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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
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:
- 19/11/2008 to 17/12/2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to GLP in accordance with recognised guideline
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Details on test material:
- No further information required.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: TOXI COOP Ltd. Cserkesz u. 90. 1103 Budapest, Hungary.
- Age at study initiation: Young adult rats, approximately 7 weeks old.
- Weight at study initiation: 235-255 g (males); 168-194 g (females)
- Fasting period before study: No
- Housing: Group caging, 5 animals per polypropylene/polycarbonate cage containing certified laboratory wood bedding.
- Diet (e.g. ad libitum): Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" (ssniff Spezialdiäten GmbH, D-59494 Soest Germany), ad libitum.
- Water (e.g. ad libitum): Animals received tap water as for human consumption from municipal supply in 500 ml bottle, ad libitum.
- Acclimation period: 5 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8-25°C
- Humidity (%): 30 - 51%
- Air changes (per hr): 8-12 air exchanges/hour
- Photoperiod: 12 hours of light daily, from 6.00 a.m. to 6.00 p.m.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Sterile water for injection, PhEUR
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle in concentrations of 2.5 to 100 mg/mL in the Central Dispensary of LAB Research Ltd. Formulations were prepared as appropriate for use within 72 hr (stored refrigerated), according to stability assessment results.
DIET PREPARATION
- Rate of preparation of diet (frequency):
Formulations were prepared as appropriate for use within 72 hr (stored refrigerated), according to stability assessment results.
- Mixing appropriate amounts with (Type of food): n/a
- Storage temperature of food: n/a
VEHICLE
- Justification for use and choice of vehicle (if other than water): Sterile water for injection, PhEUR
- Concentration in vehicle: Test material concentrations used were 2.5, 15 and 100 mg/mL
- Lot/batch no. (if required): 7810108 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of formulations and assessment of test item stability in this vehicle in the conditions employed on the study was performed in the Analytical Laboratory of LAB Research Ltd.
Stability tests indicated an up to 24 hour stability at room temperature; in addition, under refrigeration conditions (5 ± 3°C), at concentrations from approximately 1 to 100 mg/mL in water, the solutions were stable for up to 72 hours, with a recovery within the acceptable range of 100 ± 10% (99-102 %). Concentration and homogeneity of formulations were evaluated by spectrophotometry on 6 replicate samples from the test item solutions, and one sample from the control, taken and analysed fresh on the first and last week of treatment. Dose formulations were homogenous; the measured concentrations varied between 101 to 106% of the nominal concentrations (2.5, 15, 100 mg/mL). These results were considered suitable for the study purposes. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- The dosing solutions were administered daily for 28 days by oral gavage, using a bulb tipped gastric gavage needle attached to a syringe. Day 0 was considered the first day of dose administration.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
25, 150 and 1000 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 animals, 5 males and 5 females were used for each dose group.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses were determined on the basis of the results of a dose range finding study with the Test Item (LAB study code: 08/777-028P) in agreement with the Sponsor.
- Rationale for animal assignment: Random - Positive control:
- Not used.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day, after treatment at approximately the same time. Detailed clinical observations were made on all animals outside the home cage in a standard arena once, prior to the first exposure and once weekly thereafter.
- Time schedule for examinations: Observation was performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions). Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity was conducted on all animals in the 4th exposure week (Day 26).
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weight was recorded with precision of 1g at randomization, on the first day of treatment, then weekly and before termination.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY:
- Time schedule for collection of blood:
Clinical pathology examinations (haematology, coagulation, and clinical biochemistry) were conducted on all animals pre-terminally.
- Anaesthetic used for blood collection: Yes (pentobarbital anaesthesia)
- Animals fasted: Yes, overnight period of food deprivation .
- How many animals: All
- Parameters checked:
Red Blood Cell (erythrocyte) count, White Blood Cell (leukocyte) count, Haemoglobin concentration, Haematocrit, Mean Corpuscular (erythrocyte) Volume, Mean Corpuscular (erythrocyte) Haemoglobin, Mean Corpuscular (erythrocyte) Haemoglobin Concentration, Red Cell (erythrocyte) volume, Platelet (thrombocyte) count, Mean Platelet Thrombocyte volume, Reticulocyte count (%), Neutrophil (%), Lymphocyte (%), Monocyte (%), Basophil (%), Eosinophil (%), Large Unstained Cells (%), Partial Thromboplastin Time (sec), Prothrombin Time (sec).
