Registration Dossier
Registration Dossier
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EC number: 226-999-5 | CAS number: 5590-18-1
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 021
Materials and methods
Test guideline
- 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
Test material
- Reference substance name:
- 3,3'-(1,4-phenylenediimino)bis[4,5,6,7-tetrachloro-1H-isoindol-1-one]
- EC Number:
- 226-999-5
- EC Name:
- 3,3'-(1,4-phenylenediimino)bis[4,5,6,7-tetrachloro-1H-isoindol-1-one]
- Cas Number:
- 5590-18-1
- Molecular formula:
- C22H6Cl8N4O2
- IUPAC Name:
- 3,3'-(1,4-phenylenediimino)bis(4,5,6,7-tetrachloro-1H-isoindol-1-one)
- Test material form:
- solid
- Details on test material:
- - Name of test material : C.I. Pigment Yellow 110
- Molecular formula : C22H6Cl8N4O2
- Molecular weight : 641.939 g/mol
- Smiles notation (if other than submission substance): C=1(c2c(c(c(Cl)c(Cl)c2C(=O)N1)Cl)Cl)Nc1ccc(cc1)NC1=NC(c2c1c(c(c(c2Cl)Cl)Cl)Cl)=O
- InChl (if other than submission substance): 1S/C22H6Cl8N4O2/c23-11-7-9(13(25)17(29)15(11)27)21(35)33-19(7)31-5-1-2-6(4-3-5)32-20-8-10(22(36)34-20)14(26)18(30)16(28)12(8)24/h1-4H,(H,31,33,35)(H,32,34,36)
- Substance type: Organic
- Physical state: Solid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: Manufactured by Sustainability Support Services (Europe) AB Shaanxi Pioneer Biotech co.,Ltd
- Expiration date of the lot/batch: 05/12/2021
- Purity test date: ≥98 %
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test item was store in sealed containers at cool and dry place. It was protected from light, moisture, and pest infestation.
- Stability under storage conditions:
- Vehicle: Distilled water
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: : Samples in triplicate for low and high dose formulation were taken for stability analysis. The stability in the dose formulation was checked at 0 and 6 hours post dose formulation preparation.
- Reactivity of the test substance with the solvent/vehicle /test medium (if applicable): NA
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- The rat is a standard laboratory rodent species and is also a recommended species.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Sipra Labs Limited, Plot No.13, IDA, Balanagar, Hyderabad, India.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: Male: 131.24 g -143.54 g; Female: 134.19 g -143.22 g
- Fasting period before study: No
- Housing: Animals were housed in autoclaved polycarbonate cages with stainless steel top grill having facilities for holding pellet feed and drinking water in polycarbonate bottles. Autoclaved corn cob was used as bedding material, and it was changed at least once a week.
- Diet (e.g. ad libitum): Rodent feed VRK Nutritional solutions was available ad libitum.
- Water (e.g. ad libitum): Aquaguard purified water was available ad libitum.
- Acclimation period: Nineteen days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1– 23.4°C
- Humidity (%): 51 – 61 %.
- Air changes (per hr): 10 Air Changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle per day
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- The test item was administered by oral gavage once daily.
Dose volume: 10 ml/kg bodyweight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulation samples were taken immediately after diluting the concentrates in vehicle (Distilled water) on the first day of treatment and on the last day of treatment for homogeneity analysis and. On the third week, samples from all dose formulations were taken for dose concentration analysis.The analyses were performed based on a validated analytical method.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Vehicle control
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Middle dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- High dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Recovery group
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Recovery group
- No. of animals per sex per dose:
- Main groups: 5 rats per sex per dose
Total of 70 rats (35 males and 35 females)
Recovery group: 5 rats per sex per dose - Control animals:
- yes, concurrent vehicle
- Details on study design:
- In a dose-range finding study, the test chemical was administered to 5 rats /sex/dose by oral gavage at doses of 0 (vehicle control), 100, 300, and 1000 mg/kb bw/day for 14 days. All animals were observed for mortality, clinical signs of toxicity and body weight. At the end of treatment all animals were sent to necropsy for gross pathological examinations. No adverse effects of treatment were observed; hence, the doses of 250, 500 and 1000 mg/kg body weight were selected for the main study.
Examinations
- Observations and examinations performed and frequency:
- MORTALITY: Twice daily
CAGE SIDE OBSERVATIONS: Yes
Acclimatization period: Once daily
Treatment period: Twice daily on first 3 days of treatment; once daily thereafter
Recovery period: Once daily
DETAILED CLINICAL OBSERVATIONS: Yes
Detailed clinical examinations were done prior to initiation of treatment and on day 8, 15, 22, and 28 of treatment (main study) and on day 8, 15, 22, 28, 36, and 42 (recovery groups). All animals were observed for changes in skin and fur, eyes, mucous membrane, occurrence of secretions and excretions, autonomic activity, changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypes and bizarre behaviour.
BODY WEIGHT: Yes
Treatment Period: Once weekly
Recovery Period: Once Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (gram/animal/day)
Acclimatization and before randomization: Once
Treatment Period: Once weekly
FOOD EFFICIENCY: Not examined
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not examined.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once during acclimatization and once during week 4
- Dose groups that were examined:
Main groups: 0 and 1000 mg/kg bw/day
Recovery groups: 0 and 1000 mg/kg bw/day
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at week 4 and 6
- Anaesthetic used for blood collection: Yes, under isoflurane
- Animals fasted: Yes, rats were fasted overnight.
- How many animals: all animals in the main groups (0, 250, 500 and 1000 mg/kg bw/day) and in the recovery groups (0 and 1000 mg/kg bw/days)
- Parameters checked in table: Yes. See Chapter 23.8.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at week 4 and 6
- Animals fasted: Yes
- How many animals: all animals in the main groups (0, 250, 500 and 1000 mg/kg bw/day) and in the recovery groups (0 and 1000 mg/kg bw/days)
- Parameters checked in table [No.?] were examined. Yes, See Chapter 23.9.
URINALYSIS: Yes
- Time schedule for collection of urine: at week 4 and 6
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined. Yes. See Chapter 23.10.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on day 28 (main groups), and on day 42 (recovery group)
- Dose groups that were examined: all animals in the main groups (0, 250, 500 and 1000 mg/kg bw/day) and in the recovery groups (0 and 1000 mg/kg bw/days)
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes
The examinations for sensory reactivity, grip strength, and motor activity assessment were performed once on day 28 for all animals (main study) and on day 42 for all animals (recovery groups).
IMMUNOLOGY: Not examined
- Time schedule for examinations: NA
- How many animals:NA
- Dose groups that were examined:NA
- Parameters checked in table [No.?] were examined.NA - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes .
All animals of the main groups (0, 250, 500 and 1000 mg/kg bw /day) were sacrificed at the end of week 4. Rats from the recovery groups (0 and 1000 mg/kg bw/day) were sacrificed at the end of week 6 of experimental period by carbon dioxide asphyxiation. All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded.
Samples of the following tissues and organs were collected and fixed:
Adrenal glands, Aorta, Bone marrow (Sternum), Brain (cerebrum, cerebellum, pons), Cecum, Cervix, Colon, Duodenum, Epididymides, Eye, Heart, Ileum, with Peyer's patches, Jejunum, Kidneys, Liver, Lungs (inflated with NBF at necropsy), Lymph nodes (mesenteric, axillary), Oesophagus, Ovaries, Pancreas, Rectum, Prostate + Seminal vesicle with coagulating glands, Pituitary, Sciatic nerve. Skeletal muscle, Spinal cord (cervical, mid-thoracic, lumbar), Spleen, Stomach, Testes , Thymus, Thyroid, Trachea, Urinary bladder (inflated with NBF at necropsy), Uterus, Vagina, All Gross lesions
ORGAN WEIGHTS MEASUREMENTS: Yes.
The following organs were weighed and recorded on the day of necropsy: Brain, Spleen, Thymus Epididymides, Heart, Kidneys, Testes, Ovaries, Liver, Adrenals, Uterus, Prostate + Seminal vesicle with coagulating glands
HISTOPATHOLOGY: Yes.
All organ and tissue samples collected during necropsy were processed, embedded and cut to 3-5µm sections then stained with haematoxylin and eosin and examined under light microscope. Full histopathology was performed on the preserved organs and tissues of all animals in the control and high dose groups (main study). Lesions were graded as mild, moderate, or severe based on vascular/degenerative/inflammatory changes in specific organs. Mild=less than 10% of the region affected; Moderate=less than 25% of the region were affected; Severe=more than 25% of the region affected. - Statistics:
- The following statistical methods were used to analyse the body weight, feed consumption, organ weights as well as clinical pathology data:
Data was summarized in tabular form. Statistical analysis was performed using SAS/STAT® Software (Version 9.3).
All the data were analysed for homogeneity using Levene’s test
The difference between the means was analysed using Dunnet’s t- test
Significant differences between control and treated groups analysed using one-way ANOVA statistics. Values were summarized as mean ± standard deviation (SD).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs of toxicity were observed inany of the groups.In addition, no abnormal findings were observed in any of the animals during the detailed clinical examinations.
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survived to planned death.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant changes in body weight or body weight gain were observed in any of the groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No signficanct changes in feed consumption were observed in any of the groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No abnormal findings were observed in any of the animals treated at at 0 or 1000 mg/kg bw/day.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related adverse effects were observed at any dose level.
