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4,4-METHYLENEBIS(2-CHLOROANILINE)

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) MBOCA is an aromatic amino compound and a chlorinated hydrocarbon that is structurally related to hexachlorophene.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C13-H12-Cl2-N2 CH2(C6H4ClNH2)2

Available Forms Sources

    A) FORMS
    1) MBOCA is an aromatic amino compound and a chlorinated hydrocarbon that is structurally related to hexachlorophene. The pure form of MBOCA is a colorless crystalline solid. It is described as tan or yellow to light grey-tan colored pellets or flakes or as a colorless or light brown crystalline solid. It may have a faint amine-like odor. Commercially available forms of MBOCA have been in pellet, liquid, and granular form and as a pre-mixed compound with polyhydric alcohols. MBOCA is used occupationally in the pure powder or liquid form. It is melted before mixing into elastomer formulation when used as a curing agent, and may become volatile in this process (ACGIH, 2001a; ATSDR, 1994; Baxter et al, 2000; Bingham et al, 2001; HSDB, 2002; Lewis, 1998; NTP , 2002; Sittig, 1991a; Verschueren, 2001; Zenz, 1994a).
    2) The diamine purity is 99.8%, typically with 0.2% free o-chloroaniline (monomer). Isomers, such as trimers and tetrameres (diamines with three- and four-ring structures joined by methylene groups), are produced as side reactions and may constitute up to 8-10% of MBOCA. The dimer makes up approximately 90-92% of MBOCA produced for coatings and cast polyurethanes. There is no commercial use for pure dimer MBOCA, other than laboratory uses (ATSDR, 1994).
    3) Commercial preparations of MBOCA will also often contain 2-chloroaniline and a compound comprised of three 2-chloroaniline moieties joined by methylene groups. In addition, MBOCA may contain some 2-chloro-4-methylaniline from the manufacturing process. No information is available on the purity of the commercial pellet form of MBOCA (HSDB, 2002; Verschueren, 2001).
    B) SOURCES
    1) MBOCA is a man-made chemical and has not been reported to occur in nature. It is produced by carbonyl condensation of ortho-chloroaniline and formaldehyde. The technical grade available in the U.S. today is primarily from Japan. Two U.S. facilities were reported to produce MBOCA for commercial sale in 1992 (Ashford, 1994a; ATSDR, 1994; HSDB, 2002; (IARC, 1997)).
    C) USES
    1) 4,4'-Methylenebis(2-chloroaniline), or MBOCA, is primarily used in the production of solid elastomeric parts. It is used as a curing agent for polyurethanes, isocyanate-containing polymers, and epoxy resin bonding systems. MBOCA is also employed in the manufacture of crosslinked urethane foams used in automobile seats and safety padded dashboards. Its purpose is to influence hardness, flexibility, and impact strength. Materials developed from MBOCA applications are used in the manufacture of specialized products, such as rigid plastic car mouldings; polyurethane foam used as crash padding; castable polyurethane elastomers, such as tires, gaskets, belts, and rollers; and solid urethane rubber molding used in gear blanks and industrial tires (ACGIH, 2001a; Baselt, 1997; Baxter et al, 2000; Sittig, 1991a; Verschueren, 2001; Zenz, 1994a).
