Zinc hexafluorosilicate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: evidence from degradation product

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline required

GLP compliance:

not specified

Details on absorption:

Inhalation

Experiments in which rats were head-only exposed to HF gas, demonstrated that over 99% of the inhaled HF does not reach the lungs but is rapidly absorbed via the lining of the upper respiratory tract. A linear relationship was observed between the HF concentration to which the rats were exposed and the plasma fluoride level. The virtually complete absorption of HF in the upper airways was determined in an experiment in which HF contents of the inhaled air was analyzed via an endotracheal tube (Morris, Smith 1982). Inhalatory uptake of fluoride has also been observed in humans and rabbits (Dinman 1976; Kirk-Othmer 1980; Largent 1960). For instance, human volunteers who breathed 1.16 to 3.9 mg HF/m3 for period of 15 to 30 days excreted F- in their urine in average daily amounts of 3.44 to 19.9 mg over the entire period of exposure. Lund et al. exposed human volunteers for 1 hour to constant concentrations of HF, ranging from 0.2 to
5.2 mg HF/m3. From 0.7 mg/m3 upwards, a linear relationship between exposure and increase in plasma fluoride levels was observed. Maximum plasma levels (ca. 18-80 ng/ml) were seen at 60 to 120 minutes after the start of the exposure (Lund et al. 1997).

Dermal

Dermal uptake of F- from liquid HF in humans has been reported by Burke et al. (1973). A man, accidentally exposed to about 5 g of HF excreted 404 mg F- in the urine over the first three days following the accident (Burke et al. 1973). From the reported data it is impossible to quantify the rate of absorption of HF after dermal exposure. In rats which were dermally exposed to 2% HF (2 ml/kg b.w., under occlusion) in water for 1 or 4 hr, serum fluoride reached levels 3 to 6 times (0.78 - 1.42 mg/l) above the level in the controls (0.25 mg/l) at one hour after the exposure. The serum levels increased with exposure time and decreased to near normal values over the next 96 hr (Derenlanko et al. 1985).

Oral

Oral uptake of HF has not been studied. However, because of the rapid absorption of fluoride from the gastro-intestinal tract, it is conceivable that HF will be rapidly absorbed after oral administration (Wallace-Durbin 1954; Van Asten et al. 1996). The absorption of orally administered fluoride depends on the presence of fluoride-binding cations such as calcium, magnesium and especially aluminium (CEPA 1993; Janssen 1989; WHO 1984) and on the formulation of the fluoride [e.g. in pharmaceutical preparations (Van Asten et al. 1996)].

Details on distribution in tissues:

After uptake fluoride is transported in the blood. 75% of the total blood fluoride concentration is present in the plasma; the remainder is associated with the red blood cells. About 50% of the fluoride in serum is bound to organic molecules, mainly in perfluoro-fatty acids (WHO 1984) and thus in a non-ionic form.

Fluoride distributes throughout all soft tissues, without particular accumulation in one of these. It may also cross the placenta and reach the unborn child. Sequestration of fluoride occurs in bone and teeth, in which it is incorporated into the mineral structures by exchange with hydroxyl groups. About half of the absorbed fluoride is deposited into bone structure. However, in younger humans and in the elderly, bone fluoride uptake is higher than in mid-age persons. Fluoride levels in plasma and in bone have been shown to be directly correlated to the level of exposure. (Morris, Smith 1982; WHO 1984; NTP 1990; Maurer et al. 1990; Maurer et al. 1993).

Details on excretion:

The major route for excretion of fluoride is via the urine. In animals and humans excretion into urine occurs through the glomerular filtration after which reabsorption in the form of HF may occur in the renal tubules, especially after decreased urinary acidity. Minor routes of excretion are via faeces, saliva (partial re-absorption after ingestion) and perspiration. Excretion via the milk is no relevant route of elimination (Thiessen 1988).

In humans plasma half-lives of 2 to 9 hr have been reported (WHO 1984). Because soft tissue fluoride levels are in equilibrium with plasma levels for these tissues similar half-lives may be assumed. After cessation of exposure, fluoride in bone will be released and eliminated from the body. In humans the half-live for bone fluoride is reported to be in the range of 8 to 20 years. (WHO 1984).

Conclusions:

Inhaled gaseous hydrogen fluoride is virtually completely absorbed in the upper airways. The extent of absorption via the dermal route cannot be specified. Fluoride from any inorganic source is absorbed as HF and circulates in the body as F- or as organically bound fluoride. The distribution of this ion and its route of excretion do not depend on the way via which it enters the body. After oral, inhalatory or dermal exposure to HF, fluoride can be found in all tissues in the body. Sequestration takes place in bone tissue in which about half of the absorbed fluoride is deposited. Secretion is mainly via the urine. In humans half-lives are in the range of 2 to 9 hr for plasma and in the range of 8 to 20 years for fluoride in bone deposits.

