Lithium benzoate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

10 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Assessment of Lithium ions.Lithium Benzoate will dissociate under biological conditions and assessment of toxicity needs to consider both Lithium and Benzoate ions

Data source

Reference

Reference Type:

publication

Title:

Evaluation of Sub-acute Oral Toxicity of Lithium Carbonate Microemulsion (Nano Size) on Liver and Kidney of Mice

Author:

Heibatullah Kalantari et al.

Year:

2015

Bibliographic source:

Jundishapur J Nat Pharm Prod. 2015 Feb; 10(1): e22312

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Mice were dosed orally with lithium carbonate in doses of 50, 100, and 200 mg/kg for ten consecutive days and effects to liver or kidneys examined.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Lithium carbonate

EC Number:

209-062-5

EC Name:

Lithium carbonate

Cas Number:

554-13-2

Molecular formula:

CH2O3.2Li

IUPAC Name:

dilithium carbonate

Specific details on test material used for the study:

Lithium carbonate was administered as either solution or as a micro-emulsion. The reason for examining the different forms of the substance was to assess if the physical form had any affect on bio-availabilty when administered orally for drug use. (Note : the research consluded that the different forms of the substnace had no imppact)

Test animals

Species:

mouse

Strain:

Swiss

Sex:

male

Details on test animals or test system and environmental conditions:

Male Swiss albino mice (age, 6 - 8 weeks old; weight, 25 - 30 g)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

10 days

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10 mice

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Clinical signs dailyBlood samples taken after termination

Sacrifice and pathology:

Objective of study to examine liver and kidney functions

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Blood samples were analysed for serum glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and creatinine (Cr) Administration in all doses resulted a significant increase in the levels of BUN and Serum activity of SGOT and SGPT in comparison to normal saline group (P < 0.05). Serum activity of ALP, SGOT, and SGPT and levels of BUN and Cr in ME base group were greater than those in normal saline group were. However, this difference was not significant.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Liver and kidney histopathologic findings confirmed the hepatotoxic and nephrotoxic effects of LC and LCME by demonstrating centrilobular necrosis, fatty changes (steatosis), and scattered lymphocytes infiltrate in hepatic parenchyma as well as glomerulonephritis and urinary protein deposition in kidneyAlthough clearly effects were seen, it is nnot know if these were adaptive or of toxic significance

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Some swelling of cells in liver and kidney that appeared to be treatment relatedAlthough clearly effects were seen, it is nnot know if these were adaptive or of toxic significance

Histopathological findings: neoplastic:

no effects observed

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

haematology

histopathology: non-neoplastic

2

Dose descriptor:

LOEL

Effect level:

ca. 50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/kg bw/day (nominal)

System:

haematopoietic

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

Although the authors found dose related effects on liver and kidney pathology and blood analysis showed statistical changes that appeared to be dose ralted, the effects are possibly adaptive and the highest dose level appeared to be tolerated by mice.The NOAEL is considered to be approximately 200 mg/kg/day for 10 days.

Executive summary:

Oral administration by gavage of lithium carbonate in two forms (solution and micro-emulsion) lead to effects in liver and kidneys and associated blood changes when dosed at levels of 50 - 200 mg/kg/day.

The significance of the effects was not discussed by the authors and these are considered to be adaptive changes.