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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
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:
A comparative study of fluoride pharmacokinetics in five species
Author:
Whitford, G.M., E.D. Hines and N.L. Birdsong-Whitford
Year:
1991
Bibliographic source:
J. Dental Research 70: 948-951, 1991

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was designed to quantitate and compare the major features of the short-term pharmacokinetics of fluoride [i.e., the plasma, renal, and extra-renal (calcified tissue) clearances] in young adult dogs, cats, rabbits, rats, and hamsters. Plasma and urine samples were collected for 7-hours after the iv administration of fluoride (0.5 mg F/kg). One objective was to obtain data that could be useful in predicting species-related differences in the susceptibility to acute toxic doses of fluoride. Another objective was to identify which of the 5 species most closely resembles the young adult human with respect to the quantitative features of the pharmacokinetics of fluoride.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Fluoride
Radiolabelling:
yes

Test animals

Species:
dog
Strain:
other: mongrel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Born and raised at the Medical College of Georgia
- Age at study initiation: 80-83 weeks
- Weight at study initiation: 18.03 +/- 1.29 kg
- Fasting period before study: Overnight
- Diet (e.g. ad libitum): Commercially available diet containing 8-28 ppm F ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 80-83 weeks


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:
intravenous
Vehicle:
physiological saline
Details on exposure:
Approximately 1 hour prior to the start of the experiment, a priming dose of hydroymethyl, 14C-inulin (1.20 uCi/kg body wt in isotonic saline) was given to each animal by intravenous injection. The sustaining dose of 14C-inulin (1.50 uCi/hr/kg body weight delivered by infusion pump) in isotonic saline was then started and administered throughout each study. Then, following the collection of a control blood sample, each experiment started (t=0) with the administration of the fluoride dose (0.5 mg F/kg, in 30 seconds, given by infusion pump).
Doses / concentrations
Remarks:
Doses / Concentrations:
A single dose of 0.5 mg fluoride/kg, in 30 seconds, given iv by infusion pump.
No. of animals per sex per dose:
3 dogs per sex per dose
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion):
- Tissues and body fluids sampled: urine, blood, plasma
- Time and frequency of sampling: Arterial blood samples were collected at 5, 15, 30, and 60 minutes and then at 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 7 hours. Urine was expressed from the bladder at frequent intervals, and the 7-hour volumes were recorded.


METABOLITE CHARACTERISATION STUDIES:
Plasma and urinary fluorde activities were determined by use of an Orion ion-specific electrode and a miniature calomel reference electrode that were coupled to a potentiometer. The urine samples were buffered with an equal volume of total ionic strength adustment buffer prior to analysis. The plasma samples were analyzed after overinight diffusion by a hexamethyldisiloxane-facilitated diffusion method. the 14C-inulin concentrations of plasma and urine were determined by liquid scintillation counting.

The pH values of dog, cat and rabbit urine samples were determined by a Radiometer BMS 3 Mk 2 Blood Micro System; pH values of rat and hamster were not determined.

The plasma (Cp), renal (Cr), extra-renal (Cer), or bone clearances of fluoride were calculated as follows: Cp = F dose/AUC t = 0 to infinity and Cr = F excreted in urine t = 0 to 7 hrs/AUC t = 0 to 7 hrs. Because fluoride is cleared from the body almost exclusively by the kidneys and calcified tissues, the extra-renal clearance was calculated as: Cer = Cp - Cr. The units for these calculations were: F dose and F excreted in urine = umol; AUC (area under time-plasma concentration curve) = umol/min/mL -1. The net AUC values for fluoride were used to calculate Cp. The AUC after the 7-hour time point was calculated by forward extrapolation of the terminal slope of the plasma [F] curve to the time at which the extrapolated and control plasma contol levels were equal. The total AUC values were used to calculate Cr. The plasma clearance of 14C-inulin was used to estimate the glomerular filtration rate (GFR), which was calculated as follows: GFR = ([14C]u X V)/[14C]p, where u and p represent urine and plasma, and V represents urinary flow rate.

Statistics:
The data were analyzed by factorial analysis of variance (ANOVA), and an alpha of 0.05 was selected a priori as the indicator for statistically significant differences. Fisher's protected least-significance difference (PLSD) test was used as the post hoc test. Results were expressed as mean +/- SE.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The 5-minute plasma fluoride concentrations were ordered as follows: dog > rabbit > rat > hamster > cat (concentrations were 110.8 +/- 14.3, 91.3 +/- 3.1, 78.4 +/- 5.3, 69.1 +/- 4.9, and 52.2 +/- 4.8 umol/L, respectively).




Details on excretion:
In terms of body weight, the plasma clearances were highest in the hamster, rat, and cat (8.60, 7.34 and 7.24 mL/min/kg, respectively), intermediate in the rabbit (5.80 mL/min/kg), and lowest in the dog (3.50 mL/min/kg). This result indicates that the hamster, rat and cat cleared fluoride from their extracellular fluids more than 2 times faster than did the dog. The plasma clearance of fluoride in the rabbit was 66% faster than that of the dog.

The renal clearance rates factored by body weight were highest in the rat and hamster (3.61 +/- 0.55 and 3.47 +/- 0.79 mL/min/kg, respectively) and lowest in the rabbit and dog (1.14 +/- 0.25 and 1.43 +/- 0.18 mL/min/kg, respectively). The renal clearance rate in the cat was 2.61 +/- 0.61 mL/min/kg.

The extra-renal (calcified tissue) clearances were highest in the hamster, cat and rabbit (>4.6 mL/min/kg), intermediate in the rat (3.73 +/- 0.21 mL/min/kg), and lowest in the dog (2.07 mL/min/kg).

The fractional renal clearances (percentages of fluoride filtered into the renal tubules that were not re-absorbed, but actually excreted in the urine) of the hamster and rat were 63.7% and 76.6%, respectively, thus approximately 2 times as high as those of the rabbit, cat, and dog (34%, 40% and 26%, respectivley).

As determined by linear regression analysis, there were statistically significant relationships between the renal clearance of fluoride (Cr/body wt) and urinary pH, urinary flow rate (mL/min/kg) and glomerular fitration rate ( mL/min/kg), in the combined dog, cat and rabbit data (pH values were not determined on the rat and hamster urine samples). When data from all species were combined, the relationship between renal clearance of fluoride and glomerular filtration rate was still significant, but that between renal clearance and urinary flow rate was not.

There were no statistically significant gender-related differences in the plasma, renal or extra-renal clearance data.

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Conclusions:
The study concluded that 1) there are major quantitative differences in the metabolic handling of fluoride among the five species (dog, cat, rat, rabbit and hamster) evaluated, and that 2) plasma, renal and extra-renal (calcified tissue) values of the young adult dog, when factored for body weight, resemble those of the young adult human most closely.