7

Selected Monoisocyanates
1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could

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1 This document was prepared by the AEGL Development Team composed of Robert Young and Carol Wood (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Managers Susan Ripple and Marc Ruijten (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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7 Selected Monoisocyanates1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Robert Young and Carol Wood (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Managers Susan Ripple and Marc Ruijten (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the doc- ument and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 200

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Selected Monoisocyanates 201 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Four monoisocyanates are considered in this chapter: ethyl isocyanate, n- butyl isocyanate, cyclohexyl isocyanate, and phenyl isocyanate. These monoiso- cyanates appear to exert toxic effects, including delayed lethality, that are simi- lar to those induced by methyl isocyanate. AEGL-1 values were not derived for methyl isocyanate because it has poor warning properties, and because systemic toxicity is possible at concentrations lower than those associated with AEGL-1 effects (NRC 2003). On the basis of similarities between the selected monoiso- cyanates and methyl isocyanate, AEGL-1 values were not derived. Data on ethyl isocyanate and cyclohexyl isocyanate were limited to rat le- thality studies that used few animals, lacked analytic measurement of concentra- tions, and had 100% mortality at nearly all test concentrations. Because of the data limitations, AEGL-2 and AEGL-3 values were based on the AEGL values for methyl isocyanate. A comparison of the available lethality data on the three chemicals suggests that use of methyl isocyanate as a surrogate and applying a modifying factor of 2, to account for the possibility that ethyl isocyanate and cyclohexyl isocyanate might be more toxic, results in sufficiently protective AEGL values. For example, when groups of three rats were exposed to ethyl isocyanate for 6 h, all rats survived at 27 ppm and no rats survived at 82 ppm. When three rats were exposed for 6 h to cyclohexyl isocyanate at 18 ppm, one

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202 Acute Exposure Guideline Levels died on day 7 post-exposure and the others were killed on day 8, presumably due to moribund condition. For comparison, the 6-h LC50 (lethal concentration, 50% lethality) for methyl isocyanate in rats was 6.1 ppm (NRC 2003). Rat lethality data were adequate to derive AEGL-3 values for n-butyl iso- cyanate and phenyl isocyanate, and AEGL-2 values were estimated as one-third of the corresponding AEGL-3 values. To derive AEGL-3 values for these com- pounds, an interspecies uncertainty factor of 3 was applied because of the lim- ited species variability exhibited by methyl isocyanate. A factor of 10 was ap- plied to account for intraspecies variability, as was done for methyl isocyanate (NRC 2003). A modifying factor 3 was also applied because data on the poten- tial developmental toxicity of n-butyl isocyanate and phenyl isocyanate were lacking; methyl isocyanate is a known developmental toxicant. AEGL values for the selected monoisocyanates are presented in Table 7-1. AEGL values for methyl isocyanate and toluene diisocyanate are presented in Table 7-2 for comparison. 1. INTRODUCTION The monoisocyanates generally occur as colorless to yellow liquids, and typically have a high vapor pressure and pungent odor. When heated, monoiso- cyanates decompose and form toxic fumes of hydrogen cyanide and nitrogen oxides (IPCS 1997, 2002). Cyclohexyl isocyanate decomposes in water, and unlike some isocyanates, it does not self-polymerize (Eastman Kodak 1990). The chemical and physical properties of ethyl, n-butyl, cyclohexyl, and phenyl isocyanate are presented in Table 7-3. Ethyl isocyanate is used as an intermediate in the manufacture of pharma- ceuticals and pesticides. It may be produced by the reaction of phosgene with amines or amine salts. The thermal cleavage of urethanes, performed using the appropriate amine, urea, and alcohol, is a common commercial production method (HSDB 2007a). n-Butyl isocyanate is used in closed systems for the manufacture of chem- icals, dyes, and pesticides (ANPON 2008). Global production of n-butyl isocya- nate is estimated at 1,000 to 5,000 metric tons per year (OECD 2005). Phenyl isocyanate is used in the production of polymers and as an intermediate in or- ganic syntheses (Richter 1986; Karol and Kramarik 1996). Current use and production information for cyclohexyl isocyanate were not found. In the sections below, general factors to consider in developing AEGL val- ues for the selected monoisocyanates are presented first, and are followed by chemical-specific data.

