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EC number: 701-129-1 | 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
- Study period:
- 2002-06-24 to 2003-06-20
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP Guideline Study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 21 September 1998
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
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 Italy s.r.l; 33049 San Pietro al Natisone (UD); Italy
- Age at study initiation: 27 - 29 days
- Weight at study initiation: males: 89 - 95 g; females. 80 - 95 g (nulluparous and non-pregnant)
- Fasting period before study: no
- Housing: polycarbonat cages, 59x38.5x20 cm with stainless steel mesh lid floor (Code 1352 G, Techniplast Gazzeda S.a.r.l, Buggugiate, Varese); 5 animals of one sex per cage;
- Diet: laboratory rodent pelleted diet; Altromin MT, Altromin D-32770 Lage, Postfach 1120, Germany; ad libitum
- Water: drinking water ad libitum
- Acclimation period: overall 17 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 2 °C
- Humidity: 55 +/- 15 %
- Air changes: approximately 15 to 20 air changes per hour
- Photoperiod: 12 hours light/12 hours dark per day
IN-LIFE DATES: From: 2002-06-24 To: 2002-10-28
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Required amount of test item was dissolved in distilled water. Formulations were prepared daily.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- The required amount of the test item was dissolved in the vehicle (distilled water). The formulations were prepared daily (concentrations of 2.5, 7.5 and 22.5 mg/mL).
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 150, 450 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 males, 10 females per dose in the treatment groups, 5 animals per sex and per dose in the recovery groups
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on the results of a range finding pre-test
- Rationale for animal assignment: randomizing
- Rationale for selecting satellite groups: control and high dose group included 5 additional animals per sex
- Post-exposure recovery period in satellite groups: 4 weeks
- Ratiuonale for animals assignment: randomizing:
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on the day of allocation to treatment groups , on the day of that treatment commenced, weekly thereafter and just prior to necropsy.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: All animals prior to commencement of the study, during week 12 of treatment
- Dose groups that were examined: Control and high dose animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Once during week 13 of the treatment period, once during week 4 of the recovery period;
- Anaesthetic used for blood collection: Yes (light ether anaesthesia)
- Animals fasted: Yes
- How many animals: all male and female animals
- Parameters checked: Haematocrit, haemoglobin, red blood cell count, reticulocyte count, mean red blood cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white blood cell count, differential leucocyte count (neutrophils, lymphocytest, eosinophils, basophils monocytes, large unstained cells), abnormalities of the blood film, platelets, prothrombin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Once during week 13 of the treatment period, once during week 4 of the recovery period;
- Animals fasted: Yes
- How many animals: all male and female animals
- Parameters checked: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, blood urea nitrogen, creatinine, glucose, albumin total bilirubin, total cholesterol, total protein sodium, potassium, calcium, chloride
URINALYSIS: Yes
- Time schedule for collection of urine: Once during week 13 of the treatment period, once during week 4 of the recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: Appearance, volume, specific gravity, pH, protein, total reducing substances, glucose, ketones, bilirubin, urobilinogen, blood, sediment
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once before commencement of treatment and one week thereafter
- Dose groups that were examined: each animal
- Battery of functions tested: sensory activity / grip strength / motor activity / other: gait, tonic movements, clonic movements
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Organs examined in necropsy and histopathology:
Abnormalities, adrenal glands, aorta, bone marrow (from sternum), brain, caecum, colon, duodenum, eyes, epididymides, femur with joint, heart, ileum (including Peyer's patches), jejeunum, kidneys, liver, lungs, lymph nodes-mesenteric, lymph nodes-cervical, mammary area, oesophagus, ovaries, pancreas, parathyroid gland; pituitary gland, prostate gland, rectum, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal column, spinal cord, spleen, stomach/forestomach, testes, thymus (when present), thyroid, trachea urinary bladder, uterus - Statistics:
- For continuous variables the significance of the differences amongst groups was assessed by analysis of variance. Differences between each treated group and the control group were assessed by Dunnett's test using a pooled error variance. The homogeneity of the data was verified by Bartlett's test before Dunnett's test. If data were found to be inhomogeneous a Modified t test (Cochran and Cox) was applied. The mean values, standard deviations and statistical analysis were calculated from the actual values in the computer without rounding off. A statistical analysis of histopathological findings was not carried out as indicated in the protocol, and, therefore, this is a deviation from protocol.
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):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, treatment-related
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- effects observed, treatment-related
- 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 SIGNS AND MORTALITY: No mortality occurred during the study. No significant daily post-dose observations were noted during the study. Detailed clinical signs with neurotoxicity assessment did not show any signs which could be correlated to the treatment with the test item.
BODY WEIGHT AND WEIGHT GAIN: No changes of toxicological significance were observed in body weight.
OPHTHALMOSCOPIC EXAMINATION: No significant findings were seen at the ophthalmic examination performed at the end of the study.
HAEMATOLOGY: No changes were seen in haematological parameters.
CLINICAL CHEMISTRY: a statistically significant increase in alkaline phosphatase was observed in high dose females at the end of the treatment period. This change, within the range of historical control data, was no longer present at the end of the recovery period. No other significant changes were noted.
URINALYSIS: An increase in urine volume, statistically significant in all treated males and high dose females, was observed at the end of treatment. This difference, within the range of historical control data, was no longer evident at the end of the recovery period.
NEUROBEHAVIOUR: Detailed clinical signs with neurotoxicity assessment did not show any signs which could be correlated to the treatment with the test item.
ORGAN WEIGHTS: No significant variations were observed in the weights of the organs.
GROSS PATHOLOGY: No macroscopic finding was described that could be considered correlated with the administration of the test item.
HISTOPATHOLOGY: NON-NEOPLASTIC: Keratinised stomach acanthosis was significantly greater than background degree in two animals from the high dose group (450 mg/kg bw/day). At this incidence this lesion is not considered treatment related.
OTHER FINDINGS: other occasional findings are those that are commonplace in the tissues of young laboratory rats and none are related to treatment.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 450 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The NOEL in this study was 450 mg/gk bw.
- Executive summary:
The test substance has been investigated with regard to its toxicity after repeated exposure in a subchronic study in accordance with OECD guideline 408 in male and female SD rats. 10 animals of either sex received vehicle, 50, 150, or 450 mg/kg bw for 90 consecutive days. A recovery high dose group was left without treatment for another 14 days. No effects were observed on body weights, food consumption, organ weights, macroscopic examination, functional observational battery, hematology and histopathology. Urine volume and plasma AP was increased in both sexes but the effects were reversible in the recovery group, the AP values were still in the range of the historical controls and none of the effects was accompanied by corresponding organ/clinical effects. Therefore they were considered to be toxicologically and biologically not relevant. The NOEL was 450 mg/kg bw.
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