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EC number: 300-346-5 | CAS number: 93925-43-0
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 13 Oct - 12 Dec 2011
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted Oct 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- adopted Oct 2008
- Deviations:
- not specified
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3050
- Version / remarks:
- adopted 2000
- Deviations:
- not specified
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Food and Consumer Product Safety Authority (VWA), Utrecht, The Netherlands
- Limit test:
- no
Test material
- Reference substance name:
- Silicic acid (H4SiO4), tetraethyl ester, reaction products with bis(acetyloxy)dioctylstannane
- EC Number:
- 300-346-5
- EC Name:
- Silicic acid (H4SiO4), tetraethyl ester, reaction products with bis(acetyloxy)dioctylstannane
- Cas Number:
- 93925-43-0
- Molecular formula:
- C4H8O2, C20H44O4SiSn, C24H52O6SiSn, C40H84O8SiSn2, C60H128O12Si2Sn3, C80H172O16Si3Sn4, C100H216O20Si4Sn5
- IUPAC Name:
- Silicic acid (H4SiO4), tetraethyl ester, reaction products with bis(acetyloxy)dioctylstannane
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Details on species / strain selection:
- Outbred, SPF-Quality
- 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 - 140 g (males); 121- 124 g (females)
- Housing: Group housing of 5 animals per sex in Macrolon cages (MIV type, height 18 cm) with
sterilized sawdust as bedding material and paper as cage-enrichment. During locomotor activity mo
nitoring, animals were housed individually in a Hi-temp polycarbonate cage without cage-enrichment
or bedding material.
- Diet: Pelleted roden diet, SM R/M-Z (Ssniff Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.4 - 21.9
- Humidity (%): 44 - 62
- Air changes (per hr): Approximately 15
- Photoperiod (hrs dark / hrs light): 12/12
IN LIFE DATES: From: 13 Oct 2011 To: 12 Dec 2011
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing, and were homogenized to visually acceptable levels. In order to obtain homogeneity, the formulations were heated in a water bath with a maximum temperature of approximately 80 °C for a maximum of approximately 20 minutes. The formulations were allowed to cool down to a temperature below 33 °C prior to dosing. Adjustment was made for specific gravity of the test substance and vehicle.
VEHICLE
- Justification for use and choice of vehicle: Based on trial formulations performed at the testing facility and on information from the sponsor
- Amount of vehicle: 5 mL/kg bw - Analytical verification of doses or concentrations:
- no
- Remarks:
- Analytical techniques such as ICP-MS, GC, HPLC and UV-Vis were not suitable for the determination of the test substance due to its hydrophobic molecular structure.
- Duration of treatment / exposure:
- at least 28 days
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were based on the results of a foregoing dose range finding study. Three females per group were orally exposed to 200 mg/kg bw/day for 10 days, 500 and 1000 mg/kg bw/day for 5 days at the same testing facility (Project 498035), respectively. At every dose group hunched posture, piloerection and reduced food consumption were observed. A weight loss was determined at 200 mg/kg bw/d in 2/3 females (up to 5%), which was reversible by end of study. At 500 mg/kg bw/day a weight loss up to 6% in 2/3 females but a weight gain (4%) in 1/3 females was observed. At 1000 mg/kg bw/day the weight loss in all females amounted up to 15%. At every dose group no abnormalities were noted during the macroscopic examination and the liver and kidney weights were considered to be normal. One female at 200 mg/kg bw/day was sacrificed in extremis on Day 10 as it showed lethargy, hunched posture, uncoordinated movements, piloerection, chromodacryorrhoea, lean appearance, ptosis and hypothermia between Days 8 and 10. Based on the results of this range finding study, dose levels suggested for the main study (28 days toxicity study) were 10, 30 and 100 mg/kg bw/day.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, all animals were observed for mortality and morbidity.
- Time schedule: At least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes, observations were made outside the cage in a standard arena.
