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EC number: 938-645-3 | CAS number: 1689515-39-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Density
- Particle size distribution (Granulometry)
- Vapour pressure
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- Stability: thermal, sunlight, metals
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- 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
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- Toxicological Summary
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- Acute Toxicity
- Irritation / corrosion
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- Genetic toxicity
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- Specific investigations
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- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
A reliable 90-day repeated dose oral toxicity study (performed according to OECD test guidelines and GLP principles) with rats is available. The NOAEL was determined to be at least 1000 mg/kg bw/day in absence of any adverse effects.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 Nov 2021 - 07 Jun 2022
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- June 2018
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- May 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- Version / remarks:
- August 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- - Physical appearance: clear yellow liquid
- Storage conditions: At room temperature
- Test item handling: No specific handling conditions required - Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl: WI(Han)
- Details on species / strain selection:
- At this time, studies in laboratory animals provide the best available basis for extrapolation to humans and are required to support regulatory submissions. Acceptable models that do not use live animals currently do not exist. The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for nonclinical toxicity test by regulatory agencies. The total number of animals to be used in this study is considered to be the minimum required to properly characterize the effects of the test item. This study has been designed such that it does not require an unnecessary number of animals to accomplish its objectives.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6-7 weeks old
- Weight at study initiation: 169 – 218 g (males); 112 – 155 g (females)
- Fasting period before study: no
- Housing: Polycarbonate cages containing sterilized wooden fibers as bedding material equipped with water bottles. Up to 5 animals of the same sex and same dosing group together. Animals were socially housed for psychological/environmental enrichment and were provided with items such as devices for hiding in, paper and/or objects for chewing, except when interrupted by study procedures/ activities
- Diet: ad libitum, SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany
- Water: ad libitum, municipal tap water
- Acclimation period: 15 days
DETAILS OF FOOD AND WATER QUALITY: It is considered that there are no known contaminants in the feed and water that could interfere with the outcome of the study.
ENVIRONMENTAL CONDITIONS
- Temperature: 21 to 23°C (actual daily mean)
- Humidity: 37 to 52% (actual daily mean)
- Air changes (per hr): ten or more
- Photoperiod: 12 hours light and 12 hours dark
IN-LIFE DATES: From: 09 Dec 2021 To: 08 Apr 2022 - Route of administration:
- oral: gavage
- Details on route of administration:
- The oral route of exposure was selected because this is a possible route of human exposure during manufacture, handling or use of the test item and is specifically requested by ECHA.
- Vehicle:
- water
- Remarks:
- Elix
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. Test item dosing formulation were stored in the refrigerator (4°C) until dosing. Adjustment were made for specific gravity of the test item. No correction was made for the purity/composition of the vehicle. A factor of 2 was used to correct for the purity/composition of the test item. High dose group (group 4) was dosed using pure test item.
VEHICLE
- Concentration in vehicle: 59, 177, 590 mg a.i./mL
- Adjusted concentration in vehicle (with a correction factor 2): 118, 354, 1180 mg/mL
- Amount of vehicle (if gavage): 1.695 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Accuracy and homogeneity were determined for formulations prepared for use on Week 1 and in Week 6 and Week 12.
Concentrations of groups 1, 2 and 3 were analysed and homogeneity of groups 2 and 3 were determined.
Analyses were performed using a validated analytical procedure (Test Facility Study No. 20297952).
Acceptance criteria for concentration analysis: mean sample concentration results within or equal to ± 10% of theoretical concentration.
Acceptance criteria for homogeneity: relative standard deviation (RSD) of concentrations of ⩽ 10% for each group. - Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Once daily, 7 days a week
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- group 2 - low dose group
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- group 3 - mid dose group
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- group 4 - high dose group
dosed as pure test item - No. of animals per sex per dose:
- - control and high dose group: 15 animals per sex per dose (10 in main group and 5 in satellite group)
- low and mid dose group: 10 animals per sex per dose - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on information provided by the results of a (14-day repeated dose toxicity study with oral exposure of PC-2020-926 in rats, Test Facility Study No. 20299085), and in an attempt to produce graded responses to the test item. There were no test item-related microscopic alterations following the administration of the test substance by Oral Gavage for 14 Days to Wistar Han Rats. A few microscopic findings of note were present in the kidney, including mixed cell inflammation in the renal pelvis of a single female dosed at 500 mg/kg bw/day) and a focus of nephroblastomatosis in another female dosed at 1000 mg/kg bw/day). These findings were within the range of background pathology encountered in rats of this age and strain. The lesion seen in the female dosed at 500 mg/kg bw/day (inflammation in the renal pelvis) is most likely the result of an ascending infection from the lower urinary tract. Regarding the focus of nephroblastematosis noted in the second female dosed at 1000 mg/kg bw/day, this is a spontaneous lesion that is encountered sporadically in specific colonies of rats, which suggest a predisposing genetic basis. For both cases, these observations are interpreted to be a spontaneous change and not related to the test item, given the single incidence in this study and the fact that we can see these lesions in untreated female rats of this strain. The high-dose level should produce some toxic effects, but not excessive lethality that would prevent meaningful evaluation. The mid-dose level is expected to produce minimal to moderate toxic effects. The low-dose level should produce no observable indications of toxicity.
- Fasting period before blood sampling for clinical biochemistry: yes (overnight with a maximum of 24 hours)
- Rationale for selecting satellite groups: satellite recovery groups scheduled for follow-up observations were kept for an appropriate period without treatment (28 days) to detect persistence of, or recovery from toxic effects
- Post-exposure recovery period in satellite groups: 28 days
- Section schedule rationale: random
- Dose range finding studies: yes (see information under "dose selection rationale")
- Other: In groups 1 (control) and 4 (high dose) 5 animals per sex per group were assigned to the recovery satellite groups. - Observations and examinations performed and frequency:
- MORTALITY: Yes
- Time schedule: at least twice daily, except on days of receipt and necropsy where frequency was at least once daily
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily; from Day 1 at 0 to 1 hours postdose during dosing
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly; from Week 1 and throughout the study, and on the day of necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly; from at least Day 1 and throughout the study.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: Weekly; from at least Day 1 and throughout the study.
WATER CONSUMPTION: Yes
- Time schedule for examinations: on regular basis throughout the study by visual inspection of the water bottles.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations and dose groups examined: pretreatment period (all animals); week 13 of dosing period (main group 1 and 4)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On days of scheduled or unscheduled necropsy Between 7.00 and 10.30 from the retro-orbital sinus at the end of the treatment period and at the end of the recovery period respectively
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes overnight with a maximum of 24 hours)
- How many animals: all main and recovery animals
- Parameters examined: White Blood Cell (WBC), Neutrophils (absolute), Lymphocytes (absolute), Monocytes (absolute), Eosinophils (absolute), Basophils (absolute), Large unstained cells (LUC) (absolute), Red Blood Cell (RBC), Reticulocytes (absolute), Red Blood Cell Distribution Width (RDW), Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Platelets
COAGULATION: Yes
- Time schedule for collection of blood: see HEMATOLOGY
- Animals fasted: see HEMATOLOGY
- How many animals: see HEMATOLOGY
- Parameters examined: Prothrombin time (PT), Activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see HEMATOLOGY
- Animals fasted: see HEMATOLOGY
- How many animals: see HEMATOLOGY
- Parameters examined: Alanine aminotransferase (ALT), Triglycerides, Aspartate aminotransferase (AST), HDL and LDL Cholesterol, Alkaline Phosphatase (ALP), Sodium, Total protein, Potassium, Albumin, Chloride, Total Bilirubin, Calcium, Urea, Inorganic Phosphate (Inorg. Phos), Creatinine, Glucose, Cholesterol
SERUM HORMONES: Yes
- Time of blood sample collection: see HEMATOLOGY
- Animals fasted: see HEMATOLOGY
- How many animals: see HEMATOLOGY
- Parameters examined: Triiodothyronine (T3), Thyroxine (T4), Thyroid-Stimulating Hormone (TSH)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once during week 13 of the dosing period
- Dose groups that were examined: the first 5 animals per sex per group of all dose groups (1-4)
- Battery of functions tested: sensory activity, grip strength and motor activity
ESTROUS STAGE DETERMINATION: Yes
- Time schedule: end of treatment on the day of necropsy
IMMUNOLOGY: No - Sacrifice and pathology:
- SACRIFICE
All main and recovery animals surviving until scheduled euthanasia were weighed, and deeply anesthetized using isoflurane and subsequently exsanguinated and subjected to a full post mortem examination. All animals surviving to scheduled necropsy were fasted overnight with a maximum of 24 hours before necropsy. Water was available.
GROSS NECROPSY
- All animals were subjected to a full post mortem examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.
-Tissue collection and preservation:
Representative samples of the tissues indicated in Table 1 below were collected from all animals and preserved in 10% neutral buffered formalin: Testes and epididymis were preserved in modified Davidson’s fixative and transferred to formalin after fixation for at least 24 hours. Gross lesions or masses were also collected from all animals if found.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 below were prepared for microscopic examination and weighed, respectively for the selected and remaining animals.
For all mail males and females of group 1 and 4 the full list of tissues mentioned in table 1 below (see section "Any other information on materials and methods incl. tables") was examined histopathologically. For all remaining animals (main animals of group 2 and 3 and recovery animals of group 1 and 4) only gross lesions and target tissues were examined histopathologically.
Target tissues identified: rectum of males and stomach of females - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels. The following pairwise comparisons were made:
Group 2 vs. Group 1
Group 3 vs. Group 1
Group 4 vs. Group 1
Numerical data collected on scheduled occasions for all variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
In-life, clinical chemistry, hematology, coagulation, organ weights data:
- Parametric/Non-parametric: Levene’s test was used to assess the homogeneity of group variances. The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal-Wallis test was found to be significant, then pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively.
- ANCOVA: The data corresponding to a response variable of interest and to a related covariate was submitted to an analysis of covariance, including only groups with at least three non-missing paired values and when found to be significant, then pairwise comparisons was conducted using Dunnett’s test.
-Incidence: A Fisher’s exact test was used to conduct pairwise group comparisons.
Functional tests data:
- Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).
- Non-parametric: Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test).
- Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. Pairwise comparisons were conducted using Fisher’s exact test whenever the overall test was significant. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Abnormal breathing sounds were noted for animals dosed at all dose levels, with a dose dependent increase in incidence with increasing dose. Abnormal breathing sounds were also noted for one control female. For a few individual animals, additional deep, laboured or shallow breathing was incidentally noted across the test material-treated groups. Moreover, retching was noted for males at 100 and 1000 mg/kg bw/day and females at 100, 300 and 1000 mg/kg bw/day. Finally, hunched posture was noted for one male each at 300 and 1000 mg/kg bw/day and one female at 1000 mg/kg bw/day, and erected fur was noted for two males at 300 mg/kg bw/day, four males at 1000 mg/kg bw/day and one female each at 300 and 1000 mg/kg bw/day.
Salivation, on some occasions accompanied by ploughing, was noted in animals dosed at 300 and 1000 mg/kg bw/day. Taking into account the nature and minor severity of the effect and its time of occurrence (i.e., after dosing), salivation was considered to be a physiological response rather than a sign of systemic toxicity. Ploughing was considered to be an adaptive response to salivation, and not directly related to treatment with the test material.
During the Recovery Period, abnormal breathing sounds and/or laboured breathing were noted on few occasions for one female at 1000 mg/kg bw/day. At the incidence observed, and as this concerned the treatment-free period, this was considered to be unrelated to treatment with the test material. No test material-related clinical signs were noted during weekly arena observations for the Main and Recovery animals.
Any other clinical signs noted during the Treatment or Recovery Period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and/or did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment with the test material.
(see Table 29-30 under "Any other information on results incl. tables") - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weights and body weight gain were considered to have been unaffected by treatment with the test material.
At 1000 mg/kg bw/day, body weight gain was significantly lower for males over Days 78-85, and significantly higher for females over Days 1-8 when compatred to controls. For one male at 1000 mg/kg bw/day, a body weight loss of 9% was noted over Days 57-64. In addition, mean body weight gain over the complete Recovery Period was significantly higher for males at 1000 mg/kg bw/day, when compared to control. As they did not result in significant differences in mean body weights and showed no trend regarding duration of dosing, these slight and incidental changes were considered to be unrelated to treatment with the test material.
(see Table 5-12 under "Any other information on results incl. tables") - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption was considered to have been unaffected by treatment with the test material.
At 300 mg/kg bw/day, food intake was slightly low for females during the Treatment Period. As this did not result in significant differences in mean food consumption, showed no trend regarding duration of dosing and did not result in a dose response, these slight and incidental changes were considered to be unrelated to treatment with the test material.
For females at 1000 mg/kg bw/day, food intake was slightly low during the Recovery Period (7.5% lower when compared to control). As this concerned the Recovery Period only, this was considered to be unrelated to treatment with the test material. - Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No ophthalmology findings were noted that were considered to be related to the test material.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Hematology parameters were considered not to have been affected by the test material in females up to 1000 mg/kg bw/day and in males up to 300 mg/kg bw/day.
In males at 1000 mg/kg bw/day, red blood cell (RBC) count and red blood cell distribution width (RDWG) were significantly decreased (0.92x and 0.95x of control, respectively), and mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were significantly increased (1.03x and 1.05x of control, respectively) at the end of the Treatment Period. All reported changes reached statistical significance but were within historical control for this rat strain at the site.
At the end of the Recovery Period, RBC counts were comparable to control, while RDWG was still decreased, and MCV and MCH were still increased (not statistically significant) in males at 1000 mg/kg bw/day.
Any other differences in hematology parameters, regardless of statistical significance, were considered to be unrelated to the test material as these occurred in the absence of a dose-related trend or only at the end of the Recovery Period.
Coagulation parameters were considered not to have been affected by treatment with the test material.
Actual mean values:
Red Blood Cell Count males: control group mean = 9.302; high dose group mean = 8.558
Red Blood Cell Distribution Width males: control group mean =12.67 ; high dose group mean = 12.04
Mean Corpuscular Volume males: control group mean = 51.75 ; high dose group mean = 53.47
Mean Corpuscular Hemoglobin males: control group mean = 17.30; high dose group mean = 18.19
HCD
HCD Red Blood Cell Count males: mean = 8.802; P5-P1: 7.9–9.55
HCD Red Blood Cell Distribution Width males: mean = 427; P5-P1: 11.3–13.6
HCD Mean Corpuscular Volume males: mean = 51.61; P5-P1: 48.9–54.6
HCD Mean Corpuscular Hemoglobin males: mean = 17.21; P5-P1: 16.3–18.9
(see Table 13-16 under "Any other information on results incl. tables") - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical chemistry parameters were considered not to have been affected by the test material in females up to 1000 mg/kg bw/day and in males up to 300 mg/kg bw/day.
