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EC number: 806-451-7 | CAS number: 42532-60-5
- 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:
- genetic toxicity in vivo, other
- Remarks:
- Combined in vivo micronucleus assay and Comet assay
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Remarks:
- No deviations occurred that negatively impacted the integrity of the study.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)
- Deviations:
- no
- Remarks:
- No deviations occurred that negatively impacted the integrity of the study.
- GLP compliance:
- yes
- Type of assay:
- other: Combined in vivo Micronucleus and Comet Assay
Test material
- Reference substance name:
- 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propanenitrile
- EC Number:
- 806-451-7
- Cas Number:
- 42532-60-5
- Molecular formula:
- C4 F7 N
- IUPAC Name:
- 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propanenitrile
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
3M Company, Lot 16
- Expiration date of the lot/batch:
March 2020
- Purity test date:
31 March, 2017
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
Ambient temperature (15-25°C)
- Solubility and stability of the test substance in the solvent/vehicle:
Since the test substance is a colorless gas , cells in culture flasks were exposed in modular incubator chambers (Billups-Rothenburg, USA) to various concentrations. The atmosphere in the chamber consisted of 19% O2, 5% CO2 and the test substance supplemented with N2. The highest concentration theoretically achievable was therefore 76% (v/v). Additional concentrations of 60, 40, 20 and 10% (v/v) (all ± 10%) were used in the chambers to expose the cells. Air (19% O2, 5% CO2, 76% N2) without the test substance was used as negative control.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:
No data
FORM AS APPLIED IN THE TEST: Gas
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The Crl:CD(SD) rat was chosen as the animal model for this study as it is an accepted rodent species for nonclinical toxicity testing by regulatory agencies.
The total number of animals used in this study was based on OECD Guidelines 474 and 489. Group size at the initiation of the study (up to 6/sex/group) was chosen to provide a minimum of 5 analyzable samples/sex/group for each endpoint. Because no difference in systemic toxicity was noted between males and females in Phase 1, only males were used for Phase 2. - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River
- Age at study initiation: 8 weeks old
- Weight at study initiation: 167-282 g
- Assigned to test groups randomly: Yes
- Fasting period before study: None
- Housing: On arrival, animals were group housed (2 to 3 animals of the same sex) until randomization. Following randomization, animals were group housed (2 animals of the same sex and same dosing group together) in solid-bottom cages containing appropriate bedding equipped with an automatic watering valve. Animals were separated during designated procedures/activities. Each cage was clearly labeled with a cage card indicating study number, group number, cage number, dosage level/exposure concentration, animal number(s), and sex. Cages were arranged on the racks in group order.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet 5CR4 meal was provided ad libitum throughout the study, except during designated procedures including acclimation to nose-only restraint and during inhalation exposure periods. The feed was analyzed by the supplier for nutritional components and environmental contaminants.
- Water (e.g. ad libitum): Municipal tap water after treatment by reverse osmosis was freely available to each animal via an automatic watering system, except during acclimation to nose-only restraint and inhalation exposure periods.
- Acclimation period: 4 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 19 January, 2019 To: 21 May, 2019
Administration / exposure
- Route of administration:
- inhalation: gas
- Vehicle:
- Air
- Details on exposure:
- TYPE OF INHALATION EXPOSURE: nose only
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted using (7.9-L) stainless steel, nose-only systems with grommets in exposure ports to engage animal holding tubes for Phase 1 and 0.74-L 12-port module CH technologies flow-past (directed-flow) nose-only exposure system for Phase 2.
- Method of holding animals in test chamber: Animal holding tubes
- Source and rate of air: Air supplied to the nose-only systems was provided from the Inhalation Department breathing quality, in-house compressed air source and a HEPA- and charcoal-filtered, temperature- and
humidity-controlled supply air source.
- Method of conditioning air:
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber: The mean temperature and mean relative humidity of the exposure atmospheres were 22 ± 3ºC and 50 ± 20%, respectively. Oxygen content of the exposure atmospheres was measured during the method development phase and was 20.9% for all groups for both phases of the study.
- Treatment of exhaust air: All nose-only system exhaust passed through the facility exhaust system, which consists of redundant exhaust blowers preceded by activated-charcoal and HEPA-filtration units.
TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed concentrations of MTDID 28136 in the exposure atmospheres was determined using a gas chromatograph (GC) equipped with a Flame Ionization Detector (FID). Samples were collected from the approximate animal-breathing zone of the exposure system.
- Samples taken from breathing zone: yes - Duration of treatment / exposure:
- Phase I: 6 hours/day for 3 days
Phase II: 6 hours/day for 2 days - Frequency of treatment:
- Daily
- Post exposure period:
- None
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- Phase I Air control
- Dose / conc.:
- 381 ppm (analytical)
- Remarks:
- Phase I
- Dose / conc.:
- 753 ppm (analytical)
- Remarks:
- Phase I
- Dose / conc.:
- 1 501 ppm (analytical)
- Remarks:
- Phase I
- Dose / conc.:
- 0 ppm
- Remarks:
- Phase II Air Control
- Dose / conc.:
- 375 ppm (analytical)
- Remarks:
- Phase II
- Dose / conc.:
- 741 ppm (analytical)
- Remarks:
- Phase II
- Dose / conc.:
- 1 494 ppm (analytical)
- Remarks:
- Phase II
- No. of animals per sex per dose:
- Phase I: 6/sex/dose
Phase II: 6 males/dose - Control animals:
- yes, concurrent no treatment
- Positive control(s):
- ositive control groups of 20 mg/kg cyclophosposphamide (CP; Micronucleus assay positive control by oral gavage) and 200 mg/kg ethyl methanesulfonate (EMS; Comet assay positive control by oral gavage) were utilized for this study.
- Justification for choice of positive control(s): Per OECD guidelines
- Route of administration: Oral gavage
- Doses / concentrations: cyclophosphamide: 20 mg/kg, ehtyl methanesulfonate: 200 mg/kg
Examinations
- Tissues and cell types examined:
- Micronucleus: Bone marrow
Comet: nasal cavity, lung, liver, and kidney tissues - Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: The doses were selected based on a previously conducted inhalation study showing effects in the nose at concentrations of 250 and 550 ppm.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): For Phase 1, filtered air (control) and test substance atmospheres were administered to Groups 1–4 as 6-hour, nose-only inhalation exposures once daily for 3 consecutive days. For Group 5, CP was administered via oral gavage on Days 1 and 2, and EMS was administered via oral gavage on Days 2 and 3.
For Phase 2, filtered air (control) and test substance atmospheres were administered to Groups 1–4 as 6-hour, nose-only inhalation exposures once daily for 2 consecutive days. For Group 5, EMS was administered via oral gavage on Days 1 and 2.
Tissues were collected 2-4 hours following sacrifice.
DETAILS OF SLIDE PREPARATION:
Micronucleus assay: Blood samples were collected from all animals at approximately 1–3 hours following the last exposure or dose. Blood (approximately 0.5 mL) was collected via the jugular vein into tubes containing K2EDTA and samples from 5 animals/sex/group. Of the 6 samples/sex/group available, 5 samples in LTSS were washed with ice cold 1% FBS solution and maintained on wet ice. The cells were then pelleted by centrifugation, and the supernatant was poured off leaving a small amount of supernatant with the pellet. The cells were re-suspended and 20 μL of suspension were added to 80 μL of staining solution containing RNase, FITC-conjugated anti-CD 71 antibodies and PE-conjugated anti-CD 61 antibodies. The samples were incubated at 2°C to 8°C for 30 minutes, re-suspended, then incubated at room temperature for an additional 30 minutes. DNA staining solution (propidium iodide; 0.3 to 2 mL) was added and then the samples were placed on wet ice for at least 5 minutes prior to the flow cytometric analysis.
