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BENZYL CHLORIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Benzyl chloride is a chlorinated derivative of toluene (Budavari, 1996). It is produced by chlorination of toluene under conditions not favoring ring chlorination (Budavari, 1996; IARC, 1982). Benzyl chloride is toxic by all routes (oral, dermal, inhalation).
    B) Benzotrichloride is a closely related compound which is thought to have similar toxicity.

Specific Substances

    1) alpha-Chlorotoluene
    2) alpha-Chlorotoluol (German)
    3) Benzene, (chloromethyl)-
    4) Benzile (cloruro di) (Italian)
    5) Benzyl chloride
    6) Benzyl chloride
    7) Benzylchlorid (German)
    8) Benzyle (chlorure de) (French)
    9) Chloromethylbenzene
    10) (Chloromethyl)benzene
    11) Chlorophenylmethane
    12) Chlorure de benzyle (French)
    13) omega-Chlorotoluene
    14) NCI-c 06360
    15) Toluene, alpha-chloro-
    16) Toluene, alpha-chloro-
    17) Tolyl chloride
    18) CAS 100-44-7
    19) BENZILE (CHLORURO DI) (ITALIAN)
    20) BENZOTRICLORURO (SPANISH)
    1.2.1) MOLECULAR FORMULA
    1) C7-H7-Cl

Available Forms Sources

    A) FORMS
    1) Benzyl chloride is a colorless to slightly yellow liquid with an irritating and unpleasant odor (HSDB , 2001; Lewis & Sr, 2000).
    2) Benzotrichloride is a closely related compound which is thought to have similar toxicity.
    B) USES
    1) Benzyl chloride is used as a chemical intermediate in the production of benzyl compounds (benzyl phthalates, benzyl alcohol, benzyl quarternary ammonium salts, benzyl esters), perfumes, dyes (C.I. 42536, Basic Violet 13), artificial resins, synthetic tannins, lubricants, photography developing reagents, chemical gum inhibitors for gasoline, and in pharmaceutical manufacturing (benzathine penicillin, phenobarbital, quarternary ammonium chloride bactericides) (IARC, 1982) EPA, 1985; (ITI, 1995; Hathaway et al, 1996; Budavari, 1996).
    2) Benzyl chloride has been used as a lacrimating chemical warfare agent in the past (IARC, 1982).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Benzyl chloride is used as a chemical intermediate in the production of benzyl compounds, perfumes, dyes, artificial resins, synthetic tannins, lubricants, photography developing reagents, chemical gum inhibitors for gasoline and in pharmaceutical manufacturing.
    B) TOXICOLOGY: Acids cause coagulation necrosis. Hydrogen ions desiccate epithelial cells, causing edema, erythema, tissue sloughing and necrosis, with formation of ulcers and eschars.
    C) EPIDEMIOLOGY: Exposure is rare. Benzyl chloride is typically available for industrial purposes.
    D) WITH POISONING/EXPOSURE
    1) Benzyl chloride exposure is unusual; limited data regarding specific human toxicity following benzyl chloride exposure is available. The following effects could be expected to occur, based on exposure data of other acids.
    2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) are at risk for subsequent stricture formation, particularly gastric outlet and esophageal. Some patients (particularly young children) may develop upper airway edema. Nausea, vomiting, diarrhea and abdominal cramping can be expected following benzyl chloride ingestion.
    3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Upper airway edema is common and often life threatening. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Other rare complications include metabolic acidosis, hemolysis, renal failure, disseminated intravascular coagulation, elevated liver enzymes, and cardiovascular collapse. Stricture formation (primarily gastric outlet and esophageal, less often oral) is likely to develop long term. Esophageal carcinoma is another long term complication.
    4) INHALATION EXPOSURE: Headache, weakness and fatigue have been reported following benzyl chloride exposure. Mild exposure may cause dyspnea, pleuritic chest pain, cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, hypoxia, stridor, pneumonitis, tracheobronchitis, and rarely acute lung injury or persistent pulmonary function abnormalities. Pulmonary dysfunction similar to asthma has been reported.
    5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent vision loss and in severe cases perforation. Benzyl chloride is a strong lacrimator.
    6) DERMAL EXPOSURE: A minor exposure can cause irritation and partial thickness burns. More prolonged or a high concentration exposure can cause full thickness burns. Complications may include cellulitis, sepsis, contractures, osteomyelitis and systemic toxicity.
    0.2.4) HEENT
    A) Severe eye irritation and lacrimation may occur. Irritation of the mucosa of the nose and throat occurs with exposure to low concentrations of vapor.
    0.2.5) CARDIOVASCULAR
    A) In fatally poisoned experimental animals, degenerative changes of the myocardium were seen. This effect has not been reported in exposed humans.
    0.2.6) RESPIRATORY
    A) Severe respiratory tract irritation with possible pulmonary edema or lung injury may develop.
    0.2.8) GASTROINTESTINAL
    A) Irritation or burns of the esophagus or gastrointestinal tract may occur.
    B) Anorexia, nausea, vomiting, diarrhea, and abdominal cramping or pain may be noted.
    0.2.9) HEPATIC
    A) Degenerative changes in the liver were observed in fatally poisoned experimental animals. This effect has not been reported in exposed humans. In male rat hepatocytes, a decrease in cell viability and an increase in leakage of cytosolic enzymes were observed.
    0.2.10) GENITOURINARY
    A) Degenerative changes were observed in the kidneys of fatally poisoned experimental animals. This effect has not been reported in exposed humans.
    0.2.14) DERMATOLOGIC
    A) Skin irritation or burns may be observed. Skin sensitization may occur.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no reproductive studies were found for benzyl chloride in humans.
    B) Fetotoxicity and a high incidence of embryolethality were observed in rat studies.
    0.2.21) CARCINOGENICITY
    A) Based on experiments done on rats, NIOSH has concluded that the carcinogenic risk from low exposure is probably negligible. There is limited evidence that workers exposed to benzyl chloride have a carcinogenic risk. In the NCI Carcinogenesis Studies (Feed) clear evidence for carcinogenicity was found in the mouse and inadequate evidence was found in the rat.

