Lithium fluoride

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Objective of study:

toxicokinetics

Conclusions:

Lithium fluoride dissociates in water into lithium ions and fluoride ions. Both ions are distributed throughout the body and are mainly excreted (80 - 90 %) unchanged via the kidneys. Due to the fast excretion, bioaccumulation is not to be assumed.

Executive summary:

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 25.9394 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is very likely (ECHA, 2014). Furthermore the compound is highly hydrophilic (log Pow = 0.23) and has a high water solubility.

Readily soluble fluoride substances are assumed to be completely and rapidly absorbed. The absorption process occurs via passive diffusion from the stomach or the intestine. The rate of absorption is most likely related to the gastric acidity. Fluoride that is not absorbed in the stomach will be rapidly absorbed in the small intestine. This assumption can be underlined by an acute oral toxicity study in Sprague Dawley rats. An LD50 of 706 mg/kg bw was obtained in male and female animals.

Considering the low vapour pressure of lithium fluoride and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. If inhaled, the high water solubility of the compound would lead complete absorption of particles in the mucus lining of the respiratory tract. The extent of absorption via inhalation is further depending on the particle size. Particulates that are deposited in the bronchioles or the nasopharynx may predominantly be swallowed via ciliary clearance or coughing and reach the GI tract. Therefore complete absorption via inhalation is highly likely.

But according to read across data of lithium bromide and lithium chloride no adverse effects were observed in two acute inhalation toxicity studies. Therefore inhalation of the test substance can be regarded as low toxicological concern.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 25.94 g/mol a dermal uptake is highly favoured. Furthermore the high water solubility of the test substance supports a moderate to high dermal absorption. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1. The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Furthermore lithium fluoride consists of a particulate at room temperature, which first has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin.

The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing with two read across substances (LiCl, LiBr). In the available acute dermal toxicity studies, the source substances did not cause any toxic effects. The LD50 was determined to be greater than 2000 mg/kg bw.

Topical application of the test substance onto the skin should also not cause any sign of irritation based on two in vitro studies. No evidence of tissue damage was observed in the in vitro studies which in turn could have favoured direct absorption into the systemic circulation. A negative Buehler assay in guinea pigs with the source substance sodium fluoride additionally supports the assumption of low dermal absorption.

Distribution, Metabolism and Excretion

Lithium

Lithium does not bind to protein and as a small cation it is quickly distributed throughout the body water both intra- and extracellularly, replacing normal cations (as K+, Na+). Lithium ions effects in the cell level are presumed to be related to interferences with processes that involve these ions such as renal tubular transport and ion channels involved in neurotransmission. Lithium has a large volume of distribution of 0.6 – 0.9 L/kg (42 L for a 70 kg adult, which is the total body water). Because of its large volume of distribution, lithium shifts into the intracellular compartment of cells. With long – term use, the intracellular concentration of lithium increases, which thereby results in an increased total body lithium load. The intracellular concentration is not reflected by the plasma level, which measures only the extracellular fluid concentration. Organ distribution is not uniform: lithium is rapidly taken up by the kidney (there is obviously a clear interaction between lithium and sodium excretion/retention altering the electrolyte balance in humans). Penetration is slower into the liver, bone and muscle. Its passage across the blood-brain barrier is slow and equilibration of the CSF lithium level reaches only approximately half the plasma concentration.

The primary route of excretion is through the kidneys. Lithium is filtered by the glumeruli and 80 % of the filtered lithium is reabsorbed in the tubules, probably by the same mechanism of sodium reabsorption. Lithium is excreted primarily in urine with less than1 % being eliminated with the feces.

The renal clearance of lithium is proportional to its plasma concentration. The excretion of lithium ions is considered to be fast. About 50 % of a single dose of lithium is excreted in 24 hours and about 90 % in 48 hours. However, trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. A single oral dose of lithium ion is excreted almost unchanged through the kidneys. A low salt intake resulting in low tubular concentration of sodium will increase lithium reabsorption and might result in retention and intoxication. Renal lithium clearance is under ordinary circumstances, remarkably constant in the same individual but decreases with age and falls when sodium intake is lowered.

