Lithium carbonate

Endpoint summary

Description of key information

Based on human data obtained from long–term routine treatment of bipolar disorder with lithium carbonate, a NOAEL for long-term oral toxicity of 6.43 mg lithium carbonate/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 value used for long-term oral toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

repeated dose toxicity: oral

Remarks:

other: statement on chronic exposure

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993, 2002, 2007, 2012

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:

6.43 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: In humans.

Critical effects observed:

not specified

Conclusions:

Based on human data obtained from routine long-term treatment of bipolar disorder with lithium, a NOAEL for long-term oral toxicity of 6.43 mg lithium carbonate/kg bw/ day was calculated.

Executive summary:

In humans, lithium/ lithium carbonate 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 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 carbonate 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 lithium/kg bw/day equivalent to 7.98 mg lithium carbonate/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 carbonate 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 carbonate NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmole lithium/L in blood/serum). When dividing the oral doses 450 to 900 mg lithium carbonate/day to 70 kg, the following values are obtained respectively: 6.43 to 12.86 mg lithium carbonate/ kg bw/day or when dividing to 60 kg the following values are obtained respectively: 7.5 to 15 mg lithium carbonate/kg bw/day, representing the optional NOAEL values for lithium carbonate 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 6.43 mg/kg bw/day 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.

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1958, 1995, 2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Principles of method if other than guideline:

No data

GLP compliance:

not specified

Remarks:

study was published in 1958

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight:
females: 140 - 180 g
males: 200 - 270 g

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

10-12 g/0.1 kg/bw /day

Duration of treatment / exposure:

up to 2 years

Frequency of treatment:

continuously

Dose / conc.:

20 other: mEq/L

Dose / conc.:

30 other: mEq/L

Dose / conc.:

50 other: mEq/L

No. of animals per sex per dose:

not indicated

Description (incidence and severity):

The daily water intake was 0.010 - 0.012 kg / 0.1 kg bw.

Key result

Dose descriptor:

NOAEL

Effect level:

13.9 mg/kg bw/day (nominal)

Based on:

other: conversion LiCl -> Li

Sex:

male

Basis for effect level:

other: Result refers to lithium

Dose descriptor:

NOAEL

Effect level:

74 mg/kg bw/day (nominal)

Based on:

other: conversion Li -> Li2CO3

Sex:

male

Basis for effect level:

other: Result refers to lithium carbonate

Key result

Critical effects observed:

no

Dose level 20 mmol lithium chloride / L:

This dose was just subtoxic; apart from slight initial disturbances, it caused no effects on health or behaviour in the adult animals over a period of up to two years.

Plasma levels: 1.5 - 2 mmol lithium

Dose level 50 mmol lithium chloride / L:

The animals appeared to be unchanged in aspect and behaviour for 3 to 5 days. Then they became progressively drowsy and asocial. They were difficult to rouse; when roused, their gait was staggering and hesitant and they rested again as soon as possible. When resting they showed fine muscular tremor and trembling; usually they sat for long periods by themselves anywhere in the box. A few days later they became unresponsive and were stuporous, with dull eyes and slightly erected, untidy and unkempt fur. They were visibly ill and emaciated. Death occurred within 2 to 3 weeks.

Plasma levels: 3 (behavioural changes) - 8 (death) mmol lithium

Conclusions:

In a 2-year study in rats ingesting drinking water containing lithium chloride in a concentration of 20 mmol no effects on health or behaviour were found, except slight, transitory initial disturbances. When a concentration of 50 mmol LiCl/L was administered, food and water intake was decreased within a few days, and the rats became progressively drowsy and asocial on the 3rd to 5th day. Their gait was staggering, and they had a fine muscular tremor. Simultaneously their weight began to drop. The deterioration progressed to stupor and death within 2-3 weeks.
Plasma levels at dose level 20 mmol/L: 1.5 - 2 mmol
Lithium Plasma levels at dose level 50 mmol/L: 3 (behavioural changes) - 8 (death) mmol lithium.