    2) MBOCA-cured polyurethanes have many commercial and military uses. They have been used in the manufacture of shoe soles; rolls and belt drives in cameras, computers, and copiers; wheels and pulleys for elevators and escalators; rolls for postage stamp machines; and cutting bars in plywood manufacturing. Military applications include ball seals on nuclear submarines, positioning strips in Poseidon missiles, and encapsulation of electrical components (ATSDR, 1994).
    3) MBOCA is also used in the manufacture of gun mounts, jet engine turbine blades, radar systems, components of home appliances, and as a wiring patting and curing agent. It is also used as a model compound in the study of carcinogenesis (Bingham et al, 2001).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) 4,4-methylenebis(2-chloroaniline) (MBOCA) is considered a poison by ingestion and intraperitoneal routes of exposure. It is primarily absorbed through the skin and also can be absorbed via the respiratory tract. Acute exposure to high levels of MBOCA may cause eye and skin irritation in humans. MBOCA exhibits the general toxicity characteristics of the aromatic amines, such as cyanosis and methemoglobinemia. Hematuria and proteinuria have been reported.
    B) MBOCA is considered a probable human carcinogen (Group 2A) by the IARC. It is suspected of causing bladder cancer in humans based on the behavior of structurally-similar compounds. It has a chemical structure similar to that of a known bladder carcinogen, benzidine.
    C) MBOCA is comprehensively genotoxic. Mutagenicity studies have shown that MBOCA or its metabolites cause genetic damage in a variety of organisms.
    D) It is known to be a mild skin irritant and caused conjunctival irritation in rabbits. There was no evidence of allergic contact dermatitis in guinea pigs. In experimental animals, clinical signs associated with acute MBOCA poisoning include inactivity, prostration, pallor, cyanosis,hypothermia, hematuria, and weight loss. Adverse hematologic effects and hepatotoxicity have been observed in dogs and rats.
    0.2.4) HEENT
    A) Mild eye irritation and burning have been reported following eye exposure to MBOCA.
    0.2.8) GASTROINTESTINAL
    A) Nausea was reported after accidental ingestion of MBOCA.
    0.2.9) HEPATIC
    A) Dogs and rats fed diets containing MBOCA have been found to have adverse liver effects, such as hyperplasia, hepatomegaly, fibrosis, necrosis, bile duct proliferation and fatty changes.
    0.2.10) GENITOURINARY
    A) Urinary symptoms, such as hematuria and proteinuria have been found in workers exposed to MBOCA. MBOCA has also been shown to cause bladder cancer in various lab animals. Because of its chemical similarity to benzidine, a known bladder carcinogen, MBOCA is suspected to cause bladder cancer in humans.
    0.2.13) HEMATOLOGIC
    A) Aromatic amines traditionally produce methemoglobinemia and cyanosis. MBOCA has been found to have some of the general toxicity characteristics of aromatic amines, but they have been reported much less frequently.
    0.2.14) DERMATOLOGIC
    A) MBOCA has been found to be a mild skin irritant, although no evidence of contact dermatitis has been found in skin testing with guinea pigs.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data are available on the reproductive effects of MBOCA in humans or animals.
    0.2.21) CARCINOGENICITY
    A) As of 2012, IARC has upgraded 4,4-methylenebis(2-choroaniline) to Group 1 (carcinogenic to humans) based on mechanistic and other relevant data following a systematic review and evaluation.

