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EC number: 619-372-6 | CAS number: 98730-04-2
- 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
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- Nanomaterial pour density
- Nanomaterial photocatalytic activity
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- 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
Key value for chemical safety assessment
Genetic toxicity in vivo
Description of key information
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 03 March 1986 to 22 September 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Two part main experiment: In the first part a single dose of 5000 mg/kg was administered to 3 groups of 8 male and 8 female Chinese hamsters. The groups were killed after 16, 24, and 48 hours. Three same sized negative control groups were treated with the vehicle and also killed after 16, 24, or 48 hours. The sensitivity of the test system was checked by treating one further group with 64 mg/kg of the known mutagen Cyclophosphamide (CPA). The animals of this group were killed 24 hours after treatment. Analytical purity: 93.9%
In the second part three groups of 8 male and 8 female hamsters were treated with a single dose of 1250, 2500, or 5000 mg/kg of CGA 154281 and killed after 24 hours. Negative and positive control groups were used. After sacrifice the bone marrow from the shafts of both femurs was removed and smears were prepared on slides. Routinely the slides of five animals/sex/dose were stained with May-Grunwald solution and scored for micronuclei. As an exception, the slides from 3 males and 7 females which were killed after 16 hours (part 1) were scored, since only three males in each group furnished well differentiated cells. From each animal the ratio of polychromatic to normochromatic erythrocytes was determined as an indicator for toxic effects on the erythropoiesis and 1000 polychromatic erythrocytes were scored for micronuclei. - GLP compliance:
- yes
- Type of assay:
- micronucleus assay
- Species:
- hamster, Chinese
- Strain:
- other: Random outbred strain
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 3 groups each consisting of 8 male and 8 female Chinese hamsters.
TEST ANIMALS
- Age at study initiation: females 6-10 weeks, males 4-9 weeks
- Weight at study initiation: females 22-32 g, males 20-35 g
- Diet: NAFAG No.924
- Water: Tap water ad libitum
- Acclimation period: 4-5 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22-23°C
- Humidity: 52-59%
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 03 March 1986 To: 22 September 1986 - Route of administration:
- oral: gavage
- Vehicle:
- 0.5% aqueous carboxymethylcellulose (CMC).
- Details on exposure:
- Part 1: The different groups of animals were killed after 16, 24, and 48 hours.
Part 2: The different groups of animals were killed after 24 hours. - Duration of treatment / exposure:
- 16 to 48 hours
- Frequency of treatment:
- Single dose
- Post exposure period:
- None.
- Remarks:
- Doses / Concentrations:
1250, 2500 or 5000 mg/kg
Basis:
nominal conc. - No. of animals per sex per dose:
- 8
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide (CPA)
- Route of administration: oral gavage
- Doses / concentrations: 64 mg/kg - Tissues and cell types examined:
- After sacrifice the bone marrow from the shafts of both femurs was removed and smears were prepared on slides.
- Details of tissue and slide preparation:
- Routinely the slides of five animals/sex/dose were stained with May-Grunwald solution and scored for micronuclei. As an exception, the slides from 3 males and 7 females which were killed after 16 hours (part 1) were scored, since only three males in each group furnished well differentiated cells.
- Evaluation criteria:
- From each animal the ratio of polychromatic to normochromatic erythrocytes was determined as an indicator for toxic effects on the erythropoiesis and 1000 polychromatic erythrocytes were scored for micronuclei.
- Statistics:
- Chi-Square test used
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- In both parts of the main experiment all hamsters survived. At all sampling times (16, 24, and 48 hours) and at all dose levels (5000, 2500, and 1250 mg/kg) no statistically significant increase of micronucleated polychromatic erythrocytes (PCEs) was observed when compared to the negative control. In the positive control groups the percentage of micronucleated PCEs was statistically significant increased, thus demonstrating the sensitivity of the test system.
- Conclusions:
- Interpretation of results (migrated information): negative
Under the given experimental conditions no evidence for a clastogenic or aneugenic activity of CGA154281 was observed in vivo. - Executive summary:
CGA154281 technical, Benoxacor, was administered by gavage to Chinese hamsters to evaluate any mutagenic activity on polychromatic erythrocytes in bone marrow cells, in vivo. In the first experiment the highest dose of 5000 mg/kg was administered and animals sacrificed 16, 24 or 48 hours later. In the second assay, doses of 1250, 2500 and 5000 mg/kg were administered and animals sacrificed after 24 hours exposure.
In the first assay, bone marrow smears showed no significant increase in micronucleated polychromatic erythrocytes.
In the second assay, bone marrow smears showed no significant increase in micronucleated polychromatic erythrocytes.
