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Description of key information

Short description of key information on bioaccumulation potential result: 
Sodium hydrogen difluoride will dissociate under physiological conditions to form its constituent ions; the fluoride ion is considered to be the toxicologically relevant species. Absorption of fluoride following oral and inhalation exposure to potassium bifluoride is predicted, however dermal absorption is unlikely under the normal conditions of use. Absorbed fluoride is rapidly and extensively distributed and a proportion may be sequestered in bones and teeth, resulting in a half-life of up to 20 years.
Short description of key information on absorption rate:
Dermal absorption of the substance (or its constituent ions) is predicted to be negligible.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - inhalation (%):
100

Additional information

Overview

The substance sodium hydrogen difluoride will hydrolyse under physiological conditions to form the hydrogen, fluoride and sodium ions. The toxicokinetics of the individual ions are discussed below. Oral and inhalation absorption of the substance are likely to be extensive, however dermal absorption is unlikely to be significant due to the physicochemical properties of the substance.

Hydrogen ion

Levels of the hydrogen ion in the body are tightly regulated though acid-base homeostasis, notably using extracellular buffers (bicarbonate) and excretion of carbon dioxide in exhaled air. Preferential renal excretion also acts to closely control plasma pH. Hydrogen ions generated from the hydrolysis of the substance will be indistinguishable from the high levels of endogenous hydrogen ions and will be extensively distributed and subject to identical physiological homeostatic control. Where human exposure occurs, hydrogen ions originating from the substance will therefore not add measurably to the levels of hydrogen ions already present in the body.

Sodium ion

Sodium ions are naturally present in the body and are critical for normal cell function. Sodium is an essential element the human diet, with a minimum daily requirement of ~500 mg/day and typical dietary intakes of many times this value. Levels of sodium ions in the body are tightly regulated through renal excretion and reabsorption. Sodium ions generated from the hydrolysis of the substance will be indistinguishable from the high levels of endogenous ions and will be extensively distributed and subject to identical physiological homeostatic control. Where human exposure occurs, sodium ions originating from the substance will therefore not add measurably to the levels of sodium ions already present in the body.

Fluoride ion

The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. Dermal absorption of fluoride is likely to be minimal except in cases where the normal skin structure is compromised as a consequence of the corrosive effects of the substance. Absorbed fluoride is distributed primarily in the blood, 75% in the plasma and 25% associated with erythrocytes. Half of the plasma fluoride may be bound to organic molecules. Fluoride is rapidly distributed and is sequestered in the bones and teeth, where exchange with hydroxyl groups results in incorporation into the bone and tooth structure. Levels of fluoride in bones and teeth are directly correlated with exposure levels. Fluoride is excreted rapidly as a consequence of glomerular filtration, with a plasma half-life of 2-9 hours. The half-life for skeletal fluoride in humans is reported to be 8-20 years.

Discussion on bioaccumulation potential result:

A comparative study (Whitford et al,1991) of fluoride pharmacokinetics in five species (dog, cat, rat, rabbit and hamster) determined that there are major quantitative differences in the metabolic handling of fluoride among the five species evaluated, and that 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. 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). 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.

In another study (Susheela et al, 1982), rabbits were administered daily oral doses of 10 mg sodium fluoride/kg body weight by gavage for various periods of time and then levels of fluoride in serum, urine, noncalcified tissues, calcified tissues, and erythrocyte membrane and hemolysate were estimated at different time intervals for the purpose of understanding how much fluoride was deposited, how much is excreted, and what quantity of fluoride was in circulation. Following sodium fluoride ingestion, the circulating level of fluoride was enhanced. The increase in fluoride content was proportionate to the duration of sodium fluoride administration, at least up to 10 months. Urinary fluoride content data revealed that, due to sodium fluoride ingestion, the amount of excreted fluoride increased up to 30 days. Thereafter, for unknown reasons, fluoride excretion gradually diminished towards normal limits. Cortical and cancellous bone differed significantly in their fluoride content. Cancellous bone, upon sodium fluoride administration, showed greater affinity for fluoride uptake, possibly due to its greater surface area exposed to circulation. Fluoride content data of non-calcified tissues showed that less fluoride was taken up when compared to calcified tissue. However, in non-calcified tissues it was evident that different organ tissues varied in their affinity for fluoride and in their fluoride content. Upon sodium fluoride administration, all soft tissues investigated, including the erythrocyte membrane and hemolysate, showed enhanced fluoride content.

Moreover, the significant literature on the toxicokinetics of fluoride has been reviewed in the EU RAR and is summarised below. Sodium hydrogen difluoride will dissociate under physiological conditions to form its constituent ions; the fluoride ion is considered to be the toxicologically relevant species.

Absorption

The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. Absorption of fluoride following oral and inhalation exposure to sodium hydrogen difluoride is predicted. Studies with HF demonstrate that the large majority of the inhaled substance is absorbed via the upper respiratory tract mucosa. Following dermal exposure to sodium hydrogen difluoride, absorption of fluoride is likely to be minimal expect in those cases (i.e. significant accidental exposure) where the normal skin structure is compromised as a consequence of the corrosive effects of the substance.

Distribution

Absorbed fluoride is distributed primarily in the blood, 75% in the plasma and 25% associated with erythrocytes. Half of the plasma fluoride may be bound to organic molecules. Fluoride is rapidly distributed and is sequestered in the bones and teeth, where exchange with hydroxyl groups results in incorporation into the bone and tooth structure. Levels of fluoride in bones and teeth are directly correlated with exposure levels.

Excretion

Free fluoride present in the plasma is excreted rapidly as a consequence of glomerular filtration, with a half-life of 2-9 hours. Sequestration results in a much longer half-life for skeletal fluoride, which in humans is reported to be 8-20 years.

Discussion on absorption rate:

The substance is a simple inorganic salt and will exist as its constituent ions under physiological conditions. Dermal absorption of the substance (or its constituent ions) is predicted to be negligible under exposure conditions where the integrity of the skin barrier is maintained.