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Isocyanates
640 Isocyanates
Isocyanates Robert Kapp & 2005 Elsevier Inc. All rights reserved.
Isocyanates are a group of low molecular weight aromatic and aliphatic compounds containing the isocyanate group (–NCO). The most widely used industrial isocyanates and their applications are listed below. The most notorious isocyanate is methyl isocyanate, involved in one of the worst industrial tragedies recorded in history. In the early morning hours of December 3, 1984, 200 000 people in Bhopal, India were exposed to methyl isocyanate. The 90 min exposure resulted in at least 2500 deaths and countless cases of severe eye and lung damage. Most of the deaths were related to the pulmonary edema.
HDI – Hexamethylene Diisocyanate *
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 822-06-0 SYNONYMS: 1,6-Diisocyanatohexane; HDI; Hexamethylene-1,6-diisocyanate; 1,6-Hexamethylene diisocyanate; HMDI CHEMICAL FORMULA: C8H12N2O2
Uses
Hexamethylene diisocyanate (HDI) is used in the preparation of dental materials, medical adsorbents, and contact lenses, and is used as a polymerizing agent in polyurethane paints and coatings. Background Information
HDI is a colorless liquid with an irritating odor. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of HDI. Workers and individuals in close proximity to an area where spray applications of polyurethane paints may be exposed.
inhalation exposure has been reported to cause irritation of the nasal tissues and respiratory tract. Dermal exposure has resulted in sensitization in several animal species. The US Environmental Protection Agency (EPA) has set the reference concentration (RfC) for HDI at 0.000 01 mg m 3 based upon the degeneration of the olfactory epithelium in rodents. EPA has not established a reference dose (RfD) for HDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of HDI in humans. A rat reproductive study found no effects in any reproductive organs. Carcinogenicity
No information is available on the carcinogenic effects of HDI in humans. Animals exposed to HDI were reported to show no evidence of carcinogenicity in a 2 year inhalation study. EPA has classified HDI as a group D (not classifiable as to human carcinogenicity.) Clinical Management
Skin or ocular exposure areas should be generously irrigated with saline. All other treatment is symptomatic. Exposure Standards and Guidelines
The (US) National Institute for Occupational Safety and Health (NIOSH) recommended exposure level (REL), averaged over a 10 h workday is 0.005 ppm (0.035 mg m 3).
MIC – Methyl Isocyanate *
Acute and Short-Term Toxicity (or Exposure)
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Acute inhalation exposure may result in pulmonary edema, coughing, and labored breathing in humans. HDI is extremely irritating to the eyes, nose, and throat. Rodent studies revealed that HDI is extremely toxic by inhalation, and moderately to highly toxic by oral ingestion.
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 624-83-9 SYNONYMS: Methyl ester of isocyanic acid; MIC CHEMICAL FORMULA: C2H3NO
Uses
Methyl isocyanate (MIC) is used as a chemical intermediate in the production of carbamate insecticides and some herbicides.
Chronic Toxicity (or Exposure)
Chronic inhalation exposure to HDI is thought to cause chronic lung irritation. In addition, chronic
Background Information
MIC is a colorless liquid with a sharp pungent odor.
Isocyanates 641 Exposure Routes and Pathways
Inhalation, ingestion and dermal contact are all possible routes of exposure. Occupational exposure can occur during the use of carbamates produced from MIC. Small amounts of MIC are found in cigarette smoke. Acute and Short-Term Toxicity (or Exposure)
The acute toxic effects of MIC are essentially similar by either route except for the intensity of the effects. When rats were administered MIC by inhalation or subcutaneous route it produced severe hyperglycemia, clinical lactic acidosis, highly elevated plasma urea, and reduced plasma cholinesterase activity with unaltered erythrocyte acetyl cholinesterase activity. Irrespective of the route of administration, MIC also caused severe hypothermia, which was not ameliorated by prior administration of atropine sulfate. Rats and mice of each sex were exposed by inhalation to MIC at 0, 1, and 3 ppm for 6 h day 1 for 4 days followed by up to a 91 day recovery period. Only animals exposed to 3 ppm exhibited exposure related changes. Most of the rats exposed at 3 ppm died within 28 days. A prominent decrease in body weight was observed along with severe lung lesions and thymus atrophy. Lesions of the nasal cavity of rats and mice were characterized by regeneration of the olfactory and respiratory epithelium. By day 28, the respiratory epithelium of rats and mice appeared normal, but olfactory regeneration was still present in the surviving rats. Severe lesions of the trachea extending to the bronchi, bronchioles, and alveoli were seen in rats exposed to 3 ppm. Acute inflammation of the airways and hyaline membranes was observed in high dose animals killed on day 7. In the 3 ppm MIC-exposed animals that died during days 8–14, there was lymphatic necrosis of the thymus, atrophy of the splenic white pulp, coagulative necrosis of the liver, and thrombosis of the left cardiac atrium. Gross examination of exposed mice showed minimal differences between exposure groups. Microscopic observations showed treatment-related changes only in the 3 ppm exposure group of mice. The changes involved primarily the bronchial system and were not as severe as those observed in rats. By day 91, bronchial fibrosis was minimal to mild in mice. One group of five male rats was exposed to 3 ppm MIC for a single 6 h exposure. The lesions in the respiratory system were essentially the same as those observed in the 4 day repeated exposure rats that were killed after 7 days. In another acute toxicity study, rats were exposed only once to 3.52 and 35.32 ppm of MIC for 10 min; in a subacute study, they were exposed to doses of
