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Administrative data

Description of key information

28-day repeated oral toxicity (OECD 407):


According to the results, the no-observed-adverse-effect-level (NOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:
Male rats: 30 mg/kg body weight/day;
Female rats: 30 mg/kg body weight/day.


The lowest-observed-adverse-effect-level (LOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:
Male rats: 100 mg/kg body weight/day;
Female rats: 100 mg/kg body weight/day.

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:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 08 Oct 2021 to 17 Feb 2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
Batch No.: 10121040902
Purity: 99.92%
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF (Beijing) Biotechnology Co., Ltd.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks (35 days) on arrival; 6 weeks (43 days) on dosing
- Weight at study initiation: 200.74~220.99 g for males and 176.57~203.61 g for females at grouping.
- Fasting period before study: Animals were fasted overnight prior to necropsy, but water was available.
- Housing: Animals were housed in Room D103 during acclimated period and test period in the barrier system of the facility. Animals were raised in suspended, stainless steel cages (L32.0cm×W28.0cm×H20.0cm) on cage racks (L167.0cm×W70.0cm× H171.0cm). There were 10 cages per layer and 4 layers per rack.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY:
All the nutrition components and contaminants were within the permitted limits described in the national standard (GB 14924.3-2010 and GB 14924.2-2001).
Water analysis was conducted routinely analyzed (annually), and all parameters were within the permitted limits described in the national drinking water standard GB 5749-2006 (Standards for Drinking water Quality).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23~25℃ (target range: 20~25℃ for temperature)
- Humidity (%): 42~66% for humidity (target range: 40%~70% for humidity)
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark
Route of administration:
oral: gavage
Details on route of administration:
Dosing volume was 10 ml/kg b.w.
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Purified water was used as the vehicle of this study. The test item was prepared before dosing on the dosing day. The theoretical weight of the test item was calculated according to the prepared volume and concentration. The test item was weighed and placed into a jar lined at the prepared volume. The vehicle was added to the jar, and kept being stirred with the glass bar during the adding of the vehicle, and the test item attached on the glass bar was washed into the jar using the vehicle. Subsequently, vehicle was added to the scale mark. After that a rotor was put into the jar and all bottles were labeled for use. Formulations were stirred on the magnetic stirring apparatus until the test item was completely dissolved.

VEHICLE
- Justification for use and choice of vehicle: Based on the solubility the test item in water, the purified water was selected as the vehicle in this study, that was also the preferred vehicle in OECD TG 407.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
In the test, the concentration analysis for all the prepared formulations in all dose groups was performed in the first day and one preparation in the fourth week of the exposure period, respectively. As the analysis, the prepared test item of different concentrations and the vehicle control were sampled and analyzed using the validated method.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 animals each sex at control and high dose group, 6 animals each sex at middle and low dose groups
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure recovery period: 14 days

- Dose range finding studies:
Firstly, there were two dose groups of 100 and 150 mg/kg b.w. and one vehicle control group with five female and five male rats in each group, respectively, and the animals were administered by gavage daily for 12 days. Subsequently there was an additional dose group of 300 mg/kg b.w. and one vehicle control group with five female and five male rats in each group, respectively, and the animals were administered by gavage daily for 10 days. The test item was dissolved in purified water and dosed to the SD rats at a volume of 10 mL/kg b.w.. The results showed that the animals at the doses of 100 and 150 mg/kg b.w. didn't show any abnormal symptom related the test item, the most animals at the dose of 300 mg/kg b.w. showed moist fur in 40-100 minutes after dosing daily.
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (once for last scheduled necropsy day), all animals were inspected for signs of morbidity and mortality at the beginning of working day and at the end of working day respectively. General clinical observations were made once a day, and the observation time was at about 50±30 minutes after each animals' dosing, and the health status and toxic signs of the animals were recorded.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were made for all animals prior to the first exposure (after grouping) and then once a week during the treatment periods, and once a week during the recovery period. The animals were taken outside the home cage for observation and all the findings were detailed recorded. Observation included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activities (e.g., lacrimation, pilo-erection, pupil size, unusual respiratory pattern), changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypes (e.g. excessive grooming, repetitive circling) or bizarre behaviors (e.g. self-mutilation, walking backwards).

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed one day before dosing (at grouping), and then once a week during the treatment and recovery periods.

