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EC number: 205-465-5 | CAS number: 141-17-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://chesar.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 May - 05 November 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 21 September 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Health and Youth Care Inspectorate, Ministry of Health, Welfare and Sport, Utrecht, The Netherlands
- Limit test:
- no
Test material
- Reference substance name:
- Bis(2-(2-butoxyethoxy)ethyl) adipate
- EC Number:
- 205-465-5
- EC Name:
- Bis(2-(2-butoxyethoxy)ethyl) adipate
- Cas Number:
- 141-17-3
- Molecular formula:
- C22H42O8
- IUPAC Name:
- bis(2-(2-butoxyethoxy)ethyl) adipate
1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl: WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: 138 to 176 g (males), 118 to 147 g (females)
- Housing: on arrival and following randomization, 5 animals of the same sex and same dosing group in polycarbonate cages (Makrolon type IV, height 18 cm) containing appropriate bedding (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. Animals were separated during designated procedures/activities. During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cageenrichment, bedding material, food and water.
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum. During motor activity measurements, animals did not have access to food for a maximum of 2 h.
- Water: municipal tap water, ad libitum
- Acclimation period: 6 days
DETAILS OF FOOD AND WATER QUALITY: analysis were performed
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 46 - 62
- Air changes (per hr): 10 or more
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 29 May 2018 To: 29 August 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- 400
- 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. The dosing formulations were prepared daily as a solution and dosed within 5 h after adding vehicle to the test item. Test item dosing formulations were kept at room temperature until dosing. The dosing formulations and vehicle were continuously stirred until and during dosing. Adjustment was made for specific gravity of the vehicle (1.125) and test item (1.1 at 25 °C). No correction was made for the purity/composition of the test item.
VEHICLE
- Justification for use and choice of vehicle: Trial preparations were performed at the test facility to select the suitable vehicle and to establish a suitable formulation procedure. Polyethylene glycol 400 (Merck, Darmstadt, Germany) was identified as suitable vehicle. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulation samples were collected for analysis in week 1, 6 and 13 for homogeneity. For homogeneity analysis, duplicate sets of samples (approximately 500 mg, accurately weighed) for each sampling time point were sent to the analytical laboratory. Homogeneity results were considered acceptable if the coefficient of variation (CV) of concentrations was ± 10%. In addition, stability was tested in samples collected in week 1. Stability of the test item in the vehicle was determined over 5 h at room temperature under normal laboratory light conditions (lowest and highest concentration). Duplicate sets of each sample (approximately 500 mg, accurately weighed) were sent to the analytical laboratory. Stability results were considered acceptable if the sample analysis results were within or equal to ± 10% of the concentration determined by the initial analysis of each formulation. For concentration analysis, duplicate sets of samples (approximately 500 mg, accurately weighed) for each sampling time point were sent to the analytical laboratory.Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% for solutions of target concentration. Analysis showed that concentrations analyzed were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%) and that no test item was detected in the vehicle formulation. Furthermore, the dose formulations were homogeneous (i.e. coefficient of variation ≤ 10%) and stable when stored at room temperature under normal laboratory light conditions for at least 5 h (i.e. differences between mean concentrations before and after storage ≤ 10%).
- Duration of treatment / exposure:
- 91 (males) or 92 (females) days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
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. The dose levels were selected based on the results of the range finding prenatal developmental study (Test Facility Study No. 20148926) and in an attempt to produce graded responses to the test item.
- Fasting period before blood sampling for clinical biochemistry:
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily, beginning on day 1 of treatment
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly, beginning on day 1 of treatment until day of necropsy
BODY WEIGHT: Yes
- Time schedule for examinations: day - 5 and then weekly (before dosing), starting on day 1
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE: No
- Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during pre-treatment and at the end of the dosing period in Week 13
- Dose groups that were examined: during pre-treatment in all animals, and at the end of the dosing in vehicle and 1000 mg/kg bw/day dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table No.1 in the "Any other information and methods incl. tables" section were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of treatment
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table No.2 in the "Any other information and methods incl. tables" section were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 13
- Dose groups that were examined: 5 animals per dose group, all dose groups
- Battery of functions tested: grip strength / motor activity / other: hearing ability
IMMUNOLOGY: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3 in the "Any other information and methods incl. tables" section.)
HISTOPATHOLOGY: Yes (see table 3 in the "Any other information and methods incl. tables" section.) - Other examinations:
- Estrous Cycle Determination
Estrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage.
- Time schedule for examinations: week 11 (Day 71) up to and including week 14 (Day 92)
- Dose groups that were examined: females of all dose groups
Sperm analysis
For all surviving males, the following assessments were performed:
1. From all males, sperm samples were taken from the proximal part of the vas deferens (right) at necropsy:
- Sperm motility was assessed from all samples.
- Sperm smears for morphological evaluation were fixed from all samples. Abnormal forms of sperm from a differential count of 200 spermatozoa (if possible) per animal were recorded. Evaluation was performed for all males of the control and high-dose group.
2. One testis and one epididymis (left) from all males were removed, placed in labeled bags, and kept in the freezer at ≤-15°C. After thawing the epididymis was weighed, homogenized and evaluated for sperm numbers. Evaluation was performed for males of the control and high dose group.
Thyroid homone analysis:
- Time schedule for collection of blood: end of treatment
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table No.2 in the "Any other information and methods incl. tables" section were examined. - 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. Numerical data collected on scheduled occasions for the listed 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. Inferential statistics were performed when possible, but excluded semi-quantitative data, and any group with less than 3 observations.
Variables for inferential analysis: body Weight and body weight gain, food consumption, organ weights, organ weight relative to body weight
Parametric/non parametric tests used: Levene’s test was used to assess the homogeneity of group variances. Datasets with at least 3 groups were compared using an overall one-way ANOVA F test when Levene’s test was not significant or the Kruskal-Wallis test when group variances were not homogeneous. When the overall F test or Kruskal-Wallis test was significant, then the above pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively. Datasets with 2 groups (the designated control group and 1 other group) were compared using a t-test if Levene’s test was not significant or Wilcoxon Rank-Sum test if it was.
The following pairwise comparisons were made: Low dose group (2) vs. Vehicle dose group (1), Mid dose group (3) vs. Vehicle dose group (1), High dose group (4) vs. Vehicle dose group (1)
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using Fisher’s exact test whenever the overall test is significant.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 100, 300 and 1000 mg/kg bw/day: salivation and ploughing was noted in all animals. For salivation a dose-related trend in severity (up to severe on several occasions in high-dose rats) and time of onset (from day 8 in low-dose rats and from day 1 or 2 at the higher dose levels) was observed. The salivation was considered to be a physiological response and/or behavioural sign of discomfort in reaction to the bolus administration of the test item rather than a sign of systemic toxicity considering its severity (mostly slight or moderate) and the time of occurrence (i.e. within half an hour after dosing).
All other clinical signs noted occurred incidentally and represented normal background findings. At the incidence observed, these findings were considered not to be treatment-related. (Please refer to table 4 in the "Any other information on results incl. tables" section.) - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 1000 mg/kg bw/day: two females died unscheduled. One female was found dead in the morning of study day 58. Prior to death, this animal showed no clinical signs of conditional decline and body weight development was normal. Possibly, its death could be related to the gavage procedure, however, this could not be confirmed by macroscopic or microscopic findings, due to cannibalism. The death was considered likely to be procedure-related rather than test-item related. Another female died during blood sampling on the scheduled day of necropsy. This death was considered to be related to the blood sampling procedure under anesthesia and was therefore regarded to be unrelated to treatment with the test item.
300 mg/kg bw/day: one females was euthanized for humane reasons on day 54 of the study, based on deep breathing and weight loss (9% between days 50-54). At macroscopic examination, red foci (multifocal) were noted in the glandular stomach. Microscopic examination showed marked mixed cell inflammation in the bronchus and moderate neutrophilic infiltration in the lumen of the larynx. These microscopic findings and the sudden onset of the moribundity suggested that the conditional decline was related to the gavage procedure rather than being test-item related - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: males gained slightly less weight than controls in most weeks of the study (reaching statistical significance in weeks 4 and 9 only). The slight non statistically significant differences in body weights gradually increased up to a mean value of 8 % lower for the high dose animals at the end of the treatment period (non-adverse, due to slight nature of the effect). (Please refer to table 5 in the "Any other information on results incl. tables" section.) Body weights and body weight gain of females showed no treatment-related changes.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: males consumed slightly less food (about 6-9%) than controls on several time periods during the study (weeks 1-2 and the second half of the 13-week treatment period) (non-adverse, due to slight nature of the effect). (Please refer to table 6 in the "Any other information on results incl. tables" section.) Food consumption of treated females was similar to that of controls over the study period.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Vehicle, 100, 300 and 1000 mg/kg bw/day: cornea opacity, cornea edema and cornea, opacity multifocal, pinpoint ocurred at similar incidences in all dose groups or only in single animals and were thus considered incidental, non-treatment-related and non-adverse. (Please refer to table 7 in the "Any other information on results incl. tables" section.) Ophthalmic examination of control and high-dose rats in the last week of the treatment period showed no test-item related ocular changes. The incidences of the findings did not indicate a relation with treatment and both the nature and incidence of the findings occurred within the normal range for rats of this age and strain.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day:
lower number of red blood cells in males (-10%) and females (-13%) (statistically significant),
lower mean corpuscular haemoglobin concentration (MCHC) in males (-9%) and females (-5%) (statistically significant),
lower red blood cell distribution width (RDW) in males (-7%)(statistically significant),
higher mean corpuscular haemoglobin (MCH) in females (+7%) (statistically significant),
higher mean corpuscular volume (MCV) in males and females (both +13%)(statistically significant), lower haemoglobin concentration in males (-9%) and females (-6%) (not statistically significant),
higher number of reticulocytes in males (+37%) and females (+30%) (not statistically significant)
All changes were regarded as non-adverse because of the minor magnitude of the change.
