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EC number: 617-769-9 | CAS number: 858956-08-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 13 June - 12 July 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- adopted 12 May 1981
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid
- EC Number:
- 617-769-9
- Cas Number:
- 858956-08-8
- Molecular formula:
- C8H8ClN3O2
- IUPAC Name:
- 6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid
1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Hsd:Sprague Dawley®
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan, Indianapolis, IN, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 243-267 g (males), 175-199 g (females)
- Housing: individually in suspended stainless steel cages (conform with the Guide for the Care and Use of Laboratory Animals, DHEW (NIH).
- Diet: Purina Certified Rodent Meal #5002, ad libitum
- Water: filtered tap water, ad libitum
- Acclimation period: 8 days
DETAILS OF FOOD AND WATER QUALITY: Yes
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 57 - 67
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Type of coverage:
- not specified
- Vehicle:
- unchanged (no vehicle)
- Remarks:
- moistened with distilled water
- Details on exposure:
- TEST SITE
- Area of exposure: control: 2 x 3 inch (males and females), 150 mg/kg bw/day: 1 x 2 inch (males) and 1 x 1 inch (females), 400 mg/kg bw/day: 2 x 2 inch (males) and 1 x 2 inch (females), 1000 mg/kg bw/day: 2 x 3 inch (males and females). (For the range of dermal doses in g, please refer to table 14 in the"Any other information on results incl. tables" section.)
- % coverage: approximately 10
- Type of wrap if used: non-irritating tape (3 inch 3M Micropore™)
- Time intervals for shavings: as needed throughout the study
REMOVAL OF TEST SUBSTANCE
- Washing: wiped with water using clean towels to remove any residual test substance and then gently patted dry with a clean pad
- Time after start of exposure: following the 6 h exposure period
TEST MATERIAL
- Amounts applied: test substance (150, 400 or 1000 mg/kg bw/day) moistened with water
- Constant volume or concentration used: no
- For solids, paste formed: yes
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes/no - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 h per day / 7 days per week for 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 150 mg/kg bw/day
- Dose / conc.:
- 400 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: The highest dose (1000 mg/kg bw/day) is the regulatory limit dose. The high level was expected to potentially exhibit some evidence of toxicity and the NOAEL was expected at the low or intermediate exposure level in both male and female rats.
- Fasting period before blood sampling for clinical biochemistry: yes
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (mortality), once daily (general inspection)
- - Cage side observations checked in table No.1 (in the "Any other information and methods incl. tables" section) were examined.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily before test substance application and weekly thereafter
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: after patch removal for signs of erythema and edema on Day 3, each Friday and on the day of the final application
- Scoring system: "Primary Skin Irritation Scoring System" developed by Draize et al.
BODY WEIGHT: Yes
- Time schedule for examinations: prior to the first patch application (days 1 and 2 for males and females, respectively) and weekly thereafter (intervals were 7 days ± 1 day)
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation and Day 24
- Dose groups that were examined: all dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 29 (males) or Day 30 (females), prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane anesthesia)
- Animals fasted: Yes (except for blood samples used for analysis of coagulation parameters)
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 29 (males) or
Day 30 (females), prior to sacrifice
- Animals fasted: Yes
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)
HISTOPATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.) - Statistics:
- Group means and standard deviations were calculated for body weight, daily body weight gain, daily food consumption, daily food efficiency, organ weight, and organ-to-body/brain weight ratio data. Data within groups were evaluated for homogeneity of variances and normality by Bartlett’s test. Where Bartlett’s test indicated homogeneous variances, treated and control groups were compared using a One-Way Analysis of Variance (ANOVA), followed by comparison of the treated groups to control by Dunnett’s t-test for multiple comparisons. Where variances were considered significantly different by Bartlett’s test, groups were compared using a non-parametric method (Kruskal-Wallis non parametric analysis of variance followed by Dunn’s test) (INSTAT Biostatistics, Graph Pad
Software, San Diego, CA). Differences among groups were judged to be significant at a probability value of p 0.05. Male and female rats were evaluated separately.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related clinical signs in any test group that were considered to be of toxicological significance.
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- 400 and 1000 mg/kg bw/day: very slight erythema graded with a score of 1 were noted for the dose sites in single animals (400 mg/kg bw/day: 1/10 males on Day 28; 1000 mg/kg bw/day: 2/10 males on Day 3 and 28, respectively).
(Please refer to table 4 in the "Any other information on results incl. tables" section.) - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: Mean body weight and daily body weight gain and overall (Days 2-29) body weight gain were statistically significantly increased in females during Week 4 and/or overall. Since during the same period, control group values for these parameters were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.
(Please refer to table 5 and 6 in the "Any other information on results incl. tables" section.) - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- 150 and 400 mg/kg bw/day: Statistically significant decreases in mean daily food consumption were observed in female rats for the test period overall (Days 2-29) and during week 3, respectively. These findings were not dose-related and thus not considered treatment-related.
(Please refer to table 7 in the "Any other information on results incl. tables" section.) - Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: an increase in mean food efficiency for the overall test period (Days 2-29) was seen in females and correlated with increased body weight gain for the same test period. Since week 4 control group values for food efficiency were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.
