Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

CHLORAMPHENICOL

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Chloramphenicol is a broad-spectrum antibiotic used for the treatment of serious gram-negative, gram-positive, and anaerobic infections. It should be reserved for infections for which other drugs are ineffective or contraindicated.

Specific Substances

    1) Chloramphenicolum
    2) CHPC
    3) Chloranfenicol
    4) Cloranfenicol
    5) Clorolifarina
    6) Kloramfenikol
    7) Laevomycetinum
    8) Chloramphen
    9) Clorolifarina
    10) NCI-c 55709
    11) NSC 3069
    12) CAS 56-75-7

Available Forms Sources

    A) FORMS
    1) Chloramphenicol sodium succinate is available as 1 gram intravenous powder for solution (Prod Info chloramphenicol sodium succinate IV injection, 2008; Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004).
    B) USES
    1) Chloramphenicol is a broad spectrum antibiotic that is rarely used in the United States. It has been used for the treatment of serious gram-negative, gram-positive, and anaerobic infections, including therapy for bacterial meningitis, brain abscess, melioidosis, rickettsial infections, typhoid fever, and invasive salmonellosis. It should be reserved for infections for which other drugs are ineffective or contraindicated (Prod Info chloramphenicol sodium succinate IV injection, 2008; Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004).

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: Chloramphenicol is a broad spectrum antibiotic that is rarely used in the United States. It is an alternative therapy for bacterial meningitis, brain abscess, meliodosis, rickettsial infections, typhoid fever, and invasive salmonellosis.
    B) PHARMACOLOGY: In therapeutic doses, chloramphenicol inhibits protein synthesis by reversibly binding to the 50S and 70S subunit of the ribosome. It is bacteriostatic in most organisms, but bacteriocidal against H. influenza, S. pneumonia, and N. meningitidis.
    C) TOXICOLOGY: Chloramphenicol causes a dose-related bone marrow suppression, as well as idiosyncratic aplastic anemia. "Gray baby syndrome" of neonates (abdominal distention, vomiting, flaccidity, cyanosis, circulatory collapse, and death) occurs due to decreased metabolism of chloramphenicol in the immature liver.
    D) EPIDEMIOLOGY: Chloramphenicol is rarely used in the United States anymore, but remains the drug of choice for typhoid fever in several countries. Consequently, exposure and fatalities are extremely rare in the United States. Fatality rates as high as 50% have been reported in patients presenting with aplastic anemia or "gray baby syndrome".
    E) WITH THERAPEUTIC USE
    1) Adverse effects include dose dependent bone marrow suppression that is generally reversible with discontinuation of therapy. Idiosyncratic aplastic anemia can occur; it is not dose-related, occurs within 5 months of treatment, has a 50% mortality rate, and confers a future risk of non-lymphocytic leukemia. "Gray baby syndrome" can occur in neonates receiving chloramphenicol. Affected infants exhibit vomiting, anorexia, respiratory distress, abdominal distention, green stools, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse. Mortality rates as high as 40% have been reported, with most surviving patients exhibiting long term sequelae.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Chloramphenicol produces nausea and vomiting in overdose. Confusion and delirium, optic neuritis, and contact dermatitis can occur.
    2) SEVERE TOXICITY: Myocardial depression resulting in cardiovascular collapse can occur within 12 hours of ingestion.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachypnea, hypothermia, and hypotension may occur as part of the "gray baby syndrome".
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Optic neuritis has been reported with long-term therapy.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Heart failure and cardiovascular collapse have been reported.
    2) Hypotension, as part of the "gray baby syndrome", may occur.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Progressive cyanosis may occur in infants with elevated plasma levels of chloramphenicol.
    2) Tachypnea is a common occurrence as part of the "gray baby syndrome".
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headache, as well as depression, confusion, delirium, and peripheral neuritis, have been reported with therapeutic use.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting and diarrhea may be noted.
    2) Glossitis, stomatitis, or enterocolitis may occur.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Bone marrow suppression, including reticulocytopenia, leukopenia, thrombocytopenia, and aplastic anemia, may be associated with chloramphenicol use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Contact dermatitis has been reported.
    0.2.20) REPRODUCTIVE
    A) Safety has not been established during pregnancy. Chloramphenicol readily crosses the placental barrier.
    B) Chloramphenicol is excreted in the breast milk.
    0.2.21) CARCINOGENICITY
    A) LEUKEMIA risk may be increased following chloramphenicol use, according to one study which depended on parental recall during interviews.
    0.2.22) OTHER
    A) Drug interactions, between chloramphenicol and other drugs, have been reported.
    B) WITH POISONING/EXPOSURE
    1) The "gray baby syndrome", consisting of vomiting, anorexia, respiratory distress, abdominal distention, green stools, lethargy, cyanosis, ashen color, and cardiovascular collapse may occur following high serum levels of chloramphenicol.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Monitor serial CBC with differential.
    C) Monitor serum electrolytes, renal function, and liver enzymes.
    D) Monitor neutropenic patients for clinical evidence of infection with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues (particularly in the perirectal region), exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Drug concentrations correlate well with toxicity, but are not readily available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Symptomatic and supportive including antiemetics, intravenous fluids, and discontinuation of exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care including cardiovascular support with intravenous fluids and vasopressors if necessary. Discontinue chloramphenicol use. Administer colony stimulating factors (filgrastim or sargramostim) to patients with severe neutropenia, and monitor carefully for evidence of infection. Transfusion of packed red cells may be needed in patients with severe anemia. Consider hemodialysis or charcoal hemoperfusion in patients with severe toxicity and metabolic acidosis.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital decontamination is recommended.
    2) HOSPITAL: Consider activated charcoal if the patient is alert and protecting the airway.
    D) AIRWAY MANAGEMENT
    1) Patients with respiratory depression should be intubated.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors to patients with severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of packed red cells may be needed in patients with severe anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days) and profound neutropenia (ANC 100 cells/mm(3) or less).
    H) FEBRILE NEUTROPENIA
    1) If fever (38.3 degrees C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam, a carbapenem (meropenem or imipenem-cilastatin), or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    I) ENHANCED ELIMINATION
    1) Hemodialysis and charcoal hemoperfusion will decrease serum concentrations and may be of benefit in patients with large overdoses, severe toxicity and elevated serum concentrations, or in patients with severe hepatic or renal dysfunction. Exchange transfusion has been shown to lower serum concentrations in neonates.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with small inadvertent ingestions can be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose, neonates who receive more than a therapeutic dose, and symptomatic patients should be sent to a healthcare facility. Patients should be observed for cardiovascular effects for 12 hours after overdose.
    3) ADMISSION CRITERIA: Patients with hemodynamic instability, neutropenia, or severe anemia should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with large overdose or significant toxicity. Patients showing signs and symptoms of bone marrow toxicity warrant a hematology consult.
    K) PITFALLS
    1) Severe toxicity can occur with therapeutic dosing. Chronic therapeutic use is likely much more dangerous than acute overdose.
    L) PHARMACOKINETICS
    1) Absorption is rapid. Oral dosing produces higher serum concentrations than intravenous at equal dosing. CSF penetration is high due to low protein binding and high lipid solubility. Primarily undergoes hepatic metabolism; 90% of chloramphenicol is glucuronidated in the liver, the remaining 10% is renally excreted unchanged.
    M) TOXICOKINETICS
    1) The glucuronidation pathway is saturable, particularly in neonates and patients with severe liver disease. These patients, as well as patients with renal insufficiency, are at increased risk of adverse effects due to increased serum concentrations.
    N) DIFFERENTIAL DIAGNOSIS
    1) Worsening infection, blood dyscrasias

