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Methoxyflurane

PubChem CID
4116
Structure
Methoxyflurane_small.png
Methoxyflurane_3D_Structure.png
Molecular Formula
Synonyms
  • methoxyflurane
  • 76-38-0
  • Methoxyfluran
  • Methoflurane
  • Penthrane
Molecular Weight
164.96 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Methoxyflurane is a clear colorless liquid with a sweet fruity odor. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Methoxyflurane is an ether in which the two groups attached to the central oxygen atom are methyl and 2,2-dichloro-1,1-difluoroethyl. It has a role as an inhalation anaesthetic, a non-narcotic analgesic, a hepatotoxic agent and a nephrotoxic agent. It is an organofluorine compound, an organochlorine compound and an ether.
An inhalation anesthetic. Currently, methoxyflurane is rarely used for surgical, obstetric, or dental anesthesia. If so employed, it should be administered with nitrous oxide to achieve a relatively light level of anesthesia, and a neuromuscular blocking agent given concurrently to obtain the desired degree of muscular relaxation. (From AMA Drug Evaluations Annual, 1994, p180) In the US, methoxyflurane is one of the products that have been withdrawn or removed from the market for reasons of safety or effectiveness.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Methoxyflurane.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2,2-dichloro-1,1-difluoro-1-methoxyethane
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C3H4Cl2F2O/c1-8-3(6,7)2(4)5/h2H,1H3
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RFKMCNOHBTXSMU-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

COC(C(Cl)Cl)(F)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C3H4Cl2F2O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

C3H4Cl2F2O

CH3OCF2CHCl2

2.3 Other Identifiers

2.3.1 CAS

76-38-0

2.3.2 Deprecated CAS

8056-95-9

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 UN Number

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 ICSC Number

2.3.12 KEGG ID

2.3.13 Metabolomics Workbench ID

2.3.14 NCI Thesaurus Code

2.3.15 Nikkaji Number

2.3.16 NSC Number

2.3.17 PharmGKB ID

2.3.18 Pharos Ligand ID

2.3.19 RTECS Number

2.3.20 RXCUI

2.3.21 Wikidata

2.3.22 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Anecotan
  • Methofluranum
  • Methoxyflurane
  • Penthrane
  • Pentrane

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
164.96 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
163.9607265 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
163.9607265 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
9.2 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
8
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
75.7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Methoxyflurane is a clear colorless liquid with a sweet fruity odor. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Colorless liquid with a fruity odor; inhalation anesthetic; [NIOSH]
Liquid
COLOURLESS LIQUID WITH CHARACTERISTIC ODOUR.
Colorless liquid with a fruity odor. [inhalation anesthetic]

3.2.2 Color / Form

Liquid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
Clear, colorless liquid
Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 364

3.2.3 Odor

Fruity
Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 364

3.2.4 Boiling Point

220.3 °F at 760 mmHg (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
105 °C
PhysProp
105 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
BP: 51 °C at 100 mm Hg
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
220 °F

3.2.5 Melting Point

-31 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
-35 °C
PhysProp
-35 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
-31 °F

3.2.6 Flash Point

145 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
145 °F
63 °C

3.2.7 Solubility

less than 1 mg/mL at 66 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
28300 mg/L (at 37 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
In water, 28,300 mg/L at 37 °C
Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Ver 5. Tucson, AZ: Univ AZ, College of Pharmacy (1992)
6.46e+00 g/L
Solubility in water, g/100ml at 37 °C: 2.83 (poor)
Slight

3.2.8 Density

1.426 at 68 °F (NTP, 1992) - Denser than water; will sink
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
1.4262 at 20 °C/4 °C; 1.4226 at 20 °C/4 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
Relative density (water = 1): 1.42
(77 °F): 1.42

3.2.9 Vapor Density

Relative vapor density (air = 1): 5.7

3.2.10 Vapor Pressure

20 mmHg at 63.9 °F ; 22.5 mmHg at 68 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
49.1 [mmHg]
49 mm Hg at 25 °C /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 7, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
Vapor pressure, kPa at 20 °C: 3.1
23 mmHg

3.2.11 LogP

2.21
HANSCH,C ET AL. (1995)
log Kow = 2.21
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 5
1.8
2.21

3.2.12 Henry's Law Constant

Henry's Law constant = 3.7X10-3 atm-cu m/mole at 25 °C
Abraham MH et al; J Pharm Sci 83: 1083-100 (1994)