Laboratory Monitoring

    A) Obtain a complete blood count and electrolytes in all patients with significant burns after acid ingestion.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, liver enzymes, serial CBC, INR, PT, PTT, fibrinogen, fibrin degradation products, type and crossmatch for blood, and monitor urine output and urinalysis. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is very little information available regarding the treatment of benzyl chloride-induced injury; the following data is derived from experience with other acids.
    B) MILD TO MODERATE ORAL TOXICITY
    1) Within the first 12 hours of exposure, if burns are absent or grade I severity, patient may be discharged when able to tolerate liquids and soft foods by mouth. If mild grade II burns, admit for intravenous fluids, slowly advance diet as tolerated. Perform barium swallow or repeat endoscopy several weeks after ingestion (sooner if difficulty swallowing) to evaluate for stricture formation.
    C) SEVERE ORAL TOXICITY
    1) Resuscitate with 0.9% saline; blood products may be necessary. Early airway management in patients with upper airway edema or respiratory distress. Early (within 12 hours) gastrointestinal endoscopy to evaluate for burns. Early bronchoscopy in patients with respiratory distress or upper airway edema. Early surgical consultation for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms or laboratory findings concerning for tissue necrosis or perforation.
    D) DILUTION
    1) Dilute with 4 to 8 ounces of water may be useful if it can be performed shortly after ingestion in patients who are able to swallow, with no vomiting or respiratory distress; then the patient should be NPO until assessed for the need for endoscopy. Neutralization, activated charcoal, and gastric lavage are all contraindicated.
    E) AIRWAY MANAGEMENT
    1) Aggressive airway management in patients with deliberate ingestions or any indication of upper airway injury. Severe edema may make intubation difficult; be prepared for surgical airway management (cricothyroidotomy) in patients with severe upper airway edema.
    F) ENDOSCOPY
    1) Should be performed as soon as possible (preferably within 12 hours, not more than 24 hours) in any patient with acid ingestion. The grade of mucosal injury at endoscopy is the strongest predictive factor for the occurrence of systemic and GI complications and mortality. The absence of visible oral burns does NOT reliably exclude the presence of esophageal burns.
    G) BRONCHOSPASM
    1) Treat with oxygen, inhaled beta agonists and consider systemic corticosteroids
    H) CORTICOSTEROIDS
    1) The use of corticosteroids to prevent stricture formation is controversial. Corticosteroids should not be used in patients with grade I or grade III injury, as there is no evidence that it is effective. Evidence for grade II burns is conflicting, and the risk of perforation and infection is increased with steroid use, so routine use is not recommended.
    I) STRICTURE
    1) A barium swallow or repeat endoscopy should be performed several weeks after ingestion in any patient with grade II or III burns or with difficulty swallowing to evaluate for stricture formation. Recurrent dilation may be required. Some authors advocate early stent placement in these patients to prevent stricture formation.
    J) SURGICAL MANAGEMENT
    1) Immediate surgical consultation should be obtained on any patient with grade III or severe grade II burns on endoscopy, significant abdominal pain, metabolic acidosis, hypotension, coagulopathy, or a history of large ingestion. Early laparotomy can identify tissue necrosis and impending or unrecognized perforation, early resection and repair in these patients is associated with improved outcome.
    K) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with an acid ingestion should be sent to a health care facility for evaluation. Patients with an endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged to home.
    2) ADMISSION CRITERIA: Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, or extensive grade II burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.
    L) PITFALLS
    1) The absence of oral burns does NOT reliably exclude the possibility of significant esophageal burns.
    2) Patients may have severe tissue necrosis and impending perforation requiring early surgical intervention without having severe hypotension, rigid abdomen, or radiographic evidence of intraperitoneal air.
    3) Patients with any evidence of upper airway involvement require early airway management before airway edema progresses.
    4) The extent of eye injury (degree of corneal opacification and perilimbal whitening) may not be apparent for 48 to 72 hours after the burn. All patients with acidic eye injury should be evaluated by an ophthalmologist.
    M) DIFFERENTIAL DIAGNOSIS
    1) Alkaline corrosive ingestion, gastrointestinal hemorrhage, or perforated viscus.
    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) Administer 100% humidified supplemental oxygen with assisted ventilation as required. Maintain airway patency. Endotracheal intubation could be required.
    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.
    0.4.4) 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.
    B) Severe eye irritation may occur and early ophthalmic consultation may be required.
    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).

