Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 15 (2013)

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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 

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 

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. 

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 

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. 

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. 

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. 

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 

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. 

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 

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. 

Selected Monoisocyanates 211 2.8. Data Adequacy and Research Needs Some of the toxicity data on the four monoisocyanates in this chapter may have uncertainty with respect to exposure concentrations, as discussed in detail in Section 2.7. As will be discussed in subsequent sections, no data relevant to AEGL-1 or AEGL-2 end points in humans or animals exposed to ethyl isocya- nate or cyclohexyl isocyanate were available. Toxicity data on ethyl isocyanate and cyclohexyl isocyanate are primarily from poorly-documented unpublished lethality studies that used small groups of rats. Thus, data on the well-studied, related compound—methyl isocyanate—were used to derive AEGL values for these two isocyanates. Additional research on the inhalation toxicity of ethyl isocyanate and cyclohexyl isocyanate might provide data suitable for the deriv- ing chemical-specific AEGL values. Animal data were adequate to derive AEGL-3 values for n-butyl isocyanate and phenyl isocyanate; AEGL-2 values were derived from corresponding AEGL-3 values. Methyl isocyanate is a developmental toxicant, and developmental effects were the basis for AEGL-2 and AEGL-3 values for this compound (NRC 2003). No inhalation data on the developmental toxicity of the four monoisocyanates in humans or animals were available. An oral study found no developmental toxici- ty in mice treated once with phenyl isocyanate at 9.8 mg/kg on gestation days 4, 7, 11, or 15 (Nehez et al. 1989). To account for the potential developmental tox- icity of n-butyl isocyanate and phenyl isocyanate, a modifying factor was ap- plied in the derivation of AEGL-2 and AEGL-3 values. Additional research on the developmental toxicity of these selected monoisocyanates might provide opportunities to refine the AEGL values for these compounds. Of the two well-studied isocyanates, toluene diisocyanate is a known and potent respiratory sensitizer, whereas methyl isocyanate is not. The potential for respiratory sensitization induced by the four monoisocyanates is not known. However, phenyl isocyanate has been found to be a potent dermal sensitizer (Karol and Kramarik 1996). A cautionary note has been included in the AEGL tables for phenyl isocyanate to indicate that individuals who have a strong reac- tion might not be protected within the definition of effects for each AEGL level; this note is the same as used for the AEGL values for toluene diisocyanate (NRC 2004). Additional research on the potential respiratory sensitization of phenyl isocyanate would be beneficial. 3. ETHYL ISOCYANATE 3.1. Human Toxicity Data No information regarding lethality, nonlethal toxicity, developmental tox- icity, genotoxicity, or carcinogenicity in humans after acute inhalation exposure to ethyl isocyanate was available. 

212 Acute Exposure Guideline Levels 3.2. Animal Toxicity Data 3.2.1. Acute Lethality Groups of three rats (strain and sex not specified) were exposed to ethyl isocyanate at 27 ppm for 6 h, 82 ppm for 6 h, or 506 ppm for 2 h and 50 min (Eastman Kodak 1964). Documentation of this study was limited to a summary table with few details. A known amount of liquid ethyl isocyanate was placed in a 6-cc test tube in a exposure chamber (24-24.5°C), and air was pumped into the chamber. Exposure concentrations were calculated from the amount of com- pound placed in the chamber and the chamber volume. Clinical signs in all the test groups were consistent with irritation. No deaths occurred in the 27-ppm group and all rats in the 82- and 506-ppm groups died within 24 h. Animals in the 27-ppm group were killed 14 days post-exposure; at necropsy, the lungs were reportedly hemorrhagic. Mortality and clinical data are summarized in Ta- ble 7-6. 3.2.2. Nonlethal Toxicity No information on the nonlethal toxicity, developmental or reproductive toxicity, genotoxicity, or carcinogenicity of ethyl isocyanate in animals was avail- able. TABLE 7-6 Lethality and Clinical Findings in Rats Exposed to Ethyl Isocyanate Calculated Clinical Signs Concentration (ppm) Duration Mortality Time of Death (time observed) 27 6h 0/3 – Blepharism, piloerection (1 min); lacrimation (15 min); dark eyes (1 h); nasal discharge (1 hr, 20 min). 82 6h 3/3 Within 24 h Blepharism, piloerection, (none during lacrimation (1 min). Gasping, exposure) dyspnea, dark eyes (20 min); ptyalism (55 min). 506 2 h, 50 min 3/3 2 h, 15 min; Blepharism, piloerection, 2 h, 20 min; lacrimation (immediately); 2 h, 50 min ptyalism (1 min); gasping, dyspnea, dark eyes (5 min); nasal discharge (15 min); prostration (1 h, 35 min); convulsions (2 h, 15 min). Source: Eastman Kodak 1964. 

Selected Monoisocyanates 213 3.3. Data Analysis for AEGL-1 Values 3.3.1. Human Data Relevant to AEGL-1 No human data relevant to deriving AEGL-1 values for ethyl isocyanate were available. 3.3.2. Animal Data Relevant to AEGL-1 No animal data relevant to deriving AEGL-1 values for ethyl isocyanate were available. 3.3.3. Derivation of AEGL-1 Values AEGL-1 values were not derived for ethyl isocyanate. The available data suggest that ethyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 values were not derived for me- thyl 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 for ethyl iso- cyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. 3.4. Data Analysis for AEGL-2 Values 3.4.1. Human Data Relevant to AEGL-2 No human data relevant to deriving AEGL-2 values for ethyl isocyanate were available. 3.4.2. Animal Data Relevant to AEGL-2 No animal data relevant to deriving AEGL-2 values for ethyl isocyanate were available. In the only available study, blepharism and lacrimation were observed in three rats exposed at 27 ppm for 6 h; that concentration was the only nonlethal exposure level examined (Eastman Kodak 1964). 3.4.3 Derivation of AEGL-2 Values The toxicologic database on ethyl isocyanate was inadequate to derive AEGL-2 values. Therefore, AEGL-2 values were determined by using the AEGL- 2 values established for the related compound methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2 to account for the possibility that ethyl 

214 Acute Exposure Guideline Levels isocyanate might be more toxic than methyl isocyanate. AEGL-2 values for ethyl isocyanate are presented in Table 7-7, and the calculations are presented in Ap- pendix A. 3.5. Data Analysis for AEGL-3 Values 3.5.1. Human Data Relevant to AEGL-3 No human data relevant to deriving AEGL-3 values for ethyl isocyanate were available. 3.5.2. Animal Data Relevant to AEGL-3 Only one study on the acute lethality of ethyl isocyanate was available. Groups of three rats were exposed by inhalation to ethyl isocyanate at three con- centrations for up to 6 h. All rats survived exposure at 27 ppm, whereas all ani- mals died at 82 ppm and 506 ppm (Eastman Kodak 1964). Documentation of the study provided few details and concentrations were calculated rather than ana- lytically confirmed. 3.5.3. Derivation of AEGL-3 Values The toxicologic database on ethyl isocyanate was inadequate to derive AEGL-3 values. As discussed in Section 2.3 (Structure-Activity Relationships), ethyl isocyanate and the other three monoisocyanates considered in this chapter are structurally similar to and exert toxic effects comparable to methyl isocya- nate. Therefore, AEGL-3 values were determined by using the AEGL-3 values established for the methyl isocyanate and dividing them by a modifying factor of 2 to account for the possibility that ethyl isocyanate might be more toxic than methyl isocyanate. A comparison of the available lethality data on the two chemicals suggests that use of methyl isocyanate as a surrogate with a modify- ing factor of 2 to account for potentially higher toxicity results in sufficiently protective AEGL values. When groups of three rats were exposed to ethyl iso- cyanate for 6 h, all rats survived at 27 ppm and no rats survived at 82 ppm. For comparison, the 6-h LC50 for methyl isocyanate in rats (6/sex) was 6.1 ppm (NRC 2003). AEGL-3 values for ethyl isocyanate are presented in Table 7-8, and the calculations are presented in Appendix A. TABLE 7-7 AEGL-2 Values for Ethyl Isocyanate 10 min 30 min 1h 4h 8h 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (0.58 mg/m3) (0.19 mg/m3) (0.099 mg/m3) (0.025 mg/m3) (0.012 mg/m3) 

Selected Monoisocyanates 215 TABLE 7-8 AEGL-3 Values for Ethyl Isocyanate 10 min 30 min 1h 4h 8h 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (1.7 mg/m3) (0.58 mg/m3) (0.29 mg/m3) (0.073 mg/m3) (0.038 mg/m3) Consideration was also given to basing AEGL-3 values on the study of ethyl isocynate conducted by Eastman Kodak (1964), in which 27 ppm caused no deaths in a group of three rats exposed for 6 h. If this approach is used, an interspecies uncertainty factor of 3 and an intraspecies uncertainty factor of 10 would be applied, as well as a modifying factor of 10 to account for the sparse database on ethyl isocyanate. Time scaling would be performed using the equa- tion Cn × t = k, with default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations. These calculations would result in AEGL-3 values of 0.30 ppm for 10 min, 0.21 ppm for 30 min, 0.16 ppm for 1 h, 0.10 ppm for 4 h, and 0.068 ppm for 8 h. However, this approach has greater uncertainty, particularly with respect to poor documentation of the study, small numbers of animals tested, and lack of analytic confirmation of the exposure concentrations (Eastman Kodak 1964). 3.6. Summary of AEGLs 3.6.1. AEGL Values and Toxicity End Points AEGL-1 values are not recommended for ethyl isocyanate because of in- sufficient data and the potential for systemic effects to occur at concentrations below those associated with irritation. AEGL-2 and AEGL-3 values for ethyl isocyanate were estimated using the AEGL values established for methyl isocy- anate (NRC 2003) and dividing them by a modifying factor of 2 to account for the possibility that ethyl isocyanate might be more toxic than methyl isocyanate. AEGL values for ethyl isocyanate are presented in Table 7-9. 3.6.2. Other Standards and Guidelines There are no other standards or guidelines for ethyl isocyanate. 4. CYCLOHEXYL ISOCYANATE 4.1. Human Toxicity Data No information regarding the lethality, nonlethal toxicity, developmental toxicity, genotoxicity, or carcinogenicity in humans following acute inhalation exposure to cyclohexyl isocyanate was available. 

216 Acute Exposure Guideline Levels TABLE 7-9 AEGL Values for Ethyl Isocyanatea Classification 10 min 30 min 1h 4h 8h AEGL-1b NR NR NR NR NR (nondisabling) AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (disabling) 0.58 (0.19 (0.099 (0.025 (0.012 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (lethal) (1.7 (0.58 (0.29 (0.073 (0.038 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) a When more than one of the monoisocyanates is detected at a scene, the lowest AEGL value should be applied to the sum total concentration of all detected monoisocyanates because of a presumed common mode of action for these chemicals. b NR, not recommended. On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to ethyl isocyanate might be associated with systemic toxicity at concentra- tions below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. 4.2. Animal Toxicity Data 4.2.1. Lethality Groups of three rats (strain and sex not specified) were exposed to cyclo- hexyl isocyanate at 17.79, 53.2, or 1,017 ppm for up to 6 h (Eastman Kodak 1990, 1992). Documentation of the study, which was conducted in 1964 and submitted to the U.S. Environmental Protection Agency under the Toxic Sub- stances Control Act Test Submission (Section 8D), consists of a tabular report. Chamber atmospheres were generated by passing air through a gas washing bot- tle or through a short open-end bubbler and diluting with clean air. The method for determining chamber concentrations was not specified, so whether the con- centrations were calculated or measured is unknown. During exposure at 17.79 ppm, clinical signs of toxicity included blinking within 5 min, rough hair coat by 10 min, vasodilatation after 1 h and 25 min, lacrimation and accelerated respira- tion at 1 h and 55 min, and dyspnea in 4 h and 25 min. One rat died on day 7 post-exposure and the remaining animals were killed on day 8, presumably due to moribund condition. All of the treated animals had enlarged and spongy lungs that exhibited collapse and were consolidated by acute inflammatory exude; congestion of the kidneys and liver was also seen. At 53.2 ppm, clinical signs were similar, but appeared slightly earlier, and also included salivation at 3 h and 50 min and gasping in 4 h and 50 min. Two animals died in 6 h and the third rat died 12 days later. At 1,017 ppm, all rats died within 4 h and 10 min after exhibiting pronounced clinical signs. Six male rats (strain not specified) were exposed whole-body to cyclohex- yl isocyanate at an average chamber concentration of 1,401 ppm (Younger La- boratories 1974). Saturated vapors (generated by passing air through a 500-mL 

Selected Monoisocyanates 217 flask containing 42.4 g of cyclohexyl isocyanate) were introduced into the chamber and the concentration was calculated from the amount of material va- porized. All animals died within 2.5 h after the start of exposure. Clinical signs of irritation were observed before death, and pulmonary hemorrhage was found at necropsy. In a similar experiment, four male and four female rats died within 2 h after the start of exposure to saturated vapor of cyclohexyl isocyanate gener- ated in the same manner (Crawford and Anderson 1974); vapor concentrations were not estimated in this study. Groups of five male and five female Wistar rats were exposed whole-body to saturated vapors of cyclohexyl isocyanate for 3 min, 10 min, or 1 h, followed by a 14-day observation period (Bayer AG 1980a). All rats exposed for 3 min survived until the end of the observation period; clinical signs of irritation were observed during exposure and persisted until 2 days post-exposure. Necropsy revealed speckled or dark red spots on the lungs in about 50% of the rats. Ani- mals exposed for 10 min died within 11 days post-exposure; clinical signs of irritation and respiratory problems were observed. All rats died during the 1-h exposure. Necropsy of the animals that died in the 10-min and 1-h groups re- vealed enlarged lungs with dark red spots, fluid in the thoracic cavity, lobulated pattern of the liver, and bloated stomach. A summary of the acute lethality data from studies of rats exposed to cyclohexyl isocyanate are presented in Table 7- 10. TABLE 7-10 Acute Lethality in Rats Exposed to Cyclohexyl Isocyanate Concentration (ppm) Duration Lethality Clinical and Necropsy Findings Reference 17.79 6h 1/3 on day 7 Irritation, lacrimation, Eastman Kodak 2/3 killed on day 8 dypsnea, inflammation in 1990, 1992 lungs, congestion of kidney and liver. 53.2 6h 2/3 during exposure Same effects as the 17.79-ppm 1/3 on day 12 group, plus salivation, and gasping. 1,017 4h 3/3 after 4 h Same effects as the 53.2-ppm group, but more severe. 1,401 1-2.5 h 6/6 Irritation, hemorrhage Younger in lungs. Laboratories 1974 Saturated 2h 8/8 None reported. Crawford and Anderson 1974 3 min 0/10 Irritation, dark spots on lungs. Bayer AG 1980a 10 min 10/10 within Respiratory problems, 11 days enlarged lungs with red spots, fluid, lobulated liver. 1h 10/10 during Same effects as the exposure 10-min group. 

