Lithium salicylate

Endpoint summary

Description of key information

Acute Toxicity - Oral LD50 550 mg/kg bw for rat (OECD TG 425), (Read-across from Dilithium Salicylate)

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:

key study

Reason / purpose for cross-reference:

read-across source

Preliminary study:

Initially, a single female Sprague Dawley rat was dosed orally by syringe and dosing needle at a dose level of 2000 mg/kg. Since the animal died, additional animals were dosed, one at a time, by a single ordered dose progression.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

550 mg/kg bw

Based on:

test mat.

95% CL:

> 209.7 - < 1 220

Mortality:

All three female rats died within approximately 4 hours following the single 2000 mg/kg bw oral dose. Two out of four female rats died by Day 1 following a single 550 mg/kg bw oral dose. Both female rats survived following a single 175 mg/kg bw oral dose.

Clinical signs:

other: At 2000 mg/kg bw abnormal physical signs included soiling and wetness of the anogenital area, ataxia, piloerection, prostration, lethargy, hunched posture, wetness of the nose/mouth area, and yellow diarrhea.

Gross pathology:

The gross necropsy of females receiving a single oral dose of 2000 mg/kg bw revealed darker than normal liver, and abnormalities of the gastrointestinal tract. Gross necropsy of the females that died following single oral dose of 550 mg/kg bw revealed abnormalities of the gastrointestinal tract, pale areas and darker than normal liver, darker than normal lungs, dark areas on the pancreas, and dark areas on the left kidney. The gross necropsy of the two surviving females following a single oral dose of 550 mg/kg bw revealed no observable abnormalities. The gross necropsy revealed no observable abnormalities in either female receiving a single oral dose of 175 mg/kg bw.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 for Lithium Salicylate was determined by read-across to Dilithium Salicylate and following oral intubation was established at 550 mg/kg bw for females. As the read-across is considered valid, this finding warrants classification of Lithium Salicylate as an acute oral toxicant Category 4 under the Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

Executive summary:

The Acute oral toxicity of Lithium Salicylate was determined by read-across to Dilithium Salicylate. This read-across approach is based on the hypothesis that the hydrolysis of the dilithium salt of salicylic acid where the carboxylic acid and hydroxyl group are present in the meta-isomer position would show similar biodegradation and toxicity patterns to the monolithium salt. The effect of the target substance (monolithium salt) is predicted based on the worst case approach as complete dissociation into Salicylic acid and lithium hydroxide is expected with the source substance liberating two lithium ions. Dilithium Salicylate was administered via oral intubation to Sprague-Dawley rats in an Up and Down ordered progression at doses of 2000, 550, and 175 mg/kg to assess the acute oral toxicity. Animals were observed daily for 14 days post dosing. Overt signs of toxicity were apparent at a dose level of 2000 mg/kg and mortality was observed in all three females within 4 hours of dosing. The incidence of death was considered dose related. All animals which survived to study termination were free of abnormalities at postmortem examination (two females at the 550 mg/kg bw dose level, and 2 at the 175 mg/kg bw dose level). All surviving animals displayed increases in body weight over their day 0 values. The LD50 for Dilithium Salicylate based on this data was established at 550 mg/kg bw for females. As the read-across is considered valid, this finding warrants classification of Lithium Salicylate as an acute oral toxicant Category 4 under the Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 Jul 2017 - 26 Dec 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

yes

Specific details on test material used for the study:

Source: ExxonMobil Research & Engineering (Paulsboro, NJ)
Lot # 17-24168
Expiration Date: 20 March 2019

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Raleigh NC and Stone Ridge NY
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 188 - 261 grams
- Fasting period before study: 16 - 20 hours
- Housing: Individually housed in suspended wire-bottom cages. Absorbent paper bedding was placed beneath the cages and changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMI Rat Chow (Diet No. 5012)
- Water (e.g. ad libitum): Tap water, ad-libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Range during study duration: 18.38 to 22.38
- Humidity (%): Range during study duration: 20.3 to 89.7%. While the humidity intermittently exceeded 70%, the fluctuations occurred gradually, during which time the temperature remained relatively consistent and within range.
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From 30 Aug 2017 To: 20 Oct 2017

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Distilled

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 500 mg/mL
- Amount of vehicle (if gavage): Dose volume was based on fasted body weight of each animal, and the dry weight of the test article.
- Justification for choice of vehicle: Per OECD TG 425 with respect toformulation of the dosing preparations, the use of an aqeous solution is recommended wherever possible; substance was soluble in vehicle throughout duration of test.
- Expiration Date: 21 Jul 2018
- Purity: Filtered through 5-micron mesh system

Doses:

Initially, a single female Sprague Dawley rat was dosed orally by syringe and dosing needle at a dose level of 2000 mg/kg. Since the animal died, additional animals were dosed, one at a time, by a single ordered dose progression (factor 3.2). This resulted in doses of 175, 550 and 2000 mg/kg bodyweight

