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Twenty-first Interim Report of the Committee on Acute Exposure Guideline Levels: Part B 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 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. The NRC’s previous name for acute exposure levels—community emergency exposure levels—was replaced by the term acute exposure guideline levels (AEGLs) to reflect the broad application of these values to planning, response, and prevention in the community, the workplace, transportation, the military, and the remediation of Superfund sites. NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop 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 [standard pressure] 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 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 following AEGL technical support documents (TSDs): aliphatic nitriles (acetonitrile, isobutyronitrile, propionitrile, chloroacetonitrile, and malononitrile), benzonitrile, and methacrylonitrile. These documents were reviewed by the committee at a meeting on May 2-4, 2012. ALIPHATIC NITRILES The committee reviewed the AEGL TSD on five aliphatic nitriles (acetonitrile, isobutyronitrile, propionitrile, chloroacetonitrile, and malononitrile) that was presented by Julie Klotzbach of SRC, Inc. Table 1 presents a summary of the proposed AEGL values for the aliphatic nitriles and their basis. The committee agreed that its previous comments (NRC 2011a) on the TSD have been adequately addressed, and that the document can be finalized for publication after a few clarifications and editorial changes are made. General Comments A statement of caution should be given for the cumulative effects of concomitant exposure to multiple aliphatic nitriles that share a common mechanism of toxicity through their biotransformation to cyanide. For each of the aliphatic nitriles with extant standards and guidelines, more substantive discussion should be added about the basis for the differences between the AEGL values and other relevant guidelines. Simply presenting the other values without discussion is not sufficiently informative. See section on Comments Relevant to All AEGL TSDs in Part A of this report (NRC 2012) for guidance. Acetonitrile AEGL Specific Comments The context for selecting the point-of-departure for AEGL-3 values should include the following data: Maternal deaths were observed after exposure to acetonitrile at 400 and 1,200 ppm in the NTP (1994) study Deaths of male rats exposed at 800 and 1,600 ppm and female rats at 1,600 ppm in the NTP (1996) study; the deaths that occurred during week 1 of the 13-week segment of the study are especially pertinent. Because the number of days of exposure preceding death of these adult rats was not reported, the rationale for selecting a higher point-of-departure can be strengthened by emphasizing embryonic and fetal end points that could occur after a single exposure. Moreover, a no-effect level of 1,200 ppm for fetal effects in the NTP (1994) study also lends support for the 6-h point-of-departure of 1,500 ppm from the Saillenfait et al. (1993) study. 2
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TABLE 1 Summary of Proposed AEGL Values for Five Aliphatic Nitriles Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors Acetonitrile AEGL-1 13 ppm 13 ppm 13 ppm 13 ppm Not Slight chest tightness and (22 mg/m3) (22 mg/m3) (22 mg/m3) (22 mg/m3) (nondisabling) recommended cooling sensation in lung (1 of 3 human volunteers at 40 ppm); MF = 3 AEGL-2 80 ppm 80 ppm 50 ppm 21 ppm 14 ppm One third of AEGL-3 values (130 mg/m3) (130 mg/m3) (84 mg/m3) (35 mg/m3) (24 mg/m3) (disabling) AEGL-3 240 ppm 240 ppm 150 ppm 64 ppm 42 ppm No-effect level for maternal (400 mg/m3) (400 mg/m3) (250 mg/m3) (110 mg/m3) (71 mg/m3) (lethality) and fetal lethality in rats (1,500 ppm, 6 h); UF = 30; n = 1.6 for time scaling Isobutyronitrile AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 0.83 ppm One