An official website of the United States government

Isoflurane

PubChem CID
3763
Structure
Isoflurane_small.png
Isoflurane_3D_Structure.png
Molecular Formula
Synonyms
  • isoflurane
  • 26675-46-7
  • 1-Chloro-2,2,2-trifluoroethyl difluoromethyl ether
  • Forane
  • 2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane
Molecular Weight
184.49 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Isoflurane is an organofluorine compound. It has a role as an inhalation anaesthetic. It is functionally related to a methoxyethane.
A stable, non-explosive inhalation anesthetic, relatively free from significant side effects.
Isoflurane is a General Anesthetic. The physiologic effect of isoflurane is by means of General Anesthesia.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Isoflurane.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C3H2ClF5O/c4-1(3(7,8)9)10-2(5)6/h1-2H
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

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

2.1.4 SMILES

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

2.2 Molecular Formula

C3H2ClF5O
C3H2ClF5O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 ICSC Number

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

Isoflurane

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
184.49 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.1
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
6
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
183.9714332 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
183.9714332 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
10
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
102
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
1
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

Clear colorless liquid with a mild odor; [Merck Index] Musty ethereal odor; [Abbott Laboratories MSDS]
Liquid
COLOURLESS LIQUID.
Colorless liquid

3.2.2 Color / Form

Clear, colorless liquid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895

3.2.3 Odor

Slight odor
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895

3.2.4 Boiling Point

48.5 °C
PhysProp
48.5 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895
49 °C
119.3 °F

3.2.5 Melting Point

48-48.5
U.S. Patent 3,535,388.

3.2.6 Solubility

4470 mg/L (at 37 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
In water, 4.47X10+3 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)
Easily miscible with organic liquids including fats and oils
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895
3.56e+00 g/L
Solubility in water: poor

3.2.7 Density

Specific gravity: 1.45
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895
Relative density (water = 1): 1.5
1.45

3.2.8 Vapor Pressure

330.0 [mmHg]
330 mm Hg at 25 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895
Vapor pressure, kPa at 20 °C: 32
330 mmHg

3.2.9 LogP

2.06
HANSCH,C ET AL. (1995)
log Kow = 2.06
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 5
2.1

3.2.10 Henry's Law Constant

Henry's Law constant = 2.87X10-2 atm-cu m/mol at 25 °C
Abraham MH et al; J Pharm Sci 83: 1085-100 (1994)

3.2.11 Stability / Shelf Life

Isoflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8

3.2.12 Decomposition

When heated to decomposition it emits toxic fumes of /fluorine and chlorine/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2135

3.2.13 Refractive Index

Index of refraction: 1.3002 at 20 °C/D
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895

3.2.14 Kovats Retention Index

Standard non-polar
454 , 454

3.2.15 Other Experimental Properties

Greenhouse Warming Potential = 0.03 (calculated; CFC-12 = 1)
Brown AC et al; Nature 341: 635-7 (1989)
Ozone depletion potential = 0.01 (relative to CFC-11 and CFC-12)
Brown AC et al; Nature 341: 635-7 (1989)
Hydroxyl radical reaction rate constant = 1.51X10-14 cu cm/molec-sec at 25 °C
Tokuhashi K et al; Int J Chem Kinet 31: 846-853 (1999)

3.3 Chemical Classes

Other Uses -> Waste Anesthetic Gases

3.3.1 Drugs

Pharmaceuticals -> Anesthetics
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
Pharmaceuticals -> Nervous system -> Anesthetics
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Anesthetics, Inhalation
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (ISOFLURANE)
Paediatric drug
General anaesthetics and oxygen > Inhalational medicines
3.3.1.2 Animal Drugs
Active Ingredients (Isoflurane) -> FDA Greenbook
Pharmaceuticals -> UK Veterinary Medicines Directorate List
S104 | UKVETMED | UK Veterinary Medicines Directorate's List | DOI:10.5281/zenodo.7802119

3.3.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
Thumbnail
Thumbnail

4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 4
View All
NIST Number
163170
Library
Main library
Total Peaks
24
m/z Top Peak
51
m/z 2nd Highest
149
m/z 3rd Highest
117
Thumbnail
Thumbnail
2 of 4
View All
NIST Number
250691
Library
Replicate library
Total Peaks
81
m/z Top Peak
51
m/z 2nd Highest
149
m/z 3rd Highest
117
Thumbnail
Thumbnail

4.3 IR Spectra

4.3.1 FTIR Spectra

Instrument Name
Bruker Tensor 27 FT-IR
Technique
Neat
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
TCI Chemicals India Pvt. Ltd.
Catalog Number
C2485
Lot Number
373KI-OP
Copyright
Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.3.2 ATR-IR Spectra

1 of 2
Instrument Name
Bio-Rad FTS
Technique
ATR-Neat
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/23989>23989</a>
Lot Number
0519641-1
Copyright
Copyright © 2019-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Instrument Name
Bruker Tensor 27 FT-IR
Technique
ATR-Neat
Source of Spectrum
Bio-Rad Laboratories, Inc.
Source of Sample
TCI Chemicals India Pvt. Ltd.
Catalog Number
C2485
Lot Number
373KI-OP
Copyright
Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For induction and maintenance of general anesthesia.
Sedation of mechanically ventilated patients

7.2 LiverTox Summary

Isoflurane is a commonly used inhalational anesthetic and has an excellent safety record. Isoflurane has been linked to rare instances of severe acute liver injury resembling halothane induced liver injury in small case series and individual case reports.