Range Of Toxicity

    A) TOXICITY: Poorly defined. Chronic therapeutic use is much more dangerous than acute overdose. Severe toxicity has been reported in an infant who received 250 mg/kg, and a young adult who received 21 g. A neonate died after receiving 1100 mg and a 70-year-old died after receiving 21 g.
    B) THERAPEUTIC DOSE: ADULT: 50 to 100 mg/kg/day IV in 4 divided doses. CHILDREN (less than 14 days old) 25 mg/kg/day IV in 4 divided doses; (greater than 14 days old) 50 mg/kg/day IV in 4 divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Chloramphenicol is a broad spectrum antibiotic that is rarely used in the United States. It is an alternative therapy for bacterial meningitis, brain abscess, meliodosis, rickettsial infections, typhoid fever, and invasive salmonellosis.
    B) PHARMACOLOGY: In therapeutic doses, chloramphenicol inhibits protein synthesis by reversibly binding to the 50S and 70S subunit of the ribosome. It is bacteriostatic in most organisms, but bacteriocidal against H. influenza, S. pneumonia, and N. meningitidis.
    C) TOXICOLOGY: Chloramphenicol causes a dose-related bone marrow suppression, as well as idiosyncratic aplastic anemia. "Gray baby syndrome" of neonates (abdominal distention, vomiting, flaccidity, cyanosis, circulatory collapse, and death) occurs due to decreased metabolism of chloramphenicol in the immature liver.
    D) EPIDEMIOLOGY: Chloramphenicol is rarely used in the United States anymore, but remains the drug of choice for typhoid fever in several countries. Consequently, exposure and fatalities are extremely rare in the United States. Fatality rates as high as 50% have been reported in patients presenting with aplastic anemia or "gray baby syndrome".
    E) WITH THERAPEUTIC USE
    1) Adverse effects include dose dependent bone marrow suppression that is generally reversible with discontinuation of therapy. Idiosyncratic aplastic anemia can occur; it is not dose-related, occurs within 5 months of treatment, has a 50% mortality rate, and confers a future risk of non-lymphocytic leukemia. "Gray baby syndrome" can occur in neonates receiving chloramphenicol. Affected infants exhibit vomiting, anorexia, respiratory distress, abdominal distention, green stools, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse. Mortality rates as high as 40% have been reported, with most surviving patients exhibiting long term sequelae.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Chloramphenicol produces nausea and vomiting in overdose. Confusion and delirium, optic neuritis, and contact dermatitis can occur.
    2) SEVERE TOXICITY: Myocardial depression resulting in cardiovascular collapse can occur within 12 hours of ingestion.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachypnea, hypothermia, and hypotension may occur as part of the "gray baby syndrome".
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) TACHYPNEA is a common finding in the "gray baby syndrome" that occurs following overdose administration of chloramphenicol to infants (Mauer et al, 1980) Biancaniello et al, 1981; (Freundlich et al, 1983).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA has been reported in infants as part of the "gray baby syndrome" following administration of chloramphenicol (Lambdin et al, 1960; Meissner & Smith, 1979; (Stevens et al, 1981).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTENSION may occur as part of the "gray baby syndrome" following intoxication with chloramphenicol (Suarez & Ow, 1992; Mauer et al, 1980) Biancaniello et al, 1981; (Stevens et al, 1981; Freundlich et al, 1983; Fripp et al, 1983).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Optic neuritis has been reported with long-term therapy.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OPTIC NEURITIS has been reported in patients receiving chloramphenicol, usually over prolonged periods (Joy et al, 1960; Cocke et al, 1966).
    a) Withdrawal of the chloramphenicol, as well as large doses of B vitamins, have been used to treat this condition (Ramilo et al, 1988).
    2) VISION LOSS: Total vision loss was reported in a 12-year-old boy who was on long-term IV chloramphenicol therapy following 2 craniotomies. The patient did not appear to have optic neuritis or intracranial findings that would account for his visual loss, according to an MRI and a neuroopthalmology consultation. Approximately 12 days after discontinuation of chloramphenicol therapy, the patient's vision loss persisted, with only the ability to distinguish between light and dark and identify shapes up close (Wiest et al, 2012).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Heart failure and cardiovascular collapse have been reported.
    2) Hypotension, as part of the "gray baby syndrome", may occur.
    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Heart failure with dilation of the ventricles was reported in one fatal case. Serum chloramphenicol concentration was 277 mcg/mL at the time of onset of symptoms (Fripp et al, 1983).
    b) IN VITRO data show impaired myocardial contractility at 94 mcg/mL, which increases in severity as serum concentration increases (Fripp et al, 1983).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cardiovascular collapse was reported in a 19-year-old anephric patient receiving therapeutic doses; serum chloramphenicol concentration was reported as 161 mcg/mL. Serum chloramphenicol succinate concentration was 75.2 mcg/mL (Phelps et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) Hypotension, possibly leading to cardiovascular collapse, may occur as part of the "gray baby syndrome" following intoxication with chloramphenicol (Suarez & Ow, 1992; Mauer et al, 1980) Biancaniello et al, 1981; (Stevens et al, 1981; Freundlich et al, 1983; Fripp et al, 1983).
    C) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 9-month-old infant, with a 2-day history of fever, poor feeding, irritability, and facial cellulitis, developed lethargy, cyanosis, tachycardia, hypotension, and respiratory distress approximately 5 days after beginning chloramphenicol therapy, 75 mg/kg/day IV. Echocardiography demonstrated cardiac dysfunction with an increase in left ventricular end-diastolic and end-systolic dimensions (2.8 cm and 2.4 cm, respectively), and a decreased ejection fraction of 33%. Laboratory analysis showed an initial serum chloramphenicol concentration of 313 mcg/mL. With supportive care and discontinuation of chloramphenicol therapy, the patient gradually recovered (Suarez & Ow, 1992).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Progressive cyanosis may occur in infants with elevated plasma levels of chloramphenicol.
