Lithium carbonate

Endpoint summary

Description of key information

Acute toxicity data are available for all three ways of exposure:

LD50 (rat, oral): 525 mg/kg bw

LD50 (rat, inhalation): > 2000 mg/m³

LD50 (rabbit, dermal): > 3000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Only data from review article available.

Principles of method if other than guideline:

Only data from review article available. No guideline or method indicated.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Control animals:

not specified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

525 mg/kg bw

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

According to the review article, the LD50 of lithium carbonate is 525 mg/kg bw after oral administration to rats.

Executive summary:

According to the review article, the LD50 of lithium carbonate is 525 mg/kg bw after oral administration to rats. Thus, lithium carbonate has to be classified as cat. 4, H302 (harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Only handbook data available

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Only handbook data available. No guideline or method indicated.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

male/female

Control animals:

not specified

Preliminary study:

Not applicable

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

723 mg/kg bw

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

640 mg/kg bw

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

According to the handbook data, the LD50 of lithium carbonate is 723 +/- 38 mg/kg bw after oral administration to female rats and 640 +/- 30 mg/kg bw to male rats.

Executive summary:

According to the handbook data, the LD50 of lithium carbonate is 723 +/- 38 mg/kg bw after oral administration to female rats and 640 +/- 30 mg/kg bw to male rats. Thus, lithium carbonate has to be classified as cat 4, H302 (harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP).

Additional remark: Since lithium carbonate hydrolyses in aqueous matrices and thereby generates basic solution due to resulting lithium hydroxide and lithium hydrogen carbonate systemic effects will always be accompanied by local effects (tissue damage), causing secondary also systemic toxicity. Consequently, the toxicity noted represents a sum of local and systemic effects.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Only handbook data available

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Only handbook data available. No guideline or method indicated.

GLP compliance:

not specified

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on study design:

Not applicable

Preliminary study:

Not applicable

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

753 mg/kg bw

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

According to the handbook data, the LD50 of lithium carbonate is 753 +/- 27.5 mg/kg bw after oral administration to mice.

Executive summary:

According to the handbook data, the LD50 of lithium carbonate is 753 +/- 27.5 mg/kg bw after oral administration to mice.

This result is in line with those obtained in rat and supports the classification of lithium carbonate:

- Cat. 4, H302 (harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

525 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988-01-18 to 1988-06-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: male: 49 days; female: 55 days
- Weight at study initiation: male: 321.0 g - 242.9 g; female: 185.0 g - 199.5 g
- Housing: animals were housed individually in an elevated, stainless steel wire mesh cage
- Diet (e.g. ad libitum): ad libitum, Purina Certified Laboratory Chow
- Water (e.g. ad libitum): ad libitum, tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6 - 23.3
- Humidity (%): 43-64

- Air changes (per hr): Exposure-time: 4 hours. The chamber was operated in dynamic mode with a consistent airflow of 35.8 litres per minute (Lpm). The chamber airflow rate was measured using a calibrated Dwyer 0-40 Lpm flowmeter and was recorded every 30 minutes. These conditions gave a calculated air change of 21.5 air changes per hour an a T99 value of 12.87.

- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: plexiglass exposure chamber, which was operated in a dynamic mode
- Exposure chamber volume: 100 L

- Source and rate of air: The chamber was operated in dynamic mode with a consistent airflow of 35.8 litres per minute (Lpm). The chamber airflow rate was measured using a calibrated Dwyer 0-40 Lpm flowmeter and was recorded every 30 minutes. These conditions gave a calculated air change of 21.5 air changes per hour and a T99 value of 12.87.

- System of generating particulates/aerosols: Following 240 minutes of exposure, the generation was discontinued and clean air was passed through the exposure chamber for an additional 30 minutes to clear the test material from the chamber. Afterwards, the chamber was opened and the animals were removed.

- Method of particle size determination: Lithium carbonate dust was determined by sampling a measured volume of test atmosphere through an Andersen Cascade Impactor. The impactor stages each contained a pre-weighed glass-fiber filter designed to retain impacted particles of sequentially dimishing size. The quantity of dust collected on each filter was determined gravimetrically.

- Treatment of exhaust air: The exposure chamber air was exhaust through a HEPA filter.
- Temperature, humidity: 20.6 - 23.3 °C, 43-64 %

TEST ATMOSPHERE
- Particle size distribution: Particle size determinations were performed twice during the exposure.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMAD and GSD of the test material aerosol were estimated from a standard second order polynomial least squares fit of the logarithm for each stage constant versus the cumulative weight distribution of the experimental data.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of lithium carbonate in the exposure chamber was determined gravimetrically by collection of the dust on preweighed filters. Samples were collected at 5 Lpm for 2 minutes on a preweighted 25-mm Gelman Type A/E glass-fiber.

Duration of exposure:

4 h

Concentrations:

Gravimetric concentration: 2.17 mg/L

No. of animals per sex per dose:

5 male, 5 female

Control animals:

no

Statistics:

The MMAD and GSD of the test material aerosol were estimated from a standard second order polynomial least squares fit of the logarithm for each stage constant versus the cumulative weight distribution of the experimental data.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2 mg/L air

Mortality:

Two male animals died before the scheduled sacrifice. In addition to the typical signs, they exhibited wheezing, rough haircoat, rhinorrhea, and low body temperature (to the touch). Most animals were normal in appearance by Test Day 9 and all were normal by termination. There did not appear to be any substantive differences in the nature, or frequency of occurrence, of the abnormal observations of the surviving male animals and female animals.

Clinical signs:

other: During the exposure period, animals were observed with test compound on the fur, increased secretory responses, labored breathing, languid behaviour and squinted eyes. The signs were also exhibited at 30 and 60 minutes post-exposure. Crust on the eyelids

Body weight:

Body weight was decreased in all male animals and one female animal at Test Day 8 compared to the pre-exposure body weights. By Test Day 15, all surviving animals had gained relative to their Test Days 1 and 8 body weights.

Gross pathology:

All animals surviving to the scheduled sacrifice were normal. The finding of pale kidney in one female animal is considered sporadic in nature. In the male animals found dead, no histopathological evaluation was performed to distinguish spontaneous postmortem changes from potential treatment related lesions. Many of the lesions in these males were considered to probably be spontaneous postmortem changes. The findings of sore and alopecia on the skin of one male animal were considered sporadic in nature. On this basis, the findings at necropsy of the two male animals which died on test were not considered related to treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

Two male rats exposed to an actual concentration of 2.17 mg/L lithium carbonate died prior to termination. Their deaths were considered treatment-related. As no additional exposures were requested, the median lethal concentration (LC50) for this test substance was estimated as greater than 2 mg/L.

Executive summary:

The acute inhalation toxicity of lithium carbonate in Sprague-Dawley rats was determined according to OECD Guideline 403 and EU method B.2. Five male and five female Sprague-Dawley rats received a single 4 hour whole-body exposure to a gravimetric concentration of 2.17 mg/L lithium carbonate.

The dust was determined to be generally respirable to the rat (73.3 % of particles less than 10 um). Two male rats died as a result of treatment. Signs of treatment included test material on the fur, increased secretory responses, labored breathing, languid behaviour, squinted eyes and crust on the eyelids. The animals that died also exhibited wheezing, rough haircoat, rhinorrhea and low body temperature (to the touch). By Test Day 8 body weights in males were diminished compared to body weights immediately prior to exposure.

Based on the mortality results of this study using combined sexes, the median lethal concentration for a 4 hour exposure to lithium carbonate was estimated to be greater than 2 mg/L. As maximum attainable concentrations were applied without revealing indications for acute toxicity, lithium carbonate has not to be classified with regard to acute toxicity according to Regulation (EC) No 1272/2008 (CLP).