third of AEGL-3 values (7.1 mg/m3) (7.1 mg/m3) (5.7 mg/m3) (3.7 mg/m3) (2.3 mg/m3) (disabling) AEGL-3 7.6 ppm 7.6 ppm 6.1 ppm 3.8 ppm 2.5 ppm No-effect level for maternal (22 mg/m3) (22 mg/m3) (17 mg/m3) (11 mg/m3) (7.1 mg/m3) (lethal) lethality (100 ppm, 6 h); UF = 30; default time scaling Propionitrile AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 3.7 ppm 3.7 ppm 3.0 ppm 1.9 ppm 1.3 ppm One third of AEGL-3 values (8.3 mg/m3) (8.3 mg/m3) (6.8 mg/m3) (4.3 mg/m3) (2.9 mg/m3) (disabling) AEGL-3 11 ppm 11 ppm 9.1 ppm 5.7 ppm 3.8 ppm No-effect level for maternal (25 mg/m3) (25 mg/m3) (20 mg/m3) (13 mg/m3) (8.6 mg/m3) (lethal) and fetal mortality (50 ppm, 6 h); UF = 30); default time scaling Chloroacetonitrile AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 8.0 ppm 8.0 ppm 5.0 ppm 2.1 ppm 1.4 ppm Derived by analogy to (25 mg/m3) (25 mg/m3) (15 mg/m3) (6.5 mg/m3) (disabling) (4.3 AEGL-2 values for mg/m3) acetonitrile AEGL-3 24 ppm 24 ppm 15 ppm 6.4 ppm 4.2 ppm Derived by analogy to (74 mg/m3) (74 mg/m3) (46 mg/m3) (20 mg/m3) (13 mg/m3) (lethal) AEGL-3 values for acetonitrile Malononitrile AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 1.2 ppm 1.2 ppm 0.77 ppm 0.32 ppm 0.22 ppm Derived by analogy to (3.3 mg/m3) (3.3 mg/m3) (2.1 mg/m3) (0.87 mg/m3) (0.59 mg/m3) (disabling) AEGL-2 values for acetonitrile AEGL-3 3.7 ppm 3.7 ppm 2.3 ppm 0.98 ppm 0.65 ppm Derived by analogy to (10 mg/m3) (10 mg/m3) (6.2 mg/m3) (2.7 mg/m3) (1.7 mg/m3) (lethal) AEGL-3 values acetonitrile Accordingly, emphasis on fetal death should be reflected in the summary table on page II-35, Appendix II-B, where detailed data were given for maternal death but not fetal resorption/nonsurviving implants. 3
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Editorial Comments The spelling errors of “Saillenfait” should be corrected throughout the TSD. Page II-20, Table II-3: data from the Saillenfait et al. (1993) and NTP (1994, 1996) studies should be added. For the NTP (1996) study, the time-to-death for male and female rats should be specified, if possible. Page II-26, Table II-9: the IDLH (immediately dangerous to life and health) value of 840 should expressed as mg/m3 not ppm. Appendix II-B, page II-35: In the “Effects” row of the table, the data on resorptions and nonsurviving implants at 1,800 ppm were for rats not hamsters. Appendix II-C: Data from the Saillenfait et al. (1993) and NTP (1994) studies should be added to the category plot and data list. Add the citation of van Raaij et al. (2003) regarding the window of vulnerability for fetal effects in the section on acetonitrile, as well as in the reference section. Isobutyronitrile In several places, the lowest exposure concentration for maternal death in the Saillenfait et al. (1993) study was reported to be 150 ppm (for example, see page III-12, line 28 and 35; page III-13, line 15). The correct concentrations used in this study were 200 and 300 ppm. Page III-25, Appendix III-C: For the sake of consistency, the data from the Saillenfait et al. (1993) study should be reported as nominal concentration of 200 and 300 ppm rather than analytic concentrations of 208 and 308 ppm. The distinction has already been made in the study description on page III-11. Page III-15: The AIHA (2002) citation was not mentioned in the text. Propionitrile Appendix IV-C, page IV-25: The data from the study by Saillenfait et al. (1993) should be added to the category plot and database. Chloroacetonitrile Page V-22: The dose units for chloroacetonitrile administered to rats in the Younger Labs (1976) study should be in mg/kg not in ppm. Page V-23: The citation for Hashimoto (1984) should be Tanii and Hashimoto (1984). Malononitrile The committee had no specific comments on malononitrile. BENZONITRILE The committee reviewed the AEGL TSD on benzonitrile that was presented by Heather Carlson- Lynch of SRC, Inc. Table 2 presents a summary of the proposed AEGL values for benzonitrile and their basis. 4
