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EC number: 235-101-0 | CAS number: 12068-53-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- July 04, 2016 - April 24, 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- October 3, 2008
- Deviations:
- yes
- Remarks:
- No analytic was performed as the test substance is a poor soluble inorganic substance, that is stable under the conditions. The test material was freshly prepared every day.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Dialuminium zinc tetraoxide
- EC Number:
- 235-101-0
- EC Name:
- Dialuminium zinc tetraoxide
- Cas Number:
- 12068-53-0
- Molecular formula:
- ZnAl2xO(3x+1), x = 1 – 9
- IUPAC Name:
- dialuminum; zinc(2+); oxygen(2-)
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- SPF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing Vital River Laboratory Animal Co., LTD.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 - 7 weeks
- Weight at study initiation: 184.5 to 213.9 g of males and 157.4 to 186.7 g of females
- Fasting period before study: none
- Housing: ≤ 5 animals of same sex were housed in polycarbonate cages (L x W x H: 400mm x 250mm x 200 mm) bedding with corn cob.
- Diet: Irradiated rodent diet (Shanghai Puluteng Bio-technology Co., Ltd, Feed Production Certificate No: Hu Si Zheng (2014) 04001), Lot. No.: M02-F-20160419004 (valid till 18. Oct 2016); ad libitum
- Water: drinking water purified by reverse osmosis, ad libitum
- Acclimation period: 6 days
DETAILS OF FOOD AND WATER QUALITY:
The bedding material evaluation for contaminants was performed according to the national standard GB 14924.2-2001. The food evaluation for nutrients was performed by the supplier according to the Chinese national standard GB 14924.3-2010, for contaminants according to GB 14924.2-2001. The total bacteria numbers evaluation of water was performed according to the national standard for drinking water GB 5749-2006 monthly in the facility and the evaluation for contaminations was performed twice a year by the supplier according to GB 5749-2006. There were no findings that could interfere with the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.85 to 24.90, automatically controlled by air conditioner (Honeywell EBI)
- Humidity (%): 46.45 to 71.20
- Photoperiod (hrs dark / hrs light): 12/12 (from 7:30 to 19:30), artificial lighting
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Water for injection
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS
The test article was accurately weighed for each dose level, and the vehicle (control article) was added to achieve the prescribed concentrations. The suspsions were stirred with a stirrer. The formulation was stored at room temperature ( 15 - 25 °C) for the use on the day.
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. (if required): M16040405 and M16061014 - Analytical verification of doses or concentrations:
- no
- Remarks:
- No analytic was performed. The test material was freshly prepared every day. During the dosing process, the formulations were continuously stirred on the magnet mixer.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10 male/10 female for control and high dose group (1000 mg/kg bw/day)
5 male/5 female for mid and low dose group (100 mg/kg bw/day and 300 mg/kg bw/day) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: Based on the result of a single dose exposure study (LD50 > 2000 mg/kg bw)
- Post-exposure recovery period in satellite groups: yes
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, consumption of food and water
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule of regular clinical observation: All animals were observed each day after dosing for signs of appearance, behavioural changes, mental state, glandular secretion, respiratory status, faecal traits and colour, genitals, mortality and other toxic manifestations.
- Time schedule of detailed clinical observations: Once before dosing, once a week from week 1 to week 4, and once in the last recovery week all animals were observed in home-cage observation, hand-held observation, open-field observation, and stimulation reflex test. The open-field observation of each animal was about 3 minutes.
- Grip strength: Once in the 4th week of treatment and last week of recovery using Grip Strength Meter.
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed once a week. The last measurement was performed prior to necropsy.
FOOD CONSUMPTION: Yes
- Time schedule: The quantity of food consumed in each cage was measured at weekly intervals throughout the study.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the scheduled day of necropsy
- Anaesthetic used for blood collection: Yes, 60 mg/kg bw pentobarbital sodium, ip
- Animals fasted: Yes, 12 hours prior to blood collection
- How many animals: 5 rats/sex of each treatment group; 5 rats/sex of control group and 1000 mg/kg bw of the recovery groups
- Parameters examined: Red blood cell count (RBC), Hematocrit (HCT), Hemoglobin concentration (HGB), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Reticulocyte count (RET), Reticulocyte count percentage (%RET), White blood cell count (WBC), Differential count of WBC (Neutrophil, Eosinophil, Basophil, Monocyte and Lymphocyte), Platelet count (PLT), Prothrombin time (PT), Activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the scheduled day of necropsy
- Animals fasted: Yes, 12 hours prior to blood collection
- How many animals: 5 rats/sex of each dose groups and 5 rats/sex of control group and 1000 mg/kg bw/day group
- Parameters checked: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Creatine kinase (CK), Lactate dehydrogenase (LDH), Total bilirubin (T-Bil), Urea nitrogen (UN) ,Creatinine (Crea), Total protein (TP), Albumin/globulin ratio (A/G ratio), Albumin (ALB), Glucose (GLU), Cholesterol (CHOL), Triglycerides (TG), Sodium (Na+), Calcium (Ca), Potassium (K+), Chloride (Cl-) and Phosphorus (P)
URINALYSIS: Yes
- Time schedule for collection of urine: the last week of dosing and recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked: Urine volume, Appearance, Glucose (GLU), Bilirubin (BIL), Ketones (KET), Specific gravity (SG), Occult blood (BLO), pH, Total protein (PRO), Urobilinogen (URO), Nitrites (NIT), White blood cell (WBC)
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
OTHERS: Sexual cycle
- Time schedule for sampling: on the scheduled day of necropsy
- How many animals: all females
- Parameters checked: Vaginal Smears - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
The macroscopic appearance of the tissues of all rats was recorded and samples of the following tissues were preserved for histopathology: adrenals, aorta, brain (medullary, cerebellar and cerebral sections), breast, caecum, colon, duodenum, epididymides, eye, fallopian tube , femur (with joint, bone marrow ), heart, hypophysis, ileum (incl. Peyer's patches), jejunum, kidneys, liver, lymph nodes (mandibular and mesentric), lungs (all lobes, mainstem bronchi), lymph nodes, mesentery lymph node, oesophagus, optic nerve, ovaries, parathyroid gland, pancreas, prostate, rectum, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle (biceps femoris), skin (groin), spinal cord (neck, chest, waist), spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus (with cervix), vagina, other macroscopically abnormal tissue.
Testes/epididymides, eye/optic nerve were fixed in modified Davidson‘s solution. All other tissues were preserved in buffered 10% formalin.
The following ogans from each animal were weighed: brain, spleen, thymus, liver, kidneys, heart, adrenals, testis, epididymides, prostate with seminal vesicle and coagulating gland, uterus, ovary thyroid parathyroid gland
HISTOPATHOLOGY: Yes
Microsccopic examination of prepared slides (from tissues indicated under gross pathology) was carried out for all animals of the control and high-dose group. - Statistics:
- Quantitative data such as body weight, food consumption (excluding recovery period data), haematology, clinical chemistry, urine volume, organ weight and ratios, number of rearing, number of faecal particles, number of urination, grip strength were presented as group mean ± standard deviation. Qualitative data (binomial categories data, unordered multi-categories data and ordinal data) such as urinary analysis, home-cage observation, hand-held observation, open-field observation (excluding number of rearing, number of faecal particles, number of urination) and stimulus response observation were presented as observed counts (frequency). When sample size was less than three, raw data of that group were directly presented without statistical comparison.
All pairwise comparison was performed between control group and each treatment group.
Analyses were performed according to sex at two-tailed probability level (α=0.05). PRISTIMA 6.1.1 was used for statistical analysis of body weight, food consumption, haematology, clinical chemistry, organ weight and ratios. The other data were statistically analyzed with Statistical Product and Service Solutions (SPSS 13.0 for Windows).
The results of histopathology were described.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No abnormalities were observed in spontaneous activity, general state, skin and hair of all groups of animals in the dosing and recovery period.
- Mortality:
- no mortality observed
- Description (incidence):
- No unscheduled deaths occurred during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences were observed in all test substance groups of animals when compared to the control during the dosing and recovery period (p>0.05).
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The food consumption was statistically significant increased for males (100 mg/kg bw/day group) on Day 7 and for females (1000 mg/kg bw/day) on recovery Day 13. A statistically significant decreased food consumption for males (1000 mg/kg bw/day) on Day 27 (p<0.05) was observed. These changes are considered to be normal test fluctuations and have no toxicological relevance.
- 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 statistically significant differences were observed in all groups of animals when compared to the control group during the dosing and recovery period (p>0.05).
