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EC number: 200-198-0 | CAS number: 54-21-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Repeated dose toxicity: Oral
NOAEL for the test chemical is considered to be 50 mg/kg bw/day in male and female rats following 2 years of exposure by diet.
Repeated dose toxicity: Inhalation
A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the given test chemical has very low vapor pressure 4.9E-9 Pa (3.68E-11 mmHg), so the potential for the generation of inhalable vapors is very low. 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 highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver.
Repeated dose toxicity: Dermal
A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Principles of method if other than guideline:
- The neurotoxic potential of the test chemical given by oral gavage at 0 (vehicle control), 138, 218, 346 and 550 mg/kg for 5 days per week, for 15 weeks in total, was evaluated in male rats using a battery of neurobehavioral tests.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Route of administration:
- oral: gavage
- Duration of treatment / exposure:
- 15 weeks
- Frequency of treatment:
- 5 times per week
- Remarks:
- 0, 138, 218, 346 and 550 mg/kg bw/day
- No. of animals per sex per dose:
- 9 to 10 male rats per dose level
- Control animals:
- yes
- Observations and examinations performed and frequency:
- Prior to dosing, at 3-week intervals, and at 3 and 6 weeks after cessation of dosing, the rats were subjected to a battery of neurobehavioral tests including undifferentiated motor activity, forelimb and hindlimb grip strengths, rotation orientation, thermal sensitivity, startle responsiveness to acoustic and air-puff stimuli, and performance of a multisensory conditioned pole-climb avoidance response task. Body weight and rectal temperatures were also recorded.
- Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One animal at 218 mg/kg, two animals at 346 mg/kg and one animal at 550 mg/kg died during 2 to 9 weeks of study. The deaths were not dose-related and were not directly attributed to the test chemicals.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant body weight reductions were observed at ≥218 mg/kg compared to control data.
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- After 15 weeks of dosing, the only neurobehavioral change was a dose-related decrease in hindlimb strength at ≥218 mg/kg. This effect persisted after 6 weeks of recovery.
- Neuropathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- After 15 weeks of dosing, the only neurobehavioral change was a dose-related decrease in hindlimb strength at ≥218 mg/kg. This effect persisted after 6 weeks of recovery.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 138 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- mortality
- other: Neurobehavior
- Remarks on result:
- other: not specified
- Dose descriptor:
- LOAEL
- Effect level:
- <= 218 mg/kg bw/day (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Conclusions:
- NOAEL for the test chemical was established at 138 mg/kg bw/day following five days of exposure per week, for 15 weeks in total, in male rats based on body weight changes and decrease hindlimb strength at ≥218 mg/kg
- Executive summary:
The chemical was given to 9 to 10 male rats per dose level at 0 (vehicle control), 138, 218, 346 and 550 mg/kg by oral gavage, five days per week, for a total of 15 weeks. Prior to dosing, at 3-week intervals, and at 3 and 6 weeks after cessation of dosing, the rats were subjected to a battery of neurobehavioral tests including undifferentiated motor activity, forelimb and hindlimb grip strengths, rotation orientation, thermal sensitivity, startle responsiveness to acoustic and air-puff stimuli, and performance of a multisensory conditioned pole-climb avoidance response task. Body weight and rectal temperatures were also recorded. One animal at 218 mg/kg, two animals at 346 mg/kg and one animal at 550 mg/kg died during 2 to 9 weeks of study. The deaths were not dose-related and were not directly attributed to the test chemicals. Significant body weight reductions were observed at ≥218 mg/kg compared to control data.After 15 weeks of dosing, the only neurobehavioral change was a dose-related decrease in hindlimb strength at ≥218 mg/kg. This effect persisted after 6 weeks of recovery. NOAEL for the test chemical was established at 138 mg/kg bw/day following five days of exposure per week, for 15 weeks in total, in male rats based on body weight changes and decrease hindlimb strength at ≥218 mg/kg
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Principles of method if other than guideline:
- The effects in rats following exposure to the test chemical by diet at 0, 1000, 5000, 10000 and 20000 ppm were evaluated during a dosing period of 2 years.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Osborne-Mendel
- Sex:
- male/female
- Route of administration:
- oral: feed
- Vehicle:
- not specified
- Details on oral exposure:
- The test chemical was mixed in commercial ground laboratory chow. Diets were prepared every other week and 10% additional methyl salicylate was added at the time of mixing to compensate for evaporation. Feed was available ad libitum.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Two years
- Frequency of treatment:
- Daily
- Remarks:
- 0 (plain diet), 1000, 5000, 10000 and 20000 ppm
- No. of animals per sex per dose:
- 25 (except the group treated at 20000 ppm which included 24 males and 26 females)
- Control animals:
- yes, plain diet
- Observations and examinations performed and frequency:
- Body weights were recorded weekly. Hematologic examinations were done at 3, 11, 17 and 22 months of study on 10 rats at each dose level. Hematologic parameters included white blood cell count, differential cell counts, hematocrit and hemoglobin values.
