a) CASE SERIES: Orth et al (1951) reported cardiac dysrhythmias in 45 of 52 patients observed during chloroform anesthesia.

a) Electrocardiographic changes and death have been reported in workers exposed to chloroform (Reichenbach, 1985).

a) CASE REPORT: A 39-year-old woman died approximately one hour after inhaling chloroform. The patient had been inhaling chloroform once or twice per month for approximately seven years. An autopsy of the patient showed pulmonary edema with focal bleeding and focal fragmentation and waviness of myocardial cells. Based on these findings, acute heart failure possibly precipitated by dysrhythmias or cardiac depression due to chloroform inhalation, was determined to be the cause of death (Harada et al, 1997).

a) CASE REPORT: A 46-year-old woman with a history of alcohol misuse presented to the emergency department unresponsive (Glasgow Coma Scale of 5) with dyspnea and cyanosis. Vital signs indicated hypotension (80/50 mmHg) and tachycardia (120 beats/min), and an initial blood gas measurement demonstrated respiratory acidosis. A urinalysis showed proteinuria and the presence of brown casts and uric acid crystals. Within 20 hours postpresentation, following supportive care, the patient was awake and alert. Interview of the patient revealed that she had daily chloroform inhalations for the last 6 days and prior to presentation, had combined chloroform inhalation with consumption of 450 mL of vodka. On hospital day 2 (27 hours post-exposure), laboratory data revealed elevated serum creatinine, BUN, and liver enzyme concentrations. Despite continuous supportive treatment, the patient's condition progressively deteriorated, with persistent hypotension, fulminant hepatic failure, acute renal failure, encephalopathy, and cardiac arrest resulting in death approximately 78 hours postexposure. A postmortem examination revealed microvesicular hepatic steatosis and tubular renal necrosis (Lionte, 2010).

a) CASE REPORT: Pulmonary infiltrates and acute respiratory distress developed in a 21-year-old man following intravenous injection (antecubital vein) of 5 mL of reagent grade chloroform.

a) Respiratory depression is common (JEF Reynolds , 1998; Boyer et al, 1998).

a) Pulmonary edema was a reported finding on autopsy of a pair of twins and in a 39-year-old woman found dead after apparently inhaling chloroform (Giusti & Chiarotti, 1981; Harada et al, 1997).

a) Stupor and hypoventilation, requiring intubation, developed in a 38-year-old man after ingestion of 230 mL of chloroform. Treatment included aggressive gastric decontamination and administration of oral N-acetylcysteine. Two days later, the patient was extubated without sequelae (Boyer et al, 1998).

a) Following ingestion, the chloroform intoxicated patient quickly becomes unconscious and remains that way for many hours (Dell'Aglio et al, 2010; Kim, 2008; Choi et al, 2006; Boyer et al, 1998; Harada et al, 1997). This may be followed by a phase of apparent recovery where the patient is awake and alert. Some patients may then deteriorate and die secondary to liver failure (Dykes, 1970).
b) CASE REPORT: A suicidal 33-year-old woman became unconscious after self-injecting 0.5 mL of chloroform intravenously. She awoke the next morning and ingested approximately 120 mL of chloroform. The patient then became unconscious, awoke several hours later, vomited, then became unconscious again. After presenting to the emergency department, the patient was awake and alert. The patient remained asymptomatic after treatment with hyperbaric oxygen, cimetidine, and N-acetylcysteine (Rao et al, 1993).
c) CASE REPORT: A 46-year-old woman with a history of alcohol misuse presented to the emergency department unresponsive (Glasgow Coma Scale of 5) with dyspnea and cyanosis. Vital signs indicated hypotension and tachycardia, and an initial blood gas measurement demonstrated respiratory acidosis. A urinalysis showed proteinuria and the presence of brown casts and uric acid crystals. Within 20 hours postpresentation, following supportive care, the patient was awake and alert. Interview of the patient revealed that she had daily chloroform inhalations for the last 6 days and prior to presentation, had combined chloroform inhalation with consumption of 450 mL of vodka. On hospital day 2 (27 hours post-exposure), laboratory data revealed elevated serum creatinine, BUN, and liver enzyme concentrations. Despite continuous supportive treatment, the patient's condition progressively deteriorated, with persistent hypotension, fulminant hepatic failure, acute renal failure, encephalopathy, and cardiac arrest resulting in death approximately 78 hours postexposure. A postmortem examination revealed microvesicular hepatic steatosis and tubular renal necrosis (Lionte, 2010).

a) Dizziness and a sensation of fainting may occur from an acute exposure to chloroform (Hathaway et al, 1996).

a) Headache, disorientation, fatigue, and mental dullness have been noted (Hathaway et al, 1996; Plunkett, 1976).

a) Anorexia may occur (Plunkett, 1976).

a) Hallucinations, dysarthria, ataxia, degenerative changes of the brain and psychotic behavior have been reported from chronic abuse (Baselt, 1995; Heilbrunn et al, 1945; EPA, 1985).

a) Chloroform may produce symptoms resembling gastroenteritis which is thought to be due to the irritant effects of the liquid on mucous membranes (Schroeder, 1965).

a) Persistent nausea, vomiting and diarrhea may occur (Schroeder, 1965; Hakim et al, 1992).

a) Hepatocellular toxicity may occur 10 to 48 hours postexposure. The patient may appear jaundiced and may have an enlarged liver. Liver enzyme and bilirubin levels may be noted to rise. Good supportive care over the next few days to weeks may lead to complete recovery (Schroeder, 1965; Rao et al, 1993; Boyer et al, 1998).
b) CASE SERIES: Liver atrophy was reported in 2 women given chloroform during premature termination of pregnancy (Townsend, 1939).

a) Fatty degeneration of the liver has been reported in industrial exposed workers (NIOSH, 1974).

a) Hepatomegaly or other signs of liver injury may be observed (Hathaway et al, 1996; Hakim et al, 1992).
b) Hepatomegaly and splenomegaly have also been reported (NIOSH, 1974).

a) COMBINATION INGESTION: A 23-year-old man presented with altered mental status 30 minutes after ingesting approximately half of the content of a 250-mL bottle of chloroform and dichloromethane. On day 2, laboratory results revealed elevated liver enzymes which reached peak levels on post-ingestion day 5. He experienced jaundice, nausea, vomiting, abdominal pain, and general weakness 3 days post-ingestion. Abdominal CT revealed severe fatty infiltration of the liver parenchyma. Following supportive care, he gradually recovered and was discharged 2 weeks after ingestion. His liver enzymes levels returned to almost the reference range 4 weeks later (Kim, 2008).
b) CASE REPORT: A 16-year-old woman developed nausea, vomiting, anorexia, yellow ocular discoloration and mild fever eleven days after ingestion of chloroform. Examination revealed jaundice and hepatomegaly and an abdominal sonography showed altered echotexture of the liver (Hakim et al, 1992).
c) CASE REPORT: Acute hepatitis with encephalopathy was reported in a 24-year-old woman who was a laboratory worker in a meat processing plant that utilized chloroform for extraction of residual antibiotics in meat. At hospital admission, she was comatose and her liver enzymes had reached peak levels (AST 4640 units/liter, ALT 3110 units/liter). The patient recovered with normalization of her liver enzyme levels following several treatments of plasmapheresis. Investigation of the patient's workplace revealed that she had been exposed to high levels of chloroform (more than 15 ppm) for two weeks due to malfunctioning of a chemical extraction hood used to collect and expel chloroform vapor (Lin et al, 2005).
d) CASE REPORT: A 39-year-old man presented to the emergency department with a 3-day history of nausea, vomiting, and malaise. At presentation, he appeared jaundice and had a partial thickness burn on his right shoulder, covering approximately 3% body surface area. His urine was also dark in color. Blood tests were consistent with a diagnosis of acute hepatitis. An abdominal ultrasound indicated hepatic steatosis. Interview of the patient revealed that, 3 days prior to presentation, he had been working with chloroform and had spilled 100 mL on his shoulder, with duration of exposure approximately 30 minutes before washing off the area. The area began to desquamate the next day, but was not painful. At the hospital, the patient's transaminase and bilirubin concentrations improved 12 hours after beginning N-acetylcysteine therapy. The patient was discharged 4 days post-admission. Follow-up 8 weeks later reported normalization of his transaminase concentrations, and a repeat abdominal ultrasound was also normal (Vlad et al, 2014).