Range Of Toxicity

    A) TOXICITY: Serious burns are less likely if the pH >3. Injury is usually greater with either a large ingestion (usually deliberate), or a high concentration acid (usually not a household product).
    B) In a case series of unintentional caustic ingestions (mixed liquid and solid, acids and bases) among children, the incidence of significant esophageal or gastric burns was 5% to 35%. However, adults with deliberate acid ingestions are more likely to develop significant esophageal and/or gastric burns (40% to 95%).
    C) Inhalation exposure to 380 ppm for 8 hours caused death in dogs. Workers with inhalation exposure to 2 ppm developed weakness, irritability, and headache. The odor threshold is 0.047 ppm.

Clinical Effects

Summary Of Exposure

    A) USES: Benzyl chloride is used as a chemical intermediate in the production of benzyl compounds, perfumes, dyes, artificial resins, synthetic tannins, lubricants, photography developing reagents, chemical gum inhibitors for gasoline and in pharmaceutical manufacturing.
    B) TOXICOLOGY: Acids cause coagulation necrosis. Hydrogen ions desiccate epithelial cells, causing edema, erythema, tissue sloughing and necrosis, with formation of ulcers and eschars.
    C) EPIDEMIOLOGY: Exposure is rare. Benzyl chloride is typically available for industrial purposes.
    D) WITH POISONING/EXPOSURE
    1) Benzyl chloride exposure is unusual; limited data regarding specific human toxicity following benzyl chloride exposure is available. The following effects could be expected to occur, based on exposure data of other acids.
    2) MILD TO MODERATE ORAL TOXICITY: Patients with mild ingestions may only develop irritation or grade I (superficial hyperemia and edema) burns of the oropharynx, esophagus or stomach; acute or chronic complications are unlikely. Patients with moderate toxicity may develop grade II burns (superficial blisters, erosions and ulcerations) are at risk for subsequent stricture formation, particularly gastric outlet and esophageal. Some patients (particularly young children) may develop upper airway edema. Nausea, vomiting, diarrhea and abdominal cramping can be expected following benzyl chloride ingestion.
    3) SEVERE ORAL TOXICITY: May develop deep burns and necrosis of the gastrointestinal mucosa. Complications often include perforation (esophageal, gastric, rarely duodenal), fistula formation (tracheoesophageal, aortoesophageal), and gastrointestinal bleeding. Upper airway edema is common and often life threatening. Hypotension, tachycardia, tachypnea and, rarely, fever may develop. Other rare complications include metabolic acidosis, hemolysis, renal failure, disseminated intravascular coagulation, elevated liver enzymes, and cardiovascular collapse. Stricture formation (primarily gastric outlet and esophageal, less often oral) is likely to develop long term. Esophageal carcinoma is another long term complication.
    4) INHALATION EXPOSURE: Headache, weakness and fatigue have been reported following benzyl chloride exposure. Mild exposure may cause dyspnea, pleuritic chest pain, cough and bronchospasm. Severe inhalation may cause upper airway edema and burns, hypoxia, stridor, pneumonitis, tracheobronchitis, and rarely acute lung injury or persistent pulmonary function abnormalities. Pulmonary dysfunction similar to asthma has been reported.
    5) OCULAR EXPOSURE: Ocular exposure can produce severe conjunctival irritation and chemosis, corneal epithelial defects, limbal ischemia, permanent vision loss and in severe cases perforation. Benzyl chloride is a strong lacrimator.
    6) DERMAL EXPOSURE: A minor exposure can cause irritation and partial thickness burns. More prolonged or a high concentration exposure can cause full thickness burns. Complications may include cellulitis, sepsis, contractures, osteomyelitis and systemic toxicity.