The lithium concentration of 20 mmol/L used in this chronic drinking water study, is comparable to the highest doses given temporarily to hospitalised patients (plasma lithium level about 2 mmol/L).

The daily water intake was 0.010 - 0.012 kg / 0.1 kg bw.
For worst case considerations, the daily lithium intake in rat is 2.0 mmol/kg bw/day which is equivalent to 13.881 lithium mg/kg bw/ day.
Thus, a worst case NO(A)EL of 13.9 mg lithium/kg bw/ day can be derived.

Executive summary:

In a 2-year study in rats ingesting drinking water containing lithium chloride in a concentration of 20 mmol no effects on health or behaviour were found, except slight, transitory initial disturbances. When a concentration of 50 mmol LiCl/L was administered, food and water intake was decreased within a few days, and the rats became progressively drowsy and asocial on the 3rd to 5th day. Their gait was staggering, and they had a fine muscular tremor. Simultaneously their weight began to drop. The deterioration progressed to stupor and death within 2-3 weeks.

Plasma levels at dose level 20 mmol/L: 1.5 - 2 mmol

Lithium Plasma levels at dose level 50 mmol/L: 3 (behavioural changes) - 8 (death) mmol Lithium.

Based on the result, a worst case NOAEL of 2.0 mmol/kg bw/day, respectively, 13.9 Lithium mg/kg bw/ day can be derived.

Reference 3

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only two dose groups, Just one sex (uncommon strain) investigated, limited number of parameters investigated in comparison to standard requirements, missing comparison to historical control data

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study was designed to define lithium treatment conditions without toxic-side effects in mice and to look for the effects of the drug on the stress proteins/chaperones expression. In order to reach lithium levels within the common therapeutic values, mice (24 males per dose group) were chronically administered with lithium for 6 months. The animals were devided in three groups: a control group receiving normal food pellets and two lithium-treated groups, a group given food pellets containing 1 g lithium carbonate/kg and a group given food pellets containing 2 g lithium carbonate/kg.

GLP compliance:

no

Remarks:

GLP was not indicated in the published data.

Limit test:

no

Species:

mouse

Strain:

other: Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10 months old
- Weight at study initiation: about 32 g
- Diet: fed on 15% proteins food pellets (SICO, Sfax, Tunesia)
- Water: Tap water, ad libitum

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Dose / conc.:

0 other: g Li2CO3/kg

Dose / conc.:

1 other: g Li2CO3/kg

Dose / conc.:

2 other: g Li2CO3/kg

No. of animals per sex per dose:

24 males

Control animals:

yes, concurrent no treatment

Sacrifice and pathology:

After 1, 3 and 6 months, 8 animals from each group were sacrificed by rapid decapitation. Blood was collected without anticoagulant, centrifuged (2000g) and the collected serum was used for the determination of lithium, creatinine and urea concentrations. Kidneys and liver were removed and stored at -80 °C.

Other examinations:

The following biochemical parameters were determined:
- Serum lithium concentrations
- Serum creatinine concentration
- Lipid peroxidation level
- Catalase (CAT) activity
- Total (Cu-Zn and Mn) superoxide-dismutase (SOD) activity
- Glutathione-peroxidase (GPX) activity

Statistics:

Statistical significance was assessed by Student’s t-test. p≤0.05 was considered statistically significant.

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male

Remarks on result:

not measured/tested

Key result

Critical effects observed:

not specified

Lithium serum concentration:

A dose-dependant increase of serum lithium concentration in mice was determined. The serum lithium concentrations increased rapidly during the first month and more slowly thereafter. The lithium concentrations were in the range of therapeutic values in humans after 6 months of treatment (1 g Li2CO3/kg: 0.51 mmol/L; 2 g Li2CO3/kg: 0.87 mmol/L).

Creatinine and urea concentrations in serum:

In the lithium-treated mice no significant changes of these markers were detected in comparison to the controls.

