Registration Dossier
Registration Dossier
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EC number: 617-769-9 | CAS number: 858956-08-8
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 02 February 2007 to 01 July 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 21 September 1998
- Deviations:
- no
- Remarks:
- no hormonal measurements performed
- 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:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 7 weeks
- Weight at study initiation: 253.0 - 256.4 g (males), 173.7 - 179.4 (females)
- Housing: individually in stainless steel, wire-mesh cages suspended above cage boards
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®, ad libitum
- Water: tap water, ad libitum
- Acclimation period: approximately 9 days
DETAILS OF FOOD AND WATER QUALITY: water samples were ananalyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 -26
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
test substance was added directly to the diet to achieve the target concentrations specified by the study design; the test diets were thoroughly mixed to ensure homogeneous distribution of the test substance throughout the diet.
DIET PREPARATION
- Rate of preparation of diet: weekly, except in two instances in which diets were prepared for 10 or 11 days, after stability was confirmed.
- Mixing appropriate amounts with: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®.
- Storage temperature of food: all diets were refrigerated until used.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Duplicate samples (concentration verification and homogeneity (from top, middle bottom of the sample) of all dietary concentrations were collected at the initial diet preparation and analyzed to verify the concentration (average of homogeneity samples) and homogeneity of test substance in the diets. Near the middle and end of the study, samples were taken to verify concentration. Duplicate samples were taken from the lowest (300 ppm) and the highest (18,000 ppm) dietary concentration of the initial diet preparation and were analyzed to verify the stability of the test substance in the diets. The 300 ppm concentration was included in the initial diet preparation to establish the stability to cover the dietary concentrations of the present study (600 to 18,000 ppm) as well as the concurrent mouse study (300 to 7000 ppm).
The certificate of analysis (COA) included in the original finalized report listed a purity of 92.2%, which did not fully account for all the inorganic impurities associated with this sample. Due to follow-up analysis of the test substance the COA was revised for the purity 90.5% that accounts for the full impurity profile. This reduction in determined purity of 1.7% had minimal impact on the reported doses determined by chemical analyses and on the values utilized for risk assessments. Therefore, the reported dose values were not adjusted. - Duration of treatment / exposure:
- approximately 90 days (94 or 95 days in males and 96 or 97 days in females)
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 600 ppm
- Remarks:
- Males: corresponding to 35 mg/kg bw/day
Females: corresponding to 45 mg/kg bw/day
- Dose / conc.:
- 2 000 ppm
- Remarks:
- Males: corresponding to 114 mg/kg bw/day
Females: corresponding to 146 mg/kg bw/day
- Dose / conc.:
- 6 000 ppm
- Remarks:
- Males: corresponding to 349 mg/kg bw/day
Females: corresponding to 448 mg/kg bw/day
- Dose / conc.:
- 18 000 ppm
- Remarks:
- Males:corresponding to 1045 mg/kg bw/day
Females:corresponding to 1425 mg/kg bw/day
- No. of animals per sex per dose:
- 15
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
The test substance is a metabolite of methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate. A previous 28-day study in rats was conducted with methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate at dietary concentrations of 600, 2000, 6000, and 20,000 ppm. No test substance-related effects occurred on ophthalmogical observations, clinical observations, clinical pathology parameters, food consumption, organ weights, gross morphological observations, or survival. A test substance-related decrease in body weight, weight gain, and food efficiency occurred in 20,000 ppm males and females. Males in the 20,000 ppm group had thyroid follicular cell hypertrophy and pancreatic acinar cell apoptosis. Females in the 20,000 ppm group had induction of hepatic ß-oxidation activity. Based on these findings, the dietary concentrations selected for the current 90-day study were 600, 2000, 6000, and 18,000 ppm.
- Rationale for selecting satellite groups: on test day 56, blood was collected from satellite animals for evaluation of test substance and/or metabolite concentration in plasma (separate report was not available).
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked: moribund/dead rats, abnormal behavior/appearance and acute clinical signs of systemic toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Day 0 and weekly thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and weekly thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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 AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and week 13
- Dose groups that were examined: all dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 14
- Anaesthetic used for blood collection: not specified
- Animals fasted: not specified
- How many animals: all dose groups
- Parameters checked in table No. 1 in the "Any other information and methods incl. tables" section were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 14
- Animals fasted: not specified
- How many animals: all dose groups
- Parameters checked in table No.2 in the "Any other information and methods incl. tables" section were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: week 14
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table No.3 in the "Any other information and methods incl. tables" section were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: pretest and weeks 4, 8, and 13
- Dose groups that were examined: all dose groups
- Battery of functions tested: motor activity / grip strength, rectal body temperature other: please refer to table No 4 in the "Any other information and methods incl. tables" section.
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (Please refer to table 5 in the "Any other information and methods incl. tables" section.)
HISTOPATHOLOGY: Yes (Please refer to table 6 in the "Any other information and methods incl. tables" section.)
Organ weights determined for organs/tissues listed in table 7 in the "Any other information and methods incl. tables" section.) - Other examinations:
- Subchronic Neurotoxicity:
On test days 94 and 95, rats were designated for neuropathology (5 rats/sex/group) analysis. Animals were anesthetized and underwent whole-body in situ perfusion.
(For tissues analysed and further details, please refer to table 8 in the "Any other information and methods incl. tables" section.)
Evaluation of test substance and/or metabolite concentration in plasma (satellite animals)
Approximately 0.5 mL of blood was collected from the satellite animals (5 rats/sex/concentration) on test day 56, for determination of plasma concentration of test substance and/or metabolites. - Statistics:
- Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.
For details on statistics please refer to table 9 in the "Any other information and methods incl. tables" section.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 600 ppm and 2000 ppm: one female of each dose group had abnormal gait. However, abnormal gait was not observed in these animals during any of the neurobehavioral evaluations. Since no dose response was evident and occurrence was limited to 1 animal/group, these observations were considered to be spurious and not treatment-related.
Other clinical signs observed throughout the study were typical for rats of this age and strain, and included hair loss, eye, ear, or nose discharge hyperactivity, high posture, protrusion in abdomen, absent teeth, clipped teeth, maloccluded teeth, ear twitch, corneal opacity and wound. These clinical signs were observed at low incidence and with no dose response.
(Please refer to table 10 in the "Any other information on results incl. tables" section.) - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- control and 6000 ppm: one control male rat and one female rat in the 6000 ppm group were accidentally killed during blood collection just prior to necropsy (non-treatment-related).
(Please refer to table 10 in the "Any other information on results incl. tables" section.) - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 18,000 ppm: significant decrease in mean body weights and body weight gains were observed in males and females. In males, mean body weight was 9% lower than that of controls on the final test day 91. Overall (test days 0-91) body weight gain in males was 15% lower (statistically significant) than that of controls. In females, mean body weight was 8% lower than that of controls on the final test day 91. Overall (test days 0-91) body weight gain in males was 18% lower (statistically significant) than that of controls.The effects were considered treatment-related and adverse.
6000 ppm: statistically significantly lower body weights and body weight gains compared to controls were observed in males and females over test days 21-28 and 14-21, respectively. (non-treatment-related and non-adverse)
600 ppm: statistically significantly lower body weights and body weight gains compared to controls were observed in females over test days 84-91 (non-treatment-related and non-adverse)..
Changes observed at 6000 and 600 ppm were considered spurious because they occurred only in one time interval and there was no dose response.
(Please refer to table 11 and 12 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):
- 18,000 ppm: mean daily food consumption was statistically significantly lower in males over test day intervals 0-7, 21-28, and 42-49 and in females over test day interval 70-77. These sporadic changes were considered incidental and not treatment-related, because overall mean food consumption was not significantly different from control.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- 18,000 ppm: significant decrease in food efficiency was observed in males and females. The overall food efficiency (test days 0-91) in males and females of this dose group was 89% and 83% of control, respectively. In addition, statistically significantly lower mean food efficiency was noted in males over test day intervals 21-28, 70-77, and 77-84 and in females over test day interval 62-70. Since the changes in mean food efficiency were consistent with decreased body weight parameters, they were considered treatment-related and adverse.
6000 ppm: statistically significant reductions in food efficiency were noted in males over test days 21-28 (non-treatment-related and non-adverse).
600 ppm: statistically significant reductions in food efficiency were noted in females over test days 84-91 (non-treatment-related and non-adverse).
Since the findings at 6000 and 600 ppm occurred only over one weekly interval, they were considered spurious, non-treatment-related and non-adverse.
(Please refer to table 13 in the "Any other information on results incl. tables" section.) - Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 600 ppm: one male had a posterior lens opacity and one female had a lens opacity and dislocation, retinal degeneration and iritis. Since effects were observed only in single animals and no dose-response relationship was visible, the observations were not considered treatment-related and non-adverse.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- (Please refer to table 14 in the "Any other information on results incl. tables" section.)
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 6000 ppm: triglyceride (69% of control), total protein and albumin (94% and 93% of control, respectively) and calcium (95% of control) were decreased in female rats. The observed statistically significant changes in group mean clinical chemistry parameters at test days 96-97 in females were considered to be non-treatment-related and non-adverse, because the change did not occur in a dose-related manner.
(Please refer to table 15 in the "Any other information on results incl. tables" section.) - Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 18,000 ppm: urine volume was decreased (52% of control) in male rats. However, urine volumes ranging from 2.0 to 14.6 mL in male rats were within the urine volume range of the male control group, 0.7 to 21.0 mL. In addition, there were no correlative clinical pathology or histopathology changes and a similar decrease in urine volume was not observed in females. Therefore, this change was considered non-treatment-related and non-adverse. Furthermore, pH was minimally decreased (91% of control) in female rats dosed. This change was considered non-adverse due to the minimal nature of the change and the lack of associated changes in other urinalysis or clinical chemistry parameters.
(Please refer to table 16 in the "Any other information on results incl. tables" section.) - 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):
- 18,000 ppm: in males, a small (9%) decrease in the mean final body weight, as compared to the control value, was associated with a similar decrease in the mean absolute liver, heart, spleen, and thymus weights. Some of these decreases were statistically significant. Since, there were no gross or microscopic pathology correlates observed and most mean relative (% body weight) organ weights were comparable to control values, the small decreases in mean absolute organ weights were interpreted to be a result of the decreased mean final body weight and not an indication of an organ-specific effect. There was a statistically significant decrease (12%) in the mean relative (% brain weight) liver weight in males, as compared to controls. This difference was also attributed to the decrease in final body weight and secondary to decrease in mean absolute liver weights.
(Please refer to table 17 in the "Any other information on results incl. tables" section.) - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All gross observations were consistent with normal background lesions in rats of this age and strain and thus non-treatment-related and non-adverse.
(Please refer to table 18 in the "Any other information on results incl. tables" section.) - Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- (Please refer to table 23 and 24 in the "Any other information on results incl. tables" section.)
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All microscopic findings were consistent with normal background lesions in rats of this age and strain and thus non-treatment-related and non-adverse.
(Please refer to table 19 in the "Any other information on results incl. tables" section.) - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- Neurobehavioral evaluation
Functional Observational Battery: There were no treatment-related or statistically significant effects/differences on forelimb or hindlimb grip strength, in footsplay and in the number of rearing movements in the open field arena in males and females of any dose group. (Please refer to table 20, 21 and 22 in the "Any other information on results incl. tables" section.)
600 and 6000 ppm: occasional occurrence of abnormal gait in either the home cage or open field were noted in one 600 ppm male and one 6000 ppm female. Since a dose-response relationship was not evident for either males or females, these incidents were considered to be spurious, non-treatment-related and non-adverse.
Motor acitivity: There were no treatment-related or statistically significant effects on duration of movement or number of movements for males or females of any dose group.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 18 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food efficiency
- Remarks on result:
- other: corresponding to 1045 and 1425 mg/kg bw/day in males and females, respectively.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 6 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effect observed
- Remarks on result:
- other: corresponding to 349 and 448 mg/kg bw/day in males and females, respectively.
