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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented, peer-reviewed publication following basic scientific principles. Under physiological conditions, the hydroxyl-ions released from lime following oral adminstration have been neutralised in the GI tract 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 carbonate. The carbonate ion is released as CO2 following reaction with gastric juice and is therefore toxicologically not relevant. The objective of the study was the evaluation intestinal absorption of calcium from various sources. In view of the the limited relevance of the anionic counter-ions discussed here, calcium released both from calcium hydroxide and calcium carbonate can be considered as structurally equivalent, and the results of the study can be used by read-across.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Gastrointestinal absorption of calcium from milk and calcium salts
Author:
Sheikh, M.S.; Santa Ana, C.A.; Nicar, M.J.; Schiller, L.R. Fordtran, J.S.
Year:
1987
Bibliographic source:
The New England Journal of Medicine 317: 532-536

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Absorption measured in human subjects.
Following GI tract lavage, various forms of Ca were administered, rectal effluent collected, Ca measured by AAS, and net absorption calculated as Ca ingested minus Ca in effluent.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
1)
- Name of test material (as cited in study report): Calcium acetate monohydrate
- Molecular formula (if other than submission substance): Ca(C2H3O2)2*H2O
- Molecular weight (if other than submission substance): 158.17 g/mol (anhydrous)
- Physical state: Solid
- Analytical purity: "Reagent grade"
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: Supplier: J.T. Baker Chemical, Phillipsburg, N.J., USA
2)
- Name of test material (as cited in study report): Calcium lactate pentahydrate
- Molecular formula (if other than submission substance): C6H10CaO6*5H2O
- Molecular weight (if other than submission substance): 218.22 g/mol (anhydrous)
- Physical state: Solid
- Analytical purity: 98 %
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: Supplier: Eastman Kodak, Rochester, N.Y., USA
3)
- Name of test material (as cited in study report): Calcium gluconate
- Molecular formula (if other than submission substance): C12H22CaO14
- Molecular weight (if other than submission substance): 448.39 g/mol (anhydrous)
- Physical state: Solid
- Analytical purity: Pharmacopeia grade
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: Supplier: Mallinckrodt
4)
- Name of test material (as cited in study report): Calcium citrate tetrahydrate
- Molecular formula (if other than submission substance): C12H10Ca3O14 * 4 H2O
- Molecular weight (if other than submission substance): 498.44 g/mol (anhydrous)
- Physical state: Solid
- Analytical purity: Analytical grade
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: Supplier: Fluka, Switzerland
5)
- Name of test material (as cited in study report): Calcium carbonate
- Molecular formula (if other than submission substance): CaCO3
- Molecular weight (if other than submission substance): 100.09 g/mol
- Physical state: Solid
- Analytical purity: Analytical grade
- Impurities (identity and concentrations): No data
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Other: Supplier: Mallinckrodt, Paris, Ky., USA

Method

Type of population:
general
Subjects:
- Number of subjects exposed: 8
- Sex: Male
- Age: 25-30 years
- Race: No data
- Demographic information: No data
- Known diseases: All subjects had normal results on a breath-hydrogen test for lactose tolerance. No other data on diseases were reported.
Ethical approval:
confirmed and informed consent free of coercion received
Remarks:
(Project approved by the Institutional Review Board for Human Protection at Baylor University Medical Center)
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
Absorption of calcium from single ingestion of various calcium sources in human volunteers. Following fasting and gastric lavage, ensuring complete defaecation, subjects received defined doses of calcium salts (in gelatine capsules), followed by a meal after 4 h and a second lavage after 6 h. An equivalent procedure was employed using whole milk as calcium source, containing 500 mg Ca (verified analytically).
Polyethylene glycol was co-adminstered as non-absorbable marker.
Examinations:
The rectal effluent was collected and calcium determined by AAS as described in a separate study (Bo-Linn et al., 1984). Net calcium absorption was calculated taking into account the ingested dose,
calcium in effluent and calcium excreted after placebo administration (correction for background losses).
Polyethylene glycol in rectal effluent was determined using a turbidometric method (Hyden, 1955).
Other parameters: 1,25 dihydroxy-vitamin D in blood samples drawn immediately before calcium administration.
Medical treatment:
none

Results and discussion

Clinical signs:
not applicable
Results of examinations:
The mean recovery of polyethylene glycol in the rectal effluent was 100.5 ± 0.4 %.
Calcium content in effluent after administration of placebo (i.e., background excretion) was 59 ± 8 mg (mean ± SE).
Considering the background level, net calcium absorption from the different sources was determined as follows (Mean ± SE):
Calcium carbonate: 39 ± 3 %
Calcium acetate: 32 ± 4 %
Calcium lactate: 32 ± 4 %
Calcium gluconate: 27 ± 3 %
Calcium citrate: 30 ± 3 %
Whole milk: 31 ± 3 %
There were no significant differences in Ca absorption among the investigated sources (ANOVA, p = 0.22).
1,25 dihydroxy-vitamin D levels in blood were 35 pg/ml on average. There were no significant differences between Ca treatment groups (ANOVA, p = 0.42).
Effectivity of medical treatment:
Not applicable
Outcome of incidence:
Not applicable

Any other information on results incl. tables

In vitro solubility tests:

Percentages of 500 mg Ca dissolved at 1 h, depending on pH, is presented in the following table:

Calcium salt

pH not adjusted

% dissolved

 

pH 5.0

pH 2.5

Calcium carbonate

1

86

100

Calcium citrate

17

23

100

Calcium gluconate

100

100

100

Calcium lactate

100

100

100

Calcium acetate

100

100

100

Results were similar at 15 and 30 minutes, except that for calcium carbonate, which showed progressively increasing dissolution over time at pH 5. In deionised water, calcium carbonate and citrate remained largely undissolved.

Applicant's summary and conclusion

Conclusions:
No significant differences were found for intestinal net calcium absorption from various sources of different solubility. Calcium was absorbed equally well even from a poorly soluble salt like calcium
carbonate. This may be due to the fact that during gastric passage stable pH regimes are encountered (pH approximately 2.5 in the stomach and 8.0 in the small intestine); therefore, physiological factors
instead of solubility of a specific salt are likely to determine bioavailability.
Since lime will be exposed to the same pH regimes if ingested it can be expected to be subjected to equivalent physiological processes. An absorption rate of approximately 30 % can therefore be assumed
for lime, e.g. by read-across from calcium carbonate