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HALOTHANE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Halothane is an anesthetic gas.

Specific Substances

    1) Bromochlorotrifluoroethane
    2) 2-bromo-2-chloro-1,1,1-trifluoroethane
    3) Ethane
    4) CAS 151-67-7
    1.2.1) MOLECULAR FORMULA
    1) C2HBrClF3

Available Forms Sources

    A) USES
    1) This material is used as an anesthetic drug (inhalation) (Budavari, 2000; Lewis, 2000).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension, acute renal failure and coagulation disorders have been reported. Hepatotoxicity (halothane hepatitis) occurs; fulminant hepatitis is more common with repeat use of halothane. Malignant hyperthermia (muscle rigidity, tachycardia, tachypnea, dysrhythmias, hypotension, hyperthermia, hyperkalemia, rhabdomyolysis) may develop in susceptible individuals.
    B) WITH POISONING/EXPOSURE
    1) Halothane exposure causes respiratory depression, bradycardia, hypotension and CNS depression. Halothane is irritating to the eyes, skin, and mucous membranes. Other effects of exposure include confusion, drowsiness, dizziness, anesthesia, analgesia and nausea.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Malignant hyperthermia is a rare complication of halothane anesthesia.
    B) WITH POISONING/EXPOSURE
    1) Primary toxic effects include hypotension, bradycardia, and respiratory depression.
    0.2.4) HEENT
    A) Mydriasis was reported in one comatose patient after ingestion of 250 mL; mydriasis was not thought to be due to anoxia. Halothane has been reported to lower intraocular pressure.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Asystole has occurred with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Asystole was reported after one case of intravenous use. Right heart failure, supraventricular, ventricular, and sinus tachycardia occurred after intravenous overdose. Sinus bradycardia may also be present in overdose. Hypotension has occurred with either intravenous or oral administration. Peripheral vasoconstriction has also been reported.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression leading to apnea may occur with as little as 2.5 mL administered intravenously. Pulmonary edema or congestion has also been reported in a number of abuse cases.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Coma may occur after ingestion or injection. Severe hypoxic encephalopathy was reported in one case.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Vomiting may occur after halothane ingestion.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatitis has been reported after halothane use. Mild alterations in liver function tests are common. Severe hepatitis is rare, is more common after repeat exposures and/or a short interval between halothane exposures; may progress to fulminant hepatic failure.
    B) WITH POISONING/EXPOSURE
    1) Hepatitis has been reported after halothane abuse. It is not a frequent effect in overdose or in a one-time abuser.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Acute renal failure has been reported after therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Transient hematuria was noted in a patient who received 2.5 mL intravenously.
    0.2.13) HEMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Coagulation defects may develop secondary to acute liver failure.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) An acneiform eruption due to hypersensitivity was reported in one patient occupationally exposed to halothane.
    0.2.17) METABOLISM
    A) WITH THERAPEUTIC USE
    1) Malignant hyperthermia has been reported after halothane use with and without succinylcholine.
    0.2.19) IMMUNOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Allergy to halothane has been reported; a type IV hypersensitivity reaction resulting in acneiform eruptions has also been seen.
    0.2.20) REPRODUCTIVE
    A) An increased risk of congenital abnormalities has been reported in the children of female operating room personnel and in the children of male anesthetists from a national survey study in the United States.
    B) Skeletal defects; ossification defects of the limbs; urogenital, craniofacial, and CNS abnormalities; limb hematomas; and cleft palate have been observed in the offspring of experimental animals exposed to halothane during pregnancy.
    C) An increased incidence of spontaneous abortion, premature delivery, infertility, and irregularities in menstrual periods have been reported in female operating room personnel. An increase in the incidence of spontaneous abortion has also been reported in the wives of male anesthetists.