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TABLE 7-1 AEGL Values for Selected Monoisocyanatesa Classification 10 min 30 min 1h 4h 8h End Point (Reference) Ethyl isocyanate AEGL-1 NR NR NR NR NR Insufficient warning properties; (non-disabling) possible systemic effects at concentrations lower than those that produce irritation. AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm Based on AEGL-2 values for (disabling) (0.58 mg/m3) (0.19 mg/m3) (0.099 mg/m3) (0.025 mg/m3) (0.012 mg/m3) methyl isocyanate AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm Based on AEGL-3 values for (lethal) (1.7 mg/m3) (0.58 mg/m3) (0.29 mg/m3) (0.073 mg/m3) (0.038 mg/m3) methyl isocyanate Cyclohexyl isocyanate AEGL-1 NR NR NR NR NR Insufficient warning properties; (non-disabling) possible systemic effects at concentrations lower than those that produce irritation. AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm Based on AEGL-2 values for (disabling) (1.0 mg/m3) (0.33 mg/m3) (0.17 mg/m3) (0.043 mg/m3) (0.020 mg/m3) methyl isocyanate AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm Based on AEGL-3 values for (lethal) (3.1 mg/m3) (1.0 mg/m3) (0.51 mg/m3) (0.13 mg/m3) (0.066 mg/m3) methyl isocyanate AEGL-3 n-Butyl isocyanate AEGL-1 NR NR NR NR NR Insufficient warning properties; (non-disabling) possible systemic effects at concentrations lower than those that produce irritation. AEGL-2 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm One third of AEGL-3 values. (disabling) (0.41 mg/m3) (0.41 mg/m3) (0.34 mg/m3) (0.21 mg/m3) (0.11 mg/m3) AEGL-3 0.31 ppm 0.31 ppm 0.25 ppm 0.16 ppm 0.078 ppm No morality in rats exposed at 14 (lethal) (1.3 mg/m3) (1.3 mg/m3) (1.0 mg/m3) (0.65 mg/m3) (0.32 mg/m3) ppm for 4 h (Pauluhn et al. 1990). (Continued) 203

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204 TABLE 7-1 Continued Classification 10 min 30 min 1h 4h 8h End Point (Reference) Phenyl isocyanateb AEGL-1 NR NR NR NR NR Insufficient warning properties; (non-disabling) possible systemic effects at concentrations lower than those that produce irritation. AEGL-2 0.012 ppm 0.012 ppm 0.0096 ppm 0.0061 ppm 0.0030 ppm One-third of AEGL-3 values. (disabling) (0.058 mg/m3) (0.058 mg/m3) (0.047 mg/m3) (0.030 mg/m3) (0.015 mg/m3) AEGL-3 0.036 ppm 0.036 ppm 0.029 ppm 0.018 ppm 0.0091 ppm 4-h BMCL05 of 1.64 ppm in rats (lethal) (0.18 mg/m3) (0.18 mg/m3) (0.14 mg/m3) (0.088 mg/m3) (0.044 mg/m3) (Bayer AG 1991a) a When more than one of the monoisocyanates is detected at a scene, the lowest AEGL should be applied to the sum total concentration of all de- tected monoisocyanates because of a presumed common mode of action. On the basis of toxicity data on methyl isocyanate, it is plausible that ex- posure to these monoisocyanates might be associated with systemic toxicity at concentrations below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below AEGL-2 values are without effect. b Phenyl isocyanate has shown dermal sensitizing effects. Its respiratory sensitizing potential is unknown. Individuals who have a strong reac- tion might not be protected within the definition of effects for each AEGL level. Abbreviations: BMCL05, benchmark concentration, 95% confidence limit with a 5% response; MF, modifying factor; NR, not recommended; and UF, uncertainty factor.