Heent

    3.4.1) SUMMARY
    A) Severe eye irritation and lacrimation may occur. Irritation of the mucosa of the nose and throat occurs with exposure to low concentrations of vapor.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Benzyl chloride can produce severe eye irritation and lacrimation from either direct contact or vapor exposure (HSDB , 2001; Grant & Schuman, 1993; ITI, 1995; Hathaway et al, 1996).
    a) In humans, 31 ppm produces unbearable eye irritation (Grant & Schuman, 1993).
    b) Cats exposed to 2 mg/L of air developed eye irritation; after 7.5 hours of exposure, turbidity of the cornea was noted the following day (Grant & Schuman, 1993).
    2) Benzyl chloride is a powerful lacrimator (Hathaway et al, 1996) Lewis, 1997).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) Irritation of the mucosa of the nose and throat occurs with exposure to low concentrations of vapor (HSDB , 2001; Hathaway et al, 1996).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Irritation of the mucosa of the nose and throat occurs with exposure to low concentrations of vapor (HSDB , 2001; Hathaway et al, 1996). Ingestion of the liquid may result in immediate and severe burns of the mouth, throat, and gastrointestinal tract (HSDB , 2001).

Cardiovascular

    3.5.1) SUMMARY
    A) In fatally poisoned experimental animals, degenerative changes of the myocardium were seen. This effect has not been reported in exposed humans.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CARDIOMYOPATHY
    a) Degenerative changes were seen in the myocardium in fatally poisoned experimental animals (Mikhailova, 1965). This effect has not been reported in exposed humans.

Respiratory

    3.6.1) SUMMARY
    A) Severe respiratory tract irritation with possible pulmonary edema or lung injury may develop.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Severe irritation of the respiratory tract can occur from exposure to vapors (Hathaway et al, 1996; ACGIH, 1986). Lung damage may occur with heavy exposure (HSDB , 2001; CHRIS , 1999).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema may occur after significant inhalation exposure (HSDB , 2001; CHRIS , 1999).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Despite its pulmonary irritant effects, benzyl chloride did not adversely effect murine lung host defenses in experimental exposure in bacterial infections (Aranyi et al, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) Weakness, dizziness and irritability may occur following large exposures (HSDB , 2001; Budavari, 1996).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Workers with chronic, low level exposure have complained of headache, weakness, and irritability (HSDB , 2001; Hathaway et al, 1996).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Insomnia and tremors involving the eyelids and digits of the hands have been described with chronic exposure (HSDB , 2001; Plunkett, 1976).
    D) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression may occur following severe, acute exposures (HSDB , 2001).
    E) INSOMNIA
    1) WITH POISONING/EXPOSURE
    a) Insomnia and tremors involving the digits of the hands have been described with chronic exposure (Plunkett, 1976).

Gastrointestinal

    3.8.1) SUMMARY
    A) Irritation or burns of the esophagus or gastrointestinal tract may occur.
    B) Anorexia, nausea, vomiting, diarrhea, and abdominal cramping or pain may be noted.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) Anorexia, nausea, vomiting, diarrhea, and abdominal cramping may occur following ingestion (HSDB , 2001; CHRIS , 1999; Plunkett, 1976).
    B) ESOPHAGITIS
    1) WITH POISONING/EXPOSURE
    a) Severe irritation and immediate burns of the mouth, throat, esophagus, or gastrointestinal tract could occur following ingestion (HSDB , 2001; CHRIS , 1999).

Hepatic

    3.9.1) SUMMARY
    A) Degenerative changes in the liver were observed in fatally poisoned experimental animals. This effect has not been reported in exposed humans. In male rat hepatocytes, a decrease in cell viability and an increase in leakage of cytosolic enzymes were observed.
    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Mildly abnormal liver function tests have been described in one group of chronically exposed workers (HSDB , 2001; Hathaway et al, 1996). Increases in serum bilirubin may occur.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Degenerative changes were observed in the liver of fatally poisoned experimental animals (Mikhailova, 1965). This effect has not been reported in exposed humans.
    b) Benzyl chloride incubated in airtight tubes containing male rat hepatocytes resulted in a significant decrease in cell viability and a significant increase in leakage of cytosolic enzymes such as LDH, AST, and ALT compared to controls (Abdel-Rahman & Saxena, 1988).

