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EC number: 926-195-0 | CAS number: 1176284-65-3
- 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
In repeated oral dose toxicity testing, no significant toxicity was observed.
Key value for chemical safety assessment
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:
- 2016-2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Guideline study under GLP
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- CiToxLab Hungary Ltd. H-8200 Veszprém, Szabadságpuszta, Hungary
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10 weeks
- Weight at study initiation: Males: 360-392 g, Females: 228-261 g
- Fasting period before study: no, fasting only before sacrifice
- Housing: males housed in groups of 4, in polycarbonate cages. Females housed singly during and after mating. Lignocell (R) and Arbocel (R) natural crinklets
- Diet (e.g. ad libitum): at lib, ssniff (R)
- Water (e.g. ad libitum): ad lib, municipal water supply
- Acclimation period: at least 5 days
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/3
- Humidity (%): 30-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: - Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): appropriate vehicle for oily liquid test material
- Concentration in vehicle: 100, 300 and 1000 mg/kg bw/d
- Amount of vehicle (if gavage): stability measured at concentrations up to 250 mg/ml at room temperature.
- Lot/batch no. (if required): BCBQ0052V, Sigma-Aldrich
- Analytical verification of doses or concentrations:
- yes
- Remarks:
- See Analytical Report #16-178-316AN. Sarvari, Z., 22 March 2017. Analysis by LC-MS. Stable in PEG 400 for 16 days at room temperature (104% recovery). Stock solution stable for 7 days at 5 degrees C.
- Details on analytical verification of doses or concentrations:
- Analysed by LC-MS.
HPLC-MS: Thermo-Finnigan Surveyor HPLC with LCQ Duo MS detector
Balance: Sartorius BP221S
Water purification system: MILLIPORE, DIRECT Q 8 UV
Analytical Technique: LC-MS
Column: Luna CN, 50×4.6 mm, 3 µm
Column temperature: 25 °C
Mobile Phase: Methanol : water = 8:2 +0.1% acetic acid
Flow: 0.5 mL/min
Detector: SIM (409.1 m/z, negative ion)
Linearity test 1: Y = -50958.8+286873*X+8325.51*X^2 R^2 = 0.9993 W: Equal.
Linearity test 2:
Y = -689226+836889*X R^2 = 0.9955 W: 1/X
Recovery and Precision of Analytical test: 93-104%
Stabillity of Test Item in Vehicle: 104-109% - Duration of treatment / exposure:
- 28 days for males, 34-44 days for females
- Frequency of treatment:
- once daily, 7 days per week.
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 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:
- 5
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to first dose, and at least weekly
BODY WEIGHT: Yes
- Time schedule for examinations: at randomisation, before treatment, at day 0, weekly and at necropsy. Females also at GD0, 3, 10, 17 and 20 and at PPD 0 and 4.
HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (pentobarital)
- Animals fasted: Yes, prior to sacrifice
- How many animals:
- Parameters checked in table [No.?] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals:
- Parameters checked in table [No.?] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: Urine sampling will be performed prior to necropsy by placing the selected animals in metabolic cages for approximately 16 hours.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
IMMUNOLOGY: No
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, on the control and high dose group animals.
Name: Euthanimal® (40% Pentobarbital sodium)
Batch No.: 1409236-06
Expiry Date: September 2017
Produced by: Alfasan Netherland BW, Kuipersweg 9, Woerden
Storage: Room temperature
Purpose of use: Euthanasia - Other examinations:
- Functional Observation Battery on 5 animals/group.
Body and organ weight: At the time of termination, body weight and weight of the following organs of all adult animals will be determined:
uterus (including cervix), testes, epididymides, prostate, seminal vesicles with coagulating glands, brain, heart, kidneys, liver, spleen and thymus, adrenals, ovaries, thyroids with parathyroids. Testes and epididymides will be weighed individually. Individual and/or paired absolute organ weight will be reported for each animal and adjusted for the body and brain weights. Paired organ weights as applicable will be summarised. Relative organ weight (to body and brain weight) will be calculated and reported.
The number of implantation sites and of corpora lutea will be recorded in the females as applicable. - Statistics:
- Data is collected using software PROVANTIS v.9. Statistical analysis is performed with the program package SPSS PC+4.0 (SPSS Hungary Kft, Budapest) or SAS v9.2 (when using Provantis).
