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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels BACKGROUND In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) asked the National Research Council (NRC) to provide technical guidance for establishing community emergency exposure levels (CEELs) for extremely hazardous substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects. NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or terrorist activities. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-2 and AEGL-3, and AEGL-1 values as appropriate will be developed for each of five exposure periods (10 and 30 min and 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life- threatening health effects or death. 1

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THE CHARGE TO THE COMMITTEE The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment. The charge to the committee is to (1) review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review NAC’s research recommendations and—when appropriate—identify additional priorities for research to fill data gaps; and (3) review periodically the recommended standard procedures for developing AEGLs. This interim report presents the committee’s conclusions and recommendations for improving the NAC’s AEGL documents for 29 chemicals: chloroacetyl chloride, dichloroacetyl chloride, methanesulfonyl chloride, trimethylacetyl chloride, bromoacetone, butane, BZ (3-quinuclidinyl benzilate), chloroacetone, epichlorohydrin, ethyl phosphorodichloridate, ethylene chlorohydrin (2- chloroethanol), isocyanates (cyclohexyl, ethyl, and phenyl isocyanates), mercaptans (ethyl, methyl, phenyl, and tert-octyl mercaptans), methacrylonitrile, methyl bromide, methyl chloride, methyl isothiocyanate, nitrogen mustards (HN-1, HN-2, and HN-3), perchloryl fluoride, piperidine, tetramethoxysilane, and trimethoxysilane. ACID CHLORIDES At its meeting held on April 5-7, 2011 the committee review the technical support documents (TSDs) on chloroacetyl and dichloroacetyl chloride (CAC and DCAC, respectively), methanesulfonyl chloride, and trimethylacetyl chloride. Presentations of the CAC and DCAC and trimethylacetyl chloride TSDs were made by Lisa Ingerman of Syracuse Research Corporation. A presentation of methanesulfonyl chloride was made by Julie Klotzbach of Syracuse Research Corporation. Although CAC and DCAC are combined into a single TSD, AEGL-specific comments below are separated. Chloroacetyl and Dichloroacetyl Chloride The following is excerpted from the Executive Summary of the TSD: Because the database for DCAC was very limited, and the available data indicated that DCAC was less toxic than CAC, all AEGL values developed for CAC were adopted for DCAC…. AEGL-1 values were derived from a multiple-exposure study in which rats, mice, and hamsters received 18-20 exposures for 6 hours/day to nominal concentrations of 0.5, 1, 2.5 or 5 ppm CAC (Dow 1982)…. The AEGL-2 values were derived using a study in which rats inhaled 32, 208, 522, or 747 ppm CAC for 1 hour (Dow 1986)…. The AEGL-3 values were also based on the Dow (1986) 1-hour inhalation rat study in which exposure was to 32, 208, 522, or 747 ppm CAC. A revised document should be submitted to the committee for review. AEGL-Specific Comments for Chloroacetyl Chloride AEGL-1 Page 26, lines 26-28: “AEGL-1 values were derived using a single 6-hour exposure to ~1 ppm (0.84 ± 0.51 ppm) because this is the highest concentration that caused conjunctival redness but no other more serious effects after one exposure.” The authors should revisit the point of departure (POD) for the 2

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AEGL-1 values. As noted by the committee as well as the technical presenter at the April meeting, the lowest exposure level associated with conjunctival redness is 0.5 ppm. AEGL-1 values must be recalculated, and corrections made throughout the text to reflect this lower exposure concentration. Page 26, lines 28-29: “A modifying factor [MF]of 2 was applied to estimate a no-effect level concentration for conjuctivitis.” Please provide justification for selecting an MF of 2 rather than 3 to estimate the no-effect level. Is a MF of 3 more appropriate considering the potential for respiratory irritation in susceptible subgroups at similar concentrations? Page 26, lines 29-31: “The same AEGL value is adopted for 10 minutes to 8 hours because mild irritant effects do not vary greatly over time.” The authors should revisit the scaling assumption, taking into consideration the biologic basis as well as consistency (see related comment for the AEGL-2 values). Not only are the concentrations corresponding to mild and significant ocular effects very close to one another, but also CAC is a respiratory irritant. Thus, in the general population, a substantial number of people susceptible to respiratory effects (e.g., those having asthma and chronic obstructive pulmonary disease [COPD]) could potentially incur adverse effects at concentrations corresponding to mild ocular effects, considering the small set of workers (assumed healthy) for which eye irritation data are available. It is also useful to acknowledge that effects may be delayed (e.g., see IPCS [1998]: “The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physical effort.”) Also, see similar comments below for AEGL-2 and AEGL-3. Page 26, lines 31-33: “A total uncertainty factor [UF]of 10 was applied: 3 for interspecies variability and 3 for intraspecies variability, because the NOEL [no-observed-effect level] for eye conjunctivitis due to local contact irritation is not expected to vary greatly among animals or humans.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with the standing operating procedures (SOP) section 2.5.3.4 (pages 88-91). This factor would produce a combined (total) UF of 30 rather than 10. Note that the UF of 3 reflected in the TSD is not necessarily consistent with the interspecies response differences noted in the Executive Summary, Section 5.2 (page 25, line 42–page 26, line 16). AEGL-2 Page 27, lines 23-25: “The AEGL-2 end point was the NOEL for impaired ability to escape due to lacrimation and eye squinting, which was estimated by applying a modifying factor of 2 to the lowest concentration tested of 32 ppm.” The authors should consider a lower POD for AEGL-2. As noted in the TSD, a CAC exposure of 0.91 in workers was “painful to the eyes and caused lacrimation” (p. 27, lines 6- 7), both effects (in relatively healthy adults) suggesting an impaired ability to escape in the general population. Additional justification should be provided for selecting an MF of 2 to estimate the no-effect level, or consideration should be given to selecting a factor of 3. Selection includes considering the potential for respiratory irritation in susceptible subgroups at similar concentrations. Page 27, lines 28-30: “To obtain protective AEGL-2 values, scaling across time was performed using n = 3 to extrapolate to exposure times [of] <1 hour (exposure duration in the key study) and n = 1 to extrapolate to exposure times [of] >1 hour.” Please note that it is not clear here what value of n is used for the exposure time of 1 h. Please revisit the assumption for scaling across time, and consider the biologic basis as well as the consistency across the AEGL values. No scaling was applied for the AEGL-1 values, yet scaling was applied to derive AEGL-2 values that are also based on ocular irritation. See the more detailed comment above for AEGL-1. Page 27, lines 31-33: The authors applied an intraspecies UF of 3 “because the AEGL-2 end point (NOEL for eye irritation sufficient to cause lacrimation and squinting) is a direct surface contact effect that is not likely to vary in severity among animals or humans.” CAC is also a respiratory irritant, and it is possible that sensitive individuals may experience respiratory effects at these levels. Section 2.5.3.3.4 of the SOP (p. 88) states that “a default UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants.… Responses of asthmatics to 3

