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EC number: 305-729-0 | CAS number: 95009-01-1
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral, other
- Remarks:
- 28 days
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- April 29, 2016 - Feb 21, 2017 (28 days exposure)
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Performed to GLP using OECD guidelines. However, some observations (not listed as a minimum gudeline requirement) were not recorded. This includes information relting to the colour of faeces and onlt limited details on the colour changes in urine. These effects are well recorded in the reproduction toxicity screening test 7.8.1
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:
- OECD 407:2008
- GLP compliance:
- yes
Test material
- Reference substance name:
- Sodium [4-[[dihydroxy[(2-hydroxy-3,5-dinitrophenyl)azo]phenyl]azo]benzenesulphonato(3-)]cuprate(1-)
- EC Number:
- 305-729-0
- EC Name:
- Sodium [4-[[dihydroxy[(2-hydroxy-3,5-dinitrophenyl)azo]phenyl]azo]benzenesulphonato(3-)]cuprate(1-)
- Cas Number:
- 95009-01-1
- Molecular formula:
- C18H9CuN6O10S.Na
- IUPAC Name:
- Reaction products of diazotized 4-aminobenzenesulfonic acid coupled with resorcinol subsequently coupled with diazotised 2-amino-4,6-dinitrophenol, copper (2+) complexes, sodium salts
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Name of test material (as cited in study report): Everlan SL65
- Substance type: Powder
- Composition of test material, percentage of components: 71.19%
- Lot/batch No.: 3010
- Storage condition of test material: Ambient
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: BioLASCO Taiwan Co., Ltd.
- Age at study initiation: about 4-week old
- Housing: Male and female rats were fed, respectively. Two rats per cage in an autoclaved polyethylene cage.
- Acclimation period: 1 week
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15%
- Photoperiod: 12-hrs dark / 12-hrs light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- - Rate of preparation of diet (frequency): everyday fresh preparation
- Concentration in vehicle: 6.25 mg/ml, 25.0 mg/ml and 100 mg/ml with water - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- everyday
Doses / concentrationsopen allclose all
- Dose / conc.:
- 62.5 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Medium dose
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- For control group: 6 males and 6 females
For low dose group: 6 males and 6 females
For medium dose group: 6 males and 6 females
For high dose group: 6 males and 6 females - Control animals:
- yes, concurrent vehicle
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- For male rats:
The body weight of medium dose (250 mg/kg bw) and high dose (1000 mg/kg bw) groups was significantly higher than control group at week 1 (p<0.05). - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- For male rats:
The feed efficiency of high dose group was significantly higher than control group at week 3 and 4 (p < 0.05). - Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- For male rats:
For medium dose group, the platelet count and monocyte were significantly higher than control group and lymphocyte was significantly lower than control group (p < 0.05). For high dose group, the WBC and neutrophil of were significantly higher than control group and lymphocyte and basophil were significantly lower than control group (p < 0.05).
For female rats:
For low dose group, the mean corpuscular volume (MCV) was significantly higher than control group and RBC, hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were significantly lower than control group (p < 0.05). For medium dose group, the mean corpuscular hemoglobin (MCH) was significantly higher than control group and RBC, hemoglobin and hematocrit were significantly lower than control group (p < 0.05). For high dose group, the WBC, platelet count and neutrophil was significantly higher than control group and RBC, hemoglobin, hematocrit, lymphocyte and basophil were significantly lower than control group (p < 0.05). - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- For male rats:
The Ca of medium dose was significantly higher than control group (p <0.05). The albumin and alkaline phosphatase (ALP) of high dose group were significantly lower than control group (p < 0.05).
For female rats:
The globulin of medium dose group was significantly lower than control group (p < 0.05). For high dose group, the P and Cl were significantly higher than control group (p < 0.05) and total protein, albumin and Na were significantly lower than control group (p < 0.05). - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No discolouration noted with same colour for controls and treated groups. Some high dose group fem
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- For male rats:
The brain absolute weight of low dose group was significantly lower than control group (p < 0.05). The spleen absolute weight of medium dose group, adrenal gland and spleen absolute weight of high dose group were significantly heavier than control group (p < 0.05). The adrenal gland, spleen and kidney relative weight of high dose group were significantly higher than control group (p < 0.05).
