Substances Included Synonyms

Therapeutic Toxic Class

A)

1) It is used in the production of fluorocarbons (Clayton & Clayton, 1994). The industrial use of carbon tetrachloride has declined significantly in recent years.

Specific Substances

1) Tetrachloromethane
2) Perchloromethane
3) CCL(4)
4) Carboneum Tetrachloratum Medicinale
5) Benzinoform
6) Carbon chloride
7) Carbon tet
8) Carbona
9) Methane tetrachloride
10) Methane, tetrachloro-
11) Tetrachlorocarbon
12) Tetrafinol
13) Tetraform
14) Tetrasol
15) Univerm
16) NIOSH/RTECS FG 4900000
17) Molecular Formula: C-Cl4
18) CAS 56-23-5
19) TETRACHLOORMETAAN (DUTCH)
20) TETRACHLOROMETANO (ITALIAN)

1.2.1) MOLECULAR FORMULA
1) CCl4

Available Forms Sources

A)

1) Carbon tetrachloride has a characteristic odor. It exists as a clear colorless heavy liquid and is nonflammable (AAR, 2000; (Budavari, 2000).

B)

1) It is produced by a variety of methods including an interaction of carbon disulfide and chlorine in the presence of iron and the chlorination of hydrocarbons (Budavari, 2000; Lewis, 2001).

C)

1) Carbon tetrachloride is a chlorinated hydrocarbon that is toxic by inhalation, ingestion, and skin absorption. Due to its toxicity, it was banned from household use in 1970 and from its use as a fumigant in 1985. It is now primarily used as a chemical intermediate in the manufacture of chlorofluorocarbon refigerants. Previously, it was used as a degreasing solvent, dry cleaning agent, fire extinguisher, grain fumigant, and anthelmintic (Budavari, 2000; Hathaway et al, 1996; Lewis, 1998).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Once used as a dry cleaning solvent, degreaser, fire extinguishing agent, spot remover, and an antihelminthic. Now used mainly as an intermediate in chemical manufacturing.
B) TOXICOLOGY: The exact mechanism of carbon tetrachloride hepatotoxicity is unclear, but is accepted to be dependent on its metabolism. Forms a toxic free-radical intermediate (tricholomethyl radical) of cytochrome P-450 metabolism, which binds to protein, lipid, and nucleic acid, and forms DNA-adducts. It is a CNS depressant through mechanisms that are not entirely clear, and it increases sensitivity of the myocardium to catecholamines, and can therefore have arrhythmogenic effects.
C) EPIDEMIOLOGY: Exposures and poisoning are rare, but deaths have been reported and are not uncommon following significant exposures.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, headache, dizziness and confusion, mucous membrane irritation, and defatting dermatitis.
2) SEVERE TOXICITY: Cardiac dysrhythmias, respiratory arrest, severe renal and hepatic damage, and coma.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Eye irritation, conjunctivitis, blurred vision, optic nerve damage, and hearing loss may occur.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Hypotension, ventricular dysrhythmias, depressed cardiac muscles, fatty degeneration, and a slowed or irregular pulse may occur.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Dizziness, headache, fatigue, confusion, altered mental status, delirium, seizures, coma, amnesia, incoherent speech, ataxia, intention tremor, and positive Rhomberg sign may occur.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Burning pain, irritation, nausea, vomiting, diarrhea, and abdominal pain may occur following ingestion. Gastrointestinal effects can occur even from dermal exposure.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Hepatic injury occurs resulting in jaundice, liver enlargement, and ascites. Hepatic damage can occur even from dermal exposure.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Polyuria followed by oliguria, and azotemia progressing to uremia may develop. Hematuria and proteinuria are common. Acute renal insufficiency is predominant in human toxicity. Renal failure can occur even from dermal exposure.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis may occur.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Aplastic anemia may occur.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Erythema, and vesiculation occasionally develop. A defatting dermatitis may develop.

0.2.17)

A) WITH POISONING/EXPOSURE

1) Carbon tetrachloride can profoundly affect lipid metabolism in experimental animals.

0.2.19)

A) WITH POISONING/EXPOSURE

1) Experimental animals treated with carbon tetrachloride had a T-cell immunosuppressive factor in the serum, increased response to lipopolysaccharide, and increased numbers of B-cells in the spleen. The serum from treated animals also enhanced B-cell function in cultured spleen cells.

0.2.20)

A) Carbon tetrachloride was fetotoxic and teratogenic in experimental animals and produced histological changes in the livers of nursing neonatal rats. It affected sperm, sperm duct, and epididymis in male rats.

0.2.21)

A) Carbon tetrachloride is a suspected human carcinogen.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive.

B) MANAGEMENT OF SEVERE TOXICITY

1) Perform endotracheal intubation in patients with CNS depression and are unable to protect their airway. Treat hypotension with IV fluids (10 to 20 mL/kg NS). If hypotension persists, administer dopamine. Avoid the use of epinephrine or other sympathomimetic amines because they may induce or aggravate dysrhythmias. Consider central venous pressure monitoring to guide further fluid therapy. Tachydysrhythmias can be caused by increased myocardial sensitivity and can be treated with propranolol or esmolol. Administer lidocaine in patients with frequent premature ventricular contractions (PVCs), coupled, multifocal, or R on T phenomenon associated with ingestion. Amiodarone is effective for the control of hemodynamically stable ventricular tachycardia, polymorphic ventricular tachycardia, and wide complex tachycardia or unclear origin. Administer procainamide as an alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. Administer inhaled beta adrenergic agonists if bronchospasm develops. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis. Consider N-acetylcysteine (NAC) in patients with significant carbon tetrachloride exposure, as NAC may decrease hepatic and renal toxicity by acting as a scavenger for the toxic metabolite

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is generally not recommended due to the potential for CNS depression and seizures and subsequent aspiration.
2) HOSPITAL: As. carbon tetrachloride is a liquid, consider aspiration of gastric contents with a nasogastric tube after ingestion of a potentially life-threatening amount of poison, if it can be performed soon after ingestion (generally within 1 hour). However, given the risk of hydrocarbon aspiration, endotracheal intubation should be strongly considered prior to gastric aspiration. Administer activated charcoal to patients with recent (within 1 hour) who are awake and able to protect their airway. Activated charcoal should not be administered to patients with CNS depression due to aspiration risk.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be performed in patients with excessive drowsiness and the inability to protect their own airway.

E) ANTIDOTE

1) None

F) ACETYLCYSTEINE

1) Human case reports and animal studies suggest that N-acetylcycsteine (NAC) may decrease hepatic and renal toxicity by acting as a scavenger for the toxic metabolite. There are no controlled human studies, but, as NAC has few adverse effects, it is recommended in patients with significant carbon tetrachloride exposure. It is probably more effective if administered early. DOSE: IV: 150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours. ORAL: 140 mg/kg initially, then 70 mg/kg every 4 hours for 17 doses.

G) ENHANCED ELIMINATION

1) There is no role for hemodialysis/hemoperfusion unless it is necessary to support patients in renal or hepatic failure.

H) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Patients with any ingestion or significant dermal or inhalation exposure should be sent to a medical facility for evaluation and treatment.
2) ADMISSION CRITERIA: All patients who have a history of intentional ingestions, radiographic evidence of ingestion, or who are symptomatic should be admitted. Those who are suspected to have ingested any carbon tetrachloride should be admitted since it has caused deaths after ingestion of as little as 3 to 5 mL.
3) CONSULT CRITERIA: Consult a medical toxicologist for assistance with medical management.

I) PITFALLS

1) Failure to recognize that dermal exposure to carbon tetrachloride can result in systemic toxicity.

J) TOXICOKINETICS

1) Carbon tetrachloride is rapidly absorbed from the gastrointestinal tract, lungs, or skin. Most is eliminated in exhaled breath; the remainder undergoes hepatic metabolism. In animals, the alpha and beta elimination half-lives are about 80 and 400 minutes, respectively, and are slightly longer after longer exposure.

K) DIFFERENTIAL DIAGNOSIS

1) Consider poisoning with other hydrocarbons, CNS depressants, and acetaminophen or other hepatotoxic agents.

0.4.3)

A) Remove from exposure and give supplemental oxygen if needed. Administer inhaled beta adrenergic agonists if bronchospasm develops. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.