Bone marrow was collected from the first 5 animals/sex/group at the time of euthanasia from the right femur of animals anesthetized by inhalation of isoflurane and euthanized by exsanguination. Five animals/sex/group in the negative control (Group 1) and test substance-treated groups were euthanized approximately 2–4 hours following the last exposure (Groups 2–4) or second dose of EMS (Group 5), and the nasal cavity was collected (Groups 1–4) or discarded without tissue collection (Group 5). Bone marrow was aspirated or flushed 2 to 3 times from the right femur into a centrifuge tube using a syringe containing heat inactivated fetal bovine serum (HI FBS). The bone marrow was centrifuged and all but approximately 0.25 mL (or a volume approximately twice that of the cell pellet) of HI FBS was decanted, and the pellet was re-suspended in the remaining HI FBS. Bone marrow smears were prepared by placing approximately 1 drop of cell suspension onto a minimum of 4 appropriately labeled, clean microscope slides. Each slide was coded so that the treatment group would not be revealed during subsequent analysis. The slides were air dried, fixed in 100% methanol for approximately 20 minutes, and allowed to air dry a second time.
Comet assay: Surviving animals were anesthetized on Day 3 (Phase 1) or on Day 2 (Phase 2), between 2 to 4 hours after the final exposure, by isoflurane inhalation followed by exsanguination (to complete euthanasia). Immediately following euthanasia, kidney, liver, lung and nasal cells
samples were collected for the Comet assay from 5 animals/sex/group. Sections of kidney, liver, lung and nasal tissue were placed in 3 mL chilled mincing solution (Hanks’ balanced salt solution with EDTA and DMSO), then minced with fine scissors to release the cells. The cell suspensions were strained into pre-labeled conical polypropylene tubes through a cell strainer and were kept on wet ice during preparation of the multi-well slides.
From each cell suspension, a 2.5 μL aliquot was mixed with 75 μL of low melting agarose. The cell/agarose suspension was applied to microscope multi-well slides. Commercially purchased (Trevigen®) pre-treated, multi-well slides were used, and these slides have 20 individual circular
areas, referred to as wells. The multi-well slides were kept at 2-8°C for at least 15 minutes to allow the gel to solidify. Multi-well slides were identified with a random code that reflects the study number, group, animal number, and organ/tissue. At least two 20-well slides were prepared
per animal per tissue. Three wells were used in scoring and the other wells were designated as a backup. Following solidification of agarose, the multi-well slides were placed in jars containing lysis solution. Following solidification of agarose, the multi-well slides were submerged in a cold solution composed of a commercially available lysis solution supplemented with 10% DMSO, on the day of use. The multi-well slides were kept in this solution at least overnight at 2-8°C. After cell lysis, slides/wells were washed with neutralization buffer (0.4 M tris hydroxymethyl
aminomethane in purified water, pH ~7.5) and placed in the electrophoresis chamber. The chamber reservoirs were slowly filled with alkaline buffer, composed of 300 mM sodium hydroxide and 1 mM EDTA (disodium) in purified water; the pH was >13. All multi-well slides remained in the buffer for 20 minutes at 2-10°C, protected from light, allowing DNA to unwind.
METHOD OF ANALYSIS:
Micronucleus assay: The frequency of micronucleated reticulocytes in peripheral blood was analyzed after flow cytometer calibration using Malaria infected biostandard and negative control standards provided in the Litron kit. Up to 20,000 RETs per animal, when possible, were analyzed.
Statistical analysis was performed on the micronucleus frequency (%MnRET) and %RET using the animal as the unit. The mean and standard deviation of %MnRET and %RET was presented for each treatment group.
Comet Assay: Electrophoresis was conducted for 30 minutes at 0.7 V/cm, at 2-12°C and protected from light. The electrophoresis time was constant for all multi-well slides. After completion of electrophoresis, the multi-well slides were removed from the electrophoresis
chamber and washed with neutralization buffer for at least 10 minutes. The multi-well slides (gels) were then dehydrated with 200-proof ethanol for at least 5 minutes, then air dried for at least 2 hours and stored at room temperature with desiccant. These multi-well slides were shipped
at ambient temperature to BioReliance by overnight shipment; upon receipt, the slides were logged in by the Test Site’s repository. Multi-well slides were stained with a DNA stain (i.e., Sybr-gold) prior to scoring. The stain solution was prepared by diluting 1 μL of Sybr-gold stain in 15 mL of 1xTBE (tris-boric acid EDTA buffer solution)
Scoring: Three wells per organ/animal were used. Fifty randomly selected, non-overlapping cells per slide/well were scored, resulting in a total of 150 cells (when possible) evaluated per animal for DNA damage, using the fully validated automated scoring system Comet Assay IV from
Perceptive Instruments Ltd. (UK).
