3

Methyl Isocyanate1

Acute Exposure Guideline Levels

SUMMARY

Methyl isocyanate (MIC) is one of the most reactive of all isocyanates and is rapidly degraded in aqueous medium (Varma and Guest 1993). Because of its reactivity, MIC is used as an intermediate in the synthesis of N-methylcarbamate and N-methylurea insecticides and herbicides (Hartung 1994). During the night of December 2–3, 1984, an estimated 30 tons of

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This document was prepared by the AEGL Development Team comprising Carol Forsyth (Oak Ridge National Laboratory) and National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member Loren Koller (Chemical Manager). The NAC reviewed and revised the document and AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid on the basis of data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 3 Methyl Isocyanate1 Acute Exposure Guideline Levels SUMMARY Methyl isocyanate (MIC) is one of the most reactive of all isocyanates and is rapidly degraded in aqueous medium (Varma and Guest 1993). Because of its reactivity, MIC is used as an intermediate in the synthesis of N-methylcarbamate and N-methylurea insecticides and herbicides (Hartung 1994). During the night of December 2–3, 1984, an estimated 30 tons of 1   This document was prepared by the AEGL Development Team comprising Carol Forsyth (Oak Ridge National Laboratory) and National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member Loren Koller (Chemical Manager). The NAC reviewed and revised the document and AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid on the basis of data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 MIC were released from a chemical plant in Bhopal, India, resulting in one of the worst industrial accidents in history (Karlsson et al. 1985). Signs of severe irritation to the respiratory tract were reported for victims of the Bhopal disaster, and autopsies revealed the cause of death to be acute pulmonary edema (Weill 1988). Long-term pulmonary and ocular sequelae have been documented in survivors. The spontaneous abortion rate (Arbuckle and Sever 1998) and the infant death rate (Varma 1987) among women who were pregnant at the time of the release were significantly increased in the months following the disaster. Numerous animal studies corroborate the epidemiological findings in humans. A compilation of case reports in industrial workers consistently noted skin and respiratory irritation in MIC-exposed workers but no definitive case of sensitization (Ketcham 1973). The mechanism of action for the pulmonary, skin, and ocular toxicity is irritation, but the mechanism of action for the systemic effects is unknown. AEGL-1 values were not derived. Although human and animal data were available for irritation levels, the irritation threshold for MIC may be above the level of concern for systemic effects. Experimental studies in humans indicate that both duration of exposure and concentration of MIC contribute to the severity of irritation. However, extrapolation from the short experimental durations to the longer AEGL time points may not be predictive of adverse health effects. It is not known at what concentration the risk for systemic effects, other than pulmonary edema, becomes a concern. The concentrations causing irritation in humans after several minutes (1–4 parts per million [ppm]) are similar to, or higher than, the concentrations resulting in embryo and fetal lethality in well conducted animal studies. Therefore, the results of controlled human exposures were not used in derivation of AEGL-1. However, it should be noted that exposures to MIC at concentrations below those used to calculate AEGL-1 might be associated with systemic toxicity. Systemic toxicity data from rats and mice were used for derivation of AEGL-2. An increase in cardiac arrhythmias occurred in rats 4 months (mo) after a 2-hour (h) exposure to 3 ppm (Tepper et al. 1987). Pregnant Swiss-Webster mice were exposed to analytically monitored concentrations of MIC at 0, 2, 6, 9, and 15 ppm for 3 h on gestation day 8 (Varma 1987). Placental weights and fetal body weights were significantly reduced at all concentrations. Exposures to concentrations at 9 ppm and 15 ppm resulted