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TOLUENE 2,6-DIISOCYANATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Toluene 2,6-diisocyanate (2,6-TDI) is the di-ortho- isocyanate (-NCO) derivative of toluene (methylbenzene).
    B) Little is known about the toxicity of 2,6-TDI apart from that of the 2,4- isomer (NIOSH, 1973). TDI in general is considered one of the most toxic of the isocyanates (HSDB , 1996). Generally the toxicity of 2,6-TDI is considered to be similar to that of the more common 2,4-TDI isomer (NIOSH, 1973; Gosselin et al, 1984).

Specific Substances

    A) SYNONYMS FOR THE PURE COMPOUND (CAS# 91-08-7):
    1) BENZENE, 1,3-DIISOCYANATO-2-METHYL-
    2) BENZENE, 2,6-DIISOCYANATO-1-METHYL-
    3) DESMODUR-T
    4) 1,3-DIISOCYANATO-2-METHYLBENZENE
    5) 2,6-DIISOCYANATOTOLUENE
    6) 2,6-DIISOCYANATO-1-METHYLBENZENE
    7) HYLENE TCPA
    8) HYLENE T ORGANIC ISOCYANATE
    9) HYLENE TIC
    10) HYLENE TM
    11) HYLENE TM-65
    12) HYLENE TRF
    13) ISOCYANIC ACID, 2-METHYL-META-PHENYLENE ESTER
    14) 2-METHYL-META-PHENYLENE DIISOCYANATE
    15) 2-METHYL-META-PHENYLENE ISOCYANATE
    16) 2-METHYL-m-PHENYLENE ESTER, ISOCYANIC ACID
    17) 2-METHYL-m-PHENYLENE ISOCYANATE
    18) NIAX TDI
    19) NIAX TDI-P
    20) 2,6-TDI
    21) 2,6-TOLUENE DIISOCYANATE
    22) TOLUENE DIISOCYANATE (65:35)
    23) TOLUENE DIISOCYANATE (80:20)
    24) TOLUENE 2,6-DIISOCYANATE
    25) m-TOLYLENE DIISOCYANATE
    26) meta-TOLYLENE DIISOCYANATE
    27) TOLYLENE 2,6-DIISOCYANATE
    28) Editor's note: Many of the utilized references do not clearly distinguish between the pure chemical and the isomer mixture. This is the case for synonyms and trade names as well as for toxicity listings and physical properties. Throughout this document, an effort was made to indicate whether the information was related to the pure chemical or the isomer mixture.
    SYNONYMS FOR THE ISOMER MIXTURE (CAS# 26471-62-5):
    1) BENZENE-, 1,3-DIISOCYANATOMETHYL-
    2) DESMODUR T100
    3) DIISOCYANATOMETHYLBENZENE
    4) 1,3-DIISOCYANATOMETHYLBENZENE
    5) DIISOCYANATOTOLUENE
    6) HYLENE-T
    7) ISOCYANIC ACID, METHYLPHENYLENE ESTER
    8) METHYL-META-PHENYLENE ISOCYANATE
    9) METHYL-M-PHENYLENE ISOCYANATE
    10) METHYLPHENYLENE ISOCYANATE
    11) MONDUR-TD
    12) MONDUR TD-80
    13) NACCONATE-100
    14) NIAX ISOCYANATE TDI
    15) RUBINATE TDI
    16) RUBINATE TDI 80/20
    17) T 100
    18) TDI
    19) TDI 80
    20) TDI 80-20
    21) TOLUENE 2,4- AND 2,6-DIISOCYANATE
    22) TOLUENE 2,4- AND 2,6-DIISOCYANATE, 80/20 MIXTURE
    23) TOLUENE DIISOCYANATES
    24) TOLYLENE DIISOCYANATE
    25) TOLYLENE ISOCYANATE
    26) Editor's note: Many of the utilized references do not clearly distinguish between the pure chemical and the isomer mixture. This is the case for synonyms and trade names as well as for toxicity listings and physical properties. Throughout this document, an effort was made to indicate whether the information was related to the pure chemical or the isomer mixture.
    SYNONYM REFERENCES
    1) (Ashford, 1994a; Grant & Schuman, 1993; HSDB, 2001; IARC, 1986a; ILO, 1998a; Lewis, 2000; OHM/TADS, 2000; RTECS, 2001)