In case of the SPSS PC+4.0 program package, the heterogeneity of variance between groups will be checked by Bartlett's test. Where no significant heterogeneity is detected, a one-way analysis of variance (ANOVA) is carried out. If the obtained result is significant, then Duncan's Multiple Range test is used to assess the significance of inter-group differences. Where significant heterogeneity is found, the normal distribution of data is examined by Kolmogorow-Smirnow test. In the case of non- normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance is applied. If a positive result is detected, the inter-group comparisons are performed using Mann-Whitney U-test. The Chi-squared test will be used for non-continuous data.
In case of the SAS 9.2 software package (within the validated Provantis system) the following decision tree is applied automatically for statistical evaluation of continuous numeric data. The normality and heterogeneity of variance between groups will be checked by Shapiro-Wilk and Levene tests using the most appropriate data format (log- transformed when justified). Where both tests show no significant heterogeneity, an Anova / Ancova (one-way analysis of variance) test is carried out. If the obtained result is positive, Dunnett (Multiple Range) test is used to assess the significance of inter- group differences; identifying differences of <0.05 or <0.01 as appropriate. - Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One control group male was found dead on day 17, due to technical error (perforation of the esophagus, confirmed at necropsy).
- Body weight and weight changes:
- no effects observed
- 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:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean prothrombin time was significantly decreased (p<0.05) in mid and high dose males, but the treat ed group values were in the normal control range, and there was no clear dose response. A similar trend was noted in females, but didn't reach statistical significance. These effects are not considered biologically relevant or a test item related effect.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Glucose concentration was significantly increased (p<0.01) in mid and high dose males, but the treat ed group values were in the normal control range. These effects are not considered toxicologically significant or related to treatment.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver weight (absolute and relative) was significantly increased (p,0.05) in both sexes at the high dose. For males (but not females) in the high dose group, this liver weight was just above the historical control range. Liver microscopic appearance and liver function tests remained unaffected. These effects are not considered a test item related adverse effect. There were significant decreases in the absolute weight of brain and epididymus for all test item related groups (males). Absolute weight of spleen was decreased significantly in high dose males, and that of the thumus in mid dose males. These were within the historical control range, with no evidence of histopathology. These were not considered a test item related adverse effect.
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- .
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- All high dose males showed a minimal increase in number of eosinophilic droplets in the kidney, compared with normal background presence in control group males. These cytoplasmic/luminal droplets had similar size to those noted in controls. Droplets were predominantly located in the proximal tubul es of the cortex. No accompanying degenerative/necrotic and inflammatory changes were recorded.
In the mid dose males, there was reduced sperm content and an occurrence of spermatocele in the epididymis (1/5) and dilation of renal tubule (1/5). In control males, there was inflammation of the prostate gland (3/5) this also occurred in 2/5 high dose males. In one high dose female, congestion/ haemorrhage of the thumus occurred. - Histopathological findings: neoplastic:
- not examined
- 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: No significant toxicity observed at the highest dose administered.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- In an OECD 422 guideline study (28-day repeated dose toxicity and reproductive toxicity screening study) in Wistar rats at doses of the test material of 100, 300 and 1000 mg/kg bw/day, there were no adverse effects noted. There were minor changes in organ weights of liver and kidney of both sexes, and in males for epididymus, brain and spleen, but these were not associated with impaired function or histopathology findings. There was no reproductive toxicity observed. The conclusion is that the substance does not exert toxic effects at any dose tested under these conditions. The NOAEL for repeated dose toxicity effects is 1000 mg/kg bw/day.
Reference
ANALYSIS OF DOSE FORMULATIONS:
The measured concentrations of ZWA 5496/100 evaluated for each dose group varied between 93% and 106% of the nominal value. No test item was detected in the control samples at any occasion. These results were within the acceptable range (90% - 110% of the nominal concentration) and were considered to be suitable for the study purposes.
All test item formulation samples were found to be homogeneous. Formulations were considered to be adequately stable under the study conditions.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- adequate
- System:
- other: no toxicity observed
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
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
Endpoint conclusion
- Endpoint conclusion:
- no study available
Mode of Action Analysis / Human Relevance Framework
Not applicable
Additional information
In repeated oral (gavage) dose toxicity testing in the rat for 28 days according to the OECD 422 protocol, no significant toxicity was observed. The NOAEL is greater than 1000 mg/kg bw/d, the highest dose tested.
Justification for classification or non-classification
In repeated oral (gavage) dose toxicity testing in the rat for 28 days according to the OECD 422 protocol, no significant toxicity was observed. The NOAEL is greater than 1000 mg/kg bw/d. The criteria for Regulation EC No. 1272/2008 for classification for specific organ toxicity, repeated exposure, are not met. The substance is not classified.
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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