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Tetrasodium [2-({4-fluoro-6-[(2-{[4-fluoro-6-({5-(hydroxykappaO)-6-[(2-{[2-(hydroxy-kappaO)-5-sulfophenyl] diazenyl-kappaN1}-4,5-dimethoxyphenyl) diazenyl-kappaN2]-7-sulfo-2-naphthyl} amino)-1,3,5-triazin-2-yl] amino} propyl) amino]-1,3,5-triazin-2-yl} amino) benzene-1,4- disulfonato(6-)] cuprate(4-)
EC number: 466-470-8 | 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:
- 12-April-2006 to 22-August-2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study with GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Guidelines for Screening, Toxicity Testing of Chemicals: Testing Methods for new Substances, enacted July 13,1974, amended December 5,1986
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- Description: Black powder
Stability of test item: Hygroscopic; stable under storage conditions
Storage conditions: at room temperature (15 - 25°C) in a desiccator in the original container away from direct sunlight.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test system: Rat, HanRcc:WIST (SPF)
Total number of animals/group: Groups 1 and 4: 10 males; 10 females
Groups 2 and 3: 5 males; 5 females
Total number of animals used: 30 males and 30 females
Age at delivery: 6 weeks
Body weight range at acclimatization: Males: 130.4 - 159.2 grams (mean 145.7 grams)
Females: 115.9 - 130.4 grams (mean 121.4 grams)
Identification: Acclimatization: Cage card and tail mark (later ear tattoo)
Treatment: Cage card and individual ear tattoo
Randomization: Computer-generated random algorithm
Acclimatization: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
Husbandry
Conditions: Standard Laboratory Conditions. Air-conditioned with 10 - 15 air changes per hour, and continuously monitored environmental conditions (temperature range: 22 ±3 °C; relative humidity range: 30 - 70 %). There was 12-hour fluorescent light/12 -hour dark cycle with music during the light period.
Accommodation: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding
Water: Community tap-water from Itingen was available ad libitum in water bottles.
Diet: Pelleted standard Provimi Kliba 3433 (batch no.01/06) rat maintenance diet was available ad libitum.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- Method: Oral, by gavage.
Daily dose levels: Group 1: 0 mg/kg body weight
Group 2: 50 mg/kg body weight
Group 3: 200 mg/kg body weight
Group 4: 1000 mg/kg body weight
Frequency of administration: Daily
Dose volume: 10 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration, homogeneity and stability (after 3 hours and 7 days) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd (Environmental Chemistry & Pharmanalytics Division) according to a HPLC method supplied by the Sponsor.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
50, 200 and 1000 mg/kg body weight
Basis:
- 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:
- the test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, bidistilled water, only.
The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed. - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- Mortality / Viability
Observations for mortality/viability were recorded twice daily.
General Cageside Observations (Daily)
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).
Detailed Clinical Observations (Weekly)
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.
Food Consumption
The food consumption was recorded once during the pretest period and weekly thereafter, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.
Body Weights
Body weights were recorded weekly during pretest, treatment and recovery and before necropsy, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.
Functional Observational Battery
During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals. - Sacrifice and pathology:
- All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
- Statistics:
- The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, clinical laboratory investigations, organ weights and ratios:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate were 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) were applied instead of the Dunnetttest when the data can not be assumed to follow a normal distribution.
• Fisher's exact-test was applied to the macroscopic findings.
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 specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- 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 specified
- Details on results:
- MORTALITY / VIABILITY
All animals survived until scheduled necropsy.
CLINICAL SIGNS
During daily observations, dark feces (with dose-related time of onset and severity) were noted in males and females treated with 200 mg/kg/day or 1000 mg/kg/day. In the latter group, this finding was observed from days 1 - 5 of recovery with diminishing severity. Dark feces were considered to be a passive test item-related effect without toxicological relevance.
During weekly observations (weeks 1-3), no signs were noted at any dose level.
FUNCTIONAL OBSERVATIONAL BATTERY
During the functional observational battery (week 4), no signs were noted at any dose level.
