Twenty-second 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 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 level (AEGL) 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.

NAC1 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.

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1 NAC completed its chemical reviews in October 2011. The committee was composed of members from EPA, DOD, many other federal and state agencies, industry, academia, and other organizations. From 1996 to 2011, the NAC discussed over 300 chemicals and developed AEGLs values for at least 272 of the 329 chemicals on the AEGLs priority chemicals lists. Although the work of the NAC has ended, the NAC-reviewed technical support documents are being submitted to the NRC for independent review and finalization.



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Twenty-second 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 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 level (AEGL) 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. NAC1 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. 1 NAC completed its chemical reviews in October 2011. The committee was composed of members from EPA, DOD, many other federal and state agencies, industry, academia, and other organizations. From 1996 to 2011, the NAC discussed over 300 chemicals and developed AEGLs values for at least 272 of the 329 chemicals on the AEGLs priority chemicals lists. Although the work of the NAC has ended, the NAC-reviewed technical support documents are being submitted to the NRC for independent review and finalization. 1

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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. 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 (e.g., general, inhalation, cardiovascular, reproductive, mechanistic, occupational); 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 published NRC guidelines; (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, boron tribromide, bromine chloride, cadmium, carbon tetrachloride, carbonyl fluoride, cyanide salts, diketene, ethyl benzene, germane, halogen fluorides (chlorine pentafluoride, bromine pentafluoride, and bromine trifluoride), hexafluoropropylene, hydrogen bromide and hydrogen iodide, methacrylaldehyde, oxygen difluoride, pentaborane, stibine, styrene, tellurium hexafluoride, tetrafluoroethylene, thionyl chloride, and toluene. These documents were reviewed by the committee at a meeting on April 22-24, 2013. ACRYLONITRILE The committee reviewed the AEGL TSD on acrylonitrile that was presented by Gary Diamond of SRC, Inc. Table 1 presents a summary of the proposed AEGL values for acrylonitrile and their basis. The committee found that its previous comments on the TSD (NRC 2012) were adequately addressed, and agreed with the proposed derivation of the AEGL values. Just one remaining clarification with respect to the derivation of AEGL-2 values is needed. AEGL Specific Comments For AEGL-2 values, the committee agreed with the chosen point of departure (POD) and the derived values. However, support for an uncertainty factor of 2 for interspecies differences in toxicokinetics should be better justified. The current justification is based on physiologically-based pharmacokinetic (PBPK) model simulations by Sweeney et al. (2003), who based their predictions for humans on scaling of the metabolism from rats, but used no experimental data. More recently, Takano et al. (2010) published a PBPK model suggesting small differences (less than two-fold) between rats and humans. The advantage of the Takano model is that it is based on experimental data on metabolism (liver microsomes), but it also has the disadvantage of considering only oral exposure. Taken together, the two PBPK studies support an uncertainty factor of 2. 2

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ALLYL ALCOHOL The committee reviewed a proposal to change the approach to deriving AEGL-1 and AEGL-2 values for allyl alcohol presented by Julie Klotzbach of SRC, Inc. Table 2 presents a summary of proposed AEGL values. The committee agreed with the proposed AEGL-2 values, and the AEGL-3 values were approved at a previous meeting (NRC 2012). However, the committee recommends a few adjustments to how the AEGL-1 values were derived. TABLE 1 Summary of Proposed AEGL Values for Acrylonitrile Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) 1.5 ppm 1.5 ppm NR NR NR No-effect level for ocular irritation (3.3 mg/m3) (3.3 mg/m3) in humans (4.6 ppm, 8 h); total UF = 3 (intraspecies) AEGL-2 (disabling) 8.6 ppm 3.2 ppm 1.7 ppm 0.48 ppm 0.26 ppm No-effect level for fetal toxicity (19 mg/m3) (6.9 mg/m3) (3.7 mg/m3) (1.0 mg/m3) (0.56 mg/m3) (reduced fetal body weight) in rats (12 ppm, 6 h); total UF = 36 (interspecies = 6, intraspecies = 6); time scaling, n = 1.1 AEGL-3 (lethal) 130 ppm 50 ppm 28 ppm 9.7 ppm 5.2 ppm BMCL05 for lethality in rats (280 mg/m3) (110 mg/m3) (61 mg/m3) (21 mg/m3) (11 mg/m3) (1,784.0, 1,024.4, 185.8 ppm for 30 min, 1 h, 8 h, respectively); total UF = 36 (interspecies = 6, intraspecies = 6); time scaling, n = 1.1 Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; NR, not recommended; UF, uncertainty factor. TABLE 2 Summary of Proposed AEGL Values for Allyl Alcohol 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) 0.27 ppm 0.27 ppm 0.27 ppm 0.27ppm 0.27 ppm RD10 (0.27 ppm) in mice; no UFs; no time scaling. Supportive evidence from human study. AEGL-2 (disabling) 11 ppm 3.5 ppm 1.7 ppm 0.73 ppm 0.33 ppm No-effect levels for decreased response to stimulus and gasping in rats; total UF = 30 (interspecies= 3, intraspecies = 10); time scaling, n = 0.95. AEGL-3 (lethal) 87 ppm 27 ppm 13 ppm 3.1 ppm 1.5 ppm LC01 values in rats; total UF = 30 (interspecies = 3, intraspecies = 10); time scaling, n = 0.95. Abbreviations: LC01, lethal concentration, 1% lethality; RD10, concentration that reduces the respiratory rate by 50%; UF, uncertainty factor. 3

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AEGL Specific Comments The committee agreed with the approach of deriving AEGL-1 values for allyl alcohol by considering the studies of Nielsen et al. (1984) and Dunlap et al. (1958) together. The proposed AEGL-1 values on the basis of the Nielsen study are based on an RD10 (concentration that reduces the respiratory rate by 10%) of 0.27 ppm in mice. No uncertainty factors were applied, no time scaling was performed, and the values were held constant over the AEGL durations. Support for these values is provided by estimates of the AEGL-1 values based on human data from the Dunlap et al. (1958) study. Slight ocular irritation and mild-to-moderate nasal irritation were reported at 0.78 ppm for 5 min. If an uncertainty factor of 3 is applied for intraspecies variability, AEGL-1 values would also be 0.27 ppm. The committee agrees with the application of that uncertainty factor, and recommends that it also be used in calculating AEGL values on the basis of the Nielsen study. This will result in AEGL-1 values of 0.09 ppm for all AEGL durations. Also, relevant primary citations should be included in the TSD. (For example, 3% of the RD50 for allyl alcohol is listed as 0.301 ppm in ASTM [2012]). Other Comments A new literature search should be performed to update the information presented in the TSD. It also appears that some of the older literature has been overlooked; a few studies of ocular irritation (e.g., Jacobs 1992; Berry and Easty 1993) and renal toxicity (e.g., Hosohata et al. 2011) appear to have been omitted. Information can also be gleaned from assessment by other agencies, such as UNEP (2005) and EPA (2009, 2013a, 2013b). The most recent EPA compilations include brief summaries of the studies by Carpenter and Smyth (1946), Carpenter et al. (1949), and others. Page 8, lines 5-9: The uses of allyl alcohol should be updated (the citations are from 1977-1996). For example, see information provided by LyondellBasell on its website (http://www.lyondellbasell.com). Also, check the accuracy of the statement that allyl alcohol is used as a fungicide and herbicide, because the Hazardous Substances Data Bank (HSDB) reference cited indicates that it was not registered for current use the United States. Page 8, lines 9-17: The production of allyl alcohol should be updated (the citations are from 1977-1996). For example, the HSDB reference identifies another manufacturer from a 2011 directory, and recent information is also available from US patent summaries (Lin et al. 2011, Engelhard et al. 1976). The TSD citation regarding production (line 13) is nearly 20 years old; the HSDB link which was cited in the TSD for physicochemical properties included information on US production from 2002 (more than 50 to 100 million pounds), as well as for previous years, which indicate that production had at least doubled since 1990. Other sources provide more up-to-date information from LyondellBasell that production volume is between 100-500 million pounds (see EPA 2006). Similarly, the TRI data from 2000 should be updated with a more recent reference (see EPA 2013a). More recent information with respect to shipping (lines 16-17) should also be sought. Page 8, line 20: Primary sources for atmospheric half-life should be referenced rather than HSDB. For example, the EPA High Production Volume Information System (EPA 2013b) identified information from several citations, such as the 1991 Handbook of Environmental Degradation Rates by Howard et al., which indicates a photo-oxidation half-life of 2.2 to 22 h, whereas Howard’s 1989 Handbook indicated a range of 6 to 14.7 h; Grosjean et al. (1993) indicate a half-life on the order of 7.4 h or 0.3 days. The latter publication is also referenced by UNEP (2005). Page 8, lines 27-28; page 9, lines 6-7; page 11, line 32: The statement that there are no reports of human fatalities is inaccurate (see Toennes et al. 2002 and Kononenko 1970). Page 23, Section 3.3 (Developmental/Reproductive Effects): A relevant study by Jenkinson and Anderson (1990) should be added, as well as information summarized in UNEP (2005). 4