7.3 Drug Classes

Breast Feeding; Lactation; Anesthetics, Inhalation
Anesthetics, Halogenated

7.4 WHO Essential Medicines

Drug
Drug Classes
General anaesthetics and oxygen > Inhalational medicines
Formulation
Respiratory - Inhalation - liquid:
Indication
Anaesthetics and therapeutic gases

7.5 FDA Approved Drugs

7.6 FDA Orange Book

7.7 FDA National Drug Code Directory

7.8 FDA Green Book

7.9 Drug Labels

Drug and label
Active ingredient and drug

7.10 Clinical Trials

7.10.1 ClinicalTrials.gov

7.10.2 EU Clinical Trials Register

7.10.3 NIPH Clinical Trials Search of Japan

7.11 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Neonatology-Paediatric Intensive Care
Drug Form
Inhalation vapour, liquid
Administration Route
Inhalation use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2022-03-11

7.12 Therapeutic Uses

FORANE (isoflurane, USP) may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
In cases of life-threatening status asthmaticus which are refractory to drug therapy, the administration of inhalation anesthetics can be life-saving as they help alleviate bronchial spasm. We had an 11-year-old female patient suffering from status asthmaticus who was moribund from severe CO2 narcosis and was not responding to any of the conventional therapies. She finally fell into ventricular fibrillation. After cardiopulmonary resuscitation, we administered 2.0% isoflurane in oxygen. Within half an hour, her high inspiratory pressure was dramatically decreased, and then the isoflurane concentration was maintained at 1.0%. After 14 hours of isoflurane anesthesia, PaCO2 decreased to the normal level and the isoflurane treatment was discontinued. The endotracheal tube was removed 4 hours later. She had an uneventful recovery and was discharged from the hospital 11 days later. With its low metabolic rate and therefore low organ toxicity, as well as its low arrhythmogenicity with remarkable bronchodilating activity, we feel isoflurane may well be superior to other inhalation anesthetics in the treatment of status asthmaticus.
Shibata Y et al; Masui 42 (1): 116-9 (1993)
Vet: Isoflurane, USP is used for induction and maintenance of general anesthesia in horses and dogs.
US Natl Inst Health; DailyMed. Current Medication Information for Isoflurane USP (isoflurane) inhalant (August 2009). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b0c8964f-24a8-4bab-ae8d-1536737e43ec

7.13 Drug Warnings

Anesthetics, Inhalation
National Library of Medicine's Medical Subject Headings online file (MeSH, 2009) https://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?mode=&term=Isoflurane
In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature, (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory depression increase as anesthesia is deepened.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
For more Drug Warnings (Complete) data for Isoflurane (24 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Isoflurane 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 FDA Pharmacological Classification

1 of 2
FDA UNII
CYS9AKD70P
Active Moiety
ISOFLURANE
Pharmacological Classes
Physiologic Effects [PE] - General Anesthesia
Pharmacological Classes
Established Pharmacologic Class [EPC] - General Anesthetic
FDA Pharmacology Summary
Isoflurane is a General Anesthetic. The physiologic effect of isoflurane is by means of General Anesthesia.
2 of 2
Non-Proprietary Name
ISOFLURANE
Pharmacological Classes
General Anesthetic [EPC]; General Anesthesia [PE]

8.4 ATC Code

N - Nervous system

N01 - Anesthetics

N01A - Anesthetics, general

N01AB - Halogenated hydrocarbons

N01AB06 - Isoflurane

N01AB06

8.5 Absorption, Distribution and Excretion

In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
It is not known whether this drug is excreted in human milk.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8

8.6 Metabolism / Metabolites

Minimal
Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.
Kharasch ED, Thummel KE; Anesthesiology 79 (4): 795-807 (1993)
Kharasch ED, Thummel KE; Anesthesiology 79 (4): 795-807 (1993)
Isoflurane undergoes minimal biotransformation in man.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8

8.7 Mechanism of Action

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

8.8 Human Metabolite Information

8.8.1 Cellular Locations

  • Cytoplasm
  • Extracellular
  • Membrane

9 Use and Manufacturing

9.1 Uses

Sources/Uses
Used as a special solvent and as an inhalation anesthetic; [Merck Index] A stable, non-explosive inhalation anesthetic, relatively free from significant side effects. [ChemIDplus]
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.
Solvent and dispersant for fluorinated materials
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 896
MEDICATION
MEDICATION (VET)

Use (kg) in Switzerland (2009): >750

Use (kg; approx.) in Germany (2009): >10000

Consumption (g per capita) in Switzerland (2009): 0.096

Consumption (g per capita; approx.) in Germany (2009): 0.12

Excretion rate: 1

Calculated removal (%): 91.9

For induction and maintenance of general anesthesia.

9.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

Trifluoroethanol is methylated with dimethyl sulfate to form the methyl ether, which is then chlorinated to the dichloromethyl ether ... This latter compound, on treatment with HF/SbCl5 forms the product.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1475
Isoflurane is prepared by chlorination of 2,2,2-trifluoroethoxydifluoromethane, itself obtained by alkylation of trifluoroethanol with difluorochloromethane.
Wollweber H; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2012). NY, NY: John Wiley & Sons; Anesthetics, General. Online Posting Date: June 15, 2000
Preparation: Croix, Terrell, DE 1814962 (1969); Terrell, US 3535425 (both to Air Reduction)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 895

9.3 Formulations / Preparations

FORANE (isoflurane, USP) is also supplied in the /250 mL/ aluminum bottles.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
FORANE (isoflurane, USP) is packaged in 100 mL and 250 mL amber-colored bottles.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
Isoflurane USP is packaged in 250mL (NDC 66794-013-25) and 100mL (NDC 66794-013-10) amber-colored bottles./Vet/
US Natl Inst Health; DailyMed. Current Medication Information for Isoflurane USP (isoflurane) inhalant (August 2009). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b0c8964f-24a8-4bab-ae8d-1536737e43ec

10 Identification

10.1 Analytic Laboratory Methods

Method: OSHA 103; Procedure: gas chromatography using a flame-ionization detector; Analyte: isoflurane; Matrix: air; Detection Limit: 23.0 ppb (174 ug/cu m) with Anasorb CMS; 23.5 ppb (177 ug/cu m) with Anasorb 747.
U.S. Department of Labor/Occupational Safety and Health Administration's Index of Sampling and Analytical Methods. Isoflurane (26675-46-7). Available from, as of July 10, 2012: https://www.osha.gov/dts/sltc/methods/toc.html
Analyte: Isoflurane; matrix: solutions; procedure: high performance liquid chromatography with ultraviolet detection at 203 nm; limit of detection: 0.2 mM
Janicki, P.K., Erskine, W.A.R., and James, M.F.M.; J.Chromatogr. 518: 250-253 (1990). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000).