Executive summary:

Remark

Although the form of fluoride to which one is exposed may influence the amount of fluoride which finally reaches the systemic circulation, the form of fluoride which circulates within the body is not dependent on the fluoride species one has contacted (e.g. Van Asten et al. 1996). Thus when data gaps for systemic effects are established for HF, these data gaps may be filled, using experimental results of other inorganic fluorides, even if these were administered via a route other than inhalation. Toxicity data on other inorganic fluorides will only be used for the hazard assessment of HF, when base set required data for HF are not available.

Reference 2

Endpoint:

basic toxicokinetics, other

Type of information:

other: evidence from degradation product

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Details on absorption:

Solutions of fluoride salts are rapidly and nearly completely absorbed from the gastrointestinal tract. Low pH in the stomach favors formation of nonionized hydrofluoric acid, which is irritating but more easily absorbed than is the fluoride ion (Carlson et aL, 1960; Taves and Guy, 1979). The presence of food can retard absorption, especially foods rich in calcium, which binds to fluoride (Trautner and Einwag, 1989).

Details on distribution in tissues:

Following absorption from the gut, fluoride is found in low concentrations in plasma and soft tissues; however, bone and teeth accumulate fluoride. Typically about 99% of the total body burden is contained in the skeleton. Uptake into bone is rapid. One metabolism study using intravenously administered radioactive fluoride indicated a half time of 13 minutes for deposition into bone (Charkes et aL, 1978). Studies have found that about 40%-50% of an increase in fluoride intake is incorporated into bone (Largent and Heyroth, 1949; Spencer et aL, 1981). Kinetic studies have demonstrated two compartments for fluoride in bone: an
"exchangeable" companment wbere fluoride concentrations fluctuate and tend to buffer changes in plasma and tissue Ievels; and a •nonexchangeable" compartment where fluoride is released only during bone remodeling (Hallet aL, 1977). Bone fluoride concentrations vary with age and depend upon total
intake. Weatberell (1966) reponed bone fluoride concentrations of 200 to 800 mg/kg (asb) in subjects 20 to 30 years of age and 1,000 to 2,500 mg/kg in
persans 70 to 80 years old. Zipkin et aL (1958) reported bone fluoride concentrations in four groups of individuals witb average ages of 56 to 76 wbo
lived in areas witb fluoride concentrations in drinking water of 0.1, 1, 2.6, or 4 ppm. The relationship between bone fluoride concentrations and water
fluoride content was linear; bone Fuoride ranged from about 800 to 7,000 ppm asb with increasing water fluoride.
In tbe adult, the fluoride content of tooth enamel is reported to be 900 to 1,000 mg/kg in persans living in areas with low fluoride concentrations in the
drinking water, about 1,500 mg/kg for people in areas with artificial fluoridation, and about 2,700 mg/kg for people in areas with 3 ppm fluoride in the drinking water (Bemdt and Stearns, 1979). The average concentration in dentin is approximately four times higher than that in the enamel (Murray, 1986).

Details on excretion:

Fluoride is excreted primarily in the urine; some appears in the sweat and feces. Fluoride will cross the placenta, but ßuoride Ievels in breast milk are
usually low. Children who are actively forming bone excrete a lower proportion of fluoride than adults, reflecting a higher degree of uptake into the bone
matrix (Zipkin et aL, 1958; International Program on Chemical Safety, 1984).

Conclusions:

Solutions of fluoride salts are rapidly and nearly completely absorbed from the gastrointestinal tract. Low pH in the stomach favors formation of nonionized hydrofluoric acid. Following absorption from the gut, fluoride is found in low concentrations in plasma and soft tissues; however, bone and teeth accumulate fluoride.

Reference 3

Endpoint:

basic toxicokinetics, other

Type of information:

other: evidence based on degradation product

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline required

GLP compliance:

not specified

Details on absorption:

Inhalation

Experiments in which rats were head-only exposed to HF gas, demonstrated that over 99% of the inhaled HF does not reach the lungs but is rapidly absorbed via the lining of the upper respiratory tract. A linear relationship was observed between the HF concentration to which the rats were exposed and the plasma fluoride level. The virtually complete absorption of HF in the upper airways was determined in an experiment in which HF contents of the inhaled air was analyzed via an endotracheal tube (Morris, Smith 1982). Inhalatory uptake of fluoride has also been observed in humans and rabbits (Dinman 1976; Kirk-Othmer 1980; Largent 1960). For instance, human volunteers who breathed 1.16 to 3.9 mg HF/m3 for period of 15 to 30 days excreted F- in their urine in average daily amounts of 3.44 to 19.9 mg over the entire period of exposure. Lund et al. exposed human volunteers for 1 hour to constant concentrations of HF, ranging from 0.2 to
5.2 mg HF/m3. From 0.7 mg/m3 upwards, a linear relationship between exposure and increase in plasma fluoride levels was observed. Maximum plasma levels (ca. 18-80 ng/ml) were seen at 60 to 120 minutes after the start of the exposure (Lund et al. 1997).