Level of lipid peroxidation and antioxidant enzymes activity in kidney and liver

No significant change in lipid peroxidation levels, expressed as TBARS concentrations, in liver and kidney of lithium-treated mice were observed. And no significant variation in activities of CAT, SOD, and GPX was oberserved during the lithium-treatment with exception of CAT activity which was increased in kidney of the 1 g Li2CO3/kg dose group after 1 month.

Effect of lithium on stress proteins:

Although the expression level of the constitutive HSP73 was not significantly modified, HSP72 was found to be down-regulated in kidney after 1 month. In liver, three protein bands were immunodetected by the anti-GRP94 antibody: 98 kDa and 96 kDa proteins corresponding to more or less glycosylated forms and/or phosphorylated forms of GRP94 and a 80 kDa protein probably being a cleavage product of GRP94. The 96 kDa and 80 kDa proteins were significantly up-regulated in liver of lithium-treated mice as compared to controls.

Executive summary:

This study was designed to define lithium treatment conditions without toxic-side effects in mice and to look for the effects of the drug on the stress proteins/chaperones expression. In order to reach lithium levels within the common therapeutic values, mice (24 males per dose group) were chronically administered with lithium for 6 months. The animals were devided in three groups: a control group receiving normal food pellets and two lithium-treated groups, a group given food pellets containing 1 g lithium carbonate/kg and a group given food pellets containing 2 g lithium carbonate/kg. After 6 months of treatment the litihum serum concentrations reached 0.51 and 0.87 mmol/L in the 1 g and 2 g lithium carbonate/kg dose group, respectively. No clinical side effects were observed.

The authors concluded, that under these experimental conditions the lithium treatment in mice resulted in serum concentrations that did not lead to significant renal insufficiency or oxidative stress.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

6.43 mg/kg bw/day

Study duration:

chronic

Species:

other: human

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Species:

other: human

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

 Repeated oral toxicity

In humans, lithium/lithium carbonate 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 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 carbonate 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 lithium/kg bw/day equivalent to 7.98 mg lithium carbonate/kg bw/day. This NOAEL value can be considered as a conservative value as it is based on a bioavailable dose in humans after absorption and on a smaller volume than its actual distribution volume.

Another way to calculate NOAEL oral for lithium carbonate 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 carbonate NOAEL oral can be calculated from the administered oral dose for long-term treatment of bipolar disorder as detailed above: 450 to 900 mg lithium carbonate/day (corresponding to the desired sustained concentrations of 0.5 -1 mmol lithium/L in blood/serum). When dividing the oral doses 450 to 900 mg lithium carbonate/day to 70 kg, the following values are obtained respectively: 6.43 to 12.86 mg lithium carbonate/ kg bw/day or when dividing to 60 kg the following values are obtained respectively: 7.5 to 15 mg lithium carbonate/kg bw/day, representing the optional NOAEL values for lithium carbonate 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 6.43 mg/kg bw/day 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.

Another weight of evidence study was performed in mice (Nciri et al., 2010). This study was designed to define lithium treatment conditions without toxic-side effects in mice and to look for the effects of the drug on the stress proteins/chaperones expression. In order to reach lithium levels within the common therapeutic values, mice (24 males per dose group) were chronically administered with lithium for 6 months. The animals were divided in three groups: a control group receiving normal food pellets and two lithium-treated groups, a group given food pellets containing 1 g lithium carbonate/kg and a group given food pellets containing 2 g lithium carbonate/kg. After 6 months of treatment the litihum serum concentrations reached 0.51 and 0.87 mmol/L in the 1 g and 2 g lithium carbonate/kg dose group, respectively. No clinical side effects were observed. The authors concluded, that under these experimental conditions the lithium treatment in mice resulted in serum concentrations that did not lead to significant renal insufficiency or oxidative stress. This result also fits with the therapeutic serum concentrations of lithium in humans between 0.5 and 1 mmol/L.