    1.2.1) MOLECULAR FORMULA
    1) C9-H6-N2-O2

Available Forms Sources

    A) FORMS
    1) The most common form of the commercially available type of toluene diisocyanate contains a mixture of 80% 2,4 TDI and 20% 2,6 TDI. Also available is a mixture containing 65% 2,4-TDI and 35% 2,6-TDI (Ashford, 1994a; CHRIS, 2000; IARC, 1986a).
    a) All isomer mixtures have similar characteristics (CHRIS, 2000).
    2) In the USA, toluene diisocyanate with the 80:20 isomer ratio is produced in two forms: type I and type II. These types differ slightly with respect to acidity and amount of hydrolyzable chloride (IARC, 1986a).
    3) Analysis of the 80:20 isomer mixture produced in the US typically shows the following (IARC, 1986a):
    1) 99.5% purity; 80+/-1% 2,4-TDI;
    2) 20+/-1% 2,6-TDI;
    3) 0.001-0.011% (varies) acidity as hydrochloric acid;
    4) 0.010-0.014% maximum hydrolyzable chloride;
    5) 0.01-0.02% maximum total chlorine.
    4) Analysis of the 80:20 isomer mixture produced in Japan typically shows the following (IARC, 1986a):
    1) 99.6% minimum purity;
    2) 78.0-81.0% 2,4-TDI;
    3) 19.0-22.0% 2,6-TDI;
    4) 0.004% maximum acidity as hydrochloric acid;
    5) 0.01% maximum hydrolytic hydrochloric acid;
    6) 0.07% maximum total hydrochloric acid.
    5) Analysis of the 65:35 isomer mixture produced in Japan typically shows the following (IARC, 1986a):
    1) 99.5% minimum purity;
    2) 63-67% 2,4-TDI;
    3) 33-37.0% 2,6-TDI;
    4) 0.010-0.013% maximum acidity as hydrochloric acid;
    5) 0.01-0.013% maximum hydrolytic hydrochloric acid;
    6) 0.05% maximum total hydrochloric acid.
    B) SOURCES
    1) It is unknown whether 2,6- TDI occurs naturally (IARC, 1986a).
    2) Toluene diisocyanate was first produced commercially in the late 1930s. It is primarily produced during a reaction between phosgene and toluenediamine (Ashford, 1994a; IARC, 1986a).
    a) During the initial reaction, toluene is nitrated to 2,4-dinitrotoluene and 2,6-dinitrotoluene. Following catalytic reduction of the nitration products to diaminotoluene and dissolution in organic solvents, the diaminotoluene isomers react with phosgene for several hours at gradually increasing temperatures. The final toluene diisocyanate is then recovered via fractionation, isolating it from generated hydrogen chloride and unreacted phosgene (IARC, 1986a).
    3) In Japan, a process was developed that generates toluene diisocyanate without the use of phosgene.
    a) In this process, carbonylation of dinitrotoluene initially produces diurethane, which is then converted thermally to toluene diisocyanate and alcohol (IARC, 1986a).
    4) The free monomer of toluene diisocyanate isomers can be detected in urethane foam fabric coating at concentrations of less than 200 mg/kg (IARC, 1986a).
    C) USES
    1) Toluene diisocyanate isomer mixtures are industrial chemicals that are manufactured in large volumes (IARC , 2000).
    2) These isomer mixtures are used as cross-linking agent for Nylon-6 (Sax & Lewis, 1987).
    3) Approximately 90% of the supply of toluene diisocyanate isomer mixtures are used in the production of flexible and rigid polyurethane foams (IARC, 1986a).
    a) These foams can be manufactured through two synthetic methods:
    1) In the 'one-shot' technique, toluene diisocyanate reacts with a di- or polyfunctional alcohol, producing the polyurethane backbone of the polymer. Reaction between excess toluene diisocyanate and water results in formation of amines. These amines in turn further react with the toluene diisocyanate, thereby introducing urea groups into the polymer chain. Interaction between these urea groups and toluene diisocyanate results in cross-linkage between chains.
    2) The second method is a prepolymer process that involves the reaction between toluene diisocyanate and a polyl. During this reaction, a prepolymer with isocyanate end groups is formed. This prepolymer is then reacted with glycols or diamines to cross-link the chains (IARC, 1986a).
    4) Toluene diisocyanate isomer mixture is also used as a component in polyurethane coatings and elastomer systems (IARC, 1986a).
    a) These coatings can be used as floor finishes, wood finishes and paints (urethane-modified alkyds), wood and concrete sealants and floor finishes (moisture-curing coatings) and as aircraft, truck and passenger car coatings (prepolymer systems) (IARC, 1986a). They are also used on leather, wire, tank linings, and masonry (ACGIH, 1991b).
    b) Because urethane elastomers are abrasion- and solvent-resistant, they are used in adhesive and sealant compounds, automobile parts, shoe soles, roller skate wheels, pond liners, blood bags, oils fields and mines. Certain elastomers are produced from pure 2,4-TDI rather than the 80:20 isomer mixture (ACGIH, 1991b; IARC, 1986a).
    c) Paints used as top coats now rarely contain toluene diisocyanate isomer mixtures. They often were replaced by isocyanates with higher molecular weights (such as 4,4-diphenyl-methane diisocyanate (MDI)) or by prepolymers (ILO, 1998).
    5) Polymeric foams generated from the commercially available 80:20 isomer mixture are biologically inert and are widely used in furniture, packing, insulation, and boat building (ACGIH, 1991b).
    6) In 1984, the US Food and Drug Administration determined that the use of 2,4-TDI and 2,6-TDI as components of adhesives that come in contact with food was acceptable. Also acceptable was the use of these toluene diisocyanates as component of polyurethane resins that form a surface contacting the food (IARC, 1986a).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Toluene 2,6-diisocyanate (2,6-TDI) is usually the minor component of a mixture with the 2,4- isomer, and their toxicity is believed to be similar.
    B) The main route of toxic exposure to 2,6-TDI is by inhalation; ingestion also occurs, and it can be absorbed through the skin. It is a strong irritant of the eyes, nose, skin and respiratory tract. At high concentrations, the vapor may induce bronchoconstriction by a pharmacologic mechanism. The most recognizable effect of overexposure is an asthma-like reaction.
    C) The sequence of effects is conjunctival irritation and lacrimation, with pharyngeal irritation, followed by a dry cough in the evening, with retrosternal chest pain, difficulty breathing and distress; this worsens at night and is better in the morning. Re-exposure produces coughing, chest pain, moist wheezing, dyspnea and distress.
    D) Symptoms of exposure may mimic those of an upper respiratory tract infection, with chest tightness, chills, cough, fever, headache, wheezing and dyspnea, and the symptoms may be delayed as much as 8 hours after exposure.
    E) Overexposure may also produce nausea, vomiting, abdominal pain, chest constriction and retrosternal soreness, a choking feeling, productive paroxysmal coughing, bronchospasms, bronchitis, occupational asthma, and sometimes temporal headache, insomnia and paranoid depression. Severe inhalation overexposure can result in pulmonary edema.
    F) Dermal contact results in an inflammatory reaction; sensitization is possible. Effects of dermal exposure include itching, redness, swelling, blistering and eczema. When splashed in the eye, 2,6-TDI produces lacrimation, keratitis and conjunctivitis.
    G) Chronic exposure can produce a sometimes insidious sensitization of the respiratory tract, with a resultant allergic respiratory reaction including asthma and loss of lung function. Chronic exposure also can result in liver disease, with jaundice, as well as anemia.
    0.2.4) HEENT
    A) Ocular, nasal and throat irritation may occur.
    0.2.6) RESPIRATORY
    A) 2,6-TDI is a respiratory irritant and may induce bronchoconstriction at high concentrations.
    0.2.7) NEUROLOGIC
    A) Acute exposure may produce euphoria or ataxia.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting may occur.
    0.2.10) GENITOURINARY
    A) Impotence may be observed.
    0.2.14) DERMATOLOGIC
    A) Dermal irritation and skin sensitization may occur.
    0.2.17) METABOLISM
    A) Cholinesterase inhibition may be observed.
    0.2.18) PSYCHIATRIC
    A) CNS effects and impotence may occur.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no reproductive studies were found specifically for 2,6-TDI in humans. However, there is one report of firefighters exposed to high levels of the mixture in a fire who suffered impotence for some time thereafter. This was thought to be due to an indirect neurological mechanism rather than to direct toxicity to the male sex organs.
    0.2.21) CARCINOGENICITY
    A) Possible tumorigenic effects may be observed.
    0.2.22) OTHER
    A) Persons with predisposing medical conditions or predisposing exposures may exhibit more sensitivity.

