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4,4-METHYLENEDIANILINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Methylenedianiline (4,4'-methylenedianiline) is a hepatotoxin and suspected human carcinogen.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C13-H14-N2 C-H2(C6-H4-N-H2)2

Available Forms Sources

    A) FORMS
    1) At room temperature, 4,4'-methylenedianiline is a pale yellow to tan or light brown crystalline solid or flakes that may have a faint amine or "fish-like" odor (AAR, 2000; ACGIH, 1991). It is a liquid at 212 degrees F (NIOSH , 2002). The crystals darken upon exposure to air (Bingham et al, 2001). It may also be found in liquid form when mixed with certain other chemicals (Lewis, 1993). It forms pearly flakes/leaflets from benzene (Lewis, 2000).
    2) It is also encountered as an orange or yellow dust and as a component of epoxy resins or molded plastics (Bastian, 1984; Cohen, 1985).
    3) It is estimated that the 4,4'-methylenedianiline produced in the United States is between 40 and 70 percent pure, whereas the imported compound has a purity of approximately 98 percent (NTP , 2000). The technical grade contains 4 percent of the 2,4-methyleneaniline isomer (NTP , 2001).
    4) An estimated 99 percent of the 4,4'-methylenedianiline produced is consumed in its crude form; the crude form may contain not more than 50 percent of 4,4'-methylenedianiline and poly-methylenedianiline (Sittig, 1991).
    B) SOURCES
    1) It is derived from aniline and formaldehyde or by hydrogenolysis of p,p'-diaminobenzophenone with LiAlH4 (Ashford, 1994; Budavari, 2000). It has been manufacturered commercially in the United States since the 1920s ((IARC, 1986)).
    C) USES
    1) An estimated 98 percent of 4,4'-methylenedianiline used the USA is used in the closed-system production of isocyanates and polyisocyanates (Bingham et al, 2001; Lewis, 2001; US DHHS, 1994).
    2) 4,4'-Methylenedianiline is used as a curing agent for epoxy resins and urethane elastomers (Bingham et al, 2001; Budavari, 2000; Lewis, 2001).
    a) It is used in the preparation of polyurethanes, poly(amide-imide) resins, Spandex fibers and azo dyes, and in the production of wire coatings (ACGIH, 1991; Bingham et al, 2001; Budavari, 2000; US DHHS, 1994; Verschueren, 2001).
    3) 4,4'-Methylenedianiline is used as an antioxidant in rubber, a corrosion inhibitor, a fuel additive, a laboratory reagent, and in the determination of tungsten and sulfates (ACGIH, 1991; Bingham et al, 2001; Lewis, 2001) US DHHS, 1994; (Budavari, 2000; Verschueren, 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) Adverse effects can result from ingestion, inhalation and dermal contact. Percutaneous absorption occurs.
    B) Acute, reversible hepatitis ("Epping jaundice") has occurred after ingestion, inhalation and dermal contact. Clinical effects include nausea, vomiting, abdominal (right upper quadrant) pain, anorexia, weakness, fever and chills, followed by jaundice, cholestasis, cholangitis, portal inflammation, increased hepatic enzyme serum levels and abnormal liver histopathology (inflammation, liver cell necrosis, eosinophil infiltration).
    C) MDA is irritating to skin, eyes and mucous membranes.
    1) Dermal contact may produce erythema and swelling. Contact dermatitis and skin sensitization to MDA has been reported. Allergic dermatitis, with rash, itching, hives and swelling, has occurred; however, such exposures are confounded by concomitant exposure to other chemicals. MDA produces an intense yellow staining of skin and nails and sometimes hair.
    2) Eye contact may result in itching, burning, lacrimation, conjunctivitis and corneal burns. Retinotoxic effects have been produced in animals after oral or inhalational administration; this has not been seen in humans except for one case of accidental ingestion (with other chemicals) that resulted in severe visual dysfunction related to gross malfunction of the retinal pigment epithelium.
    D) The spleen and kidneys are also adversely affected by exposure. One case of transient cardiac ischemia after exposure to MDA dusts has been documented.
    E) Toxic fumes of aniline and nitrogen oxides can be produced when MDA is heated to decomposition. Methemoglobinemia and pulmonary edema are key potential effects of these chemicals. Refer to the ANILINE MEDITEXT(R) Medical Management for more information.
    0.2.3) VITAL SIGNS
    A) Fever and hypotension (rare) have been reported.
    0.2.5) CARDIOVASCULAR
    A) Acute cardiomyopathy has been reported in one case of extremely high-level inhalational and dermal MDA exposure.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, and anorexia can occur.
    0.2.9) HEPATIC
    A) Transient hepatotoxicity has occurred in humans following ingestion, inhalation, and dermal contact with MDA.
    0.2.10) GENITOURINARY
    A) Dark, brown urine has been reported.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia has been produced in some experimental animals species but has not been reported in human MDA exposures.
    0.2.14) DERMATOLOGIC
    A) Irritation, rashes, and sensitization have been reported from exposure to MDA and other chemicals. Jaundice can occur secondary to acute hepatitis and has been reported following ingestion of MDA-contaminated food and in workers exposed to MDA-containing resins.
    0.2.15) MUSCULOSKELETAL
    A) Weakness, myalgia, and arthralgia can occur.
    0.2.16) ENDOCRINE
    A) MDA can severely depress adrenocortical response to stress in rats.
    0.2.19) IMMUNOLOGIC
    A) Allergic contact dermatological reactions can occur in sensitized individuals acutely exposed to MDA.
    0.2.20) REPRODUCTIVE
    A) There is little information concerning possible reproductive effects of MDA in humans or experimental animals.
    B) MDA administered to laboratory animals has caused endometrium proliferation and decreased the secretion of testicular hormones in response to stimuli. The significance of these results for human reproduction is unknown.
    0.2.21) CARCINOGENICITY
    A) Little human data exist. One case of bladder cancer slightly in excess of the expected incidence was reported in a study of 10 MDA-exposed workers with a history of hepatotoxicity. Based on experimental animal research, MDA is labeled as anticipated to be carcinogenic or as a possible human carcinogen.
    0.2.22) OTHER
    A) Toxic fumes of aniline and nitrogen oxides may be produced when MDA is heated to decomposition.

Laboratory Monitoring

    A) Monitor liver enzymes and bilirubin. ECG is advisable in patients with chest pain or other evidence of possible cardiac involvement.
    B) Monitor BUN, serum creatinine, and fluid and electrolyte status.
    C) In cyanotic or hypoxic patients, monitor methemoglobin level, arterial blood gases with O2 saturation, CBC, and ECG. A chest x-ray may also be indicated for differential diagnosis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL
    1) 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.
    2) 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.
    3) 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.
    4) 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.
    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.
    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) Remove contaminated clothing and protective equipment, avoiding secondary exposure of others.
    2) 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).
    3) 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.
    4) 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.
    5) 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.
    6) 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.
    7) A dermatologic consult is suggested if sensitization and allergic dermatitis is suspected.
    8) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Range Of Toxicity

    A) Adverse effects have resulted from ingestion, inhalation and dermal exposure to MDA. The exact doses and duration of exposure was not know in most cases. MDA is a suspected carcinogen.