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Page 24, Section 3.5 (Carcinogenicity): The citations are outdated with respect to EPA’s classification, and the IARC determination should be cited. More recent publications may also be relevant (e.g., Wang et al. 2012). Page 25, lines 20-22: Given that reproductive/developmental toxicity is not limited by the portal of entry, the restriction to “inhaled” ally alcohol is not warranted. (This is also true for similar statements about carcinogenicity.) All relevant information on allyl alcohol should be considered. Pages 28-30, Section 4.1 (Metabolism and Mechanism of Toxicity): Relevant references appear to have been omitted from this section. An updated literature search should be performed, and recent compilations reviewed for relevant information on the mechanism of action of allyl alcohol (see UNEP 2005 and EPA 2009). Page 30, Section 4.2 (Structure-Activity Relationships): More recent references should be consulted and added to this section (see Irvin 2006). Pages 30-31, Section 4.3 (Susceptible Populations): A search should be conducted for more recent information, and the section should include consideration of other conditions, such as renal toxicity. Page 38, Table 15; page 39, lines 1-36: The standards for allyl alcohol set by other organizations should be verified to ensure they reflect the most up-to-date values, and the supporting references updated accordingly. Given Japan’s interest per sponsorship of the UNEP (2005) report, consider including the Japanese occupational exposure limit. Pages 39-40, Section 8.3 (Data Adequacy and Research Needs): This section should be updated after the updated literature search is performed and more recent compilations of data are consulted (e.g., UNEP 2005, EPA 2009). Relevant References The following are several references that should be included in the updated TSD. Other relevant information should be sought through an updated literature search. Atzori, L., M. Dore, and L. Congiu. 1989. Aspects of allyl alcohol toxicity. Drug Metabol. Drug Interact. 7(4):295-319. Berry, M., and D.L. Easty. 1993. Isolated human and rabbit eye: Models of corneal toxicity. Toxicol. In Vitro 7(4):461-464. Hosohata, K., H. Ando, Y. Fujiwara, and A. Fujimura. 2011. Vanin-1: A potential biomarker for nephrotoxicant- induced renal injury. Toxicology 290(1):82-88. Huang, L., A.N. Heinloth, Z.B. Zeng, R.S. Paules, and P.R. Bushel. 2008. Genes related to apoptosis predict necrosis of the liver as a phenotype observed in rats exposed to a compendium of hepatotoxicants. BMC Genomics 9:288, doi:10.1186/1471-2164-9-288. Huang, J., W. Shi, J. Zhang, J.W. Chou, R.S. Paules, K. Gerrish, J. Li, J. Luo, R.D. Wolfinger, W. Bao. T.M. Chu, Y. Nikolsky, T. Nikolskaya, D. Dosymbekov, M.O. Tsyganova, L. Shi, X. Fan, J.C. Corton, M. Chen, Y. Cheng, W. Tong, H. Fang, and P.R. Bushel. 2010. Genomic indicators in the blood predict drug-induced liver injury. Pharmacogenetics J. 10(4):267-277. Irwin, R.D. 2006. NTP Technical Report on the Comparative Toxicity Studies of Allyl Acetate (CAS No. 591-87-7), Allyl Alcohol (CAS No. 107-18-6) and Acrolein (CAS No. 107-02-8) Administered by Gavage to F344/N Rats and B6C3F1 Mice. Toxicity Report 48. NIH 06-443. U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/ST_rpts/tox048.pdf [accessed June 13, 2013]. Jacobs, G.A. 1992. OECD eye irritation tests on allylalcohol and dimethylsulphoxide. J. Am. Coll. Toxicol. 11(6):729. Jacobs, G.A., and M.A. Martens. 1989. An objective method for the evaluation of eye irritation in vivo. Food Chem. Toxicol. 27(4):255-258. Jenkinson, P.C., and D. Anderson. 1990. Malformed foetuses and karyotype abnormalities in the offspring of cyclophosphamide and allyl alcohol-treated male rats. Mutat. Res. 229(2):173-184. Kononenko, V.I. 1970. Fatal poisoning with allyl alcohol [in Russian]. Sud. Med. Ekspert 13(3):50-51. 5

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Li, A.A., J. Fowles, M.I. Banton, C. Picut, and D.T. Kirkpatrick. 2012. Acute inhalation study of allyl alcohol for derivation of acute exposure guideline levels. Inhal. Toxicol. 24(4):213-226. Reid, W.D. 1972. Mechanism of allyl alcohol-induced hepatic necrosis. Experientia 28(9):1058-1061. Rikans., L.E., Y. Cai, and K.R. Hornbrook. 1994. Allyl alcohol cytotoxicity in isolated rat hepatocytes: Mechanism of cell death does not involve an early rise in cytosolic free calcium. Arch. Toxicol. 69(1):24-29. Toennes, S.W., K. Schmidt, A.S. Fandiño, and G.F. Kauert. 2002. A fatal human intoxication with the herbicide allyl alcohol (2-propen-1-ol). J. Anal. Toxicol. 26(1):55-57. Watkins, J.B., and C.D. Klaasen. 1983. Chemically-induced alteration of UDP-glucuronic acid concentration in rat liver. Drug Metab. Dispos. 11(1):37-40. Wang, H.T., Y. Hu, D. Tong, J. Huang, L. Gu, X.R. Wu, F.L. Chung, G.M. Li, and M.S. Tang. 2012. Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. J. Biol. Chem. 287(15):12379-12386. BORON TRIBROMIDE The committee reviewed the AEGL TSD on boron tribromide that was presented by Lisa Ingerman of SRC, Inc. Table 3 presents a summary of the proposed AEGL values for boron tribromide and their basis. The committee agreed that its previous comments on the TSD (NRC 2011) were adequately addressed. It is appropriate to take one-third of the AEGL values for hydrogen bromide to determine AEGL values for boron tribromide, because three moles of hydrogen bromide are produced from hydrolysis of one mole of boron tribromide. However, the proposed AEGL values must be revised in light of changes to the AEGL values for hydrogen bromide specified later in this report. BROMINE CHLORIDE The committee reviewed the AEGL TSD on bromine chloride that was presented by Heather Carlson-Lynch of SRC, Inc. Table 4 presents a summary of the proposed AEGL values for bromine chloride and their basis. The committee agreed with the derivation of the proposed AEGL-2 and AEGL-3 values, but disagreed with the proposal to derive AEGL-1 values by analogy with chlorine. General Comments Bromine chloride is an unstable gas that spontaneously dissociates into a mixture of bromine chloride, bromine, and chlorine in a 60:20:20 ratio. When these gases come into contact with water (and presumably biological fluids), bromine chloride and the two halogens react to become their respective weak and strong acids: 2BrCl ↔ Br2 + Cl2 // Br2 + H2O ↔ HOBr + HBr // Cl2 + H2O ↔ HOCl + HCl 2BrCl +2H2O ↔ HBr + HOBr +HCl +HOCl TABLE 3 Summary of Proposed AEGL Values for Boron Tribromide Reviewed by the Committee End Point, Derivation Classification 10 min 30 min 1h 4h 8h Factors AEGL-1 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm Analogy with (nondisabling) (3.4 mg/m3) (3.4 mg/m3) (3.4 mg/m3) (3.4 mg/m3) (3.4 mg/m3) hydrogen bromidea AEGL-2 33 ppm 14 ppm 7.3 ppm 3.7 ppm 3.7 ppm Analogy with (disabling) (340 mg/m3) (140 mg/m3) (75 mg/m3) (38 mg/m3) (38 mg/m3) hydrogen bromidea AEGL-3 250 ppm 83 ppm 40 ppm 10 ppm 10 ppm Analogy with (lethality) (2,600 mg/m3) (850 mg/m3) (410 mg/m3) (100 mg/m3) (100 mg/m3) hydrogen bromidea a AEGL values for hydrogen bromide are presented later in this document. 6

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TABLE 4 Summary of Proposed AEGL Values for Bromine Chloride Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) 0.50 ppm 0.50 ppm 0.50 ppm 0.50 ppm 0.50 ppm Analogy with chlorine (NRC 2004a) (2.4 mg/m3) (2.4 mg/m3) (2.4 mg/m3) (2.4 mg/m3) (2.4 mg/m3) AEGL-2 (disabling) 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.2 ppm One-third of AEGL-3 values. (15 mg/m3) (15 mg/m3) (12 mg/m3) (7.6 mg/m3) (5.7 mg/m3) AEGL-3 (lethal) 9.5 ppm 9.5 ppm 7.6 ppm 4.8 ppm 3.5 ppm BMCL05 for lethality in rats (45 mg/m3) (45 mg/m3) (36 mg/m3) (23 mg/m3) (17 mg/m3) (39.5 ppm, 7 h); total UF = 10 (interspecies = 3, intraspecies =3); default time scaling. Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; UF, uncertainty factor. Any scenario in which AEGL values would be used will involve exposure to a halogen-interhalogen mixture, not bromine chloride alone. The introduction to the TSD should make this explicit, along with the potential impact of relative humidity on the exposure mixture. The dataset for bromine chloride consists of a single acute lethality study in rats. That study is weak; only six male rats per group were tested, and the investigators expressed uncertainty with respect to the composition of the exposure atmosphere and the actual exposure concentrations. Furthermore, the study was not peer reviewed. AEGL Specific Comments The committee disagrees with the proposal to establish AEGL-1 values on the basis of the AEGLs for chlorine. In the absence of relevant data specific to bromine chloride, no AEGL-1 values should be recommended. The committee agrees with the proposed approach to deriving AEGL-3 values, but recommends that consideration be given to applying a modifying factor to account for the sparse database on bromine chloride. The committee agrees that AEGL-2 values can be determined by dividing the AEGL-3 values by 3. Other Comments Reference is made throughout the TSD that the toxicity of bromine chloride is expected to be between those of bromine and chlorine. A discussion of this hypothesis and the lack of data to confirm it should only be presented in Sections 4.3 (Structure-Activity Relationships), 8.1 (AEGL Values and Toxicity End Points), and 8.3 (Data Adequacy and Research Needs). The description of the uncertainties associated with the concentrations of bromine chloride in the LC50 study by Dow Chemical Co. (1977) should be expanded. No attempt was made to speciate the components of the exposure, other than to note that bromine chloride is reported to be 40% dissociated; the ratio of the mixture would be 60:20:20 for bromine chloride, bromine, and chlorine, respectively. However, the discussion is presented in terms of exposure to bromine chloride, so it is uncertain whether the concentrations analyzed were 20, 40, 80, and 120 ppm of bromine chloride or a mixture of halogens. All rats showed symptoms of respiratory irritation at all exposure concentrations. Determination of the concentrations to which the rats were exposed was based on a separate, single exposure performed after the LC50 determination. This was further complicated by the evidence of stratification of concentrations 7

