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METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Methylcyclopentaldienyl manganese tricarbonyl (MMT; CI-2) is a complex organic compound containing about 25 percent manganese. It is used as a smoke abatement and antiknock additive for internal combustion and gas turbine engines (ACGIH, 1991; HSDB , 1999; Hathaway et al, 1996; Lyznicki et al, 1999).
    B) Concentrated MMT is highly toxic, but it has a low toxicity when mixed with fuels (ACGIH, 1991).

Specific Substances

    1) Manganese, tricarbonyl methylcyclopentadienyl
    2) 2-Methylcyclopentadienyl manganese tricarbonyl
    3) AK-33X
    4) CI-2
    5) Combustion improver-2
    6) Manganese, (Methylcyclopentadienyl) tricarbonyl
    7) Methylcyclopentadienyl manganese tricarbonyl
    8) MMT
    9) CAS 12108-13-3
    1.2.1) MOLECULAR FORMULA
    1) C9-H7-Mn-O3

Available Forms Sources

    A) FORMS
    1) In performing a risk assessment of MMT use, the US EPA considered that the main potential health hazards for the general public were the combustion products of this fuel additive: manganese tetroxide (Mn3O4) containing both Mn(+2) and Mn(+3) and a manganese phosphate product containing only Mn(+2) (Davis, 1998; Frumkin & Solomon, 1997). These combustion products are released as inhalable submicron particles in vehicle exhaust (Davis, 1998; Frumkin & Solomon, 1997).
    B) USES
    1) MMT is a gasoline and other fuel additive intended to improve combustion and decrease smoke (ACGIH, 1991; HSDB , 1999)
    2) MMT has been considered as a replacement for tetraethyl lead as an antiknock agent (Friberg et al, 1979; Davis, 1998; Frumkin & Solomon, 1997; Lyznicki et al, 1999).
    3) About 70 million pounds of MMT have been sold for use as a leaded gasoline additive since 1976 and limited use was allowed until leaded gasoline was phased out in the USA in 1995 (Davis, 1998; Davis, 1998). The allowable concentration of MMT in fuels in the USA is 0.031 grams (as Mn) per US gallon (Davis, 1998; Davis, 1998). MMT is currently allowed in unleaded gasoline in the USA and Canada (Davis, 1998; Davis, 1998) Frumkin & Soloman, 1997; (Lyznicki et al, 1999).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) HUMANS - Human exposure data are minimal. Available data suggest respiratory that irritation and CNS manganese toxicity (similar to Parkinsonism) are possible.
    B) EXPERIMENTAL ANIMALS - Toxic via all routes in concentrated form; when mixed with fuels, it has a low toxicity. Experimental animals given lethal doses developed CNS excitation (hyperactivity, mild clonic seizures) and coma.
    0.2.4) HEENT
    A) MMT is a moderate eye irritant.
    0.2.6) RESPIRATORY
    A) Experimental animals exposed to lethal doses develop slow and labored respiration. Chronic inhalation produced chronic bronchitis, lung abscesses, and interstitial pneumonia.
    0.2.7) NEUROLOGIC
    A) Headache and giddiness were noted in one human dermal exposure.
    B) Experimental animals have developed excitement, hyperactivity, muscle spasms, tremors, seizures, and coma after lethal doses.
    0.2.8) GASTROINTESTINAL
    A) Nausea has occurred in humans. Anorexia and weight loss occurred after both acute and chronic exposures in experimental animals.
    0.2.14) DERMATOLOGIC
    A) MMT is readily absorbed through intact skin when dissolved in petroleum distillates. It is NOT irritating on single skin contact and is NOT known to be a skin sensitizing agent. MMT induced mild skin irritation in the rabbit in the Standard Draize Test.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no reproductive studies were found for MMT in humans.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of MMT in humans.

Laboratory Monitoring

    A) Manganese levels may be of some use in determining the extent of exposure. Blood manganese levels should be interpreted with caution. Elevated urinary manganese levels do not correlate with neurologic symptoms in patients with chronic intoxication.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Human exposure data are very limited. Signs and symptoms (based on experimental animal data) appear to be CNS and pulmonary. Chelation has been of very limited, if any, value. Support respiration and control seizures.
    B) EMESIS: Ipecac-induced emesis is not recommended because there is so little information about the effects of overdose in humans.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    E) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    F) MANGANESE INTOXICATION - Removal from exposure is the first priority. Chelating agents, levodopa, anticholinergics, and 5-hydroxytryptophan have all been tried.
    G) Provide good respiratory supportive care.
    0.4.3) INHALATION EXPOSURE
    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.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: 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. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Dermal exposure to as little as 5 to 15 mL has caused nausea, headache, giddiness, and "thick tongue" within 3 to 5 minutes. Toxic human doses in humans exposed by other routes have not been established.

