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HEXACHLOROBUTADIENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hexachlorobutadiene is a chlorinated hydrocarbon encountered as a by-product of hydrocarbon chlorination and as a pesticide.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C4-Cl6

Available Forms Sources

    A) FORMS
    1) Hexachlorobutadiene is a clear, colorless liquid, and has a faint to mild turpentine-like odor (HSDB, 2000; (ILO, 1998).
    B) SOURCES
    1) Hexachlorobutadiene is produced as a by-product of tetrachloroethylene, trichloroethylene, and carbon tetrachloride production (HSDB, 2000).
    2) Hexachlorobutadiene is most commonly encountered in the United States as a byproduct in the chlorination of various hydrocarbons. It is also used as a pesticide, as a solvent, and as an intermediate in lubricant and rubber production (Clayton & Clayton, 1994).
    C) USES
    1) Hexachlorobutadiene is used as both a heat transfer fluid and as a solvent for elastomers (AAR, 1998; HSDB, 2000).
    2) Hexachlorobutadiene is used as a chemical intermediate in the manufacture of rubber compounds, as well as a fluid for gyroscopes (ATSDR, 1994).
    3) It has had some usage as a pesticide, but is primarily encountered as an unwanted byproduct of certain processes associated with the chlorination of hydrocarbons (ACGIH, 1991).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Hexachlorobutadiene may be toxic or fatal by inhalation, ingestion, and dermal exposure. Inhalation produces dizziness, dullness, headaches, tremors and coma. Ingestion results in nausea and vomiting. Skin and eye contact produce redness and irritation. Dermal absorption can occur. Damage to the respiratory, renal and hepatic systems may occur. Chronic exposure has produced liver and kidney damage in animals.
    B) When heated to decomposition, hexachlorobutadiene emits toxic fumes of chlorine and chlorinated products of combustion.
    0.2.3) VITAL SIGNS
    A) Hypotension has been reported.
    0.2.4) HEENT
    A) Eye and nose irritation have been reported in animals exposed to 250 ppm for 4 hours, and at 110 ppm for 6 hours.
    0.2.6) RESPIRATORY
    A) Dyspnea, chronic bronchitis, and congestion and hemorrhage in the lungs may occur.
    0.2.7) NEUROLOGIC
    A) Nervous function disorders and CNS depression may occur.
    0.2.9) HEPATIC
    A) Chronic liver disease has been reported. Fatty degeneration of the liver may occur.
    0.2.10) GENITOURINARY
    A) Degeneration of renal cortical tubules, damage to renal proximal tubules, renal tubular necrosis, increased plasma urea, and increased urinary excretion of coproporphyns may occur.
    0.2.12) FLUID-ELECTROLYTE
    A) Changes in blood electrolytes may occur.
    0.2.14) DERMATOLOGIC
    A) Hemorrhagic and necrotic skin lesions may occur.
    0.2.19) IMMUNOLOGIC
    A) Immunologic depression and decreased antibody formation have been noted in experimental animals.
    0.2.20) REPRODUCTIVE
    A) Soft tissue anomalies and central nervous system developmental abnormalities have occurred in experimental animals.
    B) Post-implantation mortality and fetotoxicity have been reported in experimental animals.
    C) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.
    0.2.21) CARCINOGENICITY
    A) Hexachlorobutadiene is on the NIOSH list of suspected carcinogens, potentially causing kidney and lung cancer.

Laboratory Monitoring

    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Chronic ingestions of 20 mg/kg in animals produced an increased urinary excretion of coproporhyrins.
    C) Monitor pulse oximetry and/or ABGs, chest x-ray, and pulmonary function tests in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic 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) Supportive care for renal or hepatic injury may be indicated in substantial exposures or chronic exposures.
    D) Do not give lipids by mouth as this may increase absorption.
    E) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    D) 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.
    E) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Range Of Toxicity

    A) Its been observed that acute oral toxicity of hexachlorobutadiene is moderate to high. It is also a confirmed animal carcinogen with unknown relevance to humans.

Clinical Effects

Summary Of Exposure

    A) Hexachlorobutadiene may be toxic or fatal by inhalation, ingestion, and dermal exposure. Inhalation produces dizziness, dullness, headaches, tremors and coma. Ingestion results in nausea and vomiting. Skin and eye contact produce redness and irritation. Dermal absorption can occur. Damage to the respiratory, renal and hepatic systems may occur. Chronic exposure has produced liver and kidney damage in animals.
    B) When heated to decomposition, hexachlorobutadiene emits toxic fumes of chlorine and chlorinated products of combustion.

Vital Signs

    3.3.1) SUMMARY
    A) Hypotension has been reported.
    3.3.4) BLOOD PRESSURE
    A) Hypotension was reported in agricultural workers exposed to 0.8 to 30 mg/m(3) hexachlorobutadiene and 0.12 to 6.7 mg/m(3) polychlorobutane (ILO, 1983).