In males at 1000 mg/kg bw/day, triglyceride concentration was increased (1.40x of control, not statistically significant and within historical control data) at the end of the Treatment Period.
At the end of the Recovery Period, triglyceride concentration in males at 1000 mg/kg bw/day was partly recovered.
Remaining differences in clinical chemistry parameters, regardless of statistical significance, were considered not test material-related based on the absence of a dose response, general overlap of individual values with the range of control values, variation in direction of change, were considered to have arisen as a result of slightly high control values, were seen at end of recovery only and/or were of a magnitude of change commonly observed in rats under similar study conditions.
Actual mean values:
Triglyceride males: control group mean = 0.956; high dose group mean = 1.338
HCD
HCD Triglyceride males: mean = 399; P5-P1: 0.36–1.52
(see Table 17-20 under "Any other information on results incl. tables") - Endocrine findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No effect was noted on T3 and TSH levels in males and females, and on T4 levels in males up to 1000 mg/kg bw/day.
In females at 100 and 1000 mg/kg bw/day, T4 levels were increased at the end of the Treatment Period (1.22x and 1.37x of control, not statistically significant at 100 mg/kg bw/day). Mean values remained within the historical control range .
At the end of the Recovery Period, T4 levels in females at 1000 mg/kg bw/day were comparable to control.
Since no histopathological changes were observed in the thyroid, the observed increase in the study was considered not toxicologically relevant.
Actual mean values:
T4 (ng/mL) – females: control group mean = 24.72; high dose group mean = 33.98
HCD
HCD T4 (ng/mL) – females: mean = 29.87; P2.5-P-97.5: 13.92 - 51.38
(see Table 17-20 under "Any other information on results incl. tables") - Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals. Grip strength was considered unaffected by treatment with the test material.
Motor activity was considered unaffected by treatment with the test material in males at all dose levels and in females up to 300 mg/kg bw/day.
For females at 1000 mg/kg bw/day, the mean total movements and ambulations were both lower compared to control (0.59x and 0.61x of control, respectively; not statistically significant for ambulations). Mean values remained within the historical control range, albeit close to the lower limit.
At the end of the Recovery Period, mean total movements and ambulations were within the same range for control animals and animals treated at 1000 mg/kg bw/day.
All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period.
Actual mean values:
Total movements – females: control group mean = 4615; high dose group mean = 2739
Total ambulations – females: control group mean = 1095; high dose group mean = 667
HCD
HCD Total movements – females: mean = 4740; P5-P95 = 2393-8076
HCD Total ambulations – females: mean = 1335; P5-P95 = 638-2271
(see Table 21-22 under "Any other information on results incl. tables") - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test material-related significantly higher kidney and liver weights (absolute and relative to body weight) were noted in females at 1000 mg/kg bw/day (see Table 2 under "Any other information on results incl. tables"). These differences were within the historical control data of the test site.
Higher kidney weight (absolute and relative to body weight, statistically significant) was present in females at 1000 mg/kg bw/day at the end of the Treatment Period. Following the Recovery Period, there was no significant difference in the kidney weight of test material-treated females compared to the control females, suggesting full recovery.
Higher liver weight (absolute and relative to body weight, statistically significant) was present in females at 1000 mg/kg bw/day at the end of the Treatment Period. Following the Recovery Period, there was no significant difference in the liver weight of test material-treated females compared to the control females, suggesting full recovery.
Other statistically significant changes at the end of the Treatment Period (lower relative pituitary gland weight, females at 100 mg/kg bw/day) or Recovery Period (higher relative brain weight, females at 1000 mg/kg bw/day) were considered to be not test material-related due to the lack of a dose-related pattern (pituitary gland) or was regarded related to the lower final body weight (brain).
Since the higher kidney and liver weights in females at 1000 mg/kg bw/day remained within the historical control data, the changes were no longer observed after recovery and in the absence of any concomitant histopathological changes, these effects were considered non-adverse.
Actual mean values:
Liver weight: control group mean = 5.3753; high dose group mean = 6.4360
Liver relative to body weight: control group mean = 2.43901; high dose group mean = 2.79153
Kidney weight: control group mean = 1.4672; high dose group mean = 1.7272
Kidney relative to body weight: control group mean = 0.66594; high dose group mean = 0.74781
HCD
HCD Liver weight: Mean = 5.56; P5-P95 = 4.634-6.472
HCD Liver relative to body weight: Mean = 2.50; P5-P95 = 2.226-2.876
HCD Kidney weight: Mean = 1.53; P5-P95 = 0.526-1.80
HCD Kidney relative to body weight: Mean = 0.69; P5-P95 = 0.588-0.807
(see also Table 23-26 under "Any other information on results incl. tables") - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test material-related gross observations.
All the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain. - Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test material-related microscopic findings were noted in the rectum of males at 1000 mg/kg bw/day and the stomach of females at 300 and 1000 mg/kg bw/day (see Table 3 under "Any other information on results incl. tables").
In the rectum, goblet cell hyperplasia was recorded in 3/10 males at 1000 mg/kg bw/day (minimal) at the end of the Treatment Period. Following the Recovery Period this finding was not present, suggesting full recovery.
In the stomach, in the non-glandular stomach, squamous cell hyperplasia often accompanied by hyperkeratosis was recorded in 1/10 females at 300 mg/kg bw/day (minimal) and in 3/10 females at 1000 mg/kg bw/day (up to mild degree) at the end of the Treatment Period. Following the Recovery Period this finding was not present, suggesting full recovery (see Table 4 under "Any other information on results incl. tables").
Focal erosion of the non-glandular and glandular portion of the stomach (minimal) was noted in 1/10 females at 1000 mg/kg/day (Main Group females) and 1/5 females at 1000 mg/kg bw/day (Recovery Group females). At this low incidence and severity, these findings were considered not to represent a test material-related effect but rather represent a procedure-related effect or an incidental finding.
There were no other test material-related histologic changes. The remainder of the recorded microscopic findings were considered to be incidental findings or were within the range of background pathology encountered in rats of this age and strain. There was no test material related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
(see also Table 27-28 under "Any other information on results incl. tables") - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks:
- corrected for water content
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- A 90-day repeated dose toxicity study was performed according to OECD TG 408 and in accordance with GLP principles. In conclusion, administration of the substance by once daily oral gavage was tolerated in Wistar Han rats at levels up to 1000 mg/kg bw/day. There were no adverse test material related alterations observed.
Based on these results, the No Observed Adverse Effect Level (NOAEL) was considered to be at least 1000 mg/kg bw/day in males and females. - Executive summary:
A 90-day repeated dose toxicity study was performed according to OECD TG 408 and in accordance with GLP principles.
The objectives of this study were to determine the potential toxicity of the substance, when given orally by gavage for 90 days to Wistar Han rats and to evaluate the potential reversibility of any findings. In addition, a No Observed Adverse Effect Level (NOAEL) was evaluated. Ten animals per sex per dose received 0 (vehicle), 100, 300 or 1000 mg/kg bw/day. An additional 5 animals per sex per dose in the recovery group received 0 or 1000 mg/kg bw/day.
Chemical analyses of formulations were conducted on Weeks 1, 6 and 12 on Groups 1-3 to assess accuracy and homogeneity. Formulation analyses confirmed that formulations were prepared accurately and homogenously for all occasions. The following parameters and end points were evaluated in this study: mortality, clinical signs, functional observation tests, body weights, food consumption, ophthalmology, stage of estrous, clinical pathology parameters (hematology, coagulation, and clinical chemistry), macroscopic examination, organ weights and microscopic examination.
No mortality occurred during the study.
At 100 mg/kg bw/day, abnormal breathing sounds, shallow breathing and retching were noted in males and/or females, which were considered to be non-adverse.
At 300 mg/kg bw/day, non-adverse abnormal breathing sounds, deep breathing, retching, hunched posture, erected fur were noted in males and/or females. Histopathological changes consisted of non-adverse squamous cell hyperplasia in the stomach in females, which was often accompanied by hyperkeratosis.
At 1000 mg/kg bw/day, abnormal breathing sounds, labored breathing, shallow breathing, retching, hunched posture and erected fur were noted in males and/or females and were considered to be non-adverse. Non-adverse decreased total movements and ambulations were noted for females. Hematological findings comprised non-adverse decreased red blood cell count and red blood cell distribution width and increased mean corpuscular volume and mean corpuscular hemoglobin in males. Red blood cell count was recovered, while red blood cell distribution width, mean corpuscular volume and mean corpuscular hemoglobin were not recovered at the end of the Recovery Period. It is noted that all reported changes on Hematology parameters were within historical control for this rat strain at the site. Nonadverse clinical chemistry findings consisted of an increase in triglyceride concentration in males, which partly recovered at the end of the Recovery Period. Hormone analysis showed an increased T4 levels in females compared to the concurrent control group however, the mean values still remained within the historical control range and levels recovered at the end of the Recovery Period. Furthermore, no histopathological changes were observed in the thyroid. Overall, the observed increase in the study was considered non-adverse and not toxicologically relevant. Histopathological changes consisted of non-adverse squamous cell hyperplasia often accompanied by hyperkeratosis in the stomach in females and goblet cell hyperplasia of the rectum in a few males. In addition, a higher kidney and liver weight was noted in females. As kidney and liver weights remained within the historical control data and changes were no longer observed after recovery and in the absence of concomitant histopathological changes, the effects on organ weights were considered non-adverse. All histopathological and organ weight changes were fully recovered at the end of the Recovery Period.No test material-related changes were noted in any of the remaining parameters investigated in this study (i.e., mortality, body weight, food consumption, ophthalmoscopy, coagulation and macroscopic pathology).
In conclusion, administration of the substance by once daily oral gavage was tolerated in Wistar Han rats at levels up to 1000 mg/kg bw/day. There were no adverse test material related alterations observed.
Based on these results, the No Observed Adverse Effect Level (NOAEL) was considered to be at least 1000 mg/kg bw/day in males and females.
Reference
The accuracy and homogeneity of the formulations of Group 4 were not determined because it was pure test material.
Accuracy
The concentrations analyzed in the formulations of Groups 2 and 3 were in agreement with target concentrations (i.e., mean sample concentration results were within or equal to 90-110% of target concentration).
No test material was detected in the Group 1 formulations.
Homogeneity
The formulations of Groups 2 and 3 were homogeneous (i.e., coefficient of variation ≤ 10%).
Table 2: Mean Percent kidney and liver Weight Differences from Control Groups
| Main Females | Recovery Females | |||||||
Dose level (mg/kg bw/day): | 100 | 300 | 1000 | 1000 | |||||
KIDNEYS |
|
|
|
| |||||
Absolute | 8 | 0 | 18** | -3 | |||||
Relative to body weight | 5 | 4 | 12** | 2 | |||||
LIVER |
|
|
|
| |||||
Absolute | 1 | -5 | 20** | -7 | |||||
Relative to body weight | -2 | -2 | 14** | -2 |
**: P≤0.01
Table 3: Summary Test Material-Related Microscopic Findings - Males
| Main Males | Recovery Males | ||||
Dose level (mg/kg bw/day): | 0 | 100 | 300 | 1000 | 0 | 1000 |
RECTUM a | 10 | 10 | 10 | 10 | 5 | 5 |
Hyperplasia, goblet cell |
|
|
|
|
|
|
Minimal | - | - | - | 3 | - | - |
a = Number of tissues examined from each group.
Table 4: Summary Test Material-Related Microscopic Findings - Females
| Main Females | Recovery Females | ||||
Dose level (mg/kg bw/day): | 0 | 100 | 300 | 1000 | 0 | 1000 |
STOMACH a | 10 | 10 | 10 | 10 | 5 | 5 |
Hyperplasia, squamous cell, non-glandular |
|
|
|
|
|
|
Minimal | - | - | 1 | 2 | - | - |
Mild | - | - | - | 1 | - | - |
a = Number of tissues examined from each group.