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Selected Monoisocyanates 205 TABLE 7-2 AEGL Values for Methyl Isocyanate and Toluene Diisocyanate Classification 10 min 30 min 1h 4h 8h Methyl isocyanate AEGL-1a NR NR NR NR NR (nondisabling) AEGL-2 0.40 ppm 0.13 ppm 0.067 ppm 0.017 ppm 0.0080 ppm (disabling) (0.94 mg/m3) (0.32 mg/m3) (0.16 mg/m3) (0.034 mg/m3) (0.020 mg/m3) AEGL-3 1.2 ppm 0.40 ppm 0.20 ppm 0.050 ppm 0.025 ppm (lethal) (2.8 mg/m3) (0.95 mg/m3) (0.47 mg/m3) (0.12 mg/m3) (0.060 mg/m3) Toluene 2,4- and 2,6-diisocyanate AEGL-1 0.02 ppm 0.02 ppm 0.02 ppm 0.01 ppm 0.01 ppm (nondisabling) (0.14 mg/m3) (0.14 mg/m3) (0.14 mg/m3) (0.07 mg/m3) (0.07 mg/m3) AEGL-2 0.24 ppm 0.17 ppm 0.083 ppm 0.021 ppm 0.021 ppm (disabling) (1.71 mg/m3) (1.21 mg/m3) (0.59 mg/m3) (0.15 mg/m3) (0.15 mg/m3) AEGL-3 0.65 ppm 0.65 ppm 0.51 ppm 0.32 ppm 0.16 ppm (lethal) (4.63 mg/m3) (4.63 mg/m3) (3.63 mg/m3) (2.28 mg/m3) (1.14 mg/m3) a Insufficient warning properties; possible systemic effects at concentrations lower than those that produce irritation. Absence of AEGL-1 values does not imply that concentra- tions below the AEGL-2 are without effect. 2. CONSIDERATIONS RELEVANT TO THE SELECTED MONOISOCYANATES 2.1. Absorption, Distribution, Metabolism, and Excretion Metabolism and disposition data are not available for ethyl isocyanate, n-butyl isocyanate, cyclohexyl isocyanate, or phenyl isocyanate. Data on the distribution of the related compound methyl isocyanate are available. Tissue radioactivity levels in guinea pigs exposed to 14C-methyl isocyanate at 0.38-15.2 ppm for 1-6 h were proportional to the concentration-time product (Kennedy et al. 1993). Radioactivity was highest in the proximal airways but was detected throughout the entire nasal respiratory epithelial layer. In the tracheobronchial region and in the lung, the radioactivity accumulated in the subepithelial level extending to the terminal bronchiole, but was not detected in the alveolar region. Isocyanates are known to form labile glutathione conjugates from which they may subsequently be released at a distal location (Zoltán and Klaassen 2001). 2.2. Mechanism of Toxicity No studies that address the mechanism(s) of toxicity for ethyl isocyanate, n-butyl isocyanate, cyclohexyl isocyanate, or phenyl isocyanate are available. Because the toxicity of these monoisocyanates are clinically similar to that de- scribed for the structurally similar compound methyl isocyanate (respiratory tract irritation with delayed lethality), these compounds might share a similar mode of action.

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206 TABLE 7-3 Chemical and Physical Data on Selected Monoisocyanates Parameter Ethyl Isocyanate n-Butyl Isocyanate Cyclohexyl Isocyanate Phenyl Isocyanate Synonyms Isocyanatoethene; isocyanic 1-Isocyanatobutane; Isocyanatocyclohexane Isocyanatobenzene; carbamil; acid, ethyl ester isocyanic acid, butyil ester isocyanic acid cyclohexyl ester phenyl carbamide CAS registry no. 109-90-0 111-36-4 3173-53-3 103-71-9 Chemical formula C3H5NO C5H9NO C7H11NO C7H5NO Molecular weight 71.1 99.1 125.17 119.12 Physical state Liquid Liquid Colorless liquida Liquid Melting point – -75°C – -30°C Boiling point 60°C 115°C 166°Ca 158-168°C Flash point – 19°C (closed cup) 48°C (closed cup)b 55.5°C (open cup) Density/specific gravity 0.9031 g/cm³ 0.88 g/cm³ at 20°C 0.98 g/cm³ at 25°C 1.0956 g/cm³ at 20°C Relative vapor density 2.45 3.0 4.3b – (air = 1) Solubility in water Insoluble Slightly soluble Decomposesa Reacts violentlyc Vapor pressure 200 mm Hg at 25°C 17.6 mm Hg at 25°C 94.6 mmHg at 20°Cd 1.15 mm Hg at 20°Cc Conversion factors 1 ppm = 2.9 mg/m3 1 ppm = 4.05 mg/m3 1 ppm = 5.11 mg/m3 1 ppm = 4.87 mg/m3 in air 1 mg/m3 = 0.34 ppm 1 mg/m3 = 0.25 ppm 1 mg/m3 = 0.196 ppm 1 mg/m3 = 0.21 ppm Source: HSDB 2007a,b, 2012, 2013 except where noted; aEastman Kodak 1990; bIPCS 1997; cICI 1977; dSigma Aldrich 2012.