3.2.13 Kovats Retention Index

Standard non-polar
706 , 708 , 701 , 701 , 701
Semi-standard non-polar
722
Standard polar
1124

3.2.14 Other Experimental Properties

Conversion factor: 1 ppm = 6.75 mg/cu m
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases. U.S. Department of Health & Human Services, Public Health Service, Center for Disease Control & Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001.
Completely stable in the presence of alkali air, light, or moisture... Combustible
Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 364
Hydroxyl radical reaction rate constant = 3.2X10-14 cu cm/molecule-sec at 25 °C /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 7, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

3.3 SpringerMaterials Properties

3.4 Chemical Classes

Other Uses -> Waste Anesthetic Gases

3.4.1 Drugs

Pharmaceuticals -> Nervous system -> Anesthetics
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.4.1.1 Human Drugs
Human drug -> Discontinued
Human drug -> Active ingredient (METHOXYFLURANE)
Paediatric drug

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.1.2 19F NMR Spectra

1 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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2 of 2
Instrument Name
SEE COMMENT
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 5
View All
NIST Number
333743
Library
Main library
Total Peaks
86
m/z Top Peak
81
m/z 2nd Highest
83
m/z 3rd Highest
85
Thumbnail
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2 of 5
View All
NIST Number
25048
Library
Replicate library
Total Peaks
15
m/z Top Peak
81
m/z 2nd Highest
83
m/z 3rd Highest
67
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4.3 IR Spectra

4.3.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
01787
Lot Number
32484
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For use in the induction and maintenance of general anesthesia
Treatment of acute pain

7.2 FDA Approved Drugs

7.3 Clinical Trials

7.3.1 ClinicalTrials.gov

7.3.2 EU Clinical Trials Register

7.4 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Pain
Drug Form
Inhalation vapour, liquid
Administration Route
Inhalation use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2021-12-03

7.5 Therapeutic Uses

Anesthetic (inhalation).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
(VET): Anesthetic.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
... Methoxyflurane /is/ indicated for the induction and maintenance of general anesthesia . However, inhalation anesthetic agents are rarely used alone; other medications are frequently administered to induce or supplement anesthesia. /Included in US product labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
... Methoxyflurane ... /is/ indicated in low doses to provide analgesia for procedures not requiring loss of consciousness. /Included in US product labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
For more Therapeutic Uses (Complete) data for METHOXYFLURANE (6 total), please visit the HSDB record page.

7.6 Drug Warnings

Inhalation anesthetics cross the placenta. Risk-benefit must be considered because studies (by retrospective survey) of operating room personnel chronically exposed to low concentrations of inhalation anesthetics indicate that pregnancies in female personnel and wives of male personnel may be subject to an increased incidence of spontaneous abortions, stillbirths, and possibly birth defects . However, the methods used in obtaining and interpreting the data in these studies have been questioned. /Inhalation anesthetics/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Because of potential nephrotoxicity, administration of methoxyflurane in concentrations sufficient to produce muscle relaxation is not recommended ; a neuromuscular blocking agent should be used concurrently if necessary. Also, it is recommended that methoxyflurane not be used during vascular surgery at or near renal blood vessels.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Caution needed in diabetes, uncontrolled or with polyuria or obesity; in renal function impairment of disease; or in toxemia of pregnancy, as methoxyflurane may increase the risk of nephrotoxicity.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Monitoring of renal function may be needed to detect possible nephrotoxicity if patient's postoperative urine output is excessive.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Methoxyflurane, a general anesthetic, is a known nephrotoxin. A case is presented that demonstrated diffuse, bilateral renal cortical calcification on CT secondary to repeated methoxyflurane inhalation.
Brennan RP et al; J Comput Assist Tomogr 12 (1): 155-6 (1988)

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Methoxyflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential.

8.2 MeSH Pharmacological Classification

Anesthetics, Inhalation
Gases or volatile liquids that vary in the rate at which they induce anesthesia; potency; the degree of circulation, respiratory, or neuromuscular depression they produce; and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration. Because of their rapid elimination, any postoperative respiratory depression is of relatively short duration. (From AMA Drug Evaluations Annual, 1994, p173) (See all compounds classified as Anesthetics, Inhalation.)

