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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: statement on chronic exposure
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993, 2002, 2007, 2012
Reliability:
1 (reliable without restriction)

Data source

Referenceopen allclose all

Reference Type:
other: expert statement
Title:
Unnamed
Year:
2012
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2002
Report date:
2002
Reference Type:
review article or handbook
Title:
Manual of clinical psychopharmacology
Author:
Schatzberg, A.F.; Cole, O.J., DeBattista, C.
Year:
2007
Bibliographic source:
American Psychiatric Publishing. ISBN 158562317
Reference Type:
review article or handbook
Title:
Toxicology: the basic science of poisons
Author:
Casarett, L.; Klassen, C.D; Curtis, D.
Year:
2007
Bibliographic source:
ISBN-10: 0-07-147051-4
Reference Type:
review article or handbook
Title:
Physiological Parameters on Laboratory animals and humans
Author:
Davis, B; Morris, T.
Year:
1993
Bibliographic source:
Pharm. res. 10: 1093

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement
GLP compliance:
not specified

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

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
6.43 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: In humans.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on human data obtained from routine long-term treatment of bipolar disorder with lithium, a NOAEL for long-term oral toxicity of 6.43 mg lithium carbonate/kg bw/ day was calculated.
Executive summary:

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 indicated above.

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 another:

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 oral route.

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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