For female rats:
The spleen absolute weight of medium and high dose groups were significantly heavier than control group (p < 0.05). The heart relative weight of medium dose group and the spleen relative weight of medium and high dose group were significantly heavier than control group (p < 0.05). - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Damage seen to cecum and colon in high dose group animals, typical of copper toxicity.
This local damage would impact on spleen activity and blood parameter changes. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Specific histopathological findings:
Male and female rats in the high dose groups presented multifocal, minimal to moderate, ulcerative necrosis and inflammation in the cecum. Male rats in the high dose groups presented multifocal, moderate, ulcerative necrosis and inflammation in the colon. Male and female rats in the middle and high dose groups presented multifocal, minimal to moderate, inflammation in the terminal bronchial and alveoli of the lungs. Female rats in the high dose groups presented multifocal, minimal to moderate, acinar hyperplasia in the mammary gland.
Non-specific histopathological findings:
Only one male rat in the control group showed a focal, slight tubular cyst in the kidney. Only one male rat in high dose group presented focal, slight mononuclear cell infiltration in the prostate gland. - Histopathological findings: neoplastic:
- not specified
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 62.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
Target system / organ toxicity
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- colon
- other: cecum
- Treatment related:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 250 mg/kg bw/day (nominal)
- System:
- respiratory system: lower respiratory tract
- Organ:
- alveoli
- bronchi
- Treatment related:
- yes
Any other information on results incl. tables
Table 1: Mortality of the rats
Sex |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
No of rate in each group |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
No of rat died during the study |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Table 2: Incidence of abnormal clinical sign
Sex |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
No of rate in each group |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
No of rat exhibited abnormal clinical sign |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Table 3: Average body weight of male rats
Recording time |
Average body weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Before study |
136.5±8.6 |
136.4±9.3 |
136.7±9.2 |
136.0±12.8 |
Week 1 |
168.8±16.4 |
183.6±12.9 |
194.3±6.5* |
186.3±11.4* |
Week 2 |
253.8±14.4 |
251.5±16.0 |
153.9±10.6 |
246.0±19.6 |
Week 3 |
311.9±15.2 |
301.8±16.5 |
305.0±17.2 |
298.2±19.9 |
Week 4 |
342.7±24.2 |
338.3±22.1 |
346.5±24.1 |
316.5±31.2 |
After fasting |
312.9±25.3 |
310.5±20.2 |
320.5±23.0 |
296.9±27.8 |
*Significant different from control group (p < 0.05)
Table 4: Average body weight of female rats
Recording time |
