Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Value:
3 mg/m³
DNEL related information
DNEL derivation method:
other: General nuisance dust OEL for chronic exposure to inert alveolar (respirable) dust used as DNEL surrogate in accordance with ECHA REACH TGD R.8
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Value:
6 mg/m³
DNEL related information
DNEL derivation method:
other: General nuisance dust OEL for chronic exposure to inert alveolar (respirable) dust used as DNEL surrogate in accordance with ECHA REACH TGD R.8

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: Use of human data from long term therapeutic use of lithium, see section 5.6.3
Modified dose descriptor starting point:
other: human therapeutic dose
Value:
41 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.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
Value:
41 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: human therapeutic dose
AF for intraspecies differences:
5
Justification:
standard worker AF
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The substances in the category are considered to be similar on the basis that they have common structures of a lithium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. As a result, it is expected that the substances will have similar, predictable properties. REACH Annex V, Entry 9, groups fatty acids and their potassium, sodium, calcium and magnesium salts, including C6 to C24, predominantly even-numbered, unbranched, saturated or unsaturated aliphatic monocarboxylic acids. Provided that they are obtained from natural sources and are not chemically modified, the substances included in REACH Annex V, Entry 9 are exempt from registration, unless they are classified as dangerous (except for flammability, skin irritation or eye irritation) or they meet the criteria for PBT/vPvB substances. The fatty acid components of the category members are therefore not expected to be hazardous. As all category members are lithium salts, any toxicity is expected to be driven by the lithium ion. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the repeated dose toxicity is expected to be similar across the category.

The category members are almost exclusively produced and used directly in grease form. They have vapour pressures of less than 10 E-10 Pa and melting points of greater than 160°C, so the potential for the generation of inhalable forms is low, also the use of the grease forms will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. Only two category substances – Fatty acids C16-18, lithium salts and lithium 12-hydroxystearate – are produced to some extent in solid form and then subsequently formulated by occupational downstream users into a grease form. From the granulometry data on the solid, generation of dusts of an inhalable size cannot be excluded. However, at the production and occupational downstream user sites, the formation of dusts/aerosols is not significant due to specific operational conditions and implemented general dust RMMs. None of the category substances have been tested by the inhalation route. However, a number of acute oral and dermal toxicity studies in rats conducted on lithium salts of myristic (C14),12-hydroxystearic (C18 hydroxylated), stearic (C18), C18 unsaturated and behenic (C22) monocarboxylic acids showed consistent evidence of a lack of acute toxicity up to the highest doses tested (2000 mg/kg or greater). An estimate of the inhalation LC50 by route-to-route extrapolation using a respiratory volume for a 250 g rat of 0.20 l/min and 100 % absorption and postulating 100% deposition and absorption (c. f. ECHA REACH TGD R.8, Table R.7-2 and ECHA CLP TGD 3.1.3.3.4i: Extrapolation oral to inhalation) result in an ATE of a minimum 10.4 mg/l/4h. This value is well above the cut off values for classification for acute toxicity hazard of dusts. Route-to-route extrapolation from comprehensive long-term oral toxicity data to long-term inhalation toxicity would result in a DNEL long-term exposure – systemic effects worker of 287 mg/m³. This value is considerably higher than the general dust limits, which apply in any case.  Although no substance specific intrinsic inhalative toxicity is expected, generally accepted OELs derived for inert (nuisance) dust/particulates not otherwise classified (PNOCs) of 10 mg/m³ for chronic and 20 mg/m³ for acute exposure to inhalable dust and of 3 mg/m³ for chronic and of 6 mg/m³ for acute exposure to alveolar (respirable) dust are applicable and must be adhered to, to avoid non-specific inhalative dust toxicity. By adherence to the general dust limits, the risk to humans can be considered to be sufficiently controlled. In accordance with ECHA REACH TGD R.8, the general dust limits are used as DNEL surrogate.

Fatty acid lithium salts would be expected to dissociate into fatty acid anions and lithium cations. Since the fatty acid anions are not considered hazardous as described above and also in the category justification document, focus can be placed on the lithium cation as a potential toxicant. 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. Like the fatty acid anions, 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 the lithium fatty acid salts in the category 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 50.68 mg/kg bw/day of lithium myristate (lithium myristate contains 2.96% lithium). Of the lithium fatty acid salts in the category, the myristate has the lowest number of carbon atoms (14) and hence the highest proportion of lithium. This represents the lowest NOAEL for the category and can be used for all the higher carbon chain category substances. 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.

An alternative way to calculate an oral NOAEL for lithium myristate is also based 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 myristate oral NOAEL can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: i.e. 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmol lithium/L in blood/serum). When converting the oral dose levels of 450 to 900 mg lithium carbonate/day to bodyweight based on a 70 kg human, the following values are obtained: 40.9 to 81.8 mg lithium myristate/kg bw/day. These values represent an optional NOAEL for lithium myristate for the oral route of administration.