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant increased glucose (GLU) levels at 300 mg/kg bw/day and 1000 mg/kg bw/day, as well as statistically significant increased phospor (P) levels at 1000 mg/kg bw/day were observed in females at the end of dosing the period when compared to the respective controls. Statistically significant decreased triglyceride (TG) levels were observed in males at 300 mg/kg bw/day at the end of dosing period compared to the control group. A statistically significant increased total bilirubin (T-Bil) level at 1000 mg/kg bw at the end of recovery was observed in males when compared to the control group. However, all these observations are not considered toxicologically relevant for the following reasons: The decrease of TG was not dose-related and the difference was slight. The increase of T-Bil occurred in the recovery period and was within the fluctuation range of animals at the same age in the laboratory (0.37 – 1.8 µmol/L). The increase of GLU and P was slight compared to the control and within the fluctuation range of females at the same age in the laboratory (GLU: 4.59 – 8.32 mmol/L, P: 1.70 – 2.96 mmol//L).
In addition, at the end of the treatment period there was no statistically significant differences between treatment and control groups in ALP, ALT, AST, urea, Crea, CK, LDH, ALB, A/G, CHOL, TP, Ca, Cl-, K+, Na+ in females and males (p> 0.05). At the end of the recovery period, the difference of blood biochemical indices at 1000 mg/kg bw/day group were not statistically significant different compared to the control groups both in females and males (p>0.05). - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No statistically significant difference in any of the urinary parameters between treament and control groups was observed at the end of treatment and recovery period (p>0.05).
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant increase in grip strength was observed in females at 1000 mg/kg bw/day in the 4th week of treatment and in males at the end of recovery period (p<0.05). Those observations are not considered toxiclogical relevant as it is an increased in grip strength only. In addition, there was no statistical significant difference from control group observed on grip strength in males at 100, 300 and 1000 mg/kg bw/day group in the 4th week of treatment as well as in females at 100 and 300 mg/kg bw/day. At the end of the recovery period treated female animals did not show a statistically significant difference compared to the controls in grip strength. Since the differences were slight and observed on grasping only, this is considered not treamtent-related.
No statistically significant differences were observed in the hand-held observations, open-field observation in animals of treatment groups compared to the control groups at the end of dosing and recovery period (p>0.05).
No statistically significant difference in any treatment group in stimulus response, i.e. alertness response, abdominal tension, auricle reflex, pinch reflex, reflexive reflex and pupil reflex was observed compared to the control group (p>0.05) on Day 5, 12 19 and 26 and on Day 12 of the recovery period. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant differences were observed in females at 1000 mg/kg bw/day with decreased thymus weight, thymus/body weight ratio and thymus/brain weight ratio compared to the control group at the end of the recovery period (p<0.05). The differences were slight (<= 16.85%) and it appeared in recovery period only. Furthermore, as no statistically significance was observed in the dosing period and no organ abnormalities were observed in the histopathological examinations, the observation was considered to be normal test fluctuations and are considered not toxicologically relevant.
No statistically significant differences of treated animals compared to the control groups were observed in the weight and weight ratio of other organs at the end of the treament period as well as at the end of the recovery period (p>0.05).
Slight increase of uterine weight was observed in individual females. The vaginal smear cycle examination, which was made on the day of necropsy, revealed that the animals with increased weight of the uterus were in the emotional period. Thus, this is the normal phenomenon of the estrus, not treatment related. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment related gross findings were observed in brain, heart, liver, lung, kidney, spleen, gastrointestinal tract and germinal system at the end of dosing and recovery period.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related pathological alterations were observed in brain, heart, liver, lung, kidney, spleen, thymus gland, ovary, uterus, testes, epididymides, pancreas, bone marrow, gastrointestinal tract and other organs at the end of dosing and recovery period.
There were no statistically significant abnormalities observed in the treatment groups compared to control groups in the histopathological examinations in ovaries/uterus/vagina with the vaginal smear cycle examination made on the day of necropsy. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related adverse effects observed
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1 Effects on Body Weight of Males (g)
Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
Pre-dosing |
10 |
201.5 ± 8.7 |
5 |
203.9 ± 6.5 |
5 |
203.2 ± 8.4 |
10 |
201.1 ± 8.2 |
Day 5 |
10 |
249.5 ± 13.4 |
5 |
249.0 ± 9.4 |
5 |
249.1 ± 10.5 |
10 |
247.4 ± 9.6 |
Day 12 |
10 |
303.8 ± 20.1 |
5 |
307.7 ± 15.4 |
5 |
303.4 ± 15.0 |
10 |
305.1 ± 16.5 |
Day 19 |
10 |
348.8 ± 25.7 |
5 |
358.8 ± 22.2 |
5 |
340.3 ± 21.5 |
10 |
350.5 ± 24.3 |
Day 26 |
10 |
392.4 ± 33.6 |
5 |
401.7 ± 29.0 |
5 |
383.3 ± 18.4 |
10 |
395.6 ± 33.3 |
Recovery day 5 |
5 |
405.7 ± 46.4 |
/ |
/ |
/ |
/ |
5 |
425.9 ± 47.3 |
Recovery day 12 |
5 |
429.7 ± 53.7 |
/ |
/ |
/ |
/ |
5 |
450.2 ± 51.4 |
Notes: * Statistical significance was noted when compared with the control (p≤0.05).
Table 2 Effects for D-Prism via Oral Gavage on Body Weight of Females (g)
Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
Pre-dosing |
10 |
173.1 ± 7.4 |
5 |
172.6 ± 8.9 |
5 |
172.3 ± 8.9 |
10 |
174.3 ± 6.3 |
Day 5 |
10 |
191.7 ± 7.9 |
5 |
191.2 ± 6.3 |
5 |
184.3 ± 9.4 |
10 |
191.9 ± 4.8 |
Day 12 |
10 |
210.4 ± 15.0 |
5 |
213.2 ± 9.5 |
5 |
206.1 ± 9.8 |
10 |
209.8 ± 11.0 |
Day 19 |
10 |
225.6 ± 18.7 |
5 |
228.7 ± 11.9 |
5 |
220.8 ± 13.2 |
10 |
221.8 ± 12.3 |
Day 26 |
10 |
231.4 ± 20.9 |
5 |
243.6 ± 18.3 |
5 |
235.9 ± 16.6 |
10 |
232.8 ± 18.6 |
Recovery day 5 |
5 |
235.6 ± 27.3 |
/ |
/ |
/ |
/ |
5 |
237.3 ± 18.8 |
Recovery day 12 |
5 |
244.0 ± 27.4 |
/ |
/ |
/ |
/ |
5 |
245.6 ± 13.4 |
Table 3 Effects on Hematology of Males
Parameters Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
WBC (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