No. of animals per sex per dose:

2000 mg/kg bw: 3 females; 550 mg/kg bw: 4 females, 175 mg/kg bw: 2 females

Control animals:

no

Details on study design:

Initially, a single female Sprague Dawley rat was dosed orally by syringe and dosing needle at a dose level of 2000 mg/kg. Since the animal died, additional animals were dosed, one at a time, by a single ordered dose progression.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at 15 minutes, 1, 2 and 4 hours post-dosing and once daily thereafter for 14 days for toxicity and pharmacological effects. Animals were observed twice daily for mortality on Day 1 to Day 14, with the exception of Animals 3 and 8 which were only observed once on study day 5. Body weights were recorded pre-test, weekly, and at death or termination in the survivors.
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical observations included, but were not limited to, evaluation of skin and fur, eyes and mucous membranes, respiratory and circulatory effects, autonomic effects such as salivation, central nervous system effects including tremors and convulsions, changes in the level of activity, gait and posture, reactivity to handling or sensory stimuli, altered strength, and stereotypies or bizarre behavior (e.g., self-mutilation, walking backwards).

Statistics:

The LD50 and 95% Confidence Limits were calculated according using AOT425 StatPgm provided by the U.S. EPA.

Preliminary study:

Initially, a single female Sprague Dawley rat was dosed orally by syringe and dosing needle at a dose level of 2000 mg/kg. Since the animal died, additional animals were dosed, one at a time, by a single ordered dose progression.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

550 mg/kg bw

Based on:

test mat.

95% CL:

> 209.7 - < 1 220

Mortality:

All three female rats died within approximately 4 hours following the single 2000 mg/kg bw oral dose. Two out of four female rats died by Day 1 following a single 550 mg/kg bw oral dose. Both female rats survived following a single 175 mg/kg bw oral dose.

Clinical signs:

other: At 2000 mg/kg bw abnormal physical signs included soiling and wetness of the anogenital area, ataxia, piloerection, prostration, lethargy, hunched posture, wetness of the nose/mouth area, and yellow diarrhea. At 550 mg/kg bw, abnormal physical signs inc

Gross pathology:

The gross necropsy of females receiving a single oral dose of 2000 mg/kg bw revealed darker than normal liver, and abnormalities of the gastrointestinal tract. Gross necropsy of the females that died folloing single oral dose of 550 mg/kg bw revealed abnormalities of the gastrointestinal tract, pale areas and darker than normal liver, darker than normal lungs, dark areas on the pancreas, and dark areas on the left kidney. The gross necropsy of the two surviving females following a single oral dose of 550 mg/kg bw revealed no observable abnormalities. The gross necropsy revealed no observable abnormalities in either female receiving a single oral dose of 175 mg/kg bw.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 for Dilithium Salicylate following oral intubation was established at 550 mg/kg bw for females. This finding warrants classification of Dilithium Salicylate as an acute oral toxicant Category 4 under the Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

Executive summary:

Dilithium Salicylate was administered via oral intubation to Sprague-Dawley rats in an Up and Down ordered progression at doses of 2000, 550, and 175 mg/kg to assess the acute oral toxicity. Animals were observed daily for 14 days post dosing. Overt signs of toxicity were apparent at a dose level of 2000 mg/kg and mortality was observed in all three females within 4 hours of dosing. The incidence of death was considered dose related. All animals which survived to study termination were free of abnormalities at postmortem examination (two females at the 550 mg/kg bw dose level, and 2 at the 175 mg/kg bw dose level). All surviving animals displayed increases in body weight over their day 0 values. The LD50 for Dilithium Salicylate based on this data was established at 550 mg/kg bw for females. This finding warrants classification of Dilithium Salicylate as an acute oral toxicant Category 4 under the Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

550 mg/kg bw

Quality of whole database:

It is a reliable study with a klimisch score of 1

Additional information

In the key study (MB Research Laboratories), female rats were administered single oral doses of Dilithium Salicylate at 2000, 550, and 175 mg/kg bw according to OECD test guideline 425 and observed for 14 days. Mortality was observed in all females treated with 2000 mg/kg bw. An LD50 value of 550 mg/kg bw was established.

Justification for classification or non-classification

The Acute oral toxicity of Lithium Salicylate was determined by read-across to Dilithium Salicylate. This read-across approach is based on the hypothesis that the hydrolysis of the dilithium salt of salicylic acid where the carboxylic acid and hydroxyl group are present in the meta-isomer position would show similar biodegradation and toxicity patterns to the monolithium salt. The effect of the target substance (monolithium salt) is predicted based on the worst case approach as complete dissociation into Salicylic acid and lithium hydroxide is expected with the source substance liberating two lithium ions. Dilithium Salicylate is slightly toxic via ingestion where the LD50 is 550 mg/kg bw. As the read-across is considered valid, this finding warrants classification of Lithium Salicylate as an acute oral toxicant Category 4 under the Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).