Laboratory Monitoring

    A) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    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) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) 2,6-TDI can be an irritant at airborne concentrations in the range of 50 to 100 ppb; sensitized individuals may react at 1 to 5 ppb.

Clinical Effects

Summary Of Exposure

    A) Toluene 2,6-diisocyanate (2,6-TDI) is usually the minor component of a mixture with the 2,4- isomer, and their toxicity is believed to be similar.
    B) The main route of toxic exposure to 2,6-TDI is by inhalation; ingestion also occurs, and it can be absorbed through the skin. It is a strong irritant of the eyes, nose, skin and respiratory tract. At high concentrations, the vapor may induce bronchoconstriction by a pharmacologic mechanism. The most recognizable effect of overexposure is an asthma-like reaction.
    C) The sequence of effects is conjunctival irritation and lacrimation, with pharyngeal irritation, followed by a dry cough in the evening, with retrosternal chest pain, difficulty breathing and distress; this worsens at night and is better in the morning. Re-exposure produces coughing, chest pain, moist wheezing, dyspnea and distress.
    D) Symptoms of exposure may mimic those of an upper respiratory tract infection, with chest tightness, chills, cough, fever, headache, wheezing and dyspnea, and the symptoms may be delayed as much as 8 hours after exposure.
    E) Overexposure may also produce nausea, vomiting, abdominal pain, chest constriction and retrosternal soreness, a choking feeling, productive paroxysmal coughing, bronchospasms, bronchitis, occupational asthma, and sometimes temporal headache, insomnia and paranoid depression. Severe inhalation overexposure can result in pulmonary edema.
    F) Dermal contact results in an inflammatory reaction; sensitization is possible. Effects of dermal exposure include itching, redness, swelling, blistering and eczema. When splashed in the eye, 2,6-TDI produces lacrimation, keratitis and conjunctivitis.
    G) Chronic exposure can produce a sometimes insidious sensitization of the respiratory tract, with a resultant allergic respiratory reaction including asthma and loss of lung function. Chronic exposure also can result in liver disease, with jaundice, as well as anemia.

