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EC number: 700-217-7 | 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Details on test material:
- - Purity: 100 w/w% (as a reaction product)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crj:CD (SD) IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at receipt: Not reported
- Age a study initiation: 5 weeks
- Weight at study initiation: 123.1-144.5 g (males); 106.9-126.4 g (females)
- Housing: Individually in wire net floor cages made of stainless steel
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Not reported
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ± 10%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
- Air Changes: 10-15 times/hr
Administration / exposure
- Route of administration:
- oral: gavage
- Details on oral exposure:
- PREPARATION OF TEST SUBSTANCE FORMULATION:
-Solvent used: 0.5 w/v% aqueous carboxymethyl cellulose sodium (CMC-Na) solution
-Preparation frequency: More than once for 7 days
-Preparation details: A 0.5 w/v% solution of CMC-Na was prepared with purified water. The test substance was precisely weighed, finely pulverized in a mortar, and suspended while dropping 0.5 w/v% aqueous CMC-Na solution to prepare 10.0, 2.0, and 0.4 w/v%. The preparation was carried out under lighting of a sodium lamp. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Method of Analysis: HPLC
Homogeneity (Relative standard deviation: 5% or less of Target)
Conducted on prepared solutions: 10.0 and 0.5 (w/v%)
Results:
Nominal conc. 10.0 (w/v%)
Actual conc. (w/v%)
Top layer of measurement: 10.0
Middle layer: 10.7
Bottom layer: 10.3
Mean actual conc. (w/v%): 10.3
Relative standard deviation: 3.4%
Nominal conc. 10.05 (w/v%)
Actual conc. (w/v%)
Top layer of measurement: 0.0516
Middle layer: 0.0504
Bottom layer: 0.0508
Mean actual conc. (w/v%): 0.0509%
Relative standard deviation: 1.2%
Stability of the test substance:
There was no change in the infrared absorption spectrum provided by the sponsor, and that measured prior to the dosage period. Also, no change could be seen after the dosage period. The calibration curve showed a correlation coefficient of R=0.999 and good linearity.
Stability in prepared solutions (100 ± 10% of Time Zero)
Conducted on prepared solutions: 10.0 and 0.5 (w/v%)
Results:
Nominal conc. 10.0 (w/v%)
Immediately after preparation: mean conc. 10.3 (w/v%)
3 days after preparation: mean conc. 1.04 (w/v%)
7 days after preparation: mean conc. 9.96 (w/v%)
Rate to the conc. (7 days) measured immediately after preparation: 96.7%
Nominal conc. 0.05 (w/v%)
Immediately after preparation: mean conc. 0.0509 (w/v%)
3 days after preparation: mean conc. 0.0505 (w/v%)
7 days after preparation: mean conc. 0.0487 (w/v%)
Rate to the conc. (7 days) measured immediately after preparation: 95.7% - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 40 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:
- Control and high dose groups consisted of 12 animals/sex, for which 6 animals/sex were used in a 14 day recovery group. Low and middle dose groups consisted of 6 animals/sex.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on no observed effects in a 14-day pretest at 50, 250, and 1000 mg/kg/day.
- Positive control:
- None
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: note than once a day for mortality and moribundity.
DETAILED CLINICAL OBSERVATIONS: Yes/No
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: The day prior to the start of dosing; days 1, 3, 8, 12, 17, 21, 26, and 28 of the dosing period; and on days 1, 5, 10, and 14 of the recovery period. Also once immediately before necropsy.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Once prior to dosing on days 3, 8, 15, and 28 for the dosing period; and on days 4, 8, and 14 for the recovery period.
FOOD EFFICIENCY: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: End of dosing and recovery periods.
- Anaesthetic used for blood collection: ether
- Animals fasted: Yes, overnight (16-20 hrs)
- How many animals: All animals
- Parameters checked in table No. 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: End of dosing and recovery periods.
- Animals fasted: Yes, overnight (16-20 hrs)
- How many animals: All animals
- Parameters checked in table No. 2 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: 16-hr urine sample: day 28 of the dosing period and day 14 of the recovery period. .
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not reported.
- Parameters checked in table No. 2 were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 3) - Statistics:
- For weight, the amount of feed intake, the hematological parameters, blood parameters, urine volume, and organ weight, an equi-variance test of the Bartlett method was performed, and if the equi-variance was recognized at a 5% meaningful level, a one-dimensional arrangement variance analysis was performed. If a meaningful difference was recognized in the variance analysis, a test of the Dunnett method was performed between the medium control group and each dosage group.
If the equi-variance was not recognized, a test of Kruskal-Wallis was performed, and if a meaningful difference was recognized, a nonparametric test of the Dunnett method was performed between the medium control group and each dosage group.
