Magnesium fluoride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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.

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

Specific details on test material used for the study:

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

Radiolabelling:

yes

Species:

other: dogs, cats, rabbits, rats, hamsters

Strain:

not specified

Route of administration:

intravenous

Vehicle:

other: physiological saline

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.

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).

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).

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

Metabolites identified:

no

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.

Reference 2

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:

data from handbook or collection of data

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.

Objective of study:

absorption

distribution

excretion

Type:

absorption

Results:

40-60 %

Type:

excretion

Results:

12 mg / day in the urine

Type:

distribution

Results:

stored primarily in bone and muscle

Details on absorption:

Magnesium absorption following oral ingestion is reported to range from 40 to 60%, with a lower percentage of absorption at higher daily intakes. The transport of magnesium into or out of cells appears to require a carrier-mediated transport system, and a Mg2+/H+ exchanger has only recently been described Arabidopsis thaliana. Magnesium decreases the absorption of fluoride, and excess calcium may partially inhibit the absorption.

Details on distribution in tissues:

In the plasma, magnesium is about 65% in the ionic form, with the remainder bound to plasma proteins. Of the approximately 20g of body burden of magnesium, most is stored primarily in bone and muscle following absorption. The reference value for magnesium in blood is 1.5-2.8 mg/dl. Intracellular concentrations of magnesium are much higher than serum concentrations.

Details on excretion:

The kidney is the primary organ involved in magnesium homeostasis, with filtration-reabsorption, but not tubular secretion, occurring. Approximately 12 mg of magnesium is excreted in the urine per day. Magnesium excretion can also occur via the sweat and breast milk. Hypermagnesiumenia has been reported in individuals with renal impairment; cardiac and neurological symptoms can occur if serum levels reach approximately 4.8-8.4 mg/dl. Unabsorbed magnesium is excreted in the feces.

Conclusions:

Magnesium absorption following oral ingestion is reported to range from 40 to 60%, with a lower percentage of absorption at higher daily intakes. Magnesium is stored primarily in bone and muscle following absorption. The kidney is the primary organ involved in magnesium excretion.

Description of key information

Magnesium fluoride is an inorganic compound with the formula MgF2. The compound is a white crystalline salt with a melting point of 1263°C, a boiling point of 2260°C. It has a density of 3.15 g/cm³ and water solubility of 0.076 g/L at 25 °C.

Magnesium is found in seawater and plant and animal tissues and is an essential element for human survival. Several enzymatic reactions in the body and physiological processes (such as muscle contraction, neuronal transmission) are dependent on the availability of magnesium. The recommended intakes vary from 30 mg / day (infants) to 420 mg / day (males over 70 years) (Patty’s Toxicology, 2001). 

Fluoride is present in small concentrations in practically all soils, water supplies and plants. Fluoride levels in surface waters generally range from 0.01 to 0.3 mg/litre. Seawater contains more fluoride than fresh water, with concentrations ranging from 1.2 to 1.5 mg/litre. Fluoride is therefore a constituent of normal diets. However, fluoride is not an essential nutrient. Therefore, no average requirement for the performance of essential physiological functions can be defined. The setting of an adequate intake is appropriate (0.05 mg/kg body weight per day) because of the beneficial effects of dietary fluoride on prevention of dental caries (EFSA Journal, 2013).

Absorption

Magnesium is absorbed mainly in the small intestine after oral exposure; the colon also absorbs some. Magnesium absorption following oral ingestion is reported to range from 40 to 60%, with a lower percentage of absorption at higher daily intakes (Patty’s Toxicology, 2001).

In humans and laboratory animals, the absorption of ingested fluoride into the general circulation occurs primarily in the stomach and intestine and is dependent upon the relative aqueous solubility of the form consumed. Soluble fluorides are almost completely absorbed from the gastrointestinal tract; however, the extent of absorption may be reduced by complex formation with aluminium, phosphorus, magnesium or calcium.

Distribution

Tissue distribution studies of magnesium indicate that of 20 g body burden in humans, the majority is intracellular in the bone and muscle including the myocardium, but some magnesium is present in every cell of the body (OECD, 2010). In the blood plasma, about 65 percent is the ionic form while the remainder is bound to protein (OECD, 2010). The blood concentration of magnesium is ca. 1.5 – 2.8 mg/dl (Patty’s Toxicology, 2001).

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. In teeth and skeletal tissue, fluoride becomes incorporated into the crystal lattice. Fluoride is present in body organs, tissues and fluids (WHO, 2002). Concentrations of fluoride in whole blood of individuals residing in a community in the USA receiving fluoridated drinking-water ranged from 20 to 60 μg/L (WHO, 2002). With prolonged intake of fluoride from drinking-water, concentrations in the blood are the same as those in drinking-water. In fact a relationship that remains valid up to a concentration in drinking-water of 10 mg/litre.

Elimination

Magnesium is excreted into the digestive tract by bile and pancreatic and intestinal juices. 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 (OECD, 2010).

Fluoride is eliminated from the body primarily in the urine. In infants, about 80–90% of a fluoride dose is retained; in adults, the corresponding figure is approximately 60%. These values can be altered by alterations in urinary flow and urinary pH (WHO, 2002).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential