Lithium

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1958, 1995, 2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: publication

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

The effects of prolonged subtoxic lithium ingestion on pregnancy in rats

Author:

Trautner, E.M.; Pennychuik, P.R., Morris, R.J.H., Gershon, S., Shankley, K.H.

Year:

1958

Bibliographic source:

Austral J Exp Biol. 1958;36:305-22

Reference 2

Reference Type:

other: publication citing the above mentioned study

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 3

Reference Type:

other: review article citing the above mentioned study

Title:

An assessment of lithium using the IEHR Evaluative Process for Assessing Human Developmental and Reproductive Toxicity of Agents. IEHR Expert Scientific Committee

Author:

Moore. J.A.; and an IEHR Expert Scientific Committee

Year:

1995

Bibliographic source:

Reprod Toxicol. 1995 Mar-Apr;9(2):175-210.

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Lithium chloride

EC Number:

231-212-3

EC Name:

Lithium chloride

Cas Number:

7447-41-8

Molecular formula:

ClLi

IUPAC Name:

Lithium chloride

Test animals

Species:

rat

Strain:

other: albino Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight:
females: 0.14 kg - 0.18 kg
males: 0.2 - 0.27 kg

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

10-12 g/0.1 kg/bw /day

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

84.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Worst case NOAEL Lithium chloride intake

2

Dose descriptor:

NOAEL

Effect level:

13.9 mg/kg bw/day (nominal)

Based on:

other: Lithium content of test material

Sex:

male/female

Basis for effect level:

other: Worst case Lithium intake

3

Dose descriptor:

NOAEL

Effect level:

2 other: mmol/kg bw/day

Based on:

other: Lithium content of test material

Sex:

male/female

Basis for effect level:

other: Worst case Lithium intake

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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 lithium /kg bw/day, respectively, 13.9 mg lithium /kg bw/ day was derived.