Registration Dossier
Registration Dossier
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EC number: 262-987-6 | CAS number: 61788-56-5
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.18 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 75
- Dose descriptor starting point:
- NOAEC
- Value:
- 88.2 mg/m³
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day
- AF for differences in duration of exposure:
- 6
- Justification:
- Default ECHA AF for subacute (28-day) to chronic extrapolation.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required
- AF for other interspecies differences:
- 2.5
- Justification:
- Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
- AF for intraspecies differences:
- 5
- Justification:
- Default ECHA AF for (healthy) worker
- AF for the quality of the whole database:
- 1
- Justification:
- Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
- AF for remaining uncertainties:
- 1
- Justification:
- Not required
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.33 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 300
- Dose descriptor starting point:
- NOAEL
- Value:
- 100 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day
- AF for differences in duration of exposure:
- 6
- Justification:
- Default ECHA AF for subacute (28-day) to chronic extrapolation.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
- AF for other interspecies differences:
- 2.5
- Justification:
- Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
- AF for intraspecies differences:
- 5
- Justification:
- Default ECHA AF for (healthy) worker
- AF for the quality of the whole database:
- 1
- Justification:
- Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
- AF for remaining uncertainties:
- 1
- Justification:
- Not required
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Additional information - workers
Lithium naphthenate would be expected to dissociate in the human body into naphthenic acid anions and lithium cations. Data have been read across from naphthenic acids and lithium salts to address each component separately. DNELs for lithium naphthenate are presented based on data for naphthenic acids as these present a worst-case scenario. However, for comparison, the DNELs derived based on the lithium cation, using data read across from fatty acids C18 (unsaturated) lithium salts are provided here to show that they would derive less conservative results.
Workers - Hazard via inhalation route - Systemic effects - Long term exposure
- Hazard assessment conclusion: no hazard identified
- Value: 3 mg/m³
- DNEL derivation method: General nuisance dust OEL for chronic exposure to inert alveolar (respirable) dust used as DNEL surrogate in accordance with ECHA REACH TGD R.8
- Explanation for hazard conclusion: No substance-specific intrinsic inhalation toxicity is expected
Workers - Hazard via inhalation route - Systemic effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
- Value: 6 mg/m³
- DNEL derivation method: General nuisance dust OEL for chronic exposure to inert alveolar (respirable) dust used as DNEL surrogate in accordance with ECHA REACH TGD R.8
- Explanation for hazard conclusion: No substance-specific intrinsic inhalation toxicity is expected
Workers - Hazard via inhalation route - Local effects - Long term exposure
- Hazard assessment conclusion: no hazard identified
Workers - Hazard via inhalation route - Local effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
Workers - Hazard via dermal route - Systemic effects - Long term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 60 mg/kg bw/day
- DNEL derivation method: Use of human data from long term therapeutic use of lithium, see section 5.6.3
- Modified dose descriptor starting point: human therapeutic dose
- DNEL value: 60 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point: published data on human serum concentrations of lithium following oral therapeutic treatment with lithium carbonate.
- Explanation for hazard conclusion: The use of human data for identification of the DNEL is justified based on the long history of safe use of lithium for treating bipolar disorder.
Workers - Hazard via dermal route - Systemic effects - Acute/short term exposure
Hazard assessment conclusion: no DNEL required: short term exposure controlled by conditions for long-term
Value: 60 mg/kg bw/day
Workers - Hazard via dermal route - Local effects - Long term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 0.172 mg/cm²
- Most sensitive endpoint: skin irritation/corrosion
- DNEL derivation method: ECHA REACH Guidance
- Overall assessment factor (AF): 5
- Dose descriptor: human therapeutic dose
- AF for intraspecies differences: 5
- Justification: standard worker AF
- Explanation for hazard conclusion: DNEL based on NOAEL from subacute dermal toxicity study, with standard worker intraspecies AF applied
Workers - Hazard via dermal route - Local effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
In humans, lithium carbonate and other soluble inorganic salts have been used for decades in psychiatric therapy for the treatment of bipolar disorder. The inorganic lithium salts dissociate in biological fluids to yield the acid anions and lithium ions. The inorganic anion is considered not to be hazardous to humans. Because the source of ionic lithium is not relevant to its physiological activity, read across from inorganic lithium salts to lithium naphthenate with respect to systemic toxicity is fully justified without restriction.