Due to the fast excretion bioaccumulation is not to be assumed. Lithium is not metabolised to any appreciable extent in the human body. In conclusion, Lithium in human body is quickly distributed and unchanged excreted. Bioaccumulation can be excluded.

Fluoride

Rapid distribution occurs by systemic circulation to the intra- and extracellular water of different tissues. In humans 99 % of the total body burden of fluoride is retained in bone and teeth. Remaining fluoride ions are distributed in highly vascularized soft tissues and blood. Fluoride normally accumulates only in calcified tissues such as bone, dentine and enamel. It does not bind to any plasma proteins and is asymmetrically distributed between plasma and red blood cells (plasma concentration is two times higher). Normal plasma fluoride concentrations range between 0.4 to 2.4 µmol/L and the plasma half-life ranges between 3 to 10 hours. From the plasma it is distributed to different tissues and organs. Generally a steady state tissue-to-plasma fluoride concentration ratio falls between 0.4 to 0.9. Steady state concentrations are achieved more rapidly between plasma and highly vascularized organs like heart, lungs and liver compared to less perfused organs/tissues like skin, adipose tissue and resting skeletal muscle. This does not apply for the kidneys, because fluoride is concentrated within the renal tubules leading to a higher concentration compared to plasma.

The primary route of excretion is through the kidneys because of the high water solubility. Renal clearance typically ranges between 30 to 50 mL/min. Rapid excretion via kidneys is also seen when only small amounts are ingested. Already after 3 hours at least 20 % of the dose can be detected in the urine. Furthermore, 10 to 90 % of the filtered fluoride can be reabsorbed from the renal tubules depending on the pH, urinary flow and renal function. Unabsorbed fluoride is excreted via faeces to a much lower extent compared to renal excretion. Less than 10 % of the amount ingested can be found in the faeces.

Due to the fast excretion bioaccumulation is not to be assumed. Fluoride like lithium is not metabolised to any appreciable extent in the human body. In conclusion, fluoride in human body is quickly distributed and unchanged excreted. Additionally fluoride is not irreversibly bound to bone. Thus, bioaccumulation can be excluded.

Description of key information

Lithium fluoride dissociates in water into lithium ions and fluoride ions. Both ions are distributed throughout the body and are mainly excreted (80 - 90 %) unchanged via the kidneys. Due to the fast excretion, bioaccumulation is not assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Lithium fluoride is a white odourless powder at room temperature with a molecular weight of 25.9394 g/mol. The water solubility is high (2.7 g/L). A log Pow of 0.23 and a BCF value of 3.162 L/kg were calculated. The test substance has a very low vapour pressure of 1.22E-21 hPa at 25 °C (calculated).

The toxicokinetic assessment of lithium fluoride focuses mainly on lithium since fluoride is naturally distributed in minerals and soil. Both, lithium and fluoride ions are ubiquitous in the environment, but lithium is the toxicological relevant moiety of the assessed substance.

Fluoride is the stable form of the super reactive fluorine and is the 17th most abundant element in the earth´s crust. It can be detected in almost all minerals and is mainly present as fluorspar-CaF2 and fluorapatite-Ca10F2(PO4)6. It enters the aquatic system through weathering of alkali or silicic sedimentary rocks or via emissions from volcanic activity. In freshwater it is typically found at concentrations below 1 mg/L. Fluoride is not of toxicological concern in nutrition and the toxicity of fluoride in humans at therapeutic doses is low. Fluoride has a low acute toxicity and as for its chronic toxicity in humans, an ADI estimate of 4 mg F-/kg bw/d was determined by the National Academy of Sciences (DGUHT, 2008)