CLINICAL CHEMISTRY: Yes
- How many animals: All
- Parameters checked:
Glucose Blood sugar concentration, Total Bilirubin concentration, Urea concentration, Cholesterol concentration, Creatinine concentration, Phosphorous concentration, Sodium concentration, Potassium concentration, Calcium concentration, Chloride concentration, Total Protein concentration, Albumin concentration, Alb/glob ration, Aspartate Aminotranferase activity, Alanine Aminotranferase activity, Alkaline Phosphatase activity, Gamma Glutamyltranferase activity, Bile Acids.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: 4th exposure week
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptivc), assessment of grip strength and motor activity was conducted on all animals. General physical condition and behaviour of animals was tested. A modified Irwin test was be performed (Irwin, S.: Comprehensive Observational Assessment: la. A systematic, Quantitative procedure for Assessing the Behavioral and Physiologic State of the Mouse, Psychopharmacologia (Berl) 13 222-257 1968).
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Gross pathology consisted of an external examination, including identification of all clinically-recorded lesions, as well as a detailed internal examination.
Gross pathology was performed on every experimental animal. Animals were euthanized by exsanguination under pentobarbital anaesthesia at the end of the observation period (following the terminal clinical pathology blood collection).
After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed macroscopically.
The following organs were weighed and recorded: with precision of 0.01g, liver, kidneys, testes, epididymides, thymus, spleen, brain and heart; with precision of 0.001g, adrenals. Paired organs were weighed together. Absolute organ weights were measured, and relative organ weights were calculated.
HISTOPATHOLOGY: Yes
Histopathological examination was performed as required by the study plan, on selected list of specified tissues from Control and High Dose rats and gross lesions from all toxicology animals. Full histopathology will be performed in Group l (control) and Group 4. Histopathology evaluation was conducted on tissues and organs retained in fixative and processed to slides from the control and high dose animals (1000 mg/kg bw/day), and on all organs with macroscopic findings from the low and mid dose groups (25, and 150 mg/kg bw/day, respectively). Organs or representative samples were embedded into paraffin. Slides were stained with haematoxylin-eosin/phloxyne and examined with light microscope.
The following organs/tissues were removed and preserved in 10% buffered formalin solution for histological processing:
Gross lesions, lymph nodes (submandibular, mesenteric) sternum, skin and female mammary gland, salivary glands (submandibular), femur and bone marrow, spinal cord (cervical, lumbar, thoracic level), pituitary, thymus, trachea, lungs (with main stem bronchi), heart, thyroid and parathyroid, oesophagus, stomach, caecum, duodenum, ileum, jejunum, colon, rectum, urinary bladder, liver, pancreas, spleen, kidneys, adrenals, prostate, ovaries, uterus with vagina, epididymes, brain (including cerebrum, cerebellum, pons and medulla oblongata), lachrymal gland with Harderian glands, seminal vesicle, muscle (quadriceps), sciatic nerve and aorta.
The eyes with the optic nerve and the testes will be preserved in modified Davidson fixative for histological processing. - Other examinations:
- None reported.
- Statistics:
- Statistical analysis was performed on the numerical data as appropriate.
The heterogeneity of variance between groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance was carried out. If the obtained result was positive, Duncan's Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If the data were not normal distributed, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there was a positive result, the inter-group comparisons were performed using Mann-Whitney U-test. The mean daily food consumption, frequency of clinical observations and necropsy and histopathology findings were calculated.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- 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:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
-No mortality occurred during the 28-day treatment period.
-No toxicologically significant systemic clinical changes were noted following administration of the test material by oral gavage, daily for 28 days.
-Day 0 was regarded as the first day of treatment. Blue faeces were observed in animals’ cages for both sexes, in the bedding, at all the dose levels tested (25, 150 and 1000 mg/kg bw/day), as of Day 1.
-At 1000 mg/kg bw/day, both the male and female animals eliminated apparently increased volumes of blue urine in the cage bedding for 27 out of 28 treatment days, commencing on Day 1.
