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EC number: 200-896-5 | CAS number: 75-73-0
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Genetic toxicity: in vivo
Administrative data
- 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:
- 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- other: OECD QSAR Toolbox
- Title:
- Unnamed
- Year:
- 2 012
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
- Type of assay:
- mammalian erythrocyte micronucleus test
Test material
- Reference substance name:
- Trifluoromethane
- EC Number:
- 200-872-4
- EC Name:
- Trifluoromethane
- Cas Number:
- 75-46-7
- Molecular formula:
- CHF3
- IUPAC Name:
- Trifluoromethane
Constituent 1
- Specific details on test material used for the study:
- - Purity: 99.9999%
Test animals
- Species:
- mouse
- Strain:
- other: Crl:CD1(ICR)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories International, Inc. (Kingston, New York)
- Age at study initiation: approximately 8 weeks of age
- Weight at study initiation: group means ranged from 31.1 to 31.8 g
- Assigned to test groups randomly: yes
- Fasting period before study: no
- Housing: All animals were housed in solid bottom cages with Shepherd's™ Cob + PLUS™ (i.e., enrichment-containing bedding). At study start, male animals were housed individually and female animals were housed 2-3 per cage. Male mice were housed on a separate rack from the female mice.
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26ºC (68-79ºF)
- Humidity (%): 30-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle
Administration / exposure
- Route of administration:
- inhalation: vapour
- Vehicle:
- - Vehicle(s)/solvent(s) used: air
- Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: All exposure chambers were constructed of glass (cylindrical) with a nominal internal volume of 19 L. Circular glass baffles inside the chamber promoted uniform chamber distribution of the test atmosphere. The chamber volume was chosen so that the total body volume of the test animals did not exceed 5% of the chamber volume.
- Method of holding animals in test chamber: During exposure, animals were individually placed in stainless steel, wire-mesh modules (sexes separated) and exposed, whole-body, inside the exposure chambers. The lower modules were placed on stainless steel stands inside the exposure chambers so that the animals were elevated from the bottom of the exposure chambers.
- System of generating particulates/aerosols: Chamber atmospheres were generated by dilution of the test substance in air and oxygen for the 30000 and 300000 ppm exposures and in air only for the 3000 ppm exposure. The test substance vapor, chamber air supply, and supplemental oxygen supply (if used) were metered into a 1-liter 3-neck glass mixing flask with Brooks model 5850E and 5851E mass flow controllers. The gas mixtures left the 3-neck flasks and entered the chambers through glass transfer tubes at the top of the exposure chambers. The air-control atmosphere was similarly generated in a separate hood without the H-30412 vapor and supplemental oxygen. Test atmospheres were exhausted from the bottom of the exposure chambers through MSA charcoal/HEPA filter cartridges prior to discharge into the fume hood.
- Temperature, humidity, pressure in air chamber: Chamber temperature was targeted at 20-24°C and chamber relative humidity was targeted at 30-70%. Temperature and humidity were measured with a VWR dial-type thermometer/hygrometer and recorded hourly during the exposure. Chamber airflow was set at the beginning of the exposure to achieve at least 10 air changes per hour and monitored continually with Brooks model 5850E or 5851E mass flow controllers. Chamber oxygen concentration was targeted to be at least 19% and measured with a Teledyne Analytical Instruments model GB300 oxygen analyzer. Chamber airflow and oxygen concentration were recorded hourly during the exposure.