218 Acute Exposure Guideline Levels 4.2.2. Nonlethal Toxicity No information on the nonlethal toxicity, developmental or reproductive toxicity, genotoxicity, or carcinogenicity of cyclohexyl isocyanate in animals was found. 4.3. Data Analysis for AEGL-1 Values 4.3.1. Human Data Relevant to AEGL-1 No human data relevant to calculating AEGL-1 values for cyclohexyl iso- cyanate were available. 4.3.2. Animal Data Relevant to AEGL-1 No animal data relevant to calculating AEGL-1 values for cyclohexyl iso- cyanate were available. 4.3.3. Derivation of AEGL-1 Values AEGL-1 values were not derived for cyclohexyl isocyanate. The available data suggest that cyclohexyl isocyanate and the three other selected monoisocy- anates considered in this chapter exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). 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 similar- ities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for cyclohexyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. 4.4. Data Analysis for AEGL-2 Values 4.4.1. Human Data Relevant to AEGL-2 No human data relevant to calculating AEGL-2 values for cyclohexyl iso- cyanate were available. 4.4.2. Animal Data Relevant to AEGL-2 No animal data relevant to calculating AEGL-2 values for cyclohexyl iso- cyanate were available. All of the concentrations of cyclohexyl isocyanate tested were associated with 100% mortality (Crawford and Anderson 1974; Younger Laboratories 1974; Bayer AG 1980a; Eastman Kodak 1990, 1992). 

Selected Monoisocyanates 219 4.4.3. Derivation of AEGL-2 Values The toxicologic database for cyclohexyl isocyanate was inadequate to de- rive AEGL-2 values. AEGL-2 values were determined by using the AEGL-2 values established for the related compound methyl isocyanate and dividing them by a modifying factor of 2 to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocyanate. AEGL-2 values for cy- clohexyl isocyanate are presented in Table 7-11, and the calculations are provid- ed in Appendix A. 4.5. Data Analysis for AEGL-3 Values 4.5.1. Human Data Relevant to AEGL-3 No human data relevant to calculating AEGL-3 values for cyclohexyl iso- cyanate were available. 4.5.2. Animal Data Relevant to AEGL-3 All of the studies on cyclohexyl isocyanate were conducted in rats, and all of the test concentrations resulted in 100% mortality (Crawford and Anderson 1974; Younger Laboratories 1974; Bayer AG 1980a; Eastman Kodak 1990, 1992). The lowest concentrations of cyclohexyl isocyanate tested in these stud- ies were 17.79 ppm for 6 h, 1,017 ppm for 4 h, and 1,401 ppm for 2.5 h or less. 4.5.3. Derivation of AEGL-3 Values The toxicologic database for cyclohexyl isocyanate was inadequate to de- rive AEGL-3 values. AEGL-3 values were determined by using the AEGL-3 values established for the related compound methyl isocyanate and dividing them by a modifying factor of 2 to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocyanate. A comparison of the available lethality data on the two chemicals suggests that this approach results in sufficiently protective AEGL values. When three rats were exposed to cyclo- hexyl isocyanate at 18 ppm for 6 h, one died on day 7 post-exposure and the other two were killed on day 8, presumably because of moribund condition. For comparison, the 6-h LC50 for methyl isocyanate in rats is 6.1 ppm (NRC 2003). AEGL-3 values for cyclohexyl isocyanate are presented in Table 7-12, and the calculations are provided in Appendix A. TABLE 7-11 AEGL-2 Values for Cyclohexyl Isocyanate 10 min 30 min 1h 4h 8h 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (1.0 mg/m3) (0.33 mg/m3) (0.17 mg/m3) (0.043 mg/m3) (0.020 mg/m3) 

220 Acute Exposure Guideline Levels TABLE 7-12 AEGL-3 Values for Cyclohexyl Isocyanate 10 min 30 min 1h 4h 8h 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (3.1 mg/m3) (1.0 mg/m3) (0.51 mg/m3) (0.13 mg/m3) (0.066 mg/m3) 4.6. Summary of AEGLs 4.6.1. AEGL Values and Toxicity End Points AEGL-1 values are not recommended for cyclohexyl isocyanate because of insufficient data and because of the potential for systemic effects to occur at concentrations below those associated with irritation. AEGL-2 and AEGL-3 values for cyclohexyl isocyanate were estimated from those established for me- thyl isocyanate and dividing them by a modifying factor of 2 to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocya- nate. AEGL values for cyclohexyl isocyanate are presented in Table 7-13. 4.6.2. Other Standards and Guidelines There are no other standards or guidelines for cyclohexyl isocyanate. 5. n-BUTYL ISOCYANATE 5.1. Human Toxicity Data 5.1.1. Acute Lethality No information regarding lethality in humans after acute inhalation expo- sure to n-butyl isocyanate was available. 5.1.2. Nonlethal Toxicity An industrial hygiene survey conducted at a facility using n-butyl isocya- nate as a chemical intermediate reported that exposure to n-butyl isocyanate at a concentration of 5-10 ppb (0.005-0.01 ppm) resulted in “noticeable” ocular irri- tation, and that normal work operations were not possible at 50 ppb (0.05 ppm) (Haskell Laboratory 1989). The report included an opinion that exposure to n- butyl isocyanate at 50 ppb (0.05 ppm) was not expected to impair ability to es- cape, but did not provide any supporting details. Concentrations of n-butyl iso- cyanate were measured using an impinger/gas chromatograph (GC) method. A later report compared measurements using this method with those obtained from XAD-7 tube/HPLC (DuPont, unpublished material, 2008), and found that the 

Selected Monoisocyanates 221 impinger/GC method underestimated n-butyl isocyanate concentrations by 40- 400%. Analysis of those data indicates that, when averaged across all of the samples, the XAD-7 tube/HPLC method gave results that were two-fold higher than the impinger/GC method (see Table 7-5). DuPont (unpublished material, 2008) also reported the findings of two in- dustrial hygiene surveys. In one assessment, subjective responses regarding ocu- lar irritation and lacrimation were obtained from five workers who were not required to wear respirators. Data collected from the workers’ personal air sam- plers indicated that “personnel did not experience eye irritation/lacrimation up to 52.8 ppb over a 7- to 8-h sample” (measured concentrations were 12.9-52.8 ppb [0.013-0.053 ppm]). In the second assessment, air monitoring data were assessed in conjunction with daily logs recording reports of ocular irritation or lacrima- tion by persons not wearing respirators. This assessment concluded that “per- sonnel without respiratory protection were not experiencing eye irritation when air sample results indicated airborne butyl isocyanate levels ranging from 8 to 40 ppb” (DuPont, unpublished material, 2008). Neither survey was sufficiently rigorous to be used as a basis for deriving AEGL values. 5.1.3. Developmental and Reproductive Effects, Genotoxicity, and Carcinogenicity No information regarding the developmental or reproductive toxicity, genotoxicity, or carcinogenicity of n-butyl isocyanate in humans was available. TABLE 7-13 AEGL Values for Cyclohexyl Isocyanatea Classification 10 min 30 min 1h 4h 8h AEGL-1b NR NR NR NR NR (nondisabling) AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (disabling) (1.0 (0.33 (0.17 (0.043 (0.020 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (lethal) (3.1 (1.0 (0.51 (0.13 (0.066 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) a When more than one of the monoisocyanates is detected at a scene, the lowest AEGL value should be applied to the sum total concentration of all detected monoisocyanates due to presumed common mode of action for these chemicals. b NR, not recommended. On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to cylcohexyl isocyanate might be associated with systemic toxicity at con- centrations below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. 

222 Acute Exposure Guideline Levels 5.2. Animal Toxicity Data 5.2.1. Acute Lethality In experiments conducted by Younger Laboratories for Monsanto Chemi- cal Company (Younger Laboratories 1956), groups of three male rats died 10-15 min after being exposed to an unspecified concentration of n-butyl isocyanate (described only as “considerably less than saturated”). Another group of three rats exposed to “relatively low” concentrations died after 45, 60, and 75 min. All rats exhibited signs of irritation and respiratory distress immediately after expo- sure began. Necropsy revealed severe edema in the nasal passages and pulmo- nary congestion. Mobay Chemical Company (1961) conducted experiments in which groups of six rats were exposed to a saturated vapor of n-butyl isocyanate (about 22,000 ppm). Although the experimental protocol specified a 6-h exposure, results showed that all six rats died within 10-15 min. No further details of the experi- ments were provided. The acute inhalation toxicity of n-butyl isocyanate in groups of six male Spartan Sprague-Dawley rats (200-300 g) was reported by IRDC (1965). Rats were exposed to n-butyl isocyanate at 5.5, 7.9, 10.9, 12.0, 18.9, 21.7, 27.9, 28.2, or 34.6 mg/m3 (1.4, 1.9, 2.7, 3.0, 4.7, 5.4, 7.0, 7.1, and 8.7 ppm) for 1 h in a 9-L, air- tight chamber, and were subsequently observed for 14 days. n-Butyl isocyanate vapor was generated by heating the compound in a U-tube submersed in a water bath, and the resulting vapor was passed through glass wool filters and calcium chloride drying tubes. Concentrations were adjusted by varying the infusion rate into the U-tube. Samples of the chamber atmosphere were analyzed spectropho- tometrically and compared to a pre-established standard curve. Clinical signs of toxicity in rats exposed to n-butyl isocyanate increased with concentration and included hypoactivity, increased grooming and escape behavior during exposure, salivation, lacrimation, dyspnea, and death. Group-specific mortality incidences and necropsy findings are presented in Table 7-14. Although no deaths occurred at 12.0 mg/m3 (3.0 ppm), deaths in the groups exposed at 7.9 and 10.9 mg/m3 (1.9 and 2.7 ppm, respectively) suggest that the absence of mortality in the 12-mg/m3 group was probably a function of the small group size. The investigators calculat- ed a 1-h LC50 of 15.2 mg/m3 (95% CI: 12.1-19.0 mg/m3), equivalent to 3.8 ppm, using the method of Litchfield and Wilcoxon (1949). As shown in Table 7-14, lethality was often delayed. A lethality assay using groups of six male ChR-CD rats exposed to n-butyl isocyanate (purity not specified) for 4 h was conducted by DuPont (Haskell La- boratory 1968). Concentrations of 12.5, 17.5, 22, 31.5, and 33.5 ppm were measured by impinger/GC analysis. Vapor was generated by metering n-butyl isocyanate into a heated (125-150°C) stainless steel T-tube. Vapor was then car- ried via measured air flow to a 16-L bell jar containing the rats. Rats exhibited irregular breathing, hyperemia, gasping, pale ears, and lacrimation during expo- sure. Post-exposure observations included 10-20% loss of body weight during 

Selected Monoisocyanates 223 the first day; respiratory distress characterized by gasping, labored breathing, congestion, and rales; red discharge from the eyes; and priapism. Lethality find- ings are presented in Table 7-15. Some deaths occurred during the 30-day ob- servation period at all test concentrations. Body weight loss and signs of respira- tory distress were observed throughout the post-exposure period. Death occurred during exposure only at the two highest concentrations. Pathology findings in- cluded dark red-colored, edematous lungs, necrosis and desquamation of res- piratory epithelium, and signs of increased capillary permeability. Surviving rats exhibited regeneration of the bronchial epithelium and proliferation of connec- tive tissue resulting in fibrotic changes and atelectasis. Bronchopneumonia was evident in many rats by post-exposure day 14. A 4-h LC50 of 15.6 ppm (95% CI: 13.3-18.2 ppm) was reported. TABLE 7-14 Lethality in Rats After Exposure to n-Butyl Isocyanate Vapor for 1 Hour Concentrationa (mg/m3) [ppm] Lethality Comments and Necropy Findings 5.5 mg/m3 (1.4 ppm) 0/6 No gross lesions in four rats; two had 8-mm areas of congestion or hemorrhage in lungs. 7.9 mg/m3 (1.9 ppm) 1/6 Death on post-exposure day 1; rat had hemorrhagic lungs. All survivors had inflated lungs and involuted thymus; four had mucus in trachea and bronchi; two had lungs with dark areas or areas of consolidation; one had gastric edema and hemorrhage. 10.9 mg/m3 (2.7 ppm) 2/6 Deaths on post-exposure days 9 and 13. Survivors had inflated lungs, and three had involuted thymus and fluid in small intestine. 12.0 mg/m3 (3.0 ppm) 0/6 All rats had inflated lungs; two had pulmonary consolidation; one had pulmonary congestion; one had lungs with dark areas; one had pulmonary hyperemia; one had mucus in the trachea. 18.9 mg/m3 (4.7 ppm) 6/6 Five deaths on post-exposure day 2, one death on post-exposure day 13. No necropsy findings reported. 21.7 mg/m3 (5.4 ppm) 4/6 Two deaths on post-exposure day 2, one death each on days 9 and 11. Survivors had lungs with dark foci/consolidation, fluid in gastrointestinal tract. 27.9 mg/m3 (7.0 ppm) 6/6 Two deaths on day of exposure, four deaths on 28.2 mg/m3 (7.1 ppm) 6/6 post-exposure day 1. 34.6 mg/m3 (8.7 ppm) 6/6 One death on day of exposure, five deaths on post-exposure day 1. All deaths on day of exposure. a Measured spectrophotometrically. Source: IRDC 1965. 