5.36 ± 0.89 |
5 |
6.49 ± 1.27 |
5 |
6.05 ± 1.94 |
5 |
6.34 ± 2.59 |
At necropsy of the recovery period |
5 |
5.36 ± 1.20 |
/ |
/ |
/ |
/ |
5 |
5.50 ± 1.56 |
NEU% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
14.8 ± 3.6 |
5 |
12.4 ± 3.5 |
5 |
14.2 ± 4.2 |
5 |
14.8 ± 2.7 |
At necropsy of the recovery period |
5 |
14.3 ± 3.3 |
/ |
/ |
/ |
/ |
5 |
18.1 ± 4.7 |
LYM% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
81.5 ± 3.6 |
5 |
83.7 ± 4.3 |
5 |
81.8 ± 3.8 |
5 |
81.7 ± 2.7 |
At necropsy of the recovery period |
5 |
81.9 ± 3.4 |
/ |
/ |
/ |
/ |
5 |
78.1 ± 5.2 |
MONO% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.6 ± 0.6 |
5 |
1.7 ± 1.0 |
5 |
1.4 ± 0.1 |
5 |
1.3 ± 0.3 |
At necropsy of the recovery period |
5 |
1.8 ± 0.3 |
/ |
/ |
/ |
/ |
5 |
1.7 ± 0.6 |
EOS% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.82 ± 0.08 |
5 |
0.94 ± 0.21 |
5 |
1.04 ± 0.09 |
5 |
1.02 ± 0.47 |
At necropsy of the recovery period |
5 |
0.96 ± 0.23 |
/ |
/ |
/ |
/ |
5 |
1.06 ± 0.24 |
BASO% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.22 ± 0.08 |
5 |
0.32 ± 0.11 |
5 |
0.28 ± 0.08 |
5 |
0.28 ± 0.08 |
At necropsy of the recovery period |
5 |
0.14 ± 0.05 |
/ |
/ |
/ |
/ |
5 |
0.20 ± 0.07 |
NEU (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.80 ± 0.27 |
5 |
0.84 ± 0.38 |
5 |
0.87 ± 0.38 |
5 |
0.88 ± 0.13 |
At necropsy of the recovery period |
5 |
0.75 ± 0.18 |
/ |
/ |
/ |
/ |
5 |
1.01 ± 0.40 |
LYM (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
4.36 ± 0.72 |
5 |
5.39 ± 0.77 |
5 |
4.94 ± 1.60 |
5 |
5.24 ± 2.38 |
At necropsy of the recovery period |
5 |
4.41 ± 1.09 |
/ |
/ |
/ |
/ |
5 |
4.28 ± 1.18 |
MONO (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.09 ± 0.03 |
5 |
0.12 ± 0.10 |
5 |
0.08 ± 0.03 |
5 |
0.08 ± 0.02 |
At necropsy of the recovery period |
5 |
0.10 ± 0.02 |
/ |
/ |
/ |
/ |
5 |
0.10 ± 0.05 |
EOS (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.046 ± 0.011 |
5 |
0.064 ± 0.022 |
5 |
0.062 ± 0.016 |
5 |
0.062 ± 0.026 |
At necropsy of the recovery period |
5 |
0.052 ± 0.016 |
/ |
/ |
/ |
/ |
5 |
0.060 ± 0.016 |
BASO (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.012 ± 0.004 |
5 |
0.024 ± 0.009 |
5 |
0.016 ± 0.009 |
5 |
0.020 ± 0.017 |
At necropsy of the recovery period |
5 |
0.010 ± 0.000 |
/ |
/ |
/ |
/ |
5 |
0.010 ± 0.007 |
RBC (1012/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
7.43 ± 0.55 |
5 |
7.20 ± 0.35 |
5 |
7.36 ± 0.25 |
5 |
7.13 ± 0.40 |
At necropsy of the recovery period |
5 |
7.25 ± 0.35 |
/ |
/ |
/ |
/ |
5 |
7.33 ± 0.28 |
HGB (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
144 ± 8 |
5 |
145 ± 5 |
5 |
146 ± 2 |
5 |
143 ± 5 |
At necropsy of the recovery period |
5 |
147 ± 4 |
/ |
/ |
/ |
/ |
5 |
148 ± 4 |
HCT (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
44.5 ± 2.4 |
5 |
44.4 ± 2.2 |
5 |
43.9 ± 1.3 |
5 |
43.3 ± 0.6 |
At necropsy of the recovery period |
5 |
41.7 ± 1.4 |
/ |
/ |
/ |
/ |
5 |
42.2 ± 1.1 |
MCV (fL) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
60.1 ± 3.2 |
5 |
61.6 ± 2.0 |
5 |
59.7 ± 2.2 |
5 |
60.8 ± 2.6 |
At necropsy of the recovery period |
5 |
57.6 ± 1.8 |
/ |
/ |
/ |
/ |
5 |
57.5 ± 1.2 |
MCH (pg) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
19.5 ± 1.2 |
5 |
20.2 ± 0.8 |
5 |
19.9 ± 0.8 |
5 |
20.1 ± 1.6 |
At necropsy of the recovery period |
5 |
20.3 ± 0.8 |
/ |
/ |
/ |
/ |
5 |
20.3 ± 0.7 |
MCHC (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
324 ± 3 |
5 |
327 ± 5 |
5 |
333 ± 11 |
5 |
331 ± 14 |
At necropsy of the recovery period |
5 |
352 ± 4 |
/ |
/ |
/ |
/ |
5 |
353 ± 6 |
PLT (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1080 ± 72 |
5 |
1087 ± 120 |
5 |
1082 ± 64 |
5 |
1084 ± 110 |
At necropsy of the recovery period |
5 |
1018 ± 103 |
/ |
/ |
/ |
/ |
5 |
912 ± 73 |
RET % (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.06 ± 0.40 |
5 |
2.04 ± 0.45 |
5 |
1.90 ± 0.26 |
5 |
2.30 ± 0.44 |
At necropsy of the recovery period |
5 |
1.91 ± 0.45 |
/ |
/ |
/ |
/ |
5 |
1.83 ± 0.25 |
RET (1012/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.152 ± 0.027 |
5 |
0.146 ± 0.029 |
5 |
0.139 ± 0.017 |
5 |
0.166 ± 0.024 |
At necropsy of the recovery period |
5 |
0.137 ± 0.024 |
/ |
/ |
/ |
/ |
5 |
0.135 ± 0.018 |
APTT (sec) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
13.9 ± 1.1 |
5 |
13.1 ± 2.0 |
5 |
13.9 ± 1.9 |
5 |
13.9 ± 1.9 |
At necropsy of the recovery period |
5 |
15.1 ± 2.1 |
/ |
/ |
/ |
/ |
5 |
13.9 ± 1.3 |
PT (sec) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
8.4 ± 0.4 |
5 |
8.6 ± 0.4 |
5 |
8.7 ± 0.9 |
5 |
8.3 ± 0.2 |
At necropsy of the recovery period |
5 |
8.9 ± 0.2 |
/ |
/ |
/ |
/ |
5 |
9.0 ± 0.4 |
Notes: * Statistical significance was noted when compared with the control (p≤0.05).
Table 4 Effects on Hematology of Females
Parameters Detection time |
Control |
100 mg/kg bw/daygroup |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
WBC (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
3.84 ± 0.64 |
5 |
3.62 ± 1.06 |
5 |
3.26 ± 1.61 |
5 |
3.57 ± 0.70 |
At necropsy of the recovery period |
5 |
3.81 ± 0.57 |
/ |
/ |
/ |
/ |
5 |
4.29 ± 1.50 |
NEU% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
13.0 ± 1.8 |
5 |
17.7 ± 4.7 |
5 |
15.9 ± 4.9 |
5 |
16.9 ± 5.4 |
At necropsy of the recovery period |
5 |
14.8 ± 5.4 |
/ |
/ |
/ |
/ |
5 |
14.5 ± 6.2 |
LYM% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
83.6 ± 2.3 |
5 |
78.2 ± 4.6 |
5 |
80.6 ± 5.4 |
5 |
79.5 ± 6.0 |
At necropsy of the recovery period |
5 |
80.4 ± 6.7 |
/ |
/ |
/ |
/ |
5 |
82.0 ± 6.0 |
MONO% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.3 ± 0.3 |
5 |
1.8 ± 0.5 |
5 |
1.4 ± 0.3 |
5 |
1.4 ± 0.6 |
At necropsy of the recovery period |
5 |
1.6 ± 0.8 |
/ |
/ |
/ |
/ |
5 |
1.4 ± 0.5 |
EOS% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.12 ± 0.52 |
5 |
1.30 ± 0.10 |
5 |
1.24 ± 0.19 |
5 |
1.24 ± 0.67 |
At necropsy of the recovery period |
5 |
2.02 ± 1.11 |
/ |
/ |
/ |
/ |
5 |
1.18 ± 0.45 |
BASO% (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.24 ± 0.11 |
5 |
0.24 ± 0.11 |
5 |
0.18 ± 0.11 |
5 |
0.16 ± 0.05 |
At necropsy of the recovery period |
5 |
0.20 ± 0.07 |
/ |
/ |
/ |
/ |
5 |
0.14 ± 0.11 |
NEU (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.49 ± 0.06 |
5 |
0.61 ± 0.05 |
5 |
0.57 ± 0.47 |
5 |
0.59 ± 0.19 |
At necropsy of the recovery period |
5 |
0.55 ± 0.15 |
/ |
/ |
/ |
/ |
5 |
0.60 ± 0.26 |
LYM (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
3.22 ± 0.60 |
5 |
2.87 ± 1.00 |
5 |
2.57 ± 1.08 |
5 |
2.87 ± 0.72 |
At necropsy of the recovery period |
5 |
3.09 ± 0.69 |
/ |
/ |
/ |
/ |
5 |
3.54 ± 1.35 |
MONO (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.05 ± 0.01 |
5 |
0.07 ± 0.03 |
5 |
0.05 ± 0.03 |
5 |
0.05 ± 0.01 |
At necropsy of the recovery period |
5 |
0.06 ± 0.02 |
/ |
/ |
/ |
/ |
5 |
0.05 ± 0.01 |
EOS (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.042 ± 0.019 |
5 |
0.048 ± 0.013 |
5 |