No evidence of mutagenic effects were found in the Chinese hamster after oral administration of Benoxacor.
Reference
Chinese hamster micronucleus test |
||||
Part 1: Percentage of micronucleated PCEs at different preparation times |
||||
Test article and concentration |
Sex |
16 hours |
24 hours |
48 hours |
CGA154281 (5000 mg/kg) |
males females mean |
0.07 0.06 0.06 |
0.00 0.08 0.04 |
0.06 0.06 0.06 |
Negative control – vehicle (0.5% CMC) |
males females mean |
0.07 0.04 0.05 |
0.04 0.04 0.04 |
0.10 0.04 0.07 |
Positive control – cyclophoshamide (64 mg/kg) |
males females mean |
|
3.68 5.46 4.57* |
|
* p>0.05 (Chi-Square test) |
Chinese hamster micronucleus test |
|||||
Part 2: Percentage of micronucleated PCEs at different dose levels sacrificed after 24 hours |
|||||
Sex |
CGA154281 1250 mg/kg |
CGA154281 2500 mg/kg |
CGA154281 5000 mg/kg |
Negative control 0.5% CMC |
Positive control 64 mg/kg CPA |
Males Females Mean |
0.02 0.00 0.01 |
0.04 0.02 0.03 |
0.04 0.06 0.05 |
0.08 0.02 0.05 |
2.00 1.58 1.79* |
* p > 0.05 (Chi-Square Test) |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Additional information from genetic toxicity in vivo:
In vitro data
The key studies are considered to be two bacterial mutation assays (Ogorek, 1987a and b), a mammalian cell gene mutation assay (Dollenmeier, 1987) and a DNA repair assay (Hertner, 1987a). These are recognised core assay types for investigating mutation in vitro.
The test material has been tested in several bacterial mutation assays, which measure the induction of point and frame shift mutations in strains of Salmonella typhimurium with and without auxiliary metabolic activation (S9). The number of studies reflects the testing of different development batches. The key studies selected represent material currently manufactured on a production scale (of purity 95.4 to 98.3%; Ogorek, 1987a and b) and demonstrate that the test substance is clearly negative at concentrations up to 5000 µg/plate. Furthermore, highly purified material (purity 99.3%) was also negative in this assay (Deparade, 1984). A weak mutagenic response was observed with an early batch of lower purity (93.9%; Deparade, 1986; Lasinski at al, 1986), however, assessment of all available studies and data, and in particular including batches of purity relevant to production material, indicates that the test substance can be concluded to be negative in the bacterial mutation assay.
The bacterial mutation assays which tested a range of purities are summarised below.
Gene mutation in vitro (Ames assays), listed in order of sample purity, with the key studies shown in bold:
Strains tested | Concentration tested | Batch & purity of test material | Result | Reference | |
non-activated | activated | ||||
4 strains: TA 98, TA100, TA1535, TA1537 | 20, 80, 320, 1280, 5120 ug/0.1 mL | HM4287/1+4 99.3% | Negative | Negative | Deparade, (1984) |
4 strains: TA 98, TA100, TA1535, TA1537 | 20, 78, 313, 1250 and 5000 µg/0.1 mL | FL870116 98.3% | Negative | Negative | Ogorek, (1987a) |
4 strains: TA 98, TA100, TA1537, TA1538 | 313, 625, 1250, 2500, 5000 ug/0.1 mL | FL881310 97.1% | Negative | Negative | Ogorek, (1988) |
3 strains: TA 98, TA1537, TA1538 | 250, 500, 1000, 2000, 3000, 4000, 5000 and 8000 µg/0.1 mL | FL870221 95.4% | Negative | Negative | Deparade, (1988a) |
3 strains: TA 98, TA1535, TA1537 | 250, 500, 1000, 2000, 3000, 4000, 5000 and 8000 µg/0.1 mL | FL870221 95.4% | Negative | Negative | Deparade, (1988b) |
4 strains: TA 98, TA100, TA1535, TA1537 | 20, 78, 313, 1250 and 5000 µg/0.1 mL | FL870221 95.4% | Negative | Negative | Ogorek, (1987b) |
5 strains: TA98, TA100, TA102, TA1535 and TA1537 | 20, 78, 313, 1250 and 5000 µg/0.1 mL (all strains) and 500, 1000, 2000, 4000 and 8000 µg/0.1 mL (strain TA98) | P.510001 93.9% | Weak response in TA98 at 2000 µg/0.1 mL and above seen in only some experiments | Weak response in TA98 at 4000 µg/0.1 mL and above seen in only some experiments | Deparade, (1986) |
5 strains: TA98, TA100, TA1535, TA1537 and TA1538 | 5, 10, 50, 250, 1000 µg/plate | FL860318 93.9% | Weak response in TA98, TA1537 and TA1538 at 1000 µg/plate | Weak response in TA98, TA1537 and TA1538 at 1000 µg/plate | Lasinski |
The test material was investigated for the induction of point mutation in a mammalian cell mutation assay in Chinese hamster V79 cells in vitro. The test material was examined at concentrations up to 120 µg/mL and no mutagenic effects were observed with or without metabolic activation (Dollenmeier, 1987). This finding supports the conclusion from the bacterial mutation assays, that the test substance is negative for the gene mutation endpoint.
