Registration Dossier

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

Referenceopen allclose all

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:
mortality
body weight and weight gain
behaviour (functional findings)
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:
body weight and weight gain
behaviour (functional findings)
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:
clinical signs
mortality
body weight and weight gain
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
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 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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity 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 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:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
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.

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
Reference
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
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
Reference
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
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.