Average body weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Before study |
148.0±6.6 |
147.7±9.3 |
148.1±5.8 |
148.1±5.4 |
Week 1 |
172.0±12.6 |
172.2±13.9 |
164.1±8.8 |
162.0±5.8 |
Week 2 |
198.9±14.0 |
202.8±16.3 |
188.5±13.2 |
192.6±7.6 |
Week 3 |
220.9±15.7 |
225.6±21.5 |
211.1±14.2 |
215.0±6.2 |
Week 4 |
239.4±18.0 |
243.3±23.1 |
227.3±17.0 |
222.3±10.6 |
After fasting |
212.6±16.0 |
217.3±20.7 |
208.9±15.7 |
205.1±8.8 |
Table 5: Average feed intake of male rats
Recording time |
Average feed intake (g/rat/day) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Week 1 |
16.2±1.5 |
17.8±0.5* |
18.4±0.9* |
18.0±0.9* |
Week 2 |
25.7±0.6 |
24.9±1.6 |
24.7±0.8 |
25.6±1.9 |
Week 3 |
26.6±1.4 |
25.7±1.4 |
26.3±1.9 |
27.6±1.2 |
Week 4 |
24.4±3.2 |
24.7±1.4 |
27.0±1.8 |
25.6±2.8 |
*Significant different from control group (p < 0.05)
Table 6: Average feed intake of female rats
Recording time |
Average feed intake (g/rat/day) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Week 1 |
15.3±0.1 |
15.3±0.5 |
13.7±0.9* |
14.7±0.9 |
Week 2 |
18.2±1.6 |
18.5±1.5 |
18.5±0.5 |
19.2±1.5 |
Week 3 |
19.5±1.1 |
18.6±1.8 |
17.8±0.7* |
19.1±0.6 |
Week 4 |
18.8±1.2 |
18.9±0.3 |
18.1±0.3 |
18.5±2.0 |
*Significant different from control group (p < 0.05)
Table 7: Average daily Feed efficiency of male rats
Recording time |
Average daily Feed efficiency (g/100 g body weight of rat/day) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Week 1 |
9.6±0.6 |
9.8±0.7 |
9.5±0.3 |
9.6±0.2 |
Week 2 |
10.1±0.7 |
9.9±0.7 |
9.8±0.2 |
10.4±0.4 |
Week 3 |
8.6±0.5 |
8.6±0.4 |
8.6±0.3 |
9.3±0.5* |
Week 4 |
7.1±0.7 |
7.3±0.3 |
7.8±0.4 |
8.1±0.8* |
*Significant different from control group (p < 0.05)
Table 8: Average daily Feed efficiency of female rats
Recording time |
Average daily Feed efficiency (g/100 g body weight of rat/day) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Week 1 |
8.9±0.7 |
8.9±0.7 |
8.4±0.7 |
9.1±0.4 |
Week 2 |
9.2±1.0 |
9.1±0.5 |
9.9±0.7 |
10.0±0.5 |
Week 3 |
8.9±0.8 |
8.3±0.6 |
8.5±0.7 |
8.9±0.2 |
Week 4 |
7.9±0.8 |
7.8±0.8 |
8.0±0.6 |
8.3±0.6 |
*Significant different from control group (p < 0.05)
Table 9: Ophthalmological examination before the study
Sex |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
No of rate in each group |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
No of rat exhibited ophthalmic abnormality |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Table 10: Ophthalmological examination at the end of the study
Sex |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
No of rate in each group |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
No of rat exhibited ophthalmic abnormality |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Table 11: Incidence of gross lesion
|
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
Male |
||||
No of rate in each group |
6 |
6 |
6 |
6 |
No of rat exhibited gross lesion |
0 |
0 |
0 |
0 |
Female |
||||
No of rate in each group |
6 |
6 |
6 |
6 |
No of rat exhibited gross lesion |
0 |
0 |
0 |
0 |
Table 12: Absolute organ weight of male rats\
Item |
