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Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The publication contains sufficient information to permit a meaningful evaluation of study results; used for read across purposes

Data source

Reference Type:
Subchronic oral toxicity study of calcium lactate in F344 rats.
Matsushima, Y., Onodera, H., Nagaoka, T., Todate, A., Shibutani, M., Maekawa, A., Kurokawa, Y. and Hayashi, Y.
Bibliographic source:
Eisei Shikenjo Hokuku 107: 78-83

Materials and methods

Principles of method if other than guideline:
13 wk feeding study with calcium lactate.
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
Calcium lactate
EC Number:
EC Name:
Calcium lactate
Cas Number:
calcium bis(2-hydroxypropanoate)
Details on test material:
Test substance: Calcium lactate pentahydrate as a food additive, which is 2-Hydroxypropanoic acid calcium salt C6H10CaO6•5H2O 308.30) [Musashino Chemical Laboratory, Ltd.], is white powder or granules and odorless or has a slight specific odor. This product contains calcium lactate at 97.0% to 101.0% when calculated as a dried product. The purity examination showed that the product was colorless and clear, that its pH was 6.0 to 8.0, that its heavy metal was 20 μg/g maximum (Pb), that its alkaline metal and magnesium were 1% maximum, and that its arsenic was 4 μg/g maximum (As2O3).

Test animals

Fischer 344/DuCrj
Details on test animals or test system and environmental conditions:
Animals: Five-week-old SPF male and female F344/DuCrj rats (Charles River Laboratories Japan, Inc.) were fed and acclimated for 1 week and then divided into 2 groups. Feeding conditions: White flakes were used as bedding in a plastic cage. The animals were fed in a animal feeding room of a semi-barrier system.

Administration / exposure

Route of administration:
other: both feed and water
Details on oral exposure:
Experiment I
Calcium lactate was dissolved in ion-exchanged water at concentrations of 5, 2.5, 1.25, 0.6, and 0.3% since it was water-soluble and stable. Each experimental group was given ad libitum one of these solutions as the drinking water for 13 weeks. The control group was similarly given only ion-exchanged water. Each group was given ad libitum elemental diet (CRF-1 manufactured by Oriental Yeast Co., Ltd.). The highest dose was set based on the fact that the maximum solubility of this product in water was 5%. Each 5 male and female rats from each group were used, and all the surviving animals were sacrificed for autopsy in the 13th week.

Experiment II
Ten male and ten female were used. Calcium lactate was mixed at 30, 20, 10, 5, and 0% in the standard blend of purified diet [B-blend powder diet (Oriental Yeast Co., Ltd.)] and given ad libitum to the animals for 20 weeks. Each 5 male and female rats from each group were autopsied in the 8th week after the start of the experiment, and the remaining rats were sacrificed for autopsy in the 20th week.

Experiment III
Twenty male rats were divided into 2 groups. One group was given the B-blend powder diet, while the other group was given at libitum the CRF-1 solid diet. The rats in both groups were given ad libitum ion-exchanged water as the drinking water. Five rats from each group were sacrificed in the 4th week after the start of the experiment and the remaining rats were sacrificed for autopsy in the 8th week.
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
13 wks for Exp I, 20 wks for Exp II and 8 wks for Exp III
Frequency of treatment:
ad libitum
Doses / concentrationsopen allclose all
Doses / Concentrations:
5, 2.5, 1.25, 0.6, and 0.3% in water
nominal in water
Doses / Concentrations:
30, 20, 10, 5, and 0% in food
nominal in diet
No. of animals per sex per dose:
Control animals:
Details on study design:
No data
Positive control:


Observations and examinations performed and frequency:


- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- 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 collection of blood: 8 wks / end of study



Sacrifice and pathology:

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Details on results:
No mortality occured in all experiments.

Exp I: body wights decreased in the high dose, still within the 10% of the control group. Minor changes in some hematological and biochemical parameters, suggesting nephrotoxicity and hepatotoxicity at the high dose group; however, not accopmpanied by histological findings. Only histopathological finding relevant to treatment in the high dose group was some mild effects: localized erosion, necrosis and atrophy in the mucosa of the grandular stomach.
Exp II: Body weights significantly reduced in the 30% group. Histological examination showed nephrocalcinosis in all groups, including the control.
Exp III: nephrocalcinosis detected only in the group fed with the synthetic diet B.

All observed effects could be attributed to calcium overload/imbalance. No lactate toxicity was observed.

Effect levels

Dose descriptor:
Effect level:
1 510 mg/kg bw/day (nominal)
Based on:
other: lactic acid (conversion on a molar basis of lactate in calcium lactate)
Basis for effect level:
other: overall effects; no severe toxicological findings detected.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

5% calcium lactate in drinking water or diet does not result in adverse effects attributable to lactate.
Executive summary:

The subchronic toxicity of calcium lactate was studied using F344 rats. In Experiment I, calcium lactate was mixed at 5, 2.5, 1.25, 0.6, and 0.3% in the drinking water and the rats were given this solution ad libitum for 13 weeks. As a result, the inhibition of body weight gain in the 5% group fell within 10% of that in the control group. Some examination values showed variations in the hematological and hematobiochemical studies, but no controversial findings were obtained in the pathohistological search. Since the highest solubility of calcium lactate is 5%, Experiments II and III were carried out by giving blended diet in order to study the toxicity at higher doses. In Experiment II, calcium lactate was mixed at concentrations of 30, 20, 10, and 5% in the B-blend powder diet and then the rats were given this diet ad libitum for 20 weeks. In Experiment III, the rats were given the CRF-1 or the B-blend powder diet ad libitum for 8 weeks. As a result, in Experiment II, nephrocalcinosis was observed in all the groups including the control group. The degree of the lesion was in reverse correlation with the administered concentrations of calcium and the lesion was seen more intensely in female rats. In Experiment III, nephrocalcinosis resulting from the administration of the B-blend diet was already observed in the 4th week. Nephrocalcinosis as observed in Experiments II and III was attributable to the small Ca/P value in the B-blend diet.

From the above results, the optimal dose for a long-term toxicity/carcinogenicity study has been determined to be 5 and 2.5% based on the values obtained from Experiments I.