a) In a long-term follow-up study 32 years after accidental exposure to methyl chloride, authors concluded that this compound may have contributed to the risk of cardiovascular disease (Rafnsson & Gudmunsson, 1997). Another follow-up cohort study conducted 47 years after the same incident also reported increased mortality due to cardiovascular diseases. In 1963, 27 crew members from an Icelandic fishing vessel were exposed to methyl chloride released from a leaking refrigerator. By 2010, 20 of 27 patients had died as compared with 75 of 135 unexposed crew members in the reference group. The Hazard ratios (HR) for all cardiovascular events, for acute coronary heart disease, for cerebrovascular diseases, and for suicides were 2.06 (95% Confidence Interval [CI] 1.02 to 4.15), 3.12 (95% CI 1.11 to 8.78), 5.35 (95% CI 1.18 to 24.35), and 13.76 (CI 95% 1.18 to 160.07), respectively. It was determined that suicide cases were due to methyl chloride-induced severe depression (Rafnsson & Kristbjornsdottir, 2014).

a) Methyl chloride can asphyxiate by displacing air (AAR, 2000) (Kizer, 1984).

a) In chronic poisoning from constant skin absorption or from inhalation of concentrations slightly higher than the maximal allowable concentration, bronchospasm is common (Arena & Drew, 1986).

a) Methyl chloride may produce respiratory depression (Harbison, 1998).

a) Diffuse theta waves, sometimes with irregular or absent alpha waves, were seen in the frontal region of persons chronically exposed to methyl choride and possibly also to other substances (Roth & Deutschova, 1964).

a) HIGH CONCENTRATIONS: Exposure to high concentrations may result in dizziness, drowsiness, headache, giddiness, incoordination, confusion, staggering gait, slurred speech, and weakness, followed by delirium, paralysis, seizures and coma (Harbison, 1998; Hansen et al, 1953; Spevak et al, 1976; Lewis, 2000).

a) LOW CONCENTRATIONS: Exposure to lower concentrations usually results in fatigue, drowsiness, and muscular weakness (Clayton & Clayton, 1994; Proctor & Hughes, 1988).

a) HIGH CONCENTRATIONS: Exposure to high concentrations may result in nausea, vomiting, diarrhea, and abdominal pain (Proctor & Hughes, 1988).

a) LOW CONCENTRATIONS: Exposure to lower concentrations usually results in mild gastrointestinal upset (Ellenhorn & Barceloux, 1988).

a) Occupational hepatic injury from methyl chloride is virtually unknown. The narcotic and irritating effects usually preclude sufficient exposure to produce hepatic injury, but the potential exists (von Oettingen, 1955).
b) Some human cases of clinical jaundice have been reported and a case of jaundice and cirrhosis was attributed to occupational methyl chloride exposure (Wood, 1951).

a) Acute nephritis may result following exposure to high concentrations. Albuminuria, hematuria, oliguria, or anuria may develop (ITI, 1995).

a) TESTICULAR DEGENERATION and infertility occurred in rats exposed to the relatively high concentration of 1500 ppm for 10 weeks (Proctor & Hughes, 1988).

a) Anemia may result following exposure to high concentrations (Proctor & Hughes, 1988).

a) Sprayed on the skin, methyl chloride produces anesthesia through freezing of the tissue as it evaporates.

a) Cyanosis may result following exposures to high concentrations (Proctor & Hughes, 1988).

a) Skin contact causes erythema and vesiculation (Arena & Drew, 1986).

a) Direct contact with the liquified material or escaping gas can cause frostbite injury (AAR, 2000). The resultant dermal freezing can have an anesthetic effect (Lewis, 2000; Budavari, 1996).

a) Listed as: Methyl chloride
b) Carcinogen Rating: 3

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).

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 .

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).

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).

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).

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):

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

a) Rewarming of a localized area should only be considered if the risk of refreezing is unlikely. Avoid rubbing the frozen area which may cause further damage to the area (Grieve et al, 2011; Hallam et al, 2010).

a) Do not institute rewarming unless complete rewarming can be assured; refreezing thawed tissue increases tissue damage. Place affected area in a water bath with a temperature of 40 to 42 degrees Celsius for 15 to 30 minutes until thawing is complete. The bath should be large enough to permit complete immersion of the injured part, avoiding contact with the sides of the bath. A whirlpool bath would be ideal. Some authors suggest a mild antibacterial (ie, chlorhexidine, hexachlorophene or povidone-iodine) be added to the bath water. Tissues should be thoroughly rewarmed and pliable; the skin will appear a red-purple color (Grieve et al, 2011; Hallam et al, 2010; Murphy et al, 2000).
b) Correct systemic hypothermia which can cause cold diuresis due to suppression of antidiuretic hormone; consider IV fluids (Grieve et al, 2011).
c) Rewarming may be associated with increasing acute pain, requiring narcotic analgesics.
d) For severe frostbite, clinical trials have shown that pentoxifylline, a phosphodiesterase inhibitor, can enhance tissue viability by increasing blood flow and reducing platelet activity (Hallam et al, 2010).

