Lithium Citrate Tetrahydrate

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to aquatic invertebrates

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

Key result

Duration:

48 h

Dose descriptor:

EC50

Remarks:

Daphnia magna

Effect conc.:

75 mg/L

Nominal / measured:

nominal

Conc. based on:

other: recalculated for Li citrate tetrahydrate

Basis for effect:

mobility

Remarks on result:

other: Based on LiOH (657652, 1997); without pH-adjustment

Duration:

48 h

Dose descriptor:

EC50

Remarks:

Daphnia magna

Effect conc.:

134.6 mg/L

Nominal / measured:

nominal

Conc. based on:

other: recalculated for Li citrate tetrahydrate

Basis for effect:

mobility

Remarks on result:

other: Based on LiOH (657652, 1997); with pH-adjustment

Duration:

24 h

Dose descriptor:

EC50

Remarks:

Daphnia magna

Effect conc.:

>= 85 - <= 1 535 mg/L

Nominal / measured:

not specified

Conc. based on:

other: recalculated for Li citrate tetrahydrate

Basis for effect:

not specified

Remarks on result:

other: Based on citric acid (OECD SIDS, 2001)

Duration:

48 h

Dose descriptor:

LC50

Remarks:

Carcinus maenas

Effect conc.:

234.8 mg/L

Nominal / measured:

not specified

Conc. based on:

other: recalculated for Li citrate tetrahydrate

Basis for effect:

not specified

Remarks on result:

other: Based on citric acid (OECD SIDS, 2001)

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1997-06-10 to 1997-07-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method C.2 (Acute Toxicity for Daphnia)

Version / remarks:

December 1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Version / remarks:

April 1984

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Analytical monitoring:

yes

Details on sampling:

- Concentrations:
nominal: 4.6; 10; 21; 46; 100 mg/L;
measured: 19.64; 43.90; 99.20 mg/L (with pH adjustment); 9.58; 19.86; 44.80 (without pH adjustment);
- Sampling method: For the analytical measurements of the test substance concentrations, duplicate samples from the freshly prepared test media of all test concentrations of both test series (with and without pH-adjustment) and the control were taken just before the start of the test.
- Sample storage conditions before analysis: All samples were deep-frozen (-20 °C) immediately after sampling. All samples are kept stored at about -20 °C to enable additional analysis.

Vehicle:

no

Details on test solutions:

- Before start of the test, two concentrated stock solutions were prepared. At each stock solution 1000 mg of test substance were dissolved in 100 mL bidistilled water, resulting in a nominal concentration of 10 g/L. At one stock solution, the pH was adjusted to pH 7.9 with 2 mol HCl, at the other stock solution the pH was not adjusted. Then, adequate volumes of both intensively stirred stock solutions were mixed into the test water to obtain the desired test concentrations. At one series of test media the pH was adjusted, at the other series not. This allowed to differentiate if a toxic effect is caused due to a pH-effect of the substance with strong basic pH, or if it is a real toxic effect of lithium (-hydroxide).
- The same five following test substance concentrations were tested in both experimental parts (with and without pH-adjustment): 4.6, 10, 21, 46 and 100 mg/L. Additionally, a control was tested in parallel (test water without addition of test substance). The test media were prepared just before introduction of Daphnia (= start of the test).

Test organisms (species):

Daphnia magna

Details on test organisms:

- The study was performed with young test animals of a clone of the species Daphnia magna Straus. The clone was originally supplied by the University of Sheffield/UK in 1992, defined from the supplier as clone 5. Since this date the clone is bred in the laboratories of RCC under similar temperature and light conditions as in the test, and in reconstituted water of similar quality regarding to pH, components of the main ions and total hardness as the test water used in the test.

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 h

Hardness:

250.0 mg/L as CaCO3

Test temperature:

20 °C

pH:

without pH-adjustment: 8.9 at 4.6 mg/L to 11.2 at 100 mg/L;
with pH-adjustment: 7.9 to 8.1 at all concentrations;

Dissolved oxygen:

without pH-adjustment: 8.5 - 8.9 mg/L;
with pH-adjustment: 8.4 - 8.8 mg/L;

Nominal and measured concentrations:

nominal: 4.6; 10; 21; 46; 100 mg/L;
measured: 19.64; 43.90; 99.20 mg/L (with pH adjustment); 9.58; 19.86; 44.80 (without pH adjustment);

Details on test conditions:

TEST SYSTEM
In each test concentration and the control, 20 Daphnia were tested, divided into two groups of ten animals, each group in 50 mL test medium in a 100-mL glass beaker. The test vessels were labelled with the RCC Project number and all necessary additional information to assure unmistakable identification. The test was performed in an air-temperated room.