Laboratory Monitoring

    A) Little halothane is found in serum, but various cell components help to solubilize halothane. When determining halothane levels, a whole blood method of determination should be used. Analysis in biological specimens may be performed by gas chromatography. A level of 200 mcg/mL was fatal in one case.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Ingestion of this inhalational anesthetic is unlikely but has occurred. Emesis is contraindicated due to rapid onset CNS depression. Absorption is rapid, gastric decontamination is unlikely to be useful unless performed very soon after ingestion.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    0.4.3) INHALATION EXPOSURE
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    D) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    E) MALIGNANT HYPERTHERMIA - treat with dantrolene, external cooling and supportive care.
    F) RESPIRATORY SUPPORT - Administer oxygen and perform endotracheal intubation as needed.
    G) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.

Range Of Toxicity

    A) ORAL - 250 mL was ingested and would have been fatal except for respiratory support. As little as 35 mL orally has been lethal.
    B) INTRAVENOUS - As little as 2.5 mL has caused severe apnea, which would have been fatal had not respiratory support been available.
    C) TOXIC BLOOD LEVEL - Blood levels of 200 mcg/mL and 7.9 mcg/mL have been fatal.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Hypotension, acute renal failure and coagulation disorders have been reported. Hepatotoxicity (halothane hepatitis) occurs; fulminant hepatitis is more common with repeat use of halothane. Malignant hyperthermia (muscle rigidity, tachycardia, tachypnea, dysrhythmias, hypotension, hyperthermia, hyperkalemia, rhabdomyolysis) may develop in susceptible individuals.
    B) WITH POISONING/EXPOSURE
    1) Halothane exposure causes respiratory depression, bradycardia, hypotension and CNS depression. Halothane is irritating to the eyes, skin, and mucous membranes. Other effects of exposure include confusion, drowsiness, dizziness, anesthesia, analgesia and nausea.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Malignant hyperthermia is a rare complication of halothane anesthesia.
    B) WITH POISONING/EXPOSURE
    1) Primary toxic effects include hypotension, bradycardia, and respiratory depression.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression may be present and lead to apnea.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Malignant hyperthermia has been reported in patients given halothane with and without suxamethonium (succinylcholine) (Khalil et al, 1999; Wilhoit et al, 1989). It is a rare complication that occurs in susceptible individuals at normal doses.
    2) Chills and fever are often associated with the hepatitis reaction seen with halothane (Klatskin & Kimberg, 1969).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension may occur with significant halothane overdose.
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Bradycardia may occur concomitantly with hypotension.
    2) Sinus tachycardia occurs often in early phases of halothane overdose.

