Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Absorption rate - oral (%):
100
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
50

Additional information

For several toxicological endpoints, read-across is applied from simple inorganic fluorides (e.g. NaF, KF) to the substance dipotassium hexafluorotitanate. Therefore, initially, the information on the toxicokinetics of “fluorides” is discussed below, followed by a justification for read-across.

Data reported in the CSR for potassium fluoride (respective endpoint study records from the KF dossier have been copied into the technical dossier for H2TiF6):

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, non-calcified 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 haemolysate, showed enhanced fluoride content.

In an earlier study, Zipkin and Likins (1957) investigated the absorption of various fluorine compounds from the gastrointestinal tract of the rat. Sodium fluoride, as well as sodium fluorosilicate (Na2SiF6), sodium fluorophosphate (Na2PO3F) and stannous fluoride (SnF2) were absorbed through the gastrointestinal tract of the rat to the same extent (mean 48.4 +/- 1.6%), whereas potassium hexafluorophosphate (KPF6), tetraethylammonium hexafluorophosphate (EtNPF6) and potassium fluoroborate (KBF4) were absorbed to a significantly greater degree (73.6 +/- 2.0%). The results suggest that the difference in rate of absorption of the two groups of fluorine compounds is related to their dissimilarity in electronic structure. In compounds with lower rates of absorption, fluorine is electrovalently bound and is present as the fluoride ion, whereas in compounds with greater rates of fluorine absorption, fluorine is covalently bound.

 

Data reported in secondary literature from the public domain:

The most recent and extensive reviews of toxicokinetics were published in 2002/2003 by WHO/EHC and ATSDR. Since both were generated at approx. the same time, their content is largely the same, which is why the slightly more extensive descriptions by ATSDR are referred to in this document in most occasions.

 

Oral absorption

Soluble fluoride compounds, such as sodium fluoride, hydrogen fluoride, and fluorosilic acid, are readily absorbed from the gastrointestinal tract. Studies in humans and animals have found that >80% of an oral dose of soluble fluoride compound is absorbed (Ericsson 1958; McClure et al. 1950, 1945; Zipkin and Likins 1957); several studies have reported 99–100% absorption efficiencies (Ekstrand et al. 1978; Trautner and Einwag 1987) (ATSDR, 2003).

Fluoride is absorbed from both the stomach and small intestine via passive diffusion. Nopakun et al. (1989) estimated that in rats, approximately 20% of total absorbed fluoride was absorbed from the stomach. Absorption of fluoride from the stomach is inversely proportional to pH (Messer and Ophaug 1993; Whitford and Pashley 1984), suggesting that fluoride is absorbed from the stomach as the undissociated hydrogen fluoride rather than the fluoride ion (Whitford and Pashley 1984). After gastric emptying, fluoride was rapidly absorbed from the small intestine (Messer and Ophaug 1993) (ATSDR, 2003).

Fluoride is mainly absorbed in the form of hydrogen fluoride, which has a pKa of 3.45. That is, when ionic fluoride enters the acidic environment of the stomach lumen, it is largely converted into hydrogen fluoride (Whitford & Pashley, 1984). Most of the fluoride that is not absorbed from the stomach will be rapidly absorbed from the small intestine (WHO/EHC, 2002).

 

Dermal absorption

Data specifically on the absorption of soluble fluorides are not available. Whereas non-dissociated hydrogen fluoride is reported to have been absorbed through skin, no quantitative information is available (ATSDR, 2003; WHO/EHC, 2002). Since non-dissociated HF will only be present at extremely acidic (low) pH values, a substantial contribution by corrosion/irritation of the skin cannot be excluded. Thus, these observations are not considered to be of relevance for the assessment of diluted “fluoride” solutions on the skin at neutral/physiological (sweat) pH conditions, where low to negligible dermal absorption may be assumed (set to 1% for risk assessment purposes).

This conclusion is supported by a scientific opinion recently published by the EU Scientific Committee on Health and Environmental Risks (SCHER, 2010) as follows: “No experimental data on the extent of dermal absorption of fluoride from dilute aqueous solutions are available. As fluoride is an ion it is thus expected to have low membrane permeability and limited absorption through the skin from dilute aqueous solutions at near neutral pH (such as drinking water used for bathing and showering). This exposure pathway is unlikely to significantly contribute to fluoride body burden.”

