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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Repeated Dose 28 day oral toxicity study in rodents (No. 407) published by the Ministry of Environmental Protection of People's Republic of China in 2013
GLP compliance:
yes
Limit test:
yes

Test material

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Specific Pathogen Free
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test System
Species: Rat
Strain: Sprague Dawley Grade: SPF
Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd. Animal Production License: SCXK. (Jing) 2016-0006
Animal Certificate No.: 11400700328644
Number of Animals: 80 animals (40 males and 40 females) purchased. 72 animals were used (36 males, 36 females)
Body Weight: The body weights were between 194.40-261.81 g for male rats and 183.50-211.74 g for female rats.

Physical Examination and Acclimatization: Physical check up and acclimation were made to all animals arrived. Healthy young adult animals were acclimatized to the laboratory conditions and housed in the facility two per cage for 6 days prior to the test. Clinical observations were performed daily until treatment. All animals were weighed and marked by the special animal markers on the hair and number written on cage cards within 24 hours after arrival.

Test conditions:
Husbandry: Animals were housed in Room D106 in the barrier system of the facility. Animals were raised in suspended, stainless steel cages on cage racks. There were 10 cages per layer, and 4 layers per rack. Animals were housed two per cage for the convenience of food consumption amount calculation for each animal per day during the test.

Environmental Controls: The temperature and humidity were automatically controlled and recorded. The target value of animal room temperature was 20°C -25°C,
of the relative humidity was 40%- 70% and light cycle was 12 hour light and 12 hour dark.

Food and Water: Animals were provided with rodent complete nutrition pellet diet supplied by Beijing keaoxieli Feed CO., LTD. Analysis report of diet was provided by the supplier. Water was purified using the HT-ROlOOO purity system. Drinking water was routinely analyzed. Diet and drinking water were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. During the test, diet and water were available to the animals ad libitum except exposure and pre-adaption.

Animal Welfare: The animal use for this study complies with the national animal welfare laws and regulations (instructive notions with respect to caring for laboratory animals) (2006, PRC Ministry of Science). The animal care and use activities required for conduct of this study were reviewed and approved by the testing facility Animal Care and Use Committee (IACUC). The spare 8 animals were euthanised by CO2

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Animals were administered with the test item solutions and control animals were administered with the vehicle once daily for 28 days. Dosing volumes were all 10mL/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The study dose designation was based on the toxicity data of the pre-study results, where male and female animals were administered by the dose groups 50mg/kg, 500mg/kg and 1000mg/kg for 7 days.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily
No. of animals per sex per dose:
Control- 12 males, 12 females
10mg/kg*bw - 6 males, 6 females
40mg/kg*bw - 6 males, 6 females
160mg/kg*bw - 12 males, 12 females
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
All animals were continuously observed for 28 days dosing period. The control animals and animals in the high dose groups were observed for another 14 days to detect the reversibility, persistence and delayed toxic effects of toxic reactions.
Sacrifice and pathology:
Animals surviving to the end of the study were euthanised by CO2 inhalation followed be exsanguinations from abdominal aorta. Spare animals were also euthanised by CO2 inhalation.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Male animals: No abnormal results observed
Female animals: Hair loss of high dose animals were observed after 7 days of administration and lasted until the end of the recovery period.
The percentage of animals exhibiting hair loss was 41.7% which was higher incidence than the control and other dose groups and was considered to be related to the test item.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male animals: No significant change in body weight observed
Female animals: Average body weights were significantly lower than those in the control group (p<=0.001), and recovered during the recovery period. The 1st recovery week's average body weight gain increased significantly as compared with those of control group (p<=0.05) The decreased weights were considered to be related to the test item.
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Urinalysis findings:
no effects observed

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
haematology
mortality
organ weights and organ / body weight ratios
urinalysis
other: coagulation examination
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 160 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
haematology
organ weights and organ / body weight ratios
urinalysis
other: coagulation examination

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
According to the above results, E Stage 3 intermediate in repeated dose 28-day oral toxicity study in SD rats under the condition of the study, female rats of 160mg/kg*bw showed decreasing bodyweight slightly and hair loss symptom, which had test-item related effects. The decreased bodyweights recovered at end of the recovery period, while the hair loss lasted until the end of the recovery period. All male rats didn't show any test item related toxicity effects.

The no observed adverse effect level (NOAEL) for repeated dose 28-day oral toxicity study in SD rats were considered to be:
Males: 160mg/kg*bw
Females: 40mg/kg*bw