Heent

    3.4.1) SUMMARY
    A) Eye and nose irritation have been reported in animals exposed to 250 ppm for 4 hours, and at 110 ppm for 6 hours.
    3.4.3) EYES
    A) EYE IRRITATION has been seen in animals with exposures of 250 ppm for four hours and 100 ppm for six hours (ACGIH, 1986).
    3.4.5) NOSE
    A) NASAL IRRITATION has been reported in animals who were exposed to 250 ppm for four hours and 100 ppm for six hours (ACGIH, 1986).

Respiratory

    3.6.1) SUMMARY
    A) Dyspnea, chronic bronchitis, and congestion and hemorrhage in the lungs may occur.
    3.6.2) CLINICAL EFFECTS
    A) BRONCHITIS
    1) Chronic bronchitis has been reported in agricultural workers exposed to 0.8 to 30 mg/m(3) hexachlorobutadiene and 0.12 to 6.7 mg/m(3) polychlorobutane (ILO, 1983).
    B) DYSPNEA
    1) Respiratory difficulty was seen in animals exposed to 100 to 250 ppm for multiple exposures of from 4 to 6 hours (ACGIH, 1986).
    C) PULMONARY HEMORRHAGE
    1) Congestion and hemorrhage were noted in the lungs of rabbits following topical application of hexachlorobutadiene (CESARS, 1986).

Neurologic

    3.7.1) SUMMARY
    A) Nervous function disorders and CNS depression may occur.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) Nervous function disorders have been reported in agricultural workers exposed to 0.8 to 30 mg/m(3) hexachlorobutadiene and 0.12 to 6.7 mg/m(3) polychlorobutane (ILO, 1983).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Moderate CNS depression has been noted in experimental animals (CESARS, 1986).

Hepatic

    3.9.1) SUMMARY
    A) Chronic liver disease has been reported. Fatty degeneration of the liver may occur.
    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) Chronic liver disease has been reported in agricultural workers exposed to 0.8 to 30 mg/m(3) hexachlorobutadiene and 0.12 to 6.7 mg/m(3) polychlorobutane (ILO, 1983).
    B) STEATOSIS OF LIVER
    1) Fatty liver degeneration was reported in rabbits exposed to pure hexachlorobutadiene by the dermal route to 0.25, 0.5, 0.75, and 1 mL/kg during an 8-hour period (HSDB , 1992).

Genitourinary

    3.10.1) SUMMARY
    A) Degeneration of renal cortical tubules, damage to renal proximal tubules, renal tubular necrosis, increased plasma urea, and increased urinary excretion of coproporphyns may occur.
    3.10.2) CLINICAL EFFECTS
    A) RENAL TUBULAR DISORDER
    1) Animals exposed to 100 to 250 ppm for several four to six hour exposures, developed degeneration of renal cortical tubules with epithelial degeneration and damage to renal proximal tubules (ACGIH, 1986).
    B) CRUSH SYNDROME
    1) Renal tubular necrosis and increased plasma urea occurred in rats given a single 50 mg/kg dose of hexachlorobutadiene IP (HSDB , 1992).
    C) ABNORMAL URINE
    1) In experimental animals, a dose of 2 mg/kg/day caused an increase of urinary excretion of coproporphyins (ACGIH, 1986).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Compensated metabolic acidosis occurred in rabbits fed hexachlorobutadiene daily for 3 months (CESARS, 1986).

Dermatologic

    3.14.1) SUMMARY
    A) Hemorrhagic and necrotic skin lesions may occur.
    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) Hemorrhagic and necrotic skin lesions were noted in rabbits following topical hexachlorobutadiene application (CESARS, 1986).

Immunologic

    3.19.1) SUMMARY
    A) Immunologic depression and decreased antibody formation have been noted in experimental animals.
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNOSUPPRESSION
    a) Immunologic depression and decreased antibody formation have been noted in hexachlorobutadiene exposed experimental animals (CESARS, 1986).

