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Administrative data

Description of key information

Based on human data obtained from long–term routine treatment of bipolar disorder with lithium (administered as lithium carbonate), a NOAEL for long-term oral toxicity of 1.2 mg lithium/kg bw/ day was calculated. Performance of repeated dermal and inhalation toxicity studies were waived. For CSA requirements NOAEL for long-term dermal toxicity and NOAEC for long-term inhalation toxicity were calculated based on the NOAEL value of 1.2 mg/kg bw/day determined for long-term oral toxicity. A NOAEL value of 12 mg/kg bw/day was calculated for long term dermal toxicity and a NOAEC value of 4.2 mg/m³ were calculated for long-term inhalation toxicity (worker).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Remarks:
expert statement
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993, 2002, 2007, 2010
Reliability:
1 (reliable without restriction)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement.
GLP compliance:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
1.2 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: In humans.
Critical effects observed:
not specified
Conclusions:
Based on human data obtained from routine long- term treatment of bipolar disorder with lithium (administered as lithium carbonate), a NOAEL for long-term oral toxicity of 1.2 mg lithium/kg bw/ day was calculated.
Executive summary:

In humans, lithium 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, equivalent to 84 to 169 mg lithium / day, 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 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/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 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 NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 84 to 169 mg lithium / day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses (84 to 169 mg lithium / day) to 70 kg, the following values are obtained respectively: 1.2 to 2.4 mg/kg bw/day or when dividing to 60 kg the following values are obtained respectively: 1.4 to 2.8 mg/kg bw/day, representing the optional NOAEL values for lithium 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 1.2 mg lithium/kg bw 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1.2 mg/kg bw/day
Study duration:
chronic
Species:
other: human

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Study duration:
chronic

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated oral toxicity

In humans, lithium 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, equivalent to 84 to 169 mg lithium / day, 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 of 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 for repeated dose toxicity by the oral route is based on human data and can be calculated and determined 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/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 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 NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 84 to 169 mg lithium / day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses (84 to 169 mg lithium / day) to 70 kg, the following values are obtained respectively: 1.2 to 2.4 mg/kg bw/day or when dividing to 60 kg the following values are obtained respectively: 1.4 to 2.8 mg/kg bw/day, representing the optional NOAEL values for lithium for the oral route.

In both ways of calculation, the values obtained are in same order of magnitude and similar to one another. Choosing to consider the worst–case value, a NOAEL repeated dose toxicity oral of 1.2 mg lithium/kg bw was determined. 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.

A weight of evidence (Trautner, 1958) which referred to animal data is available and was also used in a read-across approach. In a 2-year study in rats administered with lithium chloride in drinking water, a NOAEL of 84.8 mg LiCl/kg bw/day corresponding to 13.9 mg lithium/kg bw/day was obtained.

Repeated dermal toxicity

Performance of a repeated dose dermal toxicity study was waived, for the following reasons in agreement with column 2 of REACH Regulation 1907/2006/EC Annex VIII section 8.6.1: animal welfare considerations, no significant rate of absorption for Li+ through the skin under non–corrosive conditions and minimal exposure due to RMM applied.

Repeated inhalation toxicity

Performance of a repeated dose toxicity study by inhalation route was waived for welfare reasons and in accordance with column 2 of REACH Regulation 1907/2006/EC Annex VIII section 8.6.1 (very low vapour pressure; inhalation exposure excluded).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on repeated dose toxicity/ specific target organ toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.