Table 5: Body weights (gram) summary (males) -Main
Sex: Male | Day(s) Relative to Start Date
| ||||||||||||||
1 | 8 | 15 | 22 | 29 | 36 | 43 | 50 | 57 | 64 | 71 | 78 | 85 | 91 | ||
0 | Mean | 193.5 | 235.9 | 270.2 | 296.3 | 317.1 | 338.5 | 350.3 | 366.9 | 377.4 | 387.4 | 395.7 | 401.7 | 411.6 | 415.7 |
mg/kg/day | SD | 10.6 | 14.1 | 18.5 | 20.5 | 23.0 | 23.3 | 25.8 | 25.4 | 29.4 | 28.9 | 28.9 | 30.9 | 31.8 | 32.1 |
Group 1 | N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
100 | Mean | 199.5 | 241.6 | 275.0 | 299.5 | 321.2 | 342.0 | 356.8 | 374.6 | 383.8 | 393.9 | 404.5 | 412.1 | 420.6 | 423.6 |
mg/kg/day | SD | 9.3 | 14.7 | 17.5 | 19.0 | 20.1 | 22.6 | 25.0 | 27.2 | 27.6 | 29.7 | 33.4 | 34.0 | 34.4 | 35.8 |
Group 2 | N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| %Diff | 3.1 | 2.4 | 1.8 | 1.1 | 1.3 | 1.0 | 1.8 | 2.1 | 1.7 | 1.7 | 2.2 | 2.6 | 2.2 | 1.9 |
300 | Mean | 197.8 | 237.0 | 268.0 | 292.0 | 312.3 | 334.5 | 350.6 | 365.2 | 377.2 | 386.4 | 397.7 | 406.6 | 414.0 | 418.6 |
mg/kg/day | SD | 14.1 | 17.1 | 18.4 | 24.4 | 26.1 | 29.2 | 28.2 | 31.8 | 32.3 | 34.4 | 33.3 | 34.4 | 35.6 | 37.6 |
Group 3 | N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| %Diff | 2.2 | 0.5 | -0.8 | -1.4 | -1.5 | -1.2 | 0.1 | -0.5 | -0.1 | -0.3 | 0.5 | 1.2 | 0.6 | 0.7 |
1000 | Mean | 196.5 | 236.8 | 269.8 | 298.0 | 318.3 | 337.9 | 350.3 | 365.3 | 373.1 | 381.3 | 390.4 | 398.5 | 401.1 | 408.1 |
mg/kg/day | SD | 12.1 | 16.0 | 19.1 | 20.8 | 23.9 | 26.0 | 28.3 | 30.4 | 31.5 | 38.2 | 36.4 | 34.8 | 35.1 | 37.0 |
Group 4 | N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
| %Diff | 1.6 | 0.4 | -0.1 | 0.6 | 0.4 | -0.2 | 0.0 | -0.5 | -1.1 | -1.6 | -1.3 | -0.8 | -2.5 | -1.8 |
Table 6: Body weigths (gram) summary (Females) -Main
Sex: Female | Day(s) Relative to Start Date | ||||||||||||||
1 [G] | 8 [G] | 15 [G1] | 22 [G] | 29 [G] | 36 [G] | 43 [G1] | 50 [G] | 57 [G] | 64 [G] | 71 [G] | 78 [G] | 85 | 91 | ||
0 | Mean | 131.6 | 147.7 | 169.2 | 183.3 | 195.1 | 206.5 | 212.5 | 219.9 | 225.8 | 228.9 | 233.2 | 236.0 | 240.5 | 241.3 |
mg/kg/day | SD | 9.6 | 9.4 | 11.2 | 14.5 | 13.8 | 13.5 | 12.2 | 15.3 | 14.7 | 13.7 | 14.5 | 16.4 | 16.0 | 15.1 |
Group 1 | N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
100 | Mean | 130.9 | 150.5 | 166.5 | 184.1 | 196.0 | 208.2 | 213.7 | 223.1 | 226.8 | 231.7 | 234.0 | 238.0 | 240.2 | 241.1 |
mg/kg/day | SD | 7.9 | 10.7 | 11.8 | 10.7 | 12.3 | 14.4 | 15.3 | 13.9 | 15.2 | 16.5 | 17.9 | 16.7 | 15.6 | 17.0 |
Group 2 | N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| %Diff | -0.5 | 1.9 | -1.6 | 0.5 | 0.4 | 0.8 | 0.5 | 1.5 | 0.4 | 1.2 | 0.3 | 0.8 | -0.1 | -0.1 |
300 | Mean | 123.8 | 139.5 | 158.3 | 174.6 | 185.8 | 195.9 | 202.6 | 210.5 | 213.0 | 217.4 | 220.8 | 224.9 | 229.0 | 229.6 |
mg/kg/day | SD | 11.0 | 11.1 | 15.5 | 15.7 | 17.4 | 18.4 | 17.3 | 18.4 | 18.2 | 18.6 | 20.3 | 18.3 | 17.1 | 17.0 |
Group 3 | N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| %Diff | -5.9 | -5.6 | -6.4 | -4.7 | -4.8 | -5.1 | -4.7 | -4.3 | -5.7 | -5.0 | -5.3 | -4.7 | -4.8 | -4.8 |
1000 | Mean | 135.7 | 156.1 | 175.5 | 192.5 | 205.7 | 214.1 | 219.3 | 231.4 | 234.9 | 236.6 | 239.5 | 243.7 | 245.0 | 244.8 |
mg/kg/day | SD | 8.7 | 9.7 | 8.4 | 9.7 | 10.3 | 10.7 | 10.3 | 12.6 | 11.6 | 11.8 | 14.4 | 12.4 | 11.9 | 13.9 |
Group 4 | N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
| %Diff | 3.1 | 5.7 | 3.7 | 5.0 | 5.4 | 3.7 | 3.2 | 5.2 | 4.0 | 3.4 | 2.7 | 3.3 | 1.9 | 1.5 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn
Table 7: Body weigths (gram) summary (Males) -Recovery
Sex: Male | Day(s) Relative to Start Date | |||||
92 | 99 | 106 | 113 | 120 | ||
0 | Mean | 419.0 | 425.6 | 432.4 | 437.0 | 440.8 |
mg/kg/day | SD | 31.8 | 30.6 | 30.8 | 33.4 | 30.9 |
Group 1 | N | 5 | 5 | 5 | 5 | 5 |
1000 | Mean | 414.4 | 424.2 | 433.6 | 441.2 | 443.2 |
mg/kg/day | SD | 33.6 | 33.7 | 32.6 | 34.3 | 35.5 |
Group 4 | N | 5 | 5 | 5 | 5 | 5 |
| %Diff | -1.1 | -0.3 | 0.3 | 1.0 | 0.5 |
Table 8: Body weigths (gram) summary (Females) -Recovery
Sex: Female | Day(s) Relative to Start Date | |||||
92 | 99 | 106 | 113 | 120 | ||
0 | Mean | 254.0 | 254.2 | 260.0 | 259.8 | 259.0 |
mg/kg/day | SD | 11.0 | 9.0 | 10.8 | 10.6 | 13.3 |
Group 1 | N | 5 | 5 | 5 | 5 | 5 |
1000 | Mean | 242.0 | 244.2 | 249.0 | 244.6 | 244.4 |
mg/kg/day | SD | 12.4 | 16.7 | 17.0 | 15.4 | 15.9 |
Group 4 | N | 5 | 5 | 5 | 5 | 5 |
| %Diff | -4.7 | -3.9 | -4.2 | -5.9 | -5.6 |
Table 9: Body weight gain (%) summary (Males) -Main
Sex: Male | Day(s) Relative to Start Date | ||||||||||||||
1 → 8 [G] | 8 → 15 [G] | 15 → 22 [G] | 22 → 29 [G] | 29 → 36 [G] | 36 → 43 [G1] | 43 → 50 [G] | 50 → 57 | 57 → 64 | 64 → 71 | 71 → 78 | 78 → 85 | 85 → 91 | 1 → 91 | ||
0 mg/kg/day Group 1 | Mean | 42.4 | 34.3 | 26.1 | 20.9 | 21.4 | 11.8 | 16.6 | 10.5 | 10.0 | 8.3 | 6.1 | 9.9 | 4.1 | 222.2 |
SD | 4.0 | 5.9 | 4.8 | 4.2 | 4.4 | 4.9 | 3.9 | 5.8 | 3.8 | 4.4 | 3.7 | 3.3 | 2.4 | 23.9 | |
N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | |
100 mg/kg/day Group 2 | Mean | 42.1 | 33.4 | 24.5 | 21.7 | 20.8 | 14.8 | 17.8 | 9.2 | 10.1 | 10.6 | 7.6 | 8.5 | 3.0 | 224.1 |
SD | 7.5 | 4.9 | 3.6 | 3.0 | 3.0 | 3.1 | 5.4 | 3.6 | 3.7 | 5.5 | 4.1 | 4.1 | 3.1 | 29.0 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
300 mg/kg/day Group 3 | Mean | 39.2 | 31.0 | 24.0 | 20.3 | 22.2 | 16.1 | 14.6 | 12.0 | 9.2 | 11.3 | 8.9 | 7.4 | 4.6 | 220.8 |
SD | 4.6 | 6.0 | 9.7 | 4.6 | 3.4 | 2.9 | 6.2 | 3.2 | 3.2 | 2.2 | 2.8 | 3.8 | 4.4 | 32.0 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
1000 mg/kg/day Group 4 | Mean | 40.3 | 33.0 | 28.2 | 20.3 | 19.6 | 12.3 | 15.0 | 7.9 | 8.1 | 9.1 | 8.1 | 2.6** | 7.0 | 211.6 |
SD | 5.0 | 5.8 | 5.6 | 7.7 | 4.5 | 5.5 | 4.6 | 4.5 | 11.3 | 5.8 | 5.4 | 3.2 | 4.8 | 30.7 | |
N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn
Table 10: Body weight gain (%) summary (females) -Main
Sex: Female | Day(s) Relative to Start Date | ||||||||||||||
1 → 8 [G] | 8 → 15 [G] | 15 → 22 [G1] | 22 → 29 [G] | 29 → 36 [G] | 36 → 43 [G] | 43 → 50 [G] | 50 → 57 | 57 → 64 | 64 → 71 | 71 → 78 | 78 → 85 | 85 → 91 | 1 → 91 | ||
0 mg/kg/day Group 1 | Mean | 16.1 | 21.5 | 14.1 | 11.9 | 11.3 | 6.1 | 7.3 | 5.9 | 3.1 | 4.3 | 2.8 | 4.5 | 0.7 | 109.7 |
SD | 4.3 | 4.9 | 4.6 | 5.3 | 4.5 | 4.4 | 4.6 | 5.4 | 4.3 | 5.8 | 4.2 | 4.3 | 4.0 | 8.5 | |
N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | |
100 mg/kg/day Group 2 | Mean | 19.6 | 16.0 | 17.6 | 11.9 | 12.2 | 5.5 | 9.4 | 3.7 | 4.9 | 2.3 | 4.0 | 2.2 | 0.9 | 110.2 |
SD | 3.9 | 3.1 | 4.4 | 4.1 | 5.0 | 3.7 | 5.2 | 4.6 | 3.1 | 3.7 | 4.1 | 4.3 | 5.1 | 11.8 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
300 mg/kg/day Group 3 | Mean | 15.7 | 18.8 | 16.3 | 11.2 | 10.1 | 6.7 | 7.9 | 2.5 | 4.4 | 3.4 | 4.1 | 4.1 | 0.6 | 105.8 |
SD | 4.6 | 5.4 | 1.5 | 3.5 | 5.0 | 3.3 | 3.0 | 3.9 | 4.3 | 5.1 | 3.7 | 3.7 | 7.0 | 12.9 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
1000 mg/kg/day Group 4 | Mean | 20.5* | 19.4 | 16.9 | 13.3 | 8.3 | 5.2 | 12.1 | 3.5 | 1.7 | 2.9 | 4.3 | 1.3 | -0.2 | 109.1 |
SD | 5.1 | 5.7 | 4.5 | 4.0 | 6.5 | 5.3 | 6.9 | 6.4 | 4.8 | 9.4 | 5.4 | 4.1 | 5.8 | 11.6 | |
N | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 | 15 |
[G] - Anova & Dunnett: * = p ≤ 0.05
[G1] - Kruskal-Wallis & Dunn
Table 11: Body weight gain (%) summary (males) -Recovery
Sex: Male | Day(s) Relative to Start Date | |||||
92 → 99 [G] | 99 → 106 [G] | 106 → 113 [G1] | 113 → 120 [G] | 92 → 120 [G] | ||
0 mg/kg/day Group 1 | Mean | 6.6 | 6.8 | 4.6 | 3.8 | 21.8 |
SD | 1.9 | 1.3 | 4.8 | 2.9 | 5.0 | |
N | 5 | 5 | 5 | 5 | 5 | |
1000 mg/kg/day Group 4 | Mean | 9.8 | 9.4 | 7.6 | 2.0 | 28.8* |
SD | 2.6 | 2.3 | 2.5 | 1.6 | 4.0 | |
N | 5 | 5 | 5 | 5 | 5 |
[G] - Anova & Dunnett: * = p ≤ 0.05
Table 12: Body weight gain (%) summary (females) -Recovery
Sex: Female | Day(s) Relative to Start Date | |||||
92 → 99 | 99 → 106 | 106 → 113 | 113 → 120 | 92 → 120 | ||
0 mg/kg/day Group 1 | Mean | 0.2 | 5.8 | -0.2 | -0.8 | 5.0 |
SD | 3.1 | 3.5 | 4.3 | 4.5 | 3.7 | |
N | 5 | 5 | 5 | 5 | 5 | |
1000 mg/kg/day Group 4 | Mean | 2.2 | 4.8 | -4.4 | -0.2 | 2.4 |
SD | 6.2 | 3.0 | 2.9 | 4.8 | 3.6 | |
N | 5 | 5 | 5 | 5 | 5 |
Table 13: Haematology summary (males) - Day 92 (end of treatment)
Sex: Male | Reporting Hematology | ||||||||||||||||
WBC (10^9/L) [G] | NEUT (10^9/L) [G] | LYMPH (10^9/L) [G] | MONO (10^9/L) [G] | EOS (10^9/L) [G] | BASO (10^9/L) [G] | LUC (10^9/L) [G] | RBC (10^12/L) [G] | RETIC (10^9/L) [G] | RDWG (%) [G] | HGB
(g/L)
[G1] | HCT (L/L) [G] | MCV (fL) [G] | MCH
(pg)
[G] | MCHC
(g/L)
[G] | PLT (10^9/L) [G] | ||
0 mg/kg/day Group 1 | Mean | 6.008 | 1.074 | 4.658 | 0.096 | 0.116 | 0.008 | 0.053 | 9.302 | 206.11 | 12.67 | 160.9 | 0.4814 | 51.75 | 17.30 | 334.2 | 723.0 |
SD | 1.263 | 0.331 | 1.013 | 0.031 | 0.023 | 0.004 | 0.013 | 0.224 | 27.72 | 0.54 | 4.7 | 0.0186 | 1.07 | 0.42 | 6.7 | 35.2 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
100 mg/kg/day Group 2 | Mean | 5.138 | 1.106 | 3.785 | 0.079 | 0.128 | 0.005 | 0.033 | 9.142 | 188.16 | 12.23 | 159.9 | 0.4724 | 51.70 | 17.53 | 339.0 | 643.8 |
SD | 1.661 | 0.366 | 1.683 | 0.021 | 0.031 | 0.007 | 0.015 | 0.549 | 25.76 | 0.35 | 7.2 | 0.0267 | 0.94 | 0.44 | 7.3 | 80.9 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
| tCtrl | 0.86 | 1.03 | 0.81 | 0.82 | 1.10 | 0.63 | 0.62 | 0.98 | 0.91 | 0.97 | 0.99 | 0.98 | 1.00 | 1.01 | 1.01 | 0.89 |
300 mg/kg/day Group 3
| Mean | 6.502 | 1.235 | 4.931 | 0.107 | 0.160 | 0.007 | 0.062 | 9.086 | 202.13 | 12.44 | 161.7 | 0.4768 | 52.52 | 17.83 | 339.6 | 674.3 |
SD | 1.688 | 0.259 | 1.532 | 0.042 | 0.040 | 0.005 | 0.022 | 0.645 | 38.11 | 0.44 | 7.5 | 0.0263 | 1.43 | 0.61 | 6.3 | 97.1 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 1.08 | 1.15 | 1.06 | 1.11 | 1.38 | 0.88 | 1.17 | 0.98 | 0.98 | 0.98 | 1.00 | 0.99 | 1.01 | 1.03 | 1.02 | 0.93 | |
1000 mg/kg/day Group 4
| Mean | 5.481 | 0.992 | 4.216 | 0.088 | 0.130 | 0.006 | 0.049 | 8.558 ** | 216.19 | 12.04 ** | 155.7 | 0.4581 | 53.47 * | 18.19 ** | 340.2 | 726.4 |
SD | 2.253 | 0.199 | 2.146 | 0.028 | 0.043 | 0.005 | 0.038 | 0.563 | 26.23 | 0.38 | 12.1 | 0.0398 | 2.05 | 0.76 | 7.5 | 69.1 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.91 | 0.92 | 0.91 | 0.92 | 1.12 | 0.75 | 0.92 | 0.92 | 1.05 | 0.95 | 0.97 | 0.95 | 1.03 | 1.05 | 1.02 | 1.00 |
[G] - Anova & Dunnett: ** = p ≤ 0.01
[G1] - Kruskal-Wallis & Dunn
Table 14: Haematology summary (Females) - Day 93 (end of treatment)
Sex: Female | Reporting Hematology | ||||||||||||||||