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Note
Pictograms displayed are for 97.1% (99 of 102) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 2.9% (3 of 102) of reports.
Pictogram(s)
Irritant
Health Hazard
Signal
Warning
GHS Hazard Statements

H336 (93.1%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]

H373 (41.2%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

Precautionary Statement Codes

P260, P261, P271, P304+P340, P319, P403+P233, 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 102 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 3 of 102 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 10 notifications provided by 99 of 102 reports by companies with hazard statement code(s).

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.

11.1.2 Hazard Classes and Categories

STOT SE 3 (93.1%)

STOT RE 2 (41.2%)

11.1.3 Fire Hazards

Not combustible. Gives off irritating or toxic fumes (or gases) in a fire.

11.1.4 Hazards Summary

A skin, eye, and respiratory tract irritant; May cause CNS and cardiovascular system effects; [ICSC] Occupational asthma confirmed three workers exposed to Sevoflurane and Isoflurane; [Malo] 2021 TLV Basis: embryo damage, maternal body weight effects, CNS impairment; [ACGIH] Mice exposed to concentrations of 0.6% for 4hr/day during gestation produced smaller litters, delayed ossification, and increased frequency of cleft palate (maternal toxicity shown by weight reduction); Chronic exposure of mice to low anesthetic or sub-anesthetic doses demonstrated no evidence of effects male or female fertility, reproductive loss, or early postnatal fetal wastage; A more recent study associated chronic exposure with fetal growth retardation; Chronic exposure in rabbits produced significantly reduced sperm concentrations and motility; [REPROTOX] May cause drowsiness or dizziness; [Abbott Laboratories MSDS]
ACGIH - Documentation of the TLVs and BEIs, 7th Ed. Cincinnati: ACGIH Worldwide, 2020.
REPROTOX - Scialli AR, Lione A, Boyle Padgett GK. Reproductive Effects of Chemical, Physical, and Biological Agents. Baltimore: The Johns Hopkins University Press, 1995.

11.2 Safety and Hazard Properties

11.2.1 Physical Dangers

The vapour is heavier than air and may accumulate in lowered spaces causing a deficiency of oxygen.

11.3 First Aid Measures

Inhalation First Aid
Fresh air, rest. Artificial respiration may be needed. Refer for medical attention.
Skin First Aid
Remove contaminated clothes. Rinse and then wash skin with water and soap.
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 .

11.4 Fire Fighting

In case of fire in the surroundings, use appropriate extinguishing media.

11.4.1 Fire Fighting Procedures

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)
The product is not flammable.Water fog, dry chemical, or carbon dioxide as appropriate for surrounding fire and materials.Do not use water jet as an extinguisher, as this will spread the fire.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)

11.5 Accidental Release Measures

11.5.1 Spillage Disposal

Personal protection: self-contained breathing apparatus. Ventilation. Collect leaking liquid in sealable containers. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

11.5.2 Cleanup Methods

Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible. Prevent entry into waterways, sewer, basements or confined areas. Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing vapor. Ventilate area and wash spill site. Place spillage in appropriately labeled container for disposal. Small quantities of liquid anesthetic agents may evaporate readily at room temperature.Large Spills: Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible. Cover with plastic sheet to prevent spreading. Absorb in vermiculite, dry sand or earth and place into containers. Following product recovery, flush area with water. Never return spills in original containers for re-use.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)

11.5.3 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

11.5.4 Preventive Measures

Safety glasses with sideshields are recommended. Face shields or goggles may be required if splash potential exists or if corrosive materials are present. Approved eye protection (e.g., bearing the ANSI Z87 or CSA stamp) is preferred. Maintain eyewash facilities in the work area.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)
As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Clean equipment and work surfaces with suitable detergent or solvent after use. After removing gloves, wash hands and other exposed skin thoroughly.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)
Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8

11.6 Handling and Storage

11.6.1 Safe Storage

Ventilation along the floor.

11.6.2 Storage Conditions

Store at room temperature 15-30 degC (59-86 °F).
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)

11.7 Exposure Control and Personal Protection

Maximum Allowable Concentration (MAK)
2.0 [ppm]

11.7.1 Threshold Limit Values (TLV)

50.0 [ppm]
TLV-TWA (Time Weighted Average)
50 ppm [2021]

11.7.2 Inhalation Risk

A harmful contamination of the air can be reached very quickly on evaporation of this substance at 20 °C.

11.7.3 Effects of Short Term Exposure

The substance is irritating to the eyes and skin. The vapour is irritating to the respiratory tract. The substance may cause effects on the central nervous system and cardiovascular system. Exposure at high levels could cause unconsciousness.

11.7.4 Personal Protective Equipment (PPE)

Airborne exposure should be controlled primarily by engineering controls such as general dilution ventilation, local exhaust ventilation, or process enclosure. Local exhaust ventilation is generally preferred to general exhaust because it can control the contaminant at its source, preventing dispersion into the work area. An industrial hygiene survey involving air monitoring may be used to determine the effectiveness of engineering controls. Effectiveness of engineering controls intended for use with highly potent materials should be assessed by use of nontoxic surrogate materials.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Isoflurane; Catalog Number: 1349003; (Revision Date: 03-09-2012)

11.7.5 Preventions

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.

