Registration Dossier

Based on human data a NOAEL for long-term oral toxicity of 4 mg lithium amide/kg bw/day was calculated. Performance of repeated dermal and inhalation toxicity studies were waived.

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

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 on chronic exposure.

GLP compliance:

no

Key result

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: NOAEL refers to lithium in human

Key result

Critical effects observed:

no

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. Based on these data, a NOAEL value of 4 mg/kg bw/day was calculated for lithium amide.

Executive summary:

No NOAEL/ DNEL/ ADI value was available for lithium amide due to the high reactivity of the substance when moistured. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium (see below). Furthermore NOAEL values derived from animal data for ammonium sulfate are available. Thereof, NOAEL values based on animal and human data could be derived and calculated for lithium amide (see 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 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 routes.

Derived NOAEL value for lithium amide

As detailed above, for calculation of the NOAEL long-term oral of lithium amide the following (human) data was available: the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day). Additionally, the molecular weights of lithium and lithium amide were considered.

A NOAEL oral of lithium amide of 4 mg/kg bw/day has been calculated based on the NOAEL of lithium.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

4 mg/kg bw/day

Study duration:

chronic

Species:

other: Weight of evidence approach in which the NOAEL value is derived from reliable human data.

Quality of whole database:

Reliable human data was used.

Reference

Endpoint:: short-term repeated dose toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:

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:

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

No NOAEL/ DNEL/ ADI value was available for lithium amide due to the high reactivity of the substance when moistured. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium (see below). Furthermore NOAEL values derived from animal data for ammonium sulfate are available. Thereof, NOAEL values based on animal and human data could be derived and calculated for lithium amide (see 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 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 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 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 routes.

Derived NOAEL value for lithium amide

As detailed above, for calculation of the NOAEL long-term oral of lithium amide the following (human) data was available: the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day). Additionally, the molecular weights of lithium and lithium amide were considered.

A NOAEL oral of lithium amide of 4 mg/kg bw/day has been calculated based on the NOAEL of lithium.

Animal data (WoE)

Results of a chronic toxicity test in rats (equivalent or similar to OECD test guideline 452) with the source substance ammonium sulfate were available. In the study, 10 males and 10 females received the test substance in concentrations of 0 (vehicle - water), 0.1, 0.6 and 3.0 % via diet for 52 weeks.

A NOAEL value of 0.6 % in both sexes was determined for repeated dose toxicity of ammonium sulfate, based significant increases in kidney and liver weights in both sexes of the highest dosing group. No effects were found on body weights, haematological or biochemical parameters, histopathology or survival in any dose group. The NOAEL of 0.6 % is equivalent to 256 mg/kg bw/d for male and 284 mg/kg bw/d for female animals.

The calculated oral NOAEL for the target substance lithium amide is 104 mg/kg bw/d for male and 111 mg/kg bw/d for female animals.

Conclusion

Due to the priority that reliable human data have compared to animal data and by demonstrating that the toxicological limiting component of lithium amide is the lithium (as detailed above), a NOAEL value of 4 mg lithium amide/ kg bw/day (based on human data) was considered for hazard and risk assessment.

Repeated dermal toxicity
Additional testing by dermal route is not applicable as data on repeated dose oral / systemic toxicity was provided. According to the REACH Regulation (EC) No 1907/2006, Annex VIII, 8.6.1, only one repeated dose toxicity study is required (with administration via the most appropriate route).

Repeated inhalation toxicity
Additional testing by inhalation route is not required as data on repeated oral / systemic toxicity is provided. According to REACH regulation 1907/2006, Annex VIII, 8.6.1 only one repeated dose toxicity study with administration via the most appropriate route is required.

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified as toxic based on repeated exposure under Regulation (EC) No 1272/2008.