WBC (10^9/L) [G] | NEUT (10^9/L) [G] | LYMPH (10^9/L) [G] | MONO (10^9/L) [G] | EOS (10^9/L) [G] | BASO (10^9/L) [G1] | LUC (10^9/L) [G] | RBC (10^12/L) [G] | RETIC (10^9/L) [G] | RDWG (%) [G] | HGB
(g/L)
[G] | HCT (L/L) [G] | MCV (fL) [G] | MCH
(pg)
[G] | MCHC
(g/L)
[G] | PLT (10^9/L) [G] | ||
0 mg/kg/day Group 1 | Mean | 3.863 | 0.430 | 3.239 | 0.061 | 0.088 | 0.005 | 0.039 | 7.942 | 222.87 | 10.97 | 149.6 | 0.4435 | 55.86 | 18.86 | 338.0 | 723.9 |
SD | 0.933 | 0.165 | 0.733 | 0.031 | 0.034 | 0.005 | 0.021 | 0.363 | 24.72 | 0.29 | 5.9 | 0.0183 | 1.25 | 0.65 | 7.0 | 110.8 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
100 mg/kg/day Group 2 | Mean | 3.189 | 0.591 | 2.431 | 0.052 | 0.089 | 0.000 * | 0.027 | 8.269 | 218.39 | 11.01 | 149.4 | 0.4477 | 54.17 ** | 18.08 ** | 333.7 | 755.7 |
SD | 0.724 | 0.239 | 0.546 | 0.023 | 0.034 | 0.000 | 0.008 | 0.290 | 25.11 | 0.35 | 5.1 | 0.0123 | 1.09 | 0.56 | 4.6 | 84.2 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
| tCtrl | 0.83 | 1.37 | 0.75 | 0.85 | 1.01 | 0.00 | 0.69 | 1.04 | 0.98 | 1.00 | 1.00 | 1.01 | 0.97 | 0.96 | 0.99 | 1.04 |
300 mg/kg/day Group 3
| Mean | 3.715 | 0.815 * | 2.664 | 0.077 | 0.117 | 0.000 * | 0.039 | 8.222 | 212.56 | 11.18 | 152.7 | 0.4513 | 54.93 | 18.59 | 338.5 | 735.2 |
SD | 1.399 | 0.505 | 0.822 | 0.046 | 0.076 | 0.000 | 0.022 | 0.269 | 25.28 | 0.35 | 4.9 | 0.0150 | 1.27 | 0.59 | 6.2 | 57.6 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 9 | |
tCtrl | 0.96 | 1.90 | 0.82 | 1.26 | 1.33 | 0.00 | 1.00 | 1.04 | 0.95 | 1.02 | 1.02 | 1.02 | 0.98 | 0.99 | 1.00 | 1.02 | |
1000 mg/kg/day Group 4
| Mean | 4.430 | 0.745 * | 3.462 | 0.077 | 0.097 | 0.005 | 0.043 | 8.106 | 215.62 | 10.83 | 149.5 | 0.4425 | 54.60 * | 18.45 | 338.1 | 801.0 |
SD | 1.372 | 0.369 | 1.159 | 0.029 | 0.025 | 0.007 | 0.026 | 0.347 | 45.04 | 0.29 | 5.3 | 0.0190 | 0.74 | 0.37 | 4.0 | 92.3 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 1.15 | 1.73 | 1.07 | 1.26 | 1.10 | 1.00 | 1.10 | 1.02 | 0.97 | 0.99 | 1.00 | 1.00 | 0.98 | 0.98 | 1.00 | 1.11 |
[G] - Anova & Dunnett
Table 15: Haematology summary (males) - Day 121 (end of recovery)
Sex: Male | Reporting Hematology | ||||||||||||||||
WBC (10^9/L) [G] | NEUT (10^9/L) [G] | LYMPH (10^9/L) [G] | MONO (10^9/L) [G] | EOS (10^9/L) [G] | BASO (10^9/L) [G] | LUC (10^9/L) [G] | RBC (10^12/L) [G] | RETIC (10^9/L) [G] | RDWG (%) [G] | HGB
(g/L)
[G] | HCT (L/L) [G] | MCV (fL) [G] | MCH
(pg)
[G] | MCHC
(g/L)
[G] | PLT (10^9/L) [G] | ||
0 mg/kg/day Group 1 | Mean | 4.578 | 0.928 | 3.414 | 0.090 | 0.114 | 0.008 | 0.024 | 8.780 | 186.72 | 12.38 | 158.4 | 0.4568 | 52.14 | 18.14 | 347.6 | 751.0 |
SD | 1.457 | 0.335 | 1.192 | 0.033 | 0.040 | 0.004 | 0.009 | 0.892 | 14.08 | 0.59 | 11.6 | 0.0420 | 1.20 | 1.01 | 16.2 | 83.3 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 4 | |
1000 mg/kg/day Group 4
| Mean | 5.108 | 0.894 | 3.978 | 0.096 | 0.112 | 0.008 | 0.022 | 8.662 | 172.64 | 11.68 * | 160.8 | 0.4676 | 54.02 | 18.60 | 344.4 | 730.0 |
SD | 2.131 | 0.347 | 1.732 | 0.063 | 0.023 | 0.004 | 0.013 | 0.557 | 31.43 | 0.26 | 4.9 | 0.0229 | 1.73 | 0.97 | 9.9 | 132.8 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
tCtrl | 1.12 | 0.96 | 1.17 | 1.07 | 0.98 | 1.00 | 0.92 | 0.99 | 0.92 | 0.94 | 1.02 | 1.02 | 1.04 | 1.03 | 0.99 | 0.97 |
[G] - Anova & Dunnett: * = p ≤ 0.05
Table 16: Haematology summary (Females) - Day 121 (end of recovery)
Sex: Female | Reporting Hematology | ||||||||||||||||
WBC (10^9/L) [G] | NEUT (10^9/L) [G1] | LYMPH (10^9/L) [G] | MONO (10^9/L) [G1] | EOS (10^9/L) [G] | BASO (10^9/L) [G1] | LUC (10^9/L) [G1] | RBC (10^12/L) [G] | RETIC (10^9/L) [G] | RDWG (%) [G1] | HGB
(g/L)
[G] | HCT (L/L) [G] | MCV (fL) [G] | MCH
(pg)
[G] | MCHC
(g/L)
[G] | PLT (10^9/L) [G] | ||
0 mg/kg/day Group 1 | Mean | 2.426 | 0.602 | 1.670 | 0.050 | 0.086 | 0.004 | 0.008 | 7.516 | 181.82 | 10.54 | 140.0 | 0.4116 | 54.78 | 18.64 | 340.2 | 710.2 |
SD | 0.783 | 0.466 | 0.754 | 0.016 | 0.015 | 0.005 | 0.004 | 0.726 | 12.28 | 0.27 | 12.5 | 0.0396 | 1.42 | 0.43 | 5.2 | 80.4 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
1000 mg/kg/day Group 4
| Mean | 1.698 | 0.310 | 1.270 | 0.030 | 0.076 | 0.004 | 0.008 | 8.260 | 153.40 | 10.40 | 149.6 | 0.4410 | 53.42 | 18.12 | 339.2 | 723.6 |
SD | 0.294 | 0.067 | 0.274 | 0.012 | 0.038 | 0.005 | 0.004 | 0.250 | 44.49 | 0.32 | 3.0 | 0.0124 | 0.90 | 0.29 | 4.1 | 40.8 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
tCtrl | 0.70 | 0.51 | 0.76 | 0.60 | 0.88 | 1.00 | 1.00 | 1.10 | 0.84 | 0.99 | 1.07 | 1.07 | 0.98 | 0.97 | 1.00 | 1.02 |
[G] - Anova & Dunnett
[G1] - Anova & Dunnett
Table 17: Clinical biochemistry summary (males) - Day 92 (end of treatment)
Sex: Male | Reporting Biochemistry | |||||||||||||||||||||
ALT (U/L) [G] | AST (U/L) [G] | ALP (U/L) [G1] | TPROT
(g/L)
[G] | ALB
(g/L)
[G] | TBIL (umol/L) [G] | UREA (mmol/L) [G1] | CREAT (umol/L) [G] | GLUC (mmol/L) [G] | CHOL (mmol/L) [G] | TRIG (mmol/L) [G] | HDL (mmol/L) [G] | LDL (mmol/L) [G] | NA (mmol/L) [G] | K (mmol/L) [G] | CL (mmol/L) [G] | CA (mmol/L) [G] | PHOS (mmol/L) [G] | T3 (ng/mL) [G] | T4 (ng/mL) [G] | TSH
(mU/L)
[G1] | ||
0 mg/kg/day Group 1 | Mean | 51.7 | 71.7 | 102.8 | 65.23 | 40.96 | 1.59 | 5.38 | 28.2 | 9.830 | 1.875 | 0.956 | 1.266 | 0.340 | 146.3 | 4.15 | 107.4 | 2.562 | 1.617 | 0.324 | 37.52 | 0.1327 |
SD | 8.2 | 7.9 | 18.5 | 2.46 | 0.97 | 0.22 | 0.74 | 3.3 | 1.323 | 0.436 | 0.371 | 0.243 | 0.073 | 0.9 | 0.50 | 1.0 | 0.140 | 0.109 | 0.059 | 5.28 | 0.0737 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
100 mg/kg/day Group 2
| Mean | 49.2 | 75.0 | 85.4 | 63.59 | 40.15 | 1.94 | 5.37 | 29.6 | 10.179 | 1.892 | 0.959 | 1.274 | 0.333 | 146.5 | 4.07 | 107.3 | 2.597 | 1.494 | 0.316 | 36.09 | 0.1350 |
SD | 12.3 | 25.7 | 13.3 | 1.73 | 1.26 | 0.26 | 0.44 | 2.0 | 1.700 | 0.192 | 0.309 | 0.116 | 0.042 | 1.4 | 0.30 | 1.6 | 0.168 | 0.183 | 0.071 | 7.27 | 0.1308 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.95 | 1.05 | 0.83 | 0.97 | 0.98 | 1.22 | 1.00 | 1.05 | 1.04 | 1.01 | 1.00 | 1.01 | 0.98 | 1.0 | 0.98 | 1.0 | 1.01 | 0.92 | 0.98 | 0.96 | 1.02 | |
300 mg/kg/day Group 3
| Mean | 51.3 | 69.7 | 95.0 | 65.35 | 41.17 | 1.59 | 5.46 | 29.0 | 9.169 | 1.853 | 1.025 | 1.258 | 0.321 | 146.6 | 3.88 | 107.3 | 2.642 | 1.600 | 0.331 | 41.68 | 0.1354 |
SD | 9.8 | 5.8 | 31.1 | 2.41 | 1.41 | 0.32 | 0.50 | 3.0 | 1.359 | 0.202 | 0.336 | 0.165 | 0.040 | 1.2 | 0.29 | 1.6 | 0.105 | 0.182 | 0.070 | 5.78 | 0.0650 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.99 | 0.97 | 0.92 | 1.00 | 1.01 | 1.00 | 1.01 | 1.03 | 0.93 | 0.99 | 1.07 | 0.99 | 0.94 | 1.0 | 0.93 | 1.0 | 1.03 | 0.99 | 1.02 | 1.11 | 1.02 | |
1000 mg/kg/day Group 4
| Mean | 53.4 | 87.5 | 92.5 | 64.27 | 41.05 | 1.82 | 5.86 | 29.6 | 10.106 | 2.010 | 1.338 | 1.362 | 145.8 | 145.8 | 4.17 | 106.9 | 2.613 | 1.791 | 0.349 | 36.79 | 0.0863 |
SD | 10.0 | 55.3 | 22.8 | 3.24 | 2.15 | 0.49 | 1.34 | 4.6 | 1.409 | 0.190 | 0.438 | 0.131 | 0.046 | 1.1 | 0.37 | 1.5 | 0.135 | 0.238 | 0.082 | 5.52 | 0.0568 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 1.03 | 1.22 | 0.90 | 0.99 | 1.00 | 1.14 | 1.09 | 1.05 | 1.03 | 1.07 | 1.40 | 1.08 | 1.06 | 1.0 | 1.0 | 1.0 | 1.02 | 1.11 | 1.08 | 0.98 | 0.65 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn
Table 18: Clinical biochemistry summary (females) - Day 93 (end of treatment)
Sex: Female | Reporting Biochemistry | |||||||||||||||||||||
ALT (U/L) [G] | AST (U/L) [G1] | ALP (U/L) [G] | TPROT
(g/L)
[G] | ALB
(g/L)
[G] | TBIL (umol/L) [G] | UREA (mmol/L) [G1] | CREAT (umol/L) [G] | GLUC (mmol/L) [G] | CHOL (mmol/L) [G] | TRIG (mmol/L) [G] | HDL (mmol/L) [G] | LDL (mmol/L) [G] | NA (mmol/L) [G] | K (mmol/L) [G] | CL (mmol/L) [G] | CA (mmol/L) [G1] | PHOS (mmol/L) [G] | T3 (ng/mL) [G] | T4 (ng/mL) [G] | TSH
(mU/L)
[G1] | ||
0 mg/kg/day Group 1 | Mean | 56.4 | 102.6 | 38.1 | 71.08 | 45.71 | 2.36 | 6.85 | 35.3 | 8.201 | 1.628 | 0.840 | 1.111 | 0.328 | 150.8 | 3.76 | 111.6 | 2.629 | 1.533 | 0.479 | 24.72 | 0.1075 |
SD | 17.9 | 58.1 | 11.8 | 2.19 | 1.64 | 0.34 | 0.71 | 3.2 | 0.851 | 0.300 | 0.317 | 0.192 | 0.050 | 1.0 | 0.20 | 1.4 | 0.082 | 0.200 | 0.107 | 5.03 | 0.0759 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
100 mg/kg/day Group 2
| Mean | 50.7 | 74.8 | 36.1 | 71.40 | 45.63 | 2.01 | 6.56 | 37.5 | 8.172 | 1.477 | 0.903 | 0.995 | 0.306 | 150.3 | 3.90 | 112.0 | 2.604 | 1.104** | 0.495 | 30.04 | 0.0829 |
SD | 8.6 | 6.8 | 6.9 | 2.28 | 1.77 | 0.36 | 0.67 | 3.4 | 0.652 | 0.279 | 0.360 | 0.189 | 0.060 | 1.2 | 0.36 | 1.5 | 0.078 | 0.192 | 0.106 | 8.18 | 0.0525 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.90 | 0.73 | 0.95 | 1.00 | 1.00 | 0.85 | 0.96 | 1.06 | 1.00 | 0.91 | 1.08 | 0.90 | 0.93 | 1.00 | 1.04 | 1.00 | 0.99 | 0.72 | 1.03 | 1.22 | 0.77 | |
300 mg/kg/day Group 3
| Mean | 46.1 | 73.4 | 38.6 | 67.05 * | 42.96 * | 1.93 | 6.60 | 34.2 | 7.832 | 1.408 | 1.013 | 0.950 | 0.287 | 147.2** | 3.85 | 109.5* | 2.671 | 1.299 | 0.414 | 24.36 | 0.0687 |
SD | 9.1 | 11.3 | 18.4 | 4.85 | 2.56 | 0.36 | 1.02 | 3.3 | 1.440 | 0.358 | 0.501 | 0.250 | 0.075 | 2.6 | 0.21 | 2.3 | 0.192 | 0.296 | 0.051 | 6.66 | 0.0504 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.82 | 0.72 | 1.01 | 0.94 | 0.94 | 0.82 | 0.96 | 0.97 | 0.96 | 0.86 | 1.21 | 0.86 | 0.88 | 0.98 | 1.02 | 0.98 | 1.02 | 0.85 | 0.86 | 0.99 | 0.64 | |
1000 mg/kg/day Group 4
| Mean | 54.3 | 67.3 * | 41.3 | 69.92 | 44.71 | 2.25 | 6.65 | 32.8 | 8.691 | 1.796 | 0.924 | 1.254 | 0.387 | 146.8** | 3.81 | 108.5** | 2.705 | 1.406 | 0.544 | 33.98* | 0.0941 |
SD | 13.0 | 5.4 | 11.7 | 2.83 | 2.07 | 0.53 | 0.82 | 2.9 | 1.021 | 0.335 | 0.388 | 0.230 | 0.084 | 0.8 | 0.27 | 1.4 | 0.122 | 0.203 | 0.115 | 7.40 | 0.0400 | |
N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
tCtrl | 0.96 | 0.66 | 1.08 | 0.98 | 0.98 | 0.95 | 0.97 | 0.93 | 1.06 | 1.10 | 1.10 | 1.13 | 1.18 | 0.97 | 1.01 | 0.97 | 1.03 | 0.92 | 1.14 | 1.37 | 0.88 |
[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01
[G1] - Kruskal-Wallis & Dunn
Table 19: Clinical biochemistry summary (males) - Day 121 (end of recovery)
Sex: Male | Reporting Biochemistry | |||||||||||||||||||||
ALT (U/L) [G] | AST (U/L) [G] | ALP (U/L) [G] | TPROT
(g/L)
[G] | ALB
(g/L)
[G] | TBIL (umol/L) [G] | UREA (mmol/L) [G1] | CREAT (umol/L) [G] | GLUC (mmol/L) [G] | CHOL (mmol/L) [G] | TRIG (mmol/L) [G] | HDL (mmol/L) [G] | LDL (mmol/L) [G] | NA (mmol/L) [G1] | K (mmol/L) [G] | CL (mmol/L) [G] | CA (mmol/L) [G] | PHOS (mmol/L) [G] | T3 (ng/mL) [G] | T4 (ng/mL) [G1] | TSH
(mU/L)
[G1] | ||
0 mg/kg/day Group 1 | Mean | 46.5 | 69.3 | 87.8 | 62.74 | 39.14 | 1.94 | 4.93 | 28.7 | 8.630 | 1.844 | 1.044 | 1.278 | 0.348 | 144.6 | 3.76 | 106.8 | 2.590 | 1.468 | 0.328 | 37.74 | 0.2830 |