    2) Tachypnea is a common occurrence as part of the "gray baby syndrome".
    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Progressive cyanosis was reported in infants who received chloramphenicol and subsequently developed elevated chloramphenicol plasma levels. The cyanosis is usually identified as a component of the "gray baby syndrome" (Suarez & Ow, 1992)(Lambdin et al, 1960; (Mauer et al, 1980; Stevens et al, 1981; Freundlich et al, 1983).
    B) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Tachypnea is a common finding in the "gray baby syndrome" that occurs following overdose administration of chloramphenicol to infants (Mauer et al, 1980) Biancaniello et al, 1981; (Freundlich et al, 1983).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headache, as well as depression, confusion, delirium, and peripheral neuritis, have been reported with therapeutic use.
    3.7.2) CLINICAL EFFECTS
    A) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has been reported in patients receiving chloramphenicol, usually over prolonged periods (Wiest et al, 2012; Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004; Joy et al, 1960; Ramilo et al, 1988)
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Headache, depression, confusion, and delirium have been reported (Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004; Levine et al, 1970).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting and diarrhea may be noted.
    2) Glossitis, stomatitis, or enterocolitis may occur.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal symptoms including nausea, vomiting, and diarrhea occasionally occur (Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004) .
    B) COLITIS
    1) WITH THERAPEUTIC USE
    a) Enterocolitis may occur (Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004).
    C) GLOSSITIS
    1) WITH THERAPEUTIC USE
    a) Glossitis and stomatitis have been reported (Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004).
    D) ABDOMINAL DISTENSION
    1) WITH THERAPEUTIC USE
    a) Abdominal distension has been reported with chloramphenicol toxicity, as part of "gray baby syndrome" and with long-term therapy (Wiest et al, 2012; Suarez & Ow, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Elevated liver enzymes were reported in a 9-month-old infant on chloramphenicol therapy, 75 mg/kg/day IV, with SGOT and SGPT peaks of 2400 units/L and 5000 units/L, respectively, occurring approximately 8 days after beginning chloramphenicol therapy (Suarez & Ow, 1992).
    B) HYPERAMMONEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 12-year-old boy was treated with chloramphenicol 1 g every 6 hours for approximately 50 days for treatment of a frontal brain abscess that required 2 craniotomies. He developed lethargy and hyperammonemia (peak serum ammonia concentration 125 micromol/L) but recovered (Wiest et al, 2012).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) LONG-TERM THERAPY: A 12-year-old boy on long-term IV chloramphenicol therapy following two craniotomies developed severe lactic acidosis (peak lactate concentration 32 mmol/L). Following 2 4-hour cycles of hemodialysis followed by 2 days of continuous venovenous hemodialysis and discontinuation of chloramphenicol, the patient's lactic acidosis resolved (Wiest et al, 2012).
    2) WITH POISONING/EXPOSURE
    a) Chloramphenicol is associated with a metabolic acidosis which is relatively resistant to the administration of bicarbonate.
    b) This effect is associated with levels below those reported for the "gray baby syndrome" (less than 50 mcg/mL), and represents an early sign of chloramphenicol intoxication. This effect preceded hypotension, hypothermia, and abdominal distension by a mean of 23 hours (Evans & Kleiman, 1986).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bone marrow suppression, including reticulocytopenia, leukopenia, thrombocytopenia, and aplastic anemia, may be associated with chloramphenicol use.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Two types of bone marrow suppression are associated with chloramphenicol use.
    b) DOSE-RELATED/REVERSIBLE: A number of studies in humans (Scott et al, 1965) Hughes, 1968; Hughes, 1973) have shown that the administration of large doses of chloramphenicol for several weeks is sometimes associated with:
    1) Reduced iron utilization for hemoglobin synthesis as indicated by rising serum iron levels.
    2) Vacuolation of erythroblasts, or a progressive increase in the marrow myeloid-erythroid ratio, a low reticulocyte count, and falling hemoglobin, suggesting interference with the production and maturation of erythroid cells.
    3) Thrombocytopenia and leukopenia with vacuolation of marrow granulocyte precursors. These changes occur regularly when the plasma chloramphenicol levels are 25 mcg/mL or greater, and are usually reversible within two weeks after discontinuation of the drug. In some cases, erythropoietic recovery may occur even if chloramphenicol is continued (Hughes, 1973).
    4) This is more likely if the reticulocyte count exceeds 0.5% and if the myeloid-erythroid ratio is less than 10:1. However, in other patients, especially if neutropenia and thrombocytopenia have already developed, more severe bone marrow depression may occur if the drug is continued.
    5) CASE REPORT: A 12-year-old boy was treated with chloramphenicol 1 g every 6 hours for approximately 50 days for treatment of a frontal brain abscess that required 2 craniotomies. He developed myelosuppression with a trough WBC of 1.25 x10(3)/mm(3), hemoglobin 7.2 mg/dL, reticulocyte count of 0.04% and platelet count of 17 x10(3)/mm(3) but recovered (Wiest et al, 2012).
    c) NOT DOSE-RELATED/NOT REVERSIBLE: PANCYTOPENIA is a rare complication (incidence 1:30,000 to 1:50,000), but has a high mortality rate (>50%). This aplastic anemia does not seem to be dose-related, and may occur weeks or months after therapy has been discontinued.
