Disodium fluorophosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Data source

Reference

Reference Type:

publication

Title:

Absorption and metabolism of the PO3F ion in the animal body.

Author:

Ericsson Y, Santesson G, Ullberg S

Year:

1961

Bibliographic source:

Arch. oral Biol. Special Supplement, 4: 160-74

Materials and methods

Objective of study:

absorption

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Double-labelled (18F, 32P) disodium fluorophosphate solved in milk was administered to rats by gavage. After a certain time, urine and blood were collected and at the termination of the chosen survival time, animals were sacrificed, the gastrointestinal tract and the femur were removed, weighed and analysed radiometrically.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium fluorophosphate

EC Number:

233-433-0

EC Name:

Disodium fluorophosphate

Cas Number:

10163-15-2

Molecular formula:

FH2O3P.2Na

IUPAC Name:

disodium fluorophosphate

Details on test material:

- Name of test material (as cited in study report): sodium monofluorophosphate

Radiolabelling:

yes

Remarks:

18F- and 32P-labelling

Test animals

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 214-395g
- Fasting period before study: The animals received no food or drinking water from the evening before nor during the experiments, which were started about noon.
- Individual metabolism cages: yes

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: milk

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The labelled fluorophosphate was dissolved in milk to the desired concentrations immediately before the ingestion.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Milk was used for the ingestion for several reasons. Relatively high concentrations of the monofluorophosphate had to be used owing to the difficulties of labelling a very small quantity of the salt with an 18F activity sufficiently high for experiments lasting up to 6 hours. The toxicity-reducing action of milk thus appeared valuable. Through its buffering action milk could further be assumed to prevent acid hydrolysis of the monofluorophosphate ion in the stomach. Finally, milk seemed to be a suitable test food of a calcium-rich type, which is of importance in connexion with fluoride ingestion.
- Concentration in vehicle: 50 mmol/L
- Amount of vehicle (if gavage): 5 mL

Duration and frequency of treatment / exposure:

Animals were treated once and than observed up to 6 hours thereafter.

Doses / concentrations

Remarks:

Doses / Concentrations:
The rats used for this experimental series weighed about 300 g. Every animal received 5 mL 50 mmol/L disodium fluorophosphate in milk. This corresponds to a dose of approximately 120 mg/kg bw assuming a molecular weight of 143.95 g/mol.

No. of animals per sex per dose / concentration:

1

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood, femur, gastrointestinal tract
- Time and frequency of sampling: urine: up to 6h (total survival time), blood: 5 min after ingestion (tail) or at termination of survival time (heart, sometimes portal vein), femur and gastrointestinal tract: at termination of survival time

Results and discussion

Preliminary studies:

It was thought that enzymes of the milk or its cells might split some of the fluorophosphate dissolved in the milk and thus introduce a source of error in the judgment of the metabolic fate in vivo of this ion. This hypothesis was tested in an experiment with six rats, of which three received the standard administration of double labelled monosodium fluorophosphate in ordinary market milk, and three the same milk that had been boiled before addition of this salt to destroy any enzymatic activity. Blood samples were drawn after 5 min (tail) and 4 hr (heart) and the femurs and collected urine were also analysed after 4 hr. This test revealed no significant or consistent differences between boiled and unboiled milk according to the above parameters.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The difference between 32P and 18F uptake is significant at the 2 and 4 h intervals with the concentration of 18F in the digestive tract being at all time points smaller than the 32P concentration. This difference may be due to splitting of the fluorophosphate and more rapid absorption of liberated fluoride, or in part to re-excretion of labelled phosphate with the digestive juices, where fluoride is hardly excreted.
Five minutes after oral administration, 0.027% and 0.008% of the administered doses of 18F and 32P could be detected in the tail blood.

Details on distribution in tissues:

BLOOD:
The blood sampled from the portal vein was naturally higher in the absorbed isotopes than the heart blood, except regarding the phosphate after 6h; after this time interval a considerable incorporation of 32P in the blood lipids may be assumed.

BONES:
The incorporation of 18F and 32P in the femur follow quite different curves. The 18F uptake was rapid and reached a maximum level 4h after ingestion. The 32P uptake is slower and continued to rise during the whole observation period.

Details on excretion:

18F was excreted much more rapidly than 32P, the differences being significant at the 2 and 4h intervals.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

It can be assumed that the monofluorophosphate anion is split to fluoride and phosphate in the body.

Any other information on results incl. tables

No data.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
It is evident that the monofluorophosphate anion is split to a great degree in the animal body, starting in the digestive tract. The resulting metabolites are assumed to be fluoride and phosphate. The absorption, distribution, and excretion of these forms vary greatly with fluoride being absorbed, distributed, and excreted faster than phosphate.

Executive summary:

Double-labelled (18F, 32P) disodium fluorophosphate (approximately 120 mg/kg bw) solved in milk was administered to rats by gavage. After a certain time, urine and blood were collected and at the termination of the chosen survival time, animals were sacrificed, the gastrointestinal tract and the femur were removed, weighed and analysed radiometrically.

The difference between 32P and 18F uptake is significant at the 2 and 4 h intervals with the concentration of 18F in the digestive tract being at all time points smaller than the 32P concentration. The compounds are absorbed and distributed in the animal body rapidly; small doses were detected in tail blood within 5 minutes after oral administration.

The incorporation of 18F and 32P into the femur occurs quite rapidly with 18F uptake being rapid and reaching a maximum level 4h after ingestion. The 32P uptake was slower and continued to rise during the whole observation period of 6h.

18F was excreted much more rapidly than 32P, the differences being significant at the 2 and 4h intervals.

It can be assumed that the monofluorophosphate anion is split to fluoride and phosphate in the body.