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 10: Summary of detailed clinical observations and mortality data
Males |
|||||
Group Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
Number |
15 |
15 |
15 |
15 |
15 |
Discharge - black – eye(s)/ear(s) |
|
|
|
|
|
Number of Observations |
2 |
|
|
7 |
4 |
Number of Animals |
1 |
|
|
2 |
1 |
Days from - to |
49 - 56 |
|
|
7 - 62 |
28 – 49 |
Discharge - brown - nose |
|
|
|
|
|
Number of Observations |
|
|
|
3 |
|
Number of Animals |
|
|
|
1 |
|
Days from - to |
|
|
|
7 – 21 |
|
Hair loss |
|
|
|
|
|
Number of Observations |
13 |
|
40 |
|
11 |
Number of Animals |
1 |
|
4 |
|
2 |
Days from - to |
7 - 91 |
|
7 - 91 |
|
21 - 91 |
Hyperreactive |
|
|
|
|
|
Number of Observations |
|
|
7 |
|
|
Number of Animals |
|
|
1 |
|
|
Days from - to |
|
|
49 - 91 |
|
|
Posture - high |
|
|
|
|
|
Number of Observations |
|
|
7 |
|
|
Number of Animals |
|
|
1 |
|
|
Days from - to |
|
|
49 - 91 |
|
|
Protrusion - abdomen |
|
|
|
13 |
|
Number of Observations |
|
|
|
1 |
|
Number of Animals |
|
|
|
7 - 91 |
|
Days from - to |
|
|
|
|
|
Teeth absent |
|
|
|
|
|
Number of Observations |
7 |
|
|
12 |
|
Number of Animals |
1 |
|
|
1 |
|
Days from - to |
49 - 91 |
|
|
14 – 91 |
|
Teeth clipped |
|
|
|
|
|
Number of Observations |
|
|
|
12 |
8 |
Number of Animals |
|
|
|
1 |
1 |
Days from - to |
|
|
|
14 – 91 |
42 – 91 |
Teeth maloccluded |
|
|
|
|
|
Number of Observations |
|
|
|
23 |
10 |
Number of Animals |
|
|
|
2 |
1 |
Days from - to |
|
|
|
7 - 91 |
28 - 91 |
Accidentally Killed |
|
|
|
|
|
Number of Observations |
1 |
|
|
|
|
Number of Animals |
1 |
|
|
|
|
Days from - to |
95 - 95 |
|
|
|
|
Neuropathology sacrifice |
|
|
|
|
|
Number of Observations |
5 |
5 |
5 |
5 |
5 |
Number of Animals |
5 |
5 |
5 |
5 |
5 |
Days from - to |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
Scheduled sacrifice |
|
|
|
|
|
Number of Observations |
9 |
10 |
10 |
10 |
10 |
Number of Animals |
9 |
10 |
10 |
10 |
10 |
Days from - to |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
Females |
|||||
Number |
15 |
15 |
15 |
15 |
15 |
Abnormal gait |
|
|
|
|
|
Number of Observations |
|
1 |
4 |
|
|
Number of Animals |
|
1 |
1 |
|
|
Days from - to |
|
91 - 91 |
70 – 91 |
|
|
Ear twitch |
|
|
|
|
|
Number of Observations |
1 |
|
|
1 |
|
Number of Animals |
1 |
|
|
1 |
|
Days from - to |
7 -7 |
|
|
70 -70 |
|
Eye corneal opacity |
|
|
|
|
|
Number of Observations |
|
9 |
|
|
|
Number of Animals |
|
1 |
|
|
|
Days from - to |
|
35 - 91 |
|
|
|
Hair loss |
|
|
|
|
|
Number of Observations |
|
18 |
7 |
6 |
16 |
Number of Animals |
|
2 |
1 |
1 |
2 |
Days from - to |
|
7 - 91 |
49 - 91 |
56 - 91 |
14 – 91 |
Wound - superficial - neck |
|
|
|
|
|
Number of Observations |
|
|
|
|
3 |
Number of Animals |
|
|
|
|
1 |
Days from - to |
|
|
|
|
14 -28 |
Accidentally Killed |
|
|
|
1 |
|
Number of Observations |
|
|
|
1 |
|
Number of Animals |
|
|
|
96 – 96 |
|
Days from - to |
|
|
|
|
|
Neuropathology sacrifice |
|
|
|
|
|
Number of Observations |
5 |
5 |
5 |
5 |
5 |
Number of Animals |
5 |
5 |
5 |
5 |
5 |
Days from - to |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
94 - 95 |
Scheduled sacrifice |
|
|
|
|
|
Number of Observations |
10 |
10 |
10 |
10 |
10 |
Number of Animals |
10 |
10 |
10 |
10 |
10 |
Days from - to |
96 - 97 |
96 - 97 |
96 - 97 |
96 - 97 |
96 - 97 |
Table 11: Mean body weights (g)
Males |
|||||
Group Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
BW:DAY0 |
256.4 |
254.7 |
253.7 |
255.3 |
253.0 |
|
11.3(15) |
13.3(15) |
13.7(15) |
13.0(15) |
10.7(15) |
BW:DAY7 |
311.7 |
310.4 |
308.9 |
309.4 |
300.6 |
|
15.8(15) |
15.3(15) |
17.6(15) |
19.8(15) |
11.8(15) |
BW:DAY14 |
358.2 |
357.1 |
356.9 |
354.6 |
345.7 |
|
21.1(15) |
17.6(15) |
22.9(15) |
36.2(15) |
15.3(15) |
BW:DAY21 |
390.4 |
390.3 |
390.2 |
384.3 |
371.9 |
|
27.3(15) |
20.4(15) |
27.8(15) |
35.5(15) |
17.7(15) |
BW:DAY28 |
429.4 |
424.7 |
424.0 |
416.1 |
401.7* |
|
31.9(15) |
24.9(15) |
30.6(15) |
36.2(15) |
17.2(15) |
BW:DAY35 |
459.7 |
451.9 |
455.3 |
450.3 |
427.2* |
|
36.0(15) |
26.2(15) |
35.6(15) |
39.6(15) |
19.7(15) |
BW:DAY42 |
486.3 |
480.3 |
482.3 |
479.9 |
452.1* |
|
38.7(15) |
29.6(15) |
39.0(15) |
41.6(15) |
23.8(15) |
BW:DAY49 |
506.3 |
497.7 |
504.1 |
498.9 |
470.1* |
|
41.9(15) |
31.8(15) |
42.8(15) |
46.1(15) |
25.3(15) |
BW:DAY56 |
520.8 |
512.8 |
517.5 |
513.1 |
483.3 |
|
47.5(15) |
36.5(15) |
41.9(15) |
49.7(15) |
26.0(15) |
BW:DAY62 |
538.7 |
531.2 |
534.6 |
533.7 |
500.2* |
|
46.0(15) |
36.2(15) |
44.0(15) |
50.2(15) |
27.1(15) |
BW:DAY70 |
551.6 |
543.6 |
551.7 |
549.5 |
514.2 |
|
46.4(15) |
38.9(15) |
46.7(15) |
45.1(15) |
26.4(15) |
BW:DAY77 |
571.0 |
560.6 |
566.7 |
566.4 |
524.5* |
|
48.1(15) |
39.7(15) |
50.2(15) |
47.9(15) |
30.4(15) |
BW:DAY84 |
578.7 |
568.5 |
575.1 |
575.3 |
526.5* |
|
48.1(15) |
42.6(15) |
51.2(15) |
50.9(15) |
31.9(15) |
BW:DAY91 |
580.7 |
572.9 |
580.3 |
578.9 |
529.4* |
|
50.4(15) |
43.6(15) |
51.4(15) |
53.0(15) |
34.9(15) |
Females |
|||||
Group Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
BW:DAY0 |
179.4 |
176.7 |
180.2 |
173.7 |
174.6 |
|
10.2(15) |
8.8(15) |
9.8(15) |
10.1(14) |
9.8(15) |
BW:DAY7 |
196.5 |
193.9 |
200.3 |
189.1 |
188.7 |
|
13.0(15) |
9.6(15) |
16.3(15) |
11.1(15) |
11.7(15) |
BW:DAY14 |
214.9 |
216.5 |
221.7 |
209.9 |
206.2 |
|
15.5(15) |
14.8(15) |
20.2(15) |
12.6(15) |
16.5(15) |
BW:DAY21 |
226.9 |
228.0 |
236.3 |
214.5 |
213.9 |
|
17.2(15) |
14.9(15) |
21.8(15) |
11.6(15) |
16.5(15) |
BW:DAY28 |
244.6 |
242.9 |
247.5 |
234.3 |
229.7 |
|
22.1(15) |
18.2(15) |
23.8(15) |
14.6(15) |
18.2(15) |
BW:DAY35 |
254.0 |
251.7 |
261.1 |
243.5 |
239.3 |
|
22.9(15) |
18.8(15) |
28.5(15) |
13.8(15) |
22.4(14) |
BW:DAY42 |
261.5 |
262.6 |
268.9 |
251.5 |
248.3 |
|
22.6(15) |
20.2(15) |
31.3(15) |
13.7(15) |
23.1(15) |
BW:DAY49 |
267.1 |
268.3 |
273.5 |
254.6 |
250.0 |
|
22.5(15) |
25.0(15) |
29.5(15) |
16.2(15) |
19.3(15) |
BW:DAY56 |
276.8 |
273.8 |
279.4 |
262.7 |
254.0* |
|
24.1(15) |
22.4(15) |
27.9(15) |
18.3(15) |
22.4(15) |
BW:DAY62 |
280.9 |
280.1 |
288.2 |
269.3 |
262.0 |
|
23.3(15) |
20.0(15) |
29.7(15) |
20.9(15) |
21.5(15) |
BW:DAY70 |
287.4 |
289.6 |
293.6 |
276.1 |
261.7* |
|
24.9(15) |
24.1(15) |
30.3(15) |
23.2(15) |
23.1(15) |
BW:DAY77 |
293.7 |
292.2 |
302.9 |
279.9 |
264.7* |
|
24.3(15) |
26.1(15) |
31.7(15) |
25.9(15) |
24.1(15) |
BW:DAY84 |
293.4 |
294.9 |
301.9 |
282.9 |
269.6 |
|
29.8(15) |
24.2(15) |
32.9(15) |
23.0(15) |
21.2(15) |
BW:DAY91 |
294.6 |
288.6 |
304.9 |
284.1 |
270.6 |
|
30.5(15) |
24.6(15) |
34.5(15) |
23.4(15) |
22.6(15) |
Data arranged as: Mean Standard deviation (Number of values included in calculation)
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn’s) significant
Table 12: Mean body weight gains (g)
Males |
|||||
Group Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
BWG:DAY0-DAY7 |
55.3 |
55.7 |
55.2 |
54.1 |
47.6* |
|
8.1(15) |
4.6(15) |
6.0(15) |
10.3(15) |
5.4(15) |
BWG:DAY7-DAY14 |
46.5 |
46.7 |
48.1 |
45.2 |
45.1 |
|
6.6(15) |
5.9(15) |
7.3(15) |
21.0(15) |
7.2(15) |
BWG:DAY14-DAY21 |
32.2 |
33.2 |
33.3 |
29.7 |
26.2 |
|
9.1(15) |
6.5(15) |
9.1(15) |
8.7(15) |
6.0(15) |
BWG:DAY21-DAY28 |
39.0 |
34.4 |
33.8 |
31.7* |
29.7* |
|
7.1(15) |
