Fifteenth 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, a committee of the NRC Committee on Toxicology prepared a report titled Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (NRC 1993). That report provides step-by-step guidance for the derivation of CEELs for EHSs.

In 1995, the National Advisory Committee on Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances (referred to as NAC) was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop AEGLs for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for prevention and emergency-response planning for potential releases of EHSs, from accidents or terrorist activities.

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, pharmacology, medicine, industrial hygiene, biostatistics, and risk assessment.

The charge to the committee is to (1) review AEGLs and supporting documentation developed by NAC for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) identify priorities for research to fill data gaps; and (3) identify guidance issues that may require modification or further development based on the toxicologic database for the chemicals reviewed.

This interim report presents the committee’s comments concerning NAC’s draft AEGL documents for 16 chemicals (boron trifluoride, bromine, dimethyldichlorosilane, epichlorohydrin, ethylene oxide, furan, methyl ethyl ketone, methyl mercaptan, methyltrichlorosilane, nitric acid, nitrogen dioxide, nitric oxide, perchloromethylmercaptan, phosphorus oxychloride, phosphorus trichloride, and trimethylchlorosilane) and 1 chemical mixture (jet fuel 8). This interim report also includes the committee’s comments regarding NAC’s white paper on physiologically based pharmacokinetic (PBPK) modeling.



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Fifteenth 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, a committee of the NRC Committee on Toxicology prepared a report titled Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (NRC 1993). That report provides step-by-step guidance for the derivation of CEELs for EHSs. In 1995, the National Advisory Committee on Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances (referred to as NAC) was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop AEGLs for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for prevention and emergency-response planning for potential releases of EHSs, from accidents or terrorist activities. 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, pharmacology, medicine, industrial hygiene, biostatistics, and risk assessment. The charge to the committee is to (1) review AEGLs and supporting documentation developed by NAC for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) identify priorities for research to fill data gaps; and (3) identify guidance issues that may require modification or further development based on the toxicologic database for the chemicals reviewed. This interim report presents the committee’s comments concerning NAC’s draft AEGL documents for 16 chemicals (boron trifluoride, bromine, dimethyldichlorosilane, epichlorohydrin, ethylene oxide, furan, methyl ethyl ketone, methyl mercaptan, methyltrichlorosilane, nitric acid, nitrogen dioxide, nitric oxide, perchloromethylmercaptan, phosphorus oxychloride, phosphorus trichloride, and trimethylchlorosilane) and 1 chemical mixture (jet fuel 8). This interim report also includes the committee’s comments regarding NAC’s white paper on physiologically based pharmacokinetic (PBPK) modeling. 1

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COMMENTS ON BORON TRIFLUORIDE At its meeting held on January 17-19, 2007, the committee reviewed the revised AEGL technical support document (TSD) on boron trifluoride. The presentation was made by Claudia Troxel of Oak Ridge National Laboratory, and James Dennison of Century Environmental Hygiene, LLC. General Comments A revised draft TSD can be finalized if the recommended revisions are made appropriately. The primary difference between this version of the boron trifluoride TSD and the version the committee reviewed in 2002 is the addition of the 2005 report by A.M. Bowden (of the Huntingdon Laboratories), which was sponsored by Honeywell International (Bowden 2005). Although the Bowden report addresses the 4-hour (h) inhalation toxicity of boron trifluoride dihydrate rather than the dimethyl ether, the report is clearly relevant, and the authors have used its data to revise the AEGL-1. As discussed in the TSD, upon contact with even low levels of moisture in the air, boron trifluoride reacts to form the dihydrate. Boron trifluoride dihydrate is strongly corrosive to the eyes and skin of rabbits. The Bowden report was not included with a copy of the revised boron trifluoride document, but the document described the data in detail on pages 11 through 13. The Bowden report appears to be a well-conducted acute inhalation study from an established laboratory recognized for the quality of its toxicology studies. The previous TSD on boron trifluoride raised a major concern for the committee because it used delayed irritancy (seen at 2 weeks after starting exposure) as the criterion upon which to base the AEGL-1. The Bowden data provide a better basis for the AEGL-1 and resolved the concern about using delayed irritancy. Additionally, the committee pointed out that in 1960 the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs) committee set the TLV for boron trifluoride at 1 part per million (ppm) (2.8 mg/m3) based partly on work that Bowden conducted on the Manhattan project at Rochester. Although these studies were not published, Stockinger and Spiegl (1953) discussed them. This is important for two reasons: (1) the only human data available for boron trichloride consist of one accidental exposure, and (2) the current AEGL-1 (2.5 mg/m3) is much closer to Stokinger’s and Spiegl’s recommendation (2.8 mg/m3) than the previous value (0.6 mg/m3). The current AEGL-1 is also a better match for the Torkelson data where the NOAEL was 1.5 ppm (Torkelson et al, 1961). The revised basis for establishing the AEGL-3 for boron trifluoride presented on page 27, uses the same data (Rusch et al. 1986) as the 2002 TSD but uses a different method (log-probit analysis with EPA benchmark dose software version 1.3.2) for interpretation of these data. Looking at the data presentation in Figure 1 (category plot on page 30) and in the probit plot on page 46, use of the different method seems reasonable and appropriate. The revised TSD provides more scientific and defensible AEGL values for boron trifluoride at all three levels. Editorial Comments The revised TSD corrects the typos found in the previous version and improves the wording in a few places. The document is not consistent in its use of NOEL and NOAEL. For example, the summary on page vii says, “The AEGL-1 is based on a NOEL for irritation.” In contrast, page 23 says, “The AEGL-1 is based on a NOAEL for irritation.” It would be helpful to the reader to add an explanation to the probit plot on page 46 (which has no log scale) to indicate how it relates to the log-probit analysis. 2