Genitourinary

    3.10.1) SUMMARY
    A) Degenerative changes were observed in the kidneys of fatally poisoned experimental animals. This effect has not been reported in exposed humans.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Degenerative changes were observed in the kidneys of fatally poisoned experimental animals (Mikhailova, 1965). This effect has not been reported in exposed humans.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH POISONING/EXPOSURE
    a) Mild leukopenia has been described in one group of chronically exposed workers (Hathaway et al, 1996).

Dermatologic

    3.14.1) SUMMARY
    A) Skin irritation or burns may be observed. Skin sensitization may occur.
    3.14.2) CLINICAL EFFECTS
    A) CHEMICAL BURN
    1) Skin burns or irritation may occur from direct contact (HSDB , 2001; CHRIS , 1999; Plunkett, 1976).
    B) DISORDER OF SKIN
    1) WITH POISONING/EXPOSURE
    a) SKIN SENSITIZATION may occur from repeated exposure (Plunkett, 1976).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no reproductive studies were found for benzyl chloride in humans.
    B) Fetotoxicity and a high incidence of embryolethality were observed in rat studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) EMBRYOTOXICITY
    a) RATS administered 208 milligrams per kilogram of benzyl chloride orally from days 1 through 19 of gestation had a high incidence of embryolethality, but no malformations were noted (IARC, 1982). No evidence of teratogenicity was seen in rats given oral doses in corn oil as high as 100 mg/kg/day on days 6 to 15 of gestation; reduced fetal length was seen (Skowrondki & Abdel-Rahman, 1986).
    b) RATS administered 0.006 mg/kg of benzyl chloride orally from days 1 through 19 of gestation demonstrated an increased rate embryolethality (IARC, 1982).
    2) FETOTOXICITY
    a) Reduced fetal length was observed when dams were treated with benzyl chloride at 100 mg/kg daily on days 6 to 15 of gestation (Skowronski & Abdel-Rahman, 1986).
    3) LACK OF EFFECT
    a) No adverse effects on the offspring or increased embryolethality were noted with oral administration of either 0.0006 or 0.00006 milligrams per kilogram, (IARC, 1982).
    b) Skowrondki & Abdel-Rahman (1986) found no evidence of teratogenicity following oral administration of benzyl chloride in doses of 0, 50, or 100 mg/kg in corn oil given daily on day 6 to 15 of gestation.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) PERINATAL DISORDER
    a) In RATS administered 208 milligrams per kilogram orally from days 1 through 19 of gestation, fertility, postnatal development, and decreased resistance to anoxia were noted in the offspring (IARC, 1982).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) HUMANS
    1) At the time of this review, no data were available to assess the potential effects of benzyl chloride exposure during lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS100-44-7 (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) IARC Classification
    a) Listed as: benzyl chloride
    b) Carcinogen Rating: 2A
    1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    3.21.2) SUMMARY/HUMAN
    A) Based on experiments done on rats, NIOSH has concluded that the carcinogenic risk from low exposure is probably negligible. There is limited evidence that workers exposed to benzyl chloride have a carcinogenic risk. In the NCI Carcinogenesis Studies (Feed) clear evidence for carcinogenicity was found in the mouse and inadequate evidence was found in the rat.
    3.21.3) HUMAN STUDIES
    A) PULMONARY CARCINOMA
    1) Respiratory tract cancers were reported in 6 workers exposed to benzyl chloride and benzoyl chloride. These six cancers occurred in relatively young workers, three of whom were nonsmokers (IARC, 1982). There were 3 cases of lung cancer and 1 case of lymphoma in a group of 41 workers in benzoyl chloride production; this was far higher than the number of expected deaths, but this study was complicated by smoking and exposure to other chemicals (Sakabe et al, 1976). A follow-up study found 2 additional deaths from lung cancer at another plant (Sakabe & Fukuda, 1977).
    2) Elevated numbers of deaths from respiratory and digestive tract cancers were seen in a group of workers exposed to benzyl chloride, toluene, benzoyl chloride, and benzotrichloride (Sorahan et al, 1983). In a follow-up study covering the period 1977 to 1984, dose-related mortality from lung cancer was confirmed, but a nested case-control approach did not provide definitive evidence that occupational exposure was a risk factor. Of the various chlorinated toluenes involved, benzotrichloride may have been more important than benzyl chloride (Sorahan & Cathcart, 1989). A retrospective study found elevated numbers of deaths from respiratory tract cancers in a group of 697 male workers exposed to benzyl chloride from 1943 through 1982 (7 actual versus 2.84 expected) (Wong, 1988).
    3) These studies may be complicated by exposure to multiple chemicals, failure to taken smoking fully into account, small sample sizes, and other factors. As a result, the elevated numbers of cancer deaths cannot be attributed solely to benzyl chloride, and the data are regarded as inadequate for designation of benzyl chloride as a human carcinogen (IARC, 1982).
    B) CARCINOMA
    1) There is limited evidence that workers in benzoyl chloride production (involving benzyl chloride exposure as well) have a carcinogenic risk (IARC, 1982).
    3.21.4) ANIMAL STUDIES
    A) SARCOMA
    1) Local sarcomas at injection sites were noted in rats administered 80 milligrams per kilogram weekly for one year (ACGIH, 1991). Lung metastases were found in these rats (ACGIH, 1986). At half this dosage, local sarcomas occurred but no metastases were produced (ACGIH, 1991). The mean tumor induction time was 500 days, and NIOSH has concluded that the carcinogenic risk from low level exposure is probably negligible (ACGIH, 1991).
    B) NEOPLASM
    1) In rat studies, benzyl chloride was found to be an equivocal tumorigenic agent by RTECS criteria with tumors at the site of application. In mouse studies, benzyl chloride was found to be an equivocal tumorigenic agent and carcinogenic by RTECS criteria with vascular, gastrointestinal, lungs, thorax or respiration and skin and appendage tumors (RTECS , 2001).
    2) Lung tumors were seen in mice given benzyl chloride IP 3 times/week for 24 weeks (HSDB , 1999; IARC, 1982). Benzyl chloride did not increase the rate of lung tumors in mice after multiple IP injections (Poirier et al, 1975).
    C) CARCINOMA
    1) Benzyl chloride was carcinogenic in feeding studies in mice given 0, 50, or 100 mg/kg per dose by gavage in corn oil, 3 times/week for 104 weeks; significant increases were seen for hemangioma/hemangiosarcomas, hepatic carcinoma; adenoma, forestomach carcinoma, and lung alveolar-bronchiolar adenoma/carcinoma in one or both sexes. Evidence was inadequate in rats given 0, 15, or 30 mg/kg per dose (Lijinsky, 1986).
    2) Benzyl chloride was not carcinogenic when applied dermally to mice twice weekly for 7 months (HSDB , 1999; IARC, 1982; Ashby et al, 1982). It was considered weakly carcinogenic by the dermal exposure route in 2 studies in mice (Fukuda et al, 1981).
    3) Overall, the evidence is sufficient for benzyl chloride to be designated as an animal carcinogen (IARC, 1982).