- Time schedule: Immediately after dosing, once prior to start of treatment and at weekly intervals prior to dosing
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD COMSUMPTION: Yes, the food consumption was measured weekly and given as food consumption in g/kg bw/day.
HAEMATOLOGY: Yes
- Anaesthetic used for blood collection: Yes (isoflurane)
- How many animals: All
- Parameters checked: white blood cells (WBC), differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), red blood cells, reticulocytes, red blood cell distribution width (RDW), haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelets, prothrombin time and activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Animals fasted: Yes, overnight for a maximum of 20 hours.
- How many animals: all
- Parameters checked: alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), total protein, albumin, total bilirubin, bile acids, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate (Inorg. Phos)
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex, grip strength, motor activity test - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Parameters checked: The weight of the following organs was recorded: liver, kidneys, adrenal glands, testes, epididymides, prostate, seminal vesicles including coagulating glands, thymus, spleen, brain, heart, ovaries, uterus including cervix and thyroid including parathyroid.
HISTOPATHOLOGY: Yes. All organ and tissue samples were processed, embedded in paraffin wax, sliced and stained with haematoxylin and eosin. The samples of all tissues collected at the scheduled sacrifice from animals in the control and high-dose group, all tissues from the high-dose female terminated in extremis, the thymus of all animals in the low-and mid-dose groups (based on possible treatment -related changes in this organ in the high-dose group), and all gross lesions were examined by a pathologist.
- The following organs and tissues were collected and fixed in a 10% buffered formalin: ovaries, adrenal glands, Peyer's patches (jejunum, ileum), brain (cerebellum, mid-brain, cortex), caecum, cervix, prostate gland, rectum, colon, duodenum, sciatic nerve, epididymides, seminal vesicles including coagulating gland, eyes including optic nerve and harderian gland, skeletal muscle, spinal cord (cervical, midthoracic, lumbar), femur including joint, spleen, heart, sternum with bone marrow, ileum, stomach, jejunum, testes, kidneys, thymus, thyroid including parathyroid, liver, trachea, lung (infused with formalin), urinary bladder, lymph nodes (mandibular, mesenteric), uterus, vagina and all gross lessions.
Following tissues/organs were not examined by the pathologist, since no signs of toxicity were noted at macroscopic examination:
pancreas, aorta, pituitary gland, preputial gland, clitoral gland, salivary glands (mandibular, sublingual), skin, female mammary gland area, larynx, oesophagus, lacrimal gland (exorbital), tongue, nasopharynx. - Statistics:
- - If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test was applied to frequency data.
Motor activity data was subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences followed by the Wilcoxon test to compare the treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw/day: Salivation was observed in 5/5 males and 2/5 females after dosing. This was considered to be a physiological response rather than a sign of systemic toxicity as it was observed after dosing. Alopecia and scabs were observed in 1/5 males, these were considered signs of no toxicological significance. Lethargy, a hunched posture, piloerection, dehydration and/or a lean appearance was observed from Day 13 in 1/5 high-dose females. This animal was sacrificed in extremis on Day 18.
30 mg/kg bw/day: Chromodacryhorrea was observed in 1/5 males on Day 2-4. This is considered to be an effect of the treatment, due to the limited duration of the effect.
10 mg/kg bw/day: Alopecia and scabs were observed in 1/5 males on Day 10-20, however, this observation is considered to be incidental.
The summary of the results of the observed clinical signs in males and females is shown in Table 1 under "Any other information on results incl. tables". - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 100 mg/kg bw/day: One female was sacrified in extremis on Day 18. No cause of death could be established based on histopathological assessment. As other animals of this dose group showed no toxicologically relevant clinical signs, this death was considered to be incidental in nature and unrelated to treatment with the test substance.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The percentages of the body weight and body weight changes were comparisons to a baseline day 0. There was no significant difference in body weight between the control group and the treatment groups.