100 and 300 mg/kg bw/day: decreased prothrombin time in males (statistically significant). This finding was considered non-treatment-related and non-adverse due to the lack of a dose-related response.
100 mg/kg bw/day: higher MCHC in females (statistically significant). This isolated finding was considered non-treatment-related and non adverse due to the lack of a dose-related response.
(Please refer to table 8 in the "Any other information on results incl. tables" section.) - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day:
higher alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) in males (+51% and +39%, respectively) (statistically significant),
higher alkaline phosphatase (ALP) in males (+54%) and females (+46%) (statistically significant),
higher bile acids in males (2.1-fold) (statistically significant). A higher mean bile acids concentration was also noted in females, but the difference from controls (1.9 fold) was not statistically significant and could be explained by the high concentration in a single animal,
lower cholesterol in males (-32%) and females (-28%) (statistically significant),
lower fasting glucose in males (-22%), (statistically significant),
higher creatinine in males (+7%)(statistically significant),
higher potassium in females (+10%).(statistically significant)
lower calcium in females (-3%) (statistically significant)
300 and 1000 mg/kg bw/day:
higher chloride in males (+2%) and (+3%) at the mid an high dose, respectively (statistically significant),
higher potassium in males (statistically significant, non-treatment-related, missing dose-related response)
100 and 300 mg/kg bw/day: higher sodium levels in males and females (statistically significant, non-treatment-related, missing dose-related response)
100 mg/kg bw/day: higher chloride in females (statistically significant, non-treatment-related, missing dose-related response)
Decreases noted in cholesterol (both sexes) and fasting glucose (males only) may also be related to the effect of
the test item on the liver. Slightly higher creatinine, chloride and potassium, and slightly lower calcium, mostly at 1000 mg/kg/day were not associated with adverse anatomic pathology alterations and therefore regarded as non-adverse.
(Please refer to table 9 in the "Any other information on results incl. tables" section.) - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: higher liver weights (absolute and relative to body weight) were noted in females (statistically significant, treatment-related, adverse), slight increase in relative kidney weights in both sexes (statistically significant, but not considered treatment-related,result of variations in terminal body weights), lower mean uterus weights (absolute and relative to body weight) in females (about -40%, not statistically significant) were considered to reflect normal physiological variation (non-treatment-related)
300 and 1000 mg/kg bw/day: increased heart weights in in mid dose males and high dose females (statistically significant, but not considered treatment-related, result of variations in terminal body weights). In the absence of a dose-related trend, the lower relative heart weight in males was regarded a chance finding.
(Please refer to table 10, 11 and 12 in the "Any other information on results incl. tables" section.) - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All macroscopic findings were within the range of background gross observations encountered in rats of this age and strain and were therefore considered non-treatment-related. (Please refer to table 13 in the "Any other information on results incl. tables" section.)
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: centrilobular hypertrophy at minimal to mild degree and periportal hepatocellular vacuolation at minimal degree in the liver (males), increased severity of pigment accumulation in the spleen (both sexes) and increased incidence and severity of diffuse vacuolation in the zona glomerulosa of the adrenal gland (both sexes) (treatment-related, non-adverse). Non-adversity was based on the nature of the finding, the low severity and the absence of any additional degenerative or proliferative changes.
300 and 1000 mg/kg bw/day: in mid dose females and high dose males and females adverse microscopic changes were observed in the liver and consisted of an increased incidence and severity (up to mild degree) of centrilobular mononuclear cell infiltrates accompanied by single cell necrosis as well as increased liver weighs (by about 20%) (treatment-related, adverse).
100 and 300 mg/kg bw/day: centrilobular mononuclear cell infiltration with single cell necrosis was observed in males of the low and mid dose group and in females of the low dose group (treatment-related, non-adverse). Non-adversity was based on the low severity/incidence of the lesions in these dose groups.
All other microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no test substance-related alteration in the prevalence, severity or histologic character of those incidental tissue alterations. (Please refer to table 14 in the "Any other information on results incl. tables" section.) - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Neurobehavioural examination - functional tests (effects observed non-treatment-related):
1000 mg/kg bw/day: one male and one female showed low values for total movements and ambulations (below the normal ranges). Habituation profiles of these animals were normal and their lower motor activity was not associated with corroborative clinical signs or changes in other measures in the neuromuscular domain (including gait, air righting reflex and grip strength). Moreover, all other high-dose animals showed normal motor activity. Therefore, the lower activity recorded for these two animals was not attributed to treatment.
Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals. In addition, forelimb and hind limb grip strength showed no treatment-related changes. (Please refer to table 15 and 16 in the "Any other information on results incl. tables" section.)
Estrous cycle determination (effects observed non-treatment-related):
1000 mg/kg bw/day: one female had irregular cycles of, subsequently, 6 and 2 days. Since irregular cycles were noted in only one female and adjacent cycles were normal, this finding was considered non-treatment-related.
Sperm analysis (effects observed non-treatment-related):
1000 mg/kg bw/day: epididymal sperm count was 35% higher compared to the control mean. Since the difference was not statistically significant and was atrributed to low counts in two control males, this finding was not considered treatment-related. (Please refer to table 17 in the "Any other information on results incl. tables" section.)
Thyroid homone analysis:
1000 mg/kg bw/day: T4 levels were lower compared to the control levels (-14% and -22% in males and females, respectively) Since statistical significance was not achieved and T4 levels in almost all high dose animals remained in the concurrent control range, these intergroup differences were considered non-treatment-related. (Please refer to table 9 in the "Any other information on results incl. tables" section.)
