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EC number: 700-330-1 | CAS number: 433733-92-7
- 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
Endpoint summary
Administrative data
Description of key information
Wistar rats were treated with the test substance for 28 consecutive days by daily oral gavage at dose levels up to 1000 mg/kg/day.
In clinical biochemistry measurements cholesterol was statistically significant decreased in males at 1000 mg/kg/day. Since the cholesterol levels were within the range considered normal for rats of this age and strain and since no corroborative findings were noted in microscopic examination, this finding was considered not toxicological relevant.
No toxicologically significant changes were noted in any of the remaining parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, macroscopic examination, organ weights and microscopic examination).
From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for the test substance of 1000 mg/kg/day was established.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 03 June - 01 July 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, July 2000.
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approximately 6 weeks.
- Weight at study initiation: around 160 g males, 135 g females
- Fasting period before study:
- Housing: Group housing of 5 animals per sex in Macrolon cages (MIV type, height 18 cm; during overnight activity monitoring individual housing in MIII type; height 15 cm.) with sterilized sawdust as bedding material and paper as cage-enrichment. No cage-enrichment was provided during overnight activity monitoring.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: At least 5 days before the start of treatment under laboratory conditions
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 – 22.3
- Humidity (%): 31 - 89
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Details on route of administration:
- Oral gavage, using a plastic feeding tube.
Formulations were placed on a magnetic stirrer during dosing. - Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing, and were homogenized to visually acceptable levels. No correction was made for the purity of the test substance.
VEHICLE
- Water - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of formulations were analyzed on a single occasion during the in-life phase for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6 hours was also determined (highest and lowest concentration).
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- vehicle
- No. of animals per sex per dose:
- 5
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: based on the pilot experiment
- Rationale for animal assignment (if not random): random - Positive control:
- not required
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality / Viability
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly.
FOOD CONSUMPTION: Weekly.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination at the end of the treatment
- Anaesthetic used for blood collection: Yes, iso-flurane anaesthesia
- Animals fasted: Yes, overnight (with a maximum of 20 hours) before blood sampling
- How many animals: all
- Parameters examined:
White blood cells
Differential leucocyte count
neutrophils, lymphocytes, monocytes,
eosinophils, basophils
Red blood cells
Reticulocytes
Red blood cell distribution width
Haemoglobin
Haematocrit
Mean corpuscular volume
Mean corpuscular haemoglobin
Mean corpuscular haemoglobin concentration
Platelets
Prothrombin time
Activated Partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination at the end of the treatment
- Animals fasted: Yes, overnight (with a maximum of 20 hours) before blood sampling
- How many animals: all
- Parameters examined:
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Total Protein
Albumin
Total Bilirubin
Urea
Creatinine
Glucose
Cholesterol
Sodium
Potassium
Chloride
Calcium
Inorganic Phosphate
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: motor activity, hearing ability, pupillary reflex, static righting reflex and grip strength - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. Tissues/organs mentioned in parentheses were not examined by the pathologist since there were no changes in macroscopic appearance indicative of (potential) toxicity.
Identification marks: not processed
Adrenal glands
(Aorta)
Brain [cerebellum, mid-brain, cortex]
Caecum
Cervix
(Clitoral gland)
Colon
Duodenum
Epididymides
(Eyes with optic nerve [if detectable] and
Harderian gland)
(Female mammary gland area)
(Femur including joint)
Heart
Ileum
Jejunum
Kidneys
(Larynx)
(Lacrimal gland, exorbital)
Liver
Lung, infused with formalin
Lymph nodes - mandibular, mesenteric
(Nasopharynx)
(Oesophagus)
Ovaries
(Pancreas)
Peyer's patches [jejunum, ileum] if detectable
(Pituitary gland)
(Preputial gland)
Prostate gland
Rectum
(Salivary glands - mandibular, sublingual)
Sciatic nerve
Seminal vesicles
(Skeletal muscle)
(Skin)
Spinal cord -cervical, midthoracic, lumbar
Spleen
Sternum with bone marrow
Stomach
Testes
Thymus
Thyroid including parathyroid [if detectable]
(Tongue)
Trachea
Urinary bladder
Uterus
Vagina
All gross lesions
ORGAN WEIGHTS:
Adrenal glands
Brain
Epididymides
Heart
Kidneys
Liver
Spleen
Testes
Thymus
HISTOPATHOLOGY: Yes
The following slides were examined by a pathologist:
- all tissues collected at the scheduled sacrifice from all Main group 1 and 4 animals,
- all gross lesions.
