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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) studies. 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 monocarboxylic acids C14-C 22 are considered to demonstrate consistent toxicokinetic properties across the category and the results for these substances will be read across to the other category members.

The substances consist of lithium salts of fatty acids. 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. Furthermore, a bioaccessibility testing program has been developed by the ERGTC to investigate whether the substances would be (available to be) absorbed and thus whether assessment of toxicokinetics is relevant. Leaching studies in distilled water have been conducted using lithium 12-hydroxystearate in base oil and no lithium was detected in the WAF at the limit of detection (<0.1 mg/L). On the basis of these results, lithium soap based grease thickeners have been concluded as not bioaccessible, indicating that no risk would be expected at a loading rate of 1000 mg/L grease.

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 lithium myristate, lithium 12 -hydroxystearate, fatty acids C16 -18 lithium salts and fatty acids C16 -18 (even numbered) saturated and C16 -20 (even numbered) unsaturated lithium salts. 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 monocarboxylic acids C14-C22 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, 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.

ERGTC bioaccessibility approach

Toxicokinetics describes the relationship between systemic exposure of a substance and its toxicity via exposure to the target tissue(s). Toxicokinetics consists of four processes involved in the interaction of a toxicant with an animal: absorption, distribution, metabolism and excretion. As toxicokinetics starts with absorption, substances are assumed to be bioaccessible and bioavailable (i.e. the substances would be present and able to cross the relevant membrane to be absorbed). The bioaccessibility testing program developed by the ERGTC is a pre-cursor to investigating toxicokinetics as it considers whether the substances would be (available to be) absorbed (i.e. if the first stage of toxicokinetics is reached) and thus whether assessment of toxicokinetics is relevant.

Bioaccessibility is the pool of a substance which is available to cross an organism’s cellular membrane from the environment, if the organism has access to the substance (McLaughlin and Lanno 2014). If a substance is not bioaccessible, it will not be bioavailable, that is able to cross the cell membrane and potentially cause a toxic effect, as shown in Figure 1 of the CSR. Bioavailability is the proportion of a substance which enters the systemic circulation (i.e. the amount absorbed through the gut wall, and which is available for distribution to target tissues), which determines the toxicokinetic profile (i.e. the amount of and how the substance is absorbed, distributed, metabolised and excreted).

The ERGTC have developed a bioaccessibility approach in order to address the interaction of grease thickeners with the base oil in which they are manufactured and the potential influence of matrix effects on the behaviour and effects of the substances on human health and the environment (for further details see Section 10 and Appendix of the CSR). The ERGTC conducted testing on the leaching of thickeners from base oil into water and FeSSIF in order to understand the bioaccessibility. The bioaccessibility results are used to evaluate the relevance and feasibility of conducting bioavailability testing, such as everted gut studies (i.e. whether the substances would be present in the gut fluid so that they would be available to cross the gut membrane and be taken up).

Lithium salts of fatty acids

In order to obtain further evidence on the bioaccessibility of lithium soap based grease thickeners, investigations were undertaken by the ERGTC (Shell 2013, for further details see Appendix of the CSR). Water Accommodated Fractions (WAFs) of grease samples were prepared at loading rates of 1000 mg/L. Test samples were smeared along the side of test vessels before adding distilled water, then stirred under ambient laboratory conditions at 250 rpm for 72 hours. Chemical analysis was undertaken on the WAFs.

The leaching studies on lithium 12-hydroxystearate (10%) in distillates (petroleum), hydrotreated heavy paraffinic (CAS 64742-54-7) and/or distillates (petroleum), solvent-dewaxed heavy paraffinic (64742-65-0) showed a lithium concentration of <0.1 mg/L in the WAF and SPME readings equivalent to background concentrations. The same results (lithium concentration of <0.1 mg/L in the WAF and SPME readings equivalent to background concentrations) were also observed in the leaching study using base grease containing both lithium 12-hydroxystearate (9%) and calcium 12-hydroxystearate (2.9%) in distillates (petroleum), hydrotreated heavy paraffinic (CAS 64742-54-7) and/or distillates (petroleum), solvent-dewaxed heavy paraffinic (64742-65-0) (Shell 2013). On the basis of these results, lithium soap based grease thickeners have been concluded to be not bioaccessible.

No data are available on the bioaccessibility of lithium 12-hydroxystearate in biological fluids. However, the concentration of lithium in the distilled water WAF (<0.1 mg/L) indicates that no risk would be expected at a loading rate of 1000 mg/L grease. Furthermore, given the low bioaccessibility in water, it is expected that the substance would have limited leaching in other aqueous solutions, such as FeSSIF.