Laboratory Monitoring

    A) Monitor blood methemoglobin level, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.
    C) Urinalysis and urine MBOCA levels should be done immediately after exposure. Kidney function tests should be performed on patients following chronic exposure to MBOCA.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Do NOT induce emesis.
    B) 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.
    C) 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.
    D) Oral exposure to MBOCA is rarely reported. Treatment should include recommendations listed in the DERMAL and INHALATION exposure sections when appropriate.
    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.
    B) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    C) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    D) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    E) Administer 100 percent supplemental oxygen to patients with symptomatic methemoglobinemia. Consider hyperbaric oxygen therapy in patients who are refractory to methylene blue therapy. Exchange transfusion may be necessary.
    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).
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    4) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    5) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    6) Administer 100 percent supplemental oxygen to patients with symptomatic methemoglobinemia. Consider hyperbaric oxygen therapy in patients who are refractory to methylene blue therapy.
    7) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) The minimum lethal human dose to this agent has not been delineated. The maximum tolerated human exposure to this agent has not been delineated.

Clinical Effects

Summary Of Exposure

    A) 4,4-methylenebis(2-chloroaniline) (MBOCA) is considered a poison by ingestion and intraperitoneal routes of exposure. It is primarily absorbed through the skin and also can be absorbed via the respiratory tract. Acute exposure to high levels of MBOCA may cause eye and skin irritation in humans. MBOCA exhibits the general toxicity characteristics of the aromatic amines, such as cyanosis and methemoglobinemia. Hematuria and proteinuria have been reported.
    B) MBOCA is considered a probable human carcinogen (Group 2A) by the IARC. It is suspected of causing bladder cancer in humans based on the behavior of structurally-similar compounds. It has a chemical structure similar to that of a known bladder carcinogen, benzidine.
    C) MBOCA is comprehensively genotoxic. Mutagenicity studies have shown that MBOCA or its metabolites cause genetic damage in a variety of organisms.
    D) It is known to be a mild skin irritant and caused conjunctival irritation in rabbits. There was no evidence of allergic contact dermatitis in guinea pigs. In experimental animals, clinical signs associated with acute MBOCA poisoning include inactivity, prostration, pallor, cyanosis,hypothermia, hematuria, and weight loss. Adverse hematologic effects and hepatotoxicity have been observed in dogs and rats.

Heent

    3.4.1) SUMMARY
    A) Mild eye irritation and burning have been reported following eye exposure to MBOCA.
    3.4.3) EYES
    A) One worker complained of a burning sensation in the eyes after MBOCA was accidentally sprayed into them. The patient was treated for conjunctivitis (Hosein & Van Roosmalen, 1978; Hathaway et al, 1996).
    B) MBOCA produced mild conjunctival irritation, but no corneal effects in the eyes of rabbits (ACGIH, 2001).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea was reported after accidental ingestion of MBOCA.
    3.8.2) CLINICAL EFFECTS
    A) INDIGESTION
    1) In one case study of accidental occupational MBOCA exposure, a worker was sprayed in the face with molten MBOCA, some of which entered his mouth. The worker complained of nausea after the exposure. There is limited data on the dose to which he was exposed (Hosein & Van Roosmalen, 1978; ATSDR, 1994).

Hepatic

    3.9.1) SUMMARY
    A) Dogs and rats fed diets containing MBOCA have been found to have adverse liver effects, such as hyperplasia, hepatomegaly, fibrosis, necrosis, bile duct proliferation and fatty changes.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Several adverse hepatic changes were noted in the liver of rats fed 50mg/kg/day of MBOCA. These changes included: hepatomegaly, fibrosis, bile duct proliferation, necrosis and fatty changes (ATSDR, 1994).
    b) Adverse hepatic effects were also seen in dogs after chronic exposure to MBOCA. Nodular hepatic hyperplasia and disruption of liver architecture were seen in 3 of 6 dogs fed 10mg/kg/day of MBOCA 3 days a week for 6 weeks, then fed 10mg/kg/day 5 days a week for 9 years. These changes were not found in the control dogs. Serum glutamic-pyruvic transaminase (SGPT) was also elevated significantly in the MBOCA-treated dogs (ATSDR, 1994).

Genitourinary

    3.10.1) SUMMARY
    A) Urinary symptoms, such as hematuria and proteinuria have been found in workers exposed to MBOCA. MBOCA has also been shown to cause bladder cancer in various lab animals. Because of its chemical similarity to benzidine, a known bladder carcinogen, MBOCA is suspected to cause bladder cancer in humans.
    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) Hematuria was reported in a group of workers exposed to MBOCA along with a few other substances at unmeasured concentrations (toluene diisocyanate, polyester resins and polyether resins). Mild symptoms were reported that cleared within one week (ACGIH, 2001).
    B) ALBUMINURIA
    1) PROTEINURIA - In a case study of accidental occupational exposure to MBOCA, a worker was sprayed in the face with molten MBOCA. 5 hours later, his urine contained 220mg/L of protein, indicating damage to the renal tubules. 11 hours later, there was only a trace of protein in the urine. Twenty-four hours after the exposure, the urine showed a low specific gravity, indicating that the renal tubule damage was only transitory (Hosein & Van Roosmalen, 1978; ATSDR, 1994).