 

In another weight of evidence publication (Trautner, 1958), a 2-year study in rat administered with lithium chloride in drinking water resulted in a NOAEL of 13.9 mg lithium/kg bw/day. This result is higher than the human NOAEL derived (1.2 mg lithium/kg bw/day) for the lithium cation. Furthermore only limited parameters (food and water intake, body weight, clinical signs) were investigated regarding repeated dose toxicity in this publication. Giving preference to the toxicological relevant ion moiety (Li), to human data and the age of the Trautner publication, the NOAEL value determined from human data (1.2 mg lithium/kg bw/day corresponding to 6.43 mg lithium carbonate/kg bw/day) was taken in to account for risk assessment.

In addition, eight other publications (performed in rats and rabbits) were included in the evaluation for repeated dose toxicity, but were rated with a reliability of 3 due to major methodological deficiencies and therefore considered as disregarded. A list of the publications is summarised below:

 

Study Guideline/GLP Species/Strain	Substance Exposure Duration Dose level Subject number	Results NOAEL	Remarks	Reliability	Reference
Rat
Subchronic repeated dose toxicity study on three parameters of rat sperm Similar to OECD 408/no GLP Rat/Wistar (males only)	Lithium carbonate oral (gavage) 48 days 0, 10, 20, 30 mg/kg bw/d 6 animals per dose group	The study sperm parameters included percentage of sperm motility, total sperm count, and determining percentage of normal and abnormal sperms, and diagnosing the type of abnormality. ↓ sperm motility, normal sperms, and total sperm count ↓ LH, FSH and testosterone ↓ relative organ weight testicles ↓ cell count (primary spermatocytes, spermatid, spermatozoa, Sertoli, Leydig)   No NOAEL reported.	Not reliable; No data on plasma levels and on systemic toxicity	RL 3	Toghyani et al., 2013; Toghiani et al., 2012
Repeated dose Toxicity Study Similar to OECD 408/no GLP Rat, Albino (males only)	Lithium carbonate Oral (flour pellets) 2, 6, 12 weeks 0, 20 mg/kg/d 15 animals per dose group	The study concludes that acute and chronic ingestion of lithium carbonate at therapeutic level is detrimental to the survival of Purkinje cerebellar neuron and patients who are prescribed lithium carbonate should be monitored carefully. No NOAEL deduction possible (single dose)	Not reliable, only one dose group, No data on plasma levels and on systemic toxicity; insufficient No. of animals	RL 3	Kohari et al., 2016
Subacute repeated dose toxicity study Similar to OECD 407/no GLP Rat, Wistar (males only)	Lithium carbonate oral (feed) 28 days 0, 2 g lithium carbonate/kg diet 12 animals per dose group	↑Serum creatinine; urea concentration ↓urea excretion Alteration of renal function   No NOAEL deduction possible (single dose)	Not reliable only one dose group; No data on systemic toxicity	RL 3	Nciri, 2012
Subchronic repeated dose toxicity study Similar to OECD 408/no GLP Rat, Albino (sex not indicated)	Lithium carbonate Oral (flour pellets) Up to 12 weeks 0, 30 mg/kg bw/d 15 animals (control), 45 animals (dose group)	Five rats from control group and 15 rats from drug treated group were sacrificed at intervals of four, eight and twelve weeks. Main effects on heart are: Degenerative changes in cardiomyocytes leading to necrosis and finally fibrosis, sub-endocardial and intramuscular hemorrhages and chronic inflammation leading to myocarditis.   No NOAEL deduction possible (single dose)	Only one dose group (however human therapeutic dose of 600-2400 mg/d was converted); No data on plasma levels; Insufficient number of control animals (15 instead of 20)	RL 3	Bhat et al, 2015
Subacute repeated dose toxicity study Similar to OECD 407/no GLP Rat, Wistar (males only)	Lithium carbonate Oral (drinking water) 30 days 0.1, 0.2 % 8 animals per dose group	The erythrocyte osmotic fragility and the levels of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured in blood samples. At 0.2 %: ↑ TSH, ↓ T3, T4 ↑ max. osmotic fragility limit ↑ MDA, ↓ GSH   At 0.1 %: ↑ max. osmotic fragility limit   No NOAEL determined.	Not reliable; No data on plasma levels, No data on systemic toxicity; insufficient number of animals and dose groups	RL 3	Toplan et al., 2013
Subacute repeated dose toxicity study Similar to OECD 407/no GLP Rat, Wistar (males only)	Lithium carbonate Oral (drinking water) 30 days 0.1, 0.2 % 8 animals per dose group	Lithium concentrations, levels of malondialdehyde (MDA) and glutathione (GSH) and superoxide dismutase (SOD) activities were measured in considered tissues. Histomorphological study was also performed on liver and kidney tissues.   At 0.2 %: ↑ MDA, ↓ GSH ↑ SOD in kidney and liver tissue   At 0.1 %: ↑ MDA, ↓ GSH ↑ SOD in kidney tissue No alteration of liver tissue   In histologic sections of both experimental liver and kidney tissues, specific degenerations were observed.   No NOAEL determined.	Not reliable; No data on plasma levels (only lithium levels in kidney and liver), No data on systemic toxicity; insufficient number of animals and dose groups	RL 3	Toplan et al., 2015
Subchronic Repeated dose Toxicity Study Similar to OECD 408/no GLP Rat, Albino (males only)	Lithium carbonate Oral (drinking water) 2, 6, 12 weeks 0, 20 mg/kg/d 15 animals per dose group	Liver and respective blood parameters (ALP, AST) were determined.   ↑ absolute and relative liver weight ↓ ALP	Not reliable, only one dose group, No data on plasma levels and on systemic toxicity; insufficient No. of animals	RL 3	Bhutto et al., 2018
Rabbit
Subacute repeated dose Toxicity Study Similar to OECD 407/no GLP Rabbit, Albino (males only)	Lithium carbonate (purity not given) oral (capsule) 4 weeks 0, 34.2 mg/kg bw/d 15 animals per dose group	Sudden withdrawal of lithium after 4 weeks of treatment led to Cholangitis (60%) and hepatitis (40%) in both withdrawal groups. It is suggested that once started, lithium therapy may be withdrawn gradually. No NOAEL deduction possible (single dose)	Not reliable, only one dose group; insufficient No. of animals	RL 3	Sharif et al., 2011
RL = reliability, ↑ = increase, ↓ decrease, µM = micromolar

