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EC number: 457-670-6 | CAS number: 157859-20-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 07 February 2017 to 12 June 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Triisopropylsilyl acrylate
- Cas Number:
- 157859-20-6
- Molecular formula:
- C12H24O2Si
- IUPAC Name:
- Triisopropylsilyl acrylate
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 7-8 weeks old
- Weight at study initiation: males: 152 – 187 g; females: 122 – 151 g
- Fasting period before study: none
- Housing: - The animals were kept in groups of 5 animals / sex / group / cage in IVC cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water (e.g. ad libitum): tap water, sulphur acidified to a pH of approximately 2.8, ad libitum
- Acclimation period: at least 5 days
DETAILS OF FOOD AND WATER QUALITY: not specified
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item and control formulations were prepared once in 7-10 days based on the stability information. The prepared formulation was stored at room temperature. The test item was weighed on a suitable precision balance into a tared plastic vial and the vehicle was added to give the appropriate final concentration of the test item. To protect from hydrolysis by humidity, formulation vials were purged with argon after the preparation before closing. Formulates were kept under magnetic stirring during the daily administration.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle has been selected as suggested by the sponsor based on the test item’s characteristics (hydrolysis in water) and testing guideline. The selected vehicle was dried corn oil.
- Concentration in vehicle: 2.53, 12.63, 25.25 mg/mL
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): MKBQ9948V
- Purity: not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Before beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about stability and homogeneity of the test item in the selected vehicle. Study pre-start stability analysis included samples from high dose and low dose group and the investigation was made. Prestart homogeneity investigation included the samples collected from various levels (top, middle and bottom) of high dose and low dose groups (6 samples).
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 7 days a week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Remarks:
- low dose group (LD)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Remarks:
- middle dose group (MD)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- high dose group (HD)
- No. of animals per sex per dose:
- 10 male and 10 female animals per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected according to the results of a previous toxicity studies and in consultation with the sponsor.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: Recovery groups of 5 animals from control and high dose group.
- Post-exposure recovery period in satellite groups: 28 days
- Section schedule rationale (if not random): random - Positive control:
- not used
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked included: clinical signs of toxicity, mortality and morbidity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first administration and at least once a week thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: Once before the assignment to the experimental groups, on the first day of administration and weekly during the treatment and recovery period.
FOOD CONSUMPTION AND COMPOUND INTAKE: Food consumption was measured weekly.
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 (if drinking water study): Not applicable
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: all the animals
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all the animals
- Parameters checked in table [No.1] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: prior to sacrifice
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked in table [No.1] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity / grip strength / motor activity
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table No 2)
HISTOPATHOLOGY: Yes (see table No 2) - Other examinations:
- Immunohistochemistry of α2µ-globulin and/or a specific staining was performed on kidney of all male animals sacrificed at the end of the treatment period of the study (40 animals) and recovery period (10 animals).
- Statistics:
- A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights was performed for each gender by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. Furthermore, statistical comparisons of data acquired during the recovery period were performed with a Student’s t-Test or Mann-Whitney U-Test when appropriate. These statistics were performed with Ascentos 1.1.3 software or GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- In this study, there were no clinical findings observed related to a systemic effect of the test item.
During the treatment period, slight to moderate salivation was noted occasionally in one male of LD group, some males and females of the MD group and the HD group. Moving the bedding was observed transitorily in all males and all females of the MD and HD group. As the symptoms of salivation and moving the bedding were noted mainly immediately after administration, these signs were considered to be a sign of discomfort due to a local reaction to the test item rather than the systemic effect of the test item. No clinical signs were observed in any recovery animals during recovery period except alopecia on lower back in one HD recovery female from day 111 to 118 was observed.
Low incidences of slight clinical signs like alopecia on various body parts, skin bruising, skin scratches/cuts on various body parts were noted in isolated males and/or females of the dose groups during the treatment period. As these slight clinical signs were mostly transient and seen in isolated animals, they were considered to be incidental.
During the weekly detailed clinical observation, no significant changes or differences between the groups were found except statistically significantly higher or lower mean score for few parameters like salivation, spontaneous activity, animal sleeps, animal moving in cage and salivation on few occasions without showing any consistency in MD or HD group females and higher mean score for salivation in HD group males when compared with the controls. There was also a statistically significantly lower mean score for animal moving in cage in male high dose recovery group in week 5 and higher mean score for salivation in the female high dose recovery group in week 8. This statistically significant effect on detailed clinical examination was not considered to be treatment related. - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred in the control or any of the dose groups during the treatment period or recovery period of this study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- In males sacrificed at the end of treatment period, a tendency towards a marginally lower mean body weight was observed in the HD group after the day 57 of treatment compared to the control group and the body weight was noted to be further slightly reduced until the end of the treatment period (up to 3%; not statistically significant). In males sacrificed at the end of the recovery period, during the treatment period and recovery period, mean body weight of the male HD recovery group remained slightly, lower compared to the control group (up to 8%; not statistically significant). In males sacrificed at the end of treatment period, body weight gain was lower from day 36 onwards in the MD group and day 8 onwards in the HD group until termination, without achieving statistical significance when compared to the controls. In males sacrificed at the end of the recovery period, statistically significantly lower group mean body weight gain was observed in the HD recovery group during day 43-50, 57-64 and statistically significantly higher group mean body weight gain was observed during day 78-85 and day 111-118 when compared with the controls.