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effect observed at this dose level
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effect observed at this dose level
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 4: Summary of clinical observations
Dose groups (mg/kg bw/day) |
Male
|
Female |
||||||
Observations From Day 1 to 93 |
Vehicle |
100
|
300 |
1000
|
Vehicle |
100
|
300 |
1000
|
eyeball, enlarged |
|
|
|
|
|
|
|
|
number of animals affected |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
number of times recorded |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
% of affected animals |
10 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
first to last seen |
79 - 86 |
- |
- |
- |
- |
- |
- |
- |
skin, lesion |
|
|
|
|
|
|
|
|
number of animals affected |
2 |
2 |
2 |
1 |
0 |
0 |
0 |
1 |
number of times recorded |
4 |
3 |
10 |
5 |
0 |
0 |
0 |
2 |
% of affected animals |
20 |
20 |
20 |
10 |
0 |
0 |
0 |
10 |
first to last seen |
9 - 44 |
9 - 16 |
9 - 51 |
9 - 37 |
- |
- |
- |
23 - 30 |
breathing, deep |
|
|
|
|
|
|
|
|
number of animals affected |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
number of times recorded |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
% of affected animals |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
0 |
first to last seen |
- |
- |
- |
- |
- |
- |
54 - 54 |
- |
salivation |
|
|
|
|
|
|
|
|
number of animals affected |
1 |
10 |
10 |
10 |
2 |
10 |
10 |
10 |
number of times recorded |
1 |
839 |
900 |
826 |
2 |
848 |
872 |
879 |
% of affected animals |
10 |
100 |
100 |
100 |
20 |
100 |
100 |
100 |
first to last seen |
62 - 62 |
8 - 91 |
2 - 91 |
1 - 91 |
54 - 62 |
7 - 92 |
1 - 92 |
1 - 92 |
skin, scab |
|
|
|
|
|
|
|
|
number of animals affected |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
number of times recorded |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
0 |
% of affected animals |
0 |
10 |
0 |
0 |
0 |
0 |
0 |
0 |
first to last seen |
- |
6 - 7 |
- |
- |
- |
- |
- |
- |
ploughing |
|
|
|
|
|
|
|
|
number of animals affected |
0 |
10 |
10 |
10 |
0 |
10 |
10 |
10 |
number of times recorded |
0 |
839 |
840 |
763 |
0 |
845 |
811 |
815 |
% of affected animals |
0 |
100 |
100 |
100 |
0 |
100 |
100 |
100 |
first to last seen |
- |
8 - 91 |
8 - 91 |
8 - 91 |
- |
8 - 92 |
8 - 92 |
8 - 92 |
Table 5: Summary of body weight gains (g)
Males |
|
Days - Change |
|
||||||
Dose group (mg/kg bw/day) |
|
-5-1 |
1-8 |
8-15 |
15-22 |
22-29 |
29-36 |
36-43 |
|
Vehicle |
Mean |
34.30 |
45.30 |
43.10 |
32.80 |
27.70 |
20.30 |
13.50 |
|
|
SD |
3.47 |
4.19 |
5.93 |
5.25 |
4.11 |
3.27 |
4.77 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
100 |
Mean |
35.00 |
46.70 |
45.80 |
36.80 |
23.40 |
21.20 |
11.50 |
|
|
SD |
2.62 |
3.77 |
5.67 |
4.54 |
5.42 |
4.32 |
2.80 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
300 |
Mean |
36.20 |
48.90 |
42.40 |
36.70 |
26.50 |
21.30 |
17.50 |
|
|
SD |
3.12 |
4.38 |
5.78 |
5.89 |
2.72 |
4.22 |
5.02 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
1000 |
Mean |
32.20 |
41.50 |
42.67 |
29.89 |
20.33b |
16.22 |
14.33 |
|
|
SD |
6.51 |
6.31 |
3.91 |
3.10 |
4.69 |
5.29 |
7.84 |
|
|
N |
10 |
10 |
9 |
9 |
9 |
9 |
9 |
|
Males |
|
Days - Change |
|||||||
Dose group |
|
43-50 |
50-57 |
57-64 |
64-71 |
71-78 |
78-85 |
85-91 |
|
Vehicle |
Mean |
11.90 |
10.00 |
9.20 |
12.80 |
9.90 |
6.50 |
4.40 |
|
|
SD |
3.57 |
5.58 |
4.71 |
4.85 |
3.41 |
5.23 |
3.63 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
100 |
Mean |
11.60 |
10.00 |
11.00 |
10.30 |
8.10 |
5.10 |
10.20 |
|
|
SD |
5.27 |
3.56 |
2.26 |
4.35 |
2.60 |
3.87 |
8.77 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
300 |
Mean |
11.60 |
13.00 |
11.00 |
10.00 |
10.20 |
6.90 |
5.20 |
|
|
SD |
3.66 |
4.88 |
4.45 |
3.43 |
3.05 |
3.03 |
3.26 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
1000 |
Mean |
10.11 |
9.56 |
4.44a |
8.22 |
7.78 |
4.11 |
2.78 |
|
|
SD |
5.25 |
5.92 |
3.54 |
5.36 |
3.67 |
3.62 |
5.70 |
|
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
|
Females |
|
Days - Change |
|||||||
Dose group |
|
-5-1 |
1-8 |
8-15 |
15-22 |
22-29 |
29-36 |
36-43 |
|
Vehicle |
Mean |
19.20 |
21.00 |
20.40 |
14.00 |
10.50 |
8.60 |
4.70 |
|
|
SD |
3.58 |
4.92 |
4.62 |
3.65 |
4.84 |
4.30 |
3.86 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
100 |
Mean |
18.40 |
23.20 |
18.60 |
15.10 |
11.20 |
11.30 |
2.80 |
|
|
SD |
2.41 |
3.74 |
3.27 |
5.40 |
4.18 |
3.02 |
5.83 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
300 |
Mean |
15.80 |
23.20 |
17.10 |
14.20 |
8.30 |
8.90 |
5.50 |
|
|
SD |
2.70 |
5.98 |
4.89 |
3.08 |
3.40 |
5.67 |
5.21 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
1000 |
Mean |
19.70 |
23.00 |
18.60 |
14.80 |
7.90 |
10.10 |
6.40 |
|
|
SD |
3.74 |
4.62 |
3.44 |
4.83 |
2.88 |
1.91 |
2.37 |
|
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
Females |
|
Days - Change |
|||||||
Dose group |
|
43-50 |
50-54 |
50-57 |
57-64 |
64-71 |
71-78 |
78-85 |
85-91 |
Vehicle |
Mean |
4.10 |
-- |
5.10 |
3.60 |
5.50 |
4.10 |
3.50 |
3.10 |
|
SD |
5.38 |
-- |
3.03 |
3.37 |
3.72 |
3.90 |
4.72 |
3.25 |
|
N |
10 |
-- |
10 |
10 |
10 |
10 |
10 |
10 |
100 |
Mean |
6.20 |
-- |
5.40 |
4.40 |
4.40 |
4.00 |
1.40 |
3.40 |
|
SD |
7.63 |
-- |
5.02 |
4.60 |
4.12 |
6.51 |
3.86 |
3.63 |
|
N |
10 |
-- |
10 |
10 |
10 |
10 |
10 |
10 |
300 |
Mean |
4.40 |
-22 .00z |
6.44 |
4.67 |
6.33 |
2.00 |
3.44 |
2.22 |
|
SD |
7.52 |
-- |
5.77 |
5.34 |
2.78 |
4.30 |
4.48 |
3.93 |
|
N |
10 |
1 |
9 |
9 |
9 |
9 |
9 |
9 |
1000 |
Mean |
5.30 |
-- |
4.70 |
1.89 |
4.89 |
2.11 |
3.00 |
-0 .67 |
|
SD |
5.31 |
-- |
3.47 |
4.40 |
3.14 |
5.93 |
2.74 |
4.42 |
|
N |
10 |
-- |
10 |
9 |
9 |
9 |
9 |
9 |
Significantly different from control group 1 value :a=p≤0.05,b=p≤0.01 (Dunnett)
Group excluded from statistical analysis (N<3): z
Table 6 Summary of food consumption (g/animal/day)
Males |
|
Days (From – To) |
||||||
Dose group (mg/kg bw/day) |
|
1-8 |
8-15 |
15-22 |
22-29 |
29-36 |
36-43 |
43-50 |
Vehicle |
Mean |
21.85y |
24.45y |
25.25y |
25.30y |
25.45y |
24.60y |
24.40y |
|
SD |
0.07 |
0.21 |
0.21 |
0.28 |
0.21 |
0.57 |
0.42 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
100 |
Mean |
21.15 |
23.70 |
25.00 |
25.40 |
24.65 |
23.35 |
23.10 |
|
SD |
