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EC number: 443-860-6 | CAS number: 302776-68-7
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: other: Chromosomal damage (clastogenicity)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2003-01-17 until 2003-03-06
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP - Guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- -
- EC Number:
- 443-860-6
- EC Name:
- -
- Cas Number:
- 302776-68-7
- Molecular formula:
- C24 H31 N O4
- IUPAC Name:
- hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland GmbH.
- Age at study initiation: An age range of about 5 - 8 weeks
- Weight at study initiation: Mean weight of about 28 g
- Assigned to test groups randomly: yes
- Housing: For the duration of at least 5 days the animals were housed in Makrolon cages. Before the start of the treatment the animals were transferred to Makrolon cages, type Ml, and housed individually under the same conditions until the end of the test.
- Diet: Standardized pelleted feed (Ratte - Maus Diät, Provimi Kliba SA, Kaiseraugst, Switzerland), ad libitum.
- Water: Drinking water ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): Humidity range of 30 - 70%.
- Photoperiod (hrs dark / hrs light): The day/night rhythm was 12 hours (12 hours light from 6.00 am- 6.00 pm and 12 hours darkness from 6.00 pm - 6.00 am).
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: Due to the insolubility of the test substance in water, DMSO was selected as the vehicle. DMSO was already demonstrated to be suitable in the in vivo micronucleus test. Historical data are also available.
- Concentration of test material in vehicle: The substance was dissolved in DMSO and was administered twice:
- 500 mg test substance/kg body weight or 4 mL/kg body weight of a solution with a concentration of 12.5 g/100 mL.
- 1000 mg test substance/kg body weight or 4 mL/kg body weight of a solution with a concentration of 25 g/100 mL.
- 2000 mg test substance/kg body weight or 4 mL/kg body weight of a solution with a concentration of 50 g/100 mL. - Duration of treatment / exposure:
- Two intraperitoneal administration at a 24-hour interval.
- Frequency of treatment:
- Two intraperitoneal administration at a 24-hour interval.
Animals of the positive control groups were treated only once. - Post exposure period:
- 24 hours after last application
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 male mice per group.
One vehicle control group. - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide (CPP): clastogenic effects
Vincristine (VCR): aneugenic effects
- Justification for choice of positive control(s): Both positive control articles (CPP and VCR) are well-defined clastogens and aneugens respectively.
- Route of administration: Intraperitoneal
- Doses / concentrations:
CPP 20 mg/kg bw , 10 mL test solution
VCR 0.15 mg/ kg bw, 10 mL test solution
Examinations
- Tissues and cell types examined:
- polychromatic erythrocytes from the bone marrow
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: Range-finding assay (see below, in "additional information on results")
TREATMENT AND SAMPLING TIMES (in addition to information in specific fields): Samples of bone marrow from the animals of the vehicle and the dose groups were taken 24 hours after the last treatment.
DETAILS OF SLIDE PREPARATION: After the animals were sacrificed and the bone marrow was prepared according to the method described by Schmid (1976, 1977) and Salamone et al.,(1980), slides were prepared and stained:
The slides were stained in eosin and methylene blue solution for 5 minutes (May Grünwald solution modified = Wrights solution), rinsed in purified water and then placed in fresh purified water for 2 or 3 minutes. They were finally stained in 7.5% Giemsa solution for 15 minutes.
After being rinsed twice in purified water and clarified in xylene, the preparations were mounted using Corbit-Balsam.
METHOD OF ANALYSIS: Microscopic evaluation. Thereby the following parameters were recorded:
1. Number of polychromatic erythrocytes
2. Number of polychromatic erythrocytes containing micronuclei
3. Number of normochromatic erythrocytes
4. Number of normochromatic erythrocytes containing micronuclei
5. Ratio of polychromatic to normochromatic erythrocytes
6. Number of small micronuclei (d < D14) and of large micronuclei (d > D14) (d = diameter of micronucleus, D = cell diameter) - Evaluation criteria:
- The test chemical is considered positive in this assay if the following criteria are met:
1. A dose-related and significant increase in the number of micronucleated polychromatic erythrocytes.
2. The proportion of cells containing micronuclei exceeded both the values of the concurrent negative control range and the negative historical control range.
A test substance is generally considered negative in this test system if:
1. There was no significant increase in the number of micronucleated polychromatic erythrocytes at any dose above concurrent control frequencies.
2. The frequencies of cells containing micronuclei were within the historical control range. - Statistics:
- The statistical evaluation of the data was carried out using the program system MUKERN.
A comparison of the number of micronuclei in polychromatic erythrocytes in the dose groups with the vehicle control group was carried out using the Wilcoxon test (one-sided) for the hypothesis of equal medians. A significance of P < / = 0.05 or P < / =0.01 was used.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
In a pretest for the determination of the acute intraperitoneal toxicity, all animals (male and female) survived the two treatments with 2,000 mg/kg body weight which was recommended as the highest dose according to the OECD Guideline. The clinical signs observed were piloerection, squatting posture and animals in a poor general state. Though there were no distinct symptomatic differences between the male and female animals, only male animals were used in the cytogenetic test.
Therefore, a dose of 2,000 mg/kg body weight was selected as the highest dose in the present cytogenetic study. 1,000 mg/kg and 500 mg/kg body weight were administered as further doses.
RESULTS OF DEFINITIVE STUDY
1. Clinical examinations:
1.1 The two intraperitoneal administrations of the vehicle in a volume of 4 mL/kg body weight were tolerated by all animals without any signs or symptoms.
1.2 Neither the single administration of the positive control substance, cyclophosphamide, in a dose of 20 mg/kg body weight nor that of vincristinein a dose of 0.15 mg/kg body weight caused any evident signs of toxicity.
1.3 The administration of the test substance led to evident signs of systemic toxicity.
2. Microscopic findings:
2.1 The two intraperitoneal administrations of DMSO in a volume of 4 mL/kg body weight led to 1.4 ‰ polychromatic erythrocytes containing micronuclei after the 24-hour sacrifice interval.
2.2 After two administrations of the highest dose of 2,000 mg/kg body weight, 1.1 ‰ polychromatic erythrocytes containing micronuclei were found after 24 hours.
2.3 In the two lower dose groups, rates of micronuclei of about 1.4 ‰ (500 mg/kg group) and 1.6 ‰ (1,000 mg/kg group) were detected.
2.4 With 18.5 ‰ the positive control substance- cyclophosphamide led to the expected clear increase in the number of polychromatic erythrocytes containing mainly small micronuclei.
2.5 With 76.6 ‰ the positive control vincristine responsible for induction of spindle poison effects also led to a clearly enhanced number of polychromatic erythrocytes containing micronuclei with the expected amount of large micronuclei, i.e. 18.7 ‰.
2.6 The number of normochromatic erythrocytes containing micronuclei did not differ to any appreciable extent in the negative control or in the various dose groups.
2.7 A slight and dose-dependent inhibition of erythropoiesis, induced by the treatment of mice with Uvinul A Plus was detected from about 500 mg/kg body weight onward.
Thus, the test substance Hexyl 2-(1-(diethylaminohydroxyphenyl)methanoyl)benzoate did not cause any increase in the rate of micronuclei, even at systemic toxic dosis.
The number of normochromatic or polychromatic erythrocytes containing small micronuclei (d < D/4) or large micronuclei (d D/4) did not deviate from the control value and was within the historical control range.
Applicant's summary and conclusion
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