Lithium amide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement

Objective of study:

toxicokinetics

Conclusions:

Lithium amide reacts heavily with water and dissociates in water into lithium ions and ammonium ions. Both ions are distributed throughout the body and are mainly excreted unchanged via the kidneys. Due to the fast excretion, bioaccumulation is not to be assumed.

Executive summary:

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 22.96 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is very likely (ECHA, 2014). Furthermore the compound is highly hydrophilic (log Pow = 0.23) and its degradation products are water soluble.

Readily soluble ammonium or lithium salts are assumed to be completely and rapidly absorbed. The absorption process occurs via passive diffusion from the stomach or the intestine. The rate of absorption is most likely related to the gastric acidity. Ions that are not absorbed in the stomach will be rapidly absorbed in the small intestine.

Considering the low vapour pressure of lithium amide and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. If inhaled, the high water solubility of the compound would lead to complete absorption of particles in the mucus lining of the respiratory tract. The extent of absorption via inhalation is further enhanced by the corrosive character of the test substance when in contact with water. Therefore complete absorption after inhalation is highly likely.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 22.96 g/mol a dermal uptake is highly favoured. Furthermore the high water solubility of the test substance supports a moderate to high dermal absorption. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1. The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. When in contact with the skin moisture the dermal penetration will be increased by the skin corrosion. These pre-requisites lead to the conclusion that the test substance is bioavailable when placed in contact to the skin.

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 ions 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 an 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 falls 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.

Ammonium

After absorption, distribution of the ammonium ion throughout the body is expected based on their relatively low molecular weight. No accumulation in the body is anticipated based on its hydrophilic character. At physiological pH of the aqueous environment like the GI tract, the ammonium ion is in equilibrium with un-ionized ammonia, according to the following equation:

NH4⁺+ H2O <--> NH3 + H3O⁺.

Ammonia is normally present in all tissues constituting a metabolic pool. Its distribution is pH dependent, since NH3 diffuses more easily than NH4+ ions. In general, NH4+ ions are considered to be less significant toxic compared to the non-ionized form ammonia. Rapid distribution occurs by systemic circulation to the intra- and extracellular water of different tissues.

The primary route of excretion is through the kidneys because of the high water solubility the small molecular weight and the ionisation of the substance.

Due to the fast excretion bioaccumulation is not to be assumed. Ammonium like lithium is not metabolised to any appreciable extent in the human body. In conclusion, ammonium in human body is quickly distributed and unchanged excreted. Thus, bioaccumulation can be excluded.

Description of key information

Lithium amide reacts heavily with water and dissociates in water into lithium ions and ammonium ions. Both ions are distributed throughout the body and are mainly excreted unchanged via the kidneys. Due to the fast excretion, bioaccumulation is not to be assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No experimental data on absorption, distribution and excretion are available for lithium amide. Therefore, the toxicokinetics assessment is based on the physicochemical properties of the substance and existing toxicological data.

The test substance is a white to gray odourless powder at room temperature with a molecular weight of 22.96 g/mol. The test substance heavily reacts with water forming lithium hydroxide and ammonia. A log Pow of 0.23 and a BCF value of 3.162 L/kg were estimated via QSAR calculation. Based on the high melting point the test substance is assumed to have a very low vapour pressure.

 

Lithium amide reacts heavily with aqueous media forming corrosive lithium hydroxide and ammonia. Due to this fact no ADME study data with lithium amide is available. Thus, the toxicokinetic assessment of lithium amide focuses mainly on lithium since ammonium is naturally distributed in minerals and soil. Both, lithium and ammonium ions are ubiquitous in the environment, but lithium is the toxicological relevant moiety of the assessed substance.

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 a 70 kg adult (in the USA) 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 a 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 numerous numbers of publications on lithium pharmacokinetics and toxicity in humans.

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 22.96 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is very likely (ECHA, 2014). Furthermore the compound is highly hydrophilic (log Pow = 0.23) and its degradation products are water soluble.

Readily soluble ammonium or lithium salts are assumed to be completely and rapidly absorbed. The absorption process occurs via passive diffusion from the stomach or the intestine. The rate of absorption is most likely related to the gastric acidity. Ions that are not absorbed in the stomach will be rapidly absorbed in the small intestine.

Considering the low vapour pressure of lithium amide and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. If inhaled, the high water solubility of the compound would lead to complete absorption of particles in the mucus lining of the respiratory tract. The extent of absorption via inhalation is further enhanced by the corrosive character of the test substance when in contact with water. Therefore complete absorption after inhalation is highly likely.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 22.96 g/mol a dermal uptake is highly favoured. Furthermore the high water solubility of the test substance supports a moderate to high dermal absorption. But dermal penetration is confined by the high hydrophilicity together with the log Pow below 1. The poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. When in contact with the skin moisture the dermal penetration will be increased by the skin corrosion. These pre-requisites lead to the conclusion that the test substance is bioavailable when placed in contact to the skin.

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 ions 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 an 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 falls 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.

Ammonium

After absorption, distribution of the ammonium ion throughout the body is expected based on their relatively low molecular weight. No accumulation in the body is anticipated based on its hydrophilic character. At physiological pH of the aqueous environment like the GI tract, the ammonium ion is in equilibrium with un-ionized ammonia, according to the following equation:

NH4⁺+ H2O <--> NH3 + H3O⁺.

Ammonia is normally present in all tissues constituting a metabolic pool. Its distribution is pH dependent, since NH3 diffuses more easily than NH4+ ions. In general, NH4+ ions are considered to be less significant toxic compared to the non-ionized form ammonia. Rapid distribution occurs by systemic circulation to the intra- and extracellular water of different tissues.

The primary route of excretion is through the kidneys because of the high water solubility the small molecular weight and the ionisation of the substance.

Due to the fast excretion bioaccumulation is not to be assumed. Ammonium like lithium is not metabolised to any appreciable extent in the human body. In conclusion, ammonium in human body is quickly distributed and unchanged excreted. Thus, bioaccumulation can be excluded.

References

ECHA (2014) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Marquardt H., Schäfer S. (2004) Toxicology. Academic Press, San Diego, USA, 2nd Edition.

http://www.bipolarworld.net/Medications/Mood%20Stabilizers/meds6.htm

WHO (1986). Environmental Health Criteria 54. Ammonia.Published under the joint sponsorship of the United Nations, Environment Programme, the International Labour Organisation and the World Health Organization.