in deaths of two dams in each group, a significant increase in complete litter resorption among surviving dams, and fetuses with significant reduc-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 tions in the lengths of the mandible and long bones. The single exposure concentration of 2 ppm for 3 h was an experimentally derived LOAEL for reduced fetal body weights in the absence of maternal toxicity. Values scaled for the derivation of the 10- and 30-minute (min), and 1-, 4-, and 8-h time points were calculated from the equation Cn×t=k where n=1. The value of n was empirically derived from regression analysis of lethality data for rats. Identical AEGL-2 values are derived based on the exposures of 3 ppm for 2 h and 2 ppm for 3 h. The experimental concentrations were reduced by a factor of 3 to estimate a threshold for effects on cardiac arrhythmias or fetal body weights. A total uncertainty factor (UF) of 30 was applied, including 3 for interspecies variation because similar developmental toxicity results have been obtained in both rats and mice and 10 for intraspecies variation because the mechanism of action for developmental toxicity is unknown. The neonatal survival study with mice conducted by Schwetz et al. (1987) was used for derivation of AEGL-3 values. Pregnant mice were exposed to MIC at 0, 1, or 3 ppm for 6 h/day (d) on gestation days 14–17. Dams were allowed to litter for evaluation of neonatal survival. No maternal toxicity was observed at either exposure concentration. A concentration-related increase in the number of dead fetuses at birth was observed in both MIC exposure groups, and an increase in neonatal mortality during lactation was observed in the 3-ppm group. No differences in neonatal body-weight gain occurred during lactation between the treated and control groups. The 6-h exposure to 1 ppm was used to derive AEGL-3 values and is considered a NOEL for pup survival during lactation. Values scaled for the derivation of the 10- and 30-min, and 1-, 4-, and 8-h time points were calculated from the equation Cn×t=k where n=1. The value of n was empirically derived from regression analysis of lethality data for rats. A total UF of 30 was applied, including 3 for interspecies variation because similar developmental toxicity results have been obtained in both rats and mice and 10 for intraspecies variation because the mechanism of action for developmental toxicity is unknown. According to Section 2.7 of the standing operating procedures (NRC 2001), 10-min values are not to be scaled from an experimental exposure time of ≥4 h. However, because n was derived from exposures ranging from 7.5 min to 4 h, extrapolation from 6 h to the 10-min AEGL-3 value is valid in this instance. The proposed values for the three AEGL classifications for the five time periods are listed in the table below.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 3–1 Summary of AEGL Values for Methyl Isocyanate Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a (Non-disabling) NR NR NR NR NR   AEGL-2 (Disabling) 0.40 ppm (0.94 mg/m3) 0.13 ppm (0.32 mg/m3) 0.067 ppm (0.16 mg/m3) 0.017 ppm (0.034 mg/m3) 0.008 ppm (0.02 mg/m3) Decreased fetal body weights (Varma 1987); cardiac arrhythmias (Tepper et al. 1987) AEGL-3 (Lethal) 1.2 ppm (2.8 mg/m3) 0.40 ppm (0.95 mg/m3) 0.20 ppm (0.47 mg/m3) 0.05 ppm (0.12 mg/m3) 0.025 ppm (0.06 mg/m3) Decreased pup survival during lactation (Schwetz et al. 1987) aExposure to MIC at concentrations below those used to calculate AEGL-1 may be associated with systemic toxicity. Abbreviations: NR, not recommended. 1. INTRODUCTION Methyl isocyanate (MIC) is one of the most reactive of all isocyanates and is rapidly degraded in aqueous medium (Varma and Guest 1993). Because of its reactivity, MIC is used as an intermediate in the synthesis of N-methylcarbamate and N-methylurea insecticides and herbicides (Hartung 1994). During the night of December 2–3, 1984, a release occurred in a chemical plant in Bhopal, India, where MIC was used as an intermediate in the production of carbamates. An estimated 30 tons of MIC were released resulting in one of the worst industrial accidents in history (Karlsson et al. 1985). Signs of severe respiratory tract irritation were reported for victims of the Bhopal disaster and autopsies revealed the cause of death to be pulmonary edema (Varma and Guest 1993). Long-term pulmonary and ocular disease have been documented in survivors (Andersson et al. 1990).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 3–2 Chemical and Physical Data for Methyl Isocyanate Parameter Value Reference Synonyms Isocyanatomethane; isocyanic acid methyl ester; MIC Budavari et al. 1996 Chemical formula C2H3NO Budavari et al. 1996 Molecular weight 57.05 Budavari et al. 1996 CAS Registry Number 624–83–9   Physical description Liquid Budavari et al. 1996 Vapor pressure 400 torr at 20.6 °C Budavari et al. 1996 Vapor density (air=1) 2.0 Hartung 1994 Melting/boiling point −45 °C/39.1 °C EPA 1986 Solubility in water 0.067 g/mL Hartung 1994 Conversion factors in air 1 ppm=2.34 mg/m3 1 mg/m3=0.43 ppm NIOSH 1997 Reactivity Exothermic reaction with water can lead to explosion EPA 1986 Numerous animal studies corroborate the epidemiological findings in humans. Unlike other isocyanates, MIC is not a sensitizer. Selected physicochemical properties of MIC are listed in Table 3–2. 2. HUMAN TOXICITY DATA 2.1. Bhopal Disaster On the night of December 2/3, 1984, an estimated 30 tons of MIC gas were released over Bhopal, India from a carbamate factory when water entered the storage tank. The reaction of water and MIC is exothermic and resulted in increased pressure and temperature until the tank’s safety valve ruptured. Total duration of the release was approximately 1 h. Atmospheric conditions maintained the MIC cloud close to the ground, and light winds moved it towards a heavily populated area. Dispersion calculations by Karlsson et al. (1985) estimate concentrations of MIC to have ranged from

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 3,000 ppm at 270 m downwind to 10 ppm at 5,500 m downwind. However, the concentrations to which the population was actually exposed are unknown. The official death toll was 2,250 individuals, with another 50,000 incapacitated and about 100,000 treated in area hospitals. In addition, about 1,000 livestock were killed. The area with the heaviest casualties was 6–7 km2 south of the factory and severe injuries occurred in a region of about 25 km2 (Karlsson et al. 1985). In general, deaths were not instantaneous but occurred in phases over the next few days following the release. Only a few deaths were recorded within the first few hours; a second phase occurred between 8 and 12 h, and the greatest number of deaths occurred between 24 and 72 h after the MIC release (Varma 1989; Varma and Guest 1993). Numerous accounts have been published detailing the effects of MIC on the population. The most frequently reported symptoms were burning and/or watering of the eyes, coughing, respiratory distress, pulmonary congestion, nausea, vomiting, muscle weakness, and CNS involvement secondary to hypoxia (Kamat et al. 1985; Misra et al. 1987; Lorin and Kulling 1986; Andersson et al. 1988; Weill 1988; Kamat et al. 1992). The frequency of reports of cough as an initial symptom most closely followed the distribution of deaths in the exposed populations (Andersson et al. 1988), deaths resulting from pulmonary edema (Weill 1988) or cardiac arrest following pulmonary edema (Varma and Guest 1993). Between areas in which deaths occurred and areas where only symptoms were reported, distance to the factory was a contributing factor, but the duration of exposure (up to 4 h) did not appear to vary (Andersson et al. 1988). Although most survivors improved within 2 weeks (wk), many had restrictive respiratory function with radiographic changes suggestive of interstitial deposits (Kamat et al. 1985). Long-term health effects from the accident have been reported for populations followed for up to 3 years (y). One hundred and five days after the accident, a survey of children residing within 2 km of the factory at the time of the accident showed that 83.5% had persistent cough, 47.5% had breathlessness, 48.1% had rhonchi, and 43.2% had wheezing compared with abnormal respiratory findings in 8.5% of children living 8–10 km away; abdominal pain and anorexia were also increased by 8.0–9.8% in children living closer to the factory (Irani and Mahashur 1986). Another survey, which included adults and children, documented persistent respiratory, ophthalmological, neuromuscular, and gastrointestinal symptoms 15