6.6(15) |
8.5(15) |
5.5(15) |
6.3(15) |
BWG:DAY28-DAY35 |
30.3 |
27.3 |
31.3 |
34.2 |
25.5 |
|
6.0(15) |
4.4(15) |
6.4(15) |
7.2(15) |
6.5(15) |
BWG:DAY35-DAY42 |
26.6 |
28.3 |
27.0 |
29.7 |
24.9 |
|
5.6(15) |
5.8(15) |
6.8(15) |
4.9(15) |
7.3(15) |
BWG:DAY42-DAY49 |
19.9 |
17.5 |
21.8 |
18.9 |
17.9 |
|
6.8(15) |
5.7(15) |
6.5(15) |
6.7(15) |
8.2(15) |
BWG:DAY49-DAY56 |
14.6 |
15.0 |
13.4 |
14.2 |
13.2 |
|
8.2(15) |
8.9(15) |
7.3(15) |
7.9(15) |
7.1(15) |
BWG:DAY56-DAY62 |
17.9 |
18.5 |
17.0 |
20.6 |
16.9 |
|
4.2(15) |
7.0(15) |
4.5(15) |
5.6(15) |
6.8(15) |
BWG:DAY62-DAY70 |
12.9 |
12.4 |
17.1 |
15.9 |
14.0 |
|
5.4(15) |
6.8(15) |
6.0(15) |
9.0(15) |
3.4(15) |
BWG:DAY70-DAY77 |
19.4 |
17.0 |
15.1 |
16.9 |
10.3* |
|
6.2(15) |
5.8(15) |
6.5(15) |
4.5(15) |
8.0(15) |
BWG:DAY77-DAY84 |
7.6 |
7.9 |
8.4 |
8.9 |
1.9* |
|
4.6(15) |
5.5(15) |
5.2(15) |
7.6(15) |
4.8(15) |
BWG:DAY84-DAY91 |
2.0 |
4.3 |
5.2 |
3.7 |
2.9 |
|
6.4(15) |
6.5(15) |
6.3(15) |
6.8(15) |
7.2(15) |
BWG:DAY0-DAY91 |
324.3 |
318.1 |
326.7 |
323.6 |
276.4* |
|
45.0(15) |
36.5(15) |
41.5(15) |
42.7(15) |
30.0(15) |
Females |
|||||
Goup Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
BWG:DAY0-DAY7 |
17.1 |
17.3 |
20.1 |
16.0 |
14.1 |
|
8.6(15) |
6.7(15) |
7.6(15) |
4.4(14) |
7.0(15) |
BWG:DAY7-DAY14 |
18.3 |
22.6 |
21.4 |
20.9 |
17.5 |
|
9.1(15) |
9.2(15) |
9.4(15) |
5.2(15) |
7.3(15) |
BWG:DAY14-DAY21 |
12.0 |
11.5 |
14.6 |
4.6* |
7.7 |
|
10.8(15) |
6.4(15) |
6.5(15) |
5.8(15) |
8.0(15) |
BWG:DAY21-DAY28 |
17.7 |
14.9 |
11.2 |
19.8 |
15.7 |
|
9.6(15) |
9.9(15) |
8.1(15) |
8.8(15) |
6.5(15) |
BWG:DAY28-DAY35 |
9.4 |
8.8 |
13.5 |
9.2 |
10.0 |
|
7.6(15) |
7.2(15) |
6.9(15) |
5.9(15) |
7.3(14) |
BWG:DAY35-DAY42 |
7.5 |
10.9 |
7.9 |
8.0 |
8.9 |
|
9.6(15) |
9.5(15) |
6.1(15) |
4.9(15) |
4.8(14) |
BWG:DAY42-DAY49 |
5.6 |
5.7 |
4.5 |
3.1 |
1.7 |
|
5.2(15) |
7.9(15) |
5.5(15) |
6.5(15) |
6.6(15) |
BWG:DAY49-DAY56 |
9.7 |
5.5 |
6.0 |
8.1 |
4.0 |
|
8.7(15) |
7.5(15) |
8.7(15) |
6.6(15) |
9.8(15) |
BWG:DAY56-DAY62 |
4.1 |
6.3 |
8.8 |
6.6 |
8.0 |
|
9.6(15) |
6.5(15) |
9.0(15) |
10.1(15) |
8.8(15) |
BWG:DAY62-DAY70 |
6.5 |
9.5 |
5.4 |
6.8 |
-0.2@ |
|
4.5(15) |
8.5(15) |
5.4(15) |
4.0(15) |
5.6(15) |
BWG:DAY70-DAY77 |
6.3 |
2.6 |
9.2 |
3.8 |
2.9 |
|
5.6(15) |
8.3(15) |
5.2(15) |
9.0(15) |
6.9(15) |
BWG:DAY77-DAY84 |
-0.3 |
2.7 |
-1.0 |
3.0 |
4.9 |
|
8.0(15) |
9.1(15) |
6.4(15) |
6.7(15) |
7.9(15) |
BWG:DAY84-DAY91 |
1.2 |
-6.3* |
3.1 |
1.3 |
1.0 |
|
8.8(15) |
7.1(15) |
9.4(15) |
6.5(15) |
6.3(15) |
BWG:DAY0-DAY91 |
115.2 |
111.9 |
124.7 |
112.5 |
94.9* |
|
26.9(15) |
19.3(15) |
26.1(15) |
17.5(14) |
16.9(14) |
Data arranged as: Mean Standard deviation (Number of values included in calculation)
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn’s) significant
Table 13: Food efficiency (body weight (g)/ food consumed (g))
Males |
|||||
Group Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
FE:DAY0-DAY7 |
0.305 |
0.310 |
0.307 |
0.295 |
0.286 |
|
0.037(15) |
0.021(15) |
0.016(15) |
0.045(15) |
0.032(15) |
FE:DAY7-DAY14 |
0.256 |
0.252 |
0.262 |
0.228 |
0.247 |
|
0.030(15) |
0.029(15) |
0.025(15) |
0.151(15) |
0.030(15) |
FE:DAY14-DAY21 |
0.179 |
0.181 |
0.186 |
0.170 |
0.151 |
|
0.046(15) |
0.032(15) |
0.039(15) |
0.052(15) |
0.031(15) |
FE:DAY21-DAY28 |
0.204 |
0.180 |
0.182 |
0.173* |
0.168* |
|
0.032(15) |
0.026(15) |
0.039(15) |
0.029(15) |
0.037(15) |
FE:DAY28-DAY35 |
0.158 |
0.143 |
0.165 |
0.175 |
0.142 |
|
0.026(15) |
0.023(15) |
0.022(15) |
0.028(15) |
0.031(15) |
FE:DAY35-DAY42 |
0.134 |
0.147 |
0.140 |
0.152 |
0.135 |
|
0.026(15) |
0.026(15) |
0.029(15) |
0.020(15) |
0.037(15) |
FE:DAY42-DAY49 |
0.102 |
0.091 |
0.114 |
0.096 |
0.097 |
|
0.033(15) |
0.028(15) |
0.029(15) |
0.028(15) |
0.040(15) |
FE:DAY49-DAY56 |
0.077 |
0.081 |
0.074 |
0.076 |
0.073 |
|
0.040(15) |
0.043(15) |
0.039(15) |
0.036(15) |
0.039(15) |
FE:DAY56-DAY62 |
0.109 |
0.111 |
0.103 |
0.124 |
0.106 |
|
0.027(15) |
0.041(15) |
0.022(15) |
0.033(15) |
0.041(15) |
FE:DAY62-DAY70 |
0.060 |
0.056 |
0.078 |
0.072 |
0.068 |
|
0.024(15) |
0.030(15) |
0.025(15) |
0.039(15) |
0.018(15) |
FE:DAY70-DAY77 |
0.101 |
0.090 |
0.076 |
0.086 |
0.056* |
|
0.027(15) |
0.031(15) |
0.028(15) |
0.018(15) |
0.042(15) |
FE:DAY77-DAY84 |
0.041 |
0.042 |
0.046 |
0.045 |
0.011* |
|
0.024(15) |
0.026(15) |
0.027(15) |
0.035(15) |
0.027(15) |
FE:DAY84-DAY91 |
0.010 |
0.023 |
0.027 |
0.018 |
0.014 |
|
0.036(15) |
0.036(15) |
0.034(15) |
0.033(15) |
0.043(15) |
FE:DAY0-DAY91 |
0.133 |
0.131 |
0.135 |
0.132 |
0.119* |
|
0.015(15) |
0.012(15) |
0.007(15) |
0.008(15) |
0.009(15) |
Females |
|||||
Goup Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
FE:DAY0-DAY7 |
0.131 |
0.142 |
0.150 |
0.138 |
0.107 |
|
0.063(15) |
0.052(15) |
0.049(15) |
0.040(14) |
0.048(15) |
FE:DAY7-DAY14 |
0.139 |
0.164 |
0.160 |
0.161 |
0.127 |
|
0.073(15) |
0.059(15) |
0.066(15) |
0.043(15) |
0.051(15) |
FE:DAY14-DAY21 |
0.088 |
0.087 |
0.109 |
0.038 |
0.055 |
|
0.073(15) |
0.052(15) |
0.044(15) |
0.048(15) |
0.057(15) |
FE:DAY21-DAY28 |
0.128 |
0.105 |
0.079 |
0.147 |
0.118 |
|
0.068(15) |
0.068(15) |
0.053(15) |
0.065(15) |
0.054(15) |
FE:DAY28-DAY35 |
0.070 |
0.065 |
0.095 |
0.068 |
0.070 |
|
0.055(15) |
0.058(15) |
0.046(15) |
0.041(15) |
0.055(14) |
FE:DAY35-DAY42 |
0.052 |
0.080 |
0.055 |
0.062 |
0.068 |
|
0.068(15) |
0.069(15) |
0.043(15) |
0.038(15) |
0.035(14) |
FE:DAY42-DAY49 |
0.040 |
0.034 |
0.034 |
0.024 |
0.014 |
|
0.039(15) |
0.049(15) |
0.040(15) |
0.049(15) |
0.054(15) |
FE:DAY49-DAY56 |
0.077 |
0.046 |
0.045 |
0.064 |
0.027 |
|
0.066(15) |
0.063(15) |
0.068(15) |
0.052(15) |
0.075(15) |
FE:DAY56-DAY62 |
0.030 |
0.057 |
0.072 |
0.055 |
0.073 |
|
0.079(15) |
0.060(15) |
0.069(15) |
0.084(15) |
0.080(15) |
FE:DAY62-DAY70 |
0.042 |
0.058 |
0.034 |
0.042 |
-0.005* |
|
0.029(15) |
0.047(15) |
0.036(15) |
0.021(15) |
0.040(15) |
FE:DAY70-DAY77 |
0.047 |
0.016 |
0.066 |
0.028 |
0.023 |
|
0.040(15) |
0.059(15) |
0.037(15) |
0.070(15) |
0.057(15) |
FE:DAY77-DAY84 |
-0.008 |
0.020 |
-0.009 |
0.023 |
0.038 |
|
0.063(15) |
0.067(15) |
0.052(15) |
0.054(15) |
0.062(15) |
FE:DAY84-DAY91 |
0.000 |
-0.050@ |
0.020 |
0.009 |
0.007 |
|
0.080(15) |
0.065(15) |
0.068(15) |
0.050(15) |
0.050(15) |
FE:DAY0-DAY91 |
0.066 |
0.064 |
0.071 |
0.067 |
0.055* |
|
0.010(15) |
0.009(15) |
0.012(15) |
0.012(14) |
0.010(14) |
Data arranged as: Mean Standard deviation (Number of values included in calculation)
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn’s) significant
Table 14 : Summary of haematology and coagulation values
Male |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
RBC (x106/µL) |
|
|
|
|
|
DAY 94-95 |
8.80 |
8.82 |
8.91 |
8.60 |
8.88 |
|
0.34(10) |
0.25(10) |
0.23(10) |
0.29(9) |
0.51(10) |
HGB (g/dL) |
|
|
|
|
|
DAY 94-95 |
15.7 |
15.4 |
15.6 |
15.5 |
15.6 |
|
0.6(10) |
0.7(10) |
0.4(10) |
0.5(9) |
0.7(10) |
HCT (%) |
|
|
|
|
|
DAY 94-95 |
47.8 |
47.0 |
47.8 |
46.8 |
47.6 |
|
2.0(10) |
2.0(10) |
1.7(10) |
1.6(9) |
2.2(10) |
MCV (fL) |
|
|
|
|
|
DAY 94-95 |
54.3 |
53.4 |
53.7 |
54.5 |
53.7 |
|
1.7(10) |
1.7(10) |
1.6(10) |
2.5(9) |
1.2(10) |
MCH (pg) |
|
|
|
|
|
DAY 94-95 |
17.8 |
17.5 |
17.6 |
18.0 |
17.5 |
|
0.6(10) |
0.5(10) |
0.4(10) |
0.6(9) |
0.5(10) |
