Registration Dossier

Administrative data

Description of key information

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. Under the conditions of the acute inhalation study, the 4-h LC50 for lithium nitrate solution is greater than 5.93 mg/L (discriminating concentration). Based on the findings in the acute dermal toxicity study, a single dermal administration of lithium nitrate in water did not induce any test item related adverse effects and a LD50 of >2000 mg/kg bw  (discriminating dose) could be derived.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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 (e.g. ad libitum): Purina Rodent Chow 5001 (pellets), ad libitum
- Water (e.g. ad libitum): 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:
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.
Body weight:
All survivors gained weight by day 14 of the study.
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. (FMC, 1999)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 426 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999-12-07 to 2000-02-14
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:
May 12th 1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
December 29th 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
August 1998
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 adults
- Weight at study initiation: 247-268 g
- Fasting period before study: no
- Housing: individually housed in stainless steel, suspended cages
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 (pellets), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 67-68
- Humidity (%): 52-61
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: a dynamically-operated, nose-only inhalation exposure chamber with 11 litres volume
- Method of holding animals in test chamber: housed in polycarbonate nose-only tubes during the exposure
- 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.
- Temperature, humidity, pressure in air chamber: Chamber, room air temperature and relative humidity were monitored continuously during the exposure with FMC wet/dry bulb hygrometers. Measurements were recorded at 30-minute intervals. The mean temperature and relative humidity in the chamber were 69 °F and 74 %, respectively. The mean temperature and relative humidity in the chamber room were 64 °F and 50 %, respectively.

TEST ATMOSPHERE
- Brief description of analytical method used: Chamber air samples were taken on German® Type A/E 37 mm glass fiber filters held in cassettes at approximately 40-minute intervals during the exposure to determine the airborne concentration of test material. The concentration was calculated by dividing the filter weight gain by the sample volume. The filters were then desiccated overnight and reweighed for determination of dry concentration. The dry concentration was then divided by the fraction of solids (0.32) to yield the formulation concentration.
- Samples taken from breathing zone: Yes, the samples were taken from the center of the chamber directly above the animal tube portals.

TEST ATMOSPHERE
- Particle size distribution: Chamber air samples were taken twice during the exposure to determine the aerodynamic particle size distribution of airborne test material. The samples were drawn through a Sierra® Model 218 cascade impactor at 2.82 liters per minute. The filters were then desiccated overnight and reweighed for determination of dry filter weight.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) and the percent of aerosol less than or equal to 1,10, and 15 microns in size were determined by logarithmic-probability plotting.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
formulation concentration: 5.93 mg/L
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations at fifteen-minute intervals during the first hour of exposure, hourly for the remainder of the exposure, upon removal from the chamber, at one hour post-exposure and daily thereafter for fourteen days
- Necropsy of survivors performed: yes
- body weight: once a week
Statistics:
Particle size distributions were determined by log-probability plotting of the data and subsequent determination of the mass median aerodynamic diameter, geometric standard deviation and other particle size parameters from the data plots. The LC50 and 95 % confidence limits were determined by a suitable logit or probit analysis.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.93 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There were no deaths during the study.
Clinical signs:
other: Treatment-related clinical signs noted during the study included dyspnea and lacrimation. All animals were normal on study day 1 and remained normal through study termination. Another sign noted that was attributed to animal exposure tube confinement was
Body weight:
At termination, all animals exhibited increases in body weight over their day 0 values.
Gross pathology:
There were no gross internal lesions observed in any animal at necropsy.
Other findings:
The results of the particle size distribution indicated the test material was respirable in size to the rat.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the four-hour LC50 for lithium nitrate solution was greater than 5.93 mg/L.
Executive summary:

A group of five male and five female Sprague-Dawley rats was exposed to a respirable aerosol of lithium nitrate solution (30 %). Animals were exposed for 4 hours at a mean, formulation concentration of 5.93 mg/L in a dynamically-operated, nose-only inhalation exposure chamber. Gravimetric airborne test material samples were taken frequently 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 daily thereafter for 14 days. Individual body weights were recorded immediately prior to exposure on day 0 and on days 7 and 14. On day 14, all animals were sacrificed and gross necropsy examinations were performed.

All animals survived to study termination. Treatment-related clinical signs noted during the study included dyspnea and lacrimation. All animals were normal from day 1 through study termination. All animals gained weight during the study. There were no gross internal lesions observed in any animal at necropsy.

Under the conditions of this study, the four-hour LC50 for lithium nitrate solution is greater than 5.93 mg/L. (FMC, 1999/2000)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5 930 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999-04-06 to 1999-04-20
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:
February 24th 1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
January 1993
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
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 adults
- Weight at study initiation: 247-274 g
- Fasting period before study: no
- Housing: Individually, in suspended stainless steel cages, wire bottom
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow 5001 (pellets), ad libitum
- Water (e.g. ad libitum): Domestic water supply (untreated with additional chlorine or HCl), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-67
- Humidity (%): 53-61
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: moistened with 0.5 mL of tap water.
Details on dermal exposure:
TEST SITE
- Area of exposure: scapular to the pelvic region
- Type of wrap if used: hypoallergenic tape