 

Inhalation absorption

Data specifically on the absorption of soluble fluorides are not available (ATSDR, 2003; WHO/EHC, 2002). However, based on particle size considerations and the associated respiratory tract dosimetry, the majority of inhaled material (almost 50% of the inhalable airborne material) will be deposited in the ET fraction subject to rapid translocation to the GI tract, whereas less than 1% will be deposited in the alveolar fraction of the lung. Assuming almost complete absorption both from the gastrointestinal and the respiratory tract, then the particle-size based inhalability suggests that it is reasonable to assume 50% inhalation absorption of airborne material.

 

Distribution

Once absorbed, fluoride is rapidly distributed throughout the body via the blood. Fluoride is distributed between the plasma and blood cells, with plasma levels being twice as high as blood cell levels (Whitford 1990). After ingestion of sodium fluoride, the plasma fluoride does not appear to be bound to proteins (Ekstrand et al. 1977a; Rigalli et al. 1996).

The elimination of fluoride from plasma following short-term exposure to sodium fluoride has been fit to a two-compartment model (Ekstrand et al. 1977a). The half-life of the terminal phase ranged from 2 to 9 hours. The rapid phase of fluoride distribution represents distribution in soft tissues, with fluoride being more rapidly distributed to well-perfused tissues. In pigs, the plasma clearance half-time of fluoride was 0.88 hours (Richards et al. 1982) (ATSDR, 2003).

 

Studies in rats and ewes suggest that the blood brain barrier is effective in preventing fluoride migration into the central nervous system (Spak et al. 1986; Whitford et al. 1979a); brain fluoride concentrations typically do not exceed 10% of plasma concentrations (Whitford et al. 1979a) (ATSDR, 2003).

 

The largest concentration of fluoride in the body is found in calcified tissues: approximately 99% of the fluoride in the body is found in bones and teeth (Hamilton 1990; Kaminsky et al. 1990). Fluoride is incorporated into bone by replacing the hydroxyl ion in hydroxyapatite to form hydroxyfluoroapatite (McCann and Bullock 1957; Neuman et al. 1950) (ATSDR, 2003).

 

Human and animal studies have shown that fluoride is readily transferred across the placenta. There appears to be a direct relationship between maternal blood fluoride levels and cord blood fluoride levels (Armstrong et al. 1970; Gupta et al. 1993; Malhotra et al. 1993; Shen and Taves 1974). At relatively low maternal blood levels, the cord blood levels were at least 60% of that of maternal blood (Brambilla et al. 1994; Gupta et al. 1993). Although cord fluoride levels were typically lower than maternal levels, one study found no statistical difference between maternal and newborn (1 day old) serum fluoride levels (Shimonovitz et al. 1995). However, a partial placental barrier may exist at high maternal fluoride levels. At higher maternal blood levels, the cord to maternal fluoride ratio is lower than at lower maternal fluoride levels (Gupta et al. 1993) (ATSDR, 2003).

 

In humans, fluoride is poorly transferred from plasma to milk (Ekstrand et al. 1981c, 1984b; Esala et al. 1982; Spak et al. 1983). A single dose of 1.5 mg sodium fluoride did not result in a significant rise in fluoride breast milk concentrations within 3 hours of the exposure (Ekstrand et al. 1981c). Although no linear correlation between fluoride levels in tap water and fluoride levels in breast milk has been found, significantly higher breast milk fluoride concentrations were found in women living in an area with high levels of naturally occurring fluoride (1–7 ppm) as compared to women in areas with low fluoride levels in tap water (0.2 ppm) (Esala et al. 1982). Fluoride levels in human milk of 5–10 μg/L have been measured (Fomon and Ekstrand 1999) (ATSDR, 2003).

 

Metabolism

Upon becoming physiologically available, fluoride anions are not known to undergo any further biotransformation whatsoever.

 

Elimination and excretion

The primary pathway for fluoride excretion is via the kidneys and urine; to a lesser extent, fluoride is also excreted in the faeces, sweat, and saliva. A study in rats suggests that the source of the small amount faecal fluoride may be fluoride that has re-entered the more distal portion of the intestine and became associated with unabsorbed cations (Whitford 1994) (ATSDR, 2003).