0.4.4)

A) Irrigate with saline or water.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed skin, including hair and nails, with soap and water. Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines. Patients with significant exposure can develop systemic toxicity.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, headache, dizziness and confusion, mucous membrane irritation, and defatting dermatitis.
2) SEVERE TOXICITY: Cardiac dysrhythmias, respiratory arrest, severe renal and hepatic damage, and coma.

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Eye irritation, conjunctivitis, blurred vision, optic nerve damage, and hearing loss may occur.

3.4.3)

A) WITH POISONING/EXPOSURE

1) CONJUNCTIVITIS: Carbon tetrachloride is an eye irritant; exposure to liquid or vapor may cause tearing and burning. Conjunctivitis may develop (Lewis, 1996).
2) VISION ABNORMAL: Blurry vision may be a symptom (Harbison, 1998). There is a possible association with damage to the optic nerve resulting in visual defects (Moeller, 1973) or blindness (Smith, 1950).

a) There have been reports that carbon tetrachloride produces constriction of visual fields, but this remains controversial. Carbon tetrachloride is strongly suspected of causing retrobulbar neuritis, optic neuritis and optic atrophy (Grant & Schuman, 1993).

B) ANIMAL STUDIES

1) DRAIZE TEST: Carbon tetrachloride was a mild eye irritant at 2200 mcg/30 seconds or 500 mg/24 hours in rabbits in a standard Draize test (RTECS , 1999).

3.4.4)

A) WITH POISONING/EXPOSURE

1) DEAFNESS: There is a possible association with hearing loss (Frey & Geipel, 1975).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Hypotension, ventricular dysrhythmias, depressed cardiac muscles, fatty degeneration, and a slowed or irregular pulse may occur.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension may occur following acute poisoning (Dreisbach & Robertson, 1987).

B) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) A weak and slowed or irregular pulse may occur with acute toxicity (Dreisbach & Robertson, 1987).

C) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Ventricular dysrhythmias, including ventricular premature beats, seen on ECG, have been reported as well as depression of cardiac muscle (Dreisbach & Robertson, 1987).

D) CARDIOMEGALY

1) WITH POISONING/EXPOSURE

a) Postmortem examinations have shown fatty degeneration and cardiomegaly following acute poisonings (Dreisbach & Robertson, 1987).

E) MYOCARDITIS

1) WITH POISONING/EXPOSURE

a) SENSITIZATION: Carbon tetrachloride has been postulated to cause myocardial sensitization to endogenous catecholamines. Although no documented cases have been described, sudden death from ventricular dysrhythmias might occur following exposure (HSDB , 1999; Lewis, 1998).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema has been reported after high concentration inhalation exposure. Hemorrhagic congestion and edema have been reported at autopsy in several cases. These effects generally do not develop until approximately 8 days after exposure, and appear to be secondary to renal injury and not a direct effect on the lungs (ATSDR, 1994).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Dizziness, headache, fatigue, confusion, altered mental status, delirium, seizures, coma, amnesia, incoherent speech, ataxia, intention tremor, and positive Rhomberg sign may occur.

3.7.2)

A) CLOUDED CONSCIOUSNESS

1) WITH POISONING/EXPOSURE

a) Confusion, delirium, dizziness, vertigo, restlessness and giddiness have been reported (ATSDR, 1994; Dreisbach & Robertson, 1987; Hathaway et al, 1996).

B) DROWSY

1) WITH POISONING/EXPOSURE

a) NARCOSIS: Carbon tetrachloride is narcotic; exposure to high concentrations of carbon tetrachloride results in depression of the central nervous system (ATSDR, 1994; Lewis, 1998; ACGIH, 1996a).
b) If the concentration is not high enough to lead to rapid loss of consciousness, other indications of central nervous system effects, such as dizziness, vertigo, headache, depression, mental confusion, and incoordination, are observed (ATSDR, 1994; Clayton & Clayton, 1994).

C) CEREBRAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Hemorrhage into the cerebral cortex, pons and cerebellum have been reported (O'Donoghue, 1985).

D) NEUROPATHY

1) WITH POISONING/EXPOSURE

a) Peripheral sensorimotor neuropathies characterized by weakness, loss of position sense, hyporeflexia, and paresthesias have developed (O'Donoghue, 1985).

E) CEREBELLAR DISORDER

1) WITH POISONING/EXPOSURE

a) Amnesia, incoherent speech and ataxia, intention tremor, positive Rhomberg sign, and signs of cerebellar dysfunction developed in a survivor of acute CCl4 poisoning by inhalation (Johnson et al, 1983).

F) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) The neurological effects are likely due to hepatic encephalopathy. However, there may also be a direct effect of CCl4 on the brain (Peters et al, 1986).

G) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) Chronic exposure has been possibly associated with myasthenic reaction, a defect in neuromuscular transmission (Glatzel, 1972).

H) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may occur (Clayton & Clayton, 1994; ACGIH, 1996a).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Burning pain, irritation, nausea, vomiting, diarrhea, and abdominal pain may occur following ingestion. Gastrointestinal effects can occur even from dermal exposure.

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) Abdominal pain, nausea, and vomiting may follow ingestion or significant inhalation exposure (Budavari, 1996; Clayton & Clayton, 1994; ATSDR, 1994). Diarrhea followed by constipation may occur. Initial presenting signs or symptoms of CCl4 inhalation or oral exposure may be abdominal pain, nausea, vomiting and diarrhea (USDHHS, 1992; Lewis, 1998).
b) DERMAL EXPOSURE: Gastrointestinal effects can occur even following dermal exposure (Perez et al, 1987).

B) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE

1) WITH POISONING/EXPOSURE

a) Burning sensation in mouth, esophagus, and stomach may occur (Dreisbach & Robertson, 1987).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Hepatic injury occurs resulting in jaundice, liver enlargement, and ascites. Hepatic damage can occur even from dermal exposure.

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Hepatic injury occurs resulting in jaundice, liver enlargement, and ascites. Liver and renal damage may be delayed several days following exposure (ATSDR, 1994; von Oettingen, 1964; Proctor et al, 1988; Proctor & Hughes, 1978).
b) Acute hepatic insufficiency is the usual cause of death from acute carbon tetrachloride poisoning (Paliard et al, 1969).
c) Orthotopic liver transplantation was done on a young man who had severe carbon tetrachloride intoxication. Marked rhabdomyolysis was present also. Failure of the transplanted liver ensued, presumably due to traces of carbon tetrachloride remaining in the patient's blood, although CC14 was reported to be at "non-toxic levels" (Nehoda et al, 1998).
d) Ethanol consumption appears to potentiate the hepatotoxic effects of acute carbon tetrachloride exposure. Only 2 of 7 men exposed to toxic levels of inhalational CCl4 developed liver toxicity consisting of increased liver enzymes and hepatomegaly. In both cases the workers consumed significant daily quantities of alcohol as opposed to the other non-affected workers (Manno & Rezzadore, 1994; Manno et al, 1996).
e) DERMAL EXPOSURE: Hepatic damage can occur even from dermal exposure (Perez et al, 1987).

B) ABNORMAL LIVER FUNCTION

1) WITH POISONING/EXPOSURE

a) Functional and destructive injury of the liver and kidney may occur from a single acute exposure, but it is much more likely to occur from repeated exposures (Clayton & Clayton, 1994).

3.9.3)

A) ANIMAL STUDIES

1) HEPATOCELLULAR DAMAGE

a) ANIMAL DATA: The vehicle used to administer CCl4 in gavage studies may influence the toxicity. Hepatic damage was more severe in mice when corn oil was used as the dosing vehicle than with Tween-60, and the no-effect dose of CCl4 was ten times lower in corn oil (Condie et al, 1986).
b) Hathaway et al (1996) report that in animals, the primary damage from intoxication is to the liver, but in humans, most fatalities have been the result of renal injury with secondary cardiac failure (Hathaway et al, 1996a).

2) HEPATIC CIRRHOSIS

a) HISTOLOGY: Histologic characterization of liver damage induced by CCl4 in rats included cirrhosis with bile duct proliferation, fibrosis, lobular distortion, parenchymal regeneration, hyperplastic nodules and single-cell necrosis (Bruckner et al, 1986). The pattern of injury is a centrizonal necrosis that may progress to include the entire hepatic lobule.