0.212, 0.265, and 0.349 ppm for 30 min daily for 6 days and were then observed for 90 days for weight gain. At the end of 90 days, damage to the viscera was evaluated. During exposure, the animals had congestion in eyes, lachrymation, nasal secretion and dyspnea, progressively increasing ataxia, immobility, and uncoordinated movements. MIC exposure greatly inhibited weight gain in the animals in a dosedependent manner. Upon microscopic examination of the viscera, pathological findings were confined to the bronchial tree, lung parenchyma, liver, and kidneys. Acute inhalation exposure of humans results in pulmonary edema (most of the Bhopal deaths were due to pulmonary edema and secondary respiratory infections from pulmonary edema). Other acute effects include, blindness, nausea, gastritis, sweating, fever, chills, and liver and kidney damage. MIC was studied in in vivo micronucleus test and chromosomal analysis of bone marrow cells. Mice were exposed for 10 min to different concentrations (2.40, 4.80, or 7.20 ml) of MIC at 0 and 24 h. Quantitative analysis failed to exhibit any significant increase in aberration rates in the three treated groups. In another micronucleus assay, mice were exposed to MIC through ip injection for 2 and 5 days in separate experiments, and bone marrow and peripheral blood were sampled 6 and 48 h after the last injection, respectively. MIC did not significantly increase the frequencies of micronucleated erythrocytes in bone marrow and pheripheral blood samples in either twice or multiply treated mice. However, a dosedependent depression in percentage polychromatic erythrocytes observed was significant. This indicates that MIC exposure led to the cytotoxic effect by inhibition of bone marrow cell proliferation. Chronic Toxicity (or Exposure)
The long-term carcinogenic and pulmonary effects of a single exposure to MIC were examined in rodents. Rats and mice were exposed to MIC by inhalation at 0, 1, 3, or 10 ppm for 2 h. After 2 years, the animals were sacrificed and tissues and organs were examined microscopically. No differences in survival rates or body weight gains were found in the MIC-exposed animals versus controls. Male and female rats exposed to 10 ppm MIC had 42% and 36% incidence, respectively, of intraluminal fibrosis of secondary bronchi; however, no evidence of this lesion was seen in controls or animals exposed to lower concentrations. For male and female mice and female rats, no neoplastic lesions were significantly associated with MIC exposure. Male rats exposed to MIC had marginally increased rates of pheochromocytomas of the adrenal medulla and adenomas of
642 Isocyanates
pancreatic acinar cells cells. EPA has not established an RfC or an RfD for MIC.
trimethylamine, may act as endogenous teratogens under certain conditions. Carcinogenicity
Reproductive Toxicity
Follow-up of exposed humans after the Bhopal incident found a high level of stillborns, spontaneous abortions and increased infant mortality. There was also a high number of survivors with pelvic inflammatory disease, excessive menstrual bleeding and suppression of lactation. Pregnant mice and rats were exposed to 9 or 20 ppm MIC to determine if the chemical was able to cross the placental barrier and directly affect the fetus. The mice were exposed on day 8 and the rats on day 10 of gestation to 9 ppm MIC for 3 h for evaluation of in vivo fetal toxicity. In other experiments the animals were exposed for 2 h to 20 ppm and the embryos removed immediately for culture. MIC exposure reduced maternal progesterone levels in mice that lost but not in mice that retained pregnancy. No relationship was observed between fetal toxicity of MIC and maternal plasma corticosterone levels. Fetal toxicity of MIC was not affected by chronic administration of progesterone or the suppression of pulmonary edema with dexamethasone. A concentration dependent decrease in growth in culture was noted in embryos exposed in utero or in vitro to MIC vapor. No fetal toxicity was noted following exposure to an acute dose, 3 mmol kg 1, of the metabolites. The results indicate that the fetal toxicity of MIC is partly independent of maternal toxicity and may result from the transfer across the placenta and the interaction with fetal tissues. Monomethylamine, dimethylamine, and trimethylamine are endogenous substances as well as metabolites of MIC. Methylamines exert several toxic effects including inhibition of protein turnover and oocyte RNA synthesis. A study conducted to determine the developmental toxicity of these methylamines using pregnant mice and mouse embryo culture used ip injections (daily from day 1 to day 17 of gestation) of trimethylamine at 2.5 and 5 mmol kg 1day 1. Trimethylamine significantly decreased fetal body weight but not the placental weight or maternal body weight gain; however, 5 of 11 mice treated with 5 mmol kg 1 trimethylamine died. Similar treatment with dimethylamine or monomethylamine did not exert any obvious maternal or fetal effects. All three methylamines, when added to embryos in culture, caused dose dependent decreases in size, DNA, RNA, and protein content as well as embryo survival; the order of toxicity was trimethylamine 4 dimethylamine 4 monomethylamine. The ability of monomethylamines to adversely affect fetal development suggests that these methylamines, especially
No information is available on the carcinogenic effects of MIC in humans. Animals exposed via inhalation gave mixed results. EPA has classified MIC as a group D (not classifiable as to human carcinogenicity.) In Vitro Toxicity Data
MIC was nonmutagenic in the Ames (Salmonella), Drosophila sex-linked recessive lethal assays. MIC induced chromosomal aberrations in cultured Chinese hamster ovary cells. Environmental Fate
MIC may be released to the environment as a result of its manufacture and use as a chemical intermediate. If MIC is released to soil, it will be expected to rapidly hydrolyze if the soil is moist, based upon the rapid hydrolysis observed in aqueous solution. If released to water, it will be expected to rapidly hydrolyze with half-lives of 20 and 9 min at 151C and 251C, respectively, calculated from measured overall hydrolysis rate constants. The products of hydrolysis may include N-carboxymethylamine, methylamine, carbon dioxide, and N,N0 -dimethylurea. Since it rapidly hydrolyzes, bioconcentration, volatilization, and adsorption to sediment and suspended solids are not expected to be significant processes. No data were located concerning biodegradation, but MIC will probably abiotically hydrolyze significantly faster than it will biodegrade. If released to the atmosphere, it will be expected to exist almost entirely in the vapor phase based upon its vapor pressure. It will be susceptible to photooxidation via vapor phase reaction with photochemically produced hydroxyl radicals. Hydrolysis of MIC in moist air may be significant based upon its rapid hydrolysis in aqueous solution. Exposure Standards and Guidelines
The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value, 8 h timeweighted average (TWA) is 0.02 ppm, with a designation that skin exposure is also an important exposure. The (US) Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), 8 h TWA is 0.02 ppm (with a skin notation). The US NIOSH REL is 0.02 ppm as a 10 h TWA, and the NIOSH immediately dangerous to life or health (IDLH) value is 3 ppm. MIC is listed by EPA as a hazardous air pollutant generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards
Isocyanates 643
requiring major sources to sharply reduce routine emissions of toxic pollutants.