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within the exposure chamber. The description of the “top”, “middle”, and “bottom” sampling positions were not otherwise described, and the breathing zone of the rats in context with these positions was not described in detail (e.g., duration of rearing behavior, which was interpreted as an escape response confirming the degree of concentration stratification). This information is important because the bottom concentration (91 ppm) during the exposure measurement experiment exceeded the LC17 value and appears to be close to the LC50, and the top and middle concentrations (average of 42 ppm) were slightly (1-3 ppm) above the no-observed-adverse-effect level (NOAEL) and the calculated BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) value. In the Section 4.3 (Structure-Activity Relationships), the toxicities of bromine and chlorine should be compared with bromine chloride to the extent possible. Lethality data seem to indicate that bromine chloride is as lethal as chlorine, whereas bromine is 1.4-2.3 times less lethal than chlorine. However, bromine appears to be more irritating to the upper respiratory tract than chlorine (NRC 2010a). The AEGL values for bromine chloride, bromine, and chlorine should be compared in Section 8.2 (Comparison with Other Standards and Guidelines). In Section 8.3 (Data Adequacy and Research Needs), a recommendation should be made that acute toxicity studies of bromine chloride are needed to refine the AEGL-3 values and develop AEGL-1 and AEGL-2 values. Such studies should include analyses of the exposure atmospheres. Studies comparing bromine chloride, bromine, and chlorine would also be helpful. CADMIUM The committee reviewed the AEGL TSD on cadmium that was presented by Gary Diamond of SRC, Inc. Table 5 presents a summary of the proposed AEGL values for cadmium and their basis. The committee found the TSD to be unacceptable and in need of major revisions. The TSD presents data on different cadmium species without providing context regarding their solubility and particle size and the implications for interpreting and extrapolating data. None of the AEGL values were adequately justified. The TSD should provide a discussion about the different cadmium species to which people may be exposed, and the relevance to understanding kinetics and lung toxicity. Cadmium oxide appears to be the most toxic species. The TSD should review the evidence as justification for focusing on that species to derive AEGL values. Exposure concentrations and AEGL values in the TSD should be expressed in terms of mg/m3 of elemental cadmium, not as the individual test species. Some specific improvements needed include:  Relevant new studies identified in an updated literature search should be added to the TSD and considered in deriving AEGL values, if appropriate. Data on engineered nanomaterials (e.g., Quantum dots) may be omitted from consideration, because these particles are usually produced in small quantities and risk of exposure to the general public is limited.  Data on tissue burdens and urinary cadmium concentrations should be discussed to provide context for kinetic considerations (e.g., Lauwerys et al. 1979). Measurements from animals and humans should be compared.  AEGL-1 values: It is unclear why a POD of 0.55 mg/m3 was chosen, when other studies have reported effects such as petechial lung hemorrhages at 0.5 mg/m3 (Buckley and Bassett 1987) and one death and biochemical lung changes at 0.45 mg/m3 (Grose et al. 1987). The AEGL values are also lower than those reported to be associated with “metal fume fever” (described on page 11, lines 19-21 of the TSD).  AEGL-2 values: It is unclear that the POD of 5.3 mg/m3 is a NOAEL. The Buckley and Bassett (1987) study reported lung changes that persisted for at least 15 days after exposure. The Grose et al. (1987) study described severe pneumonitis in rats 72 h after exposure at 4.5 mg/m3. 8

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CARBON TETRACHLORIDE The committee reviewed the AEGL TSD on carbon tetrachloride that was presented by Gary Diamond of SRC, Inc. Table 6 presents a summary of the proposed AEGL values for carbon tetrachloride and their basis. The committee agreed that its previous comments (NRC 2010b) were addressed, but recommends revisions to how the AEGL-2 and AEGL-3 values were derived. AEGL Specific Comments The committee agreed with the proposal not to establish AEGL-1 values. TABLE 5 Summary of Proposed AEGL Values for Cadmium Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) 0.13 mg/m3 0.13 mg/m3 0.10 mg/m3 0.063 mg/m3 0.041 mg/m3 Respiratory irritation in rats (0.55 mg/m3, 6 h); total UF = 10 (interspecies = 3, intraspecies = 3); default time scaling AEGL-2 (disabling) 1.4 mg/m3 0.96 mg/m3 0.76 mg/m3 0.40 mg/m3 0.20 mg/m3 Overt respiratory tract irritation and pathology in rats (5.3 mg/m3, 3 h); total UF = 10 (interspecies = 3, intraspecies = 3); default time scaling AEGL-3 (lethal) 8.5 mg/m3 5.9 mg/m3 4.7 mg/m3 1.9 mg/m3 0.93 mg/m3 Threshold for lethality in rats (2-h LC50 of 112 mg/m3); total UF = 10 (interspecies = 3, intraspecies = 3); default time scaling Abbreviations: LC50, lethal concentration, 50% lethality; UF, uncertainty factor. TABLE 6 Summary of Proposed AEGL Values for Carbon Tetrachloride Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) NR NR NR NR NR Insufficient data AEGL-2 (disabling) 45 ppm 29 ppm 22 ppm 13 ppm 9.5 ppm Fetal toxicity (decreased body (280 mg/m3) (180 mg/m3) (140 mg/m3) (82 mg/m3) (60 mg/m3) weight, shorter crown-to-rump length) in rats (300 ppm, 7 h, GD 6-15); total UF = 10 (intraspecies); MF = 3 (extrapolating from an effect level); time scaling, n = 2.5 AEGL-3 (lethal) 1,100 ppm 680 ppm 520 ppm 300 ppm 220 ppm Estimated LC01 in rats(5,153.5 ppm, (6,920 mg/m3) (4,227 mg/m3) (3,270 mg/m3) (1,887 mg/m3) (1,384 mg/m3) 1 h); total UF = 10 ( intraspecies); time scaling, n = 2.5 Abbreviations: GD, gestation day; LC01,lethal concentration, 1% response; MF, modifying factor; NR, not recommended; UF, uncertainty factor. 9

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In examining the basis of the AEGL-2 values, the committee discovered a few methodology issues with the study by Schwetz et al. (1974) that were not identified in previous reviews of the TSD. Tests for the two dose (300 and 1,000 ppm) groups were conducted in two separate experiments, each with its own concurrent controls. The experimental variability over the three-fold dose range rendered these results inconclusive for identifying any fetal end points for deriving AEGL values. For example, when compared with concurrent controls, the incidence of delayed sternebral ossification was statistically significant only at 1,000 ppm, with a substantially lower incidence in the concurrent control group; however, when the control data were combined, total skeletal abnormalities (predominantly delayed ossification) was significant only at 300 ppm. Similarly, compared with the combined controls, fetal subcutaneous edema (potentially pertinent to acute exposure scenarios) was only significant at 300 ppm; however, no significant increase in total soft tissue abnormalities was detected at either dose. Data on each set of concurrent controls and for individual litters were unavailable for further analysis. The committee concluded that the Schwetz et al. study should not be used as the basis for deriving AEGL-2 values. No gross abnormalities at either test concentration were found, and a clear dose-response relationship in skeletal and soft-tissue anomalies was lacking. Findings of lower fetal body weight and shorter crown-rump length are likely to be associated with the sustained lower maternal weight over gestation days 6-15. Several studies in humans (page 15, Table 2) were considered for establishing a POD for AEGL-2 values. Considering the database on acute exposures in humans and the severity of end points observed at concentrations ranging from 317 to 2,382 ppm for fractions of an hour, the committee recommended that the 4-h exposure at 76 ppm in the Davis (1934) study be considered as the POD for AEGL-2 values. That starting point is based on a NOAEL for effects on the central nervous system (CNS) and liver. Use of this POD will result in AEGL-2 values that will also be protective of possible fetal effects that could occur at maternal exposures as low as 300 ppm for 7 h (estimated POD of 100 ppm for 7 h) throughout gestation days 6-15 in rats (Schwetz et al. 1974). Time scaling should be performed for all the AEGL durations (with n = 2.5, as described in the TSD). For AEGL-3 values, the committee recommends that an uncertainty factor for interspecies differences be based on modeling of the LC50 values for carbon tetrachloride, which would yield a factor of 1.5. CARBONYL FLUORIDE The committee reviewed the AEGL TSD on carbonyl fluoride that was presented by Julie Klotzbach of SRC, Inc. Table 7 presents a summary of the proposed AEGL values for carbonyl fluoride and their basis. The committee approved the proposed AEGL values with a few clarifications and modifications. TABLE 7 Summary of Proposed AEGL Values for Carbonyl Fluoride Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) NR NR NR NR NR Insufficient data AEGL-2 (disabling) 0.35 ppm 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm One-third of AEGL-3 values (0.95 mg/m3) (0.95 mg/m3) (0.76 mg/m3) (0.46 mg/m3) (0.23 mg/m3) AEGL-3 (lethal) 1.0 ppm 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm BMCL05 for lethality in rats (2.7 mg/m3) (2.7 mg/m3) (2.2 mg/m3) (1.4 mg/m3) (0.70 mg/m3) (5.2 ppm, 4 h); total UF = 10 (interspecies = 3, intraspecies = 3); default time scaling Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; NR, not recommended; UF, uncertainty factor. 10