1) Regeneration changes appear early, at 24 hours, and continue into the 168th hour following single subcutaneous injections of CCl4 into rats (Wirtschaffer & Cronyn, 1964).

3) ENCEPHALOPATHY

a) HYPERAMMONEMIA: Carbon tetrachloride poisoning in rats produced hyperammonemia and hepatic encephalopathy. ATP levels were decreased in livers of rats with hepatic encephalopathy and Mg2+-ATPase activity was increased. The hyperammonemia may play a role in hepatic encephalopathy (Yamamoto & Sugihara, 1987).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Polyuria followed by oliguria, and azotemia progressing to uremia may develop. Hematuria and proteinuria are common. Acute renal insufficiency is predominant in human toxicity. Renal failure can occur even from dermal exposure.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Polyuria, followed by oliguria, anuria and azotemia progressing to uremia may develop (Budavari, 1996). Proteinuria, hemoglobinuria and glucosuria are also common (ATSDR, 1994).
b) Often liver injury is moderate or even absent, while acute renal insufficiency predominates in the human clinical picture (Paliard et al, 1969).
c) Prior to hemodialysis many patients died from nephrotoxicity (Proctor et al, 1988).
d) DERMAL EXPOSURE: Renal failure can occur even from dermal exposure (Perez et al, 1987).

B) ALBUMINURIA

1) WITH POISONING/EXPOSURE

a) Proteinuria and hematuria are common renal effects following acute toxicity (Dreisbach & Robertson, 1987).

C) CRUSH SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute tubular necrosis appears to result from damage to the proximal tubule and Loop of Henle (Finkel, 1983).
b) CASE REPORT: A 31-year-old man with an acute occupational inhalation exposure developed acute tubular necrosis with anuria and elevated BUN and creatinine. He recovered following 17 days of hemodialysis (Manno & Rezzadore, 1994).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis may occur.

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis occurred in a case of inhalation of CCl4 fumes from cleaning machinery (Hadi & El Mikatti, 1981).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Aplastic anemia may occur.

3.13.2)

A) APLASTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) There is a possible association between exposure to carbon tetrachloride and aplastic anemia (Straus, 1954).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Erythema, and vesiculation occasionally develop. A defatting dermatitis may develop.

3.14.2)

A) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) Carbon tetrachloride is a skin irritant (Lewis, 1996). Erythema, hyperemia, wheals, and vesiculations may be seen (HSDB , 2000).

B) DERMATITIS

1) WITH POISONING/EXPOSURE

a) DEFATTING: Skin contact can lead to dermatitis through defatting action (Budavari, 1996; Clayton & Clayton, 1994).

3.14.3)

A) ANIMAL STUDIES

1) DERMATITIS

a) IRRITATION: Carbon tetrachloride was a mild skin irritant at 4 mg or at 500 mg/24 hours in rabbits in a standard Draize test (RTECS , 1999).

Immunologic

3.19.1)

A) WITH POISONING/EXPOSURE

1) Experimental animals treated with carbon tetrachloride had a T-cell immunosuppressive factor in the serum, increased response to lipopolysaccharide, and increased numbers of B-cells in the spleen. The serum from treated animals also enhanced B-cell function in cultured spleen cells.

3.19.3)

A) ANIMAL STUDIES

1) SPLEEN DISORDER

a) DETAILED ANIMAL STUDIES: Mice treated with carbon tetrachloride at 500 mg/kg/day for 7 days have a T-cell immunosuppressive factor(s) in the serum. In addition, the serum from treated animals enhanced B-cell function in cultured spleen cells, and treated animals showed increased response to lipopolysaccharide, a T-cell independent antigen. Increased numbers of B-cells were seen in the spleens of treated animals (Delaney & Kaminski, 1994).

Reproductive

3.20.1)

A) Carbon tetrachloride was fetotoxic and teratogenic in experimental animals and produced histological changes in the livers of nursing neonatal rats. It affected sperm, sperm duct, and epididymis in male rats.

3.20.2)

A) CONGENITAL ANOMALY

1) ANIMAL STUDIES

a) RATS - Carbon tetrachloride was fetotoxic and teratogenic, producing stunted fetuses and musculoskeletal abnormalities in rats when given by inhalation at 300 ppm/7 hours from the 6th to 15th day of pregnancy. Hepatobiliary abnormalities and fetotoxicity were produced by parenteral administration of 2,384 mg/kg 18 days after conception (RTECS , 1999).
b) RATS - Pregnant rats were less susceptible to liver injury by carbon tetrachloride than nonpregnant rats (Douglas & Clower, 1968). However, carbon tetrachloride did cause liver damage in rat fetuses when given late in gestation (Tsirelnikov & Dobrovolskaya, 1973).
c) RATS - According to Barlow & Sullivan (1982), the later in the pregnancy CC14 is given, the less liver damage occurs in experimental animals. CC14 was not teratogenic when given orally at 0.3 mL or subcutaneously at 0.8 mL between days 7 to 11 of gestation in the rat, but some litters were resorbed (Barlow & Sullivan, 1982).
d) RABBITS - CCl4 was not teratogenic in rabbits in inadequately reported studies (Barlow & Sullivan, 1982).

B) LACK OF EFFECT

1) ANIMAL STUDIES

a) MICE - Carbon tetrachloride was not teratogenic or fetotoxic in mice exposed on day 1, 6, or 11 of gestation at doses of 1/10 and 1/100 the LD50. It did inhibit in vitro fertilization, however, at concentrations above 0.5 mM (Hamlin et al, 1993).

3.20.3)

A) PLACENTAL BARRIER

1) HUMAN - CCl4 was found in cord blood in humans, suggesting that it crosses the placenta (Barlow & Sullivan, 1982; Dowty, 1976).

B) ANIMAL STUDIES

1) Carbon tetrachloride induced post-implantation mortality in rats when given orally at 2 g/kg 7 to 8 days after mating and affected extra-embryonic structures (eg, placenta) when given at 3 g/kg 14 days after conception (RTECS , 1999).
2) HEPATOCELLULAR DAMAGE

a) RATS - CCl4 given by inhalation at 300 or 1000 ppm for 7 hours per day on days 6 to 15 of pregnancy caused greatly reduced food consumption and decrease in body weights with maternal hepatotoxicity. No gross malformations were seen but one litter was entirely resorbed (not statistically significant). Fetal body weights and lengths were lower, undoubtedly results of the decreased feeding in the dams. The fetal rat was more resistant to liver damage from CCl4 than the dam (Barlow & Sullivan, 1982).

3.20.4)

A) LACTATION PUERPERAL DECREASED

1) ANIMAL STUDIES

a) RATS - Weaning or lactation index was reduced in rats given carbon tetrachloride by inhalation at 250 ppm for 8 hours 10 to 15 days after conception (RTECS , 1999).
b) RATS - CCl4 given to rat dams on the 10th day after birth produced histological changes in the livers of the nursing neonatal rats, suggesting that CCl4 in potentially toxic amounts is transported through the milk (Barlow & Sullivan, 1982).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS56-23-5 (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: Carbon tetrachloride
b) Carcinogen Rating: 2B

1) 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.

3.21.2)

A) Carbon tetrachloride is a suspected human carcinogen.