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1993-10-04 to 1994-02-1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

1984

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Weight at study initiation: males: 250 g ± 8.5 g; females: 244g ± 18.1 g
- Housing: animals were individually housed in stainless steel suspended rat cages
- Diet (e.g. ad libitum): ad libitum, Purina Laboratory Rodent Chow 5001
- Water (e.g. ad libitum): ad libitum, fresh tap water
- Acclimation period: animals were acclimated for a minimum of 5 days prior to study start


ENVIRONMENTAL CONDITIONS
- Temperature (degree C): 18.9 - 22.8
- Humidity (%): 40 - 69
- Air changes (per hr): the exposure was conducted for 4 hours. At the end of the exposure, the chamber was cleared for 30 minutes by drawing room air through it at the same flow rate (30.4 litres per minute) prior to removing the animals
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The Rochester type exposure chamber was made of stainless steel and glass and was operated dynamically.
- Exposure chamber volume: 150 litres
- Source and rate of air: The calculated 99 % equilibrium time for the chamber at a flow rate of 30.4 litres per minute was, therefore, 22.7 minutes (equivalent to 12.2 "air changes per hour").

- Method of holding animals in test chamber: The test animals were assigned to and housed in individual compartments of a wire mesh cage bank (all on the same horizontal level) during the exposure. The cage position assignment ensured equal distribution of both sexes throughout the cage bank.
- Method of particle size determination: The aerodynamic particle size distribution was determined by gravimetric analysis of the amount of test material collected on the impactor stages and subsequent determination of the MMAD, GSD and the percent of aerosol less than or equal to 1, 10, and 15 microns in size by logarithmic-probability plotting.

- Treatment of exhaust air: The chamber air was exhaust from the bottom of the chamber and passes through an orifice tube system which continuously monitored airflow and then through a commercial filter box.

- Temperature, humidity in air chamber: 20 °C, 75 %


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Chamber air samples were also taken twice during the exposure to determine the aerodynamic particle size distribution of airbone material. The samples were drawn through a Sierra Series 218 cascade impactor at 2.78 litres per minute.

- MMAD (Mass median aerodynamic diameter)/GSD (Geometric st. dev.): less than or equal to 1, 10, and 15 microns in size by logarithmic-probability plotting

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Concentrations:

Maximum-attainable concentration of 0.8 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Other examinations performed: clinical signs, body weight, cross necropsy

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.8 mg/L air

Mortality:

There were no deaths during the study.

Clinical signs:

other: Clinical signs noted during the exposure of animals not obscured by the test atmosphere included lacrimation, material on fur and squinting eyes. Clinical signs noted upon removal from the chamber and/or at one hour post exposure included chromodacryorrhe

Body weight:

Most animals lost weight through day 2 of the study and then began to gain weight in a normal pattern. One female also lost weight on day 7 then began to gain weight in a normal pattern. At termination all animals exhibited increases in body weight over their day 0 values.

Gross pathology:

The only finding noted during necropsy was a calculus approximately 6 mm in diameter in the bladder of one female. This observation is not considered to be treatment related.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the test material caused no mortality when administered for four hours to Sprague Dawley rats at a mean, maximum attainable chamber concentration of 0.80 mg/L. Based on this, the LC 50 for lithium carbonate is considered to be greater than 0.80 mg/L.

Executive summary:

The acute inhalation toxicity of lithium carbonate in Sprague-Dawley rats was determined according to OECD Guideline 403 and EU method B.2. A group of five male and five female Sprague-Dawley rats was exposed to lithium carbonate for 4 hours at a mean, maximum-attainable concentration of 0.80 mg/L in a dynamically-operated, whole-body inhalation exposure chamber. Gravimetric airborne test material samples were taken hourly during the exposure. Particle size samples were taken twice during the exposure. Observations for toxicity and mortality were performed frequently during the exposure, upon removal of the rats from the chamber, at one hour post-exposure and twice daily thereafter for 13 days; on day 14 observations were performed once. Individual body weights were recorded immediately prior to exposure on day 0 and on day 1, 2, 4, 7 and 14. On day 14, all animals were sacrificed and gross necropsy examinations were performed. Clinical signs noted during the study included chromodacryorrhea, decreased feces, decreased locomotion, lacrimation, nasal discharge, oral discharge and rales. Most of these signs diminished by day 2 post-exposure and all animals were normal from the day 4 observations through study termination. At termination all animals exhibited increases in body weight over their day 0 values. No treatment ralated lesions were noted during necropsy. Under the conditions of this study, the test material caused no mortality at a maximum attainable concentration of 0.80 mg/L. Based on this, the LC50 for lithium carbonate is considered to be greater than 0.80 mg/L. As maximum attainable concentrations were applied without revealing indications for acute toxicity, lithium carbonate has not to be classified regarding acute toxicity after inhalation exposure according to Regulation (EC) No 1272/2008 (CLP).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 000 mg/m³ air