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AEGL Specific Comments The committee agrees that no AEGL-1 values should be recommended. The rationale should acknowledge that if AEGL values were to be derived from the limited data on no-effect levels of carbonyl fluoride, the AEGL-1 values would be very close to the AEGL-2 values for the 10- and 30-min durations and higher than the AEGL-2 values for the longer durations. The committee agrees that it is appropriate to derive AEGL-2 values by taking one-third of the AEGL-3 values. It might also be useful to show that deriving AEGL-2 values from the limited data on carbonyl fluoride (e.g., NOAEL for dyspnea) would result in higher values than those proposed. Given the steep exposure-response curve, that approach would provide less margin for error. Other Comments Page 8, lines 5-6; page14, lines 10-11: The argument that the steep concentration-response curve of carbonyl fluoride is an indication of a little variation in toxic effects within a population is not appropriate. The steeper the concentration-response curve is, the larger the resulting differences in effect from increases in concentration and from factors that increase susceptibility. The argument should be omitted, even though it is identified as an appropriate consideration in the Standing Operating Procedures (NRC 2001, Section 2.5.3.4.4). Page 12, line 39, and following pages: The discussions in Sections 3.7, 4.1, 4.2, and 4.3 refer to phosgene, hydrogen fluoride, and pyrolysis products of polytetrafluoroethylene. This is helpful for understanding what is known regarding the toxicity of carbonyl fluoride, but no comparisons are made to the AEGLs developed for hydrogen fluoride or phosgene. A comparison of the AEGL values for these chemicals with those of carbonyl fluoride would be helpful. Page 17, lines 5-6: The NIOSH and ACGIH® STEL values exceed the AEGL-3 values for the 10-min and 30-min durations by a factor of 5, and the 8-h TWA values exceed the AEGL-3 value for 8 h by almost an order of magnitude. An explanation about what might account for the differences should be added (NRC 2001, Appendix J). Page 17, Section 8.3: The section on Data Adequacy and Research Needs should also acknowledge the lack of animal data to derive AEGL-1 and AEGL-2 values. A recommendation should be added that additional studies on genotoxicity and reproductive and developmental toxicity would also help to strengthen the basis of the AEGL values for carbonyl fluoride. A discussion that pyrolysis of polytetrafluoroethylene yields high amounts of carbonyl fluoride should be added to the summary of the TSD, as well as the introductory section. Information should be included that pyrolysis products are composed of a large number of compounds, can be of variable composition, and pose significant analytic challenges. Pyrolysis products of polytetrafluoroethylene include a number of highly toxic compounds in addition to carbonyl fluoride, including perfluoroisobutylene, which is approximately 10-fold more toxic than phosgene (Patocka and Bajgar 1998; IPCS 2004). Because the Scheel et al. (1968a) study involved exposure to carbonyl fluoride and other compounds pyrolized from polytetrafluoroethylene, the study should be used only to support the uncertainty factor of 3 for interspecies variability, for reasons noted in Section 8.3 of the TSD. CYANIDE SALTS The committee reviewed the AEGL TSD on sodium cyanide, potassium cyanide, and calcium cyanide that was presented by Heather Carlson-Lynch of SRC, Inc. Table 8 presents a summary of the proposed AEGL values for the three cyanide salts and their basis. The committee approved the AEGL values, and made a few suggestions for clarifications before the document is finalized. 11

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Page 6, lines 39-40: In summarizing the Pauluhn (1987) study, clarify the context for the relative humidity range presented. From the study description, it appears that four distinct relative humidities are reported for the input air (29, 38, 47, and 51%), and four for the chamber exhaust (48, 53, 51, 54, and 54%); each represents the average of three measurements taken at the beginning, middle, and end of the given exposures. Thus, the actual range of relative humidities across these exposures (five concentrations) is unknown. The highest average relative humidity reported for the chamber exhaust (54%) was associated with the two highest concentrations, while the lowest average relative humidity reported for the chamber exhaust (48%) corresponded to the lowest concentration. Both are similar, on the order of 50%. Also, mention of this study (in line 39) should refer to the 1987 study (not the 1983 study). The other study by Pauluhn (1986), a 4-h exposure study cited in Pauluhn (1987), should be mentioned in the summary of the lethality studies (page 7, first paragraph). Page 6, lines 42-44: The justification for deriving AEGL-2 values by dividing AEGL-3 values by 3 should make it clear that this is a general approach for chemicals with a steep concentration-response curve for lethality and not because of data specific to thionyl chloride. Page 7, lines 1-6: Include the 4-h Pauluhn (1986) data, and check the inputs to the benchmark calculations to confirm those estimates are appropriate. Page 7, lines 7-10: Justify the statement that the animal model is appropriate (e.g., per citation); male outbred CD rats served as the animal model for sulfur dioxide (Cohen et al. 1973), whereas male and female Wistar rats serve as the basis for the AEGL-3 derivations for thionyl chloride. Also, clarify that the mechanism of action for direct-acting irritants of the eyes and respiratory tract is not expected to substantially differ across species. Page 8, lines 14-15: Replace the qualitative comparison to hydrolysis of phosgene (unless relevance is justified) with quantitative information to support the statement in line 14 that hydrolysis is very rapid. Page 9, Table 2 (Chemical and Physical Properties): The HSDB “2013” reference is misleading because information for this chemical in that database has not been updated for years; check other standard sources, as it appears other values have been reported. Given its importance to the inhalation toxicity of thionyl chloride, hydrolysis rates should be included in the table. Page 10, lines 8-9 (Section 2.2.2, Case Reports): Delete the statement that the case reports lack exposure and duration data. Duration data are provided in the summary by Grieco (1962) and in EPA/OPPT (2000). Page 10, lines 29, 32, 36-37, 39 (Section 2.2.2, Case Reports): Clarify that the first worker was “entirely well 4 years after the exposure” (line 29) to avoid the impression that corticosteroids returned the patient to normal health after the six-month therapy period. Clarify that the second worker (from the same factory) was admitted to the ophthalmology department for his corneal burns (line 32), developed a spontaneous pnuemothorax with progressive respiratory failure, developed atelectasis and repeated lung infections, and continued to be severely ill, was considered to have end-stage lung disease and was sent to a transplant center for a heart-lung transplantation but during the wait his conditions gradually improved (lines 36-37), and he subsequently underwent bilateral corneal transplantation for blindness due to his chemical corneal injury (line 39). Page 10, line 43, to page 11, line 2: Regarding the summary of the USEPA/OPPT (2000) case report, the TSD should explain that the worker had entered an area where another employee (who was on supplied air) was rinsing out emptied thionyl chloride-containing drums with water. This will illustrate the relevance of this case report. The TSD should also provide additional relevant information regarding the symptoms, notably “impaired cerebellar function -- ataxia, markedly impaired hand-eye coordination, slurred speech; significantly impaired memory (short, intermediate and long term); and impaired executive function and judgment. All clinical signs improved dramatically during the first 6 hours following exposure. Twenty-four hours after the exposure, cerebellar function and standard memory/executive/judgment screening tests were within normal limits; however, no baseline data for the employee were available. At 72 hours post exposure, all subjective concerns were completely resolved”. 34

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Page 11, lines 17-18 (Section 2.4, Developmental/Reproductive Toxicity): This section should indicate whether any relevant data are available on the hydrolysis products sulfur dioxide or hydrogen chloride. Page 11, line 22 (Section 2.5, Genotoxicity): The section currently indicates that there are no data “relevant to the derivation of AEGL values for thionyl chloride”. Clarification is needed on whether there are any genotoxicity data. This section should also indicate whether any relevant data are available on sulfur dioxide or hydrogen chloride. Page 11, line 26 (Section 2.6, Carcinogenicity): This section should indicate whether any relevant data are available on sulfur dioxide or hydrogen chloride. Page 11, lines 30-33 (Section 2.7, Summary): Correct the statement about the lack of exposure and duration data regarding lethal and nonlethal human exposures to thionyl chloride. Also, bronchiolitis obliterans and blindness from corneal burns should be included in the description of effects. Pages 11-12 (Section 3.1.1, Rats): This section should include information for the 4-h exposure duration study by Pauluhn (1986), which is referenced in the Pauluhn (1987) study. This section should also include the data from Flury and Zernik (1931), which Kinkead and Einhaus (1984) cite in support of the reported lethality for cats from a 20-min exposure to thionyl chloride at 17.5 ppm. That report was dismissed because the concentration appeared inconsistent with their rat data. However, because of thionyl chloride’s rapid hydrolysis, the toxicity results reflected exposure to sulfur dioxide and hydrogen chloride; only 11 ppm was measured at the highest test concentration, whereas concentrations of sulfur dioxide and hydrogen chloride were calculated to be 661 ppm and 1,322 ppm, respectively. The difference in toxicity might at least in part reflect the deeper deposition in the lung and greater effect severity for thionyl chloride (presumably studied by Flury and Zernik) compared with the hydrolysis products essentially tested by Kinkead and Einhaus. The TSD should provide the cat data and discuss potential explanations for differences. Page 11, line 45, to page 12, line 11 (Section 3.1.1, Kinkead and Einhaus): This summary is misleading because of confusion about the data for thionyl chloride and for its two hydrolysis products. In the first sentence, clarify that although the original chemical was 99% pure thionyl chloride, the rats were exposed to the hydrolysis products. Also clarify that the exposure concentrations listed (page 12, line 5) are calculated values (not measured concentrations) and that they reflect sulfur dioxide plus hydrochloric acid, not thionyl chloride. Furthermore, most deaths occurred within 24 h after exposure ended, and the calculated LC50 of 1,480 ppm is for sulfur dioxide and hydrochloric acid. The calculated LC50 for thionyl chloride was much lower (500 ppm; 95% confidence limits: 420-660 ppm). This estimated lethal concentration is very similar to the LC50 identified from the Nachreiner study, and its much lower value suggests that the calculated values for the BMCL05 (196 ppm) and BMC01 (227 ppm) should be much lower than presented. Page 12, lines 13-22 (Section 3.1.1, Pauluhn): Check the unit conversions presented in the TSD, as Pauluhn reported concentrations in mg/m3 and provided a conversion factor to indicate ppm. Clarify that the listed LC50 (converted from 6,200 mg/m3 reported by Pauluhn) is an approximate value. This value was calculated from the geometric mean of the concentrations for groups 3 and 4, and was the delineation point between no fatalities and deaths in 4 of 5 animals (both sexes), with signs in group 3 of dyspnea and apathy that did not reverse within the subsequent 14- day observation period. Also incorporate the 4-h LC50 data summarized from the Pauluhn (1986) study, which converts to 1,117 ppm (95% confidence limits: 884-1,411) based on the data summarized in Pauluhn (1987) and the conversion factor provided therein. Page 12, lines 34-40 (Section 3.1.1, Nachreiner): This text should be corrected and clarified (and edited). Confidence limits should be provided to better characterize the study (see the summary on page 5 of Nachreiner [1993]). The reported relative humidity was approximate; it could not be monitored during exposure using the nose-only apparatus. The description should also indicate that mouth breathing was observed for all test groups, provide information regarding post-exposure time to death, and acknowledge mean concentrations, as well as issues related to the controls. 35

