Twenty-first Interim Report of the Committee on Acute Exposure Guideline Levels: Part A

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.



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Twenty-first Interim Report of the Committee on Acute Exposure Guideline Levels: Part A 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 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 following AEGL technical support documents (TSDs): acrylonitrile, allyl alcohol, epichlorohydrin, ethylene chlorohydrin, ethyl phosphorodichloridate, hexane, ketene, lewisite, mercaptans (ethyl mercaptan, methyl mercaptan, phenyl mercaptan, and tert-ocyl mercaptan), methanesulfonyl chloride, methyl isothiocyanate, monoisocyanates (n-butyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and phenyl isocyanate), nitric acid, 3-quinuclidinyl benzilate, tear gas, titanium tetrachloride, trimethylacetyl chloride, and vinyl acetate monomer. These documents were reviewed by the committee at a meeting on May 2-4, 2012. COMMENTS RELEVANT TO ALL AEGL TSDs Sources for General Information TSDs often cite references that are periodically updated (e.g., Patty’s Industrial Hygiene, Merck Index), particularly in reference to chemical and physical properties. The most recent editions of these references should be used as much as possible to ensure that the most current information is being provided. Sometimes material in an earlier edition is revised in a later edition. In addition, information from common secondary sources should be verified by reviewing the primary references; if more current versions of the primary references are available, those newer references should be consulted for the most current information. Extant Standards and Guidelines The section in the TSDs on Extant Standards and Guidelines should provide substantive discussion of the comparison of AEGLs values and other relevant guidelines (see NRC 2001). Simple side-by-side comparisons of values are not adequate. It is particularly important to provide substantive context when there are substantial differences between the values. The discussion should examine possible reasons for the differences, such as (1) the documented quantitative derivation process for AEGLs compared with the processes used by other organizations, (2) different data requirements for the guidelines, (3) different target populations, (4) duration of exposure, (5) end point of concern (immediate vs delayed effects), and (6) other considerations. For example, occupational guidelines are intended to protect the working adult population from adverse effects from exposure to a chemical over a working lifetime, whereas AEGL values are intended to protect the general population (including sensitive subpopulations) from adverse effects from a one-time exposure to the chemical. Because standards and guidelines are periodically updated, it is important that the most recent publication or listing of standards for each organization be consulted and referenced to document that the standard is still current. The discussion of the values should note the date the guideline was issued to provide historical context, and also reference the supporting (probably older) documentation of the standard. Footnotes to the table on Extant Standards and Guidelines should indicate that ACGIH®, TLV®, ® AIHA , and possibly other terms are registered trademarks. 2

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ACRYLONITRILE The committee reviewed the AEGL TSD on acrylonitrile that was presented by Julie Klotzbach of SRC, Inc. Table 1 presents a summary of the proposed AEGL values for acrylonitrile and their basis. The committee recommended that the basis for those AEGL values be re-evaluated, and that the revised TSD be reviewed again at a future meeting. AEGL Comments The committee is concerned that the developmental toxicity end points presented in Section 3.3 were not adequately considered in the selection of the point-of-departure for AEGL values for acrylonitrile. The argument that the results are inconsistent between the study by Murray et al. (1978), which found fetal malformations (lowest-effect level of 80 ppm, and a no-effect level of 40 ppm), and the study by Saillenfait et al. (1993), which reported lower fetal weight and negative absolute maternal weight gain (lowest-effect level [LOEL] of 25 ppm, and a no-effect level [NOEL] of 12 ppm), are not an adequate basis for excluding the end points from consideration. Consideration should be given to whether in vitro studies of embryotoxicity could help with interpretation of studies (e.g., Saillenfait et al.1992; 2004). If appropriate, it might be possible to translate the in vitro concentration from these studies to inhalation concentrations by applying the pharmacokinetic model described in EPA’s 2011 toxicological review of acrylonitrile (EPA 2011). Below are comments on the use of developmental toxicity data specific to the AEGL-2 and AEGL-3 values. AEGL-2 Values: In the TSD, an arbitrary threshold of 100 ppm was presumed for developmental toxicity, and was compared with the proposed 2-h AEGL point-of-departure of 305 ppm in adult nonpregnant rats in the study by Dudley and Neal (1942). However, further consideration should be given to reductions in maternal weight gain observed in both the Saillenfait et al. (1993) and Murray et al. (1978) studies, which had a LOEL range of 25-40 ppm and a NOEL of 12 ppm. In the Murray study, effect on maternal weight gain was evident at the first measurement, supporting the relevance of the end point to a single exposure scenario. Thus, the lower NOEL value from the Saillenfait study could be pertinent to AEGL-2 values if it is affirmed that there are no corresponding detrimental fetal effects. TABLE 1 Summary of Proposed AEGL Values for Acrylonitrile Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 1.5 ppm 1.5 ppm 1.5 ppm 1.5 ppm 1.5 ppm No-effect level for notable (nondisabling) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) (3.3 mg/m3) discomfort (eye irritation) in human subjects (4.6 ppm, 8 h); UF = 3 AEGL-2 81 ppm 30 ppm 16 ppm 4.5 ppm 2.4 ppm No-effect level for (180 mg/m3) (65 mg/m3) (35 mg/m3) (9.8 mg/m3) (5.2 mg/m3) (disabling) impairment of escape (tremors, convulsion) in rats (305 ppm, 2 h); UF = 36; n = 1.1 for time scaling AEGL-3 130 ppm 50 ppm 28 ppm 9.7 ppm 5.2 ppm No-effect level for (280 mg/m3) (110 mg/m3) (61 mg/m3) (21 mg/m3) (11 mg/m3) (lethality) lethality (30-min, 1-h, and 8-h BMCL05) in rats; UF = 36; n = 1.1 for time scaling Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; UF, uncertainty factor. 3

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AEGL-3 Values: The proposed point-of-departure for AEGL-3 values was based on lethality in adult rats. However, severe fetal malformations that might lead to mortality after birth should be considered a pertinent end point for AEGL-3 values. The Murray et al. (1978) study involved oral and inhalation exposures, but only the inhalation data from the study was presented in the TSD. Consideration of the results from both the oral and inhalation studies provide clearer evidence of the teratogenic potential of acrylonitrile. For example, although not specifically noted for the inhalation data, the investigators reported that oral exposure resulted in multiple skeletal malformations, and that these same fetuses had visceral malformations. Moreover, sodium sulfide stain of the uterus found pregnancies in rats that appeared to be non-pregnant at an air concentration 80 ppm and at an oral dose of 65 mg/kg/day. The investigators stated that these data were not included in the report of fetal resorption incidences. It is noteworthy that the investigators concluded that “. . . it is unlikely that the malformations were caused by maternal toxicity alone since there was no apparent correlation between the degree of toxicity seen in the individual dams and the occurrence of malformation in their offspring, and the types of malformations seen in this study have not occurred at an increased incidence in previous studies in this laboratory in which rats were stressed to an even greater degree” (p. 551). Thus, the investigators’ conclusion of a NOEL of 40 ppm is relevant for AEGL-3 values. There is some degree of uncertainty that detrimental fetal effects with low historical occurrence (e.g., omphalocele) were present at 40 and 80 ppm, although the increase was not statistically significant. ALLYL ALCOHOL The committee reviewed the AEGL TSD on allyl alcohol that was presented by Julie Klotzbach of SRC, Inc. Table 2 presents a summary of the proposed AEGL values for allyl alcohol and their basis. The committee also reviewed a submission from Lyondell Chemical Company (2012) on the study it performed to support the derivation of AEGL values. AEGL Specific Comments The committee agreed that the AEGL-3 values for allyl alcohol were appropriately derived, but recommended revisions to the derivation of the AEGL-2 and AEGL-1 values before the TSD is finalized. For the AEGL-2 values, the committee disagreed with the proposal to use the rat study by Kirkpatrick (2008). The ocular irritation reported in the human volunteer study by Dunlap et al. (1958) should be regarded as an AEGL-2 effect. In that study, one of seven subjects reported slight ocular irritation at 12.5 ppm for 5 min, and five of five reported moderate or more marked ocular irritation at 25 ppm for 5 min. Considering 12.5 ppm as the NOEL for moderate to marked ocular irritation and applying an uncertainty factor of 3 for intraspecies variability, the upper limit of AEGL-2 values is 4 ppm. That value is relevant to the 10-min AEGL, and can be adopted for the 30-min and 1-h values. AEGL-2 values for the longer durations should be calculated as one-third of the AEGL-3 values. For the AEGL-1 values, the committee found the Dunlap study was too limited to provide the sole basis for AEGL-1 values. Instead, the measurements of sensory irritation in mice for a variety of allyl derivatives should be used (see Nielsen et al. 1984; Nielsen and Bakbo 1985). Those studies report an RD50 value (concentration that reduces the respiratory rate by 50%) for allyl alcohol of 3.9 ppm. A point- of-departure can be estimated by calculating 3% of the RD50 value (see Nielsen et al. 1984). The sensory irritation studies by Nielsen et al. show that the different allyl derivatives, including allyl alcohol and its aldehyde metabolite acrolein, are equally potent (have approximately equal RD50 values). Furthermore, the time courses for respiratory depression are very similar for the alcohol and the aldehyde. Collectively, this suggests that the sensory irritation is caused by the allyl moiety and not by the metabolism from alcohol to aldehyde. Thus, no uncertainty factors are needed to calculate the AEGL-1 values. Because sensory irritation is an almost instantaneous effect, the same value can be applied for all exposure durations. The AEGL-1 value of 0.12 ppm is in a similar range as that for acrolein (0.03 ppm) and close to the TLV® (0.5 ppm). 4