Grip Strength
No test item-related changes in the mean fore- or hindlimb grip strength were noted at any dose level.
Locomotor Activity
Minor differences noted in the mean locomotor activity of the test item-treated rats were considered to be of no toxicological relevance.
FOOD CONSUMPTION
No differences of toxicological relevance were noted in the mean absolute or relative daily food consumption at any dose level tested.
BODY WEIGHT
The mean body weights of the test item-treated rats compared favorably with those of the control rats.
CLINICAL LABORATORY INVESTIGATIONS
Hematology
No test item-related changes were noted in the hematology parameters at any dosen level.
Clinical Biochemistry
At 1000 mg/kg/day, reductions in blood glucose, increased total bilirubin, elevated cholesterol, triglycerides (females only), phospholipids (males only) and phosphorus were noted after four weeks' treatment. With the exception of total bilirubin, all differences remained within the ranges of the historical control values, but may indicate minor adaptive changes in liver metabolism. The elevation in total bilirubin was considered to be a possible artifact induced by staining of the plasma.
Urinalysis
No test item-related changes were noted in the urinalysis parameters at any dose level.
ORGAN WEIGHTS
No differences of toxicological relevance were noted in the mean absolute or relative organ weights at any dose level after four weeks' treatment or two weeks' subsequent recovery.
MACROSCOPIC / MICROSCOPIC FINDINGS
At the end of the treatment period, a violet discoloration of the ileum, cecum, colon and rectum was recorded in all males and females treated with 1000 mg/kg/day, while black discoloration of the kidneys was seen in all males and females treated with 1000 mg/kg/day at the end of treatment and recovery periods. Since the microscopic examination of intestinal organs did not reveal any changes associated to the discoloration, no toxicological meaning was attributed to it.
Microscopically patchy fatty change (with small droplets) was seen in the liver of animals treated with 1000 mg/kg/day. After two weeks of recovery, the liver of males returned to normal, whereas changes were still present in a few females. Eosinophilic granules (hyaline droplets) were observed in the renal tubules (mainly proximal) of some male rats treated with 1000 mg/kg/day. In addition dark pigments were seen in the renal tubules of some males and females treated with 1000 mg/kg/day. Neither granules nor pigmentation were associated with any other morphological change such as degeneration or inflammation. The pigmentation was probably associated to the black discoloration reported at necropsy. After two weeks of recovery, the kidneys returned to normal.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Dark feces observed at 200 mg/kg bw and above were considered to be a passive test item-related effect without toxicological relevance.
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, 50 mg body weight/day of the test item was established as the no-observed-effect-level (NOEL), and 1000 mg/kg body weight/day of the test item as the no-observed-adverse-effect-level (NOAEL).
- Executive summary:
In this subacute toxicity study, the test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, bidistilled water, only.
The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed.
Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during acclimatization, treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4.
At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.
From the animals of the low and middle dose groups, liver and kidneys were examined to establish a no-effect level.
And the oral administration of the test item to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no mortality, no clinical signs of toxicological relevance during daily or weekly observations (weeks 1-3), no effects upon functional observational battery (week 4), including changes in grip strength and locomotor activity. The mean daily food consumption and mean body weights were unaffected. The organ weights and ratios of test item-treated rats compared favorably to those of the controls.
No test item-related changes were noted in the hematology parameters at any dose level. All differences of clinical biochemistry remained within the ranges of the historical control values, but may indicate minor adaptive changes in liver metabolism. The elevation in total bilirubin was considered to be a possible artifact induced by staining of the plasma. No test item-related changes were noted in the urinalysis parameters at any dose level. No differences of toxicological relevance were noted in the mean absolute or relative organ weights at any dose level after four weeks' treatment or two weeks' subsequent recovery. No test item-related changes were noted in the macroscopic/microscopic findings.
Based on the results of this study, 50 mg body weight/dayof the test item was established as the no-observed-effect-level (NOEL), and1000 mg/kg body weight/day of the test item as the no-observed-adverse-effect-level (NOAEL).
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