ACRYLONITRILE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2-Propenenitrile
2) Acritet
3) Acrylon
4) Carbacryl
5) Cyanoethylene
6) Fumigrain
7) VCN
8) Ventox
9) Vinyl Cyanide
10) Vinyl kyanid (Czech)
11) CAS 107-13-1
12) METHACRYLONITRILE, INHIBITED
13) VCN (ACRYLONITRILE)
14) VINYL KYANID

1.2.1) MOLECULAR FORMULA
1) C3-H3-N

Available Forms Sources

1) Acrylonitrile is available as a technical grade which is greater than 99% pure; the major impurities include water (0.5% maximum), acetone, acetonitrile, acetaldehyde, iron, peroxides, and hydrogen cyanide (Snyder et al, 1990).
2) Acetonitrile in a polymerization grade may include dimethylformamide, hydrogen peroxide, hydroxyanisole, methyl acrylate, phenyl ether-bi-phenyl mixture, sodium metasulfite, sulfuric acid, and titanium dioxide (Snyder et al, 1990).

1) Acrylonitrile is produced by ammoxidation (propylene + ammonia and oxygen in the presence of a catalyst such as bismuth phosphomolybdate or a uranium-based compound); by the addition of hydrogen cyanide to acetylene using cuprous chloride as a catalyst; and by the dehydration of ethylene cyanohydrin (Ashford, 1994; Baselt, 1997; Baselt & Cravey, 1995; Clayton & Clayton, 1994; Howard, 1989; Lewis, 1997).
2) Acrylonitrile does not occur naturally, but may be introduced to the environment through wastewater or fugitive emissions in manufacturing. The compound is a known component of cigarette smoke and is also released in the burning of polyacrylonitrile plastic. (Ashford, 1994; Baselt, 2000; Baselt & Cravey, 1995; Clayton & Clayton, 1994; Howard, 1989; Lewis, 1997).

1) Acrylonitrile is widely utilized in synthetics, surface coatings, plastics, and adhesives manufacturing, especially in the form of acrylic and modacrylic fibers (ACGIH, 1991; Baselt, 2000; Budavari, 2001; Clayton & Clayton, 1994).
2) This compound also functions as a pesticide fumigant (Budavari, 2001; Hayes & Laws, 1991).
3) Acrylonitrile is a major chemical intermediate, employed in creating such products as pharmaceuticals, antioxidants, and dyes, as well as in organic synthesis (Budavari, 2001; Clayton & Clayton, 1994).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Acrylonitrile is a heavily produced unsaturated nitrile. It is widely utilized in synthetics, surface coatings, plastics, and adhesives manufacturing, especially in the form of acrylic and modacrylic fibers. It also functions as a pesticide fumigant. This compound is a major chemical intermediate, employed in creating such products as pharmaceuticals, antioxidants, and dyes, as well as in organic synthesis.
B) TOXICOLOGY: Acrylonitrile can be toxic by the inhalation, ingestion, and dermal exposure routes. Much of the toxicity of acrylonitrile is thought to be due to metabolic generation of cyanide; symptoms are similar to those induced by cyanide, but with slower onset. However, acrylonitrile is metabolized to a lesser extent in humans than in rodents; therefore cyanide toxicity may play a lesser role in humans than toxicity of the parent compound or its more proximate metabolites.
C) EPIDEMIOLOGY: Exposures are uncommon, but deaths have been reported.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, sneezing, eye irritation, headache, weakness, and irritability may occur with mild to moderate exposures.
2) SEVERE TOXICITY: Lactic acidosis, tachycardia, gastrointestinal hemorrhage, anemia, leukocytosis, renal dysfunction, hepatitis, rhabdomyolysis, seizures, coma, respiratory failure, and death have been reported with more severe exposures. Dermal contact may result in erythema, dermatitis, a burning sensation, and blister formation.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Tachycardia has been reported following acute exposures.

0.2.20)

A) Acrylonitrile is embryotoxic and teratogenic in animals; however, there is no evidence of teratogenic effects at doses below maternal toxic levels.

0.2.21)

A) Acrylonitrile is carcinogenic in laboratory animals. Evidence of carcinogenicity in humans is limited.
B) Acrylonitrile is a SUSPECTED HUMAN CARCINOGEN. A number of epidemiological studies of persons occupationally exposed to acrylonitrile have found excess cancers of the colon, prostate, and respiratory system, and excess deaths from lymphatic, stomach, and lung cancer. Acrylonitrile forms adducts with biological macromolecules. Adducts with human globin have been detected in the blood of exposed workers and of cigarette smokers.
C) The US Environmental Protection Agency classified it in Group B1 (probable human carcinogen), based on increased lung cancer in exposed workers and tumors in two strains of rats exposed by more than one route (IRIS , 1996).

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Administer intravenous fluids and monitor carefully for evidence of more severe toxicity. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment should include ventilatory support and hydroxocobalamin or the cyanide antidote kit. Seizures should be considered an indication of severe toxicity and should be treated with benzodiazepines and hydroxocobalamin. Consider neurologic consult and continuous EEG monitoring for the sedated, chemically paralyzed, and intubated patient.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended due to the potential for seizures and profound depression and subsequent aspiration risk.
2) HOSPITAL: Activated charcoal may be beneficial if administered shortly after oral exposure. However, these patients are at risk for aspiration due to the potential for seizures and profound CNS depression. Activated charcoal should be reserved for the awake, alert, non-seizing patient, or the intubated patient. Consider orogastric lavage for patients with very recent ingestions who are alert and can protect their airway or are intubated.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe CNS depression.

E) CYANIDE ANTIDOTE

1) A cyanide antidote, either hydroxocobalamin or the sodium nitrite/sodium thiosulfate kit, should be administered to symptomatic patients.

F) HYDROXOCOBALAMIN

1) Hydroxocobalamin should be given if any laboratory or clinical signs or symptoms of cyanide toxicity develop. ADULT: Administer 5 g (two 2.5 g vials, each reconstituted with 100 mL sterile 0.9% saline) as an IV infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition. PEDIATRIC: Limited experience; a dose of 70 mg/kg has been used in pediatric patients.

G) ANTIDOTE

1) An alternative, a sodium nitrite/sodium thiosulfate kit, is administered as follows: SODIUM NITRITE: ADULT: 300 mg (10 mL of 3% solution) IV at a rate of 2.5 to 5 mL/min; PEDIATRIC: (with normal hemoglobin concentration) 0.2 mL/kg of a 3% solution (6 mg/kg) IV at a rate of 2.5 to 5 mL/min, not to exceed 10 mL (300 mg). A second dose, one-half of the first dose, may be administered 30 minutes later if there is inadequate clinical response. Use with caution if carbon monoxide poisoning is also suspected. SODIUM THIOSULFATE: Follow sodium nitrite with IV sodium thiosulfate. ADULT: 50 mL (12.5 g) of a 25% solution; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose. A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear. ALTERNATE ANTIDOTES: Kelocyanor(R) (dicobalt-EDTA) and 4-DMAP (4-dimethylaminophenol) are among the cyanide antidotes in clinical use outside the US.

H) ENHANCED ELIMINATION PROCEDURE

1) Antidotes increase elimination, however, the role of hemodialysis is uncertain.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Home observation should not be considered, as even a small volume exposure in an initially asymptomatic patient may result in severe toxicity. A patient with an inhalational exposure in an industrial setting should seek medical care as the amount and duration of exposure can be difficult to quantify.
2) OBSERVATION CRITERIA: All patients with a potential acrylonitrile exposure should be referred to a healthcare facility.
3) ADMISSION CRITERIA: Patients should be admitted to an ICU setting and monitored for at least 24 hours as toxicity is expected to be delayed while cyanide is being produced via hepatic metabolism.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with significant toxicity or in whom the diagnosis is unclear.

J) TOXICOKINETICS

1) Acrylonitrile is readily absorbed by the inhalation, ingestion, and dermal route. Absorption was shown to be 90% to 98% following oral or inhalational exposure and was reported to be rapid. In human volunteers exposed to airborne concentrations of 5 or 10 mg/m(3) of acrylonitrile, 52% of the inhaled dose was retained. Acrylonitrile was absorbed through the skin of the forearm of workers at a rate of 0.6 mg/cm(2)/hr . Metabolism of acrylonitrile follows 2 pathways: conjugation with glutathione and oxidation by cytochrome P450, resulting in formation of the epoxide 2-cyanoethylene oxide. In humans, detoxification of 2-cyanoethylene oxide occurs via the epoxidehydrolase pathway. Acrylonitrile is metabolized to a lesser extent in humans than in rodents; therefore, cyanide toxicity may play a lesser role in humans than toxicity of the parent compound or its more proximate metabolites.

