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EC number: 233-433-0 | CAS number: 10163-15-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Specific investigations: other studies
Administrative data
- Endpoint:
- specific investigations: other studies
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Scientifically sound study
Data source
Reference
- Reference Type:
- publication
- Title:
- Chemical stability and mode of gastrointestinal absorption of sodium monofluorophosphate.
- Author:
- Setnikar I, Arigoni R.
- Year:
- 1 988
- Bibliographic source:
- Arzneimittelforschung. 1988 Jan;38(1):45-9. PMID: 3365276
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The ability of different body fluids and tissue homogenates to catalyse the hydrolysis of monofluorophosphate was tested
- GLP compliance:
- no
- Type of method:
- in vitro
- Endpoint addressed:
- basic toxicokinetics
Test material
- 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 (sodium MFP)
- Analytical purity:
sodium MFP, USP grade;
Formulation 1: tablets (Tridine®, manufacturer: Opfermann Arzneimittel, Wiehl (Fed.Rep. of Germany)) containing Na2FPO3 38 mg, calcium gluconate
500 mg, calcium citrate 500 mg;
Formulation II: tablets (experimental , formulation) containing
Na2FPO3 76 mg, calcium carbonate 1203 mg, calcium glycerophosphate
358 mg.
- Impurities (identity and concentrations): see above
- Composition of test material, percentage of components: see above
- Stability under test conditions: not reported, expected to be stable
- Storage condition of test material: not reported
Constituent 1
Test animals
- Species:
- other: rats, dogs, humans
- Strain:
- other: rat: Sprague Dawley, dog: mongrel
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: rats: 250 - 320 g
- no further details given
Administration / exposure
- Route of administration:
- other: not applicable
- Vehicle:
- other: not applicable
- Details on exposure:
- not applicable
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- not applicable
- Duration of treatment / exposure:
- not applicable
- Frequency of treatment:
- not applicable
- Post exposure period:
- not applicable
Doses / concentrations
- Remarks:
- Doses / Concentrations:
not applicable
Basis:
- No. of animals per sex per dose:
- not applicable
- Control animals:
- no
- Details on study design:
- not applicable
Examinations
- Examinations:
- not applicable
- Positive control:
- not applicable
Results and discussion
- Details on results:
- - Acid phosphatase is practically ineffective in MFP hydrolysis (Table 1)
- Alkaline phosphatase is highly effective in MFP hydrolysis at neutral and alkaline conditions (Table 1)
- MFP is not significantly hydrolysed in gastric juices neither in human nor dog (Tables 2 and 3) except for the basic hydrolysis rate due to low pH
- MFP is hardly hydrolysed in human blood, plasma or haemolysed cells (Table 4)
- MFP hydrolysis is fast in rat intestine homogenates and the activity is inhibited by denaturation of proteins (boiling) (Table 5)
- MFP hydrolysis is very fast in rat liver homogenates (kcat= 71.5 µmol x mL/(min x mg protein), KM given without parameter) and the activity is inhibited by denaturation of proteins (boiling) (data only available as graph)
- MFP hydrolysis is pH-dependent, with complete hydrolysis within 4 h at pH < 0.8, while at pH > 2.2 only 0.1 to .1 % are hydrolysed (Table 6)
- Formulation I and II both raise the pH of human gastric fluids above 2.6 thereby impairing the hydrolysis of MPF (Table 3 and 7)
- The pKas of fluorophosphoric acid at 37 °C are ca. 0.8 and 5.08
- metabolic fate of sodium MFP:
Based on the presented results the authors conclude that sodium MFP passes the gastric environment almost un-hydrolysed if the pH is raised above 2.2 by administration with food or in appropriate formulations. MFP is absorbed readily in the intestine and then cleaved there or in the liver by phosphatase (e. g. alkaline phosphatase). Serum MFP cleavage is negligible. Co-administration of Calcium salts is proposed to inactivate the traces of fluoride formed in the gastric tract by precipitation as calcium fluoride.