(Please refer to table 8 in the "Any other information on results incl. tables" section.) - Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 150 mg/kg bw/day: Red cell distribution width was slightly increased in females compared to control. Since there were no corresponding red cell mass findings, the statistically significant change in mean haematology results was not considered to be adverse or treatment-related.
(Please refer to table 9 in the "Any other information on results incl. tables" section.) - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 150 and 1000 mg/kg bw/day: creatinine was statistically significantly decreased in males compared to control. Due to the absence of a dose-response relationship and the small magnitude of the change it is not considered treatment-related or adverse.
(Please refer to table 10 in the "Any other information on results incl. tables" section.) - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: absolute adrenal weights were significantly increased in females compared to controls.
150 mg/kg bw/day: both absolute and relative ovarian weights and kidney-to-brain weight ratios were significantly decreased in females compared to controls.
Since there were no microscopic correlates observed for these findings, they were determined to be toxicologically insignificant.
(Please refer to table 11, 12 and 13 in the "Any other information on results incl. tables" section.) - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: a lung adhesion in 1 female had no corresponding microscopic finding.
400 mg/kg bw/day: an epididymal mass (2.0 x 2.0 mm) from 1 male was histologically confirmed as a small sperm granuloma.
Control: 1 male exhibited a small appearing right testis and epididymis which were confirmed microscopically as mild unilateral tubular atrophy and intratubular cellular debris, respectively.
All these incidental findings were considered unrelated to treatment and, as such, toxicologically insignificant. All other macroscopic changes were observed at comparable incidences in the control and treated groups, and/or commonly observed in untreated rats. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: minimal focal lobular atrophy in the pancreas of 1/10 males. Slight focal fibrosis in the salivary glands in 1/10 females These observations were considered
unrelated to treatment due to their isolated occurrences, focal distribution and their common occurrence in untreated rats.
All other microscopic changes were of comparable incidence and severity in the test substance-treated and control animals, and are commonly observed in untreated laboratory rats. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 4: Mean weekly dermal irritation score
Group |
1 |
2 |
3 |
4 |
|
Dose Level (mg/kg/day) |
0 |
150 |
400 |
1,000 |
|
Number Of Animals In Group |
10 |
10 |
10 |
10 |
|
Males |
|
||||
Day |
3 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.1/0.0 |
10 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
|
|
17 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
24 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
|
|
28 |
0.0/0.0 |
0.0/0.0 |
0.1/0.0 |
0.1/0.0 |
Females |
|
||||
Day |
3 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
10 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
|
|
17 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
|
24 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
|
28 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
0.0/0.0 |
Table 5: Mean daily body weight (g)
Group |
1 |
2 |
3 |
4 |
|
Dose Level (mg/kg/day) |
0 |
150 |
400 |
1,000 |
|
Number Of Animals In Group |
10 |
10 |
10 |
10 |
|
Males |
|
||||
Day |
|
||||
Initial (Day 1) |
Mean |
255.8 |
257.4 |
255.7 |
255.8 |
SD |
7.4 |
6.4 |
6.1 |
6.5 |
|
8 |
Mean |
284.0 |
279.8 |
278.8 |
282.8 |
SD |
11.9 |
12.7 |
9.5 |
9.4 |
|
15 |
Mean |
308.2 |
300.6 |
300.5 |
303.6 |
SD |
15.2 |
14.4 |
10.6 |
12.6 |
|
21 |
Mean |
319.2 |
314.6 |
311.2 |
313.5 |
SD |
14.9 |
17.1 |
12.9 |
14.1 |
|
28 |
Mean |
336.2 |
331.2 |
324.2 |
339.6 |
SD |
14.1 |
21.1 |
11.8 |
19.0 |
|
Females |
|
|
|
|
|
Initial (Day 2) |
Mean |
184.7 |
183.1 |
182.1 |
183.6 |
|
SD |
6.3 |
6.2 |
4.9 |
6.7 |
8 |
Mean |
198.1 |
195.0 |
199.8 |
199.0 |
|
SD |
9.2 |
6.1 |
8.0 |
7.8 |
15 |
Mean |
207.3 |
205.2 |
206.9 |
206.6 |
|
SD |
12.1 |
4.5 |
10.2 |
6.8 |
21 |
Mean |
222.6 |
216.9 |
215.8 |
225.3 |
|
SD |
10.8 |
7.6 |
9.1 |
9.3 |
28 |
Mean |
222.8 |
220.3 |
222.9 |
233.6* |
|
SD |
7.4 |
8.9 |
8.7 |
8.3 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test.