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Page 12, line 42, to page 13, line 3: Revise this interpretation to reflect the correct LC50 value calculated for thionyl chloride by Kinkead and Einhaus (1984), to provide the correct relative humidity data corresponding to the exposure concentrations, and to include the Pauluhn (1986) data. Provide context for higher toxicity at lower relative humidity as outlined in previous comments (less hydrolysis in ambient air prior to inhalation resulting in deeper deposition of thionyl chloride in the lung, where hydrolysis to sulfur dioxide and hydrogen chloride produces greater direct contact effects of those corrosive irritants with local tissue compared with the result when hydrolysis products are inhaled at the outset). Ensure that the important role of relative humidity is clearly presented. See the study summaries for sulfur dioxide in NRC (2010c). For example, the discussion explains that the increased response identified in Bethel et al. (1985) compared with other studies may be attributed to the lower relative humidity for that study (35% vs. 70-85%). Similarly, the summary of Rahlenbeck and Kahl (1996) describes controlling for humidity to assess the relationship between mortality and air pollution. The key study by Linn et al. (1985) used for the AEGL-1 values specifically addresses the role of relative humidity (as well as temperature). The study found that respiratory effects were more severe at lower humidity regardless of temperature. (The response at lower humidity and temperature is more than double that at higher humidity and temperature.) Discussion of Table 9 should provide a summary of toxicity data for sulfur dioxide and hydrogen chloride that includes relative humidity data. Page 13, lines 5-12. Provide additional information on the rate of thionyl chloride hydrolysis to address the differences indicated here. Correct the statement that additional information was not identified (lines 11-12). For example, see Driver et al. (2003) and related resources. Such data indicate that the rate estimated by Nachreiner is reasonable. Correct the statement that Kinkead and Einhaus did not detect any parent compound (lines 7-8), as described in the study and reflected in the comment on pages 11-12 (Section 3.1.1, Rats), which indicates that thionyl chloride was measured at the highest test concentration. Also, provide the further context from Kinkead and Einhaus (1984), who describe: “Sampling for thionyl chloride analysis was done once during each exposure. The chamber was allowed to achieve a stable total chloride contaminant concentration as indicated by the chloride ion electrode analysis before impinger sampling was initiated.” Thus, among other factors, it is reasonable to consider that the sampling may not have begun within 5 min of the start of the exposure, which could alone explain the results given the rapid hydrolysis of thionyl chloride at the average relative humidities indicated for those exposure conditions (in particular because the concentrations clearly ranged higher per the average representing three measurements during the 1-h period). Page 14, Table 3: Include additional lethality data, such as from Pauluhn (1986) and Flury and Zernik (1931), with qualification as indicated. Correct the calculated LC50 and BMC values for the Kinkead and Einhaus (1984) to reflect their calculated LC50 for thionyl chloride. Correct the discrepancy in the last row (highest concentration) of the Pauluhn entry, which shows 5/5 male, 5/5 female, and 10/10 combined mortality, whereas the text in the “Effects at Lethal Exposure” column states 90% mortality, and the report appears to indicate that only 4/5 females died. Given the differences per sex in the Nachreiner study (and also at the highest concentration in the Pauluhn study), provide mortality percentages for males and females separately in the “Effects at Lethal Exposure” column to facilitate comparisons between studies. If an average is also intended to be given, rather than a combined average, present the mortality percentage for males to represent the more sensitive subgroup. Page 15, line 37 (Section 3.3, Developmental/Reproductive Toxicity): The section should be revised to address the hydrolysis products of thionyl chloride that would be distributed systemically. For example, see corresponding discussion in the AEGL TSD for sulfur dioxide (NRC 2010c). Page 15, line 41 (Section 3.4, Genotoxicity): The section should be revised to address the hydrolysis products of thionyl chloride that would be distributed systemically. For example, see corresponding discussion in the AEGL TSD for sulfur dioxide (NRC 2010c). Page 15, line 45: (Section 3.5, Carcinogenicity): Revise the sentence “There are no data to suggest that thionyl chloride is a carcinogen.” If any data exist they should be provided, otherwise state 36

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no data were found. Also address the hydrolysis products, which would be distributed systemically. For example, see the corresponding discussion in the AEGL TSD for sulfur dioxide (NRC 2010c). Page 16, lines 6-7 (Section 3.6, Summary): Revise to correct the values as indicated (such as the LC50 value calculated for thionyl chloride by Kinkead and Einhaus). Include the LC50 value identified in Pauluhn (1987) from Pauluhn (1986), which are described as corresponding in order of magnitude to the value calculated in the 1987 study. Clarify what the calculated value represents and provide the corresponding relative humidities. Page 16, lines 13-20 (Section 4.1, Metabolism and Disposition): Revise the text to clarify that following inhalation of thionyl chloride and its hydrolysis to sulfur dioxide and hydrogen chloride in the lung, these two products enter the blood stream (across the exchange boundary of the respiratory system) and are distributed throughout the body. Page 16, lines 24-42 (Section 4.2, Mechanism of Toxicity): Revise the text to address previous comments. Correct the LC50 information and include additional relevant data, including from Pauluhn (1986). Ensure that the correct relative humidity is clearly identified for each key value, and provide more supporting context for humidity considerations. Page 17, lines 8-9 (Section 4.3, Structure-Activity Relationships): Revise the text to acknowledge the roles of sulfur dioxide and hydrogen chloride. Page 17, lines 15-21 (Section 4.4.1, Susceptible Populations): Revise the text to provide context for direct-acting irritants. Information should be included on thionyl chloride, in addition to that for sulfur dioxide. Gender differences should also be discussed, given that it is mentioned elsewhere and serves as part of the rationale for the intraspecies uncertainty factor. Information about gender differences in the rapid hydrolysis products of thionyl chloride should be included. More specific (at least semiquantitative) information should be provided, including data from the key human study underlying the AEGL-1 and AEGL-2 values for sulfur dioxide and relevant information on hydrogen chloride. Page 18, Section 6.2, lines 10-19 (Summary of Animal Data Relevant to AEGL-2): The discussion should be revised to better characterize the data from the candidate Pauluhn (1987) study, such that the study can at least serve to support the AEGL-2 values estimated by scaling from the AEGL-3 values. Page 18, lines 23-35 (Section 6.3, Derivation of AEGL-2): Revise this section in response to previous comments, including the comments regarding page 6, lines 8-16, 39-40, and 42-44, as well as comments that identify corrections and clarifications regarding the characterization of information from the respective animal studies. The relative humidity value (and its basis) corresponding to each exposure concentration estimate should be provided. In light of the revisions, ensure that appropriate data and assumptions underlie the AEGL-3 values, and present the correct nonlethal toxicity data. Discuss the data underlying the AEGL-2 values for sulfur dioxide and hydrogen chloride to provide supporting context for the AEGL-2 values for thionyl chloride. Page 19, lines 10-16 (Section 7.2): Provide further context for these data (e.g., see comments regarding page 12, lines 34-40), including information on the estimated relative humidities and additional lethality data. Page 19, lines 20-25: Correct values and provide further context, as identified in previous comments (for example, the comments regarding page 12, lines 42-ff). Page 19, lines 31-33, and Appendix D: The current EPA benchmark dose software is version 2.4, from April 2013. Check input values and assumptions and compare with the current model. Page 19, lines 36-38: Revise per comments on page 7, lines 7-10. Page 19, lines 38-46: Revise per comments on the same text elsewhere. Page 20, lines 28 and 35 (Section 8.2, Comparison with Other Standards and Guidelines): Verify the accuracy of the information presented in this section. A number of other occupational exposure limits (OELs) exist. For example, see SER (2013b), which includes OELs for Switzerland, Belgium, Spain, Norway, Finland, and Denmark (including limits of about 5 mg/m3 for 15-min exposures). Standards expressed in mg/m3 should be presented in those units. Page 20, lines 29-30: The MAC is referenced but no value is provided in Table 8; provide the status of the MAC and, if available, reinstate the MAC definition in the table and footnote on page 25. 37

