Lithium acetate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Lithium acetate anhydrous and lithium acetate dihydrate are both white, odourless solids with the formula LiOOCCH3 and CH3COOLi * 2 H2O, respectively. Lithium acetate has a molecular weight of 65.99 g/mol while its dihydrate has a molecular weight of 102.02 g/mol. Both compounds are very soluble in water (> 10000 mg/L).
The substance completely dissociates in water forming lithium cation (Li+) and the corresponding acetate anion (CH3COO- or acetic acid C2H4O2). Therefore the log Pow of the anion (acetic acid) was evaluated in a weight of evidence approach. Different literature sources report the partition coefficient within the range of -0.31 to -0.17 for acetic acid. The theoretical, calculated (EPIWIN) log Pow of acetic acid is 0.09.
The toxicokinetic assessment of lithium acetate focuses mainly on lithium as it is the moiety with the pharmacological activity. Further, the acetate anion is the conjugated base of acetic acid, which is used in the food industry as a preservative against bacteria and fungi. As acetic acid is considered harmless, no acceptable daily intake (ADI) limit is set (FAO/WHO Expert Committee on Food Additives, 2000). Estimations of the daily intake of acetic acid vary from about 1 g to 2.1 g/day for subjects older than 2 years. No adverse health effects are reported at these intakes (SCOEL, 2012).
Lithium has been neither known as an essential element for life nor has known biological use but according to various reports there is growing evidence that lithium may be an essential mineral in the human diet. The average daily lithium intake of 70 kg adult (in the U.S.A.) is between 0.65 and 3.1 mg/day and in some lithium-rich places like Chile, the total lithium intake may reach 10 mg/day without evidence of adverse effects to the local population. Major dietary sources of lithium are grains and vegetables, dairy products and meat. A recommended daily intake (RDA) of 1.0 mg lithium/day for 70 kg adult was proposed, corresponding to 14.3 µg/kg bw. Intake of lithium can occur as part of a psychiatric therapy in the treatment of bipolar affective disorders as lithium ion (Li+) (administered as any of several lithium salts) has proved to be useful as a mood-stabilizing drug.
Since lithium has been used as a psychiatric drug for almost half a century, there are many numbers of publications on lithium pharmacokinetics and toxicity in humans.

Dermal absorption
The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds. Based on the hydrophilic character of lithium acetate and the barrier function of the stratum corneum against salts, dermal absorption is expected to be very poor. It is supported by an acute dermal toxicity study with lithium acetate dihydrate that revealed a LD50 value >2000 mg/kg bw without any local or systemic effects. The assumption that absorption is negligible is further confirmed by the negative results of an EPISKIN assay (OECD 439) with lithium acetate anhydrous and a Corrositex assay with lithium acetate dihydrate, respectively. Further, no sensitization was observed in a sensitization studies with the read-across substances lithium chloride and lithium carbonate. Additionally, acetic acid is an important industrial chemical that is also used in food industry as acidity regulator (E260). Its harmonised classification and labelling listed in Annex VI of Regulation (EU) No 1272/2008 does not include skin sensitising properties. Based on the results of the read across substances it is concluded, that lithium acetate is not skin sensitizing.
 
Resorption after oral uptake:
Upon oral uptake, lithium acetate will reach the stomach in form of lithium ions and acetate ions. Lithium- and acetate ions will be readily and almost completely absorbed from the gastrointestinal tract due to their low molecular weight (< 500 g/mol). Additionally, the low log Pow of both ions favors them for absorption by passive diffusion and therefore they can cross lipophilic membranes. They are also small and water soluble enough to be carried through the epithelial barrier by the bulk passage of water. In a study with lithium acetate an LD0 of 1500 mg/kg bw was determined. Based on this result the substance in classified as cat. 4 H302.
 
Resorption after inhalation:
The vapour pressure of lithium acetate is negligible (Modified Gain method: 2.59E-006 Pa at 25 °C) and therefore exposure to vapour is toxicologically not relevant. If lithium ions reach the lung resorption after inhalation is assumed to be low due to the very low log Pow. Thus, upon inhalation, the bioavailability of lithium acetate is expected to be low.
 
Distribution, Metabolism and Excretion
Lithium:
Lithium does not bind to protein and as a small cation it is quickly distributed throughout the body water both intra- and extracellularly, replacing normal cations (as K+, Na+). Lithium ion effects in the cell level are presumed to be related to interferences with processes that involve these ions such as renal tubular transport and ion channels involved in neurotransmission. Lithium has a large volume of distribution of 0.6-0.9 L/kg (for a 70 kg human a 42 L of volume of distribution). Because of its large volume of distribution, lithium shifts into the intracellular compartment of cells. With long-term use, the intracellular concentration of lithium increases, which thereby results in increased total body lithium load. The intracellular concentration is not reflected by the plasma level, which measures only the extracellular fluid concentration. Organ distribution is not uniform: Lithium is rapidly taken up by the kidney (there is obviously a clear interaction between lithium and sodium excretion/retention altering the electrolyte balance in humans). Penetration is slower into the liver, bone and muscle. Its passage across the blood-brain barrier is slow and equilibration of the CSF lithium level reaches only approximately half the plasma concentration.
The primary route of excretion is through the kidneys. Lithium is filtered by the glumeruli and 80 % of the filtered lithium is reabsorbed in the tubules, probably by the same mechanism of sodium reabsorption. Lithium is excreted primarily in urine with less than1 % being eliminated with the feces.
The renal clearance of lithium is proportional to its plasma concentration. The excretion of lithium ions is considered to be fast. About 50 % of a single dose of lithium is excreted in 24 hours and about 90 % in 48 hours. However, trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. A single oral dose of lithium ion is excreted almost unchanged through the kidneys. A low salt intake resulting in low tubular concentration of sodium will increase lithium reabsorption and might result in retention and intoxication. Renal lithium clearance is under ordinary circumstances, remarkably constant in the same individual but decreases with age and also when sodium intake is lowered.
Due to the fast excretion bioaccumulation is not to be assumed. Lithium is not metabolised to any appreciable extent in the human body. In conclusion, lithium in human body is quickly distributed and unchanged excreted. Bioaccumulation can be excluded.
 
Acetate ion/Acetic acid:
The acetate ion (the anion of acetic acid) is a normally occurring metabolite in catabolism or in anabolic synthesis (e.g. in formation of glycogen, cholesterol synthesis, degradation of fatty acids, and acetylation of amines). The estimated plasma level of the acetate ion in the human body is about 50-60 µmol/L (3.0-3.6 mg/L) and 116 µmol/L (7 mg/L) in cerebrospinal fluid. Daily turnover of the acetate ion in humans is estimated to be about 7.5 µmol/kg/min (45 g/day; SCOL, 2012). Via the citric acid cycle, acetate is rapidly metabolised to carbon dioxide, which will be eliminated from the body, predominantly via the exhaled air and in smaller quantities also via urine and faeces. Acetic acid can also be used as a building block e.g. in the biosynthesis of fatty acids (efsa, 2011)
 
 
References:

ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.
European Food Safety Authority (efsa, 2011): Scientific Opinion on Flavoring Group Evaluation 309 (FGE.309): Sodium Diacetate. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids. EFSA Journal, 9(7):2163.
Scientific Committee on Occupational Exposure (SCOEL, 2012): Recommendation from the Scientific Committee on Occupational Exposure Limits for acetic acid. SCOEL/SUM/98, June 2012.