MDI – 4,40 -Methylenediphenyl Diisocyanate *
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 101-68-8 SYNONYMS: 4,40 -Diphenylmethane diisocyanate; Methylene bis(4-phenyl isocyanate); Methylene di-p-phenylene ester of isocyanic acid CHEMICAL FORMULA: C15H10N2O2
Uses
4,40 -Methylenediphenyl diisocyanate (MDI) is used to produce polyurethane foams.
Carcinogenicity
No information is available on the carcinogenic effects of MDI in humans. Animals exposed to polymeric MDI were reported to increase the incidence of pulmonary adenomas. EPA has classified MDI as a group D (not classifiable as to human carcinogenicity). Exposure Standards and Guidelines
The (US) OSHA PEL 8 h TWA is 0.02 ppm (0.2 mg m 3). The (US) NIOSH REL is 0.005 ppm (0.05 mg m 3) as a 10 h TWA, and the NIOSH IDLH value is 75 mg m 3.
TDI – Toluene Diisocyanate *
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Background Information
MDI is a light-yellow fused solid or it may occur in crystalline form. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of MDI. Workers and individuals in close proximity to the plant may inhale emissions from urethane foam production manufacturing facilities. Acute and Short-Term Toxicity (or Exposure)
Acute inhalation exposure may result in sensitization and asthma in humans. Dermal contact with MDI resulted in dermatitis and eczema in plant workers. Animal studies revealed skin and eye irritation in rabbits, extreme toxicity by inhalation and moderate toxicity by oral ingestion in rodents. Chronic Toxicity (or Exposure)
Chronic inhalation exposure to MDI is one of the leading causes of asthma in plant workers. In addition, chronic inhalation exposure can cause dyspnea, immune disorders as well as nasal and lung lesions. EPA has set the RfC for MDI at 0.0006 mg m 3 based upon irritation of nasal membranes in rodents. EPA has not established an RfD for MDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of MDI in humans; however, some effects (decreased placental and fetal weights and increased skeletal variations) were noted in a rat study.
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 584-84-9 SYNONYMS: 2,4-TDI; 2,4-Toluene diisocyanate CHEMICAL FORMULA: C9H6N2O2
Uses
Toluene diisocyanate (TDI) is commonly used as the 2,4 and 2,6 isomers. It is used as a chemical intermediate in the production of polyurethane materials including foams, coatings and elastomers, as a crosslinking agent for nylon-6, and as a hardener in polyurethane adhesives and finishes. Polyurethane elastomers made from TDI are used in coated fabrics and clay-pipe seals. Polyurethane coatings made from TDI are used in floor finishes, wood finishes and sealers, and in coatings for aircraft, tank trucks, truck trailers, and truck fleets. Background Information
TDI is a colorless, yellow, or brown liquid with a sharp pungent odor. The major metabolites of TDI in animals and humans are toluenediamines and their acetylated products. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of TDI. Workers and individuals in close proximity to the plant may inhale emissions from urethane foam production manufacturing facilities. It can be present as a unreacted impurity in materials, for example, TDI has been found in a urethane foam fabric coating in a concentration of o200 mg kg 1. Toxicokinetics
The toxicokinetics of TDI (2,4- and 2,6-toluenediisocyanates) in chronically exposed workers at two
644 Isocyanates
flexible foam polyurethane production plants have been reported. The half-life in urine ranged from 5.8 to 11 days for 2,4- and 2,6-toluenediamines. The differences in exposure were reflected by the plasma toluenediamine concentrations. The mean half-life in plasma was 21 days for 2,4-toluenediamine and 21 days for 2,6-toluenediamine, The study showed that the half-life in plasma of chronically exposed workers for 2,4- and 2,6-toluenediamine was twice as long as for volunteers with short-term exposure. An indication of a two-phase elimination pattern in urine was found. The first phase was related to the more recent exposure and the second, much slower one was probably related to release of toluenediamines in urine from TDI adducts in the body. Two men were exposed to TDI atmospheres in a stainless-steel test chamber. The effective exposure period was 4 h. The isomeric composition of the air in the test chamber was 30% 2,4-TDI and 70% 2,6-TDI. In plasma, 2,4and 2,6-toluenediamine showed a rapid-phase elimination half-life of B2–5 h, and that for the slow phase was greater than 6 days. A connection was observed between the concentrations of 2,4- and 2,6-TDI in air and the levels of 2,4- and 2,6-toluenediamine in plasma. The cumulated amount of 2,4-toluenediamine excreted in the urine over 24 h was B15–19% of the estimated inhaled dose of 2,4-TDI, and that of 2,6toluenediamine was B17–23% of the inhaled dose of 2,6-TDI. In another study, five men were exposed to TDI atmospheres for 7.5 h in a stainless-steel test chamber. The urinary elimination of the toluenediamines showed a possible biphasic pattern, with rapid first phases for 2,4-toluenediamine (mean half-life for the concn in urine, 1.9 h) and for 2,6-toluenediamine (mean half-life for the concn in urine, 1.6 h). The cumulative amount of 2,4-toluenediamine excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-toluenediamine in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-toluenediamine was 5 mg l 1 in the 6–8 h sample, and the corresponding value for 2,6toluenediamine was 8.6 mg l 1. Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4and 2,6-toluenediamine in urine is feasible.