3.21.3)

A) CARCINOMA

1) SUSPECT HUMAN CARCINOGEN: Carbon tetrachloride is a suspect human carcinogen (ACGIH, 2000).
2) ENHANCEMENT: Carbon tetrachloride may enhance the carcinogenicity of other substances (Takizawa, 1975).
3) Effects of chronic exposure to carbon tetrachloride include liver cancer in persons with acute poisoning (Tracey & Sherlock, 1968), which might occur with prior chronic exposure, even in the absence of cirrhosis (Hernberg, 1984), and a possible association with brain tumors (Bond et al, 1983), lymphatic leukemias, and lymphosarcomas (Wilcosky, 1984). Carbon tetrachloride can cause liver cancer after a single, high-dose exposure (Greim, 1977). Epidemiological results have been inconclusive because of mixed exposures (Hathaway et al, 1991).
4) A case-control study conducted in Montreal, Canada of occupational exposures to any of 6 chlorinated solvents (carbon tetrachloride, methylene chloride, 1,1,1-trichloroethane, chloroform, trichloroethylene, and tetrachloroethylene) and association with cancer found an increased risk of prostate cancer with tetrachloroethylene exposure and an increased risk of melanoma with trichloroethylene exposure. The analysis that included 3730 cancer cases (occurring from 1979 to 1985) and 533 population controls focused on the following 11 cancer types: esophagus, stomach, colon, rectum, liver, pancreas, prostate, bladder, kidney, melanoma, and non-Hodgkin lymphoma. An association was observed between tetrachloroethylene exposure and risk of prostate cancer (odds ratio [OR], 2.2; 95% CI, 0.8 to 5.7 for any exposure and OR, 4.3; 95% CI, 1.4 to 13 for substantial exposure), as well as between trichloroethylene exposure and melanoma risk (OR, 3; 95% CI, 1.2 to 7.2 for any exposure and OR, 3.2; 95% CI, 1 to 9.9 for substantial exposure). There was also an association between substantial exposure to chlorinated alkenes (ie, trichloroethylene and tetrachloroethylene) in general and melanoma risk (OR, 2.6; 95% CI, 1 to 7.1). Substantial exposure was defined as a degree of confidence that the exposure actually occurred of probable or definite, a medium or high solvent concentration and frequency of exposure, and a duration of exposure that was greater than 5 years. While an association between substantial exposure to chloroform and risk of pancreatic cancer exists (OR, 10.6; 95% CI, 1.2 to 93), this was based on only 2 exposed workers. The majority of ORs were close to null or like the chloroform and pancreatic association, were based on very small numbers, thereby providing limited power to detect real risk (Christensen et al, 2013).

B) HEPATIC NEOPLASM MALIGNANT

1) Elevated risk for LIVER CANCER has occurred in persons with previous acute poisoning (Tracey & Sherlock, 1968).
2) Increased risk for LIVER CANCER may occur from chronic exposure even in the absence of cirrhosis (Hernberg, 1984).

C) LEUKEMIA

1) There is a possible association with BRAIN TUMORS, LYMPHATIC LEUKEMIAS, and LYMPHOSARCOMAS (Wilcosky, 1984; Clayton & Clayton, 1994).

D) BREAST CARCINOMA

1) In an retrospective study of occupational carbon tetrachloride exposures, Cantor et al (1995) showed evidence of association for increased risk of BREAST CANCER in whites in CCl4 exposed groups as opposed to controls. Further study is warranted given the methodological limitations of this study.

3.21.4)

A) CARCINOMA

1) Carbon tetrachloride has been carcinogenic in animals (AMA, 1985).

a) It was an equivocal tumorigenic agent for liver tumors in rats given 15,600 mg/kg subcutaneously for 12 weeks (RTECS , 1988).
b) It was neoplastic for liver tumors in mice at 4400 mg/kg orally for 19 weeks (RTECS , 1988).
c) It was an equivocal tumorigenic agent for liver tumors when given parenterally to mice at 305 g/kg over 30 weeks (RTECS , 1988).
d) It was an equivocal tumorigenic agent for liver tumors in hamsters when given orally at 9250 mg/kg over 30 weeks (RTECS , 1988).
e) It was neoplastic for liver tumors in mice at an oral dose of 12 g/kg over 88 days (RTECS , 1988).
f) It was an equivocal tumorigenic agent in rats given subcutaneously at 100 g/kg over 25 weeks (RTECS , 1988).
g) It was an equivocal tumorigenic agent in rats when given subcutaneously at 31 g/kg over 12 weeks (RTECS , 1988).
h) It was carcinogenic in rats, producing liver tumors at a subcutaneous dose of 182 g/kg over 70 weeks (RTECS , 1988).
i) It was neoplastic in mice for liver tumors at 8580 mg/kg over 9 weeks (RTECS , 1988).
j) It was neoplastic in mice for liver tumors when given orally at 57,600 mg/kg over 12 weeks (RTECS , 1988).
k) ENHANCEMENT: Carbon tetrachloride may enhance the carcinogenicity of other substances (Takizawa, 1975).
l) Carbon tetrachloride has caused liver tumors in several experimental animal studies as a consequence of liver damage (Reuber & Glover, 1970) Della Porta et al, 1961).

Genotoxicity

A)

B)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Obtain an ECG and initiate continuous cardiac monitoring.
C) Monitor serum electrolytes, renal function, hepatic enzymes, and bilirubin.
D) Monitor urine output.
E) Carbon tetrachloride is opaque. A chest x-ray or abdominal flat plate radiograph may confirm exposure.
F) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes, renal function, hepatic enzymes, and bilirubin.
2) Although carbon tetrachloride levels may be available from some labs, it is unlikely the results would affect therapy.

a) Blood levels of carbon tetrachloride in acutely poisoned patients ranged from 0.1 to 31.5 mg/L (Ruprah et al, 1985).
b) Whole-blood concentration of CCl4 four hours after acute ingestion of over 200 ml was 31.5 mg/l, the highest ever recorded at that hospital (Mathieson et al, 1985).

3) If acidosis is suspected, monitor arterial blood gases.
4) Individual serum bile acids appear to be very sensitive indicators of liver damage and may be used as early indicators of carbon tetrachloride-induced liver injury as measured by high performance liquid chromatography. This appears to be much more sensitive than measuring liver enzyme or bilirubin levels (Bai et al, 1992).

4.1.3)

A) MONITORING

1) Monitor urine output.

4.1.4)

A) OTHER

1) ECG

a) Obtain an ECG and initiate continuous cardiac monitoring.

Radiographic Studies

A)

1) Carbon tetrachloride is radiopaque, and some ingestions may be able to be confirmed with an abdominal radiograph (Dally et al, 1987; Bagnasco et al, 1978).

B)

1) A chest radiograph should be considered in patients with respiratory symptoms.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients who have a history of intentional ingestions, radiographic evidence of ingestion, or who are symptomatic should be admitted. Those who are suspected to have ingested any carbon tetrachloride should be admitted since it has caused deaths after ingestion of as little as 3 to 5 mL.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist for assistance with medical management.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with any ingestion or significant dermal or inhalation exposure should be sent to a medical facility for evaluation and treatment.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) Prehospital decontamination is generally not recommended due to the potential for CNS depression and seizures and subsequent aspiration.

6.5.2)

A) EMESIS/NOT RECOMMENDED

1) Emesis is NOT recommended due to the potential for CNS depression and seizures.

B) ASPIRATION

1) As carbon tetrachloride is a liquid, consider aspiration of gastric contents with a nasogastric tube after ingestion of a potentially life-threatening amount of poison, if it can be performed soon after ingestion (generally within 1 hour). However, given the risk of hydrocarbon aspiration, endotracheal intubation should be strongly considered prior to gastric aspiration.

C) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

D) EXPERIMENTAL THERAPY

1) CHOLESTYRAMINE: Carbon tetrachloride-induced liver cirrhosis results in bile acids not being detoxified in the enterohepatic circulation. In rat studies administration of cholestyramine, which has a strong affinity for bile acids in the intestine, prevents their enteral resorption and decreases the induction of cirrhosis (De Heer et al, 1980).

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Obtain an ECG and initiate continuous cardiac monitoring.
3) Monitor serum electrolytes, renal function, hepatic enzymes, and bilirubin.
4) Monitor urine output.
5) Carbon tetrachloride is opaque. A chest x-ray or abdominal flat plate radiograph may confirm exposure.
6) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

B) SUPPORT

1) Intensive supportive care has resulted in recovery even in patients with severe renal and hepatic involvement.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

D) VENTRICULAR ARRHYTHMIA

1) SUMMARY

a) Tachydysrhythmias can be caused by increased myocardial sensitivity and can be treated with propranolol or esmolol.
b) Administer lidocaine in patients with frequent premature ventricular contractions (PVCs), coupled, multifocal, or R on T phenomenon associated with ingestion.
c) Amiodarone is effective for the control of hemodynamically stable ventricular tachycardia, polymorphic ventricular tachycardia, and wide complex tachycardia of unclear origin.
d) Procainamide is an alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective.
e) Although no documented cases have been reported, it has been speculated that carbon tetrachloride exposure could lower the myocardial threshold to the arrhythmogenic effects of epinephrine.

1) Administration of epinephrine should most likely be avoided due to the possibility of inducing ventricular dysrhythmias.