11.8 Regulatory Information

New Zealand EPA Inventory of Chemical Status
Isoflurane: Does not have an individual approval but may be used under an appropriate group standard

11.8.1 FDA Requirements

Isoflurane: ... For induction and maintenance of general anesthesia in horses and dogs.
21 CFR 529.1186 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of July 10, 2012: https://www.ecfr.gov
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including isoflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 5, 2012: https://www.fda.gov/cder/ob/
The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Isoflurane is included on this list.
US FDA/Center for Veterinary Medicine; The Green Book - On Line, Active Ingredients. Isoflurane (26675-46-7). Available from, as of July 10, 2012: https://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/default.htm

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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

12.1.2 Hepatotoxicity

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and halogenated anesthetic agents. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from isoflurane is very rare, only isolated case reports and small case series having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to isoflurane hepatitis can be caused by shock or ischemia, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

12.1.3 Carcinogen Classification

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

12.1.4 Health Effects

May lead to cardiac arrhythmias and death (Rarely). In susceptible individuals, Isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure.(L1471)

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

There is no published experience with isoflurane during breastfeeding. Because the serum half-life of isoflurane in the mother is short and the drug is not expected to be absorbed by the infant, no waiting period or discarding of milk is required. Breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse. When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. In one study, breastfeeding before general anesthesia induction reduced requirements of sevoflurane and propofol compared to those of nursing mothers whose breastfeeding was withheld or nonnursing women. It is possible that requirements for other anesthetic agents would be affected similarly.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

A randomized, but nonblinded, study in women undergoing cesarean section compared epidural anesthesia with bupivacaine to general anesthesia with intravenous thiopental 4 mg/kg and succinylcholine 1.5 mg/kg for induction followed by nitrous oxide and isoflurane. The time to the first breastfeed was significantly shorter (107 vs 228 minutes) with the epidural anesthesia than with general anesthesia. This difference was probably caused by the anesthesia's effects on the infant, because the Apgar and neurologic and adaptive scores were significantly lower in the general anesthesia group of infants.

A randomized study compared the effects of cesarean section using general anesthesia, spinal anesthesia, or epidural anesthesia, to normal vaginal delivery on serum prolactin and oxytocin as well as time to initiation of lactation. General anesthesia was performed using propofol 2 mg/kg and rocuronium 0.6 mg/kg for induction, followed by sevoflurane and rocuronium 0.15 mg/kg as needed. After delivery, patients in all groups received an infusion of oxytocin 30 international units in 1 L of saline, and 0.2 mg of methylergonovine if they were not hypertensive. Fentanyl 1 to 1.5 mcg/kg was administered after delivery to the general anesthesia group. Patients in the general anesthesia group (n = 21) had higher post-procedure prolactin levels and a longer mean time to lactation initiation (25 hours) than in the other groups (10.8 to 11.8 hours). Postpartum oxytocin levels in the nonmedicated vaginal delivery group were higher than in the general and spinal anesthesia groups.

A retrospective study of women in a Turkish hospital who underwent elective cesarean section deliveries compared women who received bupivacaine spinal anesthesia (n = 170) to women who received general anesthesia (n = 78) with propofol for induction, sevoflurane for maintenance and fentanyl after delivery. No differences in breastfeeding rates were seen between the groups at 1 hour and 24 hours postpartum. However, at 6 months postpartum, 67% of women in the general anesthesia group were still breastfeeding compared to 81% in the spinal anesthesia group, which was a statistically significant difference.

12.1.6 Exposure Routes

The substance can be absorbed into the body by inhalation of its vapour and by ingestion.
Inhalation

12.1.7 Symptoms

Inhalation Exposure
Cough. Sore throat. Dizziness. Drowsiness. Headache. Unconsciousness.
Skin Exposure
Redness. Dry skin.
Eye Exposure
Redness. Pain.
Ingestion Exposure
See Inhalation.
The predicted effects of acute overexposure by inhalation of Isoflurane, USP include headache, dizziness or (in extreme cases) unconsciousness. (L1471)

12.1.8 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.

Asthma - Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergenic agents.

ACGIH Carcinogen - Not Classifiable.

12.1.9 Acute Effects

12.1.10 Toxicity Data

LC50 (rat) = 15,300 ppm/3hr
LC50=15300 ppm/3 hrs (inhalation by rat)

12.1.11 Treatment

Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen. (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.12 Interactions

Isoflurane potentiates the muscle relaxant effect of all muscle relaxants, most notably nondepolarizing muscle relaxants, and MAC (minimum alveolar concentration) is reduced by concomitant administration of N2O.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
Increasing numbers of people use cocaine recreationally and may require anesthesia care, having recently abused the drug. However, no data currently exist concerning potential interactions between toxic levels of cocaine and volatile anesthetic agents. This study investigated the effects of cocaine infusion on systemic hemodynamics, myocardial metabolism, and regional organ blood flow in relation to depth of isoflurane anesthesia. Prospective, randomized, controlled trial /was conducted in/ twelve miniature pigs. An open-chest swine model was used. Isoflurane (ISO) was the sole anesthetic, administered at 0.75 and 1.5 minimum alveolar concentration (MAC), and cocaine was infused (n = 6) at a rate of 0.5 mg/kg/min. Control animals (n = 6) received an equivalent amount of normal saline. Systemic and pulmonary arterial pressures and thermodilution cardiac output data were collected at 0.75 MAC and 1.5 MAC ISC. Regional myocardial and blood flows to other organs were measured using radiolabeled microspheres. Arrhythmias and altered ventricular conduction were noted only in the cocaine group, along with significant elevations in diastolic arterial pressure, coronary perfusion pressure, and systemic vascular resistance. Increased subendocardial blood flow occurred during cocaine infusion (p = 0.03); subepicardial perfusion was unchanged. Cerebral (p < 0.01) and spinal cord (p < 0.05) blood flows were reduced in animals receiving cocaine. Other organ blood flows were unchanged with depth of anesthesia or cocaine administration, with the exception of splenic blood flow (p < 0.04). Moderately toxic cocaine levels occurring during isoflurane at 0.75 MAC and 1.5 MAC are associated with hemodynamic abnormalities, a marked increase in systemic vascular resistance, and a tendency to produce cardiac arrhythmias. A reversal of endo/epicardial myocardial perfusion ratio occurs associated with cocaine infusion during ISO anesthesia. This is probably not related to a primary redistribution of subendocardial blood flow and may be related to a combination of increased myocardial oxygen demand and epicardial coronary vasoconstriction. The reductions in cerebral and spinal cord perfusion observed may explain, in part, the neurologic sequelae of cocaine toxicity.
Boylan JF et al; J Cardiothorac Vasc Anesth 10 (6): 772-7 (1996)
Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known. We conducted the present study to evaluate the effect of isoflurane on injury produced by cortical injection of NMDA in vivo and to compare it with dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were anesthetized with isoflurane. NMDA 50 nmoles (5-uL volume) were stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane groups, the end-tidal concentration of isoflurane was maintained at either electroencephalogram (EEG)-burst suppression (BS) doses (2.2%-2.3%, n = 12) or a 1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before the NMDA injection. In the awake group and the dizocilpine group, anesthesia was discontinued on completion of the NMDA injection, and the animals were allowed to awaken. In the animals in the control group (n = 10), 20 uL of artificial cerebrospinal fluid was injected into the cortex. Injury to the cortex was evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses, isoflurane reduced the injury produced by a cortical NMDA injection compared with the awake state (1.74+/-0.49 and 0.96+/-0.46 vs 2.34+/-0.56 cu mm; P = 0.02). Dizocilpine reduced cortical injury (0.56+/-0.27; P = 0.01) compared with the awake state. Injury in the control group was limited to the trauma produced by cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury was not different from the control group. Isoflurane can reduce N-methyl-D-aspartate-mediated cortical injury in vivo in a dose-dependent manner. These data are consistent with the previously demonstrated ability of isoflurane to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.
Harada H et al; Anesth Analg 89 (6): 1442-7 (1999)
b-amyloid protein (Ab)-induced neurotoxicity is the main component of Alzheimer's disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Ab levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Ab-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naive mice, and naive mice were treated with Ab and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined...the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Ab-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Ab-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Ab-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Ab-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Ab-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.
Xu Z et al; Curr Alzheimer Res 8 (7): 741-52 (2011)
For more Interactions (Complete) data for Isoflurane (8 total), please visit the HSDB record page.

