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Description of key information

Repeated dose toxcity: Oral

Repeated dose oral toxicity study was performed to determine the toxic nature of sodium salt of salicylic acid. The test chemical was dissolved in saline at dose level of 0 or 300 mg/kg/day and fed by the oral intubation route of exposure fr 7 days to male albino rats. The rats were killed 1 hrs after the last of 7 daily adminiistrations. The animals were observed for clinical chemistry parameters including liver and plasma lipids and triglyceride and free fatty acid.No change in plasma FFA levels was observed 90 minutes after the last of 7 daily administrations of salicylate. Similarly, liver and plasma triglyceride levels of salicylate-treated animals were comparable to those of the saline-treated control group. Based on the observations made, no observed adverse effect level (NOAEL) for male rats is considered to be 300 mg/Kg/day when they were treated orally and repeatedly for 7 days with sodium salicylate.

Repeated dose toxicity: Inhalation

The test substance has very low vapor pressure, so the potential for the generation of inhalable forms is low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Sodium salicylate (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Repeated dose oral toxicity study was performed to determine the toxic nature of sodium salt of salicylic acid
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material :sodium salicylate
- Molecular formula : C7H6O3.Na
- Molecular weight : 160.1035 g/mol
- Substance type: organic
- Physical state: solid
- Smilies notation: c1(c(cccc1)O)C(=O)[O-].[Na+]
- Inchi: 1S/C7H6O3.Na/c8-6-4-2-1-3-5(6)7(9)10;/h1-4,8H,(H,9,10);/q;+1/p-1
Species:
rat
Strain:
other: Albino
Details on species / strain selection:
No data
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Holtzman Company, Madison, Wisconsin.
- Age at study initiation: No data
- Weight at study initiation: 160-200 g
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): Ground laboratory diet
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data
Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
physiological saline
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in saline at dose level of 0 or 300 mg/Kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Saline
- Concentration in vehicle: 0 or 300 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
7 days
Frequency of treatment:
Daily
Remarks:
0 or 300 mg/Kg/day
No. of animals per sex per dose:
Total: 11
0 mg/kg/day: 5 males
300 mg/Kg/day: 6 males
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 7 days treatment
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. Plasma free fatty acid levels and liver and plasma triglyceride levels were determined.

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: 16 hrs prior to termination
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, liver weight was measured
HISTOPATHOLOGY: No data
Other examinations:
No data
Statistics:
No data
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No change in plasma FFA levels was observed 90 minutes after the last of 7 daily administrations of salicylate. Similarly, liver and plasma triglyceride levels of salicylate-treated animals were comparable to those of the saline-treated control group.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Liver weight was unaffected was
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant effects were noted at the mentioned dose level
Critical effects observed:
not specified

Table: Effect Of Seven Successive Daily Oral Doses Of 300 Mg/Kg Of Salicylic Acid (As Sodium Salicylite) On Plasma Free Fatty Acids And Liver And Plasma Triglyceride Concentrations

Treatment

No. of rats

Liver weight (%)

Triglyceride concentration

Plasma FFA (µeq/L)

Liver (mg/g)

Plasma (mg/100 mL)

Control

5

3.64 ± 0.10

8.8 ± 1.3

28 ± 1

463 ± 62

Saline

6

385 ± 0.12

10.6 ± 1.0

26 ± 4

316 ± 33

 

Conclusions:
The no observed adverse effect level (NOAEL) for male rats is considered to be 300 mg/Kg/day when they were treated orally and repeatedly for 7 days with sodium salicylate.
Executive summary:

Repeated dose oral toxicity study was performed to determine the toxic nature of sodium salt of salicylic acid. The test chemical was dissolved in saline at dose level of 0 or 300 mg/kg/day and fed by the oral intubation route of exposure fr 7 days to male albino rats. The rats were killed 1 hrs after the last of 7 daily administrations. The animals were observed for clinical chemistry parameters including liver and plasma lipids and triglyceride and free fatty acid. No change in plasma FFA levels was observed 90 minutes after the last of 7 daily administrations of salicylate. Similarly, liver and plasma triglyceride levels of salicylate-treated animals were comparable to those of the saline-treated control group. Based on the observations made, no observed adverse effect level (NOAEL) for male rats is considered to be 300 mg/Kg/day when they were treated orally and repeatedly for 7 days with sodium salicylate.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from K2 publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxcity: Oral

Data available for the target chemical was reviewed to determine the toxic nature of Sodium salicylate. The studies are as mentioned below:

Repeated dose oral toxicity study was performed by Wooles et al (Toxicology And Applied Pharmacology, 1967) to determine the toxic nature of sodium salt of salicylic acid. The test chemical was dissolved in saline at dose level of 0 or 300 mg/kg/day and fed by the oral intubation route of exposure fr 7 days to male albino rats. The rats were killed 1 hrs after the last of 7 daily adminiistrations. The animals were observed for clinical chemistry parameters includingliver and plasma lipids and triglyceride and free fatty acid.No change in plasma FFA levels was observed 90 minutes after the last of 7 daily administrations of salicylate. Similarly, liver and plasma triglyceride levels of salicylate-treated animals were comparable to those of the saline-treated control group. Based on the observations made, no observed adverse effect level (NOAEL) for male rats is considered to be 300 mg/Kg/day when they were treated orally and repeatedly for 7 days with sodium salicylate.

In another study performed by Barbour and Fisk (Journal of Applied and Pharmaceutical therapuetics, 1933), subchronic repeated dose oral toxcity study was conducted to evaluate the toxic effects of repeated administration of sodium salicylate to rats orally. Twenty-three rats were given 0, 400, 500 or 600 mg/kg/day sodium salicylate by gavage on a daily basis for 49 days. The animals were weighed weekly and subjected to histopathologic examination. Pathologic changes were produced in the livers and kidneys in rats after administration of various doses 400-600 mg/kg/day) of sodium salicylate as necrosis. Based on the observations made, the Low observed Adverse Effect level (LOAEL) for sodium salicylate is considered to be 400 mg/Kg/day.

In the same study by Barbour and Fisk, subacute repeated dose oral toxicity study was also conducted to evaluate the toxic effects of repeated oral administration of sodium salicylate to dogs. Four dogs were administered 0 or 300 mg/kg/day of sodium salicylate by gavage on a daily basis for 2 weeks. The animals were observed for clinical sliver function test was performed usingthe Rosenthal bromsulphalein dye excretion test. The animals were subjected to gross pathology and histopatholgy. 3 Dogs passed through a short period of anorexia. The dogs remained active with excellent appetites during the course of the experiment. Microscopic examination of the livers of these dogs revealed widespread vacuolization, but only moderate degrees of necrosis, limited to the centers of the lobules. On the other hand, the kidneys in all dogs showed widespread necrosis and degeneration of the tubules, the glomeruli only being left intact. In general sodium salicylate produced more marked changes in the kidneys than in the livers.Sodium salicylate are capable of inducing damage in the parenchyma of both liver and kidneys. Based on these considerations, The Low observed Adverse Effect level (LOAEL) for sodium salicylate is considered to be 300 mg/Kg/day upon repeated exposure to dogs.

In the same study by Wooles et al (Toxicology And Applied Pharmacology, 1967), repeated dose oral toxicity study was performed to determine the toxic nature of sodium salt of salicylic acid. The test chemical was dissolved in saline at dose level of 0 or 300 mg/kg/day and fed by the oral intubation route of exposure fr 7 days to male albino rats. The animals were observed for clinical chemistry parameters includingliver and plasma lipids and cholesterol, triglyceride and free fatty acid. The animals were necropsied and the liver weight was measured.Liver triglyceride concentration of rats fed the control diet was not affected by prolonged salicylate administration. However, an 84% increase in plasma triglyceride concentration was observed in the salicylate-treated group fed the control diet. Prolonged salicylate administration produced a mean 20% increase in liver weight. Based on the observations made, low observed adverse effect level (LOAEL) for male rats is considered to be 300 mg/Kg/day when they were treated orally and repeatedly for 7 days with sodium salicylate.

Repeated dose toxicity: Inhalation

The test substance has very low vapor pressure, so the potential for the generation of inhalable forms is low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Sodium salicylate (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Based on the above studies it can be concluded that the substance sodium salicylate does not exhibits repeated dose toxicity by the oral route, inhalation and dermal route. Some of the oral route studies summarized indicates the toxic effect of the test chemical at higher dose levels used. However, the daily use level of soduim salicylate is very low. Considering this, the test chemical is not toxic at low dose levels below 300 mg/Kg/day. Based on these considerations, Sodium salicylate is considered to be not toxic at low dose levels of use.

Justification for classification or non-classification

Based on the above studies it can be concluded that the substance sodium salicylate does not exhibits repeated dose toxicity by the oral route, inhalation and dermal route. Some of the oral route studies summarized indicates the toxic effect of the test chemical at higher dose levels used. However, the daily use level of sodium salicylate is very low. Considering this and based on the latest study summarized, the test chemical is not toxic at low dose levels below 300 mg/Kg/day. Based on these considerations, Sodium salicylate is considered to be not toxic at low dose levels of use.