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respiratory irritants may range from mild to severe. A UF of less than 10 might be used when scientific evidence shows that a smaller UF will be protective of health.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with the SOP. AEGL-3 Page 28, lines 35-38: “An intraspecies uncertainty factor of 3 was applied because the threshold for lethality from direct destruction of respiratory tissue is not expected to vary greatly among humans, based on the steep dose-response seen in the animal studies.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with Section 2.5.3.3.4 of the SOP (p. 88). See the similar comment above for AEGL-2. AEGL-Specific Comments for Dichloroacetyl Chloride Page 7, lines 10-12: “Because the database for DCAC was very limited, and the available data indicated that DCAC was less toxic than CAC, all AEGL values developed for CAC were adopted for DCAC.” The authors should reconsider the available information to derive separate AEGL values for DCAC. For example, see DuPont (2004, 2006) and EPA (2008a,b, 2010a,b; 2011a,b,c). EPA (2008b) considers dichloroacetic acid (DCA) as an analog for DCAC and stated that “Acute toxicity of DCAC and/or DCA is low via the oral route, but is moderate via inhalation and dermal exposure.” Such statements suggest that the TSD authors could consider other toxicity information, including information for DCA, as part of a weight-of-evidence approach to support the derivation of AEGL values for DCAC. To illustrate for information related to the AEGL-3, a male rat LC50 (lethal concentration to 50% of the exposed population) for a 4-h vapor exposure was identified as about 2,000 ppm (not an analytic measurement), and 8 min was indicated as the maximum exposure time to saturated vapor that produced no deaths (as summarized in EPA [2011b], as cited in Smyth et al. [1951], which is included in the TSD, and Smyth and Carpenter [1948], which is not). Note that the information from Smyth and colleagues might reflect a nominal concentration, and actual analytic levels could be quite low; thus, DCAC could be worse than CAC. It would be useful to evaluate additional information to determine if measurements were made for these earlier studies. Other acute toxicity information highlighted in EPA (2011b) includes data from Yount et al. (1982). This original study is not readily available online; it could be helpful to pursue it and other studies, such as the Ciba-Geigy report (cited as V. Traina et al. [1977] in EPA 2011b) for additional insights regarding relative toxicity. More information regarding relative toxicities is also indicated in Woodard et al. (1941), as cited in WHO (2004), and other sources. Comparisons between the acetyl chlorides and associated fate and metabolic products should also be considered for potential insights, including the corresponding chloroacetic acids, hydrogen chloride, and phosgene. Other Comments for CAC and DCAC Multiple pages and sections: Various sections of the TSD reflect outdated or missing information. The TSD authors need to ensure that the literature summaries for the chemicals have been updated for documents that have been in the AEGL-development process for several years. The date of the most recent literature review should be included in the TSD (perhaps the cover page and the executive summary). The TSD should be revised to include current information and additional data potentially useful to the AEGL derivations (particularly DCAC) and supporting material. The following sources contain more recent information (including production and use data): the EPA High Production Volume (HPV) Program, including risk-based prioritization analyses (EPA 2008a,b), the Chemical Assessment 4

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and Management Program (EPA 2010a, 2011a), the Inventory Update Reporting (EPA 2010b), and the HPV Information System (HPVIS, EPA 2011b,c) as well as DuPont (2004, 2006). Page 7, line 43: In light of the potential for respiratory effects, the committee suggests deleting “protective” from “To obtain protective AEGL-2 values….” because data are insufficient to clearly support that statement (here and elsewhere in the document). Page 8, Table 1, Summary of AEGL Values: In the “End Point (reference)” column, clarify that these entries reflect an estimated NOEL (not a study-reported NOEL), and include the PODs, UFs, and MFs used. The authors should consider providing additional information in the footnote on odor detectability to indicate that lower odor thresholds have been reported and to indicate how close the detectable levels are to the concentration associated with discomfort. Page 10, Table 2, Chemical and Physical Properties of CAC and DCAC: Please re-evaluate the information presented in this table. Information available via several common sources include many values that differ (in some cases, substantially) from those reported in Table 2. Information sources include the National Library of Medicine Hazardous Substances Data Bank (HSDB) (note EPA [2008b] refers to HSDB [2007], compared to the 2003 HSDB citation in the TSD) and the HPVIS (EPA 2011b) as well as material safety data sheets and the International Program on Chemical Safety (IPCS 1997) (e.g., the latter includes explosive limit information for DCAC). Page 10, Section 2.1. Acute Lethality (also Section 2.2. Nonlethal Toxicity): It would be helpful to check the current literature to determine if relevant data are available (e.g., Zou et al. 2008) to add to the human data sections. Page 10, lines 6-8: “Based on the adverse effects of inhalation exposure in humans, it is likely that exposure to sufficiently high concentrations of CAC would result in death.” The authors should consider deleting this statement as it could apply to all chemicals, not only CAC. Page 10, lines 8-9: “Reported effects include chest tightness, laryngospasm, pulmonary edema, bronchospasm, and bronchopneumonia (HSDB 2003a).” Please clarify who reported these effects. Is it from an occupational exposure or a research study? Page 10, Section 2.2. Nonlethal Toxicity (also Section 3.2. Nonlethal Toxicity): Consider adding further subsections to address other end points (e.g., cardiovascular for humans and immunotoxicity and hepatotoxicity for animals). Some potential sources are Cai et al. 2006; Khan et al. 1997; and König et al. (2008). Page 11, line 31 (also page 12, Table 3): “Dahlberg and Myrin (1971) described scenarios in 10 welding shops in which welders were exposed to DCAC….” Please clarify what “scenario” means. Do the authors mean workplace exposures or accidents? The committee suggests using a different word. Page 13, Section 2.6. Carcinogenicity, lines 41-43: “No studies examining the carcinogenic activity of CAC or DCAC were located.” We suggest checking the current literature for information regarding potential carcinogenicity (notably for DCAC). Page 13, lines 41-43: “Treatment of male or female Sherman albino rats with 1000 ppm (range of 700-1390 ppm) CAC for 4 hours killed either 2/6, 3/6, or 4/6 animals after 14 days in a range-finding test (Carpenter et al. 1949).” Please check whether additional information might be available (possibly in subsequent studies) regarding the specific concentrations that killed the animals. It is not clear whether the target was 1,000 ppm or whether actual concentrations were in the noted range. These mortality data are not useful in terms of deriving guideline levels unless the specific concentrations resulting in the different percent mortalities are known. Page 14, lines 7-8; lines 9-10: “It was not specified whether the air concentrations were analytical or nominal (assume nominal).” Please provide the basis for the assumption that the concentration is nominal, or delete “(assume nominal)” from the text (lines 7-8). “Results were not given other than that all animals inhaling ≥16 mg/L (3462 ppm) died on study, and that 5 rats inhaling 2381- 6480 ppm died within the first 2-3 minutes of exposure.” Please clarify what is meant by this sentence (lines 11-12). Also, the committee suggests rewording “died on study” to “died during the exposure.” The suggested revision also applies to page 20, line 14, and page 21, line 24. 5

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Page 16, Table 4, The “Effects, Comments” column is not aligned with the concentration and mortality entries in the other columns. It is difficult to determine which effects are associated with which concentrations; please align the columns in Table 4. Page 17, Table 5, Chloroacetyl Chloride Multiple-Exposure Animal Studies: For the Dow (1982) summary, please add the statement that death occurred in mice and rats at 2.5 and 5.0 ppm (and include the number of deaths per total number or animals exposed). Please check whether more specific information could be provided regarding effects observed following the initial exposure; some overviews of this study indicate effects at lower concentrations throughout the study period. Page 18, lines 31-34: “No mice died at ≤649 ppm, all mice inhaling ≥3030 ppm died during the 2-hour exposure, and 18 mice inhaling 2381-6480 ppm died within the first 2-3 minutes of exposure. Over the 5-day period, all mice died at ≥10 mg/L (2164 ppm).” Please clarify this information, as there is some confusion regarding all mice dying at or above 3,030 ppm and then all mice dying at or above 2,164 ppm. Also, please indicate how many mice were included in the 2381-6486 exposure group (i.e. 18 our of how many mice died)? Page 19, line 2: Please clarify whether “detachment of mucosa” reflects sloughing of mucosa. Page 19, lines 31-32: The text states that “exposure to ~4 ppm for 5-10 minutes caused ‘respiratory embarrassment’ (i.e. respiratory difficulty or distress) in a range-finding study (Dow 1970a).” This study was not readily available to check how the original authors defined “respiratory embarrassment”; we suggest revising this sentence to use more readily understandable terminology. Page 20, Section 3.4. Developmental and Reproductive Toxicity: The text states that “No animal studies were located that evaluated developmental and/or reproductive toxicity of CAC or DCAC.” Relevant information is available. The description of a developmental toxicity study was included in the DuPont (2004) submission to EPA for DCAC under the Chemical Right-to-Know Program, as part of the proposed test plan package. Recognizing general route differences, the data indicative of fetal soft tissue malformations, notably the cardiovascular system and ascending aorta and right ventricle, could be relevant to the weight-of evidence evaluation for the AEGL-3. See the subsequent update of that submittal, which included responses to EPA comments regarding use of the analog dichloroacetic acid (DuPont 2006). These reports should be reflected in the TSD. A number of other studies are highlighted in EPA information sources (2008a,b, 2011b) that also warrant consideration in the TSD. Page 20, Section 3.5. Genotoxicity: The most recent information provided in the TSD is from 1994. Please review the literature for updated information. Page 23, line 20–page 24, line 21, Section 4. Special Considerations: Please review information in EPA (2011b), EPA TSDs for the Integrated Risk Information System (IRIS) program, Agency for Toxic Substances and Disease Registry (ATSDR) toxicologic profiles for related chemicals, and the primary literature, such as Chiu et al. (2009), to update the appropriate subsections (including analog information considered relevant)—particularly Section 4.1. Metabolism and Disposition; Section 4.2. Mechanisms of Toxicity; and Section 4.3. Structure Activity Relationships. Page 24, line 23–page 25, line 27, Section 4.4. Other Relevant Information: As described in the preceding comment, please review recent information to update Section 4.4.1. Species Variability (much more information is available in the literature than is reflected here; consider adding a concise summary table). This section could be expanded (or a subsection could be added) to address gender variability. The authors should consider adding a further subsection to address potential joint (combined) toxicity from fate products and metabolites that could coexist during the durations of interest, unless this information is added to Section 4.4.4 (Concurrent Exposure Issues). This further subsection would benefit from the inclusion of additional information for atmospheric fate in Section 1 (Introduction). For example, CAC can form when dichloroethylene (DCE) is released to air. The toxicities of each compound could be jointly considered (as well as other fate products) during exposures lasting up to 8 h. Consider that 1,1-DCE in air forms CAC, phosgene, and formaldehyde; certain data indicate that the atmospheric half-life of this parent can be 4 h when hydroxyl radical concentrations are only 20% above average concentrations (e.g., see ATSDR 2004, 2007; Forkert 2001; EPA 2011b). Similarly, trichloroethylene 6