In case of long-term human treatment, the recommended dose is 450 to 900 mg/day lithium carbonate, corresponding to a therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application of lithium carbonate in humans, there is no evidence that lithium is of concern with respect to repeated dose oral toxicity at the therapeutic doses indicated. The No Observed Adverse Effect Level (NOAEL) for lithium naphthenate for repeat dose toxicity by the oral route is therefore based on human data and can be calculated in two ways that complement each other.
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 consists 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 lithium/kg bw/day, equivalent to 60 mg/kg bw/day of lithium naphthenate (lithium naphthenate contains 2.5% lithium). 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. Further, this value can be used as a starting value for route-to-route extrapolation from the oral repeated dose toxicity to the dermal route as necessary (with no requirement for an additional Assessment Factor).
The experimental results from the repeated dose dermal toxicity study on fatty acids C18 (unsaturated) lithium also permitted consideration of long term local effects on the skin. The NOAEL for this effect was 111.25 mg/kg/day, which converts to 0.86 mg/cm2 based on the area of rat skin exposed in the subacute study (average weight of the rats in the study was 311g, the body surface area was calculated as being approximately 9.1 x bw(g)0.66, and the approximate surface area exposed was 10%). The human data on serum blood concentrations of lithium ion following long term therapeutic treatment with lithium carbonate for bipolar disease is protective of human exposure and sufficient to determine a human NOAEL and DNEL. The above data support a DNEL based on human data for the lithium ion. As such, an oral NOAEL for repeated dose toxicity of 60 mg/kg bw/day was chosen.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.29 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 150
- Dose descriptor starting point:
- NOAEC
- Value:
- 43.5 mg/m³
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day
- AF for differences in duration of exposure:
- 6
- Justification:
- Default ECHA AF for subacute (28-day) to chronic extrapolation.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required
- AF for other interspecies differences:
- 2.5
- Justification:
- Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
- AF for intraspecies differences:
- 10
- Justification:
- Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
- AF for the quality of the whole database:
- 1
- Justification:
- Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
- AF for remaining uncertainties:
- 1
- Justification:
- Not required
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.17 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 600
- Dose descriptor starting point:
- NOAEL
- Value:
- 100 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day
- AF for differences in duration of exposure:
- 6
- Justification:
- Default ECHA AF for subacute (28-day) to chronic extrapolation.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
- AF for other interspecies differences:
- 2.5
- Justification:
- Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
- AF for intraspecies differences:
- 10
- Justification:
- Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
- AF for the quality of the whole database:
- 1
- Justification:
- Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
- AF for remaining uncertainties:
- 1
- Justification:
- Not required
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.17 ng/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 600
- Dose descriptor starting point:
- NOAEL
- Value:
- 100 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study; the NOAEL was set at 100 mg/kg bw/day
- AF for differences in duration of exposure:
- 6
- Justification:
- Default ECHA AF for subacute (28-day) to chronic extrapolation.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
- AF for other interspecies differences:
- 2.5
- Justification:
- Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
- AF for intraspecies differences:
- 10
- Justification:
- Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
- AF for the quality of the whole database:
- 1
- Justification:
- Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.
- AF for remaining uncertainties:
- 1
- Justification:
- Not required
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Additional information - General Population
Lithium naphthenate would be expected to dissociate in the human body into naphthenic acid anions and lithium cations. Data have been read across from naphthenic acids and lithium salts to address each component separately. DNELs for lithium naphthenate are presented based on data for naphthenic acids as these present a worst-case scenario. However, for comparison, the DNELs derived based on the lithium cation, using data read across from fatty acids C18 (unsaturated) lithium salts are provided here to show that they would derive less conservative results.
General population - Hazard via inhalation route - Systemic effects - Long term exposure
- Hazard assessment conclusion: no hazard identified
General population - Hazard via inhalation route - Systemic effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
General population - Hazard via inhalation route - Local effects - Long term exposure
- Hazard assessment conclusion: no hazard identified
General population - Hazard via inhalation route - Local effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
General population - Hazard via dermal route - Systemic effects - Long term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 60 mg/kg bw/day
- DNEL derivation method: Use of human data from long term therapeutic use of lithium, see section 5.6.3
- Modified dose descriptor starting point: human therapeutic dose
- DNEL value: 60 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point: published data on human serum concentrations of lithium following oral therapeutic treatment with lithium carbonate.