low as 0.02 ppm. TDI is a potent respiratory irritant and sensitizer, even at low airborne concentrations. Chronic bronchitis, chronic restrictive pulmonary disease, and hypersensitivity pneumonitis have also been described among TDI-exposed people. The mechanism of TDI-induced asthma is still unknown. TDI may produce a true hemorrhagic syndrome affecting the bone marrow and producing primarily thrombocyte series suppression. Chronic Toxicity (or Exposure)
Chronic inhalation exposure results in severe lung effects that are characterized by asthma-like reactions characterized by dyspnea, wheezing, and bronchial constriction. The US EPA has neither established an RfC (for inhalation exposure) nor an RfD (for oral exposure) for TDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of TDI. Carcinogenicity
Rats and mice were administered commercial grade TDI (80% 2,4- and 20% 2,6-) in corn oil by gavage at doses of 60 or 120 mg kg 1 body weight, 5 days per week for 105 or 106 weeks. Other groups of rats and mice received 120 or 240 mg kg 1 on the same schedule. The results indicated that commercial grade TDI in corn oil was carcinogenic for rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females. TDI was not carcinogenic for male mice, but was carcinogenic for female mice, causing hemangiomas or hemangiosarcomas (combined), as well as hepatocellular adenomas. The International Agency for Research on Cancer (IARC) has judged that TDI is a group B chemical, that is, there is inadequate evidence for the carcinogenicity of TDI in humans, there is sufficient evidence for the carcinogenicity of TDI in experimental animals, and the overall evaluation is that TDI is possibly carcinogenic to humans. The (US) National Toxicology Program (NTP) lists TDI as an anticipated human carcinogen.
Acute and Short-Term Toxicity (or Exposure)
In laboratory animals, TDI has caused inflammation and necrosis when applied directly to the skin, conjunctivitis when applied to the eyes, and rhinitis, laryngitis, tracheitis, bronchitis, and pneumonia when inhaled. All workers develop eye, nose, and throat irritation at 0.5 ppm exposure to TDI. Sensitized individuals may manifest symptoms at levels as
In Vitro Toxicity Data
TDI was mutagenic in the Ames Salmonella assay, and induced chromosome aberrations after a 24 h treatment in the absence of metabolic activation in human whole blood lymphocyte cultures. To investigate the role of pharmacological mechanisms in TDI-induced occupational asthma, the effects of TDI
Isodrin 645
on rat trachea ring and lung parenchymal strip were studied in vitro. The most prominent effect observed was a stimulation of metacholine-induced contraction of the tracheal ring by 1 mmol l 1 TDI. It was concluded that the pharmacological effect of TDI may result from an autonomic imbalance between cholinergic and B-adrenergic neural control.
Exposure Standards and Guidelines
The (US) OSHA PEL, 8 h TWA is 0.02 ppm (0.14 mg m 3). See also: Bhopal; Carbamate Pesticides.
Further Reading Environmental Fate
TDI’s production and uses may result in its release to the environment through various waste streams. If released to air, TDI will exist solely as a vapor in the ambient atmosphere and will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2.7 days. Atmospheric degradation may also occur through contact with clouds, fog, or rain. If released to water or moist soil, toluenediisocyanate is not expected to leach or adsorb to solids due to its rapid degradation reaction with water. It is not expected to bioconcentrate in aquatic organisms.
Cohrssenn BC (2001) Cyanides and nitriles. In: Bingham E, Cohrssen B, and Powell CH (eds.) Patty’s Toxicology, 5th edn., vol. 4, pp. 1373–1456. New York: Wiley. Dart RC (2004) Miscellaneous chemical agents. In: Dart DC (ed.) Medical Toxicology, 3rd edn., pp. 1184–1186. Philadelphia, PA: Lippincott Williams and Wilkins.
Relevant Websites http://toxnet.nlm.nih.gov – TOXNET, Specialized Information Services, National Library of Medicine. Search for Isocyanates. http://www.tc.gc.ca – Isocyanates (from Transport Canada). http://www.cdc.gov – US National Institute for Occupational Safety and Health (NIOSH). Isocyanates (NIOSH Safety and Health Topic).
Isodrin
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K S Rao
Uses
& 2005 Elsevier Inc. All rights reserved.
Isodrin, a cyclodiene insecticide has been discontinued and is no longer used in the United States.
CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 465-73-6 SYNONYMS: 1,4;5,8-Dimethanonaphthalene,1,2,3,4,10,10-hexachloro-, 4,4a,5,8,8a hexahydro-endo, Compound 711; Experimental Insecticide 711; SD 3418 CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Cyclodiene; Insecticide CHEMICAL FORMULA: C12H8Cl6 CHEMICAL STRUCTURE: Cl Cl
Cl Cl
Cl
Cl Cl Cl
Cl Cl
Cl
Cl
Exposure Routes and Pathways Exposure to isodrin can occur by inhalation, or ingestion; however, the primary exposure is through the dermal route to mixers, loaders, and applicators, during and after normal use.
Toxicokinetics Isodrin is metabolized by biooxidation to endrin. Isodrin and its metabolite, endrin, have high fat:water partition coefficients and, therefore, tend to accumulate in adipose tissue. At a constant rate of intake, however, the concentration of the insecticide in adipose tissue reaches an equilibrium and remains relatively constant. Following cessation of exposure, it is slowly eliminated from the body. In vitro studies have shown that mixed-function oxidase of mouse liver converts isodrin to endrin. Mice excrete 10% of the orally administered dose in urine. Four unidentified metabolites were present in urine, three probably are glucuronide or sulfate conjugates. Feces is
Isocyanates Robert Kapp & 2005 Elsevier Inc. All rights reserved.
