2-Butanol, 2-methyl-, lithium salt (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Expert statement

Test material

Test material information

Constituent 1

Test animals

Details on test animals or test system and environmental conditions:

no test animals, Expert statement

Administration / exposure

Details on exposure:

no test animals, Expert statement

Duration and frequency of treatment / exposure:

no test animals, Expert statement

Doses / concentrations

Remarks:

Doses / Concentrations:
no test animals, Expert statement

No. of animals per sex per dose / concentration:

no test animals, Expert statement

Positive control reference chemical:

no test animals, Expert statement

Details on study design:

no test animals, Expert statement

Details on dosing and sampling:

no test animals, Expert statement

Statistics:

no test animals, Expert statement

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

LiOH:
Following oral uptake the Li+ cation and OH- anion dissociate in the stomach. Lithium is rapidly absorbed in the gastrointestinal tract. Blood levels peak after single doses between two to four hours and full absorption occurs in about 8 hours.
Tert-amyl alcohol:
The most likely route of exposures are via the oral route, followed by inhalation. Uptake of tert-amyl alcohol or the parent compound via the skin can be practically excluded, based on physical chemical properties. Following oral uptake, tert-amyl alcohol is partially absorbed in the GI-tract. Exposure via inhalation may lead to uptake via the lungs, however, absorption is likely to be lower than via the oral route.

Details on distribution in tissues:

LiOH:
Lithium is not protein bound and distributes throughout the body and then gradually accumulates in various tissues.
Tert-amyl alcohol:
Following uptake, distribution in the body is likely to be limited, due to the compounds low water solubility.

Details on excretion:

LiOH:
Approximately 95% of a single dose of Li+ is eliminated in the urine. From one- to two-thirds of an acute dose is excreted during a 6- to 12-hour initial phase of excretion, followed by slow excretion over the next 10 to 14 days.
Ter-amyl alcohol:
Substantial fractions of tert-amyl alcohol are excreted in urine and respired in air. The fraction of the tertiary alcohols excreted unchanged is substantially higher than those of the primary or secondary alcohols. The fraction of tert-amyl alcohol becoming bioavailable is relatively small.

Metabolite characterisation studies

Details on metabolites:

Metabolites indentified: not measured.

LiOH:
Lithium is not protein bound and not metabolised.
Ter-amyl alcohol:
Several phase I metabolic reactions, including reduction and hydrolysis reactions, catalysed by cytochrome P-450-dependent monooxygenase enzymes may occur. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolism in subsequent steps. Finally, remaining amounts of the parent compound and formed metabolites are expected to be excreted in urine or bile. Following oral administration of tert-amyl alcohol to rabbits, small amounts of conjugated glucuronic acid were found in the urine. However, dogs excreted no glucuronic acid following administration of the tertiary alcohol.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation based on study results.

Executive summary:

LTA disintegrates as soon as in contact with water. The hydrolysis reaction is spontaneous and takes place instantaneous. Thus, the toxicokinetic profile of LTA is determined by the compound's hydrolysis products LiOH and tert-amyl alcohol, respectively.
Both, LiOH and tert-amyl alcohol are of relatively low acute toxicity. For LiOH the subacute oral LOAEL was determined in rats at 9.1 mg/kg bw/day and the inhalation LOAEL at 8.0 mg/m3/4h. For tert-amyl alcohol the subchronic inhalation NOEL in mice was determined at 1000 ppm, in rats at 225 ppm and in dogs a subchronic inhalation NOAEL was estimated at 225 ppm. Subacute dermal administration of tert-amyl alcohol to rabbits revealed a NOAEL of 344 mg/kg bw/day.
Local irritation may occur, due to the alkaline properties inherent to the hydroxide anion in LiOH. Tert-amyl alcohol also revealed skin and eye irritation. Both hydrolysis products of LTA did not show sensitisation potential.
Both the hydrolysis products and the parent compound did not show genotoxic potential. Both, LiOH and tert-amyl alcohol were not mutagenic when tested in an Ames test. The parent compound LTA was shown to be not mutagenic and not clastogenic in an Ames test and an in vitro chromosome aberration test, respectively.
Of a single dose of Li+ 95 % are eliminated in the urine. 80 % of the filtered Li+ is reabsorbed by the proximal renal tubules and clearance of Li+by the kidney is about 20 % of that for creatinine, ranging between 15 and 30 ml/minute. Less than 1% of ingested Li+ leaves the human body in the faeces, and 4 % to 5 % is secreted in sweat.
For tert-amyl alcohol bioaccumulation is not likely to occur, based on structure and associated physical-chemical characteristics (logBCF = 0.5). A large fraction is excreted unchanged via urine and respiration. Once bioavailable, the substance or its metabolites are expected to be little distributed throughout the body fluids, but rapidly excreted via urine (non-conjugated forms) or via faces (high molecular weight conjugated forms). Formation of toxic tert-amyl alcohol metabolites is unlikely. No indication for either compound to bioaccumulate was found.