In females, a tendency towards a marginally lower mean body weight was observed in the MD and HD groups from day/week 1 of treatment compared to the control group and the body weight was noted to be further slightly reduced until the end of the treatment period (up to 6.4%) without achieving statistical significance. In females sacrificed at the end of the recovery period, during the treatment period and recovery period, mean body weight of the female HD recovery group was statistically significantly lower on day 8 compared to the control group (up to 4.4%). However, on other days of the treatment period and all days of the recovery period, group mean body weight was comparable with the controls. In females sacrificed at the end of the treatment period, body weight gain was statistically significantly lower in LD and MD groups during day 22-29 when compared with the controls. Overall mean daily weight gain (Day 1-90) during the treatment period was slightly lower in the female HD group when compared to the controls. In females sacrificed at the end of the recovery period, statistically significantly lower body weight gain was observed in the HD recovery group during day 1-8 when compared with the controls.
As differences in body weight gain were marginal and values were within the normal range of variation for animals of this strain, effects on body weight and body weight gain were not considered as an adverse effect of the test item - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The test item had no effect on food consumption in this study. Mean daily food intake of male and female animals was in the normal range of variation throughout the treatment and recovery periods of this study.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No ophthalmologic findings were observed in any of the animals of this study.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- In males and females sacrificed at the end of the treatment period and recovery period, no test item-related effect of toxicological relevance was observed for haematology and coagulation parameters.
In males sacrificed at the end of the treatment period, statistical analysis of haematology and coagulation data revealed, statistically significantly lower HCT group mean values in LD and group mean reticulocytes values in HD group when compared with the controls. In males sacrificed at the end of the recovery period, statistically significantly lower WBC count was observed in HD recovery group when compared with the recovery controls.
In females sacrificed at the end of the treatment period, there was a marginally but statistically significantly lower mean value of mean corpuscular volume (MCV) and higher value of mean corpuscular haemoglobin concentration (MCHC) in the HD group compared with the controls. Statistical analysis also revealed a statistically significantly lower group mean basophil count in LD and MD groups without following a dose-related pattern when compared with the controls. In females sacrificed at the end of the recovery period, no statistically significant effect was observed for any haematology parameter when compared with the recovery controls.
As the respective haematology values were within the normal range of variation for animals of this strain and age, differences are not assumed to be biologically relevant even though they were statistically significant.
All haematological parameters and blood coagulation parameters in males and females sacrificed at the end of treatment and recovery periods were in the normal range of variation and no statistically significant or test item-related effects were observed. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- In males and females sacrificed at the end of the treatment period and recovery period, no test item-related effect of toxicological relevance was observed for clinical biochemistry parameters.
In males sacrificed at the end of treatment period, statistical analysis of clinical biochemistry data revealed, statistically significantly higher TBA group mean values in the HD group when compared with the controls. In males sacrificed at the end of the recovery period, marginally but statistically significantly higher ALAT was observed in the HD recovery group when compared with the controls.
In females sacrificed at the end of the treatment period, no statistically significant effect was observed for any of the clinical biochemistry parameters when compared with the controls. In females sacrificed at the end of the recovery period, statistically significantly lower group mean values for TP, Alb and Na was observed in the HD recovery group when compared with the recovery controls.
As the respective clinical biochemistry values were either within the normal range of variation for animals of this strain and age and/or no such effect was observed at the end of the treatment period, these differences are assumed not to be biologically relevant even though they were statistically significant.
All clinical biochemistry parameters in males and females sacrificed at the end of treatment and recovery period were in the normal range of variation and no statistically significant or test item-related effects were observed. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- The test item had no toxicologically relevant effect on urinary parameters analysed at the end of the treatment period and recovery period of this study.
Slightly higher leukocyte levels were found in the urine of the majority of male animals (all groups including controls) at the end of the treatment period, and in few control and HD males sacrificed at the end of the recovery period. In females, this finding was observed in a few animals of all groups (including controls) sacrificed at the end of treatment period and in only a few animals of control recovery group. No such finding was observed in HD recovery females sacrificed at the end of recovery period.
In males and females, all other urinary parameters were in the normal range of variation and no test item-related differences between the dose groups and control group were observed. - Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No relevant and test item related effects were observed in any of the parameters of the functional observation battery at the end of the treatment period and at the end of the recovery period.
Before initiation of treatment, there was a statistically significantly higher group mean score for head touch, ground righting reflex, air righting reflex in males treatment groups and head touch, fear, defecation and equilibrium reflex in MD and HD female groups when compared with the controls. As this effect was observed before initiation of the treatment, no toxicological significance can be attributed to these findings. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The test item had no toxicologically relevant effect on organ weights determined at the end of the treatment period and recovery period of this study. All group mean and individual values for the male and female organs weights (absolute and relative to body weight and brain weight) from the test item treated groups were comparable with the control group.
No statistically significant effect on organs weights was observed in male and females sacrificed at the end of treatment period and recovery period except statistically significantly higher relative (to body weight) kidney weights in HD recovery males when compared with respective control group. This effect on kidney weight in HD male recovery animals was not considered to be test item related as no such effect was observed in males sacrificed at the end of the treatment period. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Few specific gross pathological changes in the uterus were recorded for a few female animals. These findings were not considered to be treatment-related and assumed to be common background findings in this strain.
Complete dilatation of uterus was observed in 3 females of LD (61, 68, 69), 2 females of MD (73, 75) and 1 female of HD (81) group.
No gross pathological findings were observed in males sacrificed at the end of the treatment period and both male and females sacrificed at the end of the recovery period - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Under the conditions of this study, accumulation of α2-microglobulin in kidneys from several test item-treated males and from control animals was observed. In addition, the comparison between group 4 (treatment and recovery period) and group 1 animals (treatment and recovery period) revealed similar α2-microglobulin accumulation. Further, the α2-microglobulin accumulation noticed after immunohistochemistry using a specific anti-Alpha 2u Globulin antibody corresponded with the presence of hyaline inclusions that was recorded in hematoxylin and eosin stained kidney sections. However, no dose dependency was observed during the histopathological evaluation.
