Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

Based on the available results and applying the weight of evidence approach, the NOAEL value can be considered to be 930 mg/kg/day. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.

 

Repeated Dose toxicity: Inhalation

A short term inhalation toxicity study need not be conducted because exposure of humans via inhalation in production and/or in use is highly unlikely based on the thorough and rigourous risk assessment provided. The estimated vapour pressure for the test chemical was 0.093 Pa or 0.0007 mmHg at 25 deg C, also the primary route of exposure oral. Hence, exposure via inhalation route is highly unlikely.

Repeated dose toxicity: Dermal

A short term dermal toxicity study need not be conducted because exposure of humans via dermal in production and/or in use is highly unlikely based on the thorough and rigourous risk assessment provided. The acute dermal LD50 of the test chemical (as per section 7.2.3) was greater than 2000 mg/kg. Also the experimental in vitro skin irritation study suggests that the test chemical was not irritating to human skin. Hence this endpoint can be considered for waiver.

Based on the available results and applying the weight of evidence approach, the NOAEL value can be considered to be 930 mg/kg/day. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.

 

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Weight of evidence approach based on various test chemicals
Justification for type of information:
Weight of evidence approach based on various test chemicals
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Weight of evidence approach based on various test chemicals
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
2. Wistar (Chbb=Thom) rats; Sprague Dawley
Sex:
male/female
Route of administration:
other: 2- oral: feed; 3. oral: gavage
Vehicle:
other: 2. diet; 3. corn oil
Details on oral exposure:
3. PREPARATION OF DOSING SOLUTIONS:
The dosing solutions were prepared by dilution in corn oil vehicle (Schneck's Food Company, Winchester, VA).

DIET PREPARATION
- Rate of preparation of diet (frequency):
Solutions were prepared fresh weekly.
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
The formulated solutions were stored under refrigeration (5°C) when not in use. For dosing, the chilled solutions were allowed to come to room temperature and were stirred with a magnetic stir bar

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage): The dosing volume was 3 ml/kg body weight
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
2. 0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test chemical intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively.
Duration of treatment / exposure:
2. 3 months
3. 90 days
Frequency of treatment:
2,3. daily
Remarks:
Study 2. 0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test chemical intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively.
Remarks:
Study 3: 0 (corn oil vehicle), 50. 200, and 800 mg/kg per day
No. of animals per sex per dose:
2. Groups of 10 male and 10 female Wistar (Chbb=Thom) rats
3. Groups of 10 male and 10 female Sprague Dawley rats
Control animals:
yes, concurrent no treatment
Details on study design:
3. - Dose selection rationale:
The high-dose level was chosen on the basis of the effects at 600 and 1800 mg/kg/day for 2 weeks and was anticipated to be the maximum tolerated dose. The other two levels (200 and 600 mg/kg/day) were selected as possible no-effect levels.
Observations and examinations performed and frequency:
2. CAGE SIDE OBSERVATIONS: Yes / No / Not specified :
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / Not specified : yes
- Time schedule: Clinical signs were observed regularly

BODY WEIGHT: Yes / No / Not specified : yes
- Time schedule for examinations: body weight were observed regularly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / Not specified : food consumption were observed reegularly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

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: Yes / No / Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified : yes
- Time schedule for examinations: water consumption were observed regularly

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified : yes
- Time schedule for examinations: Ophthalmoscopy was performed on animals in the control and top-dose groups, pretest and prior to sacrifice.
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / Not specified : yes
- Time schedule for collection of blood: Samples for clinical chemistry and haematology were takenon day 86.
- Anaesthetic used for blood collection: Yes (identity) / No / Not specified
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes / No / Not specified : yes
- Time schedule for collection of blood: Samples for clinical chemistry and haematology were taken on day 86.
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes / No / Not specified : yes
- Time schedule for collection of urine: Urine analysis samples were obtained on day 80.
- Metabolism cages used for collection of urine: Yes / No / Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / Not specified
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: Yes / No / Not specified
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

OTHER:
3. CAGE SIDE OBSERVATIONS: Yes / No / Not specified
: yes
- Time schedule:
All rats were observed daily by careful cageside observation for overt signs of toxicity. Animals were observed twice daily, at a minimum of 6-h intervals for signs of mortality
or morbidity.
- Cage side observations checked in table [No.?] were included.
: yes

DETAILED CLINICAL OBSERVATIONS: Yes / No / Not specified
: yes
- Time schedule:
Physical examinations were performed weekly; any abnormalities in housing. food, water, or clinical signs involving general appearance, behavior, excretion, respiration, skin, pelage. or eyes were recorded.

