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Reference
Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement
Conclusions:
Lithium phosphate dissociates in water into lithium ions and phosphate ions. Once absorbed, both ions are excreted via the kidneys.

Executive summary:

Dermal absorption

The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to highly lipophilic compounds. Due to the hydrophilic character of lithium phosphate and the barrier function of the stratum corneum against salts, the dermal absorption of lithium phosphate is expected to be very poor. It is supported by an acute dermal toxicity study that revealed an LD50 value >3000 mg/kg bw without any local or systemic effects for the structural and chemical similar compound lithium carbonate. The assumption that absorption is negligible is further confirmed by the results of an EPISKIN assay (OECD 439) and two Corrositix test with lithium phosphate. The tests showed that lithium phosphate is not irritating or corrosive to the skin. Further, no sensitization was observed in the local lymphnode assay (LLNA) with the read-across substance sodium hydrogenorthophosphate.

Resorption after oral uptake:

Upon oral uptake, lithium phosphate will reach the stomach in form of lithium ions and phosphate ions. Lithium ions and phosphate 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. A weight of evidence approach was performed with read-across data from lithium sulfate and lithium nitrate. The available read-across data showed LD50 values >300 mg/kg (cat. 4, H302). Because phosphate is an essential element, and phosphate ions are a natural constituent of food, phosphate has less toxicological relevance.

Resorption after inhalation:

The vapour pressure of lithium phosphate is negligible (Modifies Gain method: 4.88E-022 Pa at 25 °C) and therefore exposure to vapour is toxicologically not relevant if the substance is handled at room temperature. 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 phosphate 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 (42 L for a 70 kg adult, which is the total body water). 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 than 1 % 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.

Phosphate ion:

Phosphate is taken up daily as it is naturally present in many foods including dairy products, meat and cereal grains. The normal concentration of phosphorus in plasma is 3-4.5 mg/dL. Once absorbed, phosphate in the extracellular fluid may exchange with the pool in bone. The skeleton is continuously remodeled, with typically 200 mg of phosphate entering and leaving the skeleton. But the principal mechanism by which the body regulates extracellular phosphate balance is renal phosphate excretion. About 700-900 mg phosphate per day are excreted via kidneys (Prasad and Bhadauria 2013).

Description of key information

Lithium phosphate dissociates completely in water into lithium ion and phosphate ions. Both ions are distributed throughout the body and are mainly excreted unchanged via the kidneys. Due to the fast excretion, bioaccumulation is not assumed.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Lithium phosphate is a colorless solid with the formula Li3PO4 and a molecular weight of 115.79 g/mol. The substance is moderately soluble in water (0.27 g/L at 25 °C) and has a very low vapor pressure calculated to be 4.88E-022 Pa at 25 °C. The substance completely dissociates in water forming lithium cation and the corresponding phosphate anion. Therefore the log Pow of the anion (phosphoric acid) in water was estimated. The theoretical, calculated (EPIWIN) log Pow of phosphoric acid is -0.77, thus very low.

The toxicokinetic assessment of lithium phosphate focuses mainly on lithium since phosphate is widly found in nature, in rocks, soil and food. Both, lithium and phosphate ions are ubiquitous in the environment, but lithium is the toxicological relevant moiety of the assessed substance.

Phosphates are naturally distributed in the nature. Phosphates and their compounds are essential for the health of all living organisms as key components of DNA, cell structures, cellular energy cycles, bones and teeth, and in the capture of the sun’s energy by plants (photosynthesis). An acceptable daily intake (ADI) of 70 mg phosphate/kg bw/day was established (FAO/WHO Expert Committee on Food Additives, 2000).

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. Due to the hydrophilic character of lithium phosphate and the barrier function of the stratum corneum against salts, the dermal absorption of lithium phosphate is expected to be very poor. It is supported by an acute dermal toxicity study that revealed an LD50 value >3000 mg/kg bw without any local or systemic effects for the structural and chemical similar compound lithium carbonate. The assumption that absorption is negligible is further confirmed by the results of an EPISKIN assay (OECD 439) and two Corrositix test with lithium phosphate. The tests showed that lithium phosphate is not irritating or corrosive to the skin. Further, no sensitization was observed in the local lymphnode assay (LLNA) with the read-across substance sodium hydrogenorthophosphate.

Resorption after oral uptake:

Upon oral uptake, lithium phosphate will reach the stomach in form of lithium ions and phosphate ions. Lithium ions and phosphate 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. A weight of evidence approach was performed with read-across data from lithium sulfate and lithium nitrate. The available read-across data showed LD50 values >300 mg/kg (cat. 4, H302). Phosphate is an essential element, and phosphate ions are a natural constituent of food and therefor phosphate has less toxicological relevance.

Resorption after inhalation:

The vapour pressure of lithium phosphate is negligible (Modifies Gain method: 4.88E-022 Pa at 25 °C) and therefore exposure to vapour is toxicologically not relevant if the substance is handled at room temperature. 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 phosphate 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 (42 L for a 70 kg adult, which is the total body water). 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 than 1 % 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.

Phosphate ion:

Phosphate is taken up daily as it is naturally present in many foods including dairy products, meat and cereal grains. The normal concentration of phosphorus in plasma is 3-4.5 mg/dL. Once absorbed, phosphate in the extracellular fluid may exchange with the pool in bone. The skeleton is continuously remodeled, with typically 200 mg of phosphate entering and leaving the skeleton. But the principal mechanism by which the body regulates extracellular phosphate balance is renal phosphate excretion. About 700-900 mg phosphate per day are excreted via kidneys (Prasad and Bhadauria 2013).

References:
ECHA (2017) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.
FAO/WHO Codex Committee on Food Additives (2000):Endorsment and/or revision of maximum levels for food additives in codex standards. Thirty-third Session, The Hague, The Netherlands, 12-16 March 2001
Nordic Council of Ministers (2002): The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals. 131.Lithium and lithium compounds.
N. Prasadand, D. Bhadauria (2013):Renal phosphate handling: Physiology. Indian Journal of Endocrinology and Metabolism, 2013 Jul-Aug; 17(4): 620–627.

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