Clinical Effects

Summary Of Exposure

    A) Adverse effects can result from ingestion, inhalation and dermal contact. Percutaneous absorption occurs.
    B) Acute, reversible hepatitis ("Epping jaundice") has occurred after ingestion, inhalation and dermal contact. Clinical effects include nausea, vomiting, abdominal (right upper quadrant) pain, anorexia, weakness, fever and chills, followed by jaundice, cholestasis, cholangitis, portal inflammation, increased hepatic enzyme serum levels and abnormal liver histopathology (inflammation, liver cell necrosis, eosinophil infiltration).
    C) MDA is irritating to skin, eyes and mucous membranes.
    1) Dermal contact may produce erythema and swelling. Contact dermatitis and skin sensitization to MDA has been reported. Allergic dermatitis, with rash, itching, hives and swelling, has occurred; however, such exposures are confounded by concomitant exposure to other chemicals. MDA produces an intense yellow staining of skin and nails and sometimes hair.
    2) Eye contact may result in itching, burning, lacrimation, conjunctivitis and corneal burns. Retinotoxic effects have been produced in animals after oral or inhalational administration; this has not been seen in humans except for one case of accidental ingestion (with other chemicals) that resulted in severe visual dysfunction related to gross malfunction of the retinal pigment epithelium.
    D) The spleen and kidneys are also adversely affected by exposure. One case of transient cardiac ischemia after exposure to MDA dusts has been documented.
    E) Toxic fumes of aniline and nitrogen oxides can be produced when MDA is heated to decomposition. Methemoglobinemia and pulmonary edema are key potential effects of these chemicals. Refer to the ANILINE MEDITEXT(R) Medical Management for more information.

Vital Signs

    3.3.1) SUMMARY
    A) Fever and hypotension (rare) have been reported.
    3.3.3) TEMPERATURE
    A) Chills and fever of greater than 39 degrees C occurred in 10 of 13 workers who developed hepatitis after processing an epoxy resin with MDA (McGill & Motto, 1974). Inhalation of vapor or dust and dermal contact with MDA likely occurred.
    3.3.4) BLOOD PRESSURE
    A) Hypotension developed in one individual who ingested a liquid containing MDA, potassium carbonate, and gamma butyrolactone (Roy et al, 1985; Hathaway et al, 1991).

Heent

    3.4.3) EYES
    A) Eye irritation may occur (US DHHS/OSHA, 1992).
    B) IMPAIRED VISION - Loss of central visual fields, color discrimination, and dark adaptation occurred in one person who drank a liquid containing MDA, potassium carbonate, and gammabutyrolactone. No additional visual changes were found 18 months later (Roy et al, 1985; Grant, 1993).
    3.4.5) NOSE
    A) ODOR - MDA has a faint, amine odor (Lewis, 1996) which is not sufficient as a warning property (Hathaway et al, 1991).

Cardiovascular

    3.5.1) SUMMARY
    A) Acute cardiomyopathy has been reported in one case of extremely high-level inhalational and dermal MDA exposure.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) Transient acute cardiomyopathy developed in a 20-year-old man within 7 days of exposure to a large amount of MDA dust. Inhalation and dermal exposure probably occurred (Brooks et al, 1979).
    a) Chest pain was present the day after exposure, but ECG results were initially normal. Seven days after exposure, LDH isoenzyme fractions one and two were elevated and ECGs showed depressed ST segments and inverted T waves, indicators of myocardial ischemia and injury. The ECG was normal one year later.

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Multiple pulmonary granulomas were present in 7 of 16 guinea pigs exposed nose-only to aerosols of MDA-polyethylene glycol (PEG) 4 hours per day, 5 days/week, for two weeks; one of 8 control animals (PEG exposure only) had pulmonary granulomas (Leong et al, 1987).
    b) No evidence of acute pulmonary irritation during MDA-PEG aerosol inhalation nor any evidence of respiratory sensitization to MDA-PEG were found (Leong et al, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) OPTIC NEURITIS
    1) Toxic optic neuritis resulting in severely impaired vision was suspected in an individual who ingested MDA, potassium carbonate, and gamma butyrolactone (Roy et al, 1985; Hathaway et al, 1991).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) MDA was tested for possible anesthetic effects in rabbits. NO anesthetic properties were observed (Tullner, 1960).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, and anorexia can occur.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) Nausea, vomiting, and anorexia have been frequently reported following MDA exposure by inhalation, dermal contact, or ingestion (McGill & Motto, 1974; Liss & Guirguis, 1994).

Hepatic

    3.9.1) SUMMARY
    A) Transient hepatotoxicity has occurred in humans following ingestion, inhalation, and dermal contact with MDA.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) Transient jaundice, severe right upper quadrant abdominal pain, and abnormally elevated hepatic serum enzyme levels occurred within hours to several days following ingestion by 84 persons of MDA-contaminated bread (so-called "Epping jaundice," named for the city in the UK where this outbreak occurred) (Kopelman et al, 1966). Similar effects have occurred as a result of MDA inhalation and dermal contact (McGill & Motto, 1974) Williams et al, 1974; (Brooks et al, 1979; Bastian, 1984; Liss & Guirguis, 1994).
    2) Liver biopsies have revealed cellular infiltration, cholestasis, and hepatic parenchymal and biliary tree damage (Kopelman et al, 1966).
    3) Recovery time has ranged from less than 7 weeks (McGill & Motto, 1974) to three months after exposure (Kopelman et al, 1966).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) No histopathological evidence of hepatic injury was found in guinea pigs exposed nose-only to aerosols of MDA and Polyethylene glycol for 4 hours/day, 5 days/week, over two weeks (Leong et al, 1987). The exposure dose of 440 mg/m(3) was more than 100 times greater than previously published high workplace exposure levels (Leong et al, 1987).
    2) Hepatic injury has occurred in rabbits, dogs, and cats fed MDA in acute toxicity studies (ACGIH, 1991) and in rabbits exposed orally or dermally to MDA-containing sweepings from the floor of a mill where workers had developed hepatitis (McGill & Motto, 1974).
    3) Hepatotoxicity has also been produced in subchronic and chronic toxicity studies involving oral and subcutaneous administration of MDA or MDA dihydrochloride to rats (ACGIH, 1991).
    4) Depletion of hepatic total glutathione in rats was found to accelerate and enhance hepatotoxicity of 4,4'-methylenedianiline (MDA), as compared to the effects of MDA exposure in rats with normal glutathione levels. Rats exposed to 50 mg/kg MDA by gavage had moderate oncosis of biliary epithelial cells, mild edema of portal triads, and alteration of enzymatic activities 6 hours following exposure. In rats with ~96% depletion of hepatic total glutathione, MDA exposure caused severe oncosis of bilary epithelial cells, marked inflammation and edema of the portal tracts, and cell death in scattered hepatocytes, with bile duct injury becoming apparent within 3 hours after exposure, and markedly more severe at 6 hours. These findings contrast those of similar studies investigating alpha-naphthylisothiocyanate as the hepatotoxin, in which glutathione-depletion appears to protect against bile duct injury from chemical exposure (Kanz et al, 2003).

Genitourinary

    3.10.1) SUMMARY
    A) Dark, brown urine has been reported.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) Dark brown urine has been reported from inhalational and dermal exposure to MDA as a resin curing agent (McGill & Motto, 1974; Bastian, 1984).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Renal damage has been produced in rabbits, dogs, and cats administered MDA orally in acute toxicity tests (ACGIH, 1991).
    b) No histopathological evidence of renal damage was detected in guinea pigs exposed nose-only to aerosols of MDA and Polyethylene glycol for 4 hours/day, 5 days/week, over two weeks (Leong et al, 1987). The dose used was more than 100 times that reported as a high workplace exposure level.