Heent

    3.4.1) SUMMARY
    A) Ocular, nasal and throat irritation may occur.
    3.4.3) EYES
    A) IRRITATION - 2,6-TDI may irritate the eyes upon direct contact with the liquid or fumes. Splashing the liquid in the eye can cause keratitis and conjunctivitis.
    1) One case of secondary glaucoma has been reported as a possible consequence of splashing this material in the eye. Permanent damage can occur if irritation goes untreated (Grant, 1986; HSDB , 1996; Sittig, 1985).
    2) 2,6-TDI is irritating to the eyes beginning at airborne concentrations of 50 to 100 ppb and is definitely irritating at 500 ppb (Grant, 1986).
    3.4.5) NOSE
    A) IRRITATION - TDI is irritating to the nose beginning at airborne concentrations of 50 to 100 ppb and is definitely irritating at 500 ppb (Grant, 1986).
    3.4.6) THROAT
    A) IRRITATION - 2,6-TDI vapors or liquid may irritate the throat (HSDB , 1996).

Respiratory

    3.6.1) SUMMARY
    A) 2,6-TDI is a respiratory irritant and may induce bronchoconstriction at high concentrations.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) 2,6-TDI may be a respiratory irritant in acute exposures greater than 100 ppb (HSDB , 1996; Karol, 1986). Firefighters exposed to 2,6-TDI and possibly other substances experienced cough and breathing difficulties, together with gastrointestinal and neurologic complaints (McKekrrow, 1970).
    2) Very high-level acute exposures to vapors or fumes of 2,6-TDI can cause a chemical pneumonitis and bronchitis accompanied by an asthma-like bronchospasm. This acute, reversible effect is thought to occur by a direct pharmacologic mechanism and hence may occur in anyone if the exposure is great enough (NIOSH, 1973).

Neurologic

    3.7.1) SUMMARY
    A) Acute exposure may produce euphoria or ataxia.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) Firefighters exposed to 2,6-TDI and possibly other substances experienced neurologic complaints of euphoria, loss of coordination, and loss of consciousness. Long-lasting symptoms of personality change, irritability, depression, and loss of memory were also reported (McKekrrow, 1970; O'Donoghue, 1985).
    B) IMPOTENCE
    1) Firefighters exposed to 2,6-TDI and possibly other substances suffered from impotence for some time after exposure. This was thought to be due to an indirect neurologic effect rather than to direct toxicity to the male genitalia (Le Quesne et al, 1976).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting may occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Firefighters exposed to 2,6-TDI and possibly other substances experienced nausea and vomiting, together with respiratory and neurologic complaints (McKekrrow, 1970).

Genitourinary

    3.10.1) SUMMARY
    A) Impotence may be observed.
    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) Firefighters exposed to 2,6-TDI and possibly other substances suffered from impotence for some time after exposure. This was thought to be due to an indirect neurologic effect rather than to direct toxicity to the male genitalia (Le Quesne et al, 1976).

Dermatologic

    3.14.1) SUMMARY
    A) Dermal irritation and skin sensitization may occur.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) 2,6-TDI may be a powerful skin irritant. Direct exposure to liquid 2,6-TDI may cause redness, swelling, and blistering if it is allowed to remain on the skin (HSDB , 1996; Sittig, 1985).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no reproductive studies were found specifically for 2,6-TDI in humans. However, there is one report of firefighters exposed to high levels of the mixture in a fire who suffered impotence for some time thereafter. This was thought to be due to an indirect neurological mechanism rather than to direct toxicity to the male sex organs.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) FETOTOXICITY
    a) Mated female CD rats exposed to 0 to 0.5 ppm TDI vapor on gestational days 6 through 15 demonstrated no significant treatment-related changes, including pre- and post-implantation loss, sex ratio/litter or fetal body weights/litter (Tyl et al, 1999b).
    b) A two-generation study on 2,6-TDI inhaled nearly continuously at levels between 0 and 0.3 ppm demonstrated no reproductive toxicity, reproductive organ pathology or effect on lactation/gestation at any exposure level (Tyl et al, 1999a).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS91-08-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Possible tumorigenic effects may be observed.
    3.21.3) HUMAN STUDIES
    A) OCCUPATIONAL EXPOSURE
    1) A study of 218 male workers occupationally exposed to 2,6-TDI found a slightly higher than expected incidence of cancer, but this was not confirmed in cases of extended absence from work (EPA, 1984).
    2) A NIOSH industry-wide study has been proposed to examine excess mortality from cancer, especially lung cancer, in TDI workers (Gerber, 1980).
    a) Previous attempts had yielded negative results, however (EPA, 1984).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) 2,6-TDI caused tumors in mice and rats when given orally, but these results are controversial (Loeser, 1983).
    2) 2,6-TDI was not carcinogenic by inhalation at doses up to 0.15 ppm (Loeser, 1983).