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released to air can form DCAC (as well as phosgene). Additional information can be found in the literature (e.g., Ou and Lo 2007; Christiansen and Francisco 2010). This information regarding potential mixture toxicity could help inform emergency-response measures in CAC and DCAC release situations. Page 24, lines 35-38: “Interspecies variability between mice, rats, and guinea pigs in a 2-hour exposure study (108-6494 ppm CAC) could not be established because mortality for single exposure concentrations was only provided for mice (Herzog 1959). A comparison of the LC100 values, which were provided for all three species, suggests that interspecies variability was not great. All animals died within 5 days of exposure to 3030 ppm (mice), 3462 ppm (rats), or 3462-3895 ppm (guinea pigs).” This study does not appear well-suited to any conclusions regarding interspecies sensitivity differences. It is possible that the exposure concentrations were so high such that it was not possible to make any meaningful interpretation by being above the threshold for all species for a 100% mortality. It is possible that interspecies differences could have been observed at lower levels, but this study does not provide that information. Page 25, Section 4.4.4. Concurrent Exposure Issues, lines 20-27: “The presence of CAC in the air can also result in inadvertent exposure of the skin, which is capable of absorbing sufficient CAC to result in death (Morris and Bost 2002).” This short section provides brief text for only one compound (CAC) and one (24-h) dermal study. Much more information is available in the literature related to toxicity following dermal exposure (including data for the DCAC analog), which would be valuable to include in this section. Page 25, line 45–page 26, line 2: Section 5.2 lists animal studies “potentially useful for developing AEGL-1 values.” The Dow (1970b) study should not be included in this list because it involved repeated exposures and the rats were examined only after a recovery period or following re- exposure after such a period. This situation complicates any attempt to determine acute effects from these data. Please delete Dow (1970b) from this list. Page 30, Section 8.2. Comparison with Other Standards and Guidelines: The proposed 1-h AEGL-2 is more than 3-fold higher than the corresponding Emergency Response Planning Guideline 2 (ERPG-2). The proposed 1-h AEGL-3 is more than 5-fold higher than the corresponding ERPG-3. The authors should include an explanation for these differences in the text (or consider revising the AEGLs, as suggested in preceding comments). This comment is consistent with the SOP, Appendix J (p. 201): “A summary discussion of important comparisons should be presented in the text and the values for recognized standards and guidelines, if available, should be presented in the table.” References ATSDR (Agency for Toxic Substances and Disease Registry). 2004. Interaction Profile for: 1,1,1-Trichlorethane, 1.1-Dichloroethane, Trichloroethylene, and Tetrachloroethylene. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. May 2004 [online]. Available: http://www.atsdr.cdc.gov/interactionprofiles/ip02.html [accessed May 1, 2011]. ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Interaction Profile for: Chloroform, 1,1-Dichloroethylene, Trichloroethylene, and Vinyl Chloride (Draft). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. August 2007 [online]. Available: http://www.atsdr.cdc.gov/interactionprofiles/ip13.html [accessed May 1, 2011]. Cai, P., R. König, M.F. Khan, S. Qui, B.S. Kaphalia, and G.A. Ansari. 2006. Autoimmune response in MRL +/+ mice following treatment with dichloroacetyl chloride or dichloroacetic anhydride. Toxicol. Appl. Pharmacol. 216(2):248-255. Carpenter, C.P., H.F. Smyth, Jr., and U.C. Pozzani. 1949. The assay of acute vapor toxicity and the grading and interpretation of results on 96 chemical compounds. J. Ind. Hyg. Toxicol. 31(6):343-346. Chiu, W.A., M.S. Okino, and M.V. Evans. 2009. Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach. Toxicol. Appl. Pharmacol. 241(1):36-60. 7