All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings. - Statistics:
- - If the variables could be assumed to follow a normal distribution, the Dunnett-test1 (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test2 (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test3 was applied to frequency data.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs of toxicity were noted during the observation period.
Incidental findings such as alopecia (in the neck or on the right cheek), scabs (in the neck) and brown staining were noted in individual animals. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological significance. - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption before or after allowance for body weight was similar between treated and control animals.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant changes occurred in haematological parameters of treated rats.
Statistically significant changes were noted in females only. Slightly decreased monocyte percentage was noted at 1000 mg/kg/day and increased red blood cell distribution width (RDW) was noted at 50 mg/kg/day. These findings were considered to be of no toxicological significance as they remained within the range considered normal for rats of this age and strain and occurred in the absence of a clear treatment-related distribution. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Cholesterol was decreased in males in a dose related distribution. Statistical significance was noted at 1000 mg/kg/day only.
A slight increase of sodium level was noted in females at 50 and 150 mg/kg/day. This finding was considered to be of no toxicological significance as it occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain. - Urinalysis findings:
- not specified
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
The variation in motor activity did not indicate a relation with treatment. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No toxicologically significant changes were noted in organ weights and organ to body weight ratios.
Absolute and relative spleen weights of females at 50 and 150 mg/kg/day were noted to be increased. These findings in females occurred as a result of a slightly lower control value and in the absence of a dose related distribution. A decreased relative spleen weight of males at 1000
mg/kg/day was noted, which was well within the range considered normal for rats of this age and strain. No corroborative findings were noted in macroscopic or microscopic examination.
Therefore changes in spleen weight were considered not to be toxicologically significant. Other finding was a decreased absolute brain weight in females at 150 mg/kg/day. This finding occurred in the absence of a dose related distribution and remained within the range considered
normal for rats of this age and strain. Therefore this finding was considered to be not toxicological relevant. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Necropsy did not reveal any toxicologically relevant alterations.
Incidental findings were considered to be of no toxicological significance since they occurred in
the absence of a treatment-related distribution, and are occasionally seen among rats used in
these types of studies. These findings included, nodules in the liver, epididymides, diaphragm
and lungs, pelvic dilation, scab formation, growing together of lungs with aorta, pale
discolouration of lungs and fluid in uterus. - Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no microscopic findings recorded which could be attributed to treatment with the test substance.
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats. - Details on results:
- MORTALITY
No mortality occurred during the study period.
CLINICAL SIGNS
No clinical signs of toxicity were noted during the observation period.
Incidental findings such as alopecia (in the neck or on the right cheek), scabs (in the neck) and brown staining were noted in individual animals. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological significance.
BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
FOOD CONSUMPTION
Food consumption before or after allowance for body weight was similar between treated and control animals.
HAEMATOLOGY
No toxicologically relevant changes occurred in haematological parameters of treated rats.
Statistically significant changes were noted in females only. Slightly decreased monocyte percentage was noted at 1000 mg/kg/day and increased red blood cell distribution width (RDW) was noted at 50 mg/kg/day. These findings were considered to be of no toxicological significance as they remained within the range considered normal for rats of this age and strain and occurred in the absence of a clear treatment-related distribution.
CLINICAL CHEMISTRY
Cholesterol was decreased in males in a dose related distribution. Statistical significance was noted at 1000 mg/kg/day only.
A slight increase of sodium level was noted in females at 50 and 150 mg/kg/day. This finding was considered to be of no toxicological significance as it occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain
NEUROBEHAVIOUR
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
The variation in motor activity did not indicate a relation with treatment.
