Castor oil, hydrogenated, lithium salt

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 lthium cations to demonstrate ADME properties. The toxicokinetic properties of the substances in the category are considered to demonstrate a predictable trend across the category.

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 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 toxicokinetic properties are expected to be predictable across the category.

No experimental toxicokinetic data are available on specific substances in the lithium salts of monocarboxylic acids C14-C22 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 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.

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. The relevance of these results on the lithium substances in the category is uncertain due to their use in situ in a grease base. References:

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

HERA (Human Health and Environmental Risk Assessment on ingredients of European household cleaning products) (2003) Fatty Acid Salts (Soap) Environmental and Human Health Risk Assessment

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%20183NEG (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

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

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