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EC number: 479-540-8 | CAS number: 61007-89-4
- 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
- Adequacy of study:
- key study
- Study period:
- 23.09. - 14.03.2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD guideline study, GLP. Eyes were not examined histopathologically. Uterus weights were not recorded and not all recommended organs were examined histopathologically.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2003
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 July 27, 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 479-540-8
- EC Name:
- -
- Cas Number:
- 61007-89-4
- Molecular formula:
- C27 H27 Mn N4 O3
- IUPAC Name:
- manganese(3+) 2-[({2-[bis(2-{[(2-oxidophenyl)methylidene]amino}ethyl)amino]ethyl}imino)methyl]benzen-1-olate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd., Biotechnology and Animal Breeding Division, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation:
males: 130 -158 g (mean 145 g)
females: 112 -133 g (mean 123 g)
- Fasting period before study: No
- Housing: In groups of five per sex in Makrolon type-4 cages
- Diet: standard diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Humidity: 30 - 70 %
- Air changes (per hr): 10 - 15
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: 23.09. - 18.11.2002
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Remarks:
- PEG 300
- Details on oral exposure:
- REPARATION OF DOSING SOLUTIONS:
The test item formulations were prepared weekly. The test item was weighed into a glass beaker on a tared Mettler balance and the vehicle added. The mixtures were prepared using a magnetic stirrer and stored at room temperature (17-23°C) in glass beakers, protected from light. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
VEHICLE
- Concentration in vehicle: 0, 10, 30 or 100 mg/mL
- Amount of vehicle: dose volume of 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of homogeneity was performed by analysing samples of each dose group from three different segments (top, middle, bottom) of the respective mixing container. Evaluation of stability was performed by analysing samples of each dose group over the storage periods of two hours and seven days at storage conditions. Analytically determined test item concentrations were in good agreement with the nominal values. The test item was homogeneously distributed in the vehicle and was stable for at least seven days.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 150 and 500 mg/kg bw/d (group 1, 2, 3 and 4, respectively)
Basis:
actual ingested
- No. of animals per sex per dose:
- Groups 1 and 4: 10 males; 10 females
Groups 2 and 3: 5 males; 5 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were based on the results of a non-GLP 5-day dose range-finding study in which the test item was administered by gavage to 2 rats per group and sex. One male and two females treated with 1000 mg/kg bw/d of the test item died spontaneously on the 4th or 5th day of treatment. Animals showed several clinical signs at 1000 mg/kg bw/d like slight to moderate emaciation, hunched posture or slightly ruffled fur e.g.
- Post-exposure recovery period in satellite groups: 14 days (control and high dose group animals only)
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28 and once daily during days 29-42 (recovery). Observations for mortality/viability were recorded twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly (weeks 1-3) thereafter.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during pretest, treatment and recovery and before necropsy.
FOOD CONSUMPTION: Yes
The food consumption was recorded once during the pretest period and weekly thereafter.
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 and after 6 weeks
- Anaesthetic used for blood collection: Yes (light isoflurane anesthesia)
- Animals fasted: Yes (18 hrs)
- How many animals: all animals
- Parameters examined: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, red cell volume distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin concentration distribution width, platelet (thrombocyte) count, reticulocyte count, reticulocyte maturity index, methemoglobin, total leukocyte count, differential leukocyte count, coagulation: thromboplastin time, activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 and after 6 weeks
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Glucose, urea, creatinine, total bilirubin, cholesterol, total triglycerides, phospholipids, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, creatine kinase, alkaline phosphatase, gamma-glutamyl-transferase, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected during the 18-hour fasting period into a specimen vial.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: Volume (18 hours), specific gravity (relative density), color, appearance, pH, nitrite, protein, glucose, ketones, urobilinogen, erythrocytes, leukocytes
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals.
- Dose groups that were examined: all animals
- Battery of functions tested:
Grip strength
Forelimb and hind limb grip strength measurements were performed using a push-pull strain gauge (Mecmesin, AFG 25N). The animals were placed with the forepaws inside a triangular grasping ring and with the hind paws outside a triangular grasping ring. Using one hand, the animals were held towards the base of the tail and steadily pulled away or towards the ring until the grip was broken. Each measurement was repeated three times, the means were calculated and recorded.