FOOD CONSUMPTION:
The ration food was added weekly, and added food weights were 550 ± 20 g (including the food box weight). The food and food boxes were weighed again 1 day (about 24 h ± 1.5 h) later after adding ration food as surplus food weight. Mean food consumption for one animal per day was calculated based on the above data. Calculation Formulation: Mean daily food consumption (g) = [added food weight (g, including weight of food box) - surplus food weight (g, including weight of food box)] / 2.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of treatment and recovery periods
- Anaesthetic used for blood collection: Yes, anesthetized by CO2 inhalation
- Animals fasted: Yes
- How many animals: All survival animals
- Parameters checked: Erythrocyte Count (RBC)
Hemoglobin (HGB)
Hematocrit (HCT)
Mean Corpuscular Volume (MCV)
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
Platelet Count (PLT)
Total Leukocyte Count (WBC)
Lymphocytes (LYMPH)
Monocytes (MONO)
Neutrophils (NEUT)
Eosinophils (EO)
Basophils (BASO)
Lymphocytes ratio (LYMPH%)
Monocytes ratio (MONO%)
Neutrophils ratio (NEUT%)
Eosinophils ratio (EO%)
Basophils ratio(BASO%)
Reticulocyte (RET)
Reticulocytes ratio(RET%)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of treatment and recovery periods
- Animals fasted: Yes
- How many animals: All survival animals
- Parameters checked:
Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
Alkaline Phosphatase (ALP)
Bile Acid (BA)
Total Bilirubin (T-BIL)
Cholesterol (CHO)
Total Protein (TP)
Albumin (ALB)
Globulin (GLB)
Albumin/Globulin Ratio (A/G)
Urea (UREA)
Creatinine (CREA)
Glucose (GLU)
Sodium (Na+)
Potassium (K+)
High-density lipoprotein (HDL)
Low-density lipoprotein (LDL)


Thyroid Hormones Analysis: Yes
- Samples: the same sample assayed for Clinical Chemistry items
- Parameters checked:
Triiodothyronine T3
Thyroid hormones T4
Thyroid stimulating hormone TSH


URINALYSIS: Yes
- Time schedule for collection of urine: In one week prior to necropsy of terminal dosing and recovery period
- Metabolism cages used for collection of urine: Yes
- Parameters checked:
Appearance
Urine volume
pH
Urine Specific Gravity (SG )
Occult Blood (BLD)
Urine Ketones (KET)
Urine Glucose (GLU)
Urine Total Protein (PRO)
Urine Bilirubin (BIL)
Urobilinogen (URO)
Nitrites (NIT)
Leukocytes (WBC)


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: In the fourth week of the exposure period
- Dose groups that were examined: all survival animals in the control and dose groups
- Battery of functions tested: general behavior, motor function and sensory function
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
During the study, dead animals were subjected to a full gross necropsy and general observation, animals surviving to the end of the study were euthanized by CO2 inhalation followed by exsanguinations from abdominal aorta and subjected to a full necropsy and general observation.
The necropsy included carefully eye examinations of the external features of the carcass, external body orifices, and the cranial, thoracic and abdominal cavities and their contents of all animals. The location, size, hardness and the color of the abnormal findings were recorded.