Clinical Effects

Summary Of Exposure

    A) HUMANS - Human exposure data are minimal. Available data suggest respiratory that irritation and CNS manganese toxicity (similar to Parkinsonism) are possible.
    B) EXPERIMENTAL ANIMALS - Toxic via all routes in concentrated form; when mixed with fuels, it has a low toxicity. Experimental animals given lethal doses developed CNS excitation (hyperactivity, mild clonic seizures) and coma.

Heent

    3.4.1) SUMMARY
    A) MMT is a moderate eye irritant.
    3.4.3) EYES
    A) CONJUNCTIVITIS - MMT is mildly to moderately irritating to the eyes (ACGIH, 1991; HSDB , 1999).

Respiratory

    3.6.1) SUMMARY
    A) Experimental animals exposed to lethal doses develop slow and labored respiration. Chronic inhalation produced chronic bronchitis, lung abscesses, and interstitial pneumonia.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Human exposure from accidental spills has resulted in respiratory distress which disappears in 24 to 48 hours (Lynam et al, 1990).
    2) In order for pulmonary absorption of manganese to occur from exposure to MMT, the particle size of combustible MMT must be less than 1 micrometer. Particles of less than 1 micrometer are respirable and reach the alveolar region. Larger particles (5 to 30 micrometer) will be deposited in the nasopharyngeal region while medium particles (1 to 5 micrometer) will reach the tracheobronchial regions. Sierra et al (1995) have reported that only 10 percent of the manganese in exposed garage workers was found to be of the respirable size.
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY INSUFFICIENCY
    a) Animals exposed to lethal doses developed slow and labored respirations (ACGIH, 1991; Hathaway et al, 1996). Chronic inhalation produced chronic bronchitis, peribronchitis, lung abscesses and interstitial pneumonia (ACGIH, 1991; Hathaway et al, 1996).

Neurologic

    3.7.1) SUMMARY
    A) Headache and giddiness were noted in one human dermal exposure.
    B) Experimental animals have developed excitement, hyperactivity, muscle spasms, tremors, seizures, and coma after lethal doses.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) CASE REPORT - "Thick tongue", giddiness, and headache were reported within 3 to 5 minutes of dermal exposure to 5 to 15 mL (ACGIH, 1991; Hathaway et al, 1996).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Experimental animals given lethal doses developed mild excitement, hyperactivity, muscle spasms, tremors, weakness, coma, and mild chronic seizures (ACGIH, 1991). A Parkinsonian-like condition and destruction of dopaminergic nigrostriatal neurons were not evident despite elevated brain manganese content in rats given as much as 50 mg MMT/kg over 5 months (Yong et al, 1986).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea has occurred in humans. Anorexia and weight loss occurred after both acute and chronic exposures in experimental animals.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) CASE REPORT - Nausea occurred in a patient who had dermal exposure to 5 to 15 mL (ACGIH, 1991; Hathaway et al, 1996).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANOREXIA
    a) Anorexia and weight loss were reported in experimental animals who did not die acutely when given lethal doses. These animals usually died a few days later. Sublethal doses also produced temporary weight loss (ACGIH, 1991; Hathaway et al, 1996).

Dermatologic

    3.14.1) SUMMARY
    A) MMT is readily absorbed through intact skin when dissolved in petroleum distillates. It is NOT irritating on single skin contact and is NOT known to be a skin sensitizing agent. MMT induced mild skin irritation in the rabbit in the Standard Draize Test.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) MMT caused mild skin irritation in rabbits in the Standard Draize Test (RTECS, 1999).
    B) LACK OF EFFECT
    1) MMT is readily absorbed through intact skin when dissolved in petroleum distillates (Clayton & Clayton, 1994). It is NOT irritating on single skin contact and is NOT known to be a skin sensitizing agent (ACGIH, 1991).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no reproductive studies were found for MMT in humans.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS - One study by Benya et al (1981) found NO effect in the rat. However, an earlier study using doses of 2 to 9 mg/kg/day found significant differences between treated and control rats in terms of maternal and fetal body weights and incidence of malformations (HSDB , 1999).
    2) MMT had no effect on the number of offspring when given to pregnant rats at a dose of 10 mg/kg on day 12 of gestation (Majima, 1985). There is no evidence of MMT causing teratogenicity, fetotoxicity, or embryotoxicity in experimental animals (Parris & Grant, 1983).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS12108-13-3 (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) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of MMT in humans.