0.49 |
0.14 |
0.14 |
0.14 |
0.07 |
0.49 |
1.41 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
% Diff G1 |
-3 .20 |
-3 .07 |
-0 .99 |
0.40 |
-3 .14 |
-5 .08 |
-5 .33 |
300 |
Mean |
21.30 |
23.25 |
24.65 |
25.10 |
24.95 |
24.40 |
24.25 |
|
SD |
1.27 |
1.06 |
0.92 |
0.71 |
1.34 |
1.98 |
1.91 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
% Diff G1 |
-2 .52 |
-4 .91 |
-2 .38 |
-0 .79 |
-1 .96 |
-0 .81 |
-0 .61 |
1000 |
Mean |
20.10 |
22.70 |
24.45 |
24.65 |
24.45 |
23.75 |
22.70 |
|
SD |
-- |
-- |
0.49 |
1.06 |
0.35 |
0.21 |
0.00 |
|
N |
1 |
1 |
2 |
2 |
2 |
2 |
2 |
|
% Diff G1 |
-8 .01 |
-7 .16 |
-3 .17 |
-2 .57 |
-3 .93 |
-3 .46 |
-6 .97 |
Males |
|
Days (From – To) |
|
|
|
|
|
|
Dose group |
|
50-57 |
57-64 |
64-71 |
71-78 |
78-85 |
85-91 |
|
Vehicle |
Mean |
23.80y |
23.40y |
23.75y |
23.50y |
22.70y |
23.15y |
|
|
SD |
0.85 |
0.85 |
0.49 |
0.99 |
1.27 |
0.78 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
100 |
Mean |
23.65 |
22.40 |
22.70 |
22.55 |
21.80 |
22.45 |
|
|
SD |
0.35 |
0.28 |
0.28 |
0.07 |
0.14 |
0.49 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
-0 .63 |
-4 .27 |
-4 .42 |
-4 .04 |
-3 .96 |
-3 .02 |
|
300 |
Mean |
23.70 |
22.90 |
23.50 |
23.10 |
22.75 |
22.95 |
|
|
SD |
2.26 |
2.55 |
2.26 |
2.26 |
1.63 |
2.33 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
-0 .42 |
-2 .14 |
-1 .05 |
-1 .70 |
0.22 |
-0 .86 |
|
1000 |
Mean |
23.15 |
22.05 |
22.20 |
22.10 |
21.45 |
22.55 |
|
|
SD |
0.35 |
0.21 |
0.28 |
0.14 |
0.35 |
1.20 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
-2 .73 |
-5 .77 |
-6 .53 |
-5 .96 |
-5 .51 |
-2 .59 |
|
Females |
|
Days (From – To) |
||||||
Dose group |
|
1-8 |
8-15 |
15-22 |
22-29 |
29-36 |
36-43 |
43-50 |
Vehicle |
Mean |
15.60y |
16.30y |
16.35y |
16.45y |
16.20y |
15.80y |
16.60y |
|
SD |
0.42 |
0.57 |
0.21 |
0.07 |
0.14 |
0.14 |
0.14 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
100 |
Mean |
15.40 |
16.05 |
16.30 |
16.55 |
16.50 |
16.25 |
16.75 |
|
SD |
0.14 |
0.35 |
0.28 |
0.07 |
0.57 |
0.92 |
0.78 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
-1 .28 |
-1 .53 |
-0 .31 |
0.61 |
1.85 |
2.85 |
0.90 |
300 |
Mean |
15.35 |
16.05 |
16.40 |
16.60 |
16.60 |
16.50 |
17.15 |
|
SD |
0.07 |
0.21 |
0.14 |
0.14 |
0.28 |
0.14 |
0.07 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
-1 .60 |
-1 .53 |
0.31 |
0.91 |
2.47 |
4.43 |
3.31 |
1000 |
Mean |
15.55 |
16.25 |
16.55 |
16.70 |
17.00 |
17.05 |
16.50 |
|
SD |
0.35 |
0.35 |
0.21 |
1.13 |
0.28 |
0.35 |
1.13 |
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
-0 .32 |
-0 .31 |
1.22 |
1.52 |
4.94 |
7.91 |
-0 .60 |
Females |
|
Days (From – To) |
||||||
Dose group |
|
50-57 |
57-64 |
64-71 |
71-78 |
78-85 |
85-91 |
|
Vehicle |
Mean |
16.40y |
15.75y |
16.20y |
16.25y |
15.85y |
16.10y |
|
|
SD |
0.28 |
0.35 |
0.28 |
0.49 |
0.78 |
0.57 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
100 |
Mean |
16.20 |
16.00 |
16.15 |
16.70 |
15.55 |
16.15 |
|
|
SD |
0.71 |
0.99 |
1.06 |
0.85 |
0.78 |
0.78 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
-1 .22 |
1.59 |
-0 .31 |
2.77 |
-1 .89 |
0.31 |
|
300 |
Mean |
16.55 |
16.50 |
16.50 |
16.65 |
16.15 |
16.70 |
|
|
SD |
0.78 |
0.00 |
0.57 |
0.21 |
0.21 |
0.57 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
0.91 |
4.76 |
1.85 |
2.46 |
1.89 |
3.73 |
|
1000 |
Mean |
16.65 |
15.35 |
16.10 |
15.95 |
15.70 |
16.25 |
|
|
SD |
0.35 |
1.34 |
0.00 |
0.07 |
0.57 |
0.78 |
|
|
N |
2 |
2 |
2 |
2 |
2 |
2 |
|
|
|
1.52 |
-2 .54 |
-0 .62 |
-1 .85 |
-0 .95 |
0.93 |
|
All Groups excluded from statistical analysis (N<3 in Control): y
Table 7: Summary of ophthalmoscopy findings
|
Males |
Females |
||||||
Findings |
Vehicle |
100 mg/kg bw/day |
300 mg/kg bw/day |
1000 mg/kg bw/day |
Vehicle |
100 mg/kg bw/day |
300 mg/kg bw/day |
1000 mg/kg bw/day |
Cornea, opacity |
6 |
1 |
|
3 |
1 |
1 |
1 |
1 |
Cornea edema |
2 |
2 |
2 |
1 |
1 |
1 |
1 |
|
Cornea, opacity multifocal, pinpoint |
|
|
2 |
1 |
|
|
|
|
Table 8: Summary of haematology and coagulation values
End Of Treatment |
Dose groups (mg/kg bw/day) |
Control |
100 |
300 |
1000 |
Males
|
|||||
WBC |
mean |
6.6 |
7.1 |
6.1 |
6.2 |
10E9/L |
st.dev |
1.7 |
1.2 |
0.9 |
0.9 |
|
n |
10 |
10 |
10 |
9 |
Neutrophils |
mean |
0.9 |
1.2 |
1.0 |
1.1 |
10E9/L |
st.dev |
0.4 |
0.2 |
0.1 |
0.4 |
|
n |
10 |
10 |
10 |
9 |
Lymphocytes |
mean |
5.5 |
5.7 |
4.9 |
4.9 |
10E9/L |
st.dev |
1.4 |
1.1 |
0.9 |
0.9 |
|
n |
10 |
10 |
10 |
9 |
Monocytes |
mean |
0.1 |
0.1 |
0.1 |
0.2 |
10E9/L |
st.dev |
0.0 |
0.1 |
0.0 |
0.1 |
|
n |
10 |
10 |
10 |
9 |
Eosinophils |
mean |
0.1 |
0.1 |
0.1 |
0.1 |
10E9/L |
st.dev |
0.0 |
0.0 |
0.0 |
0.0 |
|
n |
10 |
10 |
10 |
9 |
Basophils |
mean |
0.0 |
0.0 |
0.0 |
0.0 |
10E9/L |
st.dev |
0.0 |
0.0 |
0.0 |
0.0 |
|
n |
10 |
10 |
10 |
9 |
Red blood cells |
mean |
9.41 |
9.23 |
9.38 |
8.45 ** |
10E12/L |
st.dev |
0.27 |
0.28 |
0.31 |
0.47 |
|
n |
10 |
10 |
10 |
9 |
Reticulocytes |
mean |
178.8 |
199.5 |
172.2 |
245.0 |
10E9/L |
st.dev |
21.9 |
19.5 |
19.3 |
64.3 |
|
n |
10 |
10 |
10 |
9 |
RDW |
mean |
12.3 |
12.9 |
12.2 |
11.4 * |
% |
st.dev |
0.5 |
0.9 |
0.6 |
0.7 |
|
n |
10 |
10 |
10 |
9 |
Haemoglobin |
mean |
10.2 |
10.1 |
10.0 |
9.3 ** |
mmol/L |
st.dev |
0.3 |
0.3 |
0.3 |
0.4 |
|
n |
10 |
10 |
10 |
9 |
Haematocrit |
mean |
0.510 |
0.499 |
0.496 |
0.514 |
L/L |
st.dev |
0.015 |
0.010 |
0.008 |
0.025 |
|
n |
10 |
10 |
10 |
9 |
MCV |
mean |
54.2 |
54.1 |
52.9 |
61.0 ** |
fL |
st.dev |
1.7 |
1.2 |
1.2 |
3.7 |
|
n |
10 |
10 |
10 |
9 |
MCH |
mean |
1.08 |
1.09 |
1.07 |
1.10 |
fmol |
st.dev |
0.04 |
0.04 |
0.02 |
0.03 |
|
n |
10 |
10 |
10 |
9 |
MCHC |
mean |
19.95 |
20.18 |
20.17 |
18.14 ** |
mmol/L |
st.dev |
0.25 |
0.43 |
0.32 |
0.61 |
|
n |
10 |
10 |
10 |
9 |
Platelets |
mean |
684 |
740 |
717 |
675 |
10E9/L |
st.dev |
109 |
43 |
68 |
73 |
|
n |
10 |
10 |
10 |
9 |
PT |
mean |
17.8 |
17.0 ** |
17.2 * |
18.0 |
s |
st.dev |
0.5 |
0.4 |
0.5 |
0.3 |
|
n |
9 |
8 |
8 |
6 |
APTT |
mean |
20.8 |
20.1 |
20.8 |
20.1 |
s |
st.dev |
1.6 |
2.1 |
1.6 |
0.9 |
|
n |
10 |
9 |
10 |
9 |
Females |
|
|
|
|
|
WBC |
mean |
3.9 |
3.8 |
3.9 |
4.6 |
10E9/L |
st.dev |
0.9 |
1.5 |
0.9 |
1.3 |
|
n |
9 |
10 |
9 |
8 |
Neutrophils |
mean |
0.4 |
0.7 |
0.6 |
0.6 |
10E9/L |
st.dev |
0.2 |
0.3 |
0.2 |
0.2 |
|
n |
9 |
10 |
9 |
8 |
Lymphocytes |