The accumulation of α2-microglobulin comprises a male-rat-specific syndrome without toxicological relevance in humans. In absence of further renal lesions, this change was considered non-adverse.
All remaining findings recorded were considered incidental or were within the range of spontaneous background alterations that may be recorded in Wistar rats at these ages.
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 effects observed.
- Remarks on result:
- other: See 'any other information on results incl. tables' and attachments for results tables
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No adverse effects observed.
- Remarks on result:
- other: See 'any other information on results incl. tables' and attachments for results tables
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Summary hematology
Table 1: Sex: male; phase: in life
|
|
C / M |
LD / M |
MD / M |
HD / M |
RBC [M/µL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
9.171a 0.501 10 |
8.867 0.387 9 -3.318 |
9.036 0.314 8 -1.469 |
9.296 0.379 10 1.363 |
HGB [g/dL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
15.84a 0.64 10 |
15.46 0.36 9 -2.43 |
15.55 0.59 8 -1.83 |
15.89 0.43 10 0.32 |
WBC [K/uL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
5.079k 1.543 10 |
4.720 0.974 9 -7.068 |
4.946 1.403 8 -2.614 |
5.604 1.437 10 10.337 |
HCT [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
50.48ad 2.35 10 |
48.39* 1.43 9 -4.14 |
48.90 1.67 8 -3.13 |
50.55 1.41 10 0.14 |
MCV [fl] day 91 |
Mean S.d. N Deviation Vs Control [%] |
55.09k 2.06 10 |
54.63 1.56 9 -0.83 |
54.14 1.45 8 -1.73 |
54.41 1.15 10 -1.23 |
MCH [pg] day 91 |
Mean S.d. N Deviation Vs Control [%] |
17.32a 0.72 10 |
17.48 0.68 9 0.91 |
17.21 0.50 8 -0.62 |
17.12 0.39 10 -1.15 |
MCHC [g/dL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
31.41a 0.52 10 |
31.93 0.72 9 1.67 |
31.84 0.46 8 1.36 |
31.45 0.59 10 0.13 |
RET [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.522ad 0.125 10 |
1.599 0.232 9 5.052 |
1.406 0.197 8 -7.605 |
1.261** 0.149 10 -17.148 |
PLT [K/uL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
716.7a 90.9 10 |
712.0 78.5 9 -0.7 |
745.6 83.7 8 4.0 |
713.7 44.6 10 -0.4 |
LYM [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
75.45a 6.79 10 |
75.36 7.64 9 -0.13 |
74.54 3.58 8 -1.21 |
78.72 3.18 10 4.33 |
NEUT [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
21.20a 6.76 10 |
21.71 7.40 9 2.41 |
22.00 3.75 8 3.77 |
17.80 3.08 10 -16.04 |
EOS [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
0.34k 0.20 10 |
0.33 0.17 9 -1.96 |
0.49 0.19 8 43.38 |
0.31 0.13 10 -8.82 |
MONO [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
2.03a 0.49 10 |
1.68 0.45 9 -17.35 |
2.01 0.65 8 -0.86 |
2.07 0.57 10 1.97 |
BASO [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
0.32k 0.11 10 |
0.31 0.09 9 -2.78 |
0.35 0.13 8 9.38 |
0.26 0.11 10 -18.75 |
LUC% [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
0.66a 0.31 10 |
0.62 0.17 9 -5.72 |
0.60 0.15 8 -9.09 |
0.82 0.32 10 24.24 |
a=ANOVA; k=KRUSKALL-WALLIS; ad=ANOVA-DUNNETT; * = p < 0.05; ** = p < 0.01
Table 2: sex: females; phase: in life
|
|
C / F |
LD / F |
MD / F |
HD / F |
RBC [M/µL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
7.562k 0.395 10 |
7.313 0.428 10 -3.293 |
7.392 0.261 10 -2.248 |
7.487 0.632 9 -0.996 |
HGB [g/dL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
13.71a 0.63 10 |
13.28 0.73 10 -3.14 |
13.53 0.28 10 -1.31 |
13.46 1.13 9 -1.86 |
WBC [K/uL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.250a 0.941 10 |
0.813 0.516 10 -34.960 |
0.858 0.611 10 -31.360 |
1.281 0.686 9 2.489 |
HCT [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
43.33a 2.29 10 |
41.30 2.28 10 -4.68 |
41.85 1.25 10 -3.42 |
41.10 3.62 9 -5.15 |
MCV [fl] day 91 |
Mean S.d. N Deviation Vs Control [%] |
57.34ad 1.72 10 |
56.48 1.37 10 -1.50 |
56.62 1.10 10 -1.26 |
54.90** 1.32 9 -4.26 |
MCH [pg] day 91 |
Mean S.d. N Deviation Vs Control [%] |
18.13a 0.37 10 |
18.19 0.61 10 0.33 |
18.31 0.36 10 0.99 |
17.99 0.54 9 -0.78 |
MCHC [g/dL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
31.66ad 0.95 10 |
32.18 0.71 10 1.64 |
32.37 0.74 10 2.24 |
32.78** 0.48 9 3.53 |
RET [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.954a 0.298 10 |
1.946 0.361 10 -0.409 |
2.011 0.222 10 2.917 |
1.924 0.286 9 -1.513 |
PLT [K/uL] day 91 |
Mean S.d. N Deviation Vs Control [%] |
691.7a 62.5 10 |
691.4 75.9 10 0.0 |
661.7 108.4 10 -4.3 |
711.7 31.1 9 2.9 |
LYM [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
73.64k 11.49 10 |
71.93 8.57 10 -2.32 |
66.48 14.60 10 -9.72 |
72.74 8.32 9 -1.22 |
NEUT [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
21.51k 9.59 10 |
25.24 8.50 10 17.34 |
29.61 13.78 10 37.66 |
23.58 8.01 9 9.61 |
EOS [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.56k 2.67 10 |
0.65 0.61 10 -58.33 |
1.22 1.08 10 -21.79 |
0.88 0.78 9 -43.73 |
MONO [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
2.39a 0.77 10 |
1.75 0.75 10 -26.78 |
2.22 0.72 10 -7.11 |
2.04 0.83 9 -14.46 |
BASO [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
0.38u 0.19 10 |
0.11** 0.12 10 -71.05 |
0.11** 0.17 10 -71.05 |
0.29 0.19 9 -23.98 |
LUC% [%] day 91 |
Mean S.d. N Deviation Vs Control [%] |
0.53k 0.39 10 |
0.31 0.30 10 -41.51 |
0.35 0.21 10 -33.96 |
0.49 0.36 9 -7.76 |
k=KRUSKALL-WALLIS; a=ANOVA; ad=ANOVA-DUNNETT; ** = p < 0.01
Table 3: sex: males recovery group; phase: in life