12.1.13 Antidote and Emergency Treatment

Treatment /of Malignant Hyperthermia/ includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. Renal failure may appear later, and urine flow should be sustained if possible.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

12.1.14 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ The maternal and neonatal effects of isoflurane and halothane combined with 50% N2O - 50% O2 were compared in 60 healthy parturients undergoing primary or repeat cesarean section. All patients had rapid sequence induction of anesthesia with sodium thiamylal 4 mg/kg followed by succinylcholine for tracheal intubation. Patients were randomly assigned to one of three groups of 20 each (inspired 0.5% isoflurane, 1% isoflurane or 0.5% halothane), combined with 50% N2O and O2. After delivery, 67% N2O in O2 was used, supplemented by butorphanol. Maternal blood loss did not differ significantly among the three groups and none of the patients developed intraoperative awareness. At the time of delivery, maternal plasma epinephrine levels were significantly above preinduction levels in the 0.5% isoflurane group but unchanged in the other two groups. Neonatal status as ascertained by Apgar scores, cord acid base status and the Neurologic and Adaptive Capacity Scores (NACS) was equally good in the three groups of patients. Serum inorganic fluoride concentrations in the mother after anesthesia were not significantly above preanesthetic levels in any of the groups and there was no biochemical evidence of renal toxicity. In all neonates fluoride ion concentrations in the first voided urine sample were less than 7 umol/L, a value well below that associated with nephrotoxicity. It is concluded that isoflurane is a safe supplement to N2O - O2 mixture for cesarean section and is a safer alternative to halothane in situations when patients receiving beta-adrenergic therapy require cesarean section since halothane might potentiate arrhythmias caused by beta adrenergic agonists.
Abboud TK et al; Acta Anaesthesiol Scand 33 (7): 578-81 (1989)
/CASE REPORTS/ We describe a patient with tetanus, who received isoflurane for sedation to facilitate controlled mechanical ventilation. Isoflurane was administered for 34 days, resulting in a sustained serum inorganic fluoride ion concentration in excess of 50 umol /per/ L and a peak serum inorganic fluoride ion concentration of 87 umol /per/ L. Although these concentrations are potentially nephrotoxic, no toxicity was evident clinically.
Stevens JJ et al; Br J Anaesth 70 (1): 107-9 (1993)
/CASE REPORTS/ Isoflurane is considered a safe inhalational anesthetic. It has a low level of biotransformation, and low hepatic and renal toxicity. In clinical concentrations, it has minimal negative inotropic effect, causes a small reduction in systemic vascular resistance, and, rarely, can cause cardiac arrhythmias. The objective of this report was to present a case of severe hemodynamic instability in a patient with idiopathic scoliosis. Male patient, 13 years old, ASA physical status I, with no prior history of allergy to medications, scheduled for surgical repair of idiopathic scoliosis. After anesthetic induction with fentanyl, midazolam, propofol, and atracurium, 1% isoflurane with 100% oxygen was initiated for anesthesia maintenance. After five minutes, the patient presented severe hypotension (MAP = 26 mmHg) associated with sinus tachycardia (HR = 166 bpm) that did not respond to the administration of vasopressors and fluids. Lung and heart auscultation, pulse oxymetry, capnography, nasopharyngeal temperature, and arterial blood gases did not change. The patient was treated for anaphylaxis and the surgery was cancelled. The clear temporal relationship between the administration of isoflurane and the symptoms suggested the diagnosis of cardiovascular intolerance to inhalational isoflurane. Two weeks later, total intravenous anesthesia was administered without complications. There are no reports of severe hemodynamic instability caused by isoflurane in previously healthy individuals. Anaphylaxis, supraventricular tachycardia with hemodynamic consequences, and increased cardiac sensitivity to isoflurane are discussed as possible causes of the hemodynamic instability. Currently, there is evidence that isoflurane can interfere in the coupling-uncoupling system of myocardial contractility by reducing cytosolic Ca2+ and/or depressing the function of contractile proteins. The fundamental molecular mechanisms of this process remain to be elucidated. This report suggests that the administration of isoflurane was the cause of the hemodynamic changes; the patient probably developed an unusual cardiovascular sensitivity to the drug.
Hobaika AB et al; Rev Bras Anestesiol 57 (2): 177-81 (2007)
/GENOTOXICITY/ The alkaline single cell gel electrophoresis (comet) assay was applied to study genotoxic properties of two inhalation anesthetics-halothane and isoflurane-in human peripheral blood lymphocytes (PBL). The cells were exposed in vitro to either halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) or isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) at concentrations 0.1-10 mM in DMSO. The anesthetics-induced DNA strand breaks as well as alkali-labile sites were measured as total comet length (i.e., increase of a DNA migration). Both analysed drugs were capable of increasing DNA migration in a dose-dependent manner. In experiments conducted at two different electrophoretic conditions (0. 56 and 0.78 V/cm), halothane was able to increase DNA migration to a higher extent than isoflurane. The comet assay detects DNA strand breaks induced directly by genotoxic agents as well as DNA degradation due to cell death. For this reason a contribution of toxicity in the observed effects was examined. We tested whether the exposed PBL were able to repair halothane- and isoflurane-induced DNA damage. The treated cells were incubated in a drug-free medium at 37 degrees C for 120 min to allow processing of the induced DNA damage. PBL exposed to isoflurane at 1 mM were able to complete repair within 60 min whereas for halothane a similar result was obtained at a concentration lower by one order of magnitude: the cells exposed to halothane at 1 mM removed the damage within 120 min only partly. We conclude that the increase of DNA migration induced in PBL by isoflurane at 1 mM and by halothane at 0.1 mM was not a result of cell death-associated DNA degradation but was caused by genotoxic action of the drugs. The DNA damage detected after the exposure to halothane at 1 mM was in part a result of DNA fragmentation due to cell death.
Jaloszynski P et al; Mutat Res 439 (2): 199-206 (1999)
For more Human Toxicity Excerpts (Complete) data for Isoflurane (10 total), please visit the HSDB record page.