Hematologic

    3.13.1) SUMMARY
    A) Aromatic amines traditionally produce methemoglobinemia and cyanosis. MBOCA has been found to have some of the general toxicity characteristics of aromatic amines, but they have been reported much less frequently.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Aromatic amines traditionally produce methemoglobinemia and cyanosis. MBOCA has been found to have some of the general toxicity characteristics of aromatic amines, but they have been reported much less frequently (ATSDR, 1994). MBOCA is classified as only mildly cyanogenic (Linch et al, 1971).
    2) Contact with MBOCA by workers in the laboratory and pilot-plant process development activities or in maintenance operations and manufacturing have not shown any cyanosis-anemia syndrome in the last 10 years (Linch et al, 1971).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) METHEMOGLOBINEMIA
    a) In a rat study where 6 rats were fed 200 mg MBOCA/kg in 10 daily doses, elevated methemoglobin levels were found in 3 of the rats, along with decreased glucose levels. All six rats showed signs of toxicity, including pallor, discomfort, slight cyanosis and depressed body weight gain during treatment. The plasma and urine were noted to be orange-yellow in color (ACGIH, 2001).
    b) Three dogs were given high doses of MBOCA initially, then increasing doses until a dose of 64mg/kg per day was reached 67 days later. The initial high doses caused signs of weakness, vomiting, pallor and cyanosis in the dogs. The methemoglobin concentration of the blood was elevated in all three dogs. Smaller doses of MBOCA caused a slight methemoglobinemia and macrocytic anemia. Elevated fecal urobilinogen levels suggested that the anemia resulted from hemolysis (ACGIH, 1991).

Dermatologic

    3.14.1) SUMMARY
    A) MBOCA has been found to be a mild skin irritant, although no evidence of contact dermatitis has been found in skin testing with guinea pigs.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) MBOCA has been found to be a mild skin irritant (Baselt, 1997).
    2) No evidence of allergic contact dermatitis was found in skin sensitization tests with guinea pigs (ACGIH, 1991).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data are available on the reproductive effects of MBOCA in humans or animals.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS101-14-4 (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: 4,4'-Methylene bis(2-chloroaniline) (MOCA)
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) As of 2012, IARC has upgraded 4,4-methylenebis(2-choroaniline) to Group 1 (carcinogenic to humans) based on mechanistic and other relevant data following a systematic review and evaluation.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) As of 2012, IARC has upgraded 4,4-methylenebis(2-choroaniline) to Group 1 (carcinogenic to humans) based on mechanistic and other relevant data following a systematic review and evaluation (International Agency for Research on Cancer, 2015).
    B) BLADDER CARCINOMA
    1) MBOCA is similar in structure to aromatic amines, which have been found to cause bladder cancer in workers who have been occupationally exposed (Ward et al, 1987).
    2) A screening study of 540 workers at a Michigan chemical plant who were exposed to MBOCA over an 11 year period found two noninvasive papillary tumors of the bladder. Both tumors occurred in men under the age of 30 who had never smoked. Since bladder cancer in young men is very uncommon, this was felt to be consistent with the theory that MBOCA induces bladder tumors in humans. The incidence of clinically apparent tumors in males of this age is only 1 per 100,000 per year (Ward et al, 1988; ATSDR, 1994).
    a) The study was limited by the fact that there were no controls and it did not provide statistical evidence for an association between MBOCA worker exposure and bladder tumors.
    3.21.4) ANIMAL STUDIES
    A) PULMONARY CARCINOMA
    1) A study of 50 male and 50 female ChR-CD rats who were fed a 23 percent protein diet containing 1000 ppm MBOCA showed a higher incidence of primary lung tumors than the control group. The overall yield was 83 tumors in 100 rats. This was credited to the ingestion of 1000 ppm MBOCA (ACGIH, 2001; HSDB , 2002).
    a) The most common malignant tumor found was adenocarcinoma of the lung. Liver tumors and miscellaneous tumors were also found, but not in a statistically significant amount (ACGIH, 2001; HSDB , 2002).
    B) CARCINOMA
    1) Another study of 25 male and 25 female rats fed a low protein diet containing MBOCA found a high incidence of tumors. Twenty-three of the male rats died with tumors (22 of these were multifocal hepatomas). Twenty of the female rats died with tumors of which 18 were multifocal hepatomas. Thirteen of the rats had primary lung tumors which were mainly carcinomas, 10 of which also had hepatomas. The control group of rats produced only 2 mammary adenomas (HSDB , 2002).
    C) BLADDER CARCINOMA
    1) MBOCA is considered to be carcinogenic to the urinary bladders of dogs. Six female beagles were fed a daily dose of 100mg MBOCA 5 days a week for up to 9 years. One dog died of incidental disease. Three of the remaining dogs were found to have papillary transitional cell carcinoma of the bladder and one had a combined transitional cell carcinoma and adenocarcinoma of the urethra. No bladder tumors were found in the 6 control dogs (ACGIH, 2001).
    a) Three of the 5 MBOCA-treated dogs were found to have hyperplastic nodules in the liver. No nodules were found in the control group (ACGIH, 2001).