a) Digits should be separated by sterile absorbent cotton; no constrictive dressings should be used. Protective dressings should be changed twice per day.
b) Perform twice daily hydrotherapy for 30 to 45 minutes in warm water at 40 degrees Celsius. This helps debride devitalized tissue and maintain range of motion. Keep the area warm and dry between treatments (Hallam et al, 2010; Murphy et al, 2000).
c) The injured extremities should be elevated and should not be allowed to bear weight.
d) In patients at risk for infection of necrotic tissue, prophylactic antibiotics and tetanus toxoid have been recommended by some authors (Hallam et al, 2010; Murphy et al, 2000).
e) Non-tense clear blisters should be left intact due to the risk of infection; tense or hemorrhagic blisters may be carefully aspirated in a setting where aseptic technique is provided (Hallam et al, 2010).
f) Further surgical debridement should be delayed until mummification demarcation has occurred (60 to 90 days). Spontaneous amputation may occur.
g) Analgesics may be required during the rewarming phase; however, patients with severe pain should be evaluated for vasospasm.
h) IMAGING: Arteriography and noninvasive vascular techniques (e.g., plain radiography, laser Doppler studies, digital plethysmography, infrared thermography, isotope scanning), have been useful in evaluating the extent of vasospasm after thawing and assessing whether debridement is needed (Hallam et al, 2010). In cases of severe frostbite, Technetium 99 (triple phase scanning) and MRI angiography have been shown to be the most useful to assess injury and determine the extent or need for surgical debridement (Hallam et al, 2010).
i) TOPICAL THERAPY: Topical aloe vera may decrease tissue destruction and should be applied every 6 hours (Murphy et al, 2000).
j) IBUPROFEN THERAPY: Ibuprofen, a thromboxane inhibitor, may help limit inflammatory damage and reduce tissue loss (Grieve et al, 2011; Murphy et al, 2000). DOSE: 400 mg orally every 12 hours is recommended (Hallam et al, 2010).
k) THROMBOLYTIC THERAPY: Thrombolysis (intra-arterial or intravenous thrombolytic agents) may be beneficial in those patients at risk to lose a digit or a limb, if done within the first 24 hours of exposure. The use of tissue plasminogen activator (t-PA) to clear microvascular thromboses can restore arterial blood flow, but should be accompanied by close monitoring including angiography or technetium scanning to evaluate the injury and to evaluate the effects of t-PA administration. Potential risk of the procedure includes significant tissue edema that can lead to a rise in interstitial pressures resulting in compartment syndrome (Grieve et al, 2011).
l) CONTROVERSIAL: Adjunct pharmacological agents (ie, heparin, vasodilators, prostacyclins, prostaglandin synthetase inhibitors, dextran) are controversial and not routinely recommended. The role of hyperbaric oxygen therapy, sympathectomy remains unclear (Grieve et al, 2011).
m) CHRONIC PAIN: Vasomotor dysfunction can produce chronic pain. Amitriptyline has been used in some patients; some patients may need a referral for pain management. Inability to tolerate the cold (in the affected area) has been observed following a single episode of frostbite (Hallam et al, 2010).
n) MORBIDITIES: Frostbite can produce localized osteoporosis and possible bone loss following a severe case. These events may take a year or more to develop. Children may be at greater risk to develop more severe events (ie, early arthritis) (Hallam et al, 2010).

a) Methyl chloride breath concentrations averaged 10 to 15 micrograms/Liter or 50 to 80 micrograms/Liter in human volunteers during a 6-hour exposure to air concentrations of 10 or 50 parts per million, respectively (Nolan et al, 1985).

1) Methyl chloride

a) TWA:
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: Not Listed
f) Note(s): See Appendix A

a) IDLH: 2000 ppm
b) Note(s): Ca

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

a) D : Not classifiable as to human carcinogenicity.

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

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

a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)

a) 8-hour TWA:

a) 8-hour TWA:100 ppm
b) Acceptable Ceiling Concentration: 200 ppm
c) Acceptable Maximum Peak above the Ceiling Concentration for an 8-hour Shift:
d) Notation(s): Not Listed

a) 1800 mg/kg

a) Female, 500 ppm for 6H at 6-18D of pregnancy -- stunted fetus; developmental cardiovascular abnormalities
b) Female, 750 ppm for 6H at 6-17D of pregnancy -- fetal death
c) Female, 500 ppm for 6H at 6-17D of pregnancy -- developmental cardiovascular abnormalities
d) 997 ppm for 6H/2Y-intermittent -- kidney tumors
e) 150 ppm for 22H/11D-continuous -- motor activity changes; thymus weight changes; death
f) 1473 ppm for 6H/90D-intermittent -- impaired liver function; liver weight changes

a) Male, 1500 ppm for 6H at 50D prior to mating -- effects to testes, epididymis, and sperm ducts
b) Male, 2000 ppm for 6H at 5D prior to mating -- effects to genetic material, and to sperm morphology, motility, and count
c) Female, 1500 ppm for 6H at 7-19D of pregnancy -- stunted fetus; developmental musculoskeletal abnormalities
d) Male, 3000 ppm for 6H at 5D prior to mating -- effects to genetic material, and to sperm morphology, motility, and count; effects to testes, epididymis, and sperm ducts
e) Male, 3000 ppm for 6H at 5D prior to mating -- effects to male fertility index
f) 997 ppm for 6H/2Y-intermittent -- testicular tumors
g) 41 mg/m(3) for 4H/26W-intermittent -- impaired liver function; changes in red blood count; weight loss or decreased weight gain
h) 1473 ppm for 6H/90D-intermittent -- weight loss or decreased weight gain