Table 6: Mean daily body weight gains (g)
Group |
1 |
2 |
3 |
4 |
|
Dose Level (mg/kg/day) |
0 |
150 |
400 |
1,000 |
|
Number Of Animals In Group |
10 |
10 |
10 |
10 |
|
Males |
|
||||
Day |
|
||||
1-8 |
Mean |
4.0 |
3.2 |
3.3 |
3.9 |
SD |
0.8 |
1.0 |
0.9 |
0.9 |
|
8-15 |
Mean |
3.5 |
3.0 |
3.1 |
3.0 |
SD |
0.7 |
0.6 |
0.5 |
0.6 |
|
15-21 |
Mean |
1.6 |
2.0 |
1.5 |
1.4 |
SD |
0.7 |
0.6 |
0.6 |
0.6 |
|
21-28 |
Mean |
2.4 |
2.4 |
1.9 |
3.7 |
SD |
0.7 |
0.7 |
0.7 |
3.2 |
|
Total(1-28) |
Mean |
2.9 |
2.6 |
2.4 |
3.0 |
SD |
0.3 |
0.5 |
0.3 |
0.7 |
|
Females |
|
|
|
|
|
2-9 |
Mean |
1.9 |
1.7 |
2.5 |
2.2 |
|
SD |
0.9 |
1.3 |
1.0 |
1.0 |
9-16 |
Mean |
1.3 |
1.5 |
1.0 |
1.1 |
|
SD |
1.0 |
0.6 |
1.2 |
1.3 |
16-23 |
Mean |
2.2 |
1.7 |
1.3 |
2.7 |
|
SD |
1.3 |
0.5 |
0.8 |
0.7 |
23-29 |
Mean |
0.0 |
0.6 |
1.2 |
1.4* |
|
SD |
1.2 |
1.1 |
1.0 |
1.4 |
Total(2-29) |
Mean |
1.4 |
1.4 |
1.5 |
1.8** |
|
SD |
0.2 |
0.4 |
0.3 |
0.3 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test.
** Statistically significant difference from control at p < 0.01 by Dunnett’s Multiple Comparisons test.
Table 7: Mean daily food consumption (g)
Group |
1 |
2 |
3 |
4 |
|
Dose Level (mg/kg/day) |
0 |
150 |
400 |
1,000 |
|
Number Of Animals In Group |
10 |
10 |
10 |
10 |
|
Males |
|
||||
Day |
|
||||
1-8 |
Mean |
22.2 |
21.5 |
21.5 |
21.8
|
SD |
1.5 |
1.2 |
1.3 |
1.0
|
|
8-15 |
Mean |
24.1 |
23.6 |
23.6 |
24.2
|
SD |
1.2 |
1.6 |
1.1 |
0.8 |
|
15-21 |
Mean |
20.3 |
20.4 |
19.8 |
20.1
|
SD |
0.8 |
1.3 |
1.0 |
1.1 |
|
21-28 |
Mean |
24.7 |
23.5 |
22.5 |
24.2
|
SD |
2.9 |
1.7 |
2.5 |
1.0 |
|
Total(1-28) |
Mean |
22.8 |
22.3 |
21.9 |
22.6
|
SD |
1.o |
1.3 |
1.2 |
0.8 |
|
Females |
|
|
|
|
|
2-9 |
Mean |
17.1 |
16.0 |
16.6 |
17.0 |
|
SD |
1.1 |
0.9 |
1.3 |
1.0 |
9-16 |
Mean |
18.3 |
17.6 |
17.9 |
17.4 |
|
SD |
1.6 |
1.1 |
1.7 |
1.3 |
16-23 |
Mean |
19.3 |
18.4 |
18.0* |
19.4 |
|
SD |
1.5 |
1.0 |
0.6 |
0.8 |
23-29 |
Mean |
18.5 |
17.3 |
17.9 |
19.7 |
|
SD |
2.6 |
1.1 |
1.0 |
1.6 |
Total (2-29) |
Mean |
18.3 |
17.4* |
17.6 |
18.4 |
|
SD |
0.9 |
0.7 |
0.8 |
0.7 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test.
Table 8: Mean daily food efficiency
Group |
1 |
2 |
3 |
4 |
|
Dose Level (mg/kg/day) |
0 |
150 |
400 |
1,000 |
|
Number Of Animals In Group |
10 |
10 |
10 |
10 |
|
Males |
|
||||
Day |
|
||||
1-8 |
Mean |
0.18 |
0.15 |
0.15 |
0.18 |
SD |
0.03 |
0.04 |
0.03 |
0.03 |
|
8-15 |
Mean |
0.14 |
0.13 |
0.13 |
0.12 |
SD |
0.03 |
0.03 |
0.02 |
0.02 |
|
15-21 |
Mean |
0.08 |
0.10 |
0.08 |
0.07 |
SD |
0.03 |
0.03 |
0.03 |
0.03 |
|
21-28 |
Mean |
0.10 |
0.10 |
0.08 |
0.16 |
SD |
0.03 |
0.03 |
0.03 |
0.15 |
|
Total(1-28) |
Mean |
0.13 |
0.12 |
0.11 |
0.13 |
SD |
0.01 |
0.02 |
0.01 |
0.03 |
|
Females |
|
|
|
|
|
2-9 |
Mean |
0.11 |
0.10 |
0.15 |
0.13 |
|
SD |
0.05 |
0.07 |
0.05 |
0.05 |
9-16 |
Mean |
0.07 |
0.08 |
0.05 |
0.06 |
|
SD |
0.05 |
0.03 |
0.07 |
0.08 |
16-23 |
Mean |
0.11 |
0.09 |
0.07 |
0.14 |
|
SD |
0.06 |
0.03 |
0.04 |
0.03 |
23-29 |
Mean |
0.01 |
0.03 |
0.06 |
0.07 |
|
SD |
0.07 |
0.06 |
0.05 |
0.07 |
Total (2-29) |
Mean |
0.07 |
0.08 |
0.08 |
0.10* |
|
SD |
0.01 |
0.03 |
0.01 |
0.02 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test.