K) DIFFERENTIAL DIAGNOSIS

1) Acetone exposure, methemoglobinemia, carbon monoxide exposure, cyanide from another source.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) OXYGEN: Administer 100% oxygen and establish vascular accesses.

0.4.4)

A) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature normal saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, an ophthalmologic examination should be performed.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. If pain and irritation persist, evaluation at a healthcare facility may be needed.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia has been reported following acute exposures.

3.3.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia has been reported and wide pulse pressure may be evident (Buchter & Peter, 1984; Vogel & Kirkendall, 1984).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) IRRITATION: The vapors are eye irritants (Baselt, 2000; Vogel & Kirkendall, 1984). Lacrimation may occur (Woutersen, 1998; ITI, 1995). Splash contact usually causes only transient signs and symptoms including lacrimation and conjunctivitis.

a) Acrylonitrile was found to cause severe eye irritation in the rabbit using the Standard Draize Test (RTECS , 2002; Woutersen, 1998).
b) When the liquid was applied as a single drop to a rabbit cornea, it caused only a transient disturbance without corneal opacification (Grant & Schuman, 1993).

2) VISION: Diminished vision has been reported following long term exposures in humans (Buchter & Peter, 1984).

3.4.4)

A) WITH POISONING/EXPOSURE

1) HEARING: Diminished hearing has been reported following long term exposures in humans (Buchter & Peter, 1984).

3.4.5)

A) WITH POISONING/EXPOSURE

1) SNEEZING is a common early symptom (Hathaway et al, 1996).

3.4.6)

A) WITH POISONING/EXPOSURE

1) Flushing, irritation and inflammation of the mucous membranes, salivation, and cyanosis of the lips have been reported (Buchter & Peter, 1984; Vogel & Kirkendall, 1984).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia and wide pulse pressure may be evident and have been reported (Buchter & Peter, 1984; Vogel & Kirkendall, 1984).

B) VASODILATATION

1) WITH POISONING/EXPOSURE

a) Vasodilatation has been reported following exposures (Vogel & Kirkendall, 1984).
b) Increased cardiac output may occur (Vogel & Kirkendall, 1984).

C) CHRONIC POISONING

1) Signs/symptoms that have been reported after long term exposure include low blood pressure (Buchter & Peter, 1984).

Respiratory

3.6.2)

A) INJURY DUE TO ASPHYXIATION

1) WITH POISONING/EXPOSURE

a) Dyspnea and asphyxia may occur in serious poisonings (Baselt, 2000; Plunkett, 1976). At least two fatalities due to industrial exposure, one from inhalation of an unknown concentration of vapor and the other a mixed dermal-inhalation exposure, have been reported (Baselt, 2000; Hathaway et al, 1996).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Serious exposures may result in respiratory tract inflammation, dyspnea, and pulmonary edema (Woutersen, 1998).

3.6.3)

A) ANIMAL STUDIES

1) RESPIRATORY ARREST

a) Lethal doses administered to animals resulted in death from respiratory arrest (Woutersen, 1998).

Neurologic

3.7.2)

A) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache is usually rapid in onset following a mild exposure, and often accompanied by nausea and lightheadedness (Baselt, 2000; Hathaway et al, 1996; ITI, 1995).

B) FATIGUE

1) WITH POISONING/EXPOSURE

a) Weakness is a common early sign reported in poisonings (ITI, 1995).

C) FEELING NERVOUS

1) WITH POISONING/EXPOSURE

a) Irritability as well as apprehension has developed in workers exposed to acrylonitrile for 20 to 45 minutes (Harbison, 1998).

D) SEIZURE

1) WITH POISONING/EXPOSURE

a) A severe, acute exposure may result in loss of consciousness, seizures and death due to respiratory failure (Woutersen, 1998).

E) CHRONIC POISONING

1) Signs/symptoms reported following chronic exposures include headache, fatigue, disturbance of memory, weakness, decreased work capacity, poor sleep, drowsiness, irritability, and dizziness (Buchter & Peter, 1984) Wilson et al, 1949).

3.7.3)

A) ANIMAL STUDIES

1) NEUROPATHY PERIPHERAL

a) RATS exposed to acrylonitrile by the oral or inhalation routes developed peripheral neuropathies (Gagnaire et al, 1998). This effect has not been reported in exposed humans.

2) SEIZURES

a) In animal studies, administration of a lethal dose resulted in excitability, seizures, paralysis, and respiratory arrest. These effects occurred independent of the route of exposure (Woutersen, 1998).

3) CEREBRAL EDEMA

a) In animal studies, a target organ following serious exposures was the brain, with cerebral edema noted (Woutersen, 1998).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting are often seen in mild intoxications (Baselt, 2000; Hathaway et al, 1996; ITI, 1995; Buchter & Peter, 1984; Vogel & Kirkendall, 1984).

B) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea may occur in mild to moderate poisoning (ITI, 1995; Buchter & Peter, 1984).

C) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Following a severe exposure, one of the target organs for toxicity is the gastrointestinal tract, with bleeding often occurring (Woutersen, 1998).
b) Three fatal cases of toxic epidermal necrosis occurred in persons who were exposed to a fumigant containing acrylonitrile and carbon tetrachloride (1:2). The immediate cause of death was septic shock and gastrointestinal hemorrhage. A 10-year-old boy who was exposed at the same time survived after topical and parenteral corticosteroid treatment (HSDB , 1990).

D) CHRONIC POISONING

1) Signs and symptoms reported following long term exposure include nausea, vomiting, and diarrhea (Buchter & Peter, 1984) Wilson et al, 1949).

Hepatic

3.9.2)

A) TOXIC HEPATITIS

1) WITH POISONING/EXPOSURE

a) Jaundice, abnormal bilirubin levels, abnormal urine specific gravity, proteinuria, and increased urobilinogen levels were seen in a group of Japanese workers exposed to airborne concentrations of 5 to 20 ppm of acrylonitrile over a 10-year period (HSDB , 2002). Other liver damage was also reported in humans (Buchter & Peter, 1984; Vogel & Kirkendall, 1984) and animal studies (Plunkett, 1976).
b) Increased liver function tests were found in a group of 26 workers with acrylonitrile and dimethylformamide exposure (Major et al, 1998).

B) ABNORMAL LIVER FUNCTION

1) CHRONIC TOXICITY

a) Signs and symptoms reported after long term exposures have included liver irritation, abnormal liver function tests and jaundice (Buchter & Peter, 1984) Wilson et al, 1949).

Genitourinary

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) Acute exposures have resulted in abnormal renal function tests in humans (Buchter & Peter, 1984).

B) KIDNEY FINDING

1) CHRONIC TOXICITY

a) Signs and symptoms after long term exposures have included kidney irritation (Wilson et al, 1949).

Acid-Base

3.11.2)

A) LACTIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Lactic acidosis may develop due to an increased rate of glycolysis (Hathaway et al, 1996).

Hematologic

3.13.2)

A) ANEMIA

1) WITH POISONING/EXPOSURE

a) Mild anemia and leukocytosis have been reported (Buchter & Peter, 1984; Vogel & Kirkendall, 1984; HSDB , 2002; Major et al, 1998).
b) Lowered RBC have been reported following chronic exposures to acrylonitrile (Buchter & Peter, 1984).

Dermatologic

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Dermal contact may result in a burning sensation, reddening of the skin, blister formation, swelling, itching, and dry, scaly, cracking and peeling of the skin (Woutersen, 1998; Vogel & Kirkendall, 1984); Antonev et al, 1970; Zeller et al, 1974; Dudley et al, 1942).
b) Repeated skin contact may cause dermatitis due to the solvent effect (Hathaway et al, 1996).
c) Development of allergic dermatitis may occur several days after initial contact (Buchter & Peter, 1984).
d) Selectivity in the persistence of acrylonitrile, particularly leather, may result in blister formation similar to a partial thickness burn when the leather material comes into extended contact with the skin (MSDS, 1964).

B) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) Prolonged skin contact with the liquid may cause the formation of large vesicles after a latent period of several hours. These resemble a second degree thermal burn, but there is usually little pain or inflammation (Hathaway et al, 1996). Spills on clothing usually evaporate rapidly causing either mild erythema or no irritation.