2) PROPRANOLOL

a) PROPRANOLOL/INDICATIONS

1) Nonselective beta-adrenergic receptor blocking agent (Prod Info propranolol HCl IV injection, 2008). May be used to treat stable, narrow-complex tachycardia if rhythm is not controlled or converted by adenosine or vagal maneuvers or if SVT is recurrent; to control ventricular rate in patients with atrial fibrillation or atrial flutter; or certain types of polymorphic ventricular tachycardia (ie, catecholaminergic, or rate associated with acute ischemia). Avoid in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excitation related atrial fibrillation or flutter (Neumar et al, 2010). Propranolol is also used in the treatment of life-threatening digitalis-induced dysrhythmias, although digitalis immune Fab is the treatment of choice (Prod Info propranolol HCl IV injection, 2008).

b) PROPRANOLOL/ADULT DOSE

1) INTRAVENOUS: 0.5 mg to 1 mg per dose IV over 1 minute. May repeat dose up to a total of 0.1 mg/kg, if needed (Neumar et al, 2010). A second dose may be repeated in 2 minutes, if necessary; however, any additional drug administration should be given at least 4 hours later (Prod Info propranolol HCl IV injection, 2008).
2) The maximum dose is 3 mg; the rate should not exceed 1 mg/min (Prod Info propranolol HCl IV injection, 2008).

c) PROPRANOLOL/PEDIATRIC DOSE

1) INTRAVENOUS: 0.01 to 0.15 mg/kg IV every 6 to 8 hours (Luedtke et al, 1997).

d) MONITORING

1) The drug should be administered with cardiac monitoring or central venous pressure monitoring. Monitor for bradycardia, hypotension and congestive heart failure (Prod Info propranolol HCl IV injection, 2008).

3) ESMOLOL

a) TACHYCARDIA SUMMARY

1) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
2) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
3) ESMOLOL/ADULT LOADING DOSE

a) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010a).

4) ESMOLOL/ADULT MAINTENANCE DOSE

a) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010a).
b) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010a).
c) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
d) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

5) CAUTION

a) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010a).

4) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010a). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010a).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

5) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010a). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010a).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010a).

6) PROCAINAMIDE

a) PROCAINAMIDE/INDICATIONS

1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010a; Vanden Hoek,TL,et al).

b) PROCAINAMIDE/ADULT LOADING DOSE

1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010a).
2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010a).
3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010a).

c) PROCAINAMIDE/CONTROLLED INFUSION

1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)

d) PROCAINAMIDE/ADULT MAINTENANCE DOSE

1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010a).

e) PROCAINAMIDE/PEDIATRIC LOADING DOSE

1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).

f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE

1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE

1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

h) MONITORING PARAMETERS

1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).

i) AVOID

1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010a).

E) ACETYLCYSTEINE

1) Thirteen patients with acute carbon tetrachloride poisoning who were treated with acetylcysteine had milder hepatic damage than six who did not receive this treatment (Ruprah et al, 1985).
2) N-acetylcysteine given within 8 to 10 hours after exposure has been reported to prevent hepatic damage from acute poisoning by CCl4 in humans (Ghezzi Laurenzi et al, 1986).
3) N-Acetylcysteine (NAC) and pyridoxine, in animals, is reported to be effective in protecting (minimizing) the development of hepatic necrosis following carbon tetrachloride intoxication (De Ferreyra et al, 1974; (Anon, 1970).
4) NAC is probably most effective if given within 16 hours following ingestion of carbon tetrachloride. Further studies are needed before this therapy can be routinely recommended. Estimated dose of NAC: Loading dose of 140 milligrams/kilogram orally as a 5% solution in cola followed by a maintenance dose of 70 milligrams/kilogram orally every 4 hours for 17 doses.
5) Gastric lavage followed by intravenous infusion of N-acetylcysteine at 150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours (Prescott protocol) was reported to be beneficial in the case of a 61-year-old man who had ingested over 200 mL of CCl4. Whole-blood CCl4 concentration four hours after ingestion was 31.5 mg/L, the highest ever recorded at the reporting hospital (Mathieson et al, 1985).
6) NAC reduced the severity of carbon tetrachloride-induced hepatotoxicity in ethanol fed rats. NAC treated rats had higher body weights, less hepatocyte necrosis and higher levels of hepatic glutathione (Simko et al, 1992).
7) NAC and DEFEROXAMINE (DFO) increased survival in rats after intraperitoneal injection of carbon tetrachloride injection better than either alone. Survival was 5% in untreated rats rising to 25% in the NAC (20 mg/kg subcutaneously) only group, 35% in the DFO (20 mg/kg subcutaneously) group, and 80% in the group receiving both NAC and DFO. The authors theorized that hepatic necrosis is potentiated by release of free iron in addition to oxidative stress. The free iron is scavenged by the DFO(Ritter et al, 2004).

F) HYPERBARIC OXYGEN THERAPY

1) HYPERBARIC OXYGEN (HBO) along with vitamin C and E reportedly reduced the anticipated toxic effects (hepatic necrosis) following alleged ingestion of 250 mL of carbon tetrachloride in one patient (Truss & Killenberg, 1982).
2) Hyperbaric oxygen was also reported to be beneficial in a 39-year-old female patient who had ingested two glassfuls of carbon tetrachloride. Other therapy (only portions of which can be considered standard treatment) included gastric lavage, activated charcoal, forced diuresis, coenzyme A/thioctic acid/NAD/cocarboxylase, hydrocortisone hemisuccinate, and Citiolone, along with antibiotics, infusions of malic and glutamic acid, ornithine and arginine (Larcan et al, 1973)
3) A third patient who ingested "30 times the lethal dose" and was treated with hyperbaric oxygen had a favorable clinical outcome (Montani & Perret, 1967).
4) HBO significantly improved survival and decreased the degree of SGPT elevation in rats poisoned with carbon tetrachloride (Burk et al, 1986). Continued review of applicable literature suggests that hyperbaric oxygen treatment is appropriate treatment for CC14 intoxication (Burkhart et al, 1991).
5) Two other experiments with orally-poisoned rats also showed decreased mortality when hyperbaric oxygen was administered (Montani & Perret, 1967; Rapin et al, 1967). Hyperbaric oxygen therapy significantly decreased elevations of SGOT, SGPT, and total bilirubin following experimental carbon tetrachloride poisoning (Montani & Perret, 1967).

a) Hepatic histologic studies in rats have shown hyperbaric oxygen therapy to be associated with a certain amount of sparing of the liver parenchyma and an earlier onset of hepatic repair and regeneration (Rapin et al, 1967).

6) In one experiment with hyperbaric oxygen administration, no decreases in hepatic carbon tetrachloride occurred (Burk et al, 1986).
7) Oxygen enhanced haloalkane-mediated inhibition of the cytochrome P450 NADPH dependent enzyme system (de Groot & Noll, 1989).
8) Lipid peroxidation appears to be an important end result of the metabolism of toxic amounts of carbon tetrachloride. Theoretically, high oxygen concentrations may propagate lipid peroxidation once it has been initiated.
9) Sodium nitrite enhances hepatotoxicity possibly by producing hypoxia secondary to methemoglobin formation (Suarez & Bhonsle, 1978). Sodium nitrite, however, may interact at the cytochrome P450 site to alter carbon tetrachloride metabolism or toxicity.
10) CONCLUSION: Early treatment with hyperbaric oxygen should be considered in human poisonings.

G) VITAMIN E

1) Very high pretreatment doses of vitamin E, 400 international units per kilogram for 7 days, protected against membrane lipid disruption induced by carbon tetrachloride in rats. Lower doses, 200 international units per kilogram, were less effective (Martinez-Calva et al, 1984).

H) CONTRAINDICATED TREATMENT

1) Never administer oils, alcohols, or fats to a person who has ingested carbon tetrachloride.
2) Avoid known enzyme-inducing agents (eg phenobarbital) as these increase toxicity.