Absolute organ weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Testis |
3.060±0.236 |
2.927±0.233 |
3.044±0.123 |
3.198±0.114 |
Adrenal gland |
0.054±0.006 |
0.056±0.004 |
0.058±0.007 |
0.064±0.007* |
Spleen |
0.613±0.130 |
0.662±0.134 |
0.784±0.103* |
0.848±0.066* |
Kidney |
3.028±0.193 |
2.978±0.302 |
3.131±0.278 |
3.238±0.515 |
Heart |
1.302±0.063 |
1.283±0.043 |
1.302±0.106 |
1.344±0.154 |
Brain |
2.047±0.027 |
1.952±0.071* |
1.997±0.091 |
2.007±0.057 |
Liver |
11.685±1.211 |
10.974±1.410 |
11.945±0.931 |
12.189±1.902 |
Thymus |
0.552±0.106 |
0.518±0.086 |
0.523±0.082 |
0.553±0.158 |
Epididymis |
0.750±0.073 |
0.723±0.060 |
0.766±0.049 |
0.827±0.089 |
Coagulating glands |
2.053±0.311 |
1.999±0.169 |
2.240±0.216 |
1.930±0.490 |
*Significant different from control group (p < 0.05)
Table 13: Absolute organ weight of female rats
Item |
Absolute organ weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Ovary |
0.095±0.019 |
0.093±0.020 |
0.080±0.018 |
0.085±0.013 |
Adrenal gland |
0.073±0.013 |
0.076±0.017 |
0.069±0.009 |
0.074±0.012 |
Spleen |
0.507±0.075 |
0.548±0.067 |
0.691±0.099* |
0.720±0.150* |
Kidney |
2.216±0.270 |
2.278±0.274 |
2.157±0.161 |
1.994±0.168 |
Heart |
0.877±0.080 |
0.942±0.105 |
0.939±0.055 |
0.881±0.065 |
Brain |
1.881±0.104 |
1.906±0.073 |
1.892±0.046 |
1.916±0.024 |
Liver |
8.500±1.391 |
9.060±1.102 |
8.757±1.364 |
8.716±0.970 |
Thymus |
0.433±0.049 |
0.472±0.074 |
0.454±0.085 |
0.424±0.109 |
Uterus |
0.793±0.214 |
0.792±0.131 |
0.847±0.258 |
0.672±0.052 |
*Significant different from control group (p < 0.05)
Table 14:Relative organ weight of male rats
Item |
Absolute organ weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Testis |
0.985±0.116 |
0.944±0.067 |
0.954±0.073 |
1.083±0.090 |
Adrenal gland |
0.017±0.002 |
0.018±0.002 |
0.019±0.002 |
0.022±0.003* |
Spleen |
0.197±0.042 |
0.214±0.043 |
0.247±0.045 |
0.287±0.029* |
Kidney |
0.972±0.080 |
0.959±0.070 |
0.977±0.058 |
1.091±0.143* |
Heart |
0.419±0.042 |
0.415±0.028 |
0.407±0.026 |
0.458±0.081 |
Brain |
0.658±0.051 |
0.630±0.030 |
0.627±0.067 |
0.681±0.062 |
Liver |
3.735±0.271 |
3.530±0.336 |
3.730±0.186 |
4.131±0.772 |
Thymus |
0.176±0.030 |
0.167±0.029 |
0.163±0.019 |
0.189±0.065 |
Epididymis |
0.241±0.030 |
0.233±0.024 |
0.241±0.033 |
0.280±0.040 |
Coagulating glands |
0.662±0.124 |
0.647±0.077 |
0.704±0.105 |
0.659±0.210 |
*Significant different from control group (p < 0.05)
Table 15: Relative organ weight of female rats
Item
|
Absolute organ weight (g) |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Ovary |
0.044±0.007 |
0.042±0.006 |
0.038±0.006 |
0.042±0.007 |
Adrenal gland |
0.034±0.005 |
0.035±0.008 |
0.033±0.003 |
0.036±0.006 |
Spleen |
0.238±0.028 |
0.252±0.015 |
0.332±0.056* |
0.352±0.077* |
Kidney |
1.041±0.079 |
1.047±0.065 |
1.034±0.068 |
0.972±0.080 |
Heart |
0.412±0.016 |
0.434±0.022 |
0.450±0.013* |
0.430±0.027 |
Brain |
0.887±0.040 |
0.883±0.068 |
0.910±0.077 |
0.935±0.038 |
Liver |
3.979±0.344 |
4.162±0.203 |
4.172±0.343 |
4.257±0.530 |
Thymus |
0.203±0.013 |
0.218±0.038 |
0.218±0.042 |
0.206±0.046 |
Uterus |
0.373±0.099 |