BODY WEIGHT: Yes / No / Not specified
: yes
- Time schedule for examinations: Individual body weights were measured prior to randomization, at initiation of dosing, and weekly thereafter. Food consumption was measured weekly

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: Yes / No / Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

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: Yes / No / Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified
: yes
- Time schedule for examinations:
Ophthalmoscopic examinations were performed using indirect ophthalmoscopic techniques, utilizing 1% Mydriacyl as the mydriatic.
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / Not specified
: yes
- Time schedule for collection of blood: Hematology determinations were performed on all animals at termination following an overnight food fast
- Anaesthetic used for blood collection: Yes (identity) / No / Not specified
: Animals were anesthetized with ketamine and all blood aamples were collected via puncture of the orbital sinus into 1-ml microtainer tubes containing EDTA
- Animals fasted: Yes / No / Not specified
: yes, over night fast
- How many animals: All animals
- Parameters checked in table [No.?] were examined.
: A Coulter Counter (Model S+IV) was used to evaluate leukocyte, erythrocyte. hematocrit, and hemoglobin tests; leukocyte differentials and cell morphohgy were evaluated using Wright's Giemsa staining procedure.

CLINICAL CHEMISTRY: Yes / No / Not specified
: yes
- Time schedule for collection of blood:
Clinical chemistry parameters were performed on all animals at termination following an overnight food fast
- Animals fasted: Yes / No / Not specified
: yes, overnight fasted
- How many animals:
All animals
- Parameters checked in table [No.?] were examined.
: Serum chemistries were determined on all animals at termination utilizing a Hitachi 737 automated chemistry analyzer. Tests evaluated included: sodium, potassium, total protein, albumin, calcium. total bilirubin, creatinine. aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH). and blood urea nitrogen (BUN).

URINALYSIS: Yes / No / Not specified
: yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.
: Urinalysis determinations of pH, glucose, protein, bilirubin, occult blood. and urobilinogen were made utilizing Ames Multistix

NEUROBEHAVIOURAL EXAMINATION: Yes / No / Not specified
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: Yes / No / Not specified
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

OTHER:
Sacrifice and pathology:
2. GROSS PATHOLOGY: Yes (see table) / No / Not specified : All animals were subjected to a gross pathological examination followed by a microscopic examination.

HISTOPATHOLOGY: Yes (see table) / No / Not specified: Control and top-dose animals received a full microscopic examination; for the low- and intermediate-dose groups, only lungs, liver, kidneys and gross lesions were examined.
3. GROSS PATHOLOGY: Yes (see table) / No / Not specified
: yes, Animals were weighed. anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys, spleen, adrenal glands, thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated. Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal.