Heent

    3.4.1) SUMMARY
    A) Mydriasis was reported in one comatose patient after ingestion of 250 mL; mydriasis was not thought to be due to anoxia. Halothane has been reported to lower intraocular pressure.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Halothane has been reported to lower intraocular pressure (Grant & Schuman, 1993).
    B) WITH POISONING/EXPOSURE
    1) Mydriasis was reported in one comatose patient after ingestion of 250 mL; mydriasis was not thought to be due to anoxia (Curelaru et al, 1968).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Asystole has occurred with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Asystole was reported after one case of intravenous use. Right heart failure, supraventricular, ventricular, and sinus tachycardia occurred after intravenous overdose. Sinus bradycardia may also be present in overdose. Hypotension has occurred with either intravenous or oral administration. Peripheral vasoconstriction has also been reported.
    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Asystole has also been reported with therapeutic use (Richards et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Asystole was reported after two cases of intravenous use (Berman & Tattersall, 1982; Dwyer & Coppel, 1989).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Sinus bradycardia may be present in overdose (Sweetman, 2000; (Berman & Tattersall, 1982).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension may occur either by intravenous or oral administration or with inhalation of high concentrations (Yamasita et al, 1984; Dwyer & Coppel, 1989; Lewis, 1998).
    D) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) Right heart failure has been reported following an intravenous overdose (Dwyer & Coppel, 1989).
    E) PERIPHERAL ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) Peripheral vasoconstriction was reported by (Berman & Tattersall, 1982).
    F) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia was reported in one fatal case (Berman & Tattersall, 1982). Supraventricular and ventricular tachycardia have also been reported following halothane exposure (Kaplan et al, 1979).
    G) HEART BLOCK
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 3-year-old boy developed complete heart block during inhalation induction using halothane and 70% nitrous oxide (Schultz, 1999). It resolved with 100% oxygen ventilation and atropine 0.4 mg IM and recurred after 2 breaths with 4% halothane followed by 20 seconds of 8% desflurane. No underlying cardiac disease or conduction abnormality was detected on further evaluation.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression leading to apnea may occur with as little as 2.5 mL administered intravenously. Pulmonary edema or congestion has also been reported in a number of abuse cases.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression leading to apnea may be seen (Yamasita et al, 1984; Harbison, 1998). Apnea was caused by as little as 2.5 mL administered intravenously (Sutton et al, 1971).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema was reported on autopsy after intravenous injection (Berman & Tattersall, 1982; Dwyer & Coppel, 1989). Pulmonary edema or pulmonary congestion has also been reported in a number of chronic abuse cases (Spencer et al, 1976), and following IV administration of 2.5 mL (Sutton et al, 1971).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Coma may occur after ingestion or injection. Severe hypoxic encephalopathy was reported in one case.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma may occur after ingestion, inhalation, or injection (Yamasita et al, 1984; Dwyer & Coppel, 1989). A patient who ingested 250 mL was comatose for 36 hours (Curelaru et al, 1968).
    B) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 65-year old woman receiving halothane inhalation for 46 hours developed prolonged encephalopathy, with coma, followed by confusion and hallucinations for 12 days (Echeverria et al, 1986). Bromide levels were 2.4 mmol/L at the time of coma and rose to 3.4 mmol/L 4 days after discontinuation of halothane.
    2) WITH POISONING/EXPOSURE
    a) Severe hypoxic encephalopathy was reported by (Block & Rosenblatt, 1980).
    b) CASE REPORT - Encephalopathy developed secondary to acute liver failure 2 days after acute exposure in a 22-year-old man; liver transplant resolved all complications (Weber et al, 1994).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Vomiting may occur after halothane ingestion.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting may occur after ingestion of halothane (Curelaru et al, 1968).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatitis has been reported after halothane use. Mild alterations in liver function tests are common. Severe hepatitis is rare, is more common after repeat exposures and/or a short interval between halothane exposures; may progress to fulminant hepatic failure.
    B) WITH POISONING/EXPOSURE
    1) Hepatitis has been reported after halothane abuse. It is not a frequent effect in overdose or in a one-time abuser.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) DIFFERENTIAL DIAGNOSIS
    1) Type I hepatotoxicity causes a minor disturbance of liver function (Sweetman, 2000; (Neuberger, 1990). It is characterized by increased serum transaminases or glutathione-S-transferase, and occurs in up to 25 to 30% of patients. Re-exposure to halothane is not necessarily associated with evidence of liver damage.
    2) Type II hepatotoxicity has clinical, serological, and immunological features compatible with an immune-mediated idiosyncratic reaction (Eghtesadi-Araghi et al, 2008; Neuberger, 1990). It is often associated with massive liver cell necrosis and can lead to fulminant hepatic failure (Munro et al, 1998).
    a) CASE SERIES - A review of 59 cases of type II halothane hepatotoxicity (HH) found that 81% (n=48) of cases were in female patients and median age of the group was 44 years, with 60% of patients over the age of 40. The mortality rate was 12.2%, and in those patients who developed encephalopathy, the mortality rate was higher at 50%. Twenty-two patients had a previous exposure to halothane, and 10 patients had a previous post-exposure reaction to halothane. The authors concluded the most prevalent risk factors to HH were female gender and previous exposure to this type of general anesthesia (Eghtesadi-Araghi et al, 2008).
    b) INCIDENCE
    1) Type I hepatotoxicity may occur in up to 25 to 30% of patients (Neuberger, 1990).
    2) The incidence of type II hepatotoxicity is in the range of 1:6000 to 1:36,000 after halothane exposure; risk factors are age over 40, female gender, obesity, previous exposure to halothane, previous adverse reactions to halothane (fever, jaundice), genetic predisposition, enzyme induction and a history of drug allergy (Eghtesadi-Araghi et al, 2008; Weber et al, 1994; Neuberger, 1990; Keaney & Cocking, 1981).
    c) PATHOLOGIC FINDINGS
    1) CASE REPORT - In a case of halothane associated acute hepatic failure in a 6-year-old boy, autopsy revealed subcapsular and parenchymal hemorrhage with massive necrosis and collapse of lobules and small collections of regenerating cells (Munro et al, 1998).
    2) There is some suggestion that patients with type II hepatitis from halothane may be at risk for sensitivity to other agents such as enflurane and less commonly isoflurane (Sweetman, 2000; Gunaratman et al, 1995).
    2) WITH POISONING/EXPOSURE
    a) INCIDENCE
    1) Hepatitis has been reported after halothane abuse. It is not a frequent effect in halothane overdose in a one-time abuser. Liver injury can occur in anesthesia personnel who inhale "waste gas" (Keiding et al, 1984).
    b) PATHOLOGIC FINDINGS
    1) CASE REPORT - At postmortem examination of a 52-year-old male who died 6 days after injecting 3 mL of liquid halothane into a vein, there was widespread acute centrizonal necrosis affecting most of the lobules. There was no evidence of an inflammatory reaction (Dwyer & Coppel, 1989).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Acute renal failure has been reported after therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Transient hematuria was noted in a patient who received 2.5 mL intravenously.
    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Transient hematuria was noted in a patient who received 2.5 mL intravenously (Sutton et al, 1971).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Acute renal failure was reported in a 45-year-old male after three surgical procedures within one month, all using halothane (Abu-Romeh et al, 1987).
    1) Renal biopsy revealed multiple foci of acute tubular necrosis and interstitial mononuclear cell infiltration. The patient also had massive halothane-induced hepatitis. The resulting hyperbilirubinemia may have caused renal vasoconstriction and contributed to renal failure; severe hyperuricemia may also have been nephrotoxic.