-These changes were ascribed to elimination of the test material or its metabolites through faeces and/or urine; moreover, in the absence of any clinical pathology alterations, they were not considered adverse effects.
-Incidences and extent of reactions observed in the treated animals were comparable to those observed in control animals, or within the historical control data, and are without any toxicological significance.
BODY WEIGHT AND WEIGHT GAIN
-No adverse effects were noted on the mean body weight and body weight gain values in the treated groups compared to control animals following daily administration of the test material at dose levels of up to and including 1000 mg/kg bw/day.
-Slightly lower mean values than control results were noted, mainly in the female animals. These were considered due to high individual values in 2 control animals, which led to a relatively high mean body weight and body weight gain values in the control female group.
-In the absence of a dose or gender-related response, these changes were considered neither toxicologically significant, nor related to the test material administration, but expected variations in the population of Wistar rats.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
-There were no test item related differences in the mean daily food consumption in any test item treated groups (25, 150, or 1000 mg/kg bw/day, male or female) when compared to the control.
OPHTHALMOSCOPIC EXAMINATION
Observation was performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions). Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma; no such observations were noted.
HAEMATOLOGY
-There were no differences that were considered toxicologically significant between the control and test item-treated groups, or any adverse effects of the test material on haematology parameters in the male and female animals.
-Statistically significant variations were noted on occasion in the mean values of different parameters, such as, but not limited to, mean corpuscular haemoglobin concentration (MCHC), reticulocite (Retic%) or lymphocyte (LY%), which were lower than control in the 1000 mg/kg bw/day males; however, the reticulocite value was statistically higher than control in the 25 mg/kg bw/day male group. Mean neutrophil (NE%) and eosinophil (EO%) values were higher than control in the male animals at the 1000 mg/kg bw/day dose level. In the female animals, statistically significant decreases were observed in the mean corpuscular volume (at 150 mg/kg bw/day), platelet values (at 25 mg/kg bw/day), and/or mean platelet volume in the females at all the dose levels tested.
-Evaluation of the mean and individual results in correlation with the control and historical haematology data did not reveal any test-item related cause of these variations. No consistent dose or gender-related response was noted, and these differences observed between the control and treated groups were considered to be incidental or individual findings, which were not related to treatment and generally remained within the historical control ranges, or were with no toxicological significance .
CLINICAL CHEMISTRY
-There were no relevant changes in the examined clinical chemistry parameters that could be attributed to the test material administration.
-Statistically significant changes of calcium (Ca) and alkaline phosphatase (ALKP) activity mean values were noted in the treated animals compared to control. Ca mean values were slightly higher in both male and female animals administered 150 and 1000 mg/kg bw/day. However, the variations were minor, and results were within the historical range for the population of Wistar rats of this age. In the 150 mg/kg bw/day female group, lower values compared to control were observed, with no similar effect at higher dose levels, or in the male animals; thus, this change was not considered toxicologically significant.
-Although these changes were statistically significant, the differences were minor, no dose related response was observed, and/or there was no consistent reaction in the male and female groups. These changes were neither considered toxicologically significant, nor indicated a test item related etiology.
NEUROBEHAVIOUR
-There were no toxicologically significant changes in the animal behaviour, general physical condition, in the reactions to different type of stimuli, grip strength or motor activity in the control or treated groups, at the evaluation performed towards the end of the treatment period.
-Minor changes were observed in the animals throughout all the dose groups, including controls when subjected to the modified Irwin test (functional observation battery). However, the variations noted demonstrated no treatment-related differences to the control, and were considered within the normal biological variation with respect to behaviour, reactions to different type of stimuli or manipulations.
- The behaviour and the general condition of the test animals were normal during the study. There was no treatment-related effect on motor activity or in the functional observation battery tests across groups of treated male or female animals and no findings indicative for neurotoxicity were observed.
ORGAN WEIGHTS
-There were no toxicologically significant changes in organ weight values noted after the test material administration daily for 28 days, at up to and including 1000 mg/kg bw/day.
-Statistically higher spleen, kidneys and testes weights relative to the brain weight were recorded at 25 and/or 1000 mg/kg bw/day (kidneys only) in the male animals.
