Absorption, Distribution and Excretion
Most halothanes are excreted unchanged via the lungs. At least 12% of the absorbed dose is metabolized to chlorine, bromine, and trifluoroacetic acid; these toxic intermediate metabolites are suspected to be a cause or contributing factor to hepatotoxicity. Halothanes are stored in adipose tissue and can be detected in the exhaled breath of obese patients up to two weeks after exposure. Oxalate crystals were detected in the urine of 6 out of 14 patients treated with halothanes. It is currently unknown whether halothanes are excreted into breast milk. 60% to 80% of halothanes are excreted unchanged via exhalation. Inhaled anesthetics can cross the placenta. Metabolism/Metabolites Halothanes are primarily metabolized in the liver, mainly via CYP2E1, followed by CYP3A4 and CYP2A6. Approximately 10% to 30% of inhaled halothanes are metabolized, and metabolites can be detected in the urine for several days after inhalation. Several intermediate metabolites have been isolated; however, trifluoroacetic acid is the major end product isolated in urine. The biotransformation of halothanes by cytochrome P450 proceeds along oxidative (acyl chloride) and reductive (free radical) pathways to produce reactive intermediates, ultimately yielding the metabolites trifluoroacetic acid and fluoride, respectively. In our acute halothane hepatotoxicity model in guinea pigs, inhibition of oxidative metabolism with deuterated halothanes alleviated the resulting damage. To elucidate whether the covalent binding of reactive intermediates to proteins (oxidative pathway) or lipids (reductive pathway) is a mechanism of necrosis, we exposed eight male Hartley guinea pigs (600–725 g) to 1% (v/v) halothane or deuterated halothane for 4 hours at 40% or 10% oxygen concentrations. Half of the animals were sacrificed immediately after exposure for binding studies; the remaining samples were collected 96 hours post-exposure for hepatotoxicity assessment. The covalent binding of halothane intermediates to liver proteins or lipids was determined by measuring the fluoride content of the bound portion. Exposure to deuterated halothane and/or 10% oxygen resulted in a 63-88% decrease in plasma trifluoroacetic acid concentration (p<0.01) (546 and 73 mM in the halothane-40% oxygen group, n=8), accompanied by a 33-60% decrease in hepatic protein binding (p<0.01) (1.36 and 0.26 nmol bound fluoride/mg protein in the halothane-40% oxygen group, n=4), a 78-84% decrease in 48-hour plasma ALT levels (p<0.05) (308 and 219 in the halothane-40% oxygen group, and 23 and 3 in the control group, n=4), and complete remission of lobular necrosis. Free radicals were detected by in vitro metabolism of halothane (rat liver microsomes) using the PBN spin trapping method. The detected free radicals included the 1-chloro-2,2,2-trifluoro-1-ethyl radical (I) identified by mass spectrometry, and lipid-type free radicals identified by high-resolution ESR spectroscopy using d14-deuterated PBN. Lipid-derived free radicals included partially structurally defined carbon-centered radicals CH2R and OR'-type oxygen-centered radicals. Mass spectrometry analysis of the spin adduct mixture also indicated the presence of I-PBN-I type PBN haloalkane diadducts. The commonly used inhaled anesthetic halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) is an analogue of HCFC-123, metabolized by hepatic CYP2E1 to trifluoroacetyl chloride, leading to trifluoroacetylation of liver proteins. These enzymes include cytochrome P450 itself and other enzymes, many of which have been shown to be present in the endoplasmic reticulum lumen and involved in the maturation of newly synthesized proteins. Both halothane and HCFC-123 can induce peroxisome proliferation in rat hepatocytes and increase β-oxidation. They can also efficiently induce excessive uncoupling of cytochrome P450 activity in rabbit liver microsomes, thereby increasing hepatic oxygen consumption and promoting the oxidation of other cytochrome P450 substrates. For more complete metabolite/metabolite data on 2-bromo-2-chloro-1,1,1-trifluoroethane (7 metabolites in total), please visit the HSDB record page. Known human metabolites of halothanes include 2-chloro-1,1-difluoroethylene, chlorotrifluoroethane, and trifluoroacetyl chloride. Halothanes are primarily metabolized in the liver, mainly via CYP2E1, and secondarily via CYP3A4 and CYP2A6.