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 wk after the accident (Naik et al. 1986). In more heavily exposed groups (defined by distance to the factory or number of symptoms), cognitive functions were impaired and consolidations were observed on chest radiographs after 1 y (Misra and Kalita 1997), with breathlessness, chest pain, and nausea/vomiting more frequent after 3 y (Andersson et al. 1990). Small airway obstruction, as measured by reductions in pulmonary function tests and/or abnormal chest radiographs, were found in victims at 1 y (Misra and Kalita 1997), 2 y (Kamat et al. 1992), and 10 y (Cullinan et al. 1997) after the accident. A study carried out 1–7 y after the accident found reductions in pulmonary function correlated with increases in inflammatory cells measured in bronchoalveolar lavage fluid and with radiographic abnormalities (Vijayan and Sankaran 1996). Immediate and long-term ocular toxicities were also a major consequence of the MIC release in Bhopal. However, no cases of blindness were attributed to exposure (Andersson et al. 1984, 1985, 1988). Immediately after the accident, tearing, photophobia, profuse lid edema, and superficial corneal ulceration were reported (Andersson et al.,1984; Dwivedi et al. 1985). Superficial interpalpebral erosion of the cornea and conjunctiva observed initially (Andersson et al. 1988) was followed about 2 mo later by the typical whorling pattern of new growth and healing of the corneal epithelium (Andersson et al. 1984, 1985). Results showed that the incidence of cataract, conjunctivitis, corneal opacity, and hyperemia of the conjunctivae remained increased 3 mo after the accident in individuals residing within 2 km of the factory. In this survey, males were more affected than females, which the author attributed to the fact that the males ran in an attempt to find safety, and thus, increased their exposure, leaving the females behind in whatever shelter was available (Maskati 1986). From a follow-up study 3 y after the accident, Andersson et al. (1990) concluded that “Bhopal eye syndrome” may include full resolution of the initial interpalpebral superficial erosion, a subsequent increased risk of ocular infections, hyperresponsive phenomena such as irritation, watering, and phlyctens, and possibly cataracts. Eye irritation, reduction in vision, and persistent corneal opacity were also reported after 6–9 mo (Raizada and Dwivedi 1987) and after 2 y (Khurrum and Ahmad 1987). Of interest here are reports comparing the effects of MIC with effects following exposure to related chemicals. In general, isocyanate exposures produce immunologic sensitization. However, evaluation of sera from Bhopal patients revealed low antibody titers that were transient (Karol et al. 1987). In a comparison to hydrogen cyanide, the absence of cyano-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 methemoglobin was noted (Misra et al. 1987), as was the fact that MIC pulmonary lesions were not characteristic of those seen after cyanide intoxication (Varma 1989; Weill 1988). Based on model predictions, the actual consequences in Bhopal, and limited animal and human toxicity data, Karlsson et al. (1985) estimated the effects of MIC in humans from “short exposure” durations (Table 3–3). Although the authors did not define “short” duration, their models were based on 1 h, which was the approximate duration of the release. It is interesting to note that the Karlsson et al. (1985) results, especially for irritation of mucus membranes, are in close agreement with the results of controlled human inhalation studies described below. 2.2. Nonlethal Toxicity 2.2.1. Case Reports Case reports have been submitted to EPA under TSCA sections 8D and 8E. One letter included a compilation of case reports in which industrial workers consistently noted skin and respiratory irritation from MIC exposure. There were no definitive cases of dermal or respiratory sensitization. All MIC-exposed workers apparently recovered completely when removed from the source of exposure. No exposure concentrations or durations were given (Union Carbide 1973). Another letter (Union Carbide 1966) described possible sensitization in a worker analyzing MIC by infrared spectroscopy. This individual had severe swelling and redness of the face after handling the chemical, but was not aware of exposure at the time (i.e., no odor or irritation was reported). Details of concurrent exposures and/or confounding factors were not included. 