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A new (modified) system for OELs was established in The Netherlands in 2007, which requires updating the information in the text, Table 8, and cited references. The Dutch Health Council’s Expert Committee on Occupational Standards recommends health-based values; the Social and Economic Council of the Netherlands (SER) provides OELs online (see SER [2013b]). Page 20, lines 24-25: Explain how the AEGL values are consistent with current standards and guidelines. Page 21, Table 9: The AEGL values for thionyl chloride should be included in the table to facilitate comparisons between the parent chemical and its hydrolysis products. Summary information on how the values were derived (for example, the end point, species, uncertainty factors), as well as relative humidity information should be included. In addition, identify the stoichiometric context for hydrogen chloride (to clarify that two moles are generated per mole thionyl chloride). Page 22 (Section 8.3, Data Adequacy and Research Needs): Correct the first sentence (claiming human data do not contain duration information). In the second sentence, indicate that quantitative concentration-response data are a key gap. The third sentence is unclear in terms of human evidence that supports the toxicologic end points identified in animal studies (the reverse is more standard). The next sentences (lines 8-10), states “Quantitative animal data are available from three studies that demonstrate a respiratory response similar to that observed in humans.” This appears to contradict other statements that the effects in animals are relatively severe and thus not useful for deriving AEGL-1 or AEGL-2 values, whereas human end points such as bronchiolitis obliterans and blindness are not reflected in animals. The statement in lines 14-16 that only 1-h studies are available should be corrected. Finally, the last sentence should be corrected because good information is available regarding the relationship between the hydrolysis rate of thionyl chloride and relative humidity. Page 24, lines 18-19: Update and check the benchmark dose modeling inputs and outputs per the spring 2013 version of the model. Page 28, lines 21-23; and page 33, summary table (UF/Rational entry): These two statements appear contradictory: “Results of the Nachreiner (1993) study indicate males are more sensitive than females” and “data on a sensitive population are lacking for thionyl chloride.” Also, verify that the results of the Nachriener (1993) study indicate male Wistar rats are more sensitive than females. Provide context for gender differences in humans with respect to the hydrolysis products of thionyl chloride, notably sulfur dioxide in exercising asthmatics. Page 28, lines 25-26; and page 33, summary table (UFs/rationale row): Delete the sentence regarding the intraspecies uncertainty factor being protective of asthmatics and other sensitive populations unless it can be justified. A factor of 10 was applied to address asthmatics alone in the derivation of AEGL values for sulfur dioxide (NRC 2010c), and there is some indication of gender differences in response to thionyl chloride. Page 35, Table D-1: Include the relative humidity information to provide that important context for the lethality data. Page 42, table: A title should be provided for the table to indicate the data presented were used in the category plot. In the column for Sex, it is unclear what the entry of “B” indicates (both sexes?). TOLUENE The committee reviewed the AEGL TSD on toluene that was presented by George Woodall of the U.S. Environmental Protection Agency. Table 23 presents a summary of the proposed AEGL values for toluene and their basis. The committee agreed that its previous comments on the TSD (NRC 2010b) were addressed, and that most of the proposed AEGL values were appropriately derived. The committee recommends that one data set be re-reviewed for its relevance to deriving AEGL-1 values before the document is finalized. 38

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TABLE 23 Summary of Proposed AEGL Values for Toluene Reviewed by the Committee 10 min 30 min 1h 4h 8h End Point, Derivation Factors AEGL-1 (nondisabling) 67 ppm 67 ppm 67 ppm 67 ppm 67 ppm No effect level for notable discomfort (250 mg/m3) (250 mg/m3) (250 mg/m3) (250 mg/m3) (250 mg/m3) and neurologic effects (200 ppm, 8 h);total UF = 3 (intraspecies) AEGL-2 (disabling) 1,400 ppm 760 ppm 560 ppm 310 ppm 250 ppm NOAEL for decrement in neurologic (5,200 mg/m3) (2,800 mg/m3) (2,100 mg/m3) (1,200 mg/m3) (940 mg/m3) function (1,600 ppm, 34 min); total UF = 3 (intraspecies); PBPK model for time scaling AEGL-3 (lethal) See belowa 5,200 ppm 3,700 ppm 1,800 ppm 1,400 ppm NOAEL for lethality (6,250 ppm, (19,500 mg/m3) (13,800 mg/m3) (6,800 mg/m3) (5,100 mg/m3) 2 h); total UF = 3 (intraspecies); PBPK model for time scaling a The 10-min AEGL-3 value of 10,000 ppm (37,500 mg/m3) is higher than 50% of the lower explosive limit of toluene in air (14,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account. Abbreviations: NOAEL, no observed adverse effect level; PBPK, physiologically based pharmacokinetic; UF, uncertainty factor AEGL Specific Comments Page 60, lines 42-43, and page 61, lines 18-19: The sentences should be revised to indicate that 200 ppm is a NOAEL for AEGL-1 effects. As currently written (“an effect that exceeds the definition of AEGL-1”), the sentences suggest that the concentration is a NOAEL for AEGL-2 effects. Page 65, lines 22-23: Toluene at 100 ppm is reported to produce fatigue, drowsiness, headache, dizziness, and feelings of intoxication. These effects are relevant to AEGL-1 values, but do not appear to have been considered for deriving AEGL-1 values. The data should be included in the discussion of relevant to studies to AEGL-1 effects, and a determination made on whether they are suitable for deriving AEGL-1 values. Other Comments A brief description of the toxicokinetic model of Benignus et al. (2006) should be provided. Because data on ethanol are cited in support of the AEGL-2 values for toluene, consideration should be given to including a table that compares air concentrations of toluene and ethanol that are associated with decrements in neurologic function. REFERENCES Andrewes, P., K.T. Kitchin, and K. Wallace. 2004. Plasmid DNA damage caused by stibine and trimethylstibine. Toxicol. Appl. Pharmacol. 194(1):41-48. ASTM International. 2012. Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals. ASTM E981- 04(2012). Åstrand, I., J. Engstrom, and P. Övrum. 1978. Exposure to xylene and ethylbenzene: I. Uptake, distribution and elimination in man. Scand. J. Work Environ. Health 4(3):185-194. 39

OCR for page 1
ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for Antimony and Compounds. U.S. Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. December 1992 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp23.pdf [accessed May 16, 2013]. Bailly, R., R. Lauwerys, J.P. Buchet, P. Mahieu, and J. Konings. 1991. Experimental and human studies on antimony metabolism: Their relevance for the biological monitoring of workers exposed to inorganic antimony. Br. J. Ind. Med. 48(2):93-97. Bardodej, Z., and E. Bardodejova. 1961. Value and application of exposure tests. X. Exposure test for ethyl benzene [in Czech]. Cesk. Hyg. 6:537-545. Barrow, C.S., Y. Alarie, J.C. Warrick, and M.F. Stock. 1977. Comparison of the sensory irritation response in mice to chlorine and hydrogen chloride. Arch. Environ. Health 32(2):68-76. Benignus, V.A., T. Coleman, C.R. Eklund, and E.M. Kenyon. 2006. A general physiological and toxicokinetic (GPAT) model for simulating complex toluene exposure scenarios in humans. Toxicol. Mech. Methods 16(1):27-36. Berry, M., and D.L. Easty. 1993. Isolated human and rabbit eye: Models of corneal toxicity. Toxicol. In Vitro 7(4):461-464. Bethel, R.A., D. Sheppard, B. Geffroy, E. Tam, J.A. Nadel, and H.A. Boushey. 1985. Effect of 0.25 ppm sulfur dioxide on airway resistance in freely breathing, heavily exercising, asthmatic subjects. Am. Rev. Respir. Dis. 131(4):659-661. Buckley, B.J., and D.J. Bassett. 1987. Pulmonary cadmium oxide toxicity in the rat. J. Toxicol. Environ. Health 21(1-2):233-250. Bui, B., T.J. Tsay, M.C. Lin, and C.F. Melius. 2007. Theoretical and experimental studies of the diketene system: Product branching decomposition rate constants and energetic of isomers. Int. J. Chem. Kinet. 39(10):580- 590. Carpenter, C.P., and H.F. Smyth. 1946. Chemical burns to the rabbit cornea. Am. J. Opthalmol. 29(11):1363-1372. Carpenter, C.P., H.F. Smyth, 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.CDC (Centers for Disease Control and Prevention). 2013. Case Definition: Arsine or Stibine Poisoning, http://emergency.cdc. gov/agent/arsine/casedef.asp [accessed May 20, 2013]. Cohen, H.J., R.T Drew, J.L. Johnson, and K.V. Rajagopalan. 1973. Molecular basis of the biological function of molybdenum: The relationship between sulfite oxidase and the acute toxicity of bisulfite and SO2. Proc. Natl. Acad. Sci. USA 70(12):3655-3659. Coombs, D.W., T.J. Kenny, and C.J. Hardy. 1992. Methacrolein (B.G. No. 108) 2-Week Repeat Dose Preliminary Inhalation Toxicity Study in Rats. BGH 50/932334. BGH 40/920648. Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Coombs, D.W., T.J. Kenny, D. Crook, W.A. Gibson. 1994. Methacrolein (B.G. No. 108) 13-Week Inhalation Toxicity Study in Rats. BGH 50/932324. Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. November 1994 [online]. Available: http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/ C0DE274286C070E285257A2C0054C6E1/$File/84990000009.pdf [accessed June 14, 2013]. Davis, P.A. 1934. Carbon tetrachloride as an industrial hazard. JAMA 103(13):962-966. Deichmann, W.B., and H.W. Gerarde. 1969. Toxicology of Drugs and Chemicals. New York: Academic Press. DeWolff, F.A. 1995. Antimony and health. BMJ 310(6989):1216-1217. DoD (U.S. Department of Defense). 2005. Potential Military Chemical/Biological Agents and Compounds. Army, Marine Corps, Navy, Air Force, Multiservice Tactics, Techniques, and Procedures. January 2005 [online]. Available: https://www.fas.org/irp/doddir/army/fm3-11-9.pdf [accessed June 14, 2013]. Dow Chemical Co. 1977. Initial Submission: Evaluation of Acute Inhalation Toxicity of Bromine Chloride in Rats with Cover Letter Dated 04/30/92. EPA Document No. 88-920002267. Driver, C.J., T.J. Johnson, Y.F. Su, M.L. Alexander, R.J. Fellows, J. Magnuson, R.S. Disselkamp, and B.A. Roberts. 2003. The Impact of Humidity, Temperature, and Ultraviolet Light on the Near-Field Environmental Fate of Pinacolyl Alcohol, Methyl Iodide, Methylphosphonic Dichloride (DCMP) and Thionyl Chloride Using an Environmental Wind Tunnel. PNNL-14172. Prepared for the U.S. Department of Energy by Pacific Northwest National Laboratory, Richland, WA. January 2003 [online]. Available: http://www.pnl.gov/ main/publications/external/technical_reports/PNNL-14172.pdf [accessed June 14, 2013]. Duckett, S. 1970. Fetal encepthalopathy following ingestion of tellurium. Experientia 26(11):1239-1241. 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. A.M.A. Arch. Ind. Health 18(4):303-311. Elkins, H.B. 1950. The Chemistry of Industrial Toxicology. New York: John Wiley & Sons. 40

