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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels BACKGROUND In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) asked the National Research Council (NRC) to provide technical guidance for establishing community emergency exposure levels (CEELs) for extremely hazardous substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects. NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or terrorist activities. 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). AEGL-2 and AEGL-3, and AEGL-1 values as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been 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 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 susceptible 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 susceptible individuals, could experience life- threatening health effects or death. 1

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THE CHARGE TO THE COMMITTEE The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment. The charge to the committee is to (1) review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review NAC’s research recommendations and—when appropriate— identify additional priorities for research to fill data gaps; and (3) review periodically the recommended standard procedures for developing AEGLs. This interim report presents the committee’s conclusions and recommendations for improving the NAC’s AEGL documents for n-butyl isocyanate. n-Butyl Isocyanate At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on n-butyl isocyanate. Presentation on the TSD was made by Heather Carlson-Lynch, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: The basis for derivation of AEGL-1 values for n-butyl isocyanate was industrial hygiene reports indicating that occupational exposure to 40 ppb (0.040 ppm) n-butyl isocyanate was without ocular irritation (DuPont, 1986; DuPont, 2008).… The 50 ppb (0.050 ppm) exposure from the DuPont (1986) report was actually 70 ppb (0.070 ppm). This was considered a protective POD for AEGL-2 derivation because the ocular irritation was neither escape impairing nor irreversible…. The 4-hour BMCL05 of 3.35 ppm from the DuPont (1968) rat study was used as the POD for AEGL-3 derivation AEGL-Specific Comments The use of the industrial hygiene data (DuPont 1986, 2008) needs to be reconsidered. At least the data needs further delineation of its limitations in the TSD text. The first “experiment” involved five individuals with one measurement each. All individuals, presumably workers, acclimated to the isocyanate irritant effects. The second experiment involved voluntary reports by supervisors. The document suggests that there were no reports on a clipboard, from which they deduced that the air levels monitored did not cause problems. The latter information, or lack of data, should not be interpreted to mean that there were no effects. The most that can be said is that no effects were reported. These limitations have an impact on the scientific credibility of the AEGL-1 and AEGL-2 values. AEGL-1 Page 9, lines 23-35: “An industrial hygiene survey (DuPont, 1986) reported that exposure to n- butyl isocyanate at a concentration of 5 to 10 ppb (0.005 to 0.01 ppm) resulted in ocular irritation. At exposure levels of 50 ppb (0.05 ppm), normal work operations were not possible but exposure at this level was not expected to impair escape ability. A more recent communication (DuPont, 2008) reported that analytical techniques (impinger/gas chromatograph method) used in sampling analysis in the earlier DuPont report were underestimating n-butyl isocyanate levels. For levels less than 20 ppb, use of the more advanced XAD7 tube/HPLC method gave n-butyl isocyanate levels that were 2 to 4 fold greater than the previous method. At higher concentrations, measurements using the newer method resulted in n- 2

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butyl isocyanate levels that were approximately 40% greater than the older method.” The discussion of the Haskell Laboratory report regarding the analytical methods is either confusing or inaccurate. Page 2 indicates that the HPLC method gave results about “40% higher” than the impinger and GLC (gas liquid chromatography), method presumably on the basis of the measurements given on that page. Then the report said that for values <20 ppb, HPLC gave values 2-4 times higher. All the values above are <20 and yet showed only about a 40% difference. The TSD document chose to take the highest reported value from DuPont (1986) for ocular irritation and then multiply it by 4. This approach does not make sense. The DuPont and Haskell Laboratory references need to be carefully reviewed, and the limitations clearly stated in the TSD text. Subsequently, the AEGL-1 values may need to be revised. Note that this issue also affects the derivations of AEGL-2 and AEGL-3 values. AEGL-2 AEGL 2 values need to be re-evaluated based on a better discussion of the analytic adjustment value (see comment above for AEGL-1). Page 17, lines 25: “The 50 ppb (0.05 ppm) exposure from the DuPont (1986) report is considered a protective POD for AEGL-2 derivation because the ocular irritation was neither escape impairing nor irreversible in humans.” The exposure at “50 ppb” was for one individual for an unspecified duration and increased by a questionable 40%; an analytic error is assumed. This datum is too weak for the derivation of AEGL-2 values. The TSD authors should consider using one-third of the AEGL-3 to develop AEGL-2 values. AEGL-3 Page 18, lines 41-45: “Subsequent analysis (DuPont, 2008) indicated that exposure levels in industrial hygiene surveys were generally underestimating n-butyl isocyanate levels by 40%. It was assumed that concentrations in the DuPont (1986) animal study conducted during the same time period were also underestimated. Consequently, the AEGL-3 values derived from the animal data were increased 1.4-fold to adjust for the underestimated levels.” AEGL-3 values need to be reevaluated given the concern about the 40% adjustment (as stated above for AEGL-1). Other Comments The comments presented here should be considered in context with the comments on other isocyanates in Part A of the Twentieth Interim Report. References DuPont (DuPont de Nemours and Co.). 1968. Acute Inhalation Toxicity: Isocyanic Acid Butyl Ester. Report No. 289-68. MR No. 581-243. Haskell Laboratory for Toxicology and Industrial Medicine. DuPont (DuPont de Nemours and Co.). 1986. Butyl Isocyanate Industrial Hygiene Survey. Personal communication, Central Research and Development Department, Haskell Laboratory for Toxicology and Industrial Medicine. DuPont (DuPont de Nemours and Co.). 2008. Reassessment of Analytical Techniques Used in Butyl Isocyanate Industrial Hygiene Survey. Personal communication, Central Research and Development Department, Haskell Laboratory for Toxicology and Industrial Medicine. 3