Dilithium sebacate

Endpoint summary

Description of key information

Fatty acids are an endogenous part of every living cell, and their absorption and metabolism are well established. Significant published evidence is available from human exposure to lithium cations to demonstrate ADME properties. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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. 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 in the 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. As the fatty acid substances listed in Annex V are exempt, it can reasonably be interpreted that they are not considered to be hazardous to human health (with the noted potential exceptions of skin and eye irritation) or the environment. Since published reviews do not distinguish between the properties of monocarboxylic or dicarboxylic acids as a category (see Appendix 1, Category Justification), then the same interpretation can be applied to the dicarboxylic acids.

In the gastrointestinal tract, it would be expected that fatty acid salts will dissociate into the fatty acid and the metal cation. Depending on the contribution of the metal ion to systemic toxicity, then overall toxicity of the salt would be expected to be no different to the toxicities of the individual acids and metal ions.

No biologically or statistically significant elevation of serum lithium concentrations was observed in healthy human volunteers when they spent 20 minutes per day, four days per week, for two consecutive weeks in a spa with a concentration of ca. 40 mg lithium/L, when compared to a control group exposed to only background levels of lithium (ca. 0.02 mg lithium/L)(McCarty JD et al, 1994[P1] [SMJ#2] ). The group sizes were 14 males per group, and 12 females in the lithium exposure group and 13 females in the control group. The lithium ion was obtained from lithium chloride. It is concluded that dermal exposure to lithium ions does not result in detectable increases in serum lithium, indicating that very low/negligible skin absorption would be expected from dermal exposure to dilithium dicarboxylate salts. This human data is supported by dermal acute toxicity values in rats of >2000 mg/kg bw for lithium carbonate (see section 5.2.1.3) and the lack of systemic toxicity following subacute dermal exposure in rats toFatty acids C18-(unsaturated) lithium salts (see section 5.6.1.3).

Overall, the fatty acid components of the category ‘dilithium salts of dicarboxylic acids C6-C10’ are not expected to be hazardous. As all category members are lithium salts, any toxicity is expected to be driven by the lithium ion.

No experimental toxicokinetic data are available on specific substances in the dilithium salts of dicarboxylic acids C6 - C10 category.

Assessments on lithium and its compounds have been carried out by or on demand of national and international authorities and have been taken into account to prepare the CSR, e.g.:

· EFSA (2010): Selected trace and ultratrace elements: Biological role, content in feed and requirements in animal nutrition – Elements for risk assessment, Technical Report submitted to EFSA by Ghent University (2010), http: //www. efsa. europa. eu/en/supporting/doc/68e. pdf

· NEG (2002): The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 131. Lithium and lithium Compounds, nr 2002:16, http: //www. inchem. org/documents/kemi/kemi/ah2002_16. pdf

· INRS (2000): France l’Institut national de recherche et de sécurité pour la prévention des accidents du travail et des maladies professionnelles (INRS): Lithium et composés minéraux, Fiche toxicologique N° 183: http: //www. inrs. fr/accueil/produits/bdd/doc/fichetox. html?refINRS=FT%20183

· RAIS (1995): Risk Assessment Information System, Formal Toxicity Summary for LITHIUM, U. S. Department of Energy (DOE), http: //rais. ornl. gov/tox/profiles/lith. html

The most comprehensive information on the toxicokinetics of lithium and its compounds is given in NEG (2002), presented as excerpts from the document as follows:

“ 7.1 Uptake

…To conclude, lithium is readily and almost completely absorbed from the gastrointestinal tract, but the absorption rate depends on the solubility of the compound. Lithium may also be extensively absorbed via the lungs, whereas absorption through skin is considered to be poor.

7.2 Distribution

7.2.2 Humans

From the systemic circulation lithium is initially distributed in the extracellular fluid and then accumulates to various degrees in different organs. The ion probably does not bind to plasma or tissue proteins to a great extent, and the final volume of distribution is similar to that of the total body water. Lithium can substitute for sodium or potassium in several transport proteins thus providing a pathway for lithium entry into cells. Lithium is distributed unevenly in the tissues. At steady-state the concentration is lower in the liver, erythrocytes and cerebrospinal fluid than in serum. In contrast, it is higher in e. g. kidneys, thyroid and bone. Brain lithium concentrations are typically less than those in serum after both acute doses and at steady state. In most studies brain lithium concentrations exhibit later peaks and slower rates of elimination than serum concentrations. Lithium crosses the placenta and is excreted in breast milk, breast milk levels being approximately 50% of that of maternal serum. The serum lithium concentrations in nursing infants have been reported to be 10-50% of the mothers’ lithium levels.

7.3 Biotransformation

Lithium is not metabolised to any appreciable extent in the human body.