I) EXPERIMENTAL THERAPY

1) CALCIUM CHANNEL BLOCKERS: In rat experiments, nifedipine or chlorpromazine prevented centrilobular hepatic necrosis arising from CC14, acetaminophen, or thioacetamide. Verapamil afforded partial protection against CC14, chloroform, and dimethylnitrosamine. Reduced intracellular calcium concentrations were associated with the protective actions of calcium channel blockers (Landon et al, 1986).

a) Several later reports of animal experiments indicate that nifedipine and other calcium channel blockers may inhibit hepatic damage caused by CC14, ethanol, and other hepatotoxins (Cutrin et al, 1992; Cutrin et al, 1994; Romero et al, 1994).
b) If these preliminary findings are later confirmed in human clinical trials, potentially valuable tools may become available for treating hepatotoxin poisonings. At this time, no recommendation can be made for this use of calcium channel blockers in humans.

2) CHOLESTYRAMINE: An anion-exchange resin pretreatment prevented hepatic necrosis but not steatosis in rats injected intraperitoneally with carbon tetrachloride (Bioulac et al, 1981). The place of this agent in therapy of human poisonings is presently undefined.
3) TRIFLUOPERAZINE: An anticalmodulin drug, prevented hepatonecrosis by carbon tetrachloride in rats without altering CCl4 concentrations in the liver or cytochrome P-450 levels or loss of glucose-6-phosphatase. This drug lowered body temperatures between 1 to 3 degrees C and did not have a protective effect when treated animals were kept normothermic. Similar results were obtained by other workers with CHLORPROMAZINE (Villarruel et al, 1986). Neither of these agents can be presently recommended for use in human poisonings.
4) COLCHICINE: Pretreatment of rats with 10 micrograms/day of colchicine for one week reduced serum hepatic enzyme elevations, improved survival, and decreased lipid peroxidation induced by carbon tetrachloride (Mourelle et al, 1988).

a) Colchicine decreased the hepatic cytochrome P450 content in these rats. Colchicine has membrane stabilizing properties. It is uncertain which effect, cytochrome P450 or membrane stabilization, is responsible for this hepatoprotection.
b) Colchicine cannot currently be recommended for cases of human poisoning (Mourelle et al, 1988).

5) Soluble tumor necrosis factor alpha receptor pretreatment decreased hepatic injury (determined by peak enzyme levels and histology) and lethality in rats orally administered 0.5 cc/100grams of a solution of 1:1 CCL4 to mineral oil (Czaja et al, 1995).

a) HYALURONIC ACID and CHONDROITIN-4-SULPHATE: Male Sprague-Dawley rats were pretreated with the glycosaminoglycans, hyaluronic acid (HA) and chondroitin-4 sulphate (C4S) to determine the effect, if any, on carbon tetrachloride (CCL4)-induced liver damage. The animals received pre-treatment with HA 25 mg/kg, C4S 25 mg/kg, or HA 12.5 mg/kg and C4S 12.5 mg/kg. The animals then received intraperitoneal injection of 1.0 ml/kg of CCL4 in 50% vegetal oil. A control group received vegetal oil injection only and a fifth group received CCL4 only. The three glycosaminoglycan treated groups received three more injections at 6, 12 and 18 hours. Only the group treated with HA 12.5 mg/kg and C4S 12.5 mg/kg demonstrated statistically significant reductions in AST, ALT, malondialdehyde, myleoperoxidase activity, and TNF-alpha levels. Significant improvement in hepatic glutathione and catalase in this group was also observed. The authors suggest that this model of free radical reduction with the combination treatment requires further study (Campo et al, 2004).

6) FOOD RESTRICTION: Effects in female Wistar rats after subcutaneous injection of 3 mL/kg CCL4 was studied after 30 days of food restriction. Food restriction either 50% or 75% of baseline produced statistically significant changes in various hepatic and lipid peroxidation parameters. The activity of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase were higher in the food restricted animals than the control group. AST, ALT and alkaline phosphatase hepatic enzyme elevations were reduced in the food restricted animals versus controls. Erythrocytes from the food restricted groups were more resistant to hydrogen peroxide peroxidation than the control group (Ramkumar et al, 2003).

Inhalation Exposure

6.7.1)

A) Remove from exposure and give supplemental oxygen if needed.

6.7.2)

A) BRONCHOSPASM

1) Administer inhaled beta adrenergic agonists if bronchospasm develops. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) Irrigate eyes with copious 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.

Dermal Exposure

6.9.1)

A) Remove contaminated clothing, including leather belts, shoes, hats, and gloves. Place all items in sealed plastic bag(s) and discard appropriately in toxic waste facility. Wash skin thoroughly with soap and water, including hair and nails. Repeat washings at least once. N.B.- Leather is a reservoir for organic solvents and lipophilic substances such as pesticides. Be certain that all skin areas in contact with contaminated leather are cleaned carefully.

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

B) SKIN ABSORPTION

1) Patients with significant exposure can develop systemic toxicity.

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) HEMODIALYSIS is probably not of any value unless instituted very early in the course of intoxication to remove unmetabolized carbon tetrachloride.
2) Hemodialysis or hemoperfusion may be necessary to support patients in renal or hepatic failure, respectively (Fogel et al, 1983).
3) Hemodialysis and total parental nutrition were used to treat one patient who made an uncomplicated recovery following ingestion of 100 ml of CCl4 and an unknown quantity of rum (Fogel et al, 1983).

B)

1) Forced diuresis is of no value.

Abstracts

Case Reports

A)

1) INHALATION: A 47-year-old epileptic man experienced unusually severe effects from working with carbon tetrachloride in a confined atmosphere for three days. The severity of toxicity in this case was attributed to ongoing treatment with phenobarbital, which could have induced high levels of microsomal activating enzymes (Mahieu et al, 1983).
2) INHALATION: Inhalation of CCl4 fumes from cleaning machinery caused headache, giddiness, nausea, vomiting, dyspnea, myocarditis, pulmonary edema with effusion, metabolic acidosis, and increased blood urea in one case. Treatment included artificial ventilation and peritoneal dialysis (Hadi & El Mikatti, 1981).
3) INHALATION: A 56-year-old man inhaled enough CCl4 from a ruptured fire extinguisher to render him unconscious and subsequently developed amnesia, incoherent speech and ataxia, intention tremor and positive Rhomberg sign (signs of cerebellar dysfunction) (Johnson et al, 1983).
4) INHALATION: Seventeen out of 25 workers had abnormal liver function tests 10 days after an outbreak of acute hepatitis. Carbon tetrachloride had been used to clean a pump in the air conditioning system and airborne levels were estimated in the range of 300 to 500 ppm (Deng et al, 1987).
5) INHALATION: Grain inspection workers were exposed to CCl4 fumigant when conducting the off odor test, which involves sniffing the fumigated grain. All CCl4 exposures measured by passive dosimeters were less than 2 ppm. Carbon disulfide, ethylene dichloride, ethylene dibromide, sulfur dioxide, and/or petroleum distillates may be mixed with the CCl4 for fumigation purposes (Deer et al, 1987).

a) Carbon disulfide and CCl4 may have been synergistic in producing neuropsychiatric symptoms in the grain workers in the absence of liver disease. However, complexities of the exposures made it impossible to prove this relationship (Peters et al, 1986).

6) DERMAL: Toxicity resulted after 3 persons applied a topical lotion for scabies that contained 67 grams carbon tetrachloride per 100 grams as an excipient. All had GI symptoms of nausea, vomiting, and colic within 2 to 48 hours. Between 24 and 48 hours 2 patients had conjunctival hemorrhage and anicteric hepatic damage. Between the third and seventh day all 3 had oligoanuric acute renal failure and 2 required peritoneal dialysis. Liver function reversed to normal after 7 days and renal function was normal after 2 to 4 weeks. The dermal as well as inhalation route of toxicity affects renal function more severely than hepatic function (Perez et al, 1987).

Range Of Toxicity

Summary

A)

Therapeutic Dose

7.2.1)

A) GENERAL

1) When formerly used as an anthelmintic, the recommended adult dose of carbon tetrachloride was 2 to 3 milliliters in capsules (von Oettingen, 1964).

7.2.2)

A) GENERAL

1) The formerly recommended pediatric anthelmintic dose of carbon tetrachloride was 0.13 milliliter/year of age up to 15 years to be followed with Epsom salts (von Oettingen, 1964).