C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH POISONING/EXPOSURE

a) Three fatal cases of toxic epidermal necrosis occurred in persons who were exposed to a fumigant containing acrylonitrile and carbon tetrachloride (1:2). The immediate cause of death was septic shock and gastrointestinal hemorrhage. A 10-year-old boy who was exposed at the same time survived after topical and parenteral corticosteroid treatment (HSDB , 1990).

3.14.3)

A) ANIMAL STUDIES

1) IRRITATION

a) Acrylonitrile was found to be a mild skin irritant in the rabbit using the Standard Open Draize Test. Using non-standard exposures, acrylonitrile was found to be a skin irritant (RTECS , 2002).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis has been reported following acute exposures (Vogel & Kirkendall, 1984).

B) PAIN

1) CHRONIC

a) Signs and symptoms reported after chronic exposure include chest pains, weakness, and decreased work capacity (Buchter & Peter, 1984).

Endocrine

3.16.3)

A) ANIMAL STUDIES

1) ADRENAL HEMORRHAGE

a) A target organ of toxicity in animal studies was the adrenals, with hemorrhagic necrosis occurring (Woutersen, 1998).

Reproductive

3.20.1)

A) Acrylonitrile is embryotoxic and teratogenic in animals; however, there is no evidence of teratogenic effects at doses below maternal toxic levels.

3.20.2)

A) ANIMAL STUDIES

1) ENCEPHALOCELE

a) In hamsters, intraperitoneal injection of acrylonitrile on day 8 of gestation resulted in exencephaly, encephaloceles, and rib abnormalities in the offspring (Willhite et al, 1981). Sodium thiosulfate injection protected the fetus from these effects, except at larger nitrile doses where thiosulfate protected the dam against overt poisoning but did not protect the fetus against malformations (Willhite et al, 1981).

1) The teratogenic effects of acrylonitrile may be related to the metabolic release of cyanide after absorption (Willhite et al, 1981).

b) Acrylonitrile is an animal teratogen (Buchter & Peter, 1984). It increased post-implantation mortality and induced CNS defects, including exencephaly, encephalocele, and rib abnormalities in hamsters exposed by the IP route on day 8 of gestation (Willhite et al, 1981). Sodium thiosulfate, a cyanide antidote, prevented the effects from lower, but not higher, doses of acrylonitrile; the protective effect of thiosulfate points to metabolically released cyanide as the teratogen (Willhite et al, 1981).

2) SKELETAL MALFORMATION

a) Acrylonitrile administered to the dams by gavage at a dose of 65 mg/kg on days 6 to 15 of gestation caused malformations in fetal rats (HSDB , 2002).
b) Musculoskeletal abnormalities were seen in fetal rats when pregnant females were exposed to an airborne concentration of 80 ppm for 6 hours on days 6 to 15 of gestation (RTECS , 2002).

3) EMBRYOTOXICITY

a) Acrylonitrile was embryotoxic in mice by the intraperitoneal route at a dose of 32 mg/kg on day 5 of gestation (RTECS , 2002).
b) Following maternal exposure, toxic effects observed in the rat embryo/fetus included developmental abnormalities of the musculoskeletal and cardiovascular systems. Central nervous system and musculoskeletal abnormalities occurred in hamster studies. Fetotoxicity, extra embryonic structures, and cytological changes including somatic cell genetic material were observed in the hamster (RTECS , 2002).
c) Acrylonitrile has been shown to have a concentration-dependent effect of decreased growth in and increased incidence of morphologically abnormal embryos. Maternal production of cyanide is suggested as the causative agent (Saillenfait & Sabate, 2000).
d) Embryolethality occurred with inhalation of 25 ppm for 6 hours/day during days 6 to 20 of gestation in rats; signs of maternal toxicity were present (Saillenfait et al, 1993). These embryotoxic effects were enhanced by experimental depletion of glutathione before acrylonitrile exposure in whole- embryo cultures (Saillenfait, 1993b). Acrylonitrile was embryotoxic in mice at an intraperitoneal dose of 32 mg/kg on day 5 of gestation (RTECS , 2002).
e) In a three-generation study in rats, 522 ppm of acrylonitrile in the drinking water (70 mg/kg/day) produced lower viability and lactation indices in all generations (Beliles et al, 1980).

4) DWARFISM

a) CYANIDE has been linked with congenital cretinism (deformities, dwarfism, and mental insufficiency) due to thyroid deficiency in regions of the world where cassava is a major part of the diet (Anon, 1972). The critical period is the first trimester, and damage can be prevented with iodine supplements (Anon, 1972). Cyanide has also been teratogenic and has affected the fertility of laboratory animals.

3.20.3)

A) ANIMAL STUDIES

1) Toxic effects were observed in the female rat including changes in the fertility index. Post-implantation mortality was observed in mouse and hamster studies (RTECS , 2002).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS107-13-1 (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: Acrylonitrile
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)

3.21.3)

A) OCCUPATIONAL EXPOSURE

1) Acrylonitrile is a SUSPECTED HUMAN CARCINOGEN. A number of epidemiological studies of persons occupationally exposed to acrylonitrile have found excess cancers of the colon, prostate, and respiratory system, and excess deaths from lymphatic, stomach, and lung cancer. Acrylonitrile forms adducts with biological macromolecules. Adducts with human globin have been detected in the blood of exposed workers and of cigarette smokers (Lawrence et al, 1996).

a) It is very difficult to exclude an agent as a human carcinogen by epidemiologic studies. The evidence available to date suggests that at the exposure levels that have occurred in North America and Western Europe acrylonitrile is not a human carcinogen or that it produces only small increases in cancer risk among humans (Coggon et al, 1998).
b) Previous epidemiologic studies taken together suggest that acrylonitrile is a human carcinogen. However, results have been inconsistent (Collins et al, 1989). Acrylonitrile is a CONFIRMED ANIMAL CARCINOGEN with UNKNOWN RELEVANCE TO HUMANS (ACGIH, 2000).

2) In a retrospective review of studies prior to 1994, Rothman (1994) could find no statistically significant difference in cancer rates between acrylonitrile-exposed workers and the general population in regards to all cancers and respiratory cancers. Because many of these studies were not properly conducted or reported, there is insufficient evidence to support confidence concerning a lack of carcinogenicity.
3) An ongoing mortality study confirmed a significant excess mortality in workers exposed to acrylonitrile and/or dimethylformamide from 1950 through 1982.

a) The excess mortality was mainly due to ischemic heart disease and not site-specific cancer. No dose response was seen, a finding which led the authors to conclude that excess deaths may have been due either to chance or lifestyle factors (Chen et al, 1988).
b) Another aspect of the same study followed cancer incidence through 1983. A significant excess of prostatic cancer was seen (Chen et al, 1987).

4) In a mortality study of 1,774 employees exposed to acrylonitrile, no significant excess total mortality or deaths due to cancer were seen. There was some increase in respiratory tract cancers, but there was no dose-related trend.

a) This was the largest study persons exposed to acrylonitrile and had the best exposure estimates at the time it was performed (Collins et al, 1989).

5) Cancer rates in one E.I. DuPont de Nemours plant were in excess of company or national averages (Clayton & Clayton, 1982; ACGIH, 1991). A later study of 2559 employees exposed to acrylonitrile in Orlon production from 1944 to 1991 found lower overall mortality and less cancer deaths than in either the general US population or amongst all dupont employees (Wood et al, 1998).
6) META-ANALYSIS - A meta-analysis of 25 epidemiological studies found only an increased incidence of bladder cancer which was not dose-related and unlikely to be due to acrylonitrile exposure (Collins & Acquavella, 1998).

a) No excess cancer deaths were found in a retrospective cohort study of 2842 Dutch acrylonitrile-exposed workers (Swaen et al, 2004).
b) In a cohort of 2763 British acrylonitrile-exposed workers, the only significantly excessive deaths were from lung cancer in workers less than 45 years of age; smoking may have been a confounder (Benn & Osborne, 1998).
c) In a study of 25,460 acrylonitrile-exposed workers, the only increased cancer risk was for lung cancer amongst those workers with the highest quintile of exposure (Blair et al, 1998).