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia has been produced in some experimental animals species but has not been reported in human MDA exposures.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia can be produced experimentally by aromatic amines, but in the industrial setting is unlikely to occur except with exposure to single-ring compounds such as aniline; MDA is a double-ring aromatic amine (ILO, 1983).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Methemoglobinemia has been produced in cats, but not dogs, exposed to MDA (Benya & Cornish, 1993).
    b) Rats and dogs chronically fed MDA had low hemoglobin levels but did not develop methemoglobinemia (Benya & Cornish, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) Irritation, rashes, and sensitization have been reported from exposure to MDA and other chemicals. Jaundice can occur secondary to acute hepatitis and has been reported following ingestion of MDA-contaminated food and in workers exposed to MDA-containing resins.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Pruritus, erythema, and vesicular rashes occurred in one worker exposed solely to MDA (Brooks et al, 1979) and in workers exposed to MDA and other chemicals (Emmett, 1976; Van Joost et al, 1987). Ingestion of MDA-contaminated bread has also caused persistent pruritus associated with cholestasis and jaundice (Kopelman et al, 1966).
    B) HYPERSENSITIVITY REACTION
    1) Positive patch test results to MDA have been reported in workers exposed to MDA (Emmett, 1976; Van Joost et al, 1987).
    C) DERMATITIS
    1) Dermal irritation and an extensive erythematous vesicular rash involving the face and neck developed in a worker within a few hours of suspected exposure to methylenedianiline and epichlorohydrin (Van Joost et al, 1987). Patch test results were positive for methylenedianiline and 7 other chemicals, but negative for epichlorohydrin.
    a) Some reports of possible sensitization responses to MDA are confounded by concurrent exposure to other chemicals which cause allergic contact dermatitis (Hathaway et al, 1991; ACGIH, 1991).
    D) JAUNDICE
    1) Jaundice secondary to hepatitis has been reported in persons who worked with MDA-containing resins without adequate hygiene or protective equipment (McGill & Motto, 1974; Brooks et al, 1979; Liss & Guirguis, 1994) and following consumption of MDA-contaminated bread ("Epping jaundice") (Kopelman et al, 1966).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) No evidence of dermal irritation or sensitization were found in guinea pigs dermally exposed to a MDA-polyethylene glycol (PEG) solution two weeks after inhalational exposure to MDA-PEG aerosols (Leong et al, 1987). The standard Draize protocol was used for irritancy testing.

Musculoskeletal

    3.15.1) SUMMARY
    A) Weakness, myalgia, and arthralgia can occur.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) Weakness has been reported in exposed workers (McGill & Motto, 1974).
    B) MUSCLE PAIN
    1) Myalgia, arthralgia, and other flu-like complaints have been reported as early symptoms following ingestion (Kopelman et al, 1966) or occupational exposure to MDA by inhalation and skin contact (McGill & Motto, 1974; Bastian, 1984).

Endocrine

    3.16.1) SUMMARY
    A) MDA can severely depress adrenocortical response to stress in rats.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) MDA has anti-thyroid activity, but is not as potent as the thiourea derivatives (Benya & Cornish, 1994).
    1) Ovariectomized female rats had increased thyroid weights ranging from 57% to 92% after oral administration of 150 to 200 mg of MDA/kg/day for up to two weeks (Tullner, 1960).
    2) ENDOCRINE DISORDER
    a) Adrenal hypertrophy occurred in ovariectomized female rats following daily oral MDA administration (Tullner, 1960).
    b) In dogs, single intravenous MDA doses ranging from 50 mg/kg to 100 mg/kg produced 7- to 8-fold decreases in the secretion of adrenal 17-hydroxycorticoid within 5 minutes of administration (Tullner, 1960). Secretion returned to normal two hours after administration.
    c) Subcutaneous MDA produced significant increases in adrenal weight in immature female rabbits (Tullner, 1960).
    d) In rats, MDA inhibited adrenal corticosterone secretion in response to surgical stress or infusion of adrenocorticotropic hormone (Harada, 1967).
    e) PROGESTATIONAL EFFECTS - Subcutaneous MDA administration caused proliferation of the endometrium of ovariectomized female rabbits, but had no progestational effects in ovariectomized, adrenalectomized rabbits indicating that the effects of MDA on the endometrium were adrenal-dependent (Tullner, 1960).
    f) ANTI-ANDROGENIC EFFECTS - In dogs, single intravenous injections of MDA significantly decreased the secretion of testicular 17-oxosteroids in response to human chorionic gonadotropin or pregnant mare serum (Yamashita, 1967; Yamashita et al, 1969). Recovery occurred within two hours.

Immunologic

    3.19.1) SUMMARY
    A) Allergic contact dermatological reactions can occur in sensitized individuals acutely exposed to MDA.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Allergic contact dermatitis, consisting of pruritus, erythema, and a papular and vesicular rash, developed in an individual suspected to have been acutely exposed to MDA and epichlorohydrin (Van Joost et al, 1987). Patch tests were positive for MDA and negative for epichlorohydrin.
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) ANIMAL STUDIES
    1) No dermal or pulmonary sensitization reactions were produced in guinea pigs exposed to MDA-polyethylene glycol (PEG) aerosols by inhalation and later challenged with MDA-PEG (Leong et al, 1987).

Reproductive

    3.20.1) SUMMARY
    A) There is little information concerning possible reproductive effects of MDA in humans or experimental animals.
    B) MDA administered to laboratory animals has caused endometrium proliferation and decreased the secretion of testicular hormones in response to stimuli. The significance of these results for human reproduction is unknown.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MDA was toxic and teratogenic when injected into chickens (McLaughlin, 1963). When given orally to pregnant rats in an attempt to induce liver damage, it caused liver damage and neural tube defects in fetuses at doses greater than the LD50 (Bourdelat, 1983).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS101-77-9 (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'-Methylenedianiline
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) Little human data exist. One case of bladder cancer slightly in excess of the expected incidence was reported in a study of 10 MDA-exposed workers with a history of hepatotoxicity. Based on experimental animal research, MDA is labeled as anticipated to be carcinogenic or as a possible human carcinogen.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) OCCUPATIONAL EXPOSURE
    a) Few data are available. Liss & Guirguis (1994) reported one case of bladder cancer among 10 workers formerly exposed to MDA and having documented hepatotoxicity; the expected incidence of bladder cancer was 0.6. This bladder cancer was detected 23 years after exposure. The cohort was followed-up for 15 to 24 years.
    b) Increases in colon cancer, lymphosarcoma, and reticulosarcoma have also been reported from mixed occupational exposures (Hathaway et al, 1991). In an epidemiological study, neither morbidity nor mortality were increased with average exposure to 0.03 to 3.8 ppm for 26 years (ACGIH, 1992).
    B) CARCINOMA
    1) MDA is anticipated to be carcinogenic (US DHHS, 1994) or is considered a possible human carcinogen (IARC, 1987) by the US National Toxicology Program (NTP) and the International Agency for Research on Cancer (IARC).
    2) The American Conference of Governmental Industrial Hygienists (ACGIH) has labeled MDA as an A2 suspected human carcinogen, but has proposed to revise this classification to A3, animal carcinogen (ACGIH, 1995). US OSHA considers MDA as a possible human carcinogen (US DHHS/OSHA, 1992).
    3) Increases in colon cancer, lymphosarcoma, and reticulosarcoma have also been reported from mixed occupational exposures (Hathaway et al, 1991). In an epidemiological study, neither morbidity nor mortality were increased with average exposure to 0.03 to 3.8 ppm for 26 years (ACGIH, 1992).
    C) LACK OF EFFECT
    1) MORTALITY
    a) A follow-up study of individuals, who were exposed to 4,4-methylenedianiline during an outbreak of jaundice in the Epping district of Sussex in 1965, was conducted to determine the incidence of mortality. The results of the study showed that mortality from all causes among men was significantly below expectations (Observed [Obs]12; Expected [Exp] 26.7; Standardized Mortality Ratio [SMR] 45). Mortality from all causes among women appeared to be close to expectations (Obs 25; Exp 30.3; SMR 82). Deaths from all neoplasms in men and women were below expectations (Obs 2; Exp 6.5; SMR 31) and at expectations (Obs 6; Exp 6.9; SMR 87), respectively. There were no observed deaths from liver or urinary bladder carcinoma (Nichols, 2004).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Lifetime oral administration of MDA as the dihydrochloride to rats and mice resulted in thyroid follicular cell carcinomas and adenomas, C-cell adenomas, hepatic carcinomas, adrenal pheochromocytomas, and malignant lymphomas (Weisburger et al, 1984; (US DHHS, 1994).
    2) MDA administered orally with a known carcinogen also increased the incidence of thyroid tumors in rats above that expected solely from the carcinogenic agent (US DHHS, 1994).
    3) MDA has induced thyroid and liver tumors in rats and mice (Grundmann & Steinhoff, 1970; Schoental, 1968; Grundmann & Steinhoff, 1970) Lamb et al, 1986). It was not carcinogenic in a feeding study in dogs (ACGIH, 1992). It enhanced induction of colon and thyroid tumors by other substances (Fukushima, 1977; Hiasa, 1984), but inhibited development of bladder cancer in rats (Fukushima, 1981).