- Explanation for hazard conclusion: The use of human data for identification of the DNEL is justified based on the long history of safe use of lithium for treating bipolar disorder.
General population - Hazard via dermal route - Systemic effects - Acute/short term exposure
Hazard assessment conclusion: no DNEL required: short term exposure controlled by conditions for long-term
Value: 60 mg/kg bw/day
General population - Hazard via dermal route - Local effects - Long term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 0.086 mg/cm²
- Most sensitive endpoint: skin irritation/corrosion
- DNEL derivation method: ECHA REACH Guidance
- Overall assessment factor (AF): 10
- Dose descriptor: human therapeutic dose
- AF for intraspecies differences: 10
- Justification: standard general population AF
- Explanation for hazard conclusion: DNEL based on NOAEL from subacute dermal toxicity study, with standard general population intraspecies AF applied
General population - Hazard via dermal route - Local effects - Acute/short term exposure
- Hazard assessment conclusion: no hazard identified
General population - Hazard via oral route - Systemic effects - Long term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 60 mg/kg bw/day
- DNEL derivation method: Use of human data from long term therapeutic use of lithium, see section 5.6.3
- Modified dose descriptor starting point: human therapeutic dose
- DNEL value: 60 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point: published data on human serum concentrations of lithium following oral therapeutic treatment with lithium carbonate.
- Explanation for hazard conclusion: The use of human data for identification of the DNEL is justified based on the long history of safe use of lithium for treating bipolar disorder.
General population - Hazard via oral route - Systemic effects - Acute/short term exposure
- Hazard assessment conclusion: DNEL (Derived No Effect Level)
- Value: 60 mg/kg bw/day
- DNEL derivation method: Use of human data from long term therapeutic use of lithium, see section 5.6.3
Lithium naphthenate would be expected to dissociate into naphthenic acid anions and lithium cations. Data have been read across to address the hazards associated with the naphthenic acid anions. In humans, lithium carbonate and other soluble inorganic salts have been used for decades in psychiatric therapy for the treatment of bipolar disorder. The inorganic lithium salts dissociate in biological fluids to yield the acid anions and lithium ions. The inorganic anion is considered not to be hazardous to humans. Because the source of ionic lithium is not relevant to its physiological activity, read across with respect to systemic toxicity is fully justified without restriction.
In case of long-term human treatment, the recommended dose is 450 to 900 mg/day lithium carbonate, corresponding to a therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application of lithium carbonate in humans, there is no evidence that lithium is of concern with respect to repeated dose oral toxicity at the therapeutic doses indicated. The No Observed Adverse Effect Level (NOAEL) for lithium naphthenate for repeat dose toxicity by the oral route is therefore based on human data and can be calculated in two ways that complement each other.
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 consists 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 lithium/kg bw/day, equivalent to 60 mg/kg bw/day of lithium naphthenate (lithium naphthenate contains 2.5% lithium). 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. Further, this value can be used as a starting value for route-to-route extrapolation from the oral repeated dose toxicity to the dermal route as necessary (with no requirement for an additional Assessment Factor).
The experimental results from the repeated dose dermal toxicity study on fatty acids C18 (unsaturated) lithium also permitted consideration of long term local effects on the skin. The NOAEL for this effect was 111.25 mg/kg/day, which converts to 0.86 mg/cm2 based on the area of rat skin exposed in the subacute study (average weight of the rats in the study was 311g, the body surface area was calculated as being approximately 9.1 x bw(g)0.66, and the approximate surface area exposed was 10%). The human data on serum blood concentrations of lithium ion following long term therapeutic treatment with lithium carbonate for bipolar disease is protective of human exposure and sufficient to determine a human NOAEL and DNEL. The above data support a DNEL based on human data for the lithium ion. As such, an oral NOAEL for repeated dose toxicity of 60 mg/kg bw/day was chosen.
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