12.1.15 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ To investigate whether free radical metabolism is changed due to isoflurane treatment and, if so, to elucidate the role of changed free radical metabolism in the nephrotoxicity. Fifteen guinea pigs were used in the study. Five were treated with isoflurane in oxygen, five with oxygen and five were controls. Animals were exposed to isoflurane and oxygen three times. Each treatment was performed for 30 min once a day for three consecutive days. Activities of free radical enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); values of antioxidant parameters, antioxidant potential (AOP), non-enzymatic superoxide radical scavenger activity (NSSA) and oxidation resistance (OR) and, level of an oxidant parameter namely, malondialdehyde (MDA) were determined in the renal tissues of the groups. Blood was also obtained for serum creatinine and urea analyses. AOP, NSSA, SOD and CAT activities were decreased; (0.0188 +/- 0.0026 vs 0.0156 +/- 0.0015, P < 0.025; 8.72 +/- 1.80 vs 6.40 +/- 1.22, P < 0.05; 76.71 +/- 18.54 vs 52.79 +/- 11.68, P < 0.025; 71.26 +/- 15.58 vs 55.39 +/- 8.83; P < 0.05, respectively) but, MDA level, OR value and GSH-Px activities increased (10.89 +/- 1.57 vs 15.87 +/- 2.97, P < 0.01; 0.84 +/- 0.34 vs 2.28 +/- 1.39, P < 0.05; 1.45 +/- 0.83 vs 3.45 +/- 1.20, P < 0.01, respectively) in kidney tissues from isoflurane-treated group compared with controls. No differences were observed between control and oxygen groups with regard to all analysis parameters except GSH-Px. Isoflurane impairs the antioxidant defence system and this oxidant stress may play a part in the isoflurane-induced renal toxicity.
Durak I et al; Can J Anaesth 46 (8): 797-802 (1999)
/LABORATORY ANIMALS: Acute Exposure/ Postoperative cognitive dysfunction (POCD) is a known phenomenon occurring after anesthesia with volatile anesthetics (VA), such as isoflurane. Recent reports suggest that VA interact with neurodegenerative disease-associated proteins including compounds with pathogenic relevance in Alzheimer disease (AD) and induce processes that may be linked to AD neuropathology. Unfortunately, our present understanding of the exact anesthetics' molecular mechanisms of action, their side effects on the brain, and their catenation with AD pathology is still limited. The present study analyzes the differential proteome of the hippocampus immediately after and 3 days after a 3-hour 1 minimal alveolar concentration isoflurane anesthesia in rats. Differential 2-dimensional electrophoresis, mass spectrometry, and functional network mapping were used to identify and functionally classify 12 different hippocampal proteins, which were significantly regulated after isoflurane anesthesia (6 up-regulated, 11 down-regulated with P<0.01). Induction of differential expression ranged from 0.05 (25-fold down-regulation) to 4.4 (4.4-fold up-regulation). Ten proteins were regulated immediately after and 7 proteins 3 days after isoflurane exposure. The proteome displays isoflurane-responsive protein candidates, which have also been shown to play a role in AD. They were grouped according to their key biologic activities, which showed that isoflurane affects selected biologic processes including synaptic plasticity, stress response, detoxification, and cytoskeleton in early and late recovery phases after anesthesia. These processes are also affected in AD.
Kalenka A et al; J Neurosurg Anesthesiol 22 (2): 144-54 (2010)
/LABORATORY ANIMALS: Acute Exposure/ It was the aim of this study to characterize the influence of isoflurane-induced heme oxygenase-1 (HO-1) expression on hepatocellular integrity after ischemia and reperfusion. Abundant experimental data characterize HO-1 as one of the most powerful inducible enzymes that contribute to the protection of the liver and other organs after harmful stimuli. Therapeutic strategies aimed at utilizing the protective effects of HO-1 are hampered by the fact that most pharmacological inducers of this enzyme perturb organ function by themselves and are not available for use in patients because of their toxicity and undesirable or unknown side effects. Rats were pretreated with isoflurane before induction of partial hepatic ischemia (1 hour) and reperfusion (1 hour). At the end of each experiment, blood and liver tissue were obtained for molecular biologic, histologic, and immunohistochemical analyses. Isoflurane pretreatment increased hepatic HO-1 mRNA, HO-1 protein, HO enzyme activity, and decreased plasma levels of AST, ALT, and alpha-GST. Histologic analysis of livers obtained from isoflurane-pretreated rats showed a reduction of necrotic areas, particularly in the perivenular region, the predominant site of isoflurane-induced HO-1 expression. In addition, sinusoidal congestion that could otherwise be observed after ischemia/reperfusion was inhibited by the anesthetic. Furthermore, isoflurane augmented hepatic microvascular blood flow and lowered the malondialdehyde content within the liver compared with control animals. Administration of tin protoporphyrin IX inhibited HO activity and abolished the isoflurane-induced protective effects.
Schmidt R et al; Ann Surg 245 (6): 931-42 (2007)
/LABORATORY ANIMALS: Acute Exposure/ The physical stability and low blood solubility of the new inhaled anesthetic, I-653, imply that this agent produces limited or no toxic effects. To test this possibility, its effects were compared with those of other volatile agents on hepatic, renal, and pulmonary specimens taken from enzyme-induced, hypoxic rats. Male Sprague-Dawley rats were pretreated with phenobarbital and exposed for 1 hr to 12% O2 and no anesthesia (control) or to 1.2 minimum alveolar concentration of one of three anesthetics: I-653, isoflurane, or halothane. Liver, kidney, and lung specimens were taken 24 hr after exposure concluded. The livers of all rats given halothane (n = 6) had swelling (20.5 +/- 5.7% of a lobule [mean +/- SD]) and centrilobular necrosis (6.7 +/- 2.1% of a lobule). Isoflurane produced only slight injury (6.7 +/- 3.5% swelling and 1.0 +/- 0.0% necrosis in 3 of 15 rats). No hepatic injury occurred in control rats (n = 20) or in those given I-653 (n = 16). Pulmonary and renal injury were not evident with any agent.
Eger EI 2nd et al; Anesth Analg 66 (12): 1227-9 (1987)
For more Non-Human Toxicity Excerpts (Complete) data for Isoflurane (18 total), please visit the HSDB record page.