Genotoxicity

    A) MDA was mutagenic in the AMES test, induced sex-linked recessive lethal mutations in Drosophila melanogaster, and produced dose-related sister chromatid exchanges in mouse bone marrow cells. It was also positive in the mouse lymphoma assay. It did not produce cytogenetic effects in human leukocytes in vitro or reciprocal translocations in Drosophila melanogaster.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver enzymes and bilirubin. ECG is advisable in patients with chest pain or other evidence of possible cardiac involvement.
    B) Monitor BUN, serum creatinine, and fluid and electrolyte status.
    C) In cyanotic or hypoxic patients, monitor methemoglobin level, arterial blood gases with O2 saturation, CBC, and ECG. A chest x-ray may also be indicated for differential diagnosis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum hepatic transaminases (ALT, AST), alkaline phosphatase, and bilirubin levels.
    2) Monitor BUN and serum creatinine. Renal toxicity is not a common finding in MDA-exposed humans, but has been reported in experimental animals.
    B) HEMATOLOGIC
    1) Methemoglobinemia has been reported in some experimental animals, but has not been reported in MDA-exposed humans (ILO, 1983). Monitor methemoglobin levels, arterial blood gases, CBC, and electrolytes in cyanotic patients. The IL-282 co-oximeter can directly measure methemoglobin saturation and oxygen saturation; pulse oximetry is not reliable (Blanc, 1994).
    a) The use of methylene blue as an antidote can result in falsely high methemoglobin levels if the co-oximeter is used (Blanc, 1994).
    2) The bedside test in which a drop of the patient's blood is placed on filter paper, allowed to dry, and compared with a dried drop of normal blood can be used while awaiting the results of direct methemoglobin analyses. The blood will usually appear chocolate brown when the methemoglobin level exceeds 15% (Blanc, 1994).
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urinalysis and fluid balance. Renal toxicity has not been commonly reported in humans, but has occurred in experimental animals exposed to MDA.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Detailed exposure monitoring and medical surveillance requirements are covered by the US OSHA MDA standard, published in Volume 29 of the Code of Federal Regulations (29 CFR) Part 1910.1050 and for the construction industry in 29 CFR 1926.60 (US DHHS/OSHA, 1992).
    2) DERMAL
    a) Patch testing may identify individuals sensitized to MDA.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray may be useful in differential diagnosis.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) MDA hemoglobin adducts can be quantitated using gas chromatography-mass spectrometry (Bailey et al, 1990).
    2) MDA can be detected in hydrolyzed urine using high performance liquid chromatography (HPLC) and ultraviolet detection (Tiljander & Skarping, 1990) or HPLC and electrochemical detection (Peterson et al, 1991; Brunmark et al, 1992).
    3) The HPLC/electrochemical detection method was found to yield results which correlated well with those produced by gas chromatography-mass spectrometry, but was considered more straight forward (derivatization not required) than gas chromatography-mass spectrometry and had good reproducibility (Peterson et al, 1991).
    B) OTHER
    1) Levels of total MDA in urine were unchanged for at least 16 days when samples were stored at 2 to 4 degrees C (Peterson et al, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit persons with significant exposure or symptoms to the hospital.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Admit symptomatic patients or individuals with significant exposure to the hospital.
    6.3.5) DISPOSITION/DERMAL EXPOSURE
    6.3.5.3) CONSULT CRITERIA/DERMAL
    A) A dermatologic consult is suggested if sensitization and allergic dermatitis is suspected.
    6.3.5.5) OBSERVATION CRITERIA/DERMAL
    A) 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.

Monitoring

    A) Monitor liver enzymes and bilirubin. ECG is advisable in patients with chest pain or other evidence of possible cardiac involvement.
    B) Monitor BUN, serum creatinine, and fluid and electrolyte status.
    C) In cyanotic or hypoxic patients, monitor methemoglobin level, arterial blood gases with O2 saturation, CBC, and ECG. A chest x-ray may also be indicated for differential diagnosis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) INHALATION EXPOSURE
    1) Move the patient from the contaminated environment to fresh air.
    B) DERMAL AND EYE EXPOSURE
    1) Remove contaminated clothing and equipment. Wash the contaminated skin with soap or mild detergent and water. If eye exposure has occurred, rinse the eyes with large amounts of water.
    C) INGESTION EXPOSURE
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) 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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is primarily supportive.
    B) OBSERVATION REGIMES
    1) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) METHEMOGLOBINEMIA
    1) In the unlikely event of methemoglobinemia, administer methylene blue.
    2) Some clinicians have recommended methylene blue administration with methemoglobin levels of >15 to 20% (Blanc, 1994).
    3) 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.
    4) 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).
    5) 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.
    D) ADRENAL CORTICAL HYPOFUNCTION
    1) ADRENAL INSUFFICIENCY - Acute MDA exposure causes severe adrenocortical dysfunction in rats. It is not known if adrenal insufficiency occurs in humans, but this possibility should be considered in acutely ill victims who do not respond to other supportive treatment. High dose steroids might be necessary to treat this condition.

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) SUPPORT
    1) Administer 100% humidified oxygen with assisted ventilation as needed. Observe the patient for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) ADRENAL CORTICAL HYPOFUNCTION
    1) ADRENAL INSUFFICIENCY - Acute MDA exposure causes severe adrenocortical dysfunction in rats. It is not known if adrenal insufficiency occurs in humans, but this possibility should be considered in acutely ill victims who do not respond to other supportive treatment. High dose steroids might be necessary to treat this condition.
    C) METHEMOGLOBINEMIA
    1) In the unlikely event of methemoglobinemia, administer methylene blue.
    2) Some clinicians recommend methylene blue if methemoglobinemia is 15 to 20% or greater (Blanc, 1994).
    3) 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.
    4) 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).
    5) 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.
    D) 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) CLOTHING
    1) Remove contaminated clothing and protective equipment, avoiding secondary exposure of others. Proper protective clothing and respiratory equipment should be worn by individuals who contact the patient prior to adequate decontamination.
    2) Contaminated clothing and equipment should be stored and transported in properly labeled, sealed, and impermeable containers, and handled and cleaned only by trained individuals as outlined in the US OSHA standard on the regulation of exposure to MDA (US DHHS/OSHA, 1992).
    B) 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).
    2) Hewitt et al (1994) have demonstrated that washing the contaminated skin within 30 minutes of exposure is critical for reducing absorption of MDA. These in vitro showed that delayed washing of the skin one or more hours after exposure did not significantly reduce MDA absorption.
    3) In vitro studies involving human skin indicated that 100% water, 100% ethanol, a 1% solution of aqueous soap, and a 10% solution of aqueous soap were equally effective in skin decontamination; however, less than 50% of an applied dose was removed by these decontamination measures.
    4) Rat skin was most effectively decontaminated with 100% ethanol or a 10% aqueous soap solution; a maximum of 33% of an applied dose was removed by these decontamination methods (Hewitt et al, 1994).
    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.
    C) METHEMOGLOBINEMIA
    1) In the unlikely event of methemoglobinemia, administer methylene blue.
    2) Some clinicians recommend methylene blue if methemoglobin is 15 to 20% or greater (Blanc, 1994).
    3) 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.
    4) 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).
    5) 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.
    D) ADRENAL CORTICAL HYPOFUNCTION
    1) ADRENAL INSUFFICIENCY - Acute MDA exposure causes severe adrenocortical dysfunction in rats. It is not known if adrenal insufficiency occurs in humans, but this possibility should be considered in acutely ill victims who do not respond to other supportive treatment. High dose steroids might be necessary to treat this condition.
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Adverse effects have resulted from ingestion, inhalation and dermal exposure to MDA. The exact doses and duration of exposure was not know in most cases. MDA is a suspected carcinogen.