2.2.2. Experimental Studies The odor threshold for MIC in air is 2.1 ppm (EPA 1986; AIHA 1989). Four subjects were each exposed for 1–5 min to MIC at 0.4, 2, 4, or 21 ppm (Kimmerle and Eben 1964). At 0.4 ppm, no odor was detected and no irritation was reported by any of the volunteers. Minor but distinct irritation of mucous membranes (particularly lacrimation) was noted without odor at 2 ppm. Ocular irritation became more pronounced at 4 ppm. Exposure to 21 ppm was intolerable for even a moment.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 3–3 Symptoms of MIC at Short Exposure Timesa Concentration (ppm) Effect in Humans 10 Irritation 30 Risk for severe injuries 100 Severe injuries and increased risk of death 300 Fatal aExposure times ≤1 h. Source: Reproduced from Karlsson et al. 1985. Eight volunteers were exposed to MIC at an analyzed concentration of 1.75 ppm for 1 min (Mellon Institute 1970). All individuals reported eye irritation, seven had tearing, and three reported nose and throat irritation. Complaints of these effects ceased within 10 min, except that one woman reported a sensation of “something in her eye” for 45 min. Six of the same individuals were subsequently exposed to MIC at 0.5 ppm for 10 min. All reported eye irritation, five had tearing, four had nose irritation, and two reported throat irritation. One person detected an odor after 3 min. Additional experimental details were not available. In a slightly larger study, seven male volunteers were exposed to nominal concentrations at 0.3, 1.0, 2.5, or 5.0 ppm for 1 min or 1 ppm for 10 min (Mellon Institute 1963a). No effects were reported for 0.3 or 1.0 ppm for 1 min. Exposure at 2.5 and 5.0 ppm resulted in eye irritation in 4/7 and 7/7, nose irritation in 2/7 and 2/7, and tearing in 1/7 and 7/7, respectively. Throat irritation was also reported by one individual, and 3/7 could detect an odor during exposure at 5.0 ppm. During the 10-min exposure at 1 ppm, eye irritation and tears were reported in 7/7 individuals by 4 and 5 min, respectively, and nose and throat irritation were reported by 3/7 after 9 min of exposure; no odor was detected. 2.3. Developmental and Reproductive Toxicity A door-to-door survey was carried out 4.5 mo after the accident in Bhopal, India, to determine the reproductive outcomes of women who were pregnant at the time of the release; the data obtained consisted of self-reported symptoms and pregnancy outcomes. The spontaneous abortion rate was 24.2% in the exposed area versus 5.6% in a control area. No specific

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 pattern of congenital defects was observed in term infants (reviewed in Arbuckle and Sever [1998] and Shepard [1995]). Similar results were obtained in a survey conducted approximately 9 mo after the accident (Varma 1987). Among 865 women reporting that they were pregnant at the time of the accident, 43.8% of these pregnancies did not result in a live birth; background rates of spontaneous abortion were not given. Of the 486 live births, 14.2% of the infants died within 30 d as compared with a background infant death rate of 2.6–3%. None of these surveys reported stage of pregnancy at the time of exposure, severity of maternal symptoms, or concentrations or duration of exposure. 2.4. Genotoxicity At 1,114 d after the MIC release in Bhopal, cytogenetic studies were conducted on peripheral blood lymphocytes from exposed men and women (Ghosh et al. 1990). The frequency of chromosomal aberrations was generally greater in exposed individuals, with females showing a higher incidence than males. Nondisjunction was rare and frequencies of sister chromatid exchanges (SCE) and depression in mitotic and replicative indices could not be related to exposure. In another study examining blood lymphocytes from MIC-exposed individuals, SCE frequencies were increased more than 3 times compared with a control population, and chromosomal breaks were observed in 10 of 14 (71.4%) MIC-exposed individuals versus 6 of 28 (21.4%) unexposed controls (Goswami 1986). 2.5. Carcinogenicity No information was found regarding the carcinogenic potential of MIC in humans. 2.6. Summary Although 2,250 deaths were reported following the MIC release in Bhopal, the concentration of MIC causing lethality in humans is unknown. Dispersion calculations estimated airborne concentrations to range from