HISTOPATHOLOGY: Yes
Histopathology was examined on the preserved organs and tissues of all the scheduled necropsy animals in the control, and high dose groups at the end of treatment period and animals that were dead during the study. The organs and tissues which were subjected to histopathological examination were:
Brain, Cerebrum
Brain, Cerebellum
Brain, Pons
Brain, Medulla Oblongata
Spinal Cord, Cervical
Spinal Cord, Thoracic
Spinal Cord, Lumbar
Eyes
Nerve, Optic
Harderian Glands
Stomach, Forestomach
Stomach, Glandular
Islets, Pancreatic
Pancreas
Intestine, Duodenum
Intestine, Ileum
Intestine, Jejunum
Intestine, Cecum
Intestine, Colon
Intestine, Rectum
Lymph Node, Peyers Patch
Liver
Kidneys
Adrenal Glands
Spleen
Heart
Thymus
Thyroid Glands
Parathyroid Glands
Trachea
Lungs
Testes (male)
Ovaries (female)
Uterus (including cervix, female)
Epididymides (male)
Coagulating Glands (male)
Prostate Gland (male)
Seminal Vesicles (male)
Vagina (female)
Urinary Bladder
Lymph node, Mesenteric
Lymph Node, Submandibular
Skeletal muscle, Biceps Femoris muscle
Nerve, Sciatic
Bone, Femur
Bone, Knee-Joint
Bone Marrow, Femur
Bone, Sternum
Bone Marrow, Sternum
Tongue
Esophagus
Pituitary Gland
Aorta
Salivary Gland, Sublingual
Salivary Gland, Submandibular
Skin
Mammary Glands
All gross lesions
Other examinations:
Organ Weight:
At sacrifices, the following organs as brain, heart, liver, spleen, lung, kidneys, adrenal glands, thymus, prostate+seminal vesicles with coagulating glands as a whole, testes (male), epididymides (male), ovaries (female) and uterus (female) were trimmed of any adherent tissue, as appropriate, and their wet weights were taken as soon as possible after dissection to avoid drying. Care was exercised when trimming the prostate complex to avoid puncture of the fluid filled seminal vesicle.
The thyroid and pituitary gland weight was determined after fixation. Trimming was done very carefully and only after fixation to avoid tissue damage. The organs and tissues weighed were:
Adrenal Glands
Brain
Prostate + Seminal Vesicles with Coagulating
Heart
Liver
Kidneys
Lungs
Ovaries
Pituitary Gland
Epididymides
Spleen
Testes
Thymus
Thyroid
Uterus
Statistics:
Data of the mean body weight and body weight gain, food consumption, hematology, coagulation, clinical chemistry, thyroid hormones, organ weight, and organ weight ratio were statistically analyzed using the Tables and statistics module of "Provantis System10.2.3.1" software.
Urinalysis data excepted for urine volume was analyzed by SPSS 17.0.
The nerve function examination data were analyzed by verified SPSS 17.0 software.
The data of clinical observation was analyzed by verified SPSS 17.0 software.
The chi-square test (χ2) was adopted. The Tables and statistics module of "Provantis System10.2.3.1" software was used for the incidence of gross pathological findings and non-graded histopathological findings. Fisher's exact probability test (one-tailed probability level) was adopted.
All the tests were two-tailed probability level except the Fisher’s exact test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Male animals
Coat Soiled was observed in males just with 1 (1 out of 12) rat affected in the high dose group, only observed on Day 11 during the treatment period.
Moist fur was observed in males in a dose-related manner, with 0 (0 out of 12), 0 (0 out of 6), 6 (6 out of 6) and 12 (12 out of 12) rats affected in the control group, and in the low, middle, and high dose groups, respectively. It was observed in males after administration off and on starting from Day 20 in the middle dose group, Day 1 in the high dose group during the treatment period.
Moist fur around mouth was observed in males in a dose-related manner, with 0 (0 out of 12), 0 (0 out of 6), 6 (6 out of 6) and 11 (11 out of 12) rats affected in the control group, and in the low, middle, and high dose groups, respectively. It was observed in males after administration off and on starting from Day 14 in the middle dose group, Day 15 in the high dose group during the treatment period.
Female animals
Moist fur was observed in females in a dose-related manner, with 0 (0 out of 12), 0 (0 out of 6), 6 (6 out of 6) and 12 (12 out of 12) rats affected in the control group, and in the low, middle, and high dose groups, respectively. It was observed in females after administration off and on starting from Day 10 in the middle dose group, Day 1 in the high dose group during the treatment period.
Moist fur around mouth was observed in females in a dose-related manner, with 0 (0 out of 12), 0 (0 out of 6), 6 (6 out of 6) and 10 (10 out of 12) rats affected in the control group, and in the low, middle, and high dose group, respectively. It was observed in females after administration off and on starting from Day 14 in the middle dose group, Day 16 in the high dose group during the treatment period.
Summary Results
Treatment-related clinical symptoms in males and females were the increased incidences in moist fur (males: control: 0 out of 12; the low dose: 0 out of 6; the middle dose: 6 out of 6; the high dose: 12 out of 12; females: control: 0 out of 12; the low dose: 0 out of 6; the middle dose: 6 out of 6; the high dose: 12 out of 12) and moist fur around mouth (males: control: 0 out of 12; the low dose: 0 out of 6; the middle dose: 6 out of 6; the high dose: 11 out of 12; females: control: 0 out of 12; the low dose: 0 out of 6; the middle dose: 6 out of 6; the high dose: 10 out of 12) in the middle and high dose groups (statistical analysis was not performed).
Treatment-related clinical symptom in males was coat soiled just with 1 (1 out of 12) rat affected in the high dose group during the treatment period.
Mortality:
mortality observed, treatment-related
Description (incidence):
During the treatment period, mortality for the control group, and in the low, middle and high dose groups in a dose-related manner were 0.0% (0 out of 12), 0.0% (0 out of 6), 16.7% (1 out of 6) and 33.3% (4 out of 12) for males, respectively, and 0.0% (0 out of 12), 0.0% (0 out of 6), 0.0% (0 out of 6) and 25.0% (3 out of 12) for females, respectively.
4 male rats (1305, 1306, 1311 and 1302) in the high dose group died on Day 11, 23, 26 and 28, respectively, during the treatment period.
1 male rats (1204) in the middle dose group died on Day 28 during the treatment period.
3 female rats (2307, 2305 and 2300) in the high dose group died on Day 11, 15 and 26, respectively, during the treatment period.
There were no dead or moribund animals for male and female animals during the recovery periods.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
According the above results, there was a treatment-related effect on body weight in males in the high dose group during the treatment period, and the total body-weight gains (0-28 day) were significantly lower (22.9%). Final body weights of males in the high dose group were reduced by 10.6% at the end of the treatment period. The treatment-related effects on body weight in males in the high dose group returned to normal at the end of recovery period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment-related effects on food consumption in both sexes at all treated groups during the treatment period, there were no treatment-related durable or tardive toxic effects on food consumption in both sexes during the recovery period.
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on Haematology in both sexes at all treated groups at the end of the treatment period, there were no treatment-related durable or tardive toxic effects on Haematology in both sexes after the recovery period.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increases (+692.9%) in T-BIL in males in the high dose group at the end of the treatment period, the change returned to normal level after the recovery period.
Endocrine findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on Thyroid Hormones in both sexes at all treated groups at the end of the treatment period, there were no treatment-related durable or tardive toxic effects on Thyroid Hormones in both sexes after the recovery period.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
There was a treatment-related effect on Urinalysis in males in the high dose group, PRO level was significantly increased in males at the end of dosing period. The above change returned to normal level at the end of recovery period. There were no treatment-related durable or tardive toxic effects on Urinalysis in both sexes after the recovery period.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
There was a treatment-related effects on sensory function in nerve function observations in males in the high dose group, the tail pinch response scores in males in the high dose group was significantly lower than that of the controls in the fourth week of the exposure period.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increases in the absolute and relative liver weights were observed in females in the high dose group at the end of the treatment period, the above changes in liver weights were associated with treatment-related effects on histopathological findings (the test substance in dead animals in the middle and high dose group induced necrosis and hemorrhage in the liver), which were considered to be a treatment-related effect.
There were no treatment-related durable or tardive toxic effects on organ weights in both sexes after the recovery period.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related gross necropsy findings.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There were treatment-related toxic pathological changes in liver of males in the middle and high dose groups and females in the high dose group, and in pancreas of males and females in the high dose group.
Treatment-related adverse histological findings consisted of necrosis and hemorrhage in the liver, acinar cell autophagic vacuoles in the pancreas in dead rats. Necrosis (4 out of 4 in males and 3 out of 3 in females) and hemorrhage (2 out of 4 in males and 1 out of 3 in females) in the liver, and acinar cell autophagic vacuoles (1 out of 3 in females) in the pancreas were observed in the high dose group, necrosis (1 out of 1 in males) in the liver and acinar cell autophagic vacuoles (1 out of 1 in males) was observed in the middle dose group. The cause of death was liver necrosis of the dead animals.
The treatment-related adverse histological findings consisted of single acinar cell necrosis and acinar cell autophagic vacuoles in the pancreas at statistically significantly higher incidences in males and females in the high dose group at the end of the treatment period. The lesion showed a recovery trend at end of the recovery period.
Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
Key result
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
liver
pancreas
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
According to the results, the no-observed-adverse-effect-level (NOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:
Male rats: 30 mg/kg body weight/day;
Female rats: 30 mg/kg body weight/day.