- Sacrifice and pathology:
- Rats that died were subjected to postmortem examinations. Surviving rats were sacrificed at the end of the dosing period to collect organ weights (heart, liver, kidneys, spleen, and testes) and to detect pathological changes. Tissues from 108 rats (29 at 0 ppm, 25 at 1000 ppm, 24 at 5000 ppm, 18 at 10000 ppm and 12 at 20000 ppm) were collected for gross pathology of viscera (thyroid to rectum). Of these 108 rats, 23 rats (12 at 0 ppm, 6 at 10000 ppm, and 5 at 20000 ppm) were subjected to microscopic examinations of thyroid, parathyroid, lung, heart, stomach, pancreas, spleen, liver, kidneys, adrenal, lymph node, small intestine, bone marrow smears, leg bone and muscle, urinary bladder, and testis and prostate or ovary and uterus.
- Statistics:
- No details but statistics were used to detect significant differences.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Visually, rats treated at 10000 and 20000 ppm had rough hair coats.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- All rats treated at 20000 ppm died within 50 weeks of treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The group of rats treated at 20000 ppm showed a drastic growth inhibition compared to the control group. At 10000 ppm, a marked decrease in mean terminal body weight (by approx. 20%) was observed compared to control data. No significant body weight effects were observed at 1000 or 5000 ppm.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No significant effects on hematology were reported.
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant absolute/relative organ weight changes were reported at 10000 ppm, but not at 1000 or 5000 ppm.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Gross lesions were more common at 5000 and 20000 ppm as compared to controls. Notably, gross pituitary lesions were more commonly observed at 5000 ppm (10 of 24 rats) than at 0 ppm (4 of 29 rats). Pneumonia was evident in 29 of 50 rats treated at 20000 ppm. Other gross lesions were common to all groups except the group of rats treated at 20000 ppm due to early deaths, presumably.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Microscopically, an increased prevalence of cancellous bone mass was observed at ≥5000 ppm compared to control data. This effect was “moderate” or “marked” in animals treated at 20000 ppm and “slight” in animals treated at 5000 and 10000 ppm. The number of osteoclasts were fewer in the affected bones, with the numbers being proportional to the magnitude of change.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no tumors attributed to the test chemical.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- <= 5 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- histopathology: non-neoplastic
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Conclusions:
- NOAEL for the test chemical was established at 1000 ppm (by conversion, approx. 50 mg/kg bw/day) following two years of dietary exposure in male and female rats.