REMOVAL OF TEST SUBSTANCE
- Washing: rinsed with water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: depending on the body weight 0.52-0.55 g (males); 0.49-0.54 g (females)
- Concentration: 2000 mg/kg bw
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation for mortality 0.5, 1, 2, 3, 4, 6 hours after dosing and daily thereafter for 14 days
- Necropsy of survivors performed: yes
- clinical signs: observation were done 0.5, 1, 2, 3, 4, 6 hours after dosing and daily thereafter for 14 days
- body weight: was recorded on the day of dosing and again on days 7, 14
- local irritation: was recorded on days 1, 3, 7, 14
Statistics:
The dermal LD50 value and corresponding 95 % confidence limits for separate and combined sexes (if possible) were calculated using a modified Logit-Linear Regression Program written by Jim Gibbons, Texas Instruments Calculator Products Division.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths were noted.
Clinical signs:
Clinical signs noted during the study included abnormal posture, exaggerated hindlimb flexion, staggered gait, abdominogenital staining, abdominal gripping, no feces, chromodacryorrhea, decreased locomotion, diarrhea and unthriftiness. All but one rat recovered by study day 2; one male displayed signs until study day 8.
Body weight:
All rats gained weight by day 14 of the study.
Gross pathology:
No gross internal lesions were observed in any animal during necropsy.
Other findings:
Local irritation: Irritation noted included erythema of the test sites in all rats on day 1. Desquamation, erythema and eschar were noted in some animals on days 3, 7 and 14.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the findings of this study, a single dermal administration of lithium nitrate did not induce mortality as well as test item related adverse effects. A LD50 of >2000 mg/kg bw was determined.
Executive summary:

Lithium nitrate was topically applied to five Sprague-Dawley rats per sex at a dosage level of 2000 mg/kg bw. The test material was in contact with the skin under an occlusive wrap for 24 hours. Observations for toxicity were conducted 0.5, 1, 2, 3, 4, and 6 hours post-dosing, and daily thereafter for fourteen days. Dermal irritation was recorded on days 1, 3, 7 and 14. Body weights were recorded weekly. Gross necropsies were performed on all animals.

No deaths were noted. Clinical signs noted during the study included abnormal posture, exaggerated hindlimb flexion, staggered gait, abdominogenital staining, abdominal gripping, no feces, chromodacryorrhea, decreased locomotion, diarrhea and unthriftiness. All but one rat recovered by study day 2; one male displayed signs until study day 8. All rats gained weight by day 14 of the study. Irritation noted included erythema of the test sites in all rats on day 1. Desquamation, erythema and eschar were noted in some animals on days 3, 7 and 14. No gross lesions were revealed during necropsy. The LD50 determined was greater than 2000 mg/kg bw in both male and female rats. (FMC, 1999)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

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 LD50 is 1317 mg/kg in male rats, 1519 mg/kg in female rats, and 1426 mg/kg in combined sexes. (FMC, 1999)

Acute inhalation toxicity

A group of five male and five female Sprague-Dawley rats was exposed to a respirable aerosol of lithium nitrate solution. Animals were exposed for 4 hours at a mean formulation concentration of 5.93 mg/L in a dynamically-operated, nose-only inhalation exposure chamber. Gravimetric airborne test material samples were taken frequently 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 daily thereafter for 14 days. Individual body weights were recorded immediately prior to exposure on day 0 and on days 7 and 14. On day 14, all animals were sacrificed and gross necropsy examinations were performed.

All animals survived to study termination. Treatment-related clinical signs noted during the study included dyspnea and lacrimation. All animals were normal from day 1 through study termination. All animals gained weight during the study. There were no gross internal lesions observed in any animal at necropsy.

Under the conditions of this study, the 4-h LC50 for lithium nitrate solution is greater than 5.93 mg/L.(FMC, 2000)

Acute dermal toxicity

Lithium nitrate was topically applied to five Sprague-Dawley rats per sex at a dosage level of 2000 mg/kg bw. The test material was in contact with the skin under an occlusive wrap for 24 hours. Observations for toxicity were conducted 0.5, 1, 2, 3, 4, and 6 hours post-dosing, and daily thereafter for fourteen days. Dermal irritation was recorded on days 1, 3, 7 and 14. Body weights were recorded weekly. Gross necropsies were performed on all animals.

No deaths were noted. Clinical signs noted during the study included abnormal posture, exaggerated hindlimb flexion, staggered gait, abdominogenital staining, abdominal gripping, no feces, chromodacryorrhea, decreased locomotion, diarrhea and unthriftiness. All but one rat recovered by study day 2; one male displayed signs until study day 8. All rats gained weight by day 14 of the study. Irritation noted included erythema of the test sites in all rats on day 1. Desquamation, erythema and eschar were noted in some animals on days 3, 7 and 14. No gross lesions were revealed during necropsy.

The LD50 is greater than 2000 mg/kg bw for both male and female rats when topically applied. (FMC, 1999)


Justification for selection of acute toxicity – oral endpoint
GLP and guideline compliant study.

Justification for selection of acute toxicity – inhalation endpoint
GLP and guideline compliant study.

Justification for selection of acute toxicity – dermal endpoint
GLP and guideline compliant study.

Justification for classification or non-classification

Based on the results of the acute oral toxicity study lithium nitrate is classified and labelled as Xn (Harmful), R22 (Harmful if swallowed) according to Directive 67/548/EEC (DSD) and acute toxicity cat. IV (H302: Harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP).

Based on the results of the acute dermal and acute inhalation toxicity study, the test substance is not subjected to classification and labelling according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).