7) Roughly a two-fold increase over expected deaths from lung cancer was seen in a group of 327 rubber workers exposed to an estimated 5 to 20 ppm of acrylonitrile (Delzell & Monson, 1982). Increased cases of respiratory cancer occurred in a cohort of 1,345 DuPont employees; risk was dependent on relative exposure and on latent time (O'Berg, 1980). Increased deaths from lung and lymphatic cancer were seen in BASF employees with mixed exposures from 12 factories in Germany (Thiess et al, 1980). A suggested increase in respiratory cancer deaths was seen in a large study, but was not dose-related (Collins et al, 1989).
8) Occupational exposure to rubber chemicals including acrylonitrile was identified as a risk factor for pancreatic cancer in a nationwide case-control study in Finland (Kauppinen et al, 1995). Excess deaths from stomach cancer occurred in a group of 934 British men involved with polymerization and spinning of acrylics; increased respiratory tract cancers were seen in one sub-group (Werner & Carter, 1981). Excess deaths from intestinal and colon tumors were seen in subgroups of Italian acrylic fiber workers, but not in the group as a whole (Mastrangelo et al, 1993).
9) While these studies taken together suggest that acrylonitrile is a human carcinogen, results have been inconsistent (Collins et al, 1989). Most of the studies suffer from deficiencies in methodology involving mixed exposures or small numbers of cases. There are 5 additional studies which reported no increased risk, but they all have deficiencies (IRIS , 1996).
10) One group of Dutch workers exposed for at least 6 months between 1956 and 1979 showed no increase in overall or cancer mortality, compared with national mortality statistics (Swaen et al, 1992).

3.21.4)

A) CARCINOMA

1) Observed tumorigenic effects in the rat included tumors of the brain and brain coverings (equivocal to carcinogenic by RTECS criteria), skin and appendages (equivocal tumorigenic agent by RTECS criteria), and sense organs and special senses (neoplastic by RTECS criteria) (RTECS , 2002).
2) In the murine model, acrylonitrile was found to be a multisite carcinogen in both male and female mice in a 2-year oral feeding study. Increased incidences of forestomach and Harderian gland neoplasms were evident in both males and females. Ovary and lung neoplasms were observed in female mice. The mechanism(s) of acrylonitrile-induced neoplasms remains unclear (Ghanayem et al, 2002).
3) The most consistent finding in rat studies is a high incidence of astrocytomas in the brain and spinal cord, followed by zymbal gland tumors followed by tumors of the small intestine, mammary gland, tongue and nonglandular stomach (Woutersen, 1998).

a) Astrocytoma induction in rats may be through an epigenetic mechanism involving oxidative stress (Jiang et al, 1998). No DNA adducts of acrylonitrile have been detected in the brains of exposed rats, also suggesting a non-genotoxic mechanism of carcinogenesis (Whysner et al, 1998).

4) Acrylonitrile has carcinogenic properties in some species of experimental animals and may be associated with a slight increase in deaths from lung cancer and other malignancies in humans (Buchter & Peter, 1984; Geiger et al, 1983).
5) There is stronger evidence for carcinogenicity in experimental animals. Rats exposed to acrylonitrile developed tumors of the brain/brain coverings, skin and appendages, and sense organs (RTECS , 2002). Tumors of the central nervous system, forestomach, lung, mammary gland, uterus, and zymbal gland of the ear canal occurred in rats given acrylonitrile in the drinking water for 2 years (Quast et al, 1980a; Gallagher, 1988).
6) Brain astrocytomas, and ear canal papillomas/adenomas and carcinomas occurred in rats fed acrylonitrile in the drinking water at levels up to 100 ppm for 2 years (Monsanto Plastics and Resins Co, 1981). CNS and other tumors were increased in rats exposed to acrylonitrile by inhalation at levels up to 80 ppm for 6 hours/day, 5 days/week for 2 years (Quast et al, 1980b).
7) Inhalation of up to 40 ppm for 4 hours/day, 5 days/week for 12 months produced mammary tumors in male rats and skin carcinomas in female rats (Maltoni et al, 1977). Tumors of the mammary gland region and forestomach occurred in female rats given 5 mg/kg of acrylonitrile in corn oil by gavage 3 times per week for 52 weeks (Maltoni et al, 1983).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor electrolytes, vital signs, mental status, renal function, and liver enzymes in symptomatic patients.
B) Obtain CBC, arterial blood gases, lactate, serum and urine thiocyanate levels, and whole blood cyanide levels after a significant exposure.
C) Monitor chest x-ray following an inhalation exposure or in patients with respiratory signs/symptoms.
D) Serum acrylonitrile concentrations may be obtained from reference laboratories to confirm exposure but are not useful to guide therapy. Treatment and disposition decisions should be based on reported exposure and symptoms; do not delay care waiting for serum acrylonitrile or cyanide concentrations.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor renal function and liver enzymes in symptomatic patients.
2) WHOLE BLOOD CYANIDE LEVELS

a) Some animal studies have been unable to demonstrate the presence of free cyanide in body tissues or fluids of animals exposed to lethal concentrations of acrylonitrile (Dudley et al, 1949). In other animal studies it was found that the toxicity was due to the liberation of hydrogen cyanide and acrylonitrile (Hashimoto et al, 1965). Cyanide is believed to play a major role in the toxicity of some animal species as measured by the rise in urinary thiocyanate concentration (Gut et al, 1975).
b) Elevated blood thiocyanate levels have been reported in individuals exposed to acrylonitrile in the normal course of their work (Lawton et al, 1943). However, significant blood cyanide levels have NOT been confirmed in human acute toxicity.

3) BLOOD AND URINARY THIOCYANATE LEVELS

a) Elevated blood and urine thiocyanate levels have been reported in individuals exposed to acrylonitrile in the normal course of their work (Wilson et al, 1949; Lawton et al, 1943). However, the correlation between blood and urine thiocyanate concentration and the level of acrylonitrile exposure or clinical symptoms has been met with limited success.

1) After 2.5 hours of rest from exposure to an atmospheric concentration of acrylonitrile below 22 ppm for 30 minutes, blood thiocyanate levels returned almost to normal (Wilson et al, 1949).
2) After more than 12 hours of rest from exposure to an atmospheric concentration of acrylonitrile above 50 ppm for 30 minutes blood thiocyanate levels did not return to normal (Wilson et al, 1949).
3) It has been suggested that an index of over exposure to acrylonitrile be considered significant in individuals whose serum thiocyanate concentration is over 3 mg/dL and urinary thiocyanate concentration over 16 mg/L in smokers, while for non-smokers corresponding values of 2 mg/dL and 2 mg/L be used (Wilson et al, 1949).
4) Plasma thiocyanate reaches a maximum level at the end of an acrylonitrile exposure. Plasma levels greater than 20 mg/L (non-smokers) or 30 mg/L (smokers) were indicative of overexposure in patients at risk (Lawton et al, 1943).

4) METABOLITES

a) Based on animal studies, analysis of the metabolites cyanoethyl mercapturic acid and thiodiglycolic acid, as well as unmetabolized acrylonitrile at high exposures, may be useful indicators of exposure (Muller et al, 1987).

B) ACID/BASE

1) Lactic acidosis may occur. Follow serum electrolytes and obtain arterial blood gases as clinically indicated for patients with significant exposure.

C) OTHER

1) HEMOGLOBIN ADDUCTS: Tobacco smokers and laboratory workers exposed to acrylonitrile have detectable levels of acrylonitrile-hemoglobin adducts in the blood (Bergmark, 1997).
2) GENOTOXIC EFFECTS: Increases in chromosomal aberrations, sister chromatid exchanges, and unscheduled DNA synthesis were found in a group of 26 workers with acrylonitrile and dimethylformamide exposure (Major et al, 1998). Increased chromosomal aberrations were also found in a group of Portuguese acrylonitrile-exposed workers (Borba et al, 1996).

4.1.3)

A) URINARY LEVELS

1) Elevated urinary thiocyanate levels have been reported in individuals exposed to acrylonitrile in the normal course of their work (Wilson et al, 1949; Lawton et al, 1943). However, the correlation between urine thiocyanate concentration and the level of acrylonitrile exposure or clinical symptoms has been met with limited success (Baselt, 2000).

a) After 2.5 hours of rest from exposure to an atmospheric concentration of acrylonitrile below 22 ppm for 30 minutes blood thiocyanate levels returned to almost normal (Wilson et al, 1949).
b) After more than 12 hours of rest from exposure to an atmospheric concentration of acrylonitrile above 50 ppm for 30 minutes blood thiocyanate levels did not return to normal (Wilson et al, 1949).
c) It has been suggested that an index of over exposure to acrylonitrile be considered significant in individuals whose serum thiocyanate concentration is over 3 mg/dL and urinary thiocyanate concentration over 16 mg/L in smokers, while for non-smokers corresponding values of 2 mg/dL and 2 mg/L be used (Wilson et al, 1949).
d) Urinary thiocyanate levels peak 24 to 48 hours after exposure. Levels greater than 2 mg/24 hours (non-smokers) or 16 mg/24 hours (smokers) were indicative of overexposure (Baselt, 2000).