Quality of whole database:

GLP and guideline compliant study.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1976-10-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

February 24th, 1987

Deviations:

yes

Remarks:

(Four rabbits per dose (two rabbits per sex) instead of five rabbits per dose were used in the study. Two instead of three dose levels were tested in the study.)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young adults
- Weight at study initiation: 2.42-2.82 kg
- Fasting period before study: no
- Housing: individullay housed in suspended, wire-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: the whole back
- % coverage: 30 % of the total body surface area
- Type of wrap if used: impervious plastic sheeting

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 24h after treatment

TEST MATERIAL
- Amount(s) applied: 2000, 3000 mg/kg bw
- Constant volume or concentration used: yes
- For solids, paste formed: yes, an aqueous slurry

VEHICLE
- water

Duration of exposure:

24 hours

Doses:

2000, 3000 mg/kg bw

No. of animals per sex per dose:

2 animals per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations for mortality, local skin reactions and behavioural abnormalities
- Necropsy of survivors performed: yes
- clinical signs: daily
- body weight: Initial, 7- and 14-day body weights were recorded

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured within the 2000 mg/kg bw testing group.
One animal of the 3000 mg/kg bw testing group died. The cause of death was not evident.

Clinical signs:

other: The test material showed no irritating properties to the skin of the albino rabbit.

Gross pathology:

Necropsy examination revealed advanced post mortem autolysis in the early died rabbit of the 3000 mg/kg bw testing group. No gross pathologic alterations were noted in any of the other rabbits.

Other findings:

No pharmacotoxic symptoms were exhibited by the rabbits following dermal exposure.

Interpretation of results:

GHS criteria not met

Conclusions:

In the acute dermal toxicity study presented an LD50 value of above 3000 mg/kg bw was determined.

Executive summary:

The acute dermal toxicity study was performed with lithium carbonate. Four male and four female New Zealand white rabbits were treated (a 24 -hour occlusive dermal application) with an aqueous lithium carbonate slurry at dose levels of 2000 mg/kg bw and 3000 mg/kg bw. One animal from the 3000 mg/kg bw testing group died under non-evident circumstances. Clinical signs or dermal symptoms were not observed during the 14 days post-treatment observation period. No effects on body weight gain were noted for these groups. Specific macroscopic alterations related to the toxic effect of lithium carbonate were not found. The acute dermal LD50 value was determined to be above 3000 mg/kg bw in male and female New Zealnd white rabbits and 2000 mg/kg bw can be determined as the discriminating dose.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1993-10-01 to 1994-04-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Version / remarks:

1984

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: Young adult
- Weight at study initiation: male: 261 g ± 4.1 g; female: 234 g ± 7.4 g
- Housing: individually housed in stainless steel suspended rat cages, wire bottom
- Diet (e.g. ad libitum): ad libitum, Purina Rodent Chow 5001 (pellets)
- Water (e.g. ad libitum): ad libitum, fresh tap water
- Acclimation period: The animals were acclimated for a minimum of 5 calender days prior to study start.


ENVIRONMENTAL CONDITIONS
- Temperature (degree C): 19 - 22.8 °C
- Humidity (%): 40 - 69
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

physiological saline

Details on dermal exposure:

TEST SITE
- Area of exposure: intact test site
- Type of wrap if used: The gauze was positioned on the intact test site and held place with hypoallergenic tape. The test site was then covered with an elastic bandage which was lined with plastic.


