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Description of key information

Assessment of the uptake of substances is included in the ongoing short-term repeat dose and reproductive screening toxicity (OECD 422) study. The results of the investigation and the implications for assessment of toxicokinetics of these substances will be reviewed when the data are available. The substances in the lithium salts of dicarboxylic acids C6-C10 are considered to demonstrate consistent toxicokinetic properties across the category and the results for the tested substance will be read across to the other category members. 


The substances consist of lithium salts of carboxylic acids, for which the 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

Assessment of the uptake of substances is included in the ongoing short-term repeat dose and reproductive screening toxicity (OECD 422) studies on dilithium adipate. The results of the investigation and the implications for assessment of toxicokinetics of these substances will be reviewed when the data are available.  


Substances in the lithium salts of dicarboxylic acids C6-C10 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 acid chain. As a result, due to the close structural similarity and the narrow range of carbon chain numbers covered in this category, the toxicokinetic properties are expected to be predictable across the category and the results from the uptake assessment will be read across to the other category members. 


Uptake mechanisms 


If a substance is considered to be bioavailable, i.e. available and able to enter an organism’s circulation, it can be absorbed through the cell membranes and be distributed to target tissues. Therefore, for bioavailable substances, the amount of a toxicant that reaches target tissue(s) is based on its toxicokinetic profile. 


Following any of the routes of exposure, the potential for absorption (the first stage of toxicokinetics) is dependent on the uptake of the substance (i.e. the amount that reaches the target tissue). Lipophilicity is one factor that determines the absorption of substances into the human body, along with other physico-chemical characteristics, all of which will play a part in the rate of absorption. A surrogate measure of lipophilicity is octanol-water partition coefficient and the lithium salts of dicarboxylic acids C6-C10 have a low potential to partition, with log Kows of <0. Therefore, taking partition coefficient values as a surrogate for lipophilicity in evaluating the toxicokinetics, the substances have a low potential for uptake.


Three routes of potential exposure are considered within REACH: oral, dermal and inhalation. The potential for inhalation exposure is not considered to be relevant for these substances given their use as grease thickeners and justifications for this are provided in the waiver statements for the relevant endpoints. 


Following oral exposure, potential for uptake of the thickeners would be expected to occur in the small intestine, where toxicants compete with nutrients for the binding sites associated with active transport mechanisms. However, as discussed above, taking partition coefficient values as a surrogate for lipophilicity in evaluating the toxicokinetics, the substances have a low potential for uptake.


Following dermal exposure, all toxicants that pass through the skin do so by passive diffusion mechanisms through the epidermis, sweat glands and hair follicles, and the passage of toxicants can be enhanced by damage to the keratinized outer layer of the skin. Once they have passed through the epidermis, they can enter the blood supply in the dermis and be distributed throughout the body. The stratum corneum (the outermost layer of the epidermis) is the rate-limiting barrier for absorption and is composed of lipophilic substances (cholesterol, cholesterol esters and ceramides). This permits lipophilic substances to pass through the epidermis and enter the circulation faster than a number of other types of substances. Although publications such as HERA (2002) reviewed dermal absorption of fatty acids and soaps and concluded that the greatest skin penetration of the human epidermis occurs with C10-14 soaps, though there was a time lag before any measurable penetration was observed, taking partition coefficient values as a surrogate for lipophilicity in evaluating the toxicokinetics, the substances have a low potential for uptake.


Lithium salts of carboxylic acids 


Cell membranes are selectively permeable, and this permeability is related to molecular size, lipophilicity, electrical charge and presence of cell membrane passive/active/facilitated transport mechanisms. Lipid solubility is an important factor in the rate of passive diffusion across the cell membrane since 75% of the cell membrane is composed of lipids. Low lipid solubility and an electrical charge associated with the substance are important factors for active (carrier-mediated) transport. 


Lithium salts of dicarboxylic acids C6-C10 are metal salts of carboxylic acids. Although carboxylic acids are, by definition, lipophilic and are absorbed in animals and humans according the mechanisms described above (passive or facilitated diffusion, or a combination of both) (HERA 2002), taking partition coefficient values as a surrogate for lipophilicity in evaluating the toxicokinetics, the substances have a low potential for uptake. Therefore, there is little reason to perform additional toxicity studies and furthermore, there is a wealth of toxicity and human exposure data already available on the carboxylic acids and lithium ions. 


Carboxylic acids (fatty acids)


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. Although this does not cover dicarboxylic acids, the presence of the additional carboxylate group on the substances is not expected to significantly alter the hazard profile. The acid components of the category members are therefore not expected to be hazardous.

The aliphatic acids, including dicarboxylates, share a common degradation pathway in which they are metabolised to acetyl-Co-A or other key metabolites in all living systems. Common biological pathways result in structurally similar breakdown products and are, together with the physico-chemical properties, responsible for similar environmental behaviour and essentially identical hazard profiles with regard to human health. Differences in metabolism or biodegradation of even and odd numbered carbon chains compounds are not expected since they are naturally occurring and therefore expected to be metabolised and biodegraded in the same manner (CoCAM 2014).


As discussed in their respective registration dossiers (see dissemination portal), the carboxylic acid components have well characterised toxicokinetic profiles. The substances show high levels of adsorption with distribution, metabolism and high levels of excretion with no bioaccumulation. The acids are metabolised with the products mainly excreted in the urine and exhaled as CO2.


The toxicokinetics of fatty acids has also 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.” 


Furthermore, 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 soaps 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.




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, NEG 2002, INRS 2000, RAIS 1995). 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. 


7.2.2 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. 


7.4.2 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 the glomerular 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/m3 for 8 hours may result in a dose of 10 mg Li (assuming 10 m3 inhaled 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.” 

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