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Christiansen, C.J., and J.S. Francisco. 2010. Atmospheric oxidation of trichloroethylene: An ab initio study. J. Phys. Chem. A 114(34):9163-9176. Dahlberg, J.A., and L.M. Myrin. 1971. The formation of dichloroacetyl chloride and phosgene from trichloroethylene in the atmosphere of welding shops. Ann. Occup. Hyg. 14(3):269-274. Dow (Dow Chemical Company). 1970a. Unreported Acute Inhalation Studies on Chloroacetyl Chloride. Study by R.J. Kociba, Toxicology Research Laboratory, Dow Chemical Company, Midland, MI. Dow (Dow Chemical Company). 1970b. Unreported Studies on Chloroacetyl Chloride. Study by B.K.J. Leong, and R.J. Kociba, Toxicology Research Laboratory, Dow Chemical Company, Midland, MI. Dow (Dow Chemical Company). 1982. Dow Chemical Company Initial Submission: Chloroacetyl Chloride: A Four-Week Inhalation Toxicity Study in Rats, Mice, and Hamsters with Cover Sheet and Letter Dated 04/21/92 (Sanitized). Prepared by J.W. Henck, K.D. Nitschke, G.C. Jersey et al. NTIS/OTS 0536493. EPA Document 88-920002593S. Dow (Dow Chemical Company). 1986. Chloroacetyl Chloride: An Acute Vapor Inhalation Study with Rats. Final Report by C.M. Streeter, J.E. Battjes, and M.A. Zimmer, December 29, 1986. Mammalian and Environmantal Toxicology Research Laboratory, Dow Chemical Company, Midland, MI. DuPont. 2004. Overall Summary for Dichloroacetyl Chloride, 201-15628B1. Memorandum from E.L. Mongan III, Manager, Environmental Stewardship, DuPont Safety, Health & Environment, Wilmington, DE, to Marianne L. Horinko, Administrator, U.S. Environmental Protection Agency, Merrifield, VA, September 29, 2004 [online]. Available: http://www.epa.gov/hpv/pubs/summaries/dichlrac/c15628.pdf [accessed May 16, 2011]. DuPont. 2006. RE: EPA Comments on the Test Plan and Robust Data Summary for Dichloroacetyl Chloride (CAS No. 79-36-7). Memorandum from Edwin L. Mongan III, Manager, Environmental Stewardship, DuPont Safety, Health & Environment, Wilmington, DE, to Stephen L. Johnson, Administrator, U.S. Environmental Protection Agency, Merrifield, VA. September 6, 2006 [online]. Available: http://www.epa.gov/hpv/pubs/summaries/dichlrac/c15628rr.pdf [accessed May 16, 2011]. EPA (U.S. Environmental Protection Agency). 2008a. Initial Risk-Based Prioritization of High Production Volume Chemicals. Chemical/Category: Dichloroacetyl Chloride (DCAC) CAS No. 79-36-7. U.S. Environmental Protection Agency Risk-Based Prioritization Document March 18, 2008 [online]. Available: http://www.epa.gov/chemrtk/hpvis/rbp/DCAC.79376.Web.RBP.3-13-08.pdf [accessed May 16, 2011]. EPA (U.S. Environmental Protection Agency). 2008b. Supporting Documents for Initial Risk-Based Prioritization of HPV Chemicals. Chemical/Category: CAS No. 79-36-7 Dichloroacetyl Chloride (DCAC). U.S. Environmental Protection Agency. March 18, 2008 [online]. Available: http://www.epa.gov/chemrtk/hpvis/ rbp/DCAC.79367.Webpost.Support%20docs.31408.pdf [accessed May 16, 2011]. EPA (U.S. Environmental Protection Agency). 2010a. Chemical Assessment and Management Program (ChAMP). U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ChAMP/ [accessed May 1, 2011]. EPA (U.S. Environmental Protection Agency). 2010b. Non-confidential 2006 IUR Records by Chemical, Including Manufacturing, Processing and Use Information: CAS (79-36-7) Acetyl Chloride, 2,2-dichloro-Inventory Update Reporting (IUR), U.S. Environmental Protection Agency [online]. Available: http://cfpub.epa. gov/iursearch/2006_iur_companyinfo.cfm?chemid=6372&outchem=both [accessed May 1, 201]. EPA (U.S. Environmental Protection Agency). 2011a. Prioritization for Acetyl Chloride, Dichloro-. Chemical Assessment and Management Program, U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/mpv_hpv_prioritizations.case_detail?caseid=4 [accessed May 1, 2011]. EPA (U.S. Environmental Protection Agency). 2011b. High Production Volume Information System (HPVIS): CAS (79-36-7) Acetyl Chloride, Dichloro-. U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=100841 [accessed May 1, 2011]. EPA (U.S. Environmental Protection Agency). 2011c. High Production Volume Information System (HPVIS): CAS (79-04-9) Acetyl Chloride, Chloro-. U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=100837 [accessed May 16, 2011]. Forkert, P.G. 2001. Mechanisms of 1,1-dichloroethylene-induced cytotoxicity in lung and liver. Drug Metab. Rev. 33(1):49-80. Herzog, S. 1959. Experimental studies on the toxicity of chloro-acetyl chloride [in Romanian]. Igiena (Bucharest) 8:135-144. HSDB (Hazardous Substances Data Bank). 2003a. Acetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Sept. 2003]. 8

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HSDB (Hazardous Substances Data Bank). 2003b. Dichloroacetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Sept. 9, 2003]. HSDB (Hazardous Substances Data Bank). 2007. 2, 2-Dichloroacetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Aug. 2, 2007](as cited in EPA 2008b). IPCS (International Programme on Chemical Safety). 1997. Dichloroacetyl Chloride. ICSC: 0869. International Programme on Chemical Safety. April 1997 [online]. Available: http://www.inchem.org/documents/icsc/ icsc/eics0869.htm [accessed May 16, 2011]. IPCS (International Programme on Chemical Safety). 1998. Chloroacetyl Chloride. ICSC: 0845. International Programme on Chemical Safety. March 1998 [online]. Available: http://www.inchem.org/documents/icsc/ icsc/eics0845.htm [accessed May 16, 2011]. Khan, M.F., B.S. Kaphalia, and G.A. Ansari. 1997. Time-dependent autoimmune response of dichloroacetyl chloride in female MRL +/+ mice. Immunopharmacol. Immunotoxicol. 19(2):265-277. König, R., P. Cai, X. Guo, and G.A. Ansari. 2008. Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride. Chem. Res. Toxicol. 21(3):572-582. Morris, E.D., and J.C. Bost. 2002. Acetic acid, halogenated derivatives: Chloroacetyl chloride. In Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons, Inc. Ou, H.H., and S.L. Lo. 2007. Photocatalysis of gaseous trichloroethylene (TCE) over TiO2: The effect of oxygen and relative humidity on the generation of dichloroacetyl chloride (DCAC) and phosgene. J. Hazard. Mater. 146(1-2):302-308. Smyth, H.F., Jr., and C.P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30(1):63-68. Smyth, H.F., Jr., C.P. Carpenter, and C.S. Weil. 1951. Range-finding toxicity data: List IV. A.M.A. Arch. Ind. Hyg. Occup. Med. 4(2):119-122. Traina, V. et al. 1977. Ciba-Geigy Pharmaceuticals Unpublished Report No. 7-77, CGS [as cited in EPA 2011b]. WHO (World Health Organization). 2004. Monochloroacetic Acid in Drinking-Water: Background Document for Development of WHO Guidelines for Drinking-Water Quality. WHO/SDE/WSH/03.04/85. Geneva: World Health Organization [online]. Available: http://www.who.int/water_sanitation_health/dwq/chemicals/ monochloroaceticacid.pdf [accessed May 17, 2011]. Woodard, G., S.W. Lange, K.W. Nelson, and H.O. Calvery. 1941. The acute oral toxicity of acetic, chloroacetic, dichloroacetic and trichloroacetic acids. J. Ind. Hyg. Toxicol. 23(2):78-82 [as cited in WHO 2004]. Yount, E.A., S.Y. Felten, B.L. O’Connor, R.G. Peterson, R.S. Powell, M.N. Yum, and R.A. Harris. 1982. Comparison of the metabolic and toxic effects of 2 chloroproprionate and dichloroacetate. J. Pharmacol. Exp. Ther. 222(2):501-508. Zou, J.F., J. Li, and Y.P. Sun. 2008. Three cases of acute chloroacetyl chloride poisoning [in Chinese]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 26(10):600. Methanesulfonyl Chloride The following is excerpted from the Executive Summary of the TSD: Data were insufficient to derive AEGL-1 values for methanesulfonyl chloride. Therefore, AEGL- 1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for methanesulfonyl chloride. This approach is justified by the steep concentration-response curve (10% mortality in rats exposed to 20 ppm and 90% mortality at 28 ppm for 4-hr; Pennwalt Corporation, 1987). A 4-hour rat BMCL05 [benchmark concentration with its lower confidence limit at a 5% extra risk] of 15.5 ppm (Pennwalt Corporation, 1987) was used as the point-of-departure (POD) for the AEGL-3 values. 9

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A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 The committee agrees that there are insufficient data at this time to derive AEGL-1 values for methanesulfonyl chloride AEGL-2 The AEGL-2 values are derived based on AEGL-3 values. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values. AEGL-3 Page 12, lines 23-27: “Inter- and intraspecies uncertainty factors of 3 each (total 10) will be applied because methanesulfonyl chloride is irritating, and much of the toxicity is likely caused by a direct chemical effect on the tissue; this type of portal-of-entry effect is not expected to vary greatly between species or among individuals.” Section 2.5.3.2.7 (p. 73) of the SOP states that “The UF for interspecies response adjustment is 10 where there are inadequate data or insufficient information about the chemical or its mechanism of action to justify an alternative UF.” The default intraspecies UF is also 10 “in the absence of data or information to the contrary” (Section 2.5.3.4, p. 89). The authors did not provide data to support reducing the default interspecies and intraspecies UF from 10 to 3. Thus, the overall UF of 100 (= 10 × 10), instead of the factor of 10 (= 3 × 3), should be used to derive AEGL-3. Other Comments Page 6, Table 1: Please add MFs to the end point (reference) column in Table 1 for AEGL-3. Page 9, line 38: “No relevant structure-activity data were located.” The NRC AEGL committee reviewed several acid chlorides together. Although data on direct comparisons may not be available, the authors should consider adding brief toxicity information about similar compounds. Page 12, lines 19-20: “Although, the model probability was low, the output of the log probit calculation excluded the default n = 3 for scaling from longer to shorter time points….” Please explain what is meant by “model probability was low.” References Pennwalt Corporation. 1987. Methanesulfonyl Chloride: Acute Inhalation Toxicity in Rats, 4-Hour Exposure. Report No. PWT 45/861670. Huntingdon Research Centre. February 23, 1987. Trimethylacetyl Chloride The following is excerpted from the Executive Summary of the TSD: 10