Table 9: Mean haematology and coagulation values
Dose Level (mg/kg/day) |
|
Control |
150 |
400 |
1000 |
Number Of Animals In Group |
|
92 |
10 |
10 |
10 |
Males |
|
|
|
|
|
Parameter |
|
|
|
|
|
Hemoglobin Cone. (g/dL) |
Mean |
16.1 |
16.0 |
16.3 |
16.3 |
SD |
0.3 |
0.5 |
0.5 |
0.6 |
|
Hematocrit (%)
|
Mean |
45.8 |
45.9 |
46.2 |
46.8 |
SD |
1.1 |
1.7 |
1.5 |
1.6 |
|
Erythrocyte Count (RBC, X 106/µL)
|
Mean |
8.70 |
8.77 |
8.71 |
8.74 |
SD |
0.30 |
0.36 |
0.42 |
0.37 |
|
Platelet Count (x 103/µL)
|
Mean |
1038 |
936 |
1005 |
901 |
SD |
154 |
157 |
158 |
191 |
|
Total Leukocyte Count (WBC, X 103/µL)
|
Mean |
10.77 |
11.72 |
11.30 |
12.05 |
SD |
2.16 |
1.95 |
1.77 |
1.71 |
|
Mean Corpuscular Volume (fL)
|
Mean |
52.7 |
52.4 |
53.1 |
53.6 |
|
SD |
1.0 |
1.4 |
1.4 |
1.5 |
Mean Corpuscular Hemoglobin (pg)
|
Mean |
18.5 |
18.3 |
18.7 |
18.7 |
|
SD |
0.6 |
0.5 |
0.4 |
0.5 |
Mean Corpuscular Hemoglobin Concentration (g/dL)
|
Mean |
35.1 |
34.9 |
35.2 |
34.8 |
|
SD |
0.5 |
0.3 |
0.4 |
0.6 |
Red Cell Distribution Width(%) |
Mean |
11.4 |
11.6 |
11.5 |
11.6 |
|
SD |
0.3 |
0.4 |
0.3 |
0.3 |
Absolute Reticulocyte Count (x 103/µL) |
Mean |
181.5 |
184.0 |
181.1 |
190.9 |
|
SD |
21.4 |
15.8 |
23.4 |
16.7 |
Absolute Neutrophils (x 103/µL)
|
Mean |
1.43 |
1.79 |
1.48 |
1.63 |
|
SD |
0.31 |
0.33 |
0.30 |
0.43 |
Absolute Lymphocytes (x 103/µL)
|
Mean |
8.84 |
9.29 |
9.22 |
9.80 |
|
SD |
1.84 |
1.59 |
1.69 |
1.58 |
Absolute Monocytes (x 103/µL)
|
Mean |
0.20 |
0.26 |
0.23 |
0.24 |
|
SD |
0.05 |
0.07 |
0.07 |
0.06 |
Absolute Eosinophils (x 103/µL)
|
Mean |
0.16 |
0.21 |
0.21 |
0.21 |
|
SD |
0.04 |
0.07 |
0.09 |
0.07 |
Absolute Basophils (x 103/µL)
|
Mean |
0.08 |
0.10 |
0.09 |
0.09 |
|
SD |
0.03 |
0.03 |
0.03 |
0.03 |
Absolute Large Unstained Cells (x 103/µL) |
Mean |
0.07 |
0.07 |
0.07 |
0.08 |
|
SD |
0.02 |
0.02 |
0.02 |
0.02 |
Coagulation parameters |
|
|
|
||
Number Of Animals In Group |
|
82 |
92 |
92 |
82 |
Prothrombin time (seconds) |
Mean |
13.0 |
12.8 |
13.3 |
13.4 |
|
SD |
0.9 |
0.9 |
1.1 |
0.6 |
Activated Partial Thromboplastin time (seconds)
|
Mean |
16.6 |
18.7 |
16.4 |
16.3 |
|
SD |
2.5 |
8.2 |
2.3 |
2.3 |
Females |
|
|
|
|
|
Number of animals evaluated |
|
72 |
10 |
10 |
10 |
Hemoglobin Cone. (g/dL) |
Mean |
15.7 |
15.7 |
15.8 |
15.8 |
|
SD |
0.4 |
0.3 |
0.5 |
0.5 |
Hematocrit (%)
|
Mean |
43.3 |
43.6 |
43.7 |
44.0 |
|
SD |
1.3 |
1.0 |
1.3 |
1.4 |
Erythrocyte Count (RBC, X 106/µL)
|
Mean |
8.33 |
8.34 |
8.35 |
8.30 |
|
SD |
0.13 |
0.23 |
0.31 |
0.27 |
Platelet Count (x 103/µL)
|
Mean |
886 |
940 |
997 |
821 |
|
SD |
183 |
186 |
271 |
167 |
Total Leukocyte Count (WBC, X 103/µL)
