Absorption, Distribution and Excretion
Most halothane is excreted by the lung unchanged. At least 12% of an absorbed dose is metabolized to chlorine, bromine, and trifluoroacetic acid, with toxic intermediates suspected of causing or contributing to hepatoxicity. Halothane is stored in fatty tissue and has been detected in the expired air of obese patients up to 2 weeks after exposure.
Urinary oxalate crystals were detected in 6 of 14 patients given halothane.
It is not known if halothane is distributed into breast milk.
60 to 80% Excreted unchanged by exhalation.
Inhalation anesthetics cross placenta.

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Metabolism / Metabolites
Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6.
Anywhere from 10 to 30 percent of inhaled halothane is metabolized, and metabolites may be detected in the urine for a period of several days after inhaling halothane. Various intermediate metabolites have been isolated; however, trifluoroacetic acid is the principal end-product isolated from the urine.
Halothane biotransformation by cytochrome p 450 produces reactive intermediates along both oxidative (acyl chloride) and reductive (free radical) pathways that ultimately generate the metabolites trifluoroacetic acid and flouride, respectively. Inhibiting oxidative metabolism with deuterated halothane reduces resultant injury in our guinea pig model of acute halothane hepatoxicity. To elucidate whether covalent binding of reactive intermediates to proteins (oxidative pathway) or lipids (reductive pathway) is a mechanism of necrosis, male outbred Hartley guinea pigs (600-725 g), N = 8, were exposed to either 1% (v/v) halothane or deuterated halothane at either 40% or 10% oxygen for 4 hr. One-half of the animals were killed immediately after exposure for binding studies; the remainder at 96 hr post exposure for evaluation of hepatotoxicity. Covalent binding of halothane intermediates to liver protein or lipid was determined by measuring the fluoride content of the bound moieties. The use of deuterated halothane and/or 10% oxygen during exposure led to 63-88% reductions (p< 0.01) in plasma trifluoroacetic acid concn (halothane-40% oxygen = 546; 73 mM, N = 8) which were accompanied by 33-60% decreases (p< 0.01) in binding to liver proteins (halothane-40% oxygen = 1.36; 0.26 nmoles bound fluoride/mg protein, N = 4), 78-84% decreases (p< 0.05) in 48 hr plasma ALT levels (halothane- 40% oxygen = 308; 219, control = 23 + 3, N = 4) and a total amelioration of centilobular necrosis.
Free radicals were detected from the in vitro metabolism of halothane (rat liver microsomes) by the PBN spin trapping method. The detected radical species include the 1-chloro-2,2,2-trifluoro-1-ethyl radical (I), as determined by mass spectral analysis, and lipid type radicals assigned by high resolution ESR spectroscopy with the use of d14-deuterated PBN. The lipid derived radicals are a carbon centered radical with the partially assigned structure CH2R and an oxygen centered radical of the OR' type. From the mass spectral analysis of the spin adduct mixture there is also evidence for a halocarbon double adduct of PBN of the type I-PBN-I.
An analogue of HCFC-123, the common inhalation anesthetic halothane (2-bromo-2-chloro-1,1,1-trifluoroethane), is metabolized by hepatic CYP2E1 to trifluoroacetyl chloride, causing trifluoroacetylation of liver proteins. These include cytochrome P450 itself and other enzymes, many of which have been identified as residing in the lumen of the endoplasmic reticulum and involved in the maturation of newly synthesized proteins. Both halothane and HCFC-123 induce peroxisome proliferation and increased beta-oxidation in rat liver cells. They are also highly effective in inducing excess uncoupled cytochrome P450 activity in rabbit liver microsomes, thus increasing hepatic oxygen consumption and facilitating the oxidation of other cytochrome P450 substrates.
For more Metabolism/Metabolites (Complete) data for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE (7 total), please visit the HSDB record page.
Halothane has known human metabolites that include 2-chloro-1,1-difluoroethene, chlorotrifluoroethane, and Trifluoroacetyl chloride.
Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6.

Toxicity Summary
Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization.

Halothane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Halothane 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. Halothane also binds to the GABA receptor, the large conductance Ca²⁺ activated potassium channel, the glutamate receptor and the glycine receptor.