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The committee agreed that its previous comments (NRC 2011b) on the TSD have been adequately addressed, but recommended one substantive change to the AEGL values. Specifically, the uncertainty factor for interspecies differences should be 10 instead of 3. The TSD currently cites small differences in the toxicity of benzonitrile in rats and mice in the study by Agaev (1977) to support a factor of 3. However, the study lacks adequate detail about the methods, and differences between two rodent species give no indication of differences between rodents and humans. Thus, an uncertainty factor of 3 cannot be justified. After the AEGL values for benzonitrile are recalculated and the supporting text revised, the committee agreed that the TSD can be finalized. METHACRYLONITRILE The committee reviewed a presentation of proposed AEGL values for methacrylonitrile by Heather Carlson-Lynch of SRC, Inc. Revisions to the originally proposed AEGL-2 and AEGL-3 values were required because of a transcription error in the data of the key study, and revisions to the AEGL-1 values were proposed after further consideration of the warning properties of the chemical. The proposed AEGL values and options considered are presented in Table 3. The committee agreed that after the TSD is revised to incorporate the proposed changes, it can be finalized for publication. TABLE 2 Summary of Proposed AEGL Values for Benzonitrile Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 33 ppm 24 ppm 19 ppm 7.3 ppm 3.7 ppm No effect level for (140 mg/m3) (100 mg/m3) (80 mg/m3) (31 mg/m3) (16 mg/m3) (disabling) impairment of escape (one-third of AEGL-3) AEGL-3 100 ppm 71 ppm 56 ppm 22 ppm 11 ppm No effect level for (420 mg/m3) (300 mg/m3) (240 mg/m3) (93 mg/m3) (46 mg/m3) (lethal) lethality (estimated lethal threshold in mice, 445 ppm, 2 h); UF = 10 (3 × 3) TABLE 3 Summary of Proposed AEGL Values for Methacrylonitrile Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 Not Not Not Not Not Poor odor warning (nondisabling) recommended recommended recommended recommended recommended properties AEGL-2 To be To be To be To be To be One-third of (disabling) determined determined determined determined determined AEGL-3 values AEGL-3 7.3 ppm 7.3 ppm 5.8 ppm 3.6 ppm 1.8 ppm One-third of the 4-h (lethal): LC50 of 109 ppm in Option 1 rats; UF = 30; default time scaling AEGL-3 3.9 ppm 3.9 ppm 3.1 ppm 2.0 ppm 0.99 ppm 4-h nonlethal (lethal): concentration of Option 2a 19.7 ppm in mice and rabbits; UF = 10; default time scaling a Option supported by the committee. 5
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AEGL Specific Comments SRC proposed not establishing AEGL-1 values because it is not clear that methacrylonitrile has adequate warning properties. The committee supports this proposal. As part of the rationale for not using the human data in the study by Pozzani et al. (1968), which was a basis for proposing AEGL-1 values in the past, the TSD should note that the focus of the study was sensory effects and it was not designed to detect systemic effects. The study also reported that the test subjects showed olfactory fatigue after a few minutes of exposure to methacrylonitrile at 2 ppm, which supports that the chemical has poor odor warning properties. SRC discovered that the point-of-departure for calculating AEGL-3 values for methacrylonitrile had to be revised because of an error in reporting that no deaths occurred in rats exposed to methyacrylonitrile at 176 ppm in the study by Pozzani et al. (1968). One male rat died at that concentration. A reevaluation of the toxicity database led to the following observations. For a 4-h exposure, the margin between the LC50 (lethal concentration, 50% lethality) and the no-effect level for lethality is narrow in mice (36 ppm vs 19.7 ppm) and rabbits (37 ppm vs 19.7 ppm). The same pattern is demonstrated in other test species, albeit at slightly higher concentrations. For example, there