Hematologic

    3.13.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Coagulation defects may develop secondary to acute liver failure.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS - Mild leukocytosis (14,000 to 19,000/mm(3)) was reported in two cases, one after oral, the other after intravenous administration (Sutton et al, 1971; Curelaru et al, 1968).
    B) BLOOD COAGULATION PATHWAY FINDING
    1) WITH THERAPEUTIC USE
    a) Coagulation disorders (prolonged PT, PTT and INR, decreased factor V concentration) often develop in patients with severe type II hepatitis and fulminant hepatic failure (Munro et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Coagulation defects developed secondary to acute liver failure in a 22-year-old man 2 days after exposure to halothane; liver transplant resolved all complications (Weber et al, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) An acneiform eruption due to hypersensitivity was reported in one patient occupationally exposed to halothane.
    3.14.2) CLINICAL EFFECTS
    A) PURPURA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Multiple ecchymoses were reported in a halothane abuser with hepatitis (Kaplan et al, 1979).
    B) ACNE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 27-year-old anesthetist experienced an acneiform eruption on her face after two weeks of working with halothane. Four months later, she suffered similar eruptions over her entire body after administering halothane. She was subsequently diagnosed as having a type IV hypersensitivity reaction to the drug (Guldager, 1987).

Immunologic

    3.19.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Allergy to halothane has been reported; a type IV hypersensitivity reaction resulting in acneiform eruptions has also been seen.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Guldager (1987) described a type IV hypersensitivity to halothane after occupational exposure. Skin biopsy revealed spongiose skin and subepidermal edema, with infiltration of polymorphonuclear leukocytes.

