Registration Dossier

Based on human data obtained from long–term routine treatment of bipolar disorder with lithium (administered as lithium carbonate), NOAEL values for long-term oral toxicity of 9.5 mg Li2SO4/kg bw/ day and 11.06 mg Li2SO4*H2O/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 used for long-term oral toxicity.

Reference

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, 2001, 2002, 2007, 2013

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement on chronic exposure. No guideline followed or indicated.

GLP compliance:

not specified

Dose descriptor:

NOAEL

Effect level:

1.2 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium

Sex:

male/female

Basis for effect level:

other: The NOAEL value refers to lithium in human

Dose descriptor:

NOAEL

Effect level:

9.5 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium sulfate

Sex:

male/female

Basis for effect level:

other: Conversion of the NOAEL lithium in humans to NOAEL lithium sulfate.

Dose descriptor:

NOAEL

Effect level:

11.06 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium sulfate monohydrate

Sex:

male/female

Basis for effect level:

other: Conversion of the NOAEL lithium in humans to NOAEL lithium sulfate.

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, also as lithium sulfate), NOAELs for long-term oral toxicity of 9.5 mg Li2SO4/kg bw/ day and 11.06 mg Li2SO4/kg bw/day were calculated.

Executive summary:

The active moiety with toxicological consequences in lithium sulfate is lithium. The sulfate anion is considered as toxicological non-relevant component. The ADI value of sulfate examined by the FAO/ WHO committee was determined and defined to be “not specified”. A term which is applied to a substance (or food component) of very low toxicity in which an establishment of an ADI expressed in a numerical form is deemed unnecessary. Thus, the NOAEL long-term oral of lithium sulfate is based on the NOAEL (human) long-term oral of lithium. The lithium NOAEL was determined based on routine long-term treatment of bipolar disorder with lithium (administered as lithium carbonate) as detailed below.

Determination of Li NOAEL oral

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. of 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 (42-63 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 a 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 mmol 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 route.

After conversion based on the lithium content, NOAEL oral values of 9.5 mg Li2SO4/kg bw/day and 11.06 Li2SO4*H2O/kg bw/day were calculated. Further, NOAEL oral value of lithium sulfate could be used as a starting value for route-to-route extrapolation of the repeated dose toxicity for the dermal and inhalation route.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

9.5 mg/kg bw/day

Study duration:

chronic

Species:

other: human

Reference

Endpoint:: short-term repeated dose toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Data waiving:: other justification
Justification for data waiving:: other:
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Repeated oral toxicity

The active moiety with toxicological consequences in lithium sulfate is lithium. The sulfate anion is considered a toxicological non-relevant component. The ADI value of sulfate, examined by the FAO/ WHO committee, was determined and defined to be “not specified”. A term that is applied to a substance (or food component) of very low toxicity. An establishment of an ADI, expressed in a numerical form, is deemed unnecessary. Thus, the NOAEL long-term oral of lithium sulfate is based on the NOAEL (human) long-term oral of lithium. The lithium NOAEL was determined based on routine long-term treatment of bipolar disorder with lithium (administered as lithium carbonate) as detailed below.

Determination of Li NOAEL oral

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. of 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 (42-63 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 a 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 mmol 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 route.

After conversion based on the lithium content, NOAEL oral values of 9.5 mg Li2SO4/kg bw/day and 11.06 Li2SO4*H2O/kg bw/day were calculated.Further, NOAEL oral value of lithium sulfate could be used as a starting value for route-to-route extrapolation of the repeated dose toxicity for the dermal and inhalation route.

In another weight of evidence (Trautner, 1958), a 2-year study in rat administered with lithium chloride in drinking water, resulted in a NOAEL of 13.9 mg lithium/kg bw/day. This result is higher than the human NOAEL derived (1.2 mg/kg bw/day). Giving preference to human data, to worst-case result and to the most reliable data, the NOAEL value determined is as explained above 1.2 mg lithium/kg bw/day corresponding to 9.5 mg Li2SO4/kg bw/day and 11.06 mg Li2SO4*H2O/kg bw/day.

Repeated inhalation toxicity

Additional testing by inhalation route is not required as data on repeated oral/systemic toxicity is provided. According to REACH Regulation (EC) No 1907/2006, Annex VIII, section 8.6.1, only one repeated dose toxicity study with administration via the most appropriate route is required. Furthermore, the vapour pressure of lithium sulfate and its monohydrate is negligible low (see IUCLID section 4.2).

However, for risk assessment determination, the NOAEC value was calculated from the NOAEL oral as detailed in IUCLID section 7 "toxicological information" under DNEL calculation of systemic effects-inhalation route.

Repeated dermal toxicity

In accordance with column 2 of REACH Regulation (EC) No 1907/2006, Annex VII, section 8.6.1, a (short-term) repeated dose toxicity study through the dermal route is not required if physico-chemical and toxicological properties suggest no potential for a significant rate of absorption through the skin. Lithium sulfate and its monohydrate are very soluble in water (>10000 mg/L) and have a log Pow below 0, i.e. both are too hydrophilic to cross the lipid rich environment of the strateum corneum. The dermal uptake for those substances is very low and the performance of a study unjustified. However, for risk assessment determination, the NOAEL dermal value was calculated from the NOAEL oral as detailed in IUCLID section 7 "toxicological information" under DNEL calculation of systemic effects - dermal route.

Based on the available information, classification with respect to repeated / specific target organ toxicity arising from repeated exposure according to Regulation (EC) No 1272/2008 (CLP) is not justified.