Eighteenth 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.

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.



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Eighteenth 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. 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. 1

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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) periodically review the recommended Standing Operating Procedures for developing AEGLs. This interim report presents the committee’s conclusions and recommendations for improving NAC’s AEGL documents for 25 chemicals: allyl alcohol, bis-chloromethyl ether, chloromethyl methyl ether, bromine pentafluoride, bromine trifluoride, chlorine pentafluoride, carbon tetrachloride, chloroform, chlorosilanes (26 selected compounds), epichlorohydrin, formaldehyde, hydrogen bromide, hydrogen iodide, methyl bromide, methyl chloride, nitric acid, nitric oxide, nitrogen dioxide, nitrogen tetroxide, piperidine, titanium tetrachloride, toluene, trimethylbenzenes (1,2,4-; 1,2,5-;and 1,3,5-TMB), vinyl acetate monomer, and vinyl chloride. ALLYL ALCOHOL At its meeting held on June 15-18, 2010, the committee reviewed the technical support document (TSD) on allyl alcohol. 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: Allyl alcohol is a colorless liquid that is a potent sensory irritant. Signs of intoxication following inhalation exposure to allyl alcohol vapor include lacrimation, pulmonary edema and congestion, and inflammation, hemorrhage, and degeneration of the liver and kidney. . . . The AEGL-1 values are based upon nasal irritation as indicated by reversible nasal inflammation observed histologically in rats 14 days after exposure to 51 ppm allyl alcohol for 1 hour; 22 ppm for 4 hours, or 10 ppm for 8 hours. . . . The AEGL-2 was obtained by dividing the AEGL-3 by 3. . . . The AEGL-3 values are based on the calculated LC01 value in rats of 2600 ppm for 10 minutes, 820 ppm for 30 minutes, 400 ppm for 1 hour, 93 ppm for 4 hours, and 45 ppm for 8 hours. Specific Comments AEGL -1 Page vii, lines 15-18: The TSD notes, “An intraspecies uncertainty factor of 3 and interspecies uncertainty factor of 3 were applied because allyl alcohol is highly irritating and corrosive, and much of the toxicity is likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species.” Because effects other than direct- acting effects appear to be occurring, these uncertainty factors should be reviewed and additional justification provided. Better justification is needed for using the Kirkpatrick (2008) study rather than the Dunlap et al. (1958) study for AEGL-1 values. Although the Kirkpatrick study is newer, it is in rats, and results are reported 14 days postexposure. Were any observations reported during or immediately post exposure? The Dunlap study used human volunteers, and the end points are relevant to deriving AEGL-1 values. Dunlap’s results are supported by Torkelson et al. (1959) and McCord (1932). Page 11, lines 4-6: “The incidences of alcohol flushing and material around the mouth exhibited a concentration-related increase at 220 and 403 ppm.” Clarification is needed on whether alcohol flushing is a direct-acting irritant effect. In humans, alcohol flushing results from excess aldehyde in the blood from buildup of this metabolite, most commonly in individuals with the slow variant of the aldehdye dehydrogenase gene. 2

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Page 21, lines 33-35: “It is currently not known if the parent alcohol is a direct irritant, or if conversion to the acrolein metabolite is required to produce irritation”; and page 23, lines 12-15: “Although the effect of mild irritation is generally not scaled across time, the empirical data indicate a time-response relationship for allyl alcohol-induced nasal irritation.” The quoted statements indicate allyl alcohol goes through some metabolic transformation to the causative agent, which is inconsistent with other statements in the TSD saying that it is a direct-acting irritant. Another example where mechanisms other than direct action by the chemical are indicated is when the default value of n = 3 was used to time-scale the 1-h AEGL-1 point of departure (POD) to 30 min. If lethality is on the continuum of effects, then the n from lethality studies should be used. Because the default values were used, it appears that the authors do not believe direct irritation is on the continuum of effects, indicating there are toxicodynamics influencing the toxicity. Such influence would not be expected for a direct-acting irritant. Page 30, line 16 (also see page 31, Table 15): “The 8-hour AEGL-3 is comparable to the 15-min NIOSH STEL [National Institute of Occupational Safety and Health, short-term exposure limit].” The NIOSH STEL is a 15-min time-weighted average exposure that should not be exceeded at any time during a workday. Using C3 = 133 ppm (taken from in Appendix A in TSD) for AEGL-1, the 15-min AEGL-1 value is 8 ppm. This is twice the NIOSH level, which is for a healthy workforce and not the general public. The 8-ppm value requires additional explanation here or in the discussion of the AEGL-2 values. AEGL -2 Page 11, lines 13-17: “Exposure to 52 and 102 ppm for 4 hours produced a concentration-related increase in the number of animals exhibiting gasping, alcohol flushing, material around the mouth, and a reduced response to cage stimulus, and an increased incidence of yellow material around the urogenital area was observed 1 hour post exposure in females exposed to 102 ppm. Histopathological examination of the nasal cavity revealed reversible changes, including degeneration of the olfactory and respiratory epithelium, chronic inflammation, and goblet cell hyperplasia.” Are these AEGL-2 effects? If so, why was this study not used as the POD for AEGL-2? Page 14, line 9: One-fifth of the RD50 (concentration of a substance that reduced the respiratory rate of test organisms by 50%) is a reasonable estimate for AEGL-2 values. How do the values compare with each other? Page 31, Table 15: The 30-min AEGL-2 is 35% greater than NIOSH’s immediately dangerous to life or health (IDLH) value. The explanation for the discrepancy should be explored. AEGL -3 Page 28, lines 1-4: “An intraspecies uncertainty factor of 3 and interspecies uncertainty factor of 3 were applied because allyl alcohol is highly irritating and corrosive, and much of the toxicity is likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species.” Since there appear to be other than direct-acting effects occurring, the values of the uncertainty factors should be reviewed and better justified. If some of the tissue irritation and systemic effects are caused by metabolism of the alcohol to an aldehyde, the amount of irritation to the tissues might be affected by whether individuals have the slow or fast form of genetic polymorphisms for aldehyde dehydrogenase. Many tissues of the body have the capacity to metabolize alcohols and aldehdyes. Page 30, line 16 (also see page 31, Table 15): “The 8-hour AEGL-3 is comparable to the 15- minute NIOSH STEL.” Delete this observation, because 8-h values should not be compared with 15-min values. 3

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Other Comments Page viii, line 13: It is noted that the POD values are no-observed-effect levels (NOELs) as there were no clinical signs of nasal irritation; yet the end point noted in the AEGL table on page ix of the TSD indicates some irritation Page viii, lines 17-18: Statements regarding the lack of interindividual variation to support the application of an uncertainty factor of 3 for intraspecies differences needs better justification. There is a wide range of responses to sensory irritants among individuals. The range is even evident from the study noted on page 3, lines 7-11, wherein all exposed individuals did not respond at the lower levels. The issue of the uncertainty factor related to variability is also present in Section 5.3 of the TSD. Page 1, line 7: Delete mention of war gas, as such compounds are no longer manufactured per international treaty. Page 6, lines 5-6: “(The primary findings in the rabbits and monkey were hemorrhage in the lungs, intestinal tract, bladder, and kidneys.)” These effects appear to be systemic and not completely related to a direct-acting irritant. Page 18, Table 8: On the basis of the data, the mouse appears to be more sensitive than the rat. Page 20, Special Considerations: Consider including discussion of the OH rate constant, given the fairly high reactivity of allyl alcohol with the hydroxyl radical (estimated half-life in air is shorter than the 8-h AEGL duration), and the potential role of associated fate products (e.g., regarding possible contribution to toxicity as human exposure duration increases to 8 h). Page 22, lines 29-31: The sentence should be revised to make the distinction that, at lower concentrations, people with pre-existing lung disease might be at special risk to the pulmonary effects of allyl alcohol, but at very high concentrations, people with lung disease and healthy individuals will probably be affected similarly by the exposure. Page 23, lines 33-34: Is acrolein contamination common in allyl alcohol? Is it possibly the causative agent of the observed ocular irritation? Page 30, graph: What is the human disabling value? Comment References 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. Kirkpatrick, D.T. 2008. Acute Inhalation Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-hour Exposure Durations). WIL-14068. WIL Research Laboratories, LLC. Ashland, OH. Sponsored by Lyondell Chemical Company, Houston, TX. McCord, C.P. 1932. The toxicity of allyl alcohol. J. Am. Med. Assoc. 98(26):2269-2270. Torkelson, T.R., M.A. Wolf, F. Oyen, and V.K. Rowe. 1959. Vapor toxicity of allyl chloride as determined on laboratory animals. Am. Ind. Hyg. Assoc. J. 20(3):217-223. bis-CHLOROMETHYL ETHER At its meeting held on June 15-18, 2010, the committee reviewed the TSD on bis-chloromethyl ether in conjunction with chloromethyl methyl ether (see below for comments on this chemical). The two TSDs are in good agreement and share some data. 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: Bis-chloromethyl ether (BCME) is a man-made chemical that is a severe respiratory, eye, nose, and skin irritant that can lead to pulmonary edema and congestion, corneal necrosis, dyspnea, and 4