Reproductive

    3.20.1) SUMMARY
    A) An increased risk of congenital abnormalities has been reported in the children of female operating room personnel and in the children of male anesthetists from a national survey study in the United States.
    B) Skeletal defects; ossification defects of the limbs; urogenital, craniofacial, and CNS abnormalities; limb hematomas; and cleft palate have been observed in the offspring of experimental animals exposed to halothane during pregnancy.
    C) An increased incidence of spontaneous abortion, premature delivery, infertility, and irregularities in menstrual periods have been reported in female operating room personnel. An increase in the incidence of spontaneous abortion has also been reported in the wives of male anesthetists.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) An increased risk of congenital abnormalities has been reported in the children of female operating room personnel and in the children of male anesthetists from a national survey study in the United States (ACGIH, 1991).
    B) ANIMAL STUDIES
    1) Skeletal defects; ossification defects of the limbs; urogenital, craniofacial, and CNS abnormalities; limb hematomas; and cleft palate have been observed in the offspring of experimental animals exposed to halothane during pregnancy (Schardein, 1993; HSDB , 2001; RTECS , 2001).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY DISORDER
    1) Halothane crosses the placenta. An increased incidence of spontaneous abortion, premature delivery, infertility, and irregularities in menstrual periods have been reported in female operating room personnel. An increase in the incidence of spontaneous abortion has also been reported in the wives of male anesthetists (ACGIH, 1991; Hathaway et al, 1996).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS151-67-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) Halothane caused unscheduled DNA synthesis in rat cells, and DNA inhibition in mouse cells. It has been positive on cytogenetic analysis in human lymphocytes, mouse fibroblasts and hamster lung cells. Halothane caused sex chromosome loss/nondisjunction in D. melanogaster. Mutations have occurred in hamster fibroblasts and mouse cells.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Little halothane is found in serum, but various cell components help to solubilize halothane. When determining halothane levels, a whole blood method of determination should be used. Analysis in biological specimens may be performed by gas chromatography. A level of 200 mcg/mL was fatal in one case.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) A level of 200 mcg/mL was fatal in one case (Block & Rosenblatt, 1980).
    2) Levels after therapeutic administration may be as high as 52 to 180 mg/L (Baselt & Cravey, 1995).