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Comment References Bowden, A.M. 2005. Boron Trifluoride Dihydrate Acute (Four-Hour) Inhalation Irritation Threshold Study in Rats. Conducted by Huntingdon Life Sciences Ltd., Cambridgeshire, England; Sponsored by Honeywell International, Inc., Morristown, NJ. Rusch, G.M., G.M. Hoffman, R.F. McConnell, and W.E. Rinehart. 1986. Inhalation toxicity studies with boron trifluoride. Toxicol. Appl. Pharmacol. 83(1):69-78. Stokinger, H.E., and C.J. Spiegl. 1953. Part A. Inhalation-toxicity studies of boron halide and certain fluorinated hydrocarbons. Pp. 2291-2311in Pharmacology and Toxicology of Uranium Compounds, C. Voegtlin, and H.C. Hodge, eds. New York: McGraw-Hill. Torkelson, T.R., S.E. Sadek, and V.K. Rowe. 1961. The toxicity of boron trifluoride when inhaled by laboratory animals. Am. Ind. Hyg. Assoc. J. 22:263-270. COMMENTS ON BROMINE At its meeting held on January 17-19, 2007, the committee reviewed the revised AEGL document on bromine. The document was presented by Sylvia Talmage of Oak Ridge National Laboratory. General Comments A revised document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comments Page 16, lines 9-13. In the first paragraph, it states that chlorine would penetrate to the lower respiratory tract more easily than bromine, and, therefore, chlorine would, produce lethality at a lower concentration than bromine. This statement is inconsistent with values for AEGL-3 listed in Table 8 on page 21. In this table, AEGL-3 values for chlorine are higher than those for bromine, suggesting that chlorine is less lethal than bromine at each time period. This relationship is consistent with TLV values noted below. Page 18, lines 6-10. What is the justification for the statement that the uncertainty factor (UF) of 3 for intraspecies differences is appropriate when the mode of action is irritation rather than via biotransformation? Page 19, lines 12-15. It states that asthmatic persons would be protected by an intraspecies UF of 3 because the concentration proposed for AEGL-2 “did not penetrate to the lower respiratory tract.” Again, it is not clear whether no penetration occurred or whether some penetration occurred with no effect on normal tissue. In any case, there are receptors in the upper respiratory tract that can trigger an asthmatic attack, so the assumption that lack of any penetration into the lower respiratory tract of asthmatic persons would make this concentration “safe” for this population is not valid. Page 21, Table 8. The TLVs for for fluorine, chlorine, and bromine are 1, 0.5, and 0.1 ppm, respectively, and the short-term exposure limits (STELs) (15 minutes [min]) are 2, 1, and 0.3 ppm, respectively. The rank order of relative toxicity for AEGLs-1 and -2 is, therefore, consistent with those values. There is, however, a disconnect for this order for AEGL-3, where chlorine appears to be the least toxic of the three halogens for each exposure duration. 3

