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 4.13 mg LiOH/kg bw/ day and 7.24 mg LiOH*H2O/kg bw/day were calculated. Performance of repeated dermal and inhalation toxicity studies were waived. For CSA requirements a NOAEL for long-term dermal toxicity of 41.35 mg/LiOH kg bw/day and 72.43 mg LiOH*H2O/kg bw/day were calculated based on the NOAEL long-term oral of LiOH. The NOAEC for long-term inhalation toxicity for worker was determined to be 14.47 mg LiOH/m³ and 25.35 mg LiOH*H2O/m³ and for the general population 6.21 mg LiOH/m³ and 10.88 mg LiOH*H2O/m³.

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993, 2002, 2007, 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

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 lithiums in human

Dose descriptor:

NOAEL

Effect level:

4.13 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium hydroxide

Sex:

male/female

Basis for effect level:

other: Conversion of the NOAEL lithium in humans to NOAEL LiOH was based on the lithium content.

Dose descriptor:

NOAEL

Effect level:

7.24 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium hydroxide monohydrate

Sex:

male/female

Basis for effect level:

other: Conversion of the NOAEL lithium in humans to NOAEL LiOH*H2O was based on the lithium content.

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 4.13 mg LiOH/kg bw/ day and 7.24 mg LiOH*H2O/kg bw/day were calculated.

Executive summary:

The active moiety with toxicological consequences in lithium hydroxide is lithium while the hydroxide ion may react with free H+, forming water which is toxicological not relevant. Thus, for lithium hydroxide anhydrous and its monohydrate the NOAEL oral calculation was based on the lithium NOAEL oral which was determined according to human data obtained from 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. 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.

-> After conversion based on the lithium content, NOAEL oral values of 4.13 mg LiOH/kg bw/day and 7.24 mg LiOH*H2O/kg bw/day were calculated. Further, NOAEL oral value of lithium hydroxide 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:

no adverse effect observed

Dose descriptor:

NOAEL

4.13 mg/kg bw/day

Study duration:

chronic

Species:

other: human

Reference

Endpoint:: sub-chronic toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:
Justification for type of information:: JUSTIFICATION FOR DATA WAIVING
Additional testing by inhalation route is not applicable as data on repeated dose oral / systemic toxicity was provided. According to the REACH Regulation No. 1907/2006, Annex VIII, 8.6.1 only one repeated dose toxicity study is required (with administration via the most appropriate route). Moreover, the vapour pressure of lithium hydroxide and its monohydrate is negligible based on the melting point of 423 °C (see IUCLID section 4.2). By testing on particle size distribution (granulometry) inhalable particles lower 10 µm were detected in some qualities (see IUCLID section 4.5.1). If relevant, respective personal protective measurements are applied (as addressed in the CSR). Toxicity after repeated inhalation exposure was scientifically sound extrapolated from systemic doses from studies with repeated oral administration according to the guidance document.
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Reference

Endpoint:: sub-chronic toxicity: dermal
Data waiving:: other justification
Justification for data waiving:: other:
Justification for type of information:: JUSTIFICATION FOR DATA WAIVING
In accordance with column 2 of REACH Regulation 1907/2006/EC Annex VIII section 8.6.1 for animal welfare reasons, a repeated dose toxicity study through the dermal route is not required for the following reasons: 1. the substance is classified and labelled as corrosive to the skin: Cat . 1B, H314 according to Regulation (EC) No 1272/2008 (CLP) and R34 according to Directive 67/548/EEC. 2. the physico-chemical and toxicological properties of lithium hydroxide anhydrous and lithiumhydroxide monohydrate suggest no potential for a significant rate of absorption through the skin under non-corrosive conditions (see IUCLID section 7.1.1 and 7.2.3).
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 hydroxide is lithium while the hydroxide ion may react with free H+, forming water which is toxicological not relevant. Thus, for lithium hydroxide anhydrous and its monohydrate the NOAEL oral calculation was based on the lithium NOAEL oral which was determined according to human data obtained from 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. 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.

-> After conversion based on the lithium content, NOAEL oral values of 4.13 mg LiOH/kg bw/day and 7.24 mg LiOH*H2O/kg bw/day were calculated. Further, NOAEL oral value of lithium hydroxide 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.

In another study (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 4.13 mg lithium hydroxide/kg bw/day.

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, and no expected significant rate of absorption for LiOH anhydrous and its monohydrate through the skin under non–corrosive conditions (scientifically unjustified).

For CSA requirements a NOAEL for long-term dermal was calculated. A NOAEL dermal of 41.35 mg LiOH/kg bw/day and 72.43 mg LiOH*H2O/kg bw/day were calculated based on the NOAEL long term oral of 4.135 mg LiOH/kg bw/day and 7.234 mg LiOH mg/kg bw/day and considering 10 % absorption through the skin (ECHA document R.7C, 2008, 7.12). Lithium hydroxide is corrosive to the skin. However, such a corrosive damage to the skin that will enable Li+ to be systemically bioavailabe is not realistic/ expected. The reasons for that (defined here as non–corrosive conditions) are time of exposure which is limited and relatively short (until burning is noticed) and consequently the limited amount of dissolved LiOH that the skin will be exposed to. Thus, the absorption percentage estimation of Li+ can be considered as worst–case estimation.

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). For CSA requirements a NOAEC value was calculated for long-term inhalation toxicity. It was extrapolated from the NOAEL value determined for long term oral toxicity and was separately calculated for workers and general population, as exposure times and inhalation rates differ (the calculations are detailed in IUCLID section 7 (“Toxicological information”).

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, 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.