- Executive summary:
The chemical was given to 25 rats per sex per dose level, by diet, at 0 (control diet), 1000, 5000, 10000 and 20000 ppm for two years. Body weights were recorded weekly. Hematologic examinations were done at 3, 11, 17 and 22 months of study on 10 rats at each dose level. Hematologic parameters included white blood cell count, differential cell counts, hematocrit and hemoglobin values. Rats that died were subjected to postmortem examinations. Surviving rats were sacrificed at the end of the dosing period to collect organ weights (heart, liver, kidneys, spleen, and testes) and to detect pathological changes. Tissues from 108 rats (29 at 0 ppm, 25 at 1000 ppm, 24 at 5000 ppm, 18 at 10000 ppm and 12 at 20000 ppm) were collected for gross pathology of viscera (thyroid to rectum). Of these 108 rats, 23 rats (12 at 0 ppm, 6 at 10000 ppm, and 5 at 20000 ppm) were subjected to microscopic examinations of thyroid, parathyroid, lung, heart, stomach, pancreas, spleen, liver, kidneys, adrenal, lymph node, small intestine, bone marrow smears, leg bone and muscle, urinary bladder, and testis and prostate or ovary and uterus. The group of rats treated at 20000 ppm showed a drastic growth inhibition compared to the control group, and none of the high-dosed rats survived longer than 50 weeks of study. At 10000 ppm, a marked decrease in mean terminal body weight (by approx. 20%) was observed compared to control data. No significant body weight effects were observed at 1000 or 5000 ppm. Visually, rats treated at 10000 and 20000 ppm had rough hair coats. No significant effects on hematology were reported. Significant absolute/relative organ weight changes were reported at 10000 ppm, but not at 1000 or 5000 ppm. Gross lesions were more common at 5000 and 20000 ppm as compared to controls. Notably, gross pituitary lesions were more commonly observed at 5000 ppm (10 of 24 rats) than at 0 ppm (4 of 29 rats). Pneumonia was evident in 29 of 50 rats treated at 20000 ppm. Other gross lesions were common to all groups except the group of rats treated at 20000 ppm due to early deaths, presumably. Microscopically, an increased prevalence of cancellous bone mass was observed at ≥5000 ppm compared to control data. This effect was “moderate” or “marked” in animals treated at 20000 ppm and “slight” in animals treated at 5000 and 10000 ppm. The number of osteoclasts were fewer in the affected bones, with the numbers being proportional to the magnitude of change. There were no tumors attributed to the test chemical. NOAEL for the test chemical was established at 1000 ppm (by conversion, approx. 50 mg/kg bw/day) following two years of dietary exposure in male and female rats.
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Principles of method if other than guideline:
- The effects in rats following exposure to the test chemical at 0 and 200 mg/kg bw/day were evaluated during a dosing period of 200 days.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- The rats (weighing about 170 g) were obtained from Woodlyn Farms, Guelph, Ontario and acclimatized to the environemntal for one week prior to first day of dosing.
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.2% gum tragacanth
- Details on oral exposure:
- Each dose solution was adjusted so that the oral dose volume was 10 ml/kg.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 200 days
- Frequency of treatment:
- Daily
- Remarks:
- 0 (vehicle control) and 200 mg/kg bw/day
- No. of animals per sex per dose:
- 20 male rats per dose level
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Each group was randomly divided into groups of 10 rats so that the same half of each group could be used for a series of clinical tests at monthly intervals. These groups of rats (10 in each treatment group) were used for the collection of urine and blood.
- Observations and examinations performed and frequency:
- The rats were monitored for body weight changes (on weekly basis) and for changes in general health. Urine was collected at monthly intervals for the analysis of pH, urine volume, alkaline phosphatase, and lactic dehydrogenase. Further urine collection was made to determine osmolarity. Blood was collected at monthly intervals for the analysis of aspartate aminotransferase and alanine aminotransferase.
- Sacrifice and pathology:
- After 200 days of dosing, all surviving rats were sacrificed and the heart, kidneys, liver, lungs, stomach and duodenum were dissected and preserved in buffered formalin. Gross examination was performed on all tissues and the gastric and duodenal mucosae were examined using a dissecting microscopic. The remaining tissues were sectioned and examined microscopically using several different stains.
- Statistics:
- Differences between treatment groups were analyzed by the unpaired Student's t-test. The significance of t values was evaluated using Dunnett's method of comparing several treatments with a single control. 4 different treatment groups were included in the study. P<0.05 was considered significant.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All rats appeared to be healthy superficially duirng the dosing period.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two rats died at 200 mg/kg, however, none of the deaths were attributed to the test chemical.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Rats treated at 200 mg/kg showed marginally lower mean body weights compared to the control group throughout most of the study. After 200 days of dosing, the average body weight was approx. 9.7% lower at 200 mg/kg in comparison to the control data.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No significant changes in the plasma concentrations of aspartate aminotransferase or alanine aminotransferase were observed.