The following endpoints of DNA damage were assessed and measured:
- Comet Tail Migration; defined as the distance from the perimeter of the Comet head to the last visible point in the tail.
- % Tail DNA; (also known as % tail intensity or % DNA in tail); defined as the percentage of DNA fragments present in the tail.
- Tail Moment (also known as Olive Tail moment); defined as the product of the amount of DNA in the tail and the tail length [(% Tail DNA x Tail Length)/100; Olive et al.1990)].
Each slide/well was also examined for indications of cytotoxicity. The rough estimate of the percentage of “clouds” was determined by scanning 150 cells per animal, when possible (percentage of “clouds” was calculated by adding the total number of clouds for all multi-well slides scored, dividing by the total number of cells scored and multiplying by 100). The “clouds”, also known as “hedgehogs”, are a morphological indication of highly damaged cells often associated with severe genotoxicity, necrosis or apoptosis. A “cloud” is produced when almost the entire cell DNA is in the tail of the comet and the head is reduced in size, almost nonexistent (Collins, 2004). “Clouds” with visible gaps between the nuclei and the comet tail were excluded from comet image analysis. - Evaluation criteria:
- Micronucleus Assay: A target of 20,000 RETs/animal was analyzed for the presence of micronuclei (MnRETs). The proportion of reticulocytes to total number of cells scored (%RETs) was determined for each animal and treatment group. The %RETs served as a parameter of the test substance cytotoxicity in peripheral blood. A reduction in the RET proportions to less than 5% of the control value was considered excessively toxic and the animal data was excluded from
evaluation.
Negative Controls
The group mean frequency of MnRETs should ideally be within the 95% control limits of the distribution of the historical negative control database. If the concurrent Filtered Air control fall outside the 95% control limits, they may be acceptable as long as these data are not extreme outliers (indicative of experimental or human error).
Positive Controls
The frequency of MnRETs for the scoring controls must be significantly greater than the concurrent control (p ≤ 0.05).
Comet Assay: Negative controls: For each tissue analyzed, the DNA damage (% Tail DNA) in the negative control group was expected to be within the historical vehicle/negative control range for that tissue.
Positive Controls: The group mean for the % Tail DNA must be significantly greater than the concurrent negative control (p < 0.05), and the response should be comparable with those observed in the historical positive control data base. - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were
conducted using two sided tests and are reported at the 1% and 5% levels.
Results and discussion
Test resultsopen allclose all
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Remarks:
- Micronucleus assay
- Toxicity:
- yes
- Remarks:
- Test substance-related body weight losses were noted in the 753 and 1501 ppm group males and 381, 753, and 1501 ppm group females during the exposure period (Days 1-3).
- Vehicle controls validity:
- not examined
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Remarks:
- Phase I Comet Assay
- Toxicity:
- yes
- Remarks:
- Test substance-related body weight losses were noted in the 753 and 1501 ppm group males and 381, 753, and 1501 ppm group females during the exposure period (Days 1-3).
- Vehicle controls validity:
- not examined
- Negative controls validity:
- valid
- Positive controls validity:
- not valid
- Remarks:
- See Remarks on Result
- Remarks on result:
- other:
- Remarks:
- With respect to the Comet assay for Phase 1 of the study, MTDID 28136 was evaluated as negative (non-DNA damaging) in male liver cells only. For the remaining tissues tested, the assay did not meet all the acceptance criteria (there was no EMS-induced positive response in the nasal cavity, lung, or kidney); therefore, it was considered invalid for these tissues and the Comet assay was repeated in Phase 2 of this study.
- Key result
- Sex:
- male
- Genotoxicity:
- negative
- Remarks:
- Phase II Comet Assay with valid positive controls across all tissues evaluated.
- Toxicity:
- yes
- Remarks:
- A test substance-related body weight loss was noted in the 1494 ppm group during the exposure period (Days 1-2).