Dermal

Dermal uptake of F- from liquid HF in humans has been reported by Burke et al. (1973). A man, accidentally exposed to about 5 g of HF excreted 404 mg F- in the urine over the first three days following the accident (Burke et al. 1973). From the reported data it is impossible to quantify the rate of absorption of HF after dermal exposure. In rats which were dermally exposed to 2% HF (2 ml/kg b.w., under occlusion) in water for 1 or 4 hr, serum fluoride reached levels 3 to 6 times (0.78 - 1.42 mg/l) above the level in the controls (0.25 mg/l) at one hour after the exposure. The serum levels increased with exposure time and decreased to near normal values over the next 96 hr (Derenlanko et al. 1985).

Oral

Oral uptake of HF has not been studied. However, because of the rapid absorption of fluoride from the gastro-intestinal tract, it is conceivable that HF will be rapidly absorbed after oral administration (Wallace-Durbin 1954; Van Asten et al. 1996). The absorption of orally administered fluoride depends on the presence of fluoride-binding cations such as calcium, magnesium and especially aluminium (CEPA 1993; Janssen 1989; WHO 1984) and on the formulation of the fluoride [e.g. in pharmaceutical preparations (Van Asten et al. 1996)].

Details on distribution in tissues:

After uptake fluoride is transported in the blood. 75% of the total blood fluoride concentration is present in the plasma; the remainder is associated with the red blood cells. About 50% of the fluoride in serum is bound to organic molecules, mainly in perfluoro-fatty acids (WHO 1984) and thus in a non-ionic form.

Fluoride distributes throughout all soft tissues, without particular accumulation in one of these. It may also cross the placenta and reach the unborn child. Sequestration of fluoride occurs in bone and teeth, in which it is incorporated into the mineral structures by exchange with hydroxyl groups. About half of the absorbed fluoride is deposited into bone structure. However, in younger humans and in the elderly, bone fluoride uptake is higher than in mid-age persons. Fluoride levels in plasma and in bone have been shown to be directly correlated to the level of exposure. (Morris, Smith 1982; WHO 1984; NTP 1990; Maurer et al. 1990; Maurer et al. 1993).

Details on excretion:

The major route for excretion of fluoride is via the urine. In animals and humans excretion into urine occurs through the glomerular filtration after which reabsorption in the form of HF may occur in the renal tubules, especially after decreased urinary acidity. Minor routes of excretion are via faeces, saliva (partial re-absorption after ingestion) and perspiration. Excretion via the milk is no relevant route of elimination (Thiessen 1988).

In humans plasma half-lives of 2 to 9 hr have been reported (WHO 1984). Because soft tissue fluoride levels are in equilibrium with plasma levels for these tissues similar half-lives may be assumed. After cessation of exposure, fluoride in bone will be released and eliminated from the body. In humans the half-live for bone fluoride is reported to be in the range of 8 to 20 years. (WHO 1984).

Conclusions:

Inhaled gaseous hydrogen fluoride is virtually completely absorbed in the upper airways. The extent of absorption via the dermal route cannot be specified. Fluoride from any inorganic source is absorbed as HF and circulates in the body as F- or as organically bound fluoride. The distribution of this ion and its route of excretion do not depend on the way via which it enters the body. After oral, inhalatory or dermal exposure to HF, fluoride can be found in all tissues in the body. Sequestration takes place in bone tissue in which about half of the absorbed fluoride is deposited. Secretion is mainly via the urine. In humans half-lives are in the range of 2 to 9 hr for plasma and in the range of 8 to 20 years for fluoride in bone deposits.

Executive summary:

Remark

Although the form of fluoride to which one is exposed may influence the amount of fluoride which finally reaches the systemic circulation, the form of fluoride which circulates within the body is not dependent on the fluoride species one has contacted (e.g. Van Asten et al. 1996). Thus when data gaps for systemic effects are established for HF, these data gaps may be filled, using experimental results of other inorganic fluorides, even if these were administered via a route other than inhalation. Toxicity data on other inorganic fluorides will only be used for the hazard assessment of HF, when base set required data for HF are not available.

Reference 4

Endpoint:

basic toxicokinetics, other

Type of information:

other: evidence based on degradation product

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Details on absorption:

Solutions of fluoride salts are rapidly and nearly completely absorbed from the gastrointestinal tract. Low pH in the stomach favors formation of nonionized hydrofluoric acid, which is irritating but more easily absorbed than is the fluoride ion (Carlson et aL, 1960; Taves and Guy, 1979). The presence of food can retard absorption, especially foods rich in calcium, which binds to fluoride (Trautner and Einwag, 1989).