Any other information on results incl. tables
Table 1: Hydrolysis rate of MFP (µmol/min) in the presence of 1 U/mL of alkaline phosphatase (ALP) at pH 11.2 or pH 7.2, or of 0.4 U/mL of acid phosphatase (AcP) at pH 4.8 or pH 7.2.
Concentration |
ALP 1 U/mL |
AcP 0.4 mU/mL |
||
pH 11.2 |
pH 7.2 |
pH 4.8 |
pH 7.2 |
|
0.28 |
2.3 |
9.3 |
<0.1 |
<0.1 |
0.28 |
2.2 a |
10.8 a |
<0.1 |
<0.1 |
178 |
10.2 |
80.6 |
<0.1 |
<0.1 |
27.79 |
55.6 |
190.8 |
<0.1 |
<0.1 |
27.79 |
57,4 b |
179.4 b |
<0.1 |
<0.1 |
277.87 |
463.1 |
528.0 |
<0.1 |
<0.1 |
a: in the presence of 0.28 mmol/L NaF; b: in the presence of 27.79 mmol/L of NaF
Table 2: Hydrolysis rate of MFP (% hydrolysed/min) in human gastric juice at 37 °C.
Subject |
pH |
Hydrolysis rate |
|
Found |
Expected a |
||
1 (basal) |
1.51 |
0.03 |
0.01 |
1 (pentag.) b |
0.96 |
0.22 |
0.27 |
2 (basal) |
1.93 |
0,01 |
0.00 |
2 (pentag.) |
1.03 |
0,17 |
0.19 |
3 (basal) |
2.06 |
0.00 |
0.00 |
3 (pentag.) |
1.13 |
0.12 |
0.10 |
1 ( + HCl) |
0.70 |
0.65 |
0.75 |
2 (+ HC1) |
0.80 |
0.48 |
0.53 |
3 (+ HCI) |
0.90 |
0.35 |
0.35 |
a: according to hydrolysis due to pH (see Table 7); b: pentagastrin
Table 3: Hydrolysis rate of MFP (% hydrolysed/min) in canine intestinal fluid adding Na2FPO3, Formulation I or Formulation II
Dog |
pH |
Hydrolysis rate. |
||||||
Before |
After addition of |
Before |
After addition of |
|||||
Form. I |
Form. II |
5 mol/L HCI |
Form. I |
Form. II |
5 mo1/1 |
|||
1 |
6.4 |
6.7 |
7.2 |
0.95 |
<0.001 |
<0.001 |
<0.001 |
0.21 |
2 |
6.8 |
7.1 |
7.5 |
1.03 |
<0.001 |
<0.001 |
<0.001 |
0.16 |
3 |
5.9 |
6.3 |
6.9 |
1.01 |
<0.001 |
<0.001 |
<0.001 |
0.19 |
4 |
6.3 |
6.5 |
7.1 |
0.98 |
<0.001 |
<0.001 |
<0.001 |
0.22 |
5 |
6.6 |
6.8 |
7.3 |
0.99 |
<0.001 |
<0.001 |
<0.001 |
0.18 |
Table 4: Hydrolysis rate of MFP (% hydrolysed/h) in human blood, plasma or hemolyzed red cells with 2 concentrations of Na2FPO3. Averages and standard deviations of 4 subjects.
Medium |
Na2FPO3 (mg/m1) |
|
0.1 |
1 |
|
Blood |
7.4±2.4 |
2.5±1.4 |
Plasma |
5.9± 1.6 |
± 1.2 |
Red cells |
9.2±1.5 |
6.5± 1.9 |
- Table 5: Hydrolysis rate of MFP (µmol/min) with rat intestine homogenate, 4 mg/ml protein.