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Selected Monoisocyanates 207 Results from human and animal studies indicate that methyl isocyanate is a severe irritant to mucous membranes. Ocular irritation was the most pro- nounced symptom reported in human experimental studies (Mellon Institute 1963, 1970; Kimmerle and Eben 1964). The most frequently reported symptoms in a population exposed to methyl isocyanate in Bhopal, India, were burning of the eyes, coughing, respiratory distress from pulmonary congestion, watering of the eyes, nausea, vomiting, muscle weakness, and central nervous system in- volvement secondary to hypoxia (Kamat et al. 1985; Lorin and Kulling 1986; Misra et al. 1987; Weill 1987; Andersson et al. 1988; Kamat et al. 1992). Hu- man (Varma and Guest 1993) and animal (Fowler and Dodd 1986) fatalities are attributed to pulmonary edema. Cyanide does not contribute significantly to the toxicity of methyl isocya- nate. Cyanomethemoglobin was not found in the population exposed to methyl isocyanate in Bhopal (Misra et al. 1987), pulmonary lesions are not characteris- tic of cyanide intoxication (Weill 1987; Varma 1989), and standard thiosul- fate/nitrite cyanide antidotes have not been successful in preventing deaths in animal studies (Nemery et al. 1985; Bucher et al. 1987; Varma et al. 1988). Fi- nally, the time-to-death in humans and animals was not consistent with that as- sociated with high dose cyanide intoxication (Varma and Guest 1993). Developmental toxicity was observed in rodents after controlled exposure to methyl isocyanate. The mechanism of the systemic toxicity is unknown. 2.3. Structure-Activity Relationships Data on the selected monoisocyanates are limited, so information on relat- ed compounds was also consulted. Toluene diisocyanate and methyl isocyanate have robust databases that include animal and human studies. The monoisocya- nates reviewed in this chapter appear more similar to methyl isocyanate than 2,4- or 2,6-toluene diisocyanate with respect to lethality and respiratory irrita- tion. Lethality benchmarks for the monoisocyanates are similar to those for me- thyl isocyanate; 4-h LC50 values in rats were 4.6 ppm for phenyl isocyanate (Bayer AG 1991a), 18 ppm for n-butyl isocyanate (Bayer AG 1978), and 5-18 ppm for methyl isocyanate (NRC 2003). For toluene diisocyanate, 4-h LC50 es- timates for rats were 14-51 ppm (NRC 2004). In addition, deaths from toluene diisocyanate occur soon after exposure (within 36 h after a 1-h exposure in a rat study [Horspool and Doe 1977]), whereas deaths from the monoisocyanates, including methyl isocyanate, can occur as late as 30 days after exposure. Little respiratory-irritation data were available for comparison of the monoisocya- nates. RD50s (concentrations that reduce the respiratory rate by 50%) were esti- mated to be 1.3 ppm for mice exposed to methyl isocyanate for 90 min (Fergu- son et al. 1986) and 2.7 ppm for rats exposed to phenyl isocyanate for 45 min

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208 Acute Exposure Guideline Levels (Pauluhn et al. 1995). RD50s for toluene diisocyanate were estimated to be 1.37- 2.12 ppm in rats exposed for 3 h, 0.39 ppm in mice exposed for 1 h, and 0.8 ppm in mice exposed for 10 min (NRC 2004). Differences exist in the sensitization potential, developmental effects, and systemic toxicity of methyl isocyanate and 2,4- or 2,6-toluene diisocyanate; however, no data are available to determine which of these structurally-related compounds is more representative of the selected monoisocyanates with respect to these end points. Karol and Kramarik (1996) noted that respiratory sensitiza- tion is a result of exposure to diisocyanates not monoisocyanates in the work- place. Toluene diisocyanate is a proven respiratory sensitizer in both human and laboratory animals (NRC 2004). Methyl isocyanate is not a respiratory sensitizer in animals (Mellon Institute 1970). No data on the sensitizing potential of ethyl isocyanate, n-butyl isocyanate, or cyclohexyl isocyanate were available. How- ever, a mouse ear-swelling test indicated that phenyl isocyanate is a potent con- tact sensitizer in mice, stimulating both cellular and humoral immune responses (Karol and Kramarik 1996). Phenyl isocyanate was more potent than toluene diisocyanate in the ear-swelling test (Karol and Kramarik 1996). The potential for respiratory sensitization by phenyl isocyanate is not known. Systemic effects have been well-documented after exposure to methyl iso- cyanate but not toluene diisocyanate. Methyl isocyanate produced fetal and neo- natal deaths after inhalation exposure, but toluene diisocyanate did not. No inha- lation data on the developmental toxicity of ethyl, n-butyl, cyclohexyl, or phenyl isocyanate in animals were available. In an oral exposure study, no evidence of developmental toxicity was observed in mice administered a single dose of phe- nyl isocyanate at 9.8 mg/kg (one-twentieth of the LD50 [lethal dose, 50% lethali- ty]) on gestation days 4, 7, 11, or 15 (Nehez et al. 1989). Cardiac arrhythmias have been reported in studies of methyl isocyanate but not in studies of toluene diisocyanate. For methyl isocyanate, systemic effects may occur at concentra- tions equal to or below those that cause irritation (NRC 2003). In summary, the selected monoisocyanates exhibit toxic effects (respirato- ry irritation and delayed lethality) that are more similar to those associated with methyl isocyanate than with toluene diisocyanate. Differences exist in the sensi- tization potential, developmental effects, and systemic toxicity of methyl isocy- anate and 2,4- or 2,6-toluene diisocyanate; however, the data are insufficient to determine which of these structurally-related compounds is more representative of the selected monoisocyanates with respect to these effects. 2.4. Species Differences Toxicity data on ethyl isocyanate, n-butyl isocyanate, cyclohexyl isocya- nate, and phenyl isocyanate in species other than the rat are lacking. Lethality data for the related compounds methyl isocyanate and toluene diisocyanate ex- hibit little species variability, as shown in Table 7-4.