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death. . . . AEGL-1 values were not recommended because effects exceeding the severity of AEGL-1 occurred at concentrations that did not produce sensory irritation in humans or animals. . . . The AEGL-2 was based on a study in which rats were exposed for 7 hours to 0.7, 2.1, 6.9, or 9.5 ppm BCME, and hamsters were exposed for 7 hours to 0.7, 2.1, 5.6, or 9.9 ppm BCME, followed by lifetime observation. . . . AEGL-3 values were derived from the single- exposure scenario of a study in which rats and hamsters were subjected to 1, 3, 10, or 30 six-hour exposures of 1 ppm BCME followed by lifetime observation. Specific Comments AEGL-1 The committee agrees with the decision to not set AEGL-1 values. AEGL-2 The committee recommends an uncertainty factor for intraspecies differences of 10 rather than 3 because BCME has a steep dose-response curve and might not be acting as a simple irritant gas. AEGL-3 For the same reasons as above, the committee recommends the use of an uncertainty factor of 10 to account for intraspecies differences. The discussion in Section 7.3 of the derivation of the AEGL-3 values should also be revised to clarify that the 7-h exposure study supports the selection of the primary study. Other Comments Section 4.1 on metabolism and disposition should be expanded to briefly discuss likely metabolites. The AEGL values will be well above the Threshold Limit Value (TLV) for BCME set by the American Conference of Governmental Industrial Hygienists. Thus, the reason for the differences between the AEGL values and the TLV should be added to the TSD. CHLOROMETHYL METHYL ETHER At its meeting held on June 15-18, 2010, the committee reviewed the TSD on chloromethyl methyl ether. 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: Chloromethyl methyl ether (CMME) is a man-made chemical that is highly flammable and a severe respiratory tract, eye, nose, and skin irritant. . . . AEGL-1 values were not recommended because no studies were available in which toxicity was limited to AEGL-1 effects. . . . AEGL-2 values for technical grade CMME were based on an acute toxicity study in which rats and hamsters were exposed to 12.5-225 ppm CMME (content of BCME not given) for 7 hours and observed for 14 days. . . . AEGL-3 values were based on the same study as the AEGL-2 values, in 5

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which rats and hamsters were exposed for 7 hours to 12.5-225 ppm CMME (content of BCME not given). Specific Comments The committee found that its previous recommendations for supporting the derivation of AEGLs for CMME were adequately addressed. The proposed AEGL-1, -2, and -3 values for CMME were approved. Other Comments Section 4.1 on metabolism and disposition should be expanded to include a brief discussion of the likely metabolic products, such as hydrogen chloride, formaldehyde, methanol, formic acid, and carbon dioxide. HALOGEN FLUORIDES At its meeting held on June 15-18, 2010, the committee reviewed the TSDs on chlorine pentafluoride, bromine pentafluoride, and bromine trifluoride. Presentations on the TSDs were made by Heather Carlson-Lynch, of Syracuse Research Cooperation. The committee observed that the AEGL values for the three halogen fluorides are linked with each other and three other compounds, hydrogen fluoride, chlorine trifluoride, and chlorine dioxide, chemicals for which TSDs have already been published (NRC 2004, 2007). Thus, on the basis of the review of the TSDs at the meeting (see details below), and excerpted analyses below on related compounds, the committee strongly recommends publication of the halogen fluorides as a single document with chlorine trifluoride, chlorine dioxide, and hydrogen fluoride as appendixes or possibly republishing chlorine trifluoride and chlorine dioxide from Volume 5 of Acute Exposure Guideline Levels for Selected Airborne Chemicals and hydrogen fluoride from Volume 4 as chapters, as well as chapters on chlorine pentafluoride, bromine pentafluoride, and bromine trifluoride. Alternatively, it should be ensured that references are made throughout the document to hydrogen fluoride, chlorine trifluoride, and chlorine dioxide. Regardless of which approach is chosen, an expansion of the analysis below showing the dissociation paths of the different agents to explain the relative toxicities is important to understand the toxicities of these agents and should be provided in whatever document or documents are developed. This information belongs in Section 4 of the TSD, Special Considerations, and should also be included in the TSD’s Executive Summary. The following are excerpts from the TSD on chlorine trifluoride (NRC 2007) and are provided as the basis for the discussion of the dissociation paths and relative toxicities below:  Chlorine trifluoride (ClF3) is unstable in air and rapidly hydrolyzes to hydrogen fluoride (HF) and a number of chlorine-containing compounds, including chlorine dioxide (ClO2). The toxic effects of ClF3 are due, at least in part, to the actions of both HF and ClO2.  In the moist respiratory tract, ClF3 is predicted to hydrolyze to ClOF, which further degrades to ClO2F and ClF (Dost et al. 1974). ClO2F rapidly hydrolyzes to ClO2, HF, and ClOx anions; the first two products predominate and are thought to be responsible for ClF3 toxicity, as the ClOx anions are relatively nontoxic.  The chemical reactivity of the halogenated fluorine compounds in order of decreasing reactivity is chlorine pentafluoride (ClF5) > ClF3 > bromine pentafluoride (BrF5) > iodine heptafluoride (IF7) > 6