    1) In premature infants and in newborns aged 2 to 4 weeks or less, the immaturity of hepatic and renal metabolic functions results in higher tissue and blood concentrations in relation to dose.
    2) Hypoplasia of the bone marrow and aplastic anemia have been reported following prolonged use of chloramphenicol OPHTHALMIC preparations as well as oral and intravenous administration (Adler et al, 1982; Brodsky et al, 1989; Carpenter, 1975; Davidson, 1974; Personal Communication, 1987; Rosenthal & Blackman, 1965; Flegg et al, 1992; Doona & Walsh, 1995; Lancaster et al, 1998).
    B) BLOOD COAGULATION DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 9-month-old infant, who initially presented with a 2-day history of fever, poor feeding, irritability, and facial cellulitis, and was started on chloramphenicol, 75 mg/kg/day IV, developed coagulopathy (PT and PTT peaks of 26 sec and 62.4 sec, respectively), approximately 6 days after beginning chloramphenicol therapy, and thrombocytopenia, with a platelet trough of 40 x 10(3)/L that occurred approximately 11 days after beginning chloramphenicol therapy. With supportive care, including administration of fresh frozen plasma and packed red blood cell transfusions, the coagulopathy and thrombocytopenia resolved (Suarez & Ow, 1992).
    b) CASE REPORT: A 12-year-old boy was treated with chloramphenicol 1 g every 6 hours for approximately 50 days for treatment of a frontal brain abscess that required 2 craniotomies. He developed a mild coagulopathy with an INR of 1.88 and a PT of 23 seconds but recovered (Wiest et al, 2012).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Contact dermatitis has been reported.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Contact dermatitis was observed in a 9-year-old patient receiving topical chloramphenicol (Kubo et al, 1987).
    b) CASE REPORT: Moyano et al (1996) reported that a 30-year-old man developed contact dermatitis on 3 separate occasions after coming into contact with medications containing chloramphenicol (Moyano et al, 1996).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions are rare, but contact dermatitis, rashes, drug fever, angioedema, urticaria, and occasional cases of anaphylaxis have been reported (Prod Info CHLOROMYCETIN(R) sodium succinate IV injection, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Safety has not been established during pregnancy. Chloramphenicol readily crosses the placental barrier.
    B) Chloramphenicol is excreted in the breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Safety has not been established during pregnancy. Exercise caution when administering during pregnancy or labor (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    B) PLACENTAL BARRIER
    1) Chloramphenicol readily crosses the placental barrier. Concentrations are lower in cord blood compared with maternal blood (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    C) FETAL/NEONATAL ADVERSE REACTIONS
    1) Gray syndrome was reported in an infant whose mother received chloramphenicol during labor (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Due to the potential for adverse reactions in nursing infant, exercise caution when administering to a lactating woman (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    2) Following the oral administration of 500 mg of chloramphenicol and thiamphenicol to a lactating mother, concentrations of 14 and 16.9 mcg/mL, respectively, were found in the breast milk in a 24 hour period.
    a) This may have resulted in 8 to 14 mg of chloramphenicol and 10 to 17 mg of thiamphenicol being received by the breast-fed infant in a 24hour period (Plomp et al, 1983).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS56-75-7 (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: Chloramphenicol
    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) LEUKEMIA risk may be increased following chloramphenicol use, according to one study which depended on parental recall during interviews.
    3.21.3) HUMAN STUDIES
    A) LEUKEMIA
    1) A population based case-control interview study in Shanghai suggests an 11-fold increased risk of acute lymphocytic leukemia (ALL) and acute non-lymphocytic leukemia (ANLL).
    a) The study was based on parental recall of drugs used over the past 10 years, and as such must be considered as needing confirmation prior to any conclusions being reached (Shu et al, 1987; Kumana et al, 1988; Shu et al, 1988).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Monitor serial CBC with differential.
    C) Monitor serum electrolytes, renal function, and liver enzymes.
    D) Monitor neutropenic patients for clinical evidence of infection with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues (particularly in the perirectal region), exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Drug concentrations correlate well with toxicity, but are not readily available.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function, and liver enzymes.
    2) Because of the wide variability in the pharmacokinetic parameters of chloramphenicol in infants and children, serum concentrations should be followed carefully in these patients (Friedman et al, 1979; Sack et al, 1980).
    3) Drug concentrations correlate well with toxicity, but are not readily available.
    B) HEMATOLOGIC
    1) Monitor serial CBC with differential.
    2) Monitoring of LEUKOCYTE and RETICULOCYTE counts during therapy is generally appropriate (Nahata, 1987).
    3) In one study of 45 pediatric patients, anemia and leukopenia were not significantly correlated with chloramphenicol plasma concentrations (Nahata, 1987). However, most authorities still recommend that concentrations be monitored, as they appear useful in determining dose adequacy and in avoiding severe toxicity, even if levels alone may not be sufficient to detect hematologic toxicity.
    C) ACID/BASE
    1) Obtain arterial blood gases to monitor for metabolic acidosis.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.
    b) Monitor neutropenic patients for clinical evidence of infection with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues (particularly in the perirectal region), exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