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Selected Monoisocyanates 209 TABLE 7-4 Lethality (LD50s) of Methyl Isocyanate and Toluene Diisocyanate in Different Species 1h 2h 3h 4h 6h Methyl isocyanate (ppm) Rat 41-45 21-27 – 5-18 6.1 Mouse – – 27 – 12 Guinea pig – – 27 11 5.4 Toluene diisocyanate (ppm) Rat 66 – – 14-51 – Mouse – – – 9.7 – Guinea pig – – – 13 – Rabbit – – – 11 – Sources: NRC 2003, 2004. 2.5. Concurrent Exposure Issues Limited data comparing the toxicity of the four selected monoisocyanates with the well-studied compound methyl isocyanate suggest similarities in toxici- ty among the monoisocyanates that may reflect a common mode(s) of action. Thus, the lowest AEGL value for any of the detected monoisocyanates at an emergency scene should be applied to the sum total concentration of all monoi- socyanates when multiple monoisocyanates are present. 2.6. Concentration-Exposure Duration Relationship The relationship between concentration and duration of exposure with re- spect to lethality was examined by ten Berge et al. (1986) for approximately 20 irritant or systemically-acting vapors and gases. The investigators analyzed indi- vidual animal data sets by probit analysis, with exposure duration and exposure concentration as independent variables. An exponential function of Cn × t = k, where the value of n ranged from 0.8 to 3.5 for different chemicals, was found to be an accurate quantitative descriptor for the chemicals evaluated. For methyl isocyanate, rat LC50 data were used to estimate an empirical value for n of 1.0. However, data were inadequate to calculate an empirical value of n for the se- lected monoisocyanates in this chapter. Thus, default values of n = 1 for ex- trapolating from shorter to longer durations and n = 3 for extrapolating from longer to shorter durations were used. 2.7. Special Considerations Some of the toxicity data on the four monoisocyanates in this chapter may have uncertainty with respect to exposure concentrations. One analysis (DuPont, unpublished material, 2008) showed that impinger/gas chromatography (GC) methods used to analyze n-butyl isocyanate underestimated concentrations when

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210 Acute Exposure Guideline Levels compared with XAD-7 tube/high performance liquid chromatography (HPLC) analysis. In 1994, 20 air samples were collected side-by-side in various areas of a production facility using the impinger and XAD-7 tube sampling methods and subsequently analyzed using GC and HPLC methods, respectively. Comparison of the data showed that the XAD-7/HPLC method generally measured higher concentrations (two-fold higher on average) than the impinger/GC method; however, the magnitude of the difference was not consistent across the samples and the measurements were not always higher (see Table 7-5). A second analy- sis (Mobay 1978) reported that the Marcali colorimetric method underestimated concentrations of phenyl isocyanate (in a rat lethality study) when compared with HPLC analysis, and that the HPLC results were more consistent with the calculated concentrations. Information in the Mobay Corp. (1978) report was insufficient to allow an independent evaluation of the differences. Whether the analytic uncertainties also apply to ethyl isocyanate and cyclohexyl isocyanates is not known; however, studies of the latter two compounds were conducted in the 1960s and concentrations were calculated rather than measured. In light of the potential analytic uncertainties, information on the method used to analyze exposure concentrations is included in the descriptions of the toxicity data for the individual monoisocyanates presented later in this chapter. TABLE 7-5 Comparison of n-Butyl Isocyanate Concentrations Obtained Using Impinger/GC and XAD-7 Tube/HPLC Methods Impinger/GC (ppb) XAD-7 Tube/HPLC (ppb) Difference 1.3 9.4 623% 1.9 11.8 521% 2.5 10.5 320% 3.8 5 32% 4.4 9.4 114% 4.5 5.7 27% 5.2 7.1 37% 5.3 4.6 -13% 5.7 5.6 -2% 6.5 10 54% 6.6 9.6 45% 6.6 11 67% 8 11.6 45% 8.1 10.1 25% 8.3 9.1 10% 8.4 12.9 54% 10.7 21.3 99% 13.6 10.4 -24% 27 40.9 51% 32.4 24.5 -24% Average percent difference 103% Source: DuPont, unpublished material, 2008.