OCR for page 1
Engelhard, B., J. Grolig, M. Martin, K.H. Reissinger, G. Scharfe, W. Schwerdtel, and W. Swodenk. 1976. Process for Production of Allyl Alcohol. Patent No. US3970713A. July 20, 1976 [online]. Available: http://www.google.com/patents/US3970713 [accessed June 13, 2013]. Engström, K., V. Riihimäki, and A. Laine. 1984. Urinary disposition of ethylbenzene and m-xylene in man following separate and combined exposure. Int. Arch. Occup. Environ. Health 54(4):355-363. EPA (U.S. Environmental Protection Agency). 2006. Non-confidential 2006 IUR Records by Chemical, Including Manufacturing, Processing and Use Information: 2-propen-1-ol (CASRN 107-18-6). Inventory Update Reporting, U.S. Environmental Protection Agency [online]. Available: http://cfpub.epa.gov/iursearch/ 2006_iur_companyinfo.cfm?chemid=2758&outchem=both [accessed June 14, 2013]. EPA (U.S. Environmental Protection Agency). 2009. Provisional Peer-Reviewed Toxicity Values for Superfund (PPRTV): Allyl Alcohol (CASRN 107-18-6). File Date: 9-29-2009. Office of Superfund Remediation and Technology Innovation, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://hhpprtv.ornl.gov/quickview/pprtv.php?chemical=Allyl+Alcohol [accessed June 14, 2013]. EPA (U.S. Environmental Protection Agency). 2012. TSCA Workplan Chemical Risk Assessment: Antimony Trioxide. External Review Draft. Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Washington, DC. December 2012 [online]. Available: http://www.epa.gov/oppt/ existingchemicals/pubs/TSCA_Workplan_Chemical_Risk_Assessment_of_ATO.pdf [accessed June 14, 2013]. EPA (U.S. Environmental Protection Agency). 2013a. Toxics Release Inventory (TRI) Program [online]. Available: http://www.epa.gov/tri/index.htm [accessed June 14, 2013]. EPA (U.S. Environmental Protection Agency). 2013b. High Production Volume Information System (HPVIS): 2-propen-1-ol (CASRN 107-18-6). U.S. Environmental Protection Agency [online]. Available: http://ofmpub.epa.gov/oppthpv/quicksearch.display?pChem=101774 [accessed June 14, 2013]. EPA/OPPT (U.S. Environmental Protection Agency/Office of Pollution Prevention and Toxics). 2000. Initial Submission: Letter from [ ] to USEPA Regarding Possible Exposure to Thionyl Chloride of a Single Employee, with Attachment Dated 09/25/00 (Sanitized). EPA Document No. 88000000227S. Fairhall, L.T., and F. Hyslop. 1947. The Toxicology of Antimony. Public Health Reports Supplement No. 195. Washington, DC: U.S. Government Printing Office. Flury, F., and F. Zernik. 1931. Schädliche Gase: Dämpfe, Nebel, Rauch- und Staubarten. Berlin: Springer. Grieco, A. 1962. Acute thionyl chloride poisoning [in Italian]. Med. Lav. 53:206-209. Grose, E.C., J.H. Richards, R.H. Jaskot, M.G. Ménache, J.A. Graham and W.C. Dauterman. 1987. A comparative study of the effects of inhaled cadmium chloride and cadmium oxide: Pulmonary response. J. Toxicol. Environ. Health 21(1-2):219-232. Grosjean, D., E. Grosjean, and E.L. Williams. 1993. Atmospheric chemistry of unsaturated alcohols. Environ. Sci. Technol. 27(12):2478-2485. Harrison, G., and W. MacKenzie. 1973. Ultrastructural Pathogenesis of Lesions Produced by Exposure to Oxygen Difluoride with Correlative Light Microscopy. AMRL-TR-72-107. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH [online]. Available: http://www.dtic.mil/dtic/tr/fulltext/u2/770292.pdf [accessed May 13, 2013]. Health Council of the Netherlands. 2004. Oxygen Difluoride: Heath-based Reassessment of Administrative Occupational Exposure Limits. No. 200/15OSH/126. Committee on Updating of Occupational Exposure Limits, Health Council of the Netherlands, The Hague. June 8, 2004 [online]. Available: http://www.gr.nl/ sites/default/files/00@15126.pdf [accessed April 11, 2013]. Hosohata, K., H. Ando, Y. Fujiwara, and A. Fujimura. 2011. Vanin-1: A potential biomarker for nephrotoxicant- induced renal injury. Toxicology 290(1):82-88. HPA (U.K. Health Protection Agency). 2012. Arsine and Stibine Incident Management, Version 2. U.K. Centre for Radiation, Chemical and Environmental Hazards, Health Protection Agency. March 2012 [online]. Available: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1202487024290 [accessed June 14, 2013]. ICRP (International Commission on Radiological Protection). 2012. Occupational Intakes of Radionuclides, Part 3. Draft Report for Consultation. Annals of the ICRP, ICRP ref. 4838-4528-4881, September 20, 2012 [online]. Available: http://www.icrp.org/docs/Occupational_Intakes_P3_for_consultation.pdf [accessed June 14, 2013]. 41

OCR for page 1
IPCS (International Programme on Chemical Safety). 1996. Antimony. UKPID Monograph, July 16, 1996 [online]. Available: http://www.inchem.org/documents/ukpids/ukpids/ukpid40.htm [accessed May 20, 2013]. IPCS (International Programme on Chemical Safety). 1998. Tellurium Hexafluoride. UKPID Monograph [online]. Available: http://www.inchem.org/documents/ukpids/ukpids/ukpid83.htm [accessed May 20, 2013]. IPCS (International Programme on Chemical Safety). 2004. Perfluoroisobutylene. IPCS: 1216 [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics1216.htm [accessed May 8, 2013].Irwin, R.D. 2006. NTP Technical Report on the Comparative Toxicity Studies of Allyl Acetate (CAS No. 591-87-7), Allyl Alcohol (CAS No. 107-18-6) and Acrolein (CAS No. 107-02-8) Administered by Gavage to F344/N Rats and B6C3F1 Mice. Toxicity Report 48. NIH 06-443. U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/ST_rpts/tox048.pdf [accessed June 13, 2013]. Jacobs, G.A. 1992. OECD eye irritation tests on allylalcohol and dimethylsulphoxide. J. Am. Coll. Toxicol. 11(6):729. Japan Bioassay Research Center. 2006. Mutagenicity Test of 1,1,2,3,3,3-hexafluoro-1-propene Using Microorganisms. Study No. 6264. Japan Industrial Safety and Health Association. September 2006. Jenkinson, P.C., and D. Anderson. 1990. Malformed foetuses and karyotype abnormalities in the offspring of cyclophosphamide and allyl alcohol-treated male rats. Mutat. Res. 229(2):173-184. Johnson, T.J., R.S. Disselkamp, Y.F. Su, R.J. Fellows, M.L. Alexander, and C.J. Driver. 2003. Gas-phase hydrolysis of SOCl2 at 297 and 309 K: Implications for its atmospheric fate. J. Phys. Chem. A 107(32):6183-6190. Kentner, M., M. Leinemann, K. Schaller, D. Weltle, and G. Lehnert. 1995. External and internal antimony exposure in starter battery production. Int. Arch. Occup. Environ. Health 67(2):119-123. Kimmerle, G. 1960. Comparative studies on the inhalation toxicity of sulfur-, selenium-, and tellurium -hexafluoride [in German]. Arch. Toxikol. 18:140-144.Kinkead, E.R., and R.L. Einhaus. 1984. Acute Toxicity of Thionyl Chloride Vapor for Rats. AFAMRL-TR-84-069. Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH [online]. Available: http://www.dtic.mil/dtic/tr/fulltext/u2/ a148952.pdf [accessed June 19, 2013]. Kononenko, V.I. 1970. Fatal poisoning with allyl alcohol [in Russian]. Sud. Med. Ekspert 13(3):50-51. Lash, L.H., and J.C. Parker. 2001. Hepatic and renal toxicities associated with perchloroethylene. Pharmacol. Rev. 53(2):177-208. Lauwerys, R., H. Roels, M. Refniers, J.P. Buchett, A. Bernard, and A. Goret. 1979. Significance of cadmium concentration in blood and in urine in workers exposed to cadmium. Environ. Res. 20:375-391. Lin, S.C., L.M. Candela, A.P. Kahn, E.I. Ross-Medgaarden, and G.A. Sawyer. 2011. Process for Producing Allyl Alcohol. Patent Application No. 20110207973. August 25, 2011. Patentdocs [online]. Available: http://www.faqs.org/patents/app/20110207973 [accessed June 13, 2013]. Linn, W.S., D.A. Shamoo, K.R. Anderson, J.D. Whynot, E.L. Avol, and J.D. Hackney. 1985. Effects of heat and humidity on the responses of exercising asthmatics to sulfur dioxide exposure. Am. Rev. Respir. Dis. 131(2):221-225. MacEwen, J.D. and E.H. Vernot. 1972. Toxic Hazards Research Unit Annual Technical Report: 1972. AD-755 358; AMRL-TR-72-62. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH [online]. Available: http://www.dtic.mil/dtic/tr/fulltext/u2/755358.pdf [accessed June 17, 2013]. Montelius, J., ed. 2000. Scientific Basis for Swedish Occupational Standards XXI. Criteria Group for Occupational Standards. NR 2000:22. National Institute for Working Life (Arbetslivsinstitutet), Stockholm, Sweden [online]. Available: http://www.inchem.org/documents/kemi/kemi/ah2000_22.pdf [accessed June 14, 2013]. Montelius, J., ed. 2001. Scientific Basis for Swedish Occupational Standards XXII. NR 2001:20. Swedish Criteria Group for Occupational Standards, National Institute for Working Life, Stockholm, Sweden [online]. Available: http://www.inchem.org/documents/kemi/kemi/ah2001_20.pdf [accessed May 10, 2013]. Montelius, J., ed. 2010. Scientific Basis for Swedish Occupational Standards XXX. NR 2010;44(5). Swedish Criteria Group for Occupational Standards, Swedish Work Environment Authority. Arbete och hälsa. Gothenburg, Sweden: University of Gothenburg [online]. Available: https://gupea.ub.gu.se/bitstream/ 2077/23241/1/gupea_2077_23241_1.pdf [accessed May 15, 2013]. Nachreiner, D.J. 1993. Thionyl Chloride: Acute Vapor Inhalation Toxicity Study in Rats. BRRC Report No. 9211153. Bushy Run Research Center, Union Carbide Chemicals and Plastics Company, Inc., Export, PA. October 19, 1993. Nielsen, G.D., J.C. Bakbo, and E. Holst. 1984. Sensory irritation and pulmonary irritation by airborne allyl 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. 42