MCHC (g/dL) |
|
|
|
|
|
DAY 94-95 |
32.7 |
32.7 |
32.7 |
33.0 |
32.7 |
|
0.6(10) |
0.5(10) |
0.6(10) |
0.5(9) |
0.7(10) |
RDW (%) |
|
|
|
|
|
DAY 94-95 |
12.6 |
12.6 |
12.6 |
12.8 |
12.7 |
|
0.6(10) |
0.6(10) |
0.5(10) |
0.5(9) |
0.6(10) |
ARET (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
153.0 |
142.8 |
159.8 |
169.2 |
148.4 |
|
32.0(10) |
30.4(10) |
23.6(10) |
16.8(9) |
36.0(10) |
PLT (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
965 |
1030 |
1012 |
1074 |
1030 |
|
147(7) |
149(10) |
131(5) |
96(6) |
93(8) |
WBC (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
10.18 |
10.55 |
11.66 |
12.05 |
9.11 |
|
2.00(10) |
3.02(10) |
3.70(10) |
3.96(9) |
2.78(10) |
ANEU (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
1.71 |
1.50 |
1.80 |
1.64 |
1.64 |
|
0.39(10) |
0.50(10) |
0.76(10) |
0.49(9) |
0.87(10) |
ALYM (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
7.96 |
8.54 |
9.26 |
9.81 |
7.03 |
|
1.91(10) |
2.78(10) |
3.36(10) |
3.45(9) |
2.47(10) |
AMON (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
0.23 |
0.24 |
0.27 |
0.24 |
0.20 |
|
0.07(10) |
0.10(10) |
0.11(10) |
0.10(9) |
0.07(10) |
AEOS (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
0.11 |
0.12 |
0.15 |
0.16 |
0.09 |
|
0.03(10) |
0.06(10) |
0.05(10) |
0.08(9) |
0.03(10) |
ABAS (x10³/µL) |
|
|
|
|
|
DAY 94-95 |
0.03 |
0.04 |
0.05 |
0.04 |
0.03 |
|
0.02(10) |
0.01(10) |
0.02(10) |
0.02(9) |
0.02(10) |
ALUC (x10³/µL) |
|
|
|
|
|
|
0.14 |
0.12 |
0.14 |
0.16 |
0.12 |
|
0.02(10) |
0.06(10) |
0.06(10) |
0.07(9) |
0.07(10) |
Summary of coagulation values |
|||||
DAY 94-95 PT (sec) |
14.9 |
14.7 |
14.7 |
14.5 |
15.4 |
0.4(9) |
0.8(10) |
0.9(10) |
0.6(10) |
0.9(10) |
|
APTT (sec) |
|
|
|
|
|
DAY 94-95 |
16.3 |
15.6 |
15.5 |
15.0 |
16.0 |
1.8(9) |
1.4(10) |
1.4(10) |
1.0(10) |
1.8(10) |
|
Female |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
RBC (x106/µL) |
|
|
|
|
|
DAY 96-97 |
8.42 |
8.37 |
8.43 |
8.53 |
8.34 |
|
0.30(10) |
0.25(10) |
0.41(10) |
0.29(10) |
0.23(10) |
HGB (g/dL) |
|
|
|
|
|
DAY 96-97 |
15.6 |
15.4 |
15.5 |
15.7 |
15.4 |
|
0.6(10) |
0.6(10) |
0.7(10) |
0.5(10) |
0.5(10) |
HCT (%) |
|
|
|
|
|
DAY 96-97 |
47.9 |
46.8 |
47.0 |
47.6 |
46.6 |
|
1.8(10) |
1.6(10) |
2.2(10) |
1.9(10) |
1.5(10) |
MCV (fL) |
|
|
|
|
|
DAY 96-97 |
56.9 |
55.8 |
55.8 |
55.8 |
55.9 |
|
1.6(10) |
1.5(10) |
1.0(10) |
1.9(10) |
1.2(10) |
MCH (pg) |
|
|
|
|
|
DAY 96-97 |
18.6 |
18.3 |
18.4 |
18.5 |
18.5 |
|
0.6(10) |
0.5(10) |
0.4(10) |
0.6(10) |
0.5(10) |
MCHC (g/dL) |
|
|
|
|
|
DAY 96-97 |
32.7 |
32.8 |
33.0 |
33.1 |
33.1 |
|
0.3(10) |
0.4(10) |
0.5(10) |
0.4(10) |
0.3(10) |
RDW (%) |
|
|
|
|
|
DAY 96-97 |
11.9 |
11.8 |
11.8 |
11.4 |
11.8 |
|
0.5(10) |
0.5(10) |
0.4(10) |
0.5(10) |
0.4(10) |
ARET (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
162.5 |
133.9 |
142.6 |
136.7 |
145.3 |
|
34.1(10) |
37.1(10) |
22.3(10) |
20.1(10) |
31.0(10) |
PLT (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
1012 |
1081 |
940 |
1032 |
1012 |
|
63(9) |
113(9) |
92(9) |
125(10) |
62(8) |
WBC (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
9.09 |
10.03 |
8.63 |
9.86 |
9.30 |
|
2.13(10) |
2.39(10) |
2.22(10) |
1.74(10) |
2.80(10) |
ANEU (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
0.92 |
1.10 |
1.10 |
1.25 |
1.04 |
|
0.56(10) |
0.90(10) |
0.50(10) |
0.78(10) |
0.35(10) |
ALYM (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
7.76 |
8.43 |
7.11 |
8.11 |
7.83 |
|
1.88(10) |
2.33(10) |
2.23(10) |
1.19(10) |
2.48(10) |
AMON (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
0.17 |
0.20 |
0.18 |
0.19 |
0.19 |
|
0.05(10) |
0.12(10) |
0.10(10) |
0.06(10) |
0.07(10) |
AEOS (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
0.10 |
0.10 |
0.10 |
0.12 |
0.09 |
|
0.05(10) |
0.03(10) |
0.03(10) |
0.06(10) |
0.03(10) |
ABAS (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
0.04 |
0.06 |
0.05 |
0.04 |
0.05 |
|
0.03(10) |
0.04(10) |
0.03(10) |
0.02(10) |
0.03(10) |
ALUC (x10³/µL) |
|
|
|
|
|
DAY 96-97 |
0.10 |
0.13 |
0.09 |
0.15 |
0.11 |
|
0.05(10) |
0.08(10) |
0.03(10) |
0.09(10) |
0.05(10) |
Summary of coagulation values |
|||||
PT (sec) |
|
|
|
|
|
DAY 96-97 |
13.5 |
13.6 |
13.3 |
13.8 |
13.3 |
0.5(9) |
0.5(10) |
1.0(10) |
0.5(9) |
0.7(10) |
|
APTT (sec) |
|
|
|
|
|
DAY 96-97 |
13.8 |
14.2 |
14.0 |
13.4 |
13.3 |
0.7(9) |
2.1(10) |
1.5(10) |
1.4(9) |
1.6(10) |
|
Data summarized as: Mean Standard Deviation (n)
Statistical Analysis: Statistical significance is indicated by the following (p < 0.05):
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn's) significant
Table 15: Summary of clinical chemistry values
Male |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
AST (U/L) |
|
|
|
|
|
DAY 94-95 |
72 |
70 |
84 |
78 |
70 |
|
10(10) |
15(10) |
21(10) |
11(10) |
16(10) |
ALT (U/L) |
|
|
|
|
|
DAY 94-95 |
26 |
26 |
27 |
30 |
24 |
|
3(10) |
3(10) |
6(10) |
5(10) |
2(10) |
SDH (U/L) |
|
|
|
|
|
DAY 94-95 |
14.8 |
12.9 |
12.5 |
13.2 |
12.0 |
|
4.2(10) |
3.4(10) |
8.2(10) |
4.1(10) |
3.6(9) |
ALKP (U/L) |
|
|
|
|
|
DAY 94-95 |
84 |
88 |
76 |
82 |
74 |
|
23(10) |
16(10) |
9(10) |
20(10) |
23(10) |
BILI (mg/dL) |
|
|
|
|
|
DAY 94-95 |
0.14 |
0.13 |
0.13 |
0.14 |
0.13 |
|
0.03(10) |
0.02(10) |
0.01(10) |
0.02(10) |
0.01(10) |
BUN (mg/dL) |
|
|
|
|
|
DAY 94-95 |
13 |
14 |
13 |
13 |
13 |
|
2(10) |
2(10) |
2(10) |
2(10) |
2(10) |
CREA (mg/dL) |
|
|
|
|
|
DAY 94-95 |
0.41 |
0.40 |
0.41 |
0.41 |
0.40 |
|
0.05(10) |
0.05(10) |
0.04(10) |
0.06(10) |
0.05(10) |
CHOL (mg/dL) |
|
|
|
|
|
DAY 94-95 |
54 |
51 |
49 |
55 |
60 |
|
9(10) |
6(10) |
10(10) |
13(10) |
17(10) |
TRIG (mg/dL) |
|
|
|
|
|
DAY 94-95 |
63 |
53 |
50 |
53 |
47 |
|
20(10) |
29(10) |
11(10) |
14(10) |
14(10) |
GLUC (mg/dL) |
|
|
|
|
|
DAY 94-95 |
132 |
136 |
145 |
142 |
131 |
|
23(10) |
34(10) |
35(10) |
26(10) |
27(10) |
TP (g/dL) |
|
|
|
|
|
DAY 94-95 |
6.7 |
6.6 |
6.7 |
6.6 |
6.5 |
|
0.3(10) |
0.3(10) |
0.2(10) |
0.2(10) |
0.2(10) |
ALB (g/dL) |
|
|
|
|
|
DAY 94-95 |
3.4 |
3.3 |
3.4 |
3.3 |
3.3 |
|
0.2(10) |
0.1(10) |
0.1(10) |
0.1(10) |
0.2(10) |
GLOB (g/dL) |
|
|
|
|
|
DAY 94-95 |
3.3 |
3.2 |
3.4 |
3.3 |
3.2 |
|
0.2(10) |
0.2(10) |
0.2(10) |
0.2(10) |
0.2(10) |
CALC (mg/dL) |
|
|
|
|
|
DAY 94-95 |
10.5 |
10.6 |
10.5 |
10.5 |
10.4 |
|
0.4(10) |
0.4(10) |
0.3(10) |
0.3(10) |
0.4(10) |
IPHS (mg/dL) |
|
|
|
|
|
DAY 94-95 |
7.8 |
7.8 |
7.8 |
8.3 |
8.3 |
|
1.3(10) |
0.9(10) |
1.3(10) |
1.8(10) |
1.5(10) |
NA (mmol/L) |
|
|
|
|
|
DAY 94-95 |
144.8 |
144.3 |
144.4 |
144.5 |
144.3 |
|
1.7(10) |
1.4(10) |
1.9(10) |
1.6(10) |
1.1(10) |
K (mmol/L) |
|||||
DAY 94-95 |
5.85 |
5.85 |
5.69 |
5.57 |
6.20 |
|
0.43(10) |
0.60(10) |
0.53(10) |
0.55(10) |
0.49(10) |
CL (mmol/L) |
|
|
|
|
|
DAY 94-95 |
101.3 |
101.4 |
100.9 |
101.8 |
101.0 |
|
1.3(10) |
1.6(10) |
1.6(10) |
2.6(10) |
1.4(10) |
Female |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
AST (U/L) |
|
|
|
|
|
DAY 96-97 |
91 |
88 |
96 |
94 |
102 |
|
51(10) |
38(10) |
55(10) |
38(10) |
51(10) |
ALT (U/L) |
|
|
|
|
|
DAY 96-97 |
46 |
40 |
47 |
43 |
39 |
|
40(10) |
24(10) |
32(10) |
17(10) |
15(10) |
SDH (U/L) |
|
|
|
|
|
DAY 96-97 |
19.8 |
17.2 |
18.7 |
16.9 |
19.8 |
|
7.6(10) |
5.4(10) |
6.5(10) |
6.1(10) |
7.0(10) |
ALKP (U/L) |
|
|
|
|
|
DAY 96-97 |
51 |
54 |
59 |