mean |
3.3 |
2.9 |
3.1 |
3.8 |
10E9/L |
st.dev |
0.8 |
1.5 |
0.7 |
1.1 |
|
n |
9 |
10 |
9 |
8 |
Monocytes |
mean |
0.1 |
0.1 |
0.1 |
0.1 |
10E9/L |
st.dev |
0.0 |
0.0 |
0.1 |
0.1 |
|
n |
9 |
10 |
9 |
8 |
Eosinophils |
mean |
0.1 |
0.1 |
0.1 |
0.1 |
10E9/L |
st.dev |
0.0 |
0.0 |
0.0 |
0.0 |
|
n |
9 |
10 |
9 |
8 |
Basophils |
mean |
0.0 |
0.0 |
0.0 |
0.0 |
10E9/L |
st.dev |
0.0 |
0.0 |
0.0 |
0.0 |
|
n |
9 |
10 |
9 |
8 |
Red blood cells |
mean |
8.29 |
8.14 |
8.35 |
7.21 ** |
10E12/L |
st.dev |
0.59 |
0.56 |
0.11 |
0.50 |
|
n |
10 |
10 |
9 |
8 |
Reticulocytes |
mean |
213.7 |
205.4 |
218.7 |
277.8 |
10E9/L |
st.dev |
35.2 |
22.2 |
33.9 |
60.0 |
|
n |
10 |
10 |
9 |
8 |
RDW |
mean |
11.0 |
11.0 |
11.1 |
11.0 |
% |
st.dev |
0.3 |
0.6 |
0.5 |
0.5 |
|
n |
10 |
10 |
9 |
8 |
Haemoglobin |
mean |
9.3 |
9.4 |
9.5 |
8.7 |
mmol/L |
st.dev |
0.7 |
0.7 |
0.2 |
0.7 |
|
n |
10 |
10 |
9 |
8 |
Haematocrit |
mean |
0.461 |
0.451 |
0.462 |
0.454 |
L/L |
st.dev |
0.035 |
0.033 |
0.012 |
0.032 |
|
n |
10 |
10 |
9 |
8 |
MCV |
mean |
55.7 |
55.5 |
55.4 |
63.0 ** |
fL |
st.dev |
1.2 |
1.3 |
1.0 |
2.2 |
|
n |
10 |
10 |
9 |
8 |
MCH |
mean |
1.13 |
1.15 |
1.14 |
1.21 ** |
fmol |
st.dev |
0.03 |
0.04 |
0.02 |
0.02 |
|
n |
10 |
10 |
9 |
8 |
MCHC |
mean |
20.25 |
20.72 * |
20.66 |
19.16 ** |
mmol/L |
st.dev |
0.34 |
0.30 |
0.35 |
0.54 |
|
n |
10 |
10 |
9 |
8 |
Platelets |
mean |
779 |
750 |
864 |
744 |
10E9/L |
st.dev |
119 |
91 |
138 |
93 |
|
n |
10 |
10 |
9 |
8 |
PT |
mean |
17.4 |
17.2 |
18.7 |
18.5 |
s |
st.dev |
1.2 |
0.6 |
2.4 |
2.2 |
|
n |
10 |
10 |
9 |
8 |
APTT |
mean |
20.7 |
20.7 |
21.0 |
19.6 |
s |
st.dev |
1.6 |
1.1 |
1.8 |
1.8 |
|
n |
10 |
10 |
9 |
8 |
+/++ Steel-test significant at 5% (+) or 1% (++) level
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Table 9: Summary of clinical chemistry values
End Of Treatment |
Dose groups (mg/kg bw/day) |
Control |
100 |
300 |
1000 |
Males |
|||||
ALAT |
mean |
39.6 |
44.2 |
45.1 |
59.9 ** |
U/L |
st.dev |
5.0 |
7.0 |
5.9 |
20.1 |
|
n |
10 |
10 |
10 |
9 |
ASAT |
mean |
69.1 |
77.2 |
81.3 |
96.1 ** |
U/L |
st.dev |
9.6 |
9.8 |
9.9 |
19.9 |
|
n |
10 |
10 |
10 |
9 |
ALP |
mean |
102 |
98 |
98 |
157 ** |
U/L |
st.dev |
22 |
20 |
19 |
47 |
|
n |
10 |
10 |
10 |
9 |
Total protein |
mean |
65.8 |
66.6 |
66.2 |
64.4 |
g/L |
st.dev |
1.3 |
3.3 |
1.7 |
1.9 |
|
n |
10 |
10 |
10 |
9 |
Albumin |
mean |
33.3 |
33.7 |
33.6 |
33.8 |
g/L |
st.dev |
0.6 |
1.3 |
0.5 |
1.1 |
|
n |
10 |
10 |
10 |
9 |
Total bilirubin |
mean |
2.6 |
2.6 |
2.8 |
2.7 |
umol/L |
st.dev |
0.2 |
0.3 |
0.3 |
0.2 |
|
n |
10 |
10 |
10 |
9 |
Urea |
mean |
7.0 |
7.4 |
7.5 |
7.5 |
mmol/L |
st.dev |
0.6 |
0.9 |
0.9 |
0.3 |
|
n |
10 |
10 |
10 |
9 |
Creatinine |
mean |
34.5 |
34.5 |
34.5 |
36.9 ** |
umol/L |
st.dev |
1.1 |
1.5 |
1.6 |
1.8 |
|
n |
10 |
10 |
10 |
9 |
Glucose |
mean |
10.44 |
10.41 |
10.05 |
8.14 ** |
mmol/L |
st.dev |
1.70 |
1.56 |
1.30 |
1.13 |
|
n |
10 |
10 |
10 |
9 |
Cholesterol |
mean |
1.95 |
1.86 |
1.78 |
1.33 ** |
mmol/L |
st.dev |
0.22 |
0.19 |
0.28 |
0.33 |
|
n |
10 |
10 |
10 |
9 |
Bile Acids |
mean |
25.2 |
25.6 |
17.3 |
53.4 ** |
umol/L |
st.dev |
13.4 |
19.3 |
8.9 |
24.3 |
|
n |
10 |
10 |
10 |
9 |
Sodium |
mean |
141.8 |
143.3 ** |
143.6 ** |
142.7 |
mmol/L |
st.dev |
1.0 |
1.1 |
0.9 |
1.2 |
|
n |
10 |
10 |
10 |
9 |
Potassium |
mean |
3.74 |
3.83 |
4.02 * |
3.82 |
mmol/L |
st.dev |
0.13 |
0.23 |
0.13 |
0.34 |
|
n |
10 |
10 |
10 |
9 |
Chloride |
mean |
102 |
103 |
104 ** |
105 ** |
mmol/L |
st.dev |
1 |
1 |
1 |
2 |
|
n |
10 |
10 |
10 |
9 |
Calcium |
mean |
2.63 |
2.66 |
2.68 |
2.63 |
mmol/L |
st.dev |
0.03 |
0.05 |
0.05 |
0.06 |
|
n |
10 |
10 |
10 |
9 |
Inorg.Phos |
mean |
1.69 |
1.63 |
1.75 |
1.78 |
mmol/L |
st.dev |
0.21 |
0.13 |
0.09 |
0.16 |
|
n |
10 |
10 |
10 |
9 |
Total T4 |
mean |
3.61 |
3.97 |
4.04 |
3.09 |
ug/dL |
st.dev |
0.59 |
0.63 |
1.04 |
0.39 |
|
n |
10 |
10 |
10 |
9 |
females |
|||||
ALAT |
mean |
36.6 |
38.7 |
37.3 |
41.6 |
U/L |
st.dev |
7.9 |
11.2 |
9.4 |
9.1 |
|
n |
10 |
10 |
9 |
9 |
ASAT |
mean |
73.5 |
83.8 |
72.8 |
71.9 |
U/L |
st.dev |
8.8 |
27.1 |
5.1 |
8.3 |
|
n |
10 |
10 |
9 |
9 |
ALP |
mean |
41 |
53 |
39 |
60 * |
U/L |
st.dev |
13 |
13 |
7 |
26 |
|
n |
10 |
10 |
9 |
9 |
Total protein |
mean |
68.4 |
66.7 |
69.6 |
65.9 |
g/L |
st.dev |
2.8 |
1.8 |
3.3 |
2.2 |
|
n |
10 |
10 |
9 |
9 |
Albumin |
mean |
36.7 |
35.9 |
37.8 |
36.2 |
g/L |
st.dev |
1.5 |
1.3 |
1.5 |
1.1 |
|
n |
10 |
10 |
9 |
9 |
Total bilirubin |
mean |
3.0 |
3.0 |
3.0 |
3.2 |
umol/L |
st.dev |
0.4 |
0.3 |
0.3 |
0.4 |
|
n |
10 |
10 |
9 |
9 |
Urea |
mean |
7.6 |
7.4 |
7.7 |
8.1 |
mmol/L |
st.dev |
0.6 |
0.6 |
1.2 |
1.1 |
|
n |
10 |
10 |
9 |
9 |
Creatinine |
mean |
40.6 |
39.2 |
38.5 |
39.0 |
umol/L |
st.dev |
2.0 |
1.7 |
3.3 |
1.6 |
|
n |
10 |
10 |
9 |
9 |
Glucose |
mean |
7.12 |
6.74 |
6.74 |
7.42 |
mmol/L |
st.dev |
1.15 |
0.63 |
1.13 |
1.28 |
|
n |
10 |
10 |
9 |
9 |
Cholesterol |
mean |
1.95 |
1.72 |
1.70 |
1.40 * |
mmol/L |
st.dev |
0.49 |
0.48 |
0.44 |
0.27 |
|
n |
10 |
10 |
9 |
9 |
Bile Acids |
mean |
19.7 |
20.2 |
19.1 |
36.6 |
umol/L |
st.dev |
8.3 |
12.2 |
12.5 |
42.9 |
|
n |
10 |
10 |
9 |
9 |
Sodium |
mean |
141.3 |
143.0 ** |
144.2 ** |
142.1 |
mmol/L |
st.dev |
1.0 |
0.7 |
0.8 |
1.1 |
|
n |
10 |
10 |
9 |
9 |
Potassium |
mean |
3.31 |
3.47 |
3.33 |
3.63 * |
mmol/L |
st.dev |
0.30 |
0.20 |
0.10 |
0.25 |
|
n |
10 |
10 |
9 |
9 |
Chloride |
mean |
105 |
106 ** |
107 ** |
106 * |
mmol/L |
st.dev |
1 |
1 |
1 |
1 |
|
n |
10 |
10 |
9 |
9 |
Calcium |
mean |
2.69 |
2.64 |
2.69 |
2.61 ** |
mmol/L |
st.dev |
0.07 |
0.05 |
0.04 |
0.06 |
|
n |
10 |
10 |
9 |
9 |
Inorg.Phos |
mean |
1.46 |
1.52 |
1.59 |
1.56 |
mmol/L |
st.dev |
0.22 |
0.09 |
0.19 |
0.14 |
|
n |
10 |
10 |
8 |
9 |
Total T4 |
mean |
2.39 |
2.54 |
2.38 |
1.86 |
ug/dL |
st.dev |
0.79 |
0.69 |
0.85 |
0.52 |
|
n |
10 |
10 |
9 |
9 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Table 10: Summary of absolute organ weights
Males |
||||||||
Group (mg/kg bw/day) |
|
Body weight |
Brain |
Epididymis |
Gland Adrenal |
Gland Prostate |
Gland Sem Ves |
Gland Thyroid |
|
|
g |
g |
g |
g |
g |
g |
g |
control |
Mean |
375.1 |
2.0836 |
1.1901 |
0.05781 |
0.8821 |
1.2902 |
0.01566 |
|
SD |
36.4 |
0.1148 |
0.1098 |
0.00720 |
0.2420 |
0.1764 |
0.00231 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