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 but, for grease thickener substances, it was not possible to determine an octanol-water partition coefficient value. The shake-flask and HPLC methods are not suitable for surface active substances, the HPLC method is also not suitable for salts of organic acids and the remaining grease thickeners were not sufficiently soluble in octanol and water for partition coefficient testing to be feasible. Therefore, although partition coefficient values would provide a surrogate for lipophilicity in evaluating the toxicokinetics and potential uptake of the substances, the studies are not technically possible.

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, if a substance is not bioaccessible, it will not be bioavailable, that is be present and able to cross the cell membrane and potentially cause a toxic effect. On the basis of the leaching results, lithium soap based grease thickeners have been concluded as not bioaccessible and it is expected that the substance would have limited leaching in other aqueous solutions, such as FeSSIF, so would not be present in the gut to cross the gut wall and be taken up in the small intestine.

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. However, 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, with low penetration of C16-18 soaps. There was a time lag before any measurable penetration was observed.

Lithium salts of fatty 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 monocarboxylic acids C14-C22 are metal salts of fatty acids. Since fatty acids are, by definition, lipophilic and are an endogenous part of every living cell, they are absorbed in animals and humans according the mechanisms described above (passive or facilitated diffusion, or a combination of both) (HERA 2002). Therefore, if they are bioaccessible (i.e. accessible for uptake) then they are likely to be bioavailable (i.e. to be absorbed across the cell membrane and enter circulation). However, since the fatty acids used in thickeners are identical or close to fatty acids found in nature, there is little reason to perform additional toxicity studies when there is a wealth of toxicity and human exposure data already available.

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. 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.

The safety of fatty acids and soaps (i.e. fatty acid salts) has been reviewed by the Cosmetics Ingredients Review (CIR 2018), who noted that fatty acids are “ubiquitous in food as dietary fats. The US Food and Drug Administration (FDA) determined that several of the fatty acids and salts of fatty acids are approved as food additives permitted for direct addition to food for human consumption… the US FDA determined that the following ingredients are food additives permitted for direct addition to food for human consumption: Aluminum Distearate, Aluminum Stearate, Aluminum Stearates, Aluminum Tristearate, Calcium Laurate, Calcium Stearate, Capric Acid, Caprylic Acid, Caproic Acid, Lauric Acid, Magnesium Palmitate, Magnesium Stearate, Myristic Acid, Oleic Acid, Palmitic Acid, Potassium Caprate, Potassium Laurate, Potassium Oleate, Potassium Palmitate, Potassium Stearate, Sodium Caprate, Sodium Laurate, Sodium Oleate, Sodium Palmitate, Sodium Stearate, Stearic Acid, and Undecylenic Acid”.

The CIR reviewed the toxicokinetics of fatty acids and soaps (citing other published references):

“Dermal Penetration

Sodium Stearate - Sodium Stearate is absorbed through both rat and human skin.

Penetration Enhancement

Oleic Acid - Oleic Acid has been studied for its ability to act as a penetration enhancer for use in topical drug delivery.

Sodium Caprate - Sodium Caprate is reported to be an oral absorption promoter that has potential for use in oral drug products containing poorly permeable molecules.

Myristic Acid - Myristic acid enhanced the dermal penetration of several drugs.

Absorption, Distribution, Metabolism, Distribution

Fatty acids share a common degradation pathway in which they are metabolized to acetyl-Coenzyme A (acetyl-CoA) or other key metabolites that are structurally similar breakdown products. No differences in metabolism are expected between even and odd numbered carbon chain compounds or saturated and unsaturated compounds.

Calcium Stearate - Limited absorption studies indicated that Calcium Stearate is slightly absorbed by isolated dog intestine.

Lauric Acid, Oleic Acid, Palmitic Acid, Stearic Acid - Fatty acids are absorbed, digested, and transported in animals and humans. Radioactivity from labelled fatty acids administered orally, intravenously, intraperitoneally, and intraduodenally has been found in various tissues and in blood and lymph. P-Oxidation of the fatty acids involves serial oxidation and reduction reactions yielding acetyl-CoA. High intake of dietary saturated fatty acids has been associated with the incidence of atherosclerosis and thrombosis.

Hydroxystearic Acid - In male rats fed a diet containing hydrogenated castor oil, Hydroxystearic Acid was deposited in abdominal fat, as well as other body lipids, along with its metabolities (hydroxypalmitic acid, hydroxymyristic acid, and hydroxylauric acid). Hydroxystearic Acid has also been detected in the feces of 12 subjects who presumably ate a normal mixture of foods.

Isostearic Acid - Studies with rat liver homogenate suggest Isostearic Acid is readily metabolized following ingestion.”

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. 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.

Lithium

As all category members are lithium salts of fatty acids and the fatty acid components of the category members are not expected to be hazardous, any toxicity is expected to be driven by the lithium ion. 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.”