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EC number: 257-775-5 | CAS number: 52238-69-4
- 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
- Remarks:
- source study on the analogous substance
- Adequacy of study:
- key study
- Study period:
- From January 10 to February 21, 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
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:
- May 12, 1981
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Similar Substance 01
- IUPAC Name:
- Similar Substance 01
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, West-Germany.
- Age at study initiation: approximately 6 weeks.
- Weight at study initiation: 192 - 233 g males; 141 - 171 g females.
- Housing: animals were housed 5 to a cage (same sex) in stainless suspended cages with wire mesh floors.
- Diet: standard pelleted laboratory animal diet (RMH-B from Hope Farms, Woerden, The Netherlands), ad libitum.
- Water: tap-water, diluted with decalcified water, ad libitum.
- Acclimation period: 14 days. An examination was perfromed prior to commencement of treatment to ensure that the animals were in a good state of health.
ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 3 °C (actual range 17 - 20 °C).
- Relative dumidity: 30 - 70 % (actual range 45 - 70 %).
- Air changes: 7.5-15 air changes per hour.
- Photoperiod: 12 hours artificial fluorescent light/12 hours dark per day.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- water prepared by reverse osmosis
- Details on oral exposure:
- TREATMENT
- Dose volume: 10 ml/kg bw
TEST SOLUTION
- Method: the test article was weighed into a glass flask on an analytical balance and the vehicle (w/w) added.
- Frequency of test article formulation: daily immediately prior to dosing.
- Homogeneity of test article in the vehicle: determination of homogeneitywas not considered necessary as the test substance formed a solution with the vehicle.
- Appearance of test article in vehicle: orange solution.
- Storage of test article formulation: at ambient temperature. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of formulations prepared prior to commencement of he study and during weeks 1 and 3 were analysed to check the accuracy of mixing.
Concentration of the test articie in vehicie was determined pretreatment and on days 1 and 15.
Actual concentrations of preparations were in agreement with the treatment levels as per protocol. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, approximately the same time each day, 7 days per week.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 5 males and 5 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on preliminary test results.
Examinations
- Observations and examinations performed and frequency:
- MORTALITY
Twice daily.
DETAILED CLINICAL OBSERVATIONS
At least once daily.
BODY WEIGHT
Weekly and on the day preceding termination, prior to overnight fasting.
FOOD CONSUMPTION
Weekly.
OPHTHALMOSCOPIC EXAMINATION
Prior to termination in week 4.
CLINICAL CHEMISTRY
Blood samples were collected under Iight ether anaesthesia immediately prior to post mortem examination, between 8.00 and 10.00 a.m.. The animals were fasted overnight before blood sampling, but water was provided. Blood samples were drawn from the retro-orbital sinus of all rats/sex/group and collected into untreated tubes for clinical biochemistry parameters (> 2.0 ml).
Parameters: glucose, urea, creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, sodium, potassium, chloride, calcium, phosphnrus, protein total, protein albumin.
HAEMATOLOGY
Blood samples were collected under Iight ether anaesthesia immediately prior to post mortem examination, between 8.00 and 10.00 a.m.. The animals were fasted overnight before blood sampling, but water was provided. Blood samples were drawn from the retro-orbital sinus of all rats/sex/group and collected into tubes prepared with EDTA (0.5 ml) for haematological parameters.
The following haematology parameters were determined from blood containing EDTA as an anti-coagulant.
Parameters: erythrocyte count, haemogiobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, red cell distribution width, platelet count, total ieucocyte count, differential leucocyte count. - Sacrifice and pathology:
- GROSS PATHOLOGY
All animals were necropsied on day 29 and descriptions of all macroscopic abnormalities recorded. All animals were anaesthetised with pentobarbital and killed by exsanguination.
Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution: adrenal glands, aorta, brain, cecum, clitoral gland, colon, duodenum, epididymides, exorbital lacrimal gland, eyes, femur including joint, head, heart, ileum, jejunum, kidneys, larynx/pharynx, liver (all lobes), lung (including mainstem bronchi), lymph nodes - cervical mesenteric, mammary gland, oesophagus, ovaries, pancreas, pituitary gland, preputial gland, prostate gland, rectum, salivary glands (sub-maxillary), sciatic nerve, seminal vesicles, skeletal muscle (gastrocnemius), skin, spinal cord (cervical, midthoracic, lumbar), spleen, sternum with bone marrow, stomach (glandular and non glandular, including pylorus), testes, thymus, thyroid (including parathyroid), tongue, trachea, urinary bladder, uterus, vagina.