100 mg/kg bw/day: In week 2, a statistically significant lower body weight gain of males (23%) compared with the control group (33%) was observed. This effect was also noted in week 3, when the animals of the high-dose group showed 50% body weight gain which was significantly lower than that of the control groups (67%). The body weight gain of the high-dose group (100%) in week 4 was not statistically significant compared with the control group (119%) due to the high standard deviation. However, this effect was considered to be of toxicological relevance.
The summary of the results of the body weight gain (%) in males and females is shown in Table 2 under "Any other information on results incl. tables". - Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In high-dose males significantly lower values of haemoglobin, haematocrit, mean corpuscular volume and mean corpuscular haemoglobin were measured, compared with the control group. However, the values of each parameter were within the range of historical control data for rats of this strain according to data published by Charles River (reference: Charles River, Clinical Laboratory Parameters for Cri:WI(Han), March 2008) and were not dose-related. Therefore, the effects were considered to be non-treatment-related.
Significantly lower relative eosinophil counts in high-dose males and higher partial thromboplastin time in low-dose males, as well as the significantly lower white blood cell counts in low- and mid-dose females and lower haematocrit level in low-dose females were observed, compared with the control group. The changes fell within the range of historical control data for rats of this strain according to data published by Charles River (reference: Charles River, Clinical Laboratory Parameters for Cri:WI(Han), March 2008. These changes in haematological parameters were slight in nature and were not observed at higher dose levels. Therefore, these changes are considered to be incidental.
The summary of the results of the haematological findings in males and females are shown in Table 3 and 4 under "any other information on results incl. tables".
Reference: Charles River, Clinical Laboratory Parameters for Cri:WI(Han), March 2008; link: http://www.criver.com/files/pdfs/rms/wistarhan/rm_rm_r_wistar_han_clin_lab_parameters_08.aspx - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly higher alkaline phosphatase activity was recorded in the high-dose females, compared with the control group. A dose-related increase was observed in the mid- and high-dose males, although this result was not statistically significant. This effect is considered to be an adaptive response, caused by the increased metabolic load on the liver due to the treatment. In high-dose females, a significant increase (> 100%) in the bile acids level was observed compared with the control group. The toxicological relevance of this observation is unclear, as no similar increase was observed in the males, but may be related to the increased hepatic load related to the treatment.
The statistically significant higher glucose level in low-dose females compared with the control group did not show a dose-related trend, and the lower creatinine level in high-dose females compared with the control group was minor in nature. Furthermore, no similar changes were observed in the males. These changes were therefore considered to have no toxicological relevance.
The summary of the results of the clinical biochemistry in males and females is shown in Table 5 under "Any other information on results incl. tables". - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No toxicologically significant effects on motor activity were noted. The parameters hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all surviving animals. The statistically significant higher motor activity (total movements) of females at 30 mg/kg bw/day occurred in the absence of a dose-related trend, and was therefore considered to be of no toxicological relevance. All groups showed a similar motor activity habituation profile; with high activity in the first interval that decreased over the duration of the test period.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- The absolute and relative thymus weight was reduced at 10 mg/kg bw/day (35% and 40% reduction of the relative weight compared with the control group for males and females, respectively), at 30 mg/kg bw/day (59% and 65% reduction of the relative weight compared with the control group for males and females, respectively) and at 100 mg/kg bw/day (77% and 81% reduction of the relative weight compared with the control group for males and females, respectively) compared with the control group. These effects were also dose-related. The effects on the thymus were also observed during the gross pathology (reduced thymus size) and histopathological examination (loss of cortical and medullary differentiation, lymphoid atrophy and hyperplasia of undifferentiated cells). Therefore, the effect on thymus weight were considered to be toxicologically relevant.
High-dose females showed a significantly higher absolute liver weight and relative liver weight. An increase in the alkaline phosphatase activity was also observed in high-dose females. Therefore, the increase in the absolute liver weight is considered to be a treatment-related, adaptive effect, due to the increased metabolic load on the liver following the treatment.
