Lithium sulphate

Endpoint summary

Description of key information

Lithium sulfate dissociates in water into lithium ions and sulfate 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

General background and toxicological profile

Lithium sulfate is a white hygroscopic salt with the formula Li2SO4. Its main use is the lithium therapy against bipolar disorders. Further it is applied in the piezoelectronics, acoustics and as an ultrasound emitter.

The toxicokinetic assessment of lithium sulfate focuses mainly on lithium as it is the molecule with the pharmacological activity. Further, sulfates are naturally distributed in minerals such as plaster stone and in drinking water. Both, lithium and sulfate ions are ubiquitous in the environment, but lithium is the toxicological relevant moiety of the assessed substance.

Sulfate is very soluble in water, ubiquitous in fresh water environments and is a common sulphur source for plants and bacteria. For humans it is important in the synthesis of digestive enzymes. The detoxification of xenobiotics occurs through submission of sulfate groups in order to elevate the water solubility and therefore the excretion of the substances. Sulfate can further be anti-inflammatory and anti-depressant.

As the sulfate ion is a natural constituent of food and is a product of sulphur metabolism in animals, an acceptable daily intake of "not specified"* ADI was established. (FAO/WHO Expert Committee on Food Additives, 2000)

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 U.S.A) is between 0.65 and 3.1 mg/day. In 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 numbers of publications on lithium pharmacokinetics and toxicity in humans.

* ADI 'not specified' is a term applicable to a food component of very low toxicity which, on the basis of the available chemical, biological, toxicological, and other data, the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background in food, does not, in the opinion of the WHO Committee, represent a hazard to health. For this reason and for those stated in the evaluation, the establishment of an ADI expressed in numerical form is deemed unnecessary.

 

Toxicokinetic assessment

Lithium sulfate is a white odourless solid with a molecular weight of 109.95 g/mol. The substance is very soluble in water (255 g/L). The partition coefficient was calculated to be – 4.38. Lithium sulfate has a low vapour pressure of 2.33E-17 Pa at 25 °C. The substance rapidly dissociates to lithium and sulfate ions.

 

Dermal absorption

The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds. When considering lithium sulfate it can be expected that the uptake will be limited and practically excluded. This is due to the hydrophilic character of lithium sulfate and the barrier function of the stratum corneum against ions. It is supported by an acute dermal toxicity study that revealed a LD50 value of > 3000 mg/kg bw without any local or systemic effects for the structural and chemical similar compound lithium carbonate. Further no sensitisation could be detected in a Buehler test with guinea pigs which supports the conclusion of a very limited absorption of lithium sulfate through the skin.

This is also supported by a study conducted in a spa with lithium. No significant elevation of serum lithium levels was reported 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, upon dermal contact, the absorption of lithium sulfate through skin and its bioavailability are considered to be very poor.

Resorption after oral uptake

Upon oral uptake, lithium sulfate will reach the stomach in form of lithium ions and sulfate ions. Lithium ions and sulfate ions will be readily and almost completely absorbed from the gastrointestinal tract due to there low molecular weight. Additionally, the low log Pow below -1 of both ions favours absorption by passive diffusion and therefore they can cross lipophilic membranes. They are also small and water soluble enough to be carried through the epithelial barrier by the bulk passage of water. This assumption is proved with a LD50 of 1065 mg/kg bw observed from clinical and /or autopsy data obtained from humans.

 

Resorption after inhalation

The vapour pressure of lithium sulfate is negligible and therefore exposure to vapour is toxicologically not relevant. 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 sulfate 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 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 (for a 70 kg human a 42 L of volume of distribution). 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 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 upon equilibration 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 than 1 % 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 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.

 

 

Sulfate

Sulfate is a natural and necessary constituent in the bodies of humans and other animals. In humans, serum sulfate levels range from 0.25 to 0.38 mmol/L. Sulfate is involved in a number of biochemical activities including the production of chondroitin sulfate and sulfation of exogenous chemicals. It relevant for detoxication by liver and improve digestion.

As a small ion, sulfate may be distributed into the blood and the extracellular compartments due to its high water solubility. Because of the good solubility sulfate will not come into contact with intracellular metabolising enzymes, so intracellular metabolism of the test substance is highly unlikely. The primary excretion route is assumed to be the kidneys. It is filtered by the kidneys through the glomerulus and excreted from the renal tubular lumen by active transport systems or by passive diffusion. Due to the fast excretion bioaccumulation is not assumed.