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Response to Comments Page 2. It notes that data indicate that bromine is less toxic than chlorine and fluorine, and the reader is directed to Table 4 in the TSD. This table compares chlorine and bromine only and does not include fluorine. Furthermore, this statement is inconsistent with the rank order of the TLVs for these elements. In any case, the fact that bromine may be more soluble and therefore undergo more scrubbing in the upper respiratory tract is not a good rationale for why it may be less toxic than a less soluble chemical. Editorial Comments Page 18, lines 15 and 16. It states in this section that “…there was no penetration to the lower respiratory tract.” There are no data to support this statement, so it should be changed to “…there is likely to be little penetration to the lower respiratory tract.” COMMENTS ON DIMETHYLDICHLOROSILANE At its previous meeting held on January 17-19, 2007, the committee reviewed the revised AEGL document on dimethyldichlorosilane. The document was presented by Cheryl Bast of Oak Ridge National Laboratory. General Comments A revised document can be finalized if the committee’s recommended revisions are made appropriately. The response to the comments has addressed the points raised; however, additional points have arisen. The rationale for deleting the comments regarding other toxic intermediates should be provided to the committee and should also be included in the response to the comments. Section 8.3 should be revised to more clearly express the limitations in the data set and the assumptions made in light of the data limitations. The derivation of AEGLs 1-3 is heavily dependent on the AEGL derivation of hydrogen chloride and the assumption that the generation of 2 moles of hydrogen chloride for every mole of dimethyldichlorosilane accounts for the toxicity of the chemical. See comments below on methyltrichlorosilane. They are applicable to the document on dimethyldichlorosilane. COMMENTS ON EPICHLOROHYDRIN At its meeting held on January 17-19, 2007, the committee reviewed the AEGL document on epichlorohydrin. The document was presented by Kowetha Davidson of Oak Ridge National Laboratory. General Comments Generally, this is a well-written document that requires a few major and some minor improvements. A revised document should be submitted to the committee for review. 4

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The AEGL-1 (5.7 ppm throughout) up to the AEGL-3 for 4 h (43 ppm) and 8 h (30 ppm) are well below the level of distinct odor awareness (LOA) of 46 ppm. It may be advantageous to highlight (e.g., on page 6, line 10) the fact that odor is not an early warning aid for exposure to epichlorohydrin. Page 43, lines 14 and 15. AEGL-2 values are summarized in Table 9. These values are supported by Wexler (1971) who stated that 20 ppm for 1 h is irritating to the eyes and nose. Clarify that irritation (at 20 ppm) is not an AEGL-2 end point and should not be used for AEGL-2 derivation. Specific Comments Page 6, line 21. Which species is referred to in the statement “Inhalation exposure of laboratory animals to epichlorohydrin causes effects similar to those reported for humans”? Page 6, line 35. A UF of 3 (NA for interspecies sensitivity and 3 for intraspecies variability). Describe further the support for choosing a UF of 3. Page 8, lines 5-7. In the table shown below and presented on page 8 of the TSD, 53 ppm (10-min AEGL-2) is not “a threefold reduction of AEGL-3” (570-ppm 10-min AEGL-3). Page 9, line 9. The text states that “Epichlorohydrin is manufactured at three sites in the United States in Louisiana and Texas.” Determine whether epichlorohydrin is produced outside the United States because AEGL documents are used in countries other than the United States. Page 10, line 33. The text states that “Gardiner et al. (1993) reported a mean odor threshold of 10 ppm and an odor recognition level of 25 ppm. The odor threshold during and after a 5-min exposure of unconditioned personnel was 10-12 ppm for 50% of the subjects and 25 ppm for 100% of the subjects.” Determine whether Gardiner et al. (1993) specify that the odor is recognized by individuals who have had previous exposure. If so, indicate that in the document. Page 11, line 45. The text states that “Two years after the accident the patient complained of nonspecific epigastric pain; a clinical examination showed pronounced fatty liver, abnormal liver function, chronic asthmatic bronchitis, and essential hypertension (not related to exposure to epichlorohydrin).” Why mention hypertension here? Clarify whether there was a preexisting hypertension. If so, it should not be mentioned because it suggests an hypertensive effect of epichlorohydrin. Page 15, lines 33 and 34. The text indicates that exposure to 20 ppm of epichlorohydrin for 1 h caused burning to the nose and mouth, 48 ppm for <2 h caused throat irritation that could last for 48 h, and >100 ppm caused pulmonary edema and 36 kidney lesions. This discussion may not be fully consistent with the odor threshold discussion on pages 10 and 11. For example, see Van Doorn et al. (unpublished report 2002). Page 16, line 11. The text indicates that the unexposed workers also had a higher frequency of chromosome aberrations than the general population but not more cancers. Cancer epidemiology is treated in a separate chapter and is said to be inconclusive. Another sentence on the inconclusive evidence 5