Isocyanates are a group of low molecular weight aromatic and aliphatic compounds containing the isocyanate group (–NCO). The most widely used industrial isocyanates and their applications are listed below. The most notorious isocyanate is methyl isocyanate, involved in one of the worst industrial tragedies recorded in history. In the early morning hours of December 3, 1984, 200 000 people in Bhopal, India were exposed to methyl isocyanate. The 90 min exposure resulted in at least 2500 deaths and countless cases of severe eye and lung damage. Most of the deaths were related to the pulmonary edema.
HDI – Hexamethylene Diisocyanate *
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 822-06-0 SYNONYMS: 1,6-Diisocyanatohexane; HDI; Hexamethylene-1,6-diisocyanate; 1,6-Hexamethylene diisocyanate; HMDI CHEMICAL FORMULA: C8H12N2O2
Uses
Hexamethylene diisocyanate (HDI) is used in the preparation of dental materials, medical adsorbents, and contact lenses, and is used as a polymerizing agent in polyurethane paints and coatings. Background Information
HDI is a colorless liquid with an irritating odor. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of HDI. Workers and individuals in close proximity to an area where spray applications of polyurethane paints may be exposed.
inhalation exposure has been reported to cause irritation of the nasal tissues and respiratory tract. Dermal exposure has resulted in sensitization in several animal species. The US Environmental Protection Agency (EPA) has set the reference concentration (RfC) for HDI at 0.000 01 mg m 3 based upon the degeneration of the olfactory epithelium in rodents. EPA has not established a reference dose (RfD) for HDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of HDI in humans. A rat reproductive study found no effects in any reproductive organs. Carcinogenicity
No information is available on the carcinogenic effects of HDI in humans. Animals exposed to HDI were reported to show no evidence of carcinogenicity in a 2 year inhalation study. EPA has classified HDI as a group D (not classifiable as to human carcinogenicity.) Clinical Management
Skin or ocular exposure areas should be generously irrigated with saline. All other treatment is symptomatic. Exposure Standards and Guidelines
The (US) National Institute for Occupational Safety and Health (NIOSH) recommended exposure level (REL), averaged over a 10 h workday is 0.005 ppm (0.035 mg m 3).
MIC – Methyl Isocyanate *
Acute and Short-Term Toxicity (or Exposure)
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Acute inhalation exposure may result in pulmonary edema, coughing, and labored breathing in humans. HDI is extremely irritating to the eyes, nose, and throat. Rodent studies revealed that HDI is extremely toxic by inhalation, and moderately to highly toxic by oral ingestion.
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 624-83-9 SYNONYMS: Methyl ester of isocyanic acid; MIC CHEMICAL FORMULA: C2H3NO
Uses
Methyl isocyanate (MIC) is used as a chemical intermediate in the production of carbamate insecticides and some herbicides.
Chronic Toxicity (or Exposure)
Chronic inhalation exposure to HDI is thought to cause chronic lung irritation. In addition, chronic
Background Information
MIC is a colorless liquid with a sharp pungent odor.
Isocyanates 641 Exposure Routes and Pathways
Inhalation, ingestion and dermal contact are all possible routes of exposure. Occupational exposure can occur during the use of carbamates produced from MIC. Small amounts of MIC are found in cigarette smoke. Acute and Short-Term Toxicity (or Exposure)
The acute toxic effects of MIC are essentially similar by either route except for the intensity of the effects. When rats were administered MIC by inhalation or subcutaneous route it produced severe hyperglycemia, clinical lactic acidosis, highly elevated plasma urea, and reduced plasma cholinesterase activity with unaltered erythrocyte acetyl cholinesterase activity. Irrespective of the route of administration, MIC also caused severe hypothermia, which was not ameliorated by prior administration of atropine sulfate. Rats and mice of each sex were exposed by inhalation to MIC at 0, 1, and 3 ppm for 6 h day 1 for 4 days followed by up to a 91 day recovery period. Only animals exposed to 3 ppm exhibited exposure related changes. Most of the rats exposed at 3 ppm died within 28 days. A prominent decrease in body weight was observed along with severe lung lesions and thymus atrophy. Lesions of the nasal cavity of rats and mice were characterized by regeneration of the olfactory and respiratory epithelium. By day 28, the respiratory epithelium of rats and mice appeared normal, but olfactory regeneration was still present in the surviving rats. Severe lesions of the trachea extending to the bronchi, bronchioles, and alveoli were seen in rats exposed to 3 ppm. Acute inflammation of the airways and hyaline membranes was observed in high dose animals killed on day 7. In the 3 ppm MIC-exposed animals that died during days 8–14, there was lymphatic necrosis of the thymus, atrophy of the splenic white pulp, coagulative necrosis of the liver, and thrombosis of the left cardiac atrium. Gross examination of exposed mice showed minimal differences between exposure groups. Microscopic observations showed treatment-related changes only in the 3 ppm exposure group of mice. The changes involved primarily the bronchial system and were not as severe as those observed in rats. By day 91, bronchial fibrosis was minimal to mild in mice. One group of five male rats was exposed to 3 ppm MIC for a single 6 h exposure. The lesions in the respiratory system were essentially the same as those observed in the 4 day repeated exposure rats that were killed after 7 days. In another acute toxicity study, rats were exposed only once to 3.52 and 35.32 ppm of MIC for 10 min; in a subacute study, they were exposed to doses of