7.4 Excretion

7.4.2 Humans

Over 95% of a single oral dose of lithium ion is excreted unchanged through the kidneys. One- to two thirds of the dose administered is excreted during a 6-12 hours initial phase, followed by slow excretion over the next 10-14 days. Less than 1% of a single dose of lithium leaves the human body in faeces and 4-5% is excreted in the sweat. Lithium is freely filtered through the glomeruli, and approximately 80% is reabsorbed together with sodium and water mainly in the proximal tubules. With repeated administration lithium excretion increases during the first 5-6 days until a steady state is reached between ingestion and excretion. Two- and three-compartment models have been used to describe lithium kinetics in man. The reported distribution half-times in serum and plasma are approximately 2-6 hours. Lithium has an elimination half-time of 12–27 hours after a single dose, but its elimination half-time can increase to as long as 58 hours in elderly individuals or patients taking lithium chronically. However, the volume of distribution and clearance are relatively stable in an individual patient, although there is a considerable variation in lithium pharmacokinetics among subjects. Excretion of lithium is directly related to theglomerular filtration rate (GFR), so factors that decrease GFR (e. g. kidney disease or normal ageing) will decrease lithium clearance. In addition, factors that increase proximal tubular reabsorption of sodium (e. g. extrarenal salt loss, decreased salt intake, or the use of diuretic drugs) decrease the clearance of lithium.

In summary, the excretion of lithium is chiefly through the kidneys. Factors that decrease GFR or increase proximal tubular reabsorption of sodium will decrease the clearance of lithium. After chronic administration of lithium the elimination half-time is increased.

14.1 Assessment of health risks…

The lithium concentrations in serum from non-patient populations have been in the order of a 1000 times lower than the concentrations found in patients taking medicines. The few available data on serum values of workers exposed to lithium essentially point in the same direction, that is, very low serum levels of lithium.

Occupational exposure to a relatively high level of 1 mg Li/m³for 8 hours may result in a dose of 10 mg Li (assuming 10 m³inhaled air and 100% absorption). In comparison the defined daily dose in Sweden in lithium treatment of affective disorders is 167 mg Li. For these reasons, systemic adverse effects due to lithium (e. g. NDI, fine hand tremor, weight gain, increased TSH values), including effects on reproduction, are unlikely to occur at occupational exposure to lithium and compounds. ”

The toxicokinetics of monocarboxylic fatty acids has been reviewed in HERA (2003) (citing other published references): Fatty acids are an endogenous part of every living cell and are an essential dietary requirement. They are absorbed, digested and transported in animals and humans. When taken up by tissues they can either be stored as triglycerides or can be oxidised via the ß-oxidation and tricarboxylic acid pathways. The ß-oxidation uses a mitochondrial enzyme complex for a series of oxidation and hydration reactions, resulting in a cleavage of acetate groups as acetyl CoA. Acetyl CoA is used mainly to provide energy but also to provide precursors for numerous biochemical reactions. Alternative minor oxidation pathways can be found in the liver and kidney (ω-oxidation and ω-1 oxidation) and in peroxisomes for ß-methyl branched fatty acids (α-oxidation). The metabolic products can then be incorporated for example into membrane phospholipids. Long chain saturated fatty acids are less readily absorbed than unsaturated or short chain acids. Several investigators have found that increasing fatty acid chain length decreased their digestibility.

The CoCAM report (2014) – i.e. the SIDS Initial Assessment Report – on the C4–C22 Aliphatic Acids category states that all sponsored fatty acids in the category (mono- and di-carboxylic) share similar metabolic pathways, and common levels and mode of health related effects. The common degradation pathways result in metabolism to acetyl-Co-A or other key metabolites in all living systems. There are common breakdown products, which together with the physico-chemical properties, are responsible for similar environmental behaviour and essentially identical hazard profiles with regard to human health. Differences in metabolism or biodegradability of even- and odd-numbered carbon chain compounds are not expected, although the final products ofodd carbon chain length β-oxidation would be acetyl-Co-A and propionyl-Co-A, the latter being converted to succinyl-Co-A, an intermediate in the Kreb’s cycle.

The observed acute oral toxicity (LD50 between 300 and 2000 mg/kg bw) provides evidence of absorption from the gastrointestinal tract. On the basis of the lack of hazard potential from the fatty acid moiety, it is considered that this acute toxic response is a result of lithium cation absorption.

HERA (2003) use a range of data to conclude that the greatest skin penetration of human epidermis was with C10 and C12 soaps. No further experimental information is provided. Another study was referenced for C10 to C18 indicating that C10, C12 and C14 soaps show a lag time of 1 hour before measurable penetration occurred, but after this the rate of penetration steadily increased. The low penetration rates of the C16 and C18 soaps suggest that little or none of these would penetrate from a short (e. g. 15 minute) wash and rinse exposure. It can be extrapolated from the data that the same low dermal penetration would be expected from the C6 -10 dicarboxylates.