ORGAN WEIGHTS
No toxicologically significant changes were noted in organ weights and organ to body weight ratios.
Absolute and relative spleen weights of females at 50 and 150 mg/kg/day were noted to be increased. These findings in females occurred as a result of a slightly lower control value and in the absence of a dose related distribution. A decreased relative spleen weight of males at 1000 mg/kg/day was noted, which was well within the range considered normal for rats of this age and strain. No corroborative findings were noted in macroscopic or microscopic examination. Therefore changes in spleen weight were considered not to be toxicologically significant.
Other finding was a decreased absolute brain weight in females at 150 mg/kg/day. This finding occurred in the absence of a dose related distribution and remained within the range considered normal for rats of this age and strain. Therefore this finding was considered to be not toxicological relevant
GROSS PATHOLOGY
Necropsy did not reveal any toxicologically relevant alterations.
Incidental findings were considered to be of no toxicological significance since they occurred in the absence of a treatment-related distribution, and are occasionally seen among rats used in these types of studies. These findings included, nodules in the liver, epididymides, diaphragm and lungs, pelvic dilation, scab formation, growing together of lungs with aorta, pale discolouration of lungs and fluid in uterus.
HISTOPATHOLOGY
There were no microscopic findings recorded which could be attributed to treatment with the test substance.
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Critical effects observed:
- not specified
- Conclusions:
- Wistar rats were treated with the test substance for 28 consecutive days by daily oral gavage at dose levels up to 1000 mg/kg/day.
In clinical biochemistry measurements cholesterol was statistically significant decreased in males at 1000 mg/kg/day. Since the cholesterol levels were within the range considered normal for rats of this age and strain and since no corroborative findings were noted in microscopic examination, this finding was considered not toxicological relevant.
No toxicologically significant changes were noted in any of the remaining parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, macroscopic examination, organ weights and microscopic examination).
From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for the test substance of 1000 mg/kg/day was established.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- exposure considerations
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Justification for type of information:
- The substance is received onto the site and it is chemically converted into the active pharmaceutical ingredient. The substance is chemically converted into the active pharmaceutical ingredient in a system designed to ensure rigorous containment of the substance. Reaction step is carried out in closed system. Charging takes place in a ventilated keg unloading booth. The dust produced by the operation is extracted. Operators are trained in the procedure and also PSS training is performed. Personal protective clothing is specified as per PSS. The waste AHT packaging is placed into a waste container which is fitted with the appropriate WDRF label and sent for disposal.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- exposure considerations
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Justification for type of information:
- The substance is received onto the site and it is chemically converted into the active pharmaceutical ingredient. The substance is chemically converted into the active pharmaceutical ingredient in a system designed to ensure rigorous containment of the substance. Reaction step is carried out in closed system. Charging takes place in a ventilated keg unloading booth. The dust produced by the operation is extracted. Operators are trained in the procedure and also PSS training is performed. Personal protective clothing is specified as per PSS. The waste AHT packaging is placed into a waste container which is fitted with the appropriate WDRF label and sent for disposal.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- exposure considerations
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
- Justification for type of information:
- The substance is received onto the site and it is chemically converted into the active pharmaceutical ingredient. The substance is chemically converted into the active pharmaceutical ingredient in a system designed to ensure rigorous containment of the substance. Reaction step is carried out in closed system. Charging takes place in a ventilated keg unloading booth. The dust produced by the operation is extracted. Operators are trained in the procedure and also PSS training is performed. Personal protective clothing is specified as per PSS. The waste AHT packaging is placed into a waste container which is fitted with the appropriate WDRF label and sent for disposal.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
The substance is received onto the site and it is chemically converted into the active pharmaceutical ingredient. The substance is chemically converted into the active pharmaceutical ingredient in a system designed to ensure rigorous containment of the substance. Reaction step is carried out in closed system. Charging takes place in a ventilated keg unloading booth. The dust produced by the operation is extracted. Operators are trained in the procedure and also PSS training is performed. Personal protective clothing is specified as per PSS. The waste AHT packaging is placed into a waste container which is fitted with the appropriate WDRF label and sent for disposal.
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