Genotoxicity

    A) MBOCA is comprehensively genotoxic. Mutagenicity studies have shown that MBOCA or its metabolites cause genetic damage in a variety of organisms.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood methemoglobin level, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.
    C) Urinalysis and urine MBOCA levels should be done immediately after exposure. Kidney function tests should be performed on patients following chronic exposure to MBOCA.
    4.1.2) SERUM/BLOOD
    A) Blood concentration of MBOCA in humans has not been reported (Baselt, 1997).
    4.1.3) URINE
    A) Urine MBOCA concentration monitoring is the most useful marker of absorption following exposure to MBOCA (Baselt, 1997). Biological monitoring of urine depends critically on the timing of the sampling and is most accurate with recent exposures (Hathaway et al, 1996).
    1) The recommended target for urine concentration to prevent significant worker exposure is 1 mcg/L (Baselt, 1997). In the early days of MBOCA manufacturing, urinary levels as high as 25mg/liter were found without observable blood alterations (Linch et al, 1971).
    2) Other aromatic amines have produced some degree of methemoglobinemia with urinary levels in the 10 to 20mg/liter range (Linch et al, 1971).
    B) Another method for measurement of urinary MBOCA is by using electron-capture gas chromatography (Baselt, 1997).
    1) The limit of detection of urinary MBOCA by electron-capture gas chromatography is 3 mcg/L. Therefore, if the target MCOCA urine level of 1 mcg/L is achieved, no urinary MBOCA will be detectable by this method.(Baselt, 1997).
    C) Urinalysis and urine cytology should be performed on workers with chronic exposure to MBOCA. Microscopic hematuria is sensitive in detecting early bladder cancer, but has a low specificity. Urine cytology has good sensitivity and specificity for invasive bladder carcinomas, but a low sensitivity for early bladder cancer (Frumkin, 1997).
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) Preplacement screening and periodic medical exams should be performed on all employees who will be potentially exposed to MBOCA. These exams should include a history of exposure to other carcinogens, alcohol and smoking habits, use of medications, and family history.

Radiographic Studies

    1) CHEST RADIOGRAPH
    a) Monitor chest x-ray in patients with respiratory tract signs or symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor blood methemoglobin level, hemoglobin, hematocrit, and plasma free hemoglobin in patients with methemoglobinemia. Monitor arterial blood gases; pulse oximetry may be unreliable (falsely high values) in patients with methemoglobinemia, especially following methylene or toluidine blue therapy.
    B) Urinalysis positive for blood with few or no RBC's is an early indication of hemolysis.
    C) Urinalysis and urine MBOCA levels should be done immediately after exposure. Kidney function tests should be performed on patients following chronic exposure to MBOCA.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS
    1) Because of the potential for gastrointestinal tract irritation and CNS depression, DO NO induce emesis.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    1) Do NOT induce emesis.
    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.
    D) Oral exposure to MBOCA is rarely reported. Treatment should include recommendations listed in the DERMAL and INHALATION exposure sections when appropriate.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Oral exposure to MBOCA is rarely reported. Treatment should include recommendations listed in the DERMAL and INHALATION exposure sections when appropriate.

