Lithium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2012

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Lithium

EC Number:

231-102-5

EC Name:

Lithium

Cas Number:

7439-93-2

Molecular formula:

Li

IUPAC Name:

lithium

Applicant's summary and conclusion

Conclusions:

Since lithium has been used as a psychiatric drug for almost half a century, there are a number of publications on lithium pharmacokinetics.
Lithium metal when not kept in heavy oil reacts with water thereby hydrogen gas and lithium hydroxide are formed. Lithium hydroxide dissociates completely in water to lithium ions and hydroxyl ions.
After oral uptake, lithium (Li+) is readily and almost completely absorbed from the gastrointestinal tract. In the stomach the hydroxyl ions neutralise the gastric acid.
The absorption of lithium (Li+) through the skin is considered to be very poor to negligible, considering realistic scenario when no corrosive conditions and damage occur. Upon inhalation (although exposure to vapour is not relevant), if lithium ions reach the lung, its bioavailability of is very low.
After absorption, lithium is quickly distributed and excreted unchanged, primarily in urine. Bioaccumulation can be excluded.

Executive summary:

General background and toxicological profile 

Lithium (Li) is a soft, silver – white (elemental) metal that belongs to the alkali metal group of chemical elements. Lithium is considered highly reactive in contact with water and flammable as the reaction forms flammable hydrogen gas and lithium hydroxide in aqueous solution. It is therefore typically stored under cover of a viscous hydrocarbon, often petroleum jelly. Since lithium metal converts to lithium hydroxide in aqueous solution and in moist air and on moist surfaces, it posses the corrosive and hygroscopic characteristics of lithium hydroxide. Additionally, because of its high reactivity, lithium never occurs free in nature, and instead, only appears in compounds, which are usually ionic. Lithium can be found in a number of pegmatitic minerals, but is also commonly obtained from brines and clays. On a commercial scale, lithium is isolated electrolytically from a mixture of lithium chloride and potassium chloride. Because of its specific heat capacity, lithium metal is often used in coolants for heat transfer applications. Its fusing quality is also important as a flux for producing ceramics, enamels and glass. Alloys of the metal are used to make high-performance aircraft parts. Lithium metal is also used in the pharmaceutical and fine-chemical industry in the manufacture of organolithium reagents, which are basis of many synthetic applications.

Lithium has been neither known as an essential element for life nor has known biological use but according to various reports there is a 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 U.S.A) 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 (0.5-3.4 mg Li/kg food), dairy products (0.50 mg Li/kg food) and meat (0.012 mg Li/kg food). 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 number of publications on lithium pharmacokinetics and toxicity in humans. Thus, concerning long-term oral toxicity the following data was considered in the dossier: the recommended dose, e.g. for therapy of acute mania and hypomania is 900 to 1800 mg/day lithium carbonate (equivalent to 169 to 338 mg lithium / day), corresponding to a therapeutic serum concentration of 1.0 to max. 1.2 mmol lithium/L. In case of long-term treatment, the recommended dose is 450 to 900 mg/day lithium carbonate (equivalent to 85 to 169 mg lithium/day), corresponding to a therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. For a 70 kg adult the recommended doses of 450 to 900 mg lithium carbonate/day are equivalent to 6.43 and 12.86 mg lithium carbonate/kg bw/day, respectively. These doses are equivalent to 1.2 mg lithium/ kg bw/day and 2.4 mg lithium /kg bw/day.

Additional toxicological data available are based on experience from handling and use and from studies performed with lithium salts in which the results (read across approach) were recalculated or revaluated for lithium (thereby staying in line with animal welfare considerations). Lithium is classified and labelled as corrosive to skin and eye (Cat. 1B (H314) and Cat. 1 (H318) according to Regulation (EC) No 1272/2008 (CLP) and corrosive (R34) according to Directive 67/548/EEC. Lithium is not expected to cause skin sensitisation and it is not expected to be mutagenic or clastogenic. These negative findings are supported by experience with long-term administration of e.g. lithium carbonate in humans for the therapy of bipolar disorder. Since lithium (ion) has been used in the treatment of bipolar affective disorders for decades, toxicity in case of sub-chronic and chronic exposure to lithium at therapeutic levels (1.2 – 2.4 mg lithium/kg bw/day) can be excluded and consequently no classification and labelling was triggered with respect to repeated dose toxicity. A new valid GLP study in rat with lithium carbonate proved no toxicity to reproduction and development.

In aqueous solutions as well as in moist air and moist skin lithium metal forms lithium ions and hydroxyl ions. Therefore the toxicokinetic assessment of lithium focuses mainly on lithium ion (Li+) and to a lesser extent on the hydroxyl ion. Opposed to the hydroxide ion which may react with free H+, forming (non-hazardous) water, Li+ is considered toxicologically relevant with respect to ADME (adsorption, distribution, metabolism and excretion).

Toxicokinetic Assessment of lithium

Lithium reacts with water and thereby lithium hydroxide and hydrogen gas are formed.