8.3 ATC Code

N - Nervous system

N02 - Analgesics

N02B - Other analgesics and antipyretics

N02BG - Other analgesics and antipyretics

N02BG09 - Methoxyflurane

8.4 Absorption, Distribution and Excretion

Elimination: Primary: 35% excreted unchanged by exhalation.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Inhalation anesthetics are rapidly absorbed into the circulation via the lungs. /Inhalation anesthetics/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
The urinary fluoride ion concentration was compared in 2 series of parturients, the one receiving methoxyflurane-nitrous oxide analgesia during labor and the other nitrous oxide analgesia. Results showed that in the methoxyflurane-nitrous oxide analgesia series, both the mothers and the neonates showed a significantly higher urinary fluoride ion concentration in comparison to the nitrous analgesia series. The urinary fluoride concentration was related to the vaporized amount of methoxyflurane.
Dahlgren BE; Acta Pharm Suec 15 (3): 211-7 (1978)

8.5 Metabolism / Metabolites

Hepatic.
Biotransformation - 50% of dose metabolized. A substantial quantity of inorganic fluoride is formed; also metabolized to other potentially nephrotoxic substances.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.

8.6 Mechanism of Action

Methoxyflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Methoxyflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Methoxyflurane also binds to the GABA receptor, the large conductance Ca2+ activated potassium channel, the glutamate receptor and the glycine receptor.
Some halogenated agents, especially methoxyflurane, because of a higher level of fluoride production, induce a renal concentrating defect that could be related to an ascending limb impairment. The mechanisms of fluoride toxicity on an immortalized cell line /was investigated/. Cells were cultured for 2, 6 or 24 hr in the presence of fluoride. Toxicity evaluation was based on: cell numbers, protein content, leucine-incorporation, lactate dehydrogenase (LDH) and N-acetyl-beta-glucosaminidase (NAG) releases, Na-K-ATPase and Na-K-2Cl activities, electron microscope studies. ... At 5 mmol after 24 hr, fluoride decreased cell numbers (-14%, *P < 0.05), protein content (-16%*), leucine incorporation (-54%*), Na-K-2Cl activity (-84%*), increased LDH (+145%*) and NAG release (+190%*). Na-K-ATPase was more sensitive and impaired from 1 mmol for 24hr and after 2 hr at 5 mmol. Crystal formation in mitochondria occurred after 6 hr at 5 mmol. Infra-red analysis and fluoride microdetermination established that crystals contained sodium, phosphate and fluoride. The results suggest that the Na-K-ATPase pump is a major target for fluoride toxicity in Henle's loop.
Cittanove ML et al; Eur J Anaesthesiol 19 (5): 341-9 (2002)
The precise mechanism by which inhalation anesthetics produce loss of perception of sensations and unconsciousness is not known. Inhaled anesthetics act at many areas in the CNS. The Meyer-Overton theory suggests that the site of action of inhalation anesthetics may be the lipid matrix of neuronal membranes or other lipophilic sites. Anesthetics may cause changes in membrane thickness, which in turn affect the gating properties of ion channels in neurons. Interference with the hydrophobic portion of neuronal ion channel membrane proteins may be an important mechanism. /Inhalation anesthetics/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.

8.7 Human Metabolite Information

8.7.1 Cellular Locations

  • Cytoplasm
  • Membrane

9 Use and Manufacturing

9.1 Uses

Sources/Uses
Used as an anesthetic; [Merck Index] A discontinued drug; [HSDB]
Merck Index - O'Neil MJ, Heckelman PE, Dobbelaar PH, Roman KJ (eds). The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 15th Ed. Cambridge, UK: The Royal Society of Chemistry, 2013.
MEDICATION: Anesthetic
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
Discontinued drug... methoxyflurane (liquid inhalation 99.9%).
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 1, 2004: https://www.fda.gov/cder/ob/
For use in the induction and maintenance of general anesthesia

9.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans

9.2 Methods of Manufacturing

... Produced industrially by the addition of methanol to 1,1-dichloro-2,2-difluoroethylene in the presence of sodium methoxide.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V3 151 (2003)

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Pictogram(s)
Flammable
Irritant
Health Hazard
Signal
Warning
GHS Hazard Statements

H226 (100%): Flammable liquid and vapor [Warning Flammable liquids]

H315 (16.7%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (16.7%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

H341 (83.3%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

Precautionary Statement Codes

P203, P210, P233, P240, P241, P242, P243, P261, P264, P264+P265, P271, P280, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P370+P378, P403+P233, P403+P235, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 6 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Flam. Liq. 3 (100%)