Reproductive

    3.20.1) SUMMARY
    A) Soft tissue anomalies and central nervous system developmental abnormalities have occurred in experimental animals.
    B) Post-implantation mortality and fetotoxicity have been reported in experimental animals.
    C) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Soft tissue anomalies were noted when hexachlorobutadiene was injected into pregnant rats during gestation (Schardein, 1985).
    2) Central nervous system developmental abnormalities and metabolic and biochemical toxic effects were noted in the offspring of rats fed hexachlorobutadiene during pregnancy (RTECS , 1992).
    3.20.3) EFFECTS IN PREGNANCY
    A) FETOTOXICITY
    1) Post-implantation mortality and fetotoxicity have been reported in experimental animals (RTECS , 1992).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS87-68-3 (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) IARC Classification
    a) Listed as: Hexachlorobutadiene
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) Hexachlorobutadiene is on the NIOSH list of suspected carcinogens, potentially causing kidney and lung cancer.
    3.21.3) HUMAN STUDIES
    A) RENAL TUBULAR DISORDER
    1) Chronic ingestion of 20 mg/kg/day for up to two years caused increased renal tubular epithelial hyperplasia, and renal tubular adenomas and adenocarcinomas. Some of the renal neoplasms noted in rats metastasized to the lungs (Clayton & Clayton, 1982).
    B) RENAL CARCINOMA
    1) Hexachlorobutadiene was rated as carcinogenic to the kidney, ureter, and bladder in the rat by RTECS criteria (RTECS , 1992).

Genotoxicity

    A) Unscheduled DNA synthesis has occurred in experimental animals. Mutations have been produced in S typhimurium and sister chromatid exchange has occurred in the hamster ovary cell.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Chronic ingestions of 20 mg/kg in animals produced an increased urinary excretion of coproporhyrins.
    C) Monitor pulse oximetry and/or ABGs, chest x-ray, and pulmonary function tests in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY: A colorimetric method has been described for measurement of hexachlorobutadiene in blood, with a detection limit of 5 mg/L (HSDB , 1992).
    B) BLOOD/SERUM CHEMISTRY
    1) This agent may cause hepatotoxicity. Monitor liver function tests in patients with significant exposure.
    C) BLOOD/SERUM CHEMISTRY
    1) This agent may cause nephrotoxicity. Monitor renal function tests and urinalysis in patients with significant exposure.
    4.1.3) URINE
    A) URINALYSIS: The following combination of tests may be useful for detecting renal dysfunction in exposed workers: examination of urine with reagent strips for the presence of glucosuria, proteinuria, and quantitative determination of at least 2 proteins (one of high molecular weight for glomerular function and one of low molecular weight for tubular function) (HSDB , 1992).
    B) OTHER: Urinary excretion of coprophorphyrins should perhaps be included as part of a medical surveillance program for potentially exposed employees (Clayton & Clayton, 1982).
    C) URINALYSIS: An ultraviolet analytical method has been described for analysis of hexachlorobutadiene in urine, with a detection limit of 0.5 mg/L (HSDB , 1992).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor CBC, urinalysis, and liver and kidney function tests in patients with significant exposure.
    B) Chronic ingestions of 20 mg/kg in animals produced an increased urinary excretion of coproporhyrins.
    C) Monitor pulse oximetry and/or ABGs, chest x-ray, and pulmonary function tests in symptomatic patients.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    B) ACTIVATED CHARCOAL/CATHARTIC
    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) SUPPORT
    1) There are no available specific treatments. Supportive care for hepatic or renal injury may be required.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    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.
    6.7.2) TREATMENT
    A) OBSERVATION REGIMES
    1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) BRONCHOSPASM
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) 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).
    D) MONITORING OF PATIENT
    1) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Its been observed that acute oral toxicity of hexachlorobutadiene is moderate to high. It is also a confirmed animal carcinogen with unknown relevance to humans.

Minimum Lethal Exposure

    A) ADULT
    1) Various investigators have rated the acute oral toxicity of hexachlorobutadiene as moderate to high (ACGIH, 1991).
    2) The ACGIH classifies hexachlorobutadiene in category A3: Confirmed animal carcinogen with unknown relevance to humans (ACGIH, 2000).
    3) The IARC places hexachlorobutadiene in Group 3: The agent (mixture, or exposure circumstance)is unclassifiable as to carcinogenicity in humans (IARC, 1999).
    4) A group of 205 vineyard workers who were exposed seasonally to hexachlorobutadiene and polychlorobutane-80 (0.8 to 30 mg/m(3) and 0.12 to 6.7 mg/m(3), respectively, in air over the fumigated zones) showed multiple toxic effects contributing to the development of hypotension, cardiac disease, chronic bronchitis, disturbances of nervous function, and chronic hepatitis (HSDB, 2000).
    B) ANIMAL DATA
    1) INHALATION - Four to seven hour exposures of 133 to 500 ppm caused death in some or all rats so exposed. All rats survived 161 ppm for 0.88 hour or 34 ppm for 3.3 hours. Most guinea pigs and cats died subsequent to exposure to 161 ppm for 0.88 hour or 34 ppm for 7.5 hours (ACGIH, 1991).
    2) DERMAL - Dermal application of 126 mg/kg was lethal to one-half of treated rabbits at seven hours and 4 of 4 rabbits in 24 hours (Clayton & Clayton, 1994).

