexes dose-dependently. A 13% decrease was observed in male and female rats of the high-dose group.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Throughout the administration period, daily water consumption was almost constant in all groups of both sexes. From the water consumption data, total calcium lactate intakes (g/rat/2yr) were calculated:
Mean total calcium lactate intake:
5% dose: 625.4 g/rat
2.5 % dose: 329.4 g/rat
0 % dose: 0 g/rat

HAEMATOLOGY
No specific dose-related changes of haematological parameters were observed.

CLINICAL CHEMISTRY
No specific dose-related changes of biochemical parameters were observed.

ORGAN WEIGHTS
Females of the high-dose group exhibited slightly, but significantly, higher kidney weights. Histologically, however, there was no difference in the severity of chronic nephropathy. A significant dose-dependent increase was observed in the relative brain weights of both male and female rats although no histological change was detected.

HISTOPATHOLOGY: NON-NEOPLASTIC
A number of non-neoplastic lesions (e.g myocardial fibrosis, bile-duct proliferation, hepatic microgranulomas and chronic nephropathy) were observed in all groups, with no difference in their incidence and/or degrees.

HISTOPATHOLOGY: NEOPLASTIC
None of the experimental groups showed a significant increase in the incidence of any specific tumors compared with the corresponding control value, and also no positive trend was noted in the occurence of any tumour. However, male rats of the high-dose group showed a slightly higher incidence of pheochromocytomas and adrenal medullary hyperplasia. However, there were no carcinogenic effects observed.
Relevance of carcinogenic effects / potential:
Calcium lactate did not cause toxicicity or carcinogenic activity in F344 rats.
This finding can be used for read-across to burnt dolomitic lime based on structural equivalence.
Dose descriptor:
NOAEL
Effect level:
2 150 mg/kg bw/day
Sex:
male
Basis for effect level:
other: This is the 5% calcium lactate dose level. The daily calcium lactate intakes of males in the 5 % group was 860 mg per rat. Assuming an average weight of 400 g for male rats, this intake would correspond to calcium lactate dose of 2150 mg/kg bw/day.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
2 280 mg/kg bw/day
Sex:
female
Basis for effect level:
other: This is the 5% calcium lactate level. The daily calcium lactate intakes of females in the 5 % group was 570 mg per rat. Assuming an average weight of 250 g for female rats, this intake would correspond to calcium lactate dose of 2280 mg/kg bw/day.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
279.5 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Calculated as Ca2+.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
296.4 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Calculated as Ca2+.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Conclusions:
Calcium lactate did not cause toxicity or carcinogenic activity in F344 rats. Thus, the high dose of 5 % represents the NOAEL for tumour formation in this study. The concentration of 5 % corresponds to calcium lactate doses of 2150 and 2280 mg/kg bw/d to male and female rats, respectively, which are equivalent to calcium doses of approximately 279.5 and 296.4 mg Ca/kg bw/d for male and female rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
391 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Neither calcium, calcium dihydroxide nor calcium carbonate are carcinogenic. Classification for carcinogenicity is not warranted.

Additional information

The long term toxicity/carcinogenicity of calcium lactate was examined in F344 rats. Calcium lactate was given ad libitum in the drinking water at levels of 0, 2.5 or 5% to groups of 50 male and 50 female rats for two years. Animals were examined daily for clinical signs and mortality. Body weights were measured once a week for the first 13 weeks and every four weeks thereafter. Water intake was measured three times a week, when the calcium lactate solutions were replaced with freshly prepared solutions. Haematology and clinical chemistry analyses were performed at the end of the study. At week 113, all surviving animals were killed and autopsied. An autopsy was performed immediately on rats that died (or were killed when moribund) during the study and those killed at the end of the study. The animals were then examined macro- and microscopically for the presence of non-neoplastic and neoplastic lesions. All organs and / or tissues were routinely fixed in 10 % buffered formalin, sectioned and stained with haematoxylin and eosin. The mortality rate in high-dosed females was slightly higher than those in the two other groups, but the difference was not statistically significant. There was a dose-dependent decrease in body weight gain for both males and females. No specific dose-related changes of haematological or biochemical parameters were observed. Females of the high-dose group exhibited slightly, but significantly, higher kidney weights. Histologically, however, there was no difference in the severity of chronic nephropathy. A significant dose-dependent increase was observed in the relative brain weights of both male and female rats although no histological change was detected. A number of non-neoplastic lesions (e.g. myocardial fibrosis, bile-duct proliferation, hepatic microgranulomas and chronic nephropathy) were observed in all groups, with no difference in their incidence and/or degrees. None of the experimental groups showed a significant increase in the incidence of any specific tumours compared with the corresponding control value, and no positive trend was noted in the occurrence of any tumour. Male rats of the high-dose group showed a slightly higher incidence of pheochromocytomas and adrenal medullary hyperplasia, however there were no carcinogenic effects observed. Calcium lactate did not cause toxicity or carcinogenic activity in F344 rats. Thus, the high dose of 5 % represents the NOAEL for tumour formation in this study. The concentration of 5 % corresponds to calcium lactate doses of 2150 and 2280 mg/kg bw/d to male and female rats, respectively, which are equivalent to calcium doses of approximately 279.5 and 296.4 mg Ca/kg bw/d for male and female rats. Accordingly, the lower NOAEL value of 279.5 mg Ca/kg bw/d (male rats) is established as a NOAEL for carcinogenicity hazard assessment.

Considering the molecular weight of calcium (40.078) and calcium oxide (56.077 g/mol), this NOAEL can be converted into a NOAEL of 391 mg/kg bw/d.

Similarly, for calcium carbonate (100.0869 g/mol) the NOAEL would be 698 mg/kg bw/day.

A human clinical study (Baron, 1999; section 7.10.1) suggests a beneficial effect of calcium supplementation on cancer risk: Calcium supplementation is associated with a significant - though moderate - reduction of the risk of recurrent colorectal adenomas.

Furthermore, epidemiological data on cement workers (cement used as a surrogate for lime; s_Vestbo_1991_cement dust) indicate no increased overall cancer risk due to inhalation of cement dust in this population.