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EC number: 203-987-8 | CAS number: 112-58-3
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- August 2018 to December 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- This study was performed for the purpose of notification in another region requesting this study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- 2016
- Deviations:
- yes
- Remarks:
- temp. value (18.1°C - 25.2°C) and rel. humidity value (max. of 77%) outside the expected ranges were recorded occasionally times during the study. These differences were considered not to adversely affect the results or integrity of the study.
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- mammalian erythrocyte micronucleus test
Test material
- Reference substance name:
- Dihexyl ether
- EC Number:
- 203-987-8
- EC Name:
- Dihexyl ether
- Cas Number:
- 112-58-3
- Molecular formula:
- C12H26O
- IUPAC Name:
- 1-(hexyloxy)hexane
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH (Address: Sandhofer Weg 7, Sulzfeld D-97633, Germany)
- Age at study initiation: Approximately 7 or 8 weeks (preliminary experiments) or 9 weeks (main test) at the treatment
- Weight at study initiation: 36.5 – 40.3 g (males, preliminary experiment I.)
29.0 – 32.0 g (females, preliminary experiment I.)
36.2 – 38.5 g (males, preliminary experiment II.)
30.0 – 31.5 g (females, preliminary experiment II.)
30.5 – 32.6 g (females, preliminary experiment III.)
26.1 – 29.4 g (females, main test)
The weight variation did not exceed ± 20 percent of the mean weight/sex at the start of the treatment.
- Assigned to test groups randomly: yes
- Fasting period before study: no
- Housing: Type II polypropylene/polycarbonate cages
- Diet (e.g. ad libitum): ssniff(R) SM R/M "Autoclavable complete diet for rats and mice ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.1-25.2°C (target: 22 ± 3°C)
- Humidity (%): 32-77% (target: 30-70%)
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: August 22, 2019 To: September 12, 2019
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: Olive oil
- Amount of vehicle (if gavage or dermal): 5 ml/kg bw - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The necessary amount of the test item was weighed into a calibrated volumetric flask or other appropriate glass container; the required volume of vehicle was added and mixed using a magnetic stirrer to obtain homogenous formulations. The concentrations of the test item formulations were selected to assure the same dosing volumes in mice for all dose levels (the treatment volume was 5 mL/kg bw in case of the negative control (in the preliminary toxicity test II. and III.) and the test item treated groups in the preliminary experiments; the treatment volume was 5 mL/kg bw in case of the negative control and the test item treated groups and 10 mL/kg bw in case of the positive control group in the main study). All the dose levels were expressed in terms of the weight of the test item in the formulations. - Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- Dose / conc.:
- 2 000 mg/kg bw/day
- No. of animals per sex per dose:
- 5
High dose group: 5+2 (Two additional mice were dosed in the High dose group to replace any animal which may die before the scheduled sacrifice time or serve as additional sample in case of borderline results. One additional animal was used for evaluation, because one animal was found dead in the High dose group before necropsy (Day 15). Bone marrow smears were also prepared from the other additional mouse, but those slides were not evaluated.) - Control animals:
- yes
- Positive control(s):
- Cyclophosphamide at 60 mg/kg bw (10 ml/kg bw) at one occasion by the ip route
Examinations
- Tissues and cell types examined:
- Bone marrow
- Details of tissue and slide preparation:
- Bone marrow was obtained from two exposed femurs of each surviving mouse immediately after sacrifice. The bone marrow was flushed into a sterile centrifuge tube from of each pair of femurs with foetal bovine serum (5 mL) using a syringe and needle. After mixing, the cell suspension was concentrated by a gentle centrifugation and the supernatant was discarded. Smears of the cell pellet were made on standard microscope slides (3 slides / animal). (Note:Bone marrow smears were prepared from the replacement mice. The bone marrow smears of one of the additional animal of High dose group was scored as it was necessary for the proper evaluation of the study. The bone marrow smears of the other additional animal were not scored. However, all the processed slides will be archived in the raw data.) Slides were air-dried at room temperature for approximately 24 hours. Dried slides were fixed in methanol for a minimum of 5 minutes and allowed to air-dry. Slides were stained with 10 % Giemsa solution for 18 minutes then thoroughly rinsed with distilled water, and then air-dried at room temperature overnight. After staining, coverslips were mounted on them.
- Evaluation criteria:
- Criteria for Identification of Micronucleated Erythrocytes:
- A bluish mauve strongly coloured uniform round or oval particle in the cell.
- The particle should be large enough for the colour to be recognisable, and it should be located inside the cells. Areas with micronucleus-like particles outside the cells should not be used for analysis.
- During focusing, the particle should stay uniform in colour /light refraction and shape within a large interval and focus in the same plane as the erythrocyte.
- The unit of damage is deemed to be the cell, and therefore cells with two or more micronuclei will be counted as single micronucleated cells.
The Micronucleus Test was considered valid if it met the following criteria:
- the frequency of micronucleated polychromatic erythrocytes found in the negative (vehicle) control was within the range of historical laboratory control data,
- the positive control item produced biologically relevant increase in the number of micronucleated polychromatic erythrocytes,
- each treated and control group included at least 5 analysable animals. - Statistics:
- Kruskal-Wallis Non Parametric ANOVA test at the Test Site
Results and discussion
Test results
- Sex:
- female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- Minor clinical signs related to treatment were observed considered to be treatment related. Increased in the liver weights by 44.2% in the High dose were observed, clearly demonstrating a systemic dose related effect as proof of systemic exposure.
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: up to 2000 mg/kg bw/d
- Solubility: soluble in vehile up to 400 mg/ml
- Clinical signs of toxicity in test animals:
- Evidence of cytotoxicity in tissue analysed:
- Rationale for exposure:
- Harvest times:
- High dose with and without activation:
- Other:
RESULTS OF DEFINITIVE STUDY
- Types of structural aberrations for significant dose levels (for Cytogenetic or SCE assay):
- Induction of micronuclei (for Micronucleus assay):
- Ratio of PCE/NCE (for Micronucleus assay):
- Appropriateness of dose levels and route:
- Statistical evaluation:
Applicant's summary and conclusion
- Conclusions:
- Di-n-hexyl ether test item was shown to have significant systemic exposure, it did not cause statistically or biologically significant increases in the frequency of micronucleated polychromatic erythrocytes in mice. Thus, there was no evidence of any genotoxic activity of the test item under the conditions of this study.
- Executive summary:
An in vivo mammalian erythrocyte micronucleus test was conducted according to OECD guideline 474 (Varga-Kanizsai B; 2019). NMRI mice received daily oral doses of 500, 1000 or 2000 mg/kg bw for 14 days. The highest dose level was chosen based on the results of preliminary studies. Minor clinical signs related to treatment were observed which were considered to be treatment related. Increaseds in the liver weights by 44.2% in the High dose were observed, clearly demonstrating a systemic dose related effect as proof of systemic exposure. Treatment with the test item did not affect the ratios of polychromatic erythrocytes among total erythrocytes. No statistically significant or biologically relevant increases in the frequency of micronucleated polychromatic erythrocytes (MNPCE) were seen for test item treated mice in any dose groups at any sampling time when compared to the corresponding negative (vehicle) control values. In conclusion, there was no evidence of any genotoxic activity of the test item under the conditions of this study.
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