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chlorine monofluoride (ClF) > bromine trifluoride (BrF3) > bromine monofluoride (BrF) (Bailey and Woytek 1994).  In the monkey, ClF3 is slightly less toxic than ClF5 but 7 times more toxic than HF. (In all three species for which data are available, ClF5 is almost exactly 10 times more toxic than HF.) In the rat and mouse, ClF3 is approximately 4 times more toxic than HF. On the basis of these observations, the committee recommends that the following discussion, suitably modified and expanded as appropriate, be included in any document or documents developed for the halogen fluorides. ClF5, ClF3, BrF5, BrF3, HF, and ClO2 are toxicologically related, and all produce the toxic effect at the point of absorption which is primarily related to the agent’s physical form (vapor, mist, and aerosol). The relative toxicities of these agents are ClO2 > ClF5 > ClF3 > BrF5 > BrF3 > HF. These toxicities could be expressed in terms of HF equivalents. ClF3 is approximately 7 times more toxic than HF, and ClF5 is approximately 10 times more toxic than HF. The relative toxicities indicate that ClO2, an intermediate in the dissociation of ClFx, plays a role in the toxicity of these agents. (In the moist respiratory tract, ClF3 is predicted to hydrolyze to ClOF, which further degrades to ClO2F and ClF [Dost et al. 1974]. ClO2F rapidly hydrolyzes to ClO2, HF, and ClOx anions; the first two products predominate and are thought to be responsible for ClF3 toxicity, as the ClOx anions are relatively nontoxic.) If a similar path exists for bromine to form BrO2, it is expected to be less toxic than ClO2, as BrO2 is less reactive than ClO2. Because the toxicity data for the individual chemicals are sparse, each chemical is compared with ClF3, and the AEGL values are derived via or supported by the comparison, the Summary and Sections 2, 3, and 4 and much of Sections 5, 6, 7, and 8.3 should be straightforward to develop. Descriptions of the toxicity of ClF3 should be reduced to cross-references to the relevant sections in the appendixes. Other redundancies could likewise be reduced. This consolidation would also strengthen the material in Section 8.3., as the larger data set generated by including all the halogen fluorides provides greater confidence. The other sections and the appendixes could be structurally awkward, so consolidation will be needed. References to the ClF3, ClO2, and HF documents will need to be rechecked as the three halogen fluoride documents are combined into one document. The summary table of AEGL values could either be a table for each compound or a table for each AEGL, the rows being the separate compounds. As noted below in the section Comments Pertaining to All TSDs, better justification is needed for reducing the intraspecies factor to 3 for direct-acting irritants. Below are comments on the specific halogen fluorides discussed at the June meeting. Chlorine Pentafluoride The following is excerpted from the Executive Summary of the TSD: Chlorine pentafluoride (ClF5) is a strong oxidizer that was once considered for use as a missile propellant. No human data were available for development of AEGL values. . . . The AEGL-1 is based on empirical data as well as analogy with hydrogen fluoride (HF) and chlorine trifluoride (ClF3). The empirical data point is a no-observed effect level for the endpoint of irritation of 3 ppm for 10 minutes in the rat. . . . The sensory irritation and reversible mild lung congestion observed in monkeys, rats, and mice following exposure to 30 ppm for 10 minutes, 20 ppm for 30 minutes, or 10 ppm for 60 minutes or following exposure of dogs to 30 ppm for 10 minutes meets the definition of the AEGL-2. . . . The AEGL-3 values are based on a lethality study with rats. 7

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Specific Comments AEGL-1 The TSD for ClF5 proposes an AEGL-1 value of 0.30 ppm for exposure durations of 10 min, 30 min, and 1 h, but it does not apply the value to exposure durations of 4 h and 8 h. The rationale provided is that the value at those durations is similar to the corresponding AEGL-2 values. The committee recommends not setting any AEGL-1 values, as the sensory warnings are too close to AEGL-2 effects. AEGL-2 The observation of “severe irritation” and “lung congestion” (on page 21, lines 27-34) are AEGL- 2 effects. The observation of “irritation without pathology” (on page 22, lines 9-11) indicates changes below the definition of the AEGL-2 and, therefore, is suitable as a POD for AEGL-2 values. Using this POD will result in a 1-h AEGL-2 value being similar to the 1-h AEGL-1 value, which reinforces the recommendation above to not set AEGL-1 values. AEGL-3 The committee approved the derivation of the AEGL-3 values for ClF5. Other Comments Page 17, lines 29-31: “Although most review sources indicate that the reaction with water is violent, both Smith (1963) and Dost and Wang (1970) reported that the reaction with water is slow. (Slow reaction indicates poor scrubbing in the upper respiratory tract.).” The discrepancy noted in this sentence would benefit from further discussion. Some of the pathology reported in Section 3 indicates, in accordance with the parenthetical statement, that ClF5 does indeed penetrate to the alveoli, and this information was used in the AEGL-2 derivation. The discrepancy might be resolved in Section 4 of a consolidated TSD that incorporates information on ClF3, HF, and ClO2. Page 17, lines 42-44: The committee recommends retaining the text that states, “The authors stated that the toxicity of ClF3 is comparable to that of ClO2 on a chlorine equivalent basis and is comparable to that of HF on a fluorine equivalent basis.” When taken in context of the relative toxicities of ClF3, ClF5, and HF, it adds to the discussion and was reported by the authors. This information (and the citation) belongs in Section 4 with the discussion on relative toxicities and mechanisms described above. Page 18, lines 4-6: “These observations suggest that the effects of ClF5 exposure may be more likely to be due to the direct irritation of the respiratory tract than to fluoride poisoning.” This is a weak statement. The entire document is based upon direct action at the point of absorption. Can it not be stated that the effects are due to direct irritation of the respiratory tract and not due to fluoride poisoning? See page 24, lines 14-15. See also similar comments on BrF5. Page 19, lines 36-47, and page 20, lines 1-4: The revised section still does not provide a clear basis for the statement that concentration is more important than duration of exposure for effects other than irritation. The committee recommends rewriting the section to state that The data from the MacEwen and Vernot studies indicate that, at least for the direct irritant responses to ClF5, concentration may be more important than exposure duration. However, for the other effects observed, the role of exposure duration versus concentration is difficult to interpret 8

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because these studies provided few qualitative and quantitative details of the pathology findings. Discordant findings could be due to the dissociation to other agents or to a metabolic pathway. Page 19, Section 4.4.2: The two paragraphs on susceptibility are found in each of the three halogen fluoride documents. The committee recommends keeping both paragraphs (some of the documents have one or both paragraphs deleted), as the information is relevant to all three compounds. Page 20: The deletion of section Concurrent Exposure Issues would indicate that no relevant data are available (see Standing Operating Procedures [NRC 2001]). Page 24, lines 13-17: The discussion of the relative toxicities of ClF3, ClF5, and HF should be moved to Section 4 (Special Considerations). Page 24, line 21-23, and Table 13: In this section, the AEGL values for ClF5 are compared with those for ClF3 and HF. The AEGLs reported for ClF3 in Table 13 are inaccurate and should be updated with the final published values (NRC 2007). The accompanying paragraph should be revised accordingly. (Specifically, the paragraph should note that the AEGL values for ClF3 are lower than those for HF. There should also be discussion about the reason for the two compounds being more similar for longer-duration AEGLs than for shorter-duration AEGLs, including the fact that the relative toxicities of the compounds should be the same if tissue destruction is the end point, unless the saturation point has been reached and toxicokinetics become the driving factor.) The committee also recommends that a table of the AEGL values for ClO2 be added to the TSD for completeness. ClO2 is a breakdown product of ClF5 and ClF3 and probably accounts for why the two halogen chlorides are much more toxic than HF in terms of HF equivalents. The revised paragraphs comparing AEGL values for ClF5 with those for ClF3, HF, and ClO2 should be moved to Section 4 (Special Considerations) rather than appear in Section 8 (Comparison with Other Standards and Guidelines), which should only consider values for ClF5. Page 25, Section 8.3: This section on data adequacy and research needs should be rewritten according to guidance in the Standing Operating Procedures (NRC 2001). Bromine Pentafluoride The following is excerpted from the Executive Summary of the TSD on BrF5: Bromine pentafluoride (BrF5) is a strong oxidizing chemical that is used as a fluorinating agent and as an oxidizer in rocket propellant fuels. No data on human exposures were available. A single study provided information on lethal and non-lethal values for the rat. . . . In the absence of empirical data, no AEGL-1 values were developed. . . . In the absence of data relevant to derivation of AEGL-2 values for BrF5, data for the structurally-related chemical, chlorine pentafluoride (ClF5), were used. . . . The AEGL-2 values for ClF5 are based on a series of exposures with four species. . . . The AEGL-3 values for BrF5 are based on the highest non-lethal value in the rat study of Dost et al. (1970), 500 ppm for 40 min. Page 6, lines 35-37: Time-scaling for BrF5 is based on a revised ClF5 time-scaling factor. Footnote b of Table 3 (on page 7) should acknowledge that by noting that the 4-h and 8-h values were time-scaled from the 60-min value. Page 9, lines 35-39, and page 10, line 2: Is this statement attributable to Darmer (1971) or to the NAC? If the NAC, the statement should be removed, as it is speculation. Page 10, lines 4-8 and 12-13: The sentence on lines 4-8 should indicate the compound to which the rats were exposed, and the sentence on lines 12-13 should specify the concentration of BrF5. Unlike ClF5, in this study of BrF5, Dost et al. (1968) reported fluoride in the bones and other organs. The TSD should build a case for no systemic effects from fluoride. 9