Li (aq) <-> LiOH + H2↑

LiOH is also rapidly formed when lithium comes in contact with moist air and skin (lithium metal tarnishes to form a black coating of lithium hydroxide). LiOH is a strong alkaline substance and dissociates completely in water (very soluble 71 to 125 g/L ) forming lithium ions and hydroxyl ions resulting in increasing pH solutions:

LiOH <-> Li+ + OH-

The hydroxide ion may react with free H+ or any acidic species that may be present, forming water:

OH- + H+ <-> H2O, K = 1.0e-14 (25°C)

Lithium is an alkali metal with a low molecular weight of 6.941 g/mol. Because of its reactivity with water/ moist air or surface it is kept in heavy oil. The ratio of distribution in organic (lipid) and aqueous matrices (octanol / water partition coefficient (log Pow)) cannot be determined for inorganic substance. Therefore it could only be estimated for lithium and was calculated to be -0.77 which is very low as expected for an alkali metal. The solubility and the vapour pressure of lithium could not be determined as well as lithium reacts violently with water producing flammable gas. However, the vapour pressure was calculated and showed indeed a very low value as expected (3.49E-029 Pa at 25°C)

Dermal absorption

Dermal absorption, the process by which a substance is transported across the skin and taken up into the living tissue of the body, is a complex process. The skin is a multilayered biomembrane with particular absorption characteristics. It is a dynamic, living tissue and as such its absorption characteristics are susceptible to constant changes. The barrier properties of skin almost exclusively reside in its outermost layer, the stratum corneum, which is composed of essentially dead keratinocytes.
Upon contact with the skin, a compound penetrates into the dead stratum and may subsequently reach the viable epidermis, the dermis and the vascular network. During the absorption process, the compound may be subject to biotransformation. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds. Upon dermal exposure, corrosive substances cause skin and tissue damage and can easily be absorbed and become systemically available. When lithium metal comes in contact with skin moisture not only lithium ions are formed but also hydroxyl ions which are responsible for the corrosive effect of lithium metal to skin. However, such corrosive situations can be excluded (except in case of accidents) as lithium metal is available only to worker in industrial use with applied RMM and is kept in heavy oil which keeps it from transforming to lithium hydroxide.
In case of dermal exposure to non-corrosive solutions, the uptake of lithium is expected to be low as the stratum corneum provides greatest barrier function against hydrophilic compounds, respectively water. Due to (1) the hydrophilic character of lithium and (2) the barrier function of the stratum corneum against the respective ions, dermal absorption can practically be excluded. For this reason the uptake of lithium is expected to be limited under non-corrosive conditions (i.e. not in case of accidents).
This is supported by a study that showed no significant elevation of lithium serum in 53 healthy volunteers spending 20 minutes/day, 4 days/week for two consecutive weeks in a spa with a concentration of approximately 40 ppm (mg/L) lithium (generated from lithium hypochlorite) as compared with unexposed controls. Thus, the authors concluded that absorption of lithium through the skin is considered to be very poor. Additionally, studies performed with lithium chloride and lithium carbonate showed no sensitisation effect to lithium and a LD50 value of > 2000 mg/kg bw obtained in an acute dermal study with lithium carbonate support the conclusion of a very limited absorption of lithium ions through the skin.
In conclusion, the absorption of lithium through skin is considered to be poor in case of non-corrosive solutions / situations. Thus, upon dermal contact, the bioavailability of lithium is expected to be very low and therefore negligible.

Resorption after oral uptake

Upon oral uptake, lithium will reach the stomach in form of lithium ion and hydroxyl ion. The hydroxyl ion in the stomach will neutralise the gastric acid. Lithium ions will be readily and almost completely absorbed from the gastrointestinal with peak plasma level occurring within 1 – 4 hours after administration.

Resorption after inhalation

The vapour pressure of lithium is negligible and therefore exposure to vapour is toxicologically not relevant. That is also true when in moist air where lithium metal tarnishes and a black layer of lithium hydroxide is formed as the vapour pressure of lithium hydroxide (respective lithium hydroxide monohydrate) is also negligible low.If lithium ions reach the lung they may be absorbed via the lung tissue but resorption after inhalation is assumed to be low due to the very low log Pow. Thus, upon inhalation, the bioavailability of lithium is expected to be low.

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 cations as K+, Na+.Lithium ions are presumed to interfere with processes that Na+ and K+ ions are involved in such as renal tubular transport and ion channels (neurotransmission).

Lithium has a large volume of distribution of 0.6 – 0.9 L/kg (for a 70 kg human a 42 L of volume of distribution).

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 CSF (Cerebrospinal Fluid) 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 re-absorption. Lithium is excreted primarily in urine, less than1 % is 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.

Renal lithium clearance is under ordinary circumstances remarkably constant in the same individual but decreases with age or 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.

Hydroxyl ion:

The hydroxide ion may react with free H+, forming water which is toxicological not relevant.