Locomotor activity
Locomotor (decreased or increased) activity was measured quantitatively with Activity Monitor AM 1052 system. Animals were randomized and monitored during the fourth treatment week for a 60-minute period and the total activity of this time period was recorded. Low beams count was reported in 15-minute intervals as well as the total activity of the measuring period. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
At autopsy the following weights were recorded from all animals: brain, heart, liver, thymus, kidneys, adrenals, spleen, testes and epididymides or ovaries
HISTOPATHOLOGY: Yes
Microscopical examinations:
Adrenal glands, bone marrow (femur), brain (cerebrum, cerebellum, brain stem), cecum, colon, duodenum, epididymides, heart, ileum (with Peyer's patches, jejunum (with Peyer's patches), kidneys, liver, lungs, lymph nodes (mesenteric, mandibular), ovaries, prostate gland, rectum, sciatic nerve, seminal vesicles, spinal cord (cervical, midthoracic, lumbar), spleen, stomach, testes, thymus, thyroid (incl. parathyroid gland), trachea, urinary bladder, uterus, vagina, gross lesions - Statistics:
- The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, organ weights and ratios, as well as clinical laboratory data :
- The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Student's t-test was applied to grip strength and locomotor activity data.
- Fisher's exact-test was applied to the macroscopic findings.
For clinical laboratory data, quantitative data were analyzed by a one-way analysis of variance (ANOVA) when the variances were considered homogeneous according to Bartlett. Alternatively, if the variances were considered to be heterogenous (p<0.05), a non-parametric Kruskal-Wallis test was used. Treated groups were then compared to the control groups using Dunnett's test if the ANOVA was significant at the 5% level and by Dunn's test in the case of a significant Kruskal-Wallis test (p<0.05).
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All animals survived until scheduled necropsy. No test item related clinical signs were noted.
BODY WEIGHT AND WEIGHT GAIN
No test item related differences in mean body weights or mean body weight gain were observed when compared with controls.
FOOD CONSUMPTION
The mean daily and relative food consumption of test item treated animals were comparable with those of the control animals.
HAEMATOLOGY
No test item related differences in parameters of hematology were noted in animals after four or six weeks when compared with controls.
CLINICAL CHEMISTRY
No test item related differences in parameters of clinical biochemistry were noted in animals after four or six weeks when compared with controls.
URINALYSIS
No test item related differences in parameters of urinalysis were noted in animals after four or six weeks when compared with controls.
NEUROBEHAVIOUR
Functional Observational Battery: No test item related clinical signs were noted in males or females (week 4).
Grip Strength: No test item related differences were seen in mean fore- or hindlimb grip strength.
Locomotor Activity: No test item related differences were seen in mean locomotor activity.
ORGAN WEIGHTS
The mean liver weights, liver to body weight- and liver to brain weight-ratios were increased in females at 500 mg/kg bw/d when compared with controls after four weeks of treatment. The mean kidney to body weight ratio was increased in females at 500 mg/kg bw/d and the mean kidney to body weight- and kidney to brain weight ratios were increased in females at 150 mg/kg bw/d when compared with controls after four weeks of treatment. These findings were considered to be test item related because a dose response relationship could be observed and these findings compare well with the described microscopic findings. However, they were fully reversible after four weeks treatment followed by a two-week recovery period. After four weeks of treatment followed by a two-week recovery period the mean kidney weight and kidney to brain weight ratio were increased in males when compared with controls. However no effects on absolute or relative kidney weights were observed in males treated at 500 mg/kg bw/d for four weeks. No other test item-related changes in organ weights, organ to body- or organ to brain weight ratios were noted.
GROSS PATHOLOGY and HISTOPATHOLOGY
In the cortex of the kidneys an increased incidence and grade of basophilic tubuli in test itemtreated animals at 500 mg/kg bw/d (group 4), especially in males of the recovery group was recorded. This finding may be a sign of an increased tubular regeneration after a preceeding tubular damage. The change was still recorded after a 14-day treatment-free recovery penod, and was regarded as an adverse effect in group 4 animals (especially in males). Adaptive effects were noted in stomach/ forestomach and liver.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects were noted at 50 mg/kg bw/d.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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