|
|
Recovery C / M |
Recovery HD / M |
RBC [M/µL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
9.192a 0.262 4 |
8.524 1.010 5 -7.272 |
HGB [g/dL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
15.95s 0.26 4 |
14.84 1.69 5 -6.96 |
WBC [K/uL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
4.898ad 1.043 4 |
2.968* 0.776 5 -39.398 |
HCT [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
48.90a 0.08 4 |
45.72 5.26 5 -6.50 |
MCV [fl] day 119 |
Mean S.d. N Deviation Vs Control [%] |
53.25a 1.55 4 |
53.66 1.35 5 0.77 |
MCH [pg] day 119 |
Mean S.d. N Deviation Vs Control [%] |
17.38a 0.28 4 |
17.42 0.44 5 0.26 |
MCHC [g/dL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
32.60a 0.50 4 |
32.50 0.51 5 -0.31 |
RET [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.712a 0.240 4 |
1.784 0.280 5 4.175 |
PLT [K/uL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
765.8s 73.8 4 |
617.8 327.0 5 -19.3 |
LYM [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
77.90a 6.31 4 |
72.38 3.22 5 -7.09 |
NEUT [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
18.30a 6.42 4 |
24.32 3.41 5 32.90 |
EOS [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
0.48a 0.10 4 |
0.42 0.16 5 -11.58 |
MONO [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
2.42a 0.60 4 |
2.10 0.41 5 -13.40 |
BASO [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
0.35s 0.06 4 |
0.32 0.08 5 -8.57 |
LUC% [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
0.60a 0.37 4 |
0.42 0.19 5 -30.00 |
a=ANOVA; s=DUNN; ad=ANOVA-DUNNETT; * = p < 0.05
Table 4: sex: females recovery group; phase: in life
|
|
Recovery C / F |
Recovery HD / F |
RBC [M/µL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
6.648s 2.947 5 |
8.268 0.226 5 24.368 |
HGB [g/dL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
14.46a 1.06 5 |
14.82 0.24 5 2.49 |
WBC [K/uL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.236a 0.714 5 |
1.520 0.475 5 22.977 |
HCT [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
44.98a 3.68 5 |
46.26 0.73 5 2.85 |
MCV [fl] day 119 |
Mean S.d. N Deviation Vs Control [%] |
57.20a 1.24 5 |
55.96 0.97 5 -2.17 |
MCH [pg] day 119 |
Mean S.d. N Deviation Vs Control [%] |
18.40a 0.64 5 |
17.94 0.40 5 -2.50 |
MCHC [g/dL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
32.20a 0.50 5 |
32.10 0.28 5 -0.31 |
RET [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.706a 0.170 5 |
1.830 0.260 5 7.268 |
PLT [K/uL] day 119 |
Mean S.d. N Deviation Vs Control [%] |
723.4a 100.3 5 |
728.0 82.3 5 0.6 |
LYM [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
76.22a 4.60 5 |
76.04 8.52 5 -0.24 |
NEUT [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
19.46a 4.02 5 |
20.48 7.62 5 5.24 |
EOS [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.38a 0.78 5 |
0.82 0.61 5 -40.58 |
MONO [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
2.32a 1.69 5 |
2.02 1.05 5 -12.93 |
BASO [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
0.26a 0.21 5 |
0.32 0.23 5 23.08 |
LUC% [%] day 119 |
Mean S.d. N Deviation Vs Control [%] |
0.38a 0.23 5 |
0.30 0.21 5 -21.05 |
s=DUNN; a=ANOVA
Summary coagulation
Table 1: In life, males
|
|
C / M |
LD / M |
MD / M |
HD / M |
PT [sec] day 91 |
Mean S.d. N Deviation Vs Control [%] |
20.25k 1.25 10 |
19.31 0.74 9 -4.64 |
20.67 1.38 9 2.06 |
20.42 1.64 10 0.84 |
APTT [sec] day 91 |
Mean S.d. N Deviation Vs Control [%] |
11.47k 3.45 10 |
9.97 2.71 9 -13.11 |
11.33 4.85 10 -1.22 |
9.70 1.60 10 -15.43 |
k=KRUSKALL-WALLIS
Table 2: In life, females
|
|
C / F |
LD / F |
MD / F |
HD / F |
PT [sec] day 91 |
Mean S.d. N Deviation Vs Control [%] |
21.24a 1.74 10 |
21.50 1.67 9 1.22 |
21.53 2.08 10 1.37 |
22.03 2.14 10 3.72 |
APTT [sec] day 91 |
Mean S.d. N Deviation Vs Control [%] |
9.37a 2.09 10 |
9.27 2.59 9 -1.10 |
9.57 1.80 10 2.13 |
9.86 1.68 10 5.23 |
a=ANOVA
Table 3: In life, recovery males
|
|
Recovery C / M |
Recovery HD / M |
PT [sec] day 119 |
Mean S.d. N Deviation Vs Control [%] |
19.18a 1.02 5 |
20.44 1.50 5 6.57 |
APTT [sec] day 119 |
Mean S.d. N Deviation Vs Control [%] |
12.64a 1.82 5 |
13.50 4.23 5 6.80 |
a=ANOVA
Table 4: In life, recovery females
|
|
Recovery C / F |
Recovery HD / F |
PT [sec] day 119 |
Mean S.d. N Deviation Vs Control [%] |
19.62a 1.43 4 |
20.10 1.71 5 2.42 |
APTT [sec] day 119 |
Mean S.d. N Deviation Vs Control [%] |
12.22a 3.68 5 |
12.84 0.99 5 5.07 |
a=ANOVA
Summary clinical biochemistry
Table 1: In life males
|
|
C / M |
LD / M |
MD / M |
HD / M |
ALAT [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
33.80a 3.81 10 |
35.18 7.63 10 4.08 |
40.61 9.71 10 20.15 |
40.16 5.52 10 18.82 |
ASAT [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
104.59k 20.02 10 |
99.12 25.07 10 -5.23 |
108.73 31.48 10 3.96 |
94.93 10.10 10 -9.24 |
AP [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
136.081u 53.601 10 |
93.862 17.596 10 -31.025 |
124.415 32.155 10 -8.573 |
173.184 95.364 10 27.265 |
Crea [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
25.5a 2.5 10 |
25.5 3.7 10 0.0 |
27.8 6.9 10 9.0 |
24.9 3.9 10 -2.4 |
TP [G/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
55.18ad 1.36 10 |
56.74 1.61 10 2.83 |
55.13 1.44 10 -0.09 |
54.32 1.37 10 -1.56 |
Alb [G/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
30.663a 0.823 10 |
30.986 1.125 10 1.053 |
30.213 0.820 10 -1.468 |
30.467 0.609 10 -0.639 |
urea [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