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Page 10, lines 12-13: The statement that systemic effects are unlikely is appropriate, but a citation is needed to support it, especially since the preceding paragraph discusses the systemic distribution of fluoride as a result of BrF5 exposure. Page 10, lines 20-22: The discussion of relative chemical reactivity of halogenated fluorine compounds should be expanded when the TSDs on ClF5, BrF5, and BrF3 are combined. The Bailey and Woytek (1994) study should be reviewed for information on specific relative toxicities. Page 12, Section 4.4.2: The two paragraphs on susceptibility are found in each of the three halogen fluoride documents. The committee recommends keeping both paragraphs (some of the documents have one or both paragraphs deleted), as the information is relevant to all three compounds. Page 16, Section 8.3: This section includes descriptive statements of the data used without assessment of data adequacy or of what, if any, additional research would be useful to improve the AEGLs. See Standing Operating Procedures (NRC 2001, page 53-57) for requirements. Bromine Trifluoride The following is excerpted from the Executive Summary of the TSD on BrF3: Bromine trifluoride (BrF3) is an extremely reactive and corrosive oxidizing agent used in nuclear reactor fuel processing; as a fluorinating agent; and, potentially, in rocket and missile fuels. . . . In the absence of empirical information on BrF3, AEGL values were based on the chemical analogue, chlorine trifluoride (ClF3). . . . The AEGL-1 values for ClF3 are based on slight irritation as evidenced by rhinorrhea (nasal discharge) observed in two of two dogs during the first 3 hours of a 6-hour exposure to an average concentration of 1.17 ppm. . . . The AEGL-2 values for ClF3 were based on signs of irritation (salivation, lacrimation, rhinorrhea, and blinking of the eyes) in two of two dogs exposed to a concentration of 5.15 ppm for 6 hours. . . . Lethality data for ClF3 (1-hour LC50 values [concentrations of a substance that is lethal to 50% of test organisms in a given time]) were available for the monkey, rat, and mouse. . . . The AEGL-3 values were based on the highest 1-hour concentration that resulted in no deaths in monkeys. No appendixes were included in this TSD. Page 6, line 21: A study reporting “obvious” lacrimation in dogs, which was used to derive AEGL-1 values, should not be characterized as mild and transient. The somewhat late onset of the obvious lacrimation might have been due to a mechanism-based delay (e.g., the main responsible chemical species might have been a metabolite or dissociation product and not BrF3 itself) or to an oversight of the onset at an earlier time point. Regardless, it was “obvious” and not mild when it was observed. Obvious lacrimation should be considered an AEGL-1 effect and not as a no-observed-adverse- effect level (NOAEL) for AEGL-1 (see Standing Operating Procedures [NRC 2001, page 41]). Page 9, lines 13-14 and 24-25: The statement that systemic effects are unlikely is appropriate, but a citation is needed to support it. Page 11, Section 4.4.2: These two paragraphs are found in each of the three halogen fluoride documents. The committee recommends keeping both paragraphs (some of the documents have one or both paragraphs deleted), as the information is relevant. Page 13, line 37: The committee recommends using “lesser toxicity” rather than “lower toxicity” when comparing BrF3 and ClF3, as the latter description might be misinterpreted. Page 17, Section 8.3: The Section states that there were no BrF3 data. The inference is that structure-activity relationships are adequate to derive AEGL values using data from ClF3 and other halogen fluorides and HF and that no further research is needed. If that is the case, then an explicit statement to that effect should be made in this section. See Standing Operating Procedures (NRC 2001, pages 53-57) for requirements. 10

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Comment References Bailey, W.I., and A.J. Woytek. 1994. Fluorine compounds, inorganic (halogens). Pp. 342-355 in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11, 4th Ed., Vol. 11. New York: John Wiley & Sons. Darmer, K.I. 1971. The acute toxicity of chlorine pentafluoride. Pp. 291-300 in Proceedings of the 2nd Annual Conference on Environmental Toxicology, 31 August, 1 and 2 September 1971. AMRL-TR-71-120. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. Dost, F.N., and C.H. Wang. 1970. Studies on Environmental Pollution by Missile Propellants. AMRL-TR-69-116. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. January 1970. Dost, F.N., D.J. Reed, A. Finch, and C.H. Wang. 1968. Metabolism and Pharmacology of Inorganic and Fluorine Containing Compounds. AMRL-TR-67-224, AD 681 161. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. August 1968. Dost, F.N., D.J. Reed, T.D. Cooper, and C.H. Wang. 1970. Fluorine distribution in rats following acute intoxication with nitrogen and halogen fluorides and with sodium fluoride. Toxicol. Appl. Pharmacol. 17(3):573-584. Dost, F.N., D.J. Reed, V.N. Smith, and C.H. Wang. 1974. Toxic properties of chlorine trifluoride. Toxicol. Appl. Pharmacol. 27(3):527-536. 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). 2004. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: National Academies Press. NRC (National Research Council). 2007. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 5. Washington, DC: National Academies Press. Smith, D.F. 1963. Chlorine pentafluoride. Science 141(3585):1039-1040. CARBON TETRACHLORIDE At its meeting held on June 15-18, 2010, the committee reviewed the TSD on carbon tetrachloride. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD: Carbon tetrachloride (CAS No. 56-23-5) is a colorless, nonflammable, heavy liquid only slightly soluble in water that is used as a laboratory and industrial solvent, an intermediate in the synthesis of trichlorofluoromethane and dichlorodifluoromethane, and was formerly used as a dry-cleaning agent, grain fumigant, anthelmintic (destructive to worms, especially parasitic varieties), and fire suppressant. . . . The AEGL-1 values were based upon a controlled exposure of human volunteer subjects to 76 ppm for four hours. . . . The AEGL-2 was also based upon human data from controlled exposure experiments in which subjects experienced CNS [central nervous system] effects characterized by headache, nausea and vomiting following 9-minute exposure to 1191 ppm carbon tetrachloride. . . . The AEGL-3 was based upon an estimated lethality threshold (1-hr LC01 of 5,135.5 ppm) using data from multiple studies on laboratory rats. Specific Comments AEGL-1 The committee approved the derivation of the AEGL-1 values for carbon tetrachloride. 11