Genotoxicity

    A) DNA damage and unscheduled DNA synthesis were detected in human cells. In animal and bacteria experiments, mutagenicity and chromosome aberrations were observed. Oncogenic transformation occurred in hamster embryo cells.
    B) Benzyl chloride has a broad spectrum of direct-acting genetic effects. It was extensively studied in the 1981 trial of the UK Environmental Mutagen Society.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain a complete blood count and electrolytes in all patients with significant burns after acid ingestion.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, liver enzymes, serial CBC, INR, PT, PTT, fibrinogen, fibrin degradation products, type and crossmatch for blood, and monitor urine output and urinalysis. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Obtain a complete blood count and electrolytes in all patients with significant burns after acid ingestion. In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests and liver enzymes.
    B) COAGULATION STUDIES
    1) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain INR, PT, PTT, fibrinogen, fibrin degradation products, and type and crossmatch for blood.
    C) ACID/BASE
    1) Monitor arterial blood gases or pulse oximetry in patients with significant inhalation exposure or signs and symptoms suggestive of upper airway burns.
    4.1.3) URINE
    A) OTHER
    1) Monitor urine output and urinalysis in patients with significant gastrointestinal burns, perforation, or bleeding.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain an upright chest x-ray in patients with signs and symptoms to evaluate for pneumomediastinum or free air under the diaphragm.
    2) The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach.
    3) Obtain a chest radiograph in patients with pulmonary signs or symptoms.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Benzyl chloride metabolites have been identified in rat whole bile samples by use of NMR spectroscopy (Ryan et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, or extensive grade II burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an acid ingestion should be sent to a health care facility for evaluation. Patients with an endoscopic evaluation that demonstrates no burns or only minor grade I burns and who can tolerate oral intake can be discharged to home.