SD | 9.6 | 9.2 | 20.5 | 2.36 | 1.34 | 0.33 | 0.50 | 1.4 | 0.482 | 0.338 | 0.541 | 0.208 | 0.047 | 0.5 | 0.25 | 1.1 | 0.082 | 0.104 | 0.070 | 3.13 | 0.2264 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
1000 mg/kg/day Group 4
| Mean | 42.0 | 62.4 | 86.9 | 63.42 | 39.10 | 1.92 | 5.41 | 29.3 | 9.218 | 1.790 | 1.176 | 1.246 | 0.338 | 145.0 | 3.86 | 107.6 | 2.542 | 1.532 | 0.286 | 40.78 | 0.2070 |
SD | 4.5 | 8.7 | 16.4 | 3.40 | 1.15 | 0.40 | 0.35 | 0.8 | 0.686 | 0.170 | 0.786 | 0.130 | 0.059 | 1.4 | 0.22 | 1.3 | 0.072 | 0.102 | 0.067 | 10.51 | 0.0911 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
tCtrl | 0.90 | 0.90 | 0.99 | 1.01 | 1.00 | 0.99 | 1.10 | 1.02 | 1.07 | 0.97 | 1.13 | 0.97 | 0.97 | 1.00 | 1.03 | 1.01 | 0.98 | 1.04 | 0.87 | 1.08 | 0.73 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn
Table 20: Clinical biochemistry summary (females) - Day 121 (end of recovery)
Sex: Female | Reporting Biochemistry | |||||||||||||||||||||
ALT (U/L) [G] | AST (U/L) [G] | ALP (U/L) [G1] | TPROT
(g/L)
[G] | ALB
(g/L)
[G] | TBIL (umol/L) [G] | UREA (mmol/L) [G1] | CREAT (umol/L) [G] | GLUC (mmol/L) [G] | CHOL (mmol/L) [G] | TRIG (mmol/L) [G] | HDL (mmol/L) [G] | LDL (mmol/L) [G] | NA (mmol/L) [G] | K (mmol/L) [G] | CL (mmol/L) [G1] | CA (mmol/L) [G] | PHOS (mmol/L) [G] | T3 (ng/mL) [G] | T4 (ng/mL) [G] | TSH
(mU/L)
[G] | ||
0 mg/kg/day Group 1 | Mean | 56.4 | 142.6 | 46.0 | 66.08 | 42.30 | 3.18 | 6.46 | 33.4 | 7.566 | 1.630 | 0.710 | 1.178 | 0.314 | 143.8 | 3.63 | 106.8 | 2.622 | 1.478 | 0.402 | 26.26 | 0.0754 |
SD | 30.7 | 155.3 | 12.3 | 2.79 | 2.06 | 0.66 | 0.69 | 3.5 | 0.732 | 0.374 | 0.247 | 0.261 | 0.103 | 1.5 | 0.41 | 1.3 | 0.098 | 0.172 | 0.038 | 3.65 | 0.0422 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
1000 mg/kg/day Group 4
| Mean | 40.2 | 77.5 | 30.0 * | 61.66 * | 39.62 | 1.94 ** | 6.62 | 35.8 | 8.112 | 1.310 | 0.576 | 0.906 | 0.248 | 143.8 | 3.64 | 108.2 | 2.592 | 1.494 | 0.448 | 25.18 | 0.0398 |
SD | 8.6 | 15.4 | 5.8 | 2.05 | 1.90 | 0.23 | 1.02 | 5.3 | 0.340 | 0.311 | 0.227 | 0.242 | 0.062 | 0.4 | 0.23 | 0.4 | 0.146 | 0.311 | 0.060 | 5.00 | 0.0295 | |
N | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
tCtrl | 0.71 | 0.54 | 0.65 | 0.93 | 0.94 | 0.61 | 1.03 | 1.07 | 1.07 | 0.80 | 0.81 | 0.77 | 0.79 | 1.00 | 1.00 | 1.01 | 0.99 | 1.01 | 1.11 | 0.96 | 0.53 |
[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01
[G1] - Kruskal-Wallis & Dunn
Table 21: Functional observations (males)
| GROUP 1 CONTROL | GROUP 2 100 MG/KG | GROUP 3 300 MG/KG | GROUP 4 1000 MG/KG | |
AT WEEK 13 HEARING |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
PUPIL L | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
PUPIL R | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
STATIC R | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
GRIP FORE | MEAN | 1836 | 1753 | 1587 | 1620 |
GRAM | ST.DEV | 144 | 126 | 272 | 180 |
| N | 5 | 5 | 5 | 5 |
GRIP HIND | MEAN | 1236 | 1025 | 1083 | 1061 |
GRAM | ST.DEV | 215 | 104 | 193 | 131 |
| N | 5 | 5 | 5 | 5 |
Total movements | MEAN | 3194 | 2383 | 2374 | 2863 |
| ST.DEV | 919 | 521 | 634 | 400 |
| N | 5 | 5 | 5 | 5 |
Ambulations | MEAN | 517 | 389 | 371 | 306 |
| ST.DEV | 155 | 123 | 123 | 108 |
| N | 5 | 5 | 5 | 5 |
END OF RECOVERY HEARING |
MEDIAN |
0 |
|
|
0 |
SCORE 0/1 | N | 5 |
|
| 5 |
PUPIL L | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
PUPIL R | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
STATIC R | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
GRIP FORE | MEAN | 1385 |
|
| 1318 |
GRAM | ST.DEV | 101 |
|
| 108 |
| N | 5 |
|
| 5 |
GRIP HIND | MEAN | 621 |
|
| 610 |
GRAM | ST.DEV | 90 |
|
| 46 |
| N | 5 |
|
| 5 |
Table 22: Functional observations (females)
| GROUP 1 CONTROL | GROUP 2 100 MG/KG | GROUP 3 300 MG/KG | GROUP 4 1000 MG/KG | |
AT WEEK 13 HEARING |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
PUPIL L | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
PUPIL R | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
STATIC R | MEDIAN | 0 | 0 | 0 | 0 |
SCORE 0/1 | N | 5 | 5 | 5 | 5 |
GRIP FORE | MEAN | 1318 | 1379 | 1385 | 1309 |
GRAM | ST.DEV | 100 | 122 | 260 | 298 |
| N | 5 | 5 | 5 | 5 |
GRIP HIND | MEAN | 753 | 757 | 758 | 731 |
GRAM | ST.DEV | 112 | 124 | 108 | 55 |
| N | 5 | 5 | 5 | 5 |
Total movements | MEAN | 4615 | 4448 | 3870 | 2739* |
| ST.DEV | 1238 | 1689 | 954 | 754 |
| N | 5 | 5 | 5 | 5 |
Ambulations | MEAN | 1095 | 968 | 1018 | 66 |
| ST.DEV | 250 | 382 | 298 | 298 |
| N | 5 | 5 | 5 | 5 |
END OF RECOVERY HEARING |
MEDIAN |
0 |
|
|
0 |
SCORE 0/1 | N | 5 |
|
| 5 |
PUPIL L | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
PUPIL R | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
STATIC R | MEDIAN | 0 |
|
| 0 |
SCORE 0/1 | N | 5 |
|
| 5 |
GRIP FORE | MEAN | 1141 |
|
| 1118 |
GRAM | ST.DEV | 51 |
|
| 143 |
| N | 5 |
|
| 5 |
GRIP HIND | MEAN | 498 |
|
| 420 |
GRAM | ST.DEV | 68 |
|
| 48 |
| N | 5 |
|
| 5 |
* indicates a p-value <0.05
Table 23: organ weights (males) - end of treatment
Sex: Male
Day(s) Relative to Start Date | 0 mg/kg/day Group 1 | 100 mg/kg/day Group 2 | 300 mg/kg/day Group 3 | 1000 mg/kg/day Group 4 | |
Terminal Body Weight (g) - [G] | Mean | 390.2 | 397.5 | 392.7 | 379.9 |
| SD | 34.3 | 31.1 | 35.0 | 38.2 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 1.9 | 0.6 | -2.6 |
Brain Weight (g) - [G] | Mean | 2.0935 | 2.1146 | 2.0818 | 2.0894 |
| SD | 0.0440 | 0.0863 | 0.0783 | 0.0921 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 1.0079 | -0.5589 | -0.1958 |
Brain (%bw) - [G] | Mean | 0.54047 | 0.53454 | 0.53342 | 0.55451 |
| SD | 0.05097 | 0.04181 | 0.04581 | 0.05655 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.09685 | -1.30435 | 2.59825 |
Epididymis Weight (g) - [G] | Mean | 1.1058 | 1.2115 | 1.1425 | 1.1034 |
| SD | 0.2424 | 0.1529 | 0.0569 | 0.0814 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 9.5587 | 3.3189 | -0.2170 |
Epididymis (%bw) - [G] | Mean | 0.28625 | 0.30616 | 0.29311 | 0.29259 |
| SD | 0.06911 | 0.04314 | 0.03155 | 0.03184 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 6.95598 | 2.39837 | 2.21606 |
Gland, Adrenal Weight (g) - [G] | Mean | 0.05769 | 0.05761 | 0.05602 | 0.04911 |
| SD | 0.00851 | 0.00549 | 0.00635 | 0.01015 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -0.13867 | -2.89478 | -14.87259 |
Gland, Adrenal (%bw) - [G] | Mean | 0.01484 | 0.01454 | 0.01438 | 0.01305 |
| SD | 0.00216 | 0.00149 | 0.00222 | 0.00291 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -2.04209 | -3.15592 | -12.06055 |
Gland, Pituitary Weight (g) [G] | Mean | 0.00824 | 0.00858 | 0.00785 | 0.00821 |
| SD | 0.00105 | 0.00140 | 0.00140 | 0.00071 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 4.12621 | -4.73301 | -0.36408 |
Gland, Pituitary (%bw) [G1] | Mean | 0.00211 | 0.00215 | 0.00200 | 0.00217 |
| SD | 0.00021 | 0.00027 | 0.00035 | 0.00014 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 1.94015 | -5.12563 | 2.58658 |
Gland, Prostate Weight (g) [G] | Mean | 0.9458 | 0.9291 | 0.8763 | 0.8380 |
| SD | 0.1549 | 0.1875 | 0.1589 | 0.1562 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.7657 | -7.3483 | -11.3978 |
Gland, Prostate (%bw) [G] | Mean | 0.24348 | 0.23503 | 0.22478 | 0.22299 |
| SD | 0.04065 | 0.05206 | 0.04463 | 0.04970 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -3.47163 | -7.68092 | -8.41815 |
Seminal Vesicle Weight (g) - [G] | Mean | 1.2683 | 1.3261 | 1.2883 | 1.2644 |
| SD | 0.1735 | 0.2229 | 0.1849 | 0.2585 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 4.5573 | 1.5769 | -0.3075 |
Seminal Vesicle (%bw) - [G] | Mean | 0.32660 | 0.33502 | 0.32943 | 0.33592 |
| SD | 0.04811 | 0.05917 | 0.04807 | 0.07580 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 2.57825 | 0.86792 | 2.85589 |
Thyroid/Parathyroid Weight (g) - [G1] | Mean | 0.01561 | 0.01824 | 0.01915 | 0.01891 |
| SD | 0.00394 | 0.00529 | 0.00305 | 0.00751 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 16.84817 | 22.67777 | 21.14029 |
Thyroid/Parathyroid (%bw) - [G] | Mean | 0.00399 | 0.00460 | 0.00492 | 0.00491 |
| SD | 0.00094 | 0.00133 | 0.00090 | 0.00171 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 15.30492 | 23.42286 | 23.16273 |
Heart Weight (g) - [G] | Mean | 1.0040 | 1.0086 | 1.0097 | 0.9653 |
| SD | 0.0791 | 0.1207 | 0.0761 | 0.0657 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.4582 | 0.5677 | -3.8546 |
Heart (%bw) - [G] | Mean | 0.25866 | 0.25349 | 0.25822 | 0.25538 |
| SD | 0.02636 | 0.01924 | 0.02185 | 0.01998 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.99783 | -0.17065 | -1.26674 |
Kidney Weight (g) - [G] | Mean | 2.3623 | 2.4359 | 2.4542 | 2.2696 |
| SD | 0.2188 | 0.3319 | 0.1431 | 0.2500 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 3.1156 | 3.8903 | -3.9241 |
Kidney (%bw) - [G] | Mean | 0.60731 | 0.61216 | 0.62858 | 0.59839 |
| SD | 0.05371 | 0.05901 | 0.05800 | 0.04842 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.79814 | 3.50222 | -1.46983 |
Liver Weight (g) - [G] | Mean | 8.7411 | 8.7143 | 8.7788 | 8.9585 |
| SD | 0.9853 | 0.9765 | 1.0136 | 0.8868 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -0.3066 | 0.4313 | 2.4871 |
Liver (%bw) - [G] | Mean | 2.23748 | 2.18929 | 2.23487 | 2.36098 |
| SD | 0.10434 | 0.11829 | 0.15663 | 0.11509 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -2.15404 | -0.11678 | 5.51955 |
Spleen Weight (g) - [G1] | Mean | 0.5104 | 0.5840 | 0.5480 | 0.5271 |
| SD | 0.0500 | 0.1114 | 0.0702 | 0.0474 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 14.4201 | 7.3668 | 3.2719 |
Spleen (%bw) - [G] | Mean | 0.13119 | 0.14625 | 0.14010 | 0.13916 |
| SD | 0.01222 | 0.02020 | 0.01873 | 0.00983 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 11.47773 | 6.78977 | 6.07030 |
Testis Weight (g) - [G] | Mean | 3.2215 | 3.7755 | 3.6595 | 3.5242 |
| SD | 0.9363 | 0.3880 | 0.3237 | 0.1842 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 17.1970 | 13.5962 | 9.3962 |
Testis (%bw) - [G] | Mean | 0.83486 | 0.95425 | 0.93987 | 0.93357 |
| SD | 0.25480 | 0.11391 | 0.12907 | 0.07621 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 14.30168 | 12.57932 | 11.82419 |
Thymus Weight (g) - [G] | Mean | 0.2759 | 0.2790 | 0.3239 | 0.3061 |
| SD | 0.0834 | 0.0786 | 0.0605 | 0.0959 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 1.1236 | 17.3976 | 10.9460 |
Thymus (%bw) - [G] | Mean | 0.06975 | 0.06991 | 0.08280 | 0.07997 |
| SD | 0.01722 | 0.01779 | 0.01446 | 0.02148 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.23340 | 18.70625 | 14.65698 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn: * = p ≤ 0.05
