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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
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:
- July - September 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Performed according to OECD 407 (2008) and GLP principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
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: Notification No. 1121002 of the Pharmaceutical and Food Safety Bureau, MHLW, No. 2 (2003) of Manufacturing Industries Bureau, METI & NO. 031121002 of Environmental Health Department, MOE (2003)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- B508
- IUPAC Name:
- B508
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): B508
- Substance type: Blue powder
- Physical state: solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc., Hino breeding center, Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 134.1-154.9 g for males and 118.4-141.5 for females
- Housing: individually in stainless steel cage with wire-mesh floor
- Diet (e.g. ad libitum): MF pelleted diet ad libitum
- Water (e.g. ad libitum): chlorinated tap water ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.3-23.7
- Humidity (%): 51.2-63.3
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: July 15 To: September 26, 2008
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5 w/v% methylcellulose
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The required amount was ground to a fine powder and mixed with the vehicle to prepare teh 10.0 w.v% for the highest dose group by stirring with a magnetic stirrer. The lower concentrations of 2.5 and 0.5 w/v% were diluted from the 10.0 w/v% solution. The solutions were prepared once per 6-10 days and stored in the dark in a refrigerator (not further specified).
VEHICLE
- Justification for use and choice of vehicle (if other than water): not indicated
- Amount of vehicle (if gavage): 10 ml/kg bw
- Lot/batch no. (if required): Metolose SM100 lot no. 7035212, Shin-Etsu Chemical Industries - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of the test substance in 10.0, 2.5 and 0.5 w/v% dose formulations of first and final preparation was within 92.0 to 108% of the nominal concentration as determined by HPLC with UV-detection at 345 nm.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
50, 250 and 1000 mg/kg bw/d
Basis:
actual ingested
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: in a 14-d range-finding study rats (number not specified) were exposed to 25, 250, 500 and 1000 mg/kg bw/d; no adverse effects attributable to the test substance wre noted in males and females of all dose groups.
- Post-exposure recovery period in satellite groups: an additional 14-day recovery group in control and at 1000 mg/kg bw/d
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 3 times a day during the dosing period; twice daily during recovery period
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before dosing, and once weekly at 2-5 hours after dosing during dosing and recovery period
BODY WEIGHT: Yes
- Time schedule for examinations: at the start of the test and on day 1, 3, 8, 12, 17, 21, 26 and 28 of dosing and on days 1, 5, 10 and 14 of recovery
FOOD CONSUMPTION :
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION : No
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at completion of dosing period/recovery period
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: Yes
- How many animals: all
- Parameters examined were those according to OECD 407, 2008.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at completion of dosing period/recovery period
- Animals fasted: Yes
- How many animals: all
- Parameters examined were those according to OECD 407, 2008, except that bilirubin instead of bile acids were measured. However, as this was not required by OECD 407 (1995), the valid guideline at the time of the test, this is not considered a deviation of the guideline.
URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the dosing period/recovery period; urinary sediment was not examined at the end of recovery as no abnormalities were noted at the end of dosing
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined were according to OECD 407, 2008.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: week 4 of dosing period for reflex test and grip strength and locomotor activity; as locomotor activity showed effects in males, also males from the recovery group were tested in week 2
- Dose groups that were examined: week 4 of dosing: all animals; week 2 of recovery: males from control and 1000 mg/kg bw/d - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, according to OECD 407, 2008
Organ weights: according to OECD 407, 2008, except that prostate + seminal vesicles with coagulating glands were not weighed. However, as this was not required by OECD 407 (1995), the valid guideline at the time of the test, this is not considered a deviation of the guideline.
HISTOPATHOLOGY: Yes, according to OECD 407, 2008 - Other examinations:
- none
- Statistics:
- Data regarding body weights, food intakes, haematological and clinical chemistry parameters, urine volume and urine osmotic pressure, organ weights, grip strength and locomotor activity count were analyzed using the Bartlett's test for homogeneity of variance. If the variances were homogeneous at a significance level of 5%, the difference between the vehicle control group and each of the treatment groups was analyzed by Dunnett's test. If the variances were not homogeneous, the difference between the vehicle control group and each of the treatment groups was analyzed by the nonparametric Dunnett's test.
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:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- 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. No adverse effects were seen at all doses. Dark indigo stool was continuously observed in all treated animals during the dosing period and up to day 4 of the recovery period.
BODY WEIGHT AND WEIGHT GAIN
No effects observed.
FOOD CONSUMPTION
No effects observed.
HAEMATOLOGY
Red blood cell count was statistically significantly decreased in males at 50 and 1000 mg/kg bw/d (both 94% of control) at the end of dosing. The ratio of eosinophils was statistcally significantly in males at 1000 mg/kg bw/d (185% of control) and activated partial thromboplastin time was statistically significantly extended in females at 1000 mg/kg bw/d (105% of control) at the end of the recovery period. As these changes were slight, not seen in the other sex and within the range of historical data in our lab (specified in the report), these effects are not considered to be toxicologically relevant for the test substance.
CLINICAL CHEMISTRY
Glucose was statistically significantly decreased in males at 250 and 1000 mg/kg bw/d at the end of dosing (85 and 86% of control, resp.) and in males at 1000 mg/kg bw/d at the end of recovery (90% of control). Total protein was statistically significantly increased in females at 1000 mg/kg bw/d at the end of dosing (107% of control). Total bilirubin was statistically significantly decreased in females at 1000 mg/kg bw/d at the end of recovery (78% of control). As these changes were slight, no correlating histopathological effects were observed, changes not seen in the other sex and within the range of historical data in our lab (specified in report), these effects are not considered to be toxicologically relevant.
URINALYSIS
No abnormalities observed at all dose levels.
NEUROBEHAVIOUR
No abnormalities for reflex behaviour and grip strength were noted. The locomotor activity was statistically significantly decreased in the 10-20 min interval in males at 1000 mg/kg bw/d However, because there were no abnormalities at other intervals and the total of 60 minutes, these changes were not considered to be attributable to administration of the test substance.
ORGAN WEIGHTS
A statistically significant increase in relative heart weight of males at 250 and 1000 mg/kg bw/d ((both 109% of control) and relative kidney weight of males at 1000 mg/kg bw/d (111% of control) at the end of dosing was observed. As these changes were not accompanied by changes in absolute weight, no histopathological effects were observed and the changes were within the historical control data, they were not considered to be toxicologically relevant.
GROSS PATHOLOGY
No treatment-related adverse effects observed. Dark-blueish contents of the intestinal tract in animals at 250 and 1000 mg/kg bw/d were seen due to the blue colour of the test substance.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects observed.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed at highest dose tested.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In the absence of treatment-related adverse effects, the NOAEL of B508 is 1000 mg/kg bw/d after oral dosing for 28 days.
- Executive summary:
Rats were given 50, 250 or 1000 mg/kg bw/d of B508 in 0.5 w/v% methylcellylose by gavage according to OECD 407 (2008) and GLP principles.No mortality and no adverse clinical signs occurred. No effects were observed on body weight, food consumption, functional behaviour, haematology and clinical chemistry parameters, urinalysis, organ weights, gross- and histopathology. Therefore, the NOAEL was established to be >= 1000 mg/kg bw/d.
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