Maximum Tolerated Exposure

    A) ANIMAL DATA
    1) Hexachlorobutadiene demonstrates high chronic toxicity. It is capable of causing lung, liver and renal injury in rats (Clayton & Clayton, 1994).
    2) Rats experienced eye and nose irritation and respiratory difficulty after repeated exposures to 250 ppm (twice for 4 hours) or 100 ppm (twelve times for 6 hours) (Hathaway et al, 1996).
    3) Rats, rabbits, and guinea pigs exposed to 3 ppm for 7 hours/day for approximately 5 months experienced liver and kidney damage. Exposure to 1 ppm caused no adverse effects (Hathaway et al, 1996).
    4) Based on animal studies, a level of 0.13 ppm in air would be without effect, and 1.3 ppm would produce reversible changes (Clayton & Clayton, 1994).
    5) Rats exposed to 5 ppm hexachlorobutadiene for 15 six-hour exposures showed no toxic symptoms (ACGIH, 1991).
    6) All rabbits survived the dermal application of 120 mg/kg for four hours or 63 mg/kg for 24 hours (Clayton & Clayton, 1994).
    7) No deleterious effects were reported in adult Japanese quail maintained for 90 days on diets containing up to 5 mg/kg-day (ACGIH, 1991).
    8) In rats, ingestion of the lowest level doses of 0.2 mg/kg-day for up to 2 years caused no effects that could be attributed to treatment. Whereas the intermediate dose level of 2.0 mg/kg-day caused a slight degree of renal toxicity, the highest dose level of 20 mg/kg-day for up to 2 years caused multiple and substantial toxicological effects, including renal tubular neoplasms (Clayton & Clayton, 1994).

Workplace Standards

    A) ACGIH TLV Values for CAS87-68-3 (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) Hexachlorobutadiene
    a) TLV:
    1) TLV-TWA: 0.02 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Kidney dam
    d) Molecular Weight: 260.76
    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 CAS87-68-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Hexachlorobutadiene
    2) REL:
    a) TWA: 0.02 ppm (0.24 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: [skin]
    1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.
    f) Note(s): See Appendix A
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS87-68-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Hexachlorobutadiene
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): C ; Listed as: Hexachlorobutadiene
    a) C : Possible human carcinogen.
    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): 3 ; Listed as: Hexachlorobutadiene
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Hexachlorobutadiene
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 3B ; Listed as: Hexachloro-1,3-butadiene
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS87-68-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: ACGIH, 1991 Budavari, 1996 Clayton & Clayton, 1994 Lewis, 2000 ) (OHM/TADS, 2000; RTECS, 2000)
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 76 mg/kg
    b) Female, 76 mg/kg (Budavari, 1996)
    c) Male, 105 mg/kg (Budavari, 1996; OHM/TADS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) Male, 21D, 64 mg/kg (ACGIH, 1991)
    b) Female, 21D, 46 mg/kg (ACGIH, 1991)
    c) Female, 65mg/kg (Budavari, 1996)
    d) 87 mg/kg
    e) 110 mg/kg (OHM/TADS, 2000)
    3) LD50- (SKIN)MOUSE:
    a) 150 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 175 mg/kg -- depressed activity and irritability.
    b) Female, 175 mg/kg (Budavari, 1996)
    c) Male, 216 mg/kg (Budavari, 1996; OHM/TADS, 2000)
    5) LD50- (ORAL)RAT:
    a) 82 mg/kg
    b) 90 mg/kg (OHM/TADS, 2000)
    c) Male, 250 mg/kg (Budavari, 1996; OHM/TADS, 2000)
    d) Female, 270 mg/kg (Budavari, 1996)
    e) Male, 580 mg/kg (Clayton & Clayton, 1994)
    f) Female, 200-400 mg/kg (Clayton & Clayton, 1994)
    g) Male, 64 mg/kg at 21D old (ACGIH, 1991)
    h) Female, 46 mg/kg at 21 D old (ACGIH, 1991)
    6) TCLo- (INHALATION)RAT:
    a) Female, 15 ppm for 6H at 6-20D of pregnancy -- Fetotoxic
    b) 100 ppm for 6H/2W-intermittent -- acute renal failure, acute tubular necrosis, weight loss or decreased weight gain, death
    c) 26 mg/m(3) for 2H/30D- intermittent -- blood changes, changes in leukocyte count, weight loss or decreased weight gain

Pharmacology Toxicology

Toxicologic Mechanism

    A) The exact mechanism by which hexachlorobutadiene exerts its toxic effects on the kidneys has yet to be established.

Physicochemical

Physical Characteristics

    A) Hexachlorobutadiene exists as a liquid at 15 degrees C and 1 atm (CHRIS, 2000).

Molecular Weight

    A) 260.76

Other

    A) ODOR THRESHOLD
    1) 0.006 ppm (OHM/TADS, 2000)
    2) 12 mg/m(3) (WHO, 1994)

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