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
- Description (incidence and severity):
- During the recovery period, the amount of feed intake was significantly increased from vehicle control at p<0.05 for males on day 8 and day 14 in the 1000 mg/kg group. This was not considered test substance related as no similar change was seen at the end of the dosing period.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- In males, at the end of the dosing period, the extension of the thromboplastin of the activated part was observed only in the 40 mg/kg group (p<0.05). This was not considered test substance related. At the end of the recovery period, no abnormalities were observed in males. In females, reduction of the average red blood cell volume, the average amount of red blood cell hemoglobin, and the extension of the thromboplastin of the activated part were observed in the 1000 mg/kg group only at the end of the recovery period. These were significantly different from vehicle control at p<0.05. These changes were not considered test substance related as no similar change was seen at the end of the dosing period.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males, at the end of the dosing period, GOT was reduced (p<0.01) and blood sugar was increased (p<0.05) in the 40 mg/kg group, and GOT was reduced in the 200 mg/kg group (p<0.01). These changes were not considered test substance related. In females, at the end of the dosing period, γ-GTP was increased (p<0.01) in the 1000 mg/kg group and GOT was reduced in the 40 mg/kg group (p<0.05). The test substance influence on the increase of γ-GTP was considered very slight without an accompanying tissue change. The change in GOT was not considered test substance related. In males, at the end of the recovery period, choline esterase (p<0.05) and total cholesterol (p<0.01) were increased in the 1000 mg/kg group. In females, at the end or the recovery period, GPT was reduced (p<0.01) in the 1000 mg/kg group. These changes were not considered test substance related.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- In males, at the end of the recovery period, the absolute brain weight was increased (p<0.05) in the 1000 mg/kg group. In females, at the end of the recovery period the absolute liver (p<0.05), kidneys (P<0.05), and adrenal (p<0.01) weights were decreased in the 1000 mg/kg group. These were not considered test substance related as no similar change was seen at the end of the dosing period.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- In females, at the end of the dosing period, the black part (1/6) of the mucous membrane of the glandular stomach was observed in the 40 mg/kg group. This was not considered test substance related. In males, at the end of the recovery period, the swelling increase (1/6) of the spleen was observed in the 1000 mg/kg group. This was not considered test substance related as no similar change was seen at the end of the dosing period.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- In males, at the end of the dosing period, an increase was observed in hyaline droplets in the kidneys (+, 2/6) in the medium control group. In females, at the end of the dosing period, a mineral precipitation (++, 1/6) of the skin and marrow boundary of the kidneys was observed in the medium control group, necrosis (+, 1/1) of the mucous membrane of the fundus gland of the glandular stomach was observed in the 40 mg/kg group, and mineral precipitation (+, 1/6) at the skin and marrow boundary of the kidneys was seen in the 1000 mg/kg group. The mineral precipitation was considered not test substance related as similar changes were observed in the control group. In males, at the end of the recovery period, local necrosis (+, 1/6) of the spleen was seen in the 1000 mg/kg group. This was not considered test substance related as no similar change was seen at the end of the dosing period.
- Histopathological findings: neoplastic:
- not examined
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
Target system / organ toxicity
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- NOEL = 200 mg/kg/day
- Executive summary:
A 28-day repeated oral gavage study with a 14-day recovery period was conducted using groups of 6 male and 6 female Crj:CD (SD) IGS rats per dose level. Rats were 5 weeks of age at study start. Dose concentrations were 0, 40, 200, and 1000 mg/kg/day for the test groups and 0 and 1000 mg/kg for the recovery groups. All rats survived and there were no test substance related effects on clinical signs, body weight and weight gain, feed consumption, hematology at the end of the dosing period, urinalysis, organ weight, and gross pathology.
At the end of the dosing period, γ-GTP was increased in females in the 1000 mg/kg/group. The test substance influence on the increase of γ-GTP was considered very slight without an accompanying tissue change. At the end of the dosing period, mineral precipitation of the skin an marrow boundary of the kidneys was observed in females in the 1000 mg/kg group; however since a similar change was also observed in the control group, it was not considered not test substance related.
In the 1000 mg/kg male recovery animals, increased choline esterase, increased total cholesterol, swelling and local necrosis of the spleen were observed. In females recovery animals, increased feed intake, reduction in the average red blood cell volume and the average amount of red blood cell hemoglobin, extension of the thromboplastin of the activated part, reduction of GPT, and reduced liver, kidney, and adrenal weight were observed on day 8 and day 14. Since no similar changes were observed at the end of the dosing period, these changes were not considered test substance related.
Based on the increased γ-GTP in females in the 1000 mg/kg/group, the NOEL in rats was estimated as 200 mg/kg/day.
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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