HISTOPATHOLOGY: Yes (see table) / No / Not specified: yes, The following tissues were evaluated from all animals in the 800 mg/kg/ day animals as well as from five randomly selected animals per gender in corn oil control animals: adrenals, thyroid, esophagus, trachea. larynx, heart, spleen, liver, kidney, stomach, duodenum, jejunum, colon, pancreas, and gross lesions
Statistics:
3. All appropriate data were subjected to Levene's test of homogeneity of variance and an analysis of variance. Nonhomogeneous data were subjected to a series of transformations in order to achieve
homogeneity . When the series of transformations were ineffective in achieving homogeneity, analysis of ranked data were performed. Group comparisons were evaluated using Dunnett's t-test at the 5.0% two-tailed probability Ievels.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
3. The daily cageside observations (conducted approximately 1 h post-dosing), noted in the high-dose animals included languid behavior, prostration, sensitivity to touch, tremors, epistaxis, wheezing,
dyspnea, and/or polypnea. These signs appeared closely related to the time of the animals' death. The findings noted at the weekly detailed observations (conducted prior to dosing). generally appeared in fewer animals and were generally not as severe as those seen at 1 h post-dosing.
Mortality:
mortality observed, treatment-related
Description (incidence):
3. Four males and two females in the high-dose group (800 mg/kg/day) died prior to termination. The deaths were considered treatment related.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2. A initial deficit in body weight in top-dose males was associated with reduced feed consumption and, although statistically significant, was less than 10%. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. The total body weight gain (initiation to Week 13) was significantly decreased for high-dose males. Otherwise, all comparisons between treatment and control animals were not statistically significant.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Food consumption was comparable in all groups at each weekly interval.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
2. A number of water consumption were altered in top-dose animals indicative of potential liver and kidney toxicity. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Ophthalmological findings:
no effects observed
Description (incidence and severity):
2. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Ophthalmoscopic evaluations did not reveal any treatment-related effects
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
2. Erythrocyte parameters were reduced in top-dose females. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Clinical hematology data were comparable in all group
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2. A number of clinical chemistry parameters were altered in top-dose animals indicative of potential liver and kidney toxicity. Plasma bilirubin was decreased dose relatedly in all male groups (Table 8), but this is not considered to be adverse in isolation.There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Clinical chemistry data revealed significantly increased blood urea nitrogen, creatinine, alkaline phosphatase, and total bilirubin values, and significantly decreased sodium values in the high-dose males. The differences for alkaline phosphatase occurred in a dose-related pattern in the males; however, only the values for the high-dose males were statistically significant. The increase in the blood urea nitrogen and creatinine resulted from moderate elevations in two animals; while the increased total bilirubin was considered to be a small change. Clinical chemistry values in females were comparable in all groups
Urinalysis findings:
no effects observed
Description (incidence and severity):
2. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Urinalysis data revealed generally decreased pH values (males: 7.50 ± 0.623, 7.75± 0.635, 6.80 ± 0.258. and 6.42 ± 0.580; females: 7.25 ± 0.755, 6.85 ± 0.474, 6.35 ± 0.412, and 6.50 ± 0.598 for Groups 1-4, respectively). The differences between treated and control animals were significant for both sexes of mid- and high-dose animals. The remaining urinalysis results were comparable in all groups.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
2. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Terminal body weight was significantly decreased in the high-dose group females, and was depressed, although not significantly, in the high-dose group males. Absolute lung weights were significantly decreased in low- and high-dose group females, but relative weights were unaffected. Absolute and relative adrenal weights were significantly increased in high-dose group males. Relative heart weight was significantly increased in the high-dose group females, and relative brain, kidney, and liver weights were increased in the high-dose group males and females.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
2. The only pathological findings of note were chronic interstitial nephritis and focal urothelial hyperplasia in top-dose males. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. At the scheduled necropsy, the kidneys of all high-dose group males had abnormalities including depressed area, pale area, mottled appearance, dilated renal pelvis, and/or granuladpittedlrough texture. Similar lesions were seen in the animals sacrificed or found dead prior to the scheduled sacrifice. The renal findings were accompanied by histopathology findings, and were considered to be treatment related. Dark areas in the glandular portion of the stomach were seen in all groups, and with slightly higher frequency in high-dose group animals. Few other gross lesions were seen at the terminal sacrifice and most were represented by a single incidence per group.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
2. The only pathological findings of note were chronic interstitial nephritis and focal urothelial hyperplasia in top-dose males.There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
3. Histopathology evaluations revealed compound-related effects in the liver, adrenal gland, and kidney. In the liver, there was centrilobular hypertrophy of hepatocytes in high-dose group animals, both in animals that died on test and in animals that were sacrificed at termination. The effect was not evident in low- and mid-dose group animals. Chronic progressive nephropathy occurred in both sexes of high-dose group animals (1/10 males and 9/10 females), The finding was also seen on 2 of 10 control males, but not in control females. This lesion was characterized by degeneration and regeneration of the tubular epithelial cells, interstitial fibrosis, and mononuclear cell infiltrates. The lesions were multifocal and primarily involved the cortex. The finding was not evident in lowand mid-dose group animals. Adrenal glands of high-dose group males and females showed hyperplasia of the zona fasciculata. No test chemical-related lesions were observed in adrenal glands of low-dose, mid-dose, or control animals. Minimal mucosal erosion occurred in the glandular stomach of two high-dose groups males, three high-dose group females, one mid-dose group female, and one low-dose group female.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
302 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: non-neoplastic
mortality
Critical effects observed:
no
Conclusions:
Based on the available results and applying the weight of evidence approach, the NOAEL value can be considered to be 930 mg/kg/day. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.
Executive summary:

Various studies have been reviewed to evaluate the toxicity potential of the test chemical when dosed repeatedly via oral route. These include in vivo experimental studies performed on rats for the test chemical. The results are mentioned below:

90 days repeated dose oral toxicity study was performed to evaluate the toxicological profile of the test chemical. Groups of 10 male and 10 female Wistar (Chbb=Thom) rats were given diets containing the test chemical dose of 0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test article intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively. Clinical signs, body weight, and feed and water consumption were monitored regularly. Samples for clinical chemistry and haematology were taken on day 86. Urine analysis samples were obtained on day 80. Ophthalmoscopy was performed on animals in the control and top-dose groups, pretest and prior to sacrifice. All animals were subjected to a gross pathological examination followed by a microscopic examination. Control and top-dose animals received a full microscopic examination; for the low- and intermediate-dose groups, only lungs, liver, kidneys and gross lesions were examined. and mid-dose groups. Plasma bilirubin was decreased dose relatedly in all male groups (Table 8), but this is not considered to be adverse in isolation. The NOAEL was 4000 ppm (equal to 302 mg/kg bw per day), based on a range of clinical chemistry and haematological changes in both sexes and interstitial nephritis and urothelial hyperplasia in males at 12 000 ppm (equal to 930 mg/kg bw per day

This result is supported by another subchronic oral toxicity study performed to determine the toxicological profile of the test chemical. For the 90-day study, male and female Sprague-Dawley-derived (Crl:CD@ BR) rats, 46 days of age at initiation (227.3-276.1 g males, 153.2-195.8 g females), were obtained from Charles River Laboratories, Inc. (Raleigh, NC). Rats were randomized, caged individually, and quarantined for two weeks prior to initiation of the studies. The dosing solutions were prepared by dilution in corn oil vehicle (Schneck's Food Company, Winchester, VA). The formulated solutions were stored under refrigeration (5°C) when not in use. For dosing, the chilled solutions were allowed to come to room temperature and were stirred with a magnetic stir bar. The dosing volume was 3 ml/kg body weight. Solutions were prepared fresh weekly. The doses were 0 (corn oil vehicle), 50. 200, and 800 mg/kg per day, and were designated Groups 1, 2.3, and 4. respectively. The high-dose level was chosen on the basis of the effects at 600 and 1800 mg/kg/ day for 2 weeks and was anticipated to be the maximum tolerated dose. The other two levels (200 and 800 mg/kg/day) were selected as possible no-effect levels. Doses were administered between the hours of 08:00 and 10:00 daily, 7 days per week for 13 weeks. The animals were sacrificed on the day following completion of treatment. Animals were observed for mortality, morbidity, changes in body weights and food consumption, haematological, clinical parameters, urinalysis. Animals were weighed, anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys, spleen, adrenal glands, thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated. Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal. 4 of 10 males and 2 of 10 females in the high-dose group died due to treatment. Other signs for this treatment group included an adverse effect upon body weight and clinicail signs of languid behavior, prostration, tremors, sensitivity to touch, epistaxis, and respiratory distress. Increases in alkaline phosphatase and creatinine (males only), and increases in adrenal (absolute and relative, females), kidney (relative, both sexes), and liver (relative, both sexes) weights were also noted. Histopathologic findings of centrilobular hepatocellular hypertrophy, adrenal cortical hyperplasia, and exacerbation of chronic progressive nephropathy confirmed by the clinical laboratory and organ weight results as being treatment related for the animals receiving 800 mg/kg per day for 90 days. Animals receiving 50 or 200 mg/kg per day (90 days) did not exhibit treatment-related findings. Hence, the NOAEL value can be considered to be 200 mg/kg/day.

Based on the available results and applying the weight of evidence approach, the NOAEL value can be considered to be 930 mg/kg/day. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
930 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch Rating 2

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
exposure considerations
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
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:
short-term repeated dose toxicity: dermal
Data waiving:
exposure considerations
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
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 toxicity: Oral

Various studies have been reviewed to evaluate the toxicity potential of the test chemical when dosed repeatedly via oral route. These include in vivo experimental studies performed on rats for the test chemical. The results are mentioned below:

90 days repeated dose oral toxicity study was performed to evaluate the toxicological profile of the test chemical. Groups of 10 male and 10 female Wistar (Chbb=Thom) rats were given diets containing the test chemical dose of 0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test article intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively. Clinical signs, body weight, and feed and water consumption were monitored regularly. Samples for clinical chemistry and haematology were taken on day 86. Urine analysis samples were obtained on day 80. Ophthalmoscopy was performed on animals in the control and top-dose groups, pretest and prior to sacrifice. All animals were subjected to a gross pathological examination followed by a microscopic examination. Control and top-dose animals received a full microscopic examination; for the low- and intermediate-dose groups, only lungs, liver, kidneys and gross lesions were examined. and mid-dose groups. Plasma bilirubin was decreased dose relatedly in all male groups (Table 8), but this is not considered to be adverse in isolation. The NOAEL was 4000 ppm (equal to 302 mg/kg bw per day), based on a range of clinical chemistry and haematological changes in both sexes and interstitial nephritis and urothelial hyperplasia in males at 12 000 ppm (equal to 930 mg/kg bw per day

This result is supported by another subchronic oral toxicity study performed to determine the toxicological profile of the test chemical. For the 90-day study, four groups of 10 males and 10 females Sprague-Dawley-derived (Crl:CD@ BR) rats, 46 days of age at initiation (227.3-276.1 g males, 153.2-195.8 g females), were obtained from Charles River Laboratories, Inc. (Raleigh, NC). Rats were randomized, caged individually, and quarantined for two weeks prior to initiation of the studies. The dosing solutions were prepared by dilution in corn oil vehicle (Schneck's Food Company, Winchester, VA). The formulated solutions were stored under refrigeration (5°C) when not in use. For dosing, the chilled solutions were allowed to come to room temperature and were stirred with a magnetic stir bar. The dosing volume was 3 ml/kg body weight. Solutions were prepared fresh weekly. The doses were 0 (corn oil vehicle), 50. 200, and 800 mg/kg per day, and were designated Groups 1, 2. 3, and 4. respectively. The high-dose level was chosen on the basis of the effects at 600 and 1800 mg/kg/ day for 2 weeks and was anticipated to be the maximum tolerated dose. The other two levels (200 and 800 mg/kg/day) were selected as possible no-effect levels. Doses were administered between the hours of 08:00 and 10:00 daily, 7 days per week for 13 weeks. The animals were sacrificed on the day following completion of treatment. Animals were observed for mortality, morbidity, changes in body weights and food consumption, haematological, clinical parameters, urinalysis. Animals were weighed, anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys, spleen, adrenal glands, thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated. Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal. 4 of 10 males and 2 of 10 females in the high-dose group died due to treatment. Other signs for this treatment group included an adverse effect upon body weight and clinicail signs of languid behavior, prostration, tremors, sensitivity to touch, epistaxis, and respiratory distress. Increases in alkaline phosphatase and creatinine (males only), and increases in adrenal (absolute and relative, females), kidney (relative, both sexes), and liver (relative, both sexes) weights were also noted. Histopathologic findings of centrilobular hepatocellular hypertrophy, adrenal cortical hyperplasia, and exacerbation of chronic progressive nephropathy confirmed by the clinical laboratory and organ weight results as being treatment related for the animals receiving 800 mg/kg per day for 90 days. Animals receiving 50 or 200 mg/kg per day (90 days) did not exhibit treatment-related findings. Hence, the NOAEL value can be considered to be 200 mg/kg/day.

Based on the available results and applying the weight of evidence approach, the NOAEL value can be considered to be 930 mg/kg/day. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.

 

Repeated Dose toxicity: Inhalation

A short term inhalation toxicity study need not be conducted because exposure of humans via inhalation in production and/or in use is highly unlikely based on the thorough and rigourous risk assessment provided. The estimated vapour pressure for the test chemical was 0.093 Pa or 0.0007 mmHg at 25 deg C, also the primary route of exposure oral. Hence, exposure via inhalation route is highly unlikely.

Repeated dose toxicity: Dermal

A short term dermal toxicity study need not be conducted because exposure of humans via dermal in production and/or in use is highly unlikely based on the thorough and rigourous risk assessment provided. The acute dermal LD50 of the test chemical (as per section 7.2.3) was greater than 2000 mg/kg. Also the experimental in vitro skin irritation study suggests that the test chemical was not irritating to human skin. Hence this endpoint can be considered for waiver.

Justification for classification or non-classification

Based on the available results, the test chemical is not likely to be toxic when dosed repeatedly via oral, dermal, inhalation route of exposure. Hence, the test chemical can be classified under the category “Not Classified” for CLP Regulation.