0.365±0.053 |
0.409±0.136 |
0.328±0.023 |
*Significant different from control group (p < 0.05)
Table 16: Hematology of male rats
Item |
Hematology |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
WBC (10^3/ul) |
11.59±1.90 |
12.46±2.39 |
13.56±1.91 |
18.58±7.34* |
RBC (10^6/ul) |
9.20±0.34 |
8.69±0.37 |
8.67±0.68 |
8.75±0.81 |
Hemoglobin (g/dl) |
17.60±0.43 |
16.97±1.16 |
16.65±0.94 |
16.72±1.06 |
Hematocrit (%) |
53.53±0.96 |
51.85±3.19 |
51.28±2.12 |
51.35±3.27 |
MCV (fL) |
58.23±2.09 |
59.65±1.37 |
59.33±2.42 |
58.87±3.28 |
MCH (pg) |
19.12±0.50 |
19.53±0.54 |
19.23±0.52 |
19.15±0.79 |
MCHC (g/dl) |
32.87±0.40 |
32.73±0.33 |
32.43±0.59 |
32.55±0.71 |
Platelet (10^3/ul) |
923.8±88.6 |
958.3±139.5 |
1136.8±83.4* |
1061.2±154.7 |
Neutrophil (%) |
11.92±3.97 |
10.78±2.77 |
15.27±2.33 |
17.40±4.73* |
Lymphocyte (%) |
84.22±4.01 |
84.68±3.67 |
79.07±1.83* |
78.27±4.93* |
Monocyte (%) |
2.87±0.56 |
3.62±0.89 |
4.87±1.41* |
3.58±0.98 |
Eosinophil (%) |
0.75±0.43 |
0.70±0.19 |
0.62±0.17 |
0.63±0.34 |
Basophil (%) |
0.25±0.05 |
0.22±0.10 |
0.18±0.08 |
0.12±0.04* |
Reticulocyte (%) |
2.00±0.81 |
1.72±0.44 |
1.42±0.39 |
1.33±0.53 |
PT (sec) |
15.80±1.28 |
15.27±2.85 |
16.03±0.96 |
14.90±1.97 |
*Significant different from control group (p < 0.05)
Table 17: Hematology of female rats
Item |
Hematology |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
WBC (10^3/ul) |
12.67±2.21 |
12.93±3.89 |
12.23±2.34 |
18.15±5.41* |
RBC (10^6/ul) |
8.90±0.40 |
8.21±0.31* |
7.89±0.23* |
8.03±0.41* |
Hemoglobin (g/dl) |
17.35±0.82 |
16.18±0.64* |
15.85±0.46* |
15.30±0.48* |
Hematocrit (%) |
53.07±2.37 |
51.20±1.63 |
48.12±1.09* |
46.58±1.55* |
MCV (fL) |
59.60±0.76 |
62.40±2.16* |
61.02±2.37 |
58.07±1.47 |
MCH (pg) |
19.50±0.19 |
19.72±0.62 |
20.10±0.44* |
19.08±0.42 |
MCHC (g/dl) |
32.70±0.23 |
31.62±0.40* |
32.93±0.83 |
32.83±0.31 |
Platelet (10^3/ul) |
976.8±119.0 |
908.2±63.0 |
1005.2±70.2 |
1111.8±102.3* |
Neutrophil (%) |
9.07±2.20 |
9.75±2.37 |
11.83±1.05 |
16.77±6.38* |
Lymphocyte (%) |
86.78±3.04 |
86.75±2.97 |
83.70±1.56 |
78.92±6.63* |
Monocyte (%) |
3.20±0.90 |
2.60±0.59 |
3.62±0.71 |
3.78±1.34 |
Eosinophil (%) |
0.70±0.26 |
0.70±0.21 |
0.60±0.27 |
0.42±0.22 |
Basophil (%) |
0.25±0.10 |
0.20±0.09 |
0.25±0.10 |
0.12±0.04* |
Reticulocyte (%) |
2.72±0.80 |
2.48±0.65 |
2.48±1.23 |
2.78±0.84 |
PT (sec) |
9.75±0.30 |
9.68±0.26 |
10.00±0.68 |
9.48±0.26 |
*Significant different from control group (p < 0.05)
Table 18: Clinical chemistry of male rats
Item |
Hematology |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Glucose (mg/dl) |
165.17±39.36 |
144.83±39.30 |
181.50±53.44 |
145.67±64.08 |
BUN (mg/dl) |
13.00±0.54 |
13.05±2.46 |
12.85±1.99 |
12.85±1.74 |
Creatinine (mg/dl) |
0.65±0.05 |
0.63±0.08 |
0.68±0.04 |
0.62±0.04 |
AST (U/L) |
90.17±14.51 |
105.83±11.37 |
120.00±51.56 |
114.67±40.13 |
ALT (U/L) |
36.83±4.12 |
39.17±6.37 |
38.17±13.23 |
32.33±5.47 |
Total protein (g/dl) |
6.43±0.41 |
6.32±0.29 |
6.77±0.30 |
6.03±0.28 |
Albumin (g/dl) |
4.73±0.18 |
4.65±0.24 |
4.95±0.24 |
4.27±0.19* |
ALP (U/L) |
218.50±47.34 |
212.00±40.06 |
219.00±46.65 |