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) Patients with hemodynamic instability, neutropenia, or severe anemia should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with small inadvertent ingestions can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with large overdose or significant toxicity. Patients showing signs and symptoms of bone marrow toxicity warrant a hematology consult.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose, neonates who receive more than a therapeutic dose, and symptomatic patients should be sent to a healthcare facility. Patients should be observed for cardiovascular effects for 12 hours after overdose.
    B) Sudden cardiovascular collapse, coma, and death have been reported following chloramphenicol overdose, usually following 10- fold dosing errors. The onset of toxic manifestations may occur 5 to 12 hours following acute overdose (Thompson et al, 1975; Mulhall et al, 1983).

Monitoring

    A) Monitor vital signs.
    B) Monitor serial CBC with differential.
    C) Monitor serum electrolytes, renal function, and liver enzymes.
    D) Monitor neutropenic patients for clinical evidence of infection with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues (particularly in the perirectal region), exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    E) Drug concentrations correlate well with toxicity, but are not readily available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) NEONATES: probably indicated, without a cathartic, for single doses exceeding 25 milligrams/kilogram. This dose would be predicted to result in a potentially toxic plasma concentration.
    2) INFANTS, CHILDREN, ADULTS: probably indicated for single doses exceeding 50 milligrams/kilogram, and for single doses exceeding 2 grams. These doses would be predicted, based on average pharmacokinetics in this age group, to result in toxic serum levels (greater than 25 microgram/milliliter).
    3) 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.
    4) 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) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Monitor serial CBC with differential.
    3) Monitor serum electrolytes, renal function, and liver enzymes.
    4) Monitor neutropenic patients for clinical evidence of infection with particular attention to odontogenic infection, oropharynx, esophagus, soft tissues (particularly in the perirectal region), exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    5) Drug concentrations correlate well with toxicity, but are not readily available.
    B) MYELOSUPPRESSION
    1) Dose-related bone marrow suppression can occur.
    2) Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    3) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). They should be administered to any patient who develops severe neutropenia after chloramphenicol treatment or overdose.
    4) Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    C) NEUTROPENIA
    1) COLONY STIMULATING FACTORS
    a) DOSING
    1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    b) SPECIAL CONSIDERATIONS
    1) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
    2) ANTIBIOTIC PROPHYLAXIS
    a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).
    D) FEBRILE NEUTROPENIA
    1) SUMMARY
    a) Due to the risk of potentially severe neutropenia following overdose with chloramphenicol, all patients should be monitored for the development of febrile neutropenia.
    2) CLINICAL GUIDELINES FOR ANTIMICROBIAL THERAPY IN NEUTROPENIC PATIENTS WITH CANCER
    a) SUMMARY: The following are guidelines presented by the Infectious Disease Society of America (IDSA) to manage patients with cancer that may develop chemotherapy-induced fever and neutropenia (Freifeld et al, 2011).
    b) DEFINITION: Patients who present with fever and neutropenia should be treated immediately with empiric antibiotic therapy; antibiotic therapy should broadly treat both gram-positive and gram-negative pathogens (Freifeld et al, 2011).
    c) CRITERIA: Fever (greater than or equal to 38.3 degrees C) AND neutropenia (an absolute neutrophil count (ANC) of less than or equal to 500 cells/mm(3)). Profound neutropenia has been described as an ANC of less than or equal to 100 cells/mm(3) (Freifeld et al, 2011).
    d) ASSESSMENT: HIGH RISK PATIENT: Anticipated neutropenia of greater than 7 days, clinically unstable and significant comorbidities (ie, new onset of hypotension, pneumonia, abdominal pain, neurologic changes). LOW RISK PATIENT: Neutropenia anticipated to last less than 7 days, clinically stable with no comorbidities (Freifeld et al, 2011).
    e) LABORATORY ANALYSIS: CBC with differential leukocyte count and platelet count, hepatic and renal function, electrolytes, 2 sets of blood cultures with a least a set from a central and/or peripheral indwelling catheter site, if present. Urinalysis and urine culture (if urinalysis positive, urinary symptoms or indwelling urinary catheter). Chest x-ray, if patient has respiratory symptoms (Freifeld et al, 2011).
    f) EMPIRIC ANTIBIOTIC THERAPY: HIGH RISK patients should be admitted to the hospital for IV therapy. Any of the following can be used for empiric antibiotic monotherapy: piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK patients should be placed on an oral empiric antibiotic therapy (ie, ciprofloxacin plus amoxicillin-clavulanate), if able to tolerate oral therapy and observed for 4 to 24 hours. IV therapy may be indicated, if patient poorly tolerating an oral regimen (Freifeld et al, 2011).
    1) ADJUST THERAPY: Adjust therapy based on culture results, clinical assessment (ie, hemodynamic instability or sepsis), catheter-related infections (ie, cellulitis, chills, rigors) and radiographic findings. Suggested therapies may include: vancomycin or linezolid for cellulitis or pneumonia; the addition of an aminoglycoside and switch to carbapenem for pneumonia or gram negative bacteremia; or metronidazole for abdominal symptoms or suspected C. difficile infection (Freifeld et al, 2011).
    2) DURATION OF THERAPY: Dependent on the particular organism(s), resolution of neutropenia (until ANC is equal or greater than 500 cells/mm(3)), and clinical evaluation. Ongoing symptoms may require further cultures and diagnostic evaluation, and review of antibiotic therapies. Consider the use of empiric antifungal therapy, broader antimicrobial coverage, if patient hemodynamically unstable. If the patient is stable and responding to therapy, it may be appropriate to switch to outpatient therapy (Freifeld et al, 2011).
    g) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011):
    1) GRAM-POSITIVE PATHOGENS: Coagulase-negative staphylococci, S. aureus (including MRSA strains), Enterococcus species (including vancomycin-resistant strains), Viridans group streptococci, Streptococcus pneumoniae and Streptococcus pyrogenes.
    2) GRAM NEGATIVE PATHOGENS: Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, Acinetobacter species, and Stenotrophomonas maltophilia.
    h) HEMATOPOIETIC GROWTH FACTORS (G-CSF or GM-CSF): Prophylactic use of these agents should be considered in patients with an anticipated risk of fever and neutropenia of 20% or greater. In general, colony stimulating factors are not recommended for the treatment of established fever and neutropenia (Freifeld et al, 2011).
    E) NEUROPATHY
    1) OPTIC NEURITIS, WITH OR WITHOUT PERIPHERAL NEURITIS: Administration of vitamins B6 and B12 has been recommended. Doses used by these authors were 500 milligrams orally twice a day of vitamin B6 and 0.5 milligram orally once a day of vitamin B12 (Ramilo et al, 1988).
    F) HYPOTHERMIA
    1) Rewarm slowly using blankets, warm IV fluids, and/or warmed mist inhalation.
    G) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Following undesired eye contact, irrigation should be considered. Chloramphenicol is absorbed systemically from the eye, and toxicity has been reported following chronic eye exposure. However, ophthalmic chloramphenicol is used therapeutically and dose-related toxicity following a single ocular exposure is unlikely.
    B) 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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Chloramphenicol is not well dialyzed. With a half-life of 1.6 to 4 hours in the setting of normal hepatic and renal function, it is unlikely that dialysis would remove drug sufficiently and rapidly to prevent toxicity (Hardman et al, 1996). However, in patients with impaired renal function, clearance is moderately increased by hemodialysis, with an increase of 58% to 72% in two patients (Slaughter et al, 1980).
    2) CASE REPORT: A 12-year-old boy on long-term IV chloramphenicol therapy following two craniotomies developed severe lactic acidosis. Following 2 4-hour cycles of hemodialysis followed by 2 days of continuous venovenous hemodialysis and discontinuation of chloramphenicol, the patient's lactic acidosis resolved (Wiest et al, 2012).
    B) HEMOPERFUSION
    1) A 78% reduction in plasma chloramphenicol level was observed with charcoal hemoperfusion for 260 minutes (Freundlich et al, 1983). Three hours of charcoal hemoperfusion on an 3200 gram 12-day-old infant reduced chloramphenicol concentrations from 98 micrograms/milliliter to 13.5 micrograms/milliliter with complete resolution of clinical toxicity (Mauer et al, 1980).
    C) EXCHANGE TRANSFUSION
    1) May be considered, especially in neonates and infants, following massive overdosage. However, the efficacy of this procedure is equivocal (Wilkinson et al, 1985; Chavers et al, 1982; Stevens et al, 1981).
    2) A neonate accidentally given 250 milligrams/kilogram was successfully treated with exchange transfusion continued over a 43 hour period, using a large exchange volume. Serum half-life was reportedly reduced from 80 hours to 6.5 hours (Kessler et al, 1980).
    3) Two sequential single-blood-volume in one patient resulted in only a 15 percent reduction in serum concentration (Freundlich et al, 1983).