The lowest-observed-adverse-effect-level (LOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:
Male rats: 100 mg/kg body weight/day;
Female rats: 100 mg/kg body weight/day.
Executive summary:

Refer to the OECD Guideline 407, a repeated Dose 28-Day Oral Toxicity Study in Sprague Dawley rats with test item was performed.


According to the results, the no-observed-adverse-effect-level (NOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:


Male rats: 30 mg/kg body weight/day


Female rats: 30 mg/kg body weight/day


The lowest-observed-adverse-effect-level (LOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:


Male rats: 100 mg/kg body weight/day


Female rats: 100 mg/kg body weight/day


For males, based on obvious increase in mortality (16.7% and 33.3%, respectively) at 100 and 300 mg/kg body weight/day; obvious increased incidences in moist fur (6 out of 6, 12 out of 12, respectively) and moist fur around mouth (6 out of 6, 11 out of 12, respectively) at 100 and 300 mg/kg body weight/day and coat soiled (1 out of 12) at 300 mg/kg body weight/day on clinical observation; significant decrease in mean body weight and body-weight gain at 300 mg/kg body weight/day; significant decrease in tail pinch response scores at 300 mg/kg body weight/day; significant increase (+692.9%) in T-BIL at 300 mg/kg body weight/day; significant increase in PRO level at 300 mg/kg body weight/day; obvious increase in the incidence of necrosis (4 out of 4) and hemorrhage (2 out of 4) in the liver at 300 mg/kg body weight/day for dead rats, and necrosis (1 out of 1) in the liver and acinar cell autophagic vacuoles (1 out of 1) in the pancreas at 100 mg/kg body weight/day for dead rats; significant increase in the incidence of single acinar cell necrosis (3 out of 4) and acinar cell autophagic vacuoles (3 out of 4) in the pancreas at 300 mg/kg body weight/day at the end of the treatment period. The above changes returned to normal at the end of recovery period.