131.00±37.16* |
r-GT (U/L) |
< 2.0 |
< 2.0 |
< 2.0 |
< 2.0 |
Cholesterol (mg/dl) |
60.17±16.92 |
57.67±10.78 |
62.83±8.52 |
68.33±11.17 |
Triglyceride (mg/dl) |
54.83±29.37 |
63.83±20.06 |
50.33±9.33 |
51.83±14.58 |
Calcium (mg/dl) |
11.42±0.49 |
11.62±0.44 |
12.30±0.66* |
11.62±0.81 |
Phosphorus (mg/dl) |
13.60±0.70 |
13.18±0.65 |
14.15±0.71 |
13.73±0.92 |
Sodium (meq/dl) |
145.83±2.79 |
145.50±2.07 |
146.83±0.75 |
144.17±2.23 |
Potassium (meq/dl) |
7.85±0.95 |
8.05±0.94 |
7.85±1.10 |
9.27±1.58 |
Chloride (meq/dl) |
101.67±1.63 |
101.33±1.75 |
101.00±1.10 |
102.00±2.45 |
Globulin (g/dl) |
1.70±0.30 |
1.67±0.10 |
1.82±0.18 |
1.77±0.18 |
Total bilirubin (ug/dl) |
< 0.04 |
< 0.04 |
< 0.04 |
< 0.04 |
Total bile acid (umol/dl) |
12.12±3.13 |
16.05±12.19 |
18.33±11.11 |
9.73±2.75 |
*Significant different from control group (p < 0.05)
Table 19: Clinical chemistry of female rats
Item |
Hematology |
|||
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Glucose (mg/dl) |
126.00±58.15 |
134.83±39.11 |
99.50±19.55 |
100.67±25.32 |
BUN (mg/dl) |
14.23±1.65 |
14.60±1.80 |
12.53±1.51 |
20.70±9.91 |
Creatinine (mg/dl) |
0.70±0.00 |
0.67±0.05 |
0.68±0.04 |
0.67±0.08 |
AST (U/L) |
108.67±27.90 |
104.83±14.88 |
107.00±28.98 |
168.17±103.97 |
ALT (U/L) |
30.00±3.90 |
30.67±6.80 |
27.17±6.01 |
37.83±15.54 |
Total protein (g/dl) |
7.18±0.30 |
6.88±0.42 |
6.77±0.25 |
5.98±0.44* |
Albumin (g/dl) |
5.47±0.25 |
5.23±0.34 |
5.27±0.26 |
4.45±0.40* |
ALP (U/L) |
97.67±23.02 |
94.67±16.35 |
96.83±14.92 |
92.00±11.21 |
r-GT (U/L) |
< 2.0 |
< 2.0 |
< 2.0 |
< 2.0 |
Cholesterol (mg/dl) |
80.33±17.28 |
90.17±20.52 |
85.83±9.62 |
69.67±7.31 |
Triglyceride (mg/dl) |
29.50±8.60 |
25.50±8.64 |
37.17±15.38 |
33.67±7.53 |
Calcium (mg/dl) |
12.30±0.30 |
12.58±0.26 |
12.50±0.27 |
12.18±0.40 |
Phosphorus (mg/dl) |
12.42±1.08 |
12.25±1.00 |
12.37±0.82 |
15.57±1.36* |
Sodium (meq/dl) |
143.50±1.38 |
142.00±1.67 |
142.67±1.75 |
140.83±1.94* |
Potassium (meq/dl) |
9.82±0.74 |
9.47±1.32 |
9.72±1.00 |
11.02±1.20 |
Chloride (meq/dl) |
101.50±1.05 |
100.33±0.52 |
102.50±1.52 |
104.33±1.21* |
Globulin (g/dl) |
1.72±0.12 |
1.65±0.10 |
1.50±0.14* |
1.53±0.08 |
Total bilirubin (ug/dl) |
< 0.04 |
< 0.04 |
< 0.04 |
< 0.04 |
Total bile acid (umol/dl) |
25.88±19.94 |
19.07±10.95 |
16.52±3.60 |
18.63±8.73 |
Table 20. Microscopic examination of urinary sediments of male rats.
Item |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||
Cell type |
RBC |
0 – 1 (hpf) |
6/6 |
5/6 |
0/6 |
0/6 |
2 – 5 (hpf) |
0/6 |
1/6 |
6/6 |
6/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
||
WBC |
0 – 1 (hpf) |
1/6 |
1/6 |
0/6 |
0/6 |
|
2 – 5 (hpf) |
5/6 |
5/6 |
6/6 |
5/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
1/6 |
||
EP |
0 – 1 (hpf) |
4/6 |
4/6 |
3/6 |
4/6 |
|
2 – 5 (hpf) |
2/6 |
2/6 |
3/6 |
2/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
||
Crystal |
None found |
1/6 |
3/6 |
1/6 |
5/6 |
|
Triple phosphates |
5/6 |
2/6 |
5/6 |
1/6 |
||
Am.urate |
0/6 |
1/6 |
0/6 |
0/6 |
||
Am.phos |
0/6 |
0/6 |
0/6 |
0/6 |
Table 21. Microscopic examination of urinary sediments of female rats.