Minimum Lethal Exposure

    A) ADULT
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) HUMAN
    1) ACUTE
    a) Exposure to 4,4'-methylenedianiline through all routes may result in toxicity, with symptoms including fever, hyperthermia, urine discoloration, skin rash, allergic dermatitis, and damage to the bile duct epithelium, resulting in jaundice, hepatitis, cholestasis, cholangitis, bile duct proliferation, myocardiopathy and impaired vision (Bingham et al, 2001).
    1) INGESTION
    a) A condition known as "Epping jaundice" is associated with ingestion of 4,4'-methylenedianiline (concentrations not specified). Affected people suffer from severe right-upper-quadrant pain, weakness, high fever, chills, jaundice, abdomen pain, nausea/vomiting and anorexia (Budavari, 2000; NTP , 2001).
    b) Eighty-four individuals developed hepatitis after eating bread baked with flour that was contaminated with 4,4'-methylenedianiline (containing 0.26 percent 4,4'-methylenedianiline). The time between ingestion and the development of symptoms ranged from several hours to more than 10 days (ACGIH, 1991; Kopelman et al, 1966).
    c) One female and five males (between the ages of 17 and 25) ingested an unknown dose of 4,4'-methylenedianiline (MDA) in an alcoholic beverage for the purpose of intoxication, believing it to be methylendioxyamphetamine (MDMA; alpha-dimethyl-1,3-benzodioxole-5-ethanamine; CAS 42542-10-9, a popular psychometric drug also known by the abbreviation "MDA"). All patients developed the same symptoms: severe colicky abdominal pain, acute jaundice, cholestasis and fever. Urine samples taken from one of the patients showed 4,4'-methylenedianiline levels of 130 mg/L (Tillman et al, 1997).
    d) Central nervous system and hepatic effects were associated with an ingestion of 8420 micrograms 4,4'-methylenedianiline per kilogram body weight (Lewis, 2000). Details of the effects were not provided in this review.
    2) INHALATION/VAPOR
    a) 4,4'-Methylenedianiline is minimally irritating to the respiratory system at 0.5 to 1 ppm; it is painfully irritating to the eyes at 4 ppm (ACGIH, 1991).
    2) CHRONIC
    a) A review of medical data on chemical plant employees did not reveal increased morbidity or mortality in workers exposed to concentrations of 0.03 to 3.8 ppm 4,4'-methylenedianiline; TWA exposure levels were reported to be 0.03 to 0.4 ppm (ACGIH, 1991).
    b) Workers exposed to 4,4'-methylenedianiline through contact with the hands for several hours daily developed toxic hepatitis. Air concentrations of up to 0.1 ppm 4,4'-methylenedianiline were recorded in the work area during the early onset of the illness. All patients recovered within seven weeks, and a follow-up more than 5 years after exposure showed no lasting sequelae (ACGIH, 1991; Hathaway et al, 1996; McGill & Motto, 1974).

Workplace Standards

    A) ACGIH TLV Values for CAS101-77-9 (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 dianiline
    a) TLV:
    1) TLV-TWA: 0.1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Liver dam
    d) Molecular Weight: 198.26
    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 CAS101-77-9 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: 4,4'-Methylenedianiline
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS101-77-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: 4,4'-Methylene dianiline
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    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): 2B ; Listed as: 4,4'-Methylenedianiline
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: 4,4'-Methylenedianiline
    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'-Diaminodiphenylmethane
    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-Methylenedianiline and Its dihydrochloride Salt
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS101-77-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Methylenedianiline; see 29 CFR 1910.1050
    2) Table Z-1 for Methylenedianiline; see 29 CFR 1910.1050:
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3:
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s):
    a) (g): [Editor's note: The format of the original source data has been corrected for this chemical.]

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: ACGIH, 1991 Bingham et al, 2001 Lewis, 2000 NTP, 2001 ) (RTECS, 2000; Verschueren, 2001
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 74 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 264 mg/kg
    b) 745 mg/kg
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 193 mg/kg
    4) LD50- (ORAL)RAT:
    a) 347 mg/kg
    b) 517 mg/kg
    c) 597 mg/kg (ACGIH, 1991)
    d) 830 mg/kg (ACGIH, 1991; Bingham et al, 2001)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 200 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) CARCINOGENICITY - Structural properties of MDA may underlie its potential carcinogenicity. MDA is structurally and chemically similar to benzidine, a known human bladder carcinogen, and other polycyclic aromatic amines which are possibly carcinogenic (ILO, 1983; Liss & Guirguis, 1994).
    B) ALLERGIC CONTACT DERMATITIS - Aromatic amines with para structures are often associated with allergic contact dermatitis and cross-sensitization (ILO, 1983). This structural characteristic is also considered mechanistically important in MDA-associated dermatitis and sensitization (Van Joost et al, 1987).
    C) METHEMOGLOBINEMIA - Methemoglobinemia can be produced experimentally by many aromatic amines. Occupational exposures are unlikely to cause methemoglobinemia unless the aromatic amine is a single-ring chemical, such as aniline (ILO, 1983). MDA is a double-ring chemical.

Physicochemical

Physical Characteristics

    A) At room temperature, 4,4'-methylenedianiline is a pale yellow to tan or light brown crystalline solid or flakes which may have a faint, amine or "fish-like" odor (AAR, 2000; ACGIH, 1991; NTP , 2001). It is a liquid at 212 degrees F (NIOSH , 2002). The crystals darken on exposure to air, with some differences in its color due to differences in purity (Bingham et al, 2001). It may also be found in liquid form when mixed with certain other chemicals (Bingham et al, 2001; Lewis, 1993). It forms pearly flakes/leaflets from benzene (Lewis, 2000).
    B) It is also encountered as an orange or yellow dust (Bastian, 1984; Cohen, 1985).

Ph

    A) Weak base (HSDB , 2002)