Table 24: organ weights (females) - end of treatment
Sex: Female
Day(s) Relative to Start Date | 0 mg/kg/day Group 1 | 100 mg/kg/day Group 2 | 300 mg/kg/day Group 3 | 1000 mg/kg/day Group 4 | |
Terminal Body Weight (g) - [G] | Mean | 220.6 | 226.2 | 213.3 | 231.0 |
| SD | 13.7 | 15.3 | 15.3 | 13.0 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 2.5 | -3.3 | 4.7 |
Brain Weight (g) - [G1] | Mean | 1.8958 | 1.9140 | 1.8589 | 1.8968 |
| SD | 0.0612 | 0.0492 | 0.0271 | 0.0563 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.9600 | -1.9464 | 0.0527 |
Brain (%bw) - [G] | Mean | 0.86149 | 0.84923 | 0.87619 | 0.82264 |
| SD | 0.04436 | 0.05478 | 0.07360 | 0.03431 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.42301 | 1.70715 | -4.50976 |
Gland, Adrenal Weight (g) - [G] | Mean | 0.05907 | 0.06330 | 0.06361 | 0.06358 |
| SD | 0.00971 | 0.01033 | 0.00735 | 0.00694 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 7.16100 | 7.68580 | 7.63501 |
Gland, Adrenal (%bw) - [G] | Mean | 0.02672 | 0.02794 | 0.02982 | 0.02754 |
| SD | 0.00369 | 0.00378 | 0.00273 | 0.00268 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 4.59109 | 11.62243 | 3.06385 |
Gland, Pituitary Weight (g) [G1] | Mean | 0.01478 | 0.01014 | 0.01116 | 0.01126 |
| SD | 0.00532 | 0.00255 | 0.00296 | 0.00167 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -31.39378 | -24.49256 | -23.81597 |
Gland, Pituitary (%bw) [G1] | Mean | 0.00666 | 0.00448 * | 0.00523 | 0.00488 |
| SD | 0.00223 | 0.00103 | 0.00130 | 0.00073 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -32.71386 | -21.48404 | -26.68346 |
Thyroid/Parathyroid Weight (g) - [G] | Mean | 0.01239 | 0.01440 | 0.01277 | 0.01443 |
| SD | 0.00220 | 0.00284 | 0.00367 | 0.00354 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 16.22276 | 3.06699 | 16.46489 |
Thyroid/Parathyroid (%bw) - [G] | Mean | 0.00564 | 0.00638 | 0.00600 | 0.00630 |
| SD | 0.00111 | 0.00132 | 0.00174 | 0.00182 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 13.19007 | 6.42890 | 11.71956 |
Heart Weight (g) - [G] | Mean | 0.6792 | 0.6821 | 0.6207 | 0.7181 |
| SD | 0.0507 | 0.0757 | 0.0536 | 0.0448 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.4270 | -8.6131 | 5.7273 |
Heart (%bw) - [G] | Mean | 0.30853 | 0.30129 | 0.29126 | 0.31131 |
| SD | 0.02475 | 0.02313 | 0.01832 | 0.01892 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -2.34775 | -5.59609 | 0.90247 |
Kidney Weight (g) - [G] | Mean | 1.4672 | 1.5831 | 1.4736 | 1.7272 ** |
| SD | 0.0838 | 0.1193 | 0.1311 | 0.1965 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 7.8994 | 0.4362 | 17.7208 |
Kidney (%bw) - [G1] | Mean | 0.66594 | 0.70065 | 0.69076 | 0.74781 ** |
| SD | 0.03215 | 0.04251 | 0.03323 | 0.07497 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 5.21116 | 3.72597 | 12.29292 |
Liver Weight (g) - [G] | Mean | 5.3753 | 5.4101 | 5.0887 | 6.4360 ** |
| SD | 0.3872 | 0.5482 | 0.4642 | 0.5899 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 0.6474 | -5.3318 | 19.7329 |
Liver (%bw) - [G] | Mean | 2.43901 | 2.39304 | 2.38706 | 2.79153 ** |
| SD | 0.14303 | 0.20287 | 0.15493 | 0.27667 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.88477 | -2.12999 | 14.45347 |
Ovary Paired (g) - [G] | Mean | 0.1361 | 0.1468 | 0.1421 | 0.1377 |
| SD | 0.0210 | 0.0210 | 0.0243 | 0.0172 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 7.8619 | 4.4085 | 1.1756 |
Ovary Paired (%bw) - [G] | Mean | 0.06164 | 0.06522 | 0.06703 | 0.05966 |
| SD | 0.00831 | 0.01101 | 0.01308 | 0.00699 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | 5.80168 | 8.74297 | -3.22236 |
Spleen Weight (g) - [G1] | Mean | 0.4167 | 0.4165 | 0.3773 | 0.4617 |
| SD | 0.0763 | 0.0388 | 0.0371 | 0.0357 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -0.0480 | -9.4552 | 10.7991 |
Spleen (%bw) - [G] | Mean | 0.18857 | 0.18411 | 0.17756 | 0.20006 |
| SD | 0.03104 | 0.01172 | 0.02108 | 0.01443 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -2.36212 | -5.83761 | 6.09656 |
Thymus Weight (g) - [G1] | Mean | 0.2929 | 0.2894 | 0.2506 | 0.2886 |
| SD | 0.0820 | 0.0706 | 0.0479 | 0.0574 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -1.1949 | -14.4418 | -1.4681 |
Thymus (%bw) - [G1] | Mean | 0.13204 | 0.12701 | 0.11827 | 0.12521 |
| SD | 0.03288 | 0.02467 | 0.02659 | 0.02594 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -3.81140 | -10.42849 | -5.17288 |
Uterus/Cervix (g) - [G] | Mean | 0.6704 | 0.6153 | 0.4746 | 0.5312 |
| SD | 0.2816 | 0.2422 | 0.0977 | 0.1136 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -8.2190 | -29.2064 | -20.7637 |
Uterus/Cervix (%bw) - [G] | Mean | 0.30787 | 0.27105 | 0.22254 | 0.23051 |
| SD | 0.13656 | 0.09880 | 0.04277 | 0.05042 |
| N | 10 | 10 | 10 | 10 |
| %Diff | - | -11.96024 | -27.71662 | -25.12699 |
[G] - Anova & Dunnett: ** = p ≤ 0.01
[G] - Anova & Dunnett
Table 25: organ weights (males) - end of recovery
Sex: Male
Day(s) Relative to Start Date | 0 mg/kg/day Group 1 | 1000 mg/kg/day Group 4 | |
Terminal Body Weight (g) - [G] | Mean | 416.2 | 417.8 |
| SD | 30.4 | 33.6 |
| N | 5 | 5 |
| %Diff | - | 0.4 |
Brain Weight (g) - [G] | Mean | 2.1002 | 2.0828 |
| SD | 0.1227 | 0.1062 |
| N | 5 | 5 |
| %Diff | - | -0.8285 |
Brain (%bw) - [G] | Mean | 0.50524 | 0.50009 |
| SD | 0.01655 | 0.03204 |
| N | 5 | 5 |
| %Diff | - | -1.01955 |
Epididymis Weight (g) - [G] | Mean | 1.2254 | 1.2330 |
| SD | 0.1105 | 0.1300 |
| N | 5 | 5 |
| %Diff | - | 0.6202 |
Epididymis (%bw) - [G] | Mean | 0.29438 | 0.29543 |
| SD | 0.01556 | 0.02716 |
| N | 5 | 5 |
| %Diff | - | 0.35575 |
Gland, Adrenal Weight (g) - [G] | Mean | 0.05264 | 0.05538 |
| SD | 0.00576 | 0.00582 |
| N | 5 | 5 |
| %Diff | - | 5.20517 |
Gland, Adrenal (%bw) - [G] | Mean | 0.01266 | 0.01333 |
| SD | 0.00117 | 0.00178 |
| N | 5 | 5 |
| %Diff | - | 5.26824 |
Gland, Pituitary Weight (g) [G1] | Mean | 0.00922 | 0.01498 |
| SD | 0.00154 | 0.00829 |
| N | 5 | 5 |
| %Diff | - | 62.47289 |
Gland, Pituitary (%bw) [G1] | Mean | 0.00221 | 0.00353 |
| SD | 0.00027 | 0.00185 |
| N | 5 | 5 |
| %Diff | - | 59.90894 |
Gland, Prostate Weight (g) [G] | Mean | 1.0258 | 0.8896 |
| SD | 0.1418 | 0.1802 |
| N | 5 | 5 |
| %Diff | - | -13.2774 |
Gland, Prostate (%bw) [G] | Mean | 0.24663 | 0.21396 |
| SD | 0.03056 | 0.04640 |
| N | 5 | 5 |
| %Diff | - | -13.24820 |
Seminal Vesicle Weight (g) - [G] | Mean | 1.3982 | 1.5228 |
| SD | 0.2755 | 0.3414 |
| N | 5 | 5 |
| %Diff | - | 8.9115 |
Seminal Vesicle (%bw) - [G] | Mean | 0.33727 | 0.36373 |
| SD | 0.06901 | 0.06780 |
| N | 5 | 5 |
| %Diff | - | 7.84566 |
Thyroid/Parathyroid Weight (g) - [G1] | Mean | 0.01610 | 0.01556 |
| SD | 0.00533 | 0.00319 |
| N | 5 | 5 |
| %Diff | - | -3.35404 |
Thyroid/Parathyroid (%bw) - [G1] | Mean | 0.00388 | 0.00370 |
| SD | 0.00129 | 0.00054 |
| N | 5 | 5 |
| %Diff | - | -4.55710 |
Heart Weight (g) - [G] | Mean | 1.0272 | 1.0704 |
| SD | 0.0534 | 0.0746 |
| N | 5 | 5 |
| %Diff | - | 4.2056 |
Heart (%bw) - [G] | Mean | 0.24756 | 0.25665 |
| SD | 0.01706 | 0.01272 |
| N | 5 | 5 |
| %Diff | - | 3.66822 |
Kidney Weight (g) - [G] | Mean | 2.3472 | 2.5980 |
| SD | 0.2748 | 0.3611 |
| N | 5 | 5 |
| %Diff | - | 10.6851 |
Kidney (%bw) - [G] | Mean | 0.56367 | 0.62134 |
| SD | 0.04690 | 0.06600 |
| N | 5 | 5 |
| %Diff | - | 10.23148 |
Liver Weight (g) - [G] | Mean | 8.8570 | 9.6144 |
| SD | 1.0204 | 1.5403 |
| N | 5 | 5 |
| %Diff | - | 8.5514 |
Liver (%bw) - [G] | Mean | 2.12282 | 2.29077 |
| SD | 0.09992 | 0.21010 |
| N | 5 | 5 |
| %Diff | - | 7.91134 |
Spleen Weight (g) - [G] | Mean | 0.6252 | 0.6066 |
| SD | 0.0440 | 0.1345 |
| N | 5 | 5 |
| %Diff | - | -2.9750 |
Spleen (%bw) - [G1] | Mean | 0.15038 | 0.14470 |
| SD | 0.00762 | 0.02485 |
| N | 5 | 5 |
| %Diff | - | -3.77737 |
Testis Weight (g) - [G] | Mean | 3.6980 | 3.7970 |
| SD | 0.1267 | 0.1574 |
| N | 5 | 5 |
| %Diff | - | 2.6771 |
Testis (%bw) - [G] | Mean | 0.89239 | 0.91195 |
| SD | 0.07222 | 0.05657 |
| N | 5 | 5 |
| %Diff | - | 2.19240 |
Thymus Weight (g) - [G] | Mean | 0.2932 | 0.2612 |
| SD | 0.0699 | 0.0988 |
| N | 5 | 5 |
| %Diff | - | -10.9141 |
Thymus (%bw) - [G] | Mean | 0.07044 | 0.06192 |
| SD | 0.01514 | 0.02120 |
| N | 5 | 5 |
| %Diff | - | -12.09428 |
[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn
Table 26: organ weights (females) - end of recovery
Sex: Female
Day(s) Relative to Start Date | 0 mg/kg/day Group 1 | 1000 mg/kg/day Group 4 | |
Terminal Body Weight (g) - [G] | Mean | 239.8 | 227.6 |
| SD | 9.6 | 15.5 |
| N | 5 | 5 |
| %Diff | - | -5.1 |
Brain Weight (g) - [G1] | Mean | 1.9122 | 1.9748 |
| SD | 0.0511 | 0.1385 |
| N | 5 | 5 |
| %Diff | - | 3.2737 |
Brain (%bw) - [G] | Mean | 0.79809 | 0.86811 ** |
| SD | 0.02740 | 0.03459 |
| N | 5 | 5 |
| %Diff | - | 8.77419 |
Gland, Adrenal Weight (g) - [G] | Mean | 0.06100 | 0.07034 |
| SD | 0.00904 | 0.01447 |
| N | 5 | 5 |
| %Diff | - | 15.31148 |
Gland, Adrenal (%bw) - [G] | Mean | 0.02552 | 0.03068 |
| SD | 0.00446 | 0.00444 |
| N | 5 | 5 |
| %Diff | - | 20.21525 |
Gland, Pituitary Weight (g) [G1] | Mean | 0.01114 | 0.01256 |
| SD | 0.00414 | 0.00060 |
| N | 5 | 5 |
| %Diff | - | 12.74686 |
Gland, Pituitary (%bw) [G] | Mean | 0.00460 | 0.00554 |
| SD | 0.00161 | 0.00042 |
| N | 5 | 5 |
| %Diff | - | 20.31781 |
Thyroid/Parathyroid Weight (g) - [G] | Mean | 0.01410 | 0.01654 |
| SD | 0.00103 | 0.00277 |
| N | 5 | 5 |
| %Diff | - | 17.30496 |
Thyroid/Parathyroid (%bw) - [G] | Mean | 0.00589 | 0.00732 |
| SD | 0.00057 | 0.00157 |
| N | 5 | 5 |
| %Diff | - | 24.25956 |
Heart Weight (g) - [G] | Mean | 0.7156 | 0.6652 |
| SD | 0.0564 | 0.0945 |
| N | 5 | 5 |
| %Diff | - | -7.0430 |
Heart (%bw) - [G] | Mean | 0.29813 | 0.29128 |
| SD | 0.01336 | 0.02578 |
| N | 5 | 5 |
| %Diff | - | -2.29654 |
Kidney Weight (g) - [G] | Mean | 1.5562 | 1.5080 |
| SD | 0.1430 | 0.1578 |
| N | 5 | 5 |
| %Diff | - | -3.0973 |
Kidney (%bw) - [G] | Mean | 0.64965 | 0.66137 |
| SD | 0.06221 | 0.02983 |
| N | 5 | 5 |
| %Diff | - | 1.80335 |
Liver Weight (g) - [G] | Mean | 5.8176 | 5.3962 |
| SD | 0.5446 | 0.6612 |
| N | 5 | 5 |
| %Diff | - | -7.2435 |
Liver (%bw) - [G] | Mean | 2.42291 | 2.36682 |
| SD | 0.14767 | 0.20047 |
| N | 5 | 5 |
| %Diff | - | -2.31522 |
Ovary Paired (g) - [G] | Mean | 0.1388 | 0.1400 |
| SD | 0.0169 | 0.0182 |
| N | 5 | 5 |
| %Diff | - | 0.8646 |
Ovary Paired (%bw) - [G] | Mean | 0.05802 | 0.06134 |
| SD | 0.00809 | 0.00477 |
| N | 5 | 5 |
| %Diff | - | 5.72474 |
Spleen Weight (g) - [G1] | Mean | 0.4208 | 0.3914 |
