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EC number: 200-913-6 | CAS number: 75-89-8
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- no data
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- significant methodological deficiencies
- Justification for type of information:
- The design of the study and the results are not clearly reported in the article. There is no data on the test substance purity.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 992
Materials and methods
- Objective of study:
- metabolism
- Principles of method if other than guideline:
- It has been clearly established previously that the expression of Trifluoroethanol (TFE) toxicity in rats is depedent on its metabolism to Trifluoroacetaldehyde (TFAld) and Trifluoroacetic acid (TFAA). While alcohol dehydrogenase, aldehyde oxidase, and aldehyde dehydrogenase have all been excluded as possible participants in TFE toxicity-related metabolism, the actual enzymes involved were unknown. The objective of this study was to elucidate the TFE metabolism associated with its toxicity.
Several experiments were performed in parallel.
1/ In vivo lethality study: TFE or TFAld and their deuterated analogs were administered by intraperitoneal injection to male rats. Rats were then observed for 6 days for lethality. In order to evaluate the effect of ethanol on the metabolism of TFE, in one experiment, ethanol was injected immediately after the intraperitoneal administration of TFE.
2/ In vivo induction study: phenobarbital was administered intraperitoneally to male rats for 2 days and animals were killed on day 4; or ethanol was administered in the drinking water for 15 days and the animals were killed on day 15.
3/ In vitro metabolism study: subcellular fractions were prepared from rat liver homogenates (mitochondria, microsomes, and cytosol) and then incubated with TFE or TFAld or their deuterated analogs and coenzyme (NAD coenzyme family). In some reactions, pyrazole or inhibitor of microsomal reactions were added prior to initiation of the reaction. The role of ethanol-inducible cytochrome P4502E1 in rat liver microsomal metabolism was probed using a monoclonal antibody to cytochrome P4502E1. - GLP compliance:
- not specified
Test material
- Reference substance name:
- 2,2,2-trifluoroethanol
- EC Number:
- 200-913-6
- EC Name:
- 2,2,2-trifluoroethanol
- Cas Number:
- 75-89-8
- Molecular formula:
- C2H3F3O
- IUPAC Name:
- 2,2,2-trifluoroethan-1-ol
- Details on test material:
- - Name of test material (as cited in study report): Trifluoroethanol (TFE)
- Physical state: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: assumed to be stable during the test (sponsor responsibility)
- Storage condition of test material: no data
- Other: source: Aldrich Chemical Co. (Milwaukee, USA)
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: obtained from a colony of the lab
- Age at study initiation: no data
- Weight at study initiation: 200-250 g
- Fasting period before study: yes, animals were fasted 12 hrs prior the intraperitoneal injection
- Housing: no data
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: yes, for at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hr/ 12hr
IN-LIFE DATES: From: To: no data
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- physiological saline
- Details on exposure:
- not applicable
- Duration and frequency of treatment / exposure:
- in vivo study: a single injection and then the animals were observed for 6 days.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- In vivo study
- Dose / conc.:
- 300 other: mM
- Remarks:
- Concentrations ip to 300 mM were used in in vitro studies
- No. of animals per sex per dose / concentration:
- 5 rats/dose.
- Control animals:
- yes, concurrent no treatment
- Positive control reference chemical:
- No
- Details on study design:
- - Subcellular fractions were prepared from rat liver homogenates by differential ultracentrifugation: mitochondria by the method of Fowler et al.,microsomes as described by Guengerich et al (1982), and cytosol was the supernatant from the 100,000 g spin. The preparations were immediately frozen and used after being thawed only once. The purity of the subcellular fractions was not determined.
- For induction studies rats were treated as follows: phenobarbital (100 mg/kg/day) was administered i.p. for 2 days and animals were killed on day 4; or ethanol was administered in the drinking water at 5% on days 1 and 2, 10% on days 3 and 4, and 20% on days 5-15 and animals were killed on day 15.
- Metabolism of TFE and TFAld. TFAld and TFAA in microsomal reaction mixtures were analyzed by gas chromatography as previously described by Fraser and Kaminsky. The rates of TFE metabolism were determined from the rates of TFAld formation. and the rates of TFAld metabolism were determined from the rates of TFAA formation.
- For investigations of the kinetics of the metabolism of TFE or TFAld or their deuterated analogs by rat hepatic subcellular fractions, TFE or TFAld (0- 200 mM) was incubated with 2 mg subcellular fraction protein at 37” in Tris-HCl buffer (50mM, pH 7.4) containing MgCl2 (10 mM) in a final volume of 1.0 mL. After preincubation at 37” for 1 min the reaction was initiated by the addition of NAD, NADH, NADP, or NADPH (1.5 mg/mL) and
terminated after 5 min (TFE) or 20 min (TFAld) by cooling in an ice bath. In all other metabolic studies TFE and TFAld concentrations were 100mM. In some reactions pyrazole (10 mM) was added prior to initiation of the reaction. Inhibitors of microsomal metabolism were preincubated for 5 min with the reaction mixture prior to initiation of the reaction.