Methods

    A) CHROMATOGRAPHY
    1) Analysis of halothane in biological specimens is most often performed by gas chromatography with either direct sample injection or head space analysis (Baselt & Cravey, 1995).
    B) OTHER
    1) Hemoglobin, albumin, red cell membranes, and triglycerides contribute significantly to the solubility of halothane. Since little is found in the serum, but an equilibrium exists between the serum and these blood components, a whole blood method of determination should be used (Pang et al, 1980).
    2) BIOLOGICAL MONITORING - A method is described using urinary halothane concentration as a biological exposure index in operating room personnel (Imbriani et al, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Little halothane is found in serum, but various cell components help to solubilize halothane. When determining halothane levels, a whole blood method of determination should be used. Analysis in biological specimens may be performed by gas chromatography. A level of 200 mcg/mL was fatal in one case.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Ingestion of this inhalation anesthetic is unlikely but has occurred. Because of the rapid absorption and rapid onset of CNS depression, prehospital decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Ingestion of this inhalational anesthetic is unlikely but has occurred. Emesis is contraindicated due to rapid onset CNS depression. Absorption is rapid, gastric lavage is not routinely recommended as it is unlikely to be useful unless performed very soon after ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    B) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) MALIGNANT HYPERTHERMIA - Dantrolene may be used for malignant hyperthermia. The dose is 1 milligram/kilogram by rapid intravenous infusion until symptoms subside (maximum dose 10 milligrams/kilogram in a single dose). Administration may be repeated if evidence of malignant hyperthermia recurs (USPDI, 2000).
    2) Initiate external cooling measures and provide adequate intravenous hydration. Monitor core temperature, arterial blood gases, ECG, vital signs, urine output, renal function and CPK.
    C) SUPPORT
    1) Aggressive respiratory support may be necessary. Prolonged periods of respiratory depression may occur.
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) BROMISM - Symptomatic patients with excessive bromide levels may require chloride diuresis.
    2) DIURESIS - Administer 0.45 percent sodium chloride in 5 percent dextrose and a diuretic such as furosemide 1 milligram/kilogram intravenously to a maximum of 40 milligrams in a single dose to obtain a urine flow of 3 to 6 milliliters/kilogram/hour.
    E) INJURY OF LIVER
    1) Although hepatitis is not a common effect in overdose, it may be seen in patients who have been chronically abusing halothane.
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) ACETYLCYSTEINE
    1) NAC was an effective pre-treatment in protecting against halothane-induced hepatotoxicity in animals (Keaney & Cocking, 1981). The importance of this finding is unknown in human overdoses, as hepatitis is not a commonly occurring effect with acute overdose.
    H) EXPERIMENTAL THERAPY
    1) METHIONINE - CASE REPORT - Windsor & Wynne-Jones (1988) reported the use of methionine to treat halothane-induced hepatitis in one case.
    a) Although serum liver enzymes had peaked eleven days postoperatively and were decreasing, serum bilirubin continued to rise and progressive jaundice ensued.
    b) DOSE - Thirty-six days post-exposure, oral methionine 250 milligrams four times a day was started. Within 6 days, the patient's serum bilirubin had decreased by 50 percent.
    c) CONCLUSION - It was not known whether the relationship between resolution of hepatitis and methionine therapy was causal or coincidental. Additional studies are needed to prove the safety and efficacy of this treatment.

Inhalation Exposure

    6.7.2) TREATMENT
    A) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    B) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) MALIGNANT HYPERTHERMIA - Dantrolene may be used for malignant hyperthermia. The dose is 1 milligram/kilogram by rapid intravenous infusion until symptoms subside (maximum dose 10 milligrams/kilogram in a single dose). Administration may be repeated if evidence of malignant hyperthermia recurs (USPDI, 2000).
    2) Initiate external cooling measures and provide adequate intravenous hydration. Monitor core temperature, arterial blood gases, ECG, vital signs, urine output, renal function and CPK.
    C) SUPPORT
    1) Stop halothane inhalation and administer 100% oxygen. Aggressive respiratory support may be necessary. Prolonged periods of respiratory depression may occur.
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) BROMISM - Symptomatic patients with excessive bromide levels may require chloride diuresis.
    2) DIURESIS - Administer 0.45 percent sodium chloride in 5 percent dextrose and a diuretic such as furosemide 1 milligram/kilogram intravenously to a maximum of 40 milligrams in a single dose to obtain a urine flow of 3 to 6 milliliters/kilogram/hour.
    E) INJURY OF LIVER
    1) Although hepatitis is not a common effect in overdose, it may be seen in patients who have been chronically abusing halothane.
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) ACETYLCYSTEINE
    1) NAC was an effective pre-treatment in protecting against halothane-induced hepatotoxicity in animals (Keaney & Cocking, 1981). The importance of this finding is unknown in human overdoses, as hepatitis is not a commonly occurring effect with acute overdose.
    H) EXPERIMENTAL THERAPY
    1) METHIONINE - CASE REPORT - Windsor & Wynne-Jones (1988) reported the use of methionine to treat halothane-induced hepatitis in one case.
    a) Although serum liver enzymes had peaked eleven days postoperatively and were decreasing, serum bilirubin continued to rise and progressive jaundice ensued.
    b) DOSE - Thirty-six days post-exposure, oral methionine 250 milligrams four times a day was started. Within 6 days, the patient's serum bilirubin had decreased by 50 percent.
    c) CONCLUSION - It was not known whether the relationship between resolution of hepatitis and methionine therapy was causal or coincidental. Additional studies are needed to prove the safety and efficacy of this treatment.
    I) DRUG ABUSE
    1) A frequent method of halothane abuse is to drip the liquid onto a pad held over the face. Halothane is readily absorbed by inhalation.
    J) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ADULT
    1) ROUTE OF EXPOSURE
    a) INJECTION
    1) A 52-year-old, previously healthy male developed asystolic cardiac arrest 6 days after he injected 3 mL of liquid halothane into a vein. He initially lost consciousness. At 40 minutes post injection he was drowsy. He was in no respiratory distress but the odor of halothane could be detected on his breath. He developed chest discomfort and a nonproductive cough approximately 1 hour post injection. He soon became dyspneic and slightly cyanotic with scattered rhonchi and rales on auscultation of his chest. He was admitted to a health care facility at 3 hours post injection with severe dyspnea, cyanosis, and hypotension. At 7 hours post injection a pulmonary artery flotation catheter was inserted (Dwyer & Coppel, 1989).
    a) TREATMENT - In an attempt to decrease peripheral vascular resistance and to improve cardiac output, an infusion of epoprostenol 5 ng/kg/minute was started. Peripheral vascular resistance decreased from 225 to 147 dyn-sec-cm(-5), as did pulmonary artery pressures (30/16 to 18/7 mm Hg) and pulmonary capillary wedge pressure (8 to 1 mm Hg). This effect was short-lived, and within 2 hours peripheral vascular resistance began to increase. Increasing the rate of epoprostenol infusion did not reverse this trend. He continued to deteriorate, and on day 6 a small pneumothorax developed, as well as bradycardia, and eventually asystolic cardiac arrest.
    b) INHALATION
    1) Acute liver failure with severe coagulopathy, encephalopathy, renal failure and respiratory insufficiency developed in a 22-year-old man 2 days after exposure to halothane. Successful liver transplant resolved all complications (Weber et al, 1994).