a) CASE REPORT: A 20-year-old woman was found unresponsive one hour after intentionally ingesting an unknown substance. An empty 100-mL bottle was found and her partner reported that the patient had purchased a bottle of chloroform several days earlier. Upon presentation to the emergency department, the patient was tachycardic (130 bpm) with no spontaneous respiration and in a deep coma, necessitating mechanical ventilation. Initial arterial blood gas measurements indicated respiratory acidosis which improved following mechanical ventilation. An abdominal radiograph revealed a radiopaque material in the small bowel, believed to be chloroform. Three days following ingestion, the patient's prothrombin time peaked at 18.4 seconds and, 5 days post-ingestion, her liver enzymes reached peak levels (AST 1513 international units/L, ALT 2717 international units/L). Following supportive care and administration of n-acetylcysteine, she gradually recovered with normalization of prothrombin time and liver enzyme levels. The patient admitted to ingesting a bottle of chloroform approximately one hour prior to presentation (Choi et al, 2006).
b) CASE REPORT: A 19-year-old man presented to the emergency department comatose after ingesting approximately 75 mL of chloroform. He was intubated and treated with n-acetylcysteine (NAC) administered as 2 IV bolus doses followed by a continuous infusion. On hospital day 2, the patient regained consciousness and was extubated. Initially, laboratory data revealed normal liver enzyme concentrations; however, on day 4, his ALT and AST concentrations began to increase, reaching peak concentrations on day 5 of 583 and 224 international units/L, respectively. His total serum bilirubin also increased with a peak of 16.3 mg/dL. With continued NAC therapy, the patient's transaminase and bilirubin concentrations began to decrease, and NAC was discontinued on day 7. The patient's liver enzyme concentrations continued to decline, and he was subsequently transferred to a psychiatric unit without developing sequelae (Dell'Aglio et al, 2010).
c) CASE REPORT: A 46-year-old woman with a history of alcohol misuse presented to the emergency department unresponsive (Glasgow Coma Scale of 5) with dyspnea and cyanosis. Vital signs indicated hypotension and tachycardia, and an initial blood gas measurement demonstrated respiratory acidosis. A urinalysis showed proteinuria and the presence of brown casts and uric acid crystals. Within 20 hours postpresentation, following supportive care, the patient was awake and alert. Interview of the patient revealed that she had daily chloroform inhalations for the last 6 days and prior to presentation, had combined chloroform inhalation with consumption of 450 mL of vodka. On hospital day 2 (27 hours post-exposure), laboratory data revealed elevated serum creatinine, BUN, and liver enzyme concentrations (ALT 1773 units/L; AST 3760 units/L). Despite continuous supportive treatment, the patient's condition progressively deteriorated, with persistent hypotension, fulminant hepatic failure, acute renal failure, encephalopathy, and cardiac arrest resulting in death approximately 78 hours postexposure. A postmortem examination revealed microvesicular hepatic steatosis and tubular renal necrosis (Lionte, 2010).
d) CASE REPORT: A 31-year-old man developed acute renal failure and hepatotoxicity after ingesting 50 mL chloroform. The patient was jaundiced and initial laboratory data (hospital day 1) revealed elevated BUN (98 mg/dL), serum creatinine (6.2 mg/dL), and potassium (5.4 mEq/L) concentrations. Bilirubin peaked on hospital day 3, with total bilirubin 17 mg/dL, and conjugated bilirubin 10 mg/dL. The patient's ALT and AST concentrations were also elevated, peaking on hospital day 3 at 3560 and 1160 international units/L, respectively. With supportive care, including decontamination with activated charcoal and gastric lavage, 5 sessions of intermittent hemodialysis, and administration of N-acetylcysteine, the patient's condition improved and he was discharged on hospital day 10 (Sridhar et al, 2011).

