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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:
other: high
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 for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium
Author:
Bo-Linn, G.W.; Davis, G.R.; Buddrus, D.J.; Morawski, S.G.; Santa Ana, C.; Fordtran, J.S.
Bibliographic source:
J Clin Invest 73(3): 640–647

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, calcium was administered by either a low calcium meal, a low calcium meal supplemented with CaCO3 or calcium citrate, or a high calcium meal. Rectal effluent collected, Ca measured by AAS, and net absorption calculated as Ca ingested minus Ca in effluent. For assessment of the significance of gastric pH on absorption, a large dose of cimetidine was administered, reducing gastric acid secretion.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Various calcium sources, either dieatary or in the form of carbonate or citrate
IUPAC Name:
Various calcium sources, either dieatary or in the form of carbonate or citrate
Details on test material:
1)
- Name of test material (as cited in study report): Calcium citrate
- Molecular formula (if other than submission substance): C12H10Ca3O14
- Molecular weight (if other than submission substance): 498.44 g/mol
- Physical state: Solid
- Analytical purity: No data
- 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: Miles Laboratories, Inc., Elkhart, IN, USA; effervescent tablets, containing calcium carbonate and citric acid; when added to water, they effervesce, thus liberating calcium citrate.

2)
- 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: No data
- 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: Marion Laboratories, Kansas City, MO, USA; Os-Cal tablets; calcium carbonate is contained as crushed oyster shell.

Method

Type of population:
general
Subjects:
- Number of subjects exposed: 16
- Sex: Male and female (12/4)
- Age: 21-36 (mean: 28) years
- Race: No data
- Demographic information: No data
- Known diseases: The above subjects were reported to be healthy. In addition, one female subject (aged 57 years) was included who had pernicious anaemia and, following s.c. injection of 6 µg/kg bw pentagastrin, gastric achlorhydria (lowest gastric pH = 7.4); four additional subjects with chronic renal disease on haemodialysis took part in the validation studies, but not in experiments on the effects of gastric acid on absorption .
- Other: No data
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:
Low calcium meal:
170 g sirloin steak, seasoned with salt and pepper, 25 g white bread with 5 g margarine, 40 g lettuce with 30 g French salad dressing, 250 mL tea with 5 g sugar, and 10 g of PEG. Ca content: 71 ± 1 mg (verified by AAS).
High calcium meal:
Ditto, except that 250 mL skim milk was substituted for the tea and 57 g Swiss cheese was melted on the steak. Ca content: 852 ± 1 mg (verified by AAS).
Meal for validation studies only:
57 g sirloin steak, 25 g white bread, 40 g lettuce with 30 g French salad dressing, 30 g Swiss cheese, 250 ml tea with 5 g sugar, and 10 g PEG. Ca content: 290 ± 3 mg (verified by AAS).

Calcium supplements:
Calcium carbonate tablets were swallowed with 200 mL water.
Calcium citrate was taken by effervescing tablets in 200 mL water after cessation of effervescence.
Supplements were taken 1 h after start of the meal (unless otherwise stated).

Procedure:
After an overnight fast, subjects underwent gastric lavage using Golytely (Braintree Scientific, Inc., Braintree, MA, USA), received either orally as 300 mL portions every 10 min, or by intragastric infusion (30 mL/min). After 4 h lavage, the rectal effluent was totally clear and contained no unabsorbed dietary nutrients (previous studies from this laboratory). The rectal effluent from the first washout was discarded.
The test meal was taken 4 h after completion of this first lavage. 12 h after the meal, without further ingestion of food or drink, the subjects underwent a second (final) lavage, lasting 3 h. The rectal effluent from this final lavage was combined with any stool (usually none) that had been passed since the meal was eaten.
Examinations:
The rectal effluent was collected and homogenised in Waring commercial blender. 10 mL 2-octonol were added as a foam suppressant. 20 mL homogenate were transferred to acid-washed glass flasks and digested with 20 ml of 16 N nitric acid to dissolve any insoluble calcium. The homogenate was then brought to 100 ml volume with deionised water in an acid-washed volumetric flask. Duplicate aliquots were analysed for calcium by atomic
spectroscopy (model 2380, Perkin-Elmer Corp., Norwalk, CT).
Homogenised but undigested samples were analysed for PEG by the method of Hyden (1955).
Medical treatment:
Not applicable

Results and discussion

Clinical signs:
Not applicable.
Results of examinations:
Sensitivity study:
Average net calcium absorption (n=9) in relation to Ca intake was found to be as follows (mean ± SE):
Intake 321 mg: 90 ± 27 mg (28.0 %)
Intake 571 mg: 198 ± 30 mg (34.7 %)
Intake 1071 mg: 318 ± 50 mg (29.7 %)

Main absorption study:
Net calcium absorption (n=6) in relation to Ca intake is presented in detail in Table 1 ("any other information on results incl. tables") below. Thus, when calcium was supplemented, net absorption was 23.6-29.7 %, whereas dietary calcium was absorbed by 15.5 %.

Gastric acid suppressed by cimetidine:
See the attached figure; precise values are never reported in the publication nor are these extractable from the figure. However, the graphical presentation demonstrates that calcium is absorbed at a similar rate from both carbonate and citrate, irrespective of gastric acid being suppressed or not.

Studies in a patient with gastric achlorhydria:
In the achlorhydric patient, net calcium absorption was higher than in normal patients, irrespective of being treated with cimetidine or not - see attached figure for details.

Studies with gastric pH maintained at 3.0 and 7.4:
Absorption was similar on test days with gastric pH maintained at 3.0 and 7.4, achieving approximately 41-43 % (see Table 2 below).
Effectivity of medical treatment:
Not applicable.
Outcome of incidence:
Not applicable.

Any other information on results incl. tables

Table 1: Net calcium absorption results from the main absorption study (n=6)

  Calcium intake [mg]  Ca in effluent [mg]  Net absorption [mg]  Net absorption [%] 
Fast  0  42 ± 5  -  -
Low Ca meal   71  110 ± 23 3 ± 22  n.a.
Low Ca meal + CaCO3 tablets   1071  860 ± 61  255 ± 58  23.8
Low Ca meal + Ca citrate   1071  802 ± 48  310 ± 52  29.0
High Ca meal  852  760 ± 49  132 ± 50  15.5

Table 2: Net calcium absorption when gastric pH is maintained at 7.4 or 3.0 by in vivo intragastric titration

 

Calcium intake [mg]

Calcium in effluent [mg]

Net calcium absorption [mg]

Net calcium absorption [%]

Fast

0

41.4 ± 4

Gastric pH 7.4

1063

645 ± 87

458 ± 87

43.1

Gastric pH 3.0

1063

662 ± 63

441 ± 63

41.5

Results are given as mean ± SE. Calcium intake was 1063 mg, mainly in the form of calcium carbonate (n = 8) (low calcium meal [minus lettuce and salad dressing] supplemented with 1000 mg calcium as CaCO3).

Applicant's summary and conclusion

Conclusions:
This study demonstrates that, contrary to intuitive expectation, gastric pH is not negatively correlated with intestinal calcium absorption. Calcium from supplement of low (CaCO3) and high (Ca-citrate) water solubility are equally well absorbed. Therefore, physiological factors in the intestine instead of solubility of a specific salt or gastric pH are likely to determine bioavailability. An intestinal absorption rate of approximately 30 % can be derived for supplementary calcium.
Since lime will be exposed to the same pH regimes if ingested, also lime can be expected to be subjected to equivalent physiological processes. An absorption rate of approximately 30 % can therefore be assumed for lime by read-across from calcium carbonate.