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for cancer should be inserted. The sentence on page 13, lines 36 and 37, could be inserted into this paragraph after the second sentence on line 5. Page 19, line 13. Check the calculation of this unusually high LC50 (979 mg/m3) and re-examine its consistency through different studies. Page 26, lines 8 and 9 versus lines 10-12. Contradictory to each other? “The only evidence of kidney damage in young rats was … and lowered blood urea nitrogen (BUN)” versus “The only effect in the exposed adult rats … was a decreased BUN … No evidence of kidney toxicity was observed in the adult rats.” Page 26, line 22. The text states that “Bromosulfophthalein (BSP) removal from the blood was decreased at all three concentrations on the day of exposure. BSP is used to assess liver function, particularly biliary function.” However, the BSP test is obsolete as a liver function test. Page 38, line 28. The text states, “Epichlorohydrin is a chloromethyl substituted oxirane (ETO) or chlorinated methyloxirane (propylene oxide).” To avoid confusion, reword the sentence to show that “oxirane” and “ethylene oxide” (ETO) refer to the same substance. Page 41, line 26. Note that 5.7 as shown in the table below and on page 41is far below the LOA of 46 ppm. Page 42, lines 25 and 26. The text mentions that severe kidney toxicity was observed in rats exposed to 150 ppm of epichlorohydrin gas mixture for 1 h. Explain why “severe kidney toxicity” was not taken as a basis for deriving AEGL-2 (instead of dividing AEGL-3 by 3). Page 43, lines 7 and 8. Perhaps this statement should be rephrased: “No definitive data were available for deriving AEGL-2 values from studies with humans or animals.” However, the author should explain why severe kidney toxicity is not “definitive data.” Page 42, lines 36-38. The text states, “Because kidney damage was observed after a single inhalation exposure to epichlorohydrin, clinical signs alone are considered inadequate for evaluating animal toxicity after inhalation exposure to epichlorohydrin vapor.” The statement is unclear. Is kidney damage not a “clinical sign”? For development of AEGLs, we are mainly interested in single inhalation exposure as is the case here. Page 43, lines 14 and 15. The text states, “AEGL-2 values are summarized in Table 9. These values are supported by Wexler (1971) who stated that 20 ppm for 1 h is irritating to the eyes and nose.” The committee suggests adding the word “only” between “is” and “irritating” to help clarify that irritation is not considered an AEGL-2 effect but is considered an effect below an AEGL-2. Editorial Comments Page 6, lines 34 and 35. Make a full sentence. Page 6, line 39. “to become more severe with increasing time ….” Page 9, line 9. Is epichlorohydrin produced outside the U.S.? (This AEGL document is intended to be used internationally.) 6

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Page 11, lines 12 and 13. Lefaux (1968) was before Wexler (1971) and should be mentioned first. Page 14, lines 27-29. Unclear. Page 14, line 40. Probably exposure “to epichlorohydrin” is meant. Page 15, line 10. What is an “epoxy-producing unit”? Page 15, line 16. Give years. Not every reader will know which years were the early years of operation of the Shell Chemical facility at Dear Park, Texas. Page15, line 20. “Finnish,” not “Finish.” Page 15, line 30. “irritation,” not “Irritation.” Page 16, lines 1 and 2 versus lines 7-9 are contradictory: Chromosome aberrations are as long lived as the cells in which they occur and some lymphocytes are long-lived. Perhaps the sweeping statement “not been associated with any long-lasting effects” in lines 1 and 2 should be deleted. Page 27, line 2; page 29, line 14; and page 31, line 2. “for 6 hours 5 days per week for 14 days.” Page 30, lines 9-14. The exposure is given in the same sentence first in ppm, then in mg/m3, then again in ppm. The units should be consistent. Page 34, line 11. Escherichia coli. Page 34, lines 12, 13, and 14. If epichlorohydrin is more effective as a mutagen without “metabolism,” it means that the metabolism leads to inactivation, not activation. Perhaps it would be best to replace “without metabolic activation” with “in absence of an exogenous metabolizing system.” Page 34, line 19. Sram et al. Page 35, line 8. systemic but mainly portal-of-entry effects. Page 37, lines 15 and 16. Mention the known metabolites. Page 38, line 28. Define the abbreviation ETO: ethylene oxide ( = oxirane). Page 41, lines 19 and 26. Note that 5.7 is far below the LOA of 46 ppm. Page 42, line 8. Wrong table number. Page 42, lines 36-38. Rephrase the text for greater clarity. For AEGLs, we are mainly interested in single inhalatory exposure. Pages 44, lines 22-23, and 45, lines 8-10: Which long-term study? Page 44, line 26. “factor of 3” (no full stop after “of”). Page 44, line 27. “and rabbits was from” (not “The range ... ranged from …”). Page 45, line 1. “the AEGL-3 values.” Page 45, line 7. “an AEGL-3 value of 19.” Page 45, line 9. If we understand this statement correctly, it would be clearer for the reader if “over a lifetime” were added (“the exposure concentration of 30 ppm (6-h duration) over a lifetime that caused no lethality …”). Pages 54, line 24, and 55, line 5. Mention species. Page 55, lines 41 and 42. Unclear. Page 62. Legend not legible (may be just a problem of copying). Comment References Dietz, F.K., M. Grandjean, and J.T. Young. 1985. Epichlorohydrin: 1-Hour LC50 Determination in Fischer-344 Rats. Lake Jackson Research Center, Health and Environmental Sciences–Texas, Dow Chemical U.S.A., Freeport, TX. Gardiner, T.H., J.M. Waechter, and D.E. Stevenson. 1993. Epoxy compounds. Pp. 329-444 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. 2, Pt. A: Toxicology, G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Laskin, S., A.R. Sellakumar, M. Kuschner, N. Nelson, S. La Mendola, G.M. Rusch, G.V. Katz, N.C. Dulak, and R.E. Albert. 1980. Inhalation carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley rats. J. Natl. Cancer Inst. 65(4):751-757. 7