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Furthermore, for comparison it would be useful to assess the relative toxicity data for titanium dioxide (TiO2) and hydrogen chloride (key transformation products in air). The re-evaluation of AEGL-1could be strengthened by developing a more integrated compilation of dose-response data to compare similar exposure durations and effect severities across species, as well as relative humidities. Human data could offer additional context (such as data on the ship crew who passed through a TiCl4 cloud this spring, see comment below). A committee member is aware of anecdotal information regarding measurements taken from an outdoor cloud at a chemical plant that had no apparent adverse effect on exposed workers. Those measurements indicated a TiCl4 concentration on the order of 15-20 mg/m3. There is no documentation of this personal anecdote, but it might provide some general context for a potential short-duration AEGL-1. AEGL-2 It would be helpful to reconsider the AEGL-2 values (including the POD) in light of available data, including data on overt ocular and nonescape-impairing, reversible respiratory tract irritation (see Standing Operating Procedures [NRC 2001], Section 2.2.2.2.2) for relevance to acute exposures. As with the AEGL-1, fuller data integration would strengthen this evaluation, including information relevant to species variability and related chemicals, as it is not clear that the various data support reducing the interspecies and intraspecies uncertainty factors to 3. This possibility is especially of interest given the variability introduced by relative humidity, as well as consideration of nanoscale materials. AEGL-3 It would be helpful to reconsider the AEGL-3 values (including the POD) in light of available data, including studies not yet cited in the TSD. As with the AEGL-2 comments, these data include information relevant to species variability and related chemicals as well as other factors, as it is not clear that the various data support lowering both the interspecies and intraspecies uncertainty factors to 3. For example, it might be useful to compile NOAELs from lethality studies for integrated evaluation. According to the Standing Operating Procedures (NRC 2001, page 44), if the AEGL value is estimated by dividing an LC50 value by 3 (or some other divisor), then the slope of the exposure-response curve or enough data points should be given to support the division by 3 (or some other divisor). This process would extend to consideration of other lethality data beyond those summarized in the study cited. Other Comments Outdated Information The TSD contains a good amount of helpful information but would benefit from updates in a number of areas to reflect more current and complete information. It appears that all references specific to TiCl4 are more than 10 years old. (The only citations from this century are three older AIHA references for the emergency response planning guideline [ERPG] and WEEL values, and the 2004 NRC AEGL volume that contains a report on hydrogen chloride.) Topics for which updates are suggested are production and use, including nanoscale material; transformation products; human data; and variability. The updated information will help inform a re-evaluation of the AEGL derivations, for which some notes are offered below. 30

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Production and Use, Including Nanoscale Materials Page vi, lines 3-7 (Executive Summary), and page 1, lines 5-10 (Introduction): The information on production and use is dated and should be updated. For example, ITA (2008) noted a “growing global demand for high-purity TiCl4 in innovative applications,” while an industry report to the SEC from this spring (TIMET 2010) recognized this area’s growth, while acknowledging recent economic turmoil: “Over the last ten years, titanium mill product demand in the military, industrial and emerging market sectors has increased, primarily due to the continued development of innovative uses for titanium products in these industries. Over the last several years, we, and the industry as a whole, have experienced significantly increased demand with periods of increased volatility.” Given the importance of TiCl4 to the production of titanium metal and other compounds anticipated for expanded applications and more widespread use, it would be helpful to update both the production and application context. The TSD states, “Titanium tetrachloride is used . . . as a military smoke screen.” Is this still the case? If it is no longer developed and used for this purpose, it would be helpful to revise the text. From a review of the considerable amount of more recent literature (see EPA [2009] and public submittals to the e-docket associated with this EPA report and many other studies since the older data reflected in the TSD), the emergence of nanoscale materials appears to be an important consideration for these AEGLs. TiCl4 is a key intermediate in the production of titanium and oxides. Thus, it would be useful to address nanoscale implications, considering both toxicokinetics (including distribution) and toxicodynamics. (Nanoscale production and use could be addressed in Chapter 1, while toxicologic information could be presented within the toxicity discussions and in Chapter 4 as Special Considerations.) Transformation Products and Toxicity Contributions Page vi, lines 4-7 (Executive Summary); page 1, lines 10-17 (Chapter 1); page 15, lines 7-8, and repeated at lines 37-38 (Chapter 4): The TSD does a good job of emphasizing the formation of hydrogen chloride; the brief description of fate products could benefit from even more direct context for airborne releases of TiCl4 and human exposures. For example, beyond increased hydrogen chloride formation under conditions of high relative humidity, exposure to water following an airborne release notably includes contact with perspiration and tears. It would also be helpful if the discussion of TiCl4 transformation products could focus on air more specifically, as the TSD seems to blur this context a bit in having only provided sequential reactions in water (page 1, lines 11-14). The source provided for the reactions is more than 45 years old and was translated from Russian. More recent standard sources for reactions in air could be tapped. Most important, TiO2 is not identified in the fate discussion despite being rapidly formed when TiCl4 is released to air. It is especially important to clearly identify this compound, given the relevance of associated toxicity data (not only relative to TiCl4 for similar exposure durations but also in light of the considerable number of recent publications on nano-TiO2). It would be useful to present a comparison of data for TiCl4 and its two key transformation products that form quickly in air, together with interpretations regarding relative toxicities (including data from Kelly [1978] cited in Archuleta and Stocum [1993]), side by side with toxicity data for nano-TiO2 to consider possible insights regarding relative toxicity. EPA’s health and environmental research online (HERO) database (EPA 2010) might be useful as part of this check of more recent potentially relevant toxicity data (including the ability to search for information specifically for TiO2). NIOSH also has a draft assessment of TiO2 that should be considered. 31

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Human Data More information has become available since the studies cited in the TSD (which are from 1998 and earlier). For example, Roy et al. (2003) discuss over 470 exposure incidents with TiCl4 between 1990 and 1999, 13 of which involved evacuation, injuries, or deaths; the authors also noted a small tanker leak in 2001 that affected workers and others nearby (see citations in that publication). Even more recent incidents involving transportation accidents (2008) and chemical plant releases (2010) suggest that AEGLs are especially needed in light of the recent identification that TiCl4 production and use is an anticipated “growth area.” In March, a 48-year-old worker exposed to TiCl4 died within 2 weeks following an explosion at a United Kingdom facility (Daily Mail Reporter 2010; ENS 2010; Grimsby Telegraph 2010; HSE 2010); the company had previously been fined for TiCl4 releases, including in 2006 and 2009. Although a temporary restricted fly zone was established in the area of the cloud, a vessel on the adjacent river sailed through it before controls were put in place. The crew received medical checks and had no indication of adverse effects (ENS 2010). These exposures might suggest a general context for the short-duration AEGL-1, taken together with the rough estimation made by committee members familiar with this issue that a visible cloud indicates a concentration on the order of 10 mg/m3 (or higher). A search of the scientific and medical literature should be performed to determine whether relevant information to support these observations is available. The United Kingdom tragedy was followed in April by the evacuation of a Louisiana community due to the release of TiCl4 from a ruptured pipeline at a local chemical plant (New Orleans News 2010; Times-Picayune 2010). Although no quantitative exposure data were found in news reports for these recent incidents, a more structured pursuit of such information might be fruitful, and additional injury and mortality information could be reflected in an updated section on human data. In addition to updating the human toxicity content with more current information, it would also strengthen the TSD to provide more information from specific key studies that were cited, such as Chen and Fayerweather et al. (1992). Variability and Uncertainty Factors A more integrated discussion and reconsideration of variability and uncertainty factors would be useful. For example, consider the current application of uncertainty factors for the AEGL-3, which reflect only a factor of 3 for interspecies and intraspecies variability, respectively. (Variability might be considered somewhat moderated under chronic conditions, and it might be less of a factor for the acute durations addressed by AEGLs.) The severity of effect is known to vary substantially with relative humidity, so consideration of perspiration and other factors relevant to “individual” hydrolysis is needed. In addition, people with underlying respiratory conditions (such as those with asthma or chronic obstructive pulmonary disease), whose numbers are a nontrivial fraction in the U.S. population, are susceptible to exacerbated effects from exposure to TiCl4 and its transformation products in air. Thus, to use only a factor of 3 to account for human variability, including sensitive subgroups, would need better justification, particularly in light of the potential need for further adjustments to address transformation products (and possibly nanoscale material). For animals, acute lethality data for dogs illustrate variability within this species alone, as do the rat data of Burgess (1977) presented in Table 4. Also, a comparison of rat and mouse LC50 data (Archuleta and Stocum 1993) suggest that interspecies differences could be roughly 9-fold. Thus, available data even within and across animal (nonhuman) species suggest similar questions regarding the use of 3 for the interspecies uncertainty factor. Archuleta and Stocum (1993) summarized the findings of the 2-year rat inhalation study by Lee et al. (1986) (exposure to TiCl4 at 0.1-10 mg/m3 [and hydrolysis products], 6 h/day, 5 days/week) as revealing no abnormal clinical signs, body-weight changes, or excess mortality. Further, the pulmonary 32