a) Liver necrosis was noted in experimental animals after exposure to chloroform vapor (Clayton & Clayton, 1994).

a) Urinary output may drop over the first 2 days following ingestion when anoxia accompanies intoxication. Administration of fluids may be useful to preserve kidney function. Urine examination demonstrated glucosuria, ketonuria, albuminuria, and the presence of granular casts and red cells (Schroeder, 1965).
b) CASE REPORT: A 46-year-old woman with a history of alcohol misuse presented to the emergency department unresponsive (Glasgow Coma Scale of 5) with dyspnea and cyanosis. Vital signs indicated hypotension and tachycardia, and an initial blood gas measurement demonstrated respiratory acidosis. A urinalysis showed proteinuria and the presence of brown casts and uric acid crystals. Within 20 hours postpresentation, following supportive care, the patient was awake and alert. Interview of the patient revealed that she had daily chloroform inhalations for the last 6 days and prior to presentation, had combined chloroform inhalation with consumption of 450 mL of vodka. On hospital day 2 (27 hours post-exposure), laboratory data revealed elevated serum creatinine (2.1 mg/dL), BUN (61.4 mg/dL), and liver enzyme concentrations. Despite continuous supportive treatment, the patient's condition progressively deteriorated, with persistent hypotension, fulminant hepatic failure, acute renal failure, encephalopathy, and cardiac arrest resulting in death approximately 78 hours postexposure. A postmortem examination revealed microvesicular hepatic steatosis and tubular renal necrosis (Lionte, 2010).
c) CASE REPORT: A 31-year-old man developed acute renal failure and hepatotoxicity after ingesting 50 mL chloroform. The patient was jaundiced and initial laboratory data (hospital day 1) revealed elevated BUN (98 mg/dL), serum creatinine (6.2 mg/dL), and potassium (5.4 mEq/L) concentrations. The patient's ALT and AST concentrations were also elevated, peaking on hospital day 3 at 3560 and 1160 international units/L, respectively. With supportive care, including decontamination with activated charcoal and gastric lavage, 5 sessions of intermittent hemodialysis, and administration of N-acetylcysteine, the patient's condition improved and he was discharged on hospital day 10 (Sridhar et al, 2011).

a) Frequent urination may be noted (Plunkett, 1976).

a) The epithelium of Henle's loop and the convoluted tubules have been affected in animals after an acute poisoning with chloroform (Arena & Drew, 1986).

a) Chloroform and hypoxia may contribute to formation of metabolic acidosis (Schroeder, 1965).
b) Respiratory acidosis was reported in a 20-year-old woman who intentionally ingested approximately 100 mL of chloroform (Choi et al, 2006).
c) Respiratory acidosis occurred in a 46-year-old woman who inhaled chloroform in combination with consumption of 450 mL of vodka (Lionte, 2010).

a) CASE REPORT: A 21-year-old man developed evidence of hemolysis (free hemoglobin in the urine, anemia, indirect bilirubin increased transiently) following intravenous injection of 5 milliliters of chloroform (Timms & Moser, 1975).
b) Mild intravascular hemolysis has also been reported following intentional inhalation exposure (Hutchens & Kung, 1985).

a) White blood cell counts of 20,000 have been reported (pp 46-49).

a) Chloroform anesthesia may cause a fall in the plasma prothrombin level; it is attributed to hepatic poisoning or injury (Cullen et al, 1940).

a) CASE REPORT: A 20-year-old woman intentionally ingested approximately 100 mL of chloroform and the next day developed a prolonged prothrombin time (14.1 seconds). Her prothrombin time peaked at 18.4 seconds 3 days post-ingestion, but gradually normalized following supportive care (Choi et al, 2006).
b) CASE REPORT: A 19-year-old man developed a prolonged prothrombin time (PT) that peaked at 21.3 seconds approximately 4 days after ingesting 75 mL of chloroform in a suicide attempt. With supportive care, his PT gradually normalized (Dell'Aglio et al, 2010).
c) CASE REPORT: A 46-year-old woman developed a prolonged prothrombin time that peaked at 86.8 seconds approximately 27 hours after combining chloroform inhalation with consumption of 450 mL of vodka (Lionte, 2010).

