Lithium bromide

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

Statement on chronic exposure

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993, 2002, 2007, 2012, 2013

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference 1

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2013

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 3

Reference Type:

review article or handbook

Title:

Manual of clinical psychopharmacology

Author:

Schatzberg, A.F.; Cole, O.J., DeBattista, C.

Year:

2007

Bibliographic source:

American Psychiatric Publishing. ISBN 158562317

Reference 4

Reference Type:

review article or handbook

Title:

Toxicology: the basic science of poisons

Author:

Casarett, L.; Klassen, C.D; Curtis, D.

Year:

2007

Bibliographic source:

ISBN-10: 0-07-147051-4

Reference 5

Reference Type:

review article or handbook

Title:

Physiological Parameters on Laboratory animals and humans

Author:

Davis, B; Morris, T.

Year:

1993

Bibliographic source:

Pharm. res. 10: 1093

Reference 6

Reference Type:

publication

Title:

Bromide in the Natural Environment: Occurrence and Toxicity

Author:

Flury, M; Papritz, A

Year:

1993

Bibliographic source:

J. Environ. Qual. 22: 747-758

Reference 7

Reference Type:

other: database

Title:

Sodium bromide

Author:

GESTIS - database on hazardous substances

Year:

2013

Bibliographic source:

http://gestis.itrust.de/nxt/gateway.dll/gestis_de/n/002900.xml?f=templat...

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

not specified

Test material

Test material information

Constituent 1

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

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

1.09 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEL value was based on the ADI value of bromide (human data) and calculated for lithium bromide based on the molecular weight.

Target system / organ toxicity

Key result

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The long-term oral (human) lithium bromide NOAEL was based on the ADI value of bromide rather than the long-term oral (human) NOAEL/ DNEL determined for lithium. Thus, long-term oral NOAEL of lithium bromide was based on the worst-case/ toxicological limiting value and was calculated to be 1.089 mg lithium bromide/ kg bw/day (rounded to 1.09 mg/kg bw/day).

Executive summary:

No NOAEL/ DNEL/ ADI value is available for lithium bromide. Nevertheless, NOAEL/ DNEL/ ADI values from human data are available for lithium and for bromide (see below). Thereof, a NOAEL value based on human data could be derived and calculated for lithium bromide as detailed below.

Deduced NOAEL/ DNEL value for lithium

In humans, lithium has been used for decades in psychiatric therapy for the treatment of bipolar disorder. In case of long-term treatment, the recommended dose is 450 to 900 mg/day lithium carbonate, equivalent to 84 to 169 mg lithium / day, and corresponding to a desired sustained therapeutic serum concentration of 0.5 to 1.0 mmol lithium/L. Based on experience with long-term application e.g. lithium carbonate for therapy in humans, there is no evidence that lithium is of concern with respect to repeated oral toxicity at medical doses as the ones indicated above.

The effect level (NOAEL) determined for lithium for repeated dose toxicity by the oral route is based on human data and can be calculated in two ways that complete one another:

One option is based on the therapeutic serum concentrations of 0.5 to 1.0 mmol lithium/L and the extracellular fluid (ECF) volume. Lithium has a large volume of distribution of 0.6-0.9 L/kg (42 L – 63 L for a 70 kg adult). It is distributed throughout the body water both extra and intracellularly. Lithium shifts into the intracellular compartments of cells because of its large volume of distribution. Although in long-term use, the intracellular concentration increases, the intracellular concentration is not reflected by the plasma level which measures only the extracellular fluid concentration. Therefore, a desired concentration of 1 mmol/L of lithium is expected to be sustained and reflected in the extracellular fluid (ECF) only and not in the intracellular fluid. Thus, the volume considered is of the ECF only which comprises of plasma, interstitial fluid (spaces between cells) and transcellular fluid (lymph, cerebrospinal fluid, synovial fluid, serous fluid, gastrointestinal secretions) and is typically 15 L (reported in different references to be between 14 – 19 L (for 70 kg adult)). Based on this data the derived NOAEL (considering a lithium concentration of 1mmol/L and an ECF volume of 15 L) is 1.5 mg/kg bw/day. This NOAEL value can be considered as a conservative value as it is based on an bioavailable dose in humans after absorption and on a smaller volume than its actual distribution volume.

Another way to calculate NOAEL oral for lithium is based as well on data taken from the routine long-term treatment of bipolar disorder. Instead of calculating the NOAEL from the therapeutic serum concentration of lithium, the lithium NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 84 to 169 mg lithium / day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses (84 to 169 mg lithium / day) to 70 kg, the following values are obtained respectively: 1.2 to 2.4 mg/kg bw/day or when dividing to 60 kg the following values are obtained respectively: 1.4 to 2.8 mg/kg bw/day, representing the optional NOAEL values for lithium for the oral route.

In both ways of calculation, the values obtained are in same order of magnitude and similar to one another. As a worst–case value, a NOAEL repeated dose toxicity oral of 1.2 mg lithium/kg bw was chosen. Further, this value could be used as a starting value for route-to-route extrapolation in calculation of the repeated dose toxicity for the dermal and inhalation routes. As no assessment factors are expected to be applied (no allometric, exposure duration, intra/interspecies, data quality factors are required), the NOAEL value of 1.2 mg/kg bw/day could be considered as the DNEL value.

Deduced NOAEL/ DNEL value for bromide

According to the FAO/WHO (1969, 1988) an ADI value (comparable to DNEL) of 1.0 mg Br-/kg bw/day was determined.

Derived NOAEL value for lithium bromide

As detailed above, for calculation of the NOAEL long-term oral of lithium bromide the following (human) data was available: the NOAEL/DNEL of lithium (1.2 mg lithium/kg bw/day) and the (smaller) ADI value (comparable to DNEL) of bromide (1.0 mg nitrate/kg bw/day). Additionally, the molecular weights of lithium, bromide and lithium bromide were considered.

The calculated NOAEL oral of lithium bromide (1.086 mg lithium bromide/kg bw/day) based on the ADI of bromide is smaller than the calculated NOAEL of lithium bromide (15.01 mg lithium bromide/kg bw/day) based on the NOAEL/ DNEL of lithium. Thus, the determined NOAEL oral of lithium bromide is 1.086 mg lithium bromide/kg bw/day (rounded to 1.09 mg lithium bromide/kg bw/day) based on the ADI value of bromide being the toxicological limiting value for lithium bromide.