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Toxicological information

Repeated dose toxicity: oral

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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

Referenceopen allclose all

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 Type:
other: publication citing the above mentioned study
Title:
Unnamed
Year:
2002
Report date:
2002
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

Constituent 1
Chemical structure
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

open allclose all
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
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
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.