59 |
46 |
|
12(10) |
13(10) |
17(10) |
24(10) |
9(10) |
BILI (mg/dL) |
|
|
|
|
|
DAY 96-97 |
0.19 |
0.20 |
0.18 |
0.19 |
0.18 |
|
0.02(10) |
0.03(10) |
0.03(10) |
0.04(10) |
0.03(10) |
BUN (mg/dL) |
|
|
|
|
|
DAY 96-97 |
15 |
15 |
16 |
15 |
15 |
|
2(10) |
2(10) |
2(10) |
2(10) |
2(10) |
CREA (mg/dL) |
|
|
|
|
|
DAY 96-97 |
0.46 |
0.44 |
0.47 |
0.45 |
0.46 |
|
0.05(10) |
0.04(10) |
0.03(10) |
0.05(10) |
0.04(10) |
CHOL (mg/dL) |
|
|
|
|
|
DAY 96-97 |
98 |
92 |
79 |
76 |
91 |
|
25(10) |
15(10) |
16(10) |
25(10) |
25(10) |
TRIG (mg/dL) |
|
|
|
|
|
DAY 96-97 |
62 |
49 |
52 |
43* |
57 |
|
16(10) |
17(10) |
13(10) |
9(10) |
22(10) |
GLUC (mg/dL) |
|
|
|
|
|
DAY 96-97 |
110 |
112 |
113 |
105 |
100 |
|
15(10) |
23(10) |
22(10) |
9(10) |
10(10) |
TP (g/dL) |
|
|
|
|
|
DAY 96-97 |
8.0 |
7.7 |
7.7 |
7.5@ |
7.8 |
|
0.4(10) |
0.4(10) |
0.4(10) |
0.4(10) |
0.6(10) |
ALB (g/dL) |
|
|
|
|
|
DAY 96-97 |
4.2 |
4.1 |
4.0 |
3.9@ |
4.1 |
|
0.3(10) |
0.3(10) |
0.3(10) |
0.2(10) |
0.4(10) |
GLOB (g/dL) |
|
|
|
|
|
DAY 96-97 |
3.7 |
3.6 |
3.7 |
3.6 |
3.7 |
|
0.2(10) |
0.2(10) |
0.2(10) |
0.2(10) |
0.2(10) |
CALC (mg/dL) |
|
|
|
|
|
DAY 96-97 |
11.2 |
11.0 |
10.9 |
10.6* |
11.0 |
|
0.5(10) |
0.4(10) |
0.2(10) |
0.3(10) |
0.5(10) |
IPHS (mg/dL) |
|
|
|
|
|
DAY 96-97 |
5.9 |
5.5 |
5.2 |
5.2 |
5.0 |
|
1.7(10) |
1.0(10) |
0.9(10) |
1.0(10) |
0.6(10) |
NA (mmol/L) |
|
|
|
|
|
DAY 96-97 |
144.9 |
144.6 |
144.0 |
144.4 |
144.8 |
|
1.5(10) |
2.1(10) |
1.6(10) |
1.3(10) |
2.0(10) |
K (mmol/L) |
|||||
DAY 96-97 |
5.67 |
5.40 |
5.60 |
5.50 |
5.44 |
|
0.46(10) |
0.29(10) |
0.38(10) |
0.44(10) |
0.41(10) |
CL (mmol/L) |
|
|
|
|
|
DAY 96-97 |
99.8 |
99.4 |
99.2 |
99.4 |
99.5 |
|
2.1(10) |
1.6(10) |
1.6(10) |
2.0(10) |
2.9(10) |
Data summarized as: Mean Standard Deviation (n)
Statistical Analysis: Statistical significance is indicated by the following (p < 0.05):
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric
Table 16 : Summary of urinalysis values
Male |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
UVOL (mL) |
|
|
|
|
|
DAY 94-95 |
12.0 |
9.7 |
10.2 |
8.3 |
6.2@ |
6.1(10) |
6.4(10) |
4.9(10) |
5.6(10) |
3.7(10) |
|
UOSM (mOsm/kg) |
|
|
|
|
|
DAY 94-95 |
1276 |
1552 |
1168 |
1728 |
1693 |
1163(10) |
1079(10) |
479(10) |
997(10) |
791(10) |
|
pH |
|
|
|
|
|
DAY 94-95 |
6.7 |
6.6 |
7.0 |
6.5 |
6.5 |
0.3(10) |
0.3(10) |
0.3(10) |
0.4(10) |
0.3(10) |
|
URO (EU/dL) |
|
|
|
|
|
DAY 94-95 |
0.2 |
0.4 |
0.2 |
0.4 |
0.3 |
0.0(10) |
0.3(10) |
0.0(10) |
0.4(10) |
0.3(10) |
|
UMTP (mg/dL) |
|
|
|
|
|
DAY 94-95 |
107 |
81 |
67 |
89 |
85 |
121(10) |
60(10) |
29(10) |
55(10) |
31(10) |
|
Female |
|
|
|
|
|
Groups Concentration (ppm) |
Control |
600 |
2000 |
6000 |
18000 |
UVOL (mL) |
|
|
|
|
|
DAY 96-97 |
5.7 |
6.8 |
6.5 |
7.7 |
4.3 |
|
2.3(10) |
4.2(10) |
4.2(10) |
3.9(10) |
2.4(9) |
UOSM (mOsm/kg) |
|
|
|
|
|
DAY 96-97 |
1211 |
1375 |
1175 |
1140 |
1860 |
|
767(10) |
974(10) |
477(10) |
1177(10) |
1627(9) |
pH |
|
|
|
|
|
DAY 96-97 |
6.8 |
6.6 |
6.5 |
6.9 |
6.2@ |
|
0.4(10) |
0.5(10) |
0.4(10) |
0.6(10) |
0.3(9) |
URO (EU/dL) |
|
|
|
|
|
DAY 96-97 |
0.2 |
0.2 |
0.2 |
0.2 |
0.2 |
|
0.0(10) |
0.0(10) |
0.0(10) |
0.0(10) |
0.0(9) |
UMTP (mg/dL) |
|
|
|
|
|
DAY 96-97 |
19 |
19 |
17 |
47 |
27 |
|
15(10) |
14(10) |
11(10) |
95(10) |
25(9) |
Data summarized as: Mean Standard Deviation (n)
Statistical Analysis: Statistical significance is indicated by the following (p < 0.05):
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn's) significant
Table 17: Summary of organ weight values
MALES |
|||||
Groups Concentration (ppm)
|
0 |
600 |
2000 |
6000 |
18000 |
Mean final body weight and absolute organ weights (g) |
|||||
Final body weight |
565 |
556 |
567 |
568 |
509* |
|
55(9) |
42(10) |
35(10) |
62(10) |
35(10) |
Adrenal glands |
0.060 |
0.060 |
0.063 |
0.064 |
0.060 |
|
0.009(9) |
0.012(10) |
0.013(10) |
0.012(10) |
0.010(10) |
Brain |
2.164 |
2.164 |
2.185 |
2.173 |
2.125 |
|
0.067(9) |
0.121(10) |
0.075(10) |
0.085(10) |
0.073(10) |
Epididymides |
1.633 |
1.569 |
1.654 |
1.600 |
1.623 |
|
0.116(9) |
0.187(10) |
0.215(10) |
0.133(10) |
0.150(10) |
Heart |
1.792 |
1.753 |
1.744 |
1.787 |
1.601* |
|
0.148(9) |
0.147(10) |
0.178(10) |
0.201(10) |
0.113(10) |
Kidneys |
4.218 |
4.109 |
4.186 |
4.146 |
4.012 |
|
0.555(9) |
0.415(10) |
0.349(10) |
0.405(10) |
0.193(10) |
Liver |
14.992 |
14.991 |
15.100 |
15.226 |
12.865* |
|
1.433(9) |
1.839(10) |
1.376(10) |
1.802(10) |
0.839(10) |
Spleen |
0.896 |
0.854 |
0.871 |
0.880 |
0.780 |
|
0.163(9) |
0.149(10) |
0.074(10) |
0.099(10) |
0.096(10) |
Testes |
3.735 |
3.484 |
3.552 |
3.553 |
3.512 |
|
0.330(9) |
0.302(10) |
0.240(10) |
0.361(10) |
0.243(10) |
Thymus |
0.299 |
0.359 |
0.346 |
0.370 |
0.270 |
|
0.058(9) |
0.133(10) |
0.081(10) |
0.094(10) |
0.072(10) |
Mean relative organ weight (% of brain weight) |
|||||
Adrenal glands/ brain * 100 |
2.780 |
2.765 |
2.891 |
2.950 |
2.802 |
|
0.414(9) |
0.587(10) |
0.623(10) |
0.528(10) |
0.447(10) |
Epididymides/ brain * 100 |
75.601 |
72.377 |
75.794 |
73.708 |
76.498 |
|
6.756(9) |
6.128(10) |
10.315(10) |
6.211(10) |
7.671(10) |
Heart/ brain * 100 |
82.835 |
81.166 |
79.826 |
82.347 |
75.480 |
|
6.639(9) |
7.342(10) |
8.029(10) |
9.590(10) |
6.747(10) |
Kidneys/ brain * 100 |
194.760 |
189.998 |
191.839 |
190.738 |
188.992 |
|
23.783(9) |
16.345(10) |
18.312(10) |
16.191(10) |
10.279(10) |
Liver/ brain * 100 |
691.668 |
693.084 |
691.514 |
701.519 |
606.506* |
|
50.435(9) |
77.623(10) |
63.465(10) |
85.394(10) |
49.654(10) |
Spleen/ brain * 100 |
41.318 |
39.697 |
39.874 |
40.504 |
36.810 |
|
6.825(9) |
7.907(10) |
3.292(10) |
4.386(10) |
5.222(10) |
Testes/ brain * 100 |
172.749 |
161.169 |
162.633 |
163.641 |
165.368 |
|
16.499(9) |
12.615(10) |
11.079(10) |
16.434(10) |
10.550(10) |
Thymus/ brain * 100 |
13.784 |
16.519 |
15.862 |
17.036 |
12.727 |
|
2.566(9) |
5.800(10) |
3.787(10) |
4.467(10) |
3.572(10) |
Mean relative organ weight (% of body weight) |
|||||
Adrenal glands/ final body * 100 |
0.011 |
0.011 |
0.011 |
0.011 |
0.012 |
|
0.002(9) |
0.002(10) |
0.002(10) |
0.002(10) |
0.002(10) |
Brain/ Final body * 100 |
0.386 |
0.391 |
0.387 |
0.386 |
0.419 |
|
0.032(9) |
0.033(10) |
0.024(10) |
0.037(10) |
0.035(10) |
Epididymides/ final body * 100 |
0.292 |
0.283 |
0.292 |
0.284 |
0.321 |
|
0.038(9) |
0.034(10) |
0.037(10) |
0.038(10) |
0.042(10) |
Heart/ final body * 100 Final body * 100 |
0.318 |
0.316 |
0.307 |
0.316 |
0.315 |
|
0.020(9) |
0.020(10) |
0.021(10) |
0.035(10) |
0.018(10) |
Kidneys/ final body * 100 Final body * 100 |
0.746 |
0.741 |
0.739 |
0.732 |
0.791 |
|
0.056(9) |
0.065(10) |
0.059(10) |
0.051(10) |
0.054(10) |
Liver/ final body * 100 Final body * 100 |
2.657 |
2.694 |
2.664 |
2.682 |
2.529 |
|
0.152(9) |
0.195(10) |
0.175(10) |
0.177(10) |
0.084(10) |
Spleen/ final body * 100 Final body * 100 |
0.159 |
0.153 |
0.154 |
0.156 |
0.153 |
|
0.024(9) |
0.021(10) |
0.009(10) |
0.019(10) |
0.017(10) |
Testes/ final body * 100 Final body * 100 |
0.664 |
0.629 |
0.628 |
0.631 |
0.693 |
|
0.065(9) |
0.061(10) |
0.045(10) |
0.081(10) |
0.065(10) |
Thymus/ final body * 100 Final body * 100 |
0.053 |
0.065 |
0.061 |
0.066 |
0.053 |
|
0.007(9) |
0.024(10) |
0.013(10) |
0.018(10) |
0.012(10) |