Monitoring

    A) Obtain a complete blood count and electrolytes in all patients with significant burns after acid ingestion.
    B) In patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions), obtain renal function tests, liver enzymes, serial CBC, INR, PT, PTT, fibrinogen, fibrin degradation products, type and crossmatch for blood, and monitor urine output and urinalysis. Serum lactate and base deficit may also be useful in these patients.
    C) Monitor pulse oximetry or arterial blood gases in patients with signs and symptoms suggestive of upper airway edema or burns.
    D) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm. The absence of these findings does NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Obtain a chest radiograph in patients with pulmonary signs or symptoms.
    E) Several weeks after ingestion, barium contrast radiographs of the upper GI tract are useful in patients who sustained grade II or III burns, to evaluate for strictures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) ACTIVATED CHARCOAL/NOT RECOMMENDED
    1) Activated charcoal is NOT recommended as it has not been shown to reduce corrosive gastrointestinal injury and may obscure endoscopy findings.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal should NOT be used. It may cause vomiting which can worsen caustic gastrointestinal injury, and may obscure endoscopy findings.
    6.5.3) TREATMENT
    A) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) BURN
    1) Observe patients carefully for the development of significant esophageal or gastrointestinal tract irritation or burns with abdominal pain, nausea, vomiting, diarrhea, bleeding, or perforation.
    2) If signs of esophageal irritation or burns are present, esophagoscopy should be performed within 24 hours of exposure to determine the extent of injury.
    3) There is little information regarding the use of endoscopy, corticosteroids or surgery in the setting of concentrated benzyl chloride ingestion. The following information is derived from experience with other corrosives.
    C) ENDOSCOPIC PROCEDURE
    1) SUMMARY: Obtain consultation concerning endoscopy as soon as possible and perform endoscopy within the first 24 hours when indicated.
    2) INDICATIONS: Most studies associating the presence or absence of gastrointestinal burns with signs and symptoms after caustic ingestion have involved primarily alkaline ingestions. Because acid ingestion may cause severe gastric injury with fewer associated initial signs and symptoms, endoscopic evaluation is recommended in any patient with a definite history of ingestion of a strong acid, even if asymptomatic.
    3) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.
    a) REFERENCES: Gaudreault et al, 1983; Symbas et al, 1983; Crain et al, 1984; (Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992; Nuutinen et al, 1994)
    4) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):
    a) Advancing across the cricopharynx under direct vision
    b) Gently advancing with minimal air insufflation
    c) Never retroverting or retroflexing the endoscope
    d) Using a pediatric flexible endoscope
    e) Using extreme caution in advancing beyond burn lesion areas
    f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).
    5) GRADING
    a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding and perforation is related to the severity of the initial burn (Zargar et al, 1991):
    b) Grade 0 - Normal examination
    c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
    d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
    e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
    f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding may occur.
    g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.
    6) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
    D) CORTICOSTEROID
    1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
    2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
    3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
    4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
    5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
    6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
    7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
    8) STUDIES
    a) ANIMAL
    1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
    2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
    3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).
    b) HUMAN
    1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
    2) META ANALYSIS
    a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
    b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
    c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).
    3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
    4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
    5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).
    a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
    b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
    c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
    d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
    e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).
    6) ADVERSE EFFECTS
    a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).
    E) SURGICAL PROCEDURE
    1) In severe cases of gastrointestinal necrosis or perforation, emergent surgical consultation should be obtained. The need for gastric resection or laparotomy in the stable patient is controversial (Chodak & Passaro, 1978; Dilawari et al, 1984).
    2) LAPAROTOMY/LAPAROSCOPY - Early laparotomy or laparoscopy should be considered in patients with endoscopic evidence of severe esophageal or gastric burns after acid ingestion to evaluate for the presence of transmural gastric or esophageal necrosis (Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993). Emergent laparotomy should be strongly considered in any patient with hypotension, altered mental status, or acidemia (Hovarth et al, 1991).
    a) STUDY - In a retrospective study of patients with extensive transmural gastroesophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (endoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died, while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).
    b) Wu & Lai (1993) reported the results of emergency surgical resection of the alimentary tract in 28 patients who had extensive corrosive injuries due to the ingestion of acids or other caustics. Operative mortality was most frequently associated with sepsis. Non-fatal bleeding, infections, biliary or bronchial fistulas were other noted complications. Morbidity and mortality were related to the severity of the damage and the extent of surgery required.
    1) Immediate postoperative management included antibiotics, extensive respiratory care, tracheobronchial toilet, maintenance of fluid, electrolyte and acid-base balance, and jejunostomy feeding or total parenteral nutrition.
    F) MONITORING OF PATIENT
    1) Monitor vital signs, CBC and electrolytes after significant ingestion. Monitor renal function tests, liver enzymes, serial CBC, INR, PTT, type and crossmatch for blood, serum lactate and base deficit, monitor urine output and urinalysis in patients with severe burns or deliberate ingestion. Monitor for occult GI hemorrhage, respiratory distress and increasing pain. Obtain chest radiograph and pulse oximetry in any patient with respiratory signs or symptoms.