Skin Irrit. 2 (16.7%)

Eye Irrit. 2 (100%)

STOT SE 3 (16.7%)

10.1.3 Health Hazards

Excerpt from NIOSH Pocket Guide for Methoxyflurane:

Exposure Routes: Inhalation, ingestion, skin and/or eye contact

Symptoms: Irritation eyes; central nervous system depression, analgesia, anesthesia, convulsions, resp depression; liver, kidney injury; In Animals: reproductive, teratogenic effects

Target Organs: Eyes, central nervous system, liver, kidneys, reproductive system (NIOSH, 2024)

10.1.4 Fire Hazards

This chemical is combustible. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Combustible. Above 63 °C explosive vapour/air mixtures may be formed.

10.1.5 Hazards Summary

See WASTE ANESTHETIC GASES.

10.1.6 Skin, Eye, and Respiratory Irritations

Potential symptoms of overexposure are eye irritation ... .
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073

10.2 Safety and Hazard Properties

10.2.1 Flammable Limits

Flammability
Combustible Liquid

10.2.2 Lower Explosive Limit (LEL)

7 % at 176 °F (NIOSH, 2024)
(176 °F): 7%

10.2.3 Explosive Limits and Potential

Explosive limits , vol% in air: 7-?

10.2.4 NIOSH Recommendations

60 Minute Ceiling Value: 2 ppm (13.5 mg/cu m). REL for exposure to waste anesthetic gas.
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety& Health. DHHS (NIOSH) Publication No. 2004-103 (2003).

10.3 First Aid Measures

Inhalation First Aid
Fresh air, rest.
Skin First Aid
Rinse skin with plenty of water or shower.
Eye First Aid
First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.
Ingestion First Aid
Rinse mouth. Refer for medical attention .

10.3.1 First Aid

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.

INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.

INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

(See general first aid procedures)

Eye: Irrigate immediately - If this chemical contacts the eyes, immediately wash (irrigate) the eyes with large amounts of water, occasionally lifting the lower and upper lids. Get medical attention immediately.

Skin: Soap wash - If this chemical contacts the skin, wash the contaminated skin with soap and water.

Breathing: Respiratory support

Swallow: Medical attention immediately - If this chemical has been swallowed, get medical attention immediately.

10.4 Fire Fighting

Fires involving this compound can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Use water spray, powder, foam, carbon dioxide.

10.5 Accidental Release Measures

10.5.1 Isolation and Evacuation

Excerpt from ERG Guide 128 [Flammable Liquids (Water-Immiscible)]:

IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area for at least 50 meters (150 feet) in all directions.

LARGE SPILL: Consider initial downwind evacuation for at least 300 meters (1000 feet).

FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

10.5.2 Spillage Disposal

Personal protection: filter respirator for organic gases and vapours adapted to the airborne concentration of the substance. Collect leaking and spilled liquid in sealable metal containers as far as possible. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

10.5.3 Disposal Methods

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

10.5.4 Preventive Measures

Work clothing that becomes wet or significantly contaminated should be removed and replaced.
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety& Health. DHHS (NIOSH) Publication No. 2004-103 (2003).
SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

10.6 Handling and Storage

10.6.1 Nonfire Spill Response

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, use absorbent paper to pick up all liquid spill material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

STORAGE PRECAUTIONS: You should protect this material for prolonged exposure to light and store it under ambient temperatures. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

10.7 Exposure Control and Personal Protection

10.7.2 Permissible Exposure Limit (PEL)

none

10.7.3 Immediately Dangerous to Life or Health (IDLH)

N.D.

See: IDLH INDEX

10.7.4 Inhalation Risk

No indication can be given about the rate at which a harmful concentration of this substance in the air is reached on evaporation at 20 °C.

10.7.5 Effects of Short Term Exposure

Exposure at high levels could cause unconsciousness.

10.7.6 Effects of Long Term Exposure

The substance may have effects on the kidneys. This may result in kidney impairment.

10.7.7 Personal Protective Equipment (PPE)

Excerpt from NIOSH Pocket Guide for Methoxyflurane:

Skin: No recommendation is made specifying the need for personal protective equipment for the body.

Eyes: PREVENT EYE CONTACT - Wear appropriate eye protection to prevent eye contact.