a) CASE REPORT: Slightly dried pink-red spots on the skin were noted on autopsy of a pair of 52-year-old male twins found dead in a case of double suicide. The pink-red spots were thought to be produced from drops of chloroform that contacted the skin surface (Giusti & Chiarotti, 1981).

a) Burns may occur (JEF Reynolds , 1998; McGee et al, 1987).
b) CASE REPORT: A 39-year-old man presented to the emergency department with a 3-day history of nausea, vomiting, and malaise. At presentation, he appeared jaundice and had a partial thickness burn on his right shoulder, covering approximately 3% body surface area. His urine was also dark in color. Blood tests were consistent with a diagnosis of acute hepatitis. An abdominal ultrasound indicated hepatic steatosis. Interview of the patient revealed that, 3 days prior to presentation, he had been working with chloroform and had spilled 100 mL on his shoulder, with duration of exposure approximately 30 minutes before washing off the area. At that time, the patient noticed a red painless area on his shoulder, which began to desquamate the next day. The burn never became painful. At the hospital, the patient's transaminase and bilirubin concentrations improved 12 hours after beginning N-acetylcysteine therapy. The patient was discharged 4 days post-admission. Follow-up 8 weeks later reported normalization of his transaminase concentrations, and a repeat abdominal ultrasound was also normal (Vlad et al, 2014).

a) Chloroform may defat the skin and produce chronic irritation with drying and cracking (Hathaway et al, 1996). Erythema and hyperemia may also occur (NIOSH, 1974).

a) Workers exposed to chlorine derivatives of methane developed persistent dermatographism and blotchiness of the skin of the hands and forearms (Fokina, 1965).

a) RABBITS: Chloroform induced mild skin irritation in the rabbit in the Standard Draize Test and in the Open Draize Test (RTECS , 1999).

a) RABBITS: In a study of experimental animals, absorption through intact skin of rabbits occurred as indicated by weight loss and degenerative changes in the kidney tubules (Clayton & Clayton, 1994).

a) RABBITS developed slight hyperemia and moderate necrosis and scar tissue formation following dermal applications of chloroform (HSDB , 1999).

a) Fetal death, fetotoxicity, a change in homeostasis and specific developmental abnormalities in the gastrointestinal system and musculoskeletal system were observed in the rat (RTECS , 1999).
b) Chloroform administered to the female mouse was observed to cause fetotoxicity and specific developmental abnormalities in the craniofacial area (including the nose and tongue) in the embryo. In the rabbit, fetotoxicity and specific developmental abnormalities in the musculoskeletal system were observed (RTECS , 1999).
c) In pregnant rats, exposure to chloroform caused an apparent decrease in the conception rate and a high incidence of fetal resorption, retarded fetal development, decreased fetal body measurements, and a low incidence of acaudate fetuses with imperforate anus (Clayton & Clayton, 1994).

a) When chloroform was given to both male and female mice, changes in growth statistics, biochemical and metabolic changes, and other postnatal effects were observed in the newborn (RTECS , 1999).

a) In a rat study, chloroform was highly embryotoxic, but not highly teratogenic. In mice, a significant increase in the incidence of cleft palate was noted among the offspring of mice inhaling chloroform from days 8 through 15 of gestation, but no effect on the incidence of pregnancy was noted (Clayton & Clayton, 1994).
b) Chloroform was found to be embryotoxic and somewhat teratogenic in experimental animal studies (Clayton & Clayton, 1994).

a) In another study, a significant increase in the incidence of cleft palate was noted among the offspring of mice inhaling chloroform from days 8 through 15 of gestation; no effect on the incidence of pregnancy was noted (Clayton & Clayton, 1994).

a) Chloroform crosses the human placenta and can be detected in fetal blood (Dowty, 1976). The only cases found where chloroform was suspected of causing human reproductive effects were two cases of eclamptic toxemia of pregnancy in women working in a laboratory where chloroform was used (Tylleskar Jensen, 1967).

