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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:
2012
Report date:
2010

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Lithium carbonate
EC Number:
209-062-5
EC Name:
Lithium carbonate
Cas Number:
554-13-2
Molecular formula:
CH2O3.2Li
IUPAC Name:
dilithium carbonate

Results and discussion

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 carbonate hydrolyses in water where lithium hydroxide and lithium hydrogen carbonate are generated. Both are responsible for a high (basic) pH.
After oral uptake, soluble lithium (Li+) is readily and almost completely absorbed from the gastrointestinal tract. In the stomach, carbonate transforms into carbon dioxide.
The absorption of lithium through the skin is considered to be very poor to negligible.
Upon inhalation, resorption and bioavailability of lithium carbonate is expected to be low.
After absorption, lithium is quickly distributed and unchanged excreted. Bioaccumulation can be excluded.
Carbonate occurs ubiquitous and represents a physiological molecule.
Executive summary:

General

The toxicokinetic assessment of lithium carbonate focuses on lithium since carbonate and one of its products of hydrolysis, hydrogen carbonate, are for example naturally present in water and represent physiological molecules. Moreover, calcium carbonate for example is not only widely present naturally but also an additive in food and beverage and used for production for dietary calcium. 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, dairy products and meat 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 µg/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/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 doses are equivalent to 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 carbonate

Lithium carbonate is an inorganic salt with a molecular weight of 73.8909 g/mol. It is soluble in water (8.4 - 13 g/L). Hydrolysis of lithium carbonate produces basic solutions by generating lithium hydroxide and lithium hydrogen carbonate. The carbonate ion is the conjugate base of an extremely weak acid (carbonic acid). It strongly attracts protons from H2O molecules to give a solution with a pH of ca. 12.

Li2CO3 + H2O -> LiHCO3+ LiOH

In contrast, the hydrogen carbonate ion (HCO3- (aq)), with its single negative charge, has lower surface charge density than the carbonate ion and is a considerably weaker base. It has e weak attraction for protons and the pH of the solution only reaches a pH of ca. 8.5. With acid (decreasing pH) the respective lithium salt and carbon dioxide are formed. 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 range 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 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. Thus, the stratum corneum provides greatest barrier function against hydrophilic compounds, respectively water. Due to (1) the hydrophilic character of Lithium carbonate and (2) the barrier function of the stratum corneum against salts, dermal absorption can practically be excluded. Dermal toxicity values revealed LD50 values > 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 hypochlorite) as compared with unexposed controls. This study result was expected due to the chemical properties of an inorganic lithium salt. Also other authors concluded that absorption of lithium through the skin is considered to be very poor.

In conclusion, the absorption of lithium through skin is considered to be poor. Thus, upon dermal contact, the bioavailability of lithium carbonate is expected to be very low and therefore negligible.

10% absorption was used for DNEL deduction. Thus, this presents a worst case.

Resorption after oral uptake

The absorption of lithium after oral intake, depending on the salt given can vary (e.g. 20 % for lithium from lithium carbonate). In the stomach, due to gastric acid, an oral uptake of carbonate will result in neutralisation of its products of hydrolysis, i.e. – as described above – the respective lithium salt and carbon dioxide are formed. Soluble lithium compounds readily and almost completely absorbed from the gastrointestinal tract revealing peak plasma levels after single oral doses about 1-4 hours after administration. Soluble lithium compounds are readily and almost completely absorbed from the gastrointestinal tract. In the stomach, carbonate results in carbon dioxide.

Resorption after inhalation

The vapour pressure of lithium carbonate 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.

In summary: Upon inhalation, resorption and 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. However, trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. 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.

Carbonate:

Carbonate is contained in every mineral and health water, but contrary to various minerals, hydrogen carbonate can be produced by the human body. The major extracellular buffer in the blood and the interstitial fluid of vertebrates is the bicarbonate buffer system, described by the following equation: H2O + CO2 ↔ H2CO3 ↔ H+ + HCO3- Hydrogen carbonate has an acid neutralizing (alkalescent) effect and is responsible for the balancing of the pH-value in the body, e.g. it reduces the acid in the digestive system. Carbon dioxide diffuses rapidly into red blood cells, where it is hydrated with water to form carbonic acid. This reaction is accelerated by carbonic anhydrase, an enzyme present in high concentrations in red blood cells. The carbonic acid formed dissociates into bicarbonate and hydrogen ions. Most of the bicarbonate ions diffuse into the plasma. Thus, also without exposure to lithium carbonate, all species formed from carbonate (CO2, bicarbonate and hydrogen ions) naturally occur in the human body. Based on the low solubility, the systemic availability of carbonate from lithium carbonate is regarded as very low. Moreover, all species formed from carbonate by hydrolysis naturally occur in the human body. Thus, its toxicological relevance linked to the uptake of lithium carbonate is regarded as very low.

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