2) Quantitation of the cyanoethyl mercapturic acid and thiodiglycolic acid metabolites and unmetabolized acrylonitrile may be useful as indicators of high-level exposure (Muller et al, 1987).
3) In a group of 26 exposed workers, urine acrylonitrile levels nearly doubled after a workshift (Major et al, 1998).
4) In a group of 34 exposed workers, post-shift urine acrylonitrile levels were higher than pre-shift levels (Perbellini et al, 1998). Tobacco smoking may be a confounder in attempts to use such measurements for biological monitoring.

B) URINALYSIS

1) Urinalysis is usually negative except for an increase in bile pigment (Lewis, 1996), although abnormal urine specific gravity, proteinuria, and increased urobilinogen levels have been reported in workers with occupational acrylonitrile exposure (HSDB, 1999).

4.1.4)

A) OTHER

1) CHEST RADIOGRAPH

a) Monitor chest x-ray following inhalation exposures or in patients with respiratory signs/symptoms.

2) MONITORING

a) Lactic acidosis may develop; follow serum electrolytes, blood lactate concentration, and monitor arterial blood gas as clinically indicated following significant exposures (Proctor et al, 1988).
b) Monitor vital signs and mental status in symptomatic patients.

Methods

1) AIR SAMPLES: Samples may be collected onto charcoal or other adsorption tubes by real-time continuous monitoring systems, portable direct-read instruments, or passive dosimeters (OSHA, 1988). Acrylonitrile can be collected from the air by adsorption onto charcoal and desorption with methanol (HSDB, 1999).

a) A collection tube with 600 mg Pittsburgh coconut base charcoal was determined to be optimal for sampling acrylonitrile airborne concentrations in the range of 0.05 to 5 ppm. Samples are desorbed with carbon disulfide (Melcher et al, 1986).

2) WATER SAMPLES: Samples are collected in narrow-mouth bottles filled to overflowing and stored in the absence of any head space at 4 degrees C. Thiosulfate (10 mg/40 mL of sample) may be added if free or combined chlorine is present at concentrations up to 5 ppm. Samples should be analyzed within 14 days (HSDB, 1999).

1) BIOLOGICAL SAMPLES: Acrylonitrile can be determined in the urine by gas chromatography (Lewalter & Muller, 1985).
2) AIR SAMPLES: There are many acceptable methods of analysis. Analysis should be by gas chromatography. NIOSH and OSHA have validated modifications of NIOSH Method S-156 for acrylonitrile levels less than 1 ppm, and details of their procedures together with the unmodified NIOSH method are given in Appendix D of 29 CFR 1910.1045.

a) Acrylonitrile can be analyzed by gas chromatography with flame ionization detection (FID) in the range of 0.015 to 1 mg per sample (HSDB , 1990). Desorbed samples can be analyzed using gas chromatography with FID or nitrogen selective detection (PND); the limits of detection are 4 mcg/10 mL for FID and 0.2 mcg/10 mL for PND (Melcher et al, 1986).

3) WATER SAMPLES: Samples can be analyzed by purge and trap gas chromatography with electrolytic conductivity detection with a detection limit of 0.5 mcg/L according to EPA Method 603 (HSDB, 1999).
4) SOLID WASTE SAMPLES: Acrylonitrile can be analyzed by gas chromatography with a flame ionization detector. The limit of detection is 0.5 mcg/L according to EPA Method 8030 (HSDB, 1999).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients should be admitted to an ICU setting and monitored for at least 24 hours as toxicity is expected to be delayed while cyanide is being produced via hepatic metabolism.

6.3.1.2) HOME CRITERIA/ORAL

A) Home observation should not be considered, as even a small volume exposure in an initially asymptomatic patient may result in severe toxicity. A patient with an inhalational exposure in an industrial setting should seek medical care as the amount and duration of exposure can be difficult to quantify.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for any patient with significant toxicity or in whom the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All patients with a potential acrylonitrile exposure should be referred to a healthcare facility.

Monitoring

Oral Exposure

6.5.1)

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

6.5.2)

A) SUMMARY

1) In symptomatic patients, skip these steps until other major emergency measures, including use of the Cyanide Antidote Kit or alternative specific cyanide antidote and other life support measures, have been instituted.

B) 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).

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Administer intravenous fluids and monitor carefully for evidence of more severe toxicity. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment should include ventilatory support and hydroxocobalamin or the cyanide antidote kit. Seizures should be considered an indication of severe toxicity and should be treated with benzodiazepines and hydroxocobalamin. Consider neurologic consult and continuous EEG monitoring for the sedated, chemically paralyzed, and intubated patient.

B) MONITORING OF PATIENT

1) Monitor electrolytes, vital signs, mental status, renal function, and liver enzymes in symptomatic patients.
2) Obtain CBC, arterial blood gases, lactate, serum and urine thiocyanate levels, and whole blood cyanide levels after a significant exposure.
3) Monitor chest x-ray following inhalation exposures or in patients with respiratory signs/symptoms.
4) Serum acrylonitrile concentrations may obtained from reference laboratories to confirm exposure but are not useful to guide therapy. Treatment and disposition decisions should be based on reported exposure and symptoms; do not delay care while waiting for serum acrylonitrile or cyanide concentrations.

C) OXYGEN

1) Administer 100% oxygen and establish and secure vascular accesses.

a) Oxygen may reverse the cyanide-cytochrome oxidase complex and facilitate the conversion to thiocyanate following thiosulfate administration (Graham et al, 1977).
b) There is fairly good evidence that 100% oxygen combined with traditional nitrite/thiosulfate therapy is better than nitrite/thiosulfate alone (Litovitz et al, 1983; Way et al, 1972).

2) Hyperbaric oxygen (HBO) therapy is approved for cyanide poisoning as a category one condition (approved for third party reimbursement and known effective as treatment) by the Undersea Medical Society (Myers & Schnitzer, 1984).

a) Hyperbaric oxygen has been suggested to improve clinical outcome, especially in those patients with CNS toxicity not responding to more traditional therapy.
b) Experimental animal studies have both confirmed and refuted this (Skene et al, 1966; Way et al, 1972; Takano et al, 1980).
c) Case reports suggest that HBO may be of value (Carden, 1970; Trapp, 1970). However, one cyanide-poisoned patient treated with supportive therapy, specific antidotes, and HBO did not survive (Litovitz et al, 1983).
d) Hyperbaric oxygen should be reserved for those patients with significant toxicity (ie, coma, seizures) who do not respond to normal supportive and antidotal therapy (Hart et al, 1985).

D) FLUID/ELECTROLYTE BALANCE REGULATION

1) Establish secure large bore IV line; consider placing at least two intravenous lines.

E) CYANIDE ANTIDOTE

1) A cyanide antidote, either hydroxocobalamin OR the sodium nitrite/sodium thiosulfate kit, should be administered to patients with symptomatic poisoning.
2) HYDROXOCOBALAMIN - CYANOKIT(R)

a) ADULT DOSE: 5 g (two 2.5 g vials each reconstituted with 100 mL sterile 0.9% saline) administered as an intravenous infusion over 15 minutes. For severe poisoning, a second dose of 5 g may be infused intravenously over 15 minutes to 2 hours, depending on the patient's condition (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
b) PEDIATRIC DOSE: A dose of 70 mg/kg has been used in pediatric patients, based on limited post-marketing experience outside the US (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
c) INDICATIONS: Known or suspected cyanide poisoning.
d) ADVERSE EFFECTS: Transient hypertension, allergic reactions (including anaphylaxis), nausea, headache, rash. Hydroxocobalamin's deep red color causes red-colored urine in all patients, and erythema of the skin in most (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
e) LABORATORY INTERFERENCE: Because of its' color, hydroxocobalamin interferes with colorimetric determination of various laboratory parameters. It may artificially increase serum creatinine, bilirubin, triglycerides, cholesterol, total protein, glucose, albumin , alkaline phosphatase and hemoglobin. It may artificially decrease serum ALT and amylase. It may artificially increase urinary pH, glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, and nitrate (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
f) HEMODIALYSIS INTERFERENCE: Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).

3) CYANIDE ANTIDOTE KIT

a) OBTAIN AND PREPARE for administration a CYANIDE ANTIDOTE KIT, consisting of sodium nitrite and sodium thiosulfate.
b) Antidotes should be administered to patients who are significantly symptomatic with unstable vital signs, metabolic acidosis, impaired consciousness, seizures, coma, or cardiorespiratory compromise.
c) SODIUM NITRITE

1) INDICATION

a) Sodium nitrite should be given initially and administered as soon as vascular access is established.
b) Further administration of sodium nitrite is dictated only by the clinical situation, provided no significant complications (hypotension, excessive methemoglobinemia) are present. Use with caution if carbon monoxide poisoning is also suspected.
c) The goal of nitrite therapy is to achieve a methemoglobin level of 20% to 30%. This level is not based on clinical data, but represents the tolerated concentration without significant adverse symptoms from methemoglobin in an otherwise healthy individual. Clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989; Johnson et al, 1989; Johnson & Mellors, 1988).

