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EC number: 209-062-5
CAS number: 554-13-2
In humans, lithium/ lithium carbonate has
been used for decades in psychiatric therapy for the treatment of
bipolar disorder. In case of long-term treatment, the recommended dose
is 450 to 900 mg/day lithium carbonate and corresponding to a desired
sustained therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L.
Based on experience with long-term application e.g. lithium carbonate
for therapy in humans, there is no evidence that lithium is of concern
with respect to repeated oral toxicity at medical doses as the ones
The effect level (NOAEL) determined for
lithium carbonate for repeated dose toxicity by the oral route is based
on human data and can be calculated in two ways that complete one
One option is based on the therapeutic serum
concentrations of 0.5 to 1.0 mmol lithium/L and the extracellular fluid
(ECF) volume. Lithium has a large volume of distribution of 0.6 - 0.9
L/kg (42 L – 63 L for a 70 kg adult). It is distributed throughout the
body water both extra and intracellularly. Lithium shifts into the
intracellular compartments of cells because of its large volume of
distribution. Although in long-term use, the intracellular concentration
increases, the intracellular concentration is not reflected by the
plasma level which measures only the extracellular fluid concentration.
Therefore, a desired concentration of 1 mmol/L of lithium is expected to
be sustained and reflected in the extracellular fluid (ECF) only and not
in the intracellular fluid. Thus, the volume considered is of the ECF
only which comprises of plasma, interstitial fluid (spaces between
cells) and transcellular fluid (lymph, cerebrospinal fluid, synovial
fluid, serous fluid, gastrointestinal secretions) and is typically 15 L
(reported in different references to be between 14 – 19 L (for 70 kg
adult)). Based on this data the derived NOAEL (considering a lithium
concentration of 1mmol/L and an ECF volume of 15 L) is 1.5 mg lithium/kg
bw/day equivalent to 7.98 mg lithium carbonate/kg bw/day. This NOAEL
value can be considered as a conservative value as it is based on an
bioavailable dose in humans after absorption and on a smaller volume
than its actual distribution volume.
Another way to calculate NOAEL oral for
lithium carbonate is based as well on data taken from the routine
long-term treatment of bipolar disorder. Instead of calculating the
NOAEL from the therapeutic serum concentration of lithium, the lithium
carbonate NOAEL oral can be calculated from the administered oral dose
for long-term treatment of bipolar disorder as detailed above: 450 to
900 mg lithium carbonate/day (corresponding to the desired sustained
concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing
the oral doses 450 to 900 mg lithium carbonate/day to 70 kg, the
following values are obtained respectively: 6.43 to 12.86 mg lithium
carbonate/ kg bw/day or when dividing to 60 kg the following values are
obtained respectively: 7.5 to 15 mg lithium carbonate/kg bw/day,
representing the optional NOAEL values for lithium carbonate for the
In both ways of calculation, the values
obtained are in same order of magnitude and similar to one another. As a
worst–case value, a NOAEL repeated dose toxicity oral of 6.43 mg/kg
bw/day was chosen. Further, this value could be used as a starting value
for route-to-route extrapolation in calculation of the repeated dose
toxicity for the dermal and inhalation routes.
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