Wash skin: No recommendation is made specifying the need for washing the substance from the skin (either immediately or at the end of the work shift).

Remove: WHEN WET OR CONTAMINATED - Work clothing that becomes wet or significantly contaminated should be removed and replaced.

Change: No recommendation is made specifying the need for the worker to change clothing after the workshift. (NIOSH, 2024)

Wear appropriate eye protection to prevent eye contact.
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety& Health. DHHS (NIOSH) Publication No. 2004-103 (2003).

(See personal protection and sanitation codes)

Skin: No recommendation

Eyes: Prevent eye contact - Wear appropriate eye protection to prevent eye contact.

Wash skin: No recommendation

Remove: When wet or contaminated

Change: No recommendation

10.7.8 Respirator Recommendations

10.7.9 Preventions

Fire Prevention
NO open flames. Above 63 °C use a closed system and ventilation.
Inhalation Prevention
Use ventilation, local exhaust or breathing protection.
Skin Prevention
Protective gloves.
Eye Prevention
Wear safety spectacles or eye protection in combination with breathing protection.
Ingestion Prevention
Do not eat, drink, or smoke during work.

10.8 Stability and Reactivity

10.8.1 Air and Water Reactions

Insoluble in water.

10.8.2 Reactive Group

Ethers

Halogenated Organic Compounds

Fluorinated Organic Compounds

10.8.3 Reactivity Profile

METHOXYFLURANE may be sensitive to prolonged exposure to light.

10.9 Transport Information

10.9.1 DOT Label

Combustible Liquid

10.10 Regulatory Information

The Australian Inventory of Industrial Chemicals
Chemical: Ethane, 2,2-dichloro-1,1-difluoro-1-methoxy-

10.10.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products, incl methoxyflurane (liquid inhalation 99.9%).
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 1, 2004: https://www.fda.gov/cder/ob/

10.11 Other Safety Information

10.11.1 Special Reports

Reichle FM, Conzen PF; Halogenated Inhalational Anesthetics; Best Pract Res Clin Anesthesiol 17 (1): 29-46 (2003)

11 Toxicity

11.1 Toxicological Information

11.1.1 Toxicity Summary

Methoxyflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Methoxyflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Methoxyflurane also binds to the GABA receptor, the large conductance Ca2+ activated potassium channel, the glutamate receptor and the glycine receptor.

11.1.2 NIOSH Toxicity Data

11.1.3 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

11.1.4 Health Effects

Detrimental effects on the kidneys. [Wikipedia]

11.1.5 Exposure Routes

The substance can be absorbed into the body by inhalation of its vapour.
inhalation, ingestion, skin and/or eye contact
Oral

11.1.6 Symptoms

Inhalation Exposure
Dizziness. Drowsiness. Unconsciousness.
Eye Exposure
Redness.
irritation eyes; central nervous system depression, analgesia, anesthesia, convulsions, resp depression; liver, kidney injury; In Animals: reproductive, teratogenic effects
Symptoms of overexposure include eye irritation, CNS depression, analgesia, anesthesia, seizures, respiratory depression, and liver and kidney damage.

11.1.7 Target Organs

Eyes, central nervous system, liver, kidneys, reproductive system

11.1.8 Adverse Effects

Neurotoxin - Acute solvent syndrome

Reproductive Toxin - A chemical that is toxic to the reproductive system, including defects in the progeny and injury to male or female reproductive function. Reproductive toxicity includes developmental effects. See Guidelines for Reproductive Toxicity Risk Assessment.

11.1.9 Acute Effects

11.1.10 Toxicity Data

LC50 (rat) = 33,500 mg/m3/4h
LD50: 3600 mg/kg (Oral, Rat) (A308)
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