Significant changes were observed in the haematology parameters; however, these were within the historical control ranges of the test facility. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related adverse effects were observed at any dose level.
Significant changes were observed in the clinical biochemistry parameters; however, these were within the historical control ranges. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No significant changes in urinalysis were observed in any of the groups.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No significant changes in sensory reactivity, motor activity, or grip strength were observed in any of the groups.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No adverse effect was observed at any dose level tested.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related gross pathological effects were observed at the end of the treatment period (main study) or at the end of the recovery period (recovery groups).
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related histopathological effects were observed at 1000 mg/kg bw/day in the main study.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related histopathological effects were observed at 1000 mg/kg bw/day in the main study.
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:
- behaviour (functional findings)
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- ophthalmological examination
- organ weights and organ / body weight ratios
- urinalysis
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
ANALYSIS OF DOSE FORMULATIONS
Dose concentration verifications were carried out for the test item fortified in distilled water at 25, 50 and 100 mg/ml. The recovery values in the prepared dose formulations were within the guideline specification. The test item was found to be homogeneously dispersed in distilled water, which was evinced from the recovery of test item from different layers (top, middle and bottom layers of distilled water).
Clinical signs - Treatment groups
Day of observation |
Control (G1) |
Low dose (G2) |
Middle dose (G3) |
High dose (G4) |
||||
M |
F |
M |
F |
M |
F |
M |
F |
|
1 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
2 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
3 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
4 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
6 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
7 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
8 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
9 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
10 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
11 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
12 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
13 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
14 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
15 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
16 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
17 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
18 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
19 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
20 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
21 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
22 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
23 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
24 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
25 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
26 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
27 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
28 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
01/5 |
Key: M – Male; F – Female; Observation/No. of animals; 01 – Normal
Clinical signs - Recovery groups
Day of observation |
Control Recovery (G1R) |
High dose Recovery (G4R) |
||
M |
F |
M |
F |
|
1 |
01/5 |
01/5 |
01/5 |
01/5 |
2 |
01/5 |
01/5 |
01/5 |
01/5 |
3 |
01/5 |
01/5 |
01/5 |
01/5 |
4 |
01/5 |
01/5 |
01/5 |
01/5 |
5 |
01/5 |
01/5 |
01/5 |
01/5 |
6 |
01/5 |
01/5 |
01/5 |
01/5 |
7 |
01/5 |
01/5 |
01/5 |
01/5 |
8 |
01/5 |
01/5 |
01/5 |
01/5 |
9 |
01/5 |
01/5 |
01/5 |
01/5 |
10 |
01/5 |
01/5 |
01/5 |
01/5 |
11 |
01/5 |
01/5 |
01/5 |
01/5 |
12 |
01/5 |
01/5 |
01/5 |
01/5 |
13 |
01/5 |
01/5 |
01/5 |
01/5 |
14 |
01/5 |
01/5 |
01/5 |
01/5 |
15 |
01/5 |
01/5 |
01/5 |
01/5 |
16 |
01/5 |
01/5 |
01/5 |
01/5 |
17 |
01/5 |
01/5 |
01/5 |
01/5 |
18 |
01/5 |
01/5 |
01/5 |
01/5 |
19 |
01/5 |
01/5 |
01/5 |
01/5 |
20 |
01/5 |
01/5 |
01/5 |
01/5 |
21 |
01/5 |
01/5 |
01/5 |
01/5 |
22 |
01/5 |
01/5 |
01/5 |
01/5 |
23 |
01/5 |
01/5 |
01/5 |
01/5 |
24 |
01/5 |
01/5 |
01/5 |
01/5 |
25 |
01/5 |
01/5 |
01/5 |
01/5 |
26 |
01/5 |
01/5 |
01/5 |
01/5 |
27 |
01/5 |
01/5 |
01/5 |
01/5 |
28 |
01/5 |
01/5 |
01/5 |
01/5 |
Key: M – Male; F – Female; Observation/No. of animals; 01 – Normal
Clinical signs - Recovery groups (Cont.)
Day of observation |
Control Recovery (G1R) |
High dose Recovery (G4R) |
||
M |
F |
M |
F |
|
29 |
01/5 |
01/5 |
01/5 |
01/5 |
30 |
01/5 |
01/5 |
01/5 |
01/5 |
31 |
01/5 |
01/5 |
01/5 |
01/5 |
32 |
01/5 |
01/5 |
01/5 |
01/5 |
33 |
01/5 |
01/5 |
01/5 |
01/5 |
34 |
01/5 |
01/5 |
01/5 |
01/5 |
35 |
01/5 |
01/5 |
01/5 |
01/5 |
36 |
01/5 |
01/5 |
01/5 |
01/5 |
37 |
01/5 |
01/5 |
01/5 |
01/5 |
38 |
01/5 |
01/5 |
01/5 |
01/5 |
39 |
01/5 |
01/5 |
01/5 |
01/5 |
40 |
01/5 |
01/5 |
01/5 |
01/5 |
41 |
01/5 |
01/5 |
01/5 |
01/5 |
42 |
01/5 |
01/5 |
01/5 |
01/5 |
Key: M – Male; F – Female; Observation/No. of animals; 01 – Normal
Mortality - Treatment groups
Days of observation |
G1 |
G2 |
G3 |
G4 |
||||
M |
F |
M |
F |
M |
F |
M |
F |
|
1 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
2 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
3 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
4 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
6 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
7 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
8 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
9 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
10 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
11 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
12 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
13 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
14 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
15 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
16 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
17 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
18 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
19 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
20 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
21 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
22 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
23 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
24 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
25 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
26 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
27 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
28 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
Key: M – Male; F – Female; No. of animals found dead/Total no. of animals
Mortality - recovery group
Days of observation |
G1R |
G4R |
||
M |
F |
M |
F |
|
29 |
0/5 |
0/5 |
0/5 |
0/5 |
30 |
0/5 |
0/5 |
0/5 |
0/5 |
31 |
0/5 |
0/5 |
0/5 |
0/5 |
32 |
0/5 |
0/5 |
0/5 |
0/5 |
33 |
0/5 |
0/5 |
0/5 |
0/5 |
34 |
0/5 |
0/5 |
0/5 |
0/5 |
35 |
0/5 |
0/5 |
0/5 |
0/5 |
36 |
0/5 |
0/5 |
0/5 |
0/5 |
37 |
0/5 |
0/5 |
0/5 |
0/5 |
38 |
0/5 |
0/5 |
0/5 |
0/5 |
39 |
0/5 |
0/5 |
0/5 |
0/5 |
40 |
0/5 |
0/5 |
0/5 |
0/5 |
41 |
0/5 |
0/5 |
0/5 |
0/5 |
42 |
0/5 |
0/5 |
0/5 |
0/5 |
Key: M – Male; F – Female; No. of animals found dead/Total no. of animals.
