Lithium Citrate Tetrahydrate

Endpoint summary

Description of key information

Read-across with lithium carbonate:
LD50 (rat, oral): 525 mg/kg bw, corresponding to 1336 mg/kg bw for lithium citrate tetrahydrate

Read-across with nitrate:
LD50 (rat, oral): 1317 (male), 1519 (female) and 1426 (combined) mg/kg bw, corresponding to 1795 mg/kg (male), 2071 mg/kg (female), and 1944 mg/kg (combined) for lithium citrate tetrahydrate.

Read-acorss with citric acid:
LD50 (mice, oral): of 5400 mg/kg, corresponding to 7926 mg/kg bw for lithium citrate tetrahydrate.
LD50 (rat, oral): Several LD50 values for citric acid in rat are reported in the OECD SIDS Initial Assessment Report. The LD50 values ranged from 3000 mg/kg to 12000 mg/kg bw, corresponding to LD50 values between 4403 and 17613 mg/kg bw for lithium citrate tetrahydrate.

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:

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

Adequacy of study:

weight of evidence

Justification for type of information:

HYPOTHESIS FOR THE ANALOGUE APPROACH
Lithium citrate tetrahydrate highly reacts with water and dissociates forming lithium hydroxide and citric acid. Thus, lithium hydroxide and citric acid were found to be suitable candidates for read-across. (Eco)toxicological properties were extrapolated to different endpoints by using the lowest effect concentration.
For further information, please refer to the read-across justification in IUCLID, section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 944 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on LiNO3 (I99-2283, 1999); rat

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 336 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on Li2CO3 (Kiso to Rinsho); rat

Sex:

female

Dose descriptor:

LD50

Effect level:

1 839 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on Li2CO3 (Kushneva et al.); rat

Sex:

male

Dose descriptor:

LD50

Effect level:

1 628 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on Li2CO3 (Kushneva et al.); rat

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 916 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on Li2CO3 (Kushneva et al.); mouse

Sex:

not specified

Dose descriptor:

LD50

Effect level:

>= 4 403 - <= 17 613 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on citric acid (OECD SIDS 2001); rat

Sex:

not specified

Dose descriptor:

LD50

Effect level:

7 926 mg/kg bw

Based on:

other: recalculated for Li citrate tetrahydrate

Remarks on result:

other: Based on citric acid (OECD SIDS 2001); mouse

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

no

Limit test:

no

Species:

mouse

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Specied: mouse, SPF, albino, source on record
- Housing: single sex groups in macrolon cages in a climate-controlled room with environmental parameters defined and on record
- Diet: ad libitum access to NAFAG 850 complete rodent maintenance diet feed
- Water: ad libitum access to water

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test substance was dissolved in food grade tap water at such concentrations that in every group 20 mL/kg, corresponding to approx. 0.4 mL per animal, were given.

Doses:

3000, 4243, 6000, 8485 and 12000 mg/kg

No. of animals per sex per dose:

5 (60 animals in total in main study)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 10 days

Preliminary study:

Range -finding study: Performed with the following doses: 2,000, 2,828, 4,000, 5,657, 8,000 and 10,000 mg/kg; 100% mortality after 24 h in highest dose group, 50% at 8,000 mg/kg, 20% at 5,657 mg/kg and 0% in all lower dose groups.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

5 400 mg/kg bw

Based on:

test mat.

Remarks:

citric acid

95% CL:

>= 4 500 - <= 6 400

Mortality:

All mortalities occurred in the first 24 h after administration.

Main study: 5 male and 5 female mice in each treatment group were administered 3,000, 4,343, 6,000, 8,485 or 12,000 mg/kg of citric acid by gavage. The test substance was dissolved in food grade tap water at such concentrations that in every group 20 mL/kg, corresponding to approx. 0.4 mL per animal, were given. Controls were administered 0.4 mL tap water by gavage. Clinical symptoms were observed 2 h and 24 h after administration. The survivors were followed-up for 10 days after dosing, mortalities were recorded daily, then survivors were sacrificed.

Conclusions:

An LD50 of 5400 mg/kg in mice is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

no

Species:

rat

Route of administration:

oral: unspecified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 000 mg/kg bw

Based on:

test mat.

Remarks:

Citric acid

Conclusions:

An LD50 of 3000 mg/kg in rats is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

no

Species:

rat

Route of administration:

oral: unspecified

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Remarks:

citric acid

Conclusions:

An LD50 of 5000 mg/kg in rats is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

not specified

Species:

rat

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

>= 6 730 mg/kg bw

Based on:

test mat.