|
Mean |
7.45 |
7.76 |
8.17 |
7.57 |
|
SD |
2.45 |
1.45 |
1.84 |
2.04 |
Mean Corpuscular Volume (fL)
|
Mean |
52.0 |
52.3 |
52.4 |
53.1 |
|
SD |
1.7 |
1.5 |
1.0 |
1.1 |
Mean Corpuscular Hemoglobin (pg)
|
Mean |
18.9 |
18.8 |
18.9 |
19.1 |
|
SD |
0.4 |
0.5 |
0.3 |
0.3 |
Mean Corpuscular Hemoglobin Concentration (g/dL)
|
Mean |
36.3 |
36.0 |
36.0 |
36.0 |
|
SD |
0.5 |
0.3 |
0.4 |
0.6 |
Red Cell Distribution Width(%) |
Mean |
10.8 |
11.4* |
11.2 |
11.3 |
|
SD |
0.2 |
0.6 |
0.2 |
0.4 |
Absolute Reticulocyte Count (x 103/µL) |
Mean |
176.2 |
204.4 |
211.9 |
218.0 |
|
SD |
45.1 |
66.4 |
30.3 |
29.7 |
Absolute Neutrophils (x 103/µL)
|
Mean |
1.60 |
1.41 |
1.38 |
1.43 |
|
SD |
0.64 |
0.77 |
0.45 |
0.44 |
Absolute Lymphocytes (x 103/µL)
|
Mean |
5.48 |
5.97 |
6.39 |
5.79 |
|
SD |
1.80 |
0.93 |
1.58 |
1.69 |
Absolute Monocytes (x 103/µL)
|
Mean |
0.11 |
0.12 |
0.12 |
0.11 |
|
SD |
0.06 |
0.05 |
0.05 |
0.06 |
Absolute Eosinophils (x 103/µL)
|
Mean |
0.17 |
0.16 |
0.16 |
0.13 |
|
SD |
0.05 |
0.07 |
0.04 |
0.04 |
Absolute Basophils (x 103/µL)
|
Mean |
0.07 |
0.08 |
0.08 |
0.07 |
|
SD |
0.05 |
0.05 |
0.04 |
0.05 |
Absolute Large Unstained Cells (x 103/µL) |
Mean |
0.03 |
0.02 |
0.04 |
0.03 |
|
SD |
0.02 |
0.02 |
0.02 |
0.02 |
Coagulation parameters |
|
|
|
|
|
Number of animals evaluated |
|
10 |
92 |
92 |
72 |
Prothrombin time (seconds) |
Mean |
14.7 |
14.8 |
14.9 |
14.9 |
|
SD |
0.3 |
0.4 |
0.5 |
0.8 |
Activated Partial Thromboplastin time (seconds)
|
Mean |
14.9 |
14.8 |
15.1 |
15.9 |
|
SD |
1.3 |
2.1 |
1.3 |
3.4 |
* statistically significant difference from control at p <0.05 by Dunnett/Tamhane-Dunnett.
2 Measurements for all animals were not performed due to a clotted sample.
Table 10: Mean clinical biochemistry data
Dose Level (mg/kg/day) |
|
Control |
150 |
400 |
1000 |
Number Of Animals In Group |
|
10 |
4-92 |
6-92 |
7-102 |
Males |
|
|
|
|
|
Parameter |
|
|
|
|
|
Aspartate Aminotransferase (U/L)
|
Mean |
88 |
94 |
90 |
90 |
SD |
12 |
6 |
10 |
12 |
|
Alanine Aminotransferase (U/L)
|
Mean |
43 |
43 |
41 |
43 |
SD |
9 |
4 |
4 |
4 |
|
Sorbital Dehydrogenase (U/L)
|
Mean |
2.0 2 |
0.8 |
1.0 |
1.7 |
SD |
2.0 |
0.5 |
1.0 |
1.4 |
|
Alkaline Phosphatase (U/L)
|
Mean |
130 |
139 |
136 |
147 |
SD |
22 |
19 |
21 |
19 |
|
Total Bilirubin (mg/dL)
|
Mean |
0.13 |
0.13 |
0.13 |
0.12 |
SD |
0.02 |
0.02 |
0.02 |
0.01 |
|
Blood Urea Nitrogen (mg/dL)
|
Mean |
16 |
17 |
16 |
16 |
|
SD |
2 |
2 |
1 |
3 |
Creatinine (mg/dL)
|
Mean |
0.32 |
0.28* |
0.29 |
0.27* |
|
SD |
0.02 |
0.03 |
0.02 |
0.03 |
Cholesterol (mg/dL)
|
Mean |
78 |
70 |
73 |
74 |
|
SD |
12 |
10 |
13 |
13 |
Triglycerides (mg/dL) |