a) Exposure to chloroform during pregnancy is NOT recommended. Chloroform diffuses readily across the placenta; it produces embryotoxicity by inhalation in animals, and strong evidence suggests chloroform may be mutagenic and carcinogenic (JEF Reynolds , 1998; Clayton & Clayton, 1994; Rosenthal, 1987).

a) Chloroform increased post-implantation deaths and caused decreased weight gain in rat fetuses exposed by maternal inhalation (Dilley, 1977). It reduced the conception rate, increased resorptions, and retarded fetal growth in another rat inhalation study (Schwetz, 1974). In mice, it impaired pregnancy, increased pre-implantation losses, retarded fetal growth, and also caused cleft palate (Murray, 1979).
b) In pregnant rats given chloroform orally at high doses up to 400 mg/kg, there was reduced fetal weight; however, maternal toxicity was also evident (Ruddick, 1983). Similar results were obtained in rats and rabbits exposed by the oral route, where chloroform was not teratogenic (Thompson, 1974).

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation. However, based on its physical properties, it may be excreted in breast milk.

a) In rats and mice, chloroform was observed to cause post-implantation mortality as well as affecting the female fertility index. Other measures of fertility were also affected in rats (RTECS , 1999).

a) Listed as: Chloroform
b) Carcinogen Rating: 2B

a) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.

a) Treatment is symptomatic and supportive.

a) Treatment is symptomatic and supportive. Treat ventricular dysrhythmias using standard ACLS protocols. Renal failure may require renal replacement therapy. Hepatic injury may be treated with N-acetylcysteine with a similar protocol to that used for acetaminophen toxicity. Rarely, hemolysis may require treatment with packed red blood cell transfusions.

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

a) LIDOCAINE/INDICATIONS
b) LIDOCAINE/DOSE
c) LIDOCAINE/MAJOR ADVERSE REACTIONS
d) LIDOCAINE/MONITORING PARAMETERS

a) AMIODARONE/INDICATIONS
b) AMIODARONE/ADULT DOSE
c) AMIODARONE/PEDIATRIC DOSE
d) ADVERSE EFFECTS

a) PROCAINAMIDE/INDICATIONS
b) PROCAINAMIDE/ADULT LOADING DOSE
c) PROCAINAMIDE/CONTROLLED INFUSION
d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
h) MONITORING PARAMETERS
i) AVOID

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) Hemodialysis has not been shown to enhance chloroform elimination; however, it may be necessary to treat renal failure in severe cases.

a) CASE REPORT: A 24-year-old woman developed acute hepatitis with encephalopathy following occupational exposure to chloroform vapors at a concentration of more than 15 ppm for 2 weeks. The patient's condition improved following several treatments with plasmapheresis (Lin et al, 2005).

a) Blood concentrations reported after fatalities have ranged from 1-12 milligrams percent (Allan et al, 1988) Glusti & Chiarotti, 1981).
b) A 39-year-old female died after inhaling chloroform and her blood chloroform concentration was approximately 32.5 micrograms/mL (Harada et al, 1997).
c) A 19-year-old man intentionally ingested approximately 75 mL of chloroform, became comatose, and subsequently developed elevated liver enzyme concentrations. His serum chloroform concentration at hospital admission was 91 mcg/mL. Following acetylcysteine therapy and supportive care, the patient recovered without sequelae (Dell'Aglio et al, 2010).

1) Chloroform

a) TWA:
b) STEL: 2 ppm (9.78 mg/m(3)) [60-minute]
c) Ceiling:
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: Not Listed
f) Note(s): See Appendix A

a) IDLH: 500 ppm
b) Note(s): Ca

a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.

a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.

a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).

a) Category 4 : Substances with carcinogenic potential for which genotoxicity plays no or at most a minor part. No significant contribution to human cancer risk is expected provided the MAK value is observed. The classification is supported especially by evidence that increases in cellular proliferation or changes in cellular differentiation are important in the mode of action. To characterize the cancer risk, the manifold mechanisms contributing to carcinogenesis and their characteristic dose-time-response relationships are taken into consideration.