Remarks:

citric acid

Conclusions:

An LD50 of >= 6730 mg/kg in rats is reported in the OECD SIDS Initial Assessment Report citric acid.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

no

Species:

rat

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

12 000 mg/kg bw

Based on:

test mat.

Remarks:

citric acid

Conclusions:

An LD50 of 12000 mg/kg in rats is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 7

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: According to OECD SIDS Initial Assessment Report (2001)

Principles of method if other than guideline:

method not stated

GLP compliance:

no

Species:

rat

Key result

Sex:

not specified

Dose descriptor:

LDLo

Effect level:

7 000 mg/kg bw

Based on:

test mat.

Remarks:

Citric acid

Conclusions:

A lowest lethal dose of 7000 mg/kg in rats is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 8

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:

data from handbook or collection of data

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

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 H302 ('Harmful if swallowed') according to Regulation (EC) 1272/2008 as the LD50 per oral route in rats is in the range of 300 < LD50 <= 2000 mg/kg.

Reference 9

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:

data from handbook or collection of data

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

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:

- Category IV (300 < LD50 <= 2000 mg/kg), hazard statement H302 (harmful if swallowed), according to Regulation (EC) No 1272/2008 (CLP).

Reference 10

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:

data from handbook or collection of data

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

Sex:

female

Dose descriptor:

LD50

Effect level:

723 mg/kg bw

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 H302 ('Harmful if swallowed') according to Regulation (EC) 1272/2008 as the LD50 per oral route in rats is in the range of 300 < LD50 <= 2000 mg/kg.

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 11

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1999-03-26 to 1999-05-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

February 24th 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

January 1993

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes

Test type:

standard acute 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
- Age at study initiation: young adults
- Weight at study initiation: 207-275 g
- Fasting period before study: yes
- Housing: individually housed in stainless steel, suspended cages
- Diet: Purina Rodent Chow 5001 (pellets), ad libitum
- Water: Fresh tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-71
- Humidity (%): 50-61
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

- Amount of vehicle (if gavage):
Dosage group 2000 mg/kg, males: 1.8 - 1.9 mL
Dosage group 2000 mg/kg females: 1.7 - 1.8 mL
Dosage group 1500 mg/kg males: 1.3 - 1.4 mL
Dosage group 1500 mg/kg females: 1.3 mL
Dosage group 1000 mg/kg males: 0.94 - 1.1 mL
Dosage group 1000 mg/kg females: 0.83 - 0.90 mL

Doses:

1000, 1500, 2000 mg/kg bw

No. of animals per sex per dose:

5 animals/dose/sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 0.5, 1, 2, 3, 4, 6 h following dosing and daily thereafter for 14 days
- Necropsy of survivors performed: yes , any animal not surviving to termination were also necropsied.
- clinical signs: 0.5, 1, 2, 3, 4, 6 h following dosing and daily thereafter for 14 days
- body weight: was recorded on days 0, 7 and 14

Statistics:

The oral LD50 value and 95 % confidence limits for separate and combined sexes were calculated using a modified Logit-Linear Regression Program written by Jim Gibbons, Texas Instruments Calculator Products Division.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 317 mg/kg bw

Based on:

test mat.

95% CL:

>= 993 - <= 1 640

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 519 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 179 - <= 1 859

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 426 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 242 - <= 1 609

Mortality:

All deaths occurred within 5 days of dosing. Data is summarized below.

Clinical signs:

other: All deaths occurred within 5 days after dosing. The most significant clinical signs were twitching, rolling over in cage, recumbency, loss of muscle control, squinting eyes and tremors. All signs subsided by study day 6.

Gross pathology:

Red liquid was found in the stomach of one decedent and red liquid was found in the intestines of another decedent. Animals sacrificed at study termination on day 14 were found to be normal at necropsy.

The summarized mortality data:

Male		Female		Combined
Dosage Level (mg/kg bw)	No. dead / No. dosed	Dosage Level (mg/kg bw)	No. dead / No. dosed	Dosage Level (mg/kg bw)	No. dead / No. dosed
2000	5/5	2000	5/5	2000	10/10
1500	4/5	1500	2/5	1500	6/10
1000	0/5	1000	0/5	1000	0/10

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the results of the acute oral toxicity study of lithium nitrate a LD50 of 1317 (male), 1519 (female) and 1426 (Combined) mg/kg bw was derived.