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Data were insufficient to derive AEGL-1 values for trimethylacetyl chloride. Therefore, AEGL-1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for trimethylacetyl chloride. This approach is justified by the steep concentration-response curve (0% mortality in rats exposed to 78 ppm for 6- hours and 100% mortality at 249 ppm for 3.5-hours (Eastman Kodak, 1992); 25% mortality in mice exposed to 115 ppm and 75% mortality at 180 ppm for 30-minutes (Hardy and Kieran, 1992).An exposure causing no death in rats (78 ppm for 6 hours; Eastman Kodak, 1992) was used as the point-of-departure (POD) for the AEGL-3 values A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 The committee agrees that data are insufficient at this time to derive AEGL-1 values for trimethylacetyl chloride. AEGL-2 Page 10, lines 38-42: The authors state that the AEGL-2 values are derived from AEGL-3 and offer several justifications for this choice, including the “0% mortality in rats exposed to 78 ppm for 6- hours” (line 40) at the AEGL-3 POD. The authors should also include that the POD was selected because exposure at 78 ppm for 6 h resulted in one AEGL-2 effect. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values. AEGL-3 Page 11, lines 24-26: “An intraspecies uncertainty factor of 3 will be applied because contact irritation is not expected to vary greatly within species.” Section 2.5.3.2.7 (p. 73) of the SOP states that “The UF for interspecies response adjustment is 10 where there are inadequate data or insufficient information about the chemical or its mechanism of action to justify and alternative UF.” The authors did not provide data to support reducing the default intraspecies UF from 10 to 3. Thus, together with the MF of 3 and the interspecies UF of 10 used in the draft TSD, the overall extrapolation factor should be 300 (=3 × 10 × 10). Other Comments Page 7, Table 1: Please add the exposure concentration to the end point (reference) column for AEGL-3 in Table 1. Also add the UFs used for estimating AEGL-3 in the same column. Page 8, lines 18-19: “Groups of three rats were exposed to 78 ppm trimethylacetyl chloride for 3.5 hours or 249 ppm trimethylacetyl chloride for 6-hours….” Please correct the exposure durations. The exposure at 78 ppm should be for 6 h instead of 3.5 h. The exposure at 249 ppm should be for 3.5 h instead of 6 h. These are correctly stated elsewhere in the TSD. Page 9, line 4: “An LC50 value of 101-182 ppm was estimated by the study authors.” Please specify that the LC50 value of 101-182 ppm is for 30 min. 11

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The AEGL-1 values are based on a study with human volunteers. The study reported NOELs and LOELs for eye irritation, considered the most sensitive irritant response to MITC (Russell and Rush 1996)…. In the absence of data that address AEGL-2 end points and with evidence of a steep concentration-response curve, the AEGL-3 values were divided by 3 to derive the respective AEGL-2 values (NRC 2001).The points of departure for the AEGL-3 were the 1-hour and 4-hour highest non-lethal concentrations of 210 and 80 ppm, respectively, in studies with the rat (Clark and Jackson 1977; Jackson et al. 1981). A revised document should be submitted to the committee for review. AEGL-Specific Comments AEGL-1 The key study for deriving AEGL-1 values is Russell and Rush (1996). However, the TSD notes that data from this study was taken from summaries (p. 25, line 40) in a California EPA document (Rubin et al 2003) and an EPA document. Section 2.3.2 (p. 51) states that “only toxicity data obtained directly from a primary reference source are used as the basis for “key” toxicity studies from which the AEGL values are derived. Additionally, all supporting data and information important to the derivation of an AEGL value are obtained solely from the primary references.” Every effort must be made to obtain the original document for review. Page 20, lines 11-13: “The study with human volunteers is the most appropriate for derivation of AEGL-1 values. The study reported NOELs and LOELs for eye irritation, considered the most sensitive irritant response to MITC (Russell and Rush 1996).” The committee disagrees that the NOEL reported by Russel and Rush (1996) is a true NOEL for AEGL-1. The odor threshold for MITC (0.2 ppm) is lower than the NOEL for eye irritation across all exposure durations. Section 2.2.2.1 of the SOP (page 40) states that “below the AEGL-1 values, there may be specific effects, such as the perception of a disagreeable odor, taste, or other sensations (mild sensory irritation). In some people, that exposure level could result in mild lacrimation or coughing.” The TSD authors should use these data as a lowest observed adverse effect (LOAEL) for AEGL-1. Page 20, lines 21-23: “An intraspecies uncertainty factor of unity is appropriate for a no-effect concentration for this sensitive end point….” The committee does not agree that the chosen POD is a NOEL. If the authors choose to use this POD, the committee recommends an intraspecies UF of 3. In addition, the human exposure to MITC was delivered through goggles. As a result, the study could not determine whether there were respiratory effects (the inhalation exposure route was eliminated). This factor is an additional reason to raise the intraspecies UF to 3. AEGL-2 It is unclear why the eye irritation data from Russell and Rush (1996) was considered insufficient to derive AEGL-2 values. Eye irritation may impair an individuals’ ability to escape—an AEGL-2 effect. This possibility is suggested by a comparison of (1) data from Russell and Rush (1996), as described in the draft TSD (p. 11, lines 1-8, and Table 2); (2) data from Klimisch (1987) and Rosskamp et al. (1978) (p. 13-14, Table 4); (3) and the proposed AEGL values (p. 22, Table 9). This potential is worth noting in the derivation section, with reference to the signs and symptoms noted in Section 4.2. Mechanisms of Toxicity. Although acute studies that address the AEGL-2 end points are unavailable, repeat-exposure studies support the AEGL-2 values. Rats exposed at 6.8 ppm for 6 h/d, 5 d/wk for 28 days showed signs of eye irritation and general discomfort during the third exposure day (Klimisch 1987). These signs were 41