 

The majority of the studies included only one dose group. One publication used two dose groups for assessment. All studies used an insufficient number of animals and only checked a very limited number of parameters. A few studies did not even provide the plasma or serum concentration of lithium. No information on systemic effects was given in parts of the study and in all cases no NOAEL was identified.

 

Repeated dermal toxicity

Due to the chemical properties of lithium carbonate, the dermal absorption is considered to be very poor and therefore a dermal toxicity study with repeated dosing is not required and was waived. For CSA requirements a NOAEL for long-term dermal exposure was calculated. A NOAEL dermal of 64.3 mg lithium carbonate/kg bw/day was calculated based on the NOAEL long term oral of 6.43 mg lithium carbonate/kg bw/day and 10 % absorption through the skin (worst-case).

 

Repeated inhalation toxicity

Performance of a repeated dose toxicity study by inhalation route was waived in accordance with column 2 of REACH Regulation (EC) No1907/2006, Annex VIII, section 8.6.1. The vapour pressure of lithium carbonate is negligible low and therefore exposure to vapour is toxicological not relevant. By testing on particle size distribution (granulometry) inhalable particles lower 10 um were detected (see IUCLID section 4.5). Thus, if relevant, respective personal protective measurements are applied.

For CSA requirements, toxicity after inhalation exposure was scientifically sound extrapolated from studies with repeated oral administration Thus, a NOAEC value was calculated from the NOAEL value determined for long-term oral toxicity (6.43 mg lithium carbonate/m³) and was separately calculated for workers and general population, as exposure times and inhalation rates differ. The NOAEC inhalation (for worker) and the NOAEC inhalation (for general population) were determined to be 22.5 mg lithium carbonate /m³/day and 9.64 mg lithium carbonate/m³/day, respectively. The calculations are detailed in IUCLID section 7 (“Toxicological information”). 

Justification for classification or non-classification

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/specific target toxicity arising from repeated exposure, 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.