0.044 ± 0.028 |
5 |
0.040 ± 0.012 |
At necropsy of the recovery period |
5 |
0.074 ± 0.030 |
/ |
/ |
/ |
/ |
5 |
0.048 ± 0.011 |
BASO (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.010 ± 0.007 |
5 |
0.010 ± 0.007 |
5 |
0.004 ± 0.005 |
5 |
0.004 ± 0.005 |
At necropsy of the recovery period |
5 |
0.008 ± 0.004 |
/ |
/ |
/ |
/ |
5 |
0.006 ± 0.009 |
RBC (1012/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
7.03 ± 0.45 |
5 |
6.84 ± 0.22 |
5 |
6.87 ± 0.12 |
5 |
6.76 ± 0.16 |
At necropsy of the recovery period |
5 |
7.13 ± 0.27 |
/ |
/ |
/ |
/ |
5 |
6.99 ± 0.18 |
HGB (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
137 ± 6 |
5 |
134 ± 5 |
5 |
137 ± 6 |
5 |
134 ± 4 |
At necropsy of the recovery period |
5 |
141 ± 3 |
/ |
/ |
/ |
/ |
5 |
138 ± 4 |
HCT (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
41.2 ± 1.7 |
5 |
40.6 ± 1.4 |
5 |
40.8 ± 1.9 |
5 |
39.8 ± 1.2 |
At necropsy of the recovery period |
5 |
40.2 ± 0.8 |
/ |
/ |
/ |
/ |
5 |
39.1 ± 1.0 |
MCV (fL) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
58.6 ± 1.2 |
5 |
59.4 ± 1.7 |
5 |
59.4 ± 2.0 |
5 |
58.9 ± 0.9 |
At necropsy of the recovery period |
5 |
56.4 ± 2.0 |
/ |
/ |
/ |
/ |
5 |
56.0 ± 0.9 |
MCH (pg) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
19.6 ± 0.6 |
5 |
19.7 ± 0.5 |
5 |
19.9 ± 0.6 |
5 |
19.9 ± 0.3 |
At necropsy of the recovery period |
5 |
19.8 ± 0.8 |
/ |
/ |
/ |
/ |
5 |
19.7 ± 0.6 |
MCHC (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
334 ± 9 |
5 |
331 ± 4 |
5 |
336 ± 11 |
5 |
338 ± 6 |
At necropsy of the recovery period |
5 |
350 ± 3 |
/ |
/ |
/ |
/ |
5 |
351 ± 6 |
PLT (109/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1150 ± 161 |
5 |
1111 ± 43 |
5 |
1061 ± 100 |
5 |
1126 ± 63 |
At necropsy of the recovery period |
5 |
991 ± 156 |
/ |
/ |
/ |
/ |
5 |
961 ± 67 |
RET % (%) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.03 ± 0.62 |
5 |
2.03 ± 0.56 |
5 |
2.14 ± 0.29 |
5 |
2.16 ± 0.64 |
At necropsy of the recovery period |
5 |
1.77 ± 0.16 |
/ |
/ |
/ |
/ |
5 |
1.66 ± 0.33 |
RET (1012/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.142 ± 0.039 |
5 |
0.139 ± 0.037 |
5 |
0.147 ± 0.020 |
5 |
0.146 ± 0.041 |
At necropsy of the recovery period |
5 |
0.127 ± 0.013 |
/ |
/ |
/ |
/ |
5 |
0.116 ± 0.024 |
APTT (sec) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
13.2 ± 1.2 |
5 |
12.2 ± 1.8 |
5 |
12.2 ± 1.7 |
5 |
12.1 ± 1.1 |
At necropsy of the recovery period |
5 |
13.7 ± 1.1 |
/ |
/ |
/ |
/ |
5 |
12.5 ± 1.8 |
PT (sec) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
7.7 ± 0.5 |
5 |
7.7 ± 0.6 |
5 |
7.6 ± 0.3 |
5 |
7.7 ± 0.3 |
At necropsy of the recovery period |
5 |
7.9 ± 0.6 |
/ |
/ |
/ |
/ |
5 |
8.0 ± 0.4 |
Table 5 Effects on Clinical Chemistry of Males
Parameters Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
ALB (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
38.8 ± 1.2 |
5 |
38.2 ± 0.7 |
5 |
38.5 ± 1.9 |
5 |
38.3 ± 1.0 |
At necropsy of the recovery period |
5 |
37.4 ± 0.9 |
/ |
/ |
/ |
/ |
5 |
38.3 ± 1.6 |
TP (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
56.8 ± 1.5 |
5 |
55.3 ± 1.9 |
5 |
55.2 ± 1.6 |
5 |
55.6 ± 0.4 |
At necropsy of the recovery period |
5 |
53.9 ± 0.3 |
/ |
/ |
/ |
/ |
5 |
55.3 ± 1.7 |
AST (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
105.8 ± 15.2 |
5 |
107.4 ± 19.8 |
5 |
105.6 ± 7.8 |
5 |
102.3 ± 21.5 |
At necropsy of the recovery period |
5 |
93.6 ± 5.7 |
/ |
/ |
/ |
/ |
5 |
88.1 ± 8.4 |
ALT (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
32.2 ± 3.0 |
5 |
31.8 ± 6.8 |
5 |
34.6 ± 7.7 |
5 |
30.4 ± 7.4 |
At necropsy of the recovery period |
5 |
30.6 ± 1.7 |
/ |
/ |
/ |
/ |
5 |
39.8 ± 9.0 |
TBIL (μmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.8 ± 0.1 |
5 |
0.7 ± 0.4 |
5 |
1.0 ± 0.2 |
5 |
0.6 ± 0.1 |
At necropsy of the recovery period |
5 |
1.0 ± 0.2 |
/ |
/ |
/ |
/ |
5 |
1.7 ± 0.4 * |
CK (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
676 ± 222 |
5 |
704 ± 260 |
5 |
652 ± 227 |
5 |
582 ± 141 |
At necropsy of the recovery period |
5 |
439 ± 65 |
/ |
/ |
/ |
/ |
5 |
458 ± 225 |
CHOL (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.30 ± 0.17 |
5 |
1.36 ± 0.37 |
5 |
1.08 ± 0.22 |
5 |
1.33 ± 0.35 |
At necropsy of the recovery period |
5 |
1.29 ± 0.27 |
/ |
/ |
/ |
/ |
5 |
1.41 ± 0.38 |
Ca (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.60 ± 0.03 |
5 |
2.59 ± 0.06 |
5 |
2.60 ± 0.08 |
5 |
2.59 ± 0.07 |
At necropsy of the recovery period |
5 |
2.52 ± 0.05 |
/ |
/ |
/ |
/ |
5 |
2.57 ± 0.03 |
TG (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.75 ± 0.22 |
5 |
0.72 ± 0.19 |
5 |
0.40 ± 0.09 * |
5 |
0.49 ± 0.05 |
At necropsy of the recovery period |
5 |
0.69 ± 0.19 |
/ |
/ |
/ |
/ |
5 |
0.67 ± 0.21 |
Crea (μmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
18.8 ± 2.2 |
5 |
18.0 ± 2.5 |
5 |
17.4 ± 1.1 |
5 |
19.6 ± 3.3 |
At necropsy of the recovery period |
5 |
19.6 ± 2.6 |
/ |
/ |
/ |
/ |
5 |
20.2 ± 0.8 |
GLU (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
6.85 ± 0.29 |
5 |
7.14 ± 0.57 |
5 |
6.26 ± 0.38 |
5 |
7.08 ± 0.67 |
At necropsy of the recovery period |
5 |
6.48 ± 0.45 |
/ |
/ |
/ |
/ |
5 |
7.31 ± 1.08 |
Urea (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
4.72 ± 0.41 |
5 |
4.70 ± 0.66 |
5 |
4.67 ± 0.63 |
5 |
4.80 ± 1.02 |
At necropsy of the recovery period |
5 |
4.32 ± 0.51 |
/ |
/ |
/ |
/ |
5 |
4.87 ± 0.64 |
P (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.76 ± 0.09 |
5 |
2.72 ± 0.09 |
5 |
2.73 ± 0.20 |
5 |
2.95 ± 0.15 |
At necropsy of the recovery period |
5 |
2.30 ± 0.08 |
/ |
/ |
/ |
/ |
5 |
2.46 ± 0.14 |
ALP (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
150.3 ± 25.1 |
5 |
149.2 ± 22.0 |
5 |
165.3 ± 45.0 |
5 |
164.8 ± 34.3 |
At necropsy of the recovery period |
5 |
123.3 ± 18.6 |
/ |
/ |
/ |
/ |
5 |
137.9 ± 35.7 |
LDH (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1137 ± 333 |
5 |
1128 ± 388 |
5 |
1087 ± 340 |
5 |
1060 ± 352 |
At necropsy of the recovery period |
5 |
868 ± 160 |
/ |
/ |
/ |
/ |
5 |
654 ± 159 |
K+(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
4.56 ± 0.28 |
5 |
4.66 ± 0.16 |
5 |
4.51 ± 0.04 |
5 |
4.53 ± 0.12 |
At necropsy of the recovery period |
5 |
4.49 ± 0.15 |
/ |
/ |
/ |
/ |
5 |
4.44 ± 0.12 |
Na+(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
143 ± 1 |
5 |
143 ± 0 |
5 |
144 ± 1 |
5 |
144 ± 1 |
At necropsy of the recovery period |
5 |
144 ± 2 |
/ |
/ |
/ |
/ |
5 |
142 ± 1 |
Cl-(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
101.8 ± 1.2 |
5 |
102.8 ± 0.5 |
5 |
102.3 ± 1.1 |
5 |
101.9 ± 0.7 |
At necropsy of the recovery period |
5 |
101.4 ± 1.3 |
/ |
/ |
/ |
/ |
5 |
100.6 ± 1.3 |
A/G |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.16 ± 0.10 |
5 |
2.26 ± 0.20 |
5 |
2.32 ± 0.18 |
5 |
2.22 ± 0.17 |
At necropsy of the recovery period |
5 |
2.29 ± 0.19 |
/ |
/ |
/ |
/ |
5 |
2.25 ± 0.18 |
Notes: * Statistical significance was noted when compared with the control (p≤0.05).