TEST ATMOSPHERE
During the exposures, the vapor concentration of the test substance was determined by gas chromatography at approximately 30-minute intervals in the test chambers and once in the control chamber. Known volumes of chamber atmosphere were continually drawn from the sampling port and were directly injected into an Agilent model 6890 Plus gas chromatograph equipped with an automated gas sample valve and a flame ionization detector. All samples were chromatographed isothermally at 80ºC on a J&W Scientific DB-5 (5%-Phenyl)- methylpolysiloxane fused silica glass column. The atmospheric concentration of the test substance was determined from a standard curve derived from gas standards. Standards were prepared prior to the exposure by injecting known volumes of the vapor test substance into Tedlar® bags containing known volumes of air. Upon completion of the exposures, sample results were transferred to the Camile Inhalation Reporting and Analysis System (CIRAS), which collated sample calculations.- Duration of treatment / exposure:
- 6 hours
- Frequency of treatment:
- Once
- Post exposure period:
- 72 hours
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm (nominal)
- Dose / conc.:
- 3 000 ppm (nominal)
- Dose / conc.:
- 30 000 ppm (nominal)
- Dose / conc.:
- 300 000 ppm (nominal)
- No. of animals per sex per dose:
- 5 animals per sex, with the exception of the highest concentration groups (300000 pm), which contained 7 animals per sex.
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- The positive control was cyclophosphamide and was administered once orally at a dose of 30 mg/kg.
Examinations
- Tissues and cell types examined:
- Body weights and clinical observations were recorded periodically throughout the study. During the exposures, the response to an alerting stimulus was determined for the animals as a group for each exposure concentration. The alerting response was determined prior to the initiation of each exposure, 3 times during exposure, and after the conclusion of the exposure period, just prior to animal removal from the exposure chamber. At the body weight determinations, each animal was handled and examined for abnormal behavior and appearance. Cage-site examinations to detect moribund or dead animals and abnormal behavior and appearance among animals were conducted at the time of loading and unloading the animals on exposure days, and at least once daily on non-exposure days.
- Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: A previous acute inhalation toxicity study has demonstrated that the approximate lethal concentration (ALC) for this substance is greater than 663000 ppm in male rats. Reduced response to sound stimulus was observed in male rats exposed to 186000 ppm. The high concentration of 300000 ppm was selected based on a previous inhalation study, knowledge about the physical/chemical properties of the test substance, and the pilot study performed prior to the main study. Prior to the main study, a pilot study was performed (in a non-GLP manner) in which a group of 3 male and 3 female mice each were exposed whole-body to a mean vapor concentration of 210000 ± 2300 ppm of the test substance for approximately 6 hours to ensure that the selected high concentration was reasonable for this study and unlikely to result in overt or excessive toxicity. Based on the results of this pilot study, target concentrations of 3000, 30000, and 300000 ppm were chosen for the main study.
TREATMENT AND SAMPLING TIMES: Sacrifice and peripheral blood collection procedures were conducted, with animals placed under general anesthesia by inhalation of isoflurane prior to sacrifice. All animals were sacrificed by carbon dioxide asphyxiation. Peripheral blood samples were collected at approximately 24, 48, and 72 hours post-exposure for micronucleus evaluation; with the exception of the positive control animals that only had blood collected at only 48 hours post dosing.
Peripheral blood samples were collected by tail vein venipuncture from all animals on study. Sample collection and analysis was conducted using the In Vivo MicroFlow® Plus Mouse Micronucleus assay kit. Approximately 60 μL of blood was collected from each animal directly into a labeled microcentrifuge tube containing 350 μL anticoagulant/diluent (anticoagulant) found in the MicroFlow Plus kit. The tubes were capped and inverted several times to mix the blood with the anticoagulant. The blood/anticoagulant mixture were stored at either room temperature or refrigerated for up to 4 hours before fixing. The blood samples were fixed in duplicate (approximately 180 μL of blood/anticoagulant mixture each) in 2 mL ultra-cold reagent-grade methanol and stored below -75ºC until processed.