5.814a 0.923 10 |
5.129 0.686 10 -11.782 |
5.641 0.719 10 -2.976 |
5.766 0.911 10 -0.826 |
TBIL [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
2.02k 0.34 10 |
2.26 0.96 10 11.88 |
2.21 0.50 10 9.41 |
2.19 0.31 10 8.42 |
TBA [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
34.497ad 5.967 10 |
31.342 10.317 10 -9.146 |
38.267 10.500 10 10.928 |
50.048** 11.752 10 45.079 |
Chol [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.624a 0.319 10 |
1.900 0.299 10 16.995 |
1.672 0.266 10 2.956 |
1.641 0.140 10 1.047 |
Gluc [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
9.540a 1.089 10 |
10.520 2.400 10 10.273 |
8.587 1.861 10 -9.990 |
9.615 1.044 10 0.786 |
Na [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
141.8k 0.9 10 |
142.2 1.4 10 0.3 |
140.9 2.1 10 -0.6 |
141.4 1.6 10 -0.3 |
K [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
4.344k 0.668 10 |
4.372 1.011 10 0.645 |
4.629 1.352 10 6.561 |
4.354 0.628 10 0.230 |
a=ANOVA;
k=KRUSKALL-WALLIS; u=KRUSKALL-WALLIS-DUNN; ad=ANOVA-DUNNETT; ** = p <
0.01
Table 2: In life females
|
|
C / F |
LD / F |
MD / F |
HD / F |
ALAT [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
29.85a 12.15 10 |
29.47 6.08 10 -1.27 |
27.47 5.25 10 -7.97 |
26.12 5.18 10 -12.50 |
ASAT [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
87.13a 18.56 10 |
81.28 9.59 10 -6.71 |
80.40 12.15 10 -7.72 |
78.51 20.37 10 -9.89 |
AP [U/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
59.410k 27.714 10 |
45.603 16.830 10 -23.240 |
58.686 22.900 10 -1.219 |
61.329 24.534 10 3.230 |
Crea [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
32.5a 4.9 10 |
31.2 4.6 9 -3.9 |
28.7 4.7 10 -11.7 |
29.4 2.4 10 -9.5 |
TP [G/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
66.12k 4.28 10 |
63.66 3.63 9 -3.73 |
65.84 4.15 10 -0.42 |
63.65 3.20 10 -3.74 |
Alb [G/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
37.573a 2.285 10 |
36.454 2.175 10 -2.978 |
37.218 3.008 10 -0.945 |
35.764 2.062 10 -4.815 |
urea [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
6.571k 0.766 10 |
6.090 0.596 9 -7.320 |
6.393 0.694 10 -2.709 |
6.489 1.173 10 -1.248 |
TBIL [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
2.32a 0.32 10 |
2.29 0.31 9 -1.34 |
2.26 0.37 10 -2.59 |
2.37 0.61 10 2.16 |
TBA [µmol/L] day 91 |
Mean S.d. N Deviation Vs Control [%] |
31.261a 32.784 10 |
22.624 9.586 9 -27.627 |
18.381 6.625 10 -41.202 |
34.996 25.785 10 11.948 |
Chol [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
1.504a 0.267 10 |
1.488 0.353 10 -1.064 |
1.417 0.216 10 -5.785 |
1.520 0.184 10 1.064 |
Gluc [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
7.504a 1.324 10 |
7.589 1.469 9 1.131 |
7.130 1.584 10 -4.984 |
7.332 1.127 10 -2.292 |
Na [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
138.6k 2.8 10 |
139.0 1.9 10 0.3 |
140.5 2.2 10 1.4 |
139.7 2.6 10 0.8 |
K [mmol/l] day 91 |
Mean S.d. N Deviation Vs Control [%] |
3.797k 0.520 9 |
3.733 0.380 10 -1.677 |
3.577 0.327 10 -5.786 |
3.692 0.204 10 -2.757 |
a=ANOVA; k=KRUSKALL-WALLIS
Table 3: In life recovery males
|
|
Recovery C / M |
Recovery HD / M |
ALAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.12ad 0.53 5 |
29.18* 3.69 5 16.16 |
ASAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
83.30a 16.08 5 |
93.72 13.59 5 12.51 |
AP [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
104.536s 19.014 5 |
96.296 36.405 5 -7.882 |
Crea [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.0a 3.4 5 |
23.0 2.1 5 -8.0 |
TP [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
53.26s 4.96 5 |
57.08 4.18 5 7.17 |
Alb [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
28.612a 2.816 5 |
31.230 2.486 5 9.150 |
urea [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
6.834a 0.557 5 |
6.408 0.292 5 -6.234 |
TBIL [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.96s 0.31 5 |
2.08 0.24 5 6.12 |
TBA [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.960a 5.055 5 |
25.348 5.567 5 -2.357 |
Chol [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.592a 0.232 5 |
1.650 0.211 5 3.643 |
Gluc [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
11.924a 2.191 5 |
9.442 0.997 5 -20.815 |
Na [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
128.2a 9.4 5 |
133.6 10.2 5 4.2 |
K [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
3.822a 0.231 5 |
3.626 0.328 5 -5.128 |
|
|
Recovery C / M |
Recovery HD / M |
ALAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.12ad 0.53 5 |
29.18* 3.69 5 16.16 |
ASAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
83.30a 16.08 5 |
93.72 13.59 5 12.51 |
AP [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
104.536s 19.014 5 |
96.296 36.405 5 -7.882 |
Crea [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.0a 3.4 5 |
23.0 2.1 5 -8.0 |
TP [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
53.26s 4.96 5 |
57.08 4.18 5 7.17 |
Alb [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
28.612a 2.816 5 |
31.230 2.486 5 9.150 |
urea [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
6.834a 0.557 5 |
6.408 0.292 5 -6.234 |
TBIL [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.96s 0.31 5 |
2.08 0.24 5 6.12 |
TBA [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
25.960a 5.055 5 |
25.348 5.567 5 -2.357 |
Chol [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.592a 0.232 5 |
1.650 0.211 5 3.643 |
Gluc [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