Feales |
|
|
|
|
|
Groups Concentration (ppm)
|
0 |
600 |
2000 |
6000 |
18000 |
Mean final body weight and absolute organ weights (g) |
|
|
|
|
|
Final body weight |
285 |
283 |
291 |
269 |
262 |
|
30(10) |
22(10) |
38(10) |
22(9) |
19(10) |
Adrenal glands |
0.066 |
0.069 |
0.071 |
0.062 |
0.068 |
|
0.010(10) |
0.010(10) |
0.014(10) |
0.015(9) |
0.013(10) |
Brain |
1.971 |
1.956 |
1.961 |
1.957 |
1.907 |
|
0.086(10) |
0.052(10) |
0.099(10) |
0.087(9) |
0.075(10) |
Heart |
1.097 |
1.118 |
1.101 |
0.994 |
1.026 |
|
0.167(10) |
0.154(10) |
0.129(10) |
0.068(9) |
0.080(10) |
Kidneys |
2.104 |
2.053 |
2.053 |
1.980 |
2.056 |
|
0.279(10) |
0.157(10) |
0.232(10) |
0.237(9) |
0.186(10) |
Liver |
8.006 |
7.784 |
7.857 |
7.306 |
7.459 |
|
0.837(10) |
0.672(10) |
0.899(10) |
0.590(9) |
0.779(10) |
Ovaries |
0.124 |
0.127 |
0.137 |
0.118 |
0.142 |
|
0.028(10) |
0.029(10) |
0.022(10) |
0.022(9) |
0.056(10) |
Spleen |
0.520 |
0.571 |
0.566 |
0.548 |
0.531 |
|
0.042(10) |
0.093(10) |
0.081(10) |
0.039(9) |
0.078(10) |
Thymus |
0.268 |
0.298 |
0.257 |
0.271 |
0.261 |
|
0.059(10) |
0.068(10) |
0.067(10) |
0.066(9) |
0.057(10) |
Uterus |
0.720 |
0.697 |
0.666 |
0.709 |
0.698 |
|
0.186(10) |
0.233(10) |
0.219(10) |
0.196(9) |
0.182(10) |
Mean relative organ weight (% of brain weight) |
|||||
Adrenal glands/ brain * 100 |
3.366 |
3.542 |
3.633 |
3.197 |
3.551 |
|
0.514(10) |
0.533(10) |
0.746(10) |
0.825(9) |
0.658(10) |
Heart/ brain * 100 |
55.717 |
57.198 |
56.201 |
50.900 |
53.898 |
|
8.439(10) |
8.008(10) |
6.274(10) |
4.226(9) |
4.775(10) |
Kidneys/ brain * 100 |
106.548 |
105.078 |
104.856 |
101.386 |
107.740 |
|
11.471(10) |
9.205(10) |
11.605(10) |
12.737(9) |
7.858(10) |
Liver/ brain * 100 |
405.992 |
398.564 |
402.451 |
373.319 |
391.640 |
|
36.623(10) |
39.299(10) |
55.286(10) |
23.693(9) |
43.691(10) |
Ovaries/ brain * 100 |
6.272 |
6.476 |
6.982 |
6.008 |
7.453 |
|
1.377(10) |
1.520(10) |
1.145(10) |
0.963(9) |
3.074(10) |
Spleen/ brain * 100 |
26.404 |
29.161 |
28.966 |
28.071 |
27.851 |
|
2.479(10) |
4.486(10) |
4.650(10) |
2.381(9) |
4.180(10) |
Thymus/ brain * 100 |
13.618 |
15.240 |
13.138 |
13.822 |
13.673 |
|
2.948(10) |
3.387(10) |
3.327(10) |
3.091(9) |
2.684(10) |
Uterus/ brain * 100 |
36.604 |
35.559 |
34.009 |
36.328 |
36.585 |
|
9.742(10) |
11.690(10) |
11.128(10) |
10.018(9) |
9.381(10) |
Mean relative organ weight (% of body weight) |
|||||
Adrenal glands/ final body * 100 |
0.024 |
0.025 |
0.024 |
0.024 |
0.026 |
|
0.005(10) |
0.004(10) |
0.004(10) |
0.007(9) |
0.005(10) |
Brain/ final body * 100 Final body * 100 |
0.698 |
0.694 |
0.686 |
0.732 |
0.731 |
|
0.063(10) |
0.055(10) |
0.120(10) |
0.062(9) |
0.054(10) |
Heart/ final body * 100 Final body * 100 |
0.386 |
0.395 |
0.380 |
0.371 |
0.392 |
|
0.043(10) |
0.045(10) |
0.036(10) |
0.023(9) |
0.020(10) |
Kidneys/ final body * 100 Final body * 100 |
0.741 |
0.726 |
0.709 |
0.740 |
0.786 |
|
0.088(10) |
0.044(10) |
0.062(10) |
0.092(9) |
0.050(10) |
Liver/ final body * 100 Final body * 100 |
2.815 |
2.755 |
2.705 |
2.738 |
2.852 |
|
0.182(10) |
0.234(10) |
0.125(10) |
0.343(9) |
0.261(10) |
Ovaries/ final body * 100 Final body * 100 |
0.043 |
0.045 |
0.048 |
0.044 |
0.054 |
|
0.009(10) |
0.011(10) |
0.010(10) |
0.008(9) |
0.020(10) |
Spleen/ final body * 100 Final body * 100 |
0.184 |
0.202 |
0.196 |
0.205 |
0.202 |
|
0.020(10) |
0.028(10) |
0.025(10) |
0.022(9) |
0.025(10) |
Thymus/ final body * 100 Final body * 100 |
0.094 |
0.105 |
0.088 |
0.102 |
0.099 |
|
0.016(10) |
0.022(10) |
0.016(10) |
0.029(9) |
0.016(10) |
Uterus/ final body * 100 Final body * 100 |
0.255 |
0.245 |
0.232 |
0.266 |
0.270 |
|
0.076(10) |
0.075(10) |
0.083(10) |
0.080(9) |
0.086(10) |
Data summarized as: Mean Standard Deviation (n)
Statistical Analysis: Statistical significance is indicated by the following (p < 0.05):
* Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant
@ Nonparametric comparison to control (Dunn's) significant
Table 18: Selected incidences of gross observations in males and females
Groups Concentration (ppm) |
Sex |
0 |
600 |
2000 |
6000 |
18000 |
Pancreas |
m |
|
|
|
|
|
no visible lesion |
|
10 |
10 |
10 |
10 |
9 |
discoloration |
|
0 |
0 |
0 |
0 |
1 |
Eye(s) |
f |
|
|
|
|
|
no visible lesion |
|
9 |
9 |
10 |
10 |
10 |
discoloration |
|
0 |
1 |
0 |
0 |
0 |
rupture |
|
1 |
0 |
0 |
0 |
0 |
Kidneys |
f |
|
|
|
|
|
no visible lesion |
|
10 |
10 |
10 |
9 |
10 |
dilatation |
|
0 |
0 |
0 |
1 |
0 |
No further visible lesions observed in males and females at any concentrations |
||||||
Table 19: Selected incidences of microscopic findings (neoplastic and non-neoplastic lesions)
Groups Concentration (ppm) |
Sex |
0 |
600 |
2000 |
6000 |
18000 |
Bone marrow |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
10 |
necrosis, focal |
|
1 |
0 |
0 |
0 |
0 |
Cecum |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
6 |
0 |
0 |
0 |
6 |
inflammation, mucosal |
|
4 |
0 |
0 |
0 |
4 |
Colon |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
10 |
inflammation, mucosal |
|
1 |
0 |
0 |
0 |
0 |
Eye(s) |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
8 |
fold/rosette, retinal |
|
1 |
0 |
0 |
0 |
2 |
Heart |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
5 |
0 |
0 |
0 |
5 |
cardiomyopathy |
|
4 |
0 |
0 |
0 |
5 |
fibrosis, endocardial, focal/multifocal |
|
1 |
0 |
0 |
0 |
0 |
Kidneys |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
6 |
0 |
0 |
0 |
2 |
chronic progressive nephropathy |
|
4 |
0 |
0 |
0 |
7 |
aggregates, lymphoid |
|
0 |
0 |
0 |
0 |
1 |
hydronephrosis, unilateral |
|
1 |
0 |
0 |
0 |
0 |
hyaline droplets |
|
1 |
0 |
0 |
0 |
0 |
Spleen |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
2 |
0 |
0 |
0 |
2 |
inflammation, subacute to chronic |
|
7 |
0 |
0 |
0 |
8 |
fatty change, median cleft |
|
3 |
0 |
0 |
0 |
1 |
fatty change, periportal |
|
1 |
0 |
0 |
0 |
0 |
Lungs |
|
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
0 |
0 |
0 |
0 |
8 |
inflammation, alveolar |
|
0 |
0 |
0 |
0 |
2 |
Mandibular lymph node |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
9 |
hyperplasia, lymphoid |
|
0 |
0 |
0 |
0 |
1 |
hyperplasia, plasma cell |
|
1 |
0 |
0 |
0 |
0 |
Mesenteric lymph node |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
0 |
0 |
0 |
0 |
9 |
erythrocytosis/hemosiderosis, sinus |
|
0 |
0 |
0 |
0 |
1 |
Nose |
|
|
|
|
|
|
examined |
m |
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
9 |
odontodysplasia; bilateral |
|
1 |
0 |
0 |
0 |
1 |
inflammation, teeth |
|
1 |
0 |
0 |
0 |
0 |
erosion/ulcer, oral mucosa |
|
1 |
0 |
0 |
0 |
1 |
Optic nerve |
m |
|
|
|
|
|
examined |
|
(9) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
0 |
not examined, missing |
|
1 |
0 |
0 |
0 |
0 |
Pancreas |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
9 |
atrophy, lobular |
|
1 |
0 |
0 |
0 |
1 |
Parathyroid glands |
m |
|
|
|
|
|
examined |
|
(9) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
0 |
not examined: missing |
|
1 |
0 |
0 |
0 |
0 |
Pituitary gland |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
0 |
cyst |
|
1 |
0 |
0 |
0 |
0 |
Prostate |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
3 |
0 |
0 |
0 |
3 |
aggregates, lymphoid |
|
7 |
0 |
0 |
0 |
7 |