Item |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
||
Cell type |
RBC |
0 – 1 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
2 – 5 (hpf) |
6/6 |
6/6 |
6/6 |
6/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
||
WBC |
0 – 1 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
|
2 – 5 (hpf) |
6/6 |
6/6 |
6/6 |
4/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
2/6 |
||
EP |
0 – 1 (hpf) |
3/6 |
3/6 |
2/6 |
2/6 |
|
2 – 5 (hpf) |
3/6 |
3/6 |
4/6 |
4/6 |
||
6 – 15 (hpf) |
0/6 |
0/6 |
0/6 |
0/6 |
||
Crystal |
None found |
2/6 |
2/6 |
3/6 |
4/6 |
|
Triple phosphates |
4/6 |
4/6 |
3/6 |
2/6 |
||
Am.urate |
0/6 |
0/6 |
0/6 |
0/6 |
||
Am.phos |
0/6 |
0/6 |
0/6 |
0/6 |
Table 22. Urinalysis of male rats.
Item |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Color |
Yellow |
6/6 |
5/6 |
6/6 |
6/6 |
Pale yellow |
0/6 |
1/6 |
0/6 |
0/6 |
|
Clarity |
Clear |
0/6 |
0/6 |
0/6 |
0/6 |
Light turbid |
6/6 |
6/6 |
6/6 |
5/6 |
|
Turbid |
0/6 |
0/6 |
0/6 |
1/6 |
|
Glucose |
Negative |
6/6 |
6/6 |
6/6 |
6/6 |
Trace |
0/6 |
0/6 |
0/6 |
0/6 |
|
Bilirubin |
Negative |
6/6 |
6/6 |
6/6 |
6/6 |
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Ketone |
Negative |
6/6 |
6/6 |
6/6 |
5/6 |
Trace |
0/6 |
0/6 |
0/6 |
1/6 |
|
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Specific gravity |
<= 1.015 |
6/6 |
6/6 |
6/6 |
4/6 |
1.016 – 1.020 |
0/6 |
0/6 |
0/6 |
2/6 |
|
1.021 – 1.025 |
0/6 |
0/6 |
0/6 |
0/6 |
|
1.026 – 1.030 |
0/6 |
0/6 |
0/6 |
0/6 |
|
1.031 – 1.035 |
0/6 |
0/6 |
0/6 |
0/6 |
|
>= 1.036 |
0/6 |
0/6 |
0/6 |
0/6 |
|
pH |
<= 6.0 |
0/6 |
0/6 |
0/6 |
0/6 |
6.5 |
0/6 |
3/6 |
0/6 |
2/6 |
|
7.0 |
5/6 |
3/6 |
3/6 |
2/6 |
|
7.5 |
1/6 |
0/6 |
2/6 |
2/6 |
|
>= 8.0 |
0/6 |
0/6 |
1/6 |
0/6 |
|
Protein |
Negative |
5/6 |
5/6 |
2/6 |
4/6 |
Trace |
1/6 |
1/6 |
4/6 |
1/6 |
|
1+ |
0/6 |
0/6 |
0/6 |
1/6 |
|
2+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Urobilinogen |
<= 1.0 |
6/6 |
6/6 |
6/6 |
5/6 |
2 |
0/6 |
0/6 |
0/6 |
1/6 |
|
Nitrite |
Negative |
6/6 |
5/6 |
1/6 |
4/6 |
Positive |
0/6 |
1/6 |
3/6 |
2/6 |
|
2+ |
0/6 |
0/6 |
2/6 |
0/6 |
|
Occult Blood |
Negative |
6/6 |
6/6 |
6/6 |
5/6 |
Trace |
0/6 |
0/6 |
0/6 |
1/6 |
|
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Leukocyte esterase (Leu/uL) |
Negative |
0/6 |
1/6 |
0/6 |
4/6 |
Trace |
5/6 |
5/6 |
5/6 |
1/6 |
|
1+ |
1/6 |
0/6 |
1/6 |
0/6 |
|
2+ |
0/6 |
0/6 |
0/6 |
1/6 |
|
3+ |
0/6 |
0/6 |
0/6 |
0/6 |
Table 23. Urinalysis of female rats.