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response at 1.0 mg/m3 was presented as typical of that seen for a nuisance dust; for comparison, the Occupational Safety and Health Administration’s limit for TiO 2 as a nuisance particulate is 10 times higher (10 mg/m3). At a concentration of 10 mg/m3 for TiCl4, Archuleta and Stocum (1993) noted that the rat pulmonary response suggests chronic exposure might result in upper respiratory tract irritation and possibly acute or chronic bronchitis. Compared with the other primary fate product, TiCl4 is considered more toxic than hydrogen chloride because it can penetrate to the deep lung where it can then hydrolyze to hydrogen chloride and cause further damage (as reflected in the TSD in other cited papers). These authors also noted that the intermittent low-level exposures to TiCl4 (0.1-1 mg/m3) did not result in progressive or cumulative changes in lungs of workers. It would be helpful to integrate relevant data in a table to help support the determinations regarding variability and uncertainty factors applied for the AEGL derivations. It would also be useful to revisit related wording in various sections, including 4.4.1 and 4.4.2. For example, in Section 4.4.1, additional explanation on why TiCl4 is expected to react more highly in the nasal cavity of rats than humans is needed. Section 4.4.2 should include references to studies that have considered the potential for increased susceptibility or sensitivity (e.g., Archuleta and Stocum 1993), and the document would be strengthened by not limiting this evaluation to TiCl4 (e.g., given the key role of hydrogen chloride). RD50 We suggest updating the references and checking the Alarie (2002) paper to verify statements presented in the TSD. It might also be helpful to consider the usefulness of the RD50 (exposure concentration producing a 50% respiratory rate decrease) to support reanalysis and checks of the AEGL derivations. (Note related context from the hydrogen chloride AEGLs.) Reproductive and Developmental Effects, Genotoxicity, and Cancer Information A literature search should be performed to determine whether any new information is available on the reproductive and developmental effects, genotoxicity, and carcinogenicity of TiCl4. It would also be helpful to consider the main fate products of TiCl4, as these might constitute coexposures because of their rapid formation in air. In light of more recent applications of TiCl4, it would also be helpful to consider nanoscale titanium. Comment References AIHA (American Industrial Hygiene Association). 2008. Case Study 11: Chemical substitution; Process containment. Pp. 156-157 in Demonstrating the Business Value of Industrial Hygiene: Methods and Findings from the Value of the Industrial Hygiene Profession Study. American Industrial Hygiene Association, May 22, 2008 [online]. Available: http://www.aiha.org/votp_NEW/pdf/votp_report.pdf [accessed July 28, 2010]. Alarie, Y. 2002. New Developments with the Alarie Test for Better Protection of Individuals Exposed to Airborne Chemicals Whether in Industrial Situations or the More General Indoor Air Situations [online]. Available: http://www.yvesalarie.com/alarietest.htm [with an extensive reference listhttp://www.yvesalarie.com/ references.htm] [accessed July 28, 2010]. Archuleta, M.M., and W.E. Stocum. 1993. Toxicity Evaluation and Hazard Review: Cold Smoke. Sandia Report SAND93-2148 UC-607. Sandia National Laboratories, Albuquerque, NM and Livermore, CA [online]. Available: http://www.osti.gov/bridge/purl.cover.jsp;jsessionid=97BD27320DB054602089C5CD22C 38187?purl=/10113369-fAO13O/native/ [accessed July 28, 2010]. 33

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Burgess, B.A. 1977. Initial Submission: Inhalation Approximate Lethal Concentration Titanium Tetrachloride (99.5%) with Cover Letter dated 09/11/92. Haskell Laboratory Report No. 630-77; Medical Research Project No. 2795. Dupont Chemical Company. Doc. # 88-920010969. Daily Mail Reporter. 2010. Factory Worker, 48, Dies after Becoming Engulfed in Toxic Gas That Leaked From Chemical Plant. Daily Mail Reporter, March 20, 2010 [online]. Available: http://www.dailymail.co.uk/ news/article-1259133/Paul-Doyley-dies-engulfed-toxic-gas-cloud-near-Cristal-Global-site-Grimsby.html [access July 28, 2010]. ENS (Environment News Service). 2010. Four Injured in Toxic Chemical Release on River Humber. Environment News Service, March 5, 2010 [online]. Available: http://www.ens-newswire.com/ens/mar2010/2010-03- 05-01.html [accessed July 28, 2010]. EPA (U.S. Environmental Protection Agency). 2009. Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen, External Review Draft. EPA/600/R-09/057. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm? deid=210206 [accessed July 28, 2010]. EPA (U.S. Environmental Protection Agency). 2010. HERO, Health and Environmental Research Online Database. Available: http://cfpub.epa.gov/ncea/hero/index.cfm [accessed July 28, 2010]; (titanium dioxide link: http://cfpub.epa.gov/ncea/hero/index.cfm?action=search.do&usage_id=146&peerreview=no¬peerrevie w=no&useAbstract=yes&startrow=1&sort=year&sortorder=desc&recordsperpage=100). Fayerweather, W.E., M.E. Karns, P.G. Gilby, and J.L. Chen. 1992. Epidemiologic study of lung cancer mortality in workers exposed to titanium tetrachloride. J. Occup. Med. 34(2):164-169. Grimsby Telegraph. 2010. Man Critical Following Firm’s Second Toxic Gas Leak-Video. Grimsby Telegraph, March 6, 2010 [online]. Available: http://www.thisisgrimsby.co.uk/news/Man-critical-following-firm-s- second-toxic-gas-leak/article-1889676-detail/article.html [accessed July 28, 2010]. HSE (Health and Safety Executive). 2010. Chief Executive’s Report to the Board, Meeting Date: 31 March 2010. Paper No: HSE/10/31. UK Government, Health and Safety Executive Board [online]. Available: http://www.hse.gov.uk/aboutus/meetings/hseboard/2010/310310/pmarb1031.pdf [accessed July 28, 2010]. ITA (International Titanium Association). 2008. DuPont Opens Facility for Growing Titanium Metals Industry. Titanium Newsletter 2008(V):2 [online]. Available: http://www.titanium.org/files/ItemFileA4403.pdf [accessed July 28, 2010] (also reported as Metal Place 2008). Kelly, D.P. 1978. Titanium Tetrachloride. Unpublished DuPont Haskell Laboratory Report (Dec. 4) (as cited in Archuleta and Stocum 1993). Kelly, D.P. 1980. Acute Inhalation Studies with Titanium Tetrachloride. Haskell Laboratory Report No. 658-80. E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. October 31, 1980. Lee, K.P., D.P. Kelly, P.W. Schneider, and H.J. Trochimowicz. 1986. Inhalation toxicity study on rats exposed to titanium tetrachloride atmospheric hydrolysis products for two years. Toxicol. Appl. Pharamcol. 83(1):30- 45. Metal Place. 2008. DuPont Opens New Facility to Serve Growing Titanium Metals Industry. Metal Place November 13, 2008 [online]. Available: http://metalsplace.com/news/articles/23657/dupont-opens-new-facility-to- serve-growing-titanium-metals-industry/ [accessed July 28, 2010]. New Orleans News. 2010. Norco Chemical Cleanup Will Last Into Night, Evaluated Residents May Not Be Able to Return Until Wednesday. New Orleans News, April 13, 2010 [online]. Available: http://www.evri.com/ media/article?title=Norco+Chemical+Cleanup+Will+Last+Into+Night&page=http://www.wdsu.com/news/ 23134006/detail.html&referring_uri=/substance/titanium-tetrachloride-0xca837&referring_title=Evri WDSU [accessed July 28, 2010]. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. Roy, P.K., A. Bhatt, and C. Rajagopal. 2003. Quantitative risk assessment for accidental release of titanium tetrachloride in a titanium sponge production plant. J. Hazard. Mater. 102(2-3):167-186. TIMET (Titanium Metals Corporation). 2010. Annual Report Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934: For the Fiscal Year Ended December 31, 2009, Form 10-K. March 1, 2010 [online]. Available: http://www.faqs.org/sec-filings/100301/titanium-metals-corp_10-k/ [accessed July 28, 2010]. Times-Picayune. 2010. Chemical Spill in Norco Closes Schools, Forces Residents Out. The Times-Picayune, April 13, 2010 [online]. Available: http://www.evri.com/media/article?title=Chemical+spill+in+Norco+closes+ 34

