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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
no data available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well-documented study on the consequences of hypercalcaemia on systemic and renal haemodynamics. Under physiological conditions, the hydroxyl- and carbonate ions released from calcined dolomite following oral adminstration have been neutralised in the GI tract or have been released as CO2 and are therefore not relevant for consideration of toxicokinetics. Therefore for assessment of the metabolic fate of the systemically relevant species of 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 gluconate. Gluconate is 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, including its retention and fate in the human body. In view of the the limited relevance of the anionic counter-ions discussed here, calcium released both from calcined dolomite and calcium gluconate can be considered as structurally equivalent (analogue), and the results of the study can be used by read-across, fulfilling the provisions of Annex XI, point 1.5 of Regulation (EC) no 1907/2006.

Data source

Reference
Reference Type:
publication
Title:
Systemic and renal vascular responses to dietary calcium and vitamin D
Author:
Zawada, E.T.; et al.
Year:
1986
Bibliographic source:
Hypertension, 8, 975-982

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The consequences of hypercalcemia on systemic and renal haemodynamics, vasoactive hormones and excretion of water and electrolytes were studied in 10 female mongrel dogs received daily oral doses of 100 mg Ca gluconate and 10000 U of vitamin D per kg bw for two weeks. 10 other dogs who did not receive Ca and vitamin D served as control animals.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Calcium gluconate
EC Number:
206-075-8
EC Name:
Calcium gluconate
Cas Number:
299-28-5
IUPAC Name:
calcium bis(2,3,4,5,6-pentahydroxyhexanoate) (non-preferred name)
Details on test material:
- Name of test material (as cited in study report): Calcium gluconate
No further details are given.

Test animals

Species:
dog
Strain:
other: mongrel dogs
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 14 and 25 kg
- Diet: ad libitum; commercial dog chow (Purina, St. Louis, MO, USA)
- water: ad libitum

No further details are given.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
exposure group: doses of 100 mg Ca gluconate and 10000 U of vitamin D per kg bw .
control animals: did not receive Ca and vitamin D
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
2 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw calcium gluconate
Basis:
nominal in diet
No. of animals per sex per dose:
10 dogs
Control animals:
yes, plain diet
Details on study design:
no data
Positive control:
No positive control substance was tested.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE : No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: Yes. (for methodological details see below "Any other information on materials and methods incl. tables")
- Parameters checked: plasma renin activity, plasma aldosterone concentration, whole blood ionized calcium (iCa), ionized potassium, ionized sodium, total serum calcium, and serum magnesium (sMg).

URINALYSIS: Yes
- urinary excretion of Na and K were determined using ion-selective electrodes
- the urinary PGE2 concentration was measured

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
- Systolic and diastolic blood pressures and mean arterial pressure in the femoral artery were determined.
- Cardiac output and cardiac index were measured.
- Total peripheral resistance and renal resistance were calculated.
- Inulin and p-aminohippuric acid (PAH) clearances were measured by standard methods.
Sacrifice and pathology:
GROSS PATHOLOGY: No data
HISTOPATHOLOGY: No data
Other examinations:
no data
Statistics:
The values reported for each dog are the average of the baseline and 3 ensuing recording periods. In the case of the urine parameters the values reported are the average of the 3 results from the separate urine collections. Statistical analysis was by the Mann-Whitney U test. Parameters designated significant in the text are those in which the Mann-Whitney test showed significance with 95 % or greater confidence. Coefficients of correlation were calculated by regression analysis. Significant results are again set at 95 % or greater confidence limits.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL CHEMISTRY
- Serum Mg levels were significantly lowered.
- Aldosterone levels and plasma renin activity were not significantly affected.

URINALYSIS & OTHER FINDINGS
- Hypercalcemia induced by dietary supplementation with Ca and vitamin D resulted in significantly lower glomerular filtration rate, effective renal plasma flow, renal blood flow, and osmolarity.
- The renal resistance was increased in hypercalcemic dogs.
- Hypercalcemia also resulted in an increased fractional excretion of water, Na, Ca, and Mg.
- Systolic blood pressure and stroke volume were decreased in hypercalcemic dogs, while total peripheral resistance was increased.
- Urinary prostaglandin excretion were not significantly affected.

Effect levels

Dose descriptor:
NOAEL
Basis for effect level:
other: The study is not appropriate for derivation of an NOAEL, since only one dose level was administered.
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
These results suggest that hypercalcemia induced by chronic dietary supplementation increases total peripheral resistance and renal vascular resistance. The study is not appropriate for derivation of a NOAEL.