The statistically significant lower prostate weight of the high-dose males and higher spleen weights of the high-dose females were non-adverse but not toxicologically relevant as the respective relative organ weight was not affected and no related histopathological results were observed. The slightly higher relative kidney weights of high-dose males may be related to a slightly lower terminal body weight. The absolute kidney weights were similar to control levels.
The higher heart weight at 30 and 100 mg/kg bw/day and the higher relative heart weight at 30 mg/kg bw/day of females showed no dose-related trend for relative weight, according to the study report the means were within the normal range and the control means were considered to be slightly low. In addition, no histopathological effects were present and no toxicological relevance was ascribed to these changes.
The summary of the results of the absolute (g) and relative (%) organ weights in males and females are shown in Table 6 and 7 under "Any other information on results incl. tables". - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A reduced size of the thymus was noted in 1/5 males at 10 mg/kg, 2/5 males and 2/5 females at 30 mg/kg, and in 5/5 males and 4/5 females at 100 mg/kg bw/day with statistical significance compared with the control group. The reduction in thymus size was dose-related in both males and females. Based on the related effects observed on the organ weights and the histopathological findings these effects were considered to be toxicologically relevant.
Other findings among the control and treated animals were incidental and therefore considered to be of no toxicological relevance.
The summary of the results of the macroscopic findings in males and females are shown in Table 8 under "Any other information on results incl. tables". - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Substance-related findings were found in the thymus and consisted of:
− Lymphoid atrophy:
10 mg/kg bw/day: 1/5 males (grade 2) and 1/5 females (grade 1)
30 mg/kg bw/day: 4/5 males (2/5: grade 1, 1/5: grade 3 and 1/5: grade 4) and and 5/5 females (1/5: grade 2, 3/5: grade 3 and 1/5: grade 4)
100 mg/kg bw/day: 5/5 males (grade 4) and 4/4 females (1/4: grade 3, 3/4: grade 4).
− Increase in lymphocytolysis:
10 mg/kg bw/day: 4/5 males (2/5: grade 1, 1/5: grade 2, 1/5: grade 3)
30 mg/kg bw/day: 1/5 males (grade 2)
− Hyperplasia of undifferentiated cells (epithelial cells /immature lymphocytes):
30 mg/kg bw/day: 2/5 males (1/5: grade 2, 1/5: grade 3) and 5/5 females (2/5: grade 2, 3/5: grade 3)
100 mg/kg bw/day: 5/5 males (grade 4) and 3/4 females (3/4: grade 3, 1/4: grade 4).
− Loss of cortical and medullary differentiation:
10 mg/kg bw/day: in 1/5 males
30 mg/kg bw/day: in 2/5 males and 5/5 females
100 mg/kg bw/day: in 5/5 males and 4/4 females
The lymphoid atrophy, increase in lymphocytolysis, hyperplasia, loss of cortical and medullary differentiation all increased in incidence and severity with increasing dose level. This tendency was seen in both males and females. Related effects were observed on organ weight and thymus size. The effects on the thymus were considered to be toxicologically relevant at all dose levels.