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schools,+forces+residents+out&page=http://www.nola.com/politics/index.ssf/2010/04/st-charles.html& referring_uri=/substance/titanium-tetrachloride-0xca837&referring_title=Evri [accessed July 28, 2010]. TOLUENE At its meeting held on June 15-18, 2010, the committee reviewed the AEGL TSD on toluene. 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: Toluene is a colorless, flammable liquid with a pungent floral or aromatic odor. . . . The AEGL-1 was based on the preponderance of data from clinical and occupational exposures and from metabolism studies with human subjects that indicated an 8-hour exposure to 200 ppm was without an effect that exceed the AEGL-1 definition, i.e., notable discomfort. . . . The AEGL-2 is based on narcosis which would impair the ability to escape. The point of departure was the NOAEL for narcosis in a 70-minute exposure of Long-Evans rats to 2400 ppm. . . . The AEGL-3 was based on a NOAEL for lethality in a study with the rat. A 2-hour exposure to 6250 ppm was not lethal but produced prostration in rats. Specific Comments AEGL-1 The discussion of the selection of the POD should be rewritten to be consistent with the definition of an AEGL-1. Specifically, the discussion should state that an exposure for 8 h to toluene at 200 ppm is a NOEL or is below an AEGL-1 effect, such as notable discomfort (rather than as “an effect that exceeds the AEGL-1 definition”). Such revisions are need on page 61, lines 18-21 and lines 42-44, and in the corresponding section in the Summary on page 7, lines 25-26. Better support is needed for using an uncertainty factor of 1 for intraspecies differences. The populations in the clinical studies should be reviewed for how well they might represent the general population, and consideration should be given to whether there are any subgroups, such as children, who might be more susceptible. AEGL-2 The committee approved the derivation of the AEGL-s values for toluene. AEGL-3 The committee approved the derivation of the AEGL-3 values for toluene. Other Comments The TSD reflects a top notch effort for the physiologically based pharmacokinetic (PBPK) modeling. All model development and extrapolations were performed using acceptable methods. However, the authors of the TSD are encouraged to review EPA’s recent IRIS technical support document on toluene, which used a five-compartment PBPK model. Consideration should be given to 35

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whether this model might lead to a more accurate estimation by being more comprehensive than the four- compartment model used in the AEGL derivations. In the TSD’s Executive Summary, there are three sections on AEGL-1 values. The first and the third sections can remain as written. However, the long middle section cites many different studies to make points about concentrations of exposure, how representative study populations are of the general public, and the effects of exercise on toluene blood concentrations. This information should be presented more succinctly to support what appears to be the main message, which is that no effects were observed after 5 days of exposure to toluene at 100 ppm in clinical settings but that exercise can more than double the blood concentration of toluene. Page 13, line 8: The statement that aplastic anemia in two subjects indicated “that the toluene was contaminated with benzene” is too strong. Contamination with other chemicals is possible but should not be presented so definitively. A more objective statement would be that the effect might possibly indicate contamination with benzene. Page 63, lines 18-20: An explanation of “minimum alveolar concentration” is needed. The discussion should reference Section 4.4.2 (Intraspecies Variability) rather than Section 4.4.1 (Interspecies Variability). It should be mentioned that the IDLH value is much lower than the 30-min AEGL-3 value, and the possible reason for the difference should be discussed in the TSD. In the appendix, the information given in the pharmacokinetic figures (on the ordinates, within the figures, and in the figure legends; e.g., Figures C-6, C-9, C-10, and C-11) is not sufficient to be self- explanatory to nonspecialists (and without expecting the reader to refer to the original literature). Simple clarifications should be made if possible. TRIMETHYLBENZENES At its meeting held on June 15-18, 2010, the committee reviewed the AEGL TSD on 1,3,5- trimethylbenzene, 1,2,4-trimethylbenzene, and 1,2,3-trimethylbenzene. 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: Trimethylbenzene (TMB) isomers, including 1,3,5-TMB, 1,2,4-TMB, and 1,2,3-TMB, are common components of fuels and mixed hydrocarbon solvents. . . . The most appropriate animal data for derivation of AEGL-1 are the neurotoxicity studies. . . . Limited data were available for derivation of AEGL-2 values. Rats repeatedly exposed to 2000 ppm for 6 hours exhibited irritation, respiratory difficulty, lethargy, and tremors (Gage 1970); therefore, 2,000 ppm was chosen as the basis for deriving the 10-min, 30-min, 1-hour, 4-hour, and 8-hour AEGL- 2 values. . . . Data are insufficient for derivation of AEGL-3 values for TMB. Specific Comments The proposed AEGL-1 and AEGL-2 values for the trimethylbenzenes were approved. The committee agrees with the decision not to set AEGL-3 values for these compounds. Comment Reference Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18. 36

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VINYL ACETATE MONOMER At its meeting held on June 15-18, 2010, the committee reviewed the AEGL TSD on vinyl acetate monomer. 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: Vinyl acetate (VA) [CASRN 108-05-4] is a colorless, flammable liquid with low solubility in water. . . . The AEGL-1 is based on a human study in which inhalation exposure of humans to 4- 20 ppm for 2 minutes resulted in minimal or slight throat irritation, exposure to 20 ppm for 4 hours produced persistent slight throat irritation, and exposure to 34 ppm for 2 hours resulted in persistent throat irritation. . . . exposure of rats for 6 hours to 1000 ppm represents a NOAEL for an AEGL-2. . . . Because the reported lethality data were unreliable, the AEGL-3 values are based on the same point of departure as the AEGL-2. Specific Comments AEGL-1 The determination of AEGL-1 for vinyl acetate should consider that, at the proposed 10-min value of 6.7 ppm, hoarseness was reported by Deese and Joyner (1969) for the same period of exposure but at lower concentrations of 4.2 and 5.7 ppm. Slight eye irritation in one of three individuals was reported at concentrations of vinyl acetate at 5.7 or 6.8 ppm. However, the usefulness of this report is questionable because it was a self survey of subjective symptoms (page 16, lines 1-4). It should be noted that these end points are not unobservable and, therefore, are not entirely subjective. It should also be noted that the results from this study, along with consideration of odor threshold, form the basis for setting the ERPG-1 (page 41, Table 19). AEGL-2 The POD for vinyl acetate of 1,000 ppm for 6 h from the study by Bogdanffy et al. (1997) in rats was used for establishing the AEGL-2 (page 7, line 31). The study reported that lesions of the olfactory epithelial cells, characterized by degeneration, necrosis, and exfoliation, occurred at 600 and 1,000 ppm. However, 1,000 ppm was selected as the NOEL because of the presumed reversibility of these end points. It should be noted that these end points are sufficiently severe and appropriate for the AEGL-2. The adverseness of the effects should not be dismissed by their presumed reversibility (see discussion under Other Comments). Thus, a POD should be at a level without those effects. The application of a total uncertainty factor is presented on page 36, line 44, to page 37, line 3. Ample support is first provided for applying a factor of 10 for intraspecies differences. This factor is followed by a decision to lower it to 3 because, if a value of 10 is used, the resulting AEGL-2 values would be lower than concentrations of vinyl acetate that did not result in serious adverse health effects in human volunteer studies. Better justification is needed for lowering the uncertainty factor for intraspecies differences from 10 to 3. Part of the reason for not using human data as the basis of the AEGL-2 values was that nasal histopathologic end points were not examined or followed up in human studies. By this same reasoning, these data should not serve as support for reducing the intraspecies uncertainty factor. 37