Abstracts

Case Reports

    A) INFANT
    1) A neonate accidentally given 250 milligrams/kilogram was successfully treated with exchange transfusion. Initial serum chloramphenicol concentration was 135 mcg/mL. Serum half-life was reduced from 80 hours to 6.5 hours (Kessler et al, 1980).

Range Of Toxicity

Summary

    A) TOXICITY: Poorly defined. Chronic therapeutic use is much more dangerous than acute overdose. Severe toxicity has been reported in an infant who received 250 mg/kg, and a young adult who received 21 g. A neonate died after receiving 1100 mg and a 70-year-old died after receiving 21 g.
    B) THERAPEUTIC DOSE: ADULT: 50 to 100 mg/kg/day IV in 4 divided doses. CHILDREN (less than 14 days old) 25 mg/kg/day IV in 4 divided doses; (greater than 14 days old) 50 mg/kg/day IV in 4 divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) 50 to 100 mg/kg/day IV in divided doses every 6 hours in the presence of normal renal and hepatic function (Prod Info chloramphenicol sodium succinate IV injection, 2008)
    7.2.2) PEDIATRIC
    A) NEONATES AND PEDIATRIC PATIENTS
    1) AGE LESS THAN 14 DAYS
    a) In neonates less than 2-weeks-old, the recommended dose is 25 mg/kg/day IV given in 4 divided doses at 6-hour intervals (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    2) AGE GREATER THAN 14 DAYS
    a) In full-term neonates at least 2-weeks-old and in pediatric patients with normal liver and kidney function, the recommended dose is 50 mg/kg/day IV given in 4 divided doses at 6-hour intervals. Some pediatric patients may require an increase of the dose to 100 mg/kg/day for severe infections (eg, bacteremia, meningitis); however, the dose should be decreased to 50 mg/kg/day as soon as possible (Prod Info chloramphenicol sodium succinate IV injection, 2008).
    3) BACTERIAL MENINGITIS
    a) 75 to 100 mg/kg/day IV divided every 6 hours (Tunkel et al, 2004; Marks et al, 1986; Aronoff et al, 1984; Congeni, 1984). MAXIMUM: 4 to 6 g/day (Tunkel et al, 2004).
    4) OTHER SERIOUS INFECTIONS
    a) 50 to 100 mg/kg/day IV divided every 6 hours. MAXIMUM: 2 to 4 g/day (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) PEDIATRIC
    a) A 5-week-old child received 1100 milligrams, which produced a plasma chloramphenicol concentration of 180 micrograms/milliliter. The child died as a result of this exposure (Baselt, 2000).
    2) ADULT
    a) A 70-year-old died 11 hours after receiving a total of 21 g of chloramphenicol intravenously (Thompson et al, 1975).

Maximum Tolerated Exposure

    A) A 26-year-old woman was accidentally given a total of 21 grams of intravenous chloramphenicol. Within 12 hours she went into shock, but eventually recovered. Her plasma chloramphenicol concentration 5.5 hours after the last dose was 201 micrograms/milliliter (Baselt, 2000).
    B) Chloramphenicol doses of 50 to 100 milligrams/kilogram and greater may result in a syndrome characterized by abdominal distention, vomiting, pallor, cyanosis, and circulatory collapse usually resulting in death ("gray baby syndrome"). Initial treatment is symptomatic and supportive.
    C) Severe toxicity (including the "gray baby syndrome") was seen in a neonate inadvertently given 250 milligrams/kilogram. She was successfully treated with exchange transfusion (Kessler et al, 1980).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Therapeutic plasma levels of chloramphenicol are 10 to 25 micrograms/ milliliter.
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Chloramphenicol toxicity was poorly predicted by either serum concentration or by daily dose administered, in one series of 45 pediatric patients age newborn to 12 years. Total dose administered was the best predictor of toxicity in this series but did not reach statistical significance (Nahata, 1989).
    2) Conservative management, due to the MARKED INDIVIDUAL VARIABILITY in the pharmacokinetics of chloramphenicol in infants and children, necessitates monitoring of serum/plasma concentrations (Friedman et al, 1979; Sack et al, 1980; Hardman et al, 1996).
    3) A 26-year-old woman who received a total of 21 grams of chloramphenicol intravenously had a plasma concentration of 201 micrograms/milliliter 5.5 hours after her last dose (Baselt, 2000).
    4) A 5-week-old child received 1100 mg of chloramphenicol, which resulted in a plasma concentration of 180 mcg/mL. The patient expired (Baselt, 2000).
    5) Severe toxicity was seen in a neonate inadvertently given 250 milligrams/kilogram. She was successfully treated with exchange transfusion. Initial serum chloramphenicol concentration was 135 mcg/mL (Kessler et al, 1980).
    6) Intractable heart failure and dilation of the ventricles was observed in a fatal case involving a neonate. Serum chloramphenicol concentration was 277 micrograms/milliliter at the time the patient became symptomatic (Fripp et al, 1983).

Workplace Standards

    A) ACGIH TLV Values for CAS56-75-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS56-75-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS56-75-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Chloramphenicol
    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
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS56-75-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 1500 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Chloramphenicol is a broad-spectrum antibiotic which interferes with bacterial mitochondrial protein synthesis by binding to the 50S subunit of bacterial ribosomes. It is usually bacteriostatic, and is effective against a wide range of gram-negative and gram-positive organisms, as well as some anaerobes.
    B) Because of this, some essential mitochondrial enzymes are inhibited. Oxidative phosphorylation is inhibited, and cellular energy is depleted. Chloramphenicol has also been shown to interfere with mitochondrial biogenesis, resulting in reduced ATP production and cytochrome oxidase activity (Fripp et al, 1983).