Table 6 Effects on Clinical Chemistry of Females
Parameters Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
ALB (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
43.9 ± 3.5 |
5 |
44.7 ± 1.5 |
5 |
42.9 ± 2.7 |
5 |
43.6 ± 2.2 |
At necropsy of the recovery period |
5 |
46.1 ± 3.3 |
/ |
/ |
/ |
/ |
5 |
42.4 ± 4.7 |
TP (g/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
61.3 ± 4.0 |
5 |
59.5 ± 2.4 |
5 |
58.3 ± 1.8 |
5 |
58.2 ± 3.6 |
At necropsy of the recovery period |
5 |
61.9 ± 3.8 |
/ |
/ |
/ |
/ |
5 |
57.6 ± 4.0 |
AST (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
105.8 ± 37.2 |
5 |
99.8 ± 16.3 |
5 |
105.5 ± 3.2 |
5 |
97.9 ± 11.8 |
At necropsy of the recovery period |
5 |
93.3 ± 14.1 |
/ |
/ |
/ |
/ |
5 |
93.5 ± 18.7 |
ALT (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
21.8 ± 4.0 |
5 |
25.2 ± 7.2 |
5 |
25.0 ± 5.7 |
5 |
25.8 ± 7.7 |
At necropsy of the recovery period |
5 |
28.0 ± 7.0 |
/ |
/ |
/ |
/ |
5 |
29.6 ± 6.1 |
TBIL (μmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.1 ± 0.2 |
5 |
1.1 ± 0.6 |
5 |
1.1 ± 0.5 |
5 |
1.5 ± 0.3 |
At necropsy of the recovery period |
5 |
1.2 ± 0.3 |
/ |
/ |
/ |
/ |
5 |
0.9 ± 0.1 |
CK (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
763 ± 537 |
5 |
555 ± 178 |
5 |
658 ± 95 |
5 |
526 ± 71 |
At necropsy of the recovery period |
5 |
486 ± 174 |
/ |
/ |
/ |
/ |
5 |
435 ± 142 |
CHOL (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1.50 ± 0.29 |
5 |
1.53 ± 0.36 |
5 |
1.56 ± 0.59 |
5 |
1.55 ± 0.42 |
At necropsy of the recovery period |
5 |
1.55 ± 0.09 |
/ |
/ |
/ |
/ |
5 |
1.40 ± 0.20 |
Ca (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.49 ± 0.06 |
5 |
2.56 ± 0.06 |
5 |
2.50 ± 0.06 |
5 |
2.58 ± 0.07 |
At necropsy of the recovery period |
5 |
2.62 ± 0.06 |
/ |
/ |
/ |
/ |
5 |
2.60 ± 0.03 |
TG (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
0.34 ± 0.17 |
5 |
0.24 ± 0.07 |
5 |
0.23 ± 0.11 |
5 |
0.24 ± 0.08 |
At necropsy of the recovery period |
5 |
0.31 ± 0.06 |
/ |
/ |
/ |
/ |
5 |
0.45 ± 0.30 |
Crea (μmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
26.0 ± 2.3 |
5 |
26.4 ± 4.7 |
5 |
24.8 ± 2.9 |
5 |
25.0 ± 2.5 |
At necropsy of the recovery period |
5 |
28.0 ± 4.2 |
/ |
/ |
/ |
/ |
5 |
31.8 ± 5.3 |
GLU (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
5.90 ± 0.15 |
5 |
6.40 ± 0.64 |
5 |
6.85 ± 0.27 * |
5 |
6.41 ± 0.20 * |
At necropsy of the recovery period |
5 |
6.55 ± 0.14 |
/ |
/ |
/ |
/ |
5 |
6.77 ± 0.54 |
Urea (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
4.82 ± 0.48 |
5 |
4.64 ± 0.41 |
5 |
5.11 ± 0.97 |
5 |
5.06 ± 0.37 |
At necropsy of the recovery period |
5 |
5.32 ± 0.64 |
/ |
/ |
/ |
/ |
5 |
6.38 ± 1.61 |
P (mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.11 ± 0.11 |
5 |
2.19 ± 0.22 |
5 |
2.17 ± 0.14 |
5 |
2.54 ± 0.13 * |
At necropsy of the recovery period |
5 |
1.88 ± 0.22 |
/ |
/ |
/ |
/ |
5 |
2.05 ± 0.34 |
ALP (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
72.5 ± 17.6 |
5 |
73.7 ± 17.2 |
5 |
72.2 ± 16.5 |
5 |
84.1 ± 33.1 |
At necropsy of the recovery period |
5 |
44.9 ± 11.7 |
/ |
/ |
/ |
/ |
5 |
57.4 ± 12.0 |
LDH (U/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
1093 ± 629 |
5 |
1019 ± 328 |
5 |
1150 ± 288 |
5 |
984 ± 180 |
At necropsy of the recovery period |
5 |
934 ± 323 |
/ |
/ |
/ |
/ |
5 |
878 ± 311 |
K+(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
4.13 ± 0.19 |
5 |
4.14 ± 0.25 |
5 |
3.95 ± 0.13 |
5 |
4.10 ± 0.22 |
At necropsy of the recovery period |
5 |
3.98 ± 0.25 |
/ |
/ |
/ |
/ |
5 |
4.00 ± 0.29 |
Na+(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
143 ± 1 |
5 |
143 ± 1 |
5 |
143 ± 1 |
5 |
144 ± 1 |
At necropsy of the recovery period |
5 |
142 ± 1 |
/ |
/ |
/ |
/ |
5 |
143 ± 1 |
Cl-(mmol/L) |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
102.7 ± 1.6 |
5 |
103.3 ± 1.2 |
5 |
103.7 ± 1.2 |
5 |
103.8 ± 0.7 |
At necropsy of the recovery period |
5 |
101.1 ± 0.5 |
/ |
/ |
/ |
/ |
5 |
101.8 ± 1.2 |
A/G |
|
|
|
|
|
|
|
|
At necropsy of the dosing period |
5 |
2.54 ± 0.28 |
5 |
3.03 ± 0.17 |
5 |
2.81 ± 0.39 |
5 |
3.04 ± 0.43 |
At necropsy of the recovery period |
5 |
2.91 ± 0.27 |
/ |
/ |
/ |
/ |
5 |
2.80 ± 0.45 |
Table 7 Effects of D-Prism via Oral Gavage on Urine parameters of Males
Parameters |
Detection time Grade |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
Urine color |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
Yellow |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
Yellow |
5 |
/ |
/ |
4 |
|
Dull yellow |
0 |
/ |
/ |
1 |
Urine clarity |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
Clear |
4 |
2 |
4 |
2 |
|
Turbidness |
1 |
3 |
1 |
3 |
|
Recovery day 14 |
|
|
|
|
|
Clear |
2 |
/ |
/ |
1 |
|
Turbidness |
3 |
/ |
/ |
4 |
GLU(mmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
BIL |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
KET(mmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
4 |
5 |
4 |
|
1.5 |
0 |
1 |
0 |
1 |
|
Recovery day 14 |
|
|
|
|
|
- |
2 |
/ |
/ |
4 |
|
1.5 |
3 |
/ |
/ |
1 |
SG |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
<=1.005 |
0 |
0 |
2 |
0 |
|
1.010 |
1 |
2 |
0 |
0 |
|
1.015 |
1 |
2 |
1 |
5 |
|
1.020 |
2 |
1 |
2 |
0 |
|
1.025 |
1 |
0 |
0 |
0 |
|
Recovery day 14 |
|
|
|
|
|
<=1.005 |
1 |
/ |
/ |
0 |
|
1.010 |
0 |
/ |
/ |
1 |
|
1.015 |
2 |
/ |
/ |
1 |
|
1.020 |
0 |
/ |
/ |
1 |
|
1.025 |
1 |
/ |
/ |
0 |
|
>1.030 |
1 |
/ |
/ |
2 |
BLO(Ery/μL) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
pH |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
7.5 |
0 |
1 |
1 |
0 |
|
8.0 |
4 |
4 |
3 |
4 |
|
8.5 |
1 |
0 |
1 |
1 |
|
Recovery day 14 |
|
|
|
|
|
6.0 |
1 |
/ |
/ |
1 |
|
8.0 |
2 |
/ |
/ |
0 |
|
8.5 |
2 |
/ |
/ |
4 |
PRO(g/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
4 |
3 |
|
0.3 |
0 |
0 |
1 |
2 |
|
Recovery day 14 |
|
|
|
|
|
- |
2 |
/ |
/ |
3 |
|
0.3 |
3 |
/ |
/ |
2 |
URO (μmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
3.2 |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
3.2 |
5 |
/ |
/ |
5 |
NIT |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
4 |
|
+ |
0 |
/ |
/ |
1 |
WBC(Leu/μL) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
4 |
5 |
5 |
5 |
|
15 |
1 |
0 |
0 |
0 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
3 |
|
15 |
0 |
/ |
/ |
2 |
Notes: * Statistical significance was noted when compared with the control (P≤0.05).