Skeletal muscle |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
0 |
0 |
0 |
0 |
9 |
Inflammation, subacute to chronic |
|
0 |
0 |
0 |
0 |
1 |
Thymus |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
0 |
hyperplasia, epithelial |
|
1 |
0 |
0 |
0 |
0 |
Thyroid gland |
m |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(10) |
within normal limits |
|
9 |
0 |
0 |
0 |
0 |
hypertrophy, follicular cell |
|
1 |
0 |
0 |
0 |
0 |
|
|
|
|
|
|
|
FEMALES |
|
|
|
|
|
|
Cecum |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
8 |
0 |
0 |
1 |
8 |
inflammation, mucosal |
|
8 |
0 |
0 |
0 |
2 |
Eye(s) |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
8 |
0 |
0 |
1 |
10 |
fold/rosette, retinal |
|
1 |
0 |
0 |
0 |
0 |
Ruptured (iatrogenic), unilateral |
|
1 |
|
|
|
0 |
Heart |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1 |
(10) |
within normal limits |
|
10 |
0 |
0 |
0 |
9 |
cardiomyopathy |
|
0 |
0 |
0 |
1 |
1 |
Kidneys |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
10 |
0 |
0 |
1 |
8 |
chronic progressive nephropathy |
|
0 |
0 |
0 |
0 |
2 |
dilated tubules, medullary |
|
0 |
0 |
0 |
0 |
1 |
Spleen |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
5 |
0 |
0 |
1 |
4 |
inflammation, subacute to chronic |
|
4 |
0 |
0 |
0 |
5 |
fatty change, median cleft |
|
1 |
0 |
0 |
0 |
2 |
necrosis, focal |
|
0 |
0 |
0 |
0 |
2 |
Mandibular lymph node |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
5 |
0 |
0 |
1 |
6 |
hyperplasia, lymphoid |
|
2 |
0 |
0 |
0 |
1 |
hyperplasia, plasma cell |
|
1 |
0 |
0 |
0 |
0 |
erythrocytosis/hemosiderosis, sinus |
|
3 |
0 |
0 |
0 |
3 |
Mesenteric lymph node |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
8 |
0 |
0 |
1 |
9 |
erythrocytosis/hemosiderosis, sinus |
|
1 |
0 |
0 |
0 |
0 |
hyperplasia, lymphoid |
|
1 |
0 |
0 |
|
1 |
Nose |
|
|
|
|
|
|
examined |
f |
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
10 |
erosion/ulcer, oral mucosa |
|
1 |
0 |
0 |
0 |
0 |
Ovaries |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
8 |
corpora lutea decreased |
|
1 |
0 |
0 |
0 |
1 |
cyst, unilateral |
|
0 |
0 |
0 |
0 |
0 |
Pancreas |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
10 |
0 |
0 |
1 |
9 |
atrophy, lobular |
|
0 |
0 |
0 |
0 |
1 |
Parathyroid glands |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(0) |
(8) |
within normal limits |
|
10 |
0 |
0 |
0 |
8 |
not examined: missing |
|
0 |
0 |
0 |
0 |
2 |
Peyers patch |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(9) |
within normal limits |
|
10 |
0 |
0 |
1 |
8 |
not examined: missing |
|
0 |
0 |
0 |
0 |
1 |
mineralization |
|
0 |
0 |
0 |
0 |
1 |
Sciatic nerve |
f |
|
|
|
|
|
examined |
|
(9) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
10 |
not examined: missing |
|
1 |
0 |
0 |
0 |
0 |
Skeletal muscle |
f |
|
|
|
|
|
examined |
|
(9) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
10 |
not examined: missing |
|
1 |
0 |
0 |
0 |
0 |
Spleen |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
10 |
0 |
0 |
1 |
9 |
aggregates, macrophage |
|
0 |
0 |
0 |
0 |
1 |
Thymus |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
9 |
hyperplasia, epithelial |
|
1 |
0 |
0 |
0 |
1 |
Thyroid gland |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
9 |
0 |
0 |
1 |
10 |
cyst, ultimobranchial |
|
1 |
0 |
0 |
0 |
0 |
Urinary bladder |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
8 |
0 |
0 |
1 |
10 |
aggregates, lymphoid |
|
2 |
0 |
0 |
0 |
0 |
Vagina |
f |
|
|
|
|
|
examined |
|
(10) |
(0) |
(0) |
(1) |
(10) |
within normal limits |
|
0 |
0 |
0 |
0 |
0 |
Estrus stage: metestrus |
|
3 |
0 |
0 |
0 |
4 |
Estrus stage: estrus |
|
5 |
0 |
0 |
0 |
5 |
Estrus stage: proestrus |
|
2 |
0 |
0 |
1 |
1 |
No further visible lesions observed in males and females at any concentrations |
||||||
Table 20: Mean forelimb and hindlimb grip strength, footsplay, body temperature, and rearing
Males |
|
|
|||||
Group |
Concentration (ppm) |
Number |
Forelimb grip strength (kg)
|
Hindlimb grip strength (kg) |
Footsplay (cm) |
Body temperature (ºC) |
Rearing (number) |
Baseline |
|
|
|
|
|
|
|
1 |
0 |
10 |
0.81 (0.18) |
0.34 (0.06) |
6.0 (1.4) |
36.4 (0.8) |
5 |
2 |
600 |
10 |
0.81 (0.11) |
0.33 (0.03) |
6.9 (1.6) |
36.2(0.6) |
4 |
3 |
2000 |
10 |
0.86 (0.15) |
0.38 (0.06) |
6.9 (1.7) |
36.2 (0.6) |
5 |
4 |
6000 |
10 |
0.78 (0.13) |
0.37 (0.07) |
6.9 (18) |
36.1(0.5) |
5 |
5 |
18,000 |
10 |
0.85 (0.12) |
0.34 (0.06) |
6.4 (1.8) |
35.9 (0.7) |
3 |
Week 4 |
|
|
|
|
|
|
|
1 |
0 |
10 |
1.26 (0.27) |
0.35 (0.05) |
7.3 (2.6) |
35.5 (1.0) |
4 |
2 |
600 |
10 |
1.17 (0.15) |
0.39(0.09) |
8.4 (2.0) |
35.6 (1.1) |
4 |
3 |
2000 |
10 |
1.17(0.23) |
0.38 (0.07) |
7.1 (2.3) |
35.8 (0.9) |
3 |
4 |
6000 |
10 |
1.18 (0.12) |
0.37 (0.05) |
8.0 (1.8 |
36.0 (1.0) |
3 |
5 |
18,000 |
10 |
1.18 (0.08) |
0.40 (0.09) |
6.9 (1.6) |
35.4 (1.0) |
4 |
Week 8 1 |
0 |
10 |
1.10 (0.21) |
0.45 (0.06) |
7.3 (2.8) |
34.8 (0.6) |
4 |
2 |
600 |
10 |
1.12 (0.14) |
0.41 (0.10) |
8.0 (1.3) |
35.1 (0.8) |
6 |
3 |
2000 |
10 |
1.19 (0.23) |
0.40 (0.10) |
7.1 (2.2) |
35.0 (0.5) |
4 |
4 |
6000 |
10 |
1.20 (0.13) |
0.46 (0.14) |
8.6 (1.5) |
34.8 (0.4) |
4 |
5 |
18,000 |
10 |
1.22 (0.16) |
0.42 (0.07) |
7.0 (2.1) |
34.9 (0.5) |
3 |
WEEK 13 |
|
|
|
|
|
|
|
1 |
0 |
10 |
0.93 (0.23) |
0.40 (0.06) |
7.4 (2.4) |
35.9 (0.9) |
4 |
2 |
600 |
10 |
1.06 (0.19) |
0.45 (0.06) |
7.9 (2.1) |
35.5 (0.6) |
4 |
3 |
2000 |
10 |
1.06 (0.24) |
0.50 (0.07) |
7.7 (1.9) |
36.0 (0.9) |
3 |
4 |
6000 |
10 |
1.15 (0.17) |
0.45 (0.10) |
8.3 (2.4) |
35.7 (0.8) |
3 |
5 |
18,000 |
10 |
1.05 (0.15) |
0.41 (0.06) |
7.9 (2.1) |
35.8 (0.9) |
3 |
Females |
|
|
|
|
|
|
|
Baseline |
|
|
|
|
|
|
|
1 |
0 |
10 |
0.74 (0.18) |
0.36 (0.08) |
5.4 (1.8) |
36.6 (1.0) |
6 |
2 |
600 |
10 |
0.74 (0.17) |
0.34 (0.07) |
5.2 (2.1) |
36.2(1.0) |
5 |
3 |
2000 |
10 |
0.77 (0.14) |
0.34 (0.10) |
6.4 (2.1) |
36.7 (0.5) |
6 |
4 |
6000 |
10 |
0.74 (0.21) |
0.32 (0.06) |
5.5 (1.5) |
36.4(1.0) |
6 |
5 |
18,000 |
10 |
0.72(0.11) |
0.30 (0.04) |
6.3 (1.4) |
36.3 (0.4) |
6 |
Week 4 |
|
|
|
|
|
|
|
1 |
0 |
10 |
1.02 (0.18) |
0.36 (0.08) |
5.6 (1.7) |
36.2 (0.4) |
8 |
2 |
600 |
10 |
0.93 (0.20) |
0.34(0.04) |
6.1 (2.1) |
35.7 (0.5) |
7 |
3 |
2000 |
10 |
0.94 (0.16) |
0.35 (0.08) |
6.4 (2.3) |
35.8 (1.1) |
6 |
4 |
6000 |
10 |
0.99 (0.16) |
0.39 (0.09) |
5.6 (1.4) |
36.2 (0.8) |
7 |
5 |
18,000 |
10 |
0.93 (0.18) |
0.37 (0.08) |
5.8 (2.2) |
36.1(1.0) |
7 |
WEEK 8 |
|
|
|
|
|
|
|
1 |
0 |
10 |
0.96 (0.26) |
0.34 (0.08) |
5.3 (1.8) |
35.7 (0.4) |
10 |
2 |
600 |
10 |
0.92 (0.20) |
0.39 (0.08) |
5.2 (1.5) |
35.8 (0.4) |
8 |
3 |
2000 |
10 |
0.93 (0.18) |
0.38 (0.08) |
6.5 (2.7) |
36.0 (0.6) |
8 |
4 |
6000 |
10 |
0.94 (0.11) |
0.40 (0.07) |
5.6 (1.3) |
35.8 (0.4) |
9 |
5 |
18,000 |
10 |
0.96 (0.19) |
0.37 (0.10) |
6.0 (2.3) |
35.7 (0.4) |
8 |
Week 13
|
|
|
|
|
|
|
|
1 |
0 |
10 |
0.72 (0.21) |
0.37 (0.11) |
5.8 (1.7) |
37.3 (1.0) |
10 |
2 |
600 |
10 |
0.70 (0.16) |
0.36 (0.07) |
6.0 (1.8) |
37.3 (1.0) |
8 |
3 |
2000 |
10 |
0.84 (0.26) |
0.39 (0.08) |
6.4 (2.4) |
36.9 (1.1) |
7 |
4 |
6000 |
10 |
0.80 (0.22) |
0.37 (0.09) |
5.8 (1.2) |
36.5 (1.4) |
9 |
5 |
18,000 |
10 |
0.82 (0.25) |
0.39 (0.08) |
6.9 (1.8) |
36.5 (0.9)# |
8 |
Data arranged as: Mean (Standard Deviation).