12.1.16 Non-Human Toxicity Values

LD50 Rat oral 4770 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2135
LC50 Rat inhalation 15,300 ppm/3 hr
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2135
LD50 Rat intraperitoneal 4280 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2135
LD50 Mouse oral 5080 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2135
For more Non-Human Toxicity Values (Complete) data for Isoflurane (6 total), please visit the HSDB record page.

12.1.17 Populations at Special Risk

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable.
US Natl Inst Health; DailyMed. Current Medication Information for Forane (isoflurane) inhalant (December 2011). Available from, as of July 23, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Isoflurane's production and administration as an anaesthetic and solvent for fluorinated materials may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 330 mm Hg at 25 °C indicates isoflurane will exist solely as a vapor in the atmosphere. Vapor-phase isoflurane 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 460 days. Isoflurane absorbs light at wavelengths <200 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight. If released to soil, isoflurane is expected to have high mobility based upon an estimated Koc of 94. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 2.87X10-2 atm-cu m/mole. Isoflurane may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, isoflurane is not 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 4 hours and 5.4 days, respectively. An estimated BCF of 11 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to isoflurane may occur through inhalation and dermal contact with this compound at workplaces where isoflurane is produced or used. Exposure to isoflurane among the general population may be limited to those administered the drug, an anaesthetic. (SRC)

12.2.2 Artificial Pollution Sources

Isoflurane's production and administration as an anaesthetic and solvent for fluorinated materials(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co., Inc., p. 895 (2006)

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 94(SRC), determined from a log Kow of 2.06(2) and a regression-derived equation(3), indicates that isoflurane is expected to have high mobility in soil(SRC). Volatilization of isoflurane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.87X10-2 atm-cu m/mole(4). Isoflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 330 mm Hg at 25 °C(5). Biodegradation data in soil were not available(SRC, 2012).
(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) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2010. Available from, as of Jun 6, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(4) Abraham MH et al; J Pharm Sci 83: 1085-100 (1994)
(5) O'Neil MJ, ed; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co., Inc., p. 895 (2006)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 94(SRC), determined from a log Kow of 2.06(2) and a regression-derived equation(3), indicates that isoflurane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(4) based upon a Henry's Law constant of 2.87X10-2 atm-cu m/mole(5). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are approximately 4 hours and 5.4 days, respectively(SRC). According to a classification scheme(6), an estimated BCF of 11(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2012).
(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) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2010. Available from, as of Jun 6, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(5) Abraham MH et al; J Pharm Sci 83: 1085-100 (1994)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), isoflurane, which has a vapor pressure of 330 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase isoflurane 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 460 days(SRC), calculated from its rate constant of 1.51X10-14 cu cm/molecule-sec at 25 °C(3). Isoflurane does absorbs light at wavelengths <200 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) O'Neil MJ, ed; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co., Inc., p. 895 (2006)
(3) Tokuhashi K et al; Int J Chem Kinet 31: 846-853 (1999)
(4) Langbein T et al; Br J Anaesth 82: 66-73 (1999)

12.2.4 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of isoflurane with photochemically-produced hydroxyl radicals has been reported as 1.51X10-14 cu cm/molecule-sec at 25 °C(1). This corresponds to an atmospheric half-life of about 460 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Isoflurane has a calculated Greenhouse Warming Potential of 0.03 relative to CFC-12 and potential ozone depletion efficiency of 0.01 (an efficiency of Br relative to Cl of alpha=50 was used)(2). Atmospheric oxidation of isoflurane is expected to yield trifluroacetate(3). Isoflurane is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). Isoflurane absorbs light at wavelengths <200 nm(5) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC). A photochemical half-life of 3,130 years has been calculated(5).
(1) Tokuhashi K et al; Int J Chem Kinet 31: 846-853 (1999)
(2) Brown AC et al; Nature 341: 635-7 (1989)
(3) Boutonnet JC et al; Hum Ecol Risk Assess 5: 59-124 (1999)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(5) Langbein T et al; Br J Anaesth 82: 66-73 (1999)