TEST MEDIUM / WATER PARAMETERS
- Reconstituted water: In bidistilled water analytical grade salts were added to following nominal concentrations, and the water was aerated to oxygen saturation:
- CaCl2x2 H2O: 2.0 mmol/L (= 294.0 mg/L)
- MgSO4x7 H2O: 0.5 mmol/L (= 123.0 mg/L)
- NaHCO3: 0.75 mmol/L (= 65.0 mg/L)
- KCl: 0.075 mmol/L (= 5.8 mg/L)
- Water Hardness: 2.5 mmol/L (= 250 mg/L) as CaCO3
- Ratio of Ca:Mg = 4:1 (based on molarity)
- Ratio of Na:K = 10:1 (based on molarity)


OTHER TEST CONDITIONS
- Adjustment of pH: one stock solution to pH 7.9 with 2 mol HCl;
- Photoperiod: 16 hrs light to 8 hrs darkness;
- Light intensity: between 200 and 1200 Lux;
- The Daphnia were not feed, and the test media were not aerated during the test period;


EFFECT PARAMETERS MEASURED:
- The immobility or mortality of the Daphnia was determined by visual control after 24 and 48 hours. Those animals not able to swim within 15 seconds after gentle agitation of the test beaker were considered to be immobile.


TEST CONCENTRATIONS
- The test concentrations were based on a range-finding test. The range finding test was not performed in compliance with GLP-Regulations, but the raw data of the range-finding test will be archived under the RCC Project number of the present study.

Reference substance (positive control):

no

Key result

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

29.4 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Remarks:

LiOH anhydrous

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 25.4 to 34.0 mg/L; without pH-adjustment

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

19.1 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Remarks:

LiOH anhydrous

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 15.1 to 24.1 mg/L; without pH-adjustment

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

76.8 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Remarks:

LiOH anhydrous

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 63.6 to 92.8 mg/L; with pH-adjustment

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

34.3 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Remarks:

LiOH anhydrous

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 29.6 to 39.7 mg/L; with pH-adjustment

Details on results:

The analytically determined test substance concentrations in the analysed test media varied in the range from 93.5 % to 103.2 % of the nominal values. In the test media the test substance concentrations were constant during the test period of 48 hours. Therefore, all reported biological results are related to the nominal concentrations of the test substance.
During the test period, the dissolved oxygen concentrations in the test media were at least 8.3 mg/L or higher. The pH-value in the freshly prepared test media without pH-adjustment ranged from pH 8.9 at the test concentration of 4.6 mg/L to pH 11.2 at 100 mg/L. At the end of the test period the pH-values had decreased to pH 8.0 - 8.7. The pH-value in the test media with pH-adjustment ranged from pH 7.9 to 8.1.

Test media without pH-adjustment:
In the control and in the test media without pH-adjustment up to and including the test concentration of nominal 10 mg test substance/L no immobility or mortality of the test animals or other signs of intoxication were determined during the test period of 48 hours.
The 24-hour EC50 of the test substance was calculated to be 29.4 mg test substance/L with 95 % confidence limits from 25.4 to 34.0 mg/L. The 24-hour EC0 was 10 mg test substance/L, the 24-hour EC 100 amounted to 46 mg test substance/L.
After 48 hours of exposure the toxicity of the test substance to Daphnia magna had further increased. The 48-hour EC50 was calculated to be 19.1 mg test substance/L with 95 % confidence limits from 15.1 to 24.1 mg/L. The 24-hour EC0 and also the 48-hour NOEC (highest concentration tested without toxic effects after 48 hours) of lithium hydroxide was 10 mg test substance/L, since no significant immobilization rate and no other signs of intoxication were observed at the test animals up to and including this test concentration. The 48-hour EC100 amounted to 46 mg test substance/L.