Range Of Toxicity

Summary

    A) ORAL - 250 mL was ingested and would have been fatal except for respiratory support. As little as 35 mL orally has been lethal.
    B) INTRAVENOUS - As little as 2.5 mL has caused severe apnea, which would have been fatal had not respiratory support been available.
    C) TOXIC BLOOD LEVEL - Blood levels of 200 mcg/mL and 7.9 mcg/mL have been fatal.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The therapeutic dose is titrated by the anesthesiologist, as needed for the length and depth of anesthesia for a particular operation. During surgical anesthesia, arterial blood levels of halothane range from 80 to 260 milligrams/liter (Baselt & Cravey, 1995).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ROUTE OF EXPOSURE
    1) ORAL -
    2) 250 milliliters was ingested, and would have been fatal except for respiratory support (Yamasita et al, 1984).
    3) As little as 35 milliliters orally has been lethal.
    C) INTRAVENOUS -
    1) As little as, 2.5 mL has caused severe apnea, which would have been fatal had not respiratory support been available (Sutton et al, 1971).
    2) Despite good supportive care, a 52-year-old, previously healthy male died 6 days after he self-administered 3 milliliters of liquid halothane intravenously (Dwyer & Coppel, 1989).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) A blood level of 200 micrograms/milliliter was fatal in one case (Block & Rosenblatt, 1980) as was 7.9 micrograms/milliliter in another case (Berman & Tattersall, 1982).
    b) Halothane may release bromine upon metabolism. A large overdose may produce clinical bromism.