Item |
Control 0 mg/kg |
Low dose 62.5 mg/kg |
Middle dose 250 mg/kg |
High dose 1,000 mg/kg |
|
Color |
Yellow |
5/6 |
6/6 |
5/6 |
2/6 |
Pale yellow |
1/6 |
0/6 |
0/6 |
0/6 |
|
Orange |
0/6 |
0/6 |
1/6 |
4/6 |
|
Clarity |
Clear |
0/6 |
0/6 |
0/6 |
0/6 |
Light turbid |
6/6 |
6/6 |
4/6 |
3/6 |
|
Turbid |
0/6 |
0/6 |
2/6 |
3/6 |
|
Glucose |
Negative |
6/6 |
6/6 |
6/6 |
6/6 |
Trace |
0/6 |
0/6 |
0/6 |
0/6 |
|
Bilirubin |
Negative |
6/6 |
6/6 |
6/6 |
6/6 |
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Ketone |
Negative |
5/6 |
6/6 |
6/6 |
6/6 |
Positive |
0/6 |
0/6 |
0/6 |
0/6 |
|
Trace |
1/6 |
0/6 |
0/6 |
0/6 |
|
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
2+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Specific gravity |
<= 1.015 |
4/6 |
3/6 |
4/6 |
3/6 |
1.016 – 1.020 |
1/6 |
0/6 |
0/6 |
3/6 |
|
1.021 – 1.025 |
1/6 |
3/6 |
2/6 |
0/6 |
|
1.026 – 1.030 |
0/6 |
0/6 |
0/6 |
0/6 |
|
1.031 – 1.035 |
0/6 |
0/6 |
0/6 |
0/6 |
|
>= 1.036 |
0/6 |
0/6 |
0/6 |
0/6 |
|
pH |
<= 6.0 |
0/6 |
0/6 |
0/6 |
0/6 |
6.5 |
1/6 |
2/6 |
0/6 |
2/6 |
|
7.0 |
3/6 |
3/6 |
3/6 |
2/6 |
|
7.5 |
1/6 |
0/6 |
2/6 |
1/6 |
|
>= 8.0 |
1/6 |
1/6 |
1/6 |
2/6 |
|
Protein |
Negative |
5/6 |
4/6 |
4/6 |
4/6 |
Trace |
0/6 |
2/6 |
1/6 |
1/6 |
|
1+ |
1/6 |
0/6 |
1/6 |
1/6 |
|
2+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Urobilinogen |
<= 1.0 |
6/6 |
6/6 |
6/6 |
5/6 |
2 |
0/6 |
0/6 |
0/6 |
1/6 |
|
Nitrite |
Negative |
2/6 |
0/6 |
6/6 |
3/6 |
Positive |
3/6 |
4/6 |
0/6 |
1/6 |
|
2+ |
1/6 |
2/6 |
0/6 |
2/6 |
|
Occult Blood |
Negative |
6/6 |
6/6 |
6/6 |
6/6 |
Trace |
0/6 |
0/6 |
0/6 |
0/6 |
|
1+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
Leukocyte esterase (Leu/uL) |
Negative |
3/6 |
3/6 |
3/6 |
3/6 |
Trace |
1/6 |
1/6 |
2/6 |
3/6 |
|
1+ |
2/6 |
2/6 |
1/6 |
0/6 |
|
2+ |
0/6 |
0/6 |
0/6 |
0/6 |
|
3+ |
0/6 |
0/6 |
0/6 |
0/6 |
Applicant's summary and conclusion
- Conclusions:
- According to OECD 407 test method, the NOAEL of Everlan SL65 for the rats was 62.5 mg/kg B.W..
- Executive summary:
This test used the procedures and OECD 407 (2008). The test article was administered to the three treatment groups by oral gavage in a dose of 62.5, 250 and 1000 mg/kg B.W. for 28 consecutive days. There were six male and six female Sprague-Dawley rat in each group. Clinical observation of the rats was carried out daily and the body weight and feed intake of the rats were recorded once a week. Results of the study indicated that rats in all group gained weight normally and did not show any abnormal clinical signs and ophthalmological examination during the study period. At end of the study, there were no significant abnormalities of the urinalysis parameters between the treatment and control groups. In haematological analysis, clinical biochemistry analysis and organ weight, results indicated that there was enlargement of the spleen with corresponding changes in the hematological profile of blood, probably as a response to the damage to the cecum and colon .
Necropsy and histopathological examination indicated that treatment-related change was found in high or middle dose group. On the basis of the test results given above, the NOAEL of Everlan SL65 for the rats was 62.5 mg/kg B.W..
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