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EPICHLOROHYDRIN The committee reviewed the AEGL TSD on epichlorohydrin that was presented by Heather Carlson-Lynch of SRC, Inc. Table 3 presents a summary of the proposed AEGL values for epichlorohydrin and their basis. The committee agreed that its previous comments (NRC 2011) on the TSD have been adequately addressed, and that the TSD can be finalized for publication after some editorial clarifications are made. Other Comments In the discussion of AEGL-2 values, a statement is made (page 43, line 31) that a decrease in respiratory rate was not considered a relevant end point for AEGL-2 values. A rationale should be added to the TSD to support this statement. Editorial Comments Page 26, Table 4, footnote a: The unit for temperature should be added. Page 41, Figure 1: The figure should be reviewed to verify that it appropriately represents the data. Page 48, Section 8.2: The discussion of other standards and guidelines for epichlorohydrin should be reorganized to discuss the guidelines that are most analogous to the AEGLs values (e.g., ERPG, IDLH) first. The discussion about the TLV® for epichlorohydrin should indicate that one of the bases for the value is upper-respiratory-tract irritation observed in the study by Gage (1959). In that study, a lowest-observed-adverse-effect level of 16 ppm was found for rabbits and 17 ppm for rats, and 9 ppm was a no-observed-adverse-effect level. TABLE 2 Summary of Proposed AEGL Values for Allyl Alcohol Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 0.62 ppm 0.62 ppm 0.62 ppm Not Not Slight to moderate nasal and (1.5 mg/m3) (1.5 mg/m3) (1.5 mg/m3) (nondisabling) recommended recommended slight ocular irritation (6.25 ppm); UF = 10 AEGL-2 11 ppm 3.5 ppm 1.7 ppm 0.73 ppm 0.33 ppm No-effect level for disabling (27 mg/m3) (8.5 mg/m3) (4.1 mg/m3) (1.8 mg/m3) (0.80 mg/m3) (disabling) effects in rats (gasping, reduced response to stimulus); UF = 30; n = 0.95 for time scaling AEGL-3 87 ppm 27 ppm 13 ppm 3.1 ppm 1.5 ppm Estimated LC01 value in rats; (210 mg/m3) (65 mg/m3) (31 mg/m3) (7.5 mg/m3) (3.6 mg/m3) (lethal) UF = 30; n = 0.95 for time scaling TABLE 3 Summary of Proposed AEGL Values for Epichlorohydrin Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm No effect level for (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (nondisabling) irritation; UF = 10 AEGL-2 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm Three-fold reduction of (200 mg/m3) (200 mg/m3) (91 mg/m3) (53 mg/m3) (25 mg/m3) (disabling) AEGL-3 values, except for 10-min value AEGL-3 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm Lethality threshold; (2200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3) (lethal) UF = 10; n = 0.87 for time scaling 5

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Page 50, References: The reference list should be cross-checked with the text to eliminate discrepancies. For example, there are references in the text for two NIOSH publications in 2003, but only one citation is provided in the reference list. On line 9, the superscript 7s should be replaced by the symbol for a registered trademark (®). Page 56, line 34: The reference for EPA’s carcinogenicity assessment of epichlorohydrin should make it clear that it refers to an assessment conducted in 1994. As currently presented, the reference only indicates that the IRIS database was accessed in 2012. Page 62: Consideration should be given to reorganizing the table that compares AEGLs values with cancer risk-based values to present the values in ascending order by concentration. In this case, the 10-6 values would be presented between the AEGL-1 and AEGL-2 values, and the 10-5 and 10-4 values would be presented after the AEGL-3 values. ETHYL PHOSPHORODICHLORIDATE The committee reviewed the AEGL TSD on ethyl phosphorodichloridate that was presented by Lisa Ingerman of SRC, Inc. Table 4 presents a summary of the proposed AEGL values for ethyl phosphorodichloridate 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. Editorial Comments Page 6, line 9: replace “estimated” with “obtained.” Page 13, line 17: replace “delayed clinical findings” with “delayed clinically manifested effects.” Page 15,line 25: clarify what is meant by “. . . yields a better concentration-response relationship.” ETHYLENE CHLOROHYDRIN (2-CHLOROETHANOL) The committee reviewed the AEGL TSD on ethylene chlorohydrin that was presented by Julie Klotzbach of SRC, Inc. Table 5 presents a summary of the proposed AEGL values for ethylene chlorohydrin and their basis. The committee agreed that its previous comments on the TSD (NRC 2011) have been adequately addressed, but made a few additional recommendations for improving the document before it is published. AEGL Specific Comments The committee recommended that more explanation be provided about why AEGL-1 values were not derived. It would appear that the AEGL-1 values would be much lower than the AEGL-2 values, and options might be explored on ways to reduce the AEGL-2 values. Other Comments Section 3.1.1: Two studies of acute lethality in rats are discussed in this section. The two-orders- of-magnitude difference in lethality values is significant and warrants a discussion of the possible reasons for the difference. It appears that the exposures in the Ambrose (1950) study were probably substantially higher than reported because (1) the bubbler could have produced significant amounts of aerosol in addition to the vapor, (2) the bubbler was above room temperature at 40ºC, whereas the temperature of the exposure delivery system and exposure chamber were likely around 25ºC (not specified), and (3) the 6