11.924a 2.191 5 |
9.442 0.997 5 -20.815 |
Na [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
128.2a 9.4 5 |
133.6 10.2 5 4.2 |
K [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
3.822a 0.231 5 |
3.626 0.328 5 -5.128 |
ad=ANOVA-DUNNETT;
* = p < 0.05; a=ANOVA; s=DUNN
Table 4: In life recovery females
|
|
Recovery C / F |
Recovery HD / F |
ALAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
32.70a 5.55 5 |
25.44 4.39 5 -22.20 |
ASAT [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
101.42a 19.86 5 |
94.44 17.33 5 -6.88 |
AP [U/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
54.378a 18.558 5 |
48.572 21.162 5 -10.677 |
Crea [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
29.0s 1.9 5 |
50.4 49.6 5 73.8 |
TP [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
62.94s 4.07 5 |
56.08* 5.30 5 -10.90 |
Alb [G/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
36.328s 2.499 5 |
31.626** 2.152 5 -12.943 |
urea [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
7.332s 0.424 5 |
10.230 7.603 5 39.525 |
TBIL [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
3.04a 0.47 5 |
3.88 2.23 5 27.63 |
TBA [µmol/L] day 119 |
Mean S.d. N Deviation Vs Control [%] |
33.438a 20.590 5 |
18.504 15.399 5 -44.662 |
Chol [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
1.342a 0.318 5 |
1.324 0.164 5 -1.341 |
Gluc [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
6.636a 1.632 5 |
5.808 0.860 5 -12.477 |
Na [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
138.0s 2.8 5 |
125.4* 10.3 5 -9.1 |
K [mmol/l] day 119 |
Mean S.d. N Deviation Vs Control [%] |
3.494s 0.201 5 |
4.048 1.674 5 15.856 |
a=ANOVA; s=DUNN; * = p < 0.05; ** = p < 0.01
Summry gross pathology
Table 1: Males
Sex Dose Group |
M C / M |
M LD / M |
M MD / M |
M HD / M |
BRAIN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, CERVIC. |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, THORAC. |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, LUMBAR |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SCIATIC NERVE, LEFT |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
HEART |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
AORTA |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
TRACHEA |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
LUNG |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
TONGUE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ESOPHAGUS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
STOMACH |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
DUODENUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
JEJUNUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ILEUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PEYER'S PATCHES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
CECUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
COLON |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
RECTUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
LIVER |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PANCREAS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
KIDNEYS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
URETERS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
URINARY BLADDER |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
TESTES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
EPIDIDYMIDES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PROSTATE GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
COAGULATING GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SEMINAL VESICLES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PITUITARY GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
THYROID GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PARATHYROID GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ADRENAL GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPLEEN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
BONE MARROW |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
THYMUS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
AXILLARY LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MESENT. LYMPH NODE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MANDIB.LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SALIVARY GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
HARDERIAN GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MAMMARY GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SKIN/SUBCUTIS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SKELETAL MUSCLE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
EYES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
FEMUR with KNEE JOIN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
STERNUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
Table 2: Females
Sex Dose Group |
F C/F |
F LD /F |
F MD/F |
F HD /F |
BRAIN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, CERVIC. |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, THORAC. |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPINAL CORD, LUMBAR |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SCIATIC NERVE, LEFT |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
HEART |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
AORTA |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
TRACHEA |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