- The role of ethanol-inducible cytochrome P4502El in rat liver microsomal metabolism was probed using R monoclonal antibody to cytochrome P4502E1, designated l-91-3 1241, which was provided by Dr. C. S. Yang, Rutgers university. Antibody was incubated with microsomes (2Omg/mL) at room temperature for 30 min. The microsomes were then diluted to a final concentration of 2mg/mL with Tris-HCl buffer, TFE or TFAld (300mM) was added, and the mixture was incubated at 37” for 1 min. The reaction was initiated with NADPH (2.0 mg/mL) and continued for S min with TFE or for 15 min with TFAld before being terminated by cooling in an ice-bath. The entire reaction volume of 0.2 mL was assayed for TFAld or TFAA. Ascites fluid at equivalent quantities to antibody was used in controls.
- For studies of the lethality of TFE and TFAld and their deuterated analogs, three doses of each test compound diluted 1 to 5 in saline were injected i.p. into groups of five rats per dose; the rats were fasted for 12 hr prior to drug administration. Rats were observed for 6 days and all moribund animals were killed. In one study, rats were injected i.p. with TFE (0.25g/kg) and then immediately with ethanol (12.5%, w/v) in saline (1.2 g ethanol/kg), followed by the same doses of ethanol at 4 and 8 hr after TFE administration. Controls received TFE and saline only.
- Dose selection rationale: the lethalities of both TFE and TFAld are very sensitive to dose, and thus LD50 studies utilized narrow dose ranges of these compounds and their deuterated analogs. For TFE, doses ranged from 0.15 to 0.25 g/kg, and for TFAld and D1-TFAld from 0.25 to 0.30 g/kg. The LD50 of TFE administered intraperitoneally to fasted rats (0.21 g/kg) was increased to 0.44 g/kg with d2-TFE, a 2.1-fold decrease in lethality. With TFAld hydrate the LD50 of approximately 0.26 g/kg was not altered when d1-TFAld hydrate was administered in place of TFAld hydrate. - Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion): not applicable
METABOLITE CHARACTERISATION STUDIES
not applicable
TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): not applicable - Statistics:
- Student t-test
Results and discussion
- Preliminary studies:
- Not applicable
Main ADME results
- Type:
- metabolism
- Results:
- Under the test conditions, hepatic P4502E1 is the primary source for metabolism of TFE on a pathway leading to toxicity. TFAld is also metabolized by P450 but not by P4502E1.
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Not applicable
- Details on distribution in tissues:
- Not applicable
- Details on excretion:
- Not applicable
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Co-administration of ethanol with TFE to rats overcame the lethal effects of the TFE. At 0.25 g TFE/kg bw 4/5 rats died, whereas at the same dose of TFE administered with ethanol, 0/5 rat died.
The NADPH-dependent microsomal metabolism of both TFE and TFAld was oxygen dependent, carbon monoxide inhibitable, and was also inhibitable by a number of P450 inhibitors including pyrasole. Taken together, these results implicate one or more forms of P450 in the metabolism of TFE and TFAld which are associated with their toxicity. The involvement of P4502E1 as a major contributor to the hepatic microsomal metabolism of TFE to TFAld is strongly supported by the observations that the reaction was inhibited by diethyldithiocarbamate, a specific inhibitor of P4502E1 and by anti P4502E1. In the case of the hepatic metabolism of TFAld to TFA, the failure of either diethyldithiocarbamate or anti P4502E1 to inhibit suggests that P4502E1 is not involved. Apparently, the fluoro substituents on TFAld prevent its metabolism by P4502E1, since acetaldehyde is a substrate for this enzyme.
Any other information on results incl. tables
Table 7.1.1/1: TFE metabolism to TFAld by rat liver subcellular fractions; the influence of cofactor and pyrazole.