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TABLE C-2 Continued 266 Source Species Sex No. of Exposures ppm Minutes Category Comments Rat 1 53.2 360 3 Mortality (3/3, two during exposure, one on day 12), irritation, lacrimation, dypsnea, inflammation in lungs, congestion of kidney and liver. Rat 1 1,017 360 3 Mortality (3/3, after 4 h), irritation, lacrimation, dypsnea, inflammation in lungs, congestion of kidney and liver, salivation, gasping. Younger Laboratories 1974 Rat 1 1,401 150 3 Mortality (6/6), no other details Crawford and Anderson 1974 Rat 1 Saturated 120 3 Mortality (8/8), no other details Bayer AG 1980a Rat 1 Saturated 3 2 No deaths, respiratory problems, enlarged lungs with red spots, fluid, lobulated liver. Rat 1 Saturated 10 3 Mortality (10/10, within 11 days), respiratory problems, enlarged lungs with red spots, fluid, lobulated liver. Rat 1 Saturated 60 3 Mortality (10/10, during exposure), respiratory problems, enlarged lungs with red spots, fluid, lobulated liver. For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality.

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TABLE C-3 Data Used in Category Plot for n-Butyl Isocyanate Source Species Sex No. of Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 0.10 10 AEGL AEGL-2 0.10 30 AEGL AEGL-2 0.083 60 AEGL AEGL-2 0.053 240 AEGL AEGL-2 0.026 480 AEGL AEGL-3 0.31 10 AEGL AEGL-3 0.31 30 AEGL AEGL-3 0.25 60 AEGL AEGL-3 0.16 240 AEGL AEGL-3 0.078 480 AEGL Haskell 1989 (industrial Human 1 0.01 480 1 hygiene report) Haskell 1989 (industrial Human 1 0.05 480 1 hygiene report) (Continued) 267

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TABLE C-3 Continued 268 Source Species Sex No. of Exposures ppm Minutes Category Comments IRDC 1965 Rat Male 1 1.4 60 1 IRDC 1965 Rat Male 1 1.9 60 SL IRDC 1965 Rat Male 1 2.7 60 SL IRDC 1965 Rat Male 1 3.0 60 2 IRDC 1965 Rat Male 1 4.7 60 SL IRDC 1965 Rat Male 1 5.4 60 SL IRDC 1965 Rat Male 1 7.0 60 3 IRDC 1965 Rat Male 1 7.1 60 3 IRDC 1965 Rat Male 1 8.7 60 3 Bayer AG 1978 Rat Both 1 106 60 SL LC50 Bayer AG 1978 Rat Male 1 22.5 240 SL LC50 Bayer AG 1978 Rat Male 1 20.0 240 SL LC50 Pauluhn and Eben 1991 Rat Male 5 0.25 360 0 Multiple exposures; no clinical signs after 6 h/d for 5 d. Pauluhn and Eben, 1991 Rat Male 5 1.3 360 0 Multiple exposure study; no clinical signs after 6 h/d for 5 d. Haskell 1968 Rat Male 1 15.6 240 SL LC50 IRDC 1965 Rat Male 1 3.8 60 SL LC50 Pauluhn et al. 1990 Rat Male 1 1.9 240 1 Transient clinical signs (hypothermia, bradypnea, mucous membrane irritation).