0.212, 0.265, and 0.349 ppm for 30 min daily for 6 days and were then observed for 90 days for weight gain. At the end of 90 days, damage to the viscera was evaluated. During exposure, the animals had congestion in eyes, lachrymation, nasal secretion and dyspnea, progressively increasing ataxia, immobility, and uncoordinated movements. MIC exposure greatly inhibited weight gain in the animals in a dosedependent manner. Upon microscopic examination of the viscera, pathological findings were confined to the bronchial tree, lung parenchyma, liver, and kidneys. Acute inhalation exposure of humans results in pulmonary edema (most of the Bhopal deaths were due to pulmonary edema and secondary respiratory infections from pulmonary edema). Other acute effects include, blindness, nausea, gastritis, sweating, fever, chills, and liver and kidney damage. MIC was studied in in vivo micronucleus test and chromosomal analysis of bone marrow cells. Mice were exposed for 10 min to different concentrations (2.40, 4.80, or 7.20 ml) of MIC at 0 and 24 h. Quantitative analysis failed to exhibit any significant increase in aberration rates in the three treated groups. In another micronucleus assay, mice were exposed to MIC through ip injection for 2 and 5 days in separate experiments, and bone marrow and peripheral blood were sampled 6 and 48 h after the last injection, respectively. MIC did not significantly increase the frequencies of micronucleated erythrocytes in bone marrow and pheripheral blood samples in either twice or multiply treated mice. However, a dosedependent depression in percentage polychromatic erythrocytes observed was significant. This indicates that MIC exposure led to the cytotoxic effect by inhibition of bone marrow cell proliferation. Chronic Toxicity (or Exposure)
The long-term carcinogenic and pulmonary effects of a single exposure to MIC were examined in rodents. Rats and mice were exposed to MIC by inhalation at 0, 1, 3, or 10 ppm for 2 h. After 2 years, the animals were sacrificed and tissues and organs were examined microscopically. No differences in survival rates or body weight gains were found in the MIC-exposed animals versus controls. Male and female rats exposed to 10 ppm MIC had 42% and 36% incidence, respectively, of intraluminal fibrosis of secondary bronchi; however, no evidence of this lesion was seen in controls or animals exposed to lower concentrations. For male and female mice and female rats, no neoplastic lesions were significantly associated with MIC exposure. Male rats exposed to MIC had marginally increased rates of pheochromocytomas of the adrenal medulla and adenomas of
642 Isocyanates
pancreatic acinar cells cells. EPA has not established an RfC or an RfD for MIC.
trimethylamine, may act as endogenous teratogens under certain conditions. Carcinogenicity
Reproductive Toxicity
Follow-up of exposed humans after the Bhopal incident found a high level of stillborns, spontaneous abortions and increased infant mortality. There was also a high number of survivors with pelvic inflammatory disease, excessive menstrual bleeding and suppression of lactation. Pregnant mice and rats were exposed to 9 or 20 ppm MIC to determine if the chemical was able to cross the placental barrier and directly affect the fetus. The mice were exposed on day 8 and the rats on day 10 of gestation to 9 ppm MIC for 3 h for evaluation of in vivo fetal toxicity. In other experiments the animals were exposed for 2 h to 20 ppm and the embryos removed immediately for culture. MIC exposure reduced maternal progesterone levels in mice that lost but not in mice that retained pregnancy. No relationship was observed between fetal toxicity of MIC and maternal plasma corticosterone levels. Fetal toxicity of MIC was not affected by chronic administration of progesterone or the suppression of pulmonary edema with dexamethasone. A concentration dependent decrease in growth in culture was noted in embryos exposed in utero or in vitro to MIC vapor. No fetal toxicity was noted following exposure to an acute dose, 3 mmol kg 1, of the metabolites. The results indicate that the fetal toxicity of MIC is partly independent of maternal toxicity and may result from the transfer across the placenta and the interaction with fetal tissues. Monomethylamine, dimethylamine, and trimethylamine are endogenous substances as well as metabolites of MIC. Methylamines exert several toxic effects including inhibition of protein turnover and oocyte RNA synthesis. A study conducted to determine the developmental toxicity of these methylamines using pregnant mice and mouse embryo culture used ip injections (daily from day 1 to day 17 of gestation) of trimethylamine at 2.5 and 5 mmol kg 1day 1. Trimethylamine significantly decreased fetal body weight but not the placental weight or maternal body weight gain; however, 5 of 11 mice treated with 5 mmol kg 1 trimethylamine died. Similar treatment with dimethylamine or monomethylamine did not exert any obvious maternal or fetal effects. All three methylamines, when added to embryos in culture, caused dose dependent decreases in size, DNA, RNA, and protein content as well as embryo survival; the order of toxicity was trimethylamine 4 dimethylamine 4 monomethylamine. The ability of monomethylamines to adversely affect fetal development suggests that these methylamines, especially
No information is available on the carcinogenic effects of MIC in humans. Animals exposed via inhalation gave mixed results. EPA has classified MIC as a group D (not classifiable as to human carcinogenicity.) In Vitro Toxicity Data
MIC was nonmutagenic in the Ames (Salmonella), Drosophila sex-linked recessive lethal assays. MIC induced chromosomal aberrations in cultured Chinese hamster ovary cells. Environmental Fate
MIC may be released to the environment as a result of its manufacture and use as a chemical intermediate. If MIC is released to soil, it will be expected to rapidly hydrolyze if the soil is moist, based upon the rapid hydrolysis observed in aqueous solution. If released to water, it will be expected to rapidly hydrolyze with half-lives of 20 and 9 min at 151C and 251C, respectively, calculated from measured overall hydrolysis rate constants. The products of hydrolysis may include N-carboxymethylamine, methylamine, carbon dioxide, and N,N0 -dimethylurea. Since it rapidly hydrolyzes, bioconcentration, volatilization, and adsorption to sediment and suspended solids are not expected to be significant processes. No data were located concerning biodegradation, but MIC will probably abiotically hydrolyze significantly faster than it will biodegrade. If released to the atmosphere, it will be expected to exist almost entirely in the vapor phase based upon its vapor pressure. It will be susceptible to photooxidation via vapor phase reaction with photochemically produced hydroxyl radicals. Hydrolysis of MIC in moist air may be significant based upon its rapid hydrolysis in aqueous solution. Exposure Standards and Guidelines
The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value, 8 h timeweighted average (TWA) is 0.02 ppm, with a designation that skin exposure is also an important exposure. The (US) Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), 8 h TWA is 0.02 ppm (with a skin notation). The US NIOSH REL is 0.02 ppm as a 10 h TWA, and the NIOSH immediately dangerous to life or health (IDLH) value is 3 ppm. MIC is listed by EPA as a hazardous air pollutant generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards
Isocyanates 643
requiring major sources to sharply reduce routine emissions of toxic pollutants.