100 |
Mean |
374.7 |
2.0428 |
1.2244 |
0.05831 |
0.8008 |
1.4507 |
0.01603 |
|
SD |
36.8 |
0.0851 |
0.0970 |
0.00938 |
0.2282 |
0.2786 |
0.00411 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
%Diff G1 |
-0 .1 |
-1 .9581 |
2.8821 |
0.86490 |
-9 .2166 |
12.4399 |
2.36271 |
300 |
Mean |
387.8 |
2.0560 |
1.2114 |
0.05979 |
0.8479 |
1.2558 |
0.01675 |
|
SD |
33.6 |
0.0735 |
0.1281 |
0.00682 |
0.2522 |
0.2168 |
0.00255 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
%Diff G1 |
3.4 |
-1 .3246 |
1.7898 |
3.42501 |
-3 .8771 |
-2 .6663 |
6.96041 |
1000 |
Mean |
344.7 |
2.0511 |
1.1616 |
0.05176 |
0.6903 |
1.1749 |
0.01590 |
|
SD |
27.4 |
0.0681 |
0.0580 |
0.00805 |
0.1408 |
0.2073 |
0.00287 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
|
%Diff G1 |
-8 .1 |
-1 .5593 |
-2 .3985 |
-10 .47301 |
-21 .7398 |
-8 .9375 |
1.53257 |
Males |
||||||||
|
|
Heart |
Kidney |
Liver |
Spleen |
Testis |
Thymus |
|
control |
Mean |
g |
g |
g |
g |
g |
g |
|
|
SD |
1.0080 |
2.4660 |
9.3318 |
0.5655 |
3.6530 |
0.2906 |
|
|
N |
0.1234 |
0.3757 |
1.5440 |
0.1083 |
0.3178 |
0.0637 |
|
100 |
Mean |
10 |
10 |
10 |
10 |
10 |
10 |
|
|
SD |
0.9990 |
2.6050 |
9.4615 |
0.5563 |
3.7483 |
0.2642 |
|
|
N |
0.0947 |
0.2145 |
1.0497 |
0.0484 |
0.3845 |
0.0722 |
|
|
%Diff G1 |
10 |
10 |
10 |
10 |
10 |
10 |
|
300 |
Mean |
-0 .8929 |
5.6367 |
1.3899 |
-1 .6269 |
2.6088 |
-9 .0847 |
|
|
SD |
0.9664 |
2.5880 |
9.6277 |
0.5626 |
3.7919 |
0.2858 |
|
|
N |
0.0628 |
0.2555 |
0.8865 |
0.0876 |
0.3279 |
0.0575 |
|
|
%Diff G1 |
10 |
10 |
10 |
10 |
10 |
10 |
|
1000 |
Mean |
-4 .1270 |
4.9473 |
3.1709 |
-0 .5128 |
3.8024 |
-1 .6518 |
|
|
SD |
0.9701 |
2.5402 |
9.2477 |
0.5166 |
3.7129 |
0.2332 |
|
|
N |
0.0927 |
0.1934 |
0.7626 |
0.0630 |
0.2191 |
0.0423 |
|
|
%Diff G1 |
9 |
9 |
9 |
9 |
9 |
9 |
|
|
|
-3 .7588 |
3.0098 |
-0 .9016 |
-8 .6551 |
1.6394 |
-19 .7446 |
|
Females |
||||||||
Group (mg/kg bw/day) |
|
Body weight |
Brain |
Gland Adrenal |
Gland Thyroid |
Heart |
Kidney |
Liver |
control |
Mean |
g |
g |
g |
g |
g |
g |
g |
|
SD |
223.8 |
1.9236 |
0.06453 |
0.01339 |
0.6761 |
1.5852 |
5.7994 |
|
N |
12.8 |
0.0888 |
0.01075 |
0.00190 |
0.0379 |
0.1127 |
0.7506 |
100 |
Mean |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
SD |
223.5 |
1.8803 |
0.06921 |
0.01389 |
0.6916 |
1.6120 |
5.6842 |
|
N |
15.5 |
0.0542 |
0.00910 |
0.00195 |
0.0600 |
0.1250 |
0.5325 |
|
%Diff G1 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
300 |
Mean |
-0 .1 |
-2 .2510 |
7.25244 |
3.73413 |
2.2926 |
1.6906 |
-1 .9864 |
|
SD |
213.4 |
1.8793 |
0.06820 |
0.01299 |
0.6957 |
1.5870 |
5.8367 |
|
N |
18.3 |
0.1129 |
0.00810 |
0.00247 |
0.0607 |
0.1268 |
0.8101 |
|
%Diff G1 |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
1000 |
Mean |
-4 .6 |
-2 .3012 |
5.68728 |
-2 .99560 |
2.8940 |
0.1136 |
0.6426 |
|
SD |
218.1 |
1.9086 |
0.05995 |
0.01453 |
0.7194 |
1.7080 |
6.8550b |
|
N |
22.6 |
0.0454 |
0.01010 |
0.00292 |
0.0815 |
0.1649 |
0.6071 |
|
%Diff G1 |
8 |
8 |
8 |
7 |
8 |
8 |
8 |
Females |
||||||||
|
|
Ovary |
Spleen |
Thymus |
Uterus |
|
|
|
control |
Mean |
g |
g |
g |
g |
|
|
|
|
SD |
0.1350 |
0.3937 |
0.2846 |
0.7898 |
|
|
|
|
N |
0.0186 |
0.0425 |
0.0475 |
0.4280 |
|
|
|
100 |
Mean |
10 |
10 |
10 |
10 |
|
|
|
|
SD |
0.1513 |
0.3997 |
0.2863 |
0.8129 |
|
|
|
|
N |
0.0191 |
0.0294 |
0.0306 |
0.3222 |
|
|
|
|
%Diff G1 |
10 |
10 |
10 |
10 |
|
|
|
300 |
Mean |
12.0741 |
1.5240 |
0.5973 |
2.9248 |
|
|
|
|
SD |
0.1328 |
0.4026 |
0.2352a |
0.7933 |
|
|
|
|
N |
0.0199 |
0.0545 |
0.0213 |
0.3912 |
|
|
|
|
%Diff G1 |
9 |
9 |
9 |
9 |
|
|
|
1000 |
Mean |
-1 .6461 |
2.2493 |
-17 .3499 |
0.4474 |
|
|
|
|
SD |
0.1365 |
0.4288 |
0.2893 |
0.4728 |
|
|
|
|
N |
0.0251 |
0.0471 |
0.0619 |
0.1671 |
|
|
|
|
%Diff G1 |
8 |
8 |
8 |
8 |
|
|
|
|
|
1.1111 |
8.9027 |
1.6339 |
-40 .1431 |
|
|
|
Significantly different from control group 1 value : a=p≤0.05,b=p≤0.01 (Dunn)
Table 11: Summary of organ weights relative to body weight
Males |
||||||||
Group (mg/kg bw/day) |
|
Brain |
Epididymis |
Gland Adrenal |
Gland Prostate |
Gland Sem Ves |
Gland Thyroid |
Heart |
|
|
% |
% |
% |
% |
% |
% |
% |
control |
Mean |
0.55840 |
0.31813 |
0.0155 |
0.23473 |
0.34545 |
0.0042 |
0.26838 |
|
SD |
0.03954 |
0.02148 |
0.0019 |
0.05825 |
0.04674 |
0.0005 |
0.01434 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
100 |
Mean |
0.54873 |
0.32851 |
0.0156 |
0.21599 |
0.38493 |
0.0043 |
0.26699 |
|
SD |
0.04436 |
0.03037 |
0.0020 |
0.06566 |
0.05075 |
0.0009 |
0.01329 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
%Diff G1 |
-1 .73141 |
3.26065 |
0.6025 |
-7 .98467 |
11.42982 |
1.9021 |
-0 .51709 |
300 |
Mean |
0.53272 |
0.31351 |
0.0154 |
0.21703 |
0.32337 |
0.0043 |
0.24992a |
|
SD |
0.03520 |
0.03331 |
0.0015 |
0.05592 |
0.04923 |
0.0006 |
0.01376 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
%Diff G1 |
-4 .59967 |
-1 .45401 |
-0 .2193 |
-7 .54035 |
-6 .39119 |
3.6075 |
-6 .87522 |
1000 |
Mean |
0.59775 |
0.33879 |
0.0151 |
0.19946 |
0.34277 |
0.0046 |
0.28179 |
|
SD |
0.04170 |
0.03066 |
0.0025 |
0.03098 |
0.06930 |
0.0008 |
0.01982 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
|
%Diff G1 |
7.04767 |
6.49182 |
-2 .5076 |
-15 .02842 |
-0 .77639 |
10.8140 |
4.99732 |
Males |
||||||||
|
|
Kidney |
Liver |
Spleen |
Testis |
Thymus |
|
|
control |
Mean |
% |
% |
% |
% |
% |
% |
% |
|
||||||||
|
SD |
0.65756 |
2.47895 |
0.15014 |
0.97666 |
0.07756 |
|
|
|
N |
0.07344 |
0.23420 |
0.01989 |
0.06736 |
0.01581 |
|
|
100 |
Mean |
10 |
10 |
10 |
10 |
10 |
|
|
|
SD |
0.69842 |
2.52911 |
0.14915 |
1.00536 |
0.07043 |
|
|
|
N |
0.05872 |
0.18531 |
0.01297 |
0.11174 |
0.01783 |
|
|
|
%Diff G1 |
10 |
10 |
10 |
10 |
10 |
|
|
300 |
Mean |
6.21360 |
2.02360 |
-0 .66122 |
2.93860 |
-9 .18779 |
|
|
|
SD |
0.66741 |
2.48456 |
0.14471 |
0.98160 |
0.07360 |
|
|
|
N |
0.03279 |
0.13234 |
0.01562 |
0.08770 |
0.01235 |
|
|
|
%Diff G1 |
10 |
10 |
10 |
10 |
10 |
|
|
1000 |
Mean |
1.49844 |
0.22631 |
-3 .61257 |
0.50572 |
-5 .10703 |
|
|
|
SD |
0.73750a |
2.68451 |
0.15068 |
1.08346 |
0.06791 |
|
|
|
N |
0.02286 |
0.11401 |
0.02146 |
0.10781 |
0.01348 |
|
|
|
%Diff G1 |
9 |
9 |
9 |
9 |
9 |
|
|
|
|
12.15681 |
8.29233 |
0.36042 |
10.93501 |
-12 .44638 |
|
|
Females |
||||||||
