Magnesium fluoride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Read-across justification is provided in Appendix 3 of the CSR.

No experimental data on absorption, distribution and excretion is available of the target substance. As in aquatic environment, the target and source substances dissociate in water into Mg2+ / Na+ cations and or halogen anions it is relevant to use available toxicokinetic data on these ions in humans and laboratory animals.

Magnesium chloride and sodium fluoride are highly soluble in water and magnesium only moderately soluble in water. As absorption of inorganic metal salts is dependent upon the relative aqueous solubility, it is expected that the source substances are absorbed more effectively than the target substance via gastrointestinal tract.

In general, gastrointestinal absorption of metals remains significant challenge as several factors influence the absorption including the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Magnesium is mainly absorbed in the small intestine and stored primarily in bone and muscle following absorption. There is an apparent obligatory urinary loss of magnesium, which amounts to about 12 mg/day and the urine is the major route of excretion under normal conditions. Unabsorbed magnesium is excreted in the feces.
The absorption of ingested fluoride into the general circulation occurs primarily in the stomach and intestine. Fluoride is rapidly distributed by the systemic circulation to the intracellular and extracellular water of tissues; however, in humans and laboratory animals, approximately 99% of the total body burden of fluoride is retained in bones and teeth. Fluoride is eliminated from the body primarily in the urine.

Thus, the toxicokinetic data on other magnesium salts and inorganic fluorides is justified in the assessment of the target substance.

Data source

Reference

Reference Type:

publication

Title:

A Comparative Study of Fluoride Pharmacokinetics in Five Species

Author:

Whitford, G.M., Biles, E.D. and Birdsong-Whitford, N.L.

Year:

1991

Bibliographic source:

J Dent Res 70(6); 948-951

Materials and methods

Objective of study:

excretion

Principles of method if other than guideline:

- Principle of test: This study was designed to quantitate and compare the major features of short-term pharmacokinetics of fluoride (the plasma, renal, extra-renal clearances) in young adult dogs, cats, rabbits, rats, and hamsters. Plasma and urine samples were collected for seven hours after of iv administration of fluoride to calculate clearance values.

- Short description of test conditions:
- Parameters analysed / observed:

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Fluorides

IUPAC Name:

Fluorides

Details on test material:

No data

Specific details on test material used for the study:

Name of test material (as cited in article): Fluoride

Radiolabelling:

yes

Test animals

Species:

other: dogs, cats, rabbits, rats, hamsters

Strain:

not specified

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: physiological saline

Doses / concentrations

No. of animals per sex per dose / concentration:

Dogs (3M, 3F)
Cats (6F)
Rabbits (5M, 4F)
Rats (6F)
Hamsters (7F)

Details on study design:

Approx. one hour prior the start of the experiment a priming dose of hydroxymethyl 14C-inulin (1.20uCi/kg bw in isotonic saline) was given to each animal by iv injection. The sustaining dose of 14C-inulin (1.5 uCi/kg bw delivered by infusion pump) in isotonic saline was then started and administered throughout each study. Then, following the colectionof control blood sample, each experiment started (t=0) wiith the administration of the fluoride dose (0.5 mg F/kg, in 30s, given by infusion pump).

Details on dosing and sampling:

- Tissues and body fluids sampled: urine, blood
- 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.

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

Main ADME results

Main ADME results 1

Type:

other: plasma clearance

Results:

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).

Main ADME results 2

Type:

other: renal clearance

Results:

The renal clearance rates per body weight were highest in the hamster and rat (ca. 3.5 mL/min/kg), intermediate in the cat (2.61 mL/min/kg), and lowest in the dog and rabbit (1.43 mL/min/kg and 1.14 mL min/kg, respectively).

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 distribution in tissues:

No data

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

The study concluded that there are major quantitative differences in the pharmacokinetics of fluoride among the five species (dog, cat, rat, rabbit and hamster) evaluated. Furthermore, the clearance rates of fluoride per body weight in plasma, renal and extra-renal (calcified tissue) of the young adult dog resemble those of human most closely.

Executive summary:

It can be concluded that among the species used in the present study, the quantitative features of the short-term pharmacokinetics of fluoride in the dog (Cp 2.7 mL/min/kg , Cr 1.1 mL/min/kg , Cer 1.7 mL/min/kg resemble those of the human (Cp 3.5 mL/min/kg , Cr 1.43 mL/min/kg , Cer 2.07 mL/min/kg) most closely. The rabbit was the species studied here least like the human.