Toxicity Summary
Halothane induces general anesthesia by acting on multiple ion channels, ultimately inhibiting nerve conduction, respiration, and myocardial contractility. Its anesthetic effect is attributed to its binding to potassium ion channels in cholinergic neurons. Halothane's effects may also be related to its binding to NMDA and calcium ion channels, leading to hyperpolarization. Halothane reduces junctional conductance by shortening the opening time and prolonging the closing time of gap junction channels. Halothane also activates calcium-dependent ATPases in the sarcoplasmic reticulum by increasing lipid membrane fluidity. Furthermore, halothane appears to bind to the D subunit of ATP synthase and NADH dehydrogenase. Halothane also binds to GABA receptors, high-conductivity calcium-activated potassium channels, glutamate receptors, and glycine receptors. Hepatotoxicity
Prospective serial blood tests typically show a slight, transient increase in serum transaminase levels within 1 to 2 weeks after major surgery and anesthesia with halothane and other halogenated anesthetics. However, ALT levels exceeding 10 times the upper limit of normal are uncommon and suggest severe hepatotoxicity. Clinically significant severe halothane-induced liver injury is rare, with an incidence of approximately 1 in 15,000 after initial exposure and approximately 1 in 1,000 after repeated exposure. This injury is characterized by an acute elevation (5 to 50-fold) in serum transaminase levels and jaundice developing within 2 to 14 days post-surgery. Alkaline phosphatase levels are usually only slightly elevated. A significant proportion of patients experience fever before jaundice develops, and up to 30% develop eosinophilia. Rash and arthralgia may also accompany liver injury. Acute liver injury may be self-limiting, resolving within 4 to 8 weeks, but can also be severe, leading to acute liver failure. A significant risk factor is prior exposure to any halogenated anesthetic, especially a history of halothane-induced hepatitis or unexplained fever and rash after anesthesia with such drugs. Other risk factors include hypotension, advanced age, obesity, and concomitant use of CYP2E1 inducers. Differential diagnosis of acute liver injury following surgery and anesthesia can sometimes be challenging. Shock or ischemia, sepsis, other specific drug-induced liver injury, and acute viral or herpes simplex hepatitis can all cause clinical presentations similar to halothane hepatitis. In fact, many cases of severe liver injury occurring shortly after surgery, attributed to halothane or other halogenated anesthetics, are likely due to shock and ischemia. Factors supporting a diagnosis of ischemic hepatitis include rapid postoperative onset, extremely high ALT, AST, and LDH levels, and a subsequent rapid decline in serum enzymes. Probability score: A (Common causes of clinically significant liver injury). Pregnancy and lactation effects. ◉ Overview of use during lactation: Halothane has been discontinued in the United States. There is currently no published experience regarding the use of halothane as an anesthetic during lactation, but trace amounts of halothane have been detected in the breast milk of an anesthesiologist who had previously used halothane in the operating room. Regarding breastfeeding after halothane anesthesia, there are currently several recommendations, ranging from discarding the first expressed breast milk during the postoperative recovery period to discarding breast milk within 24 to 48 hours postoperatively. While stopping breastfeeding within 24 hours postoperatively may not be necessary, short-acting anesthetics are preferred. One study showed that breastfeeding before induction of general anesthesia reduced the need for sevoflurane and propofol compared to breastfeeding mothers who stopped breastfeeding or non-breastfeeding women. The need for other anesthetics may also be similarly affected.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

---

Toxicity Data
LC50 (rat) = 29,000 ppm

---

Interactions
One report showed that a 19-month-old boy developed malignant hyperthermia after receiving succinylcholine treatment following halothane anesthesia.
Volunteers exposed to 120 mg/m³ (15 ppm) halothane and 615 mg/m³ (500 ppm) nitrous oxide for 4 hours experienced significant impairment in psychophysiological function…
Muscle relaxants such as non-depolarizing galamine and tubocurarine can be enhanced by halothane; therefore, if used, the dosage should be reduced. Antibiotics with neuromuscular blocking effects, such as streptomycin, should also be used with caution. Morphine enhances the respiratory depressant effects of halothane; use of morphine during anesthesia may lead to postoperative nausea and vomiting. Chlorpromazine can also enhance the depressant effects of halothane.
Halothane may prevent or alleviate trimethylphenidate-induced tachycardia.
For more complete data on interactions of 2-bromo-2-chloro-1,1,1-trifluoroethanes (27 in total), please visit the HSDB records page.

---

Non-human toxicity values
Rat LD50 (oral administration): 5,680 mg/kg
Guinea pig LD50 (oral administration): 6,000 mg/kg
Mouse LC50 (inhalation): 22,000 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

Inhaled Anesthetics

General Anesthesia—Halothane…is indicated for the induction and maintenance of general anesthesia. However, inhaled anesthetics are rarely used alone; they are usually used in combination with other drugs to induce or assist anesthesia. /Included in the US product label/
Cesarean Section:…Halothane…is indicated for use in low concentrations as an adjunct to other general anesthetics during cesarean delivery. /Not included in the US product label/
Veterinary Use: Halothane is a potent anesthetic that is effective in maintaining anesthesia in large animals. Compared to methoxyflurane, halothane can alter the depth and level of anesthesia more rapidly.
Drug Warnings

Halothane reduces sympathetic activity, increases vagal tone, inhibits cardiac contractility, and causes venous dilation. Cardiac output, arterial blood pressure, and pulse rate are typically reduced, and the degree of reduction is proportional to the depth of anesthesia. Overdose may result in severe hypotension and circulatory failure. Supraventricular arrhythmias or junctional rhythms may be observed during anesthesia induction or deep anesthesia. With adequate ventilation, a small dose of epinephrine (1–1.5 μg/kg) can be administered subcutaneously or submucosally in combination with halothane. However, exceeding this dose may be dangerous, as this anesthetic can increase the heart's sensitivity to catecholamines. Administration of lidocaine during epinephrine use can reduce the risk of arrhythmias. Halothane should not be used in patients with a history of jaundice or acute liver injury following prior exposure to this drug, unless other significant causes of liver injury have been confirmed. Contraindications: Halothane should not be used in animals known to have recently received aminoglycoside antibiotics due to the potential for adverse interactions. Animals receiving phenobarbital or other potent enzyme-inducing drugs should not be anesthetized with halothane, as this may cause liver damage (halothane hepatitis). Animals with heart disease or chronic congestive heart failure should not be anesthetized with halothane. Until more information is available regarding the behavioral effects of halothane, veterinary anesthesiologists should likely avoid using this drug in pregnant animals during the first and second trimesters of pregnancy.
Halothane reduces muscle tone in pregnant uterus and is generally not recommended for use in postpartum women due to increased risk of postpartum hemorrhage. Halothane should not be used in patients with arrhythmias.
For more complete data on drug warnings for 2-bromo-2-chloro-1,1,1-trifluoroethane (out of 12), please visit the HSDB record page.

---

Pharmacodynamics
Halothane is an inhaled general anesthetic used to induce and maintain general anesthesia. It lowers blood pressure and often reduces pulse and inhibits respiration. It induces muscle relaxation and reduces pain sensitivity by altering tissue excitability. It achieves this by reducing gap junction-mediated intercellular coupling and altering the activity of action potential channels.

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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