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saturated vapor concentration of ethylene chlorohydrin at 20ºC is about 6,500 ppm and would be higher at 25ºC and 40ºC. A mixed aerosol/vapor exposure seems likely, even with the air flow being ≤570 ml/min. Edits to the discussion might include: “Air was passed through this tower and into the exposure chamber (neither air temperature nor air flow was specified, but air flow was noted as never exceeding 570 ml/min). No indication (other than the air flow value) was given that the possibility of aerosolization of the test material was considered. The inhalation exposure concentrations associated with specific dilutions of ethylene chlorohydrin in water were not measured or estimated (whether vapor phase, aerosol, or mixed) in the study report.” The section of the TSD on extant standards and guidelines require the following revisions and verifications:  Table 9: All of the extant standards and guidelines and their values and definitions should be verified. For example, several of the guidelines are described as time-weighted averages in the “Guideline” column, but then have a “ceiling” notation associated with the value presented. A review of the most recent ACGIH® (2012) publication on TLV®s indicates that there is TLV-STEL but not a TLV- TWA for ethylene chlorohydrin.  In Table 9, ceiling limits should be presented in a way that shows they cross all the AEGL durations. The entry into the Guideline column should include appropriate notation that it represents a ceiling value (e.g., REL-C, TLV-C).  In Table 9, skin notations should be specified in the footnotes rather than in the tables to avoid confusion about their meaning.  Page 18, lines 1-2: The MAK documentation should be consulted to verify that the value does not represent a ceiling concentration. Notation of a peak limitation “II (1)” suggests that the value is the functional equivalent of a ceiling notation (DFG 2012). TABLE 4 Summary of Proposed AEGL Values for Ethyl Phosphorodichloridate 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 0.37 ppm 0.25 ppm 0.20 ppm 0.13 ppm 0.063 ppm One-third of (2.4 mg/m3) (1.7 mg/m3) (1.3 mg/m3) (0.86 mg/m3) (0.40 mg/m3) (disabling) AEGL-3 values AEGL-3 1.1 ppm 0.76 ppm 0.60 ppm 0.38 ppm 0.19 ppm Four-hour threshold for (7.3 mg/m3) (5.0 mg/m3) (4.0 mg/m3) (2.5 mg/m3) (1.3 mg/m3) (lethal) lethality (BMCL05 of 38 ppm) in rats; UF = 100; default time scaling TABLE 5 Summary of Proposed AEGL Values for Ethylene Chlorohydrin 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 2.1 ppm 1.5 ppm 1.2 ppm 0.47 ppm 0.23 ppm One-third of (6.9 mg/m3) (4.9 mg/m3) (3.9 mg/m3) (1.5 mg/m3) (0.76 mg/m3) (disabling) AEGL-3 values AEGL-3 6.4 ppm 4.4 ppm 3.5 ppm 1.4 ppm 0.70 ppm Nonlethal effects in mice (21 mg/m3) (14 mg/m3) (12 mg/m3) (4.6 mg/m3) (2.3 mg/m3) (lethal) (280 ppm for 120 min); UF = 100; default time scaling 7

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 The MAC value from the Netherlands should be checked for relevant notations (e.g., ceiling value, skin notation).  The footnotes to Table 9 should be revised to reflect the revisions made in response to the preceding bullets. Also, the PEL-TWA and MAK values should be defined according to their respective agencies. Those values are currently described as being analogous to the TLV-TWA. However, the definition of the TLV-TWA will not appear in the revised set of footnotes because such a value for ethylene chlorohydrin not been established by ACGIH®.  Page 18, line 8: “value” should be added after IDLH. The discussion of database adequacy gives a misleading impression that the database on ethylene chlorohydrin is fairly robust (e.g., “the animal data are sufficient for describing lethal and nonlethal exposures”), when the database for deriving AEGL-3 values for ethylene chlorohydrin is relatively weak. The animal database consists of one dose-ranging study that used a small number of animals. Although a decision was made to use the study to derive AEGL-3 values in the absence of other data, an impression should not be given that the database on lethality was adequate. Editorial Comments Table 1: The saturated vapor concentration should be calculated (see Perez and Soderholm [1991] for formulae). Page 10, line 44: “low” should be “flow.” Page 11, lines 4-5: “. . . and that for most exposures-related deaths occurred following . . .” Page 11, line 24: “death” should be “cause.” Page 13, line 29: Delete “the” before ethylene chlorohydrin. Page 13, line 32: The citation to the study in rabbits should be added (i.e., NTP 1983b). Page 14, lines 16-17: Specify that “Radio-labeled” carbon dioxide was detected, to clarify that the carbon dioxide was one of the metabolites of the radio-labeled ethylene chlorohydrin. Page 15, line 45: The heading for this section should be changed to Inter- and Intra-Species Variability, because more than just species differences are covered. Page 17, lines 23-24: The sentence should be moved to line 14, after the first sentence. This will allow for a better transition to the discussion of the lethality data. Page 17, line 29: The sentence should cite Table 9 (not Table 10). Page 18, lines 7: The sentence should be revised to be: “The AEGL-2 value for 30 minutes is comparable but less than the NIOSH IDLH, as would be expected from the differences between the respective target populations.” The subsequent phrase and sentence on lines 8-11 can be deleted since they simply repeat the definition of IDLH and AEGL-2 values. References: The references should be cross-checked with the text to ensure accuracy. Several references appear in the reference list but do not seem to be referenced in the text (e.g., AIHA® 2006, Budavari et al. 1996). There are some discrepancies in the years cited in the text and those in the reference list (e.g., HSDB 2012 in Table 1, but HSDB 2007 in reference list). HEXANE The committee reviewed the AEGL TSD on hexane that was presented by Julie Klotzbach of SRC, Inc. Table 6 presents a summary of the proposed AEGL values for hexane and their basis. The committee agreed that its previous comments (NRC 2010a) on the TSD have been adequately addressed, and that the document can be finalized for publication after a few editorial changes are made. 8

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Editorial Comments There appear to be conflicting results of studies considered as a basis for deriving AEGL-3 values. Thus, an explanation should be added to the TSD that the Raje et al. (1984) study was preferred over the Swann et al. (1974) study because the quality of the study was better and there were concerns about one death occurring in the Swann study. Animal lethality data should be included in the category plot on page 42. KETENE The committee reviewed the AEGL TSD on ketene that was presented by Lisa Ingerman of SRC, Inc. Table 7 presents a summary of the proposed AEGL values for ketene and their basis. The committee agreed that its previous comments (NRC 2010a) on the TSD have been adequately addressed, and that the document can be finalized for publication after a few editorial changes. Editorial Comments The structural formula for ketene should be corrected. It currently shows the carbonyl carbon with an incorrect valence state. TABLE 6 Summary of Proposed AEGL Values for Hexane 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 4,000 ppma 2,900 ppma 2,900 ppma 2,900 ppma 2,900 ppma AEGL-2 One-third of (14,000 mg/m3) (10,000 mg/m3) (10,000 mg/m3) (10,000 mg/m3) (10,000 mg/m3) AEGL-3 values (disabling) See belowb See belowc See belowc See belowc See belowc AEGL-3 No lethality in rats; (lethal) UF = 10; default time scaling for the 10-min value a The proposed value is greater than 10% of the lower explosive limit of hexane in air of 1.1 % (11,000 ppm). Therefore, safety considerations against hazard of explosion must be taken into account. b The proposed 10-min AEGL-3 value of 12,000 ppm (42,000 mg/m3) is greater than the lower explosive limit of hexane in air of 1.1 % (11,000 ppm). Therefore, extreme safety considerations against hazard of explosion must be taken into account. c The proposed value is greater than 50% of the lower explosive limit of hexane in air of 1.1 % (11,000 ppm). Therefore, extreme safety considerations against hazard of explosion must be taken into account. The respective calculated AEGL-3 values for 30-min, 1-h, 4-h, and 8-h are similar: 8,600 ppm (30,000 mg/m3). TABLE 7 Summary of Proposed AEGL Values for Ketene 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 0.08 ppm 0.08 ppm 0.063 ppm 0.040 ppm 0.029 ppm One-third of AEGL-3 (0.14 mg/m3) (0.14 mg/m3) (0.11 mg/m3) (0.069 mg/m3) (0.050 mg/m3) (disabling) values AEGL-3 0.24 ppm 0.24 ppm 0.19 ppm 0.12 ppm 0.088 ppm Nonlethal concentration (0.41 mg/m3) (0.41 mg/m3) (0.33 mg/m3) (0.21 mg/m3) (0.15 mg/m3) (lethal) to mice (1 ppm, 7 h); UF = 10; default time scaling 9