METHOD OF ANALYSIS: The micronucleus evaluation was conducted by flow cytometry. Samples were analyzed by flow cytometry on a BD FACSCalibur™ running Cell Quest Pro Software. Micronucleus evaluations were conducted on 5 animals/sex/group. At the highest concentration, 5 males and 5 females were selected for evaluation based on survival until the scheduled sacrifice and then animal number order. Whenever feasible, at least 20000 RETs were analyzed per blood sample for induction of micronuclei, and toxicity as indicated by the frequency of immature erythrocytes (%RETs) among the total (RETs plus NCEs). The samples were analyzed and evaluated using the In Vivo MicroFlow® Plus Mouse Micronucleus assay kit. The frequency of micronucleated reticulocytes (%MN-RETs) was used as a measure of induction of aneugenic or clastogenic alterations by the test substance. Analysis was conducted on samples from the negative (air) control and high concentration group at the 24 hour time point, all groups at the 48-hour time point, and samples from the negative (air) control and all test substance concentration group at the 72-hour time point. Analysis was not conducted on samples for the low and intermediate concentration groups at the 24-hour time point since no positive response was observed at the high concentration group for this time point. A second analysis of an additional 20000 RETs was conducted on the duplicate fixed samples taken from male mice at the 72 hour time point to confirm the initial findings, resulting in a total of 40000 RETs analyzed.- Evaluation criteria:
- Data were evaluated using scientific judgment taking into account both statistical and biological significance. Results not meeting the indicated criteria for positive or negative findings were evaluated on a case-by-case basis. Further investigation of an equivocal result were required to obtain a conclusive finding. The test substance was judged negative if the following conditions were met:
No statistically significant concentration-related increases in the group mean MN-RETs above the concurrent negative control value occurred at any concentration of the test substance.
The MN-RET values of the test substance treated animals were within reasonable limits of the recent (past 3 years) laboratory historical control range.
The test substance was judged positive if the following conditions were met:
The group mean MN-RETs was statistically significantly increased at one or more concentrations of the test substance compared to the concurrent negative control values.
An accompanying statistically significant concentration-response increase in MN-RETs was observed. - Statistics:
- A test was considered valid if all of the following conditions were met: The range of MN-RET values in the negative control animals were within reasonable limits of the laboratory historical control range. The positive control should have induced a significant increase in the frequency of MNRETs as compared to the negative control group, judged by biological and/or statistical significance (p <= 0.05).
Descriptive statistics (e.g., mean, standard deviation) was performed for exposure concentration and environmental data.
Micronucleus data was evaluated using scientific judgment taking into account both statistical and biological significance. For each treatment group, the mean and standard deviation of %RETs and %MN-RETs was calculated. Data was transformed prior to analysis using an arcsine square root or Freeman-Tukey function. This transformation is appropriate for proportions since the distribution of the transformed data more closely approximates a normal distribution than does the nontransformed proportion. The individual animal was considered the experimental unit. All data analyses was one-tailed and conducted at a significance level of 5%.
Transformed data for %RETs and %MN-RETs was analyzed separately for normality of distribution and equal variance using the Shapiro-Wilk and Levene’s tests, respectively. Data from the positive control group was not included in evaluating normality or variance homogeneity of distribution.
For those data that are normally distributed and have equal variance, parametric statistics (e.g., analysis of variance (ANOVA) and Dunnett’s test) was performed using the transformed data. For those data that are normally distributed but have unequal variance, a robust ANOVA and unequal-variance Dunnett test was done. For those data that are not normally distributed, nonparametric statistics (e.g., Kruskal-Wallis and Dunn’s tests) utilizing nontransformed data was performed.
See table 1 for body weight statistics.
Results and discussion
Test results
- Key result
- Sex:
- male/female
- Genotoxicity:
- positive
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
Chamber Distribution of Vapor: Prior to the exposure, a study of chamber vapor concentration distribution was performed. Vapor samples were collected from the top and bottom modules and at the reference port of the exposure chamber, averaged and individual samples from the modules compared to the overall average. Samples taken from the modules demonstrated differences that were less than 10% from the overall mean vapor concentration; therefore, the test material atmosphere was considered to be homogenously distributed in the locations where animals were exposed.
The mean value of the chamber atmosphere measured at the reference port was approximately 1.3% different from the mean value determined at the modules; therefore the use of the reference port for air sampling was considered adequate.
Chamber Concentrations: Air control mice were exposed to a 0 ppm atmosphere. Animals in the 3000, 30000, and 300000 ppm target concentration group were exposed to vapor concentrations of 3000 ± 51, 30000 ± 340, and 300000 ± 7700 ppm H-30412 (mean ± standard deviation), respectively. The chamber concentrations were considered adequate for the conduct of the study.