Lithium has been neither known as an essential element for life nor has known biological use but according to various reports there is growing evidence that lithium may be an essential mineral in the human diet. The average daily lithium intake of a 70 kg adult (in the USA) is between 0.65 and 3.1 mg/day and in some lithium-rich places like Chile; the total lithium intake may reach 10 mg/day without evidence of adverse effects to the local population. Major dietary sources of lithium are grains and vegetables, dairy products and meat. A recommended daily intake (RDA) of 1.0 mg lithium/day for a 70 kg adult was proposed, corresponding to 14.3 µg/kg bw. Intake of lithium can occur as part of a psychiatric therapy in the treatment of bipolar affective disorders as lithium ion (Li+, administered as any of several lithium salts) has proved to be useful as a mood-stabilizing drug.

Since lithium has been used as a psychiatric drug for almost half a century, there are numerous publications on lithium pharmacokinetics and toxicity in humans.

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 25.9394 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is very likely (ECHA, 2014). Furthermore the compound is highly hydrophilic (log Pow = 0.23) and has a high water solubility.

Readily soluble fluoride substances are assumed to be completely and rapidly absorbed. The absorption process occurs via passive diffusion from the stomach or the intestine. The rate of absorption is most likely related to the gastric acidity. Fluoride that is not absorbed in the stomach will be rapidly absorbed in the small intestine. This assumption can be underlined by an acute oral toxicity study in Sprague Dawley rats. An LD50 of 706 mg/kg bw was obtained in male and female animals.

Considering the low vapour pressure of lithium fluoride and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. If inhaled, the high water solubility of the compound would lead complete absorption of particles in the mucus lining of the respiratory tract. The extent of absorption via inhalation is further depending on the particle size. Particulates that are deposited in the bronchioles or the nasopharynx may predominantly be swallowed via ciliary clearance or coughing and reach the GI tract. Therefore complete absorption via inhalation is highly likely.

But according to read across data of lithium bromide and lithium chloride no adverse effects were observed in two acute inhalation toxicity studies. Therefore inhalation of the test substance can be regarded as low toxicological concern.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 25.94 g/mol a dermal uptake is highly favoured. Furthermore the high water solubility of the test substance supports a moderate to high dermal absorption. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1. The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Furthermore lithium fluoride consists of a particulate at room temperature, which first has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when in contact to the skin.

The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing with two read across substances (LiCl, LiBr). In the available acute dermal toxicity studies, the source substances did not cause any toxic effects. The LD50 was determined to be greater than 2000 mg/kg bw.

Topical application of the test substance onto the skin should also not cause any sign of irritation based on two in vitro studies. No evidence of tissue damage was observed in the in vitro studies which in turn could have favoured direct absorption into the systemic circulation. A negative Buehler assay in guinea pigs with the source substance sodium fluoride additionally supports the assumption of low dermal absorption.

Distribution, Metabolism and Excretion

Lithium

Lithium does not bind to protein and as a small cation it is quickly distributed throughout the body water both intra- and extracellularly, replacing normal cations (as K+, Na+). Lithium ions effects in the cell level are presumed to be related to interferences with processes that involve these ions such as renal tubular transport and ion channels involved in neurotransmission. Lithium has a large volume of distribution of 0.6 – 0.9 L/kg (42 L for a 70 kg adult, which is the toal body water). Because of its large volume of distribution, lithium shifts into the intracellular compartment of cells. With long – term use, the intracellular concentration of lithium increases, which thereby results in an increased total body lithium load. The intracellular concentration is not reflected by the plasma level, which measures only the extracellular fluid concentration. Organ distribution is not uniform: lithium is rapidly taken up by the kidney (there is obviously a clear interaction between lithium and sodium excretion/retention altering the electrolyte balance in humans). Penetration is slower into the liver, bone and muscle. Its passage across the blood-brain barrier is slow and equilibration of the CSF lithium level reaches only approximately half the plasma concentration.

