Calcium oxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic 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 publication. 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 systemic toxicity. Therefore for assessment of any systemic effects 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 of any effects of calcium. 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.

Data source

Reference

Reference Type:

publication

Title:

Effects of dietary calcium, phosphorus, calcium:phosphorus ratio and vitamin K on performance, bone strength and blood clotting status of pigs

Author:

Hall, D.D.; et al.

Year:

1991

Bibliographic source:

J Anim Sci, 69, 646-655

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The effects of various calcium:phosphorus ratios in corn-soybean meal diets having deficient, adequate and excess levels of dietary P on rate and efficiency of body weight gain and bone strength of pigs were evaluated.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Calcium carbonate

EC Number:

207-439-9

EC Name:

Calcium carbonate

Cas Number:

471-34-1

Molecular formula:

CH2O3.Ca

IUPAC Name:

calcium carbonate

Details on test material:

- Name of test material (as cited in study report): Calcium carbonate
No further details are given.

Test animals

Species:

pig

Strain:

other: Hampshire-Yorkshire crossbred pigs

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: from the University of Kentucky swine research herd
- Weight at study initiation: 16-18 kg
- Housing: The pigs were housed in raised pens with expanded metal floors in a temperature controlled building.
- Diet: ad libitum; the basal diet consisted of corn and soybean meal calculated to contain 0.8 % lysine. The basal diet also contained an
antibiotic (chlortetracycline, 110 mg/kg). Prior to and during the time this research was conducted, vitamin K was not added to any of the diets in the herd from which the experimental pigs originated.
- Water: ad libitum

No further details are given.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

- Levels of Ca and P in basal diet were achieved by adjusting the amounts of ground calcitic limestone and dicalcium phosphate.
- Trace minerals and vitamins (but not vitamin K) were added to meet or exceed NRC (1979) standards.
- Because of the high level of Ca added to certain diets, Zn was included at 200 mg/kg.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

- Exp. 1: 28 days.
- Exp. 2: each diet was fed for 42 days.
- Exp. 3: 28 d without Vit. K; after 28 d, vitamin K was added to half of the diets, and the experiment was continued for an additional 22 days.

Frequency of treatment:

continously

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.3% Ca
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.6 % Ca
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0.9 % Ca
Basis:
nominal in diet

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1.2 % Ca
Basis:
nominal in diet

Doses / concentrations 5

Remarks:

Doses / Concentrations:
1.8 and 2.7 % Ca
Basis:
nominal in diet

No. of animals per sex per dose:

Exp. 1: each diet was fed to 4 pen-replicates of 2 pigs (one barrow and one gilt)/pen.
Exp. 2: each diet was fed to three pen-replicates (two pens of one pig each and one pen of two pigs; two barrows, two gilts/ treatment).
Exp. 3: each of the 12 diets was fed to three pen-replicates of two pigs (one barrow and one gilt) each.

Control animals:

not specified

Details on study design:

- Rationale for animal assignment (if not random): The pigs were allotted randomly to treatments from outcome groups based on weight within sex and ancestry.

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: no data

DETAILED CLINICAL OBSERVATIONS: no data

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

FOOD EFFICIENCY: No data

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

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes, blood was collected from all pigs by jugular puncture.
- Time schedule for collection of blood: at the initiation of experiment 2 and 3, on day 28 in exp. 2, and at the end of the experiment
- How many animals: all animals
- Parameters checked: whole blood and prothrombin clotting times were determined (all experiments)

CLINICAL CHEMISTRY: Yes, blood was collected from all pigs by jugular puncture.
- Time schedule for collection of blood: at the initiation of experiment 3, and at the end of the experiment
- How many animals: all animals
- Parameters checked: Ca was analysed in plasma (exp. 3)

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: No data
HISTOPATHOLOGY: No data

Other examinations:

At the termination of each trial, the pigs from two replications were killed (electrically stunned and bled) and the third and fourth metatarsals and metacarpals were removed from each rear and front foot. The two femurs also were removed. Breaking strength was determined on these bones using an Instron instrument: Fresh bones were placed in a horizontal position on two supports placed 3.5 cm apart for the metatarsals and metacarpals and 8.5 cm apart for the femurs. The amount of force, applied at the center of the bone, required to break the bone was defined as breaking strength. The procedures were similar to those described by Cromwell et d. (1972).
These same bones also were removed from all pigs that died during the experiment.

Statistics:

The data in each experiment were analysed as a randomised complete block design by variance procedures (Steel and Torrie, 1980) using the GLM procedure of SAS (1985). In all cases, the pen was considered as the experimental unit. In the fust model, Ca:P ratio, P level, vitamin K, replication within trial and the appropriate interactions were included in the model. The second model included Ca, vitamin K, replication within trial and the interactions.
Replication x treatment within trial was considered the error term. For pigs that died, gain, feed intake and feed/gain up to time of death were included in the data set.

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

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):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

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 SIGNS AND MORTALITY
- Reversal of haemorrhagic condition induced by feeding high dietary Ca for 28 days was observed after addition of vitamin K as indicated by a return to basal prothrombin values by day 50.

BODY WEIGHT AND WEIGHT GAIN
- Increasing the Ca:P ratio from 1:1 to 2:1 or 3:1 tended to reduce rate and efficiency of weight gain at all phosphorus levels.

HAEMATOLOGY
- The prothrombin and whole blood clotting times were increased in pigs fed the high Ca level (2.7 %) without addition of vitamin K for 28 days, but were normal in pigs fed high dietary Ca with added vitamin K (5 mg/kg diet).

OTHER FINDINGS
- Increasing the Ca:P ratio to 2:1 resulted in an increased bone strength only when P was at or above the dietary requirement.
- Bone breaking strength was markedly reduced in pigs fed the deficient P level (0.3 %) compared with the two higher levels of 0.6 and 0.9 % P.

Effect levels

Dose descriptor:

NOAEL

Basis for effect level:

other: The study is not appropriate for derivation of an NOAEL, since effects of Ca-P interactions at various Ca:P ratios were investigated.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The results indicate that excessive levels of dietary Ca interfered with normal blood clotting mechanisms in growing pigs fed a grain-soy bean meal diet without supplemental vitamin K. Obviously the gut synthesis of vitamin K may not meet the pigs' requirements for vitamin K, especially when diets are fortified with high levels of Ca. The study is not appropriate for derivation of an NOAEL.