Molecular Weight

    A) 198.29

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.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 49 CFR 172.101: Department of Transportation - Table of Hazardous Materials. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 11, 2005.
    5) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    6) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    9) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    10) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    11) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    12) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    13) AAR: Emergency Handling of Hazardous Materials in Surface Transportation, Bureau of Explosives, Association of American Railroads, Washington, DC, 2000.
    14) ACGIH: Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed, Am Conference of Govt Ind Hyg, Inc, Cincinnati, OH, 1986.
    15) ACGIH: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed, Am Conference of Govt Ind Hyg, Inc, Cincinnati, OH, 1991.
    16) ACGIH: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed, Am Conference of Govt Ind Hyg, Inc, Cincinnati, OH, 1992, pp 998-1001.
    17) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    18) ATSDR: Public Health Statement for 4,4'-Methylenedianiline. Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Atlanta, GA, USA. 1998. Available from URL: http://www.atsdr.cdc.gov/toxprofiles/phs122.html. As accessed Accessed 2002 26 Mar.
    19) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    20) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    21) Ansell-Edmont: SpecWare Chemical Application and Recommendation Guide. Ansell-Edmont. Coshocton, OH. 2001. Available from URL: http://www.ansellpro.com/specware. As accessed 10/31/2001.
    22) Ashford R: Ashford's Dictionary of Industrial Chemicals, Wavelength Publications Ltd, London, England, 1994.
    23) Bailey E, Brooks AG, & Bird I: Monitoring exposure to 4,4'-methylenedianiline by the gas chromatography-mass spectrometry determination of adducts to hemoglobin. Anal Biochem 1990; 190:175-181.
    24) Bastian PG: Occupational hepatitis caused by methylenedianiline. Med J Aust 1984; 141:533-535.
    25) Bata Shoe Company: Industrial Footwear Catalog, Bata Shoe Company, Belcamp, MD, 1995.
    26) Benya TJ & Cornish HH: Aromatic nitro and amino compounds, in: Clayton GD & Clayton FE (Eds), Patty's Industrial Hygiene and Toxicology, Vol 2A, Toxicology, 4th ed, John Wiley & Sons, New York, NY, 1993.
    27) Best Manufacturing: ChemRest Chemical Resistance Guide. Best Manufacturing. Menlo, GA. 2002. Available from URL: http://www.chemrest.com. As accessed 10/8/2002.
    28) Best Manufacturing: Degradation and Permeation Data. Best Manufacturing. Menlo, GA. 2004. Available from URL: http://www.chemrest.com/DomesticPrep2/. As accessed 04/09/2004.
    29) Bingham E, Cohrssen B, & Powell CH: Patty's Toxicology, Vol 4. 5th ed, John Wiley & Sons, New York, NY, 2001.
    30) Blanc P: Methemoglobinemia, in: Olson KR (Ed), Poisoning & Drug Overdose, 2nd ed, Appleton & Lange, Norwalk, CT, 1994, pp 217-219.
    31) Boss Manufacturing Company: Work Gloves, Boss Manufacturing Company, Kewanee, IL, 1998.
    32) Bourdelat D: Bull Assoc Anat (Nancy) 1983; 67:375-382.
    33) Brooks LJ, Neale JM, & Pieroni DR: Acute myocardiopathy following tripathway exposure to methylenedianiline. JAMA 1979; 242:1527-1528.
    34) Brunmark P, Dalene M, & Skarping G: Gas chromatography-negative-ion chemical ionization mass spectrometry of hydrolysed human urine and blood plasma for the biomonitoring of occupational exposure to 4,4'-methylenebisaniline. Analyst 1995b; 120:41-45.
    35) Brunmark P, Persson P, & Skarping G: Determination of 4,4'-methylenedianiline in hydrolysed human urine by micro liquid chromatography with ultraviolet detection. J Chromatogr 1992; 579:350-354.
    36) Budavari S: The Merck Index, 12th ed. on CD-ROM. Version 12:3a. Chapman & Hall/CRCnetBASE. Whitehouse Station, NJ. 2000.
    37) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    38) ChemFab Corporation: Chemical Permeation Guide Challenge Protective Clothing Fabrics, ChemFab Corporation, Merrimack, NH, 1993.
    39) Chemsoft(R) : Electronic EPA, NIOSH, & OSHA Methods(TM). Windowchem(TM) Software. Fairfield, CA. 2000.
    40) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    41) Cocker J, Nutley BP, & Wilson HK: A biological monitoring assessment of exposure to methylene dianiline in manufacturers and users. Occup Environ Med 1994; 51:519-522.
    42) Cocker J: Assessment of occupational exposure to 4,4'-diaminodiphenylmethane (methylene dianiline) by gas chromatography-mass spectrometry analysis of urine. Br J Ind Med 1986; 43:620-625.
    43) Cohen SR: Yellow staining caused by 4,4'-methylenedianiline exposure. Arch Dermatol 1985; 121:1022-1027.
    44) Comasec Safety, Inc.: Chemical Resistance to Permeation Chart. Comasec Safety, Inc.. Enfield, CT. 2003. Available from URL: http://www.comasec.com/webcomasec/english/catalogue/mtabgb.html. As accessed 4/28/2003.
    45) Comasec Safety, Inc.: Product Literature, Comasec Safety, Inc., Enfield, CT, 2003a.
    46) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    47) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    48) Dalene M, Skarping G, & Brunmark P: Assessment of occupational exposure to 4,4'-methylenedianiline by the analysis of urine and blood samples. Internat Arch Occup Environ Health 1995; 67:67-72.
    49) Darby TD: Toxicol Appl Pharmacol 1978; 46:449-453.
    50) DuPont: DuPont Suit Smart: Interactive Tool for the Selection of Protective Apparel. DuPont. Wilmington, DE. 2002. Available from URL: http://personalprotection.dupont.com/protectiveapparel/suitsmart/smartsuit2/na_english.asp. As accessed 10/31/2002.
    51) DuPont: Permeation Guide for DuPont Tychem Protective Fabrics. DuPont. Wilmington, DE. 2003. Available from URL: http://personalprotection.dupont.com/en/pdf/tyvektychem/pgcomplete20030128.pdf. As accessed 4/26/2004.
    52) DuPont: Permeation Test Results. DuPont. Wilmington, DE. 2002a. Available from URL: http://www.tyvekprotectiveapprl.com/databases/default.htm. As accessed 7/31/2002.
    53) Dunipace AJ, Beaven R, Noblitt T, et al: Mutagenic potential of toluidine blue evaluated in the Ames test. Mutat Res 1992; 279(4):255-259.
    54) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    55) ERG: Emergency Response Guidebook. A Guidebook for First Responders During the Initial Phase of a Dangerous Goods/Hazardous Materials Incident, U.S. Department of Transportation, Research and Special Programs Administration, Washington, DC, 2004.
    56) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    57) Emmett EA: Allergic contact dermatitis in polyurethane plastic moulders. J Occup Med 1976; 18:802-804.
    58) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    59) Foureman P, Mason JM, & Valencia R: Chemical mutagenesis testing in drosophila. X. Results of 70 coded chemicals tested for the national toxicology program. Environ Mol Mutagen 1994; 23:208-227.
    60) Fukushima S: Carcinogenesis 1981; 2:1033-1037.
    61) Fukushima S: Toxicol Appl Pharmacol 1977; 40:561-570.
    62) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    63) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    64) Grant WM: Toxicology of the Eye, 4th ed, Charles C Thomas, Springfield, IL, 1993.
    65) Grundmann E & Steinhoff D: Zeitschr Krebsforch 1970; 74:28-39.
    66) Guardian Manufacturing Group: Guardian Gloves Test Results. Guardian Manufacturing Group. Willard, OH. 2001. Available from URL: http://www.guardian-mfg.com/guardianmfg.html. As accessed 12/11/2001.
    67) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    68) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    69) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2004; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    70) Harada Y: The effect of 4,4'-methylenedianiline on adrenal corticosterone secretion in the rat. Tohoku J Exp Med 1967; 91:315-322.
    71) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    72) Hathaway GJ, Proctor NH, & Hughes JP: Chemical Hazards of the Workplace, 3rd ed, Van Nostrand Reinhold Company, New York, NY, 1991, pp 395-397.
    73) Hathaway GJ, Proctor NH, & Hughes JP: Chemical Hazards of the Workplace, 4th ed, Van Nostrand Reinhold Company, New York, NY, 1996.
    74) Herman MI, Chyka PA, & Butlse AY: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111-113.
    75) Hewitt PG, Hotchkiss SAM, & Caldwell J: Decontamination procedures after in vitro topical exposure of human and rat skin to 4,4'-methylenebis(2-chloroaniline) and 4,4'-methylenedianiline. Fundam Appl Toxicol 1995; 26:91-98.
    76) Hiasa Y: J Natl Cancer Inst 1984; 72:471-476.
    77) Hix WR & Wilson WR: Toluidine blue staining of the esophagus: a useful adjunct in the panendoscopic evaluation of patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1987; 113(8):864-865.
    78) Hjelt K, Lund JT, Scherling B, et al: Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84(4):365-370.
    79) Ho R, Hardigree AA, & Larimer FW: Comparative mutagenicity study of potentially carcinogenic industrial compounds. Environ Mutagen 1979; 1:167-168.
    80) Howard PH, Boethling RS, & Jarvis WF: Handbook of Environmental Degradation Rates, Lewis Publishers, Chelsea, MI, 1991.
    81) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    82) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    83) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    84) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    85) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    86) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    87) IARC: International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7, International Agency for Research on Cancer, World Health Organization, Geneva, Switzerland, 1987.