Chamber Environmental Conditions: During all exposures, the chamber temperature, humidity, and oxygen concentrations were 20-23ºC, 32-51%, and 21%, respectively. The chamber airflow was 10 L/min which provided 32 air changes per hour. The chamber environmental conditions were considered adequate for the conduct of the study.
Clinical Observations and Mortality: Prior to the exposure, no abnormalities were detected in any study animal. All mice exposed in this study to either 0, 3000, 30000, or 300000 ppm H-30412 displayed normal startle responses before, during (3 times), and after the exposure. No mortality was observed for any animal in any group during the 6-hour exposure period. One male from the 300000 ppm exposure group was found dead on day 1 post-exposure. The rest of the animals survived the subsequent posttreatment period and no abnormalities were detected.
Body Weights and Body Weight Gains: Male mice lost group averages of 0.2 to 1.9 grams of body weights one day after exposure to 0, 3000, 30000, 300000 ppm H-30412, or cyclophosphamide (CP) while female mice lost 0.3 to 1.1 grams in all groups except the one exposed to 30000 ppm. Male mice in the 300000 ppm group lost a statistically significant (p<0.05) amount of body weight between study start and day one. No other statistically significant body weight losses were observed in any exposure group for the remainder of the study.
Micronucleus Evaluation: A statistically significant test substance-related increase in the frequency of MN-RETs was observed in male mice at the highest exposure level (300000 ppm) at the 72 hour time point. This increase in MN-RETs occurred in a dose-related manner. A statistically significant increase in the frequency of MN-RETs was also observed in female mice at the intermediate exposure level (30000 ppm) at the 48 hour time point; however, this increase was observed at an intermediate exposure level only and was within historical negative control ranges. The increased frequency of MN-RETs observed with the female mice is not considered to be biologically relevant. There were no statistically significant, test substance related, decreases in %RET in any of the test substance exposed groups. No target cell toxicity was observed on the study; there were no statistically significant, test substance related, decreases in %RET in any of the test substance exposed groups. The negative (air) and positive control groups exhibited a response consistent with the %MN-RETs historical control data.
Any other information on results incl. tables
Table 2: Micronucleus Evaluation for Male Mice | |||||
| Group 1 0 ppm | Group 2 3000 ppm | Group 3 30000 ppm | Group 4 300000 ppm | Group 5 30 mg/kg CP |
RET % |
|
|
|
|
|
24-hr | 1.69 0.42 (5) | a | a | 1.82 0.36 (5) | b |
48-hr | 1.79 0.24 (5) | 2.09 0.41 (5) | 2.05 0.62 (5) | 2.07 0.73 (5) | 0.65* 0.09 (5) |
72-hr | 2.25 0.33 (5) | 2.53 0.48 (5) | 2.07 0.56 (5) | 1.99 0.82 (5) | b |
| |||||
MN-RET (%) |
|
|
|
|
|
24-hr | 0.14 0.01 (5) | a | a | 0.19 0.07 (5) | b |
48-hr | 0.15 0.03 (5) | 0.15 0.05 (5) | 0.25 0.10 (5) | 0.23 0.07 (5) | 0.86@ 0.28 (5) |
72-hr | 0.15 0.03 (5) | 0.16 0.05 (5) | 0.24 0.08 (5) | 0.42* 0.22 (5) | b |
|
|
|
|
|
|
Data arranged as: Mean Standard deviation (Number of values included in calculation)
a Group not evaluated at this time point. b Group not included at this time point. * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. |
Table 3: Micronucleus Evaluation for Female Mice | |||||
| Group 1 0 ppm | Group 2 3000 ppm | Group 3 30000 ppm | Group 4 300000 ppm | Group 5 30 mg/kg CP |
RET % |
|
|
|
|
|
24-hr | 1.97 0.62 (5) | a | a | 1.85 0.70 (5) | b |
48-hr | 1.75 0.56 (5) | 1.57 0.45 (5) | 2.45 0.63 (5) | 2.13 0.53 (5) | 1.28 0.49 (5) |
72-hr | 2.25 0.50 (5) | 2.05 0.63 (5) | 2.76 0.49 (5) | 2.63 1.09 (5) | b |
| |||||
MN-RET (%) |
|
|
|
|
|
24-hr | 0.16 0.07 (5) | a | a | 0.19 0.05 (5) | b |
48-hr | 0.14 0.03 (5) | 0.18 0.03 (5) | 0.21* 0.04 (5) | 0.18 0.05 (5) | 0.60* 0.15 (5) |
72-hr | 0.16 0.05 (5) | 0.19 0.07 (5) | 0.23 0.07 (5) | 0.24 0.06 (5) | b |
|
|
|
|
|
|
Data arranged as: Mean Standard deviation (Number of values included in calculation)
a Group not evaluated at this time point. b Group not included at this time point. * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): positive only in males at the 72-hour time point at a dose that is considerably above those recommended and not representative of a credible or physiological exposure situation.