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reversible between exposures. Rats exposed at 10 ppm for 4 h/d, 5 d/wk for 12-13 weeks did not show clinical signs (Rosskamp et al. 1978). These concentrations are close to the derived 4- and 8-h AEGL-2 values. No clinical signs were seen at 1 or 1.7 ppm in the studies. The TSD should be modified to reflect the supporting data from the repeat-exposure studies. AEGL-3 The data for key studies for deriving AEGL-3 values is from Russell and Rush (1996) and were taken from summaries (p. 23, line 31, and p. 24, line 19). SOP Section 2.3.2 (p. 51) stated that “only toxicity data obtained directly from a primary reference source are used as the basis for “key” toxicity studies from which the AEGL values are derived. Additionally, all supporting data and information important to the derivation of an AEGL value are obtained solely from the primary references.” Every effort must be made to obtain the original document for review. Page 21, line 42, to page 22, line 7: “Interspecies and intraspecies uncertainty factors of 3 each for a total of 10 are generally applied to chemicals for which the mode of action is that of a direct-acting irritant (NRC 2001). However, application of a total uncertainty factor of 10 to the 4-hour study (80 ppm/10 = 8 ppm) results in values inconsistent with the repeat-exposure studies of Klimisch (1987) and Rosskamp et al. (1978). In those studies, clinical signs were either not observed or were not life- threatening in spite of 4-6 hour daily exposures to 6.8-10 ppm. Therefore, interspecies and intraspecies uncertainty factors of 1 and 3, respectively, were applied. An intraspecies uncertainty factor of 3 is considered sufficient to protect the sensitive population with respiratory disease (NRC 2001).” The material being referenced from the SOP (NRC 2001) is taken from p. 90, Section 2.5.3.4.4. This guidance (a UF of 3 for direct acting irritants) is true in general, but in the case of respiratory irritants, specific guidance is found in the SOP on p. 87, Section 2.5.3.3.4. “Therefore, a default [intraspecies] UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants.” Where the weight of the evidence indicates that the UFs applied would result in proposed AEGL values at odds with human data, modification is required, as it appears to be here. Please modify the references to the SOP to use the appropriate guidance. This comment also applies to the material on p. 19, lines 10-16 of the draft TSD. Other Comments Page 6-7, Executive Summary: The level of detail presented is excessive for a summary. The paragraphs on derivation of the AEGL-1 and AEGL-3 values should be condensed. The paragraph on the derivation of the AEGL-2 values should be reduced to the first and last sentences (suitably modified). Because human volunteers were used in the key study for AEGL-1, the TSD authors should state that the volunteers met the criteria for using human subjects. Page 8, lines 7-8: “Metam sodium (active ingredient MITC) is the third most commonly used agricultural pesticide….” Please correct this sentence. MITC is not an ingredient of metam sodium. Metam sodium decomposes to MITC in the soil. Page 9, Table 1 Chemical and Physical Properties: Insert the saturated vapor concentration. Page 9, line 15: “MITC is marketed as a propesticide….” Please define propesticide. Page 13, lines 24: “Histopathological examination revealed….” Please clarify for which exposure groups the histopathology results apply. Page 21, lines 19-22: “Rats exposed to 6.8 ppm for 6 hours/day, 5days/week for 28 days showed signs of eye irritation and general discomfort during the third exposure day (Klimisch 1987). These signs were reversible between exposures. Rats exposed to 10 ppm for 4 hours/day, 5 days/week for 12-13 weeks did not show clinical signs.” The phrasing on page 21 to describe the time period when eye irritation was noted is slightly different from that used in a previous section of the TSD. On p. 13, lines 42

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18-23 state, “By the third exposure day, rats that inhaled 6.8 or 34 ppm developed clinical signs including eyelid closure, somnolence, and ruffled fur.” Was the irritation not looked for until the third day, was irritation noted progressively among more of the animals until, “by the third day,” all showed signs of irritation, or was irritation undeveloped until the third day? Page 23, Table 10: Delete Table 10. It is unnecessary since there are no other extant standards aside from AEGLs. Page 23, Section 8.3. Data Adequacy and Research Needs: This section only notes that adequate data were available to develop AEGL values. The SOP (p. 53-57) provides specific guidance on the material to be presented in Section 8.3. The two sentences in the draft TSD do not seem sufficient to address the guidance in the SOP. The need for additional research to assess the impact of ocular and respiratory irritation on escape impairment could be noted here. References Clark, G.C., and G.C. Jackson. 1977. Methylisothiocyanate Acute Inhalation Toxicity: 1 Hour LC50 in Rats. Schering AG Study SHG 132/77372, Schering Report T6. Huntingdon Research Centre, UK. Jackson, G.C., G.C. Clark, D.E. Prentice, R.M. Read, C. Gopinath, and C. Cherry. 1981. Methyl Isothiocyanate Acute Inhalation Toxicity in Rats: 4 Hour Exposure. RZ No. 81/082. Huntingdon Research Centre, UK. Klimisch, H.J. 1987. Study of the Subchronic Inhalation Toxicity of Methyl Isothiocyanate in Wistar Rats (4 Weeks Study). BASF No. 87/0244. Department of Toxicology, BASF AG, Germany. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. Rosskamp, G., G. Schobel, A. Bhargava, et al. 1978. Methyl Isothiocyanate. ZK 3.318: A 12-13 Week Inhalation Study in the Rat. Project ID 374/77. Schering AG. Rubin, A.L., M. Silva, J. Gee, T. Moore, and T. Thongsinthusak. 2003. Risk Characterization Document: Methyl Isothiocyanate (MITC) Following the Agricultural Use of Metam Sodium. California Environmental Protection Agency, Sacramento, CA [online]. Available: http://www.cdpr.ca.gov/docs/risk/rcd/mitc_ sb950.pdf [accessed May 24, 2011]. Russell, M.J., and T.I. Rush. 1996. Methyl Isothiocyanate: Determination of Human Olfactory Detection Threshold and Human no Observable Effect Level for Eye Irritation. Report No. RR96-049B. Sensory Testing Laboratory, University of California, Davis, CA. NITROGEN MUSTARDS (HN1, HN2, and HN3) At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSD) on nitrogen mustards. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation. Please note that line numbers were not added to the TSD; hence, comments below will refer to page and section numbers. The following is excerpted from the Executive Summary of the TSD: No exposure-response data were available regarding AEGL-1 type effects following exposure of human or animals to nitrogen mustard vapors… [and] no AEGL-1 values have been recommended…. The AEGL-2 values for HN1, HN2, and HN3 were developed based upon the lower limits of the previously noted eye injury thresholds from studies with human volunteer subjects; 37, 40, and 20 mg-min/m3, respectively, for HN1, HN2, and HN3.… Lethality thresholds (LCt50) for rats were used as the basis for AEGL-3 values; 860, 2000, and 670 mg- min/m3 for HN1, HN2, and HN3, respectively. A revised document should be submitted to the committee for review. 43

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AEGL-Specific Comments Page 8, Executive Summary, Paragraph 3: “By consensus, the National Advisory Committee for Acute Exposure Guideline Levels chose the more conservative AEGL-2 values for HN2 as the AEGL- 2 values for all of the reviewed nitrogen mustards and the more conservative AEGL-3 values for HN3 as the AEGL-3 values for all of the reviewed nitrogen mustards. Individual AEGL-2 and AEGL-3 values for HN1, HN2, and HN3 are, however, presented in the text body.” Common AEGL values for all three HNs should be considered, as the data suggest (see Appendix D, Category Plots for Nitrogen Mustards, pp. 56- 58). If separate values are retained a better justification is needed because the category plots appear to indicate commonality. The TSD authors should consider how likely the individual HNs would be encountered in the environment. Will people be exposed to mixtures or the separate chemicals? The key studies used to derive AEGL values report nitrogen mustard concentrations as mg·min/m3, which is different from the ppm or mg/m3 units usually discussed in chemical TSDs. If possible, the TSD authors should evaluate and compare the range of exposure durations (that is, convert the mg·min/m3to mg/m3) for HN1, HN2, and HN3. It appears that the maximum exposure concentration for HN2 (~ 55 mg/m3) is almost 10-fold greater than the highest exposure concentrations for either HN1 or HN3. How does this comparison affect the data analysis and calculations for AEGLs? Page 16, Section 2.6. Summary: “All of the toxic effects of nitrogen mustard appear to involve a latency period; several hours for ocular responses and several days for dermal blistering.” The purpose of setting exposure limits to facilitate emergency response and recovery is at odds with AEGL-2 concentrations that prevent escape-impairing effects but lead to adverse delayed effects (that is,10-24 h post-exposure). Note the ocular effects of HN2 exposure (p. 15—“At 6 to 10 hours post exposure additional effects developed (e.g., photophobia, blepharospasm, pain severe enough to prevent sleep). At 24 hours, these effects continued but pain decreased.” It is insufficient to say people will escape but end up in hospital emergency rooms later. Please add discussion on exposures to nitrogen mustards resulting in delayed adverse health effects. Are the proposed AEGL values sufficiently protective? The time-scaling used for the AEGL derivations should be revisited. The TSD text and appendixes indicate that time PODs are different for each HN and AEGL because the LCt and ECt (effective dose) cover different time spans. However, a quick comparison of numerical AEGL values (as well as the shape of the AEGL curves in the category plots) suggests that the same time POD was used for all. AEGL-1 Page 24, Section 5.3: “AEGL-1 values for nitrogen mustards are not recommended (Table 11) due to insufficient data and because adverse effects are reported to occur in the absence of detection of the agents.” The authors should search for AEGL-1-relevant data from treatment protocols or related documentation. For example, Section 2.2 (p. 11) reports that HN2 at 0.036 mg/m3 was used as a treatment for mycosis fungoides. It seems that there must have been some subclinical effects even if they are not adverse. Just because there are no clinical effects does not mean we should not recommend an AEGL-1. AEGL-2 Pages 25-27, Section 6.3: For HN1 and HN3, an MF of 3 was applied “to account for possible latent effects on the respiratory tract.” For HN2, an MF of 10 was used to account for “a deficient database…to estimate an AEGL-2 NOEL” and for “uncertainties regarding the number of test subjects.” The authors should re-evaluate the use and selection of MFs or provide better justifications for their use. For AEGL-2, the observed effect is eye irritation. Although it was stated that a respirator was used for HN2 studies (the highest exposure concentrations were for HN2), there were no statements regarding respirator use in the HN1 or HN3 studies. 44