Body weights - Treatment groups/males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Day 1 |
Mean |
139.6 |
140.1 |
140.6 |
140.4 |
SD |
4.77 |
3.57 |
2.49 |
2.62 |
|
N |
5 |
5 |
5 |
5 |
|
Day 8 |
Mean |
152.4 |
153.4 |
153.9 |
153.0 |
SD |
4.85 |
3.88 |
2.36 |
2.28 |
|
N |
5 |
5 |
5 |
5 |
|
Day 15 |
Mean |
166.4 |
166.2 |
167.1 |
167.1 |
SD |
5.45 |
2.77 |
1.59 |
2.87 |
|
N |
5 |
5 |
5 |
5 |
|
Day 22 |
Mean |
182.3 |
181.3 |
182.4 |
182.0 |
SD |
5.85 |
3.24 |
2.02 |
2.30 |
|
N |
5 |
5 |
5 |
5 |
|
Day 28 |
Mean |
194.5 |
194.1 |
195.3 |
195.6 |
SD |
5.42 |
3.50 |
2.17 |
3.28 |
|
N |
5 |
5 |
5 |
5 |
|
Body weights - Treatment groups/females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Day 1 |
Mean |
139.7 |
139.6 |
139.8 |
140.4 |
SD |
3.16 |
2.85 |
2.71 |
1.97 |
|
N |
5 |
5 |
5 |
5 |
|
Day 8 |
Mean |
152.6 |
152.9 |
153.5 |
154.3 |
SD |
3.06 |
2.47 |
2.12 |
2.41 |
|
N |
5 |
5 |
5 |
5 |
|
Day 15 |
Mean |
165.4 |
164.9 |
166.8 |
168.3 |
SD |
4.45 |
1.26 |
1.94 |
1.85 |
|
N |
5 |
5 |
5 |
5 |
|
Day 22 |
Mean |
181.9 |
180.4 |
182.1 |
184.0 |
SD |
4.87 |
1.50 |
1.70 |
1.17 |
|
N |
5 |
5 |
5 |
5 |
|
Day 28 |
Mean |
194.4 |
193.8 |
196.2 |
197.0 |
SD |
4.76 |
1.88 |
2.92 |
2.58 |
|
N |
5 |
5 |
5 |
5 |
|
Body weights -Recovery groups/males
|
Group 1R |
Group 4R |
|
Day 1 |
Mean |
140.7 |
140.9 |
SD |
2.06 |
1.57 |
|
N |
5 |
5 |
|
Day 8 |
Mean |
154.0 |
153.8 |
SD |
2.86 |
1.18 |
|
N |
5 |
5 |
|
Day 15 |
Mean |
167.9 |
167.0 |
SD |
2.84 |
1.51 |
|
N |
5 |
5 |
|
Day 22 |
Mean |
182.6 |
182.1 |
SD |
2.87 |
1.95 |
|
N |
5 |
5 |
|
Day 29 |
Mean |
197.6 |
197.8 |
SD |
3.80 |
2.12 |
|
N |
5 |
5 |
|
Day 36 |
Mean |
212.8 |
212.4 |
SD |
4.05 |
2.48 |
|
N |
5 |
5 |
|
Day 42 |
Mean |
225.1 |
223.8 |
SD |
4.05 |
1.93 |
|
N |
5 |
5 |
|
Body weights -Recovery groups/females
|
Group 1R |
Group 4R |
|
Day 1 |
Mean |
140.7 |
140.6 |
SD |
1.49 |
1.69 |
|
N |
5 |
5 |
|
Day 8 |
Mean |
153.4 |
154.4 |
SD |
2.03 |
2.27 |
|
N |
5 |
5 |
|
Day 15 |
Mean |
166.9 |
168.1 |
SD |
1.88 |
3.35 |
|
N |
5 |
5 |
|
Day 22 |
Mean |
181.8 |
183.3 |
SD |
1.58 |
3.19 |
|
N |
5 |
5 |
|
Day 29 |
Mean |
197.0 |
197.8 |
SD |
1.78 |
3.74 |
|
N |
5 |
5 |
|
Day 36 |
Mean |
212.5 |
212.6 |
SD |
1.89 |
4.17 |
|
N |
5 |
5 |
|
Day 42 |
Mean |
224.3 |
223.8 |
SD |
1.90 |
4.01 |
|
N |
5 |
5 |
|
Body weight gain (%) - Treatment groups/male
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Day 1 |
Mean |
0.0 |
0.0 |
0.0 |
0.0 |
SD |
0.00 |
0.00 |
0.00 |
0.00 |
|
N |
5 |
5 |
5 |
5 |
|
Day 8 |
Mean |
9.2 |
9.4 |
9.5 |
8.9 |
SD |
0.45 |
0.68 |
0.40 |
0.58 |
|
N |
5 |
5 |
5 |
5 |
|
Day 15 |
Mean |
19.2 |
18.6 |
18.9 |
19.0 |
SD |
0.83 |
1.49 |
1.11 |
0.67 |
|
N |
5 |
5 |
5 |
5 |
|
Day 22 |
Mean |
30.6 |
29.4 |
29.8 |
29.6 |
SD |
0.72 |
1.78 |
1.09 |
0.94 |
|
N |
5 |
5 |
5 |
5 |
|
Day 28 |
Mean |
39.4 |
38.5 |
39.0 |
39.3 |
SD |
1.32 |
2.37 |
1.32 |
0.43 |
|
N |
5 |
5 |
5 |
5 |
|
Body weight gain (%) - Treatment groups/females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Day 1 |
Mean |
0.0 |
0.0 |
0.0 |
0.0 |
SD |
0.00 |
0.00 |
0.00 |
0.00 |
|
N |
5 |
5 |
5 |
5 |
|
Day 8 |
Mean |
9.3 |
9.6 |
9.8 |
9.9 |
SD |
0.48 |
0.72 |
0.78 |
0.57 |
|
N |
5 |
5 |
5 |
5 |
|
Day 15 |
Mean |
18.5 |
18.2 |
19.3 |
19.9 |
SD |
0.79 |
2.07 |
1.01 |
0.85 |
|
N |
5 |
5 |
5 |
5 |
|
Day 22 |
Mean |
30.2 |
29.3 |
30.2 |
31.0 |
SD |
0.64 |
2.02 |
1.73 |
1.21 |
|
N |
5 |
5 |
5 |
5 |
|
Day 28 |
Mean |
39.2 |
38.9 |
40.3 |
40.3 |
SD |
0.39 |
1.68 |
1.52 |
1.83 |
|
N |
5 |
5 |
5 |
5 |
|
Body weight gain (%) - Recovery groups/males
|
Group 1R |
Group 4R |
|
Day 1 |
Mean |
0.0 |
0.0 |
SD |
0.00 |
0.00 |
|
N |
5 |
5 |
|
Day 8 |
Mean |
9.5 |
9.1 |
SD |
0.79 |
0.68 |
|
N |
5 |
5 |
|
Day 15 |
Mean |
19.4 |
18.6 |
SD |
0.65 |
1.21 |
|
N |
5 |
5 |
|
Day 22 |
Mean |
29.8 |
29.3 |
SD |
0.72 |
1.37 |
|
N |
5 |
5 |
|
Day 29 |
Mean |
40.5 |
40.4 |
SD |
0.79 |
1.57 |
|
N |
5 |
5 |
|
Day 36 |
Mean |
51.3 |
50.8 |
SD |
0.99 |
1.82 |
|
N |
5 |
5 |
|
Day 42 |
Mean |
60.0 |
58.8 |
SD |
0.96 |
1.68 |
|
N |
5 |
5 |
|
Body weight gain (%) - Recovery groups/females
|
Group 1R |
Group 4R |
|
Day 1 |
Mean |
0.0 |
0.0 |
SD |
0.00 |
0.00 |
|
N |
5 |
5 |
|
Day 8 |
Mean |
9.0 |
9.9 |
SD |
0.63 |
0.43 |
|
N |
5 |
5 |
|
Day 15 |
Mean |
18.6 |
19.5 |
SD |
1.12 |
1.42 |
|
N |
5 |
5 |
|
Day 22 |
Mean |
29.2 |
30.4 |
SD |
1.31 |
1.26 |
|
N |
5 |
5 |
|
Day 29 |
Mean |
40.0 |
40.7 |
SD |
1.47 |
1.40 |
|
N |
5 |
5 |
|
Day 36 |
Mean |
51.0 |
51.2 |
SD |
1.56 |
1.65 |
|
N |
5 |
5 |
|
Day 42 |
Mean |
59.4 |
59.2 |
SD |
1.32 |
1.65 |
|
N |
5 |
5 |
|
Feed consumption (G/animal/day) – Treatment group/males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Week 1 |
Mean |
15.98 |
15.93 |
15.88 |
16.01 |
SD |
2.84 |
2.88 |
2.91 |
2.91 |
|
Week 2 |
Mean |
15.97 |
15.99 |
15.93 |
16.03 |
SD |
2.96 |
2.86 |
2.99 |
2.92 |
|
Week 3 |
Mean |
15.92 |
15.99 |
16.03 |
15.99 |
SD |
2.86 |
2.99 |
2.94 |
2.93 |
|
Week 4 |
Mean |
18.60 |
18.64 |
18.51 |
18.64 |
SD |
3.41 |
3.44 |
3.52 |
3.38 |
|
Feed consumption (G/animal/day) – Recovery group/males
|
Group 1R |
Group 4R |
|
Week 1 |
Mean |
15.96 |
16.02 |
SD |
2.83 |
2.92 |
|
Week 2 |
Mean |
15.98 |
15.95 |
SD |
2.86 |
2.88 |
|
Week 3 |
Mean |
15.96 |
15.86 |
SD |
2.83 |
2.96 |
|
Week 4 |
Mean |
15.73 |
15.90 |
SD |
2.71 |
2.95 |
|
Week 5 |
Mean |
15.95 |
15.96 |
SD |
2.91 |
2.83 |
|
Week 6 |
Mean |
18.48 |
18.57 |
SD |
3.56 |
3.45 |
|
Feed consumption (G/animal/day) – Treatment group/females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Week 1 |
Mean |
15.98 |
15.93 |
15.96 |
15.93 |
SD |
2.74 |
2.78 |
2.89 |
2.85 |
|
Week 2 |
Mean |
15.95 |
15.94 |
15.89 |
15.97 |
SD |
2.84 |
2.86 |
2.83 |
2.82 |
|
Week 3 |
Mean |
15.91 |
15.91 |
15.90 |
15.93 |
SD |
2.82 |
2.82 |
2.82 |
2.80 |
|
Week 4 |
Mean |
18.65 |
18.59 |
18.60 |
18.57 |
SD |
3.35 |
3.25 |
3.28 |
3.22 |
|
Feed consumption (G/animal/day) – Recovery group/females
|
Group 1R |
Group 4R |
|
Week 1 |
Mean |
15.93 |
15.92 |
SD |
2.85 |
2.84 |
|
Week 2 |
Mean |
15.91 |
15.96 |
SD |
2.83 |
2.83 |
|
Week 3 |
Mean |
15.90 |
15.94 |
SD |
2.81 |
2.85 |
|
Week 4 |
Mean |
15.91 |
15.94 |
SD |
2.82 |
2.86 |
|
Week 5 |
Mean |
15.85 |
15.85 |
SD |
2.83 |
2.87 |
|
Week 6 |
Mean |
18.65 |
18.64 |
SD |
3.40 |
3.45 |
|
OPTHALMOSCOPY
Group:Control (G1)