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 3,000 ppm at 270 m downwind to 10 ppm at 5,500 m downwind. Persistent ocular and pulmonary pathology has been described for the survivors of the accident. There was an increase in self-reported spontaneous abortions and a decrease in the number of live births among women pregnant at the time. The chemical has been confirmed to be an irritant to mucous membranes in both experimental and epidemiological studies. Eye irritation, usually with lacrimation, was the most common symptom reported in controlled inhalation studies at concentrations of MIC ranging from approximately 1 ppm to 5 ppm. MIC has not definitively been shown to be a sensitizer. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality LC50 values for guinea pigs, rats, and mice are summarized in Table 3– 4. An LC50 for rabbits was not found in the available literature. Acute lethality studies, including clinical effects where available, are discussed below by species. 3.1.1. Rabbits Two rabbits per group were exposed to MIC at 5.4 ppm for 6.75, 3.5, or 2 h or at 1.8 ppm for 7 h (Dow Chemical 1990). Although the concentrations were listed as nominal, the report stated that the analytical method (infrared absorption) was adequate for monitoring concentrations as low as 1.8 ppm. A description of the exposure chamber was not included. All animals exposed at 5.4 ppm died 1–2 wk postexposure, apparently due to respiratory infections. Animals exposed at 1.8 ppm survived. At 5.4 ppm for durations ≥3.5 h, the eyes were red and had evidence of corneal injury when observed with fluorescein. Ocular damage was slight in animals exposed at 5.4 ppm for 2 h and equivocal in animals exposed at 1.8 ppm for 7 h. No experimental details or further discussion was included. Male albino rabbits were exposed in a flow-through chamber to a monitored concentration of MIC at 1,260 ppm for 30 min (Pant et al. 1987). Although numbers of deaths were not stated, it is unlikely most animals survived exposure at this concentration. At necropsy, lung weights were

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 inhaled methyl isocyanate in Charles Foster rats. Ecotoxicol. Environ. Safety 18:68–74. Shelby, M.D., J.W.Allen, W.J.Caspary, S.Haworth, J.Ivett, A.Kligerman, C.A. Luke, J.M.Mason, B.Myhr, R.R.Tice, R.Valencia, and E.Zeiger. 1987. Results of in vitro and in vivo genetic toxicity tests on methyl isocyanate. Environ. Health Perspect. 72:183–187. Shepard, T.H. (Ed.) 1995. Catalog of Teratogenic Agents, 8th Ed. Baltimore: The Johns Hopkins University Press. 274 pp. Singh, R.K., R.Dayal, A.K.Srivastava, and N.Sethi. 1994. Teratological studies on methyl isocyanate in Charles Foster rats (part I). Biol. Memoirs 20:117– 123. Sriramachari, S., and K.Jeevaratnam. 1994. Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats. II. Pulmonary histopathology in the subacute and chronic phases. Arch. Toxicol. 69:45–51. Stevens, M.A., S.Fitzgerald, M.G.Ménache, D.L.Costa, and J.R.Bucher. 1987. Functional evidence of persistent airway obstruction in rats following a two-hour inhalation exposure to methyl isocyanate. Environ. Health Perspect. 72:89–94. ten Berge, W.F., A.Zwart, and L.M.Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapors and gases. J. Hazard. Mat. 13:301–309 Tepper, J.S., M.J.Wiester, D.L.Costa, W.P.Watkinson, and M.F.Weber. 1987. Cardiopulmonary effects in awake rats four and six months after exposure to methyl isocyanate. Environ. Health Perspect. 72:95–103. Troup, C.M., D.E.Dodd, E.H.Fowler, and F.R.Frank. 1987. Biological effects of short-term, high-concentration exposure to methyl isocyanate. II. Blood chemistry and hematologic evaluations. Environ. Health Perspect. 72:21–28. Union Carbide (Union Carbide Corporation). 