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.
    6.7.2) TREATMENT
    A) PULMONARY ABSORPTION
    1) Inhalation of vapors can cause systemic poisoning resulting in methemoglobinemia and hemolysis.
    B) MONITORING OF PATIENT
    1) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and any other necessary indices of hemolysis.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) Exchange transfusion may be required in severe cases or those refractory to methylene blue therapy (Mier, 1988).
    5) Hyperbaric oxygen therapy may be used to ensure adequate oxygenation in patients with severe methemoglobinemia while preparations are being made for emergency exchange transfusion.
    D) OXYGEN
    1) Patients with methemoglobinemia should be given supplemental oxygen.
    E) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Maintain liberal urine output (2 to 4 mL/kg/hr) to help prevent renal damage from RBC breakdown products.
    F) SUPPORT
    1) Frequent vital signs monitoring and supportive care are required.
    G) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    H) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    I) ENHANCED ELIMINATION PROCEDURE
    1) HEMODIALYSIS
    a) No case reports of hemodialysis for methemoglobinemia following MBOCA exposure were found in the literature.
    2) EXCHANGE TRANSFUSION
    a) In cases of refractory methemoglobinemia or where methylene blue therapy was unsuccessful, exchange transfusion may be useful in decreasing methemoglobin levels (Mier, 1988).
    J) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA
    a) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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) 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).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) SKIN ABSORPTION
    1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    2) Dermal exposure to MBOCA may cause systemic absorption and toxicity from methemoglobinemia and hemolysis.
    C) MONITORING OF PATIENT
    1) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and any other necessary indices of hemolysis.
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) Exchange transfusion may be required in severe cases or those refractory to methylene blue therapy (Mier, 1988).
    5) Hyperbaric oxygen therapy may be used to ensure adequate oxygenation in patients with severe methemoglobinemia while preparations are being made for emergency exchange transfusion.
    E) OXYGEN
    1) Patients with methemoglobinemia should be given supplemental oxygen.
    F) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Maintain liberal urine output (2 to 4 mL/kg/hr) to help prevent renal damage from RBC breakdown products.
    G) SUPPORT
    1) Frequent vital signs monitoring and supportive care are required.
    H) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    I) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    J) ENHANCED ELIMINATION PROCEDURE
    1) HEMODIALYSIS
    a) No case reports of hemodialysis for methemoglobinemia following MBOCA exposure were found in the literature.
    2) EXCHANGE TRANSFUSION
    a) In cases of refractory methemoglobinemia or where methylene blue therapy was unsuccessful, exchange transfusion may be useful in decreasing methemoglobin levels (Mier, 1988).
    K) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA
    a) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    L) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) The minimum lethal human dose to this agent has not been delineated. The maximum tolerated human exposure to this agent has not been delineated.

Minimum Lethal Exposure

    A) GENERAL
    1) The minimum lethal human dose to this agent has not been delineated.
    2) No studies were located regarding death in humans or animals after inhalation or dermal exposure to MBOCA (ATSDR, 1994).
    3) Studies were not located on increased mortality in humans for MBOCA exposure from the oral route of exposure (ATSDR, 1994).
    4) Decreased lifespan was noted in rats after chronic oral exposure to MBOCA. A standard diet containing 0, 12.5, 25, or 50 mg/kg/day or a protein-deficient diet with 0, 6.25, 12.5, or 25 mg/kg/day MBOCA were fed to male rats for 18 months. Decreased lifespan was observed in the rats fed 25 mg/kg/day in either diet, and rats fed the highest concentration (50 mg/kg/day) in the standard diet also had a shortened lifespan. A Lowest Observed Adverse Effect Level (LOAEL) for death in rats after chronic exposure of 25 mg/kg/day was set forth by ATSDR (ATSDR, 1994).