The test substance has been examined in a DNA-repair assay using material typical of current manufacture and does not induce DNA-damage in rat hepatocytes at concentrations up to 20 µg/mL, a dose limited by the toxicity of the test material. This key assay is reported by Hertner, 1987a. Furthermore, no DNA-damage was induced in a DNA-repair test on human fibroblasts tested at concentrations up to 62.5 µg/mL (Meyer, 1986), or in rat hepatocytes and human fibroblasts tested with highly purified material (Puri, 1985a and b). Evidence for a possible weak induction of DNA-repair was reported in rat hepatocytes with an early developmental batch of lower purity (Puri, 1986), however a negative result was reported for the same purity of material in human fibroblasts (Meyer, 1986). Assessment of all available data, and in particular including batches of purity relevant to production material, indicates that the test substance is negative in the DNA repair assay in vitro.
Autoradiographic DNA repair assays, listed in order of sample purity, with the key study shown in bold:
Test system | Concentration tested | Batch & purity of test material | Result | Reference |
Human fibroblasts | 0.25, 1.25, 6.25, 31.25 ug/ml | KGL 3339-6 99.7% | No effects on DNA | Puri, (1985a) |
Rat hepatocytes | 1,5, 25, 125ug/ml | Not reported 99.7% | No effects on DNA | Puri, (1985b) |
Rat hepatocytes | original study: 0.008 to 20 ug/ml confirmatory study: 0.0004 to 10 ug/ml | FL870116 98.3% | No effects on DNA | Hertner, (1987b) |
Rat hepatocytes | original study: 0.3 to 30 ug/ml confirmatory study: 0.1 to 20 ug/ml | FL870211 95.4% | No effects on DNA | Hertner, (1987a) |
Human fibroblasts | 0.5, 2.5, 12.5, 62.5 ug/ml | P. 510001 93.9% | No effects on DNA | Meyer, (1986) |
Rat hepatocytes | original study: 0.12 to15 ug/ml confirmatory study: 0.125 to 20 ug/ml | P. 510001 Purity 93.9% | Marginal induction of DNA damage | Puri, (1986) |
In vivo data
The key study in vivo is a bone marrow micronucleus assay in the Chinese hamster (Stasser, 1986). This assay tests for clastogenic and aneugenic activity and is a recognised core assay type for investigating mutation in vivo. The test material (93.9% purity) was tested at dose levels up to 5000 mg/kg b.w and samples of bone marrow cells were taken for cytogenetic analysis at 16, 24 and 48 hours after oral dosing. No significant increases in micronucleated polychromatic erythrocytes were found. Benoxacor is negative in this assay for clastogenic and aneugenic activity.
Summary
The test material has been examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. All in vitro studies conducted with material representative of currently manufactured technical material or material of higher purity were negative. Weak genotoxic responses in vitro were only obtained with early developmental material of lower purity levels. A sample of such lower purity material was tested for mutagenicity in vivo and gave a negative result. It is concluded that the available data indicate that benoxacor has no significant genotoxicity.
Justification for selection of genetic toxicity endpoint
One reliable, GLP- and guideline-conform in vivo genotoxicity study was available demonstrating that the substance is not mutagenic. This finding is supported by a set of available reliable and valid in vitro genotoxicity assays focussing on different endpoints of genotoxicity.
Justification for classification or non-classification
The available data on genotoxicity are adequate for the risk assessment, classification and labelling. The mutagenic potential of benoxacor has been assessed in a number of core genotoxicity assays in vivo and in vitro, covering a range of endpoints including gene mutation, DNA repair and clastogenicity. The data indicate the test material is not genotoxic.
Based on the results, the substance does not meet the criteria for classification under the Directive 2001/59/EC, Annex VI, 4.2.2 as well as the criteria in the Regulation (EC) No. 1272/2008, Annex I, Part 3, 3.5, as amended by Regulation (EC) No. 286/2011.
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