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Page 6, line 5 and lines 7-8: The two sentences begin with the same clause and could give the impression that an inadvertent duplication occurred. Consideration should be given to rephrasing or combining the two sentences. Page 27, Section 4.3.2: This section on intraspecies variability and susceptible subpopulations should begin with a statement that the only indication of potential intraspecies sensitivity was in the variability of time-to-death at certain exposure parameters, and that this was not considered strong enough in the absence of other data to warrant concern about a potential sensitive subpopulation. The discussion should also note that there is a similar lack of information for the structurally analogous chemical phosgene. Page 27, lines 8-10, and page 30, line 24: Statements regarding “Considering the potential for sensitive human subpopulations” in the context of discussing the uncertainty factor for intraspecies differences should be removed because the phrasing is ambiguous. The Standing Operating Procedures for developing AEGL values indicates that an uncertainty factor of 10 is the appropriate default value for respiratory irritants, unless data exist to support a different value. In the case of ketene, an uncertainty factor of 3 is justified because (1) there appears to be no indication in either the ketene or phosgene literature (as cited in NRC [2002]) of a sensitive human population, (2) ketene produces minor respiratory irritation in animals, and (3) the only indication of intraspecies variability appears to be in the time-to- death data. Page 31, lines 16-17: The statement that the AEGLs values for ketene and phosgene are “generally consistent” should be qualified. Although the 8-h values are very similar, there are much larger differences for the shorter durations (e.g., 7.5-fold difference between the 10-min AEGL-2 values, 15-fold difference between the 10-min AEGL-3 values). The supporting discussion should note the differences in the available data used to obtain the exponents for the time-scaling equations. Page 32, lines 13-14: The 8-h AEGL value for ketene is 5.5 times lower (not higher) than the TWA occupational values. Table 12: The table includes several rows for values derived by other agencies, but no entries appear. The values should be inserted, if available, or the rows deleted. LEWISITE The committee reviewed the AEGL TSD on lewisite that was presented by Julie Klotzbach of SRC, Inc. Table 8 presents a summary of the proposed AEGL values for lewisite and their basis. The committee agreed that its previous comments (NRC 2011b) on the TSD have been adequately addressed, and that the document can be finalized for publication. Editorial Comments Page 19, line 6: Change to “According to a secondary source . . . “ Page 25, line 37: Change Frank to Franke. Page 25, line 38: Change to “Office of the Assistant Chief of Staff for Intelligence” MERCAPTANS The committee reviewed the individual AEGL TSDs on ethyl mercaptan, methyl mercaptan, phenyl mercaptan, and tert-octyl mercaptan that were presented by Lisa Ingerman of SRC, Inc. Table 9 presents a summary of the proposed AEGL values for the four mercaptans and their basis. The committee agreed that its previous comments (NRC 2011a) on the TSDs have been adequately addressed, and that the documents can be finalized for publication after a few editorial clarifications are made. 10

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TABLE 8 Summary of Proposed AEGL Values for Lewisite 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 0.15 ppm 0.055 ppm 0.030 ppm 0.0083 ppm 0.0044 ppm One-third of (1.3 mg/m3) (0.47 mg/m3) (0.25 mg/m3) (0.070 mg/m3) (0.037 mg/m3) (disabling) AEGL-3 values AEGL-3 0.46 ppm 0.16 ppm 0.087 ppm 0.025 ppm 0.013 ppm Dog LC01 values (3.9 mg/m3) (1.4 mg/m3) (0.74 mg/m3) (0.21 mg/m3) (0.11 mg/m3) (lethal) TABLE 9 Summary of Proposed AEGL Values for Mercaptans Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors Ethyl Mercaptan AEGL-1 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm No-effect level for (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) (nondisabling) respiratory changes associated with odor avoidance in rabbits; UF = 10 AEGL-2 150 ppm 150 ppm 120 ppm 77 ppm 37 ppm One-third of (380 mg/m3) (380 mg/m3) (310 mg/m3) (200 mg/m3) (94 mg/m3) (disabling) AEGL-3 values AEGL-3 450 ppm 450 ppm 360 ppm 230 ppm 110 ppm LC01 in mice; UF = 10; (1100 mg/m3) (1100 mg/m3) (910 mg/m3) (580 mg/m3) (280 mg/m3) (lethal) default time scaling Methyl Mercaptan AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 40 ppm 29 ppm 23 ppm 14 ppm 7.3 ppm One-third of (80 mg/m3) (57 mg/m3) (43 mg/m3) (28 mg/m3) (14 mg/m3) (disabling) AEGL-3 values AEGL-3 120 ppm 86 ppm 68 ppm 43 ppm 22 ppm LC01 in rats; UF = 10; (240 mg/m3) (170 mg/m3) (130 mg/m3) (85 mg/m3) (43 mg/m3) (lethal) default time scaling Phenyl Mercaptan AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 1.0 ppm 0.70 ppm 0.53 ppm 0.33 ppm 0.17 ppm One-third of (4.5 mg/m3) (3.2 mg/m3) (2.4 mg/m3) (1.5 mg/m3) (0.77 mg/m3) (disabling) AEGL-3 values AEGL-3 3.0 ppm 2.1 ppm 1.6 ppm 1.0 ppm 0.52 ppm LC01 in rats; UF = 10; (14 mg/m3) (9.5 mg/m3) (7.2 mg/m3) (4.5 mg/m3) (2.3 mg/m3) (lethal) default time scaling tert-octyl Mercaptan AEGL-1 Not Not Not Not Not Insufficient data (nondisabling) recommended recommended recommended recommended recommended AEGL-2 0.77 ppm 0.77 ppm 0.60 ppm 0.40 ppm 0.19 ppm One-third the (4.6 mg/m3) (4.6 mg/m3) (3.6 mg/m3) (2.4 mg/m3) 1.1 mg/m3) (disabling) AEGL-3 values AEGL-3 2.3 ppm 2.3 ppm 1.8 ppm 1.2 ppm 0.58 ppm Threshold for lethality (14 mg/m3) (14 mg/m3) (11 mg/m3) (7.2 mg/m3) (3.5 mg/m3) (lethal) (BMCL05) in female rats; UF = 10; default time scaling Editorial Comments on Ethyl Mercaptan Page 8, Table 1: Because vapor pressure and saturated vapor concentration vary with temperature, the temperature for the calculated saturated vapor concentration should be added. 11

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TABLE 10 Summary of Proposed AEGL Values for Methanesulfonyl Chloride 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 0.40 ppm 0.40 ppm 0.21 ppm 0.053 ppm 0.026 ppm One-third of (1.9 mg/m3) (1.9 mg/m3) (0.98 mg/m3) (0.25 mg/m3) (0.12 mg/m3) (disabling) AEGL-3 values AEGL-3 1.2 ppm 1.2 ppm 0.62 ppm 0.16 ppm 0.078 ppm 4-hour rat BMCL05 of (5.6 mg/m3) (5.6 mg/m3) (2.9 mg/m3) (0.75 mg/m3) (0.37 mg/m3) (lethal) 15.5 ppm; UF = 100; default time scaling TABLE 11 Summary of Proposed AEGL Values for Methyl Isothiocyanate Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm Highest concentration (nondisabling) ( 0.81 mg/m3) (0.81 mg/m3) (0.81 mg/m3) (0.81 mg/m3 ) (0.81 mg/m3) without notable discomfort (eye irritation) in humans; UF = 3 AEGL-2 21 ppm 21 ppm 17 ppm 10 ppm 5.3 ppm One-third of (63 mg/m3) (63 mg/m3) (51 mg/m3) (30 mg/m3) (16 mg/m3) (disabling) AEGL-3 values AEGL-3 63 ppm 63 ppm 50 ppm 31 ppm 16 ppm Highest 4-h nonlethal (190 mg/m3) (190 mg/m3) (150 mg/m3) ( 94 mg/m3) (47 mg/m3) (lethal) concentration in rats; UF = 3; default time scaling MONOISOCYANATES The committee reviewed the AEGL TSD on four monoisocyanates—n-butyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and phenyl isocyanate—that was presented by Heather Carlson- Lynch of SRC, Inc. Table 12 presents a summary of the proposed AEGL values for those monoisocyanates 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. NITRIC ACID The committee reviewed the AEGL TSD on nitric acid that was presented by Julie Klotzbach of SRC, Inc. Table 13 presents a summary of the proposed AEGL values for nitric acid and their basis. The committee agreed that its previous comments (NRC 2010b) on the TSD have been adequately addressed, and that the document can be finalized for publication. 3-QUINUCLIDINYL BENZILATE The committee reviewed the AEGL TSD on 3-quinuclidinyl benzilate that was presented by Lisa Ingerman of SRC, Inc. Table 14 presents a summary of the proposed AEGL values for 3- quinuclidinyl benzilate 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 editorial clarifications are made. 14