Maximum Tolerated Exposure

    A) GENERAL
    1) The maximum tolerated human exposure to this agent has not been delineated.
    2) ATSDR reports a chronic-duration minimum risk level (MRL) of 0.003 mg/kg/day, derived due hepatic effects in dogs and calculated from a LOAEL of 10 mg/kg/day (ATSDR, 1994).
    3) Of 5 beagle dogs surviving 9 years of oral doses of 10 mg/kg/d MBOCA, 3 developed papillary transitional cell carcinomas of the urinary bladder and 1 developed urethral adenocarcinoma and transitional cell carcinoma (Bingham, et al, 2001).
    4) MBOCA has been shown to be a potent, multitarget carcinogen in animals. Dietary administration of MBOCA induced hemangiosarcomas in mice of both sexes, hepatomas in female mice, pulmonary tumors, Zymbal gland caricinomas and mammary adenocarcinomas in rats of both sexes, and hepatocellular carcinomas in male rats (Bingham, et al, 2001).
    5) Rats fed 1000 ppm MBOCA for two years in a standard diet developed lung tumors and accompanying liver changes. MBOCA fed to mice of both sexes for 18 months at a dose of 1 or 2 g/kg led to a statistically significant incidence of hepatoma in female mice (Hathaway et al, 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS101-14-4 (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) 4,4'-Methylene bis(2-chloroaniline) [MBOCA; MOCA(R)]
    a) TLV:
    1) TLV-TWA: 0.01 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A2
    2) Codes: BEI, Skin
    3) Definitions:
    a) A2: Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) 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): Bladder cancer; MeHb-emia
    d) Molecular Weight: 267.17
    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 CAS101-14-4 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: 4,4'-Methylenebis(2-chloroaniline)
    2) REL:
    a) TWA: 0.003 mg/m(3)
    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: [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: Not Listed

    C) Carcinogenicity Ratings for CAS101-14-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A2 ; Listed as: 4,4'-Methylene bis(2-chloroaniline) [MBOCA; MOCA(R)]
    a) A2 :Suspected Human Carcinogen: Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as a confirmed human carcinogen; OR, the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic type(s), or by mechanism(s) considered relevant to worker exposure. The A2 is used primarily when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals with relevance to humans.
    2) EPA (U.S. Environmental Protection Agency, 2011): 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): 1 ; Listed as: 4,4'-Methylene bis(2-chloroaniline) (MOCA)
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: 4,4'-Methylenebis(2-chloroaniline)
    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: 4,4'-Methylene-bis(2-chloroaniline)
    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: 4,4-Methylenebis(2-chloraniline) (MBOCA)
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS101-14-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 64 mg/kg -- morbidity
    2) LD50- (ORAL)MOUSE:
    a) 640 mg/kg -- changes to sense organs and special senses, ataxia, cyanosis
    3) LD50- (ORAL)RAT:
    a) 1140 mg/kg -- changes to sense organs and special senses, ataxia, cyanosis
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >5 g/kg -- morbidity

Physicochemical

Physical Characteristics

    A) MBOCA is a colorless or light brown crystalline solid with a faint amine-like odor. The commercial product is generally in the form of tan-colored pellets or flakes, but it has been available commercially in liquid or granular form and as a pre-mixed compound with polyhydric alcohols. It may occur as flakes from alcohol. It is solid at room temperature. It also exists as a pure powder, or as a liquid when melted and used as a curing agent (ACGIH, 2001; Baselt, 1997) Baxter, 2000; Bingham, et al, 2001; (Budavari, 2000; HSDB , 2002) NTP, 2001; (Verschueren, 2001; Zenz, 1994).

Ph

    A) MBOCA is a weak base (HSDB , 2002).

Molecular Weight

    A) 267.15

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
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