Table 8 Effects of D-Prism via Oral Gavage on Urine parameters of Females
Parameters |
Detection time Grade |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
Urine color |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
Yellow |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
Yellow |
5 |
/ |
/ |
5 |
Urine clarity |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
Clear |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
Clear |
4 |
/ |
/ |
4 |
|
Turbidness |
0 |
/ |
/ |
1 |
|
Dirty |
1 |
/ |
/ |
0 |
GLU(mmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
BIL |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
KET(mmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
SG |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
<=1.005 |
2 |
2 |
2 |
1 |
|
1.010 |
2 |
3 |
3 |
0 |
|
1.015 |
1 |
0 |
0 |
3 |
|
1.020 |
0 |
0 |
0 |
1 |
|
Recovery day 14 |
|
|
|
|
|
<=1.005 |
1 |
/ |
/ |
2 |
|
1.010 |
2 |
/ |
/ |
1 |
|
1.015 |
1 |
/ |
/ |
1 |
|
1.020 |
0 |
/ |
/ |
1 |
|
1.025 |
1 |
/ |
/ |
0 |
BLO(Ery/μL) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
pH |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
7.5 |
0 |
0 |
1 |
1 |
|
8.0 |
4 |
4 |
3 |
4 |
|
8.5 |
1 |
1 |
1 |
0 |
|
Recovery day 14 |
|
|
|
|
|
6.5 |
1 |
/ |
/ |
1 |
|
7.0 |
0 |
/ |
/ |
2 |
|
7.5 |
1 |
/ |
/ |
0 |
|
8.0 |
3 |
/ |
/ |
1 |
|
8.5 |
0 |
/ |
/ |
1 |
PRO(g/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
5 |
URO (μmol/L) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
3.2 |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
3.2 |
5 |
/ |
/ |
5 |
NIT |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
4 |
4 |
4 |
4 |
|
+ |
1 |
1 |
1 |
1 |
|
Recovery day 14 |
|
|
|
|
|
- |
4 |
/ |
/ |
4 |
|
+ |
1 |
/ |
/ |
1 |
WBC(Leu/μL) |
|
|
|
|
|
|
Day 28 |
|
|
|
|
|
- |
5 |
5 |
5 |
5 |
|
Recovery day 14 |
|
|
|
|
|
- |
5 |
/ |
/ |
4 |
|
15 |
0 |
/ |
/ |
1 |
Table 9 Effects on Organ Weight and Ratios of Males
Parameters Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
|||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
||
Terminal Body weight (g) |
|
|
|
|
|
|
|
|
|
End of Dosingperiod |
5 |
385.860 ± 21.770 |
5 |
387.180 ± 31.442 |
5 |
364.880 ± 17.616 |
5 |
375.640 ± 25.621 |
|
End of recovery period |
5 |
410.240 ± 50.549 |
/ |
/ |
/ |
/ |
5 |
436.600 ± 51.849 |
|
Organ weight (g) |
|
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.0238 ± 0.0036 |
5 |
0.0254 ± 0.0036 |
5 |
0.0242 ± 0.0045 |
5 |
0.0193 ± 0.0049 |
|
End of recovery period |
5 |
0.0292 ± 0.0074 |
/ |
/ |
/ |
/ |
5 |
0.0326 ± 0.0043 |
|
Liver |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
11.433 ± 1.055 |
5 |
11.611 ± 1.741 |
5 |
10.327 ± 1.220 |
5 |
10.679 ± 0.960 |
|
End of recovery period |
5 |
11.171 ± 1.270 |
/ |
/ |
/ |
/ |
5 |
12.166 ± 1.971 |
|
Spleen |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.772 ± 0.084 |
5 |
0.857 ± 0.184 |
5 |
0.852 ± 0.077 |
5 |
0.804 ± 0.110 |
|
End of recovery period |
5 |
0.715 ± 0.099 |
/ |
/ |
/ |
/ |
5 |
0.855 ± 0.115 |
|
Kidney |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.670 ± 0.153 |
5 |
2.765 ± 0.350 |
5 |
2.705 ± 0.165 |
5 |
2.534 ± 0.295 |
|
End of recovery period |
5 |
2.904 ± 0.363 |
/ |
/ |
/ |
/ |
5 |
2.963 ± 0.324 |
|
Adrenal gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.057 ± 0.005 |
5 |
0.056 ± 0.004 |
5 |
0.061 ± 0.011 |
5 |
0.048 ± 0.009 |
|
End of recovery period |
5 |
0.049 ± 0.009 |
/ |
/ |
/ |
/ |
5 |
0.053 ± 0.008 |
|
Testis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.846 ± 0.843 |
5 |
2.809 ± 1.175 |
5 |
3.251 ± 0.207 |
5 |
3.112 ± 0.299 |
|
End of recovery period |
5 |
3.368 ± 0.156 |
/ |
/ |
/ |
/ |
5 |
3.200 ± 0.278 |
|
Epididymis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.981 ± 0.089 |
5 |
0.897 ± 0.196 |
5 |
0.946 ± 0.109 |
5 |
0.910 ± 0.074 |
|
End of recovery period |
5 |
1.176 ± 0.057 |
/ |
/ |
/ |
/ |
5 |
1.183 ± 0.097 |
|
Thymus gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.605 ± 0.112 |
5 |
0.632 ± 0.117 |
5 |
0.537 ± 0.074 |
5 |
0.591 ± 0.202 |
|
End of recovery period |
5 |
0.489 ± 0.135 |
/ |
/ |
/ |
/ |
5 |
0.456 ± 0.134 |
|
Heart |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
1.277 ± 0.110 |
5 |
1.427 ± 0.391 |
5 |
1.333 ± 0.114 |
5 |
1.247 ± 0.101 |
|
End of recovery period |
5 |
1.377 ± 0.161 |
/ |
/ |
/ |
/ |
5 |
1.446 ± 0.184 |
|
Brain |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.031 ± 0.084 |
5 |
1.972 ± 0.097 |
5 |
1.975 ± 0.013 |
5 |
1.937 ± 0.102 |
|
End of recovery period |
5 |
1.980 ± 0.122 |
/ |
/ |
/ |
/ |
5 |
2.054 ± 0.080 |
|
Prostate + seminal vesicle + coagulation gland |
|
|
|
|
|
|
|
||
End of Dosing period |
5 |
2.295 ± 0.253 |
5 |
2.102 ± 0.215 |
5 |
2.290 ± 0.351 |
5 |
2.117 ± 0.191 |
|
End of recovery period |
5 |
2.996 ± 0.302 |
|
|
|
|
5 |
2.744 ± 0.383 |
|
Organ/Body Weight Ratio (%) |
