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7 Selected Monoisocyanates Acute Exposure Guideline Levels
Pages 200-276

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From page 200...
... Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
From page 201...
... Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Four monoisocyanates are considered in this chapter: ethyl isocyanate, nbutyl isocyanate, cyclohexyl isocyanate, and phenyl isocyanate.
From page 202...
... . A modifying factor 3 was also applied because data on the potential developmental toxicity of n-butyl isocyanate and phenyl isocyanate were lacking; methyl isocyanate is a known developmental toxicant.
From page 203...
... (0.038 mg/m3) methyl isocyanate Cyclohexyl isocyanate AEGL-1 NR NR NR NR NR Insufficient warning properties; (non-disabling)
From page 204...
... 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. On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to these monoisocyanates might be associated with systemic toxicity at concentrations below those associated with irritation.
From page 205...
... 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 described for the structurally similar compound methyl isocyanate (respiratory tract irritation with delayed lethality)
From page 206...
... 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.
From page 207...
... Lethality benchmarks for the monoisocyanates are similar to those for methyl 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)
From page 208...
... 2.4. Species Differences Toxicity data on ethyl isocyanate, n-butyl isocyanate, cyclohexyl isocyanate, and phenyl isocyanate in species other than the rat are lacking.
From page 209...
... 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 toxicity among the monoisocyanates that may reflect a common mode(s)
From page 210...
... 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.
From page 211...
... 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)
From page 212...
... 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)
From page 213...
... 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)
From page 214...
... 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 modifying factor of 2 to account for potentially higher toxicity results in sufficiently protective AEGL values.
From page 215...
... AEGL Values and Toxicity End Points AEGL-1 values are not recommended for ethyl isocyanate because of insufficient 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 isocyanate (NRC 2003)
From page 216...
... 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 concentrations below those associated with irritation.
From page 217...
... 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)
From page 218...
... The available data suggest that cyclohexyl isocyanate and the three other selected monoisocyanates considered in this chapter exert toxic effects, including delayed lethality, that are similar to those induced by methyl isocyanate (see Section 2.3)
From page 219...
... 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.
From page 220...
... 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 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.
From page 221...
... 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 concentrations below those associated with irritation.
From page 222...
... 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.
From page 223...
... Some deaths occurred during the 30-day observation period at all test concentrations. Body weight loss and signs of respiratory distress were observed throughout the post-exposure period.
From page 224...
... 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.
From page 225...
... Clinical signs included hypoactivity, increased grooming (during exposure) , escape behavior (during exposure)
From page 226...
... 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.
From page 227...
... that were marginally different 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 disturbance of ventilatory perfusion.
From page 228...
... 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)
From page 229...
... 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 justified 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)
From page 230...
... , applying a modifying factor of 3 (to account for potential 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)
From page 231...
... 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.
From page 232...
... PHENYL ISOCYANATE 6.1. Human Toxicity Data No information regarding lethality, nonlethal toxicity, developmental toxicity, genotoxicity, or carcinogenicity in humans after acute inhalation exposure to phenyl isocyanate was available.
From page 233...
... 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)
From page 234...
... 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.
From page 235...
... Necropsy findings confirmed pulmonary damage. In an acute inhalation toxicity study in rats, groups of five male and five female young adult Wistar rats were exposed to phenyl isocyanate (99.9% pure)
From page 236...
... Source: Bayer AG 1991a. TABLE 7-25 Summary of Rat Lethality Benchmarks for Phenyl Isocyanate Study (analytic method)
From page 237...
... Phenyl isocyanate concentrations were determined by the Marcali 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.
From page 238...
... 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)
From page 239...
... . On the basis of similarities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for phenyl isocyanate.
From page 240...
... AEGL-2 values could be calculated by applying a total uncertainty factor of 30 (3 for interspecies 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)
From page 241...
... . Finally, a modifying factor of 3 was applied to account for potential developmental toxicity of phenyl isocyanate on the basis of data on methyl isocyanate.
From page 242...
... On the basis of toxicity data on methyl isocyanate, it is plausible that exposure to phenyl isocyanate may be associated with systemic toxicity at concentrations below those associated with irritation. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 values are without effect.
From page 243...
... 1987. Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice.
From page 244...
... 1992. Initial Submission: Acute Inhalation Toxicity Test with Cyclohexyl Isocyanate in Rats with Cover Letter Dated 08/10/92.
From page 245...
... 1980. Phenyl Isocyanate: Subacute Inhalation Toxicity Study in Rats.
From page 246...
... Pp. 198-249 in Acute Exposure Guideline Levels Selected Airborne Chemicals, Vol.
From page 247...
... 1993. The Bhopal accident and methyl isocyanate toxicity.
From page 248...
... 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 isocyanate might be more toxic than methyl isocyanate.
From page 249...
... 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)
From page 250...
... 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.
From page 251...
... . On the basis of similarities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for n-butyl isocyanate.
From page 252...
... 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)
From page 253...
... . On the basis of similarities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for phenyl isocyanate.
From page 254...
... 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)
From page 255...
... . Modifying factor: 3 to account for potential developmental toxicity of phenyl isocyanate, on the basis of data on methyl isocyanate.
From page 256...
... 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)
From page 257...
... 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)
From page 258...
... 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)
From page 259...
... 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)
From page 260...
... . On the basis of similarities between the selected monoisocyanates and methyl isocyanate, AEGL-1 values were not derived for phenyl isocyanate.
From page 261...
... . Modifying factor: 3, to account for potential developmental toxicity of phenyl isocyanate on the basis of data on methyl isocyanate.
From page 262...
... 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.
From page 263...
... 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.
From page 264...
... 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)
From page 265...
... 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)
From page 266...
... 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)
From page 267...
... 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)
From page 268...
... 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.
From page 269...
... 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)
From page 270...
... 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
From page 271...
... 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.
From page 272...
... 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.
From page 273...
... 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)
From page 274...
... 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.
From page 275...
... 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)
From page 276...
... 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)


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