 

Renal excretion is the major route of fluoride removal from the body; it typically equals 35–70% of intake in adults (Ekstrand et al. 1978; Machle and Largent 1943). The fluoride ion is filtered from the plasma as it passes through the glomerular capillaries followed by a varying degree (10–70%) of tubular reabsorption; there is no evidence of tubular secretion of fluoride (Schiffl and Binswanger 1982; Whitford 1990). Renal clearance rates in humans can range from 12.4 to 71.4 mL/minute with average values of 36.4–41.8 mL/minute (Schiffl and Binswanger 1982; Waterhouse et al. 1980) (ATSDR, 2003).

 

Mechanism of action

A number of mechanisms are involved in the toxicity of fluoride to bone. Fluoride ions are incorporated into bone by substituting for hydroxyl groups in the carbonate-apatite structure to produce hydroxyfluoroapatite, thus altering the mineral structure of the bone (Chachra et al. 1999). Unlike hydroxyl ions, fluoride ions reside in the plane of the calcium ions, resulting in a structure that is electrostatically more stable and structurally more compact (Grynpas 1990). Following administration of fluoride, there is a shift in the mineralization profile towards higher densities and increased hardness (Chachra et al. 1999). However, the structure of the bone (cortical thickness and the trabecular architecture of the femoral head) was largely unchanged in rabbits by fluoride administration. Chachra et al. (1999) suggest that the shift in mineralization could be due to either hypermineralization of older (denser) fractions or to a greater packing density of the hydroxyapatite crystals. Although high-dose fluoride administration is associated with an increase in bone mass,in vivoandin vitroanimal studies have found a negative association between fluoride-induced new bone mass and bone strength, suggesting that the quality of the new bone was impaired by the fluoride (Silva and Ulrich 2000; Turner et al. 1997). Because bone strength is thought to derive mainly from the interface between the collagen and the mineral (Catanese and Keavney 1996), alteration in mineralization probably affects strength. The wider crystals, which are formed after fluoride exposure, are presumably not as well associated with collagen fibrils and thus, do not contribute to mechanical strength. Turner et al. (1997) found that the crystal width was inversely correlated with bending strength of the femur. Thus, although there is an increase in hardness and bone mass and unaltered structure, the mechanical strength of bone is decreased with long-term, high-dose administration of fluoride (Chachra et al. 1999) (ATSDR, 2003).

 

Summary and conclusions on toxicokinetics and absorption rates

Upon ingestion, soluble fluorides are rapidly and almost completely (>80-100%) absorbed in the gastrointestinal tract. It is assumed that in the stomach, absorption (20%) occurs in the form of HF, whereas the remainder is absorbed in the small intestine. Inhalation absorption of commercially available grades of K2TiF6can be estimated to amount to approx. 50%, whereas dermal absorption is considered to be low to negligible (1%).

Once absorbed, fluoride is rapidly distributed throughout the body via blood, and rapidly eliminated predominantly renally with plasma clearance half-times (in pigs) for fluoride of 0.88 hours. The resulting largest concentrations of fluoride in the body are observed in calcified tissues (i.e., bones and teeth).

 

Argumentation for read-across from potassium fluoride to potassium hexafluorotitanate:

Read-across between sodium fluoride and potassium fluoride can be considered as justified (cfr. CSR for potassium fluoride) assuming (i) similar dissociation behaviour under physiological conditions and (ii) similar absorption and distribution/elimination kinetics once becoming systemically available as “fluoride” anions. The substance K2TiF6is characterised by a moderate to high water solubility of 12.8 g/L, which is very similar to that of sodium fluoride (ca. 40 g/L), and is assumed to dissociate in a similar way upon uptake via ingestion or inhalation. Based on (i) the similarities in water solubility as a surrogate for bioavailability, (ii) the fact that the majority of “fluoride” toxicity and toxicokinetic studies were in fact generated for sodium fluoride, and (iii) the titanium moiety of the substance will hydrolyse to a poorly soluble precipitate (i.e. titanium oxides or -hydroxides), it is assumed that the toxic potential is driven by the fluoride content. Thus, unrestricted read-across between K2TiF6and sodium/potassium fluoride is considered justified.

 

References for key secondary literature (primary sources can be found therein):

WHO (2002): Environmental Health Criteria 227: Fluorides. World Health Organization, Geneva, 2002.

ATSDR (2003): Toxicological profile for fluorides, hydrogen fluoride and fluorine. U.S. Department of health and human services. Public Health Service. Agency for Toxic Substances and Disease Registry, September 2003.

SCHER (2010): Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water, adopted at 7th plenary on 18 May 2010.