- Vehicle controls validity:
- not examined
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks:
- All valid assay criteria were met (EMS positive controls produced the expected response) for all of the tissues tested.
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, exposure of male and female rats to MTDID 28136 via nose-only inhalation for 6 hours/day for up to 3 days at target exposure concentrations of 375, 750, and 1500 ppm resulted in a negative response for induction of bone marrow micronuclei formation and a negative response for induction of DNA damage in the nasal cavity, lung, liver, and kidney tissues.
- Executive summary:
The potential for MTDID 28136 to induce micronuclei or cause DNA damage in rat liver, lung, kidney and nasal tissue was evaluated in Sprague Dawley Rats. The study was conducted according to OECD 474 and 489 in compliance with OECD GLP. Rats were administered filtered air (0 ppm control) or MTDID 28136 via nose-only inhalation exposures at target concentrations of 375, 750, and 1500 ppm. Positive control groups of 20 mg/kg cyclophosposphamide (CP; Micronucleus assay positive control by oral gavage) and 200 mg/kg ethyl methanesulfonate (EMS; Comet assay positive control by oral gavage) were utilized for this study. Due to failure of the EMS positive control, this study was performed in two phases. For Phase 1, MTDID 28136 or filtered air was administered to male and female rats (N= 6/sex/exposure concentration) once daily for 3 consecutive days, for 6 hours/day. The mean exposure concentration levels of MTDID 28136 for Phase 1 were 0, 381, 753, and 1501 ppm. Due to the lack of response in the EMS positive control group for the comet assay, a second phase was conducted for only the comet endpoint. For Phase 2, 6 males/group were exposed to 0, 375, 741, and 1494 ppm MTDID 28136 6 hours/day for 2 consecutive days. For the positive control, EMS was again administered via oral gavage at 200 mg/kg. Target tissues analyzed by the Comet assay included the nasal cavity, lung, liver, and kidney. In phase 1, all animals survived to the scheduled euthanasia. There were no test substance-related clinical observations noted at any exposure concentration. Test substance-related body weight losses were noted in the 753 and 1501 ppm group males and 381, 753, and 1501 ppm group females during the exposure period (Days 1-3). For phase 1, there were no significant increase in the number of micronuclei in the test substance-exposed rats compared to the filtered air controls in both males and females. The filtered air control values were compatible with the expected range of percent micronucleated reticulocytes (%MnRETs). There was a statistically significant increase in MnRETs in the CP positive control group as compared to the concurrent control group. All criteria for a valid assay were met. Under the conditions of this study, the administration of MTDID 28136 at exposure concentrations up to and including 1501 ppm was concluded to be negative in the micronucleus assay. With respect to the Comet assay for Phase 1 of the study, MTDID 28136 was evaluated as negative (non-DNA damaging) in male liver cells only. For the remaining tissues tested, the assay did not meet all the acceptance criteria (there was no EMS-induced positive response in the nasal cavity, lung, or kidney); therefore, it was considered invalid for these tissues and the Comet assay was repeated in Phase 2 of this study. For phase 2 of this study, it was determined that there was no sex difference in toxicity, and only male rats were used. Male rats were exposed to 0, 375, 741, and 1494 ppm MTDID 28136 for 6 hours/day for two days. All animals survived to the scheduled euthanasia. There were no clinical observations noted for males at any exposure concentration. A test substance-related body weight loss was noted in the 1494 ppm group during the exposure period (Days 1-2). Test substance-related lower food consumption was also noted for 375, 741, and 1494 ppm groups during the exposure period (Days 1-2); however, these differences did not occur in an exposure-related manner. For Phase 2, MTDID 28136 was evaluated as negative (non-DNA damaging) with the in vivo alkaline Comet Assay of the nasal tissue, lung, liver, and kidney tissues. All valid assay criteria were met (EMS positive controls produced the expected response) for all of the tissues tested. Based on the results of this study, exposure of male and female rats to MTDID 28136 via nose-only inhalation for 6 hours/day for up to 3 days at target exposure concentrations of 375, 750, and 1500 ppm resulted in a negative response for induction of bone marrow micronuclei formation and a negative response for induction of DNA damage in the nasal cavity, lung, liver, and kidney tissues.
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