-In the female animals, the mean thymus weights (absolute and relative to brain weight) were apparently lower than those recorded in the control animals. Additionally, decreases in the liver mean weight relative to the body weight were observed at 150 mg/kg bw/day.
-As these changes were within the historical range, had low magnitude and were not correlated with pathological findings, they were considered incidental and not related to treatment.
-All other examined organ weights (absolute and relative to the body and brain weights) were similar in the control and test item treated groups.
GROSS PATHOLOGY
-All rats survived until the scheduled termination of the study.
-At macroscopic evaluation, blue discoloration of the digestive content, stomach, small intestine (jejunum, ileum), colon, cecum, kidneys, mesenteric, mediastinal, cervical and/or mandibular lymph nodes were observed in 1/10, 9/10 and 10/10 animals from the Low, Mid and High Dose, respectively. These findings were considered to be test item-related.
-Additionally, blue discoloration of the lungs was recorded in two Mid Dose rats and one High Dose rat.
-All other macroscopic changes were regarded as incidental or procedure-related.
HISTOPATHOLOGY
-At microscopic evaluation, test item-related minimal focal/multifocal intracytoplasmic deposit of blue pigment in the jejunum, ileum, cecum, colon, mesenteric and/or cervical lymph nodes was observed in all High Dose animals. These findings corresponded with the gross observations.
-Minimal multifocal accumulation of blue pigmented macrophages in the lungs noted in one High Dose female and two Mid Dose rats occasionally associated with mixed cell infiltrate suggest possible oesophageal reflux of the test item in these animals and correlated with macroscopic changes. No perforation was seen histologically.
-All other microscopic changes were regarded as incidental or procedure-related.
HISTORICAL CONTROL DATA
-Incidences and extent of reactions observed in the treated animals were comparable to those observed in control animals, or within the historical control data, and are without any toxicological significance.
-No consistent dose or gender-related response was noted, and these differences observed between the control and treated groups were considered to be incidental or individual findings, which were not related to treatment and generally remained within the historical control ranges, or were with no toxicological significance.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Histology changes
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Histology changes
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
The test material administered daily by oral gavage for 28 days in Wistar rats did not lead to any toxicologically significant adverse effects at dose levels of 25, 150 or 1000 mg/kg bw/day.
The faeces of all animals administered up to, and including, 1000 mg/kg bw/day, and the urine of the high dose animals (1000 mg/kg bw/day) were coloured blue for 27 out of 28 days of treatment. At necropsy, blue discoloration of the digestive content, stomach, small intestine (jejunum, ileum), colon, cecum, kidneys, mesenteric, mediastinal, cervical and/or mandibular lymph nodes were observed in all the animals, with an apparent dose response. Test item-related minimal focal/multifocal intracytoplasmic deposit of blue pigment in the jejunum, ileum, cecum, colon, mesenteric and/or cervical lymph nodes were observed microscopically at 1000 mg/kg bw/day. There were no adverse findings on the organ weights.
Applicant's summary and conclusion
- Conclusions:
- In conclusion, in the conditions of this study, the no observed adverse effect level (NOAEL) for INK BH11 C based on histology changes is considered 1000 mg/kg bw/day, and the no observed effect level (NOEL), 150 mg/kg bw/day.
- Executive summary:
In A 28-day oral gavage toxicity study in Wistar rat (LAB Research study code: 08/777-100P) the test material was found to have a NOAEL of 1000 mg/kg bw/day and a NOEC of 150 mg/kg bw/day.
The study was conducted to OECD and GLP standards.
There were no mortalities during the 28-day treatment period and no toxicologically significant systemic clinical changes were noted.
The faeces of all animals administered up to, and including, 1000 mg/kg bw/day, and the urine of the high dose animals (1000 mg/kg bw/day) were coloured blue for 27 out of 28 days of treatment. At necropsy, blue discoloration of the digestive content, stomach, small intestine (jejunum, ileum), colon, cecum, kidneys, mesenteric, mediastinal, cervical and/or mandibular lymph nodes were observed in all the animals, with an apparent dose response. Test item-related minimal focal/multifocal intracytoplasmic deposit of blue pigment in the jejunum, ileum, cecum, colon, mesenteric and/or cervical lymph nodes were observed microscopically at 1000 mg/kg bw/day. There were no adverse findings on the organ weights.
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Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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