Minimum Lethal Exposure

A)

B)

C)

D)

E)

F)

G)

Maximum Tolerated Exposure

A)

B)

C)

D)

E)

F)

1) (Bingham et al, 2001b; Hathaway et al, 1996).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) Carbon tetrachloride blood levels in acutely poisoned patients ranged from 0.1 to 31.5 milligrams/liter (Ruprah et al, 1985).
b) 2 to 5 milligrams/deciliter have been considered toxic blood CCl4 levels (Winek, 1976).
c) Whole-blood concentration of CCl4 four hours after acute ingestion of over 200 milliliters was 31.5 milligrams/liter, the highest ever recorded at the reporting hospital (Mathieson et al, 1985).
d) A 75-year-old man died after ingesting an unknown quantity of CC14. Postmortem GC-FID head space assays of CC14 in urine (328.5 mg/L) and bile (169.8 mg/L) revealed extensive excretion of CC14. CC14 concentration in systemic venous blood was 143.4 mg/L, and in arterial blood, 57.5 mg/L, suggesting significant pulmonary clearance of CC14. Brain levels of CC14 ranged from 175.3 mg/kg to 243 mg/kg, depending upon sample site. Lowest CC14 level was 58.6 mg/kg in liver (Tombolini & Cingolani, 1996).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Carbon tetrachloride

a) TLV:

1) TLV-TWA: 5 ppm
2) TLV-STEL: 10 ppm
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A2
2) Codes: Skin
3) Definitions:

a) A2: Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.
b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): Liver dam
d) Molecular Weight: 153.84

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS56-23-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Carbon tetrachloride
2) REL:

a) TWA:
b) STEL: 2 ppm (12.6 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

3) IDLH:

a) IDLH: 200 ppm
b) Note(s): Ca

1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

C) Carcinogenicity Ratings for CAS56-23-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A2 ; Listed as: Carbon tetrachloride

a) A2 :Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.

2) EPA (U.S. Environmental Protection Agency, 2011): Likely to be carcinogenic to humans ; Listed as: Carbon tetrachloride
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): 2B ; Listed as: Carbon tetrachloride

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.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Carbon tetrachloride

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

5) MAK (DFG, 2002): Category 4 ; Listed as: Carbon tetrachloride

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.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS56-23-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Carbon tetrachloride
2) Table Z-1 for Carbon tetrachloride:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3:

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

3) Table Z-2 for Carbon tetrachloride (Z37.17-1967):

a) 8-hour TWA:10 ppm
b) Acceptable Ceiling Concentration: 25 ppm
c) Acceptable Maximum Peak above the Ceiling Concentration for an 8-hour Shift:

1) Concentration: 200 ppm
2) Maximum Duration: 5 min. in any 4 hrs

d) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) ACGIH, 1996 Budavari, 2000 Lewis, 2000 ITI, 1995 OHM/TADS, 2002 RTECS, 2002

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 572 mg/kg
b) 4620 mg/kg (OHM/TADS, 2002)
c) 4675 mg/kg
d) 4.1 g/kg (Budavari, 2000)

2) LD50- (ORAL)MOUSE:

a) 8263 mg/kg
b) 9123 mg/kg (OHM/TADS, 2002)
c) 12.1-14.4 g/kg (ACGIH, 1996; Budavari, 2000)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 31 g/kg -- behavioral changes
b) 30.4 g/kg (ACGIH, 1996; Budavari, 2000)

4) LD50- (INTRAPERITONEAL)RAT:

a) 1500 mcL/kg

5) LD50- (ORAL)RAT:

a) 2350 mg/kg
b) 2920 mg/kg (OHM/TADS, 2002)
c) 2.92 g/kg (Budavari, 2000)
d) 2.8 g/kg (ACGIH, 1996)

6) LD50- (SKIN)RAT:

a) 5070 mg/kg

7) TCLo- (INHALATION)HUMAN:

a) 20 ppm -- nausea or vomiting
b) 45 ppm for 3D -- gastrointestinal and behavioral changes
c) 317 ppm for 30M -- nausea or vomiting

8) TCLo- (INHALATION)MOUSE:

a) 20 ppm for 12W-Intermittent -- hepatitis; changes in serum composition; changes to biochemistry

9) TCLo- (INHALATION)RAT:

a) Female, 250 ppm for 8H at 10-15D of pregnancy -- affected viability and lactation index of newborn
b) Female, 300 ppm for 7H at 6-15D of pregnancy -- fetotoxicity (except death); developmental abnormalities
c) 400 ppm for 1H/46D-Intermittent -- changes in liver weight
d) 200 ppm for 7H/27W-Intermittent -- hepatitis; fatty liver degeneration; death
e) 50 ppm for 3H/8W-Intermittent -- fatty liver degeneration
f) 400 ppm for 8H/46W-Intermittent -- stuctural changes in nerve or sheath; death
g) 41 mg/m(3) for 4H/8D-Intermittent -- thyroid hypofunction
h) 61 mg/m(3) for 90D-Continuous -- fatty liver degeneration; other changes to the liver

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

1) The hepatic mixed-function oxidase system metabolizes carbon tetrachloride to the trichloromethyl radical. This initiates lipid peroxidation, protein-lipid cross links and trichloromethyl adducts with DNA, protein and lipid (Thomas & Aust, 1986).
2) The trichloromethyl radical may poison the cytochrome P-450. It may be released from the cytochrome P-450 or may be converted to chloroform via a one-electron reduction and abstraction of a proton. Further reduction may release hydrochloric acid and carbon monoxide (Kalf et al, 1987).
3) The trichloromethyl radical may alternatively react with oxygen to form a trichloromethyl peroxy free radical, which may react to form PHOSGENE. This may play a significant role in mediation of CCl4 hepatotoxicity (Kalf et al, 1987).
4) Thus the proportionation between these two pathways of CCl4 toxicity -- trichloromethyl radical versus trichloromethyl peroxy radical -- may depend on the availability of oxygen. More oxygen would result in formation of relatively more of the peroxy radical, which is much more potent than the CCl3. radical in initiating lipid peroxidation but would suppress the formation of chloroform (Burk et al, 1984).
5) Hepatic injury may be secondary to dissociation of CCl4 to a free radical CCl3, leading to lipid peroxidation and subsequent hepatocellular injury.

a) Ulicna et al (1995) have shown in rat studies that liver regeneration ability is good and hepatotoxicity is reversible.

6) Phenobarbital and other enzyme-inducing agents can dramatically increase the toxicity of carbon tetrachloride. Ingestion of ethanol, either simultaneously with carbon tetrachloride or while chronically exposed, will increase the hepatotoxicity.
7) You et al (1984) demonstrated a protective effect of pre-treatment with cinchona alkaloids in rats against carbon tetrachloride hepatotoxicity. The authors postulate that microsomal enzymes are inhibited, thus inhibiting the bioactivation of CCl4 and reducing hepatotoxicity.
8) Carbon tetrachloride caused direct inhibition of glutamate- dehydrogenase and succinate cytochrome c-reductase in vitro, resulting in decreased respiration in rat liver mitochondria (Francavilla et al, 1970).
9) Carbon tetrachloride poisoning in rats produced hyperammonemia and hepatic encephalopathy. ATP levels were decreased in livers of rats with hepatic encephalopathy and Mg2+-ATPase activity was increased. The hyperammonemia may play a role in hepatic encephalopathy (Yamamoto & Sugihara, 1987).
10) Seifert et al (1994) demonstrated in rat studies that myofibroblasts and fat-storing cells appear to be the main cell types interacting in the initial phase of liver fibrogenesis induced by carbon tetrachloride.

C)

1) Recent studies have focused on intracellular calcium homeostasis. The metabolism of carbon tetrachloride disrupts the hepatocyte ATP dependent Ca++ pump. Intracellular cytoplasmic Ca++ rises. The calcium may be a toxic second messenger that activates mechanisms which destroy cellular membranes, resulting in cell death (Recknagel et al, 1989).

