Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Since lithium has been used as a psychiatric drug for almost half a century, there are a number of publications on lithium pharmacokinetics.
Lithium chloride is a highly soluble salt that dissociates in Lithium and chloride ions in water.
After oral uptake, lithium chloride is readily and almost completely absorbed from the gastrointestinal tract. The absorption of lithium through the skin is considered to be very poor to negligible. Upon inhalation, resorption and bioavailability of lithium chloride is expected to be low. After absorption, lithium is quickly distributed and unchanged excreted. Bioaccumulation can be excluded. Chloride occurs ubiquitous and is an essential element of the human body. Thus, in the sum, the toxicological relevance of lithium chloride is regarded as very low.
Executive summary:

General

Lithium chloride is hygroscopic salt with the formula LiCl. This white ionic compound is not only very soluble in water (569 g/L) but also in other polar solvents (alcohol, acetone). Lithium chloride is used in the production of lithium metal by electrolysis, as a brazing flux for aluminium, as electrolytes in lithium battery technology, desiccant for drying air streams, in organic synthesis, or in biochemical applications. In the 1940s, lithium chloride was recommended as a salt substitute for patients with high sodium levels, but this is no longer done because of the risk of lithium poisoning. This substance is also reported as drug to treat bipolar disorder (but rarely used compared to lithium carbonate).

The toxicokinetic assessment of lithium chloride focuses on lithium since chloride is for example naturally present in water and represent a physiological molecule. Both, lithium and chloride ions are ubiquitous in the environment.

Chloride is the most abundant anion in humans and all animal species. Chloride is an essential element of the human body being responsible for metabolism. As counter-ion to sodium, most of chloride is dissolved extracellularly. The intracellular concentration of chloride is ca. 100-140 ug/mL. The chloride concentration in blood plasma is ca. 3.55-3.90 mg/mL. Chloride plays an important biological role in the regulation of the acid-base balance of the body, and maintains electrochemical neutrality by anion exchange with bicarbonate (the chloride shift) in the CO2 transport in the blood red cells and the osmotic tension of blood and tissues. An average human body (70 kg) contains 70 - 95 g chloride. Moreover, chloride is ubiquitously present in the environment (in minerals, soil, sediment, animals, and plants) but also an additive in food. The main human exposure to chloride is the normal dietary intake (ca. 3.5-9 g chloride per day), the recommended daily intake is published as 3.4 g chloride/ day. EU’s drinking water standard is 250 mg chloride /L.

Lithium has been neither known as an essential element for life nor has known biological uses but according to various reports there is growing evidence that lithium may be an essential mineral in the human diet. As published, the average daily lithium intake of a 70 kg adult (American) is between 0.65 and 3.1 mg/day. 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) but in some lithium-rich places like in Chile, the total lithium intake may reach 10 mg/day without evidence of adverse effects to the local population. The minimum human adult (physiological) lithium requirement is estimated to be less than 0.1 mg/day. A provisional recommended daily intake (RDA) of 1.0 mg lithium/day for a 70 kg adult was proposed, corresponding to 14.3 ug/kg body weight.

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/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.

This information on dosage is consistent throughout nearly all publications. Only very slight differences were noted, e.g. therapeutic lithium ranges for long-term treatment of 0.6 mmol/L - 1 mmol/L or recommended 12-hours serum Lithium concentrations of 0.5 to 0.8 mmol/L in general and 0.9 to 1.2 mmol/L in some cases in Sweden.

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 values are equivalent to 516 - 1033 mg lithium chloride/day or 7.38 - 14.75 mg lithium chloride/kg bw/day or 1.2 mg Lithium/ kg bw/day and 2.4 mg lithium /kg bw/day.

Since Lithium has been used as a psychiatric drug for almost half a century, there are a number of publications on lithium pharmacokinetics.

Toxicokinetic Assessment of Lithium chloride

Lithium chloride is an inorganic salt with a molecular weight of 42.395 g/mol. It is very soluble in water (569 g/L) and readily undergoes dissociation, forming lithium and chloride ions.

The partition coefficient (octanol / water) log Pow in order to assess the ratio of distribution in organic (lipid) and aqueous matrices cannot be determined for an inorganic salt, but is expected to be in the rage of negative values.

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 subse-quently reach the viable epidermis, the dermis and the vascular network. During the absorp-tion 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. Thus, the stratum corneum provides greatest barrier function against hydrophilic compounds, respectively water. Due to (1) the hydrophilic character of lithium chloride and (2) the barrier function of the stratum corneum against salts, dermal absorption can practically be excluded. The dermal toxicity value revealed a LD50 > 2000 mg/kg bw, which further supports this conclusion. 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 chloride) as compared with unexposed controls. This study result was expected due to the chemical properties of an inorganic salt as lithium chloride. Also other authors concluded that absorption of lithium through the skin is considered to be very poor. 10% absorption will be appropriate for DNEL deduction as this presents a worst case. In conclusion, the absorption of lithium through skin is considered to be poor. Thus, upon dermal contact, the bioavailability of lithium chloride is expected to be very low and therefore negligible.

Resorption after oral uptake

After oral administration lithium chloride is readily and almost completely absorbed from the gastrointestinal tract revealing lithium peak plasma levels after single oral doses peaked at 30-60 minutes (i.e. faster than in case of Lithium carbonate uptake due to the higher water solubility) and plateau levels were reached at 12-24 hours.

Resorption after inhalation

The vapour pressure of Lithium chloride is negligible low and therefore exposure to vapour is toxicologically not relevant. If Lithium reaches the lung it 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 carbonate is expected to be low.

Distribution, Metabolism and Excretion

Lithium:

Lithium is not bound to proteins, but is quickly distributed throughout the body water both intra- and extracellularly. Excretion of lithium is fast (> 50% and > 90% within 24 and 48 hours, respectively) and takes place almost completely via urine. Organ distribution is not uniform: Lithium is rapidly taken up by the kidney, but distributed more slowly into the liver, bone muscle or the brain. There is obviously a clear interaction between Lithium and sodium excretion/retention in the kidney, altering the electrolyte balance in humans. A single oral dose of Lithium ion is excreted almost unchanged through the kidneys. 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.

Chloride:

Chloride is also distributed throughout the body water, mainly extracellularly and to a low extent intracellularly. Chloride is filtered by the kidneys through the glomerulus and excreted from the renal tubular lumen by active transport systems, and also by passive diffusion. Chloride is the most abundant anion in humans and all animal species and it is an essential element being responsible for metabolism. Chloride is important for the regulation of the acid-base balance of the body, and maintains electrochemical neutrality by anion exchange with bicarbonate (the chloride shift) in the CO2 transport in the blood red cells and the osmotic tension of blood and tissues. Chloride is taken up daily as it is naturally present in drinking water and also a food and food additives. Based on the high solubility, the systemic availability of chloride from lithium chloride is assumed to be high. But due to its important role for metabolism, regulation of the acid-base balance, etc. and the daily uptake by drinking water and food, the toxi-cological relevance of chloride linked to the uptake of lithium chloride is regarded as very low.