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UCC (Union Carbide Corporation). 1983. Epichlorohydrin Repeated Inhalation, Preliminary Metabolic Studies, Revision of Acute Toxicity Data, and Human Sensory Response. RI-UP-HEASD 8S SU HS FN Submission. U.S. Environmental Protection Agency, Doc. I.D. 878212138. Wexler, B. 1971. Determination of epichlorohydrin contamination in an industrial facility for the manufacturing of epoxy resins [in Romanian]. Mater. Plast. 8:322-323. COMMENTS ON ETHYLENE OXIDE At its meeting held on January 17-19, 2007, the committee reviewed the revised AEGL document on ethylene oxide. The document was presented by Kowetha Davidson of Oak Ridge National Laboratory. General Comments A revised draft can be finalized if the recommended revisions are made appropriately. Specific Comments Page 62, lines 10-12, 31, 32, and 35-39. 100 ppm is proposed as the NOAEL although it states that “fetal body weight was slightly, but significantly decreased.” Presumably this significant decrease is considered as biologically insignificant. If so, give the percentage of the decrease (and, if possible, give a literature quotation that confirms that such a percentage decrease of fetal body weight is considered biologically insignificant). However, if the decrease in fetal body weight in question is considered biologically significant, 100 ppm cannot be taken as the NOAEL. Page 64, lines 1 and 2. AEGL-2 was based on neurotoxicity and developmental toxicity studies, but time extrapolation for AEGL-2 was done using rat lethality data and ten Berge’s equation (ten Berge et al. 1986). This is acceptable if the former are on the continuum of effects finally leading to lethality (e.g., all of them alkylation-driven). If so, it should be stated that these effects are on the continuum, and it should describe the basis of the conclusion. If not, the default values should not be used. Page 88, lines 4-6. The word “neuropathy” should be crossed out. Distal axonal degeneration is the morphological basis of the neuropathy, which in turn must be of extracellular origin (supposedly myelin damage through ETO-induced oxidation). Axonal degeneration and neuropathy are not synonymous. Also, the sentence should be improved for clarity. What does “respectively” refer to? Editorial Comments Page 6, line 14. The phrase “dose in mg/kg bw” does not make sense in this context. Omit or qualify by saying, e.g., “internal dose in mg/kg bw at given external dose”if that is what is meant. Page 8, line 4. Omit the phrase “the vapor density indicates that it is heavier than air” because it may be misleading. Page 9, line 16. Correct the flammability value. Range is from 3% to 100%, as stated in the text. Page 35, lines 7 and 20. Write out “Maximum nerve conduction velocity” in full and omit abbreviation “MCV” because term occurs only twice. Page 40, line 34. Change to read “conducted a developmental toxicity study in mice….” Page 40, line 41. Change to read “see Table 16” (not Table 15). Page 41, line 17. Change to read “length reduction at 2,100.” 8

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Page 57, line 20. Change to read “with heterozygous.” Page 58, line 3. Unclear. What are “newborn adult levels”? Page 58, line 16. Unclear. What is “proportionally similar”? Page 58, lines 21 and 22. Something is missing in the sentence “The genotypic diversity….” Page 62, line 44. Change to read “were significantly increased”. Page 63, line 27. Change to read “the dosimetry” (instead of dosmetric). Page 63, line 28. Change to read “not expected to differ” (omit the word “be”). Page 65, line 30. Change “Deah” to “Death”. Page 87, line 35. The phrase “dose in mg/kg bw” does not make sense in this context. Omit or qualify by saying, e.g., “internal dose in mg/kg bw at given external dose” if that is what is meant. Page 89, line 20. The phrase “dose in mg/kg bw” does not make sense in this context. Omit or qualify by saying, e.g., “internal dose in mg/kg bw at given external dose” if that is what is meant. Comment Reference ten Berge, W.F.; Zwart, A.; Appelman, L.M. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13:301-309. COMMENTS ON FURAN At its meeting held on January 17-19, 2007, the committee reviewed the revised AEGL document on furan. The document was presented by Claudia Troxel of Oak Ridge National Laboratory. General Comments The authors have provided a good-faith response to the previous review and addressed nearly all of the areas of concern. The revised document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comments Page vii, line 29. This line states that the key study “actually evaluated the acute inhalation toxicity of several chemicals,” giving rise (from the text, as written) to the interpretation that the Terrill et al. (1989) study examined mixed furan, 2-methyl furan, furfuryl alcohol, and furfural exposures rather than individual studies of each congener. Please drop the text that describes chemicals other than furan. They have no bearing on the furan AEGL as Section 3.1.2 describes the results of the furan inhalation trials. Page vii, lines 20 and 21. This provides no useful information (“Therefore, the differences in furan kinetics in humans could be compared to those in rodents.”). Page vii provides a description of the interspecies 10-fold factor utilized in AEGL-2 and AEGL-3 derivations, but it is not clear why the available PBPK parameters were not used for the interspecies dose scaling and why the authors relied upon a default factor of 10. Please either revise (or at least compare and contrast) the derivation to incorporate results of interspecies furan extrapolation using the published PBPK parameters or explain why the PBPK approach for extrapolation of the rat data to humans is not useful here and why the interspecies dose extrapolation should be conducted using a default UF. At a minimum, the text should state and explain the margin of exposure (as summarized on page 19, lines 11-14) and indicate why a 9