224 Acute Exposure Guideline Levels TABLE 7-15 Lethality in Male Rats Exposed to n-Butyl Isocyanate for 4 Hours Mortality 14-Days 30-Days Concentrationa (ppm) During Exposure Post-Exposure Post-Exposure 12.5 0/6 0/6 2/6 17.5 0/6 2/6 3/6 22 0/6 2/6 5/6 31.5 2/6 6/6 6/6 53.5 2/6 6/6 6/6 a Measured by impinger/GC. Source: Haskell Laboratory 1968. A series of studies on n-butyl isocyanate were conducted by Bayer AG In- stitute for Toxicology for Miles, Inc. (Bayer AG 1978), which submitted the reports (in German) to EPA’s toxic substances control act test submissions (TSCATS Section 8E) database. The studies included: 1- and 4-h lethality ex- periments in rats; another 1-h lethality study in rats; a study of cholinesterase activity in rats exposed to a lethal concentration; and a study of nonlethal effects in rats exposed for 4 h. The study of nonlethal effects was published by Pauluhn et al. (1990), and is described in Section 5.2.2.1. Salient portions of the acute lethality studies were translated to describe the other studies. In a 1-h inhalation study, groups of five male and five female Wistar rats were exposed to n-butyl isocyanate at 156, 520, or 978 mg/m3. Vapors were generated at room tempera- ture and distributed through the chamber with a fan, and were analyzed by flame ionization detection (FID). Mortality incidences were recorded 14 days post- exposure (see Table 7-16). A 1-h LC50 of 425 mg/m3 (95% CI: 280-646 mg/m3) or its equivalent of 105 ppm (95% CI: 70-162 ppm) was reported for males and females. Labored breathing was apparent as soon as exposure was initiated at all concentrations. During the post-exposure period, animals exhibited dull and unkempt coat, stiff gait, tearing, and labored breathing. Areas of the ocular and nasal mucosa were reddened and swollen. In the 4-h lethality study, groups of five male rats were exposed to n-butyl isocyanate at 90 or 285 mg/m3 (22 or 70 ppm) and groups of five female rats were exposed at 90, 285, or 469 mg/m3 (22, 70, and 116 ppm) (Bayer AG 1978). Mortality data from this study are presented in Table 7-16. A 4-h LC50 of 80 mg/m3 (18 ppm) was reported for female rats; the 4-h LC50 for males was less than 90 mg/m3 (22.5 ppm). Clinical observations were observed in all groups and were consistent with those reported in the 1-h study. In a second 1-h inhalation study, groups of five male and five female Wistar rats were exposed to n-butyl isocyanate at 375, 887, or 932 mg/m3 (94, 222, and 233 ppm), and followed for 28 days (Bayer AG 1978). The experimental design prevented dermal contact with the vapor, although details of the apparatus were not provided. Concentrations were analyzed by FID. Mortality incidences were 

Selected Monoisocyanates 225 recorded at 28 days post-exposure (see Table 7-16). The 1-h LC50 values estimated for male and female rats were 500 mg/m3 (125 ppm) and 600 mg/m3 (150 ppm), respectively. Animals in all the exposure groups exhibited labored breathing, and sedation was observed in some. Mucosal irritation was observed. Necropsy find- ings included pulmonary edema, emphysema, and “spotty changes”; pale liver and spleen; lobular appearance of the liver; and distended stomach and intestines. Lethality benchmarks for n-butyl isocyanate are presented in Table 7-17. 5.2.2. Nonlethal Toxicity 5.2.2.1. Rats IRDC (1965) exposed groups of six rats to n-butyl isocyanate at concen- trations of 5.5, 7.9, 10.9, 12.0, 18.9, 21.7, 27.9, 28.2, or 34.6 mg/m3 for 1 h. Clinical signs included hypoactivity, increased grooming (during exposure), escape behavior (during exposure), salivation, lacrimation, and dyspnea. Alt- hough these responses were reportedly related to concentration, it was unclear which (if any) were associated with the nonlethal exposures. Deaths occurred in all but the 5.5 mg/m3-ppm and 12.0 mg/m3-groups (see Section 5.2.1). TABLE 7-16 Lethality in Rats Exposed to n-Butyl Isocyanate for 1 or 4 Hours Concentration Lethality Time of Death 1-h, 14-day follow-up 156 mg/m3 (39 ppm) 0/5 (males) 0/5 (females) 520 mg/m3 (130 ppm) 3/5 (males) 8-14 days post-exposure 4/5 (females) 9-13 days post-exposure 978 mg/m3 (245 ppm) 5/5 (males) 1-3 days post-exposure 5/5 (females) 1 h to 12 days post-exposure 1-h, 28-day follow-up 375 mg/m3 (94 ppm) 1/10 (males) 10 days post-exposure 2/10 (females) 12 and 21 days post-exposure 887 mg/m3 (222 ppm ) 10/10 (males) 8 h to 24 days post-exposure 9/10 (females) 4-16 days post-exposure 932 mg/m3 (233 ppm) 10/10 (males) 6 h to 12 days post-exposure 10/10 (females) 2-22 days post-exposure 4-h, 14-day follow-up 90 mg/m3 (22 ppm) 4/5 (males) 7-10 days post-exposure 3/5 (females) 11-12 days post-exposure 285 mg/m3 (70 ppm) 5/5 (males) 1 h to 8 days post-exposure 4/5 (females) 9-14 days post-exposure 469 mg/m3 (116 ppm) 5/5 (females) 2 h to 4 days post-exposure a Measured by flame ionization detection. Source: Bayer AG 1978. 

226 Acute Exposure Guideline Levels TABLE 7-17 Lethality Benchmarks for n-Butyl Isocyanate Study (analytic method) Lethality Benchmark Comments IRDC 1965 1-h LC50: 3.8 ppm Deaths delayed 1-13 days (spectrophotometry) Haskell Laboratory 1968 4-h LC50: 15.6 ppm Post-exposure deaths; time (impinger/GC) to death was a function of concentration. Bayer AG 1978 (FID) 1-h LC50: 105 ppm (males and Followed for 14 days females) 1-h LC50: ~125 ppm (males) Followed for 28 days 1-h LC50: ~150 ppm (females) Followed for 28 days 4-h LC50: <22.5 ppm (males) Followed for 14 days 4-h LC50: ≈18 ppm (females) Followed for 14 days Pulmonary function, arterial blood gases, acid-base status, and bronchio- alveolar lavage fluid (BALF) composition were analyzed in groups of 20 male Wistar rats (WISW SPF-Cpb; 9-12 weeks old) exposed to n-butyl isocyanate (technical grade, 99.5%) at target concentrations of 0, 8, 25, or 50 mg/m3 for 4 h (Pauluhn et al. 1990). Analytic concentrations of 7.6, 23.5, and 55.2 mg/m3 (equivalent to 1.9, 5.9, and 14 ppm) were determined by HPLC analysis of three samples (sampling rate of 0.5 L/min). The animals were exposed using a head- nose only dynamic method that prevented mixing of the test atmosphere with exhaled air and also prevented hydrolytic degradation and aerosol formation. Rats exposed to n-butyl isocyanate at 7.6 mg/m3 exhibited only transient clinical signs (hypothermia, bradypnea, and mucous membrane irritation) during the first day. In the 23.5- and 55.2-mg/m3 groups, signs of severe respiratory distress were observed that resolved within 1week in the 23.5-mg/m3 group but persisted through the 4-week observation period in the 55.2-mg/m3 group. At the highest concentration, decreased body temperature (data not provided in report) was detected 10-min post-exposure. Observations at 4 weeks post-exposure included minor (but statistically insignificant relative to controls) changes in some pul- monary function parameters, significantly decreased arterial oxygen, increased arterioalveolar oxygen difference, and significantly increased blood proteins, lactate dehydrogenase (LDH) activity levels, and relative lung weight. Histo- pathologic examinations of the lungs revealed the greatest effect in rats exposed at the highest concentration, which included gross findings of consolidation, distention, hemorrhagic areas, edema, and pleural effusions. Microscopic chang- es included increased numbers of alveolar macrophages, perivascular round-cell infiltration, focal fibroproliferative reactions, emphysema, thickening of the sep- ta, and pneumonia in rats exposed at 23.5 mg/m3 or higher; the effects were de- scribed as occurring “marginally” in the 23.5-mg/m3 group. In summary, a 4-h exposure of male rats to n-butyl isocyanate at 7.6 mg/m3 produced minor transi- 

Selected Monoisocyanates 227 ent clinical effects that fully resolved within 24 h. More notable effects were observed at 23.5 mg/m3, which resolved within 1 week, and persistent clinical effects and notable histopathologic findings consistent with significant pulmo- nary injury were found at 55.2 mg/m3. 5.2.2.2. Guinea Pigs Tests of n-butyl isocyanate-bovine serum albumin conjugate in groups of four male Hartley guinea pigs induced only a weak, transient response (Haskell Laboratory 1982). The experiments involved multiple head-only exposures for 10-min/day, 5 days/week until a positive respiratory response occurred. During exposure, guinea pigs were placed in Lucite® body plethysmographs which were connected to an air pressure transducer to assess changes in respiratory rate. Three guinea pigs developed a positive response to n-butyl isocyanate after 2 weeks but the response was transient and of insufficient duration to allow for assessing the response to a challenge with other isocyanates. The concentration of n-butyl isocyanate-bovine serum albumin conjugate that generated the transi- ent response was not specified. 5.2.3. Repeated Exposure In a lung function study, groups of 20 male Wistar rats were exposed (head-nose only) to n-butyl isocyanate vapors at target concentrations of 0 (con- ditioned air), 1, 5, 15, or 25 mg/m3 (0, 0.25, 1.25, 3.75, 6.25 ppm) for 6 h/day for 5 days, and were observed for 5 weeks (Pauluhn and Eben 1991). Analytic concentrations of 0, 1.09, 6.22, 14.67, and 25.97 mg/m3 (0, 0.27, 1.55, 3.67, and 6.49 ppm) were determined by HPLC analysis of nitro-reagent reaction product. Twelve rats in the 25 mg/m3-group died 2 weeks after exposure; no deaths oc- curred in the other groups. No clinical signs of toxicity were observed in rats of the 1- or 5 mg/m3-groups. At 15 and 26 mg/m3, rats exhibited unkempt appear- ance, labored breathing, reduced motility, hypothermia, and serous nasal dis- charge. Overall evaluation of lung function revealed no significant differences in the 1-mg/m3 group compared with the control group. Rats in the 15-mg/m3 group exhibited some effects (BALF composition) that were marginally differ- ent from controls. On the basis of clinical signs, pulmonary function test results, and BALF analysis, the investigators concluded that delayed lethality was the result of obstructive and progressive lung damage with associated severe dis- turbance of ventilatory perfusion. 5.2.4. Developmental and Reproductive Effects No information on the developmental or reproductive toxicity of n-butyl isocyanate vapor in animals was available. 

228 Acute Exposure Guideline Levels 5.2.5. Genotoxicity n-Butyl isocyanate was not mutagenic in Salmonella typhimurium strains TA 1535,TA 1537, TA 98, or TA 100 with or without metabolic activation (OECD 2005). In the mouse lymphoma assay, n-butyl isocyanate was genotoxic only in the absence of metabolic activation, but it was not determined if this was the result of gene mutation or chromosomal aberrations (OECD 2005). No in vivo genotoxicity data were available. 5.2.6. Carcinogenicity No information on the carcinogenicity of n-butyl isocyanate vapor in ani- mals was available. 5.3. Data Analysis for AEGL-1 5.3.1. Human Data Relevant to AEGL-1 Data relevant to AEGL-1 effects in humans are limited to industrial hy- giene reports noting that exposure to n-butyl isocyanate at concentrations as high as 40-50 ppb (0.040-0.050 ppm) did not cause ocular irritation in workers (Haskell Laboratory 1989; DuPont, unpublished material, 2008). However, the reports were not sufficiently rigorous or well documented to form the basis of AEGL-1 values for n-butyl isocyanate. 5.3.2. Animal Data Relevant to AEGL-1 Reliable exposure-response data for AEGL-1 severity effects in animals were not available for n-butyl isocyanate. Signs of irritation and respiratory dis- tress were observed in surviving rats in lethality studies, but the severity of the nonlethal effects was not specified. 5.3.3. Derivation of AEGL-1 Values AEGL-1 values were not derived for n-butyl isocyanate or any of the other three selected monoisocyanates. The available data suggest that n-butyl isocyanate and the other monisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 val- ues were not derived for methyl isocyanate because it has poor warning properties, and because systemic toxicity is possible at concentrations lower than those asso- ciated with AEGL-1 effects (NRC 2003). On the basis of similarities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not de- rived for n-butyl isocyanate. Absence of AEGL-1 values does not imply that con- centrations below the AEGL-2 values are without effect. 

Selected Monoisocyanates 229 5.4. Data Analysis for AEGL-2 5.4.1. Human Data Relevant to AEGL-2 The industrial hygiene report of DuPont (Haskell Laboratory 1989) pro- vided the only information on n-butyl isocyanate relevant to AEGL-2 effects in humans. The report stated that exposure to n-butyl isocyanate at 50 ppb (0.05 ppm) for an unspecified duration was considered incompatible with normal work operations, but would not impair escape. However, no details of exposure estimates or health evaluations were provided; thus, the data were considered unsuitable for deriving AEGL-2 values. 5.4.2. Animal Data Relevant to AEGL-2 A single 4-h exposure of rats to n-butyl isocyanate at a concentration 23.5 mg/m3 (5.9 ppm) resulted in signs of severe respiratory distress which resolved within 1 week, whereas exposure at 55.2 mg/m3 (14 ppm) resulted in persistent clinical effects (Pauluhn et al. 1990). Histopathologic findings at 55.2 mg/m3 were consistent with significant pulmonary injury; “marginal” pulmonary histo- pathologic findings were reported at 23.5 mg/m3, but details of the incidence and severity of effects were not provided (Pauluhn et al. 1990); thus, it is difficult to evaluate whether the findings were consistent with AEGL-2 effects. In a repeated exposure study, rats exposed to n-butyl isocyanate at 15 mg/m3 (3.8 ppm) for 6 h/day for 5 consecutive days had minor changes in BALF composition but no significant histopathologic findings; in rats similarly ex- posed at 25 mg/m3 (6.3 ppm), 60% mortality (12/20) occurred during post- exposure week 2 (Pauluhn and Eben 1991). 5.4.3. Derivation of AEGL-2 Values The available human data and single-exposure animal toxicity data were in- adequate for deriving AEGL-2 values for n-butyl isocyanate. Therefore, AEGL-2 values were determined by adjusting the AEGL-3 values for n-butyl isocyanate; each of the corresponding AEGL values was divided by 3. This approach is justi- fied by the steep concentration-response curve observed in a mortality study; no rats died after a 1-h exposure at 39 ppm, and 70% (7/10) died at 130 ppm (Bayer AG 1978). AEGL-2 values for n-butyl isocyanate are presented in Table 7-18, and their derivation is presented Appendix A. TABLE 7-18 AEGL-2 Values for n-Butyl Isocyanate 10 min 30 min 1h 4h 8h 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm (0.41 mg/m3) (0.41 mg/m3) (0.34 mg/m3) (0.21 mg/m3) (0.11 mg/m3) 