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Urinalysis data showed markedly increased levels of lactic dehydrogenase at 200 mg/kg compared to the control data throughout the study period. From week 20 to 24 of treatment, a marked decrease was observed at 200 mg/kg, which may indicate that tolerance was developing. Increased urine levels of alkaline phosphatase at 200 mg/kg compared to controls were observed at week 12, 16 and 24 of study, but not at week 4, 8 or 20 of study. The pH of the urine samples remained normal throughout the study period. Urinary volumes were significantly lower at 200 mg/kg compared to the control group during the last three months of study. Urinary volumes were not weight-adjusted. Therefore, the observed effect on urine volume at 200 mg/kg could not be directly attributed to the test chemical. The osmolarity of the urine was significantly higher at 200 mg/kg compared to the control group in the fourth and fifth months of study, but not thereafter.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross abnormalities were found, and the examination of the gastric and duodenal mucosae did not reveal any lesions.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Pathological findings included chronic pneumonia (1 rat at 0 mg/kg), necrosis in the heart (2 rats at 200 mg/kg), a cyst in the kidneys (1 rat each at 0 and 200 mg/kg), and lastly chronic pyelonephritis (4 rats at 0 mg/kg). The pathological changes were described as minor in nature and none of them were attributed to the test chemical. No lesions were observed in the liver.
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- <= 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- urinalysis
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Conclusions:
- LOAEL for the test chemical was established at 200 mg/kg bw/day following 200 days of exposure in male rats based on marginal body weight changes and mild toxicological effects on the kidneys.
- Executive summary:
The chemical was given to 20 male rats per dose level at 0 and 200 mg/kg bw/day by oral gavage for a total of 200 days. The rats were monitored for body weight changes (on weekly basis) and for changes in general health. Urine was collected at monthly intervals for the analysis of pH, urine volume, alkaline phosphatase, and lactic dehydrogenase. Further urine collection was made to determine osmolarity. Blood was collected at monthly intervals for the analysis of aspartate aminotransferase and alanine aminotransferase. After 200 days of dosing, all surviving rats were sacrificed and the heart, kidneys, liver, lungs, stomach and duodenum were dissected and preserved in buffered formalin. Gross examination was performed on all tissues and the gastric and duodenal mucosae were examined using a dissecting microscopic. The remaining tissues were sectioned and examined microscopically using several different stains. Two rats died at 200 mg/kg, however, none of the deaths were attributed to the test chemical. Rats treated at 200 mg/kg showed marginally lower mean body weights compared to the control group throughout most of the study. After 200 days of dosing, the average body weight was approx. 9.7% lower at 200 mg/kg in comparison to the control data. All rats appeared to be healthy superficially. No significant changes in the plasma concentrations of aspartate aminotransferase or alanine aminotransferase were observed. Urinalysis data showed markedly increased levels of lactic dehydrogenase at 200 mg/kg compared to the control data throughout the study period. From week 20 to 24 of treatment, a marked decrease was observed at 200 mg/kg, which may indicate that tolerance was developing. Increased urine levels of alkaline phosphatase at 200 mg/kg compared to controls were observed at week 12, 16 and 24 of study, but not at week 4, 8 or 20 of study. The pH of the urine samples remained normal throughout the study period. Urinary volumes were significantly lower at 200 mg/kg compared to the control group during the last three months of study. Urinary volumes were not weight-adjusted. Therefore, the observed effect on urine volume at 200 mg/kg could not be directly attributed to the test chemical. The osmolarity of the urine was significantly higher at 200 mg/kg compared to the control group in the fourth and fifth months of study, but not thereafter. No gross abnormalities were found, and the examination of the gastric and duodenal mucosae did not reveal any lesions. Pathological findings included chronic pneumonia (1 rat at 0 mg/kg), necrosis in the heart (2 rats at 200 mg/kg), a cyst in the kidneys (1 rat each at 0 and 200 mg/kg), and lastly chronic pyelonephritis (4 rats at 0 mg/kg). The pathological changes were described as minor in nature and none of them were attributed to the test chemical. No lesions were observed in the liver. LOAEL for the test chemical was established at 200 mg/kg bw/day following 200 days of exposure in male rats based on marginal body weight changes and mild toxicological effects on the kidneys.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- Adopted 1995
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No details provided.