Genotoxicity

    A) Mutations and chromosome aberrations may occur.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Some, but not all, individuals have IgE antibodies which can react with a p-tolyl isocyanate antigen (Butcher, 1980). For these individuals, periodic monitoring of serum for titers of such antibodies may be a useful tool to detect subclinical responses to 2,6-TDI (Patterson et al, 1983; Rosenberg & Savolainen, 1986).
    B) BLOOD/SERUM CHEMISTRY
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    C) MONITORING
    1) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

    A) CHROMATOGRAPHY
    1) Airborne levels of 2,6-TDI in the vicinity of polyurethane gluing operations were determined by liquid chromatography and were found to be less than 0.1 mcg/m(3) (Skarping et al, 1996).
    2) Levels of 2,6-TDI in blood and urine from exposed workers were determined by gas chromatography-mass spectrometry after acid hydrolysis of plasma and derivitization with pentafluoropropionic anhydride (Lind et al, 1996).
    B) OTHER
    1) Airborne levels of TDI can be monitored in the ppb range (Purnell & Walker, 1981). Samples can be collected by impinger or fritted bubbler and reduced to the diamine, followed by diazotization and coupling and colorimetric measurement (Sittig, 1985).
    2) Airborne 2,6-TDI was sampled by means of solid sorbent media; results were comparable to those of the NIOSH Method P&CAM 5505 (Revision #1) (Sesana et al, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

Monitoring

    A) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY -
    1) Move victims of inhalation exposure from the toxic environment and administer 100 percent humidified supplemental oxygen with assisted ventilation as required. Exposed skin and eyes should be copiously flushed with water.
    B) DILUTION -
    1) In ingestion exposures, emesis should not be induced because of the potential for irritant effects and CNS depression. Immediate dilution with milk or water might be beneficial.
    C) ORAL EXPOSURE -
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    2) 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.
    3) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    D) INHALATION EXPOSURE -
    1) 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.
    2) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    3) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    E) EYE EXPOSURE -
    1) 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.
    F) DERMAL EXPOSURE -
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Do not induce emesis.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) IRRITATION SYMPTOM
    1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
    C) OBSERVATION REGIMES
    1) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    D) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.

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) IRRITATION SYMPTOM
    1) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    2) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).
    a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.
    1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).
    3) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
    4) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
    B) BRONCHOSPASM
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    D) OBSERVATION REGIMES
    1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    E) FOLLOW-UP VISIT
    1) Patients who develop respiratory sensitization or decreased pulmonary function require long-term followup.
    2) EXPOSURE CESSATION - Patients who develop respiratory sensitization should be precluded from further exposure.
    F) 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) 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).
    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) ACUTE ALLERGIC REACTION
    1) EXPOSURE CESSATION - Patients who develop dermal sensitization may need to be precluded from further exposure.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) EFFICACY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) 2,6-TDI can be an irritant at airborne concentrations in the range of 50 to 100 ppb; sensitized individuals may react at 1 to 5 ppb.