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dose of furan metabolites in human liver at AEGL-2 and AEGL-3 of 1.7 ppm or 4.8 ppm for 4 h is within the acceptable risk range. Page 1, line 17. The first sentence of the second paragraph on page 1 is incomplete. It is important that the public understand furan is a ubiquitous material present in cooked foods (snacks, biscuits, bread crust, roasted wheat flour, roasted coffee beans) (Becalski et al. 2005; Zoller et al. 2007). The U.S. Food and Drug Administration (FDA) carried out a large survey of various foods to determine their furan content and found concentrations ranged from nondetectable to 100 ppb (http://www.cfsan.fda.gov/~dms.furanexp/sld09.htm). FDA calculations found that mean daily furan exposure ranged from 0.26 µg/kg-day for adults to 0.41 µg/kg-day for infants. It is important to point out that for most people, coffee is the primary source of furan exposure and that coffee brews from espresso- type machines (considered to have the best aroma) had the highest amounts of furan compared with other brews. Page 2, line 23. The NTP (1993) report referenced is badly dated as human exposure data. The annual production quantities and numbers of facilities that produce, handle, or otherwise consume furan should be revisited. Move the references to furan exposure from the section on “Nonlethal Toxicity” to the section dealing with environmental exposure. It appears Section 2.2 could be rewritten to state, “No data were available regarding acute nonlethal toxicity of furan.” Page 9, lines 38-40. Move or enhance the descriptions of the rats that inhaled 100, 500, 1,050 or 3,850 ppm to the section on nonlethal toxicity. Do the Kedderis et al. (1993) and Kedderis and Held (1996) publications provide descriptions of the health and/or behavior of the rats used in the kinetic studies that could be used to support or detract from the AEGL-2 and AEGL-3 values derived from the Terrill (1989) data? Because the rats used in the kinetic studies survived their single 4-h exposures to as high as 208 ppm without apparent ill effect (page 10, line 6) or even up to 3,850 ppm (page 9, line 40), how can one justify a 4-h AEGL-2 of <2 ppm and a 4-h AEGL-3 of <5 ppm unless there is an over-riding carcinogenic concern? As carcinogenicity was not considered (page 19), it is not clear how the AEGLs are justified when the rats used in controlled inhalation studies conducted at up to 4 h survived exposures with “initial” concentrations of as great as 3,850 ppm (page 9, line 40)? It may be that the proposed AEGLs are more the consequence of the concentrations (to 2,851 ppm) and duration (1 h) used in the Terrill protocol than the fact that groups of three rats can tolerate up to 3,850 ppm for 4 h (Kedderis et al., 1993). Page 10, lines 4-7. In discussing the results of the Terrill report, move or enhance the descriptions of the rats that inhaled furan for 4 h at 52, 107 or 208 ppm (12 rats/group). Also, refer to comment from page 9, lines 38-40. Page 19, lines 6-8. This discussion is weak. Where a material can induce nongenotoxic changes that lead to production of tumors, it is usually implied that the mode of action can be handled by a threshold or sigmoid dose-response relationship, and it does not follow that “it is not expected that a one- time exposure up to 8 h would induce cancer.” Rather, the reader needs to know whether the metabolized dose to the target organ (liver) has a margin of safety at the AEGL-2 and AEGL-3 values that is sufficiently large so that other noncarcinogenic factors (body weight reduction) can drive the furan AEGL. Editorial Comments Page vii, line 35. Delete “Toxicity signs during exposure”; change to: “Signs of furan intoxication during exposure included…” Page viii, line 17. The Terrill report was not inadequate because “the study actually evaluated the acute inhalation toxicity of several chemicals”; rather, the description of the results was not as precise as the reader might wish. Page 10, line 29. Change to “Michaelis-Menten”. 10