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Page 25, Section 6.3: “The threshold values were based upon reversible effects following vapor exposures of relatively short maximum durations (7-67 minutes) but included post exposure observation up to 24 days.” Please clarify how the listed exposure range was chosen, or adjust the range. The exposure durations listed on pp. 14-15 for the HN1 and HN2 studies are 5-67 min and 0.5-10 min, respectively, and one of the cited HN3 studies had an exposure duration of 7 min. AEGL-3 Page 28, Section 7.2: For HN1 “Adjustment regarding individual variability was also limited to 3 because of the action of nitrogen mustards on cellular components would not be expected to greatly differ, and because additional downward adjustment would result in AEGL-3 values inconsistent with AEGL-2 values and available human data.” Use of the intraspecies UF of 3 is justified by proximity of AEGL-2 values; however, the statement that the intraspecies UF of 3 is justified as the default for similar action across species is not correct (see SOP, p. 87, top) because these compounds are, presumably, respiratory irritants. Use the correct SOP citation for this justification—adjustment for weight of evidence (see SOP, Section 2.5.3.3.4., p. 88). Note that changes need to be made in Appendixes A and C to match. Page 28, Section 7.3: Citing the SOP—presumably Section 2.2.2.3.2. (p. 44)—the TSD states that the estimation of the lethality threshold was done by dividing the LCt50 by 3,. The TSD should note that this section requires information on the slope of the dose-response curve; in its absence, using 3 as the divisor is the acceptable default, but the lack of data should be noted. In addition, this paragraph should note that the rat is the most sensitive to HN1 and HN2, and the mouse is more sensitive to HN3. Other Comments Because most if not all PODs are LCt50 values and because the n value in the ten Berge equation depends on the direction of the time-scaling, the time chosen for each POD should be clearly indicated in a consistent manner. For example, on p. 43 (AEGL-2 derivation), “time = 120 min” is given in “calculations,” but on p. 46 (AEGL-3 derivation), the only time information is given as a range: “experimental exposure durations of 10-100 minutes.” Cover Page: Please insert structure diagrams or chemical formula for the nitrogen mustards. Pages 6-9, Executive Summary: The summary is lengthy. Consider whether some material can be shortened or left out, provided that essential background information remains. Page 7, Executive Summary, Paragraph 3: “The identified thresholds represent a response consistent with the overall continuum of nitrogen mustard toxicity.…” If there is a continuum, are data available to calculate n? Page 7, Executive Summary, Paragraph 3: “(The modifying factor was increased to 10 for HN2 AEGL-2 derivation due to more severed effects (NOAEL-to-LOAEL adjustment).” Why is this a parenthetical statement? It is important information for the AEGL derivation. Justify why an MF is used instead of an alternative UF. Onset of symptoms was delayed. Also note that “severed effects” should be “severe effects” Page 8, Executive Summary, Footnote B: “By consensus vote.…” It is more important to provide the rationale for selecting AEGL values rather than the “vote”. Please provide the rationale. Pages 10-11, Tables 1, 2, and 3: Please insert the saturated vapor concentrations. Page 11, Table 2: Two additional synonyms for HN2 should be added to Table 2: chlormethine and mustine. Page 12, Section 2.2.1: “The container with vesicant was kept in a water bath to maintain constant temperature.” What was the temperature? 45

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Pages 15-16, Section 2.6. Summary: Please add a statement that there are no inhalation data to assess respiratory tract effects in humans, although it can reasonably be expected based on the mechanism of action and on notations in the studies cited that exposed subjects were protected from inhaling the test materials. Pages 16-22, Section 3.1. Animal Lethality: State explicitly in this section that dose-response data were not available, as this is important in the AEGL-3 derivation section. In addition, although there is a wealth of LCt50 values, there is no mention of pathology of any sort. Is there any information on what caused all the animals to die? The presumption seems to be that death was probably due to respiratory tract irritation and its sequelae, given the presumption that a direct-acting irritant and vesicant would have similar effects on the mucosa of the respiratory tract and given the references to some people using oronasal masks, precluding respiratory tract exposure during some controlled exposures used to derive AEGL-2 values. Page 23, Section 2.4. Genotoxicity: “The genotoxicity of nitrogen mustards has been extensively reviewed (Fox and Scott, 1980).” The authors should consider adding information from more recent reviews, e.g., Povirk 1994. Page 23, Section 3.5. Carcinogenicity: “No studies are available regarding carcinogenicity in animals following inhalation exposure to nitrogen mustards. A high incidence of spindle-cell sarcomas was observed in male and female rats given subcutaneous injections of HN3 (0.1 or 0.25 mg/kg/day or 1.0 mg/kg/wk for 6 months) but no such tumors were detected in controls (Sýkora et al. 1981).” This sentence is not informative. Nitrogen mustards should be viewed in the light of what is known about mutagens and carcinogens of this type. There is literature on skin cancers associated with exposure to nitrogen mustards. There is also developing literature on the role of anti-cancer alkylating agents on induction of a different type of cancer. The cancers most frequently seen are leukemias. Also, are there assessments from the International Agency for Research on Cancer or the National Toxicology Program? If not, please explicitly state so. Page 23, Section 4.1. Metabolism and Disposition: This section describes results of several vapor penetration studies and notes that the immonium ion is excreted in urine. Was the immonium ion excretion measured in these experiments? Page 24, Section 4.2. Mechanisms of Toxicity: “A key reaction that is likely important to the biological activity of nitrogen mustard is the formation of a cyclic onium cation (immonium for nitrogen mustards) in the presence of polar solvents such as water (Somani, 1992). The immonium ion can react with nucleophiles such as nitrogen in the base components of nucleic acids and sulfur in SH-groups in proteins and peptides.” Please address the following:  The TSD text identifies a “cyclic onium cation.” To clarify, please provide the structural formula for the immonium ion (and for the sulfonium ion mentioned in Section 4.3. Structure-Activity Relationships  Is the immonium ion linked to vesicant properties?  Note that some sources identify “immonium” as a nonstandard term, preferring “iminium” or perhaps “aziridinium”. Perhaps all of these terms should be included in the discussion. Page 24, Section 4.3. Structure-Activity Relationships: If possible, add a comparison table of reactivity or reaction rates of the three HNs (e.g., alkylation rate). Note that similar rates would support the use of common AEGL values. Page 25, Section 6.1. Human Data Relevant to AEGL-2: “The ocular effects…are reversible and appear to develop post exposure.” Because the duration of this latency period could be critical to escape impairment, some discussion is needed on the length of time required after exposure to manifest effects. The cited studies had short exposure periods lasting from 0.5 to 67 min. The HN2 study noted that effects were reported 8-15 min post-exposure, and the HN1 study reported an average latency of 12 h (with no range given). AEGL exposure periods of 4 to 8 h are well outside this data set and present the 46