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TABLE 12 Summary of Proposed AEGL Values for Selected Monoisocyanates Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors Ethyl isocyanate AEGL-1 Not Not Not Not Not Insufficient warning (nondisabling) recommended recommended recommended recommended recommended properties; systemic effects possible at concentrations lower than those associated with irritation. AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm Based on AEGL-2 values (0.58 mg/m3) (0.19 mg/m3) (0.099 mg/m3) (0.025 mg/m3) (0.012 mg/m3) (disabling) for methyl isocyanate; MF = 2 AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm Based on AEGL-3 values (1.7 mg/m3) (0.58 mg/m3) (0.29 mg/m3) (0.073 mg/m3) (0.038 mg/m3) (lethality) for methyl isocyanate; MF = 2 Cyclohexyl isocyanate AEGL-1 Not Not Not Not Not Insufficient warning (nondisabling) recommended recommended recommended recommended recommended properties; systemic effects possible at concentrations lower than those associated with irritation. AEGL-2 0.20 ppm 0.065 ppm 0.034 ppm 0.0085 ppm 0.0040 ppm Based on AEGL-2 values (1.0 mg/m3) (0.33 mg/m3) (0.17 mg/m3) (0.043 mg/m3) (0.020 mg/m3) (disabling) for methyl isocyanate; MF = 2 AEGL-3 0.60 ppm 0.20 ppm 0.10 ppm 0.025 ppm 0.013 ppm Based on AEGL-3 values (3.1 mg/m3) (1.0 mg/m3) (0.51 mg/m3) (0.13 mg/m3) (0.066 mg/m3) (lethal) for methyl isocyanate; MF = 2 n-Butyl isocyanate AEGL-1 Not Not Not Not Not Insufficient warning (nondisabling) recommended recommended recommended recommended recommended properties; systemic effects possible at concentrations lower than those associated with irritation. AEGL-2 0.10 ppm 0.10 ppm 0.083 ppm 0.053 ppm 0.026 ppm One-third AEGL-3 values (0.41 mg/m3) (0.41 mg/m3) (0.34 mg/m3) (0.21 mg/m3) (0.11 mg/m3) (disabling) AEGL-3 0.31 ppm 0.31 ppm 0.25 ppm 0.16 ppm 0.078 ppm No mortality in rats, (1.3 mg/m3) (1.3 mg/m3) (1.0 mg/m3) (0.65 mg/m3) (0.32 mg/m3) (lethal) 14 ppm, 4 h; UF = 30; MF = 3; default time scaling Phenyl isocyanate AEGL-1 Not Not Not Not Not Insufficient warning (nondisabling) recommended recommended recommended recommended recommended properties; systemic effects possible at concentrations lower than those associated with irritation. AEGL-2 0.012 ppm 0.012 ppm 0.0096 ppm 0.0061 ppm 0.0030 ppm One-third AEGL-3 values (0.058 mg/m3) (0.058 mg/m3) (0.047 mg/m3) (0.030 mg/m3) (0.015 mg/m3) (disabling) AEGL-3 0.036 ppm 0.036 ppm 0.029 ppm 0.018 ppm 0.0091 ppm BMCL05 (1.64 ppm) from (0.18 mg/m3) (0.180 mg/m3) (0.14 mg/m3) (0.088 mg/m3) (0.044 mg/m3) (lethal) rat 4-h study; UF = 30; MF = 3; default time scaling 15

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TABLE 13 Summary of Proposed AEGL Values for Nitric Acid Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm No-effect level for notable (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (nondisabling) discomfort (changes in pulmonary function: vital capacity, respiratory resistance, and FEV1) in humans of 1.6 ppm; UF = 10 AEGL-2 43 ppm 30 ppm 24 ppm 6.0 ppm 3.0 ppm No-effect level for inability (110 mg/m3) (77 mg/m3) (62 mg/m3) (15 mg/m3) (7.7 mg/m3) (disabling) to escape (eye closure) in rats of 470 ppm for 1 h; UF = 3; default time scaling AEGL-3 170 ppm 120 ppm 92 ppm 23 ppm 11 ppm No-effect level for lethality (440 mg/m3) (310 mg/m3) (240 mg/m3) (59 mg/m3) (28 mg/m3) (lethal) (estimated LC01 of 919 ppm) in rats; UF = 10; default time scaling TABLE 14 Summary of Proposed AEGL Values for 3-Quinuclidinyl Benzilate 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 0.067 mg/m3 0.022 mg/m3 0.011 mg/m3 AEGL-2 Not Not Estimated threshold (disabling) recommended recommended for incapacitation in human volunteers (20 mg-min/m3); UF = 10; MF = 3; default time scaling 1.2 mg/m3 0.41 mg/m3 0.21 mg/m3 AEGL-3 Not Not Estimated lethality (lethal) recommended recommended threshold (3,700 mg- min/m3); UF = 100; MF = 3; default time scaling Editorial Comments For the AEGL-2 values, context and a rationale should be provided for why one-third of the ICT50 (a concentration-time product causing incapacitation of 50% of the test subjects) was used to determine the point-of-departure. TEAR GAS The committee reviewed the AEGL TSD on tear gas that was presented by Lisa Ingerman of SRC, Inc. Table 15 presents a summary of the proposed AEGL values for tear gas and their basis. The committee recommends a few changes in how those AEGL values were derived. 16

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TABLE 15 Summary of Proposed AEGL Values for Tear Gas 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 0.083 mg/m3 0.083 mg/m3 0.083 mg/m3 0.083 mg/m3 0.083 mg/m3 AEGL-2 Estimated no-effect (disabling) level for impaired ability to escape (ocular/nasal/throat irritation, cough in humans); UF = 3; MF = 3 140 mg/m3 29 mg/m3 11 mg/m3 1.5 mg/m3 1.5 mg/m3 AEGL-3 Threshold for lethality (lethal) (LC01) in rats; UF = 10; n = 0.70 for time scaling AEGL Specific Comments The committee suggests that military handbooks on warfare agents be consulted for relevant information on tear gas that might be used as a basis for AEGL values (e.g., Langford 2004; Gupta 2009). For the AEGL-2 values, consideration should be given to whether the effects observed in the Beswick study are from irritation or if other mechanisms are involved. Nausea was observed in the study, which raises the possibility of systemic toxicity. If other mechanisms are involved, it will not be appropriate to apply the same AEGL value to all durations. The committee has reconsidered its previous recommendation that an uncertainty factor of 3 for intraspecies variation in the derivation of AEGL-2 and AEGL-3 values not be supported by the fact that responses of volunteers with conditions such as jaundice, hepatitis, or peptic ulcer were similar to those of “normal” volunteers when exposed to tear gas. It recommends that the discussion in the previous draft be reinstated, and expanded to include important relevant information that in the study by Punte et al. volunteers included people with seasonal allergies and asthma. Editorial Comments Section 6.1: The description of the Beswick study should be edited to make it clear how many subjects were exposed. This will clarify that the subsequent description of symptoms occurred in other subjects exposed at the same concentrations. TITANIUM TETRACHLORIDE The committee reviewed the AEGL TSD on titanium tetrachloride that was presented by Heather Carlson-Lynch of SRC, Inc. Table 16 presents a summary of the proposed AEGL values for titanium tetrachloride and their basis. The committee found that its previous comments on the TSD (NRC 2010b) were not adequately addressed, and continues to recommend further systematic evaluation of existing information, including a more thorough consideration of relevant literature to provide context for the derivation of AEGL values in the TSD. The committee judged that the TSD should be reviewed again before finalization. AEGL Specific Comments The TSD for titanium tetrachloride continues to propose no AEGL-1 values on the basis that no relevant data are available. It would be helpful to reconsider the previous comments regarding this 17