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Pauluhn et al. 1990 Rat Male 1 14.0 240 3 Pulmonary function changes even at 4 wk post-exposure, pathologic findings in lungs. Pauluhn et al. 1990 Rat Male 1 5.9 240 2 Notable pulmonary effects that resolved within 1 wk. Bayer AG 1978 Rat Both 1 39 60 2 No mortality Bayer AG 1978 Rat Both 1 130 60 SL Mortality (7/10) Bayer AG 1978 Rat Both 1 245 60 3 Mortality (10/10) Bayer AG 1978 Rat Both 1 94 60 SL Mortality (3/20) Bayer AG 1978 Rat Both 1 222 60 SL Mortality (19/20) Bayer AG 1978 Rat Both 1 233 60 3 Mortality (20/20) Bayer AG 1978 Rat Both 1 22 240 SL Mortality (7/10) Bayer AG 1978 Rat Both 1 70 240 SL Mortality (9/10) Bayer AG 1978 Rat Female 1 116 240 3 Mortality (5/5) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality. 269

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TABLE C-4 Data Used in Category Plot for Phenyl Isocyanate 270 Source Species Sex No. of Exposures ppm Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 0.012 10 AEGL AEGL-2 0.012 30 AEGL AEGL-2 0.0096 60 AEGL AEGL-2 0.0061 240 AEGL AEGL-2 0.0030 480 AEGL AEGL-3 0.036 10 AEGL AEGL-3 0.036 30 AEGL AEGL-3 0.029 60 AEGL AEGL-3 0.018 240 AEGL AEGL-3 0.0091 480 AEGL SA 1954 Rat 1 67 60 3 SA 1954 Rat 1 67 120 3 SA 1954 Rat 1 67 150 3 Mobay 1978 Rat Both 1 12.6 60 SL LC50 ICI 1980 Rat Both 1 3.9 60 SL LC50

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ICI 1977, Mobay 1978 Rat Both 1 0.358 60 1 No clinical signs, minor histopathologic findings. ICI 1977, Mobay 1978 Rat Both 1 1.325 60 1 Minor clinical signs, pulmonary damage at necropsy. ICI 1977; Mobay 1978 Rat Both 1 1.45 60 2 Minor clinical signs, notable histopathologic effects. ICI 1977, Mobay 1978 Rat Both 1 2.167 60 SL 2/4 males, 2/4 females dead 5-12 d post-exposure. ICI 1977, Mobay 1978 Rat Both 1 4.368 60 SL 1/4 males, 3/4 females dead at 4-8 d post-exposure. ICI 1977, Mobay 1978 Rat Both 1 6.08 60 SL 2/4 males, 2/4 females dead at 8-13 d post-exposure. ICI 1977, Mobay 1978 Rat Both 1 7.942 60 3 100% lethality at 7-12 d post- exposure. ICI 1977, Mobay 1978 Rat Both 1 9.187 60 SL 4/4 males, 3/4 females dead at 1-14 d post-exposure. ICI 1980 Rat Both 11 0.05 360 0 No clinical signs, no histopathologic findings. ICI 1980 Rat Both 11 0.5 360 2 Respiratory distress on first day of exposure. Bayer AG 1981 Rat Both 1 1,600 3 3 Dead at 3-11 d. Bayer AG 1981 Rat Both 1 1,600 10 3 Dead at 3-24 h post-exposure. Bayer AG 1981 Rat Both 1 1,600 30 3 Dead at 32-59 min post-exposure. SA 1954 Rat 1 29 240 1 No deaths but effects uncertain. (Continued) 271

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TABLE C-4 Continued 272 Source Species Sex No. of Exposures ppm Minutes Category Comments Bayer AG 1991b Rat 5 0.03 240 0 No clinical signs after multiple exposures. Bayer AG 1991b Rat 5 0.10 240 0 No clinical signs after multiple exposures. Bayer AG 1991b Rat 5 0.70 240 1 Serous nasal discharge after 5 d, no findings for BAL and LDH analysis. Pauluhn et al. 1995 Rat Male 1 0.20 45 0 Threshold for respiratory tract irritation. Pauluhn et al. 1995 Rat Male 10 0.20 240 0 No clinical signs, no histopathologic findings. Pauluhn et al. 1995 Rat Male 10 0.80 240 0 No clinical signs, no histopathologic findings. Pauluhn et al. 1995 Rat Male 10 1.50 240 1 Signs of irritation, histopathologic findings after full exposure duration. Bayer AG 1991a Rat Both 1 0.14 240 0 Bayer AG 1991a Rat Both 1 1.1 240 0 Bayer AG 1991a Rat Both 1 2.4 240 SL Mortality (1/10) Bayer AG 1991a Rat Both 1 3.1 240 0 Bayer AG 1991a Rat Both 1 5.7 240 SL Mortality (7/10) Bayer AG 1991a Rat Both 1 9.7 240 3 Mortality (10/10) Bayer AG 1991a Rat Both 1 18 240 3 Mortality (10/10) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality.

