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Description of key information

Based on human data a NOAEL for long-term oral toxicity of 6.67 mg lithium phosphate/kg bw/day was calculated. Performance of repeated dermal and inhalation toxicity studies were waived.

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
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:
6.67 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
Li3PO4
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 phosphate based on the molecular weight.
Key result
Dose descriptor:
NOAEL
Effect level:
85.35 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
Li3PO4
Sex:
male/female
Basis for effect level:
other: The NOAEL value was based on the ADI value of phosphate (human data, 70 mg/kg bw/day) and calculated for lithium phosphate based on the molecular weight.
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
Dose descriptor:
NOAEL
Effect level:
70 mg/kg bw/day (nominal)
Based on:
other: NOAEL/ADI phosphate
Sex:
male/female
Basis for effect level:
other: NOAEL refers to ADI of phosphate 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 6.67 mg/kg bw/day was calculated for lithium phosphate. Based on the ADI value for phosphate of 70 mg/kg bw/day a NOAEL value of 85.35 mg/kg bw/day for lithium phosphate was calculated.



Executive summary:

No NOAEL/ DNEL/ ADI value is available for lithium phosphate. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for phosphate (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium phosphate 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 for a 70 kg adult, wich is the total body water). 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.

Deduced NOAEL/ DNEL value for phosphate

According to the evaluation of JECFA, 2001 (Joint FAO/WHO Expert Committee on Food Additives), an ADI value (comparable to DNEL) of 70 mg phosphate/kg bw/day was determined.

Derived NOAEL value for lithium phosphate

As detailed above, for calculation of the NOAEL long-term oral of lithium phosphate 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 phosphate (70 mg phosphate/kg bw/day). Additionally, the molecular weights of lithium and phosphate were considered.

The calculated NOAEL oral of lithium phosphate (6.67 mg lithium phosphate/kg bw/day) based on the NOAEL of lithium is smaller than the calculated NOAEL of lithium phosphate (85.35 mg lithium phosphate/kg bw/day) based on the ADI of phosphate. Thus, the determined NOAEL oral of lithium phosphate is 6.67 mg lithium phosphate/kg bw/day based on the NOAEL value of lithium being the toxicological limiting value for lithium phosphate.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
6.67 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
Additional testing by the inhalation route is not required 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 is negligible (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.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
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 as the physico-chemical properties suggest no potential for a significant rate of absorption through the skin (see IUCLID section 4).
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated oral toxicity

No NOAEL/ DNEL/ ADI value is available for lithium phosphate. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for phosphate (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium phosphate 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 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 for a 70 kg adult, which is the total body water). 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. 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 phosphate

According to the evaluation of JECFA, 2001 (Joint FAO/WHO Expert Committee on Food Additives), an ADI value (comparable to DNEL) of 70 mg phosphate/kg bw/day was determined.

Derived NOAEL value for lithium phosphate

As detailed above, for calculation of the DNEL long-term oral of lithium phosphate the following human data were available; the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day) and the ADI value (comparable to DNEL) of phosphate (70 mg phosphate/kg bw/day). The available read-across data were recalculated for lithium phosphate, considering the molecular weight of lithium and phosphate.

The calculated NOAEL oral of lithium phosphate (6.67 mg lithium phosphate/kg bw/day) based on the NOAEL of lithium is smaller than the calculated NOAEL of lithium phosphate (85.35 mg lithium nitrate/kg bw/day) based on the ADI of phosphate. Thus, the determined NOAEL oral of lithium phosphate is 6.67 mg lithium phosphate/kg bw/day based on the ADI value of lithium being the toxicological limiting value for lithium phosphate.

Repeated inhalation toxicity

Additional testing by the inhalation route is not required 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 is negligible (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.

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 as the physico-chemical properties suggest no potential for a significant rate of absorption through the skin (see IUCLID section 4).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
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.