Mean |
20 |
16 |
20 |
18 |
|
SD |
2 |
2 |
5 |
4 |
Glucose (mg/dL) |
|
104 |
112 |
107 |
111 |
|
|
8 |
7 |
5 |
12 |
Total Protein (g/dL)
|
Mean |
6.2 |
6.2 |
6.1 |
6.2 |
|
SD |
0.2 |
0.2 |
0.2 |
0.2 |
Albumin (g/dL) |
Mean |
3.4 |
3.3 |
3.3 |
3.4 |
|
SD |
0.2 |
0.2 |
0.2 |
0.2 |
Number of animals evaluated |
|
10 |
6-102 |
8-102 |
7-102 |
Globulin (g/dL)
|
Mean |
2.8 |
2.9 |
2.8 |
2.8 |
|
SD |
0.2 |
0.2 |
0.1 |
0.2 |
Calcium (mg/dL)
|
Mean |
10.0 |
9.9 |
10.0 |
10.2 |
|
SD |
0.3 |
0.2 |
0.3 |
0.4 |
Inorganic Phosphorus (mg/dL)
|
Mean |
7.5 |
7.5 |
7.5 |
7.8 |
|
SD |
0.4 |
0.3 |
0.6 |
0.4 |
Sodium (mmol/L)
|
Mean |
141.0 |
138.1 |
138.7 |
140.4 |
|
SD |
4.3 |
3.0 |
2.8 |
4.3 |
Potassium (mmol/L)
|
Mean |
5.23 |
5.10 |
5.32 |
5.13 |
|
SD |
0.13 |
0.39 |
0.59 |
0.36 |
Chloride (mmol/L) |
Mean |
101.9 |
101.0 |
101.3 |
102.1 |
|
SD |
2.7 |
2.0 |
1.8 |
2.1 |
Females |
|
|
|
|
|
Number of animals evaluated |
|
72 |
10 |
10 |
10 |
Aspartate Aminotransferase (U/L)
|
Mean |
105 |
97 |
98 |
101 |
|
SD |
17 |
17 |
19 |
33 |
Alanine Aminotransferase (U/L)
|
Mean |
40 |
39 |
42 |
40 |
|
SD |
5 |
6 |
6 |
10 |
Sorbital Dehydrogenase (U/L)
|
Mean |
8.1 |
9.7 |
7.3 |
9.2 |
|
SD |
3.5 |
2.5 |
3.1 |
2.4 |
Alkaline Phosphatase (U/L)
|
Mean |
108 |
116 |
105 |
118 |
|
SD |
24 |
30 |
18 |
20 |
Total Bilirubin (mg/dL)
|
Mean |
0.14 |
0.14 |
0.13 |
0.14 |
|
SD |
0.02 |
0.01 |
0.02 |
0.01 |
Blood Urea Nitrogen (mg/dL)
|
Mean |
21 |
22 |
21 |
22 |
|
SD |
2 |
3 |
3 |
4 |
Creatinine (mg/dL)
|
Mean |
0.40 |
0.40 |
0.38 |
0.37 |
|
SD |
0.04 |
0.03 |
0.03 |
0.03 |
Cholesterol (mg/dL)
|
Mean |
80 |
79 |
78 |
72 |
|
SD |
15 |
14 |
9 |
16 |
Triglycerides (mg/dL) |
Mean |
21 |
24 |
20 |
21 |
|
SD |
4 |
5 |
3 |
5 |
Glucose (mg/dL) |
Mean |
98 |
96 |
101 |
103 |
|
SD |
7 |
12 |
9 |
10 |
Total Protein (g/dL)
|
Mean |
6.5 |
6.5 |
6.6 |
6.6 |
|
SD |
0.3 |
0.2 |
0.3 |
0.3 |
Albumin (g/dL) |
Mean |
3.6 |
3.5 |
3.5 |
3.6 |
|
SD |
0.2 |
0.1 |
0.1 |
0.2 |
Number of animals evaluated |
|
10 |
10 |
10 |
10 |
Globulin (g/dL)
|
Mean |
3.0 |
3.0 |
3.1 |
3.1 |
|
SD |
0.2 |
0.2 |
0.3 |
0.2 |
Calcium (mg/dL)
|
Mean |
10.5 |
10.5 |
10.6 |
10.6 |
|
SD |
0.2 |
0.3 |
0.3 |
0.4 |
Inorganic Phosphorus (mg/dL)
|
Mean |
6.9 |
6.8 |
6.9 |
7.0 |
|
SD |
0.6 |
0.5 |
0.5 |
0.7 |
Sodium (mmol/L)
|
Mean |
141.5 |
138.4 |
138.7 |
140.6 |
|
SD |
3.5 |
3.6 |
3.6 |
2.3 |
Potassium (mmol/L)
|
SD |
4.65 |
4.54 |
4.46 |
4.41 |
|
Mean |
0.41 |
0.24 |
0.50 |
0.30 |
Chloride (mmol/L) |
SD |
102.3 |
100.6 |
101.4 |
102.6 |
|
|
2.9 |
1.8 |
1.9 |
1.6 |
* statistically significant difference from control at p <0.05 by Dunnett/Tamhane-Dunnett.
