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EC number: 442-640-7 | 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
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:
- 2002-Jan-8 to 2002-Jun-28
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3050
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 442-640-7
- EC Name:
- -
- Cas Number:
- 479541-17-8
- Molecular formula:
- Hill formula: C32H26CuFN9Na4O19S5
- IUPAC Name:
- Tetrasodium 2-(4-fluoro-6-(2-(2-sulfonatoethansulfonyl)ethyl amino)-1,3,5-triazin-2-ylamino)-5-hydroxy-6-(2-(2-hydroxy-5- sulfonatophenylazo)-4,5-dimethoxyphenylazo)-7-sulfonatonaphthalene-1-sulfonatocuprate(II)
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): Reaktiv Oliv F00-0149
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: Harlan Winkelmann GmbH Gartenstrasse 27 D-33178 Borchen
- Age at study initiation: approximately 6 weeks
- Housing: In transparent macrolon cages (type IV) on soft wood granulate in an air-conditioned rooms, 5 animals per cage, separated according to sex
- Diet (e.g. ad libitum): ssniff R/M-H (V 1534), exept fot the period in which the animals were kept in diuresis cages
- Water (e.g. ad libitum): Tap water in plastic bottles ad libitum, exept fot the period in which the animals were kept in diuresis cages
- Acclimation period: at least five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20 %
- Photoperiod (hrs dark / hrs light): 12 hours light / dark cycle
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 62.5, 250, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 62.5 mg/kg bw/day
Male: 5 animals at 250 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 62.5 mg/kg bw/day
Female: 5 animals at 250 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Acute oral toxicity testing of Reaktiv Oliv F00-0149 at a dose of 2000 mg/kg in the rat (only this dose was tested) showed that the median lethal dose (LD50) is above 2000 mg/kg body weight in both male and female animals. All the animals tolerated the dose of 2000 mg/kg without any signs of intoxication.Based on these results, dose levels of 0, 62.5, 250 and 1000 mg/kg body weight per day were selected for the present study.
- Rationale for selecting satellite groups: control and high dose group
- Post-exposure recovery period: 14 days
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Survival control of the animals was examined twice daily (on weekends and public holidays once daily).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The behavior and general health condition of the animals were observed once daily.
- Once before the first treatment and once a week thereafter, detailed clinical observations were performed in all animals outside the home cage in a standard arena ('open field'). Additionally, the animals were examined for opacity of the refracting media of the eyes, damage to the oral mucosa, and impairment of dental growth.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weights of all animals were determinated before the start of the study and then twice weekly throughout the study.
FOOD CONSUMPTION:
-Food consumption was determined continuously (two times per week).
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of the study and after the recovery period, hematological examinations were performed on all animals
- Anaesthetic used for blood collection: Yes - Blood samples were taken from the retrobulbar venous plexus in narcosis (intraperitoneal injection of 67 + 6.7 mg/kg body weight Ketamine-Hydrochloride + Xylazine)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Erythrocyte counts (RBC), Heinz Body Counts, Hematocrit (packed cell volume), Hemoglobin, Mean corpuscular hemoglobin
(MCH), Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), Reticulocyte counts, Differential leukocyte counts, Leukocyte counts (WBC), Coagulation time (clotting time), Thrombocyte counts (platelets)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After blood sampling for hematological testing, the animals were killed by section of the vena cava cranialis in deep narcosis and exsanguinated.
- Parameters checked: γ-Glutamyltranspeptidase, Alanine Aminotransferase (ALAT or GPT), Albumin, Albumin / Globulin ratio (calculated), Alkaline phosphatase, Aspartate Aminotransferase (ASAT or GOT), Bilirubin direct, Bilirubin total, Calcium, Chloride (Cl-), Cholesterol, Creatinine, Globulin (calculated), Glucose, Inorganic Phosphorous, Potassium (K+), Sodium (Na+), Total Protein, Triglycerides, Urea, Uric Acid
URINALYSIS: Yes
- Time schedule for collection of urine: Urine analysis was performed in all animals a few days before termination of the study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: Appearence, Bilirubin, Blood, Color, Glucose, Ketone bodies, Microscopic Examination (Sediment), pH, Protein, Urobilinogen
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once before the first treatment and thereafter once a week detailed clinical observations were performed in all animals outside the home cage in a standard arena
- Battery of functions tested: Each animal was assessed for changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity such as lacrimation, salivation, nasal discharge, piloerection, pupil size, and unusual respiratory pattern. Changes in gait, posture, and response to handling as well as the presence of clonic or tonic movements, tremor, and any other abnormal motor movements (such as excessive grooming, repetitive circling or other stereotypes) or bizarre behavior (e.g. self-mutilation, walking backwards) were also recorded. In addition, defecation and urination were evaluated. At the termination of the study sensory reactivity to stimuli of different types (auditory, visual, and proprioceptive) was evaluated including startle reflex (click response), response to approach with the finger to the nose of the animal, and righting reflex. The presence and absence of pupillary constriction was assessed using a pen flashlight directed into the eye. Assessments of motor function were performed including measurement of motor activity, and forelimb and hindlimb grip strength. The animals were evaluated for motor activity during a 60-minute period in an 16-station automated motor activity monitoring device. Activity counts were recorded by the interruption of photocells in 3-minute-intervals to give a total of 20 intervals. A strain gauge device measured fore- and hindlimb grip strength. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- After exsanguination, all animals were necropsied and checked for macroscopically visible abnormalities. The autopsy included macroscopic examination of the skin, orifices, eyes, teeth, oral mucosa and internal organs.