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AEGL-3 The description for the AEGL determination needs clarification. It states that “the 4-hour mortality data provided by Smyth and Carpenter (1973 . . . produce BMCL05 values ranging from 226 ppm in mice to 1791 ppm in rats. The 226-ppm value appears unreasonable in context of other available data. For example, a group of 10 mice survived exposure to [vinyl acetate] for 6 h/day, 5 days/week, for 4 weeks” (page 38, lines 22-26). First, no concentration was given for the mice that survived the vinyl acetate exposure. Second, the argument for the unacceptable BMDL05 in mice is unconvincing. Presuming that the mice were exposed to vinyl acetate at 226 ppm for 6 h/day, 5 days/week, for 4 weeks, the BMCL05 would mean that 95% of the exposed mice are expected to survive, this being the lower end of the 95% confidence interval. Hence, survival of 10 mice in a group of 10 does not convincingly argue for the unreasonableness of BMCL05 at 226 ppm. Even if the exposure was for 6 h and given repeatedly, the outcome between acute versus repeated exposure would depend on the end-point-specific mechanism or mode of action, which could entail recovery between the daily exposure or the development of tolerance. It was stated that “because the exposure concentrations in the Smyth and Carpenter (1973) study were not measured, but corrected using a curve based on gas chromatographic analysis of calculated concentrations, it is possible that the exposure concentrations reported are not accurate. Therefore, these data were not used for derivation of the AEGL-3” (page 42, lines 31-35). However, data from the same study were used in deriving the AEGL-1 values. This apparent discrepancy about the data criteria should be addressed. The TSD proposed to use the same POD for AEGL-3 as used for AEGL-2 values (1,000 ppm for 6 h), but handled the uncertainty factors differently. As with the AEGL-2 derivation, an uncertainty factor of 3 was applied for interspecies sensitivity but an uncertainty factor of 1 (instead of 3) was applied for intraspecies variability. In light of the discussion about the lack of evidence for the reversibility of nasal olfactory epithelial lesions (see discussion under Other Comments), and the expected revision of the POD for AEGL-2, the POD for AEGL-3 should be reevaluated and justification provided for the selection of the uncertainty factor to account for intraspecies differences. Other Comments Olfactory epithelial degeneration, necrosis, and exfoliation reported by Bogdanffy et al. (1997) in rats were the end points for AEGL-2 and AEGL-3 values. Although the study did not include a recovery phase, the lesions were judged as reversible based on a personal communication with S.R. Frame (2004). However, without data, such communication should not be viewed as providing definitive evidence. A full recovery of olfactory epithelia would include regeneration of the same cell type and not mere unspecified cell replacement. Thus, reversibility for these end points from vinyl acetate exposure can only be noted as “presumed reversible” at best. Revisions are needed to reconcile the following statements:  The text on page 35, lines 18-19, states, “Human exposure to 20 ppm resulted in one of three individuals reporting persistent slight throat irritation.” However, the text on page 35, line 23, states that 20 ppm was used to derive AEGL-1 values because “exposure to 20 ppm represents a no-effect level for notable discomfort.”  The text on page 35, lines 27-28, states, “Because irritation is considered a threshold effect and therefore should not vary over time, the AEGL-1 value is not scaled across time . . . . However, both time and exposure level seem to be an important descriptor elsewhere. For example, the text on page 35, lines 19-22, states, “While exposure to 34 ppm for 2 h resulted in one of three individuals complaining of persistent throat irritation, exposure to 72 ppm for 4 h resulted in irritation severe enough that the exposed subjects expressed an unwillingness to work at this concentration.” 38

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The reason for significant differences between AEGL values and pertinent time-specific standards recommended by ACGIH should be discussed in the text. Comment References Bogdanffy, M.S., N.L. Gladnick, T. Kegelman, and S.R. Frame. 1997. Four-week inhalation cell proliferation study of the effects of vinyl acetate on rat nasal epithelium. Inhal. Toxicol. 9(4):331-350. Deese, D.E., and R.E. Joyner. 1969. Vinyl acetate: A study of chronic human exposure. Am. Ind. Hyg. Assoc. J. 30(5):449-457. Smyth, H.F., and C.P. Carpenter. 1973. Initial Submission: Vinyl Acetate: Single Animal Inhalation and Human Sensory Response with Cover Letter Dated 08/27/92. Carnegie-Mellon Institute. Submitted by Union Carbide Corporation. Doc. No. 88-920010328. VINYL CHLORIDE At its meeting held on June 15-18, 2010, the committee reviewed the AEGL TSD on vinyl chloride. A presentation on the TSD was made by Bob Benson, of the U.S. Environmental Protection Agency. The following is excerpted from the Executive Summary of the TSD: Vinyl chloride (VC) is a colorless, flammable gas with a slightly sweet odor. . . . The AEGL-1 was based on the study . . . with 4-7 volunteers, two individuals experienced mild headache during 3.5 and during 7.5 hours (3.5 hours, 0.5 hours break, 3.5 hours) of exposure to 491 ppm…. The AEGL-2 was based on prenarcotic effects observed in human volunteers. . . . The AEGL-3 was based on cardiac sensitization and the no effect level for lethality. Specific Comments The proposed AEGL-1, -2, and -3 values for vinyl chloride were approved. Other Comments Better justification is needed for using an uncertainty factor of 1 for interspecies differences in deriving the AEGL-3 values. A short discussion of the dog cardiac-sensitization model and how it is specifically designed to maximize cardiac response should be added (see paper by Brock et al. 2003). Arrhythmias can be seen in mice, but it is very difficult to interpret because the heart rate can be 500-700 beats per minute. The TSD should mention whether the Single Exposure Carcinogen Database was consulted for relevant information. The table in Appendix C, which presents AEGL values on the basis of carcinogenic effects, should also include the relevant AEGL values that are based on noncancer effects to allow for easier comparison. It would be preferable to structure the table in the traditional format of presented AEGL values (that is, the exposure durations should be the column headings and the AEGL values should constitute the row designations). 39

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Comment Reference Brock, W.J., G.M. Rusch, and H.J. Trochimowicz. 2003. Cardiac sensitization: Methodology and interpretation in risk assessment. Regul. Toxicol. Pharmacol. 38(1):78-90. COMMENTS PERTAINING TO ALL TSDs For all TSDs, when substantial discrepancies are found between AEGL values and other guideline values (e.g., IDLHs, STELs, and WEELs), the possible reasons should be explored and discussed. It is important that the TSD summaries be updated to reflect revisions to the main text of the TSDs. For chemicals thought to be direct-acting respiratory irritants, an uncertainty factor of 3 to account for intraspecies differences is often used rather than a default factor of 10. This is usually supported by a statement that response to sensory irritants is not expected to vary greatly among individuals. However, there is often wide variability in responses to such chemicals. Better justification and supporting references should be provided for departing from the default value of 10 (see Standing Operating Procedures [NRC 2001, pages 87-88]). Comment Reference NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. 40