|
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.0061 ± 0.0006 |
5 |
0.0066 ± 0.0013 |
5 |
0.0066 ± 0.0013 |
5 |
0.0051 ± 0.0013 |
|
End of recovery period |
5 |
0.0071 ± 0.0015 |
/ |
/ |
/ |
/ |
5 |
0.0076 ± 0.0018 |
|
Liver |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.962 ± 0.200 |
5 |
2.989 ± 0.284 |
5 |
2.826 ± 0.229 |
5 |
2.843 ± 0.177 |
|
End of recovery period |
5 |
2.727 ± 0.089 |
/ |
/ |
/ |
/ |
5 |
2.781 ± 0.258 |
|
Spleen |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.200 ± 0.025 |
5 |
0.220 ± 0.037 |
5 |
0.234 ± 0.021 |
5 |
0.215 ± 0.032 |
|
End of recovery period |
5 |
0.177 ± 0.032 |
/ |
/ |
/ |
/ |
5 |
0.199 ± 0.044 |
|
Kidney |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.692 ± 0.029 |
5 |
0.713 ± 0.042 |
5 |
0.741 ± 0.025 |
5 |
0.673 ± 0.046 |
|
End of recovery period |
5 |
0.710 ± 0.069 |
/ |
/ |
/ |
/ |
5 |
0.680 ± 0.018 |
|
Adrenal gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.015 ± 0.002 |
5 |
0.015 ± 0.002 |
5 |
0.017 ± 0.003 |
5 |
0.013 ± 0.003 |
|
End of recovery period |
5 |
0.012 ± 0.002 |
/ |
/ |
/ |
/ |
5 |
0.012 ± 0.002 |
|
Testis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.735 ± 0.204 |
5 |
0.721 ± 0.289 |
5 |
0.891 ± 0.020 |
5 |
0.831 ± 0.085 |
|
End of recovery period |
5 |
0.832 ± 0.118 |
/ |
/ |
/ |
/ |
5 |
0.739 ± 0.082 |
|
Epididymis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.254 ± 0.016 |
5 |
0.233 ± 0.055 |
5 |
0.259 ± 0.022 |
5 |
0.243 ± 0.017 |
|
End of recovery period |
5 |
0.290 ± 0.034 |
/ |
/ |
/ |
/ |
5 |
0.275 ± 0.044 |
|
Thymus gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.156 ± 0.023 |
5 |
0.163 ± 0.029 |
5 |
0.147 ± 0.018 |
5 |
0.156 ± 0.045 |
|
End of recovery period |
5 |
0.118 ± 0.021 |
/ |
/ |
/ |
/ |
5 |
0.104 ± 0.023 |
|
Heart |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.331 ± 0.014 |
5 |
0.366 ± 0.083 |
5 |
0.365 ± 0.024 |
5 |
0.332 ± 0.023 |
|
End of recovery period |
5 |
0.336 ± 0.020 |
/ |
/ |
/ |
/ |
5 |
0.331 ± 0.006 |
|
Brain |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.528 ± 0.039 |
5 |
0.511 ± 0.027 |
5 |
0.542 ± 0.026 |
5 |
0.516 ± 0.019 |
|
End of recovery period |
5 |
0.488 ± 0.056 |
/ |
/ |
/ |
/ |
5 |
0.476 ± 0.056 |
|
Prostate + seminal vesicle + coagulation gland |
|
|
|
|
|
|
|
||
End of Dosing period |
5 |
0.596 ± 0.071 |
5 |
0.543 ± 0.026 |
5 |
0.626 ± 0.071 |
5 |
0.565 ± 0.050 |
|
End of recovery period |
5 |
0.735 ± 0.072 |
/ |
/ |
/ |
/ |
5 |
0.633 ± 0.095 |
|
Organ/Brain Weight Ratio (%) |
|
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
1.174 ± 0.206 |
5 |
1.293 ± 0.196 |
5 |
1.227 ± 0.223 |
5 |
0.999 ± 0.265 |
|
End of recovery period |
5 |
1.469 ± 0.363 |
/ |
/ |
/ |
/ |
5 |
1.583 ± 0.191 |
|
Liver |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
563.56 ± 55.53 |
5 |
588.41 ± 81.37 |
5 |
523.15 ± 63.32 |
5 |
551.35 ± 43.01 |
|
End of recovery period |
5 |
564.14 ± 56.55 |
/ |
/ |
/ |
/ |
5 |
591.17 ± 84.69 |
|
Spleen |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
37.98 ± 3.77 |
5 |
43.30 ± 8.26 |
5 |
43.14 ± 3.83 |
5 |
41.55 ± 5.81 |
|
End of recovery period |
5 |
36.08 ± 4.06 |
/ |
/ |
/ |
/ |
5 |
41.59 ± 5.30 |
|
Kidney |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
131.68 ± 10.62 |
5 |
139.85 ± 11.34 |
5 |
137.03 ± 8.71 |
5 |
130.57 ± 10.20 |
|
End of recovery period |
5 |
146.27 ± 11.58 |
/ |
/ |
/ |
/ |
5 |
144.26 ± 15.15 |
|
Adrenal gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.82 ± 0.36 |
5 |
2.84 ± 0.30 |
5 |
3.08 ± 0.54 |
5 |
2.48 ± 0.54 |
|
End of recovery period |
5 |
2.47 ± 0.41 |
/ |
/ |
/ |
/ |
5 |
2.59 ± 0.34 |
|
Testis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
141.05 ± 43.73 |
5 |
141.01 ± 56.59 |
5 |
164.66 ± 10.67 |
5 |
160.62 ± 12.05 |
|
End of recovery period |
5 |
170.47 ± 10.68 |
/ |
/ |
/ |
/ |
5 |
156.18 ± 17.65 |
|
Epididymis |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
48.43 ± 5.67 |
5 |
45.37 ± 9.38 |
5 |
47.92 ± 5.64 |
5 |
46.93 ± 2.19 |
|
End of recovery period |
5 |
59.42 ± 1.67 |
/ |
/ |
/ |
/ |
5 |
57.68 ± 5.86 |
|
Thymus gland |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
29.90 ± 6.22 |
5 |
32.10 ± 6.42 |
5 |
27.22 ± 3.84 |
5 |
30.44 ± 9.85 |
|
End of recovery period |
5 |
24.85 ± 7.58 |
/ |
/ |
/ |
/ |
5 |
22.02 ± 5.73 |
|
Heart |
|
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
63.00 ± 6.98 |
5 |
71.93 ± 16.98 |
5 |
67.52 ± 6.07 |
5 |
64.32 ± 2.83 |
|
End of recovery period |
5 |
69.56 ± 7.49 |
/ |
/ |
/ |
/ |
5 |
70.30 ± 7.77 |
|
Prostate + seminal vesicle + coagulation gland |
|
|
|
|
|
|
|
||
End of Dosing period |
5 |
113.31 ± 15.53 |
5 |
106.41 ± 6.45 |
5 |
115.97 ± 17.93 |
5 |
109.34 ± 8.80 |
|
End of recovery period |
5 |
151.15 ± 9.34 |
/ |
/ |
/ |
/ |
5 |
133.66 ± 19.02 |
Notes: * Statistical significance was noted when compared with the control (p≤0.05).