2) ADULT DOSE

a) 10 mL of a 3% solution (300 mg) administered intravenously at a rate of 2.5 to 5 mL/minute (Prod Info NITHIODOTE intravenous injection solution, 2011). Frequent blood pressure monitoring must accompany sodium nitrite injection and the rate slowed if hypotension occurs.
b) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011).

3) PEDIATRIC DOSE

a) The recommended pediatric sodium nitrite dose is 0.2 mL/kg of a 3% solution (6 mg/kg) administered intravenously at a rate of 2.5 to 5 mL/minute, not to exceed 10 mL (300 mg) (Prod Info NITHIODOTE intravenous injection solution, 2011).
b) If there is inadequate clinical response, an additional dose of sodium nitrite at half the amount of the initial dose may be administered 30 minutes following the first dose (Prod Info NITHIODOTE intravenous injection solution, 2011; Berlin, 1970).
c) PRESENCE OF ANEMIA: If there is a reason to suspect the presence of anemia, the following initial sodium nitrite doses should be given, depending on the child's hemoglobin (sodium nitrite should not exceed the doses listed below; fatal methemoglobinemia may result) (Berlin, 1970):

1) Hemoglobin: 8 g/dL - Initial 3% sodium nitrite dose: 0.22 mL/kg (6.6 mg/kg)
2) Hemoglobin: 10 g/dL - Initial 3% sodium nitrite dose: 0.27 mL/kg (8.7 mg/kg)
3) Hemoglobin: 12 g/dL (average child) - Initial 3% sodium nitrite dose: 0.33 mL/kg (10 mg/kg)
4) Hemoglobin: 14 g/dL - Initial 3% sodium nitrite dose: 0.39 mL/kg (11.6 mg/kg)

4) It is highly recommended that total hemoglobin and methemoglobin concentrations be rapidly measured (30 minutes after dose), when possible, before repeating a dose of sodium nitrite to be sure that dangerous methemoglobinemia will not occur, especially in the pediatric patient.
5) Monitor blood pressure frequently and treat hypotension by slowing infusion rate and giving crystalloids and vasopressors. Consider possible excessive methemoglobin formation if patient deteriorates during therapy.
6) Excessive methemoglobinemia and hypotension are potential complications of nitrite therapy.
7) In individuals with G6PD deficiency, therapy with methemoglobin-inducing agents is contraindicated because of the likelihood of serious hemolysis.

d) SODIUM THIOSULFATE

1) Sodium thiosulfate is the second component of the cyanide antidote kit. It is supplied as 50 mL of a 25% solution and it is administered intravenously. There are no adverse reactions to thiosulfate itself. The pediatric dose is adjusted for weight and not hemoglobin concentration.
2) Sodium thiosulfate supplies sulfur for the rhodanese reaction, and is recommended after sodium nitrite, hydroxocobalamin, or 4-DMAP (4-dimethylaminophenol) administration (Marrs, 1988a; Hall & Rumack, 1987).
3) DOSE

a) Follow sodium nitrite with IV sodium thiosulfate. ADULT: Administer 50 mL (12.5 g) of a 25% solution IV; PEDIATRIC: 1 mL/kg of a 25% solution (250 mg/kg), not to exceed 50 mL (12.5 g) total dose (Prod Info NITHIODOTE intravenous injection solution, 2011).
b) A second dose, one-half of the first dose, may be administered if signs of cyanide toxicity reappear (Prod Info NITHIODOTE intravenous injection solution, 2011).
c) Sodium thiosulfate is usually used in combination with sodium nitrite but may be used alone (Prod Info sodium thiosulfate IV injection, 2003).
d) Sodium thiosulfate can be administered without sodium nitrite in patients at risk to develop further methemoglobinemia (ie excessive methemoglobinemia or hypotension after initial sodium nitrite administration or in the presence of methemoglobinemia or carboxyhemoglobin in patients with smoke inhalation due to fire). Sodium thiosulfate can also be used in combination with hydroxocobalamin to treat cyanide poisoning (Howland, 2011)
e) CONTINUOUS INFUSION: It has been suggested that a continuous infusion of sodium thiosulfate be given after the initial bolus to maintain high thiosulfate levels. Low sodium intravenous fluids are required to avoid sodium overload. If large amounts of sodium thiosulfate are required, hemodialysis may be necessary to maintain a physiologic serum sodium level (Turchen et al, 1991).
f) ADVERSE EVENTS: Sodium thiosulfate does not usually produce significant toxicity. Possible adverse events include hypotension, headache, nausea, vomiting, disorientation, and prolonged bleeding time (Prod Info NITHIODOTE intravenous injection solution, 2011).

F) ACETYLCYSTEINE

1) N-acetylcysteine (NAC) and cysteine have been effective in protecting against acrylonitrile hepatotoxicity in rats (Buchter & Peter, 1984) . Their value in the clinical setting has not been proven, but NAC doses similar to those used for the treatment of acetaminophen (paracetamol) poisoning have been suggested.

a) DOSING: N-Acetylcysteine 150 mg/kg infused IV in 200 mL of 5% dextrose over 60 minutes, followed by 50 mg/kg in 500 milliliters 5% dextrose over 4 hours and 100 mg/kg in 1 liter 5% dextrose over the next 16 hours, giving a total of 300 mg/kg of N-acetylcysteine over 20 hours (Buchter & Peter, 1984).

G) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
2) Acidosis may be difficult to correct prior to administration of antidotes in serious cyanide poisoning cases (Hall & Rumack, 1986).

H) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

I) METHEMOGLOBINEMIA

1) While overwhelming lethal methemoglobinemia has been reported following sodium nitrite therapy for cyanide poisoning in a child (Berlin, 1970), such instances are rare and usually occur in situations where the patient has been given excessive nitrite doses.

a) Inducing a "therapeutic methemoglobin level" of 20% to 30% may not be necessary to insure satisfactory clinical outcome because clinical response has been reported to occur with methemoglobin levels in the range of 3.6% to 9.2% (DiNapoli et al, 1989) (Johnson et al, 1989; Johnson & Mellors, 1988).

2) If excessive methemoglobinemia occurs, some authors recommend that methylene or toluidine blue should not be used, as they could cause release of cyanide from the cyanmethemoglobin complex.

a) In this instance, emergency exchange transfusion has been suggested (Berlin, 1970).
b) Hyperbaric oxygen therapy could be used to support the patient while preparations for exchange transfusion are being made.

3) However, methylene or toluidine blue have been used successfully in this setting without worsening the course of cyanide poisoning (van Heijst et al, 1987).

a) There is some controversy over whether or not the induction of methemoglobinemia is the sodium nitrite mechanism of action in cyanide poisoning.

1) In cyanide poisoned rats, administration of toluidine blue to prevent the development of methemoglobinemia in rats treated with either sodium nitrite/ sodium thiosulfate, or 4-dimethylaminophenol did not affect the ability of these agents to restore cytochrome oxidase activity (Holmes et al, 1982) (Way, 1983) (Tadic, 1992).

b) As long as intensive care monitoring and further antidote doses are readily available, methylene or toluidine blue can most likely be safely administered in this setting.

J) DICOBALT EDETATE

1) Kelocyanor(R) (dicobalt-EDTA) is a highly effective cyanide chelating agent currently used clinically in Europe, Israel, and Australia (Davison, 1969; Hillman et al, 1974). It is not available in the United States.
2) Kelocyanor(R) is supplied in 20 mL ampules containing 300 mg of dicobalt-EDTA and 4 grams of dextrose in water for injection (Prod Info, 1978)(Prod Info, 1986)(Prod Info, 1987).
3) DOSE

a) ADULT DOSE: One to two 20 mL ampules (300 to 600 mg) injected IV over about 1 to 5 minutes (Prod Info, 1978) (Prod Info, 1986) (Prod Info, 1987) (Davison, 1969).