230 Acute Exposure Guideline Levels For comparison, consideration was given to possible AEGL-2 values based on the repeated-exposure study of Pauluhn and Eben (1991). The no- effect level relevant to AEGL-2 values in that study was 3.8 ppm; only minor changes in BALF composition were observed. If 3.8 ppm is used as the point of departure (assuming a 6 h duration), AEGL-2 values could be calculated by ap- plying a total uncertainty factor of 30 (3 for interspecies differences and 10 for intraspecies variability), applying a modifying factor of 3 (to account for poten- tial developmental toxicity of n-butyl isocyanate based on data for the related compound methyl isocyanate), and performing time scaling with the equation Cn × t = k (using default values of n = 3 for extrapolation to shorter durations and n = 1 for extrapolation to longer durations). The resulting AEGL-2 values would be 0.097, 0.097, 0.077, 0.048, and 0.032 ppm for 10-min, 30-min, 1-h, 4-h, and 8-h durations, respectively. These values are consistent with those ob- tained by adjusting the AEGL-3 values. 5.5. Data Analysis for AEGL-3 5.5.1. Human Data Relevant to AEGL-3 No data on lethality in humans exposed to n-butyl isocyanate vapor were available. 5.5.2. Animal Data Relevant to AEGL-3 Lethality data on inhalation exposure to n-butyl isocyanate are only avail- able for rats exposed for 1 or 4 h (IRDC 1965; Haskell Laboratory 1968; Bayer AG 1978); lethality benchmarks from these studies are presented in Table 7-17. In addition to lethality studies, a pulmonary function study (Pauluhn et al. 1990) identified a nonlethal concentration of 14 ppm for a 4-h exposure. Table 7-19 compares these studies. The 1-h studies identified divergent LC50 and nonlethal concentrations, despite using similar group sizes. Likewise, the 4-h studies also had inconsistent results; 14 ppm was not lethal to male rats in the study by Pauluhn et al. (1990), whereas LC50 values of 15.6 and about 20 ppm were iden- tified in the studies by DuPont (Haskell Laboratory 1968) and Miles, Inc. (Bayer AG 1978). The Pauluhn et al. (1990) study was selected as the basis for deriving AEGL-3 values. The study was the only one to use HPLC analysis, a method that appears to be more reliable than either spectrophotometric methods or GC analy- sis. Furthermore, the study was published, and used large group sizes (20 per ex- posure). 5.5.3. Derivation of AEGL-3 Values The highest nonlethal concentration of 14 ppm in the 4-h rat study by Pauluhn et al. (1990) was selected as the point of departure for deriving AEGL-3 values. That study tested a larger number of rats and used a more reliable analytic 

Selected Monoisocyanates 231 technique (HPLC analysis) for measuring exposure concentrations than other stud- ies. An interspecies uncertainty factor of 3 was applied on the basis of LC50 data on the related compound methyl isocyanate, which showed relatively little inter- species differences (about a 2-fold difference in 6-h LC50s among rats, mice, and guinea pigs; see Section 2.4). An intraspecies uncertainty factor was 10 was also applied. Both uncertainty factors are consistent with those applied in the derivation of AEGL-3 values for methyl isocyanate (NRC 2003). Finally, a modifying factor of 3 was applied to account for potential developmental toxicity of n-butyl isocya- nate on the basis of data on methyl isocyanate. Time scaling was performed using the equation Cn × t = k. Default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used. Because of uncertainties associated with extrapolat- ing a 4-h point of departure to a 10-min value, the 30-min AEGL-3 values was adopted as the 10-min value. AEGL-3 values for n-butyl isocyanate are present- ed in Table 7-20, and the calculations are presented in Appendix A. 5.6. SUMMARY OF AEGLS 5.6.1. AEGL Values and Toxicity End Points AEGL-1 values are not recommended for n-butyl isocyanate or any of the other selected monoisocyanates because of insufficient data and the potential for systemic effects to occur at concentrations below those associated with irritation. AEGL-2 values for n-butyl isocyanate were derived by dividing the AEGL-3 val- ues by 3, because of the lack of reliable data on AEGL-2 end points. A concentra- tion causing no mortality in rats exposed for 4 h (Pauluhn et al. 1990) was used as the basis of AEGL-3 values for n-butyl isocyanate. AEGL values are summarized in Table 7-21. TABLE 7-19 Comparison of Lethality Data on n-Butyl Isocyanate Highest Nonlethal Concentration Sampling and Follow-up No. of (or Lowest Lethal LC50 Study Analysis Method (days) Animals Concentration) (ppm) (ppm) 1 hour IRDC 1965 Spectrophotometry 14 6 males 1.4 3.8 Bayer AG 1978 FID 14 5 males, 39 105 5 females Bayer AG 1978 FID 28 10 males None (94) ~125 10 females None (94) ~150 4 hours Haskell Impinger/GC 30 6 males None (12.5) 15.6 Laboratory 1968 Bayer AG 1978 FID 14 5 males None (22) <22.5 5 females None (22) 18 Pauluhn et al. 1990 HPLC 28 20 males 14 Not applicable 

232 Acute Exposure Guideline Levels TABLE 7-20 AEGL-3 Values for n-Butyl Isocyanate 10 min 30 min 1h 4h 8h 0.31 ppm 0.31 ppm 0.25 ppm 0.16 ppm 0.078 ppm (1.3 mg/m3) (1.3 mg/m3) (1.0 mg/m3) (0.65 mg/m3) (0.32 mg/m3) TABLE 7-21 AEGL Values for n-Butyl Isocyanatea Classification 10 min 30 min 1h 4h 8h AEGL-1b NR NR NR NR NR (nondisabling) AEGL-2 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm (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 (lethal) (1.3 mg/m3) (1.3 mg/m3) (1.0 mg/m3) (0.65 mg/m3) (0.32 mg/m3) a When more than one of the monoisocyanates is detected at a scene, the lowest AEGL value should be applied to the sum total concentration of all detected monoisocyanates because of a presumed common mode of action. b NR, not recommended. On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to n-butyl isocyanate may be associated with systemic toxicity at concen- trations below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 value are without effect. 5.6.2. Other Exposure Criteria Standards and guidelines for exposure to n-butyl isocyanate are presented in Table 7-22. Emergency response planning guidelines (ERPGs) for n-butyl isocyanate were derived in 1994 (AIHA 2011). The 1-h ERPG-1 value was based on an industrial hygiene survey (Haskell Laboratory 1989); this study was not used to derive AEGL values because it lacked adequate documentation. The ERPG-2 was also based on the survey study, which concluded that 0.05 ppm was not expected to impede escape. Finally, the ERPG-3 of 1 ppm is based on a calculated LC01 of 6.8 ppm for rats exposed to n-butyl isocyanate for 4 h (Haskell Laboratory 1968). As noted earlier in this chapter, these data were not used to derive AEGL values because of the uncertainty associated with the ana- lytic method (gas chromatograph) used to measured n-butyl isocyanate. 6. PHENYL ISOCYANATE 6.1. Human Toxicity Data No information regarding lethality, nonlethal toxicity, developmental tox- icity, genotoxicity, or carcinogenicity in humans after acute inhalation exposure to phenyl isocyanate was available. 

Selected Monoisocyanates 233 TABLE 7-22 Standards and Guidelines for n-Butyl Isocyanate Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm AEGL-3 0.31 ppm 0.31 ppm 0.25 ppm 0.16 ppm 0.078 ppm a ERPG-1 (AIHA) 0.01 ppm ERPG-2 (AIHA) 0.05 ppm ERPG-3 (AIHA) 1.0 ppm a ERPG (emergency response planning guidelines, American Industrial Hygiene Associa- tion) (AIHA 2011) ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor. ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversi- ble or other serious health effects or symptoms that could impair an individual’s ability to take protective action. ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life- threatening health effects. 6.2. Animal Toxicity Data 6.2.1. Acute Lethality Four albino rats exposed to phenyl isocyanate at a concentration of 0.33 mg/L (about 67 ppm) died after 1 h (2 rats), 2 h, and 2.5 h of exposure (SA 1954). In a second experiment, all rats survived exposure to phenyl isocyanate at 0.14 mg/L (about 29 ppm) for 4 h. Concentrations were determined by spectrophoto- metric analysis and comparison with a standard curve. No other information was provided in the report. Groups of four male and four female Alderley Park rats were exposed for 1 h to phenyl isocyanate (purity not specified) in a 17-L chamber at concentrations of 0.358, 1.325, 1.45, 2.167, 4.368, 6.08, 7.942, or 9.187 ppm, and were observed for 14 days (see Table 7-23) (ICI 1977; Mobay 1978). Concentrations of phenyl isocyanate was determined by a colorimetric technique (Marcali method; phenyl isocyanate content in absorption media determined by spectrophotometric analysis and comparison with a standard curve). The 1-h LC50 was estimated to be 3.9 ppm (95% CI: 2.9-5.3 ppm). Most deaths occurred 8-12 days after exposure. In a pre- liminary summary of this study, Mobay Corp. (1978) reported that the chamber concentrations had been analyzed by both the Marcali method and by HPLC anal- ysis, and that the two methods gave divergent results. According to Mobay (1978), the HPLC values were closer to the calculated concentrations. The original report (ICI 1977) did not discuss analysis of the chamber concentrations by HPLC, and 

234 Acute Exposure Guideline Levels Mobay (1978) did not provide individual exposure concentrations measured by HPLC. On the basis of the HPLC results, Mobay (1978) estimated a 1-h LC50 of 12.6 ppm (95% CI: 8.4-19.0 ppm). Uncertainty with respect to the reliability of the Marcali method for analyzing exposure concentrations, coupled with lack of doc- umentation on the exposure concentrations estimated by HPLC analysis, limits the use of this study for calculating AEGL values. TABLE 7-23 Lethality in Rats Exposed to Phenyl Isocyanate for 1 Hour Concentrationa (ppm) Lethality Comments 0.358 0/8 No clinical signs; small hemorrhagic sites on lungs of one male and one female found at necropsy. 1.325 0/8 No clinical signs in females; slight body weight loss and signs of toxicity (piloerection, wheezing, hunched posture) in males; four males with evidence of lung damage at necropsy; all animals had increased lung weight. 1.45 0/8 Slight wheezing after exposure; reversible body weight loss in males; no clinical signs in females; no significant findings at necropsy. 2.167 2/4 males Males: deaths on days 5 and 12; increased lung weight 2/4 females and focal hemorrhage. Females: deaths on days 7 and 12; increased lung weight and focal hemorrhage, 4.368 1/4 males Males: death on day 8; respiratory distress; pulmonary 3/4 females hemorrhage; air in intestines; increased lung weight. Females: deaths on days 4, 5, 8; respiratory distress; pulmonary hemorrhage; air in intestines; increased lung weight. 6.08 2/4 males Males: deaths on days 10 and 12; labored respiration; 2/4 females hunched posture; focal pulmonary hemorrhage; air in intestines; increased lung weight. Females: deaths on days 8 and 13; labored respiration; hunched posture; focal pulmonary hemorrhage; air in intestines; increased lung weight. 7.942 4/4 males Males: deaths on days 7, 9, and 8 (two rats); signs of severe 4/4 females respiratory distress; all animals moribund; focal pulmonary hemorrhage; air in intestines; increased lung weight. Females: deaths on days 8 (two rats) and 12 (two rats); signs of severe respiratory distress; all animals moribund; focal pulmonary hemorrhage; air in intestines; increased lung weight. 9.187 4/4 males Males: deaths on days 1, 9, 11, and 14; severe respiratory 3/4 females distress; moribund; necropsy findings indicative of severe pulmonary damage. Females: deaths on days 6, 9, and 14; severe respiratory distress; moribund; necropsy findings indicative of severe pulmonary damage. a Analyzed by Marcali method. Sources: Adapted from ICI 1977 and Mobay 1978. 

Selected Monoisocyanates 235 In an experiment in which groups of five male and five female Wistar rats were exposed to a saturated atmosphere of phenyl isocyanate (about 1,600 ppm at 20°C) for 3, 10, or 30 min, all rats died (Bayer AG 1981). Time to death was in- versely related to exposure duration: 8-11 days for the 3-min exposure, 3-24 h for the 10-min exposure, and 32-59 min for the 30-min exposure. The observation period was 14 days. The only gender-related differences in findings occurred in the group exposed for 10 min; male rats died as early as 3 h after exposure where- as all female rats died at 24 h. Signs of toxicity (ocular and nasal irritation and respiratory distress) appeared very quickly, and rats that survived the first week experienced body weight loss. Necropsy findings confirmed pulmonary damage. In an acute inhalation toxicity study in rats, groups of five male and five fe- male young adult Wistar rats were exposed to phenyl isocyanate (99.9% pure) for 4 h at measured concentrations of 0.7, 5.4, 15.2, 11.7, 27.9, 47.1, and 87.8 mg/m3 (equivalent to 0.14, 1.1, 3.1, 2.4, 5.7, 9.7, and 18 ppm) (Bayer AG 1991a). Con- trols were exposed to clean air only. On the basis of clinical signs and gross pa- thology findings, the primary target of toxicity appeared to be the respiratory tract. Most rats died within 9 days. The investigators reported a 4-h LC50 of 22 mg/m3 (95% CI: 19-27 mg/m3) for males and females combined; mortality data are pre- sented in Table 7-24. No mortality occurred at concentrations of 0.7 and 5.4 mg/m3 (0.14 and 1.1 ppm, respectively). In summary, lethality data for phenyl isocyanate vapor are only available for rats. Lethality benchmarks for phenyl isocyanate are summarized in Table 7-25. 6.2.2. Nonlethal Toxicity In the 4-h study of phenyl isocyanate in rats (Bayer AG 1991a) described in Section 6.2.1, no clinical signs of toxicity were observed at 0.7 mg/m3 (0.14 ppm). Exposure at 5.4 mg/m3 (1.1 ppm) resulted in slightly slowed and labored breathing in some rats. At 11 and 15.2 mg/m3 (2.4 and 3.1 ppm), these symp- toms were accompanied by unkempt ruffled fur, coughing sounds, serous nasal secretions, and decreased locomotor activity, tachypnea, cyanosis, high-stepping gait, and emaciated appearance; one death occurred among the 20 rats exposed at these two concentrations. Rats in the highest exposure groups (27.9 mg/m3 [5.7 ppm] and higher), which experienced significant mortality, also exhibited rattling sounds, lethargy, and prostration. Reflex testing on the day of exposure or shortly thereafter revealed no signs of neurological effects. Marginal hypo- thermia was noted in rats exposed to phenyl isocyanate at 15.2 mg/m3; higher concentrations were associated with marked hypothermia as well as depressed body weight. At necropsy, inflated lungs were found in rats exposed at 15.2 mg/m3 and higher that survived the observation period. Rats that died before the observation period ended had inflated, edematous, mucous-filled lungs; hydro- thorax; reddened nasal areas; bloody mucous-filled gastrointestinal tracts; red- dened mucosa of the small intestines; pale liver, spleen, and kidneys; and lobular appearance of the liver. 

