Registration Dossier

Based on human data a NOAEL for long-term oral toxicity of 1.09 mg lithium bromide/kg bw/ day was calculated. Performance of repeated dermal and inhalation toxicity studies were waived. For CSA requirements NOAEL for long-term dermal toxicity and NOAEC for long-term inhalation toxicity were calculated based on the NOAEL long-term oral value. A NOAEL value of 10.9 mg/kg bw/day was calculated for long-term dermal toxicity and a NOAEC value of 3.8 mg/m³ was calculated for long-term inhalation toxicity (worker) as detailed in IUCLID section 7 "Toxicological information".

Reference

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)

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

not specified

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.

Key result

Critical effects observed:

not specified

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.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1.09 mg/kg bw/day

Study duration:

chronic

Species:

other: human

Reference

Endpoint:: sub-chronic toxicity: inhalation
Data waiving:: study scientifically not necessary / other information available
Justification for data waiving:: a sub-chronic toxicity study (90 days) does not need to be conducted because a reliable chronic toxicity study is available, conducted with an appropriate species and route of administration
Justification for type of information:: Additional testing by the inhalation route is not required as data on repeated dose oral/systemic toxicity was provided. According to the REACH Regulation (EC) No 1907/2006, Annex VIII, 8.6.1 only one repeated dose toxicity study is required with administration via the most appropriate route. Moreover, the vapour pressure of lithium bromide is negligible due to the high melting point (see IUCLID section 4.2). Toxicity after repeated inhalation exposure was extrapolated from systemic doses from studies with repeated oral administration according to the guidance document.
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Dose descriptor:

NOAEC

3.8 mg/m³

Study duration:

chronic

Endpoint conclusion:

no study available

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Data waiving:: other justification
Justification for data waiving:: other:
Critical effects observed:: not specified

Endpoint conclusion:

no study available

Dose descriptor:

NOAEL

10.9 mg/kg bw/day

Study duration:

chronic

Endpoint conclusion:

no study available

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.

Human data

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. of 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 mmol 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/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.

Animal data (WoE)

Results of a combined repeated dose and reproductive/developmental toxicity screening test in rats (OECD test guideline 422) with the test substance lithium bromide (55.6 % purity) were available. In the study, 13 males and 13 females were administered with the test substance in concentrations of 0 (vehicle - water), 5, 20, 80 mg/kg bw/day) by gavage for 42 days to males and to females from 14 days before mating to day 4 of lactation.

A NOEL value of 5 mg/kg bw/day in both sexes was determined for repeated dose toxicity of lithium bromide, based, in males on reduction in urine specific gravity, changes in urinal and plasma creatinine concentrations and reduction in relative renal weight to the body weight in the 20 mg/kg and more-treated groups. In females, reduction in plasma concentrations of albumin were evident in these groups. A NOEL value of 5 mg/kg bw/day for reproductive/developmental toxicity was determined in both sexes of animals, and 80 mg/kg/day for the offspring. No NOAEL value was determined.

Due to the priority that reliable human data have on animal data, the NOAEL value based on human data was considered for hazard and risk assessment.

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on repeated dose toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.