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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Documentation insufficient for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
secondary source
Title:
Nutrition and kidney calcification in rats
Author:
Ritskes-Hoitinga J, Lemmens AG, Beynen AC
Year:
1989
Bibliographic source:
Lab Anim.; 23(4):313-8; PMID: 2811270

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Female RIV-TOX rats were fed semipurified diets with different calcium and phosphate concentrations for 4 weeks. Nephrocalcinosis was determined chemically (by the analysis of calcium and phosphorus in the kidney) and histologically (by Von Kossa and H&E staining of kidney slices). In a separate experiment indicators of kidney function were assessed and distribution of calcification in different organs was examined by gross necropsy.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium dihydrogen phosphate
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: RIV-TOX
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: National Institute for Public Health and Environmental Protection, Bilthoven, the Netherlands
- Age at study initiation: 5 weeks
- Diet (e.g. ad libitum): semipurified diet containing defined amounts of calcium an phosphate
- Water (e.g. ad libitum): no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Duration and frequency of treatment / exposure:
4 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
are given in table 1
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
Nephrocalcinosis was determined chemically (by the analysis of calcium and phosphorus in the kidney) and histologically (by Von Kossa and H&E staining of kidney slices).
In a separate experiment, distribution of calcifcation in different organs was examined by gross necropsy.
Indicators of kidney function were: water intake, urinary volume, urine and plasma osmolarity, plasma urea and creatinine, urinary creatinine and urea excretion, urea and creatinince clearance and urinary albumin.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
An increase in dietary phosphorus level resulted in increased kidney calcium and high histological calcification scores. In rats fed diets with a low dietary phosphorus concentration (0.20%) no kidney calcification could be detected after 4 weeks.
Table 1 shows that there is more calcification on diets with calcium:phosphorus rations less than one compared to higher ratios. At a constant calcium level, a decrease on calcium:phosphorus ratio from 1.25 to 0.63 produced an increase in nephrocalcinosis. But an increase in calcium:phosphorus ratio by increasing calcium up to 0.50% (while keeping phosphorus constant at 0.40%) also increased nephrocalcinosis. At high calcium levels of 0.75 % and thus relatively high calcium_phosphorus ratios (1.88), nephrocalcinosis was minimal (kidney calcium: 0.1 ±0.2%, mean ±SD, n=6).
Dietary phosphorus induced kidney calcification is associated with considerable kidney damage throughout the whole corticomediullary layer. Of the parameters of kidney function, only urinary albumin excretion was increased significantly in rats fed the 0.6% phosphorus diet compared with those fed the diet containing 0.4% phosphorus.
The 0.6% phosphorus diet caused extensive calcification of the kidneys but no calcification was found in lung, stomach, aorta, liver, and heart, suggesting a preferred deposition of calcium phosphates in the kidneys. Macroscopically, the calcified kidneys were enlarged and had a flattened elongated appearance compared to control kidneys. Kidney weight, expressed as a percentage of body weight, was increased by about 25% in rats fed the high phosphorus

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Effect of dietary calcium:phosphorus ratio on nephrocalcinosis in female rats

Diet Ca [%]

0.25

0.25

0.50

0.50

Diet P [%]

0.20

0.40

0.40

0.80

Ca:P ratio

1.25

0.63

1.25

0.63

Kidney calcium content
[% dry weight]

0.4±

1.3±1.4

3.0±3.2

4.5±2.4

Mean ±SD, n=6

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Nephrocalcinosis in female rats is increased at calcium:phosphate ratios of <1 and at calcium concentrations between 0.25-0.75%. This calcification affects kidney function as increased urinary albumin excretion was noted in rats fed the high phosphorus diet. Calcification solely takes place in the kidneys which were enlarged and had an increased weight of about 25% compared to control animals’ kidneys.
Executive summary:

Female RIV-TOX rats were fed semipurified diets with different calcium and phosphate concentrations for 4 weeks. Nephrocalcinosis was determined chemically (by the analysis of calcium and phosphorus in the kidney) and histologically (by Von Kossa and H&E staining of kidney slices). In a separate experiment indicators of kidney function were assessed and distribution of calcifcation in different organs was examined by gross necropsy.

Nephrocalcinosis in female rats is increased at calcium:phosphate ratios of <1 and at calcium concentrations between 0.25-0.75%. The values given here indicate an increase in renal calcium content but are afflicted with high intra-individual variations. The observed calcification affects kidney function as increased urinary albumin excretion was noted in rats fed the high phosphorus diet. Calcification solely takes place in the kidneys which were enlarged and had an increased weight of about 25% compared to control animals’ kidneys.