S. No. |
Parameter |
Pre Dose |
Week 4 |
1 |
Cornea |
1 (10) |
1 (10) |
2 |
Iris |
1 (10) |
1 (10) |
3 |
Conjunctivae |
1 (10) |
1 (10) |
4 |
Chemosis |
1 (10) |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group:Low dose (G2)
S. No. |
Parameter |
Pre Dose |
1 |
Cornea |
1 (10) |
2 |
Iris |
1 (10) |
3 |
Conjunctivae |
1 (10) |
4 |
Chemosis |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group:Middle dose (G3)
S. No. |
Parameter |
Pre Dose |
1 |
Cornea |
1 (10) |
2 |
Iris |
1 (10) |
3 |
Conjunctivae |
1 (10) |
4 |
Chemosis |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group:High dose (G4)
S. No. |
Parameter |
Pre Dose |
Week 4 |
1 |
Cornea |
1 (10) |
1 (10) |
2 |
Iris |
1 (10) |
1 (10) |
3 |
Conjunctivae |
1 (10) |
1 (10) |
4 |
Chemosis |
1 (10) |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group Vehicle Control Recovery(G1R)
S. No. |
Parameter |
Pre Dose |
1 |
Cornea |
1 (10) |
2 |
Iris |
1 (10) |
3 |
Conjunctivae |
1 (10) |
4 |
Chemosis |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
GroupHigh Dose Recovery(G4R)
S. No. |
Parameter |
Pre Dose |
1 |
Cornea |
1 (10) |
2 |
Iris |
1 (10) |
3 |
Conjunctivae |
1 (10) |
4 |
Chemosis |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
DETAILED CLINICAL EXAMINATIONS
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
GroupCONTROL(G1)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
GroupLow Dose(G2)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
GroupIntermediate Dose(G3)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
GroupHigh Dose(G4)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
Group Vehicle Control Recovery(G1R)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
Day 36 |
Day 42 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OF DETAILED CLINICAL EXAMINATIONS
GroupHigh Dose Recovery(G4R)
S.NO |
Parameter |
Pre Dose |
Day 8 |
Day 15 |
Day 22 |
Day 28 |
Day 36 |
Day 42 |
1 |
Body Posture |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
2 |
Gait |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
3 |
Skin |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
4 |
Fur |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
5 |
Eyes |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
6 |
Mucous membrane |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
7 |
Respiratory pattern |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
8 |
Salivation |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
9 |
Response to handling |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
10 |
Convulsions |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
11 |
Stereotypic behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
12 |
Bizzare Behaviour |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
1(10) |
Key: 1(10) – Observation(No of animals), 1-Normal
SUMMARY OFSENSORY REACTIVITY ASSESSMENT
Group:Control (G1)
S. No. |
Activity |
Day 28 |
1 |
Pupil reflex |
1 (10) |
2 |
Pinna reflex |
1 (10) |
3 |
Proprioceptive reflex |
1 (10) |
4 |
Approach reflex |
1 (10) |
5 |
Nociceptive reflex |
1 (10) |
6 |
Righting reflex |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group:Low dose (G2)
S. No. |
Activity |
Day 28 |
1 |
Pupil reflex |
1 (10) |
2 |
Pinna reflex |
1 (10) |
3 |
Proprioceptive reflex |
1 (10) |
4 |
Approach reflex |
1 (10) |
5 |
Nociceptive reflex |
1 (10) |
6 |
Righting reflex |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
SUMMARY OF SENSORY REACTIVITY ASSESSMENT(Contd.,)
Group:Middle dose (G3)
S. No. |
Activity |
Day 28 |
1 |
Pupil reflex |
1 (10) |
2 |
Pinna reflex |
1 (10) |
3 |
Proprioceptive reflex |
1 (10) |
4 |
Approach reflex |
1 (10) |
5 |
Nociceptive reflex |
1 (10) |
6 |
Righting reflex |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
Group:High dose (G4)
S. No. |
Activity |
Day 28 |
1 |
Pupil reflex |
1 (10) |
2 |
Pinna reflex |
1 (10) |
3 |
Proprioceptive reflex |
1 (10) |
4 |
Approach reflex |
1 (10) |
5 |
Nociceptive reflex |
1 (10) |
6 |
Righting reflex |
1 (10) |
Key: 1 (10) – Observation (No. of animals); 1 – Normal.
SUMMARY OF GRIP STRENGTH MEASUREMENT
MALES
TREATMENT & RECOVERY |
Grip Strength |
||
Fore limb |
Hind limb |
||
Group 1 |
Mean |
206.00 |
209.33 |
SD |
30.311 |
34.595 |
|
Group 2 |
Mean |
213.33 |
219.33 |
SD |
33.914 |
34.831 |
|
Group 3 |
Mean |
204.00 |
202.67 |
SD |
31.922 |
14.606 |
|
Group 4 |
Mean |
213.33 |
184.67 |
SD |
14.142 |
32.371 |
|
Group 1R |
Mean |
211.33 |
193.93 |
SD |
18.649 |
39.555 |
|
Group 4R |
Mean |
218.67 |
198.67 |
SD |
20.494 |
25.990 |
|
SUMMARY OF GRIP STRENGTH MEASUREMENT(Contd.,)
FEMALES
TREATMENT & RECOVERY |
Grip Strength |
||
Fore limb |
Hind limb |
||
Group 1 |
Mean |
182.67 |
153.73 |
SD |
47.690 |
75.098 |
|
Group 2 |
Mean |
232.00 |
216.67 |
SD |
27.348 |
16.499 |
|
Group 3 |
Mean |
193.33 |
216.67 |
SD |
44.785 |
27.489 |
|
Group 4 |
Mean |
222.67 |
241.20 |
SD |
43.297 |
14.923 |
|
Group 1R |
Mean |
191.27 |
192.67 |
SD |
34.055 |
33.283 |
|
Group 4R |
Mean |
174.67 |
207.33 |
SD |
29.871 |
22.659 |
|
SUMMARY OF MOTOR ACTIVITY ASSESSMENT
MALES
TREATMENT & RECOVERY |
IR Activity Meter |
||||
Slow Movements (cm/seconds) |
Fast movements (cm/seconds) |
Slow Stereotypic movements (seconds) |
Fast stereotypic movements (seconds) |
||
Group 1 |
Mean |
74.25 |
331.40 |
22.67 |
205.07 |
SD |
18.872 |
132.768 |
5.157 |
62.752 |
|
Group 2 |
Mean |
69.60 |
267.33 |
21.05 |
184.80 |
SD |
33.065 |
152.481 |
8.190 |
71.821 |
|
Group 3 |
Mean |
69.00 |
238.27 |
24.93 |
165.20 |
SD |
21.710 |
117.110 |
5.410 |
73.774 |
|
Group 4 |
Mean |
70.13 |
289.20 |
19.73 |
174.73 |
SD |
33.574 |
143.031 |
7.188 |
87.180 |
|
Group 1R |
Mean |
66.40 |
258.60 |
24.40 |
169.80 |
SD |
23.860 |
117.622 |
5.376 |
55.035 |
|
Group 4R |
Mean |
56.13 |
178.20 |
24.20 |
133.73 |
SD |
24.819 |
92.009 |
7.453 |
59.448 |
|
SUMMARY OF MOTOR ACTIVITY ASSESSMENT(Contd.,)
FEMALES
TREATMENT & RECOVERY |
IR Activity Meter |
||||
Small movements (cm/seconds) |
Fast movements (cm/seconds) |
Small Stereotypic movements (seconds) |
Fast stereotypic movements (seconds) |
||
Group 1 |
Mean |
70.27 |
205.47 |
26.27 |
162.53 |
SD |
18.432 |
109.393 |
6.493 |
68.649 |
|
Group 2 |
Mean |
65.80 |
187.07 |
26.20 |
156.40 |
SD |
19.921 |