For females, based on obvious increase in mortality (25.0%) at 300 mg/kg body weight/day; obvious increased incidences in moist fur (6 out of 6, 12 out of 12, respectively), and moist fur around mouth (6 out of 6; 10 out of 12, respectively) at 100 and 300 mg/kg body weight/day after administration on clinical observation; significant increase in the absolute and relative liver weights at 300 mg/kg body weight/day; obvious increase in the incidence of necrosis (3 out of 3) and hemorrhage (1 out of 3) in the liver, acinar cell autophagic vacuoles (1 out of 3) in the pancreas at 300 mg/kg body weight/day for dead rat; significant increase in the incidence of single acinar cell necrosis (5 out of 5) and acinar cell autophagic vacuoles (5 out of 5) in the pancreas at 300 mg/kg body weight/day at the end of the treatment period. The changes above returned to normal at the end of recovery period.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable without restrictions
System:
gastrointestinal tract
Organ:
liver
pancreas

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Refer to the OECD Guideline 407, a repeated Dose 28-Day Oral Toxicity Study in Sprague Dawley rats with test item was performed.


According to the results, the no-observed-adverse-effect-level (NOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:


Male rats: 30 mg/kg body weight/day


Female rats: 30 mg/kg body weight/day


The lowest-observed-adverse-effect-level (LOAEL) for test item in the repeated dose 28-day oral toxicity study in SD rats under the condition of the study was considered to be as following:


Male rats: 100 mg/kg body weight/day


Female rats: 100 mg/kg body weight/day


For males, based on obvious increase in mortality (16.7% and 33.3%, respectively) at 100 and 300 mg/kg body weight/day; obvious increased incidences in moist fur (6 out of 6, 12 out of 12, respectively) and moist fur around mouth (6 out of 6, 11 out of 12, respectively) at 100 and 300 mg/kg body weight/day and coat soiled (1 out of 12) at 300 mg/kg body weight/day on clinical observation; significant decrease in mean body weight and body-weight gain at 300 mg/kg body weight/day; significant decrease in tail pinch response scores at 300 mg/kg body weight/day; significant increase (+692.9%) in T-BIL at 300 mg/kg body weight/day; significant increase in PRO level at 300 mg/kg body weight/day; obvious increase in the incidence of necrosis (4 out of 4) and hemorrhage (2 out of 4) in the liver at 300 mg/kg body weight/day for dead rats, and necrosis (1 out of 1) in the liver and acinar cell autophagic vacuoles (1 out of 1) in the pancreas at 100 mg/kg body weight/day for dead rats; significant increase in the incidence of single acinar cell necrosis (3 out of 4) and acinar cell autophagic vacuoles (3 out of 4) in the pancreas at 300 mg/kg body weight/day at the end of the treatment period. The above changes returned to normal at the end of recovery period.


For females, based on obvious increase in mortality (25.0%) at 300 mg/kg body weight/day; obvious increased incidences in moist fur (6 out of 6, 12 out of 12, respectively), and moist fur around mouth (6 out of 6; 10 out of 12, respectively) at 100 and 300 mg/kg body weight/day after administration on clinical observation; significant increase in the absolute and relative liver weights at 300 mg/kg body weight/day; obvious increase in the incidence of necrosis (3 out of 3) and hemorrhage (1 out of 3) in the liver, acinar cell autophagic vacuoles (1 out of 3) in the pancreas at 300 mg/kg body weight/day for dead rat; significant increase in the incidence of single acinar cell necrosis (5 out of 5) and acinar cell autophagic vacuoles (5 out of 5) in the pancreas at 300 mg/kg body weight/day at the end of the treatment period. The changes above returned to normal at the end of recovery period.

Justification for classification or non-classification

28-day repeated oral toxicity (OECD 407):


There were treatment-related toxic pathological changes in live of males in the 100 and 300 mg/kg bw dose groups and females in the 300 mg/kg dose group, and in pancreas of males and females in the 300 mg/kg dose group.


Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.9.1, this substance should be classified as Category 2 for STOT RE endpoint.