1) If there is sufficient clinical improvement 5 minutes after giving the first 1 to 2 ampules (300 to 600 mg), an additional 20 milliliter ampule (300 mg) may be administered intravenously over about 1 to 5 minutes (Prod Info, 1978) (Prod Info, 1986) (Prod Info, 1987) (Davison, 1969).
2) Manufacturers recommend that the intravenous site where Kelocyanor(R) has been injected be flushed with 50 milliliters of 5% dextrose in water (Prod Info, 1978) (Prod Info, 1986) (Prod Info, 1987).
3) Kelocyanor(R) can be used with other standard cyanide antidotes (Prod Info, 1978).

b) PEDIATRIC DOSE: Pediatric doses have not been established by manufacturers. In Israel the recommended pediatric dose is 0.5 mL/kg, not to exceed 20 mL (Personal Communication, Uri Taitelman, MD, 1963).

4) PRECAUTIONS

a) Serious adverse effects include hypotension, cardiac dysrhythmias, decreased cerebral blood flow, and angioedema (Dodds & McKnight, 1985; Wright & Vesey, 1986). These adverse reactions are magnified when a patient does not have cyanide intoxication. It may be prudent to reserve the use of Kelocyanor(R) in confirmed cyanide poisonings. The inherent problems in delaying treatment while waiting for confirmation is apparent and relegates this antidote to limited clinical usefulness unless cyanide poisoning can be confirmed readily (Pronczuk de Garbino & Bismuth, 1981; Tyrer, 1981). Therefore, KELOCYANOR(R) SHOULD NOT BE USED IN CASES of MILD CYANIDE POISONING or DIAGNOSTIC UNCERTAINTY (Peden et al, 1986; Tyrer, 1981).
b) ADVERSE EFFECTS may include nausea, vomiting, tachycardia, hypotension, hypertension, anaphylactoid reactions, massive facial and neck edema, chest pain, diaphoresis, nervousness, tremulousness, gastrointestinal hemorrhages, seizures, cardiac irregularities, and rashes (Prod Info, 1986) (Prod Info, 1987) (Davison, 1969; Tyrer, 1981; Hillman et al, 1974).

K) 4-DIMETHYLAMINOPHENOL HYDROCHLORIDE

1) 4-Dimethylaminophenol (4-DMAP) is a methemoglobin-inducing agent used in some European countries for the treatment of acute cyanide poisoning. A more rapid onset of methemoglobin production is observed following administration of 4-DMAP than following sodium nitrite. Methemoglobin peaks at 5 minutes after 4-DMAP versus 30 minutes after sodium nitrite (Kruszyna et al, 1982) (Moore et al, 1987) (Weger, 1990).
2) The dose of 4-DMAP is 3 mg/kg and is coadministered with thiosulfate.
3) Excessive methemoglobinemia may be a major complication following the use of this agent (van Dijk et al, 1986). Hemolysis may occur with therapeutic doses (van Heijst et al, 1987).

L) EXPERIMENTAL THERAPY

1) STROMA-FREE METHEMOGLOBIN SOLUTION

a) Stroma-free methemoglobin, oxidized hemoglobin to the ferric form in which the cell membrane has been removed, attenuates lethality and prevents hemodynamic changes in animal models (Breen et al, 1996) (Ten Eyck et al, 1985). The advantage to this treatment is that it provides exogenous methemoglobin without compromising oxygen-carrying capacity of native hemoglobin. Removal of the cell membrane eliminates the antigenicity problem (Marrs, 1988).
b) It has not been studied in human poisoning cases and is not available for human administration.

2) ALPHA-KETOGLUTARIC ACID

a) Alpha-ketoglutaric acid has a molecular configuration that renders it amenable to nucleophilic binding of cyanide.
b) Prophylactic treatment studies demonstrate attenuated lethality and synergy with sodium thiosulfate (Bhattacharya et al, 1991) (Dulaney et al, 1991) (Hume et al, 1995) (Norris et al, 1990).
c) Alpha-ketoglutaric acid is also being tested as a replacement for sodium nitrite in combination with sodium thiosulfate in animal models where it has been efficacious in experimental cyanide poisoning (Moore et al, 1986).
d) In vitro and animal studies show that alpha-ketoglutaric acid binds with cyanide and thereby antagonizes cyanide-induced inhibition of brain cytochrome oxidase (Norris et al, 1990).
e) Alpha-ketoglutaric acid administered with sodium thiosulfate abolished the cyanide-induced decrease in brain gamma-aminobutyric acid in mice (Yamamoto, 1990).
f) It has not been studied in human poisoning cases and is not available for human administration.

3) CHLORPROMAZINE

a) Chlorpromazine has been studied in various experimental animal models as a possible cyanide antidote. Conflicting reports of efficacy have been published (Pettersen & Cohen, 1985).
b) Experimental animal and in vitro studies show that chlorpromazine can decrease peroxidation of lipid membranes and prevent cyanide-induced calcium influx believed to be responsible for neurotoxicity (Johnson et al, 1986; Maduh et al, 1988).
c) It has not been studied in human poisoning cases.

4) OTHER INVESTIGATIONAL ANTIDOTES

a) Experimental animal studies to identify alternate cyanide antidotes have tested phenoxybenzamine, centrophenoxine, naloxone hydrochloride, etomidate, para-aminopropiophenone, and calcium-ion-channel blockers (Amery et al, 1981; Ashton et al, 1980; Bright & Marrs, 1987; Burrows & Way, 1976; Dubinsky et al, 1984; Johnson et al, 1986; Leung et al, 1984; Bright & Marrs, 1987; Marrs, 1988; Rump & Edelwijn, 1968; Vick & Froehlich, 1985).

M) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

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

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

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

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

1) Hemodialysis might be an effective adjunct by correcting resistant acidemia and by increasing thiocyanate clearance, thereby favoring thiosulfate-cyanide reaction to thiocyanate (Wesson et al, 1985).
2) It has, however, been used in only one reported case of cyanide poisoning, and antidote therapy with sodium nitrite and sodium thiosulfate was also administered (Wesson et al, 1985).
3) Limited experimental animal studies using historical controls and only a few animals have shown some potential effectiveness of hemodialysis when combined with thiosulfate infusion in cyanide poisoning (Gonzales & Sabatini, 1989).
4) Hemodialysis cannot be considered standard therapy for cyanide poisoning.

1) Charcoal hemoperfusion has been used in one reported case of cyanide poisoning (Kreig & Saxena, 1987).

a) The patient also received supportive measures and sodium nitrite/thiosulfate antidotes.
b) The outcome in this case was no different from that of other patients treated similarly without hemoperfusion.
c) Hemoperfusion cannot be considered standard therapy for cyanide poisoning.

Abstracts

Case Reports

1) A 57-year-old locksmith reports 14 years of acrylonitrile exposure resulted in signs and symptoms of disturbance in memory, weakness, headache, dizziness, drowsiness, diminished hearing and vision, and low blood pressure (Buchter & Peter, 1984). The patient was also exposed to prussic acid, ammonia, phosphoric acid, propylene, hydrochloric acid, and sulfuric acid.

1) A 24-year-old man was sprayed by acrylonitrile when a valve burst while he was unloading the chemical. His face, eyes, and body were covered with the chemical (Vogel & Kirkendall, 1984).

a) The patient experienced nausea, vomiting, dizziness, and flushing. His body was washed for 45 minutes and each eye was irrigated with normal saline. He received amyl nitrite, sodium nitrite, and sodium thiosulfate treatments.
b) The patient was initially oriented but shortly he began to hallucinate. His vital signs were normal. There was mild conjunctivitis and no corneal clouding. The remainder of the physical examination was normal except for a systolic murmur.
c) CBC, serum electrolytes, glucose, renal and liver functions, calcium, phosphorus, bleeding and prothrombin times were normal except for WBC of 26,400 and potassium of 3.3 mEq/L. There was no acidosis. Methemoglobin (after nitrite treatments) was 10.3%. Cyanide level was 13 mcg/dL. Thiocyanate level was 1.3 mg/dL. CPK was 188 units.
d) The patient received 15 doses of sodium nitrite/thiosulfate in the first 72 hours. When the methemoglobin dropped below 10% the patient usually began to hallucinate, became excited and tremulous, developed tachycardia, wide pulse pressure, increase in cardiac output, and vasodilation. With one such episode, he had 2 generalized seizures that responded to diazepam and phenytoin. On other occasions hallucinations, tremulousness, and tachycardia were quickly reversed with sodium nitrite and sodium thiosulfate.
e) On the second hospital stay the patient spiked a temperature of 38.3 degrees C (101 F) without an obvious source of infection; cyanide level was 18.4 mcg/dL, and thiocyanate remained 1.3 mg/dL.
f) Abnormal laboratory tests (peak values) over the patient's hospital course included SGPT (233), SGOT (293), LDH (2,235), CPK (49,800) with positive myoglobinuria.
g) The patient was discharged 5 days after admission with normal neurologic functions, except he had difficulty realizing that his hallucinations were not real, and normal liver function tests.