MDI – 4,40 -Methylenediphenyl Diisocyanate *
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 101-68-8 SYNONYMS: 4,40 -Diphenylmethane diisocyanate; Methylene bis(4-phenyl isocyanate); Methylene di-p-phenylene ester of isocyanic acid CHEMICAL FORMULA: C15H10N2O2
Uses
4,40 -Methylenediphenyl diisocyanate (MDI) is used to produce polyurethane foams.
Carcinogenicity
No information is available on the carcinogenic effects of MDI in humans. Animals exposed to polymeric MDI were reported to increase the incidence of pulmonary adenomas. EPA has classified MDI as a group D (not classifiable as to human carcinogenicity). Exposure Standards and Guidelines
The (US) OSHA PEL 8 h TWA is 0.02 ppm (0.2 mg m 3). The (US) NIOSH REL is 0.005 ppm (0.05 mg m 3) as a 10 h TWA, and the NIOSH IDLH value is 75 mg m 3.
TDI – Toluene Diisocyanate *
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Background Information
MDI is a light-yellow fused solid or it may occur in crystalline form. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of MDI. Workers and individuals in close proximity to the plant may inhale emissions from urethane foam production manufacturing facilities. Acute and Short-Term Toxicity (or Exposure)
Acute inhalation exposure may result in sensitization and asthma in humans. Dermal contact with MDI resulted in dermatitis and eczema in plant workers. Animal studies revealed skin and eye irritation in rabbits, extreme toxicity by inhalation and moderate toxicity by oral ingestion in rodents. Chronic Toxicity (or Exposure)
Chronic inhalation exposure to MDI is one of the leading causes of asthma in plant workers. In addition, chronic inhalation exposure can cause dyspnea, immune disorders as well as nasal and lung lesions. EPA has set the RfC for MDI at 0.0006 mg m 3 based upon irritation of nasal membranes in rodents. EPA has not established an RfD for MDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of MDI in humans; however, some effects (decreased placental and fetal weights and increased skeletal variations) were noted in a rat study.
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CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 584-84-9 SYNONYMS: 2,4-TDI; 2,4-Toluene diisocyanate CHEMICAL FORMULA: C9H6N2O2
Uses
Toluene diisocyanate (TDI) is commonly used as the 2,4 and 2,6 isomers. It is used as a chemical intermediate in the production of polyurethane materials including foams, coatings and elastomers, as a crosslinking agent for nylon-6, and as a hardener in polyurethane adhesives and finishes. Polyurethane elastomers made from TDI are used in coated fabrics and clay-pipe seals. Polyurethane coatings made from TDI are used in floor finishes, wood finishes and sealers, and in coatings for aircraft, tank trucks, truck trailers, and truck fleets. Background Information
TDI is a colorless, yellow, or brown liquid with a sharp pungent odor. The major metabolites of TDI in animals and humans are toluenediamines and their acetylated products. Exposure Routes and Pathways
Inhalation and dermal exposure can occur during the manufacture and use of TDI. Workers and individuals in close proximity to the plant may inhale emissions from urethane foam production manufacturing facilities. It can be present as a unreacted impurity in materials, for example, TDI has been found in a urethane foam fabric coating in a concentration of o200 mg kg 1. Toxicokinetics
The toxicokinetics of TDI (2,4- and 2,6-toluenediisocyanates) in chronically exposed workers at two
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flexible foam polyurethane production plants have been reported. The half-life in urine ranged from 5.8 to 11 days for 2,4- and 2,6-toluenediamines. The differences in exposure were reflected by the plasma toluenediamine concentrations. The mean half-life in plasma was 21 days for 2,4-toluenediamine and 21 days for 2,6-toluenediamine, The study showed that the half-life in plasma of chronically exposed workers for 2,4- and 2,6-toluenediamine was twice as long as for volunteers with short-term exposure. An indication of a two-phase elimination pattern in urine was found. The first phase was related to the more recent exposure and the second, much slower one was probably related to release of toluenediamines in urine from TDI adducts in the body. Two men were exposed to TDI atmospheres in a stainless-steel test chamber. The effective exposure period was 4 h. The isomeric composition of the air in the test chamber was 30% 2,4-TDI and 70% 2,6-TDI. In plasma, 2,4and 2,6-toluenediamine showed a rapid-phase elimination half-life of B2–5 h, and that for the slow phase was greater than 6 days. A connection was observed between the concentrations of 2,4- and 2,6-TDI in air and the levels of 2,4- and 2,6-toluenediamine in plasma. The cumulated amount of 2,4-toluenediamine excreted in the urine over 24 h was B15–19% of the estimated inhaled dose of 2,4-TDI, and that of 2,6toluenediamine was B17–23% of the inhaled dose of 2,6-TDI. In another study, five men were exposed to TDI atmospheres for 7.5 h in a stainless-steel test chamber. The urinary elimination of the toluenediamines showed a possible biphasic pattern, with rapid first phases for 2,4-toluenediamine (mean half-life for the concn in urine, 1.9 h) and for 2,6-toluenediamine (mean half-life for the concn in urine, 1.6 h). The cumulative amount of 2,4-toluenediamine excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-toluenediamine in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-toluenediamine was 5 mg l 1 in the 6–8 h sample, and the corresponding value for 2,6toluenediamine was 8.6 mg l 1. Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4and 2,6-toluenediamine in urine is feasible.