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proposal (see NRC 2010b), including the suggestion to check for potentially relevant studies that have not yet been reflected in the TSD. For example, some references noted in the previous comments did not appear to have been considered in the revised TSD, and others not explicitly identified in those comments are also not yet reflected. Such information could potentially support the derivation of AEGL-1 values. It may also be helpful to consider context from relevant occupational benchmarks, evaluations, and derivations from the National Institute for Occupational Safety and Health (Moseley et al. 1980; NIOSH 2009), including documentation related to a transformation product of titanium tetrachloride (e.g., NIOSH 2011) and information on concentrations at which a visible cloud would form, as human exposures were reported for such cases without adverse health effects. SRC did not pursue the committee’s previous suggestion of using an RD50-based approach to derive AEGL-1 values because no RD50 estimate for mice was identified and because the RD50 for rats produced AEGL-1 values that exceed the point of departure for AEGL-2 values. However, the committee suggests that this approach be revisited by considering relative toxicities of transformation products that would be formed immediately upon release of titanium tetrachloride, in the same manner as is done for similar chemicals (e.g., others that form hydrogen chloride upon release). RD50 values for hydrogen chloride are available (see NRC 2009). Such information taken together with information provided in Kelly (1980) for relative toxicities of titanium tetrachloride and hydrogen chloride (accounting for stoichiometry), as well as other data not yet reflected in the TSD, may suggest a basis for deriving AEGL- 1 values. Furthermore, the point of departure for the AEGL-2 values warrants revisiting, because it is from a repeat inhalation study (see discussion below). It may be helpful to review other relevant applications of the RD50 approach (e.g., see NRC 2009). The TSD should provide a more integrated compilation of dose-response data to facilitate evaluation of effect severities across species, exposure durations, and end points, including consideration of fate products and variations in relative humidity. Such a compilation in tabular form might help to clarify options for derivation of AEGL-1 values. For the AEGL-2, SRC proposed two options that are based on a 4-week exposure study (Kelly 1979). The committee disagrees with the statement that “acute animal toxicity data are not appropriate for AEGL derivation,” and recommends that its previous comments on the use of repeat- exposure studies for deriving AEGL-2 values be considered again. The study by Kelly (1980) appears to be relevant, and more detailed information about toxic symptoms at individual concentrations could be sought by contacting the investigator. Relevant context might also be found in the NRC AEGLs report for hydrogen chloride (NRC 2004) and a more recent derivation of a 1-hour emergency exposure guidance level (NRC 2009). TABLE 16 Summary of Proposed AEGL Values for Titanium Tetrachloride 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 17 mg/m3 17 mg/m3 7.7 mg/m3 1.6 mg/m3 0.72 mg/m3 AEGL-2 No-effect level for (disabling) irreversible or other serious, long-lasting health effects or an impaired ability to escape (10 mg/m³ for 6 h/d, 5 d/wk for 4 wk) UF = 10; n = 0.88 for time scaling 95 mg/m3 33 mg/m3 14 mg/m3 5.1 mg/m3 2.3 mg/m3 AEGL-3 One-third of rat LC50 (lethal) values; UF = 30; n = 0.88 for time scaling 18

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Consideration should be given to using an intraspecies uncertainty factor of 10 in deriving AEGL-2 and AEGL-3 values, given that the specific mode of action is not yet clearly defined. Furthermore, variability in particle sizes can affect both toxicokinetics and toxicodynamics. With formation of titanium oxide and oxychlorides upon release of the tetrachloride, recent studies have characterized the impact of particle size (vs. concentration) on differential clearance, distribution, and relative toxicity for very small particles. (For example, K.P. Lee, H.J. Trochimowicz, C.F. Reinhardt, and others have assessed translocation of fine/ultrafine titanium dioxide particles following inhalation exposure in rats, while R. Kumazawa and others have assessed the effects of these small particles on neutrophil function.) Given the variability issues noted above, consideration should be given to whether the default approach of calculating an LC01 based on one-third the LC50 values is appropriate. A tabulated presentation of relevant data across species (beyond rats), exposure durations, end points, and effect levels would facilitate such an evaluation. Other Comments A short discussion should be added about nanoscale particles formed in the air and lungs (vs. those formed by milling), and that nanoscale titanium dioxide is likely to be a coexposure with titanium tetrachloride. Page 6, lines 5-12, and page 9, lines 1-14: Production information should be updated with more recent information. For example, the reference cited in the current draft to support the statement that titanium tetrachloride “is still used in the production of military smoke screens” is more than ten years old. It would be useful to qualify such statements per the time frame indicated or refer to other recent reviews (e.g., EPA 2009). Page 6, lines 40-42: The substantial role of humidity in the toxicity of titanium tetrachloride and its transformation products should receive more emphasis (including quantitative context) to ensure that humidity is appropriately accounted for in the event of a release. Page 6, line 45 to page 7, line 6: The discussion should clarify that histopathology was only performed on the respiratory tract in the Kelly (1980) study. Page 7, lines 12-13: The discussion should acknowledge that clinical effects in rats exposed at 10 mg/m3 returned to normal after the 2-week recovery period, whereas rats exposed at 5 mg/m3 had results similar to controls (which suggest a no adverse effect level). Page 7, lines 20-21: The discussin should clarify that collagenized fibrosis still remained 12 months post-exposure, especially in the respiratory bronchioles and adjoining alveolar walls. Page 8, Table S.1, lines 20-25 (footnotes): Differential toxicity implications of both relative humidity and nanoscale titanium should be discussed further in the text (not just in footnotes to the table), including more quantitative context, to support practical implementation of AEGL values. Page 20, lines 24-25: It is unclear why this section is proposed for deletion. As noted earlier, further consideration should be given to using RD50s as a basis for AEGL-1 values. Page 22, lines 10-20: Titanium dioxide has been identified as an immediate transformation product of titanium tetrachloride. Recent toxicity studies of this chemical might provide information on potential mode of action and joint toxicity of titanium tetrachloride with its conversion products. Page 23, lines 1-2: More recent references should be included to support the statement that “the toxic effects of titanium tetrachloride are unlikely to be similar to those induced by either titanium dioxide or HCl alone.” Relevant information includes quantitative context from Kelly (1979), the role of oxychlorides and fine/ultrafine particles, and joint toxicity. In addition, studies on differential clearance and translocation beyond the respiratory tract would also be relevant. Page 23, lines 7-13 (Species Variability): More quantitative context should be provided in the discussion of species variability. Such context would include considering the potential impacts of 19