    88) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    89) IARC: Monographs on the Evaluation of Carcinogenicity of Chemicals to Humans. 4,4'-Methylenedianiline and its Dihydrochloride, CAS No.: 101-77-9. International Agency for Research on Cancer, World Health Organization. Geneva, Switzerland. 1986. Available from URL: http://193.51.164.11/htdocs/Monographs/ Vol39/4,4'-Methylenedianiline.html. As accessed Accessed March 13, 2002.
    90) ICAO: Technical Instructions for the Safe Transport of Dangerous Goods by Air, 2003-2004. International Civil Aviation Organization, Montreal, Quebec, Canada, 2002.
    91) ILC Dover, Inc.: Ready 1 The Chemturion Limited Use Chemical Protective Suit, ILC Dover, Inc., Frederica, DE, 1998.
    92) ILO : Encyclopedia of Occupational Health and Safety, 4th ed. Vol 1-4. (CD ROM Version). International Labour Organization. Geneva, Switzerland. 1998.
    93) ILO: Encyclopaedia of Occupational Health and Safety, 3rd ed, vol 1, International Labour Organization, Geneva, Switzerland, 1983, pp 141-144.
    94) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    95) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    96) Kanz MF, Dugas TR, Liu H, et al: Glutathione depletion exacerbates methylene toxicity to bilary epithelial cells and hepatocytes in rats. Toxicol Sci 2003; 74(2):447-456.
    97) Kappler, Inc.: Suit Smart. Kappler, Inc.. Guntersville, AL. 2001. Available from URL: http://www.kappler.com/suitsmart/smartsuit2/na_english.asp?select=1. As accessed 7/10/2001.
    98) Kiese M , Lorcher W , Weger N , et al: Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. Eur J Clin Pharmacol 1972; 4(2):115-118.
    99) Kimberly-Clark, Inc.: Chemical Test Results. Kimberly-Clark, Inc.. Atlanta, GA. 2002. Available from URL: http://www.kc-safety.com/tech_cres.html. As accessed 10/4/2002.
    100) Kopelman H, Robertson MH, & Sanders PG: The Epping jaundice. Br Med J 1966; 26:514-516.
    101) LaCrosse-Rainfair: Safety Products, LaCrosse-Rainfair, Racine, WI, 1997.
    102) LaVoie E, Tulley L, & Fow E: Mutagenicity of aminophenyl and nitrophenyl ethers, sulfides, and disulfides. Mutat Res 1979; 67:123-131.
    103) Leong BKJ, Lund JE, & Groehn JA: Retinopathy from inhaling 4,4'-methylenedianiline aerosols. Fundam Appl Toxicol 1987; 9:645-658.
    104) Levine MJ: Contact Dermatitis 1983; 9:488-490.
    105) Lewis RJ: Hawley's Condensed Chemical Dictionary, 12th ed, Van Nostrand Reinhold Company, New York, NY, 1993, pp 362.
    106) Lewis RJ: Hawley's Condensed Chemical Dictionary, 14th ed, John Wiley & Sons, Inc, New York, NY, 2001.
    107) Lewis RJ: Sax's Dangerous Properties of Industrial Materials, 10th ed, Van Nostrand Reinhold Company, New York, NY, 2000.
    108) Lewis RJ: Sax's Dangerous Properties of Industrial Materials, 9th ed, Van Nostrand Reinhold Company, New York, NY, 1996.
    109) Lindenmann J, Matzi V, Kaufmann P, et al: Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report. Inhal Toxicol 2006; 18(13):1047-1049.
    110) Liss GM & Guirguis SS: Follow-up of a group of workers intoxicated with 4,4'-methylenedianiline. Am J Ind Med 1994; 26:117-124.
    111) MAPA Professional: Chemical Resistance Guide. MAPA North America. Columbia, TN. 2003. Available from URL: http://www.mapaglove.com/pro/ChemicalSearch.asp. As accessed 4/21/2003.
    112) MAPA Professional: Chemical Resistance Guide. MAPA North America. Columbia, TN. 2004. Available from URL: http://www.mapaglove.com/ProductSearch.cfm?id=1. As accessed 6/10/2004.
    113) Mar-Mac Manufacturing, Inc: Product Literature, Protective Apparel, Mar-Mac Manufacturing, Inc., McBee, SC, 1995.
    114) Marigold Industrial: US Chemical Resistance Chart, on-line version. Marigold Industrial. Norcross, GA. 2003. Available from URL: www.marigoldindustrial.com/charts/uschart/uschart.html. As accessed 4/14/2003.
    115) Marquez A & Todd M: Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract 1959; 10:1548-1550.
    116) McGill DB & Motto JD: An industrial outbreak of toxic hepatitis due to methylenedianiline. N Engl J Med 1974; 6:278-282.
    117) McLaughlin J Jr: Toxicol Appl Pharmacol 1963; 5:760-771.
    118) Memphis Glove Company: Permeation Guide. Memphis Glove Company. Memphis, TN. 2001. Available from URL: http://www.memphisglove.com/permeation.html. As accessed 7/2/2001.
    119) Mirsalis JC, Tyson CK, & Steinmetz KL: Measurement of unscheduled DNA synthesis and s-phase synthesis in rodent hepatocytes following in vivo treatment: testing of 24 compounds. Environ Mol Mutagen 1989; 14:155-164.
    120) Montgomery Safety Products: Montgomery Safety Products Chemical Resistant Glove Guide, Montgomery Safety Products, Canton, OH, 1995.
    121) NFPA: Fire Protection Guide to Hazardous Materials, 12th ed, National Fire Protection Association, Quincy, MA, 1997.
    122) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    123) NIOSH : Criteria Documents Criteria for a Recommended Standard: Special Hazard Review With Control Recommendations for 4,4'-Methylinebis(2-chloroaniline). Center for Disease Control, (NIOSH). Atlanta, GA. 1973. Available from URL: http://www.cdc.gov/niosh/78-188.html. As accessed Accessed 2002 April 11. City ST and Pub added 6-18-03 ER.
    124) NIOSH : Pocket Guide to Chemical Hazards. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    125) NIOSH : Pocket Guide to Chemical Hazards. National Institute for Occupational Safety and Health. Cincinnati, OH. 1994.
    126) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    127) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    128) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    129) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    130) NTP : NTP Technical Report Number TR-001061. 4,4'-Methylenedianiline. National Toxicology Program, US Department of Human Health Services, National Institutes of Health. Research Triangle Park, NC. 2001. Available from URL: http://ntp-server.niehs.nih.gov/ htdocs/CHEM_H&S/NTP_Chem1/Radian101-77-9.html. As accessed Accessed 2002 March 26.
    131) NTP : Ninth Report on Carcinogens. 4,4'-Methylenedianiline and its Dihydrochloride. National Toxicology Program, US Department of Human Health Services, National Institutes of Health. Research Triangle Park, NC. 2000. Available from URL: http://ehp.niehs.nih.gov/roc/ninth/ rahc/4_4methylenedianiline.pdf. As accessed Accessed 2002 March 26. 6/18/03 - URL connects to 10th edition.
    132) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    133) Nat-Wear: Protective Clothing, Hazards Chart. Nat-Wear. Miora, NY. 2001. Available from URL: http://www.natwear.com/hazchart1.htm. As accessed 7/12/2001.
    134) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    135) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    136) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    137) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    138) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    139) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    140) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    141) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    142) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    143) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    144) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    145) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    146) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    147) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    148) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    149) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    150) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    151) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    152) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    153) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    154) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    155) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    156) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    157) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    158) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    159) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    160) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    161) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    162) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    163) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    164) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    165) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    166) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    167) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    168) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    169) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    170) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    171) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    172) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    173) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    174) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    175) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    176) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    177) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    178) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    179) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    180) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    181) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    182) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    183) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    184) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    185) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    186) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    187) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    188) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    189) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    190) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    191) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    192) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    193) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    194) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    195) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    196) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    197) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    198) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    199) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    200) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    201) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    202) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    203) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    204) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    205) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    206) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    207) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    208) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    209) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    210) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    211) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    212) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    213) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    214) Neese Industries, Inc.: Fabric Properties Rating Chart. Neese Industries, Inc.. Gonzales, LA. 2003. Available from URL: http://www.neeseind.com/new/TechGroup.asp?Group=Fabric+Properties&Family=Technical. As accessed 4/15/2003.
    215) Nemec K: Antidotes in acute poisoning. Eur J Hosp Pharm Sci Pract 2011; 17(4):53-55.
    216) Nichols L: The epping jaundice outbreak: mortality after 38 years of follow-up. Int Arch Occup Environ Health 2004; 77:592-594.
    217) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    218) North: Chemical Resistance Comparison Chart - Protective Footwear . North Safety. Cranston, RI. 2002. Available from URL: http://www.linkpath.com/index2gisufrm.php?t=N-USA1. As accessed April 30, 2004.
    219) North: eZ Guide Interactive Software. North Safety. Cranston, RI. 2002a. Available from URL: http://www.northsafety.com/feature1.htm. As accessed 8/31/2002.
    220) Parodi S, Zunino A, & Ottaggio L: Lack of correlation between the capability of inducing sister-chromatid exchanges in vivo and carcinogenic potency, for 16 aromatic amines and azo derivatives. Mutat Res 1983; 108:225-238.
    221) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    222) Peterson JC, Estiva EC, & Lyttle DS: High-performance liquid chromatographic determination of 4,4'-methylenedianiline in human urine. J Chromatogr 1991; 564:205-212.
    223) Playtex: Fits Tough Jobs Like a Glove, Playtex, Westport, CT, 1995.
    224) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    225) Product Information: PROVAYBLUE(TM) intravenous injection, methylene blue intravenous injection. American Regent (per FDA), Shirley, NY, 2016.
    226) Product Information: methylene blue 1% IV injection, methylene blue 1% IV injection. American Regent, Inc (per manufacturer), Shirley, NY, 2011.
    227) Product Information: methylene blue 1% intravenous injection, methylene blue 1% intravenous injection. Akorn, Inc. (per manufacturer), Lake Forest, IL, 2011.
    228) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 5/31/2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    229) Rannug A: in: Jarvisalo J et al (Eds), Industrial Hazards of Plastics and Synthetic Elastomers, Alan R Liss, New York, NY, 1984, pp 407-419.
    230) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    231) River City: Protective Wear Product Literature, River City, Memphis, TN, 1995.
    232) Robert A, Ducos P, & Francin JM: Determination of urinary 4,4'-methylenedianiline and its acetylated metabolites by solid phase extraction and HPLC analysis with UV and electrochemical detection. Internat Arch Occup Environ Health 1995; 68:44-51.
    233) Roy CW, McSorley PD, & Syme IG: Methylenedianilene: A new toxic cause of visual failure with hepatitis. Human Toxicol 1985; 4:61-66.
    234) Safety 4: North Safety Products: Chemical Protection Guide. North Safety. Cranston, RI. 2002. Available from URL: http://www.safety4.com/guide/set_guide.htm. As accessed 8/14/2002.
    235) Schoental R: Nature 1968; 219:1162-1163.
    236) Schutze D, Sagelsdorff P, & Sepai O: Synthesis and quantification of DNA adducts of 4,4'-methylenedianiline. Chem Res Toxicol 1996; 9:1103-1112.
    237) Sepai O, Schutze D, & Heinrich U: Hemoglobin adducts and urine metabolites of 4,4'-methylenedianiline after 4,4'-methylenediphenyl diisocyanate exposure of rats. Chem Biol Interact 1995; 97:185-198.
    238) Servus: Norcross Safety Products, Servus Rubber, Servus, Rock Island, IL, 1995.
    239) Shepherd G & Keyes DC: Methylene blue. In: Dart,RC, ed. Medical Toxicology, 3rd ed. 3rd ed, Philadelphia, PA, 2004, pp -.
    240) Shimizu H: Jpn J Ind Health 1982; 24:498-503.
    241) Sittig M: Handbook of Toxic and Hazardous Chemicals and Carcinogens, 3rd ed, Noyes Publications, Park Ridge, NJ, 1991.
    242) Skarping G, Dalene M, & Littorin M: 4,4'-Methylenedianiline in hydrolysed serum and urine from a worker exposed to thermal degradation products of methylene diphenyl diisocyanate elastomers. Internat Arch Occup Environ Health 1995; 67:73-77.
    243) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    244) Standard Safety Equipment: Product Literature, Standard Safety Equipment, McHenry, IL, 1995.
    245) Stanford SC , Stanford BJ , & Gillman PK : Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24(10):1433-1438.
    246) Teunis BS, Leftwich EI, & Pierce LE: Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101:527-531.
    247) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    248) Tiljander A & Skarping G: Determination of 4,4'-methylenedianiline in hydrolysed human urine using liquid chromatography with UV detection and peak identification by absorbance ratio. J Chromatogr 1990; 511:185-194.
    249) Tillman HL, van Pelt FN, & Martz W: Accidental intoxication with methylene dianiline p,p'-diaminodiphenylmethane: acute liver damage after presumed ecstasy consumption. J Toxicol Clin Toxicol 1997; 35(1):35-40.
    250) Tingley: Chemical Degradation for Footwear and Clothing. Tingley. South Plainfield, NJ. 2002. Available from URL: http://www.tingleyrubber.com/tingley/Guide_ChemDeg.pdf. As accessed 10/16/2002.
    251) Trelleborg-Viking, Inc.: Chemical and Biological Tests (database). Trelleborg-Viking, Inc.. Portsmouth, NH. 2002. Available from URL: http://www.trelleborg.com/protective/. As accessed 10/18/2002.
    252) Trelleborg-Viking, Inc.: Trellchem Chemical Protective Suits, Interactive manual & Chemical Database. Trelleborg-Viking, Inc.. Portsmouth, NH. 2001.
    253) Tullner WW: Endocrine effects of methylenedianiline in the rat, rabbit and dog. Endocrinology 1960; 66:470-474.
    254) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    255) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    256) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    257) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    258) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    259) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    260) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    261) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. U.S. Food and Drug Administration. Silver Spring, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. As accessed 2011-07-26.
    262) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    263) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    264) US DHHS/OSHA: 4,4' Methylenedianiline (MDA) for General Industry, US Department of Labor, Occupational Health and Safety Administration, Washington, DC, 1992, pp 3135.
    265) US DHHS: Seventh Annual Report on Carcinogens 1994. US Department of Health and Human Services, National Toxicology Program, Prepared by Technical Resources, Inc, Rockville, Maryland, 1994.
    266) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    267) Van Joost T, Heule F, & De Boer J: Sensitization to methylenedianiline and para-structures. Contact Dermatitis 1987; 16:246-248.
    268) Vaudaine M: J Toxicol Med 1982; 2:207-213.
    269) Verschueren K: Handbook of Environmental Data on Organic Chemicals. 4th ed. CD-ROM version. Wiley-Interscience. Hoboken, NJ. 2001.
    270) Vock EH, Hoymann HG, & Heinrich U: P-32-postlabeling of a DNA adduct derived from 4,4'-methylenedianiline, in the olfactory epithelium of rats exposed by inhalation to 4,4'-methylenediphenyl diisocyanate. Carcinogenesis 1996; 17:1069-1073.
    271) Wells Lamont Industrial: Chemical Resistant Glove Application Chart. Wells Lamont Industrial. Morton Grove, IL. 2002. Available from URL: http://www.wellslamontindustry.com. As accessed 10/31/2002.
    272) Winek CL, Collom WD, & Martineau P: Toluidine blue intoxication. Clin Toxicol 1969; 2:1-3.
    273) Workrite: Chemical Splash Protection Garments, Technical Data and Application Guide, W.L. Gore Material Chemical Resistance Guide, Workrite, Oxnard, CA, 1997.
    274) Yamashita K, Nakasone K, & Kawao K: Inhibitory effect of methylenedianiline on testicular 17-oxosteroid secretion produced by pregnant mare serum. Tohoku J Exp Med 1969; 97:175-180.
    275) Yamashita K: Inhibition by methylenedianiline of testicular 17-oxosteroid secretion stimulated by human chorionic gonadotrophin. J Endocrinol 1967; 37:429-432.
    276) do Nascimento TS, Pereira RO, de Mello HL, et al: Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol 2008; 58(6):651-664.