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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement.

Test material

Constituent 1
Chemical structure
Reference substance name:
Lithium bromide
EC Number:
231-439-8
EC Name:
Lithium bromide
Cas Number:
7550-35-8
Molecular formula:
BrLi
IUPAC Name:
lithium bromide

Results and discussion

Applicant's summary and conclusion

Conclusions:
Lithium bromide dissociates completely in water/ body fluids into lithium ions and bromide ions. Both ions are distributed throughout the body and are mainly excreted unchanged via the kidneys. Bioaccumulation can be excluded for both ions due to their hydrophilic characteristics and additionally, for lithium ions, due to the fast excretion.
Executive summary:

Toxicokinetic Assessment of lithium bromide

Lithium bromide dissociates in water thereby Li and Br ions are formed.

LiBr (aq) <-> Li+ + Br-

Lithium bromide occurs as a crystalline salt with a molecular weight of 86.845 g/mol. The ratio of distribution in organic (lipid) and aqueous matrices (octanol / water partition coefficient (log Pow)) could not be determined (LiBr is an inorganic substance) and was therefore calculated/ estimated to -0.37 (25°C) which is expectedly very low. The vapour pressure of lithium bromide was estimated to be very low (solid substance) and the water solubility is very high (166.5 g/100 mL (20°C)).

Dermal absorption

Upon contact with the skin, a compound penetrates into the dead keratinocytes (stratum corneum) and may subsequently reach the viable epidermis, the dermis and the vascular network. During the absorption process, the compound may be subject to biotransformation. 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 physico-chemical characteristics of LiBr together with the known barrier function of the stratum corneum against the respective ions, dermal absorption can practically be excluded. Indeed, lithium bromide is a skin irritant (it is known to be a hygroscopic substance), thus, possible damage to the skin surface may occur and enhance penetration. Nevertheless, such situations can be excluded using non-irritating concentrations, short exposure time or gloves. Lithium bromide is available only to worker in industrial use with applied RMM.

Moreover, LD50 value of > 2000 mg/kg bw obtained in an acute dermal study with lithium bromide support the conclusion of a very limited absorption of lithium bromide through the skin. On the other hand lithium bromide has been identified as a skin sensitizer. Thus, some uptake must have occurred although it is supposed to be a very small fraction of the applied dose.

Regarding lithium ion, a study showed no significant elevation of lithium serum in 53 healthy volunteers spending 20 minutes/day, 4 days/week for two consecutive weeks in a spa with a concentration of approximately 40 ppm (mg/L) lithium (generated from lithium hypochlorite) as compared with unexposed controls. Thus, the authors concluded that absorption of lithium through the skin is considered to be very poor.

In conclusion, the absorption of lithium bromide through the skin is considered to be very poor in case of solutions (not-irritating) and in case of the substance in its solid form (hygroscopic, irritating) when RMM are applied. Thus, upon dermal contact, the bioavailability of lithium bromide is expected to be very low. For DNEL derivation, 10 % absorption was used representing a worst case.

Resorption after oral uptake

Upon oral uptake, lithium bromide will reach the stomach in form of lithium ion and bromide ion. Lithium ions will be readily and almost completely absorbed from the gastrointestinal tract with peak plasma level occurring within 1 – 4 hours after administration. As with the lithium ions, bromide ions are also readily and completely absorbed from the gastrointestinal tract. Because Br- and Cl- compete for reabsorption, the half-life time of Br- in the organism is relatively long (12 days in humans).

Resorption after inhalation

The vapour pressure of lithium bromide is negligible and therefore exposure to vapour is toxicologically not relevant. If lithium and bromide ions reach the lung they may be absorbed via the lung tissue but resorption after inhalation is assumed to be low due to the very low log Pow. Thus, upon inhalation, the bioavailability of lithium bromide, its respective ions, 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 cations as K+, Na+. Lithium ions are presumed to interfere with processes that Na+ and K+ ions are involved in such as renal tubular transport and ion channels (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).

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 CSF (Cerebrospinal Fluid) 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 re-absorption. Lithium is excreted primarily in urine, less than 1 % is 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. Only trace amounts can still be found 1 to 2 weeks after the ingestion of a single lithium dose. Thus, a single oral dose of lithium ion is excreted almost unchanged through the kidneys.

Renal lithium clearance is under ordinary circumstances remarkably constant in the same individual but decreases with age or when sodium intake is lowered.

In conclusion, 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.

Bromide ion:

After complete absorption in the gastrointestinal tract, Br- distribution in the extracellular fluid includes penetration of the blood brain barrier. Bromide ion concentration in the cerebrospinal fluid are about 30 % of those in blood, and are strongly influenced by the body´s chloride intake and metabolism as bromide and chloride are always present in body fluids in steady state at levels dependent upon intake.

The fact that Br- and Cl- compete for reabsorption influences the half-life time of Br- in the organism. The normal half-life time, 12 days in humans, may be considerably increased if the diet is deficient in salt.

Bromide ion is readily excreted by the kidney and increased chloride intake will increase the excretion of bromide while the partial reabsorption in the kidneys is in competition with Cl-.

In conclusion: Although the half-life time of bromide is relatively long, bromide (as an ion) is hydrophilic and will not bioaccumulate in fat tissue, therefore, bioaccumulation of bromide is not assumed. Bromide is not metabolised to any appreciable extent in the human body.

In conclusion, bromide (as lithium) is quickly distributed and unchanged excreted in the human body. Bioaccumulation can be excluded.