Test media with pH-adjustment:
In the test media with pH-adjustment the toxic effect of the test substance (Note: The test substance in the experimental part with pH-adjustment is LiCl instead of LiOH due to the pH-adjustment by means of HCl. The toxic effects are caused with high possibility by the lithium-ion) was slightly lower compared to the effects without pH-adjustment. Thus a part of the toxic effect of lithium hydroxide was obviously caused due to the strong basic pH.
The 24-hour EC50 of the test substance (see above) after pH-adjustment to approximately pH 8 was calculated to be 76.8 mg/L with 95 % confidence limits from 63.6 to 92.8 mg/L. The 24-hour EC0 was 21 mg/L, the 24-hour EC100 amounted to > 100 mg/L.
The 48-hour EC50 was calculated to be 34.3 mg/L with 95 % confidence limits from 29.6 to 39.7 mg/L. The 48-hour EC0 and also the 48-hour NOEC (highest concentration tested without toxic effects after 48 hours) of the test substance after the pH-adjustment was 21 mg/L. The 48-hour EC100 amounted to 46 mg/L.
In the test media with pH-adjustment no remarkable observations were made concerning the appearance of the test substance in the test media.
In the test media without pH-adjustment a small precipitate was observed at the test concentrations of 21 and 46 mg/L at the bottom of the testbeakers at the observations after 24 and 48 hours. At 100 mg/L the freshly prepared test media were turbid, and the precipitate was observed after 24 and 48 hours at the bottom and also at the medium surface. However, as the good recoveries of the analytical results demonstrate this was not the test substance which precipitated. Thus, it was possibly a precipitate out of the test water caused by the high pH-values.

Information on results incl. tables see attached document.

Validity criteria fulfilled:

yes

Conclusions:

Lithium hydroxide (55.2 %) was tested for short term aquatic toxicity in Daphnia in an 48-hour static test according to EU Method C.2 and OECD Guideline 202. Without pH-adjustment the 48 hour EC50-value was 19.1 mg/L. With pH-adjustment the 48-hour EC50-value 34.3 mg/L for lithium hydroxide anhydrous. Based on these data, the calculated EC50 without pH-adjustment for lithium hydroxide monohydrate was 33.5 mg/L and with pH-adjustment 60.1 mg/L.

Executive summary:

The acute toxicity of the test substance lithium hydroxide (55.2 %) to Daphnia magna was determined in a 48-hour static test according to the EU method Annex Part C.2 and the OECD Guideline No. 202. The nominal concentrations tested were 4.6, 10, 21, 46 and 100 mg test substance/L, and in parallel a control. At one series of test media the pH was adjusted to approximately pH 8 by HCl, at the other series not. This allowed to differentiate if a toxic effect is caused due to a pH-effect of the test substance with a strong basic pH, or if it is a real toxic effect of lithium(-hydroxide). The analytical determined test substance concentrations in the analysed test media varied in the range from 93.5 % to 103.2 % of the nominal values. In the test media the test substance concentrations were constant during the test period of 48 hours. Therefore, all reported biological results are related to the nominal concentrations of the test substance. Without pH-adjustment the 48 hour EC50-value was 19.1 mg/L and with pH-adjustment the 48-hour EC50-value 34.3 mg/L for lithium hydroxide anhydrous. Based on these data, the calculated EC50 without pH-adjustment for lithium hydroxide monohydrate was 33.5 mg/L and with pH-adjustment 60.1 mg/L. Consequently the LC50 values of 34.3 mg/L and 60.1 mg/L represent the relevant figures for lithium hydroxide anhydrous and lithium hydroxide monohydrate, respectively. It is obvious that lithium hydroxide monohydrate was the test material (due to the indicated purity: 55.2%) but the study results and study title refer to lithium hydroxide anhydrous.

Reference 3

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

supporting study

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

Test organisms (species):

other aquatic crustacea: Carcinus maenas

Water media type:

saltwater

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

160 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Remarks:

citric acid

Basis for effect:

mortality

Conclusions:

An LC50 of 160 mg/L in the aquatic crustacea, Carcinus maenas, is reported in the OECD SIDS Initial Assessment Report for citric acid.

Reference 4

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

supporting study

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

Test organisms (species):

Daphnia magna

Duration:

24 h

Dose descriptor:

EC0

Effect conc.:

1 206 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

1 535 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC100

Effect conc.:

2 083 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC0

Effect conc.:

73 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

85 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Duration:

24 h

Dose descriptor:

EC100

Effect conc.:

98 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

not specified

Additionally to the short-term toxicity data the EC0 and EC100 of a "long-term exposure in soft water" with Daphnia magna is indicated:

EC0 = 80 mg/L

EC100 = 120 mg/L

A.N. Khomenco et al: Gidrokhim. Mater. 50: 96-101, 1969

Conclusions:

In the OECD SIDS Initial Assessment Report for citric acid several effect data with Daphnia magna are reported. The indicated EC50 values after 24 hours of exposure with citric acid range from 85 to 1535 mg/L. Based on the results citric acid appears to be of low toxicity to daphnia magna.