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potential for effects to develop during the long exposure periods. Discussion should include the possibility that effects might occur during the long duration exposures (4-h and 8-h AEGL time periods) because there are no data to assess the effect of long-term continuous exposure. Page 29, Section 8.1. AEGL Values and Toxicity End Points: “The AEGL-2 value took into consideration sensitive responders and possible respiratory effects.” Although the derivation described in Section 6.3., pp. 25-27, is quite thorough, it is not clear that “sensitive responders” are either identified or addressed in the process. The intraspecies UF was set at 3 to account for the expected range of human variability (the default value for direct-acting irritants) and the possibility of respiratory irritation (where the default value for this UF would normally be 10). However, no “sensitive responders” were identified in the AEGL-2 derivation section. The authors should consider changing the TSD wording from “sensitive responders” to “the expected range of human variability” or something similar. Page 29, Section 8.1. AEGL Values and Toxicity End Points: A statement should be added on the lack of data to assess respiratory tract effects. A related statement should also be added to Section 8.3. Data Adequacy and Research Needs (page 31). Page 43, Derivation of AEGL-3 for Nitrogen Mustards: Please check the calculation for 1-h AEGL-3 “C3 × 60 min.” Why is C3 used instead of C1, as was done for the other time-points? References Fox, M., and D. Scott. 1980. The genetic toxicology of nitrogen and sulphur mustard. Mutat. Res. 75(2):131-168. Povirk, L.F., and D.E. Shuker. 1994. DNA damage and mutagenesis induced by nitrogen mustards. Mutat. Res. 318(3):205-206.Somani, S.M. 1992. Toxicokinetics and toxicodynamics of mustard. Pp. 13-50 in Chemical Warfare Agents. New York: Academic Press. Sýkora, I., V. Vortel, O. Marhan, and A. Dynterova. 1981. Carcinogenicity of thichloromethine hydrochloride (TS-160 Spofa) and morphological damage after its intraamniotic injection. Neoplasma 28(5):565-574. PERCHLORYL FLUORIDE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on perchloryl fluoride. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: The AEGL-1 values were derived from the concentration, 24 ppm, at which dogs and rats were exposed for 6 hours/day, 5 days/week for 26 weeks. At this concentration, all animals survived, exhibited no clinical signs, no signs of irritation and the only long-term effect observed was increased fluoride deposition in the bone and urine over the course of the 26 weeks…. In the absence of appropriate chemical-specific data, AEGL 2 values were set at one-third of the AEGL-3 values (NRC 2001)…. The AEGL-3 values were based on a concentration of 224 ppm which induced moderate cyanosis and hyperpnea in dogs during a 4-hour exposure. This document can be finalized if the following comments are adequately addressed. AEGL-Specific Comments The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 for perchloryl fluoride. 47

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Other Comments Cover Page: Please add the structural diagram for perchloryl fluoride. Page 12, lines 32-22: “In some of the guinea pigs, Bordetella bronchoseptica was isolated, thus making all of the results of this study questionable.” Please explicitly state in the TSD that these data were not considered for derivation of the AEGLs. Also please make correct the spelling of bronchiseptica. References NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. PIPERIDINE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on piperidine. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: The AEGL-1 values were based on the no-effect-level (20 ppm for 6 hours) for nasal irritation in rats…. The AEGL-2 values were based on exposure of rats to piperidine at 200-ppm for 6 hours, which caused nasal irritation without salivation or evidence of eye irritation…. The AEGL-3 values were based on the LC01 calculated from a 4-hour acute inhalation study in rats. This document can be finalized AEGL-Specific Comments The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 values for piperidine. Other Comments The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately. PROPANE At is meeting held on April 5-7, 211, the committee reviewed the AEGL technical support document (TSD) on propane. A presentation on the TSD was made by Mark Follansbee, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: 48

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The AEGL-1 derivation is based on observations in a study with volunteers on the warning properties of short exposures to propane (Patty and Yant 1929).… The AEGL-2 derivation is based on cardiac sensitization. In a well-performed cardiac sensitization test beagle dogs were exposed to a propane concentration of 50,000, 100,000, or 200,000 ppm (Reinhardt et al. 1971)…. The same study as for AEGL-2 is used as starting point for AEGL-3. This document can be finalized AEGL-Specific Comments The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 values for propane. Other Comments The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately. References Patty, F.A., and W.P. Yant. 1929. Odor Intensity and Symptoms Produced by Commercial Propane, Butane, Pentane, Hexane, and Heptane Vapor. Report of Investigation No 2979. Washington, DC: U.S. Department of Commerce, Bureau of Mines. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, Jr., and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol “sniffing”. Arch. Environ. Health 22(2):265-279. TRIMETHOXYSILANE AND TETRAMETHOXYSILANE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs) on trimethoxysilane and tetramethoxysilane. The presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: AEGL-1 values were not derived for either trimethoxysilane or tetramethoxysilane because of limited data. AEGL-2 values for trimethoxysilane were derived by taking 1/3 of AEGL-3 values…. AEGL-3 values were determined by using mortality data from 1 and 4 hour LC50 rat inhalation studies (Nachreiner and Dodd 1988)…. AEGL-2 values for tetramethoxysilane were derived from a repeat dose inhalation study in which rats were exposed for 6 hours/day, 5 days/week for 28 days at concentrations up to 45 ppm (Kolesar et al 1989)…. AEGL-3 values were derived from an LC50 4-hour rat inhalation study (Dow Corning Corp., 1992). This document can be finalized. 49

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AEGL-Specific Comments The committee approves the derivations of AEGL-1, AEGL-2, and AEGL-3 for trimethoxysilane and tetramethoxysilane. Other Comments The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately. References Dow Corning Corporation. 1992. Initial Submission: The Acute Vapor Inhalation Toxicity of Tetramethoxysilane and Trimethoxysilane with Rats (Final Report) with Cover Letter Dated April 9, 1992. Document ID No. 88920001842. Microfiche No. OTS0539103. Kolesar, G.B., W.H. Siddiqui, R.G. Geil, R.M. Malczewski, and E.J. Hobbs. 1989. Subchronic inhalation toxicity of tetramethoxysilane in rats. Fundam. Appl. Toxicol. 13(2):285-295. Nachreiner, D.J., and D.E. Dodd. 1988. Trimethoxysilane: Acute Vapor Inhalation Toxicity Study in Rats. Project Report No. 50-147. Union Carbide- Bushy Run Research Center. COMMENTS PERTAINING TO ALL TECHNICAL SUPPORT DOCUMENTS The chemical structure of the compounds should be included on the title page of every TSD. Whenever substantial discrepancies are found between AEGL values and other guideline values (e.g., IDLHs, STELs, and workplace environmental exposure limits [WEELs]), the possible reasons should be explored and discussed in the text. The SOP, Appendix J, p. 201, of the NRC (2001) report stated that “A summary discussion of important comparisons should be presented in the text and the values for recognized standards and guidelines, if available, should be presented in the table.” The authors need to ensure that the literature on the chemicals have been updated for documents that have been several years in the AEGL-development process. The date of the most recent literature review should be included in the TSD. For citations to the SOP (NRC 2001), it would be helpful if the TSD authors included a page number or section number as part of the citation. The SOP is a 200-page document, and it may not be readily apparent to target emergency response and preparedness audiences to which section the TSD authors may be referring. For the “Summary of AEGL Values” table included in each TSD ( located in the Executive Summary), please make certain that any applied UF or MF are listed in the “End Point (Reference)” column of the summary table. For the “Chemical and Physical Data” table included in each TSD (located in Section 1. Introduction), please include the vapor pressure (if available) and (calculated) saturated vapor concentration. For the “Extant Standards and Guidelines” table included in each TSD (located in Section 8.2. Comparisons with Other Standards and Guidelines), please make certain the reported guidelines are the most updated available values. A number of the TSDs include out-of-date values. Please make certain that all listed URLs in the references are still active, and add the date that the Web site was accessed. 50

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References NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. STANDING OPERATIONING PROCEDURES For many chemicals, the data are insufficient to develop AEGL-1 values. The AEGL SOP should offer some guidance on appropriate statements on how to communicate with (or what to communicate to) emergency responders and the public in the absence of AEGL-1 values. 51