Under the conditions of this study, the test substance induced biologically relevant increases in micronucleated reticulocytes in mouse peripheral blood. It was concluded that the test substance was positive in this in vivo study.
This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability). - Executive summary:
The test substance was evaluated for its ability to induce micronucleated reticulocytes (MN-RETs) in peripheral blood cells in male and female Crl:CD1(ICR) mice according to OECD Guideline 474. Based on previous inhalation studies, knowledge about the physical/chemical properties of the test substance, and on rangefinding results, concentrations of 0, 3000, 30000, and 300000 ppm were selected for the study. Test substance vapor was administered to groups of animals by whole-body inhalation exposure once for 6 hours. An air exposed group served as the negative control. The positive control was cyclophosphamide and was administered once orally at a dose of 30 mg/kg body weight. All exposure groups, negative (air) control groups, and positive control groups contained 5 animals per sex, with the exception of the highest concentration groups (300000 pm), which contained 7 animals per sex. Peripheral blood samples were collected at approximately 24, 48, and 72 hours post-exposure for micronucleus evaluation; with the exception of the positive control animals that only had blood collected 48 hours post dosing. All surviving animals were weighed and observed for mortality and clinical signs of toxicity daily and sacrificed humanely after the final bleed.
Male mice lost group averages of 0.2 to 1.9 grams of body weights one day after exposure to 0, 3000, 30000, 300000 ppm of the test substance, or cyclophosphamide (CP) while female mice lost 0.3 to 1.1 grams in all groups except the one exposed to 30000 ppm. Male mice in the 300000 ppm group lost a statistically significant (p<0.05) amount of body weight between study start and day one. No other statistically significant body weight losses were observed in any exposure group for the remainder of the study.
Prior to the exposure, no abnormalities were detected in any study animal. All mice exposed in this study to either 0, 3000, 30000, or 300000 ppm of the test substance displayed normal startle responses before, during (3 times), and after the exposure. All mice survived the 6-hour exposure. One male from the 300000 ppm exposure group was found dead on day 1 post-exposure. The rest of the animals survived the subsequent post-treatment period and no abnormalities were detected.
A statistically significant test substance related increase in the frequency of MN-RETs was observed in male mice at the highest exposure level (300000 ppm) at the 72 hour time point. This increase in MN-RETs occured in a dose related manner. A statistically significant increase in the frequency of MN-RETs was also observed in female mice at the intermediate exposure level (30000 ppm) at the 48 hour time point; however, this increase was observed at an intermediate exposure level only and was within historical negative control ranges. The increased frequency of MN-RETs observed with the female mice is not considered to be biologically relevant. No target cell toxicity was observed on the study; there were no statistically significant, test substance related, decreases in %RET in any of the test substance exposed groups. The negative (air) and positive control groups exhibited a response consistent with the %MN-RETs historical control data.
All criteria for a valid study were met. Under the conditions of this study, the test substance induced biologically relevant increases in micronucleated reticulocytes in mouse peripheral blood. The test substance was concluded to be positive in this in vivo study.
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