The primary route of excretion is through the kidneys. Lithium is filtered by the glumeruli and 80 % of the filtered lithium is reabsorbed in the tubules, probably by the same mechanism of sodium reabsorption. Lithium is excreted primarily in urine with less than1 % being eliminated with the feces.

The renal clearance of lithium is proportional to its plasma concentration. The excretion of lithium ions is considered to be fast. About 50 % of a single dose of lithium is excreted in 24 hours and about 90 % in 48 hours. However, trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. A single oral dose of lithium ion is excreted almost unchanged through the kidneys. A low salt intake resulting in low tubular concentration of sodium will increase lithium reabsorption and might result in retention and intoxication. Renal lithium clearance is under ordinary circumstances, remarkably constant in the same individual but decreases with age and falls when sodium intake is lowered.

Due to the fast excretion bioaccumulation is not to be assumed. Lithium is not metabolised to any appreciable extent in the human body. In conclusion, Lithium in human body is quickly distributed and unchanged excreted. Bioaccumulation can be excluded.

Fluoride

Rapid distribution occurs by systemic circulation to the intra- and extracellular water of different tissues. In humans 99 % of the total body burden of fluoride is retained in bone and teeth. Remaining fluoride ions are distributed in highly vascularized soft tissues and blood. Fluoride normally accumulates only in calcified tissues such as bone, dentine and enamel. It does not bind to any plasma proteins and is asymmetrically distributed between plasma and red blood cells (plasma concentration is two times higher). Normal plasma fluoride concentrations range between 0.4 to 2.4 µmol/L and the plasma half-life ranges between 3 to 10 hours. From the plasma it is distributed to different tissues and organs. Generally a steady state tissue-to-plasma fluoride concentration ratio falls between 0.4 to 0.9. Steady state concentrations are achieved more rapidly between plasma and highly vascularized organs like heart, lungs and liver compared to less perfused organs/tissues like skin, adipose tissue and resting skeletal muscle. This does not apply for the kidneys, because fluoride is concentrated within the renal tubules leading to a higher concentration than in plasma.

The primary route of excretion is through the kidneys because of the high water solubility. Renal clearance typically ranges between 30 to 50 mL/min. Rapid excretion via kidneys is also seen when only small amounts are ingested. Already after 3 hours at least 20 % of the dose can be detected in the urine. Furthermore, 10 to 90 % of the filtered fluoride can be reabsorbed from the renal tubules depending on the pH, urinary flow and renal function. Unabsorbed fluoride is excreted via faeces to a much lower extent compared to renal excretion. Less than 10 % of the amount ingested can be found in the faeces.

Due to the fast excretion bioaccumulation is not to be assumed. Fluoride like lithium is not metabolised to any appreciable extent in the human body. In conclusion, fluoride in human body is quickly distributed and unchanged excreted. Additionally fluoride is not irreversibly bound to bone. Thus, bioaccumulation can be excluded.

References

ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Marquardt H., Schäfer S. (2004) Toxicology. Academic Press, San Diego, USA, 2nd Edition.

CMAJ. 2007 March 27; 176(7): 921-923. negative anion gap and elevated osmolar gap due to lithium overdose, Manish M. Sood and Robert Richardson

http://www.bipolarworld.net/Medications/Mood%20Stabilizers/meds6.htm

Krebs, Robert E. (2006). The History and Use of Our Earth's Chemical Elements: A Reference Guide. Westport, Conn.: Greenwood Press.ISBN 0-313-33438-2

Scientific Basis for Swedish Occupational Standards XXIV (2003) Lithium and lithium compounds; pg 60 - 69

Hammond, C. R. (2000). The Elements, in Handbook of Chemistry and Physics 81st edition. CRC press.ISBN 0-8493-0481-4.

World Health Organisation (2002). Environmental Health Criteria 227, FLUORIDES. ISBN 92-4 157227-2

Sloof et al. (1989):www.rivm.nl/bibliotheek/rapporten/758474010.pdf