79.657 |
5.324 |
43.531 |
|
Group 3 |
Mean |
47.07 |
100.40 |
25.67 |
97.27 |
SD |
14.152 |
45.687 |
5.234 |
23.325 |
|
Group 4 |
Mean |
63.06 |
251.54 |
24.20 |
171.40 |
SD |
22.179 |
126.300 |
2.140 |
57.951 |
|
Group 1R |
Mean |
72.67 |
265.67 |
25.93 |
181.67 |
SD |
19.323 |
84.563 |
3.971 |
42.345 |
|
Group 4R |
Mean |
57.20 |
173.20 |
23.80 |
138.80 |
SD |
12.238 |
71.867 |
3.632 |
33.738 |
|
HEMATOLOGY SUMMARY – MALES
Week -04
|
RBC |
Hb |
PCV |
MCV |
MCH |
MCHC |
Reticulocyte |
|
x106Cells/µL |
g/dL |
% |
fL |
pg |
g/dL |
% |
||
Group 1 |
Mean |
8.87 |
15.92 |
49.80 |
56.14 |
17.96 |
31.96 |
1.84 |
SD |
0.245 |
0.438 |
1.510 |
0.550 |
0.336 |
0.422 |
0.036 |
|
Group 2 |
Mean |
8.80 |
15.90 |
49.28 |
56.00 |
18.08 |
32.28 |
1.79 |
SD |
0.223 |
0.424 |
1.008 |
0.758 |
0.327 |
0.327 |
0.036 |
|
Group 3 |
Mean |
8.54 |
14.94 |
47.06@ |
55.10 |
17.50 |
31.76 |
1.86 |
SD |
0.151 |
0.365 |
1.011 |
0.616 |
0.265 |
0.251 |
0.045 |
|
Group 4 |
Mean |
8.73 |
15.20 |
48.14 |
55.20 |
17.52 |
31.74 |
1.86 |
SD |
0.517 |
0.560 |
2.142 |
1.525 |
0.712 |
0.541 |
0.070 |
|
@Significant at p ≤ 0.05 level with group 1
HEMATOLOGY SUMMARY – MALES
Week -04
|
PLT |
WBC |
DC (%) |
PT |
APTT |
|||||
X103cells/µl |
X103cells/ µl |
Neut |
Lymph |
Mono |
Eos |
Baso |
Sec |
Sec |
||
Group 1 |
Mean |
947.20 |
19.92 |
13.00 |
83.40 |
2.60 |
1.00 |
0.00 |
16.40 |
44.00 |
SD |
114.220 |
5.308 |
2.550 |
2.191 |
0.548 |
0.000 |
0.000 |
0.548 |
1.581 |
|
Group 2 |
Mean |
884.20 |
17.16 |
13.20 |
83.00 |
2.80 |
1.00 |
0.00 |
17.00 |
44.80 |
SD |
126.476 |
3.421 |
2.588 |
2.739 |
0.837 |
0.000 |
0.000 |
1.000 |
1.483 |
|
Group 3 |
Mean |
960.40 |
17.46 |
15.20 |
81.20 |
2.40 |
1.20 |
0.00 |
16.20 |
44.00 |
SD |
108.367 |
6.159 |
2.280 |
2.168 |
0.548 |
0.447 |
0.000 |
1.095 |
2.000 |
|
Group 4 |
Mean |
766.20# |
18.40 |
15.00 |
81.20 |
2.80 |
1.00 |
0.00 |
16.40 |
43.00 |
SD |
72.651 |
6.499 |
2.550 |
2.588 |
0.447 |
0.000 |
0.000 |
1.140 |
2.121 |
|
#Significant at p ≤ 0.05 level with group 1
HEMATOLOGY SUMMARY – MALES
Week -06
|
RBC |
Hb |
PCV |
MCV |
MCH |
MCHC |
Reticulocyte |
|
x106Cells/µL |
g/dL |
% |
fL |
pg |
g/dL |
% |
||
Group 1R |
Mean |
9.32 |
15.78 |
49.42 |
53.04 |
16.95 |
31.94 |
1.79 |
SD |
0.610 |
0.726 |
2.685 |
1.081 |
0.417 |
0.513 |
0.038 |
|
Group 4R |
Mean |
9.13 |
15.72 |
49.54 |
54.36 |
17.26 |
31.74 |
1.87 |
SD |
0.589 |
0.349 |
1.638 |
2.813 |
0.956 |
0.378 |
0.068 |
|
HEMATOLOGY SUMMARY – MALES
Week -06
|
PLT |
WBC |
DC (%) |
PT |
APTT |
|||||
x103cells/µL |
x103cells/ µL |
Neut |
Lymph |
Mono |
Eos |
Baso |
Sec |
Sec |
||
Group 1R |
Mean |
982.60 |
18.00 |
13.80 |
81.80 |
3.00 |
1.40 |
0.00 |
15.80 |
42.40 |
SD |
26.293 |
2.055 |
2.588 |
3.033 |
0.000 |
0.548 |
0.000 |
0.837 |
2.074 |
|
Group 4R |
Mean |
812.00# |
14.62 |
16.20 |
79.20 |
2.80 |
1.60 |
0.20 |
16.20 |
43.40 |
SD |
63.589 |
5.286 |
3.962 |
4.817 |
0.447 |
0.548 |
0.447 |
1.304 |
2.408 |
|
#Significant at p ≤ 0.05 level with group 1
HEMATOLOGY SUMMARY – FEMALES
Week -04
|
RBC |
Hb |
PCV |
MCV |
MCH |
MCHC |
Reticulocyte |
|
x106Cells/µL |
g/dL |
% |
fL |
pg |
g/dL |
% |
||
Group 1 |
Mean |
8.37 |
15.76 |
47.10 |
56.38 |
18.94 |
33.48 |
1.82 |
SD |
0.512 |
0.439 |
1.996 |
2.519 |
0.802 |
0.614 |
0.029 |
|
Group 2 |
Mean |
8.31 |
15.82 |
47.08 |
56.66 |
19.04 |
33.60 |
1.79 |
SD |
0.335 |
0.460 |
1.835 |
1.016 |
0.451 |
0.561 |
0.059 |
|
Group 3 |
Mean |
7.56@ |
14.88 |
43.48@ |
57.58 |
19.70 |
34.26 |
1.85 |
SD |
0.397 |
0.342 |
1.572 |
1.171 |
0.704 |
0.581 |
0.076 |
|
Group 4 |
Mean |
8.00 |
15.50 |
45.38 |
56.84 |
19.42 |
34.16 |
1.78 |
SD |
0.582 |
0.620 |
2.213 |
1.504 |
0.698 |
0.451 |
0.087 |
|
@Significant at p ≤ 0.05 level with group 1,
HEMATOLOGY SUMMARY – FEMALES
Week -04
|
PLT |
WBC |
DC (%) |
PT |
APTT |
|||||
X103cells/µl |
X103cells/ µl |
Neut |
Lymph |
Mono |
Eos |
Baso |
Sec |
Sec |
||
Group 1 |
Mean |
990.80 |
23.08 |
12.60 |
83.20 |
2.80 |
1.40 |
0.00 |
16.40 |
43.60 |
SD |
85.920 |
2.772 |
2.074 |
2.168 |
0.447 |
0.548 |
0.000 |
1.140 |
1.817 |
|
Group 2 |
Mean |
965.00 |
15.74 |
14.00 |
81.40 |
3.00 |
1.60 |
0.00 |
16.00 |
43.00 |
SD |
109.968 |
4.039 |
2.550 |
2.510 |
0.000 |
0.548 |
0.000 |
0.707 |
2.236 |
|
Group 3 |
Mean |
948.20 |
20.88 |
11.40 |
84.40 |
3.00 |
1.20 |
0.00 |
15.80 |
42.40 |
SD |
117.647 |
7.134 |
4.450 |
6.189 |
1.732 |
0.447 |
0.000 |
0.837 |
1.673 |
|
Group 4 |
Mean |
866.20 |
17.62 |
19.60 |
76.60 |
2.60 |
1.20 |
0.00 |
16.80 |
43.40 |
SD |
96.650 |
3.259 |
18.501 |
18.188 |
0.548 |
0.447 |
0.000 |
1.095 |
1.140 |
|
HEMATOLOGY SUMMARY – FEMALES
Week -06
|
RBC |
Hb |
PCV |
MCV |
MCH |
MCHC |
Reticulocytes |
|
x106Cells/µL |
g/dL |
% |
fL |
pg |
g/dL |
% |
||
Group 1R |
Mean |
8.52 |
15.04 |
45.68 |
53.64 |
17.66 |
32.92 |
1.81 |
SD |
0.223 |
0.351 |
1.052 |
1.754 |
0.709 |
0.482 |
0.054 |
|
Group 4R |
Mean |
8.58 |
15.28 |
46.72 |
54.46 |
17.80 |
32.72 |
1.83 |
SD |
0.381 |
0.614 |
2.087 |
0.483 |
0.265 |
0.526 |
0.013 |
|
|
PLT |
WBC |
DC (%) |
PT |
APTT |
|||||
x103cells/µL |
x103cells/ µL |
Neut |
Lymph |
Mono |
Eos |
Baso |
Sec |
Sec |
||
Group 1R |
Mean |
803.60 |
21.78 |
14.40 |
81.20 |
3.20 |
1.20 |
0.00 |
16.20 |
42.40 |
SD |
105.296 |
1.942 |
2.510 |
3.271 |
0.447 |
0.447 |
0.000 |
0.837 |
2.510 |
|
Group 4R |
Mean |
1012.80# |
13.32# |
22.20 |
73.80 |
2.80 |
1.20 |
0.00 |
15.60 |
41.60 |
SD |
113.601 |
4.966 |
11.054 |
10.710 |
0.447 |
0.447 |
0.000 |
0.548 |
2.408 |
|
#Significant at p≤0.05 level with grou
CLINICAL BIOCHEMISTRY SUMMARY – MALES
WEEK -04
|
GLU |
Urea |
CREA |
BLI |
ALT |
AST |
ALP |
TPO |
|
mmol /L |
mmol /L |
µmol /L |
µmol /L |
U/L |
U/L |
U/L |
g/L |
||
Group 1 |
Mean |
102.40 |
42.00 |
0.70 |
0.08 |
57.80 |
128.80 |
352.80 |
7.24 |
SD |
10.78 |
6.60 |
0.00 |
0.01 |
7.40 |
6.06 |
41.15 |
0.17 |
|
Group 2 |
Mean |
100.60 |
39.00 |
0.68 |
0.10! |
54.60 |
133.60 |
357.00 |
7.22 |
SD |
12.10 |
4.30 |
0.04 |
0.01 |
12.12 |
8.65 |
76.78 |
0.16 |
|
Group 3 |
Mean |
102.80 |
45.60 |
0.66 |
0.08 |
56.40 |
128.40 |
442.80 |
7.18 |
SD |
6.98 |
7.20 |
0.05 |
0.01 |
8.35 |
12.70 |
42.53 |
0.23 |
|
Group 4 |
Mean |
95.60 |
41.20 |
0.66 |
0.10# |
60.40 |
150.80# |
411.60 |
7.50 |
SD |
12.78 |
5.89 |
0.05 |
0.01 |
6.35 |
11.65 |
88.60 |
0.28 |
|
#Significant at p≤0.05 level with group 1.