Under both methods of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, an oral NOAEL for repeated dose toxicity of 40.9 (rounded to 41) mg/kg bw/day was chosen. 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 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/cm­2based 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.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: Use of human data from long term therapeutic use of lithium, see section 5.6.3
Modified dose descriptor starting point:
other: human therapeutic dose
Value:
41 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
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
Value:
41 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
AF for intraspecies differences:
10
Justification:
Standard AF for general population
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:
41 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: Use of human data from therapeutic use of lithium, see section 5.6.3
Modified dose descriptor starting point:
other: human therapeutic dose
Value:
41 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
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: Use of human data from therapeutic use of lithium, see section 5.6.3
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The substances in the category are considered to be similar on the basis that they have common structures of a lithium ion varying only by the length of the fatty acid chain and the presence of unsaturated and/or hydroxyl functional groups. As a result, it is expected that the substances will have similar, predictable properties. REACH Annex V, Entry 9, groups fatty acids and their potassium, sodium, calcium and magnesium salts, including C6 to C24, predominantly even-numbered, unbranched, saturated or unsaturated aliphatic monocarboxylic acids. Provided that they are obtained from natural sources and are not chemically modified, the substances included in REACH Annex V, Entry 9 are exempt from registration, unless they are classified as dangerous (except for flammability, skin irritation or eye irritation) or they meet the criteria for PBT/vPvB substances. The fatty acid components of the category members are therefore not expected to be hazardous. As all category members are lithium salts, any toxicity is expected to be driven by the lithium ion. Due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the repeated dose toxicity is expected to be similar across the category.

The category members are almost exclusively produced and used directly in grease form. They have vapour pressures of less than 10 E-10 Pa and melting points of greater than 160°C, so the potential for the generation of inhalable forms is low, also the use of the grease forms will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. Only two category substances – Fatty acids C16-18, lithium salts and lithium 12-hydroxystearate – are produced to some extent in solid form and then subsequently formulated by occupational downstream users into a grease form. From the granulometry data on the solid, generation of dusts of an inhalable size cannot be excluded. However, at the production and occupational downstream user sites, the formation of dusts/aerosols is not significant due to specific operational conditions and implemented general dust RMMs. None of the category substances have been tested by the inhalation route. However, a number of acute oral and dermal toxicity studies in rats conducted on lithium salts of myristic (C14),12-hydroxystearic (C18 hydroxylated), stearic (C18), C18 unsaturated and behenic (C22) monocarboxylic acids showed consistent evidence of a lack of acute toxicity up to the highest doses tested (2000 mg/kg or greater). An estimate of the inhalation LC50 by route-to-route extrapolation using a respiratory volume for a 250 g rat of 0.20 l/min and 100 % absorption and postulating 100% deposition and absorption (c. f. ECHA REACH TGD R.8, Table R.7-2 and ECHA CLP TGD 3.1.3.3.4i: Extrapolation oral to inhalation) result in an ATE of a minimum 10.4 mg/l/4h. This value is well above the cut off values for classification for acute toxicity hazard of dusts. Route-to-route extrapolation from comprehensive long-term oral toxicity data to long-term inhalation toxicity would result in a DNEL long-term exposure – systemic effects worker of 287 mg/m³. This value is considerably higher than the general dust limits, which apply in any case.  Although no substance specific intrinsic inhalative toxicity is expected, generally accepted OELs derived for inert (nuisance) dust/particulates not otherwise classified (PNOCs) of 10 mg/m³ for chronic and 20 mg/m³ for acute exposure to inhalable dust and of 3 mg/m³ for chronic and of 6 mg/m³ for acute exposure to alveolar (respirable) dust are applicable and must be adhered to, to avoid non-specific inhalative dust toxicity. By adherence to the general dust limits, the risk to humans can be considered to be sufficiently controlled. In accordance with ECHA REACH TGD R.8, the general dust limits are used as DNEL surrogate.

Fatty acid lithium salts would be expected to dissociate into fatty acid anions and lithium cations. Since the fatty acid anions are not considered hazardous as described above and also in the category justification document, focus can be placed on the lithium cation as a potential toxicant. 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. Like the fatty acid anions, 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 the lithium fatty acid salts in the category 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 50.68 mg/kg bw/day of lithium myristate (lithium myristate contains 2.96% lithium). Of the lithium fatty acid salts in the category, the myristate has the lowest number of carbon atoms (14) and hence the highest proportion of lithium. This represents the lowest NOAEL for the category and can be used for all the higher carbon chain category substances. 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.

An alternative way to calculate an oral NOAEL for lithium myristate is also based 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 myristate oral NOAEL can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: i.e. 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmol lithium/L in blood/serum). When converting the oral dose levels of 450 to 900 mg lithium carbonate/day to bodyweight based on a 70 kg human, the following values are obtained: 40.9 to 81.8 mg lithium myristate/kg bw/day. These values represent an optional NOAEL for lithium myristate for the oral route of administration.

Under both methods of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, an oral NOAEL for repeated dose toxicity of 40.9 (rounded to 41) mg/kg bw/day was chosen. 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 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/cm­2based 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.