Toxicologic Mechanism

    A) The reversible form of bone marrow suppression is believed to result from chloramphenicol binding to 70S ribosomes, which causes mitochondrial ultrastructural changes and a decrease in mitochondrial protein synthesis. With impaired production of mitochondrial membrane-binding proteins and enzymes such as ferrochelatase, mitochondrial heme synthesis is blocked (Nahata, 1986).
    B) Although the mechanism of chloramphenicol- induced dose-independent aplastic anemia is uncertain, it has been theorized that p- nitrosulfathiazole groups on the molecule may inhibit DNA synthesis in marrow stem cells of predisposed individuals. Cells may be further affected by marrow-produced toxic metabolites of chloramphenicol (Yunis, 1989).
    C) An alternate hypothesis regarding the mechanism of chloramphenicol-induced dose-independent aplastic anemia suggests that previous exposure to the drug is important, implicating a form of hypersensitivity reaction (Nahata, 1986).
    D) The mechanism of the "gray baby syndrome" has yet to be elucidated, but rat studies have shown that high serum chloramphenicol concentrations block mitochondrial electron transport at the site of NADH dehydrogenase, which results in reduced oxygen consumption with disruption of energy metabolism (Nahata, 1986).

Physicochemical

Physical Characteristics

    A) crystals

Molecular Weight

    A) 323.14

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) Adler AG, McElwain GE, & Merli GJ: Systemic effects of eye drops. Arch Intern Med 1982; 42:2293-2294.
    14) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    15) Aronoff SC, Reed MD, O'Brien CA, et al: Comparison of the efficacy and safety of ceftriaxone to ampicillin/chloramphenicol in the treatment of childhood meningitis. J Antimicrob Chemother 1984; 13(2):143-151.
    16) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed, Chemical Toxicology Institute, Foster City, CA, 2000.
    17) Bennett WM: Guide to drug dosage in renal failure. In: Clinical Pharmacokinetics Drug Data Handbook 1989, ADIS Press, Auckland, New Zealand, 1989.
    18) Brodsky E, Biger Y, & Zeidan Z: Topical application of chloramphenicol eye ointment followed by fatal bone marrow aplasia. Isr J Med Sci 1989; 25:54.
    19) Budavari S: The Merck Index, 11th ed, Merck & Co, Inc, Rahway, NJ, 1989.
    20) Carpenter G: Chloramphenicol eye drops and marrow aplasia. Lancet 1975; 2:326-327.
    21) Chavers B, Kjellstrand CM, & Mauer SM: Exchange transfusion in acute chloramphenicol toxicity (letter). J Pediatr 1982; 101:652.
    22) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    23) Cocke JG Jr, Brown RE, & Geppert LJ: Optic neuritis with prolonged use of chloramphenicol. J Pediatr 1966; 68:27.
    24) Committee on Infectious Diseases, American Academy of Pediatrics, Pickering LK, Baker CJ, et al: Red Book(R): 2009 Report of the Committee on Infectious Diseases, 28th ed., 28th ed.. American Academy of Pediatrics, Elk Grove Village, IL, 2009.
    25) Congeni BL: Comparison of ceftriaxone and traditional therapy of bacterial meningitis. Antimicrob Agents Chemother 1984; 25(1):40-44.
    26) Craft AW, Brocklebank JT, & Hey EN: The "grey toddler" - chloramphenicol toxicity. Arch Dis Child 1974; 49:235-237.
    27) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    28) Davidson SI: Systemic effects of eye drops. Trans Ophthalmol Soc UK 1974; 94:487-495.
    29) Doona M & Walsh JB: Use of chloramphenicol as topical eye medication: time to cry halt?. Br Med J 1995; 310:1217-1218.
    30) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    31) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    32) Evans LS & Kleiman MB: Acidosis as a presenting feature of chloramphenicol toxicity. J Pediatr 1986; 108:475-477.
    33) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    34) Flegg P, Cheong I, & Welsby PD: Chloramphenicol: are concerns about aplastic anaemia justified?. Drug Safety 1992; 7:167-169.
    35) Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52(4):e56-e93.
    36) Freundlich M, Cynamon H, & Tames A: Management of chloramphenicol intoxication in infancy by charcoal hemoperfusion. J Pediatr 1983; 103:485-487.
    37) Friedman CA, Lovejoy FC, & Smith AL: Chloramphenicol disposition in infants and children. J Pediatr 1979; 95:1071-1077.
    38) Fripp RR, Carter MC, & Werner JC: Cardiac function and acute chloramphenicol toxicity. J Pediatr 1983; 103:487-490.
    39) Glazko AJ, Wolf LM, Dill WA, et al: Biochemical studies on chloramphenicol (Chloromycetin(R)). II. Tissue distribution and excretion studies. J Pharmacol Exp Ther 1949; 96:445-459.
    40) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    41) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    42) Hardman JG, Limbird LE, & Molinoff PB: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill, New York, NY, 1996.
    43) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    44) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    45) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    46) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    47) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    48) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    49) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    50) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    51) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    52) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    53) Joy RJT, Scalettar R, & Sodee DB: Optic and peripheral neuritis. Probable effect of prolonged chloramphenciol therapy. JAMA 1960; 173:1731.
    54) Kauffman RE, Thirumoorthi MC, & Buckley JA: Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children. J Pediatr 1981; 99:963-967.
    55) Kessler DL, Smith AL, & Woodrum DE: Chloramphenicol toxicity in a neonate treated with exchange transfusion. J Pediatr 1980; 96:140-141.
    56) Kubo Y, Nonaka S, & Yoshida H: Contact sensitivity to chloramphenicol. Contact Dermatitis 1987; 17:245-247.
    57) Kumana CR, Chau RY, & Chan TK: Chloramphenicol use and childhood leukemia (letter). Lancet 1988; 1:476.
    58) Lancaster T, Swart AM, & Jick H: Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database. Br Med J 1998; 316:667.
    59) Levine PH, Regelson W, & Holland JF: Chloramphenicol-associated encephalopathy. Clin Pharmacol Ther 1970; 11:194-199.
    60) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    61) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    62) Marks WA , Stutman HR , Marks MI , et al: Cefuroxime versus ampicillin plus chloramphenicol in childhood bacterial meningitis: a multicenter randomized controlled trial. J Pediatr 1986; 109(1):123-130.
    63) Mauer SM, Chavers BM, & Kjellstrand CM: Treatment of an infant with severe chloramphenicol intoxication using charcoal-column hemoperfusion. J Pediatr 1980; 96:136-139.
    64) McCrumb FR Jr, Snyder MJ, & Hicken WJ: The use of chloramphenicol acid succinate in the treatment of acute infections. Antibiot Ann 1957-1958; 5:837-841.
    65) Moyano JC, Alvarez M, & Fonseca JL: Allergic contact dermatitis to chloramphenicol. Allergy 1996; 51(1):67-69.
    66) Mulhall A, deLouvois J, & Hurley R: Chloramphenicol toxicity in neonates: its incidence and prevention. Br Med J 1983; 287:1424-1427.