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- 7 days per week
- Remarks:
- 0 (vehicle control), 15, 150 and 1000 mg/kg bw/day
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No details provided.
- Observations and examinations performed and frequency:
- Mortality, clinical signs, food intake, body weight changes, clinical chemistry, hematology, urinalysis
- Sacrifice and pathology:
- Organ weights, gross findings and microscopic findings
- Statistics:
- No details provided.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs were restricted to excessive salivation in some of the animals treated at 1000 mg/kg during week 2-3 of study.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Male rats treated at ≥150 mg/kg showed smaller weight gains compared to control data. This effect was not dose-dependent and therefore not attributed to the test chemical. For female rats, no significant body weight effects were observed.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Rats treated at 1000 mg/kg showed increased mean prothrombin and activated partial thromboplastin times compared to control data. These effects were attributed to the test chemical.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Increased albumin/globulin ration (male and females) and increased triglyceride levels (females only) were observed at 1000 mg/kg, however, none of these effects were attributed to the test chemical as there were no histological correlates in the organs/tissues examined.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- >= 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Remarks on result:
- other: not specified
- Dose descriptor:
- LOAEL
- Effect level:
- <= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- haematology
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Conclusions:
- NOAEL for the test chemical was established at 150 mg/kg bw/day based on increases in prothrombin and activated partial thromboplastin times at the highest dose level.
- Executive summary:
The chemical was given to 5 rats per gender per dose level at 0 (vehicle control), 15, 150 and 1000 mg/kg bw/day by oral gavage for 28 days. All animals survived the treatment period. Clinical signs were restricted to excessive salivation in some of the animals treated at 1000 mg/kg during week 2-3 of study. Male rats treated at ≥150 mg/kg showed smaller weight gains compared to control data. This effect was not dose-dependent and therefore not attributed to the test chemical. For female rats, no significant body weight effects were observed. Food intake was unaffected by treatment. Rats treated at 1000 mg/kg showed increased mean prothrombin and activated partial thromboplastin times compared to control data. These effects were attributed to the test chemical. Increased albumin/globulin ration (male and females) and increased triglyceride levels (females only) were observed at 1000 mg/kg, however, none of these effects were attributed to the test chemical as there were no histological correlates in the organs/tissues examined. No other significant effects on hematology or clinical chemistry were reported. Urinalysis data revealed no significant effects attributed to the test chemical. Organ weights were unaffected by treatment and there were no treatment-related macroscopic or microscopic findings. NOAEL for the test chemical was established at 150 mg/kg bw/day based on increases in prothrombin and activated partial thromboplastin times at the highest dose level.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from peer reviewed publication.
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- 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
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Quality of whole database:
- Waiver
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Repeated dose toxicity: Oral
Data available from the various sources was reviewed to determine the toxic nature of the given test chemical. The studies are as mentioned below:
Study 1
The chemical was given to 5 rats per gender per dose level at 0 (vehicle control), 15, 150 and 1000 mg/kg bw/day by oral gavage for 28 days. All animals survived the treatment period. Clinical signs were restricted to excessive salivation in some of the animals treated at 1000 mg/kg during week 2-3 of study. Male rats treated at ≥150 mg/kg showed smaller weight gains compared to control data. This effect was not dose-dependent and therefore not attributed to the test chemical. For female rats, no significant body weight effects were observed. Food intake was unaffected by treatment. Rats treated at 1000 mg/kg showed increased mean prothrombin and activated partial thromboplastin times compared to control data. These effects were attributed to the test chemical. Increased albumin/globulin ration (male and females) and increased triglyceride levels (females only) were observed at 1000 mg/kg, however, none of these effects were attributed to the test chemical as there were no histological correlates in the organs/tissues examined. No other significant effects on hematology or clinical chemistry were reported. Urinalysis data revealed no significant effects attributed to the test chemical. Organ weights were unaffected by treatment and there were no treatment-related macroscopic or microscopic findings. NOAEL for the test chemical was established at 150 mg/kg bw/day based on increases in prothrombin and activated partial thromboplastin times at the highest dose level.