11.1.11 Interactions

/Other nephrotoxic agents/ may increase the risk of severe nephrotoxicity if administered prior to, during, or following administration of methoxyflurane; concurrent or sequential use is generally not recommended.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Caution should be used in concurrent administration /of citrate-anticoagulated blood (massive transfusions) or systemic lincomycins or nondepolarizing neuromuscular blocking agents or systemic polymyxins/ with halogenated anesthetics /including methoxyflurane/, because of the possibility of additive neuromuscular blockade; although increased or prolonged skeletal muscle weakness and respiratory depression or paralysis [apnea] may occur, clinical significance is minimal if the patient is being mechanically ventilated; however, dosage of nondepolarizing neuromuscular blocking agents should be decreased to 1/3 of the usual dose or as determined using a peripheral nerve stimulator ; treatment with anticholinesterase agents or calcium salts may help reverse the blockade, but calcium salts are not recommended if tubocurarine has been given because they may potentiate, rather than reverse, its effects.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
/Chronic alcohol ingestion/ may increase anesthetic requirement /of methoxyflurane/.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
Concurrent use /of amiodarone/ with inhalation anesthetics /including methoxyflurane/ may potentiate hypotension and increase the risk of atropine-resistant bradycardia
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
For more Interactions (Complete) data for METHOXYFLURANE (18 total), please visit the HSDB record page.

11.1.12 Human Toxicity Excerpts

/CASE REPORTS/ Methoxyflurane, a general anesthetic, is a known nephrotoxin. A case is presented that demonstrated diffuse, bilateral renal cortical calcification on CT secondary to repeated methoxyflurane inhalation.
Brennan RP et al; J Comput Assist Tomogr 12 (1): 155-6 (1988)
/CASE REPORTS/ A young woman presented with a novel multisystem disease: painful periostitis, osteosclerosis, hypertension, and renal dysfunction. The similarity of some of this clinical picture to fluoride intoxication led to the discovery of massively elevated fluoride levels in serum, urine, and bone. Although initially an enigma, the source of fluoride was later found to be the illicit use of an anesthetic agent, methoxyflurane. This agent is one of a class of organofluorides that, by virtue of biotransformation, is a known cause of inorganic fluoride exposure. Though the drug is potentially nephrotoxic as generally used, exposure to it is transient and has not previously led to discernible bone disease.
Klemmer PJ, Hadler NM; Ann Intern Med 89 (5 Pt 1): 607-11 (1978)
/SIGNS AND SYMPTOMS/ Potential symptoms of overexposure are eye irritation; CNS depression, analgesia; anesthesia, seizures, respiratory depression; liver and kidney injury.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1073
/CASE REPORTS/ A veterinarian's assistant who sniffed methoxyflurane as a euphoriant developed fulminant hepatitis and died of hepatic failure. ...
Min KW et al; South Med J 70 (11): 1363-4 (1977)

11.1.13 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats have indicated that exposure to doses equivalent to 67 hours of 0.2% methoxyflurane caused fetal growth retardation.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004.
/LABORATORY ANIMALS: Acute Exposure/ Effects of acute exposure (2 hr) to either 1.5% halothane or 0.5% methoxyflurane were investigated in the Sprague Dawley rat. Pituitary (PIT) and central nervous system (CNS) substance P (SP)-like and beta-endorphin (beta-end)-like immunoreactivities were evaluated immediately after anesthetic exposure (2 hr), after righting reflex (4 hr) or 24 hr postexposure (24 hr). Only halothane significantly reduced SP-like immunoreactivity in olfactory bulbs in both the 2-hr and 4-hr groups. Halothane elevated SP-like immunoreactivity of hippocampus at all three time periods, and in the hypothalamus at 2 hr. Both anesthetics significantly depleted thalamic concentrations of SP-like immunoreactivity. Methoxyflurane anesthesia resulted in a drastic decrease in SP-like immunoreactivity in PIT at all three time periods. ... Both anesthetics significantly decreased beta-end-like immunoreactivity in the olfactory bulbs and thalami at 2, 4, and 24 hr. ... Halothane significantly elevated PIT beta-end-like immunoreactivity at 2 and 24 hr, while methoxyflurane significantly lowered it in the 4-hr group, but elevated the levels of the same in the 24-hr group. Brain stem beta-end immunoreactivity were significantly reduced at 2 h by both anesthetics, and at 4 hr by methoxyflurane. Results indicate that halothane and methoxyflurane may differ significantly in their actions on SP and beta-end secreting neurons in the CNS.
Karuri AR et al; Brain Res Bull 45 (5): 501-6 (1998)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Male Fischer 344 rats were exposed to air or to 50 ppm. methoxyflurane vapor for a period of 14 weeks. At the end of this period, half of the rats in each group were killed; the remainder breathed air only for a further four weeks (recovery period) before being killed. During the exposure period, growth of the methoxyflurane-exposed rats was markedly depressed, though food consumption was similar in the two groups. Both water consumption and urine volume were increased by methoxyflurane, possibly due to the nephrotoxic effect of fluoride, the concentration of which exceeded 50 micromolar in the sera of all exposed rats. At the end of the exposure period, livers of all exposed rats, but no controls, showed focal hepatocellular degeneration and necrosis, and evidence of liver cell regeneration. Fatty change was prominent. During the recovery period, water consumption and urine volumes returned to near-normal levels. At the end of the recovery period, focal necrosis was still observed in the livers, although fatty change was no longer present. No histological abnormalities were observed in the kidneys of any rats.
Plummer JL et al; Acta Pharmacol Toxicol (Copenh) 57 (3): 176-83 (1985)