D)

1) It was not effective in preventing liver injury from carbon tetrachloride by intraperitoneal injection (in corn oil) in mice (Merola et al, 1967). It was effective in preventing liver damage in rats and hamsters if given before or immediately after CCl4 treatment but not at 6 hours post-treatment (Marzella et al, 1986).
2) Lipid peroxidation was greatly increased by CCl4 under conditions of hypoxia in rat liver microsomes in vitro; CCl4 stimulated oxygen uptake (Noll & De Groot, 1984; Burk et al, 1984). Liver injury was more severe in rats treated with CCl4 under hypoxic conditions (Shen et al, 1982).
3) CCl4-treated rats produced much less CHCl3, ethane and CO2 in hyperbaric oxygen than under ambient conditions and survival was increased. This suggests that hyperbaric oxygen suppressed the formation of the CCl3. radical and/or promoted the formation of the peroxy radical instead (Burk et al, 1984) 1986).
4) High oxygen concentrations (hyperoxia) suppressed lipid peroxidation measured as the formation of ethane and thiobarbituric acid reactants in isolated rat hepatocytes (Stacey et al, 1982). The metabolism of carbon tetrachloride may be altered by hyperoxia (Burkhart et al, 1991).
5) HYPERVENTILATION induced by inhalation of 2 to 3 L/minute of carbon dioxide reduced liver and kidney damage by CCl4 in rats and increased the rate of elimination via the lung (Koppel, 1985).
6) CHOLESTYRAMINE (an anion-exchange resin) pre-treatment prevented hepatic necrosis but not steatosis in rats injected intraperitoneally with carbon tetrachloride (Bioulac et al, 1981).
7) TRIFLUOPERAZINE, an anticalmodulin drug, prevented hepatonecrosis by carbon tetrachloride in rats without altering CCl4 concentrations in the liver or cytochrome P-450 levels or loss of glucose-6-phosphatase. This drug lowered body temperatures between 1 to 3 degrees C and did not have a protective effect when treated animals were kept normothermic. Similar results were obtained by other workers with CHLORPROMAZINE (Villarruel et al, 1986).
8) N-ACETYLCYSTEINE shows promise in preventing hepatic damage in clinical poisonings. It appears to work by repleting the supply of reduced glutathione in the hepatocytes (Ghezzi Laurenzi et al, 1986).

a) Thirteen patients with acute carbon tetrachloride poisoning who were treated with acetylcysteine had milder hepatic damage than six who did not receive this treatment (Ruprah et al, 1985).
b) N-acetylcysteine given within 8 to 10 hours after exposure has been reported to prevent hepatic damage from acute poisoning by CCl4 in humans (Ghezzi Laurenzi et al, 1986).
c) N-Acetylcysteine (NAC) and pyridoxine, in animals, is reported to be effective in protecting (minimizing) the development of hepatic necrosis following carbon tetrachloride intoxication (De Ferreyra et al, 1974; (Anon, 1970).
d) NAC is probably most effective if given within 16 hours following ingestion of carbon tetrachloride. Further studies are needed before this therapy can be routinely recommended. Estimated dose of NAC: Loading dose of 140 milligrams/kilogram orally as a 5% solution in cola followed by a maintenance dose of 70 milligrams/kilogram orally every 4 hours for 17 doses.

9) VITAMIN E can protect against CCl4-mediated hepatotoxicity in animals. The effect is even greater with vitamin E plus selenium. These compounds act as antioxidants (Yurdakok et al, 1985).

a) Vitamin E prevented alterations in liver membrane phospholipid structure by CCl4 in rats when given for 7 days prior to CCl4 treatment (Martinez-Calva et al, 1984).

10) DANTROLENE SODIUM, a muscle relaxant used to treat spasticity, inhibited hepatotoxicity induced by CCl4 in rats but had no effect on lipid peroxidation. This drug inhibits release of calcium from the sarcoplasmic reticulum (Steinhauer et al, 1986).
11) MALOTILATE (diisopropyl 1,3-dithiol-2-ylidene-malonate), a drug showing promise in treatment of cirrhosis and chronic hepatitis, also prevents fibrotic changes induced by carbon tetrachloride.

a) When given to rats starting in the 5th week of an 11-week regimen of subcutaneous carbon tetrachloride treatment, malotilate prevented fibrotic changes in the liver, although hypertrophy and fatty changes still occurred (Igarishi et al, 1986).
b) Malotilate prevented fibrotic and biochemical changes in rat livers induced by intraperitoneal injection of CCl4 for 10 weeks when given in the diet at 0.2 percent starting in the last 2 or 5 weeks of CCl4 treatment (Katoh & Sugimoto, 1982).
c) Malotilate normalized cholesterol levels in hypocholesterolemic fatty livers induced by carbon tetrachloride in rats (Wakasugi et al, 1985).
d) Malotilate may exert its effects by stimulating RNA and protein synthesis (Imaizumi et al, 1982).

12) Colchicine pretreatment in rats reduced hepatotoxicity, improved survival, and decreased lipid peroxidation. Colchicine decreased the cytochrome P450 content of hepatocytes. Colchicine also has membrane stabilizing properties that may contribute to this hepatoprotection.
13) CARBON TETRACHLORIDE ITSELF, when given to experimental animals in small doses, protects against a subsequent large dose for 3-5 days. This protective effect may be due to destruction of cytochrome P-450 (Mehendale, 1984).

E)

1) CHLORDECONE, a chlorinated hydrocarbon pesticide with a ketone group, is a strong synergist for hepatotoxicity of CCl4 in animals while its close structural analogs lacking the ketone function, mirex and photomirex, are inactive. Chlordecone appears to act by enhancing bioactivation of CCl4 while at the same time preventing repair in the liver (Mehendale, 1984).
2) ETHANOL can exacerbate the effects of CCl4 in rats. It appears to exert its effects by induction of microsomal enzymes and increasing the metabolic activation of CCl4 (Teschke et al, 1984).
3) Polybrominated biphenyls and benzo(a)pyrene have synergistically enhanced carbon tetrachloride toxicity (Proctor & Hughes, 1978).
4) PHENYLPROPANOLAMINE potentiated carbon tetrachloride-induced hepatic necrosis in mice. This reaction was probably mediated through alpha-2-adrenoreceptor stimulation (Roberts et al, 1991).
5) EPINEPHRINE and norepinephrine have potentiated carbon tetrachloride-induced liver damage in mice as evidenced by histopathologic examination and measurement of serum aminotransferase activities (Roberts et al, 1991).

Physicochemical

Physical Characteristics

A)

Ph

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

Molecular Weight

A)

Other

A)

1) >10 ppm in air (ACGIH, 1996)
2) 10 ppm in air; 0.52 mg/L in water (Sittig, 1991)
3) Recognition in air: 2.14x10 ppm (chemically pure) (HSDB , 2002)
4) Recognition in water: 50 mg/L (HSDB , 2002)
5) Approximately 79 ppm; odor strong at 176 ppm (Bingham et al, 2001)

Animal Toxicology

Clinical Effects

11.1.5)

A) SUMMARY - Poisoning is usually acute, with signs evident within the first 24 to 36 hours. Signs consist of CNS, GI, liver, and kidney effects.
B) INHALATION - Can cause CNS depression and narcosis (Oehme, 1987).
C) ORAL - Can cause CNS depression, narcosis, muscle weakness, ataxia, fatty degeneration of the liver, and centrilobular liver necrosis if larger quantities are absorbed. Hepatic effects are usually accompanied by severe renal failure. Gastroenteritis of the upper gastrointestinal tract occurs, and constipation is followed by diarrhea with blood-stained feces (Oehme, 1987).
D) PARENTERAL INJECTION - May cause localized tissue necrosis and may lead to lameness (Oehme, 1987).

Treatment

11.2.1)

A) HORSE

1) There is no specific antidote. General supportive and symptomatic treatment is recommended after decontamination.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) HORSE

a) Reduce additional absorption with use of activated charcoal, laxatives, and saline purges to rapidly empty the GI tract (Oehme, 1987).

11.2.5)

A) HORSE

1) General supportive and symptomatic treatment is recommended following decontamination (Oehme, 1987).

Range Of Toxicity

11.3.2)

A) HORSE

1) As little as 0.25 mL/kg may produce serious liver damage in some individuals, while 3 mL/kg may produce no signs in other individuals. Concentrations of less than 1 ppm are detectable by the healthy horse's nose and may be responsible for most horses rejecting feed containing this (Oehme, 1987).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) HORSE

1) There is no specific antidote. General supportive and symptomatic treatment is recommended after decontamination.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) HORSE

a) Reduce additional absorption with use of activated charcoal, laxatives, and saline purges to rapidly empty the GI tract (Oehme, 1987).

References

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FeedBack

CARBON TETRACHLORIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Other

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

General Bibliography