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Comment References Becalski, A., D. Forsyth, V. Casey, B.P. Lau, K. Pepper, and S. Seaman. 2005. Development and validation of a headspace method for determination of furan in food. Food Addit. Contam. 22(6): 535-540. Kedderis, G.L., and S.D. Held. 1996. Prediction of furan pharmacokinetics from hepatocyte studies: Comparison of bioactivation and hepatic dosimetry in rats, mice and humans. Toxicol Appl Pharmacol. 140(1):124-130. Kedderis, G.L., M.A. Carfagna, S.D. Held, R. Batra, J.E. Murphy, and M.L. Gargas. 1993. Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vitro. Toxicol. Appl. Pharmacol. 123(2):274-282. NTP (National Toxicology Program). 1993. Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-09) in F344N rats and B6C3F1 Mice (Gavage Studies). Technical Report 402. NIH 93- 2857. U. S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Toxicology Program, Research Triangle Park, NC. Terrill, J.B., W.E. van Horn, D. Robinson, and D.L. Thomas. 1989. Acute inhalation toxicity of furan, 2- methylfuran, furfuryl alcohol, and furfural in the rat. Am. Ind. Hyg. Assoc. J. 50(5):A359-A361. Zoller, O., F. Sager, and H. Reinhard. 2007. Furan in food: Headspace method and product survey. Food Addit. Contam. 24(Suppl. 1):91-107. COMMENTS ON JET FUEL 8 At its meeting held on January 17-19, 2007, the committee reviewed the revised AEGL document on jet fuel 8. The document was presented by Sylvia Talmage of Oak Ridge National Laboratory. General Comments A revised document should be submitted to the committee for review. With all the references to JP-5, why not include JP-5 in the title? The claim is made that JP-5 is a subset of JP-8. Page 8, lines 11-16, describe the distillation specification for JP-5. Provide the same for JP-8 to validate that JP-5 is a subset of JP-8. Also, there is a need to address the source of benzene. The committee suggests incorporating the following information as an explanation for benzene: — Only the studies of Carlton and Smith (2000) discuss benzene exposures measured during maintenance operations on military aircraft fuel tanks. The exposures were measured inside the fuel tanks or on personnel removing foam from the tanks. The later operation involves the generation of aerosols as the foam is pulled out of the tank. Benzene is more water soluble than other jet fuel components and concentrates in the small amount of water remaining after many refuelings. This can result in measurable benzene concentrations during these operations even though the levels of benzene in the bulk fuel are not detectable (see Appendix A). Benzene is not a component of concern for JP-8 AEGLs. — Aerosols are not generated during refueling operations. Aerosols will only be developed during aircraft foam removal operations (occupational exposure) or aircraft engine cold starts (occupational exposure). — While these exposures are based on reported mixed aerosol and vapor concentrations, the primary exposure is to the vapor. Exposure to aerosols will probably result in deep lung 11