Group (mg/kg bw/day) |
|
Brain |
Gland Adrenal |
Gland Thyroid |
Heart |
Kidney |
Liver |
Ovary |
control |
Mean |
% |
% |
% |
% |
% |
% |
% |
|
|
0.86159 |
0.0289 |
0.0060 |
0.30240 |
0.70923 |
2.59247 |
0.06058 |
|
SD |
0.05597 |
0.0048 |
0.0009 |
0.01375 |
0.05009 |
0.32206 |
0.00943 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
100 |
Mean |
0.84435 |
0.0310 |
0.0062 |
0.30964 |
0.72227 |
2.54130 |
0.06786 |
|
SD |
0.05406 |
0.0036 |
0.0009 |
0.02016 |
0.04813 |
0.11461 |
0.00910 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
%Diff G1 |
-2 .00053 |
7.3580 |
4.0112 |
2.39290 |
1.83943 |
-1 .97381 |
12.03147 |
300 |
Mean |
0.88446 |
0.0320 |
0.0061 |
0.32681a |
0.74485 |
2.72978 |
0.06200 |
|
SD |
0.06995 |
0.0030 |
0.0012 |
0.02617 |
0.03862 |
0.24753 |
0.00539 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
|
%Diff G1 |
2.65433 |
10.8381 |
2.1268 |
8.07136 |
5.02358 |
5.29637 |
2.35777 |
1000 |
Mean |
0.88217 |
0.0275 |
0.0066 |
0.32993a |
0.78421b |
3.15242 b |
0.06242 |
|
SD |
0.08159 |
0.0037 |
0.0014 |
0.02071 |
0.04232 |
0.21928 |
0.00805 |
|
N |
8 |
8 |
7 |
8 |
8 |
8 |
8 |
|
%Diff G1 |
2.38831 |
-4 .8216 |
9.3446 |
9.10242 |
10.57337 |
21.59899 |
3.04074 |
Females |
||||||||
|
|
Spleen |
Thymus |
Uterus |
|
|
|
|
control |
Mean |
% |
% |
% |
|
|
|
|
|
|
0.17605 |
0.12699 |
0.35102 |
|
|
|
|
|
SD |
0.01824 |
0.01865 |
0.18264 |
|
|
|
|
|
N |
10 |
10 |
10 |
|
|
|
|
100 |
Mean |
0.17904 |
0.12851 |
0.36804 |
|
|
|
|
|
SD |
0.01031 |
0.01480 |
0.15613 |
|
|
|
|
|
N |
10 |
10 |
10 |
|
|
|
|
|
%Diff G1 |
1.70044 |
1.19996 |
4.84611 |
|
|
|
|
300 |
Mean |
0.18829 |
0.11036 |
0.36826 |
|
|
|
|
|
SD |
0.01537 |
0.00751 |
0.17956 |
|
|
|
|
|
N |
9 |
9 |
9 |
|
|
|
|
|
%Diff G1 |
6.95674 |
-13 .09221 |
4.90872 |
|
|
|
|
1000 |
Mean |
0.19804 |
0.13413 |
0.21903 |
|
|
|
|
|
SD |
0.02761 |
0.03454 |
0.08351 |
|
|
|
|
|
N |
8 |
8 |
8 |
|
|
|
|
|
%Diff G1 |
12.49191 |
5.62264 |
-37 .60137 |
|
|
|
|
Significantly different from control group 1 value :a=p≤0.05,b=p≤0.01 (Dunn)
Table 12: Mean percent liver weight differences from control groups
|
Males |
Females |
||||
Dose Level (Mg/Kg bw/day): |
100 |
300 |
1000 |
100 |
300 |
1000 |
|
|
|
|
|
|
|
Liver |
|
|
|
|
|
|
Absolute |
1 |
3 |
-1 |
-2 |
1 |
18** |
Relative To Body Weight |
2 |
0 |
8 |
-2 |
5 |
22** |
**: P<0.01 |
|
|
|
|
|
|
Table 13: Summary of gross pathology findings
|
Males |
Female |
|||||||||
Dose group (mg/kg bw/day) |
Vehicle |
100 |
300 |
1000 |
Vehicle |
100 |
300 |
1000 |
|||
Number of animals |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Adipose Tissue |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Bone, Femur |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Bone, Sternum |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Bone Marrow, Femur |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Bone Marrow, Sternum |
|||||||||||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Brain |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Cervix |
|
|
|
|
|
|
|
|
|||
Submitted |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|||
Epididymis |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|||
Esophagus |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Eye |
|
|
|
|
|
|
|
|
|||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
No Visible Lesions |
9 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|||
Enlargement |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
||
Galt |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Adrenal |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Clitoral |
|
|
|
|
|
|
|
|
|
||
Submitted No Visible Lesions Focus GLAND, COAGULATING |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
- |
- |
- |
- |
8 |
10 |
9 |
8 |
|
||
Focus |
- |
- |
- |
- |
2 |
0 |
1 |
0 |
|
||
Gland; Coagulating |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
No Visible Lesions |
10 |
10 |
10 |
8 |
- |
- |
- |
- |
|
||
Abnormal Appearance |
0 |
0 |
0 |
1 |
- |
- |
- |
- |
|
||
Gland, Harderian |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Lacrimal |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Mammary |
|
|
|
|
|||||||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Parathyroid |
|
|
|
|
|
||||||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Pituitary |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Preputial |
|
|
|
|
|
|
|||||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
No Visible Lesions |
10 |
10 |
10 |
8 |
- |
- |
- |
- |
|
||
Small |
0 |
0 |
0 |
1 |
- |
- |
- |
- |
|
||
Gland, Prostate |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
Gland, Salivary, Mandibular |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Salivary, Sublingual |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Gland, Seminal Vesicle |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
Gland, Thyroid |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Heart |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Kidney |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
9 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Dilatation |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
||
Large Intestine, Cecum |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Large Intestine, Colon |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Large Intestine, Rectum |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
0 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Larynx |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Liver |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
9 |
10 |
9 |
9 |
10 |
10 |
8 |
8 |
|
||
Hernia |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
||
Discoloration |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
0 |
|
||
Abnormal Consistency |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
|
||
Small |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
|
||
Lung |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Lymph Node Iliac |
|
|
|
|
|
|
|
|
|
||
Submitted |
- |
- |
- |
- |
1 |
0 |
0 |
0 |
|
||
No Visible Lesions |
- |
- |
- |
- |
- |
- |
- |
- |
|
||
Lymph Node, Mandibular |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
9 |
9 |
9 |
7 |
|
||
Discoloration |