LUNG |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
TONGUE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ESOPHAGUS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
STOMACH |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
DUODENUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
JEJUNUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ILEUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PEYER'S PATCHES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
CECUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
COLON |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
RECTUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
LIVER |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PANCREAS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
KIDNEYS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
URETERS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
URINARY BLADDER |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
OVARIES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
OVIDUCTS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
UTERUS(dilatation complete) |
|
|
|
|
Total affected /examined: |
0/10 |
3/10 |
2/10 |
1/10 |
CERVIX |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
VAGINA |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PITUITARY GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
THYROID GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
PARATHYROID GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
ADRENAL GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SPLEEN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
BONE MARROW |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
THYMUS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
AXILLARY LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MESENT. LYMPH NODE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MANDIB.LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SALIVARY GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
HARDERIAN GLANDS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
MAMMARY GLAND |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SKIN/SUBCUTIS |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
SKELETAL MUSCLE |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
EYES |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
FEMUR with KNEE JOIN |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
STERNUM |
|
|
|
|
Total affected /examined: |
0/10 |
0/10 |
0/10 |
0/10 |
Table 3: Recovery males and recovery females
Sex Dose Group |
M RECOVERY C/M |
M RECOVERY HD/M |
F RECOVERY C/F |
F RECOVERY HD/F |
BRAIN |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SPINAL CORD, CERVIC. |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SPINAL CORD, THORAC. |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SPINAL CORD, LUMBAR |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SCIATIC NERVE, LEFT |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
HEART |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
AORTA |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
TRACHEA |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
LUNG |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
TONGUE |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
ESOPHAGUS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
STOMACH |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
DUODENUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
JEJUNUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
ILEUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
PEYER'S PATCHES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
CECUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
COLON |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
RECTUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
LIVER |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
PANCREAS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
KIDNEYS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
URETERS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
URINARY BLADDER |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
TESTES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
|
|
EPIDIDYMIDES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
|
|
PROSTATE GLAND |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
|
|
COAGULATING GLANDS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
|
|
SEMINAL VESICLES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
|
|
OVARIES |
|
|
|
|
Total affected /examined: |
|
|
0/5 |
0/5 |
OVIDUCTS |
|
|
|
|
Total affected /examined: |
|
|
0/5 |
0/5 |
UTERUS(dilatation complete) |
|
|
|
|
Total affected /examined: |
|
|
0/5 |
0/5 |
CERVIX |
|
|
|
|
Total affected /examined: |
|
|
0/5 |
0/5 |
VAGINA |
|
|
|
|
Total affected /examined: |
|
|
0/5 |
0/5 |
PITUITARY GLAND |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
THYROID GLAND |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
PARATHYROID GLANDS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
ADRENAL GLANDS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SPLEEN |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
BONE MARROW |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
THYMUS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
AXILLARY LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