1966. Compilation of toxicology on methyl isocyanate—TSCA informational submittal with cover letter dated 121784. EPA/OTS; Doc #88–8500718. 189 pp. Union Carbide (Union Carbide Corporation). 1973. MIC—Sensitization characteristics with cover sheets and letter dated 012591. EPA/OTS; Doc #86– 910000666D. Uraih, L.C., F.A.Talley, K.Mitsumori, B.N.Gupta, J.R.Bucher, and G.A. Boorman. 1987. Ultrastructural changes in the nasal mucosa of Fischer 344 rats and B6C3F1 mice following an acute exposure to methyl isocyanate. Environ. Health Perspect. 72:77–88. Varma, D.R. 1987. Epidemiological and experimental studies on the effects of methyl isocyanate on the course of pregnancy. Environ. Health Perspect. 72:153–157. Varma, D.R. 1989. Hydrogen cyanide and Bhopal. Lancet 2:567–568. Varma, D.R., J.S.Ferguson, and Y.Alarie. 1988. Inhibition of methyl isocyanate toxicity in mice by starvation and dexamethasone but not by sodium thiosulfate, atropine, and ethanol. J. Toxicol. Environ. Health 24:93–101.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Varma, D.R., and I.Guest. 1993. The Bhopal accident and methyl isocyanate toxicity. J. Toxicol. Environ. Health 40:513–529. Varma, D.R., I.Guest, S.Smith, and S.Mulay. 1990. Dissociation between maternal and fetal toxicity of methyl isocyanate in mice and rats. J. Toxicol. Environ. Health 30:1–14. Vijayan, V.K., and K.Sankaran. 1996. Relationship between lung inflammation, changes in lung function and severity of exposure in victims of the Bhopal tragedy. Eur. Respir. J. 9:1977–1982. Vijayaraghavan, R., and M.P.Kaushik. 1987. Acute toxicity of methyl isocyanate and ineffectiveness of sodium thiosulphate in preventing its toxicity. Ind. J. Exp. Biol. 25:531–534. Weill, H. 1988. Disaster at Bhopal: The accident, early findings and respiratory health outlook in those injured. Physiology 23:587–590.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX A Time-Scaling Calculations Data: LC50 Values in the Rat (Mellon Institute 1970) Time (min) Concentration (ppm) Log Time Log Concentration 7.5 541 0.8751 2.7332 15 216 1.1761 2.3345 30 76.6 1.4771 1.8842 60 41.3 1.7782 1.6160 120 27.4 2.0792 1.4378 240 17.5 2.3802 1.2430 Regression Output: Intercept 3.4828 Slope −0.9880 R Squared 0.9642 Correlation −0.9818 Observations 6 n=1.01 k=3351.62

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX B Derivation of AEGL Values Derivation of AEGL-1 An AEGL-1 was not recommended because the irritation threshold for MIC may be above the level of concern for systemic effects such as spontaneous abortion and fetal or infant death. It is not known at what concentration the risk for these systemic effects becomes a concern. The concentrations causing irritation in humans after several minutes (1–4 ppm) are similar to, or higher than, the concentrations resulting in embryo and fetal lethality in well conducted animal studies. Therefore, it should be noted that exposures to MIC at concentrations below those used to calculate AEGL-1 might be associated with systemic toxicity. The absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Derivation of AEGL-2 Key Studies: Varma (1987) and Tepper et al. (1987) Toxicity end point: Decreased fetal body weights in offspring from mice exposed at 2 ppm for 3 h on GD 8 and cardiac arrhythmias in rats exposed at 3 ppm for 2 h; the concentrations were reduced by a factor of 3 to estimate a threshold for effects. Scaling: C1×t=k (based on regression analysis of LC50 values in the rat). Uncertainty factors: Total uncertainty factor: 30 Interspecies: 3. A factor of 3 was applied for interspecies variation because similar results have been obtained in both rats and mice. Intraspecies: 10. A factor of 10 was applied for intra-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3   species variation because the mechanism of action for developmental toxicity is unknown. Calculations: (C1/uncertainty factors)×t=k   ([0.67 ppm]/30)1×3 h=0.067 ppm·h; or ([1 ppm]/30)1×2 h=0.067 ppm·h 10-min AEGL-2: ([0.067 ppm·h]/0.167 h)1=0.40 ppm 30-min AEGL-2: ([0.067 ppm·h]/0.5 h)1=0.13 ppm 1-h AEGL-2: ([0.067 ppm·h]/1 h)1=0.067 ppm 4-h AEGL-2: ([0.067 ppm·h]/4 h)1=0.017 ppm 8-h AEGL-2: ([0.067 ppm·h]/8 h)1=0.008 ppm Derivation of AEGL-3 Key Study: Schwetz et al. (1987) Toxicity end point: Experimentally derived NOEL for pup mortality during lactation in mice exposed at 1 ppm for 6 h on gestation days 14–17 Scaling: C1×t=k (based on regression analysis of LC50 values in the rat). Uncertainty factors: Total uncertainty factor: 30 Interspecies: 3. A factor of 3 was applied for interspecies variation because similar results have been obtained in both rats and mice. Intraspecies: 10. A factor of 10 was applied for intraspecies variation because the mechanism of action for developmental toxicity is unknown.