0 |
0 |
0 |
0 |
1 |
1 |
0 |
1 |
|
||
Lymph Node, Mesenteric |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Muscle, Diaphgram |
|
|
|
|
|
|
|
|
|
||
Submitted |
1 |
0 |
0 |
0 |
- |
- |
- |
- |
|
||
No Visible Lesions |
1 |
- |
- |
- |
- |
- |
- |
- |
|
||
Muscle, Skeletal |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Nasopharynx |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Nerve, Optic |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Nerve, Sciatic |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Ovary |
|
|
|
|
|
|
|
|
|
||
Submitted |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
Pancreas |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Skin |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Small Intestine, |
|
|
|
|
|
|
|
|
|
||
Duodenum |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Small Intestine, Ileum |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Small Intestine, |
|
|
|
|
|
|
|
|
|
||
Jejunum |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Spinal Cord |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Spleen |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Stomach |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
9 |
10 |
9 |
9 |
9 |
7 |
9 |
6 |
|
||
Focus |
1 |
0 |
1 |
0 |
0 |
1 |
0 |
1 |
|
||
Irregular Surface |
0 |
0 |
0 |
0 |
1 |
2 |
0 |
1 |
|
||
Testis |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
- |
- |
- |
- |
|
||
Thymus |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
9 |
9 |
10 |
8 |
9 |
8 |
|
||
Focus |
0 |
0 |
1 |
0 |
0 |
1 |
0 |
0 |
|
||
Discoloration |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
|
||
Tongue |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Trachea |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Urinary Bladder |
|
|
|
|
|
|
|
|
|
||
Submitted |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
|
||
Uterus |
|
|
|
|
|
|
|
|
|
||
Submitted |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
- |
- |
- |
- |
5 |
4 |
4 |
7 |
|
||
Fluid Accumulation |
- |
- |
- |
- |
5 |
6 |
5 |
1 |
|
||
Vagina |
|
|
|
|
|
|
|
|
|
||
Submitted |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
No Visible Lesions |
- |
- |
- |
- |
10 |
10 |
9 |
8 |
|
||
Table 14: Summary test item-related microscopic findings – scheduled euthanasia animals
|
Males |
Females |
||||||
Dose level (mg/kg):
|
Vehicle |
100 |
300 |
1000 |
Vehicle |
100 |
300 |
1000 |
LIVER a |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
Centrilobular infiltrate, mononuclear |
|
|
|
|
|
|
|
|
Minimal |
- |
2 |
4 |
3 |
- |
1 |
3 |
2 |
Mild |
- |
- |
2 |
4 |
- |
- |
2 |
5 |
Centrilobular single cell necrosis |
|
|
|
|
|
|
|
|
Minimal |
- |
- |
2 |
2 |
- |
1 |
1 |
3 |
Mild |
- |
- |
- |
3 |
- |
- |
1 |
2 |
Hypertrophy, centrilobular |
|
|
|
|
|
|
|
|
Minimal |
- |
- |
- |
3 |
- |
- |
- |
- |
Mild |
- |
- |
- |
3 |
- |
- |
- |
- |
Vacuolation, periportal |
|
|
|
|
|
|
|
|
Minimal |
- |
- |
- |
4 |
- |
- |
- |
1 |
SPLEEN a |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
Pigment |
|
|
|
|
|
|
|
|
Minimal |
7 |
7 |
8 |
- |
3 |
2 |
5 |
1 |
Mild |
3 |
1 |
2 |
4 |
7 |
8 |
4 |
3 |
Moderate |
- |
- |
- |
5 |
- |
- |
- |
4 |
ADRENAL GLAND a |
10 |
10 |
10 |
9 |
10 |
10 |
9 |
8 |
Vacuolation, zona glomerulosa |
|
|
|
|
|
|
|
|
Minimal |
1 |
2 |
1 |
5 |
- |
- |
- |
2 |
Mild |
- |
- |
- |
3 |
- |
- |
- |
3 |
a = Number of tissues examined from each group.
Table 15: Summary of functional tests
Males |
Dose (mg/kg bw/day) |
group 1 control |
group 2 100 |
group 3 300 |
group 4 1000 |
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 |
1411 |
1387 |
1420 |
1281 |
Gram |
st.dev |
166 |
165 |
252 |
129 |
|
n |
5 |
5 |
5 |
5 |
Grip Hind |
mean |
634 |
688 |
706 |
593 |
Gram |
st.dev |
124 |
72 |
83 |
40 |
|
n |
5 |
5 |
5 |
5 |
Females |
Dose (mg/kg bw/day) |
group 1 control |
group 2 100 |
group 3 300 |
group 4 1000 |
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 |
1101 |
1193 |
1060 |
1248 |
Gram |
st.dev |
72 |
141 |
148 |
79 |
|
n |
5 |
5 |
5 |
5 |
Grip Hind |
mean |
569 |
502 |
550 |
483 |
Gram |
st.dev |
78 |
112 |
60 |
55 |
|
n |
5 |
5 |
5 |
5 |
Table 16: Motor activity test summary
Males |
Dose (mg/kg bw/day) |
group 1 control |
group 2 100 |
group 3 300 |
group 4 1000 |
Total Movements |
mean1 |
2411 |
2421 |
2897 |
2710 |
|
st.dev |
616 |
828 |
868 |
1227 |
|
n |
5 |
5 |
5 |
5 |
Ambulations |
mean1 |
435 |
424 |
494 |
613 |
|
st.dev |
235 |
221 |
169 |
353 |
|
n |
5 |
5 |
5 |
5 |
Females |
Dose (mg/kg bw/day) |
group 1 control |
group 2 100 |
group 3 300 |
group 4 1000 |
Total Movements |
mean1 |
3630 |
3216 |
3656 |
3024 |
|
st.dev |
908 |
829 |
684 |
1157 |
|
n |
5 |
5 |
5 |
5 |
Ambulations |
mean1 |
950 |
705 |
956 |
840 |
|
st.dev |
219 |
183 |
125 |
352 |
|
n |
5 |
5 |
5 |
5 |
Table 17: Summary of sperm analysis
Dose Group (mg/kg bw/day) |
|
Vehicel |
100 |
300 |
1000 |
Necropsy Nr of cells exam |
mean |
270 |
284 |
240 |
331 |
|
st.dev |
58 |
98 |
35 |
113 |
|
n |
10 |
10 |
10 |
9 |
Motile sperm |
mean |
76 |
78 |
72 |
81 |
% |
st.dev |
11 |
5 |
14 |
6 |
|
n |
10 |
10 |
10 |
9 |
Progressiv.sperm |
mean |
10 |
15 |
16 |
15 |
% |
st.dev |
7 |
5 |
7 |
9 |
|
n |
10 |
10 |
10 |
9 |
Spermcount epi |
mean |
454.4 |
--- |
--- |
500.9 |
10e6/Gram |
st.dev |
107.1 |
--- |
--- |
135.8 |
|
n |
8 |
0 |
0 |
9 |
Normal morph |
mean |
163 |
--- |
--- |
170 |
No of cells |
st.dev |
14 |
--- |
--- |
10 |
|
n |
10 |
0 |
0 |
9 |
Detached head |
mean |
1 |
--- |
--- |
1 |
No of cells |
st.dev |
1 |
--- |
--- |
2 |
|
n |
10 |
0 |
0 |
9 |
Abnormal head |
mean |
0 |
--- |
--- |
0 |
No of cells |
st.dev |
0 |
--- |
--- |
0 |
|
n |
10 |
0 |
0 |
9 |
Coiled tail |
mean |
25 |
--- |
--- |
24 |
No of cells |
st.dev |
9 |
--- |
--- |
11 |
|
n |
10 |
0 |
0 |
9 |
Other tail |
mean |
10 |
--- |
--- |
4 |
No of cells |
st.dev |
8 |
--- |
--- |
3 |
|
n |
10 |
0 |
0 |
9 |
Abnormal neck |
mean |
1 |
--- |
--- |
0 |
No of cells |
st.dev |
1 |
--- |
--- |
0 |
|
n |
10 |
0 |
0 |
9 |
Combined |
mean |
0 |
--- |
--- |
0 |
No of cells |
st.dev |
0 |
--- |
--- |
0 |
|
n |
10 |
0 |
0 |
9 |
Applicant's summary and conclusion
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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