Workplace Standards

    A) ACGIH TLV Values for CAS151-67-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Halothane
    a) TLV:
    1) TLV-TWA: 50 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: Not Listed
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    c) TLV Basis - Critical Effect(s): Liver dam; CNS impair; vasodilation
    d) Molecular Weight: 197.39
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS151-67-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Halothane
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling: 2 ppm (16.2 mg/m(3)) [60-minute]
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s): [*Note: REL for exposure to waste anesthetic gas.]
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS151-67-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Halothane
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Halothane
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS151-67-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Lewis, 2000 RTECS, 2001
    1) LD50- (ORAL)RAT:
    a) 5680 mg/kg -- excitable and antipsychotic behavior
    2) TCLo- (INHALATION)MOUSE:
    a) Female, 3000 ppm for 4H for 9W prior to mating and 1-21D of pregnancy -- urogential system abnormalities; altered litter size and fertility
    b) Female, 14,000 ppm for 1H at 8-10D of pregnancy -- post-implantation mortality
    c) Female, 15,000 ppm for 40M 3W prior to mating -- maternal changes; lactation or weaning index effected; and effects on newborn
    d) Female, 1 pph for 3H for 13D of pregnancy -- abnormal development of craniofacial structure, musculoskeletal system, and other abnormalities
    e) 300 ppm for 24H for 5W- continuous -- decreased weight gain or weight loss and changes to liver
    f) 1000 ppm for 4H 9W prior to mating and 1-7D of pregnancy -- changes in growth statistics
    3) TCLo- (INHALATION)RAT:
    a) 2500 ppm for 8H for 8W- intermittent -- degenerative changes of the brain and coverings, urine volume increased
    b) 100 ppm for 8H at 2-22D of pregnancy -- behavioral changes
    c) 12,500 ppm for 2H for 3D of pregnancy -- reproductive effects (Lewis, 2000)
    d) Female, 10 ppm for 8H 1-22D post-pregnancy -- teratogenic effects; nontransmissible changes produced in the offspring (Lewis, 2000)
    e) Female, 8000 ppm for 6H at 7-9D of pregnancy -- caused abortion
    f) Female, 1600 ppm for 8H at 1-21D of pregnancy -- fetotoxicity
    g) Female, 8000 ppm for 12H for 9D of pregnancy -- developmental abnormalities to the musculoskeletal system and caused post- implantation mortality
    h) Female, 10 ppm for 8H at 1-22D of pregnancy -- cytological changes to somatic cell and genetic material; abnormalities to the central nervous system
    i) Female, 10 ppm for 8H at 1-22D of pregnancy -- urogential system abnormalities and cytological changes to somatic cell and genetic material
    j) 300 ppm for 24H for 5W-continuous -- caused liver changes and decreased weight gain or caused weight loss
    k) 500 ppm for 6H for 9D- intermittent -- kidney, ureter, bladder, gastrointestinal, and biochemical changes
    l) 5126 mg/m(3) for 4H for 17W- intermittent -- blood serum altered; recordings from specific arc as of CNS; true cholinesterase
    m) 10,000 ppm for 1H for 7D- intermittent -- caused vitamin deficiency and liver changes
    n) 50 ppm for 24H for 4W-continuous -- changes to liver: hepatitis; weight; degeneration

Pharmacology Toxicology

Toxicologic Mechanism

    A) Halothane in high concentrations, has a direct toxic effect on cell membranes and increases cell permeability and cell destruction (Berman & Tattersall, 1982).
    B) It has been shown to elicit a parsympathomimetic effect on the cardiovascular system, and has been purported to sensitize the myocardium to catecholamines (Tolas et al, 1967).
    C) It is also a cerebral vasodilator.
    D) HEPATOTOXICITY -
    1) There is considerable evidence that halothane hepatitis may be more of a hypersensitivity reaction than a direct toxic action (Dienstag, 1980), but, since halothane produces several potentially hepatotoxic metabolites, the exact mechanism is still uncertain.

Physicochemical

Physical Characteristics

    A) Halothane is a colorless, highly volatile, nonflammable liquid with a sweetish odor. It is light-sensitive (Budavari, 2000; Lewis, 1998; Lewis, 2000).

Molecular Weight

    A) 197.38

Other

    A) ODOR THRESHOLD
    1) 33 ppm (ACGIH, 1991)

References

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