- Endotracheal fixation of the lungs
- Organ weights of Adrenals, Brain, Epidymides, Heart, Kidneys, Liver, Spleen, Testes, Thymus
HISTOPATHOLOGY: Yes
- From all animals, tissues and organs were preserved in a suitable fixative (buffered formalin) and/or further processed for histopathological investigations.
- Adrenals, Bone marrow / sternum, Brain with medulla oblongata, Epididymides, Heart, Small Intestine 2 jejunum, Large Intestine 2 colon, Kidneys, Liver, Lungs, Lymph nodes 1 mandibular, Lymph nodes 2 iliac, Nerve sciatic nerve, Ovaries with oviducts, Prostate, Seminal vesicle, Spinal cord 1 cervical, Spleen, Stomach,
Testes, Thymus, Thyroid gland with parathyroids, Trachea, Urinary bladder, Uterus, All other gross lesions
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- 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, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- Clinical observations:
No mortality occurred during the study period.
There were no effects reported in behavior and state of health. At 1000 mg/kg bw/d, black discolored feces were observed in males from study day 15 onwards up to approx. one week of the recovery period. In addition males and females exhibited broken-off incisors during the 2nd week of
recovery.
Body weights were statistically significantly decreased in male rats receiving 1000 mg/kg bw/d. This finding persisted during the recovery period. In male rats receiving 250 mg/kg bw/d body weights were slightly decreased, attaining statistically significance only on days 5 and 8. The food consumption was distinctly decreased in the males receiving 1000 mg/kg bw/d and slightly decreased in females at the same dose level during the recovery period.
Neurotoxicological measurements including "open field" observations, assessment of sensory function, and forelimb and hindlimb grip strength were not influenced by the administration of the test substance in all groups.
Laboratory findings:
Hematology revealed statistically significant increased red blood cell counts for the 1000 mg/kg bw/d males and hemoglobin for the males and females as well as decreased reticulocytes for the males, respectively at the end of the recovery period.
Clinical biochemistry revealed the following statistically significant findings in males and females receiving 1000 mg/kg bw/d that were considered to be toxicologically significant: increased of total bilirubin (males, final and recovery), increased of direct bilirubin (males, recovery), increased of urea nitrogen (males and females, recovery), decreased glucose (females, final and recovery), decreased triglycerides (males, final and recovery).
No treatment-related findings of toxicologically significance were noted by urinalysis.
Effects in organs:
In male rats receiving 1000 mg/kg bw/d decreased liver, spleen, and thymus weights were observed at the end of the study and also after the recovery period. Increased testes and epididymides weights were detected only at the end of the recovery period. These findings were considered to be
primarily due to the decrease in terminal body weights in this group.
At necropsy grey to dark brown discolored kidneys, testes and ovaries were observed in all males and females receiving 1000 mg/kg bw/d. This discoloration was still present after the recovery period of two weeks.
Histopathology revealed marked dose dependent mixed-cellular infiltration in the submucosa of the glandular stomach was observed in animals of both sexes given 250 and 1000 mg/kg bw/d. These findings has been attributed to (local) irritating properties of the test substance.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- (local)
- Effect level:
- 62.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: cellular infiltrations in the stomach which can be attributed to irritating properties of the test substance
- Dose descriptor:
- LOAEL
- Remarks:
- (local)
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: based on mixed-cellular infiltration in the submucosa of the glandular stomach.
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic)
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Dose descriptor:
- LOAEL
- Remarks:
- (systemic)
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs, body weight changes, food consumption, hematologic parameters, clinical chemistry, urinalysis, organ weights, gross pathology
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Under conditions of this study the systemic NOAEL for subacute oral administration of Reactive Olive F00-0149 is 250 mg/kg bw/d. The LOAEL is 1000 mg/kg/d, based on clinical signs, body weight changes, hematologic parameters, clinical chemistry, urinalysis, organ weights, and gross pathology.
- Executive summary:
In a subacute toxicity study Reactive Olive F00-0149 was administered to 5 Sprague Dawley rats/sex/dose by gavage in deionized water at doses of 0, 62.5, 250, 1000 mg/kg bw/day for 28 days. 5 animals/sex in the control and high dose group was used as recovery groups.
Adverse effects were seen in clinical signs, body weight changes, food consumption, hematologic parameters, clinical chemistry, urinalysis, organ weights, gross pathology, and non-neoplastic histopathology. Repeated oral administration of the test item at dose levels of 62.5 or 250 mg/kg body weight to rats was generally well tolerated troughout the treatment and recovery period. Doses of 1000 mg/kg bw caused impairment of body weight development in particular for the males as well as cellular infiltrations in the stomach which can be attributed to irritating properties of the test substance. A threshold dose for these findings was identified at 250 mg/kg body weight. With regard to the present study the NOAEL is 62.5 mg/kg bw/d for local (irritating) effects. The NOAEL for systemic effects is 250 mg/kg/d.
This subacute toxicity study in rats is acceptable and satisfies the guideline requirement for a subacute oral study (OPPTS 870.3050; OECD 407) in rats.
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