Lithium nitrate

Endpoint summary

Description of key information

Lithium nitrate dissociates completely in water into lithium ions and nitrate 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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

General background and toxicological profile 

Lithium nitrate is a colourless, hygroscopic salt with the formula LiNO3. It is not only very soluble in water (1020 g/L) but also in other polar solvents. Lithium nitrate is used for the production of other lithium compounds. Further it can be used for curing of rubber mixtures and as a heat transfer medium in cooling circuits.

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

Nitrates are very water soluble and play an important role as nutrient for plants. Nitrate anions are nearly non-toxic. Just like other salts an oral uptake of high amounts lead to osmotic problems in the human body. Nitrate can be metabolised/reduced to nitrite by bacteria of the gastro-intestinal tract in the human body. It is known that increases of pathogenic germs can be reduced by uptake of nitrate. Nitrite can also be metabolised to the messenger nitric oxide. This messenger can dilate blood vessels and stimulates the blood flow. Further the composed nitrite can reversibly oxidise the oxy haemoglobin to met haemoglobin which results in a deficit of oxygen transport via blood stream. As infants at the age of up to three months are more susceptible to this reaction the WHO (World Health Organisation) has stated an acceptable daily intake (ADI) of 3.7 mg/kg bw/day for adults. Due to the high susceptibility of infants, the acceptable concentration of nitrate especially in drinking water (<10 mg/L) and baby food was lowered (250 mg/L).

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 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 many numbers of publications on lithium pharmacokinetics and toxicity in humans.

Toxicokinetic Assessment of lithium nitrate

Lithium nitrate is a white crystalline odourless solid with a molecular weight of 68.95 g/mol. The substance is very soluble in water (1020 g/L). The Partition coefficient was calculated to be - 0.79. Lithium nitrate has a very low vapour pressure calculated to be 1.4E-15 Pa at 25 °C. The substance rapidly dissociates to lithium and nitrate 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 nitrate it can be expected that the uptake will be limited. This is due to the hydrophilic character of lithium nitrate and the barrier function of the stratum corneum against ions. This is supported by an acute dermal toxicity study that revealed a LD50 value of > 2000 mg/kg bw without any local or systemic effects. Further no sensitisation could be detected in a maximisation test with guinea pigs. This supports the conclusion of a very limited absorption of lithium nitrate through the skin.

This conclusion is further 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 nitrate through skin and its bioavailability are considered to be very poor.

Resorption after oral uptake:

Upon oral uptake, lithium nitrate will reach the stomach in form of lithium ions and nitrate ions. Lithium ions and nitrate ions will be readily and almost completely absorbed from the gastrointestinal tract due to their low molecular weight. Additionally, the low log Pow between -1 and 4 of both ions favours them for 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 by an acute oral toxicity study resulting in a LD50 of 1426 mg/kg bw/day.

Resorption after inhalation:

The vapour pressure of lithium nitrate is negligible and therefore exposure to vapour is toxicologically not relevant. If lithium ions reach the lung resorption after inhalation is assumed to be low due to the very low log Pow. Thus, upon inhalation, the bioavailability of lithium nitrate 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 ion 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 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 also 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.

 

Nitrate ion:

Nitrate is a small ion which may be distributed into the blood and the extracellular compartiments due to its high water solubility. Because of the good solubility nitrate will not come in contact with intracellular metabolising enzymes, so intracellular metabolism of the substance is highly unlikely. Nitrate is taken up daily as it is naturally present in drinking water. Further it is a food additive. Nitrate can be metabolised/reduced to nitrite by bacteria of the gastro-intestinal tract and further to the messenger nitric oxide. The primary route of excretion is through the kidneys. 80 – 90 % will be excreted unchanged through urine. Nitrate 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 to be assumed. (SCC, 2012)