Lithium carbonate

Repeated dose toxicity: oral

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

Reference

Reference 1

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2012

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 3

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 4

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 5

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

Test material information

Constituent 1

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.