Table 11: mean Organ weights
Dose Level (mg/kg/day) |
|
Control |
150 |
400 |
1000 |
Number Of Animals In Group |
|
10 |
10 |
10 |
10 |
Males |
|
|
|
|
|
Organ |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.082 |
0.068 |
0.066 |
0.063
|
|
SD |
0.027 |
0.013 |
0.016 |
0.012 |
Brain |
Mean |
2.01 |
2.00 |
1.98 |
2.00 |
|
SD |
0.14 |
0.13 |
0.13 |
0.12 |
Heart |
Mean |
1.18 |
1.14 |
1.17 |
1.23
|
|
SD |
0.09 |
0.10 |
0.11 |
0.07
|
Kidneys (paired) |
Mean |
2.63 |
2.56 |
2.46 |
2.54 |
|
SD |
0.30 |
0.26 |
0.23 |
0.19 |
Liver |
Mean |
9.58 |
9.05 |
9.05 |
9.19 |
|
SD |
0.90 |
0.76 |
0.65 |
0.72 |
Spleen |
Mean |
0.76 |
0.73 |
0.69 |
0.73 |
|
SD |
0.06 |
0.09 |
0.08 |
0.07 |
Thymus |
Mean |
0.490 |
0.464 |
0.455 |
0.435 |
|
SD |
0.095 |
0.081 |
0.046 |
0.077 |
Epididymides (paired) |
Mean |
1.295 |
1.315 |
1.321 |
1.315 |
|
SD |
0.123 |
0.154 |
0.096 |
0.095
|
Testes (paired) |
Mean |
3.59 |
3.53 |
3.57 |
3.71 |
|
SD |
0.39 |
0.33 |
0.17 |
0.22 |
Females |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.073 |
0.071 |
0.077 |
0.084* |
|
SD |
0.007 |
0.009 |
0.011 |
0.011 |
Brain |
Mean |
1.84 |
1.89 |
1.87 |
1.92
|
|
SD |
0.09 |
0.09 |
0.06 |
0.18 |
Heart |
Mean |
0.89 |
0.89 |
0.85 |
0.88
|
|
SD |
0.07 |
0.05 |
0.07 |
0.05
|
Kidneys (paired) |
Mean |
1.70 |
1.59 |
1.73 |
1.77
|
|
SD |
0.11 |
0.16 |
0.17 |
0.13 |
Liver |
Mean |
6.43 |
6.32 |
6.42 |
6.79
|
|
SD |
0.61 |
0.58 |
0.42 |
0.40 |
Spleen |
Mean |
0.59 |
0.58 |
0.61 |
0.62 |
|
SD |
0.07 |
0.09 |
0.04 |
0.06 |
Thymus |
Mean |
0.348 |
0.348 |
0.370 |
0.367 |
|
SD |
0.053 |
0.054 |
0.048 |
0.068 |
Ovaries (paired) |
Mean |
0.162 |
0.130* |
0.145 |
0.156
|
|
SD |
0.035 |
0.020 |
0.022 |
0.024
|
Uterus |
Mean |
0.438 |
0.381 |
0.453 |
0.583
|
|
SD |
0.140 |
0.072 |
0.109 |
0.350 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test
Table 12: Mean organ body weight ratios
Dose Level (mg/kg/day) |
|
Control |
150 |
400 |
1000 |
Number Of Animals In Group |
|
10 |
10 |
10 |
10 |
Males |
|
|
|
|
|
Organ |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.270 |
0.228 |
0.225 |
0.21 |
|
SD |
0.085 |
0.039 |
0.056 |
0.039
|
Brain |
Mean |
6.67 |
6.74 |
6.79 |
6.73
|
|
SD |
0.50 |
0.32 |
0.35 |
0.50 |
Heart |
Mean |
3.90 |
3.85 |
3.99 |
4.12
|
|
SD |
0.30 |
0.42 |
0.34 |
0.22
|
Kidneys (paired) |
Mean |
8.72 |
8.63 |
8.41 |
8.52 |
|
SD |
0.91 |
0.67 |
0.69 |
0.51 |
Liver |
Mean |
31.74 |
30.50 |
30.94 |
30.85
|
|
SD |
2.50 |
1.59 |
1.40 |
1.49 |
Spleen |
Mean |
2.53 |
2.47 |
2.37 |
2.45 |
|
SD |
0.17 |
0.24 |
0.22 |
0.13 |
Thymus |
Mean |
1.616 |
1.559 |
1.556 |
1.457 |
|
SD |
0.262 |
0.227 |
0.118 |
0.246 |
Epididymides (paired) |
Mean |
4.297 |
4.438 |
4.534 |
4.415 |
|
SD |
0.437 |
0.521 |
0.455 |
0.183
|
Testes (paired) |
Mean |
11.93 |
11.87 |
12.22 |
12.48 |
|
SD |
1.44 |
0.74 |
0.57 |
0.62 |
Females |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.371 |
0.361 |
0.392 |
0.418 |
|
SD |
0.034 |
0.046 |
0.061 |
0.063 |
Brain |
Mean |
|
|
|
9.48
|
|
SD |
9.35 |
9.68 |
9.48 |
1.04 |
Heart |
Mean |
0.44 |
0.33 |
0.52 |
4.36
|
|
SD |
4.52 |
4.57 |
4.32 |
0.32
|
Kidneys (paired) |
Mean |
0.28 |
0.28 |
0.26 |
