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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The test parameters evaluated in this study do not totally comply with a specific test guideline, but are well documented and scientifically acceptable. The study was not in GLP compliance.

Data source

Reference
Reference Type:
publication
Title:
Fate of fluoride following its administration into a biological system - an in vivo study
Author:
Susheela, A.K., Y.D. Sharma, Mohan Jha, M. Singh, B. Jagannath and S.K. Jain
Year:
1982
Bibliographic source:
Fluoride 15(4): 173-177, 1982

Materials and methods

Objective of study:
other: pharmacokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Rabbits were administered daily oral doses of 10 mg sodium fluoride/kg body weight by gavage for various periods of time and then levels of fluoride in serum, urine, noncalcified tissues, calcified tissues, and erythrocyte membrane and hemolysate were estimated at different time intervals for the purpose of understanding how much fluoride was deposited, how much is excreted, and what quantity of fluoride was in circulation.
GLP compliance:
no

Test material

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

Test animals

Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: 2 months
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data-


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Duration and frequency of treatment / exposure:
Rabbits were treated with sodium fluoride (10 mg/kg) by daily gavage for at least 10 months; some animals used to evaluate urinary fluoride levels were treated for up to 25 months
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg/kg body weight
Details on study design:
In rabbits administered daily oral doses of 10 mg sodium fluoride/kg body weight administered by gavage for various periods of time, serum fluoride levels, urinary fluoridie levels, fluoride levels in non-calcified tissues (skeletal muscle, liver and kidney), and fluoide levels in erythrocyte membrane and hemolysate were estimated at different time intervals for the purpose of understanding how much fluoride was deposited, how much was excreted, and what quantity of fluoride was in circulation.

Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion):
- Tissues and body fluids sampled: Serum, urine, non-calcified tissues (skeletal muscle, liver and kidney), calcified tissue (cortical bone from diphyseal region of femur and cancellous bone from the iliac crest region of the pelvic girdle), and erythrocyte membrane and hemolysate.
- Time and frequency of sampling: Serum fluoride levels were taken at intervals of 1, 2, 3, 6, 8 and 10 months, urinary fluoride levels were assessed at 1, 5, 10, 12, 15, 16, 30, 45 and 46 days, and at 10-11 and 20-25 months, fluoride levels in non-calcified tissues (skeletal muscle, liver and kidney) were assessed at 6 months, and fluoide levels in erythrocyte membrane and hemolysate were assessed at 3 and 6 months.

- Serum fluoride was determined by using a fluoride ion specific electrode in a PHM 84 Research pH meter (radiometer).

- The pH of the urine was adjusted to 5 mL with 0.1 M acetate buffer (pH 5.2) and then the fluoride ion concentration was determined by a fluoride ion specific electrode.

- After ashing, fluoride content in samples of skeletal muscle, liver and kidney that were determined by fluoride ion specifice electrode.

- Marrow free cortical and cancellous bone were defatted in an ether-acetone mixture (1:1 v/v) and dried in acetone and then the fluoride in dry defatted bone ash was determined using a PHM 84 Research pH meter (radiometer) with a fluoride ion specific electrode.

- Erythrocytes were separated by centrifugation at 300 X g for 10 minutes at 4 degrees. Fluoride content of erythrocyte fluid (hemolysate) and that of the membrane was determined by the fluoride ion specific electrode using a PHM 84 Research pH meter (radiometer).





Statistics:
No specific statistical methods were reported. Fluoride levels were expressed as mean +/- standard deviations.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Serum Fluoride Level in Rabbits Following Daily Sodium Fluoride Oral Administration (10 mg/kg)
ppm Fluoride (Mean +/- SD)
Normal 0.07 +/- 0.02
1 month treated (5)* 0.29 +/- 0.04
2 months treated (5)* 0.35 +/- 0.08
3 months treated (5)* 0.40 +/- 0.02
6 months treated (3)** 0.36 +/- 0.08
8 months treated (3)** 0.45 +/- 0.06
10 months treated (3)** 0.50 +/- 0.01
Number in ( ) = Number of experiments.
* P value <0.05; ** P value < 0.005

Fluoride Level (ppm - wet tissue wt.) in Non-Calcified Tissues Following Daily Sodium Fluoride Oral Administration (10 mg/kg) for 6 Months
Tissue Normal [Mean +/- SD] NaF Treated [Mean +/- SD]
Skeletal muscle 0.22 +/- 0.05 0.41 +/- 0.05*
Liver 0.17 +/- 0.05 0.41 +/- 0.12*
Kidney 0.16 +/- 0.04 0. 50 +/- 0.10*
Four experiments in each group. * All treatment values significant at P < 0.005.

Fluoride Level (ppm - dry defatted bone ash) in Calcified Tissues Following Daily Sodium Fluoride Oral Administration (10 mg/kg)
Cortical Bone [Mean +/- SD] Cancellous Bone [Mean +/- SD]
Normal 805 +/- 43.7 895 +/- 57.7
6 months 3873 +/- 468.2* 5870 +/- (2)*
8 months 3817 +/- 407.2* 7467 +/- 550.8*
10 months 3700 +/- 264.6* 7550 +/- 477.0*
Three experiments at each month, except two experiments at 6 months, as indicated by (2).
* P value for bone fluoride <0.005.

Fluoride Level (ppm) of Rabbit Erythrocyte Membrane and Hemolysate Following Daily Sodium Fluoride Oral Administration (10 mg/kg)
Erythrocyte Membrane* Hemolysate**
Normal 0.032 +/- 0.006 0.006 +/- 0.004
3 months 0.042 +/- 0.009*** 0.081 +/- 0.013****
6 months 0.043 +/- 0.005*** 0.082 +/- 0.013****
* ppm Fluoride in membrane suspension containing 10 mg protein/mL
** ppm Fluoride/g % hemoglobin of hemolysate
*** P value < 0.05; **** P value < 0.005
Details on excretion:
Urinary Fluoride Content Following Daily Sodium Fluoride Oral Administration (10 mg/kg)
Mean +/- SD
Normal 1.46 +/- 0.62
1 Day treated 1.50 +/- 0.00
5 Days treated 2.83 +/- 0.66
10 Days treated 2.94 +/- 2.20
12 Days treated 2.02 +/- 2.90
15 Days treated 4.39 +/- 3.22
16 Days treated 5.18 +/- 2.88
30 Days treated 5.66 +/- 4.06
45 Days treated 4.12 +/- 1.15
46 Days treated 3.63 +/- 3.32
10-11 months treated 2.59 +/- 1.52
20-25 months treated 1.64 +/- 1.22

Applicant's summary and conclusion

Conclusions:
- Following sodium fluoride ingestion, the circulating level of fluoride was enhanced. The increase in fluoride content was proportionate to the duration of sodium fluoride administration, at least up to 10 months.
- Urinary fluoride content data revealed that, due to sodium fluoride ingestion, the amount of excreted fluoride increased up to 30 days. Thereafter, for unknown reasons, fluoride excreation gradually diminished towards normal limits.
- Cortical and cancellous bone differed significantly in their fluoride content. Cancellous bone, upon sodium fluoride administration, showed greater affinity for fluoride uptake, possibly due to its greater surface area exposed to circulation.
- Fluoride content data of non-calcified tissues showed that less fluoride was taken up when compared to calcified tissue. However, in non-calcified tissues it was evident that different organ tissues varied in their affinity for fluoride and in their fluoride content. Upon sodium fluoride administration, all soft tissues investigated, including the erythrocyte membrane and hemolysate, showed enhanced fluoride content.