Methoxyflurane

164.97

164.97

1737766

200-956-0

30905R8O7B

1636

110432

1993

DTXSID7025556

Liquid|Clear, colorless liquid

N - Nervous system

2909191800

9.23000

2.02930

Methoxyflurane is a clear colorless liquid with a sweet fruity odor. (NTP, 1992)

1.4226 g/cm³ @ Temp: 20 °C

-35 °C

105 °C

37°C

1.386

Miscible with alcohol, acetone, chloroform, ether, fixed oils and benzene. Immiscible with water.

-70°C

23 mmHg

Relative vapour density (air = 1): 5.7

Combustible Liquid

Explosive limits , vol% in air: 7-?

Fruity

0.00 atm-m3/mole|Henry's Law constant = 3.7X10-3 atm-cu m/mole at 25 °C

Conversion factor: 1 ppm = 6.75 mg/cu m|Completely stable in the presence of alkali air, light, or moisture... Combustible|Hydroxyl radical reaction rate constant = 3.2X10-14 cu cm/molecule-sec at 25 °C /Estimated/

Insoluble in water.

Ethers

METHOXYFLURANE may be sensitive to prolonged exposure to light.

Combustible Liquid

III

3

3271

10

23-24/25

KN7820000

Xi

Stability

P201, P202, P210, P233, P240, P241, P242, P243, P261, P264, P271, P280, P281, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P370+P378, P403+P233, P403+P235, P405, P501

H226

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

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products, incl methoxyflurane (liquid inhalation 99.9%).

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

This chemical is combustible. (NTP, 1992)|Combustible. Above 63 °C explosive vapour/air mixtures may be formed.

|Warning|H226 (100%): Flammable liquid and vapor [Warning Flammable liquids]|P201, P202, P210, P233, P240, P241, P242, P243, P261, P264, P271, P280, P281, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P370+P378, P403+P233, P403+P235, P405, and P501|Aggregated GHS information provided by 6 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this compound can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)|Use water spray, powder, foam, carbon dioxide.

Excerpt from ERG Guide 128 [Flammable Liquids (Water-Immiscible)]: As an immediate precautionary measure, isolate spill or leak area for at least 50 meters (150 feet) in all directions. LARGE SPILL: Consider initial downwind evacuation for at least 300 meters (1000 feet). FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, use absorbent paper to pick up all liquid spill material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this material for prolonged exposure to light and store it under ambient temperatures. (NTP, 1992)

Skin: No recommendation is made specifying the need for personal protective equipment for the body. Eyes: Wear appropriate eye protection to prevent eye contact. Wash skin: No recommendation is made specifying the need for washing the substance from the skin (either immediately or at the end of the work shift). Remove: Work clothing that becomes wet or significantly contaminated should be removed and replaced. Change: No recommendation is made specifying the need for the worker to change clothing after the work shift. (NIOSH, 2016)|Wear appropriate eye protection to prevent eye contact.|(See protection codes)

Explosive limits , vol% in air: 7-?

Work clothing that becomes wet or significantly contaminated should be removed and replaced.|SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

Potential symptoms of overexposure are eye irritation ... .

60 Minute Ceiling Value: 2 ppm (13.5 mg/cu m). REL for exposure to waste anesthetic gas.

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

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

Exposure at high levels could cause unconsciousness.

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

NO open flames. Above 63 °C use a closed system and ventilation.

Use ventilation, local exhaust or breathing protection.

Protective gloves.

Wear safety spectacles or eye protection in combination with breathing protection.

LD50=3600 mg/kg (Orally in rats). Symptoms of overexposure include eye irritation, CNS depression, analgesia, anesthesia, seizures, respiratory depression, and liver and kidney damage.

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

Methoxyflurane's former production and use as an anesthetic(1) may have resulted in its release to the environment through various waste streams(SRC). Methoxyflurane may still be produced in low quantities and used as a research chemical(2).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 2.21(2) and a regression-derived equation(3), indicates that methoxyflurane is expected to have moderate mobility in soil(SRC). Volatilization of methoxyflurane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.7X10-3 atm-cu m/mole(4). The potential for volatilization of methoxyflurane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 49 mm Hg(SRC), determined from a fragment constant method(5).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 380(SRC), determined from a log Kow of 2.21(2) and a regression-derived equation(3), indicates that methoxyflurane is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 3.7X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.5 hours and 5 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 10(SRC), from the log Kow(2)and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Alkyl halides such as methoxyflurane have the potential to hydrolyze(3); however, the rate of this reaction is unknown.|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methoxyflurane, which has an estimated vapor pressure of 49 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase methoxyflurane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 498 days(SRC), calculated from its rate constant of 3.2X10-14 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3).