REMOVAL OF TEST SUBSTANCE
- Washing: The test sites were wiped with clean gauze moistened with methanol, then rinsed with tap water.
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

Doses corresponding to a dosage level of 2000 mg/kg were individually calculated based on the body weight of each animal on the day of dosing.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and clinical signs (local irritation excluded): 0.5, 1, 2, 3, 4 and 6 hours on the day of dosing and twice daily thereafter for 13 days; on day 14 the animals were observed once description of the local irritation was recorded on days 1, 3, 7 and 14 of the study, body weights: on days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, local irritation, body weight, necropsy

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths.

Clinical signs:

other: All rats remained healthy during the study.

Gross pathology:

There were no gross internal lesions observed in any animals at necropsy.

Mean Body Weights ± SD

	Day 0	Day 7	Day 14
Male	261 ± 4.1	312 ± 3.4	350 ± 5.4
Female	234 ± 7.4	254 ± 7.0	264 ± 7.2

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the LD50 is greater than 2000 mg/kg in male and female rats when topically applied.

Executive summary:

The toxic effects of lithium carbonate in Sprague-Dawley rats were investigated according to OECD Guideline 402 and EU method B.3 on acute dermal toxicity. Ten Sprague-Dawley rats (5 males and 5 females) were treated with lithium carbonate Pharmaceutical Grade (Typical Wt% = 99.7; Guaranteed Wt% = 99) at a dosage level of 2000 mg/kg. The test material was in contact with the intact skin for 24 hours under an occlusive wrap. Observations for toxicity were conducted at 0.5, 1, 2, 3, 4 and 6 hours on the day of dosing and twice daily thereafter for 13 days; on day 14 they were conducted once. A description of local irritation was recorded on day 1, 3, 7 and 14. Body weights were recorded on days 0, 7 and 14 of the study. A gross necropsy was performed on all animals. There were no deaths. All rats remained healthy and gained weight by day 14 of the study. No irritations was noted on any of the test sites. All animals appeared normal at necropsy. Under the conditions of this study, the LD50 is grater than 2000 mg/kg in male and female rats when topically applied. Therefore, lithium carbonate has not to be classified regarding acute toxicity after dermal exposure according to Regulation (EC) No 1272/2008 (CLP).

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1996-21-15 to 1996-11-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Version / remarks:

1984

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: Young adult
- Weight at study initiation: male: 266 g ± 6.4 g; female: 246 g ± 4.6 g
- Housing: individually housed in stainless steel suspended rat cages, wire bottom
- Diet (e.g. ad libitum): ad libitum, Purina Rodent Chow 5001 (pellets)
- Water (e.g. ad libitum): ad libitum, fresh tap water
- Acclimation period: The animals were acclimated for a minimum of 5 calender days prior to study start.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C - 22.2°C
- Humidity (%): 41 % - 59%
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent/ 12 hours dark

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dermal application on intact skin
- % coverage: At least 10 % of the body surface
- Type of wrap if used: A self-adhesive, elastic bandage, lined with plastic, will be wrapped around the trunk of the rat and adhered securely.


REMOVAL OF TEST SUBSTANCE
- Washing:The test material will be wiped away with a clean gauze pad moistened with tap water.
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

Doses corresponding to a dosage level of 2000 mg/kg were individually calculated based on the body weight of each animal on the day of dosing.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for toxicity: approximately 0.5, 1, 2, 3, 4 and 6 hours following dosing and daily thereafter for 14 days; body weights: on days 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, local irritation, necropsy

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths.

Clinical signs:

other: All rats remained healthy during the study.

Gross pathology:

There were no gross internal lesions observed in any animal during necropsy.

Interpretation of results:

not classified

Conclusions:

Under the conditions of this study, the LD50 is greater than 2000 mg/kg in male and female rats when topically applied.