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Calculations: (C1/uncertainty factors)×t=k   ([1 ppm]/30)1×6 h=0.2 ppm·h 10-min AEGL-2: ([0.2 ppm·h]/0.167 h)1=1.2 ppm 30-min AEGL-2: ([0.2 ppm·h]/0.5 h)1=0.40 ppm 1-h AEGL-2: ([0.2 ppm·h]/1 h)1=0.20 ppm 4-h AEGL-2: ([0.2 ppm·h]/4 h)1=0.05 ppm 8-h AEGL-2: ([0.2 ppm·h]/8 h)1=0.025 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL ISOCYANATE (CAS No. 624–83–9) AEGL-1a 10 min 30 min 1 h 4 h 8 h NR NR NR NR NR aExposure to MIC at concentrations below those used to calculate AEGL-1 may be associated with systemic toxicity Abbreviation: NR, not recommended. AEGL-2 10 min 30 min 1 h 4 h 8 h 0.40 ppm 0.13 ppm 0.067 ppm 0.017 ppm 0.008 ppm Key references: (1) Varma, D.R. 1987. Epidemiological and experimental studies on the effects of methyl isocyanate on the course of pregnancy. Environ. Health Perspect. 72:153–157. (2) Tepper, J.S., M.J.Wiester, D.L.Costa, W.P.Watkinson, and M.F.Weber. 1987. Cardiopulmonary effects in awake rats four and six months after exposure to methyl isocyanate. Environ. Health Perspect. 72:95–103. Test species/strain/number: Female mouse/Swiss-Webster/11–24; male rat/F344/number not stated. Exposure route/concentrations/durations: Inhalation at 2, 6, 9, or 15 ppm for 3 h on GD 8 (2 ppm was determinant for AEGL-2). Inhalation at 3, 10, or 30 ppm for 2 h (3 ppm was determinant for AEGL-2). Effects: 2, 6, 9, and 15 ppm, reduced fetal body weights; 9 and 15 ppm, increases in complete litter resorption and maternal mortality; 30 ppm, mortality of all animals; 10 ppm, increased minute ventilation during CO2 challenge and increased wet and dry lung weights 4 mo after exposure; 3 and 10 ppm, increase in cardiac arrhythmias 4 mo after exposure. End point/concentration/rationale: Reduced fetal body weight and increased cardiac arrhythmias; experimental concentration reduced by a factor of 3 to estimate a threshold for effects.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Uncertainty factors/rationale: Total uncertainty factor: 30 Interspecies: 3—developmental toxicity did not vary greatly among species. Intraspecies: 10—the mechanism of developmental toxicity is unknown. Modifying factor: None Animal to human dosimetric adjustment: Insufficient data Time scaling: C1×t=k Data quality and support for the AEGL values: AEGL-2 values for MIC were based on two well conducted animal studies and are supported by human data.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 10 min 30 min 1 h 4 h 8 h 1.2 ppm 0.40 ppm 0.20 ppm 0.05 ppm 0.025 ppm Key reference: Schwetz, B.A., Adkins, B., Jr., Harris, M., Moorman, M., and Sloane, R. 1987. Methyl isocyanate: reproductive and developmental toxicology studies in Swiss mice. Environ. Health Perspect. 72:149–152. Test species/strain/number: Mouse/Swiss (CD-1)/39–44 Exposure route/concentrations/durations: Inhalation at 1 or 3 ppm for 6 h/d on gestation days 14–17 (1 ppm was determinant for AEGL-3). Effects: 3 ppm, decreased pup survival during lactation day 0–4; 1 ppm, no effects on pup survival. End point/concentration/rationale: No effect level for pup mortality Uncertainty factors/rationale: Total uncertainty factor: 30 Interspecies: 3—developmental toxicity did not vary greatly among species. Intraspecies: 10—the mechanism of developmental toxicity is unknown. Modifying factor: none Animal to human dosimetric adjustment: Insufficient data Time Scaling: C1×t=k Data quality and support for the AEGL values: AEGL-3 values for MIC were based on a well conducted animal study and supported by other animal data.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX D CATEGORY PLOT FOR METHYL ISOCYANATE FIGURE D-1 Category plot of human and animal data compared to AEGL values.