Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

No experimental toxicokinetic data are available on Reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide.

 

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 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 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. ”

 

The results from an acute oral toxicity study on the read across substance Reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide indicated that the LD50 value was in excess of 2000 mg/kg bw. According to the data provides as part of the NONS registration of this substance, there were no deaths and no clinical signs were observed. Therefore, it is not possible to ascertain whether any systemic absorption of the substance occurred.

 

A 28-day sub-acute toxicity study on Reaction products of hydrogenated tallow alkyl amines with sebacic acid and calcium hydroxide gave a NOAEL of 1000 mg/kg/day. Since calcium is not considered a hazardous ion, then the results from this study provide an indication of the potential toxicity of the organic anion.

 

Overall, there is limited information on the toxicokinetics of Reaction mass of amines, hydrogenated tallow alkyl and azelaic acid and lithium hydroxide and it is not possible to quantify absorption, distribution, metabolism or excretion. Nevertheless, information on the tokicokinetic behaviour of the lithium ion is available.

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

· 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