Registration Dossier

Based on human data a NOAEL for long-term oral toxicity of 4.11 mg lithium nitrate/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 long-term oral value.

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

statement on chronic exposure

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993, 2002, 2007, 2008, 2013

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement

GLP compliance:

not specified

Remarks:

Doses / Concentrations:

Basis:

Dose descriptor:

NOAEL

Effect level:

4.11 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the ADI value of nitrate (human data) and calculated for lithium nitrate based on the molecular weight.

Critical effects observed:

not specified

Conclusions:

The long-term oral (human) lithium nitrate NOAEL was based on the ADI value of nitrate rather than the long-term oral (human) NOAEL/ DNEL determined for lithium. Thus, long-term oral NOAEL of lithium nitrate was based on the worst-case/ toxicological limiting value and was calculated to be 4.11 mg lithium nitrate/ kg bw/day.

Executive summary:

No NOAEL/ DNEL/ ADI value is available for lithium nitrate. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for nitrate (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium nitrate as detailed below.

Deduced NOAEL/ DNEL value for lithium

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 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. As no assessment factors are expected to be applied (no allometric, exposure duration, intra/interspecies, data quality factors are required), the NOAEL value of 1.2 mg/kg bw/day could be considered as the DNEL value.

Deduced NOAEL/ DNEL value for nitrate

According to the evaluations of JECFA, 1995 (Joint FAO/WHO Expert Committee on Food Additives), an ADI value (comparable to DNEL) of 3.7 mg nitrate/kg bw/day was determined. This value also covers the effects of the nitrite produced (metabolised/ reduced from nitrate by bacteria of the human gastro-intestinal tract).

Derived NOAEL value for lithium nitrate

As detailed above, for calculation of the NOAEL long-term oral of lithium nitrate the following (human) data was available: the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day) and the ADI value (comparable to DNEL) of nitrate (3.7 mg nitrate/kg bw/day). Additionally, the molecular weights of lithium, nitrate and lithium nitrate were considered.

The calculated NOAEL oral of lithium nitrate (4.11 mg lithium nitrate/kg bw/day) based on the ADI of nitrate is smaller than the calculated NOAEL of lithium nitrate (11.92 mg lithium nitrate/kg bw/day) based on the NOAEL/ DNEL of lithium. Thus, the determined NOAEL oral of lithium nitrate is 4.11 mg lithium nitrate/kg bw/day based on the ADI value of nitrate being the toxicological limiting value for lithium nitrate.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

4.11 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

No NOAEL/ DNEL/ ADI value is available for lithium nitrate. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for nitrate (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium nitrate as detailed below.

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 1 mmol/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. As no assessment factors are expected to be applied (no allometric, exposure duration, intra/interspecies, data quality factors are required), the NOAEL value of 1.2 mg/kg bw/day could be considered as the DNEL value.

Deduced NOAEL/ DNEL value for nitrate

According to the evaluations of JECFA, 1995 (Joint FAO/WHO Expert Committee on Food Additives), an ADI value (comparable to DNEL) of 3.7 mg nitrate/kg bw/day was determined. This value also covers the effects of the nitrite produced (metabolised/ reduced from nitrate by bacteria of the human gastro-intestinal tract).

Derived NOAEL value for lithium nitrate

As detailed above, for calculation of the NOAEL long-term oral of lithium nitrate the following (human) data was available: the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day) and the ADI value (comparable to DNEL) of nitrate (3.7 mg nitrate/kg bw/day). Additionally, the molecular weights of lithium, nitrate and lithium nitrate were considered.

The calculated NOAEL oral of lithium nitrate (4.11 mg lithium nitrate/kg bw/day) based on the ADI of nitrate is smaller than the calculated NOAEL of lithium nitrate (11.92 mg lithium nitrate/kg bw/day) based on the NOAEL/ DNEL of lithium. Thus, the determined NOAEL oral of lithium nitrate is 4.11 mg lithium nitrate/kg bw/day based on the ADI value of nitrate being the toxicological limiting value for lithium nitrate.

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 and 138 mg lithium nitrate/kg bw/day was obtained.

Giving preference to reliable human data and to worst-case result, the NOAEL value determined from human data (4.11 mg lithium nitrate/kg bw/day corresponding to 7.32 mg lithium chloride/kg bw/d) was considered for risk assessment

Repeated dermal toxicity

In accordance with column 2 of REACH Regulation 1907/20067EC Annex VII section 8.6.1, a (short-term) repeated dose toxicity study through the dermal route is not required if due to the physico-chemical and toxicological properties no potential for a significant rate of absorption through the skin is to be expected. Lithium nitrate is very soluble in water (>10000 mg/L) and has a log Pow below 0, i.e. it is too hydrophilic to cross the lipid rich environment of the stratum corneum. The dermal uptake for the substance is very low and the performance of a study is unjustified. For CSA requirements a NOAEL for long term dermal exposure was calculated.

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. Furthermore the vapour pressure of lithium nitrate is negligible due to the high melting point of the substance (see IUCLID section 4.2).

Toxicity after repeated inhalation exposure was extrapolated from systemic doses from studies with repeated oral administration according to the guidance document.

However, for risk assessment determination, and according to the guidance document, toxicity after repeated inhalation exposure was extrapolated from systemic doses determined in studies with repeated oral administration.

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.