CLINICAL BIOCHEMISTRY SUMMARY – MALES
WEEK -04
|
ALB |
GLB |
CHOL |
TRIGL |
Na |
K |
Cl |
GGT |
A/G |
|
g/L |
g/L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
U/L |
_ |
||
Group 1 |
Mean |
2.33 |
4.92 |
60.60 |
69.40 |
139.22 |
4.85 |
98.20 |
2.20 |
0.48 |
SD |
0.03 |
0.19 |
5.55 |
14.86 |
0.79 |
0.20 |
1.12 |
0.64 |
0.03 |
|
Group 2 |
Mean |
2.41 |
4.82 |
52.00 |
71.20 |
138.80 |
4.89 |
99.64 |
1.74 |
0.50 |
SD |
0.10 |
0.22 |
14.35 |
20.73 |
0.43 |
0.29 |
1.17 |
1.30 |
0.03 |
|
Group 3 |
Mean |
2.31 |
4.88 |
57.40 |
62.60 |
139.42 |
32.14 |
80.96 |
21.64 |
0.47 |
SD |
0.06 |
0.20 |
7.57 |
10.06 |
1.32 |
60.86 |
42.44 |
44.04 |
0.02 |
|
Group 4 |
Mean |
2.27 |
5.24 |
57.60 |
80.40 |
139.70 |
4.74 |
99.78 |
2.84 |
0.43# |
SD |
0.11 |
0.31 |
9.21 |
22.68 |
0.75 |
0.16 |
0.73 |
2.34 |
0.04 |
|
#Significant at p≤0.05 level with group 1.
CLINICAL BIOCHEMISTRY SUMMARY – MALES - RECOVERY
WEEK -06
|
GLU |
Urea |
CREA |
BLI |
ALT |
AST |
ALP |
TPO |
|
mmol /L |
mmol /L |
µmol /L |
µmol /L |
U/L |
U/L |
U/L |
g/L |
||
Group 1R |
Mean |
115.20 |
42.20 |
0.62 |
0.09 |
55.20 |
113.20 |
404.20 |
7.46 |
SD |
16.16 |
5.50 |
0.08 |
0.02 |
4.71 |
7.36 |
122.76 |
0.25 |
|
Group 4R |
Mean |
116.80 |
38.80 |
0.66 |
0.08 |
46.80# |
119.00 |
214.80# |
7.26 |
SD |
19.14 |
5.97 |
0.05 |
0.01 |
5.45 |
4.30 |
48.53 |
0.30 |
|
|
ALB |
GLB |
CHOL |
TRIGL |
Na |
K |
Cl |
GGT |
A/G |
|
g/L |
g/L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
U/L |
_ |
||
Group 1R |
Mean |
2.23 |
5.24 |
49.40 |
63.60 |
140.64 |
4.98 |
100.84 |
2.12 |
0.42 |
SD |
0.15 |
0.21 |
9.63 |
15.84 |
0.82 |
0.08 |
1.47 |
1.31 |
0.03 |
|
Group 4R |
Mean |
2.21 |
5.04 |
47.20 |
51.80 |
140.72 |
4.98 |
101.32 |
1.02 |
0.47 |
SD |
0.17 |
0.23 |
12.91 |
24.26 |
1.02 |
0.40 |
1.56 |
0.58 |
0.07 |
|
#Significant at p ≤ 0.05 level with group 1
CLINICAL BIOCHEMISTRY SUMMARY – FEMALES
WEEK -04
|
GLU |
Urea |
CREA |
BLI |
ALT |
AST |
ALP |
TPO |
|
mmol /L |
mmol /L |
µmol /L |
µmol /L |
U/L |
U/L |
U/L |
g/L |
||
Group 1 |
Mean |
90.00 |
47.60 |
0.74 |
0.11 |
56.60 |
134.40 |
272.00 |
7.34 |
SD |
4.69 |
8.73 |
0.05 |
0.03 |
10.45 |
11.26 |
93.73 |
0.15 |
|
Group 2 |
Mean |
89.00 |
47.60 |
0.74 |
0.10 |
55.80 |
143.80 |
261.20 |
7.70 |
SD |
10.56 |
4.83 |
0.05 |
0.01 |
8.96 |
27.00 |
71.51 |
0.51 |
|
Group 3 |
Mean |
101.00 |
49.40 |
0.70 |
0.10 |
53.80 |
144.20 |
292.60 |
7.50 |
SD |
9.54 |
9.66 |
0.00 |
0.03 |
6.34 |
15.30 |
85.39 |
0.22 |
|
Group 4 |
Mean |
89.20 |
50.00 |
0.76 |
0.10 |
57.60 |
139.00 |
327.60 |
7.28 |
SD |
17.22 |
4.74 |
0.13 |
0.02 |
3.78 |
15.10 |
38.42 |
0.24 |
|
CLINICAL BIOCHEMISTRY SUMMARY – FEMALES
WEEK -04
|
ALB |
GLB |
CHOL |
TRIGL |
Na |
K |
Cl |
GGT |
A/G |
|
g/L |
g/L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
U/L |
_ |
||
Group 1 |
Mean |
2.44 |
4.90 |
68.20 |
80.40 |
139.32 |
4.54 |
99.78 |
2.44 |
0.49 |
SD |
0.09 |
0.16 |
7.43 |
27.21 |
0.63 |
0.35 |
1.57 |
2.01 |
0.03 |
|
Group 2 |
Mean |
2.45 |
5.26 |
81.40 |
64.20 |
140.28 |
4.49 |
101.34 |
1.72 |
0.46 |
SD |
0.14 |
0.40 |
12.50 |
21.25 |
1.70 |
0.30 |
2.53 |
1.60 |
0.02 |
|
Group 3 |
Mean |
2.36 |
5.16 |
86.20 |
61.40 |
140.00 |
4.83 |
101.80 |
2.68 |
0.45 |
SD |
0.09 |
0.26 |
12.05 |
11.87 |
1.09 |
0.09 |
1.14 |
1.31 |
0.03 |
|
Group 4 |
Mean |
2.27 |
5.02 |
74.80 |
68.60 |
139.76 |
4.50 |
101.98 |
2.36 |
0.46 |
SD |
0.31 |
0.56 |
11.65 |
15.63 |
1.11 |
0.34 |
1.55 |
1.24 |
0.10 |
|
CLINICAL BIOCHEMISTRY SUMMARY – FEMALES - RECOVERY
WEEK -06
|
GLU |
Urea |
CREA |
BLI |
ALT |
AST |
ALP |
TPO |
|
mmol /L |
mmol /L |
µmol /L |
µmol /L |
U/L |
U/L |
U/L |
g/L |
||
Group 1R |
Mean |
111.80 |
35.60 |
0.64 |
0.12 |
50.60 |
123.40 |
308.60 |
7.20 |
SD |
8.35 |
5.68 |
0.05 |
0.06 |
7.33 |
8.35 |
84.15 |
0.25 |
|
Group 4R |
Mean |
136.20# |
43.60 |
0.76# |
0.09 |
56.60 |
130.40 |
176.40# |
7.48 |
SD |
19.77 |
7.50 |
0.05 |
0.02 |
5.22 |
12.28 |
44.00 |
0.54 |
|
|
ALB |
GLB |
CHOL |
TRIGL |
Na |
K |
Cl |
GGT |
A/G |
|
g/L |
g/L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
mmol /L |
U/L |
_ |
||
Group 1R |
Mean |
2.18 |
5.02 |
57.80 |
64.80 |
139.06 |
4.53 |
100.90 |
1.16 |
0.43 |
SD |
0.20 |
0.22 |
9.88 |
12.07 |
0.83 |
0.17 |
0.49 |
0.90 |
0.05 |
|
Group 4R |
Mean |
2.46 |
5.00 |
61.20 |
41.40 |
140.74# |
4.60 |
102.44# |
1.18 |
0.49 |
SD |
0.20 |
0.37 |
14.32 |
30.22 |
0.81 |
0.21 |
1.18 |
1.00 |
0.03 |
|
#Significant at p ≤0.05 level with group 1R
URINANALYSIS – SUMMARY MALES
TREATMENT (Week 4)
|
pH |
SPECIFIC GRAVITY |
VOLUME |
|
(pH) |
(SG) |
mL |
||
Group 1 |
Mean |
7.40 |
1.010 |
12.40 |
SD |
1.02 |
0.01 |
1.67 |
|
Group 2 |
Mean |
6.80 |
1.017 |
12.40 |
SD |
0.45 |
0.01 |
1.67 |
|
Group 3 |
Mean |
7.40 |
1.007 |
10.40 |
SD |
0.55 |
0.01 |
1.67 |
|
Group 4 |
Mean |
6.90 |
1.020 |
11.00 |
SD |
0.55 |
0.01 |
1.41 |
|
RECOVERY (Week 6)
|
pH |
SPECIFIC GRAVITY |
VOLUME |
|
(pH) |
(SG) |
mL |
||
Group 1R |
Mean |
7.20 |
1.011 |
12.40 |
SD |
0.76 |
0.01 |
1.67 |
|
Group 4R |
Mean |
7.00 |
1.013 |
12.40 |
SD |
0.71 |
0.01 |
1.67 |
|
URINANALYSIS – SUMMARY FEMALES
TREATMENT (Week 4)
|
pH |
SPECIFIC GRAVITY |
VOLUME |
|
(pH) |
(SG) |
mL |
||
Group 1 |
Mean |
6.90 |
1.015 |
9.60 |
SD |
0.55 |
0.01 |
1.67 |
|
Group 2 |
Mean |
6.90 |
1.017 |
10.00 |
SD |
0.55 |
0.01 |
1.67 |
|
Group 3 |
Mean |
6.90 |
1.015 |
10.80 |
SD |
0.55 |
0.01 |
2.28 |
|
Group 4 |
Mean |
7.00 |
1.016 |
9.60 |
SD |
0.71 |
0.01 |
1.14 |
|
RECOVERY (Week 6)
|
pH |
SPECIFIC GRAVITY |
VOLUME |
|
(pH) |
(SG) |
mL |
||
Group 1R |
Mean |
7.50 |
1.009 |
10.00 |
SD |
0.00 |
0.00 |
1.67 |