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Hepatotoxicity
Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and anesthesia with halothane and other halogenated anesthetics. Appearance of ALT levels above 10 times the upper limit of normal, however, is uncommon and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from halothane is rare, occurring in ~1/15,000 cases after initial exposure, but in ~1/1,000 cases after repeated exposures. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 14 days of surgery. There are usually minimal increases in alkaline phosphatase levels. Fever occurs before onset of jaundice in a high proportion of patients and eosinophilia in up to 30%. Rash and arthralgias can also accompany the onset of hepatic injury. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and lead to 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. Other risk factors are hypotension, older age, obesity and concurrent use of CYP 2E1 inducers. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to halothane hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis. Indeed, many cases of severe liver injury arising soon after surgery and attributed to halothane or other halogenated anesthetics in the literature probably represent liver injury from shock and ischemia. Factors favoring the diagnosis of ischemic hepatitis are rapid onset after surgery, extremely high values for ALT, AST and LDH, and subsequent rapid fall in serum enzymes.
Likelihood score: A (well known cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Halothane is no longer available in the United States. There is no published experience with the therapeutic use of halothane as an anesthetic during breastfeeding, but trace amounts were found in the milk of a practicing anesthesiologist who had administered halothane in the operating room. Various recommendations have been made regarding breastfeeding after halothane anesthesia, from discarding the first pumping after recovery to discarding breastmilk for 24 to 48 hours after the surgical procedure. Although withholding breastfeeding for 24 h is probably unnecessary, a short-acting anesthetic is preferred. 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
Relevant published information was not found as of the revision date.

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Toxicity Data
LC50 (rat) = 29,000 ppm

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Interactions
A report of malignant hyperthermia in a 19 month old boy who was anaesthetised with halothane and then received suxamethonium.
Significantly impaired psychophysiological performance has been demonstrated in volunteers exposed for 4 hr to 120 mg/cu m (15 ppm) halothane plus 615 mg/cu m (500 ppm) nitrous oxide ... .
The effects of non-depolarizing muscle relaxants such as gallamine and tubocurare are enhanced by halothane and if required they should be given in reduced dosage. Antibiotics such as streptomycin that possess neuromuscular blocking activity should also be used with caution. Morphine increases the depressant effects of halothane on respiration and its use during anaesthesia may be followed by post-operative nausea and vomiting. Chlorpromazine also enhances depressant effect of halothane.
Halothane may prevent or reduce trimethaphan-induced tachycardia.
For more Interactions (Complete) data for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE (27 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 White rat intragastric 5,680 mg/kg
LD50 Guinea pig intragastric 6,000 mg/kg
LC50 Mouse inhalation 22000 ppm/10 minutes

[1]. Does halothane interfere with the release, action, or stability of endothelium-derived relaxing factor/nitric oxide?. Anesthesiology. 1994;80(2):417-426.

Therapeutic Uses
Anesthetics, Inhalation
Anesthesia, general- ... halothane ... /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/
For cesarean section: ... halothane ... /is/ indicated in low concentrations to supplement other general anesthetics during delivery by cesarean section./NOT included in US product labeling/
MEDICATION (VET): Halothane is a potent anesthetic and capable of maintaining anesthesia effectively in large animals. The level and depth of anesthesia can be more rapidly changed than as noted with methoxyflurane.

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Drug Warnings
Halothane diminishes sympathetic activity, augments vagal tone, depresses the contractility of the heart, and induces venodilation. Cardiac output, arterial pressure, and pulse rate are reduced, usually in proportion to the depth of anesthesia. Severe hypotension and circulatory failure may occur with overdosage. Supraventricular arrhythmias or nodal rhythm may be observed during induction or deep anesthesia. Small doses of epinephrine (1 to 1.5 ug/kg) may be administered subcutaneously or submucosally with halothane when adequate ventilation is assured. Exceeding this dose is potentially hazardous, however, since this anesthetic sensitizes the heart to catecholamines. The administration of lidocaine during epinephrine use decreases the risk of arrhythmias.
Halothane should not be given to patients who developed jaundice or acute liver damage after previous exposure to this drug unless other obvious causes for the hepatic damage have been demonstrated.
CONTRAINDICATIONS. Because of a probable adverse interaction, halothane should not be used in animals known to have recently received aminoglycoside antibiotics. Animals receiving phenobarbital or other potent enzyme-inducing drugs should not be subjected to halothane anesthesia because of potential injury to the liver (halothane hepatitis). Animals afflicted with cardiopathies or chronic congestive heart failure should not receive halothane. Until more information is available on behavioral effects of halothane, veterinary anesthesiologists probably should avoid its use in pregnant animals during the first and second trimesters.
Halothane reduces muscle tone in the pregnant uterus and generally its use is not recommended in obsterics because of the increased risk of postpartum hemorrhage. Halothane should not be used for patients with cardiac arrhythmias.
For more Drug Warnings (Complete) data for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE (12 total), please visit the HSDB record page.

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Pharmacodynamics
Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. 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.

C2HBRCLF3

197.3792

195.89

151-67-7

3562

Colorless to light yellow liquid

1.9±0.1 g/cm3

53.4±8.0 °C at 760 mmHg

-180 °F (NIOSH, 2024)
50-50.5
-118 °C
-118 °C
-180 °F
-180 °F

-13.9±18.4 °C

268.8±0.1 mmHg at 25°C

1.389

2.3

0

3

0

7

60.4

0

C(C(F)(F)F)(Br)Cl

BCQZXOMGPXTTIC-UHFFFAOYSA-N

InChI=1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H

2-bromo-2-chloro-1,1,1-trifluoroethane

BRN 1736947; Fluothane; Halothane

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 50 mg/mL (~253.32 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)