236 Acute Exposure Guideline Levels TABLE 7-24 Lethality in Rats Exposed to Phenyl Isocyanate for 4 Hours Exposure Mortality Concentration (ppm) Females Males Total 0.14 0/5 0/5 0/10 1.1 0/5 0/5 0/10 2.4 0/5 1/5 1/10 3.1 0/5 0/5 0/10 5.7 3/5 4/5 7/10 9.7 5/5 5/5 10/10 18 5/5 5/5 10/10 a Analyzed by high performance liquid chromatography. Source: Bayer AG 1991a. TABLE 7-25 Summary of Rat Lethality Benchmarks for Phenyl Isocyanate Study (analytic method) Lethality Benchmark Comments SA1954 (not specified) 1-2.5 h at 67 ppm 100% lethality 4 h at 29 ppm No deaths. ICI 1977; Mobay 1978 1-h LC50: 12.6 ppm Deaths at 8-12 d post-exposure (Marcali method and HPLC) (by HPLC) or 3.9 ppm (by Marcali method) Bayer AG 1991a (HPLC) 4-h LC50: 4.6 ppm Most deaths at 9 d post-exposure Bayer AG 1981 3 min at 1,600 ppm 10/10 died at 8-11 d (saturated vapor; not measured) 10 min at 1,600 ppm 10/10 died at 3-24 h 30 min at 1,600 ppm 10/10 died at 32-59 min In a pilot study by Pauluhn et al. (1995), groups of four male Wistar rats exposed (nose-only) to analytically determined phenyl isocyanate concentrations of 0, 1.9, 5.14, or 12.92 mg/m3 (0, 0.4, 1.1, and 2.7 ppm) for 45 min exhibited a concentration-related decrease in respiratory rate (approximately 20-50% de- crease relative to controls). On the basis of data presented graphically, the high- est exposure (12.92 mg/m3) resulted in a decrease in respiratory rate of about 50%, suggesting that the RD50 for phenyl isocyanate in rats is about 13 mg/m3 (2.7 ppm). The investigators reported an estimated threshold exposure for upper respiratory tract sensory irritation of 1.1 mg/m3 (0.2 ppm). A bradypnoic re- sponse was observed, but no evidence of changes in minute volume or tidal vol- ume were found. 6.2.3. Repeated Exposure Groups of 10 male and 10 female young-adult Wistar rats were exposed to phenyl isocyanate at 0, 0.12, 0.57, or 3.14 mg/m3 (0, 0.03, 0.1, or 0.7 ppm) for 6 

Selected Monoisocyanates 237 h/day for 5 days, and were observed for 3 weeks (Bayer AG 1991b). Concentra- tions of phenyl isocyanate were determined by HPLC analysis. No rats died at any concentration. No significant clinical signs were observed in the rats ex- posed at 0.03 or 0.1 ppm, and no effects on body weight or rectal temperature were found. Rats exposed at 0.7 ppm exhibited serous nasal discharge but had no cumulative effects. Lung lavage fluid and LDH analysis on days 7-8 of the experiment revealed no significant treatment-related effects in the 0.7-ppm group. Although there were no observations reported after just one exposure, results of this study indicated that multiple 6-h exposures to phenyl isocyanate at 0.1 ppm were without serious effect and multiple exposures at concentrations as high as 0.7 ppm did not result in significant toxicologic consequences. In a study by ICI (1980), groups of eight male and eight female Alderley Park, Wistar-derived rats were exposed to phenyl isocyanate at concentrations of 0.05 ppm or 0.5 ppm for 6 h/day for 11 days. The original protocol specified a 3-week study duration, but severe respiratory distress in the rats necessitated a shorter duration. Control groups included rats exposed to clean air or petroleum ether (the diluent used with the test article). Test atmospheres were generated by heating a known amount of phenyl isocyanate and diluting the vapor with petro- leum ether. Exposures were conducted in 60-L Perspex chambers that allowed for individual housing of the rats. Airflow was 15-45 L/min depending on the exposure group. Phenyl isocyanate concentrations were determined by the Mar- cali method, and were found to vary from the target concentrations by 25% or more. Rats in the control groups and the 0.05-ppm group exhibited no clinical signs and results of post-mortem exams were unremarkable. Two rats in the 0.5- ppm group died (on days 9 and 11), and most exhibited signs of respiratory dis- tress and overall poor condition as early as the first exposure day. The investiga- tors concluded that, under the conditions of this experiment, 0.05 ppm was close to a no-effect level. However, uncertainty with respect to the reliability of the Marcali analytic method limits the utility of this study for deriving AEGL val- ues. In a 2-week study, groups of 20 male Wistar rats were exposed (nose- only) for 6 h/day, 5 days/week to phenyl isocyanate at concentrations of 0, 1.04, 4.1, 7.18, or 10.39 mg/m3 (0, 0.2, 0.8, 1.5, or 2.1 ppm) (Pauluhn et al. 1995). With the exception of Goblet cell hyperplasia in the nasal and paranasal regions and main bronchi of rats in the 4-mg/m3 group, the incidences of histopathologic lesions in rats of the 1- or 4-mg/m3 groups was not significantly different than controls. Rats in these groups were free of clinical signs. Findings in the two highest exposure groups were indicative of significant airway injury and decre- ments in pulmonary function consistent with the clinical signs of respiratory- tract irritation. Most of the signs observed in the 7- and 10-mg/m3 groups re- gressed during the first post-exposure week, although sporadic recurrence of irregular breathing patterns and wheezing was observed. Necropsy findings in these groups included macroscopic lung lesions (hepatoid foci and red areas or complete redness of the lung surface) and pleural adhesions. 

238 Acute Exposure Guideline Levels 6.2.4. Developmental and Reproductive Effects No information regarding the developmental and reproductive toxicity of phenyl isocyanate vapor in animals was available. 6.2.5. Genotoxicity Phenyl isocyanate was not toxic in Salmonella at concentrations of 2,500- 12,500 µg/plate. There was no significant evidence of mutagenic effects in Sal- monella/microsome tests (Bayer AG 1980b). Results of a mouse micronucleus test revealed no evidence of a clastogenic effect from phenyl isocyanate at 30 mg/kg (Bayer AG 1990). 6.2.6. Carcinogenicity No information regarding the carcinogenicity of phenyl isocyanate vapor in animals was available. 6.3. Data Analysis for AEGL-1 6.3.1. Human Data Relevant to AEGL-1 No data regarding AEGL-1 severity effects in humans exposed to phenyl isocyanate are available. 6.3.2. Animal Data Relevant to AEGL-1 Pauluhn et al. (1995) estimated a threshold for upper respiratory tract sen- sory irritation of 1.1 mg/m3 (0.2 ppm) in a study of Wistar rats exposed to phe- nyl isocyanate for 45 min. A bradypnoic response was observed, but no evi- dence of changes in minute volume or tidal volume was found. In a follow-up multiple exposure study (6 h/day, 5 days/week for 2 weeks), rats exposed to phenyl isocyanate at concentrations up to 0.2 ppm had no discernible effects (Pauluhn et al. 1995). The incidence of histopathologic lesions in the 1- or 4- mg/m3 (0.2 or 0.8 ppm) groups was not significantly different from those of con- trols. Rats in these exposure groups were also free of clinical signs. 6.3.3. Derivation of AEGL-1 Values AEGL-1 values were not derived for phenyl isocyanate. The available data suggest that phenyl isocyanate and the other three selected monisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 values were not derived for me- thyl isocyanate because it has poor warning properties, and because systemic 

Selected Monoisocyanates 239 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 for phenyl isocyanate. Absence of AEGL-1 values does not imply that concentrations be- low the AEGL-2 values are without effect. 6.4. Data Analysis for AEGL-2 6.4.1. Human Data Relevant to AEGL-2 No information regarding AEGL-2 severity effects in humans following inhalation exposure to phenyl isocyanate was available. 6.4.2. Animal Data Relevant to AEGL-2 Studies with rats indicate that respiratory-tract irritation and subsequent tissue damage are the critical effects from exposure to phenyl isocyanate vapor. No rats died after exposure to phenyl isocyanate at 0.03, 0.1, or 0.7 ppm for 6 h/day for 5 days, and observed for 3 weeks (Bayer AG 1991b). No significant clinical signs were observed in rats exposed at 0.03 or 0.1 ppm, and no effects on body weight or rectal temperature were found. Rats exposed at 0.7 ppm ex- hibited serous nasal discharge but no cumulative effects. Lung lavage fluid and LDH analysis on days 7-8 revealed no significant treatment-related effects in the 0.7-ppm group. Although no observations were reported after just one exposure, results of this study indicated that multiple 6-h exposures to phenyl isocyanate at 0.1 ppm were without serious effect and multiple exposures to concentrations as high as 0.7 ppm did not result in significant toxicologic consequences. Pauluhn et al. (1995) reported that rats exposed to phenyl isocyanate up to 4 mg/m3 (0.8 ppm) for 6 h/day, 5 days/week for 2 weeks exhibited no clinical signs of toxici- ty, no gross lesions in the respiratory tract, no significant findings regarding BAL analysis, and no effects on organ and body weights. The only histopatho- logic finding was Goblet cell hyperplasia in the nasal and paranasal regions and main bronchi. In another study, hypothermia and respiratory-tract irritation were observed in rats exposed at 5 mg/m3 (1.1 ppm) for 4 h (Bayer AG 1991a). 6.4.3. Derivation of AEGL-2 Values Animal data relevant to AEGL-2 values were available for phenyl isocya- nate. However, those data would lead to 4- and 8-h AEGL-2 values that are very similar to AEGL-3 values (see below). Therefore, to provide adequate protec- tion, AEGL-3 values were divided by 3 to derive AEGL-2 values for phenyl isocyanate. This approach is recommended by NRC (2001) for compounds with a steep concentration-response relationship. Mortality data from a study of rats exposed to phenyl isocyanate for 4 h indicates a steep relationship; no rats died at 3.1 ppm and 70% died at 5.7 ppm (Bayer AG 1991a). AEGL-2 values for 

240 Acute Exposure Guideline Levels phenyl isocyanate presented in Table 7-26, and the calculations are presented in Appendix A. If AEGL-2 values were calculated on the basis of the available animal data for phenyl isocyanate, the most relevant point of departure would be the esti- mated threshold for respiratory-tract injury. In the Pauluhn et al. (1995) study, 0.8 ppm would be a no-effect level for AEGL-2 severity effects. AEGL-2 values could be calculated by applying a total uncertainty factor of 30 (3 for interspe- cies differences and 10 for intraspecies variability), applying a modifying factor of 3 (to account for potential developmental toxicity of n-butyl isocyanate on the basis of data for the related compound methyl isocyanate), and performing time scaling with the equation Cn × t = k (using default values of n = 3 for extrapola- tion to shorter durations and n = 1 for extrapolation to longer durations). This approach would results in 4- and 8-h AEGL-2 values of 0.01 and 0.007 ppm, respectively. Because these values are very close to the 4- and 8-h AEGL-3 val- ues of 0.018 and 0.009 ppm for this compound, this approach was not used to derive AEGL-2 values for phenyl isocyanate. 6.5. Data Analysis for AEGL-3 6.5.1. Human Data Relevant to AEGL-3 No information regarding AEGL-3 severity effects in humans following vapor exposure to phenyl isocyanate was available. 6.5.2. Animal Data Relevant to AEGL-3 Only rat lethality data are available for phenyl isocyanate. The candidate studies include a 1-h study using groups of four male and four female rats (ICI 1977; Mobay 1978) and a 4-h study using five male and five female rat (Bayer AG 1991a). ICI (1977) and Mobay (1978) reported different LC50 values, de- pending on the analytic technique used to measure phenyl isocyanate; an LC50 of 3.9 ppm measured by Marcali colorimetric analysis or 12.6 ppm measured by HPLC analysis. The highest nonlethal concentration was 1.45 ppm, as measured by the Marcali method. Uncertainty with respect to the reliability of the Marcali method for analyzing exposure concentrations, coupled with lack of documenta- tion on the exposure concentrations estimated by HPLC analysis, limited the use of this study for deriving AEGL-3 values. TABLE 7-26 AEGL-2 Values for Phenyl Isocyanate 10 min 30 min 1h 4h 8h 0.012 ppm 0.012 ppm 0.0096 ppm 0.0061 ppm 0.0030 ppm (0.058 mg/m3) (0.058 mg/m3) (0.047 mg/m3) (0.030 mg/m3) (0.015 mg/m3) 

Selected Monoisocyanates 241 In the Bayer AG (1991a) study, groups of five male and five female young-adult Wistar rats were exposed to phenyl isocyanate for 4 h at concentra- tions of 0.7, 5.4, 15.2, 11.7, 27.9, 47.1, and 87.8 mg/m3 (0.14, 1.1, 3.1, 2.4, 5.7, 9.7, and 18 ppm). Concentrations were determined by HPLC analysis. The in- vestigators reported a 4-h LC50 of 22 mg/m3 (95% CI: 19-27 mg/m3); the highest nonlethal concentration was 5.4 mg/m3. Benchmark dose modeling of the data resulted in BMCL05 (benchmark concentration, 95% confidence limit with a 5% response) and BMC01 (benchmark concentration with 1% response) estimates of 1.64 and 1.73 ppm, respectively. This study was selected for use in deriving AEGL-3 values for phenyl isocyanate. Monsanto (SA 1954) reported a nonlethal concentration of 29 ppm for phenyl isocyanate in a 4-h study of four rats; however, this study was not con- sidered as a basis for deriving AEGL values because the number of animals test- ed was small, the sex and strain of rat were not specified, and no additional de- tails were provided in the report. In addition, the nonlethal concentration in this study was much higher than concentrations associated with lethality (3.1 ppm and higher) in a later study with better documentation (Bayer AG 1991a). 6.5.3. Derivation of AEGL-3 Values The 4-h BMCL05 value of 1.64 ppm calculated from the rat lethality data reported by Bayer AG (1991a) was used as the basis for deriving AEGL-3 val- ues for phenyl isocyanate. This point of departure is supported by data from a study of repeated 6-h exposures to phenyl isocyanate, in which 2.1 ppm was not lethal to 20 male rats exposed for 2 weeks (Pauluhn et al. 1995). Interspecies and intraspecies uncertainty factors of 3 and 10, respectively, were applied. An interspecies uncertainty factor of 3 was considered appropriate on the basis of mortality data on the related compound methyl isocyanate that indicated limited species differences; about a two-fold difference in 6-h LC50s for rats, mice, and guinea pigs was found (see Section 2.4). A factor of 3 is also consistent with that used for deriving AEGL values for methyl isocyanate. A factor of 10 was ap- plied to account for intraspecies variability, and was also consistent with the factor applied in the derivation of AEGL-3 values for methyl isocyanate (NRC 2003). Finally, a modifying factor of 3 was applied to account for potential de- velopmental toxicity of phenyl isocyanate on the basis of data on methyl isocya- nate. Time scaling was performed using the equation Cn × t = k, with default values of n =1 for extrapolating to longer durations and n = 3 for extrapolating to shorter durations. Because of the uncertainties associated with extrapolating a 4-h point of departure to a 10-min value, the 30-min AEGL-3 was adopted as the 10-min value. AEGL-3 values for phenyl isocyanate are presented in Table 7-27, and the calculations are presented in Appendix A. 