low as 0.02 ppm. TDI is a potent respiratory irritant and sensitizer, even at low airborne concentrations. Chronic bronchitis, chronic restrictive pulmonary disease, and hypersensitivity pneumonitis have also been described among TDI-exposed people. The mechanism of TDI-induced asthma is still unknown. TDI may produce a true hemorrhagic syndrome affecting the bone marrow and producing primarily thrombocyte series suppression. Chronic Toxicity (or Exposure)
Chronic inhalation exposure results in severe lung effects that are characterized by asthma-like reactions characterized by dyspnea, wheezing, and bronchial constriction. The US EPA has neither established an RfC (for inhalation exposure) nor an RfD (for oral exposure) for TDI. Reproductive Toxicity
No information is available in the reproductive or developmental effects of TDI. Carcinogenicity
Rats and mice were administered commercial grade TDI (80% 2,4- and 20% 2,6-) in corn oil by gavage at doses of 60 or 120 mg kg 1 body weight, 5 days per week for 105 or 106 weeks. Other groups of rats and mice received 120 or 240 mg kg 1 on the same schedule. The results indicated that commercial grade TDI in corn oil was carcinogenic for rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females. TDI was not carcinogenic for male mice, but was carcinogenic for female mice, causing hemangiomas or hemangiosarcomas (combined), as well as hepatocellular adenomas. The International Agency for Research on Cancer (IARC) has judged that TDI is a group B chemical, that is, there is inadequate evidence for the carcinogenicity of TDI in humans, there is sufficient evidence for the carcinogenicity of TDI in experimental animals, and the overall evaluation is that TDI is possibly carcinogenic to humans. The (US) National Toxicology Program (NTP) lists TDI as an anticipated human carcinogen.
Acute and Short-Term Toxicity (or Exposure)
In laboratory animals, TDI has caused inflammation and necrosis when applied directly to the skin, conjunctivitis when applied to the eyes, and rhinitis, laryngitis, tracheitis, bronchitis, and pneumonia when inhaled. All workers develop eye, nose, and throat irritation at 0.5 ppm exposure to TDI. Sensitized individuals may manifest symptoms at levels as
In Vitro Toxicity Data
TDI was mutagenic in the Ames Salmonella assay, and induced chromosome aberrations after a 24 h treatment in the absence of metabolic activation in human whole blood lymphocyte cultures. To investigate the role of pharmacological mechanisms in TDI-induced occupational asthma, the effects of TDI
Isodrin 645
on rat trachea ring and lung parenchymal strip were studied in vitro. The most prominent effect observed was a stimulation of metacholine-induced contraction of the tracheal ring by 1 mmol l 1 TDI. It was concluded that the pharmacological effect of TDI may result from an autonomic imbalance between cholinergic and B-adrenergic neural control.
Exposure Standards and Guidelines
The (US) OSHA PEL, 8 h TWA is 0.02 ppm (0.14 mg m 3). See also: Bhopal; Carbamate Pesticides.
Further Reading Environmental Fate
TDI’s production and uses may result in its release to the environment through various waste streams. If released to air, TDI will exist solely as a vapor in the ambient atmosphere and will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2.7 days. Atmospheric degradation may also occur through contact with clouds, fog, or rain. If released to water or moist soil, toluenediisocyanate is not expected to leach or adsorb to solids due to its rapid degradation reaction with water. It is not expected to bioconcentrate in aquatic organisms.
Cohrssenn BC (2001) Cyanides and nitriles. In: Bingham E, Cohrssen B, and Powell CH (eds.) Patty’s Toxicology, 5th edn., vol. 4, pp. 1373–1456. New York: Wiley. Dart RC (2004) Miscellaneous chemical agents. In: Dart DC (ed.) Medical Toxicology, 3rd edn., pp. 1184–1186. Philadelphia, PA: Lippincott Williams and Wilkins.
Relevant Websites http://toxnet.nlm.nih.gov – TOXNET, Specialized Information Services, National Library of Medicine. Search for Isocyanates. http://www.tc.gc.ca – Isocyanates (from Transport Canada). http://www.cdc.gov – US National Institute for Occupational Safety and Health (NIOSH). Isocyanates (NIOSH Safety and Health Topic).
Isodrin
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K S Rao
Uses
& 2005 Elsevier Inc. All rights reserved.
Isodrin, a cyclodiene insecticide has been discontinued and is no longer used in the United States.
CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 465-73-6 SYNONYMS: 1,4;5,8-Dimethanonaphthalene,1,2,3,4,10,10-hexachloro-, 4,4a,5,8,8a hexahydro-endo, Compound 711; Experimental Insecticide 711; SD 3418 CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Cyclodiene; Insecticide CHEMICAL FORMULA: C12H8Cl6 CHEMICAL STRUCTURE: Cl Cl
Cl Cl
Cl
Cl Cl Cl
Cl Cl
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Exposure Routes and Pathways Exposure to isodrin can occur by inhalation, or ingestion; however, the primary exposure is through the dermal route to mixers, loaders, and applicators, during and after normal use.
Toxicokinetics Isodrin is metabolized by biooxidation to endrin. Isodrin and its metabolite, endrin, have high fat:water partition coefficients and, therefore, tend to accumulate in adipose tissue. At a constant rate of intake, however, the concentration of the insecticide in adipose tissue reaches an equilibrium and remains relatively constant. Following cessation of exposure, it is slowly eliminated from the body. In vitro studies have shown that mixed-function oxidase of mouse liver converts isodrin to endrin. Mice excrete 10% of the orally administered dose in urine. Four unidentified metabolites were present in urine, three probably are glucuronide or sulfate conjugates. Feces is