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toxicokinetic differences among species on joint toxicity and interpretation of available studies. A summary table of data relevant to species variability would be very helpful to facilitate comparisons. Page 23, lines 16-21 (Susceptible Populations): This statement appears to support an uncertainty factor of 10 because of lack of information on mode of action and susceptibility, in addition to the variable humidity and variations in sizes and forms of the transformation products, as affected by the nature of the release and the exposure setting (e.g., see Roy et al. 2003 and Kapias and Griffiths 2005). A literature search should be conducted for relevant information to inform the interspecies adjustment (for example, see general susceptibility considerations noted by Testud and Lambert-Chhum [2004] and others). Page 23, lines 37-40 (Concurrent Exposure Issues): This section should be revised to better explain the nature and importance of the concurrent exposure issue, which is inherent to any release of titanium tetrachloride. Page 24, Section 4.4.5 (Factors Affecting Toxicity of Titanium Tetrachloride: Nanoscale Uses and Humidity): This section whould be revised so the implications of both nanoscale titanium particles and humidity are clear and can be incorporated in the practical implementation of the AEGLs if titanium tetrachloride is released (particularly if the area happens to be very humid). Page 24, lines 36-37: Regarding the statement that no odor threshold data are available, some context may exist (e.g., see the indicator in AIHA® 2011). Additional information might now be available on titanium tetrachloride because of its use in nanoscale titanium dioxide production. Page 26, lines 1-2: To avoid a possible misinterpretation that 10 mg/m3 is a no-observed adverse- effect level, it would be useful to acknowledge the results of clinical lab tests for that exposure group, and to explain dose-dependent acute inflammation of the respiratory tract after 20 days of exposure (6 hours per day, 5 days a week for 4 weeks). Page 26, lines 16-17: The following sentence seems more relevant to AEGL-1 values: “Because of the irritating properties of this chemical, the AEGL-2 should be based on irritation.” The data should be reassessed for relevance to the AEGL-2 bases. Page 26, lines 44-47: “An intraspecies uncertainty factor of 3 was chosen because the mechanism of action, direct contact irritation, is not expected to vary greatly among subpopulations.” This statement may not adequately reflect the available data. Furthermore, the mechanism of action may not be clearly known (e.g., see comments on the previous draft TSD). Page 27, lines 10-32: For the AEGL-2 derivation, consideration should be given to how values for hydrogen chloride were derived in NRC (2009). An uncertainty factor of 10 could be considered based on variability across species and the potential for differential susceptibility in humans. The committee recommends that AEGL-2 values not be derived by dividing the AEGL-3 values by 3, given that relevant data exist. See page 29, lines 33-35, regarding the indication that species differences in the transport and deposition of titanium oxide hydrates and/or oxychloride particles (that are postulated to deliver irritant hydrogen chloride to the deep lungs) cannot be ruled out. The same logic applies for using that uncertainty factor of 10 to derive the AEGL-2 values. Page 30, lines 14-16: The following sentence could be interpreted as somewhat misleading: “Although no clinical signs were reported at this concentration, exposure to the next higher concentration (resulting in labored breathing) approached the lethality threshold concentration.” It is important to clarify that the next higher concentration is substantially higher (representing the widest dose spacing of the study). The statement also contrasts with opposite argument that seems to be made earlier (see page 26, lines 19-23) in stating that it is unclear whether the effect was only seen after repeated exposures, in which case it could be considered a no-effect level for AEGL-2 end points. Page 31, Table 13 (line 5): More recent references should be used to support current standards and guidelines. For example, the AIHA® ERPGs are still cited in the TSD as a 2004 reference, while a more current source is available. Page 31, lines 1-2 and 20-25: The following statement in the TSD only applies to the molar basis: “The Kelly (1980) study reported a 16-fold higher potency of titanium tetrachloride compared to that expected from HCl alone.” On a weight basis, Kelly indicates the difference is 4-fold. 20

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Page 32, Section 8.3 (Data Adequacy and Research Needs): A valuable opportunity seems to exist with regard to contacting the author of the key studies (Kelly) for information that could potentially address limitations noted in this section, and provide further insight for the derivation of improved AEGLs for titanium tetrachloride. Editorial Comments Values and unit conversions should be checked to ensure technical accuracy and consistency. It is unclear that it is appropriate for all values to be presented in mg/m3, so further rationale should be provided for why this was done. Page 7, line 9: Clarify that the “measured concentrations” were 4-week averages that ranged higher and lower over that time. Page 9, lines 31-33: The following statement should be revisited: “Animal studies in rats, mice, and dogs are available but the studies are of limited usefulness because of poor reporting of experimental procedures and results, or because they were repeated exposure studies,” given that the Kelly (1980) study was well-designed and conducted and that the Kelly (1979) repeated-exposure study was used to derive AEGL values. Examples of Potentially Relevant References Not Cited in TSD ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Titanium Tetrachloride. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry [online]. Available: http://www.atsdr.cdc.gov/ToxProfiles/ tp101.pdf [accessed June 18, 2012]. Beloskurskaia, G.I., E.M. Purysheva, A.I. Pronchenkov, R.N. Esenalieva, and E.I. Turamsheva. 1972. Health status of workers of the main occupational groups engaged in the production of titanium as revealed by complex dynamic studies [in Russian]. Gig. Tr. Prof. Zabol. 16(10):29-32. Bisse, E., and D.J. Vonderschmitt. 1978. Immobilization of glucose dehydrogenase by titanium tetrachloride. FEBS Lett. 93(1):102-104. Cadosch, D., M. Sutanto, E. Chan, A. Mhawi, O.P. Gautschi, B. von Katterfeld, H.P. Simmen, and L. Filgueira. 2010. Titanium uptake, induction of RANK-L expression, and enhanced proliferation of human T- lymphocytes. J. Orthop. Res. 28(3):341-347. Elo, R., K. Määattä, E. Uksila, and A.U. Arstila. 1972. Pulmonary deposits of titanium dioxide in man. Arch. Pathol. 94(5):417-424. EPA (U.S. Environmental Protection Agency). 2010. Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen. EPA/600/R-09/057F. National Center for Environmental Assessment-RTP Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid= 230972 [accessed July 6, 2012]. Kapias, T., and R.F. Griffiths. 2005. Accidental releases of titanium tetrachloride (TiCl4) in the context of major hazards—spill behaviour using REACTPOOL. J. Hazard. Mater. 119(1):41-52. Moseley, C., D. Garabrant, and L. Fine. 1980. Health Hazard Evaluation Report No. HE-79-17-751 at RMI Metals Reduction Plant, Ashtabula, OH. NTIS PB 82-103243. Health Hazard and Technical Assistance Branch, National Institute for Occupational Safety and Health, Cincinnati, OH. October 1980. NIOSH (National Institute for Occupational Safety and Health). 2009. Approaches to Safe Nanotechnology: Managing the Health and Safety Concerns Associated with Engineered Nanomaterials. DHHS (NIOSH) Publication No. 2009-125. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/docs/2009-125/pdfs/2009-125.pdf [accessed July 5, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2011. Occupational Exposure to Titanium Dioxide. Current Intelligence Bulletin 63. DHHS (NIOSH) Publication No. 2011-160. [online]. Available: http://www.cdc.gov/niosh/docs/2011-160/ [accessed June 25, 2012]. 21

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Park, T., R. DiBenedetto, K. Morgan, R. Colmers, and E. Sherman. 1984. Diffuse endobronchial polyposis following a titanium tetrachloride inhalation injury. Am. Rev. Respir. Dis. 130(2):315-317. Roy, P.K., A. Bhatt, and C. Rajagopal. 2003. Quantitative risk assessment for accidental release of titanium tetrachloride in a titanium sponge production plant. J. Hazard. Mater. 102(2-3):167-186. Testud, F., and R. Lambert-Chhum. 2004. Reactive airway dysfunction syndrome: More flexible application of diagnostic criteria are important for occupational accident victims [in French]. Rev. Pneumonol. Clin. 60(3):154-157. TRIMETHYLACETYL CHLORIDE The committee reviewed the AEGL TSD on trimethylacetyl chloride that was presented by Lisa Ingerman of SRC, Inc. Table 17 presents a summary of the proposed AEGL values for trimethylacetyl chloride and their basis. The committee agreed that its previous comments on the TSD (NRC 2011a) were adequately addressed, and that the document can be finalized for publication after a few clarifications are made. Other Comments For clarity, the TSD should include the rationale for exploring whether data on phosgene could be used in the development of AEGL values for trimethylacetyl chloride, and should explain why the phosgene data were not used. Considerations should also be given to moving the comparison of the AEGLs values for trimethylacetyl chloride and phosgene from Section 8.2 (Comparison with Other Standards and Guidelines) to Section 8.1 (AEGLs Values and Toxicity End Points). Editorial Comments Page 5, line 13: delete “the” before “a mouse study.” Page 7, lines 4-6: consider splitting the sentence into two sentences. Page 11, line 14: add “exposure” after “Phosgene.” Page 11, line 25: the uncertainty factor is 10 not 9. VINYL ACETATE MONOMER The committee reviewed the AEGL TSD on vinyl acetate monomer that was presented by Heather Carlson-Lynch of SRC, Inc. Table 18 presents a summary of the proposed AEGL values for vinyl acetate monomer and their basis. The committee agreed that its previous comments (NRC 2010b) on the TSD have been adequately addressed, and that the document can be finalized for publication after a few editorial clarifications are made. Editorial Comments Section 6.3: In the discussion of AEGL-2 values, the olfactory degeneration/necrosis should not be described as “reversible,” because there are no data to support that contention. Page 7, line 5, and page 39, line 35: Suggest the following revisions for clarity: “Application of a higher total uncertainty factor of 30 would reduce the AEGL-3 values below concentrations that—albeit at shorter exposure durations—did not result in serious health effects . . .Data in human volunteers showed no serious health effects as . . ..” The reference to Frame (2004) is a personal communication and should be cited as such in the text rather than the reference list. 22