MESENT. LYMPH NODE |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
MANDIB.LYMPH NODES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SALIVARY GLANDS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
HARDERIAN GLANDS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
MAMMARY GLAND |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SKIN/SUBCUTIS |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
SKELETAL MUSCLE |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
EYES |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
FEMUR with KNEE JOIN |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
STERNUM |
|
|
|
|
Total affected /examined: |
0/5 |
0/5 |
0/5 |
0/5 |
Microscopic findings
Table 1: Incidence and Mean Severity of Main Findings in Kidneys
Treatment period |
|
|
|
|
Dose (mg/kg) |
1 |
2 |
3 |
4 |
Finding / Groups |
|
|
|
|
Total Animals/Sex Affected / Mean Severity |
10 M |
10 M |
10 M |
10 M |
Hyaline inclusions |
10/1.3 |
9/1.6 |
10/1.7 |
10/1.6 |
Recovery period |
|
|
|
|
Total Animals/Sex Affected / Mean Severity |
5 M |
|
|
5 M |
Hyaline inclusions |
4/1.3 |
|
|
5/1.8 |
Table 2: Treatment groups: Summary of column statistics on relative positive area for α2-microglobulin
Group |
1 |
2 |
3 |
4 |
Number of values |
20 |
20 |
20 |
20 |
Minimum |
0.0 |
0.0300 |
0.5500 |
0.2900 |
25% Percentile |
0.2525 |
1.510 |
2.218 |
0.8600 |
Median |
0.6000 |
2.435 |
4.245 |
1.275 |
75% Percentile |
2.258 |
5.200 |
6.063 |
2.523 |
Maximum |
4.840 |
6.780 |
7.840 |
2.870 |
Mean |
1.283 |
2.994 |
4.239 |
1.517 |
Std. Deviation |
1.459 |
2.172 |
2.181 |
0.8840 |
Std. Error of Mean |
0.3262 |
0.4857 |
0.4877 |
0.1977 |
Lower 95% CI of mean |
0.6003 |
1.977 |
3.218 |
1.103 |
Upper 95% CI of mean |
1.966 |
4.011 |
5.259 |
1.931 |
Shapiro-Wilk normality test |
||||
W |
0.7939 |
0.9060 |
0.9581 |
0.9091 |
P value |
0.0007 |
0.0536 |
0.5070 |
0.0614 |
Passed normality test (alpha=0.05)? |
No |
Yes |
Yes |
Yes |
P value summary |
*** |
ns |
ns |
ns |
Sum |
25.66 |
59.88 |
84.77 |
30.34 |
Table 3: Treatment period - Single animal/kidney values of positive area in µm2
Group |
Animal No. |
Kidney 1 |
Kidney 2
|
Control (1) |
1 |
2,54 |
3,48 |
Control (1) |
2 |
0,56 |
1,41 |
Control (1) |
3 |
0,72 |
0,89 |
Control (1) |
4 |
0,31 |
0,2 |
Control (1) |
5 |
0,25 |
0,63 |
Control (1) |
6 |
0,49 |
1,35 |
Control (1) |
7 |
0,07 |
0,1 |
Control (1) |
8 |
0 |
0,26 |
Control (1) |
9 |
0,57 |
3,14 |
Control (1) |
10 |
3,85 |
4,84 |
Low dose (2) |
11 |
1,51 |
0,61 |
Low dose (2) |
12 |
5,38 |
5,11 |
Low dose (2) |
13 |
2,36 |
2,61 |
Low dose (2) |
14 |
4,7 |
5,69 |
Low dose (2) |
15 |
1,83 |
5,23 |
Low dose (2) |
16 |
1,69 |
2,51 |
Low dose (2) |
17 |
0,12 |
0,03 |
Low dose (2) |
18 |
1,22 |
2,72 |
Low dose (2) |
19 |
1,57 |
1,51 |
Low dose (2) |
20 |
6,7 |
6,78 |
Medium dose (3) |
21 |
7,23 |
7,84 |
Medium dose (3) |
22 |
5,5 |
5,74 |
Medium dose (3) |
23 |
4,52 |
3,28 |
Medium dose (3) |
24 |
2,33 |
5,49 |
Medium dose (3) |
25 |
6,88 |
6,67 |
Medium dose (3) |
26 |
1,84 |
3,87 |
Medium dose (3) |
27 |
3,97 |
6,17 |
Medium dose (3) |
28 |
1,35 |
0,55 |
Medium dose (3) |
29 |
1,71 |
2,18 |
Medium dose (3) |
30 |
2,62 |
5,03 |
High dose (4) |
31 |
0,54 |
0,89 |
High dose (4) |
32 |
2,04 |
2,69 |
High dose (4) |
33 |
0,29 |
1,26 |
High dose (4) |
34 |
0,85 |
1,08 |
High dose (4) |
35 |
1,29 |
1,84 |
High dose (4) |
36 |
0,33 |
1,21 |
High dose (4) |
37 |
1,36 |
2,87 |
High dose (4) |
38 |
0,54 |
2,83 |
High dose (4) |
39 |
2,2 |
2,69 |
High dose (4) |
40 |
0,91 |
2,63 |
Table 4: Recovery groups: Summary of column statistics on relative positive area for α2-microglobulin
Groups |
1 |
4 |
Number of values |
10 |
10 |
Minimum |
0.3800 |
2.230 |
25% Percentile |
1.743 |
2.945 |
Median |
2.115 |
3.560 |
75% Percentile |
3.933 |
5.173 |
Maximum |
5.920 |
6.870 |
Mean |
2.700 |
4.045 |
Std. Deviation |
1.607 |
1.470 |
Std. Error of Mean |
0.5082 |
0.4650 |
Lower 95% CI of mean |
1.550 |
2.993 |
Upper 95% CI of mean |
3.850 |
5.097 |
Shapiro-Wilk normality test |
||
W |
0.9410 |
0.9309 |
P value |
0.5643 |
0.4569 |
Passed normality test (alpha=0.05)? |
Yes |
Yes |
P value summary |
ns |
ns |
Sum |
27.00 |
40.45 |
Table 5: Treatment period - Single animal/kidney values of positive area in µm2
Group |
Animal No. |
Kidney 1 |
Kidney 2
|
Control (1) |
41 |
0,38 |
2,02 |
Control (1) |
42 |
2,1 |
1,45 |
Control (1) |
43 |
3,79 |
4,36 |
Control (1) |
44 |
2,13 |
1,84 |
Control (1) |
45 |
3,01 |
5,92 |
High dose (4) |
46 |
3,32 |
3,8 |
High dose (4) |
47 |
4,67 |
6,87 |
High dose (4) |
48 |
2,81 |
2,23 |
High dose (4) |
49 |
2,99 |
5 |
High dose (4) |
50 |
3,07 |
5,69 |
See attached documents for body and organ weights, pathology and
histopatholagy report.
Applicant's summary and conclusion
- Conclusions:
- In the 90-day repeated dose oral toxicity study with tri(isopropyl)silyl acrylate (CAS 157859-20-6), conducted according to OECD Test Guideline 408 and in compliance with GLP, the reported NOAEL for specific target organ toxicity was greater than 100 mg/kg bw/day (the highest dose tested) based on no test item related effect observed on mortality, clinical signs, body weight development, food consumption, functional observation battery, weekly detailed clinical observations, haematology and blood coagulations, clinical biochemistry, urinalysis, gross pathological findings, organ weight and histopathology.
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