Details on distribution in tissues:

Following absorption from the gut, fluoride is found in low concentrations in plasma and soft tissues; however, bone and teeth accumulate fluoride. Typically about 99% of the total body burden is contained in the skeleton. Uptake into bone is rapid. One metabolism study using intravenously administered radioactive fluoride indicated a half time of 13 minutes for deposition into bone (Charkes et aL, 1978). Studies have found that about 40%-50% of an increase in fluoride intake is incorporated into bone (Largent and Heyroth, 1949; Spencer et aL, 1981). Kinetic studies have demonstrated two compartments for fluoride in bone: an
"exchangeable" companment wbere fluoride concentrations fluctuate and tend to buffer changes in plasma and tissue Ievels; and a •nonexchangeable" compartment where fluoride is released only during bone remodeling (Hallet aL, 1977). Bone fluoride concentrations vary with age and depend upon total
intake. Weatberell (1966) reponed bone fluoride concentrations of 200 to 800 mg/kg (asb) in subjects 20 to 30 years of age and 1,000 to 2,500 mg/kg in
persans 70 to 80 years old. Zipkin et aL (1958) reported bone fluoride concentrations in four groups of individuals witb average ages of 56 to 76 wbo
lived in areas witb fluoride concentrations in drinking water of 0.1, 1, 2.6, or 4 ppm. The relationship between bone fluoride concentrations and water
fluoride content was linear; bone Fuoride ranged from about 800 to 7,000 ppm asb with increasing water fluoride.
In tbe adult, the fluoride content of tooth enamel is reported to be 900 to 1,000 mg/kg in persans living in areas with low fluoride concentrations in the
drinking water, about 1,500 mg/kg for people in areas with artificial fluoridation, and about 2,700 mg/kg for people in areas with 3 ppm fluoride in the drinking water (Bemdt and Stearns, 1979). The average concentration in dentin is approximately four times higher than that in the enamel (Murray, 1986).

Details on excretion:

Fluoride is excreted primarily in the urine; some appears in the sweat and feces. Fluoride will cross the placenta, but ßuoride Ievels in breast milk are
usually low. Children who are actively forming bone excrete a lower proportion of fluoride than adults, reflecting a higher degree of uptake into the bone
matrix (Zipkin et aL, 1958; International Program on Chemical Safety, 1984).

Conclusions:

Solutions of fluoride salts are rapidly and nearly completely absorbed from the gastrointestinal tract. Low pH in the stomach favors formation of nonionized hydrofluoric acid. Following absorption from the gut, fluoride is found in low concentrations in plasma and soft tissues; however, bone and teeth accumulate fluoride.

Description of key information

Fluoride:

Although the form of fluoride to which one is exposed may influence the amount of fluoride which finally reaches the systemic circulation, the form of fluoride which circulates within the body is not dependent on the fluoride species one has contacted (e.g. Van Asten et al. 1996) Solutions of fluoride salts are rapidly and nearly completely absorbed from the gastrointestinal tract. Low pH in the stomach favors formation of nonionized hydrofluoric acid. Following absorption from the gut, fluoride is found in low concentrations in plasma and soft tissues; however, bone and teeth accumulate fluoride.

Zinc (refer to Bioaccumulation for studies):

Due to homeostatic control mechanisms, bioaccumulation is not relevant to essential elements in general and to zinc in particular.

In experimental work, high BCF factors are observed at the lowest zinc exposure levels, due to the fact that organisms will concentrate zinc to satisfy internal physiological needs for the essential element. For the same reason of homeostasis, the BCF will strongly decrease when exposure concentrations increase. This results in a general negative relationship between BCF and exposure (McGeer et al 2003).

On bioaccumulation, the EU risk assessment report (ECB 2008) concluded that“secondary poisoning is considered to be not relevant in the effect assessment of zinc. Major decision points for this conclusion are the following. The accumulation of zinc, an essential element, is regulated in animals of several taxonomic groups, for example in molluscs, crustaceans, fish and mammals. In mammals, one of the two target species for secondary poisoning, both the absorption of zinc from the diet and the excretion of zinc, are regulated. This allows mammals, within certain limits, to maintain their total body zinc level (whole body homeostasis) and to maintain physiologically required levels of zinc in their various tissues, both at low and high dietary zinc intakes. The results of field studies, in which relatively small differences were found in the zinc levels of small mammals from control and polluted sites, are in accordance with the homeostatic mechanism. These data indicate that the bioaccumulation potential of zinc in both herbivorous and carnivorous mammals will be low."