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TABLE 17 Summary of Proposed AEGL Values for Trimethylacetyl Chloride 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 0.20 ppm 0.20 ppm 0.16 ppm 0.10 ppm 0.070 ppm One-third of (0.98 mg/m3) (0.98 mg/m3) (0.78 mg/m3) (0.49 mg/m3) (0.34 mg/m3) (disabling) AEGL-3 values AEGL-3 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.20 ppm 6-h exposure causing no (2.9 mg/m3) (2.9 mg/m3) (2.3 mg/m3) (1.5 mg/m3) (0.98 mg/m3) (lethal) mortality in the rat (78 ppm); UF 100; MF = 3; default time scaling TABLE 18 Summary of Proposed AEGL Values for Vinyl Acetate Monomer Reviewed by the Committee End Point, Classification 10 min 30 min 1h 4h 8h Derivation Factors AEGL-1 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm 6.7 ppm No-effect level for notable (24 mg/m3) (24 mg/m3) (24 mg/m3) (24 mg/m3) (24 mg/m3) (nondisabling) discomfort in humans (20 ppm, 4 h); UF = 3 AEGL-2 46 ppm 46 ppm 36 ppm 23 ppm 15 ppm No-effect level for serious, (160 mg/m3) (160 mg/m3) (130 mg/m3) (81 mg/m3) (53 mg/m3) (disabling) long-lasting histopathologic nasal lesions in rats (200 ppm, 6 h); UF = 10; default time scaling AEGL-3 230 ppm 230 ppm 180 ppm 110 ppm 75 ppm Highest nonlethal (810 mg/m3) (810 mg/m3) (630 mg/m3) (390 mg/m3) (260 mg/m3) (lethal) concentration in rats or mice (1,000 ppm, 6 h/day, 28 days); UF = 10; default time scaling REFERENCES Ambrose, A.M. 1950. Toxicological studies of compounds investigated for use as inhibitors of biological processes. II. Toxicity of ethylene chlorohydrin. AMA Arch. Ind. Hyg. Occup. Med. 21(5):591-597. DFG (Deutsche Forschungsgemeinschaft). 2012. Substance Overview for 2-Chloroethanol. The MAK Collection for Occupational Health and Safety [online]. Available: http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mbe10707/full [accessed May 22, 2012]. Dudley, H.C., and P.A. Neal. 1942. Toxicology of acrylonitrile (vinyl cyanide). I. Study of the acute toxicity. J. Ind. Hyg. Toxicol. 24(2):27-36. Dunlap, M.K., J.K. Kodama, J.S. Wellington, H.H. Anderson, and C.H. Hine. 1958. The toxicity of allyl alcohol. 1. Acute and chronic toxicity. AMA. Arch. Ind. Health 18(4):303-311. Gage, J.C. 1959. The toxicity of epichlorohydrin vapour. Br. J. Ind. Med. 16(1):11-14. Gupta, R.C., ed. 2009. Handbook of Toxicology of Chemical Warfare Agents. Boston: Elsevier/Academic Press. Kelly, D.P. 1979. Four-Week Inhalation Study with Titanium Tetrachloride (TiCl4). Haskell Laboratory Report No. 459-79, October 1, 1979. Kelly, D.P. 1980. Acute Inhalation Studies with Titanium Tetrachloride. Haskell Laboratory Report No. 658-80. E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. October 31, 1980. 23

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Kirkpatrick, D.T. 2008. Acute Inhalation Toxicity Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-Hour Exposure Durations). Study No. WIL-14068. WIL Research Laboratories, LLC., Ashland, OH; Sponsored by Lyondell Chemical Company, Houston, TX. Langford, R.E. 2004. Introduction to Weapons of Mass Destruction, Radiological, Chemical, and Biological. Hoboken, NJ: Wiley-Interscience. Lyondell Chemical Company. 2012. Re: Proposed AEGL Value for Allyl Alcohol. Letter to Susan Martel, NAS Committee on Toxicology, Washington, DC, from Marcy Banton, Manager, Toxicology and Risk Assessment, Lyondell Chemical Company, Houston, TX. April 19, 2012. Murray, F.J., K.D. Nitschke, J.A. John, A.A. Crawford, J.S. Murray, L.W. Rampy, and B.A. Schwetz. 1978. Teratologic Evaluation of Inhaled Acrylonitrile Monomer in Rats. Toxicological Research Laboratory, Health and Environmental Research, Dow Chemical USA, Midland, MI. Neilsen, G.D., and J.C. Bakbo. 1985. Sensory irritating effects of allyl halides and a role for hydrogen bonding as a likely feature at the receptor site. Acta Pharmacol. Toxicol. 57(2):106-116. Neilsen, G.D., J.C. Bakbo, and E. Holst. 1984. Sensory irritation and pulmonary irritation by airborne ally acetate, allyl alcohol, and allyl ether compared to acrolein. Acta Pharmacol. Toxicol. 54(4):292-298. 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). 2002. Phosgene. Pp. 13-70 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: The National Academies Press. NRC (National Research Council). 2004. Hydrogen chloride. Pp. 77-122 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The National Academies Press. NRC (National Research Council). 2009. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Vol. 3. Washington, DC: The National Academies Press. NRC (National Research Council). 2010a. Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels. Washington, DC: The National Academies Press. NRC (National Research Council). 2010b. Eighteenth Interim Report of the Committee on Acute Exposure Guideline Levels. Washington, DC: The National Academies Press. NRC (National Research Council). 2011a. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. NRC (National Research Council). 2011b. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. Perez, C., and S.C. Soderholm. 1991. Some chemicals requiring special consideration when deciding whether to sample the particle, vapor, or both phases of an atmosphere. Appl. Occup. Environ. Hyg. 6(10):859-864. Raje, R.R., M. Greening, and M.T. Fine. 1984. Blood n-hexane concentration following acute inhalation exposure in rats. Res. Commun. Chem. Pathol. Pharmacol. 46(2):297-300. Saillenfait, A.M., I. Langonne, J.P. Sabate, and J. De Ceaurriz. 1992. Embryotoxicity of acrylonitrile in whole- embryo culture. Toxicol. In Vitro 6(3):253-260. Saillenfait, A.M., P. Bonnet, J.P. Guenier, and J. De Ceaurriz. 1993. Relative developmental toxicities of inhaled aliphatic mononitriles in rats. Fundam. Appl. Toxicol. 20(3):365-375. Saillenfait, A.M., J.P. Sabaté, and C. Gaspard. 2004. Effects of aliphatic nitriles in micromass cultures of rat embryo limb bud cells. Toxicol. In Vitro 18(3):311-318. Swann, H.E., B.K. Kwon, G.K. Hogan, and W.M. Snellings. 1974. Acute inhalation toxicology of volatile hydrocarbons. Am. Ind. Hyg. Assoc. J. 35(9):511-518. 24