Executive summary:

Groups of five male and female Sprague-Dawley rats were orally administered lithium nitrate by a 25 % (w/v) preparation in tap water. Observations for toxicity were conducted 0.5, 1, 2, 3, 4, and 6 hours post-dosing, and daily thereafter for fourteen days. Body weights were recorded weekly and prior to necropsy. Gross necropsies were performed on all animals. All deaths occurred within 5 days of dosing. The most significant clinical signs were twitching, rolling over in cage, recumbency, loss of muscle control, squinting eyes and tremors. All signs subsided by study day 6; surviving rats remained healthy and gained weight until study termination. Red liquid was found in the stomach of one and in the intestine of another decedent. Animals sacrificed at study termination on day 14 were found to be normal at necropsy. The LD50 values determined were 1317 mg/kg in male rats, 1519 mg/kg in female rats, and 1426 mg/kg in combined sexes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 336 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity via oral route

An acute oral toxicity study with lithium citrate tetrahydrate is not available. Consequently read-across was applied using characteristically similar compounds. A weight of evidence approach was performed with read-across data from lithium nitrate, lithium carbonate and citric acid.

 

Read-across with lithium nitrate (FMC, Albemarle, I99-2283, 1999)

The acute oral toxicity of lithium nitrate was investigated in a study according to OECD guideline 401. Groups of five male and female Sprague-Dawley rats were orally administered lithium nitrate by a 25 % (w/v) preparation in tap water. Observations for toxicity were conducted 0.5, 1, 2, 3, 4, and 6 hours post-dosing, and daily thereafter for fourteen days. Body weights were recorded weekly and prior to necropsy. Gross necropsies were performed on all animals. The LD50 values in mg/kg bw and the corresponding 95 % confidence limits are as follows: Male: 1317 (993-1640); Female: 1519 (1179-1859); Combined: 1426 (1242-1609). All deaths occurred within 5 days of dosing. The most significant clinical signs were twitching, rolling over in cage, recumbency, loss of muscle control, squinting eyes and tremors. All signs subsided by study day 6; surviving rats remained healthy and gained weight until study termination. Red liquid was found in the stomach of one and in the intestines of another decedent. Animals sacrificed at study termination on day 14 were found to be normal at necropsy. The recalculated LD50 values for lithium citrate tetrahydrate are 1795 mg/kg in male rats, 2071 mg/kg in female rats, and 1944 mg/kg in combined sexes. Based on these results the substance has to be classified as H302 'Harmful if swallowed' according to Regulation (EC) 1272/2008 as the LD50 per oral route in rats is in the range of 300 < LD50 <= 2000 mg/kg.

 

Read-across with lithium carbonate (Kiso to Rinsho 1973; Kushneva 1999)

According to Kushneva et al. (1999) an LD50 of lithium carbonate of 723 +/- 38 mg/kg bw after oral administration to female rats and LD50 of 640 +/- 30 mg/kg bw to male rats is reported. The recalculated acute oral LD50 values for lithium citrate tetrahydrate are 1839 mg/kg bw in females and 1628 mg/kg bw in males. Kiso to Rinsho (1973) reported an LD50 of lithium carbonate of 525 mg/kg bw after oral administration to rats. This value correspond to an acute oral LD50 of 1336 mg/kg bw for lithium citrate tetrahydrate. Thus, even when considering the lower study result, the substance has to be classified as H302 'Harmful if swallowed' according to Regulation (EC) 1272/2008 as the LD50 per oral route in rats is in the range of 300 < LD50 <= 2000 mg/kg.

 

Read-across with citric acid (OECD 2001)

Acute oral toxicity data for citric acid are reported in the OECD SIDS Initial Assessment Report for citric acid (2001). In mice an LD50 of 5400 mg/kg is reported for citric acid, which correspond to an LD50 of 7926 mg/kg bw for lithium citrate tetrahydrate. Several LD50 values for citric acid in rat are reported in the OECD SIDS Initial Assessment Report. The LD50 values ranged from 3000 mg/kg to 12000 mg/kg bw. The recalculated acute oral LD50 values for lithium citrate tetrahydrate in rat are between 4403 and 17613 mg/kg bw. Based on these results, a low acute toxicity by oral application in both rat and mouse is expected for lithium citrate tetrahydrate.

Conclusion:

Acute oral toxicity data are available for the read-cross substances lithium nitrate, lithium carbonate and citric acid. Since citric acid is generally recognized as safe (GRAS) direct food additive by the Food and Drug Administration (FDA) a low acute oral toxicity was expected. This assumption is supported by the available data with citric acid and it was confirmed that lithium is the relevant toxicological moiety of lithium citrate tetrahydrate. The available experimental data with the lithium salts were considered valid and the lowest LD50 of 525 mg Li2CO3/kg bw, corresponding to 1336 mg/kg bw for the target substance is chosen as key value.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008:
The available experimental test data with the read-across substances are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on acute toxicity, the test substance is classified as cat. 4, H302 (Harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.