242 Acute Exposure Guideline Levels 6.6. Summary of AEGLs 6.6.1. AEGL Values and Toxicity End Points AEGL-1 values are not recommended for phenyl isocyanate because of in- sufficient data, and because of the potential for systemic effects to occur at con- centrations below those associated with irritation. Although data on AEGL-2 end points for phenyl isocyanate were availa- ble, calculations using those data would result in AEGL-2 values very close to AEGL-3 values. Therefore, AEGL-2 values were derived from the AEGL-3 values for phenyl isocyanate by dividing them by 3 to provide adequate protec- tion. The BMCL05 calculated using data from a 4-h lethality study (Bayer AG 1991a) was used as the point of departure for AEGL-3 values for phenyl isocya- nate. AEGL values for phenyl isocyanate are presented in Table 7-28. 6.6.2. Other Exposure Criteria Only two exposure guidelines for phenyl isocyanate were found. The Swedish Work Environment Authority (SWEA 2005) has a level limit value (occupational limit for one working day) of 0.005 ppm and a 5-min ceiling value (occupational limit for a 5-min period) of 0.01 ppm. TABLE 7-27 AEGL-3 Values for Phenyl Isocyanate 10 min 30 min 1h 4h 8h 0.036 ppm 0.036 ppm 0.029 ppm 0.018 ppm 0.0091 ppm (0.18g (0.18 mg/m3) (0.14 mg/m3) (0.088 mg/m3) (0.044 mg/m3) TABLE 7-28 AEGL Values for Phenyl Isocyanatea Classification 10 min 30 min 1h 4h 8h AEGL-1b NR NR NR NR NR (nondisabling) AEGL-2 0.012 ppm 0.012 ppm 0.0096 ppm 0.0061 ppm 0.0030 ppm (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 (lethal) (0.18 mg/m3) (0.18 mg/m3) (0.14 mg/m3) (0.088 mg/m3) (0.044 mg/m3) 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 detected monoisocyanates because of a presumed common mode of action. Phenyl isocyanate has shown dermal sensitizing ef- fects. Its respiratory sensitizing potential is unknown. Individuals who have a strong reac- tion might not be protected within the definition of effects for each level. b NR, not recommended. On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to phenyl isocyanate may be associated with systemic toxicity at concentra- tions below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. 

Selected Monoisocyanates 243 7. REFERENCES AIHA (American Industrial Hygiene Association). 2011. Current ERPG Values. The AIHA 2011 Emergency Response Planning Guidelines and Workplace Environ- mental Exposure Level Handbook. American Industrial Hygiene Association, Fair- fax, VA. Andersson, N., M.K. Muir, V. Mehra, and A.G. Salmon. 1988. Exposure and response to methyl isocyanate: Results of a community based survey in Bhopal. Br. J. Ind. Med. 45(7):469-475. ANPON (Jiangsu Anpon Electrochemical Company, Ltd). 2008. n-Butyl Isocynate: Product Description [online]. Available: http://anpon.en.alibaba.com/product/l0276009/5102 6270/Intermediate~ChemicalslN_Buty [accessed Jan. 25, 2008]. Bayer AG. 1978. n-Butylisocyanat: Untersuchungen zur aktuen Toxizität. Report No. 7442/3. Bayer AG Institut für Toxikologie, Wuppertal-Elberfeld, Germany. April 7, 1978. Submitted to EPA by Miles Inc., Pittsburg, PA with Cover Lettar Dated 8/10/92. EPA Document No. 88-920005842. Microfiche No.OTS0543303. Bayer AG. 1980a. Cyclohexylisocyanat Gewerbetoxikologische Untersuchungen. Report No. 9152/5. Bayer AG Institut für Toxikologie, Wuppertal-Elberfeld, Germany. May 13, 1980. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Let- ter Dated 12/10/90. EPA Document No. 86-910000200. Microfiche No. OTS0528 432. Bayer AG. 1980b. Phenylisocyanat: Salmonella/Mikrosmen-Test zur Untersuchung auf Punktmutagene Wirkung. Report No. 9170/3. Bayer AG Institut für Toxikologie, Wuppertal, Germany. May 20, 1980. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Letter Dated 12/10/90. EPA Document No. 86-910000 199. Microfiche No. OTS0528431. Bayer AG. 1981. Phenyl Isocyanat: Untersuchungen zur Gewerbetoxikologie. Report No. 9694/5. Bayer AG Institut für Toxikologie, Wuppertal-Elberfeld, Germany. January 20, 1981. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Let- ter Dated 12/10/90. EPA Document No. 86-910000198. Microfiche No. OTS052 8430. Bayer AG. 1990. Phenylisocyanate: Micronucleus Test on the Mouse. Study No. T6033839. Report No. 19566. Bayer AG. Fachbereich Toxicology, Wuppertal, Germany. September 9, 1990. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Letter Dated 12/27/90. EPA Document No. 86-10000575. Microfiche No. OT S0530311. Bayer AG. 1991a. Phenylisocyanat: Untersuchungen zur akuten Inhalationstoxizität an der Ratte. Study No. T7037386. Report No. 20354. Bayer AG Institut für Toxikologie, Wuppertal, Germany. June 12, 1991. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Letter Dated 8/16/91. EPA Document No. 88-910000236. Microfiche No. OTS0533666. Bayer, AG. 1991b. Phenylisocyanate: Untersuchungen zur orientierenden subakuten Inhalationstoxizität an der Ratte. Study No. T6039581. Report No. 20132. Bayer AG Institut für Toxikologie, Wuppertal, Germany. March 28, 1991. Submitted to EPA by Mobay Corporation, Pittsburgh, PA. EPA Document No. 86-910000828. Microfiche No. OTS0530419. Bucher, J.R., B.N. Gupta, B. Adkins, Jr., M. Thompson, C.W. Jameson, J.E. Thigpen, and B.A. Schwetz. 1987. Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies. Environ. Health Perspect. 72:53-61. 

244 Acute Exposure Guideline Levels Crawford, C.R., and R.H. Anderson. 1974. Acute Toxicity Studies of Cyclohexyl Isocya- nate. Report No. 40870. CHEMAGRO Division of Baychem Corporation, June 14, 1974. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Letter Dated 12/10/90. EPA Document No. 86-910000203. Microfiche No. OTS0528435. Eastman Kodak. 1964. Toxicity and Health Hazard Summary: Ethyl Isocyanate. Submitted to EPA by Eastman Kodak, Co., Rochester, NY with Cover Letter Dated 10/29/90. EPA Document No. 86-910000051. Microfiche No. OTS0528345. Eastman Kodak. 1990. Health and Safety Study on Cyclohexyl Isocyanate with Attach- ments. Submitted to EPA from Eastman Kodak Company, Rochester, NY with Cov- er Letter Dated 10/29/90. EPA Document No. 86-910000052. Microfiche No. OTS0 528346. Eastman Kodak. 1992. Initial Submission: Acute Inhalation Toxicity Test with Cyclohexyl Isocyanate in Rats with Cover Letter Dated 08/10/92. Eastman Kodak Co, Rochester, NY. EPA Document No. 88-920005123. Microfiche No. OTS0544097. Ferguson, J.S., M. Schaper, M.F. Stock, D.A. Weyel, and Y. Alarie. 1986. Sensory and pulmonary irritation with exposure to methyl isocyanate. Toxicol. Appl. Pharmacol. 82(2):329-335. Fowler, E.H., and D.E. Dodd. 1986. Acute inhalation studies with methyl isocyanate vapor. II. Respiratory tract changes in guinea pigs, rats, and mice. Fundam. Appl. Toxicol. 6(4):756-771. Haskell Laboratory. 1968. Acute Inhalation Toxicity of Isocyanic Acid Butyl Ester in Rats. Haskell Laboratory for Toxicology and Industrial Medicine Report No. 289-68. MR No. 581-243. December 19, 1968. Submitted to EPA by DuPont, Wilmington, DE with Cover Lettar Dated 10/15/92. EPA Document No. 88-9200010305. Microfiche No. OTS 0571701. Haskell Laboratory. 1982. Guinea Pig Respiratory Response to Isocyanates. Report No. 681-81. Du Pont de Nemours and Co., Haskell Laboratory for Toxicology and Indus- trial Medicine, Newark, DE. January 5, 1982. Submitted to EPA by DuPont, Wil- mington, DE, with Cover Lettar Dated 12/26/90. EPA Document No. 86-910000448. Microfiche No. OTS 0530206. Haskell Laboratory. 1989. Butyl Isocyanate Industrial Hygiene Survey. Letter to G.L. Kennedy, from D.P. Kelly, Central Research and Development Department, Haskell Laboratory for Toxicology and Industrial Medicine. January 4, 1989. Horspool, G.M., and J.E. Doe. 1977. Toluene Di-isocyanate: Acute Inhalation Toxicity in the Rat. Study No. HR0082. Report No. CTL/T/1097. Imperial Chemicals Industries Limited, Central Toxicology Laboratory, Macclesfield, Cheshire, UK. HSDB (Hazardous Substances Data Bank). 2007a. Ethyl Isocyanate. CAS No. 109-90-0. TOXNET, Specialized Information Services, U.S. Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [ac- cessed May 6, 2013]. HSDB (Hazardous Substances Data Bank). 2007b. n-Butyl Isocyanate. CAS No. 111-36-4. TOXNET, Specialized Information Services, U.S. Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [ac- cessed May 6, 2013]. HSDB (Hazardous Substances Data Bank). 2012. Phenyl Isocyanate. CAS No. 103-71-9. TOXNET, Specialized Information Services, U.S. Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [ac- cessed May 6, 2013]. 

Selected Monoisocyanates 245 HSDB (Hazardous Substances Data Bank). 2013. Ciclohexylisocyanate. CAS No. 3173-53- 3. TOXNET, Specialized Information Services, U.S. Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [ac- cessed May 6, 2013]. ICI (Imperial Chemical Industries, Ltd). 1977. Phenyl Isocyanate: Acute Inhalation Tox- icity. Study No. HR0081. Report No. CTL/T/1098. Imperial Chemical Industries, Ltd., Central Toxicology Laboratory, Macclesfield, Cheshire, UK. October 1977. Submitted to EPA by Mobay Corporation, Pittsburgh, PA with Cover Letter Dated 12/10/90. EPA Document No. 86-910000202. Microfiche No. OTS 0528434. ICI (Imperial Chemical Industries, Ltd). 1980. Phenyl Isocyanate: Subacute Inhalation Toxicity Study in Rats. Study No. MR0004. Report. No. CTL/T/1349. Imperial Chemical Industries, Ltd., Central Toxicology Laboratory, Macclesfield, Cheshire, UK. Submitted to EPA by Dow Chemical Company with Cover Letter Dated 06/04/92. EPA Document No. 88-920003412. Microfiche No. OTS0540063. IPCS (International Programme on Chemical Safety). 1997. Cyclohexyl isocyanate. Interna- tional Chemical Safety Card ICSC: 0856 [online]. Available: http://www.inchem. org/documents/icsc/icsc/eics0856.htm [accessed May 6, 2013]. IPCS (International Programme on Chemical Safety). 2002. Phenyl Isocyanate. Internation- al Chemical Safety Card ICSC: 1131 [online]. Available: http://www.inchem.org/ documents/icsc/icsc/eics1131.htm [accessed May 6, 2013]. IRDC (International Research and Development Corporation). 1965. Acute Inhalation Toxicity (LC50) in the Male Albino Rat: PAPI, MDI (Pure, Distilled), MDI (Precut, 3% total) and BUNCO (n-Butyl isocyanate). Report No. 203-004. January 29, 1965. Submitted to EPA by Dow Chemical Company, Midland. MI with Cov- er Lettar Dated 8/17/92. EPA Document No. 88-920005285. Microfiche No. OTS 0544179. Kamat, S.R., A.A. Mahashur, A.K. Tiwaris, P.V. Potdar, M. Gaur, V.P. Kolhatkar, P. Vaidya, D. Parmar, R. Rupwate, T.S. Chatterjee, K. Jain, M.D. Kelkar, and S.G. Kinare. 1985. Early observations on pulmonary changes and clinical morbidity due to the isocyanate gas leak at Bhopal. J. Postgrad. Med. 31(2):63-72. Kamat, S.R., M.H. Patel, P.V. Pradhan, S.P. Taskar, P.R. Vaidya, V.P. Kolhatkar, J.P. Gopalani, J.P. Chandarana, N. Dalal, and M. Naik. 1992. Sequential respiratory, psychologic, and immunologic studies in relation to methyl isocyanate exposure over two years with model development. Environ. Health Perspect. 97:241-253. Karol, M.H., and J.A. Kramarik. 1996. Phenyl isocyanate is a potent chemical sensitizer. Toxicol. Lett. 89(2):139-146. Kennedy, A.L., G. Singh, Y. Alarie, and W.E. Brown. 1993. Autoradiographic analyses of guinea pig airway tissues following inhalation exposure to 14C-labeled methyl isocyanate. Fundam. Appl. Toxicol. 20(1):57-67. Kimmerle, G., and A. Eben. 1964. On the toxicity of methyl isocyanate and its quantita- tive determination in air [in German]. Arch. Toxikol. 20:235-241. Litchfield, J.T., and F. Wilcoxon. 1949. Simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96(2): 99-113. Lorin, H.G., and P.E. Kulling. 1986. The Bhopal tragedy – what has Swedish disaster medicine planning learned from it? J. Emerg. Med. 4(4):311-316. Mellon Institute. 1963. The Feasibility of Using Methyl Isocyanate as a Warning Agent in Liquid Carbon Monoxide. Special Report 26-23. March 15, 1963. Submitted to EPA by Rhone-Poulenc, Inc., Princeton, NJ with Cover Letter Dated 12/7/90. EPA Document No. 86-910000271. Microfiche No. OTS0528503. 