|
Group 4R |
Mean |
6.90 |
1.011 |
11.40 |
SD |
0.55 |
0.01 |
1.95 |
|
ORGAN WEIGHTS (GRAM) – SUMMARY MALES
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Body Weight (G) |
Mean |
188.0 |
187.8 |
190.0 |
190.4 |
225.5 |
226.6 |
SD |
1.98 |
1.75 |
2.94 |
3.41 |
2.64 |
2.26 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Brain
|
Mean |
1.5208 |
1.7276 |
1.6722 |
1.7332 |
1.7308 |
1.7912 |
SD |
0.22996 |
0.18949 |
0.20302 |
0.16879 |
0.0703 |
0.1121 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Heart |
Mean |
1.3622 |
1.1748 |
1.1898 |
1.1592 |
1.5672 |
1.4318 |
SD |
0.55108 |
0.13315 |
0.08900 |
0.19831 |
0.6597 |
0.2005 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Liver |
Mean |
10.7768 |
11.9598 |
12.3826 |
11.6450 |
12.2516 |
12.1372 |
SD |
0.96180 |
1.42941 |
1.38330 |
2.27308 |
1.9339 |
1.6098 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Spleen |
Mean |
0.8832 |
0.8862 |
0.9058 |
1.0700 |
0.9642 |
0.8568 |
SD |
0.15267 |
0.18838 |
0.23423 |
0.22823 |
0.2554 |
0.1664 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Kidneys
|
Mean |
1.9130 |
2.3662 |
2.2266 |
2.1862 |
2.3560 |
2.4162 |
SD |
0.09315 |
0.31861 |
0.29819 |
0.35972 |
0.2038 |
0.2492 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHTS (GRAM) – SUMMARY MALES (CONTD.)
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Adrenals |
Mean |
0.0786 |
0.0736 |
0.0730 |
0.0846 |
0.0900 |
0.0762 |
SD |
0.01876 |
0.02028 |
0.01166 |
0.02758 |
0.0294 |
0.0199 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Testes |
Mean |
2.6902 |
2.5696 |
2.5204 |
2.7464 |
2.4740 |
2.5856 |
SD |
0.43755 |
0.28320 |
0.25850 |
0.18720 |
0.1792 |
0.1397 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Epididymes |
Mean |
1.2890 |
1.1456 |
1.2376 |
1.3560 |
1.5204 |
1.2406 |
SD |
0.18165 |
0.09788 |
0.21020 |
0.17377 |
0.3331 |
0.1656 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Thymus |
Mean |
1.0384 |
0.8776 |
1.2882 |
1.0558 |
1.2958 |
1.6642 |
SD |
0.32879 |
0.21025 |
0.25352 |
0.19113 |
0.3700 |
0.5540 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Pro + Sem. Vesical with Coagulating glands |
Mean |
0.5738 |
0.4596 |
0.4090 |
0.6230 |
0.4750 |
0.4074 |
SD |
0.24899 |
0.14134 |
0.11354 |
0.63532 |
0.1850 |
0.1806 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHTS (GRAM) – SUMMARY FEMALES
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
||||
Body Weight (G) |
Mean |
183.6 |
183.6 |
185.9 |
184.7 |
222.7 |
227.2 |
|||
SD |
3.08 |
3.56 |
3.72 |
3.85 |
2.59 |
2.61 |
||||
N |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Brain
|
Mean |
1.5868 |
1.6318 |
1.7080 |
1.6560 |
1.5964 |
1.6218 |
|||
SD |
0.11644 |
0.18147 |
0.16832 |
0.11120 |
0.1598 |
0.1828 |
||||
N |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Heart |
Mean |
0.7894 |
0.8420 |
0.8842 |
1.0262# |
0.8322 |
0.9012 |
|||
SD |
0.07433 |
0.07927 |
0.08066 |
0.19578 |
0.0669 |
0.1068 |
||||
N |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Liver |
Mean |
7.5688 |
6.8344 |
8.5234 |
8.9648 |
7.3988 |
7.1562 |
|||
SD |
1.39591 |
0.66916 |
1.24858 |
0.70799 |
1.0276 |
0.6172 |
||||
N |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Spleen |
Mean |
0.8416 |
0.6292 |
0.7840 |
0.8542 |
0.6492 |
0.6170 |
|||
SD |
0.23081 |
0.07286 |
0.20496 |
0.18374 |
0.1478 |
0.1407 |
||||
N |
5 |
5 |
5 |
5 |
5 |
5 |
||||
Kidneys
|
Mean |
1.4710 |
1.4272 |
1.5918 |
1.7734# |
1.5310 |
1.5238 |
|
||
SD |
0.15456 |
0.10609 |
0.20817 |
0.15517 |
0.1065 |
0.0870 |
|
|||
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
|||
#Significant at p ≤ 0.05 level with group 1.
ORGAN WEIGHTS (GRAM) – SUMMARY FEMALES (CONTD.)
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Adrenals |
Mean |
0.0888 |
0.0738 |
0.1058 |
0.1138 |
0.0840 |
0.0864 |
SD |
0.01925 |
0.01375 |
0.01791 |
0.01671 |
0.0354 |
0.0100 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Ovaries |
Mean |
0.4436 |
0.4368 |
0.4282 |
0.3584 |
0.2512 |
0.4246 |
SD |
0.24545 |
0.14870 |
0.06111 |
0.08873 |
0.0887 |
0.1754 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Uterus |
Mean |
0.1386 |
0.2108 |
0.2110 |
0.1978 |
0.2238 |
0.1784 |
SD |
0.03879 |
0.19715 |
0.11964 |
0.04727 |
0.1753 |
0.0963 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Thymus |
Mean |
0.5072 |
0.3848 |
0.4190 |
0.4840 |
0.3182 |
0.3098 |
SD |
0.23162 |
0.09232 |
0.08428 |
0.05829 |
0.1121 |
0.0822 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHT RATIO – SUMMARY
ORGAN WEIGHTS RATIO (%) – SUMMARY MALES
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Body Weight (G) |
Mean |
188.0 |
187.8 |
190.0 |
190.4 |
225.5 |
226.6 |
SD |
1.98 |
1.75 |
2.94 |
3.41 |
2.64 |
2.26 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Brain
|
Mean |
0.8097 |
0.9197 |
0.8811 |
0.9105 |
0.7677 |
0.7905 |
SD |
0.12965 |
0.09784 |
0.11473 |
0.08662 |
0.0325 |
0.0519 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Heart |
Mean |
0.7234 |
0.6257 |
0.6267 |
0.6093 |
0.6970 |
0.6318 |
SD |
0.28820 |
0.07217 |
0.05489 |
0.10704 |
0.3007 |
0.0888 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Liver |
Mean |
5.7312 |
6.3700 |
6.5133 |
6.1234 |
5.4337 |
5.3526 |
SD |
0.50647 |
0.76796 |
0.67993 |
1.22570 |
0.8610 |
0.6795 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Spleen |
Mean |
0.4699 |
0.4724 |
0.4760 |
0.5639 |
0.4273 |
0.3778 |
SD |
0.08238 |
0.10296 |
0.12012 |
0.12963 |
0.1112 |
0.0713 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHTS RATIO (%) – SUMMARY MALES (CONTD.)