Description of key information

Read-across with lithium hydroxide:

Lithium hydroxide (55.2 %) was tested for short-term aquatic toxicity in Daphnia in a 48-hour static test according to EU Method C.2 and OECD Guideline 202. Without pH-adjustment the 48 hour EC50-value was 19.1 mg/L. With pH-adjustment the 48-hour EC50-value was 34.3 mg/L for lithium hydroxide anhydrous. Based on these data, the calculated EC50 without pH-adjustment for lithium citrate is 75 mg/L and with pH-adjustment 134.6 mg/L.

Read-across with citric acid:

Several effect data with Daphnia magna are indicted in the OECD SIDS Initial Assessment Report. The indicated EC50 values for Daphnia magna after 24 hours of exposure with citric acid range from 85 to 1535 mg/L. This corresponds to an EC50 range of 124.8 to 2252.9 mg/L for lithium citrate tetrahydrate.

Additionally, an LC50 for the saltwater crab Carcinus maenas of 160 mg/L is reported, which corresponds to an LC50 value of 234.8 mg/L for lithium citrate tetrahydrate.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

134.6 mg/L

Marine water invertebrates

Marine water invertebrates

Effect concentration:

234.8 mg/L

Additional information

A short-term toxicity study on aquatic invertebrates with lithium citrate tetrahydrate is not available. Consequently, read-across was applied using lithium hydroxide and citric acid.

 

Read-across with lithium hydroxide (FMC, Albemarle, 657652, 1997):

The acute toxicity of the test substance lithium hydroxide (55.2 %, i.e. test material was lithium hydroxide monohydrate but for the results the purity was considered, thus they refer to lithium hydroxide anhydrous) to Daphnia magna was determined in a 48-hour static test according to the EU method Annex Part C.2 and the OECD Guideline No. 202. The nominal concentrations tested were 4.6, 10, 21, 46 and 100 mg test substance/L, and in parallel a control. At one series of test media the pH was adjusted to approximately pH 8 by HCl, at the other series not. This allowed to differentiate if a toxic effect is caused due to a pH-effect of the test substance with a strong basic pH, or if it is a real toxic effect of lithium(-hydroxide). The analytical determined test substance concentrations in the analysed test media varied in the range from 93.5 % to 103.2 % of the nominal values. In the test media the test substance concentrations were constant during the test period of 48 hours. Therefore, all reported biological results are related to the nominal concentrations of the test substance.

Without pH-adjustment the 48 hour EC50-value was 19.1 mg/L and with pH-adjustment the 48-hour EC50-value 34.3 mg/L for lithium hydroxide anhydrous. Based on these data, the calculated EC50 without pH-adjustment for lithium citrate tetrahydrate is 75 mg/L and with pH-adjustment 134.6 mg/L. The value with pH-adjustment is the relevant value in this context (LiOH impact not relevant).

 

Read-across with citric acid (OECD SIDS 2001)

Additionally, aquatic toxicity data for citric acid are reported in the OECD SIDS Initial Assessment Report for citric acid (2001). An LC50 for the saltwater crab Carcinus maenas of 160 mg/L is reported, which corresponds to an LC50 value of 234.8 mg/L for lithium citrate tetrahydrate.

Further, several effect data with Daphnia magna are indicted in the OECD SIDS Initial Assessment Report. The indicated EC50 values for Daphnia magna after 24 hours of exposure with citric acid range from 85 to 1535 mg/L. This corresponds to an EC50 range of 124.8 to 2252.9 mg/L for lithium citrate tetrahydrate.

The low toxicity of citric acid to daphnia is further confirmed in a long-term toxicity test with daphnia magna in "soft-water", which is assumed not to buffer the acidic effect of the test substance. The EC0 was found to be 80 mg/L and the EC100 was 120 mg/L, resulting in a geometric mean EC50 of 98 mg/L.

Based on the results citric acid appears to be of low toxicity to Daphnia magna and Carcinus maenas.

 

Conclusion:

Short-term toxicity data with aquatic invertebrates are available for the read-across substances lithium hydroxide and citric acid. The magnitude of the calculated LC/EC50 values show that lithium is the relevant toxicological moiety of lithium citrate tetrahydrate with respect to acute toxicity in aquatic invertebrates. The result of the Daphnia magna acute immobilization study with lithium hydroxide is considered as valid and the EC50 of 134.6 mg/L for lithium citrate tetrahydrate is chosen as key value.