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) The lowest published lethal concentration in humans is 1 g/m(3) for 1 hour (RTECS , 1996).
2) Acrylonitrile has caused fatalities in humans by both dermal and inhalation exposure (Baselt, 2000; Hayes & Laws, 1991).
3) Acrylonitrile has the same toxic action as hydrogen cyanide or alkali cyanides, but the toxic action is slower to develop based on slower absorption of the fatal dose of low vapor concentration, as well as slower metabolic release of the cyanide ion (Clayton & Clayton, 1994; Hayes & Laws, 1991; Raffle et al, 1994).
4) The slow onset of symptoms may explain the disproportionate number of deaths among infants and the elderly who already suffer from serious chronic disease (Hayes & Laws, 1991).
5) If the vapor concentration is sufficiently high, or if the compound is ingested, slow absorption is not a factor and the toxic action could take place only moments after exposure (Hayes & Laws, 1991).
6) Acrylonitrile poisoning also takes on a second form which is apparently completely different from the poisoning results of cyanide exposure (Hayes & Laws, 1991).

a) This form appears as a serious dermatitis, and has been observed following both exposure to acrylonitrile only and exposure to a carbon tetrachloride/acrylonitrile mixture utilized for fumigation. Carbon tetrachloride does not produce this result alone (Hayes & Laws, 1991).
b) The intact acrylonitrile molecule is thought to cause the severe dermatitis related to this form of poisoning (Hayes & Laws, 1991).

1) A 10-year-old girl died about 4 hours after an application of about 50 mL of an acrylonitrile formulation to treat head lice (Hayes, 1982; Hayes & Laws, 1991).
2) A 67-year-old man with heart disease, emphysema, and hypertension died after returning to a house which had been fumigated with a mixture of acrylonitrile and methylene chloride. Serious symptoms of illness did not begin until 14 hours after returning to the house, and death occurred just under 6 hours later (Hayes, 1982; Hayes & Laws, 1991).
3) Three fatal cases of toxic epidermal necrosis occurred in persons who were exposed to a fumigant containing acrylonitrile and carbon tetrachloride (1:2). The immediate cause of death was septic shock and gastrointestinal hemorrhage. A 10-year-old boy who was exposed at the same time survived after topical and parenteral corticosteroid treatment (HSDB , 1990).

Maximum Tolerated Exposure

1) The lowest published toxic concentration for a human is 16 ppm for 20 minutes (RTECS , 1996).
2) No deleterious effects were reported in human volunteers exposed to 5.4 to 10.9 mg/m(3) (2.4 to 5 ppm) for 8 hours (Jakubowski et al, 1987).

1) Three fatal cases of toxic epidermal necrosis occurred in persons who were exposed to a fumigant containing acrylonitrile and carbon tetrachloride (1:2). The immediate cause of death was septic shock and gastrointestinal hemorrhage. A 10-year-old boy who was exposed at the same time survived after topical and parenteral corticosteroid treatment (HSDB , 1990).

1) Human studies involving chronic work-related exposure to acrylonitrile have resulted in heightened cancer rates of the lung, prostate, stomach, respiratory tract, colon, bladder, brain, and lymphatic and hematopoietic systems (ACGIH, 1991; Hathaway et al, 1996).

a) A positive correlation was observed between length of exposure durations and increased exposure severity to the increased risk of cancers of all sites (Hathaway et al, 1996).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) HUMAN - Concentrations as low as 16 parts per million for 30 minutes may produce headache, nausea, and irritability (HSDB , 2002).
b) The lowest published toxic concentration for humans was 16 parts per million for 20 minutes (RTECS , 2002).

Workplace Standards

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) Acrylonitrile

a) TLV:

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

b) Notations and Endnotes:

1) Carcinogenicity Category: A3
2) Codes: Skin
3) Definitions:

a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): CNS impair; LRT irr
d) Molecular Weight: 53.05

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 CAS107-13-1 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Acrylonitrile
2) REL:

a) TWA: 1 ppm
b) STEL:
c) Ceiling: 10 ppm [15-minute]
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s): See Appendix A

3) IDLH:

a) IDLH: 85 ppm
b) Note(s): Ca

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

C) Carcinogenicity Ratings for CAS107-13-1 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Acrylonitrile

2) EPA (U.S. Environmental Protection Agency, 2011): B1 ; Listed as: Acrylonitrile

a) B1 : Probable human carcinogen - based on limited evidence of carcinogenicity in humans.

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: Acrylonitrile

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: Acrylonitrile

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 2 ; Listed as: Acrylonitrile

a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Acrylonitrile

a) R : RAHC = Reasonably anticipated to be a human carcinogen

D) OSHA PEL Values for CAS107-13-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Acrylonitrile; see 29 CFR 1910.1045
2) Table Z-1 for Acrylonitrile; see 29 CFR 1910.1045:

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

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 46 mg/kg (RTECS , 2002a)

B) LD50- (ORAL)MOUSE:

1) 27 mg/kg (RTECS , 2002a)

C) LD50- (SUBCUTANEOUS)MOUSE:

1) 25 mg/kg (RTECS , 2002a)

D) LD50- (SUBCUTANEOUS)MOUSE:

1) 35 mg/kg (Lewis, 1996a)

E) LD50- (INTRAPERITONEAL)RAT:

1) 65 mg/kg (RTECS , 2002a)

F) LD50- (ORAL)RAT:

1) 78 mg/kg (RTECS , 2002a)

G) LD50- (SKIN)RAT:

1) 148 mg/kg (RTECS , 2002a)

H) LD50- (SUBCUTANEOUS)RAT:

1) 75 mg/kg (RTECS , 2002a)

I) TCLo- (INHALATION)HUMAN:

1) 16 ppm for 20M (RTECS , 2002a)

J) TCLo- (INHALATION)RAT:

1) female: 25 ppm for 6H -- at 6-20D of pregnancy; caused fetotoxicity (RTECS , 2002a)

K) TCLo- (INHALATION)RAT:

1) female: 40 ppm for 6H--at 6-15D of pregnancy(RTECS , 2002a)

L) TCLo- (INHALATION)RAT:

1) female: 80 ppm for 6H--at 6-15D of pregnancy; caused abnormal musculoskeletal system development (RTECS , 2002a)

M) TCLo- (INHALATION)RAT:

1) 5 ppm for 52W-I (RTECS , 2002a)

Pharmacology Toxicology

Toxicologic Mechanism

1) There is conflicting animal data regarding the role of cyanide in the toxicity of acrylonitrile. The toxicity to animals differs between species and the route of intoxication. Some animal studies have been unable to demonstrate the presence of free cyanide in body tissues or fluids of animals exposed to lethal concentrations of acrylonitrile (Dudley et al, 1949).
2) Cyanide is believed to play a major role in the toxicity of some animal species as measured by the rise in urinary thiocyanate concentration (Gut et al, 1975). In some animal studies the acute symptomatology closely resembles that produced by acute cyanide toxicity while in other studies the toxicity is a protracted process and produces lesions that are not typically observed following cyanide exposure. The traditional cyanide antidotes have exhibited both protective and antidotal action in some studies but are ineffective in others (Willhite et al, 1981) Hashimoto et al, 1965).
3) Elevated blood and urine thiocyanate levels have been reported in individuals exposed to acrylonitrile in the normal course of their work (Lawton et al, 1943). However, significant blood cyanide levels have not been confirmed in human toxicity.
4) Acrylonitrile may owe at least some of its toxicity to hepatic metabolism to cyanide which inhibits cellular respiration. Some experimental animal studies indicate that not all acrylonitrile toxicity is due to cyanide; some toxicity is caused by the parent compound (Dudley et al, 1949).
5) Pre-induction of microsomal mixed function oxidases with Arochlor 1254 greatly enhanced the toxicity of acrylonitrile and caused a three-fold increase in cyanide levels in rats (HSDB, 1999).

1) (14C)-Acrylonitrile bound irreversibly to DNA, RNA, and protein in the presence of a source of metabolic activation (HSDB, 1999).

Physicochemical

Physical Characteristics

Molecular Weight

Other

1) 21.6 ppm (ACGIH, 1991)

Animal Toxicology

References

General Bibliography

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ACRYLONITRILE

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

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Cardiovascular

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Hematologic

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Musculoskeletal

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Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

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Patient Disposition

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Oral Exposure

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Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

General Bibliography