The rate constant for the vapor-phase reaction of methoxyflurane with photochemically-produced hydroxyl radicals has been estimated as 3.2X10-14 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 498 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Methoxyflurane is not expected to undergo direct photolysis since it does not absorb light in the environmental UV spectrum (>290 nm)(2). Alkyl halides may be susceptible to hydrolysis(3); however, the rate of this reaction for methoxyflurane is unknown.

An estimated BCF of 10 was calculated for methoxyflurane(SRC), using a log Kow of 2.21(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of methoxyflurane is estimated as 380(SRC), using a log Kow of 2.21(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that methoxyflurane is expected to have moderate mobility in soil.

The Henry's Law constant for methoxyflurane is 3.7X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that methoxyflurane is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5 days(SRC. Methoxyflurane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of methoxyflurane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 49 mm Hg(SRC), determined from a fragment constant method(3).

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

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

Anesthetic (inhalation).|(VET): Anesthetic.|... Methoxyflurane /is/ indicated for the induction and maintenance of general anesthesia . However, inhalation anesthetic agents are rarely used alone; other medications are frequently administered to induce or supplement anesthesia. /Included in US product labeling/|... Methoxyflurane ... /is/ indicated in low doses to provide analgesia for procedures not requiring loss of consciousness. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for METHOXYFLURANE (6 total), please visit the HSDB record page.

Inhalation anesthetics cross the placenta. Risk-benefit must be considered because studies (by retrospective survey) of operating room personnel chronically exposed to low concentrations of inhalation anesthetics indicate that pregnancies in female personnel and wives of male personnel may be subject to an increased incidence of spontaneous abortions, stillbirths, and possibly birth defects . However, the methods used in obtaining and interpreting the data in these studies have been questioned. /Inhalation anesthetics/|Because of potential nephrotoxicity, administration of methoxyflurane in concentrations sufficient to produce muscle relaxation is not recommended ; a neuromuscular blocking agent should be used concurrently if necessary. Also, it is recommended that methoxyflurane not be used during vascular surgery at or near renal blood vessels.|Caution needed in diabetes, uncontrolled or with polyuria or obesity; in renal function impairment of disease; or in toxemia of pregnancy, as methoxyflurane may increase the risk of nephrotoxicity.|Monitoring of renal function may be needed to detect possible nephrotoxicity if patient's postoperative urine output is excessive.|Methoxyflurane, a general anesthetic, is a known nephrotoxin. A case is presented that demonstrated diffuse, bilateral renal cortical calcification on CT secondary to repeated methoxyflurane inhalation.

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

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.)

Elimination: Primary: 35% excreted unchanged by exhalation.|Inhalation anesthetics are rapidly absorbed into the circulation via the lungs. /Inhalation anesthetics/|The urinary fluoride ion concentration was compared in 2 series of parturients, the one receiving methoxyflurane-nitrous oxide analgesia during labor and the other nitrous oxide analgesia. Results showed that in the methoxyflurane-nitrous oxide analgesia series, both the mothers and the neonates showed a significantly higher urinary fluoride ion concentration in comparison to the nitrous analgesia series. The urinary fluoride concentration was related to the vaporized amount of methoxyflurane.

Hepatic.|Biotransformation - 50% of dose metabolized. A substantial quantity of inorganic fluoride is formed; also metabolized to other potentially nephrotoxic substances.

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

Exposure Routes: inhalation, ingestion, skin and/or eye contact Symptoms: Irritation eyes; central nervous system depression, analgesia, anesthesia, convulsions, respiratory depression; liver, kidney injury Target Organs: Eyes, central nervous system, liver, kidneys, reproductive system (NIOSH, 2016)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)|(See procedures)

Fresh air, rest.

Rinse skin with plenty of water or shower.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

/CASE REPORTS/ Methoxyflurane, a general anesthetic, is a known nephrotoxin. A case is presented that demonstrated diffuse, bilateral renal cortical calcification on CT secondary to repeated methoxyflurane inhalation.|/CASE REPORTS/ A young woman presented with a novel multisystem disease: painful periostitis, osteosclerosis, hypertension, and renal dysfunction. The similarity of some of this clinical picture to fluoride intoxication led to the discovery of massively elevated fluoride levels in serum, urine, and bone. Although initially an enigma, the source of fluoride was later found to be the illicit use of an anesthetic agent, methoxyflurane. This agent is one of a class of organofluorides that, by virtue of biotransformation, is a known cause of inorganic fluoride exposure. Though the drug is potentially nephrotoxic as generally used, exposure to it is transient and has not previously led to discernible bone disease.|/SIGNS AND SYMPTOMS/ Potential symptoms of overexposure are eye irritation; CNS depression, analgesia; anesthesia, seizures, respiratory depression; liver and kidney injury.|/CASE REPORTS/ A veterinarian's assistant who sniffed methoxyflurane as a euphoriant developed fulminant hepatitis and died of hepatic failure. ...

Anecotan

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

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

Dizziness. Drowsiness. Unconsciousness.

Redness.

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

Human Drugs -> EU pediatric investigation plans