8.74
|
|
SD |
8.63 |
8.12 |
8.78 |
0.70 |
Liver |
Mean |
0.37 |
0.60 |
0.80 |
33.52
|
|
SD |
32.69 |
32.33 |
32.57 |
1.95 |
Spleen |
Mean |
2.29 |
2.52 |
1.67 |
3.04 |
|
SD |
3.00 |
2.97 |
3.08 |
0.31 |
Thymus |
Mean |
0.33 |
0.39 |
0.20 |
1.816 |
|
SD |
1.779 |
1.776 |
1.882 |
0.358 |
Ovaries (paired) |
Mean |
0.301 |
0.245 |
0.262 |
0.769
|
|
SD |
0.823 |
0.667* |
0.736 |
0.122
|
Uterus |
Mean |
0.165 |
0.104 |
0.102 |
2.874
|
|
SD |
2.246 |
1.941 |
2.288 |
1.749 |
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test
Table 13: Mean organ to brain weight ratios
Dose Level (mg/kg/day) |
|
Control |
150 |
400 |
1000 |
Number Of Animals In Group |
|
10 |
10 |
10 |
10 |
Males |
|
|
|
|
|
Organ |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.041 |
0.034 |
0.033 |
0.031 |
|
SD |
0.013 |
0.007 |
0.009 |
0.005
|
Heart |
Mean |
0.58 |
0.57 |
0.59 |
0.61
|
|
SD |
0.03 |
0.05 |
0.04 |
0.04 |
Kidneys (paired) |
Mean |
1.31 |
1.28 |
1.24 |
1.27
|
|
SD |
0.11 |
0.05 |
0.11 |
0.09
|
Liver |
Mean |
4.76 |
4.53 |
4.56 |
4.60 |
|
SD |
0.31 |
0.31 |
0.26 |
0.36 |
Spleen |
Mean |
0.38 |
0.37 |
0.35 |
0.37
|
|
SD |
0.03 |
0.03 |
0.03 |
0.04 |
Thymus |
Mean |
0.243 |
0.231 |
0.230 |
0.218 |
|
SD |
0.044 |
0.032 |
0.020 |
0.040 |
Epididymides (paired) |
Mean |
0.645 |
0.659 |
0.668 |
0.659 |
|
SD |
0.061 |
0.079 |
0.067 |
0.059 |
Testes (paired) |
Mean |
1.79 |
1.76 |
1.80 |
1.86 |
|
SD |
0.20 |
0.14 |
0.11 |
0.143
|
Females |
|
|
|
|
|
Adrenals (paired) |
Mean |
0.040 |
0.037 |
0.041 |
0.044 |
|
SD |
0.004 |
0.005 |
0.006 |
0.007 |
Heart |
Mean |
0.48 |
0.47 |
0.46 |
0.46
|
|
SD |
0.04 |
0.03 |
0.04 |
0.02 |
Kidneys (paired) |
Mean |
0.93 |
0.84* |
0.93 |
0.93
|
|
SD |
0.07 |
0.06 |
0.08 |
0.08
|
Liver |
Mean |
3.51 |
3.34 |
3.45 |
3.56
|
|
SD |
0.32 |
0.26 |
0.26 |
0.30 |
Spleen |
Mean |
0.32 |
0.31 |
0.33 |
0.32
|
|
SD |
0.04 |
0.04 |
0.03 |
0.04 |
Thymus |
Mean |
0.190 |
0.184 |
0.199 |
0.192 |
|
SD |
0.027 |
0.026 |
0.026 |
0.036 |
Ovaries (paired) |
Mean |
0.088 |
0.069** |
0.078 |
0.082 |
|
SD |
0.019 |
0.012 |
0.010 |
0.012 |
Uterus |
Mean |
0.238 |
0.200 |
0.243 |
0.306
|
|
SD |
0.070 |
0.032 |
0.060 |
0.181
|
* Statistically significant difference from control at p < 0.05 by Dunnett’s Multiple Comparisons test
** Statistically significant difference from control at p < 0.01 by Dunnett’s Multiple Comparisons test
Table 14: Range of dermal doses (g)
Dose group (mg/kg bw/day |
Control |
150 |
400 |
1,000 |
Number of animals (males) |
10 |
10 |
10 |
10 |
Days |
|
|
|
|
1-7 |
0 |
0.042-0.045 |
0.11-0.12 |
0.27-0.29 |
8-14 |
0 |
0.044-0.051 |
0.12-0.13 |
0.30-0.33 |
15-20 |
0 |
0.047-0.055 |
0.12-0.14 |
0.31-0.35 |
21-27 |
0 |
0.049-0.058 |
0.13-0.15 |
0.32-0.37 |
28 |
0 |
0.053-0.062 |
0.13-0.15 |
0.34-0.42 |
Number of animals (females) |
10 |
10 |
10 |
10 |
Days |
|
|
|
|
1-7 |
0 |
0.030-0.034 |
0.077-0.084 |
0.19-0.21 |
8-14 |
0 |
0.031-0.035 |
0.082-0.095 |
0.21-0.23 |
15-20 |
0 |
0.034-0.036 |
0.084-0.097 |
0.21-0.24 |
21-27 |
0 |
0.035-0.039 |
0.089-0.100 |
0.23-0.26 |
28 |
0 |
0.036-0.041 |
0.095-0.100 |
0.24-0.27 |
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