# Statistically significant trend compared to the control at p < 0.05 by Jonckheere-Terpstra trend test.
Table 21: Summary of selected functional observational battery findings
Males |
Baseline |
Week 4 |
Week 8 |
Week 13 |
||||||||||||||||
Concentration |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
Number examined |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Home cage - Posture |
||||||||||||||||||||
Limbs spread out or lying on one side |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Curled up |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Sitting, standing or rearing normally, alert |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Jumping |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Removal from cage: |
||||||||||||||||||||
Ease of removal: |
||||||||||||||||||||
Too easy (rat sits quietly, no resistance) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Some resistance (rears, follows observer's hand) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Difficult (runs around cage, may attack) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Ease of handling: |
||||||||||||||||||||
Too easy |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Easy (alert, limbs pulled up against body) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Difficult |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Arousal: |
||||||||||||||||||||
Very low (stupor, little or no responsiveness) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Low |
0 |
1 |
2 |
1 |
2 |
1 |
2 |
3 |
2 |
2 |
0 |
0 |
0 |
1 |
2 |
1 |
3 |
1 |
2 |
0 |
Normal (alert, exploratory movements) |
10 |
9 |
8 |
9 |
8 |
9 |
8 |
7 |
7 |
8 |
10 |
10 |
10 |
9 |
8 |
9 |
7 |
9 |
8 |
10 |
High (slight excitement, tense, sudden movements) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Manipulations: |
||||||||||||||||||||
Approach & touch: |
||||||||||||||||||||
No reaction |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Normal |
10 |
10 |
8 |
10 |
8 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Increased reaction (jumps away or attacks) |
0 |
0 |
2 |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Tail pinch: |
||||||||||||||||||||
no response |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
normal |
10 |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
exaggerate response |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Auditory stimulus:
|
||||||||||||||||||||
No reaction |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Normal reaction(rat flinches or flicks ear) |
10 |
10 |
10 |
10 |
8 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Exaggerated reaction (rat jumps, flips) |
0 |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Posture: |
||||||||||||||||||||
normal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
abnormal |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
1 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Gait/coordinations |
||||||||||||||||||||
normal |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
unbalance, swaying, uncoordinated |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
ataxic |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
unable to move |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Additional observations: |
||||||||||||||||||||
Waddling |
||||||||||||||||||||
absent |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
High posture |
||||||||||||||||||||
absent |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Females |
||||||||||||||||||||
Baseline |
Week 4 |
Week 8 |
Week 13 |
|||||||||||||||||
Concentration |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
control |
600 |
2000 |
6000 |
18000 |
Number examined |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Home Cage - Posture |
||||||||||||||||||||
Limbs spread out or lying on one side |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Curled up |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Sitting, standing or rearing normally, alert |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Jumping |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Removal from cage: |
||||||||||||||||||||
Ease of removal: |
||||||||||||||||||||
Too easy |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Some resistance |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Difficult |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Ease of handling: |
||||||||||||||||||||
Too easy |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Easy (alert, limbs pulled up against body) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Difficult |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Posture: |
||||||||||||||||||||
normal |
0 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
8 |
8 |
0 |
0 |
0 |
0 |
0 |
9 |
0 |
8 |
9 |
0 |
abnormal |
10 |
10 |
10 |
10 |
10 |
1 |
10 |
10 |
2 |
2 |
10 |
10 |
10 |
10 |
10 |
1 |
10 |
2 |
1 |
10 |
Arousal: |
||||||||||||||||||||
Very low (stupor, little or no responsiveness) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Low |
0 |
0 |
1 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
1 |
0 |
1 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Normal |
10 |
10 |
9 |
9 |
10 |
6 |
10 |
8 |
8 |
9 |
8 |
10 |
8 |
8 |
9 |
8 |
9 |
8 |
9 |
10 |
High (slight excitement, tense, sudden movements) |
0 |
0 |
0 |
1 |
0 |
3 |
0 |
1 |
2 |
1 |
1 |
0 |
1 |
2 |
1 |
2 |
1 |
1 |
1 |
0 |
Manipulations: |
||||||||||||||||||||
Approach & touch: |
||||||||||||||||||||
No reaction |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Normal |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Increased reaction (jumps away or attacks) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Auditory stimulus:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
No reaction |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Normal reaction(rat flinches or flicks ear) |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Exaggerated reaction (rat jumps, flips) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Tail pinch: |
||||||||||||||||||||
no response |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
normal |
10 |
9 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
exaggerate response |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Additional observations: |
||||||||||||||||||||
Ear twitch |
||||||||||||||||||||
absent |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
8 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Extra digit left hindlimb: |
||||||||||||||||||||
absent |
0 |
0 |
0 |
0 |
0 |
10 |
9 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
High posture: |
||||||||||||||||||||
absent |
0 |
0 |
0 |
0 |
0 |
9 |
10 |
10 |
8 |
8 |
0 |
0 |
10 |
10 |
10 |
10 |
0 |
8 |
9 |
10 |
present |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
2 |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
1 |
0 |
Corneal opacity – left eye: |
||||||||||||||||||||
absent |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
0 |
9 |
0 |
0 |
0 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Bent tail |
||||||||||||||||||||
absent |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
10 |
10 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
9 |
0 |
present |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
Table 22: Motor activity assessment: mean number of movements
Male |
||||||||||||||||
Group |
Concentration |
Successive 10 minute intervals |
||||||||||||||
|
ppm |
N |
1 |
|
2 |
|
3 |
|
4 |
|
5 |
|
6 |
|
Total |
|
Baseline |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
136 |
(18) |
137 |
(17) |
110 |
(28) |
72 |
(44) |
45 |
(64) |
29 |
(40) |
529 |
(150) |
2 |
600 |
10 |
122 |
(18) |
117 |
(43) |
8 8 |
(43) |
40 |
(51) |
13 |
(17) |
17 |
(33) |
396 |
(108) |
3 |
2000 |
10 |
123 |
(20) |
126 |
(25) |
120 |
(23) |
88 |
(51) |
45 |
(54) |
23 |
(47) |
525 |
(148 |
4 |
6000 |
10 |
131 |
(19) |
133 |
(25) |
104 |
(42) |
55 |
(37) |
8 |
(6) |
10 |
(8) |
441 |
(86) |
5 |
18,000 |
10 |
143 |
(11) |
142 |
(17) |
107 |
(49) |
71 |
(50) |
41 |
(60) |
22 |
(45) |
526 |
(175) |
Week 4 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
130 |
(12) |
133 |
(17) |
117 |
(23) |
112 |
(28) |
102 |
(41) |
96 |
(47) |
689 |
(93) |
2 |
600 |
10 |
118 |
(17) |
127 |
(8) |
119 |
(28) |
113 |
(31) |
114 |
(42) |
86 |
(50) |
676 |
(106 |
3 |
2000 |
10 |
124 |
(15) |
128 |
(14) |
121 |
(19) |
126 |
(25) |
121 |
(46) |
107 |
(48) |
725 |
(134) |
4 |
6000 |
10 |
43 |
(15) |
137 |
(17) |
137 |
(21) |
130 |
(8) |
107 |
(45) |
86 |
(48) |
740 |
(110) |
5 |
18,000 |
10 |
146 |
(18) |
133 |
(25) |
119 |
(34) |
98 |
(61) |
63 |
(65) |
68 |
63) |
627 |
(224) |
Week 8 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
132 |
(14) |
131 |
(25) |
121 |
35) |
114 |
(25) |
106 |
(20) |
99 |
(36) |
702 |
(87) |
2 |
600 |
10 |
131 |
(19) |
138 |
(18) |
132 |
27) |
126 |
(31) |
110 |
(41) |
105 |
(37) |
742 |
(142) |
3 |
2000 |
10 |
135 |
(20) |
139 |
(22) |
133 |
13) |
128 |
(15) |
119 |
(37) |
118 |
(43) |
771 |
(117) |
4 |
6000 |
0 |
3 |
(19) |
115 |
(28) |
115 |
32) |
101 |
(45) |
86 |
(51) |
71 |
(51) |
622 |
(158) |
5 |
18,000 |
10 |
149 |
(15) |
146 |
(17) |
117 |
37) |
118 |
(33) |
87 |
(58) |
94 |
(55) |
711 |
(161) |
Week 13 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
133 |
(18) |
127 |
(22) |
110 |
(32) |
99 |
(26) |
91 |
(43) |
79 |
(44) |
638 |
(75) |
2 |
600 |
10 |
132 |
(21) |
134 |
(18) |
113 |
(27) |
107 |
(30) |
96( |
(42) |
95 |
(40) |
676 |
(132) |
3 |
2000 |
10 |
131 |
(12) |
129 |
(16) |
116 |
(29) |
96 |
(36) |
93 |
(34) |
97 |
(46) |
662 |
(126) |
4 |
6000 |
10 |
137 |
(14) |
129 |
(20) |
102 |
(37) |
102 |
(29) |
94 |
(38) |
79 |
(37) |
642 |
(113) |
5 |
18,000 |
10 |
149 |
(14) |
138 |
(21) |
93 |
(37) |
116 |
(23) |
79 |
(51) |
75 |
(42) |
649 |
(104) |
Female |
||||||||||||||||
Group |
Concentration |
Successive 10 minute intervals |
||||||||||||||
|
ppm |
N |
1 |
|
2 |
|
3 |
|
4 |
|
5 |
|
6 |
|
Total |
|
Baseline |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
138 |
(15) |
117 |
(43) |
108 |
(42) |
80 |
(34) |
50 |
(51) |
52 |
(49) |
545 |
(138) |
2 |
600 |
10 |
134 |
(12) |
109 |
(42) |
72 |
(41) |
74 |
(64) |
36 |
(46) |
26 |
(49) |
452 |
(162) |
3 |
2000 |
10 |
134 |
(13) |
119 |
(29) |
82 |
(53) |
80 |
(55) |
65 |
(52) |
65 |
(32) |
505 |
(150) |
4 |
6000 |
10 |
132 |
(11) |
125 |
(25) |
99 |
(42) |
89 |
(44) |
49 |
(47) |
49 |
(36) |
528 |
(111) |
5 |
18,000 |
10 |
130 |
(19) |
134 |
(21) |
103 |
(38) |
87 |
(45) |
47 |
(44) |
32 |
(36) |
533 |
(112) |
Week 4 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
137 |
(22) |
124 |
(38) |
124 |
(23) |
101 |
(39) |
90 |
(56) |
89 |
(53) |
664 |
(133) |
2 |
600 |
10 |
132 |
(19) |
120 |
(28) |
105 |
(44) |
106 |
(54) |
92 |
(51) |
95 |
(60) |
650 |
(154) |
3 |
2000 |
10 |
134 |
(10) |
133 |
(21) |
118 |
(41) |
95 |
(49) |
82 |
(48) |
84 |
(62) |
626 |
(168) |
4 |
6000 |
10 |
127 |
(16) |
122 |
(46) |
108 |
(34) |
90 |
(58) |
95 |
(64) |
126 |
(35) |
679 |
(190) |
5 |
18,000 |
10 |
129 |
(20) |
133 |
(16) |
105 |
(33) |
90 |
(47) |
96 |
(43) |
76 |
(42) |
630 |
(107) |
Week 8 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
137 |
(16) |
133 |
(18) |
110 |
(28) |
124 |
(22) |
105 |
(45) |
89 |
(41) |
698 |
(120) |
2 |
600 |
10 |
142 |
(20) |
137 |
(22) |
118 |
(43) |
119 |
(35) |
120 |
(46) |
101 |
(62) |
736 |
(168) |
3 |
2000 |
10 |
135 |
(14) |
148 |
(17) |
96 |
(49) |
113 |
(33) |
103 |
(45) |
83 |
(55) |
679 |
(142) |
4 |
6000 |
0 |
137 |
(18) |
123 |
(41) |
112 |
(50) |
118 |
(47) |
86 |
(45) |
81 |
(63) |
657 |
(144) |
5 |
18,000 |
10 |
127 |
(24) |
141 |
(17) |
106 |
(39) |
109 |
(29) |
101 |
(45) |
107 |
(47) |
691 |
(92) |
Week 13 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
1 |
0 |
10 |
142 |
(15) |
129 |
(14) |
93 |
(38) |
118 |
(23) |
104 |
(42) |
97 |
(50) |
682 |
(117) |
2 |
600 |
10 |
143 |
(23) |
124 |
(11) |
97 |
(32) |
98 |
(26) |
109 |
(47) |
103 |
(52) |
674 |
(119) |
3 |
2000 |
10 |
131 |
(12) |
119 |
(27) |
108 |
(48) |
95 |
(45) |
93 |
(45) |
101 |
(45) |
647 |
(183) |
4 |
6000 |
10 |
131 |
(18) |
127 |
(12) |
113 |
(44) |
110 |
(23) |
106 |
(35) |
83 |
(53) |
670 |
(96) |
5 |
18,000 |
10 |
140 |
(15) |
132 |
(28) |
107 |
(29) |
78 |
(51) |
101 |
(46) |
63 |
(43) |
620 |
(128) |
Data arranged as: Mean (Standard Deviation).
N = Number examined.
There were no statistically significantdifferencescompared to the control group at p < 0.05.
Table 23: Incidences of gross observations in neuropathology
Males |
|
|
|
|
|
Concentration |
Control |
600 |
2000 |
6000 |
18000 |
Number of animals of study |
5 |
5 |
5 |
5 |
5 |
Kidneys |
|
|
|
|
|
no visble lesions |
5 |
5 |
5 |
4 |
5 |
dilatation |
0 |
0 |
0 |
1 |
0 |
Males |
|
|
|
|
|
Concentration |
Control |
600 |
2000 |
6000 |
18000 |
Number of animals of study |
5 |
5 |
5 |
5 |
5 |
No gross lesions were observed in any of the female neuropathology rats. |
|||||
Table 24: Selected incidences and lesion grades of microscopic findings (neoplastic and non-neoplastic lesions) in neuropathology analysis
Males |
|
|
|
|
|
|
Concentration |
Control |
600 |
2000 |
6000 |
18000 |
|
Number of animals of study |
5 |
5 |
5 |
5 |
5 |
|
Gastrocnemius muscle |
|
|
|
|
|
|
examined |
5 |
0 |
0 |
0 |
5 |
|
within normal limits |
5 |
0 |
0 |
0 |
4 |
|
aggregates, macrophage |
0 |
0 |
0 |
0 |
1 |
|
minimal |
0 |
0 |
0 |
0 |
1 |
|
Eye |
|
|
|
|
|
|
examined |
5 |
0 |
0 |
0 |
5 |
|
within normal limits |
5 |
0 |
0 |
0 |
4 |
|
fold/rosette, retinal |
0 |
0 |
0 |
0 |
1 |
|
minimal |
0 |
0 |
0 |
0 |
1 |
|
Females |
|
|
|
|
|
|
Concentration |
Control |
600 |
2000 |
6000 |
18000 |
|
Number of animals of study |
5 |
5 |
5 |
5 |
5 |
|
All observations within normal limits |
||||||
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