The summary of the results of the macroscopic findings in males and females are shown in Table 9 under "Any other information on results incl. tables". - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks on result:
- other: Toxicologically relevant effects were observed at the lowest dose level and therefore a NOAEL could not be determined
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- systemic
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (nominal)
- System:
- immune system
- Organ:
- thymus
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 1: Clinical Signs Summary: Males and Females
Sign (max. grade) (location) |
Treatment Days |
||||||||||||||||||||||||||||
MALES | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | |
Group 1 (control) | no clinical signs noted | ||||||||||||||||||||||||||||
Group 2 (10 mg/kg bw/day) | |||||||||||||||||||||||||||||
Skin / fur | |||||||||||||||||||||||||||||
Alopecia (3) (Neck) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | - | - | - | - | |
Scabs (3) (Neck) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | |
Group 3 (30 mg/kg bw/day) | |||||||||||||||||||||||||||||
Secretion / excretion | |||||||||||||||||||||||||||||
Chromodacryorrhoes (3) (Periorbital region left) | G | - | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
% | - | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | |
Group 4 (100 mg/kg bw/day) | |||||||||||||||||||||||||||||
Skin / fur | |||||||||||||||||||||||||||||
Alopecia (3) (Neck) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | |
Scabs (3) (Neck) | G | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | - | - | - | - | - | - | - | - | |
Secretion / excretion | |||||||||||||||||||||||||||||
Salivation (3) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | A | A | A | A | |
FEMALES | |||||||||||||||||||||||||||||
Group 1 (control) | no clinical signs noted | ||||||||||||||||||||||||||||
Group 2 (10 mg/kg bw/day) | no clinical signs noted | ||||||||||||||||||||||||||||
Group 3 (30 mg/kg bw/day) | no clinical signs noted | ||||||||||||||||||||||||||||
Group 4 (100 mg/kg bw/day) | |||||||||||||||||||||||||||||
Behaviour | |||||||||||||||||||||||||||||
Lethargy (3) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - | |
Posture | |||||||||||||||||||||||||||||
Hunched Posture (1) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - | |
Skin / fur | |||||||||||||||||||||||||||||
Pilorection (1) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - | |
Secretion / excretion | |||||||||||||||||||||||||||||
Salivation (3) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 5 | 5 | 5 | 5 | |
Various | |||||||||||||||||||||||||||||
Dehydrated (3) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - | |
Lean (1) | G | - | - | - | - | - | - | - | - | - | - | - | - | - | 1 | 1 | 1 | 1 | 1 | - | - | - | - | - | - | - | - | - | - |
% | - | - | - | - | - | - | - | - | - | - | - | - | - | 2 | 2 | 2 | 2 | 2 | - | - | - | - | - | - | - | - | - | - |
