Registration Dossier

Based on ADI/NOAEL values of lithium (human data), a NOAEL for long-term oral toxicity of 11.41 mg lithium acetate/kg bw/day and 17.64 mg lithium acetate dihydrate bw/day was calculated. Performance of repeated dermal and inhalation toxicity studies were waived.

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Expert statement on chronic exposure

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993, 2002, 2007, 2010, 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Qualifier:

no guideline followed

Principles of method if other than guideline:

Results based on 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: NOAEL refers to lithium in humans.

Key result

Dose descriptor:

NOAEL

Effect level:

11.41 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium acetate

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the NOAEL value of lithium (human data, 1.2 mg/kg bw/day) and calculated for lithium acetate based on the moleculare weight.

Key result

Dose descriptor:

NOAEL

Effect level:

17.64 mg/kg bw/day (nominal)

Based on:

other: NOAEL lithium acetate dihydrate

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the NOAEL value of lithium (human data, 1.2 mg/kg bw/day) and calculated for lithium acetate dihydrate based on the moleculare weight.

Dose descriptor:

NOAEL

Effect level:

>= 100 - <= 210 mg/kg bw/day (nominal)

Based on:

other: NOAEL/ADI of acetic acid

Sex:

male/female

Basis for effect level:

other: The NOAEL refers to acetic acid in humans.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 110 - <= 231 mg/kg bw/day (nominal)

Based on:

other: recalculated for lithium acetate anhydrous

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the ADI value of acetic acid (human data, 100 - 210 mg/kg bw/day) and calculated for lithium acetate anhydrous based on the moleculare weight.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 170 - <= 357 mg/kg bw/day (nominal)

Based on:

other: recalculated for lithium acetate dihydrate

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the ADI value of acetic acid (human data, 100 - 210 mg/kg bw/day) and calculated for lithium acetate dihydrate based on the moleculare weight.

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, NOAEL values of 11.41 and 17.64 mg/kg bw/day was calculated for lithium acetate and lithium acetate dihydrate, respectively.

Executive summary:

No NOAEL/ DNEL/ ADI value was available for lithium acetate. Nevertheless, NOAEL/ DNEL/ ADI values form human data are available for lithium (see below). Thereof, NOAEL values based on human data could be derived and calculated for lithium acetate and lithium acetate dihydrate (see 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.

Deduced NOAEL/ DNEL value for acetic acid

According to the evaluation of SCOEL, 2012 (Recommendation from the Scientific Committee on Occupational Exposure Limits for acetic acid), an ADI value (comparable to DNEL) between 1 and 2.1 g acetic acid/day was determined for humans older than 2 years. Using the default body weight of a two year old child, the ADI value results to 100 to 210 mg/kg bw/d.

Derived NOAEL values for lithium acetate and the corresponding dihydrate

As detailed above, for calculation of the DNEL long-term oral of lithium acetate 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 acetic acid (100 – 210 mg/kg bw/day). Additionally, the molecular weights of lithium and acetic acid were considered.

The calculated NOAEL oral of lithium acetate and lithium acetate dihydrate (11.41 mg/kg bw/day and 17.64 mg/kg bw/day, respectively) based on the NOAEL of lithium are much smaller than the calculated NOAEL of lithium acetate and the corresponding dihydrate (110 - 231 mg/kg bw/day and 170 – 357 mg/kg bw/d, respectively) based on the ADI of acetic acid. Thus, the determined NOAEL oral of lithium acetate (dihydrate) is 11.41 mg/kg bw/day based on the ADI value of lithium being the toxicological limiting value for lithium acetate.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

11.41 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:: sub-chronic toxicity: inhalation
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Reference

Endpoint:: sub-chronic toxicity: dermal
Data waiving:: study scientifically not necessary / other information available
Justification for data waiving:: other:
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Repeated oral toxicity

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

According to the evaluation of SCOEL, 2012 (Recommendation from the Scientific Committee on Occupational Exposure Limits for acetic acid), an ADI value (comparable to DNEL) between 1 and 2.1 g acetic acid/day was determined for humans older than 2 years. Using the default body weight of a two year old child, the ADI value results to 100 to 210 mg/kg bw/d.

Derived NOAEL values for lithium acetate and the corresponding dihydrate

As detailed above, for calculation of the DNEL long-term oral of lithium acetate 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 acetic acid (100 – 210 mg/kg bw/day). Additionally, the molecular weights of lithium and acetic acid were considered.

The calculated NOAEL oral of lithium acetate and lithium acetate dihydrate (11.41 mg/kg bw/day and 17.64 mg/kg bw/day, respectively) based on the NOAEL of lithium are much smaller than the calculated NOAEL of lithium acetate and the corresponding dihydrate (110 - 231 mg/kg bw/day and 170 – 357 mg/kg bw/d, respectively) based on the ADI of acetic acid. Thus, the determined NOAEL oral of lithium acetate (dihydrate) is 11.41 mg/kg bw/day based on the ADI value of lithium being the toxicological limiting value for lithium acetate.

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 Regulation (EC) No 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 acetate is negligible due to the high melting point of the substance (see IUCLID section 4.2).

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance does not need to be classified and labelled for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.