Minimum Lethal Exposure

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

Maximum Tolerated Exposure

    A) Most toxicological studies do not specify which toluene diisocyanate isomer was used in their study. In many studies, the commercial 80:20 isomer mixture was used. There is no known important distinction in toxicological effects between the 2,4- and the 2,6-isomer (ACGIH, 1991).
    B) The US EPA established an Inhalation Reference Concentration (RfC) of 7x10(-5) mg/m(3) for the 80:20 isomer mixture. This value was calculated using an Uncertainty factor of 30, and a Multiplication factor of 1 (IRIS , 2001).
    C) Human studies:
    1) The lowest toxic dose for humans by inhalation was 80 ppb (RTECS , 1996). However, previously sensitized individuals may react at exposures much lower than this in the 1 to 2 ppb range (Karol, 1986).
    2) Exposure to airborne levels greater than 100 ppb caused primary respiratory tract irritation, while exposure to levels less than approximately 30 ppb did not (Karol, 1986).
    3) Nine workers of polyurethane foam producing plant were exposed to high concentrations of toluene diisocyanate vapors. All developed microcystic corneal epithelial edema, accompanied with the impression of foggy or smoky vision, but without discomfort. It was found that exposure for one day was sufficient to develop the edema. While visual acuity was only minimally reduced using the Snellen chart, slit-lamp examination showed microcystic changes in the corneal epithelium. This change was spontaneously reversible within 12 to 48 hours following exposure for one day, or within several days after repeated daily exposure. It was later suspected that amines, rather than the diisocyanates, used in the manufacture of polyurethane foams were responsible for the development of the edema and the haziness of vision (Grant, 1993).
    4) Toluene diisocyanates reportedly form antigenic complexes with proteins, thereby transforming lymphocytes in sensitized individuals and inducing formation of specific antibodies (HSDB , 2001a).
    5) "If the breathing zone concentration reaches 0.5 ppm, the possibility of respiratory response is imminent. Depending on length of exposure and level of concentration above 0.5 ppm, respiratory symptoms will develop with a latent period of 4 to 8 hours. Higher concentrations produce a sensation of oppression or constriction of the chest" (Hathaway et al., 1996).
    6) Respiratory sensitization has occurred after repeated exposure to levels of 0.02 ppm and below. Initial symptoms often occur at night. Susceptibility to toluene diisocyanate-induced asthma does not require a prior history of atopy or allergic conditions. Following sufficient exposure to toluene diisocyanates, any individual may become sensitized to this compound. Nightly symptoms may develop even long after the end of a work shift. Individuals with toluene diisocyanate-induced asthma may continue to show dyspnea, wheezing and bronchial hyperreactivity for 2 or more years after cessation of exposure. Due to current work practices, skin sensitization is uncommon. Little relation seems to exist between skin sensitivity and respiratory sensitivity to toluene diisocyanates (Hathaway et al., 1996).
    7) Two and a half percent of workers exposed to 0.02 ppm (0.14 mg/m(3)) of toluene diisocyanate isomer mixture developed bronchial hypersensitivity. Individuals sensitized to this mixture developed severe respiratory symptoms when exposure continued. In most cases, improvement occurs when exposure ceases (IARC, 1986).
    8) Dose-dependent changes in the rate of loss of pulmonary function were described in a cohort of workers exposed to toluene diisocyanate isomer mixture. An excess rate was observed at a concentration of 0.002 to 0.003 ppm (0.01 to 0.021 mg/m(3)) (IARC, 1986).
    9) No respiratory effects were observed following exposure to approximately 0.001 ppm (0.007 mg/m(3)) for five to ten years (IARC, 1986).
    10) Exposure to toluene diisocyanate isomer mixture may cause chronic restrictive pulmonary disease and hypersensitivity pneumonitis. Exposure to high concentrations or repeatedly low concentrations of toluene diisocyanate isomer mixture has been associated with the development of chronic bronchitis. Sensitized workers may develop persistent respiratory symptoms even after exposure was terminated (IARC, 1986).
    11) Exposure to very high concentrations of toluene diisocyanate isomer mixture can have effects on the nervous system, and can lead to headache, poor memory, difficulty concentrating, confusion, changes in personality, irritability and depression (IARC, 1986).
    12) One report describes the development of an adenocarcinoma in the lung of a 47-year old non-smoking spray painter. The worker had been exposed to toluene diisocyanate isomer mixture and 4,4'-methylenediphenyl diisocyanate for 15 years. It was suggested that the lung disease was caused by exposure to isocyanates. IARC states however, that this report was inadequate to evaluate the carcinogenicity of toluene diisocyanantes (IARC, 1986) IARC, 1999).