G: Median value of the highest individual daily grades
%: Percent of affected animals (0=less than 5%, 1=between 5% and 15%,..., A=more than 95%)
-: Observation performed, sign not present
Table 2: Body Weight Gain (%) Summary: Males and Females
MALES | |||||
Treatment | Control | 10 mg/kg bw | 30 mg/kg bw | 100 mg/kg bw | |
Day 1 | Mean | 0 | 0 | 0 | 0 |
Week 1 | ST. DEV | 0.0 | 0.0 | 0.0 | 0.0 |
N | 5 | 5 | 5 | 5 | |
Day 8 | Mean | 33 | 30 | 28 | 23* |
Week 2 | ST. DEV | 4.1 | 3.0 | 5.0 | 7.0 |
N | 5 | 5 | 5 | 5 | |
Day 15 | Mean | 67 | 61 | 55 | 50* |
Week 3 | ST. DEV | 7.9 | 5.6 | 8.2 | 13.4 |
N | 5 | 5 | 5 | 5 | |
Day 22 | Mean | 99 | 90 | 86 | 83 |
Week 4 | ST. DEV | 8.9 | 5.9 | 9.8 | 15.5 |
N | 5 | 5 | 5 | 5 | |
Day 28 | Mean | 119 | 105 | 105 | 100 |
Week 4 | ST. DEV | 11.4 | 5.7 | 11.3 | 18.0 |
N | 5 | 5 | 5 | 5 | |
FEMALES | |||||
Treatment | Control | 10 mg/kg bw | 30 mg/kg bw | 100 mg/kg bw | |
Day 1 | Mean | 0 | 0 | 0 | 0 |
Week 1 | ST. DEV | 0.0 | 0.0 | 0.0 | 0.0 |
N | 5 | 5 | 5 | 5 | |
Day 8 | Mean | 16 | 19 | 15 | 16 |
Week 2 | ST. DEV | 3.4 | 3.3 | 3.5 | 3.4 |
N | 5 | 5 | 5 | 5 | |
Day 15 | Mean | 33 | 36 | 31 | 29 |
Week 3 | ST. DEV | 5.7 | 6.5 | 5.8 | 12.8 |
N | 5 | 5 | 5 | 5 | |
Day 22 | Mean | 46 | 52 | 44 | 47 |
Week 4 | ST. DEV | 5.1 | 9.4 | 8.9 | 5.4 |
N | 5 | 5 | 5 | 4 | |
Day 28 | Mean | 50 | 60 | 52 | 53 |
Week 4 | ST. DEV | 7.9 | 10.6 | 13.0 | 4.9 |
N | 5 | 5 | 5 | 4 |
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 3: Haemotology Summary: Males
End of Treatment | Control | 10 mg/kg bw/day | 30 mg/kg bw/day | 100 mg/kg bw/day | |
Eosinophils (%) | Mean | 0.6 | 0.7 | 0.4 | 0.2+ |
ST. DEV | 0.1 | 0.2 | 0.3 | 0.1 | |
N | 5 | 5 | 5 | 5 | |
Haemoglobin | Mean | 10.0 | 9.9 | 9.7 | 9.2* |
mmol/L | ST. DEV | 0.4 | 0.1 | 0.1 | 0.6 |
N | 5 | 5 | 5 | 5 | |
Haematocrit | Mean | 0.459 | 0.456 | 0.442 | 0.429* |
L/L | ST. DEV | 0.011 | 0.009 | 0.009 | 0.026 |
N | 5 | 5 | 5 | 5 | |
MCV | Mean | 55.2 | 54.6 | 54.7 | 51.7** |
fL | ST. DEV | 1.1 | 0.7 | 1.6 | 0.9 |
N | 5 | 5 | 5 | 5 | |
MCH | Mean | 1.21 | 1.19 | 1.20 | 1.11 |
fmol | ST. DEV | 0.04 | 0.02 | 0.06 | 0.03 |
N | 5 | 5 | 5 | 5 |
+/++ Steel−test significant at 5% (+) or 1% (++) level
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 4: Haemotology Summary: Females
End of Treatment | Control | 10 mg/kg bw/day | 30 mg/kg bw/day | 100 mg/kg bw/day | |
WBC | Mean | 7.8 | 5.7* | 5.3** | 6.4 |
10E9/L | ST. DEV | 1.5 | 1.1 | 0.6 | 1.0 |
N | 5 | 5 | 5 | 4 | |
Haematocrit | Mean | 0.423 | 0.398* | 0.415 | 0.414 |
L/L | ST. DEV | 0.009 | 0.015 | 0.010 | 0.011 |
N | 5 | 5 | 5 | 4 |
+/++ Steel−test significant at 5% (+) or 1% (++) level
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 5: Clinical Biochemistry Summary: Females and Males
End of Treatment | Control | 10 mg/kg bw | 30 mg/kg bw | 100 mg/kg bw | |
FEMALES | |||||
ALP | Mean | 116 | 146 | 143 | 213* |
ST. DEV | 42 | 68 | 24 | 29 | |
N | 5 | 5 | 5 | 4 | |
Creatinine | Mean | 42.4 | 45.0 | 43.1 | 37.8* |
umol/L | ST. DEV | 2.2 | 3.2 | 2.1 | 1.9 |