| SD | 0.0223 | 0.0478 |
| N | 5 | 5 |
| %Diff | - | -6.9867 |
Spleen (%bw) - [G] | Mean | 0.17580 | 0.17162 |
| SD | 0.01300 | 0.01342 |
| N | 5 | 5 |
| %Diff | - | -2.37705 |
Thymus Weight (g) - [G] | Mean | 0.2656 | 0.2180 |
| SD | 0.0429 | 0.0323 |
| N | 5 | 5 |
| %Diff | - | -17.9217 |
Thymus (%bw) - [G] | Mean | 0.11060 | 0.09586 |
| SD | 0.01639 | 0.01350 |
| N | 5 | 5 |
| %Diff | - | -13.32804 |
Uterus/Cervix (g) - [G] | Mean | 0.6696 | 0.5598 |
| SD | 0.2254 | 0.1107 |
| N | 5 | 5 |
| %Diff | - | -16.3978 |
Uterus/Cervix (%bw) - [G1] | Mean | 0.27920 | 0.24616 |
| SD | 0.09299 | 0.04749 |
| N | 5 | 5 |
| %Diff | - | -11.83234 |
[G] - Anova & Dunnett: ** = p ≤ 0.01
[G1] - Kruskal-Wallis & Dunn
Table 27: microscopic pathology (males & females) - end of treatment
Removal Reason(s): TERMINAL EUTHANASIA Summary: Incidence
Number of Animals: |
0
mg/kg/ day Group 1 | Male
100 300
mg/kg/ mg/kg/ day day Group Group 2 3 |
1000
mg/kg/ day Group 4 |
0
mg/kg/ day Group 1 | Female
100 300
mg/kg/ mg/kg/ day day Group Group 2 3 |
1000
mg/kg/ day Group 4 | ||
10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
ARTERY, AORTA |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
BONE MARROW, STERNUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
BONE, STERNUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
BRAIN |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
CERVIX |
|
|
|
|
|
|
|
|
Examined | . | . | . | . | 10 | 0 | 0 | 10 |
No Visible Lesions | . | . | . | . | 10 | . | . | 10 |
EPIDIDYMIS |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | . | . | . | . |
No Visible Lesions | 9 | . | . | 9 | . | . | . | . |
Sperm, decreased; lumen | 1 | . | . | 0 | . | . | . | . |
.... marked | 1 | . | . | 0 | . | . | . | . |
Infiltration, mononuclear cell; | 0 | . | . | 1 | . | . | . | . |
interstitial |
|
|
|
|
|
|
|
|
.... minimal | 0 | . | . | 1 | . | . | . | . |
ESOPHAGUS |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
EYE |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 9 | 10 | . | . | 9 |
Hemorrhage; acute | 0 | . | . | 1 | 0 | . | . | 1 |
.... minimal | 0 | . | . | 1 | 0 | . | . | 1 |
GALT |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, ADRENAL |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 9 | 10 | . | . | 10 |
Vacuolation; zona fasciculata | 0 | . | . | 1 | 0 | . | . | 0 |
.... minimal | 0 | . | . | 1 | 0 | . | . | 0 |
GLAND, CLITORAL |
|
|
|
|
|
|
|
|
Examined | . | . | . | . | 0 | 1 | 1 | 0 |
Dilatation; ductular | . | . | . | . | . | 1 | 1 | . |
.... minimal | . | . | . | . | . | 1 | 1 | . |
GLAND, COAGULATING |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | . | . | . | . |
No Visible Lesions | 10 | . | . | 10 | . | . | . | . |
GLAND, MAMMARY |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, PARATHYROID |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, PITUITARY |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, PREPUTIAL |
|
|
|
|
|
|
|
|
Examined | 0 | 0 | 1 | 0 | . | . | . | . |
Dilatation; acinar | . | . | 1 | . | . | . | . | . |
.... minimal | . | . | 1 | . | . | . | . | . |
GLAND, PROSTATE |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | . | . | . | . |
No Visible Lesions | 8 | . | . | 10 | . | . | . | . |
Infiltration, mononuclear cell; | 2 | . | . | 0 | . | . | . | . |
interstitial |
|
|
|
|
|
|
|
|
.... minimal | 2 | . | . | 0 | . | . | . | . |
GLAND, SALIVARY, |
|
|
|
|
|
|
|
|
MANDIBULAR |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, SALIVARY, |
|
|
|
|
|
|
|
|
SUBLINGUAL |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
GLAND, SEMINAL VESICLE |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | . | . | . | . |
No Visible Lesions | 10 | . | . | 10 | . | . | . | . |
GLAND, THYROID |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 8 | . | . | 7 | 7 | . | . | 7 |
Cyst; ultimobranchial | 0 | . | . | 0 | 2 | . | . | 2 |
.... minimal | 0 | . | . | 0 | 2 | . | . | 2 |
Hypertrophy; follicular cell | 1 | . | . | 2 | 0 | . | . | 0 |
.... minimal | 1 | . | . | 2 | 0 | . | . | 0 |
Ectopia; thymic | 1 | . | . | 1 | 1 | . | . | 1 |
.... minimal | 1 | . | . | 1 | 1 | . | . | 1 |
HEART |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 9 | 10 | . | . | 10 |
Infiltration, mononuclear cell; | 0 | . | . | 1 | 0 | . | . | 0 |
myocardial |
|
|
|
|
|
|
|
|
.... minimal | 0 | . | . | 1 | 0 | . | . | 0 |
KIDNEY |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 3 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 1 | . | 2 | 5 | 8 | . | . | 7 |
Basophilia; tubular | 6 | . | 0 | 2 | 1 | . | . | 1 |
.... minimal | 6 | . | 0 | 2 | 1 | . | . | 1 |
Accumulation; hyaline droplets | 7 | . | 0 | 2 | 0 | . | . | 0 |
.... minimal | 5 | . | 0 | 2 | 0 | . | . | 0 |
.... mild | 2 | . | 0 | 0 | 0 | . | . | 0 |
Infiltration, mononuclear cell; | 3 | . | 0 | 1 | 1 | . | . | 3 |
interstitial |
|
|
|
|
|
|
|
|
.... minimal | 3 | . | 0 | 1 | 1 | . | . | 3 |
Dilatation; cortical, tubular | 0 | . | 0 | 1 | 0 | . | . | 0 |
.... minimal | 0 | . | 0 | 1 | 0 | . | . | 0 |
Dilatation; pelvis | 0 | . | 1 | 0 | 0 | . | . | 0 |
.... minimal | 0 | . | 1 | 0 | 0 | . | . | 0 |
LARGE INTESTINE, CECUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
LARGE INTESTINE, COLON |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
LARGE INTESTINE, RECTUM |
|
|
|
|
|
|
|
|
Examined | 10 | 10 | 10 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | 10 | 10 | 7 | 10 | . | . | 10 |
Hyperplasia; goblet cell | 0 | 0 | 0 | 3 | 0 | . | . | 0 |
.... minimal | 0 | 0 | 0 | 3 | 0 | . | . | 0 |
LIVER |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 5 | . | . | 5 | 8 | . | . | 10 |
Infiltration, mononuclear cell | 5 | . | . | 5 | 2 | . | . | 0 |
.... minimal | 5 | . | . | 5 | 2 | . | . | 0 |
Atrophy | 2 | . | . | 0 | 0 | . | . | 0 |
.... minimal | 1 | . | . | 0 | 0 | . | . | 0 |
.... mild | 1 | . | . | 0 | 0 | . | . | 0 |
LUNG |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 1 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 9 | . | 0 | 7 | 9 | . | . | 8 |
Aggregate; alveolar, macrophage | 0 | . | 1 | 1 | 0 | . | . | 0 |
.... minimal | 0 | . | 0 | 1 | 0 | . | . | 0 |
.... moderate | 0 | . | 1 | 0 | 0 | . | . | 0 |
Infiltration, mixed cell; | 1 | . | 0 | 1 | 1 | . | . | 2 |
perivascular |
|
|
|
|
|
|
|
|
.... minimal | 1 | . | 0 | 1 | 1 | . | . | 2 |
Metaplasia; osseous | 0 | . | 0 | 1 | 0 | . | . | 0 |
.... minimal | 0 | . | 0 | 1 | 0 | . | . | 0 |
LYMPH NODE, |
|
|
|
|
|
|
|
|
MANDIBULAR |
|
|
|
|
|
|
|
|
Examined | 10 | 2 | 0 | 10 | 10 | 1 | 0 | 10 |
No Visible Lesions | 8 | 0 | . | 9 | 7 | 0 | . | 10 |
Hemorrhage; acute | 2 | 2 | . | 1 | 3 | 1 | . | 0 |
.... minimal | 2 | 2 | . | 1 | 2 | 1 | . | 0 |
.... mild | 0 | 0 | . | 0 | 1 | 0 | . | 0 |
LYMPH NODE, MESENTERIC |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
MUSCLE, SKELETAL |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 5 | . | . | 9 | 9 | . | . | 9 |
Degeneration; myofiber | 5 | . | . | 0 | 1 | . | . | 1 |
.... minimal | 5 | . | . | 0 | 1 | . | . | 1 |
Infiltration, mononuclear cell | 1 | . | . | 1 | 0 | . | . | 0 |
.... minimal | 1 | . | . | 1 | 0 | . | . | 0 |
NERVE, OPTIC |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
NERVE, SCIATIC |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
OVARY |
|
|
|
|
|
|
|
|
Examined | . | . | . | . | 10 | 0 | 1 | 10 |
No Visible Lesions | . | . | . | . | 10 | . | 1 | 10 |
PANCREAS |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 9 |
Atrophy; acinar | 0 | . | . | 0 | 0 | . | . | 1 |
.... minimal | 0 | . | . | 0 | 0 | . | . | 1 |
SKIN |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
SMALL INTESTINE, |
|
|
|
|
|
|
|
|
DUODENUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
SMALL INTESTINE, ILEUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
SMALL INTESTINE, |
|
|
|
|
|
|
|
|
JEJUNUM |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
SPINAL CORD |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
SPLEEN |
|
|
|
|
|
|
|
|
Examined | 10 | 1 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 1 | 1 | . | 3 | 0 | . | . | 0 |
Pigment | 9 | 0 | . | 6 | 10 | . | . | 10 |
.... minimal | 8 | 0 | . | 6 | 9 | . | . | 9 |
.... mild | 1 | 0 | . | 0 | 1 | . | . | 1 |
Extramedullary hematopoiesis | 3 | 0 | . | 2 | 6 | . | . | 5 |
.... minimal | 2 | 0 | . | 0 | 4 | . | . | 4 |
.... mild | 1 | 0 | . | 2 | 2 | . | . | 1 |
STOMACH |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 1 | 10 | 10 | 10 | 10 | 10 |
No Visible Lesions | 8 | . | 1 | 5 | 7 | 10 | 8 | 4 |
Hyperplasia; basal cell; glandular | 0 | . | 0 | 1 | 0 | 0 | 0 | 1 |
.... minimal | 0 | . | 0 | 1 | 0 | 0 | 0 | 1 |
Hyperplasia; squamous cell; | 0 | . | 0 | 0 | 0 | 0 | 1 | 3 |
non-glandular |
|
|
|
|
|
|
|
|
.... minimal | 0 | . | 0 | 0 | 0 | 0 | 1 | 2 |
.... mild | 0 | . | 0 | 0 | 0 | 0 | 0 | 1 |
Vacuolation; epithelial, limiting | 0 | . | 0 | 0 | 2 | 0 | 0 | 2 |
ridge |
|
|
|
|
|
|
|
|
.... minimal | 0 | . | 0 | 0 | 2 | 0 | 0 | 2 |
Erosion; non-glandular | 0 | . | 0 | 0 | 0 | 0 | 0 | 1 |
.... minimal | 0 | . | 0 | 0 | 0 | 0 | 0 | 1 |
Infiltration, lymphocytic; | 2 | . | 0 | 3 | 1 | 0 | 1 | 1 |
submucosal, glandular |
|
|
|
|
|
|
|
|
.... minimal | 2 | . | 0 | 3 | 1 | 0 | 1 | 1 |
Infiltration, lymphocytic; limiting | 0 | . | 0 | 0 | 0 | 0 | 0 | 1 |
ridge |
|
|
|
|
|
|
|
|
.... minimal | 0 | . | 0 | 0 | 0 | 0 | 0 | 1 |
Infiltration, mixed cell; | 1 | . | 0 | 1 | 0 | 0 | 0 | 1 |
submucosal, glandular |
|
|
|
|
|
|
|
|
.... minimal | 1 | . | 0 | 1 | 0 | 0 | 0 | 1 |
TESTIS |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | . | . | . | . |
No Visible Lesions | 6 | . | . | 8 | . | . | . | . |
Degeneration/atrophy; tubular | 4 | . | . | 2 | . | . | . | . |
.... minimal | 2 | . | . | 2 | . | . | . | . |
.... mild | 1 | . | . | 0 | . | . | . | . |
.... marked | 1 | . | . | 0 | . | . | . | . |
THYMUS |
|
|
|
|
|
|
|
|
Examined | 10 | 1 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | 0 | . | 10 | 10 | . | . | 10 |
Hemorrhage; acute | 0 | 1 | . | 0 | 0 | . | . | 0 |
.... minimal | 0 | 1 | . | 0 | 0 | . | . | 0 |
TRACHEA |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
URINARY BLADDER |
|
|
|
|
|
|
|
|
Examined | 10 | 0 | 0 | 10 | 10 | 0 | 0 | 10 |
No Visible Lesions | 10 | . | . | 10 | 10 | . | . | 10 |
UTERUS |
|
|
|
|
|
|
|
|
Examined | . | . | . | . | 10 | 2 | 0 | 10 |
No Visible Lesions | . | . | . | . | 10 | 2 | . | 10 |
VAGINA |
|
|
|
|
|
|
|
|
Examined | . | . | . | . | 10 | 0 | 0 | 10 |
Diestrus | . | . | . | . | 5 | . | . | 7 |