Study 2
The chemical was given to 20 male rats per dose level at 0 and 200 mg/kg bw/day by oral gavage for a total of 200 days. The rats were monitored for body weight changes (on weekly basis) and for changes in general health. Urine was collected at monthly intervals for the analysis of pH, urine volume, alkaline phosphatase, and lactic dehydrogenase. Further urine collection was made to determine osmolarity. Blood was collected at monthly intervals for the analysis of aspartate aminotransferase and alanine aminotransferase. After 200 days of dosing, all surviving rats were sacrificed and the heart, kidneys, liver, lungs, stomach and duodenum were dissected and preserved in buffered formalin. Gross examination was performed on all tissues and the gastric and duodenal mucosae were examined using a dissecting microscopic. The remaining tissues were sectioned and examined microscopically using several different stains. Two rats died at 200 mg/kg, however, none of the deaths were attributed to the test chemical. Rats treated at 200 mg/kg showed marginally lower mean body weights compared to the control group throughout most of the study. After 200 days of dosing, the average body weight was approx. 9.7% lower at 200 mg/kg in comparison to the control data. All rats appeared to be healthy superficially. No significant changes in the plasma concentrations of aspartate aminotransferase or alanine aminotransferase were observed. Urinalysis data showed markedly increased levels of lactic dehydrogenase at 200 mg/kg compared to the control data throughout the study period. From week 20 to 24 of treatment, a marked decrease was observed at 200 mg/kg, which may indicate that tolerance was developing. Increased urine levels of alkaline phosphatase at 200 mg/kg compared to controls were observed at week 12, 16 and 24 of study, but not at week 4, 8 or 20 of study. The pH of the urine samples remained normal throughout the study period. Urinary volumes were significantly lower at 200 mg/kg compared to the control group during the last three months of study. Urinary volumes were not weight-adjusted. Therefore, the observed effect on urine volume at 200 mg/kg could not be directly attributed to the test chemical. The osmolarity of the urine was significantly higher at 200 mg/kg compared to the control group in the fourth and fifth months of study, but not thereafter. No gross abnormalities were found, and the examination of the gastric and duodenal mucosae did not reveal any lesions. Pathological findings included chronic pneumonia (1 rat at 0 mg/kg), necrosis in the heart (2 rats at 200 mg/kg), a cyst in the kidneys (1 rat each at 0 and 200 mg/kg), and lastly chronic pyelonephritis (4 rats at 0 mg/kg). The pathological changes were described as minor in nature and none of them were attributed to the test chemical. No lesions were observed in the liver. LOAEL for the test chemical was established at 200 mg/kg bw/day following 200 days of exposure in male rats based on marginal body weight changes and mild toxicological effects on the kidneys.