N | 5 | 5 | 5 | 4 | |
Bile acids | Mean | 21.4 | 19.1 | 15.4 | 51.9** |
umol/L | ST. DEV | 11.4 | 10.2 | 5.3 | 9.8 |
N | 5 | 5 | 5 | 4 | |
MALES | |||||
ALP | Mean | 283 | 278 | 414 | 504 |
ST. DEV | 66 | 122 | 65 | 226 | |
N | 5 | 5 | 5 | 5 | |
Creatinine | Mean | 36.5 | 38.1 | 35.9 | 35.8 |
umol/L | ST. DEV | 1.4 | 1.9 | 2.0 | 1.3 |
N | 5 | 5 | 5 | 5 | |
Bile acids | Mean | 45.5 | 74.5 | 47.9 | 55.1 |
umol/L | ST. DEV | 15.2 | 39.6 | 20.6 | 14.1 |
N | 5 | 5 | 5 | 5 |
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 6: Organ Weights (g): Males and Females
End of Treatment | Control | 10 mg/kg bw | 30 mg/kg bw | 100 mg/kg bw | |
MALES | |||||
Thymus (g) | Mean | 0.550 | 0.332** | 0.209** | 0.116** |
ST. DEV | 0.106 | 0.070 | 0.084 | 0.020 | |
N | 5 | 5 | 5 | 5 | |
FEMALES | |||||
Thymus (g) | Mean | 0.406 | 0.255** | 0.144** | 0.082** |
ST. DEV | 0.061 | 0.062 | 0.027 | 0.030 | |
N | 5 | 5 | 5 | 4 | |
Liver (g) | Mean | 5.01 | 5.40 | 5.28 | 6.08** |
ST. DEV | 0.51 | 0.15 | 0.37 | 0.43 | |
N | 5 | 5 | 5 | 4 |
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 7: Relative Organ Weight (%) Summary: Males and Females
End of Treatment | Control | 10 mg/kg bw | 30 mg/kg bw | 100 mg/kg bw | |
MALES | |||||
Thymus (%) | Mean | 0.192 | 0.124** | 0.078** | 0.045** |
ST. DEV | 0.036 | 0.027 | 0.028 | 0.009 | |
N | 5 | 5 | 5 | 5 | |
FEMALES | |||||
Thymus (%) | Mean | 0.239 | 0.144** | 0.083** | 0.046** |
ST. DEV | 0.030 | 0.033 | 0.015 | 0.016 | |
N | 5 | 5 | 5 | 4 | |
Liver (%) | Mean | 2.95 | 3.05 | 3.07 | 3.43** |
ST. DEV | 0.26 | 0.04 | 0.14 | 0.11 | |
N | 5 | 5 | 5 | 4 |
*/** Dunnett−test based on pooled variance significant at 5% (*) or 1% (**) level
Table 8: Macroscopic Findings Summary: Males and Females
End of Treatment | Control | 10 mg/kg bw/day | 30 mg/kg bw/day | 100 mg/kg bw/day |
MALES | ||||
Thymus | ||||
reduced size | 0 | 1 | 2 | 5 ## |
FEMALES | ||||
Thymus | ||||
reduced size | 0 | 0 | 2 | 4 ## |
# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level
Table 9: Summary of histopathological findings: Males and Females
Dose [mg/kg bw/day] |
Lymphoid atrophy | Increase in lymphocytolysis | Hyperplasia of undifferentiated cells (epithelial cells /immature lymphocytes) | Loss of cortical and medullary differentiation |
MALES | ||||
10 | 1/5: grade 2 | 2/5: grade 1 1/5: grade 2 1/5: grade 3 |
- | 1/5 |
30 | 2/5: grade 1 1/5: grade 3 1/5: grade 4 |
1/5 males: grade 2 | 1/5: grade 2 1/5: grade 3 |
2/5 |
100 | 5/5: grade 4 | - | 5/5 males: grade 4 | 5/5 |
FEMALES | ||||
10 | 1/5: grade 1 | - | ||
30 | 1/5: grade 2 3/5: grade 3 1/5: grade 4 |
- | 2/5: grade 2 3/5: grade 3 |
5/5 |
100 | 1/4: grade 3 3/4: grade 4 |
- | 3/4: grade 3 1/4: grade 4 |
4/4 |
Applicant's summary and conclusion
- Conclusions:
- Based on the effects on the reduced thymus weight, the reduced thymus size and histopathological findings in the thymus at 10 mg/kg bw/day, the substance is classified as STOT-RE 1, H372, oral, thymus.
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