ORGAN WEIGHTS
The following organ weights (and terminal body weight) were recorded at termination on the scheduled date of necropsy listed: adrenal glands, kidneys, liver, spleen, testes.
HISTOPATHOLOGY
All organ and tissue samples for histopathology were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and azophloxine. All slides for histopathological examination were dispatched to testing laboratory.
Slides of adrenals, heart, kidneys, liver and spleen, collected at termination from animals of the control and high dose group were examined by a pathologist. All abnormalities were described and included in the report. - Statistics:
- The following statistical methods were used to analyse the body weight, food consumption, organ weights and ciinicai iaboratory data: Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnett—test (many to one t-test) based on a pooied variance estimate was applied for the comparison of the treated groups and the control groups.
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
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).
Individual values, means, standard deviations and statistics were rounded off before printing. For example, test statistics were calculated on the basis of exact values for means and pooled variances and then rounded off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of a reaction to treatment or behavioral change by treated rats in comparison with the controls.
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weight gain by males and females treated with test item was noted as marginally increased compared to controls, but this difference did not achieve a consistent level of statistical significance and was considered the result of normal biological variation.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food intake of treated rats was similar to that of the controls at all times.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no abnormalities noted in either treated or control rats at the ophthalmoscopic examination prior to termination.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Among males receiving 200 mg/kg, significantly low values for sodium and calcium were noted, however in the absence of corroborative changes in other electrolyte values or a treatment-related distribution, it was considered that these decreases had arisen fortuitously.
Treated females showed significantly decreased glucose levels when compared to controls. However, when the control values were examined, it was considered that they were at the upper end of the normal biological range and the values obtained for treated females were within the normal biological range. These statistically significant differences were therefore considered the result of high control values and not the result of treatment.
Females receiving 200 mg/kg had significantly decreased levels of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT), however, as there was no evidence of a significant decrease in females receiving 1000 mg/kg and it was considered that these decreases could be associated with the lighter liver weights noted for this group, the decrease of these enzyme levels was therefore considered not of toxicological significance.
Other differences noted between control and treated rats that achieved a level of statistical significance were considered to have arisen fortuitously and not to be as a result of treatment. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no differences that were considered to have arisen as a result of treatment. Minor statistically significant changes from control values for red blood cell numbers in males receiving 50 mg/kg/day and for white blood cell numbers in females receiving 50 or 100 mg/kg/day were not, in the absence of a treatment-related distribution, considered to be of toxicological significance.
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females receiving 200 mg/kg had statistically significantly lighter livers when compared to control values. However, in the absence of a treatment related distribution, this difference was considered to have arisen fortuitously and not to be of toxicologicai significance.
There were no differences in the organ weights of treated males or females receiving 50 or 1000 mg/kg when compared to control values. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Macroscopic observation showed haemorrhages in the glandular stomach of one female receiving 200 mg/kg/day and in the cervical lymph nodes of one female receiving 1000 mg/kg. In the absence of a treatment-related distribution these findings, which may have occurred as a result of terminal procedures, were considered not to be toxicologically significant.
Any other macroscopically noted abnormalities were within the range of those normally seen for rats of this age and strain and were not treatment-related. - Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No microscopic observations were noted that were related to treatment with the test item. Those that were observed were among those commonly found in rats of this age and strain.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- NOEL (28d) (rat males/females) ≥ 1000 mg/kg bw day
- Executive summary:
In the subacute 28-day toxicity study, the substance was administered daily by gavage to SPF-bred Sprague-Dawley rats.
A 10-day range finding study was performed (with 3 rats/sex/group at dose levels of 50, 200 and 1000 mg/kg/day) to provide a basis for selection of dose levels for the 28-day study. No differences of biological significance were observed in clinical appearance, body weight, food consumption, macroscopic appearance or liver weights between the treated groups of the dose range finding study.
The main study was comprised of four groups. The 5 males and 5 females were assigned to each group. The dose levels used were 0, 50, 200 and 1000 mg/kg bw/day.
No evidence of a toxic reaction to test item was noted at any of the three treatment levels.
From the results obtained, a No Observed Effect Level of 1000 mg/kg/day was established.
Conclusion
NOEL (28d) (rat males/females) ≥ 1000 mg/kg bw day
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