were no deaths of dogs at 40 ppm for 7 h, but 100% death at 52.5 ppm. One dog vomited at 20 ppm. Although rats appear to be less sensitive, the wide range of 4-h LC50 values (378-700 ppm) is alarming when considering the narrow margin for lethality observed in other test species. SRC presented two options for recalculating the AEGL-3 values (see Table 3). The committee judged that Option 2 was the better approach for deriving AEGL-3 values, because the overall database supported a point-of-departure of 19.7 ppm and it is preferable to use an empirical no-effect level rather than estimating a no-effect level by adjusting an LC50 value (as was done in Option 1). The committee supports SRC’s proposal to derive AEGL-2 values by calculating one-third of the AEGL-3 values, because of the lack of data to support a point-of-departure for AEGL-2 end points. Editorial Comments Page 13, Table 5, and page 18, Table 6: Tables should be corrected to indicate that one rat died within 3 h after exposure to methacrylonitrile at 176 ppm. Page 16, lines 17-19: The description of fetal body-weight reduction appears to be in error, because it refers to acrylonitrile not methacrylonitrile. The Saillenfait et al. (1993) study reported lower fetal body weight occurred only at 100 ppm and was accompanied by lower maternal weight gain. Page 18, Table 6: (1) The table should indicate that there were no deaths in dogs (not 100% mortality) after exposure to methacrylonitrile at 40 ppm for 7 h; (2) the entry in the “Effects” column for rats exposed at 110 ppm should indicate that the 17% mortality was on day 1, and that mortality was 33% (2 of 6 rats) in males; and (3) the entry in the “Effects” column for rats exposed at 109.3 ppm should indicate that the 28% mortality was on day 1, and that mortality was 58% (7 of 12 rats) in males. Appendix C: The text should be corrected to indicate that the death of one rat was observed at 176 ppm. REFERENCES Agaev, F.B. 1977. Experimental basis of the maximum allowable concentration of benzonitrile in the air of the workplace [in Russian]. Gig. Tr. Prof. Zabol. 6:34-37. NRC (National Research Council). 1993. Guidelines for Developing Community Emergency 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: National Academy Press. NRC (National Research Council). 2011a. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part B. Washington, DC: The National Academies Press. 6
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NRC (National Research Council). 2011b. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. NRC (National Research Council). 2012. Twenty-first Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. NTP (National Toxicology Program). 1994. Inhalation Developmental Toxicity Studies: Acetonitrile in Rats. Final Report. NTP Report No. TER91039, NTIS No. DE94008272. National Institute of Environmental Health Sciences, U.S. Department of Health and Human Services, Research Triangle Park, NC. NTP (National Toxicology Program). 1996. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 75-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP Technical Report Series No. 447. National Institute for Environmental Health Sciences, U.S. Department of Health and Human Services, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/ LT_rpts/tr447.pdf [accessed June 25, 2012]. Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacrylonitrile. Am. Ind. Hyg. Assoc. J. 29(3):202-210. Saillenfait, A.M., P. Bonnet, J.P. Gurnier, and J. de Ceaurriz. 1993. Relative developmental toxicities of inhaled aliphatic mononitriles in rats. Fundam. Appl. Toxicol. 20:365-375. van Raaij, M.T.M., P.A.H. Janssen, and A.H. Piersma. 2003. The Relevance of Developmental Toxicity Endpoints for Acute Limit Setting. RIVM Report 601900004/2003. RIVM (National Institute for Public Health and the Environment), Bilthoven, The Netherlands [online]. Available: http://www.epa.gov/oppt/aegl/pubs/meetings/mtg35b.pdf [accessed July 6, 2012]. 7