Genotoxicity

    A) MMT was not mutagenic in bacteria. No other genetic studies were found at the time of this review.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Manganese levels may be of some use in determining the extent of exposure. Blood manganese levels should be interpreted with caution. Elevated urinary manganese levels do not correlate with neurologic symptoms in patients with chronic intoxication.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Results of blood manganese levels should be interpreted with caution; elevated blood levels may be found in asymptomatic workers exposed to high concentrations of manganese.
    2) Normal Levels - Blood - 0.08 to 0.26 mcg/100 mL; Urine - 0.1 to 0.8 mcg/100 mL; CSF - 0.4 to 1.2 mcg/100 mL (Friberg et al, 1979).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Elevated urinary concentrations of manganese do not correlate with neurological symptoms in patients with chronic intoxication (Friberg et al, 1979). They may be useful in acute intoxication. EDTA challenge test is NOT diagnostic.

Methods

    A) SAMPLING
    1) Serum analysis for manganese may be influenced by the anticoagulant used. Heparin has been found to contain significant concentrations of manganese (Friberg et al, 1979).
    B) MULTIPLE ANALYTICAL METHODS
    1) Many different methods are available for analysis for blood or water samples of manganese. Considerable variation has been shown to exist between the methods. Thirty laboratories were sent a water sample containing 12 mcg/L. Results ranged from 2.8 to 18 mcg/L.
    2) MMT levels in biological tissues and fluids can be determined by gas chromatography (Hanzlik, 1979).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Manganese levels may be of some use in determining the extent of exposure. Blood manganese levels should be interpreted with caution. Elevated urinary manganese levels do not correlate with neurologic symptoms in patients with chronic intoxication.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS
    1) EMESIS: Ipecac-induced emesis is not recommended because there is so little information about the effects of overdose in humans.
    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) TREATMENT
    A) 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).
    B) PROCEDURE EDUCATION
    1) In the initial stage, removal from exposure to manganese may result in a remission of symptoms.
    C) CHELATION THERAPY
    1) Chelation has been of limited value for manganese intoxication (Cook et al, 1974; Huang et al, 1989; Kosai & Boyle, 1956; Penalver, 1957; Rodier, 1955; Whitlock et al, 1966; Wynter, 1962).
    2) Chelation enhances urinary excretion and mobilization of manganese from the blood and tissues without restoring normal physiologic function. Chronic neurologic defects persist in the absence of significant blood or tissue concentrations. Manganese poisoning does not appear to be correlated with blood or urinary manganese levels (Clayton & Clayton, 1994).
    3) Chelation therapy may be effective early in the psychiatric phase of manganese intoxication, prior to development of permanent neurological damage (Rodier, 1955). Whether there would be beneficial effects in chronic MMT poisoning is unknown.
    4) Calcium disodium EDTA is of variable efficacy producing temporary improvement at times and positive results when given early in manganese intoxication; no improvement was noted when used in patients with chronic intoxication (Cook et al, 1974; Huang et al, 1989; Kosai & Boyle, 1956; Penalver, 1957; Rodier, 1955; Whitlock et al, 1966; Wynter, 1962).
    5) Dimercaprol (BAL) does not alter chronic neurologic deficits due to manganese intoxication (Wynter, 1962).
    D) PARKINSONISM
    1) LEVODOPA -
    a) The response to levodopa (3.5 grams daily) is generally positive. Doses up to 12 grams a day have been given without major side effects; there is a suggestion that patients with chronic manganism can tolerate higher doses of levodopa than patients with parkinsonism (Rosenstock et al, 1971).
    b) In one case reported by Mena et al (1970), L-dopa increased the weakness, muscular hypotension, tremor, and hypokinesia. This patient was then aided with 5-OH tryptophan. It is possible that concomitant administration of carbidopa might result in greater benefit. To date, there have been no reported cases in which this drug has been tried.
    c) In general the response to levodopa appears to be a function of the neurological pattern of the patient's symptoms. Symptomatic improvement has been reported to continue after dose stabilization.
    d) Cook et al (1974) state that levodopa is less effective or ineffective in the absence of rigidity or dystonia.
    2) ANTICHOLINERGICS -
    a) Trihexyphenidyl hydrochloride (Artane(R)) has been reported to reduce intention tremor in a patient with known manganism. DOSE: 1 to 5 mg daily in divided doses (Hine & Pasi, 1975).
    3) L-5-HYDROXYTRYPTOPHAN -
    a) L-5-HYDROXYTRYPTOPHAN (a serotonin precursor): up to 3 grams daily was given with good results to a patient with manganism whose symptoms failed to respond to levodopa (Mena et al, 1970).
    E) SUPPORT
    1) Provide good respiratory supportive care.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    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) DECONTAMINATION
    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) DECONTAMINATION
    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).