    13) Between 1957 and 1962, 42 cases of occupational toluene intoxication were reported from 14 plants in Massachusetts. For 14 of these cases, average vapor concentration of toluene diisocyanates in the workroom was about 0.03 ppm; in a few samples, the average concentration were greater than 0.05 ppm. In 11 cases, the average concentration was measured at 0.015 ppm, and in 9 cases the average concentration was below 0.01 ppm. In the remaining cases, no measurements were possible. It was found that all plants with average concentrations greater than 0.01 ppm had cases with related respiratory illness. No such illnesses were reported in plants with average concentrations of 0.007 ppm or less (ACGIH, 1991).
    14) Although repeated exposure to lower concentrations of the isomer mixture has been shown to produce chronic-like syndromes in humans, and may be related to hypersensitization, exposure to moderately elevated levels of the mixture (mean 0.07 ppm, peak 0.2 ppm) does not result in interstitial pulmonary fibrosis (ACGIH, 1991).
    15) An investigation of 83 cases of occupational intoxication following exposure to the isomer mixture showed that the maximum incidence occurred at a concentration of approximately 0.1 ppm, whereas very few complaints were noted when the concentration was approximately 0.01 ppm. Another study showed a high incidence of illness at concentrations between 0.03 and 0.07 ppm, but no complaints when the concentration was kept below 0.03 ppm (ACGIH, 1991).
    16) In one study, respiratory sensitization was observed in workers who were only exposed to toluene diisocyanate vapors during trimming and sewing of polyurethane cushions. Air concentration was measured at only 0.003 ppm (Zenz, 1994).
    17) In a plant manufacturing polyurethane foam ice chests and picnic jugs, workers were exposed to 0.005 ppm of the isomer mixture during normal operations but had been exposed to unknown relatively high concentrations of the mixture during spills in the past. Nine of 13 symptomatic workers showed decreased forced vital capacity (FVC) and decreased forced expiratory volume in one second (FEV1) (ACGIH, 1991).
    18) Even in asymptomatic workers, ventilatory capacity can be reduced over a work shift following exposure to toluene diisocyanate vapors at low (below 0.02 ppm and 0.001 ppm) or high (greater than 0.9 ppm) concentrations. In the latter, an acute loss of forced expiratory volume (FEV1) of 0.18L over 8 hours has been reported (Zenz, 1994).
    19) During an 18-month period, respiratory sensitization was observed in 5% of 99 workers, who were exposed to the isomer mixture usually below 0.02 ppm. It was assumed that the sensitization was a result of exposure to higher concentrations in spill situations (ACGIH, 1991).
    20) Four of 47 office workers became sensitized from exposure to exhaust air containing "unknown but probably quite low" concentrations of the isomer mixture. The air inlet of the office was 23 feet from the ventilation outlet of a nearby isomer mixture-manufacturing plant (ACGIH, 1991).
    D) Animal studies:
    1) Results from a study performed in guinea pigs suggested that exposure to 29 ppb of toluene diisocyanates (97.8% of 2,4-TDI and 2.2% of 2,6-TDI) had a direct, dose-dependent effect on tracheal smooth muscle activity (HSDB, 2001).
    2) Commercial grade isomer mixture was found to be carcinogenic in F344/N rats. Exposure resulted in increased number of subcutaneous fibromas and fibrosarcomas in male and female animals; pancreatic acinar cell adenomas in male animals; pancreatic islet cell carcinomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in female animals. The same isomer mixture was not considered to be carcinogenic for male B6C3F1 mice but was judged carcinogenic for female B6C3F1 mice. Exposure of female mice resulted in hemangiomas or hemangiosarcomas and hepatocellular adenomas. Concentrations of the isomer mixture (administered via gavage, dissolved in corn oil) used for both rats and mice were as follows: male rats 23 or 49 mg/kg; female rats and female mice 49 or 108 mg/kg; male mice 108 or 202 mg/kg (ACGIH, 1991; NTP , 1986).
    3) In one animal study, where mice and rats of both genders were exposed to the commercial isomer mixture, the pattern of multiple tumor sites was similar to that seen following exposure to 2,4-diamino toluene. Since common metabolites are produced from 2,4-TDI and 2,4-diamino toluene, it was suggested that 2,4-TDI contained in commercial mixture is responsible for the mixture's carcinogenic effect (Hathaway et al., 1996).
    4) Inhalation exposure of rats and mice to production-grade isomer mixture at concentrations of 0.05 ppm and 0.15 ppm did not show evidence for carcinogenicity. Exposure durations were 6 hours/day, 5 days/week, 108 to 110 weeks (rats) or 104 weeks (mice). Exposures in this study were later found to be below the maximum tolerated dose, based on mortality and gross body weight data (ACGIH, 1991).
    5) Eleven male Fischer 344 rats were orally exposed to 2,6-TDI in corn oil. At 900 mg/kg body weight, the compound polymerized in the gastrointestinal tract. The polymer lined the stomach, thereby preventing the migration of food into the intestine. No such effect was seen at a dose of 60 mg/kg (NTP , 1986).