12.2.5 Environmental Bioconcentration

An estimated BCF of 11 was calculated in fish for isoflurane(SRC), using a log Kow of 2.06(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) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2010. Available from, as of Jun 5, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.6 Soil Adsorption / Mobility

The Koc of isoflurane is estimated as 94(SRC), using a log Kow of 2.06(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that isoflurane is expected to have high 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. nn (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2010. Available from, as of Jun 5, 2012: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Swann RL et al; Res Rev 85: 17-28 (1983)

12.2.7 Volatilization from Water / Soil

The Henry's Law constant for isoflurane is 2.87X10-2 atm-cu m/mole(1). This Henry's Law constant indicates that isoflurane 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 4 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 5.4 days(SRC). Isoflurane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Isoflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 330 mm Hg(3).
(1) Abraham MH et al; J Pharm Sci 83: 1085-100 (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) O'Neil MJ, ed; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co., Inc., p. 895 (2006)

12.2.8 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 33,152 workers (27,151 of these were female) were potentially exposed to isoflurane in the US(1). Occupational exposure to isoflurane may occur through inhalation and dermal contact with this compound at workplaces where isoflurane is produced or adminstered. Exposure to isoflurane among the general population may be limited to those administered the drug, an anaesthetic(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Jun 6, 2012: https://www.cdc.gov/noes/
A mean urine concentration of isoflurane in twenty-four workers in an anesthesia and intensive care unit was 14.3 nmol/L at the end of typical workshifts. This corresponds to an environmental exposure of 43 nmol/cu m. The subjects had a workshift of 6 hours and were exposed to various anesthetic mixtures 30-36 hrs/week for 2-27 years(1). Monitoring of operating theaters in seven unspecified hospitals in and around Toronto, Ontario, Canada indicated a mean isoflurane exposure levels of 1.4, 2.2, 9.1, 1.8, 22.3, 10.5, and 3.2 mg/cu m(2).
(1) Franco G et al; Appl Occup Environ Hyg 7: 677-81 (1992)
(2) Sass-Kortsak AM et al; Am Ind Hyg Assoc J 53: 203-9 (1992)

13 Associated Disorders and Diseases

Associated Occupational Diseases with Exposure to the Compound

Asthma, occupational [Category: Airway Disease]

Solvents, acute toxic effect [Category: Acute Poisoning]

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: Drug

18.5 KEGG: ATC

18.6 KEGG: JP15

18.7 KEGG: Animal Drugs

18.8 KEGG: Drug Groups

18.9 WHO ATC Classification System

18.10 FDA Pharm Classes

18.11 ChemIDplus

18.12 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.13 ChEMBL Target Tree

18.14 UN GHS Classification

18.15 NORMAN Suspect List Exchange Classification

18.16 EPA DSSTox Classification

18.17 PFAS and Fluorinated Organic Compounds in PubChem

18.18 EPA Substance Registry Services Tree

18.19 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
  2. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  3. 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
  4. Drug Gene Interaction database (DGIdb)
    LICENSE
    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
  5. 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
  6. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  7. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  8. 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/
  9. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  10. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  11. 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
  12. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. Hazardous Substances Data Bank (HSDB)
  14. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  15. ILO-WHO International Chemical Safety Cards (ICSCs)
  16. New Zealand Environmental Protection Authority (EPA)
    LICENSE
    This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International licence.
    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  17. Occupational Safety and Health Administration (OSHA)
    LICENSE
    Materials created by the federal government are generally part of the public domain and may be used, reproduced and distributed without permission. Therefore, content on this website which is in the public domain may be used without the prior permission of the U.S. Department of Labor (DOL). Warning: Some content - including both images and text - may be the copyrighted property of others and used by the DOL under a license.
    https://www.dol.gov/general/aboutdol/copyright
  18. ChEBI
  19. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  20. LiverTox
  21. NCI Thesaurus (NCIt)
    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
  22. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  23. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  24. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
    LICENSE
    Copyright (c) 2022 Haz-Map(R). All rights reserved. Unless otherwise indicated, all materials from Haz-Map are copyrighted by Haz-Map(R). No part of these materials, either text or image may be used for any purpose other than for personal use. Therefore, reproduction, modification, storage in a retrieval system or retransmission, in any form or by any means, electronic, mechanical or otherwise, for reasons other than personal use, is strictly prohibited without prior written permission.
    https://haz-map.com/About
  25. Therapeutic Target Database (TTD)
  26. DailyMed
  27. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  28. Drugs and Lactation Database (LactMed)
  29. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  30. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  31. EU Clinical Trials Register
  32. FDA Approved Animal Drug Products (Green Book)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  33. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  34. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    ISOFLURANE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  35. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  36. Japan Chemical Substance Dictionary (Nikkaji)
  37. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Drugs listed in the Japanese Pharmacopoeia
    http://www.genome.jp/kegg-bin/get_htext?br08311.keg
  38. Metabolomics Workbench
  39. NIPH Clinical Trials Search of Japan
  40. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  41. SpectraBase
    ETHANE, 1-CHLORO-1-(DIFLUOROMETHOXY)-2,2,2-TRIFLUORO-
    https://spectrabase.com/spectrum/7mfUOi55Dcp
    1-Chloro-2,2,2-trifluoroethyl difluoromethyl ether
    https://spectrabase.com/spectrum/LtAdlRv4AgO
    1-Chloro-2,2,2-trifluoroethyl difluoromethyl ether
    https://spectrabase.com/spectrum/2zh7YGTCehP
  42. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  43. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  44. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  45. Springer Nature
  46. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  47. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  48. Wikidata
  49. Wikipedia
  50. Wiley
  51. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  52. PubChem
  53. GHS Classification (UNECE)
  54. EPA Substance Registry Services
  55. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  56. PATENTSCOPE (WIPO)
  57. NCBI
CONTENTS