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Diss Factsheets

Administrative data

Description of key information

Based on human data a NOAEL for long-term oral toxicity of 4.48 mg lithium fluoride/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:
4.48 mg/kg bw/day (nominal)
Based on:
test mat.
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 fluoride based on the molecular weight.
Key result
Dose descriptor:
NOAEL
Effect level:
5.46 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 fluoride (human data, 4 mg/kg bw/day) and calculated for lithium fluoride 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:
4 mg/kg bw/day (nominal)
Based on:
other: NOAEL/ADI fluoride
Sex:
male/female
Basis for effect level:
other: NOAEL refers to ADI of fluoride 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 4.48 mg/kg bw/day was calculated for lithium fluoride. Based on the ADI value for fluoride of 4 mg/kg bw/day a NOAEL value of 5.46 mg/kg bw/day for lithium fluoride was calculated.



Executive summary:

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

Deduced NOAEL/ DNEL value for fluoride
According to the evaluation of DGUHT, 2008 (Deutsche Gesellschaft für Umwelt- und Humantoxikologie), an ADI value (comparable to DNEL) of 4 mg fluoride/kg bw/day was determined.

Derived NOAEL value for lithium fluoride
As detailed above, for calculation of the DNEL long-term oral of lithium fluoride 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 fluoride (4 mg fluoride/kg bw/day). Additionally, the molecular weights of lithium, fluoride were considered.

The calculated NOAEL oral of lithium fluoride (4.48 mg lithium fluoride/kg bw/day) based on the NOAEL of lithium is smaller than the calculated NOAEL of lithium fluoride (5.46 mg lithium fluoride/kg bw/day) based on the ADI of fluoride. Thus, the determined NOAEL oral of lithium fluoride is 4.48 mg lithium fluoride/kg bw/day based on the ADI value of lithium being the toxicological limiting value for lithium fluoride.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
4.48 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.

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:
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:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No NOAEL/ DNEL/ ADI value is available for lithium fluoride. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for fluoride (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium fluoride 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 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 fluoride
According to the evaluation of DGUHT, 2008 (Deutsche Gesellschaft für Umwelt- und Humantoxikologie), an ADI value (comparable to DNEL) of 4 mg fluoride/kg bw/day was determined.

Derived NOAEL value for lithium fluoride
As detailed above, for calculation of the DNEL long-term oral of lithium fluoride 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 fluoride (4 mg fluoride/kg bw/day). Additionally, the molecular weights of lithium, fluoride were considered.

The calculated NOAEL oral of lithium fluoride (4.48 mg lithium fluoride/kg bw/day) based on the NOAEL of lithium is smaller than the calculated NOAEL of lithium fluoride (5.46 mg lithium fluoride/kg bw/day) based on the ADI of fluoride. Thus, the determined NOAEL oral of lithium fluoride is 4.48 mg lithium fluoride/kg bw/day based on the ADI value of lithium being the toxicological limiting value for lithium fluoride.

Due to the priority that reliable human data have compared to animal data and by demonstrating that the toxicological limiting component of lithium fluoride is the lithium (as detailed above), a NOAEL value of 4.48 mg lithium fluoride/ 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.

Justification for classification or non-classification

Based on the available information, classification with respect to repeated / specific target organ toxicity arising from repeated exposure according to Regulation (EC) No 1272/2008 (CLP) is not justified.