Range Of Toxicity

Summary

    A) Dermal exposure to as little as 5 to 15 mL has caused nausea, headache, giddiness, and "thick tongue" within 3 to 5 minutes. Toxic human doses in humans exposed by other routes have not been established.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Minimum lethal human exposure is unknown.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) HUMANS - ACGIH occupational exposure limits for Mn are 1000 mcg/m(3) for fume and 5000 mcg/m(3) for dust (Sierra et al, 1995).
    2) PARTICLE SIZE (Mn) - Sierra et al (1995) have reported that in order for Mn to be respirable (deposited into the alveolar region) it must be of a diameter of less than 1 micrometer. In their study of garage mechanics, only 10 percent of the Mn from combustible MMT was in the respirable range.
    3) GENERAL POPULATION EXPOSURES - Studies from Canada where MMT has been used as a gasoline additive since 1976 have not found significant environmental deposition of manganese (Lyznicki et al, 1999). Although there may be subtle subclinical neurological effects from chronic low-level manganese exposure, these occur only with exposure levels higher than those predicted to occur from use of MMT in motor fuels (Lyznicki et al, 1999).
    B) ROUTE OF EXPOSURE
    1) DERMAL - Dermal exposure to 5 to 15 milliliters caused nausea, headache, giddiness, and "thick tongue" within 3 to 5 minutes (ACGIH, 1991).
    C) ANIMAL DATA
    1) DOGS - Inhalation of 12 milligrams per cubic meter for 100 days produced NO weight changes nor gross or microscopic changes (ACGIH, 1991).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Normal Levels - Blood - 0.08 to 0.26 mcg/100 mL; Urine - 0.1 to 0.8 mcg/100 mL; CSF - 0.4 to 1.2 mcg/100 mL (Friberg et al, 1979).

Workplace Standards

    A) ACGIH TLV Values for CAS12108-13-3 (American Conference of Governmental Industrial Hygienists, 2010):
    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) 2-Methylcyclopentadienyl manganese tricarbonyl, as Mn
    a) TLV:
    1) TLV-TWA: 0.2 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Skin
    3) Definitions:
    a) 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; lung, liver, and kidney dam
    d) Molecular Weight: 218.1
    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 CAS12108-13-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Methyl cyclopentadienyl manganese tricarbonyl (as Mn)
    2) REL:
    a) TWA: 0.2 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    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):
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS12108-13-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: 2-Methylcyclopentadienyl manganese tricarbonyl, as Mn
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Methyl cyclopentadienyl manganese tricarbonyl (as Mn)
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS12108-13-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: (RTECS, 1999; Lewis, 1996 ACGIH, 1991
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 152 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 34 mg/kg
    b) 230 mg/kg
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 12 mg/kg
    b) 12 mg/kg
    c) 23 mg/kg
    4) LD50- (ORAL)RAT:
    a) 23-39 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) MMT was shown to be an effective inhibitor of mitochondrial respiration associated with NADT-linked substrates in rats (Autissier et al, 1977).
    B) MMT administration at 0.5, 1, or 2.5 mg/kg body weight of rats caused large increases in lavage albumin and protein content with smaller increases in lactate dehydrogenase levels (Clay & Morris, 1989). In rats, MMT-induced pneumotoxicity can be inhibited by phenobarbital pretreatment (Hanzlik et al, 1980), but is enhanced with piperonyl butoxide pretreatment in mice (Haschek et al, 1982).
    C) Experiments in mice suggest that MMT itself (organic manganese) or a closely related metabolite and not elemental manganese is responsible for seizure activity which may be the result of MMT inhibition at the GABA-A receptor linked chloride channel (Fishman et al, 1987).

Physicochemical

Physical Characteristics

    A) MMT is a dark orange or yellow liquid with a faint, but pleasant herbaceous odor (ACGIH, 1991; Lewis, 1996).

Molecular Weight

    A) 219.10

Other

    A) ODOR THRESHOLD
    1) Currently not available (CHRIS , 2002)

References

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