Concentration of Na2FPO3 |
Hydrolysed FPO3 |
0.14 |
4.6 |
0.47 |
15.7 |
1.56 |
52.1 |
5.21 |
119.8 |
17.36 |
126.2 |
34.73 |
119.3 |
69.46 |
112.3 |
138.94 |
107.4 |
277.87 |
117.6 |
Table 6: Hydrolysis rate of MFP (% hydrolysed/min) at different pH values and at 37 °C in a solution of 0.7557 mg/mL of Na2FPO3
pH adjustment |
Time (h) |
|||||||
0 |
0.5 |
2 |
4 |
|||||
pH |
% fluoride |
pH |
% fluoride |
pH |
% fluoride |
pH |
% fluoride |
|
HCl |
0.43 |
8.6 |
0.38 |
56.6 |
0.34 |
85,1 |
0,31 |
100 |
|
0.78 |
8.1 |
|
|
0,73 |
43,4 |
0.67 |
100 |
|
0.98 |
8.1 |
|
|
0.92 |
23_ |
0,89 |
67,5 |
|
1.12 |
7.4 |
|
|
1.08 |
13.8 |
1.05 |
34.1 |
|
132 |
7.7 |
|
|
1.31 |
10,3 |
1.29 |
19.2 |
|
1,56 |
7.9 |
|
|
|
|
1,55 |
16.6 |
|
1.64 |
7.5 |
|
|
|
|
1.62 |
12.3 |
Citrate |
2.28 |
7.6 |
|
|
|
|
2.28 |
7.7 |
|
3.02 |
7.3 |
|
|
|
|
3.01 |
7.5 |
|
3.98 |
6.7 |
|
|
|
|
3.97 |
7.7 |
Phosphate |
6.81 |
7.8 |
|
|
|
|
6.80 |
8.3 |
|
7.50 |
8.0 |
|
|
|
|
7.48 |
8.4 |
NaOH |
13,03 |
6.9 |
|
|
|
|
13.01 |
8.0 |
Table 7: Hydrolysis rate of MFP (% hydrolysed/min) in human gastric juice to which Formulation I or Formulation II were added
Subject |
pH |
Hydrolysis rate |
||||
Before |
After |
Before |
After |
|||
Form. I |
Form. II |
Form. I |
Form. II |
|||
1 |
0.96 |
2.78 |
3.15 |
0.22 |
<0.001 |
<0.001 |
2 |
1.03 |
2.85 |
3.22 |
0.17 |
<0.001 |
<0.001 |
3 |
1.13 |
2.66 |
3.18 |
0.12 |
<0.001 |
<0.001 |
Applicant's summary and conclusion
- Conclusions:
- The kinetics of sodium monofluorophosphate (sodium MFP) hydrolysis was analysed. pH dependence of the un-catalysed reaction was determined and the ability of different body fluids, tissue homogenates and solutions of alkaline phosphatase and acid phosphatase to catalysed the reaction was determined.
Sodium MPF is stable in solutions with a pH > 2.2. In liver an intestine mark able protein based catalytic activity is present while blood shows hardly any such activity and no activity was found in gastric juices. - Executive summary:
In the present study (Setnikar, 1988) the kinetic of sodium monofluorophosphate (sodium MFP) hydrolysis was analysed using the detection of formed fluoride ions potentiometrically by a fluoride ion specific electrode. The catalytic activity of the following body fluids, homogenates and purified enzymes was tested: rat liver homogenate; rat intestine homogenate; dog intestinal juice; human gastric juice; human whole blood, serum and blood cells; purified alkaline phosphatase; purified acid phosphatase. In addition the pH dependence of the un-catalysed reaction was determined.
It was found that sodium MPF is stable in solutions with a pH > 2.2. In liver an intestine mark able protein based catalytic activity is present while blood shows hardly any such activity and no activity was found in gastric juices. Alkaline phosphatase has a mark able activity to cleave MFP both at neutral and alkaline pH while the catalytic activity of acid phosphatase for this reaction is negligible both at neutral and acidic pH.
Concerning the metabolic fate of MFP based on the presented results the authors conclude that sodium MFP passes the gastric environment almost un-hydrolysed if the pH is raised above 2.2 by administration with food or in appropriate formulations. MFP is absorbed readily in the intestine and then cleaved there or in the liver by phosphatase (e. g. alkaline phosphatase) which leads to the release of fluoride. Serum MFP cleavage is negligible. Co-administration of calcium salts is proposed to inactivate the traces of fluoride formed in the gastric tract by precipitation as calcium fluoride.
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