246 Acute Exposure Guideline Levels Mellon Institute. 1970. Acute Inhalation Toxicity, Human Response to Low Concentrations, Guinea Pig Sensitization, and Cross Sensitization to Other Isocyanates. Special Re- port 33-19. March 6, 1970. Submitted to EPA by Rhone-Poulenc, Inc., Princeton, NJ with Cover Letter Dated 12/7/90. EPA Document No. 86-910000268. Microfiche No. OTS0528500. Misra, N.P., R. Pathak, K.J. Gaur, S.C. Jain, S.S. Yesikar, P.C. Manoria, K.N. Sharma, B.M. Tripathi, B.S. Asthana, H.H. Trivedi, V.K. Sharma, Y. Malhotra, A. Verma, D.K. Bhargava, and G. Batni. 1987. Clinical profile of gas leak victims in acute phase after Bhopal episode. Indian J. Med. Res. 86(suppl.):11-19. Mobay. 1961. Toxicity and Safe Handling of Isocyanates. Mobay Chemical Company, Pittsburgh, PA. EPA Document No. FYI-0794-1022. Microfiche No. OTS0001022. Mobay, 1978. Letter to EPA from Mobay Chemical Corporation Submitting Information on Phenyl Isocyanate with Attachments. June 8, 1978. EPA Document No. 88- 7800178. Microfiche No. 0200682. Nehez, M., G.W. Fischer, I. Nehez, H. Scheufler, and I. Desi. 1989. Investigations on the acute toxic, cytogenetic, and embroyotoxic activity of phenyl isocyanate and di- ethoxyphosphoryl isocyanate. Ecotoxicol. Environ. Saf. 17(2):258-263. Nemery, B., S. Sparrow, and D. Dinsdale. 1985. Methyl isocyanate: Thiosulphate does not protect. Lancet 326(8466):1245-1246. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2003. Methyl isocyanate. Pp. 384-443 in Acute Expo- sure Guideline Levels Selected Airborne Chemicals, Vol. 3. Washington, DC: Na- tional Academies Press. NRC (National Research Council). 2004. Toluene 2,4- and 2,6-diisocyanate. Pp. 198-249 in Acute Exposure Guideline Levels Selected Airborne Chemicals, Vol. 4. Wash- ington, DC: National Academies Press. OECD (Organization for Economic Co-Operation and Development). 2005. Investigation of High Production Volume Chemicals. SIDS Initial Assessment Profile: n-Butyl isocyanate, CAS Reg. No. 111-36-4. Organization for Economic Co-Operation and Development, Paris, France. Pauluhn, J., and A. Eben. 1991. Altered Lung Function in Rats after Subacute Exposure to n-Butyl Isocyanate. Bayer AG, Wuppertal, Germany. Submitted to EPA by Mobay Corporation, Pittsburgh, PA, with Cover Letter Dated 06/06/91. EPA Doc- ument No. 86-910000864. Microfiche No. OTS0530451. Pauluhn, J., A. Eben, and G. Kimmerle. 1990. Functional, biochemical, and histological evidence of airway obstruction in rats following a four-hour acute inhalation expo- sure to n-butyl isocyanate. Exp. Pathol. 40(4):197-203. Pauluhn, J., W. Rüngeler, and U. Mohr. 1995. Phenyl isocyanate-induced asthma in rats following a 2-week exposure period. Fundam. Appl. Toxicol. 24(2):217-228. Richter, R.H. 1986. Isocyanates. Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons, Inc. SA (Scientific Associates). 1954. Toxicological Investigations of Octadecyl Isocyanate and Phenyl Isocyanate. Monsanto Project No. SA-39. Scientific Associates, St. Louis, MO. June 17, 1954. Submitted to EPA by Monsanto Company, St. Louis, 

Selected Monoisocyanates 247 MO with Cover Letter Dated 08/11/92. EPA Document No. 88-920007667. Micro- fiche No. OTS0545863. Sigma Aldrich. 2012. Material Safety Data Sheet for Cyclohexyl Isocyanate. Sigma Aldrich [online]. Available: http://www.sigmaaldrich.com/catalog/ProductDetail.do?D7= 0&N5=SEARCH_CONCAT_PNO%7CBRAND_KEY&N4=C105198%7CALDRIC H&N25=0&QS=ON&F=SPEC [accessed May 6, 2013]. SWEA (Swedish Work Environment Authority). 2005. P. 46 in Occupational Exposure Limit Value and Measures against Air Contaminants. AFS 2005:17 [online]. Availa- ble: http://www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed May 7, 2013]. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality re- sponse relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309. Varma, D.R. 1989. Hydrogen cyanide and Bhopal. Lancet 2(8662):567-568. Varma, D.R., and I. Guest. 1993. The Bhopal accident and methyl isocyanate toxicity. J. Toxicol. Environ. Health 40(4):513-529. 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(1):93-101. Weill, H. 1987. Disaster at Bhopal: The accident, early findings and respiratory health outlook in those injured. Bull. Eur. Physiopathol. Respir. 23(6):587-590. Younger Laboratories. 1956. Toxicological Investigation of n-Butyl Isocyanate. Younger Laboratories, Saint Lous, MO. September 10, 1956. Monsanto Project No. Y-56-55. Submitted to EPA by Monsanto Chemical Company, Pittsburg, PA, with Cover Let- tar Dated 12/10/90. EPA Document No. 86-910000209. Microfiche No. OTS05 28441. Younger Laboratories, 1974. Toxicological Investigation of Cyclohexyl Isocyanate. Young- er Laboratories, Saint Louis, MO, October 31, 1974. Submitted to EPA by Mobay Corporation, Pittsburg, PA with Cover Letter Dated 12/10/90. EPA Document No. 86-910000204. Microfiche No. OTS0528436. Zoltán, G., and C.D. Klaassen. 2001. Mechanisms of toxicity. P. 35-82 in Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. 

248 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR SELECTED MONOISOCYANATES Ethyl Isocyanate Derivation of AEGL-1 Values AEGL-1 values were not derived for ethyl isocyanate because of insuffi- cient data. The available data suggest that ethyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 values were not derived for methyl isocyanate because it has poor warning prop- erties, 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for ethyl isocyanate. Absence of AEGL-1 values does not im- ply that concentrations below the AEGL-2 values are without effect. Derivation of AEGL-2 Values The toxicologic database on ethyl isocyanate was inadequate to derive AEGL-2 values. AEGL-2 values were determined by using the AEGL-2 values established for the related compound methyl isocyanate (NRC 2003) and divid- ing them by a modifying factor of 2 to account for the possibility that ethyl iso- cyanate might be more toxic than methyl isocyanate. Calculations: 10-min AEGL-2: 0.40 ppm ÷ 2 = 0.20 ppm 30-min AEGL-2: 0.13 ppm ÷ 2 = 0.065 ppm 1-h AEGL-2: 0.067 ppm ÷ 2 = 0.034 ppm 4-h AEGL-2: 0.017ppm ÷ 2 = 0.0085 ppm 8-h AEGL-2: 0.008 ppm ÷ 2 = 0.0040 ppm Derivation of AEGL-3 Values The toxicologic database on ethyl isocyanate was inadequate to derive AEGL-3 values. As discussed in Section 2.3 (Structure-Activity Relationships), ethyl isocyanate and the three other monoisocyanates considered in this chapter 

Selected Monoisocyanates 249 are structurally similar to and exert toxic effects comparable to methyl isocya- nate. AEGL-3 values were determined by using the AEGL-3 values established for methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2 to account for the possibility that ethyl isocyanate might be more toxic than me- thyl isocyanate. A comparison of the available lethality data on the two chemi- cals suggests that this approach results in sufficiently protective AEGL values. When groups of three rats were exposed to ethyl isocyanate for 6 h, all rats sur- vived at 27 ppm and no rats survived at 82 ppm. For comparison, the 6-h LC50 for methyl isocyanate in rats (6/sex) was 6.1 ppm (NRC 2003). Calculations: 10-min AEGL-3: 1.2 ppm ÷ 2 = 0.60 ppm 30-min AEGL-3: 0.40 ppm ÷ 2 = 0.20 ppm 1-h AEGL-3: 0.20 ppm ÷ 2 = 0.10 ppm 4-h AEGL-3: 0.050 ppm ÷ 2 = 0.025 ppm 8-h AEGL-3: 0.025 ppm ÷ 2 = 0.013 ppm Cyclohexyl Isocyanate Derivation of AEGL-1 Values AEGL-1 values were not derived for cyclohexyl isocyanate because of in- sufficient data. The available data suggest that cyclohexyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed le- thality, that are similar to those induced by methyl isocyanate (see Section 2.3). 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for cyclohexyl isocyanate. Absence of AEGL- 1 values does not imply that concentrations below the AEGL-2 values are with- out effect. Derivation of AEGL-2 Values The toxicologic database on cyclohexyl isocyanate was inadequate to de- rive AEGL-2 values. AEGL-2 values were determined by using the AEGL-2 values established for the related compound methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2 to account for the possibility that cy- clohexyl isocyanate might be more toxic than methyl isocyanate. 

250 Acute Exposure Guideline Levels Calculations: 10-min AEGL-2: 0.40 ppm ÷ 2 = 0.20 ppm 30-min AEGL-2: 0.13 ppm ÷ 2 = 0.065 ppm 1-h AEGL-2: 0.067 ppm ÷ 2 = 0.034 ppm 4-h AEGL-2: 0.017ppm ÷ 2 = 0.0085 ppm 8-h AEGL-2: 0.008 ppm ÷ 2 = 0.0040 ppm Derivation of AEGL-3 Values The toxicologic database on cyclohexyl isocyanate was inadequate to de- rive AEGL-3 values. AEGL-3 values were determined by using the AEGL-3 values established for methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2 to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocyanate. A comparison of the available le- thality data on the two chemicals suggests that this approach results in suffi- ciently protective AEGL values. When three rats were exposed to cyclohexyl isocyanate at 18 ppm for 6 h, one died on day 7 post-exposure and the other two were killed on day 8, presumably because of moribund condition. For compari- son, the 6-h LC50 for methyl isocyanate in rats is 6.1 ppm (NRC 2003). Calculations: 10-min AEGL-3: 1.2 ppm ÷ 2 = 0.60 ppm 30-min AEGL-3: 0.40 ppm ÷ 2 = 0.20 ppm 1-h AEGL-3: 0.20 ppm ÷ 2 = 0.10 ppm 4-h AEGL-3: 0.050 ppm ÷ 2 = 0.025 ppm 8-h AEGL-3: 0.025 ppm ÷ 2 = 0.013 ppm n-Butyl Isocyanate Derivation of AEGL-1 Values AEGL-1 values were not derived for n-butyl isocyanate because of insuf- ficient data. The available data suggest that n-butyl isocyanate and the three oth- er selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 

Selected Monoisocyanates 251 values were not derived for methyl isocyanate because it has poor warning prop- erties, 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for n-butyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. Derivation of AEGL-2 Values The toxicologic database on n-butyl isocyanate was inadequate to derive AEGL-2 values. In particular, the 4-h study by Pauluhn et al. (1990) lacked data on the incidence and severity of histopathologic findings. AEGL-2 values were determined by dividing the AEGL-3 values for n-butyl isocyanate by 3 (NRC 2001). This approach is justified by the steep concentration-response curve ob- served in mortality studies; no rats died after a 1-h exposure at 39 ppm, and 70% (7/10) died at 130 ppm (Bayer AG 1978). Calculations: 10-min AEGL-2: 0.31 ppm ÷ 3 = 0.10 ppm 30-min AEGL-2: 0.31 ppm ÷ 3 = 0.10 ppm 1-h AEGL-2: 0.25 ppm ÷ 3 = 0.083 ppm 4-h AEGL-2: 0.16 ppm ÷ 3 = 0.053 ppm 8-h AEGL-2: 0.078 ppm ÷ 3 = 0.026 ppm Derivation of AEGL-3 Values Key study: Pauluhn, J., A. Eben, and G. Kimmerle. 1990. Functional, biochemical, and histological evidence of airway obstruction in rats following a four-hour acute inhalation exposure to n-butyl isocyanate. Exp. Pathol. 40:197-203. Critical effect: Highest nonlethal concentration (14 ppm) in a 4-h rat study. Study tested more animals and used a more reliable analytic method (HPLC analysis) to measure concentrations of n-butyl isocyanate than other studies. 

252 Acute Exposure Guideline Levels Time scaling: The exposure concentration-exposure duration relationship for many irritant and systemically acting vapors and gases may be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence data to determine an empirical value of n, default values of n = 1 for extrapolating to longer durations and n = 3 for extrapolating to shorter durations were used. The 10-min AEGL-3 value was set equal to the 30-min value because of the uncertainties associated with extrapolating a 4-h point of departure to a 10-min value (NRC 2001). (14 ppm)1 × 4 h = 56 ppm-h (14 ppm)3 × 4 h = 10,976 ppm-h Uncertainty factors: 3 for interspecies differences; 6-h LC50s for the related compound methyl isocyanate differed about two-fold between rats, mice, and guinea pigs (see Section 2.4). A factor of 3 is also consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). 10 for intraspecies variability; this factor is consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Modifying factor: 3 to account for potential developmental toxicity of n-butyl isocyanate, on the basis of data on methyl isocyanate. Calculations: 10-min AEGL-3: 0.31 ppm (set equal to the 30-min AEGL-3) 30-min AEGL-3: C3 × 0.5 h = 10,976 ppm-h C = 28 ppm 28 ppm ÷ 90 = 0.31 ppm 1-h AEGL-3: C3 × 1 h = 10,976 ppm-h C = 22 ppm 22 ppm ÷ 90 = 0.25 ppm 

Selected Monoisocyanates 253 4-h AEGL-3: 14 ppm ÷ 90 = 0.16 ppm 8-h AEGL-3: C1 × 8 h = 56 ppm-h C = 7 ppm 7 ppm ÷ 90 = 0.078 ppm Phenyl Isocyanate Derivation of AEGL-1 Values AEGL-1 values were not derived for phenyl isocyanate because of insuffi- cient data. The available data suggest that phenyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 values were not derived for methyl isocyanate because it has poor warning prop- erties, 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for phenyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. Derivation of AEGL-2 Values Data on phenyl isocyanate were not used to derive AEGL-2 value because they would lead to 4- and 8-h AEGL-2 values that are very similar to AEGL-3 values (see below). Therefore, AEGL-3 values for phenyl isocyanate were di- vided by 3 to derive AEGL-2 values. This approach is justified by the steep con- centration-response curve observed in mortality studies; in a 4-h study, no rats (0/10) died after exposure at 3.1 ppm and 70% (7/10) died after exposure at 5.7 ppm (Bayer AG 1991a). If AEGL-2 values were to be calculated from animal data for phenyl iso- cyanate, the point of departure would be a no-effect level of 0.8 ppm identified in a repeated exposure study (Pauluhn et al. 1995). An uncertainty factor of 3 for interspecies differences and a factor of 10 intraspecies variability would be ap- plied. Time scaling would be performed using the equation Cn × t = k, with de- fault values of n = 3 for extrapolating to shorter durations and n =1 for extrapo- lating to longer durations. This approach would lead to 4- and 8-h AEGL-2 values of 0.01 and 0.007 ppm, respectively. These values are very close to the AEGL-3 values of 0.018 and 0.009 ppm for this compound, so this approach was not used to derive AEGL values. Calculations: 10-min AEGL-2: 0.036 ppm ÷ 3 = 0.012 ppm 

254 Acute Exposure Guideline Levels 30-min AEGL-2: 0.036 ppm ÷ 3 = 0.012 ppm 1-h AEGL-2: 0.029 ppm ÷ 3 = 0.0096 ppm 4-h AEGL-2: 0.018 ppm ÷ 3 = 0.0061 ppm 8-h AEGL-2: 0.0091 ppm ÷ 3 = 0.0030 ppm Derivation of AEGL-3 Values Key study: Bayer, AG. 1991a. Phenyl isocyanate; Untersuchungen zur akuten inhalationstoxizität an der Ratte. Report No.. 20354. Study No. T7037386, Bayer AG Institut für Toxikologie, Wuppertal-Elberfeld, Germany. Critical effect: Estimated lethality threshold in rats (4-h BMCL05 of 1.64 ppm) Time scaling: The exposure concentration-exposure duration relationship for many irritant and systemically acting vapors and gases may be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence data to determine an empirical value of n, default values of n = 1 for extrapolating to longer durations and n = 3 for extrapolating to shorter durations were used. The 10-min AEGL-3 value was set equal to the 30-min value because of the uncertainties associated with extrapolating a 4-h point of departure to a 10-min value (NRC 2001). (1.64 ppm)1 × 4 h = 6.56 ppm-h (1.64 ppm)3 × 4 h = 17.644 ppm-h Uncertainty factors: 3 for interspecies differences; 6-h LC50s for the related compound methyl isocyanate differed about two-fold between rats, mice, and guinea pigs; see Section 2.4). A factor of 3 is also consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). 