Subcellular fraction and cofactor |
TFAld (nmol/min/mg protein) |
% inhibition by pyrazole (10 mM) * |
Microsome ** |
|
|
None |
0.29 ± 0.02 |
0.0 |
NAD |
0.46 ± 0.04 |
0.0 |
NADP |
0.36 ± 0.03 |
0.0 |
NADH |
2.30 ± 0.15 |
0.0 |
NADPH |
4.73 ± 0.10 |
33.0 |
Boiled |
0.07 ± 0.01 |
- |
Cytosol |
|
|
None |
0.85 ± 0.05 |
0.0 |
NAD |
1.14 ± 0.25 |
0.0 |
NADP |
0.37 ± 0.04 |
0.0 |
NADH |
0.38 ± 0.04 |
0.0 |
NADPH |
0.33 ± 0.02 |
0.0 |
Mitochondria |
|
|
None |
0.37 ± 0.03 |
0.0 |
NAD |
0.33 ± 0.04 |
0.0 |
NADP |
0.30 ± 0.05 |
0.0 |
NADH |
0.86 ± 0.02 |
0.0 |
NADPH |
2.63 ± 0.12 |
33.2 |
Boiled |
0.21 ± 0.06 |
- |
*: Pyrazole inhibition is designated as 0 when pyrazole produced no significant (P<0.01) decrease in rate. A ‘-‘ indicates that the experiment was not conducted.
**: Values are Means ± SD with N=3 different microsomal preparations.
Applicant's summary and conclusion
- Conclusions:
- Under the test conditions, hepatic P4502E1 is the primary source for metabolism of TFE on a pathway leading to toxicity. TFAld is also metabolized by P450 but not by P4502E1.
- Executive summary:
In a metabolism study, Trifluoroethanol (TFE) at 0.25 g/kg or Trifluoroacetaldehyde (TFAld) or their deuterated analogs were administered intraperitoneally to male Whistar rats. Rats were then observed for 6 days for lethality. In order to evaluate the effect of ethanol on the metabolism of TFE, in one experiment, ethanol was injected immediately after the intraperitoneal administration of TFE.TFE and TFAld or their deuterated analogs and coenzymes (NAD coenzyme family) were also incubated in vitro with subcellular fractions prepared from rat liver (microsomes, cytosol or mitochondria) at concentrations from 0 to 300 M. In some experiments, pyrazole or inhibitor of microsomal reactions were added prior to initiation of the reaction. The role of ethanol-inducible cytochrome P4502E1 in rat liver microsomal metabolism was probed using a monoclonal antibody to cytochrome P4502E1.The objective of this study was to elucidate the TFE metabolism associated with its toxicity.
Co-administration of ethanol with TFE to rats overcame the lethal effects of the TFE. At 0.25 g TFE/kg 4/5 rats died, whereas at the same dose of TFE administered with ethanol 0/5 died.
The rates of metabolism of TFE to TFAld were determined in subcellular rat liver preparations in the presence of various cofactors, with and without the presence of the inhibitor pyrazole. The microsomal fraction produced the highest rates of metabolism/mg protein with NADPH as cofactor. Pyrazole (10 mM) only inhibited NADPH-supported microsomal metabolism. The NADPH-dependent microsomal metabolism of TFE to TFAld was statistically significantly inhibitable by all of the reagents tested, particularly by diethyldithiocarbamate, a specific inhibitor of P4502E1. The NADPH-dependent, ethanol-induced microsomal metabolism of TFE to TFAld was dose-dependently inhibited by a monoclonal antibody to rat hepatic cytochrome P4502E1. At an antibody ratio of 2 mg/mg microsomal protein, the reaction was inhibited by 81%.
The rates of metabolism of TFAld to TFA were also determined in subcellular rat liver preparations in the presence of various cofactors, and with or without the presence of the inhibitor pyrazole. With microsomes TFAld oxidation was supported most effectively by NADPH, with NADH being 27% as effective. Only the NADPH-dependent metabolism was inhibited by 10 mM pyrazole. Cytosolic and mitochondrial enzymes catalyzed the metabolism of TFAld, but in a lower extent copared to microsome enzymes. Furthermore, the NADPH-dependent microsomal metabolism of TFAld to TFAA was not statistically significantly inhibitable by diethyldithiocarbamate. The NADPH-dependent microsomal metabolism of TFAld to TFAA was not inhibited by the anti P4502E1.
The NADPH-dependent microsomal metabolism of both TFE and TFAld was oxygen dependent, carbon monoxide inhibitable, and was also inhibitable by a number of P450 inhibitors including pyrasole.
Taken together, these results implicate one or more forms of P450 in the metabolism of TFE and TFAld which are associated with their toxicity. The involvement of P4502E1 as a major contributor to the hepatic microsomal metabolism of TFE to TFAld is strongly supported by the observations that the reaction was inhibited by diethyldithiocarbamate and by anti P4502E1. In the case of the hepatic metabolism of TFAld to TFAA, the failure of either diethyldithiocarbamate or anti P4502E1 to inhibit suggests that P4502E1 is not involved. Apparently, the fluoro substituents on TFAld prevent its metabolism by P4502E1, since acetaldehyde is a substrate for this enzyme.
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