OCR for page 1
NRC (National Research Council). 2000. Arsine. Pp. 65-112 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 1. Washington, DC: The National Academies 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. Hydrogen cyanide. Pp. 211-276 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: The National Academies Press. NRC (National Research Council). 2004a. Chlorine. Pp. 11-76 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The National Academies Press. NRC (National Research Council). 2004b. 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). 2007. Chlorine trifluoride. Pp. 53-91 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 5. Washington, DC: The National Academies Press. NRC (National Research Council). 2010a. Bromine. Pp. 13-45 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 9. 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). 2010c. Sulfur dioxide. Pp. 393-448 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 8. Washington, DC: The National Academies Press. NRC (National Research Council). 2011. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. NRC (National Research Council). 2012. Twenty-first Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. Odum, J., and T. Green. 1984. The metabolism and nephrotoxicity of tetrafluoroethylene in the rat. Toxicol. Appl. Pharmacol. 76(2):306-318. OSHA (Occupational Safety and Health Information). 2004. Chemical Sampling Information: Stibine [online]. Available: http://www.osha.gov/dts/chemicalsampling/data/CH_267900.html [accessed May 20, 2013]. Patocka, J., and J. Bajgar. 1998. Toxicology of Perfluoroisobutene. ASA Newsletter [online]. Available: http://www.asanltr.com/ASANews-98/pfib.html [accessed May 8, 2013]. Pauluhn, J. 1986. Thionylchlorid - Untersuchung zur akuten Inhalationstoxizitat an Ratten. Report No. 14332. Bayer AG. February 12, 1986 [as cited in Pauluhn 1987]. Pauluhn, J. 1987. Study for Acute Inhalation Toxicity in Rats in Accordance with OECD Guideline No. 403 (Exposure: 1 x 1 Hour). Report No. 15403. Bayer AG, Wuppertal, Germany. Price, N.H., W.G. Yates, S.D. Allen, and S.W. Waters. 1979. Toxicity evaluation for establishing IDLH values (Final Report) NTIS TR 1518-005. Utah Biomedical Test Laboratory, Salt Lake City, UT. Rahlenbeck, S.I., and H. Kahl. 1996. Air pollution and mortality in East Berlin during the winters of 1981-1989. Int. J. Epidemiol. 25(6):1220-1226. Scheel, L.D., W.C. Lane, and W.E. Coleman. 1968. The toxicity of polytetrafluoroethylene pyrolysis products - including carbonyl fluoride and a reaction product, silicon tetrafluoride. Am. Ind. Hyg. Assoc. J. 29(1):41-48. Schwetz, B.A., B.K..J. Leong, and P.J. Gehring. 1974. Embryo- and fetotoxicity of inhaled carbon tetrachloride, 1,1- dichloroethane and methyl ethyl ketone on rats. Toxicol. Appl. Pharmacol. 28(3):452-464. SCOEL (Scientific Committee of Occupational Exposure Limits). 2010. Recommendation from the Scientific Committee of Occupational Exposure Limits for Cyanide (HCN, KCN, and NaCN), June 2010. SCOEL/SUM/115. SCOEL Recommendation List, Social Affairs and Inclusion, European Commission [online]. Available: http://ec.europa.eu/social/main.jsp?catId=148&langId=en&intPageId=684 [accessed May 10, 2013]. SER (Social and Economic Council of the Netherlands). 2007. The Dutch OEL System as January 1, 2007 [online]. Available; http://www.ser.nl/sitecore/content/Internet/en/OEL_database/OEL_system.aspx [accessed May 20, 2013]. SER (Social and Economic Council of the Netherlands). 2013a. OEL Database: Stibine [online]. Available: http://www.ser.nl/en/grenswaarden/stibine.aspx [accessed May 20, 2013]. SER (Social and Economic Council of the Netherlands). 2013b. OEL Database: Thyonilchloride [online]. Available: http://www.ser.nl/en/grenswaarden/thionylchloride.aspx [accessed May 20, 2013]. Smith, R.E., J.M. Steele, R.E. Eakin, and D.B. Cowie. 1948. The tissue distribution of radioantimony inhaled as stibine. J. Lab. Clin. Med. 33(5):635-643. 43

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Stavert, D.M., D.C. Archuleta, M.J. Behr, and B.E. Lehnert. 1991. Relative acute toxicities of hydrogen fluoride, hydrogen chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing rats. Fundam. Appl. Toxicol. 16(4):636-655. Steinberg, H.H., S.C. Massari, A.C. Miner, and R. Rink. 1942. Industrial exposure to tellurium: Atmosphere studies and clinical evaluation. J. Ind. Hyg. Toxicol. 24:183-192. Stewart, R.D., H.C. Dodd, E.D. Baretta, and A.W. Schaffer. 1968. Human exposure to styrene vapor. Arch. Environ. Health 16(5):656-662. Stock, A., and O. Guttman. 1904. Ueber den Antimonwasserstoff und das gelbe Antimon. Ber. Deut. Chem. Ges. 3(1)7:885-900. Sundar, S., and J. Chakravarty. 2010. Antimony toxicity. Int. J. Environ. Res. Public Health 7(12):4267-4277. Sweeney, L.M., M.L. Gargas, D.E. Strother, and G.L. Kedderis. 2003. Physiologically based pharmacokinetic model parameter estimation and sensitivity and variability analyses for acrylonitrile disposition in humans. Toxicol. Sci. 71(1):27-40. Takano, R., N. Murayama, K. Horiguchi, M. Kitajima, M. Kumamoto, F. Shono, and H. Yamazaki. 2010. Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling. Regul. Toxicol. Pharmacol. 58(2):252-258. Toennes, S.W., K. Schmidt, A.S. Fandiño, and G.F. Kauert. 2002. A fatal human intoxication with the herbicide allyl alcohol (2-propen-1-ol). J. Anal. Toxicol. 26(1):55-57. UNEP (United Nations Environment Programme). 2005. 2-Propen-1-ol, CAS No: 107-18-6. OECD SIDS Initial Assessment Report for SIAM 21 [online]. Available: http://www.inchem.org/documents/sids/sids/ 107186.pdf [accessed June 18, 2013]. Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42(2):417- 423.Voegtlin, C., H.W. Smith, M.M. Crane, K.D. Wright, and M.A. Connell. 1920. Quantitative studies in chemotherapy: 1. The trypanocidal action of antimony compounds. J. Pharmacol. Exper. Therap. 15(5):453-473. Wang, H.T., Y. Hu, D. Tong, J. Huang, L. Gu, X.R. Wu, F.L. Chung, G.M. Li, and M.S. Tang. 2012. Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. J. Biol. Chem. 287(15):12379-12386. Webster, S.H. 1946. Volatile hydrides of toxicological importance. J. Ind. Hyg. Toxicol. 28:167-182. Weeks, M.H., D.G. Burke, E.E. Bassett, J.R. Johnson, and M.K. Christensen. 1964. Pentaborane: Relationship between inhaled lethal and incapacitating dosages in animals. J. Pharmacol. Exp. Ther. 145(3):382-385. Weir, F.W., V.M. Seabaugh, M.M. Mershon, D.G. Burke, and M.H. Weeks. 1964. Short exposure inhalation toxicity of pentaborane in animals. Toxicol. Appl. Pharmacol. 6:121-131. Young, M. 1979. Walk-through Survey Report of Standard Industries, Inc. (Reliable Battery Company) San Antonio, Texas. National Institute for Occupational Safety and Health, Center for Disease Control, Cincinnati, OH. 44