Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral, other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From May 30, 2016 to January 04, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Everdirect SH12
- Substance type: Powder
- Composition of test material, percentage of components: 69.96 %
- Lot/batch No.: 3506
- Storage condition of test material: Ambient

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Source: BioLASCO Taiwan Co., Ltd.
- Age at study initiation: about 4-week old
- Housing: Male and female rats were fed, respectively. Two rats per cage in an autoclaved polyethylene cage.
- Acclimation period: 1 week
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15%
- Photoperiod: 12-hrs dark / 12-hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Doses / concentrationsopen allclose all
Dose / conc.:
62.5 mg/kg bw/day (nominal)
Remarks:
Low dose group
Dose / conc.:
250 mg/kg bw/day (nominal)
Remarks:
Medium dose group
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High dose group
No. of animals per sex per dose:
For male: six
For female: six
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
For male rats:
The mean corpuscular hemoglobin concentration (MCHC) of low dose group and lymphocyte in all treatment groups were lower than control group (ρ<0.05). The eosinophil of low and high dose groups and monocyte of medium dose group were higher than control group (ρ<0.05).
For female rats:
The hematocrit (Hct) and mean corpuscular volume (MCV) of medium and high dose groups were significantly lower than control group (ρ<0.05). The mean corpuscular hemoglobin concentration (MCHC) of medium and high dose groups were significantly higher than control group (ρ<0.05).
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
For male rats:
The triglyceride (TG) of high dose group was significantly higher than control group (ρ<0.05).
For female rats:
The alkaline phosphatase (ALP) and the total bile acid (TBA) of low dose group were significantly lower than control group (ρ<0.05). The Ca and globulin of low dose group were significantly higher than control group (ρ<0.05). The alanine aminotransferase (ALT), the triglyceride (TG) and the total bile acid (TBA) of medium dose group were significantly lower than control group (ρ<0.05). The creatinine and the triglyceride (TG) of high dose group were significantly lower than control group (ρ<0.05).
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
For male rats:
The absolute weight of kidney in high dose groups was significantly higher than control group (ρ<0.05). The relative organ weight of kidney in high dose group was significantly higher than control group (ρ<0.05).
For female rats:
The absolute weight of adrenal gland in high dose groups was significantly lower than control group (ρ<0.05). The relative organ weight of adrenal gland in high dose group was significantly lower than control group (ρ<0.05).
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Kidney
Only one male rat in the high dose group showed a focal, slight tubular cyst in the kidney. Two Female rats in the control and one male rat in the high dose groups showed focal, slight tubular infarct in the kidney. Only one female rat in the control group showed focal, slight tubular regeneration in the kidney.
Liver
Only one female rat in the control group presented focal, slight necrosis in the liver.
Lung
One male rat in the control and one female rat in the high dose groups presented focal to multifocal, minimal to slight inflammation in the lungs.
Thyroid gland
Only one female rat in the high dose group presented focal, slight, mononuclear cell infiltration in the thyroid gland. Only one female rat in the high dose group presented focal, slight, macrophage infiltration in the thyroid gland.

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 1 000 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 efficiency
ophthalmological examination
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
According to OECD 407 test method, the NOAEL of Everdirect SH12 for the rats was great than 1000 mg/kg B.W..
Executive summary:

This test using the procedures outlined in the SuperLab Study Plan for M62-151100083001EN and OECD 407 (OECD, 2008).The test article was administered to the three treatment groups by oral gavage in a dose of 62.5, 250 and 1000 mg/kg B.W. for 28 consecutive days. There were six male and six female Sprague-Dawley rats in each group. Clinical observation of the rats was carried out daily and the body weight and feed intake of the rats were recorded once a week. Results of the study indicated that rats in all group gained weight normally and did not show any abnormal clinical signs and ophthalmological examination during the study period. At end of the study, there were no significant abnormalities of the urinalysis,haematologyand clinical biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated that no treatment-related change was found. On the basis of the test results given above, the NOAEL of Everdirect SH12 for the rats was great than 1000 mg/kg B.W..