Executive summary:

The toxic effects of lithium carbonate in Sprague-Dawley rats were investigated according to OECD Guideline 402 and EU method B.3 on acute dermal toxicity. Lithium carbonate was topically applied to five Sprague-Dawley rats/sex at a dosage level of 2000 mg/kg. The test material was in contact with the intact skin for 24 hours under an occlusive wrap. Observations for toxicity were conducted at approximately 0.5, 1, 2, 3, 4 and 6 hours following dosing and daily thereafter for 14 days. A description of local irritation was recorded on days 1, 3, 7 and 14. Body weights were recorded on days 0, 7 and 14 of the study. A gross necropsy was performed on all animals. There were no deaths. All rats remained healthy and gained weight by day 14 of the study. No irritations was noted on any of the test sites. There were no gross internal lesions noted during necropsy. Under the conditions of this study, the LD50 is grater than 2000 mg/kg in male and female rats when topically applied. Therefore, lithium carbonate has not to be classified regarding acute toxicity after dermal exposure according to Regulation (EC) No 1272/2008 (CLP).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Quality of whole database:

The study is scientifically valid, similar to an OECD guideline study and performed not as a limit test (thereby confirmed the LD50 and LD0 values).

Additional information

Acute oral toxicity

According to handbook data, the LD50 of lithium carbonate is 723 +/- 38 mg/kg bw after oral administration to female rats and 640 +/- 30 mg/kg bw to male rats and according to a review article, the LD50 of lithium carbonate is 525 mg/kg bw after oral administration to rats. Thus, even when considering the lower study result, the substance has to be classified as cat 4, H302 (harmful if swallowed) according to Regulation (EC) No 1272/2008.

Remark on key values acute toxicity for chemical safety assessment:

For risk characterisation, acute DNEL (oral route) was not assessed from the presented animal data but was derived from the long-term DNEL (oral route) which was based on human data (see IUCLID section 7: toxicological information).

Acute inhalation toxicity

It could be shown in two inhalation studies, performed with the maximal attainable concentrations of 0.80 mg/L that the LC50 is higher than 0.80 mg/L and estimated to be higher than 2 mg/L. In conclusion, the LC50 (inhalation, rat) of lithium carbonate is equal or higher than 2.0 mg/L and the substance is therefore not to be classified according to Regulation (EC) No 1272/2008 (CLP).

Remark on key values acute toxicity for chemical safety assessment:

For risk characterisation, acute DNEL (inhalation route) was not assessed from the presented animal data but was derived from the long-term DNEL (oral route) which was based on human data (see IUCLID section 7: toxicological information).

Acute dermal toxicity

A LD50 value of greater than 3000 mg/kg bw and LD0 value of 2000 mg/kg bw were determined in an acute dermal study that examined lithium carbonate in doses of 2000 mg/kg bw and 3000 mg/kg bw. In two additional acute dermal studies performed as limit tests a LD50 value of > 2000 mg/kg bw was determined. Thus, in conclusion, the LD50 (dermal rat) of lithium carbontae is greater than 3000 mg/kg bw and the substance is not to be classified according to Regulation (EC) No 1272/2008 (CLP).

Justification for classification or non-classification

Acute oral toxicity

According to the handbook data, the LD50 of lithium carbonate is 723 +/- 38 mg/kg bw after oral administration to female rats and 640 +/- 30 mg/kg bw to male rats and according to a review article the LD50 of lithium carbonate is 525 mg/kg bw after oral administration to rats.

Thus, lithium carbonate has to be classified as cat. 4, H302 (harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP).

Acute inhalation toxicity

It could be shown in two inhalation studies, performed with the maximal attainable concentrations of 0.80 mg/L that the LC50 is higher than 0.80 mg/L and estimated to be higher than 2 mg/L.

The substance is therefore not to be classified according to Regulation (EC) No 1272/2008 (CLP).

Acute dermal toxicity

The LD50 (dermal, rat) of lithium carbonate is higher than 3000 mg/kg bw and the substance is therefore not classified according to Regulation (EC) No 1272/2008 (CLP).

Additional remark: Since lithium carbonate hydrolyses in aqueous matrices and thereby generates a basic solution due to resulting lithium hydroxide and lithium hydrogen carbonate, systemic effects will always be accompanied by local effects (tissue damage), causing secondary also systemic toxicity. Consequently, the toxicity noted represents a sum of local and systemic effects.