11.2 Ecological Information

11.2.1 Environmental Fate / Exposure Summary

Methoxyflurane's former production and use as an anesthetic may have resulted in its release to the environment through various waste streams. Methoxyflurane may still be produced in low quantities and used as a research chemical. If released to air, an estimated vapor pressure of 49 mm Hg at 25 °C indicates methoxyflurane will exist solely as a vapor in the ambient atmosphere. Vapor-phase methoxyflurane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 498 days. If released to soil, methoxyflurane is expected to have moderate mobility based upon an estimated Koc of 380. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 3.7X10-3 atm-cu m/mole. Methoxyflurane may volatilize from dry soil surfaces based upon its estimated vapor pressure. If released into water, methoxyflurane is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.5 hours and 5 days, respectively. An estimated BCF of 10 suggests bioconcentration in aquatic organisms is low. Methoxyflurane contains functional groups that may be susceptible to hydrolysis; however, the rate of this potential reaction is not known. Occupational exposure to methoxyflurane may occur through inhalation and dermal contact with this compound at workplaces where methoxyflurane is still produced or used. The general population is not expected to be exposed to this compound since it was primarily used as an anesthetic and this use has been discontinued. (SRC)

11.2.2 Artificial Pollution Sources

Methoxyflurane's former production and use as an anesthetic(1) may have resulted in its release to the environment through various waste streams(SRC). Methoxyflurane may still be produced in low quantities and used as a research chemical(2).
(1) O'Neil MJ, ed; Merck Index, 13th ed, Whitehouse Station, NJ Merck & Co. p 1073 (2001)
(2) SRI International. 2003 Directory of Chemical Producers. SRI Consulting, Menlo Park, CA p. 538 (2003)

11.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 2.21(2) and a regression-derived equation(3), indicates that methoxyflurane is expected to have moderate mobility in soil(SRC). Volatilization of methoxyflurane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.7X10-3 atm-cu m/mole(4). The potential for volatilization of methoxyflurane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 49 mm Hg(SRC), determined from a fragment constant method(5).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 5 (1995)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(4) Abraham MH et al; J Pharm Sci 83: 1083-1100 (1994)
(5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 2.21(2) and a regression-derived equation(3), indicates that methoxyflurane is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 3.7X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.5 hours and 5 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 10(SRC), from the log Kow(2)and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Alkyl halides such as methoxyflurane have the potential to hydrolyze(3); however, the rate of this reaction is unknown.
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 5 (1995)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(4) Abraham MH et al; J Pharm Sci 83: 1083-1100 (1994)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
(6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methoxyflurane, which has an estimated vapor pressure of 49 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase methoxyflurane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 498 days(SRC), calculated from its rate constant of 3.2X10-14 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

11.2.4 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of methoxyflurane with photochemically-produced hydroxyl radicals has been estimated as 3.2X10-14 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 498 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Methoxyflurane is not expected to undergo direct photolysis since it does not absorb light in the environmental UV spectrum (>290 nm)(2). Alkyl halides may be susceptible to hydrolysis(3); however, the rate of this reaction for methoxyflurane is unknown.
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Barrett AM; Nunn JF; Brit J Anaesth 44: 306-312 (1972)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)

11.2.5 Environmental Bioconcentration

An estimated BCF of 10 was calculated for methoxyflurane(SRC), using a log Kow of 2.21(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 5 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

11.2.6 Soil Adsorption / Mobility

The Koc of methoxyflurane is estimated as 380(SRC), using a log Kow of 2.21(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that methoxyflurane is expected to have moderate mobility in soil.
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 5 (1995)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(3) Swann RL et al; Res Rev 85: 17-28 (1983)

