Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Lithium hexafluorophosphate is reactive and unstable in water and air. Reaction in contact with water proceeds rapidly, with release of hydrogen fluoride (forming hydrofluoric acid). Under ambient conditions, the substance LiPF6 may even be represented as an equilibrium state: 
LiPF6 ↔ LiF + PF5
The following rapid hydrolysis reaction sequences can therefore occur:
LiPF6 → LiF + PF5, followed by PF5 + 4H2O → 5HF + H3PO4
or LiPF6 + H2O → LiF + 2HF + POF3, followed by POF3 + 3H2O → 3HF + H3PO4
Both of these can be summarised as:
LiPF6 + 4H2O → 5HF + LiF + H3PO4
This release of HF occurs within 4 seconds in water (Unpublished stability and degradation report, 2011).  Subsequently, the lithium fluoride hydrolysis product will dissociate, releasing F- ions.
 
The corrosivity of LiPF6 is thus due in large part to the local generation of HF/hydrofluoric acid through reaction with water at the site of contact with skin or other membranes. The consequent potential for serious local tissue damage at any site of LiPF6 contact makes strict containment necessary, severely restricting the possibilities for exposure leading to absorption and systemic distribution of the fluoride, lithium and phosphate hydrolysis products. However much is known about absorption, distribution and excretion of these in animals and man: expert reviews for HF/F-, lithium salts/Li+ and inorganic phosphates are available, summarising this information.
Fluoride is retained in bones and teeth; lithium distribution in the body generally follows that of total body water and human therapeutic administration has not produced evidence of marked bioaccumulation. Phosphate is subject to homeostatic regulation in the body.
All of these hydrolysis products are ubiquitous in the environment, at levels which are most unlikely to be significantly affected by release of LiPF6 during its intended use. No concerns regarding bioaccumulation are therefore raised.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

HF is transported rapidly across biological membranes (believed to be a passive process), diffusing more easily than fluoride ions (US NRC, 2006) and then generating fluoride ions under physiological conditions within the body: such fluoride intake has been demonstrated following HF exposure by inhalation (in rats, rabbits and man) and by skin contact (in rats and man) (HF: EU Risk Assessment Report, 2001). Absorption from the Gastrointestinal tract after ingestion of HF would also be rapid and extensive, although sequestration of F- ions by cationic gut contents and gastric acidity may affect the rate and extent of fluoride absorption. Fluoride half-life in the GI tract is about 30 minutes, with high absorption efficiency (typically 70 – 90%: nearly 100% for soluble inorganic fluorides (US NRC, 2006). Following ingestion of soluble fluoride compounds, this absorption occurs principally by diffusion of HF (formed from F- under acidic stomach conditions), principally in the stomach and small intestine. Peak plasma fluoride concentration has been recorded in man within 30 minutes after ingestion of sodium fluoride tablets (WHO EHC 227, 2002). It has been observed that rats may require higher chronic exposure to fluoride to achieve comparable plasma and bone concentrations (about 5 times higher concentration in water to establish similar plasma concentrations; incorporation into bone about 18 times more in man than in rats under normal dietary conditions) (US NRC, 2006).

 

Absorbed fluoride is rapidly and extensively distributed in the body: it is not subject to homeostatic regulation in circulating blood, but is concentrated in kidney tubules and is retained in the bones and teeth. Up to 99% of the total fluoride body burden is concentrated in bones and teeth of man and animals, with up to 75% or more of daily absorbed fluoride being incorporated in skeletal tissues in children. However if human daily fluoride intake becomes low, levels of skeletal fluoride can be depleted via urinary excretion: renal clearance into the urine is the major route of fluoride elimination from the body. Human transplacental transfer of serum fluoride has also been reported (WHO EHC 227, 2002).

 

Like fluoride, lithium is widely distributed in nature and occurs at low levels in the normal human diet. It is readily absorbed after ingestion of soluble lithium salts: rat plasma levels increased within 30 minutes of single doses of lithium chloride or carbonate, with in vitro studies suggesting a passive diffusion process in the small intestine. Human studies have confirmed similarly rapid lithium absorption after ingestion of lithium chloride, and somewhat slower absorption from lithium carbonate (peak plasma concentration after 1-4 hours). Absorption of inhaled lithium via the lungs has also been reported in human patients subjected to mechanical ventilation by equipment with lithium chloride coated exchangers. Repeated dermal contact with lithium in spa water and lithium succinate in ointment did not lead to elevation of serum lithium levels in two human studies. Thus absorption of lithium is rapid and near-complete following ingestion and perhaps also extensive following inhalation, but dermal absorption is not expected to be significant (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 131, 2002).

 

Absorbed lithium is widely distributed in the body: in animals, accumulation in the bones and endocrine glands has been reported. In mice and rats, concentration in different areas of the brain have been described. In man, little tissue or plasma binding is believed to occur and systemic distribution follows that of total body water, but lithium can replace sodium or potassium in active transport systems, entering cells. Under steady state conditions, lithium levels in kidneys, thyroid and bone are above those in serum; peak concentrations in the brain are typically lower and later than those in serum. Transplacental transfer is known to occur. Elimination occurs mainly in the urine, via glomerular filtration in the kidneys: serum half-life in animal studies was found to be from 11 to 23 hours. In man, more than 95% of an oral dose of lithium ion is excreted unchanged, with up to 2/3 of this being eliminated in 6-12 hours and the remainder over the next 10-14 days. With repeated therapeutic administration, a steady-state balance between ingestion and excretion can be achieved: serum half-life on cessation of treatment can then be about 22 to 28 hours. In animals and in man, the rate of lithium elimination is dependent on renal clearance (glomerular filtration) rate and is related to sodium balance (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 131, 2002; Hunter, 1998).

 

Inorganic phosphate is an essential cellular component, necessary for various biological processes. Most phosphorus uptake occurs by absorption of inorganic phosphate: although an active uptake process (mediated by hydroxyvitamin D) has been documented, the relative constancy of total phosphorus over a wide range of intake levels indicates a predominance of passive uptake. Up to 80% absorption from the gastrointestinal tract (distal to the duodenum) has been reported (Deftos, 2010). Homeostatic regulation of serum phosphate levels is regulated to a large extent by the rate of renal elimination in urine: here glomerular filtration occurs, together with resorption in the proximal tubules (a process inversely related to parathyroid hormone level. Following cellular uptake from circulating blood, absorbed phosphate not filtered out in the kidneys is stored in bone as a calcium phosphate complex: some 85% of phosphorus in the body is held in bone (Institute of Medicine, 1997; Deftos, 2010). Release of phosphate from this bone-cartilage complex can also provide a feedback control for homeostasis. (Sapir-Koren and Livshits, 2011).

 

Intravenous infusion of a neutral phosphate solution at an increasing rate in adult volunteers showed that after proximal tubule resorption of phosphorus in exceeded, increased urinary elimination rises in response to increasing intake, slowing the rate of increase in plasma phosphorus levels (Institute of Medicine, 1997).