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Kidneys
|
Mean |
1.0176 |
1.2608 |
1.1713 |
1.1494 |
1.0450 |
1.0658 |
SD |
0.05456 |
0.17507 |
0.15281 |
0.19641 |
0.0917 |
0.1047 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Adrenals |
Mean |
0.0417 |
0.0393 |
0.0384 |
0.0445 |
0.0400 |
0.0336 |
SD |
0.00971 |
0.01104 |
0.00616 |
0.01438 |
0.0133 |
0.0087 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Testes
|
Mean |
1.4320 |
1.3682 |
1.3275 |
1.4429 |
1.0976 |
1.1409 |
SD |
0.24391 |
0.14935 |
0.14716 |
0.09710 |
0.0841 |
0.0605 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Epididymes |
Mean |
0.6850 |
0.6099 |
0.6505 |
0.7128 |
0.6751 |
0.5476 |
SD |
0.09126 |
0.04943 |
0.10455 |
0.09461 |
0.1519 |
0.0745 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Thymus |
Mean |
0.5532 |
0.4668 |
0.6775 |
0.5538 |
0.5738 |
0.7345 |
SD |
0.17793 |
0.10902 |
0.13025 |
0.09314 |
0.1594 |
0.2452 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Pro + Sem. Vesical with Coagulating glands |
Mean |
0.3049 |
0.2449 |
0.2147 |
0.3284 |
0.2107 |
0.1796 |
SD |
0.13065 |
0.07613 |
0.05707 |
0.33245 |
0.0826 |
0.0790 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHTS RATIO (%) – SUMMARY FEMALES
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Body Weight (G) |
Mean |
183.6 |
183.6 |
185.9 |
184.7 |
222.7 |
227.2 |
SD |
3.08 |
3.56 |
3.72 |
3.85 |
2.59 |
2.61 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Brain
|
Mean |
0.8645 |
0.8900 |
0.9186 |
0.8970 |
0.7163 |
0.7142 |
SD |
0.06122 |
0.10638 |
0.08771 |
0.06611 |
0.0652 |
0.0832 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Heart |
Mean |
0.4300 |
0.4584 |
0.4756 |
0.5562 |
0.3737 |
0.3971 |
SD |
0.03948 |
0.03897 |
0.04171 |
0.11063 |
0.0302 |
0.0508 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Liver |
Mean |
4.1145 |
3.7229 |
4.5865 |
4.8520 |
3.3202 |
3.1529 |
SD |
0.69366 |
0.35077 |
0.68639 |
0.35283 |
0.4416 |
0.3069 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Spleen |
Mean |
0.4570 |
0.3428 |
0.4212 |
0.4612 |
0.2914 |
0.2720 |
SD |
0.11788 |
0.03867 |
0.10886 |
0.09231 |
0.0654 |
0.0649 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Kidneys
|
Mean |
0.8006 |
0.7783 |
0.8574 |
0.9602 |
0.6875 |
0.6711 |
SD |
0.07398 |
0.06938 |
0.12291 |
0.08426 |
0.0484 |
0.0439 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ORGAN WEIGHTS RATIO (%) – SUMMARY FEMALES (CONTD.)
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1R |
Group 4R |
|
Adrenals |
Mean |
0.0484 |
0.0403 |
0.0568 |
0.0616 |
0.0376 |
0.0381 |
SD |
0.01034 |
0.00790 |
0.00892 |
0.00924 |
0.0155 |
0.0047 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
ovaries |
Mean |
0.2401 |
0.2373 |
0.2302 |
0.1945 |
0.1130 |
0.1864 |
SD |
0.12868 |
0.07796 |
0.03161 |
0.04990 |
0.0406 |
0.0761 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Uterus
|
Mean |
0.0753 |
0.1152 |
0.1131 |
0.1071 |
0.1002 |
0.0788 |
SD |
0.02016 |
0.10839 |
0.06295 |
0.02551 |
0.0781 |
0.0435 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
Thymus
|
Mean |
0.2766 |
0.2096 |
0.2254 |
0.2619 |
0.1426 |
0.1365 |
SD |
0.12572 |
0.04993 |
0.04549 |
0.03004 |
0.0494 |
0.0367 |
|
N |
5 |
5 |
5 |
5 |
5 |
5 |
|
SUMMARY OF GROSS PATHOLOGY
Male
Gross observation |
Group |
||||
control (G1) |
Low dose (G2) |
Intermediate dose(G3) |
High dose (G4) |
||
External |
|||||
NAD |
5/5 |
5/5 |
5/5 |
5/5 |
|
Internal |
|||||
NAD |
5/5 |
5/5 |
5/5 |
5/5 |
|
Female
Gross observation |
Group |
|||
control (G1) |
Low dose (G2) |
Intermediate dose(G3) |
High dose (G4) |
|
External |
||||
NAD |
5/5 |
5/5 |
5/5 |
5/5 |
Internal |
||||
NAD |
5/5 |
5/5 |
5/5 |
5/5 |
Key: M – Male; F – Female; No. of animals showing observation/Total no. of animals.
SUMMARY OF HISTOPATHOLOGY
ORGAN |
OBSERVATIONS |
Control (G1) |
High dose (G4) |
||
M |
F |
M |
F |
||
Liver |
Sinusoidal Haemorrhage |
1/5 |
2/5 |
3/5 |
0/5 |
Foci of centrilobular/ Periportalnecrosis//Inflammation |
1/5 |
2/5 |
2/5 |
1/5 |
|
No Abnormality Detected (NAD) |
3/5 |
1/5 |
2/5 |
4/5 |
|
Lungs |
Alveolar Haemorrhage |
1/5 |
0/5 |
1/5 |
0/5 |
Alveolar wall Thickening /Peribronchiolar Lymphoid tissue hyperplastia/ Alveolar inflammation |
2/5 |
2/5 |
2/5 |
1/5 |
|
No Abnormality Detected (NAD) |
2/5 |
3/5 |
2/5 |
4/5 |
|
Spleen |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Heart |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Aorta |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Kidneys |
Tubular /interstitial inflammation |
1/5 |
3/5 |
1/5 |
3/5 |
No Abnormality Detected (NAD) |
4/5 |
2/5 |
4/5 |
2/5 |
|
Adrenals |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Brain |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Pituitary |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Thyroid andthyroid |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Trachea |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Oesophagus |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Jejunum |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Duodenum |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Key: M – Male; F – Female; No. of animals showing observation/Total no. of animals.
SUMMARY OF HISTOPATHOLOGY (Contd.,)
ORGAN |
OBSERVATIONS |
Control (G1) |
High dose (G4) |
||
M |
F |
M |
F |
||
Ileum |
Submucosal lymphoid tissue hyperplastia |
1/5 |
1/5 |
0/5 |
0/5 |
No Abnormality Detected (NAD) |
4/5 |
4/5 |
5/5 |
5/5 |
|
Colon |
Sub mucosal lymphoid tissue hyperplasia |
2/5 |
0/5 |
1/5 |
0/5 |
No Abnormality Detected (NAD) |
3/5 |
5/5 |
4/5 |
5/5 |
|
Rectum |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Caecum |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Lymph nodes |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Pancreas |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Thymus |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Urinary bladder |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Testes |
No Abnormality Detected (NAD) |
5/5 |
- |
5/5 |
- |
Epididymis |
No Abnormality Detected (NAD) |
5/5 |
- |
5/5 |
- |
Prost+Seminal Vesicles+coagula Ting glands |
No Abnormality Detected (NAD) |
5/5 |
- |
5/5 |
- |
Ovary |
No Abnormality Detected (NAD) |
- |
5/5 |
- |
5/5 |
Uterus |
No Abnormality Detected (NAD) |
- |
5/5 |
- |
5/5 |
Cervix+Vagina |
No Abnormality Detected (NAD) |
- |
5/5 |
- |
5/5 |
Stomach |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Skeletal muscle |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Sciatic nerve |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Eye |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Spinal cord |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Sternum |
No Abnormality Detected (NAD) |
5/5 |
5/5 |
5/5 |
5/5 |
Key: M – Male; F – Female; No. of animals showing observation/Total no. of animals.
Applicant's summary and conclusion
- Conclusions:
- The toxicity of the registered substance following repeated oral exposure was tested in a 28-day study (OECD 407) using male and female Wistar rats. No treatment related adverse effect was observed. The study-derived NOAEL was 1000 mg/kg bw/day.
- Executive summary:
The study was performed according to OECD 407 and GLP. The test substance was given by oral gavage to 5 rats per sex per dose level at 0 (distilled water), 250, 500 and 1000 mg/kg bw/day. In addition, recovery groups treated with 0 (distilled water) or 1000 mg/kg bw/day were included to study the reversibility of treatment-related effects (if any). Male and female Wistar rats of the treatment groups were dosed for 28 days, rats in the recovery groups were allowed to recover for 14 days after the final dose. The observation and examinations performed in the study were mortality, clinical signs, detailed clinical signs, body weight, food consumption, sensory reactivity, assessment of grip strength, motor activity assessment, ophthalmoscopy, clinical pathology (hematology and clinical chemistry), urinalysis, gross pathology at termination, organ weight, and histopathology on the preserved organs and tissues. Results: All animals survived to planned death, and there were no clinical signs of toxicity. No test item-related changes were noted in body weight or body weight gain and feed consumption of both sexes from any of the dose levels during the experimental period. No significant changes in sensory reactivity, grip strength, or motor activity were observed in any of the animals during treatment or recovery. No abnormalities were observed during the ophthalmological examinations. No treatment-related adverse effect was observed on haematological and clinical biochemistry parameters of both sexes from any dose groups. No significant changes in urinalysis were observed in any of the groups. No changes were noted in organ weights of both sexes from any dose levels. No treatment-related histopathological effects were observed at 1000 mg/kg bw/day in the main study. Conclusion: The study-derived NOAEL was 1000 mg/kg bw/day.
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