a) 8-hour TWA:

a) 623 mg/kg

a) 1750 mg/kg (OHM/TADS, 2001)
b) 118-1400 mg/kg (Bingham et al, 2001)
c) 1100 mg/kg (ATSDR, 1997)
d) 36 mg/kg
e) Male, 1120 mg/kg (ATSDR, 1997)
f) Female, 1400 mg/kg at 1 time/day for 14D (ATSDR, 1997)

a) 3283 mg/kg (ITI, 1995)
b) 704 mg/kg

a) Female, 1379 mg/kg for 24H (IPCS, 1994)
b) Female, 894 mg/kg for 14D (IPCS, 1994)
c) 894 mg/kg

a) 444-2000 mg/kg (Bingham et al, 2001)
b) 1875 mg/kg (OHM/TADS, 2001)
c) 450 mg/kg (OHM/TADS, 2001)
d) 300 mg/kg (OHM/TADS, 2001)
e) Male, 14 days old, 450 mg/kg (IPCS, 1994)
f) Male, 1200 mg/kg (IPCS, 1994)
g) Male, 908 mg/kg (ATSDR, 1997; HSDB, 2001)
h) Male, 908 mg/kg for 14D (IPCS, 1994)
i) Male, 2000 mg/kg for 14D (IPCS, 1994)
j) Male, young adult, 1337 mg/kg/once (ATSDR, 1997)
k) Male, 14 days old, 446 mg/kg (ATSDR, 1997)
l) Male, old adult, 1188 mg/kg (ATSDR, 1997)
m) Male, 2000 mg/kg (ATSDR, 1997)
n) Female, 2180 mg/kg (ATSDR, 1997)
o) Female, 14 days old, 450 mg/kg (IPCS, 1994)
p) Female, 1117 mg/kg (ATSDR, 1997; HSDB, 2001)
q) Female, 1117 mg/kg for 14D (IPCS, 1994)
r) Male, 908 mg/kg (HSDB, 2001; Lewis, 2000)
s) 300 mg/kg (ITI, 1995)
t) 695 mg/kg - change in motor activity; ataxia; respiratory stimulation

a) 10 mg/m(3) for 1Y -- central nervous system effects; gastrointestinal effects (Lewis, 2000)
b) 5000 mg/m(3) for 7M -- hallucinations
c) 10 mg/m(3) for 1Y -- anorexia, nausea

a) Female, 100 ppm for 7H at 1-7D of pregnancy -- changes in female fertility index; fetotoxicity (except death); post- implantation mortality
b) Female, 100 ppm for 7H at 8-15D of pregnancy
c) Female, 100 ppm for 7H at 8-15D of pregnancy -- craniofacial abnormalities
d) 100 ppm for 6H/7D-intermittent -- weight loss/weight gain; changes in liver weight
e) 12 ppm for 6H/13W-intermittent -- death

a) Female, 20,100 mcg/m(3) for 1H at 7-14D of pregnancy -- fetotoxicity; fetal death
b) Female, 30 ppm for 7H at 6-15D of pregnancy -- fertility effects; fetotoxicity (except death); developmental abnormalities of the musculoskeletal system
c) Female, 300 ppm for 7H at 6-15D of pregnancy -- decrease in female fertility index; post-implantation mortality
d) Female, 100 ppm for 7H at 6-15D of pregnancy -- homeostasis; abnormalities of the gastrointestinal system
e) Female, 20,100 mcg/m(3) for 1H at 7-14D of pregnancy - teratogenic (Lewis, 2000)
f) 50 ppm for 7H/26W-intermittent -- fibrosis; pneumoconiosis; changes in bladder weight; liver changes
g) 90 ppm for 6H/13W-intermittent -- hepatitis; acute renal failure; acute tubular necrosis; weight loss/decreased weight gain
h) 300 ppm for 6H/7D-intermittent -- changes to sense organs; changes to musculoskeletal system
i) 592 mg/m(3) for 2.5H/2W-intermittent -- changes in food intake; changes to liver; changes to kidney, ureter, and bladder