Lithium bromide

Endpoint summary

Description of key information

Lithium bromide dissociates completely in water/body fluids into lithium ions and bromide ions. Both ions are distributed throughout the body and are mainly excreted unchanged via the kidneys. Bioaccumulation can be excluded for both ions due to their hydrophilic characteristics and additionally, for lithium ions, due to the fast excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

General background and toxicological profile

Lithium bromide (LiBr) is an ionic compound of lithium and bromide. It is a white, hygroscopic salt. Because of its hygroscopic character lithium bromide is used as desiccant in air conditioning systems. Further, the salt is useful as a reagent in organic synthesis and sometimes used in hot tubs and spas as mild germicidal agents. Lithium bromide was used as a sedative and psychoactive and therefore used in the treatment of bipolar disorder. Chronic use of lithium bromide in low doses like 225 mg lithium bromide/day can lead to bromism (a syndrome with multiple neurological symptoms). Therefore, due to chronic toxicity lithium bromide is not any longer favoured and used for the treatment of bipolar disorder. The bromide ion is antiepileptic and bromide salts are still used as such, particularly in veterinary medicine.

Lithium bromide completely dissociates in water forming lithium cation and the corresponding bromide anion. Both ions are naturally occurring and ubiquitous in the environment.

The main natural source of bromide is seawater and it can also be found in rainwater and ground water. Bromide occurs naturally in food for human and feed for animals. Seafood and deep sea plants generally have high levels of bromide, while foods derived from land have variable amounts (e.g nuts and grains). The mean daily intake of Br- by humans was estimated to be 7.6 to 7.8 mg Br- / person/ day. The average concentration of bromide in human blood is 5.3 +/- 1.4 mg/L and varies with age and gender. However, since bromide occurs in relatively high concentration in seawater and many type of seafood, bromide concentrations in the blood are heavily influenced by seafood contributions to the diet. In the body bromide is used by eosinophils (white blood cells specialized in dealing with multi-cellular parasites). Despite of this use by the body, bromide is not known to be strictly necessary for animal life, as its functions may generally be replaced by chloride. Bromide and chloride are always present in body fluids of animals in steady state at levels dependent upon intake. Bromide has a low acute toxicity and as for its chronic toxicity in humans, an ADI estimate of 1.0 mg Br-/kg bw was determined by the FAO (Food and Agriculture Organization)/WHO (World Health Organization).

Lithium as well as bromide have been neither known as an essential element for life nor have known biological use. Nevertheless, 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. 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. 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 many publications on lithium pharmacokinetics and toxicity in humans. 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. The DNEL long-term, systemic, oral determined for lithium based on its therapeutic serum concentration and the therapeutic daily oral dose was 1.2 mg lithium/kg bw/day.

Considering the molecular weight ratio and due to the chronic toxicity of the lithium ion (DNEL long-term, oral of 1.2 mg lithium/kg bw/day in comparison to the ADI of bromide of 1 mg bromide/kg bw/day), the lithium bromide DNEL was based on the ADI value of the bromide ion (DNEL long-term oral = 1.09 mg lithium bromide/kg bw/day).

Toxicological data available for lithium bromide (based on studies performed with lithium bromide or based on read-across approach) resulted in classification and labelling of lithium bromide for acute toxicity (Acute Tox 4), skin and eye irritation (Skin and Eye Irrit. 2) and skin sensitisation (Skin Sens. 1) according to Regulation (EC) No 1272/2008 (CLP). Lithium bromide is not expected be mutagenic or clastogenic and no classification and labelling was triggered with respect to repeated dose toxicity and to toxicity of reproduction and development.

As was already indicated in aqueous solutions as well as in body fluids, lithium bromide dissociates completely to Li and Br ions. Therefore the toxicokinetic assessment of lithium bromide focuses on both ions as both ions are considered toxicologically relevant with respect to ADME (adsorption, distribution, metabolism and excretion).

Toxicokinetic Assessment of lithium bromide

Lithium bromide dissociates in water thereby Li and Br ions are formed.

LiBr (aq) <-> Li+ + Br-

Lithium bromide appears as a crystalline salt with a molecular weight of 86.845 g/mol. The ratio of distribution in organic (lipid) and aqueous matrices (octanol / water partition coefficient (log Pow)) could not be determined (LiBr is an inorganic substance) and was therefore calculated/ estimated to -0.37 (25°C) which is expectedly very low. The vapour pressure of lithium bromide was estimated to be very low (solid substance) and the water solubility is very high (166.5 g/100 mL (20°C)).

Dermal absorption

Upon contact with the skin, a compound penetrates into the dead keratinocytes (stratum corneum) 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.

Due to the physico-chemical characteristics of LiBr together with the known barrier function of the stratum corneum against the respective ions, dermal absorption can practically be excluded. Indeed, lithium bromide is a skin irritant (it is known to be a hygroscopic substance), thus, possible damage to the skin surface may occur and enhance penetration. Nevertheless, such situations can be excluded using non-irritating concentrations, short exposure time or gloves. Lithium bromide is available only to worker in industrial use with applied RMM.

Moreover, LD50 value of > 2000 mg/kg bw obtained in an acute dermal study with lithium bromide support the conclusion of a very limited absorption of lithium bromide through the skin. On the other hand lithium bromide has been identified as a skin sensitizer. Thus, some uptake must have occurred although it is supposed to be a very small fraction of the applied dose.

Regarding lithium ion, a study 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.

In conclusion, the absorption of lithium bromide through the skin is considered to be very poor in case of solutions (not-irritating) and in case of the substance in its solid form (hygroscopic, irritating) when RMM are applied. Thus, upon dermal contact, the bioavailability of lithium bromide is expected to be very low. For DNEL derivation, 10 % absorption was used representing a worst case.

Resorption after oral uptake

Upon oral uptake, lithium bromide will reach the stomach in form of lithium ion and bromide ion. Lithium ions will be readily and almost completely absorbed from the gastrointestinal tract with peak plasma level occurring within 1 – 4 hours after administration. As with the lithium ions, bromide ions are also readily and completely absorbed from the gastrointestinal tract. Because Br- and Cl- compete for reabsorption, the half-life time of Br- in the organism is relatively long (12 days in humans).

Resorption after inhalation

The vapour pressure of lithium bromide is negligible and therefore exposure to vapour is toxicologically not relevant. If lithium and bromide 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 bromide, its respective ions, 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 than 1 % 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. Only trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. Thus, 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.

In conclusion, 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.

Bromide ion:

After complete absorption in the gastrointestinal tract, Br- distribution in the extracellular fluid includes penetration of the blood brain barrier. Bromide ion concentration in the cerebrospinal fluid are about 30 % of those in blood, and are strongly influenced by the body´s chloride intake and metabolism as bromide and chloride are always present in body fluids in steady state at levels dependent upon intake.

The fact that Br- and Cl- compete for reabsorption influences the half-life time of Br- in the organism. The normal half-life time, 12 days in humans, may be considerably increased if the diet is deficient in salt.

Bromide ion is readily excreted by the kidney and increased chloride intake will increase the excretion of bromide while the partial reabsorption in the kidneys is in competition with Cl-.

In conclusion: Although the half-life time of bromide is relatively long, bromide (as an ion) is hydrophilic and will not bioaccumulate in fat tissue, therefore, bioaccumulation of bromide is not assumed. Bromide is not metabolised to any appreciable extent in the human body.

In conclusion, bromide (as lithium) is quickly distributed and unchanged excreted in the human body. Bioaccumulation can be excluded.