Selected Monoisocyanates 255 10 for intraspecies variability; this factor is consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Modifying factor: 3 to account for potential developmental toxicity of phenyl isocyanate, on the basis of data on methyl isocyanate. Calculations: 10-min AEGL-3: Set equal to the 30-min AEGL-3 of 0.036 ppm 30-min AEGL-3: C3 × 0.5 h = 17.644 ppm-h C = 3.2 ppm 3.2 ppm ÷ 90 = 0.036 ppm 1-h AEGL-3: C3 × 1 h = 17.644 ppm-h C = 2.6 ppm 2.6 ppm ÷ 90 = 0.029 ppm 4-h AEGL-3: C × 4 h = 6.56 ppm-h C = 1.64 ppm 1.64 ppm ÷ 90 = 0.018 ppm 8-h AEGL-3: C × 8 h = 6.56 ppm-h C = 0.82 ppm 0.82 ppm ÷ 90 = 0.0091 ppm 

256 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR SELECTED MONOISOCYANATES Derivation Summary for Ethyl Isocyanate AEGL-1 Values for Ethyl Isocyanate 10 min 30 min 1h 4h 8h NR NR NR NR NR Data adequacy: AEGL-1 values were not derived for ethyl isocyanate because of inadequate data. The available data suggest that ethyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for ethyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. AEGL-2 Values for Ethyl Isocyanate 10 min 30 min 1h 4h 8h 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (0.58 mg/m3) (0.19 mg/m3) (0.099 mg/m3) (0.025 mg/m3) (0.012 mg/m3) Modifying factor: 2, to account for the possibility that ethyl isocyanate might be more toxic than methyl isocyanate. Data adequacy: The toxicologic database on ethyl isocyanate was inadequate to derive AEGL-2 values. AEGL-2 values were determined by using the AEGL-2 values established for the related compound methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2. AEGL-3 Values for Ethyl Isocyanate 10 min 30 min 1h 4h 8h 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (1.7 mg/m3) (0.58 mg/m3) (0.29 mg/m3) (0.073 mg/m3) (0.038 mg/m3) Modifying factor: 2, to account for the possibility that ethyl isocyanate might be more toxic than methyl isocyanate. Data adequacy: The toxicologic database for ethyl isocyanate was inadequate to derive AEGL-3 values. As discussed in Section 2.3 (Structure-Activity Relationships), ethyl isocyanate and the other three monoisocyanates considered in this chapter are structurally similar to and exert toxic effects comparable to methyl isocyanate. 

Selected Monoisocyanates 257 A comparison of the available lethality data on the chemicals suggests that use of methyl isocyanate as a surrogate for ethyl isocyanate and applying a modifying factor of 2 to account for potentially higher toxicity results in sufficiently protective AEGL values. 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. For comparison, the 6-h LC50 for methyl isocyanate in rats (6/sex) was 6.1 ppm (NRC 2003). Derivation Summary for Cyclohexyl Isocyanate AEGL-1 Values for Cyclohexyl Isocyanate 10 min 30 min 1h 4h 8h NR NR NR NR NR Data adequacy: AEGL-1 values were not derived for cyclohexyl isocyanate because of inadequate data. The available data suggest that cyclohexyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for cyclohexyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. AEGL-2 Values for Cyclohexyl Isocyanate 10 min 30 min 1h 4h 8h 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm (1.0 mg/m3) (0.33 mg/m3) (0.17 mg/m3) (0.043 mg/m3) (0.020 mg/m3) Modifying factor: 2, to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocyanate. Data adequacy: The toxicologic database for cyclohexyl isocyanate was inadequate to derive AEGL-2 values. AEGL-2 values were determined by using the AEGL-2 values established for the related compound methyl isocyanate (NRC 2003) and dividing them by a modifying factor of 2. AEGL-3 Values for Cyclohexyl Isocyanate 10 min 30 min 1h 4h 8h 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm (3.1 mg/m3) (1.0 mg/m3) (0.51 mg/m3) (0.13 mg/m3) (0.066 mg/m3) Modifying factor: 2, to account for the possibility that cyclohexyl isocyanate might be more toxic than methyl isocyanate. (Continued) 

258 Acute Exposure Guideline Levels AEGL-3 Values for Cyclohexyl Isocyanate Continued Data adequacy: The toxicologic database for cyclohexyl isocyanate was inadequate to derive AEGL-3 values. AEGL-3 values were determined by using the AEGL-3 values established for the related compound methyl isocyanate and dividing them by a modifying factor of 2. A comparison of the available lethality data on the two chemicals suggests that this approach results in sufficiently protective AEGL values. When three rats were exposed to cyclohexyl isocyanate at 18 ppm for 6 h, one died on day 7 post-exposure and the other two were killed on day 8, presumably because of moribund condition. For comparison, the 6-h LC50 for methyl isocyanate in rats is 6.1 ppm (NRC 2003). Derivation Summary for n-Butyl Isocyanate AEGL-1 Values for n-Butyl Isocyanate 10 min 30 min 1h 4h 8h NR NR NR NR NR Data adequacy: AEGL-1 values were not derived for n-butyl isocyanate because of inadequate data. The available data suggest that n-butyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for n-butyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. AEGL-2 Values for n-Butyl Isocyanate 10 min 30 min 1h 4h 8h 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm (0.41 mg/m3) (0.41 mg/m3) (0.34 mg/m3) (0.21 mg/m3) (0.11 mg/m3) Data adequacy: The toxicologic database on n-butyl isocyanate was inadequate to derive AEGL-2 values. In particular, the 4-h study by Pauluhn et al. (1990) lacked data on the incidence and severity of histopathologic findings. In the absence of adequate data, the AEGL-3 values for n-butyl isocyanate were divided by 3 to derive AEGL-2 values (NRC 2001). This approach is justified by the steep concentration- response curve observed in mortality studies; no rats died after a 1-h exposure at 39 ppm, and 70% (7/10) died at 130 ppm (Bayer AG 1978). 

Selected Monoisocyanates 259 AEGL-3 Values for n-Butyl Isocyanate 10 min 30 min 1h 4h 8h 0.31 ppm 0.31 ppm 0.25 ppm 0.16 ppm 0.078 ppm (1.3 mg/m3) (1.3 mg/m3) (1.0 mg/m3) (0.6 mg/m3) (0.32 mg/m3) Reference: Pauluhn, J., A. Eben, and G. Kimmerle. 1990. Functional, biochemical, and histological evidence of airway obstruction in rats following a four-hour acute inhalation exposure to n-butyl isocyanate. Exp. Pathol. 40:197-203. Test species/Strain/Sex/Number: Rat, Wistar, males, 20/group Exposure route/Concentrations/Durations: Inhalation; 0, 8, 25, 50 mg/m3 (0, 1.9, 5.9, 14 ppm) for 4 h Effects: No deaths (assessed up to 28 days post-exposure) End point/Concentration/Rationale: Estimated lethality threshold of 14 ppm (4-h nonlethal concentration). Study tested more animals, had a 28-day follow-up period, and used a more reliable analytic method (HPLC analysis) to measure concentrations of n-butyl isocyanate than other studies. Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 3, because 6-h LC50s for the related compound methyl isocyanate differed about two-fold between rats, mice, and guinea pigs (see Section 2.4). A factor of 3 is also consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Intraspecies: 10, is consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Modifying factor: 3, to account for potential developmental toxicity of n-butyl isocyanate on the basis of data on methyl isocyanate. Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; default values of n = 1 for extrapolating to longer durations and n = 3 for extrapolating to shorter durations. The 10-min AEGL-3 value was set equivalent to the 30-min value because of uncertainties associated with extrapolating a 4-h point of departure to a 10-min value (NRC 2001). Data adequacy: Although lethal and nonlethal toxicity data are available for only one species, data on the related compound methyl isocyanate provide support for the AEGL derivations. Derivation Summary for Phenyl Isocyanate AEGL-1 Values for Phenyl Isocyanate 10 min 30 min 1h 4h 8 hr NR NR NR NR NR Data adequacy: AEGL-1 values were not derived for phenyl isocyanate because of inadequate data. The available data suggest that phenyl isocyanate and the three other selected monoisocyanates exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3). AEGL-1 values were (Continued) 

260 Acute Exposure Guideline Levels AEGL-1 Values for Phenyl Isocyanate Continued 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 monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for phenyl isocyanate. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect. AEGL-2 Values for Phenyl Isocyanate 10 min 30 min 1h 4h 8h 0.012 ppm 0.012 ppm 0.0096 ppm 0.0061 ppm 0.0030 ppm (0.058 mg/m3) (0.058 mg/m3) (0.047 mg/m3) (0.030 mg/m3) (0.015 mg/m3) Data adequacy: AEGL-3 values for phenyl isocyanate were divided by 3 to derive AEGL-2 values (NRC 2001). This approach is justified by the steep concentration- response relationship; in a 4-h lethality study in rats, there was no mortality (0/10) at 3.1 ppm and 70% (7/10) mortality at 5.7 ppm (Bayer AG 1991a). If AEGL-2 values were to be calculated from animal data on phenyl isocyanate, the point of departure would be a no-effect level of 0.8 ppm identified in a repeated exposure study (Pauluhn et al. 1995). An uncertainty factor of 3 for interspecies differences and a factor of 10 intraspecies variability would be applied. Time scaling would be performed using the equation Cn × t = k, with default values of n = 3 for extrapolating to shorter durations and n =1 for extrapolating to longer durations. This approach would lead to 4- and 8-h AEGL-2 values of 0.01 and 0.007 ppm, respectively. These values are very close to the AEGL-3 values of 0.018 and 0.009 ppm for this compound, so this approach was not used to derive AEGL values. AEGL-3 Values for Phenyl Isocyanate 10 min 30 min 1h 4h 8h 0.036 ppm 0.036 ppm 0.029 ppm 0.018 ppm 0.0091 ppm (0.18 mg/m3) (0.18 mg/m3) (0.14 mg/m3) (0.088 mg/m3) (0.044 mg/m3) Reference: Bayer, AG. 1991a. Phenyl isocyanate; Untersuchungen zur akuten Inahlationstoxizität an der Ratte. Bercht- Nr. 20354. Studien-Nr. T7037386, Bayer AG Institut für Toxikologie. Test species/Strain/Sex/Number: Rat, Wistar, 4 males and 4 females per group Exposure route/Concentrations/Durations: Inhalation; 0, 2.1, 10.4, 20.8, 31.3, 64.6, 82.9, or 150.2 mg/m3 (0, 0.4, 2.2, 4.4, 6.6, 7.7, 17.4, and 31.3 ppm) for 4 h Effects: Lethality End point/Concentration/Rationale: Estimated lethality threshold (4-h BMCL05 1.64 ppm) Uncertainty factors/Rationale: Total uncertainty factor adjustment: 30 

Selected Monoisocyanates 261 Interspecies: 3, because 6-h LC50s for the related compound methyl isocyanate differed about two-fold between rats, mice, and guinea pigs (see Section 2.4). A factor of 3 is also consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Intraspecies: 10, is consistent with the one used for deriving AEGL-3 values for methyl isocyanate (NRC 2003). Modifying factor: 3, to account for potential developmental toxicity of phenyl isocyanate on the basis of data on methyl isocyanate. Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; default values of n = 1 for extrapolating to longer durations and n = 3 for extrapolating to shorter durations. The 10-min AEGL-3 value was set equivalent to the 30-min value because of uncertainties associated with extrapolating a 4-h point of departure to a 10-min value (NRC 2001). Data adequacy: Although lethal and nonlethal toxicity data are available for only one species, data on the related compound methyl isocyanate provide support for the AEGL values. 

262 Accute Exposure Guideline Levels AP PPENDIX C CATEGORY C PLOTS P FOR SELECTED S M MONOISOCY YANATES FIGUR RE C-1 Category y plot of toxicity y data and AEGL L values for ethyyl isocyanate. FIGUR RE C-2 Category y plot of toxicity y data and AEGL L values for cycllohexyl isocyanaate. 

Selecteed Monoisocyanates 2263 FIGUR RE C-3 Category y plot of toxicity y data and AEGL L values for n-buutyl isocyanate. FIGUR RE C-4 Category y plot of toxicity y data and AEGL L values for phennyl isocyanate. 

264 Acute Exposure Guideline Levels TABLE C-1 Data Used in Category Plot for Ethyl Isocyanate No. of Source Species Sex 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 0.20 10 AEGL AEGL-2 0.065 30 AEGL AEGL-2 0.034 60 AEGL AEGL-2 0.0085 240 AEGL AEGL-2 0.0040 480 AEGL AEGL-3 0.60 10 AEGL AEGL-3 0.20 30 AEGL AEGL-3 0.10 60 AEGL AEGL-3 0.025 240 AEGL AEGL-3 0.013 480 AEGL Eastman Rat 1 27 360 2 Kodak 1964 Rat 1 82 360 3 Mortality (3/3) Rat 1 506 170 3 Mortality (3/3) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality. 

TABLE C-2 Data Used in Category Plot for Cyclohexyl 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 0.20 10 AEGL AEGL-2 0.065 30 AEGL AEGL-2 0.034 60 AEGL AEGL-2 0.0085 240 AEGL AEGL-2 0.0040 480 AEGL AEGL-3 0.60 10 AEGL AEGL-3 0.20 30 AEGL AEGL-3 0.10 60 AEGL AEGL-3 0.025 240 AEGL AEGL-3 0.013 480 AEGL Eastman Kodak 1990, 1992 Rat 1 17.79 360 3 Mortality (3/3), irritation, lacrimation, dypsnea, inflammation in lungs, congestion of kidney and liver. 265 (Continued) 

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. 

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 

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). 

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 

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 

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 

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. 

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 

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 

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) 

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