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EC number: 232-152-0 | CAS number: 7789-24-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
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
- 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.
Reference
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
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
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
- 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
Reference
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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