    67) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    68) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    69) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    70) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    71) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    72) Nahata MC & Powell DA: Comparative bioavailability and pharmacokinetics of chloramphenicol after intravenous chloramphenicol succinate in premature infants and older patients. Pharmacol Ther 1983; 6:23-32.
    73) Nahata MC: Chloramphenicol. In: Evans WE, Schentag JJ, Jusko WJ et al (Eds): Applied Pharmacokinetics, 2nd ed, Applied Therapeutics, Inc. Spokane, WA, 1986.
    74) Nahata MC: Lack of predictability of chloramphenicol toxicity in pediatric patients. J Clin Pharmacol Therap 1989; 14:297-303.
    75) Nahata MC: Serum concentrations and adverse effects of chloramphenicol in pediatric patients. Chemotherapy 1987; 33:322-327.
    76) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    122) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    125) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    126) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    127) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    128) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    129) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    130) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    131) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    132) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    133) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    134) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    135) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    136) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    137) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    138) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    139) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    140) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    141) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    142) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    143) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    144) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    145) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    146) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    147) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    148) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    149) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    150) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    151) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    152) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    153) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    154) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    155) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    156) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    157) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    158) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    159) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    160) Personal Communication: Personal Communication: C. Rudd. Parke Davis, Morris Plains, NJ, 1987.
    161) Phelps SJ, Tsiu W, & Barrett FF: Chloramphenicol-induced cardiovascular collapse in an anephric patient. Pediatr Infect Dis J 1987; 6:285-288.
    162) Plomp TA, Thiery M, & Maez RAA: The passage of thiamphenicol and chloramphenicol into human milk after single and repeated oral administration. Vet Hum Toxicol 1983; 25:167-172.
    163) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    164) Powell DA & Nahata MC: Chloramphenicol: new perspectives on an old drug. Drug Intell Clin Pharm 1982; 16:295-300.
    165) Product Information: CHLOROMYCETIN(R) sodium succinate IV injection, sterile chloramphenicol sodium succinate iv injection. Monarch Pharmaceuticals,Inc, Bristol, TN, 2004.
    166) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    167) Product Information: chloramphenicol sodium succinate IV injection, chloramphenicol sodium succinate IV injection. APP Pharmaceuticals, LLC, Schaumburg, IL, 2008.
    168) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    169) Rajchgot D, Prober C, Soldin S, et al: Chloramphenicol pharmacokinetics in the newborn. Dev Pharmacol Ther 1983; 6:305-314.
    170) Ramilo O, Kinane BT, & McCracken GH: Chloramphenicol neurotoxicity. Pediatr Infect Dis J 1988; 7:358-359.
    171) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    172) Rosenthal RL & Blackman A: Bone marrow hypoplasia following use of chloramphenicol eye drops. JAMA 1965; 191:136-137.
    173) Sack CM, Koup JR, & Smith AL: Chloramphenicol pharmacokinetics in infants and young children. Pediatrics 1980; 66:579-584.
    174) Scott JL, Finegold SM, & Belkins GA: A controlled double-blind study of the hematologic toxicity of chloramphenicol. N Engl J Med 1965; 272:1137.
    175) Shankaran S & Kauffman RE: Use of chloramphenicol palmitate in neonates. J Pediatr 1984; 105:113-116.
    176) Shu XO, Gao YT, & Linet MS: Chloramphenicol use and childhood leukemia in Shanghai (letter). Lancet 1988; 1:476-477.
    177) Shu XO, Gao YT, & Linet MS: Chloramphenicol use and childhood leukemia in Shanghai. Lancet 1987; 2:934-937.
    178) Slaughter RL, Cerra FB, & Koup JR: Effect of hemodialysis on total body clearance of chloramphenicol. Am J Hosp Pharm 1980; 37:1083-1086.
    179) Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-3205.
    180) Stevens DC, Kleiman MB, & Lietman PS: Exchange transfusion in acute chloramphenicol toxicity. J Pediatr 1981; 99:651-653.
    181) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    182) Suarez CR & Ow EP : Chloramphenicol toxicity associated with severe cardiac dysfunction. Pediatr Cardiol 1992; 13(1):48-51.
    183) Thompson WL, Anderson SE Jr, & Lipsky JJ: Overdose of chloramphenicol. JAMA 1975; 234:149-150.
    184) Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39(9):1267-1284.
    185) Tuomanen EL, Powell KR, & Marks MI: Oral chloramphenicol in the treatment of Hemophilus influenzae meningitis. J Pediatr 1981; 99:968-974.
    186) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    187) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    188) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    189) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    190) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    191) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    192) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    193) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    194) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    195) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    196) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    197) Vozeh S, Schmidlin O, & Taeschner W: Pharmacokinetic drug data. In: Clinical Pharmacokinetics Drug Data Handbook 1989, ADIS Press, Auckland, New Zealand, 1989.
    198) Weiss CF, Glazko AJ, & Westen JK: Chloramphenicol in the newborn infant: a physiologic explanation of its toxicity when given in excessive doses. N Engl J Med 1960; 262:787-794.
    199) Wiest DB , Cochran JB , & Tecklenburg FW : Chloramphenicol toxicity revisited: a 12-year-old patient with a brain abscess. J Pediatr Pharmacol Ther 2012; 17(2):182-188.
    200) Wilkinson JD, Pollack MM, & Costello J: Chloramphenicol toxicity: hemodynamic and oxygen utilization effects. Pediatr Infect Dis 1985; 4:69-72.
    201) Yogev R & Davis AT: Oral chloramphenicol in the therapy of Haemophilus influenzae meningitis. Infection 1981; 9:42-44.
    202) Yunis AA: Chloramphenicol toxicity: 25 years of research. Am J Med 1989; 87(3N):44N-48N.