11.2.7 Volatilization from Water / Soil

The Henry's Law constant for methoxyflurane is 3.7X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that methoxyflurane is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5 days(SRC. Methoxyflurane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of methoxyflurane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 49 mm Hg(SRC), determined from a fragment constant method(3).
(1) Abraham MH et al; J Pharm Sci 83: 1083-1100 (1994)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

11.2.8 Probable Routes of Human Exposure

Occupational exposure to methoxyflurane may occur through inhalation and dermal contact with this compound at workplaces where methoxyflurane is produced or used. The general population is not expected to be exposed to this compound since it was primarily used as an anesthetic and this use has been discontinued. (SRC)

12 Associated Disorders and Diseases

Associated Occupational Diseases with Exposure to the Compound
Solvents, acute toxic effect [Category: Acute Poisoning]

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Chemical Co-Occurrences in Literature

13.6 Chemical-Gene Co-Occurrences in Literature

13.7 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

14.5 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Chemical-Target Interactions

15.2 Drug-Drug Interactions

15.3 Drug-Food Interactions

Avoid alcohol. Ingesting alcohol may increase the CNS depressant effects of methoxyflurane.

15.4 Pathways

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: ATC

17.5 KEGG: Drug Groups

17.6 WHO ATC Classification System

17.7 ChemIDplus

17.8 CAMEO Chemicals

17.9 ChEMBL Target Tree

17.10 UN GHS Classification

17.11 NORMAN Suspect List Exchange Classification

17.12 EPA DSSTox Classification

17.13 PFAS and Fluorinated Organic Compounds in PubChem

17.14 EPA Substance Registry Services Tree

17.15 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Ethane, 2,2-dichloro-1,1-difluoro-1-methoxy-
    https://services.industrialchemicals.gov.au/search-inventory/
  2. CAMEO Chemicals
    LICENSE
    CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data.
    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification
    https://cameochemicals.noaa.gov/browse/react
  3. ILO-WHO International Chemical Safety Cards (ICSCs)
  4. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  5. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  6. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  7. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  8. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  9. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  10. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  11. Hazardous Substances Data Bank (HSDB)
  12. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  13. The National Institute for Occupational Safety and Health (NIOSH)
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    The information provided using CDC Web site is only intended to be general summary information to the public. It is not intended to take the place of either the written law or regulations.
    https://www.cdc.gov/Other/disclaimer.html
    Ether, 2,2-dichloro-1,1-difluoroethyl methyl
    https://www.cdc.gov/niosh-rtecs/KN7752E0.html
  14. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
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    https://haz-map.com/About
  15. ChEBI
  16. Open Targets
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    https://platform-docs.opentargets.org/licence
  17. Toxin and Toxin Target Database (T3DB)
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    http://www.t3db.ca/downloads
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    http://www.ebi.ac.uk/Information/termsofuse.html
  19. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  20. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  21. Drug Gene Interaction database (DGIdb)
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    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  22. Therapeutic Target Database (TTD)
  23. European Medicines Agency (EMA)
    LICENSE
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    https://www.ema.europa.eu/en/about-us/legal-notice
  24. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  25. EU Clinical Trials Register
  26. Japan Chemical Substance Dictionary (Nikkaji)
  27. KEGG
    LICENSE
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
  28. Metabolomics Workbench
  29. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  30. NIST Mass Spectrometry Data Center
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    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  31. SpectraBase
    Ethane, 2,2-dichloro-1,1-difluoro-1-methoxy-
    https://spectrabase.com/spectrum/BHtlBWigvxY
    Ethane, 2,2-dichloro-1,1-difluoro-1-methoxy-
    https://spectrabase.com/spectrum/EASQp701KgJ
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    https://spectrabase.com/spectrum/7jvcF05Xg4d
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    https://spectrabase.com/spectrum/I5hwhPhEEbA
    1-METHOXY-3,3-DICHLORO-2,2-DIFLUOROETHANE
    https://spectrabase.com/spectrum/CvnmQ8zg9DB
  32. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  33. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    Methoxyfluorane
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  34. PharmGKB
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  35. Pharos
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    https://pharos.nih.gov/about
  36. Springer Nature
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
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    https://www.whocc.no/copyright_disclaimer/
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    https://www.nlm.nih.gov/copyright.html
  43. PubChem
  44. GHS Classification (UNECE)
  45. EPA Substance Registry Services
  46. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  47. PATENTSCOPE (WIPO)
  48. NCBI
CONTENTS