Study 3
The chemical was given to 9 to 10 male rats per dose level at 0 (vehicle control), 138, 218, 346 and 550 mg/kg by oral gavage, five days per week, for a total of 15 weeks. Prior to dosing, at 3-week intervals, and at 3 and 6 weeks after cessation of dosing, the rats were subjected to a battery of neurobehavioral tests including undifferentiated motor activity, forelimb and hindlimb grip strengths, rotation orientation, thermal sensitivity, startle responsiveness to acoustic and air-puff stimuli, and performance of a multisensory conditioned pole-climb avoidance response task. Body weight and rectal temperatures were also recorded. One animal at 218 mg/kg, two animals at 346 mg/kg and one animal at 550 mg/kg died during 2 to 9 weeks of study. The deaths were not dose-related and were not directly attributed to the test chemicals. Significant body weight reductions were observed at ≥218 mg/kg compared to control data.After 15 weeks of dosing, the only neurobehavioral change was a dose-related decrease in hindlimb strength at ≥218 mg/kg. This effect persisted after 6 weeks of recovery. NOAEL for the test chemical was established at 138 mg/kg bw/day following five days of exposure per week, for 15 weeks in total, in male rats based on body weight changes and decrease hindlimb strength at ≥218 mg/kg
Study 4
The chemical was given to 25 rats per sex per dose level, by diet, at 0 (control diet), 1000, 5000, 10000 and 20000 ppm for two years. Body weights were recorded weekly. Hematologic examinations were done at 3, 11, 17 and 22 months of study on 10 rats at each dose level. Hematologic parameters included white blood cell count, differential cell counts, hematocrit and hemoglobin values. Rats that died were subjected to postmortem examinations. Surviving rats were sacrificed at the end of the dosing period to collect organ weights (heart, liver, kidneys, spleen, and testes) and to detect pathological changes. Tissues from 108 rats (29 at 0 ppm, 25 at 1000 ppm, 24 at 5000 ppm, 18 at 10000 ppm and 12 at 20000 ppm) were collected for gross pathology of viscera (thyroid to rectum). Of these 108 rats, 23 rats (12 at 0 ppm, 6 at 10000 ppm, and 5 at 20000 ppm) were subjected to microscopic examinations of thyroid, parathyroid, lung, heart, stomach, pancreas, spleen, liver, kidneys, adrenal, lymph node, small intestine, bone marrow smears, leg bone and muscle, urinary bladder, and testis and prostate or ovary and uterus. The group of rats treated at 20000 ppm showed a drastic growth inhibition compared to the control group, and none of the high-dosed rats survived longer than 50 weeks of study. At 10000 ppm, a marked decrease in mean terminal body weight (by approx. 20%) was observed compared to control data. No significant body weight effects were observed at 1000 or 5000 ppm. Visually, rats treated at 10000 and 20000 ppm had rough hair coats. No significant effects on hematology were reported. Significant absolute/relative organ weight changes were reported at 10000 ppm, but not at 1000 or 5000 ppm. Gross lesions were more common at 5000 and 20000 ppm as compared to controls. Notably, gross pituitary lesions were more commonly observed at 5000 ppm (10 of 24 rats) than at 0 ppm (4 of 29 rats). Pneumonia was evident in 29 of 50 rats treated at 20000 ppm. Other gross lesions were common to all groups except the group of rats treated at 20000 ppm due to early deaths, presumably. Microscopically, an increased prevalence of cancellous bone mass was observed at ≥5000 ppm compared to control data. This effect was “moderate” or “marked” in animals treated at 20000 ppm and “slight” in animals treated at 5000 and 10000 ppm. The number of osteoclasts were fewer in the affected bones, with the numbers being proportional to the magnitude of change. There were no tumors attributed to the test chemical. NOAEL for the test chemical was established at 1000 ppm (by conversion, approx. 50 mg/kg bw/day) following two years of dietary exposure in male and female rats.
The most relevant NOAEL was the NOAEL value of approx. 50 mg/kg bw/day in male and female rats following exposure to the test chemical by diet for 2 years.
Repeated dose toxicity: Inhalation
A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the given test chemical has very low vapor pressure 4.9E-9 Pa (3.68E-11 mmHg), so the potential for the generation of inhalable vapors is very low. 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 highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver.
Repeated dose toxicity: Dermal
A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. Also, the acute dermal toxicity value for test chemical (as provided in section 7.2.3) is >2000 mg/kg body weight. Given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.
Justification for classification or non-classification
Sodium salicylate is regarded to be classified as Not Classified for STOT RE by the oral route. The decision is based on several repeated dose toxicity studies in which rats have been exposed to sodium salicylate or various read-across chemicals that share the same active metabolite as sodium salicylate for periods ranging from 4 weeks to 2 years. No significant or severe target organ toxicity nor any changes of less severe nature involving multiple organs were observed at any dose level that would justify a classification for STOT RE as per CLP guidance values.
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