Workplace Standards

    A) ACGIH TLV Values for CAS91-08-7 (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) Toluene-2,4- or 2,6-diisocyanate (or as a mixture)
    a) TLV:
    1) TLV-TWA: (0.005 ppm)
    2) TLV-STEL: (0.02 ppm)
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: SEN
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    b) SEN: The designation SEN refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. The notation does not imply that this is the critical effect or that this is the sole basis for the TLV. Although, for those TLVs that are based on sensitization, the TLV is meant to protect workers from induction of this effect, but cannot protect workers who have already become sensitized. The notation should be used to assist in identifying sensitization hazards and reducing respiratory, dermal, and conjunctival exposures to sensitizing agents in the workplace. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): (Resp sens)
    d) Molecular Weight: 174.15
    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:
    1) See Notice of Intended Changes; Adopted values enclosed in parentheses are those for which changes are proposed in the Notice of Intended Changes.
    b) Notice of Intended Changes
    1) Toluene-2,4- or 2,6-diisocyanate (or as a mixture)
    a) TLV:
    1) TLV-TWA: 0.001 ppm
    2) TLV-STEL: 0.003 ppm
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: IFV, SEN, 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) IFV: Inhalable fraction and vapor.
    c) SEN: The designation SEN refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. The notation does not imply that this is the critical effect or that this is the sole basis for the TLV. Although, for those TLVs that are based on sensitization, the TLV is meant to protect workers from induction of this effect, but cannot protect workers who have already become sensitized. The notation should be used to assist in identifying sensitization hazards and reducing respiratory, dermal, and conjunctival exposures to sensitizing agents in the workplace. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    d) 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): Asthma
    d) Molecular Weight: 174.15
    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 CAS91-08-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS91-08-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Toluene-2,4- or 2,6-diisocyanate (or as a mixture)
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Toluene-2,4- or 2,6-diisocyanate (or as a mixture)
    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.
    3) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    6) MAK (DFG, 2002): Category 3A ; Listed as: Toluene-2,6-diisocyanate
    a) Category 3A : Substances for which the criteria for classification in Category 4 or 5 are fulfilled but for which the database is insufficient for the establishment of a MAK value.
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS91-08-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACGIH, 1991 HSDB, 2001b RTECS, 2001b; RTECS, 2001c
    1) TCLo- (INHALATION)HUMAN:
    a) 50 ppb -- Changes in Sense Organs and Special Senses; Changes in Lung, Thorax or Respiration (RTECS, 2001c)
    B) Toxicity data following exposure to isomer mixture:
    1) LD50- (ORAL)MOUSE:
    a) 1950 mg/kg (RTECS, 2001b)
    2) LD50- (ORAL)RAT:
    a) 5800 mg/kg (OHM/TADS, 2001)
    b) 4130 mg/kg (RTECS, 2001b)
    3) TCLo- (INHALATION)HUMAN:
    a) 0.5 ppm (OHM/TADS, 2001)
    4) TCLo- (INHALATION)MOUSE:
    a) 1 ppm for 6H/5D intermittent -- Weight loss or decreased weight gain; Death (RTECS, 2001b)
    5) TCLo- (INHALATION)RAT:
    a) 100 ppb for 6H/81D intermittent -- Changes in Lung, Thorax, or Respiration (RTECS, 2001b)
    b) 10 mcg/m(3) for 24H/22W continuous -- Changes in Recordings from specific areas of CNS; Changes in bone marrow; Effects on true cholinesterase (RTECS, 2001b)
    c) 2 ppm for 6H/5D intermittent -- Death (RTECS, 2001b)
    d) 2830 ppb for 6H/3W intermittent -- Structural or functional change in trachea or bronchi; Changes in erythrocyte (RBC) count; Weight loss or decreased weight gain (RTECS, 2001b)
    7.7.2) RISK ASSESSMENT VALUES
    A) Toxicity data following exposure to isomer mixture:
    1) NOEL- (INHALATION)GUINEA_PIG:
    a) 0.02 ppm for 6H (ACGIH, 1991)
    b) 0.05 ppm for 6H (ACGIH, 1991)
    2) NOEL- (INHALATION)RABBIT:
    a) 0.1 ppm for 6H once a week for 58W (ACGIH, 1991)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Generally the toxicity of 2,6-TDI is considered to be similar to that of the more common 2,4-TDI isomer (NIOSH, 1973).
    B) The mechanism(s) of development of TDI asthma in humans is unknown. It may be complex or may even vary from one individual to another or within the same individual at different times (Styles, 1978).
    1) Sensitized individuals can react to both 2,6-TDI and the 2,4- isomer but in different ways, suggesting complex mechanisms of sensitization (Barkman, 1984).
    2) The allergy may be reversible if further exposure ceases, with varying lengths of time required for reversal in different individuals (Karol, 1986).
    a) For individuals with no other allergies, as little as 4 to 6 months without exposure may be sufficient to reverse the sensitization (Karol, 1986).
    b) For atopic individuals as long as several years may be required (Karol, 1986).
    3) The severity of the sensitization may increase with increased duration of exposure (NIOSH, 1973).
    4) With TDI, there may be a significant latent period of up to 17 years for development of sensitization (NIOSH, 1973).
    5) Delayed airway hyperresponsiveness to TDI was inhibited by antiasthma drugs (Mapp et al, 1987), was inhibited by prednisone (Febbri et al, 1985) and was not inhibited by atropine (Paggiaro et al, 1987).
    C) TDI-induced airway hyperresponsiveness has been shown to be mediated by several substances in a guinea pig model:
    1) Tachykinins may mediate the response of TDI in guinea pigs (Thompson et al, 1987).
    2) Airway edema induced by TDI may be mediated by granulocytes in guinea pigs (Sheppard et al, 1986).
    3) The airway response in guinea pigs was inhibited by hydroxyurea (Thompson, 1986).
    4) The airway response in guinea pigs was not mediated by arachidonic acid metabolites (Gordon et al, 1988).
    D) TDI easily reacts with proteins in the body, and this property may explain its activity as an allergen (EPA, 1984).
    E) 2,6-TDI inhibited serum cholinesterase activity in vitro and was more active than the more common 2,4-TDI isomer. This is a possible mode of action for its respiratory irritation (Brown, 1982).
    1) As a cholinesterase inhibitor, 2,6-TDI could possibly produce a localized pattern of parasympathetic autonomic muscarinic effects in the respiratory system. Such a pattern would include wheezing, edema, tightness in the chest, bronchospasm, bronchoconstriction, cough, bradypnea, and dyspnea (Ecobichon & Joy, 1982).
    F) Markers of chronic inflammatory processes, CD25 and VLA-1, TNF alpha and IL-1 beta were increased in bronchial biopsy tissue from individuals with TDI-induced asthma, in comparison with tissue from normal subjects (Maestrelli et al, 1995).
    1) Levels were not decreased in asthmatic subjects by 21 days after TDI challenge, in comparison with samples taken 2 days after challenge.
    2) This result suggests that persistent activation of lymphocytes and chronic expression of pro-inflammatory cytokines are involved in TDI-induced asthma (Maestrelli et al, 1995)

Physicochemical

Physical Characteristics

    A) Toluene-2,6-diisocyanate has properties similar to the 2,4- isomer of toluene diisocyanate (Lewis, 1998).
    B) The isomer mixture is a clear to pale yellow liquid ((OHM/TADS, 2001)).
    C) The isomer mixture is liquid at room temperature. It darkens when exposed to light. It is heavier than water and will react with water to form carbon dioxide. It is colorless in water ((OHM/TADS, 2001)).
    D) When exposed to water, toluene diisocyanate isomers break down into their corresponding diaminotoluenes (2,6-diaminotoluene dihydrochloride) (IARC, 1986).

Molecular Weight

    A) 174.16
    B) 80:20 isomer mixture: 174.15 (ACGIH, 1991)

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