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) OXYGEN
    1) Move patients with inhalation exposure from the toxic environment and administer 100% humidified supplemental oxygen with assisted ventilation as required.
    B) AIRWAY MANAGEMENT
    1) Assure airway patency and oxygenation. Endotracheal intubation could be necessary if severe irritation of the upper airway occurs.
    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) 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).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Prolonged flushing and early ophthalmic consultation may be required.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) 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) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy.
    B) ACUTE ALLERGIC REACTION
    1) If hypersensitivity reactions occur, treatment with systemic corticosteroids or antihistamines may be required.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in benzyl chloride poisoning.

Range Of Toxicity

Summary

    A) TOXICITY: Serious burns are less likely if the pH >3. Injury is usually greater with either a large ingestion (usually deliberate), or a high concentration acid (usually not a household product).
    B) In a case series of unintentional caustic ingestions (mixed liquid and solid, acids and bases) among children, the incidence of significant esophageal or gastric burns was 5% to 35%. However, adults with deliberate acid ingestions are more likely to develop significant esophageal and/or gastric burns (40% to 95%).
    C) Inhalation exposure to 380 ppm for 8 hours caused death in dogs. Workers with inhalation exposure to 2 ppm developed weakness, irritability, and headache. The odor threshold is 0.047 ppm.

Minimum Lethal Exposure

    A) ANIMAL DATA
    1) Inhalation exposure to 380 ppm for 8 hours caused death in dogs (ACGIH, 1986).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) Odor threshold - 0.047 ppm (CHRIS , 1999)
    2) INHALATION - Workers with inhalation exposure to 2 ppm developed weakness, irritability, and headache (Hathaway et al, 1996).
    B) CONCENTRATION LEVEL
    1) Exposure to 16 ppm for one minute is intolerable in humans, and 31 ppm exposure is unbearably irritating to the eyes and nose (Hathaway et al, 1996; Grant & Schuman, 1993). A single breath of air containing a concentration of 35 ppm or more can produce irritation of the nasal mucosa (ACGIH, 1986).
    2) A 10 second exposure to 8 ppm or a 5 minute exposure to 1.5 ppm causes eye irritation (ACGIH, 1986). A concentration of 2 mg/L caused immediate eye irritation in cats, while 7.5 hours exposure to the same concentration caused turbidity of the cornea (Grant & Schuman, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS100-44-7 (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) Benzyl chloride
    a) TLV:
    1) TLV-TWA: 1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Not Listed
    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.
    c) TLV Basis - Critical Effect(s): Eye, skin, and URT irr
    d) Molecular Weight: 126.58
    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 CAS100-44-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Benzyl chloride
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling: 1 ppm (5 mg/m(3)) [15-minute]
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 10 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS100-44-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Benzyl chloride
    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): B2 ; Listed as: Benzyl chloride
    a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.
    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): 2A ; Listed as: benzyl chloride
    a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Benzyl chloride
    5) MAK (DFG, 2002): Category 1 ; Listed as: alpha-Chlorinated toluenes: benzyl chloride
    a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.
    6) MAK (DFG, 2002): Category 2 ; Listed as: Benzyl chloride
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS100-44-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Benzyl chloride
    2) Table Z-1 for Benzyl chloride:
    a) 8-hour TWA:
    1) ppm: 1
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 5
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Lewis, 2000 RTECS, 2001
    1) LD50- (ORAL)MOUSE:
    a) 1500 mg/kg
    2) LD50- (ORAL)RAT:
    a) 1231 mg/kg
    3) LD50- (SUBCUTANEOUS)RAT:
    a) 1 g/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Benzyl chloride is a direct irritant of eyes, skin, and mucous membranes, and may cause skin sensitization (ACGIH, 1986; Plunkett, 1976; Hathaway et al, 1996).
    B) Benzyl chloride has been positive in mutagenicity testing and has a possible carcinogenic potential (IARC, 1982).

Physicochemical

Physical Characteristics

    A) Benzyl chloride is a colorless to slightly yellow very refractive liquid with a pungent, aromatic, rather unpleasant, sharp irritating odor (HSDB , 2001; Lewis & Sr, 2000; Budavari, 1996; CHRIS , 1999) NFPA, 1997; (ACGIH, 1986).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 126.59 (Lewis & Sr, 2000)

Other

    A) ODOR THRESHOLD
    1) 0.047 ppm (CHRIS , 2002)

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