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Selected Monoisocyanates 273 APPENDIX D BENCHMARK DOSE MODELING FOR PHENYL ISOCYANATE Probit Model with 0.95 Confidence Level Probit 1 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 2 4 6 8 10 dose 09:43 03/19 2011 FIGURE D-1 Probit model (with 0.95 confidence level) of phenyl isocyanate data from 4-h lethality study (Bayer AG 1991a). Probit Model. (Version: 3.2; Date: 10/28/2009) Input Data File: C:\Documents and Settings\BayerAG1991.dax.(d) Gnuplot Plotting File: C:\Documents and Settings\ BayerAG1991.plt Sat Mar 19 10:43:49 2011 BMDS_Model_Run The form of the probability function is: P[response] = CumNorm(Intercept+Slope*Dose), where CumNorm(.) is the cumulative normal distribution function Dependent variable = Col2 Independent variable = Col1 Slope parameter is not restricted

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274 Acute Exposure Guideline Levels Total number of observations = 6 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 Default Initial (and Specified) Parameter Values Background = 0 Specified Intercept = -2.56468 Slope = 0.462909 Asymptotic Correlation Matrix of Parameter Estimates Intercept Slope Intercept 1 -0.94 Slope -0.94 1 (***The model parameter(s) background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix) Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard Error Lower Confidence Limit Upper Confidence Limit Intercept -3.51993 0.86272 -5.21083 -1.82903 Slope 0.69465 0.185701 0.330683 1.05862 Analysis of Deviance Table No. of Model Log (likelihood) Parameters Deviance TestDF P-value Full model -9.35947 6 Fitted model -10.8144 2 2.90976 4 0.573 Reduced model -36.6519 1 54.5848 5 <0.0001 AIC: 25.6287 Goodness of Fit Scaled Estimated Dose Probability Expected Observed Size Residual 0.1400 0.0003 0.003 0.000 10 -0.056 1.1100 0.0030 0.030 0.000 10 -0.173 2.4100 0.0325 0.325 1.000 10 1.205 3.1300 0.0892 0.892 0.000 10 -0.990 5.7500 0.6824 6.824 7.000 10 0.120 9.7100 0.9994 9.994 10.000 10 0.079 Chi-square = 2.49; DF = 4; P-value = 0.6472

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Selected Monoisocyanates 275 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMC = 2.70217 BMCL05 = 1.64064 BMC01 Probit Model. (Version: 3.2; Date: 10/28/2009) Input Data File: C:\Documents and Settings\BayerAG1991a.dax(d) Gnuplot Plotting File: C:\Documents and Settings\ BayerAG1991a.plt Sat Mar 19 10:44:31 2011 BMDS_Model_Run The form of the probability function is: P[response] = CumNorm(Intercept+Slope*Dose), where CumNorm(.) is the cumulative normal distribution function Dependent variable = Col2 Independent variable = Col1 Slope parameter is not restricted Total number of observations = 6 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 Default Initial (and Specified) Parameter Values Background = 0 Specified Intercept = -2.56468 Slope = 0.462909 Asymptotic Correlation Matrix of Parameter Estimates Intercept Slope Intercept 1 -0.94 Slope -0.94 1 (***The model parameter(s) –background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix)

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276 Acute Exposure Guideline Levels Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard Error Lower Confidence Limit Upper Confidence Limit Intercept -3.51993 0.86272 -5.21083 -1.82903 Slope 0.69465 0.185701 0.330683 1.05862 Analysis of Deviance Table No. of Model Log (likelihood) Parameters Deviance Test DF P-value Full model -9.35947 6 Fitted model -10.8144 2 2.90976 4 0.573 Reduced model -36.6519 1 54.5848 5 <0.0001 AIC: 25.6287 Goodness of Fit Scaled Estimated Dose Probability Expected Observed Size Residual 0.1400 0.0003 0.003 0.000 10 -0.056 1.1100 0.0030 0.030 0.000 10 -0.173 2.4100 0.0325 0.325 1.000 10 1.205 3.1300 0.0892 0.892 0.000 10 -0.990 5.7500 0.6824 6.824 7.000 10 0.120 9.7100 0.9994 9.994 10.000 10 0.079 Chi-square = 2.49; DF = 4; P-value = 0.6472 Benchmark Dose Computation Specified effect = 0.01 Risk Type = Extra risk Confidence level = 0.95 BMC01 = 1.72968 BMCL = 0.591986