Table 10 Effects of D-Prism via Oral Gavage on Organ Weight and Ratios of Females
Parameters Detection time |
Control |
100 mg/kg bw/day group |
300 mg/kg bw/day group |
1000 mg/kg bw/day group |
||||
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
n |
Mean± SD |
|
Terminal Body weight (g) |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
228.660 ± 15.507 |
5 |
230.340 ± 16.748 |
5 |
223.860 ± 20.493 |
5 |
227.640 ± 18.307 |
End of recovery period |
5 |
228.840 ± 26.364 |
/ |
/ |
/ |
/ |
5 |
228.900 ± 11.755 |
Organ weight (g) |
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.0189 ± 0.0046 |
5 |
0.0192 ± 0.0029 |
5 |
0.0245 ± 0.0039 |
5 |
0.0195 ± 0.0063 |
End of recovery period |
5 |
0.0299 ± 0.0120 |
/ |
/ |
/ |
/ |
5 |
0.0221 ± 0.0057 |
Liver |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
6.431 ± 0.699 |
5 |
6.350 ± 0.492 |
5 |
6.614 ± 0.648 |
5 |
6.044 ± 0.307 |
End of recovery period |
5 |
6.192 ± 0.787 |
/ |
/ |
/ |
/ |
5 |
6.128 ± 0.568 |
Spleen |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.646 ± 0.212 |
5 |
0.572 ± 0.135 |
5 |
0.673 ± 0.194 |
5 |
0.622 ± 0.065 |
End of recovery period |
5 |
0.540 ± 0.119 |
/ |
/ |
/ |
/ |
5 |
0.547 ± 0.071 |
Kidney |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
1.739 ± 0.095 |
5 |
1.698 ± 0.148 |
5 |
1.723 ± 0.121 |
5 |
1.666 ± 0.185 |
End of recovery period |
5 |
1.633 ± 0.309 |
/ |
/ |
/ |
/ |
5 |
1.619 ± 0.052 |
Adrenal gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.062 ± 0.004 |
5 |
0.064 ± 0.008 |
5 |
0.062 ± 0.009 |
5 |
0.059 ± 0.009 |
End of recovery period |
5 |
0.061 ± 0.005 |
/ |
/ |
/ |
/ |
5 |
0.055 ± 0.009 |
Ovary |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.102 ± 0.009 |
5 |
0.099 ± 0.012 |
5 |
0.104 ± 0.020 |
5 |
0.097 ± 0.016 |
End of recovery period |
5 |
0.092 ± 0.011 |
/ |
/ |
/ |
/ |
5 |
0.085 ± 0.011 |
Uterus |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.616 ± 0.147 |
5 |
0.567 ± 0.127 |
5 |
0.545 ± 0.097 |
5 |
0.578 ± 0.239 |
End of recovery period |
5 |
0.447 ± 0.071 |
/ |
/ |
/ |
/ |
5 |
0.548 ± 0.167 |
Thymus gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.470 ± 0.124 |
5 |
0.412 ± 0.060 |
5 |
0.445 ± 0.067 |
5 |
0.400 ± 0.119 |
End of recovery period |
5 |
0.417 ± 0.029 |
/ |
/ |
/ |
/ |
5 |
0.349 ± 0.053 * |
Heart |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.854 ± 0.068 |
5 |
0.876 ± 0.075 |
5 |
0.859 ± 0.155 |
5 |
0.840 ± 0.132 |
End of recovery period |
5 |
0.865 ± 0.111 |
/ |
/ |
/ |
/ |
5 |
0.822 ± 0.077 |
Brain |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
1.823 ± 0.097 |
5 |
1.822 ± 0.106 |
5 |
1.855 ± 0.071 |
5 |
1.896 ± 0.055 |
End of recovery period |
5 |
1.813 ± 0.062 |
/ |
/ |
/ |
/ |
5 |
1.816 ± 0.094 |
Organ/Body Weight Ratio (%) |
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.0082 ± 0.0015 |
5 |
0.0084 ± 0.0012 |
5 |
0.0110 ± 0.0016 |
5 |
0.0086 ± 0.0027 |
End of recovery period |
5 |
0.0129 ± 0.0049 |
/ |
/ |
/ |
/ |
5 |
0.0097 ± 0.0028 |
Liver |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
2.807 ± 0.122 |
5 |
2.758 ± 0.113 |
5 |
2.960 ± 0.230 |
5 |
2.662 ± 0.125 |
End of recovery period |
5 |
2.709 ± 0.213 |
/ |
/ |
/ |
/ |
5 |
2.679 ± 0.228 |
Spleen |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.286 ± 0.102 |
5 |
0.247 ± 0.044 |
5 |
0.297 ± 0.057 |
5 |
0.275 ± 0.036 |
End of recovery period |
5 |
0.236 ± 0.043 |
/ |
/ |
/ |
/ |
5 |
0.238 ± 0.021 |
Kidney |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.761 ± 0.028 |
5 |
0.737 ± 0.028 |
5 |
0.771 ± 0.032 |
5 |
0.731 ± 0.039 |
End of recovery period |
5 |
0.710 ± 0.067 |
/ |
/ |
/ |
/ |
5 |
0.708 ± 0.021 |
Adrenal gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.027 ± 0.002 |
5 |
0.028 ± 0.005 |
5 |
0.028 ± 0.005 |
5 |
0.026 ± 0.003 |
End of recovery period |
5 |
0.027 ± 0.004 |
/ |
/ |
/ |
/ |
5 |
0.024 ± 0.004 |
Ovary |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.045 ± 0.005 |
5 |
0.043 ± 0.006 |
5 |
0.047 ± 0.009 |
5 |
0.043 ± 0.008 |
End of recovery period |
5 |
0.041 ± 0.004 |
/ |
/ |
/ |
/ |
5 |
0.037 ± 0.005 |
Uterus |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.271 ± 0.073 |
5 |
0.245 ± 0.050 |
5 |
0.247 ± 0.056 |
5 |
0.253 ± 0.097 |
End of recovery period |
5 |
0.195 ± 0.022 |
/ |
/ |
/ |
/ |
5 |
0.238 ± 0.065 |
Thymus gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.208 ± 0.061 |
5 |
0.179 ± 0.025 |
5 |
0.199 ± 0.028 |
5 |
0.174 ± 0.042 |
End of recovery period |
5 |
0.184 ± 0.015 |
/ |
/ |
/ |
/ |
5 |
0.153 ± 0.022 * |
Heart |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.374 ± 0.033 |
5 |
0.381 ± 0.032 |
5 |
0.382 ± 0.043 |
5 |
0.368 ± 0.034 |
End of recovery period |
5 |
0.379 ± 0.039 |
/ |
/ |
/ |
/ |
5 |
0.359 ± 0.021 |
Brain |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
0.799 ± 0.054 |
5 |
0.793 ± 0.060 |
5 |
0.834 ± 0.071 |
5 |
0.837 ± 0.072 |
End of recovery period |
5 |
0.800 ± 0.083 |
/ |
/ |
/ |
/ |
5 |
0.795 ± 0.047 |
Organ/Brain Weight Ratio (%) |
|
|
|
|
|
|
|
|
Thyroid and parathyroid glands |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
1.034 ± 0.211 |
5 |
1.053 ± 0.128 |
5 |
1.326 ± 0.235 |
5 |
1.036 ± 0.359 |
End of recovery period |
5 |
1.638 ± 0.649 |
/ |
/ |
/ |
/ |
5 |
1.217 ± 0.304 |
Liver |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
352.67 ± 31.78 |
5 |
349.18 ± 28.85 |
5 |
356.34 ± 29.81 |
5 |
319.16 ± 22.59 |
End of recovery period |
5 |
341.10 ± 39.02 |
/ |
/ |
/ |
/ |
5 |
337.94 ± 33.09 |
Spleen |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
35.25 ± 10.38 |
5 |
31.44 ± 7.26 |
5 |
36.20 ± 10.06 |
5 |
32.88 ± 4.21 |
End of recovery period |
5 |
29.65 ± 5.83 |
/ |
/ |
/ |
/ |
5 |
30.16 ± 4.09 |
Kidney |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
95.48 ± 5.64 |
5 |
93.46 ± 9.96 |
5 |
92.93 ± 6.23 |
5 |
87.98 ± 10.84 |
End of recovery period |
5 |
89.92 ± 16.23 |
/ |
/ |
/ |
/ |
5 |
89.29 ± 5.25 |
Adrenal gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
3.38 ± 0.27 |
5 |
3.52 ± 0.61 |
5 |
3.33 ± 0.56 |
5 |
3.13 ± 0.48 |
End of recovery period |
5 |
3.34 ± 0.31 |
/ |
/ |
/ |
/ |
5 |
3.00 ± 0.36 |
Ovary |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
5.60 ± 0.59 |
5 |
5.45 ± 0.88 |
5 |
5.62 ± 1.01 |
5 |
5.15 ± 0.90 |
End of recovery period |
5 |
5.10 ± 0.60 |
/ |
/ |
/ |
/ |
5 |
4.68 ± 0.79 |
Uterus |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
33.95 ± 8.87 |
5 |
31.15 ± 6.79 |
5 |
29.34 ± 4.92 |
5 |
30.38 ± 12.26 |
End of recovery period |
5 |
24.65 ± 3.89 |
/ |
/ |
/ |
/ |
5 |
30.25 ± 9.62 |
Thymus gland |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
26.07 ± 8.01 |
5 |
22.62 ± 3.05 |
5 |
23.91 ± 2.97 |
5 |
21.12 ± 6.33 |
End of recovery period |
5 |
23.03 ± 1.68 |
/ |
/ |
/ |
/ |
5 |
19.28 ± 3.06 * |
Heart |
|
|
|
|
|
|
|
|
End of Dosing period |
5 |
46.90 ± 4.39 |
5 |
48.18 ± 4.35 |
5 |
46.25 ± 7.68 |
5 |
44.29 ± 6.54 |
End of recovery period |
5 |
47.65 ± 5.65 |
/ |
/ |
/ |
/ |
5 |
45.31 ± 4.38 |
Applicant's summary and conclusion
- Conclusions:
- As no adverse effects were observed up to the highest dose group the NOAEL was considered to be >= 1000 mg/kg bw/day for female and male rats.
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