Estrus | . | . | . | . | 2 | . | . | 3 |
Proestrus | . | . | . | . | 3 | . | . | 0 |
Table 28: microscopic pathology (males & females) - end of recovery
Removal Reason(s): RECOVERY EUTHANASIA Summary: Incidence
Number of Animals: | Male 0 1000
mg/kg/ mg/kg/ day day Group Group 1 4 | Female 0 1000
mg/kg/ mg/kg/ day day Group Group 1 4 | ||
5 | 5 | 5 | 5 | |
KIDNEY |
|
|
|
|
Examined | 0 | 1 | 0 | 1 |
No Visible Lesions | . | 0 | . | 1 |
Cyst; cortical | . | 1 | . | 0 |
.... mild | . | 1 | . | 0 |
LARGE INTESTINE, RECTUM |
|
|
|
|
Examined | 5 | 5 | . | . |
No Visible Lesions | 5 | 5 | . | . |
LIVER |
|
|
|
|
Examined | 1 | 0 | . | . |
Atrophy | 1 | . | . | . |
.... minimal | 1 | . | . | . |
LUNG |
|
|
|
|
Examined | . | . | 1 | 0 |
Hemorrhage; acute, alveolar | . | . | 1 | . |
.... minimal | . | . | 1 | . |
STOMACH |
|
|
|
|
Examined | 0 | 1 | 5 | 5 |
No Visible Lesions | . | 1 | 4 | 3 |
Vacuolation; epithelial, limiting ridge | . | 0 | 1 | 1 |
.... minimal | . | 0 | 1 | 1 |
Erosion; glandular | . | 0 | 0 | 1 |
.... minimal | . | 0 | 0 | 1 |
THYMUS |
|
|
|
|
Examined | . | . | 0 | 1 |
Hemorrhage; acute | . | . | . | 1 |
.... minimal | . | . | . | 1 |
UTERUS |
|
|
|
|
Examined | . | . | 2 | 1 |
No Visible Lesions | . | . | 2 | 1 |
Table 29: clinical observations (males & females) - Main
Observation Type: All Types From Day 1 (Start Date) to 93 (Start Date) |
0 mg/kg/day Group 1 | Male 100 300 mg/kg/day mg/kg/day Group 2 Group 3 |
1000 mg/kg/day Group 4 |
0 mg/kg/day Group 1 | Female 100 300 mg/kg/day mg/kg/day Group 2 Group 3 |
1000 mg/kg/day Group 4 | ||
Retching |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 1 | 0 | 6 | 0 | 1 | 3 | 9 |
Number of Times Recorded | 0 | 1 | 0 | 8 | 0 | 1 | 10 | 13 |
% of Affected Animals | 0 | 10 | 0 | 40 | 0 | 10 | 30 | 60 |
First to Last seen | - | 44 - 44 | - | 43 - 48 | - | 44 - 44 | 44 - 49 | 43 - 48 |
Salivation |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 10 | 15 | 0 | 0 | 4 | 15 |
Number of Times Recorded | 0 | 0 | 96 | 1223 | 0 | 0 | 25 | 1205 |
% of Affected Animals | 0 | 0 | 100 | 100 | 0 | 0 | 40 | 100 |
First to Last seen | - | - | 12 - 91 | 7 - 91 | - | - | 12 - 89 | 7 - 92 |
Breathing, Deep |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Number of Times Recorded | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
% of Affected Animals | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 0 |
First to Last seen | - | - | - | - | - | - | 91 - 92 | - |
Breathing, Labored |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Number of Times Recorded | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
% of Affected Animals | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 |
First to Last seen | - | - | - | - | - | - | - | 81 - 81 |
Breathing, Abnormal Sounds |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 3 | 3 | 10 | 1 | 1 | 5 | 6 |
Number of Times Recorded | 0 | 7 | 10 | 36 | 11 | 3 | 15 | 20 |
% of Affected Animals | 0 | 30 | 30 | 67 | 7 | 10 | 50 | 40 |
First to Last seen | - | 9 - 91 | 8 - 91 | 8 - 91 | 61 - 90 | 74 - 76 | 42 - 92 | 3 - 91 |
Breathing, Shallow |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 2 | 0 | 1 | 0 | 0 | 0 | 1 |
Number of Times Recorded | 0 | 6 | 0 | 1 | 0 | 0 | 0 | 1 |
% of Affected Animals | 0 | 20 | 0 | 7 | 0 | 0 | 0 | 7 |
First to Last seen | - | 89 - 91 | - | 89 - 89 | - | - | - | 89 - 89 |
Hunched Posture |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 |
Number of Times Recorded | 0 | 0 | 13 | 2 | 0 | 0 | 0 | 1 |
% of Affected Animals | 0 | 0 | 10 | 7 | 0 | 0 | 0 | 7 |
First to Last seen | - | - | 23 - 35 | 28 - 29 | - | - | - | 81 - 81 |
Fur, Erected |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 2 | 4 | 0 | 0 | 1 | 1 |
Number of Times Recorded | 0 | 0 | 7 | 9 | 0 | 0 | 2 | 1 |
% of Affected Animals | 0 | 0 | 20 | 27 | 0 | 0 | 10 | 7 |
First to Last seen | - | - | 23 - 35 | 42 - 67 | - | - | 91 - 92 | 81 - 81 |
Fur, Loss |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Number of Times Recorded | 0 | 0 | 75 | 0 | 0 | 0 | 0 | 0 |
% of Affected Animals | 0 | 0 | 10 | 0 | 0 | 0 | 0 | 0 |
First to Last seen | - | - | 26 - 92 | - | - | - | - | - |
Skin, Lesion, Dorsal Cervical |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Number of Times Recorded | 0 | 0 | 9 | 0 | 0 | 0 | 0 | 0 |
% of Affected Animals | 0 | 0 | 10 | 0 | 0 | 0 | 0 | 0 |
First to Last seen | - | - | 12 - 29 | - | - | - | - | - |
Skin, Scab, Dorsal Cervical |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Number of Times Recorded | 0 | 0 | 8 | 0 | 0 | 0 | 0 | 0 |
Skin, Scab, Dorsal Cervical (Continued...) |
|
|
|
|
|
|
|
|
% of Affected Animals | 0 | 0 | 10 | 0 | 0 | 0 | 0 | 0 |
First to Last seen | - | - | 18 - 25 | - | - | - | - | - |
Ploughing |
|
|
|
|
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 10 | 0 | 0 | 0 | 12 |
Number of Times Recorded | 0 | 0 | 2 | 33 | 0 | 0 | 0 | 36 |
% of Affected Animals | 0 | 0 | 10 | 67 | 0 | 0 | 0 | 80 |
First to Last seen | - | - | 43 - 44 | 43 - 47 | - | - | - | 43 - 47 |
Table 30: clinical observations (males & females) - Recovery
Observation Type: All Types From Day 92 (Start Date) to 121 (Start Date) | Male 0 1000 mg/kg/day mg/kg/day Group 1 Group 4 | Female 0 1000 mg/kg/day mg/kg/day Group 1 Group 4 | ||
Breathing, Labored |
|
|
|
|
Number of Animals Affected | 0 | 0 | 0 | 1 |
Number of Times Recorded | 0 | 0 | 0 | 1 |
% of Affected Animals | 0 | 0 | 0 | 20 |
First to Last seen | - | - | - | 106 - 106 |
Breathing, Abnormal Sounds |
|
|
|
|
Number of Animals Affected | 0 | 0 | 0 | 1 |
Number of Times Recorded | 0 | 0 | 0 | 4 |
% of Affected Animals | 0 | 0 | 0 | 20 |
First to Last seen | - | - | - | 106 - 121 |
Fur, Erected |
|
|
|
|
Number of Animals Affected | 0 | 0 | 1 | 0 |
Number of Times Recorded | 0 | 0 | 1 | 0 |
% of Affected Animals | 0 | 0 | 20 | 0 |
First to Last seen | - | - | 121 - 121 | - |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- The study was performed with the registered substance, according to OECD/EC guidance and GLP principles (Klimisch 1 study).
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
A 90-day repeated dose toxicity study was performed according to OECD TG 408 and in accordance with GLP principles.
The objectives of this study were to determine the potential toxicity of the substance, when given orally by gavage for 90 days to Wistar Han rats and to evaluate the potential reversibility of any findings. In addition, a No Observed Adverse Effect Level (NOAEL) was evaluated.
Chemical analyses of formulations were conducted on Weeks 1, 6 and 12 on Groups 1-3 to assess accuracy and homogeneity. Formulation analyses confirmed that formulations were prepared accurately and homogenously for all occasions. The following parameters and end points were evaluated in this study: mortality, clinical signs, functional observation tests, body weights, food consumption, ophthalmology, stage of estrous, clinical pathology parameters (hematology, coagulation, and clinical chemistry), macroscopic examination, organ weights and microscopic examination.
No mortality occurred during the study.
At 100 mg/kg bw/day, abnormal breathing sounds, shallow breathing and retching were noted in males and/or females, which were considered to be non-adverse.
At 300 mg/kg bw/day, non-adverse abnormal breathing sounds, deep breathing, retching, hunched posture, erected fur were noted in males and/or females. Histopathological changes consisted of non-adverse squamous cell hyperplasia in the stomach in females, which was often accompanied by hyperkeratosis.
At 1000 mg/kg bw/day, abnormal breathing sounds, labored breathing, shallow breathing, retching, hunched posture and erected fur were noted in males and/or females and were considered to be non-adverse. Non-adverse decreased total movements and ambulations were noted for females. Hematological findings comprised non-adverse decreased red blood cell count and red blood cell distribution width and increased mean corpuscular volume and mean corpuscular hemoglobin in males. Red blood cell count was recovered, while red blood cell distribution width, mean corpuscular volume and mean corpuscular hemoglobin were not recovered at the end of the Recovery Period. It is noted that all reported changes on Hematology parameters were within historical control for this rat strain at the site. Nonadverse clinical chemistry findings consisted of an increase in triglyceride concentration in males, which partly recovered at the end of the Recovery Period. Hormone analysis showed an increased T4 levels in females compared to the concurrent control group however, the mean values still remained within the historical control range and levels recovered at the end of the Recovery Period. Furthermore, no histopathological changes were observed in the thyroid. Overall, the observed increase in the study was considered non-adverse and not toxicologically relevant. Histopathological changes consisted of non-adverse squamous cell hyperplasia often accompanied by hyperkeratosis in the stomach in females and goblet cell hyperplasia of the rectum in a few males. In addition, a higher kidney and liver weight was noted in females. As kidney and liver weights remained within the historical control data and changes were no longer observed after recovery and in the absence of concomitant histopathological changes, the effects on organ weights were considered non-adverse. All histopathological and organ weight changes were fully recovered at the end of the Recovery Period.
No test material-related changes were noted in any of the remaining parameters investigated in this study (i.e., mortality, body weight, food consumption, ophthalmoscopy, coagulation and macroscopic pathology).
In conclusion, administration of the substance by once daily oral gavage was tolerated in Wistar Han rats at levels up to 1000 mg/kg bw/day. There were no adverse test material related alterations observed.
Based on these results, the No Observed Adverse Effect Level (NOAEL) was considered to be at least 1000 mg/kg bw/day in males and females.
Records with supporting studies on structural analogues are included for information purposes.
Justification for classification or non-classification
Based on the available data, the registered substance is not classified for repeated dose exposure according to CLP Regulation (EC) No. 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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