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collapsed alveolar septa, and so forth, which falls within the AEGL-2 definition of “exposed to life- threatening health effects.” Editorial Comments Pages 7-9. Why are references presented after the summary? Page 12, line 20. Insert “occupational” after “manifestation.” Page 14, line 17. Are these numbers odds ratios or relative risks? Page 15, lines 19-23. This sentence needs to be reconstructed. Page 15, line 39. Change “ambient” to “outdoor.” Page 36, line 2. Change “theory” to “hypothesis.” Page 37, line 40-42. This sentence does not make sense. Comment References Abe, M. 1967. Effects of mixed SO2-NO2 gas on human pulmonary function: Effects of air pollution on the human body. Bull. Tokyo Med. Dent. Univ.14(4):415-433. Bauer, M.A., Utell, M.J., Morrow, P.E., Speers, D.M., and Gibb, F.R. 1985. Route of inhalation influences airway responses to 0.30 ppm nitrogen dioxide in asthmatic subjects. Am. Rev. Respir. Dis. 131:A171. Gardner, D.E., R.S. Holzman, and D.L. Coffin. 1969. Effect of nitrogen dioxide on pulmonary cell population. J. Bacteriol. 98(3):1041-1043. Gardner, D.E., D.L. Coffin, M.A. Pinigin, and G.I. Sidorenko. 1977. Role of time as a factor in the toxicity of chemical compounds in intermittent and continuous exposures. Part I. Effects of continuous exposure. J. Toxicol. Environ. Health 3(5-6):811-820. Gardner, D.E., F.J. Miller, E.J. Blommer, and D.L. Coffin. 1979. Influence of exposure mode on toxicity of NO2. Environ. Health Perspect. 30:23-29. Illing, J.W., F.J. Miller, and D.E. Gardner. 1980. Decreased resistance to infection in exercised mice exposed to NO2 and O3. J. Toxicol. Environ. Health 6(4):843-851. Kerr, H.D., Kulle, T.J., McIlhany, M.L., and Swidersky, P. 1978. Effects of nitrogen dioxide on pulmonary function in human subjects. An environmental chamber study. Report: ISS EPA/600/1-78/025; Order no. PB-281 186, 20 pp. Kerr, H.D., Kulle, T.J., McIlhany, M.L., and Swidersky, P. 1979. Effects of nitrogen dioxide on pulmonary function in human subjects: An environmental chamber study. Environ. Research 19:392-404. Larsen, R.I., D.E. Gardner, and D.L. Coffin. 1979. An air quality data analysis system for interrelating effects, standards, and needed source reductions: Part 5. NO2 mortality in mice. J. Air Pollut. Control Assoc. 29(2):133-137. Maigetter, R.Z., J.D. Fenters, J.C. Findlay, R. Ehrlich, and D.E. Gardner. 1978. Effect of exposure to nitrogen dioxide on T and B cells in mouse spleens. Toxicol. Lett. 2:157-161. Miller, F.J., J.A. Graham, J.W. Illing, and D.E. Gardner. 1980. Extrapulmonary effects of NO2 as reflected by pentobarbital-induced sleeping time in mice. Toxicol. Lett. 6(4-5):267-274. Orehek, J., J.P. Massari, P. Gayrard, C. Grimaud, and J. Charpin. 1976. Effect of short-term low level NO2 exposure on bronchial sensitivity of asthmatic patients. J. Clin. Invest. 57(2): 301-307. Selgrade, M.K., M.L. Mole, F.J. Miller, G.E. Hatch, D.E. Gardner, and P.C. Hu. 1981. Effects of NO2 inhalation and vitamin C deficiency on protein and lipid accumulation in the lung. Environ. Res. 26(2):422-437. 26

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COMMENTS ON NITRIC OXIDE At its meeting held on January 17-19, 2007, the committee reviewed the AEGL document on nitric oxide. The document was presented by Carol Wood of Oak Ridge National Laboratory. General Comments Because nitric acid (HNO3), nitrogen dioxide (NO2), nitric oxide (NO) are reactants or products of the same chemical reactions, the committee recommends these be sections of the same chapter within the AEGL publication. A revised document should be submitted to the committee for review. There is a need to address the potential for public exposure to NO. The combined TSD for HNO3, NO2, and NO should address the likelihood of elevated exposures to NO resulting from episodic releases of bulk NO or other chemicals that react to form NO. If there is a potential for public exposure to high concentrations of NO, the combined TSD for HNO3, NO2, and NO needs to address the toxicology of NO to a greater extent and reconsider the default to NO2 AEGL values because NO converts to NO2. Specific Comments Page 5, line 23. This line states, “exposures below 80 ppm NO should not constitute a health hazard.” However, at 50 ppm, there was increase lung weight, and at 25 ppm, there were histopathologic changes. Please explain. Page 12, lines 13 and 14. A better way to state this would be that NO attenuated any bronchoconstriction due to methachol. Page 18, lines 11 and 12. Can changes in behavior be used for AEGL-1? Page 19, lines 24 and 25. This line states, “Lethality studies … were confounded by possible NO2 contamination….” This result was not reported in all studies. In a study using rats by Stavert and Lehnert (1990) and in a study using mice by Pfleser (1935), there were deaths with no evidence of lung injury, increase in lung weight, or histopathologic changes. Because those effects are associated with NO2 and not with NO, their absence indicates there was no confounding by NO2. The results of those studies should be considered in setting the AEGL-3 for NO. Page 23, Section 4.3. Change title of section to “Chemical Transformation of Nitrogen Oxides.” Page 25, line 12. This line refers to only one abstract (Wilhelm et al. 1998); however, there is another one ( Mihalko et al. 1998;). Although they are only abstracts, they report effects in dogs that may be relevant to AEGL-1 (decreased arterial oxygen ) at 320-ppm and 640-ppm exposure and AEGL-3 effect (death) at 640 ppm. Page 27, lines 16-20. The descriptions of the results of Pflesser (1935) and Stavert and Lehnert (1990) in the TSD indicate that NO2 was not a contaminant. Editorial Comments Page 18, line 36. Correct spelling of histological. Comment References Mihalko, P.J., C.R. Hassler, R.R. Moutvic, T. Vinci, R.L. Hamlin, and S.J. Waters. 1998. Effects of inhaled nitric oxide on cardiovascular and pulmonary function in the dog. Toxicologist 42:250. 27

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Pflesser, G. 1935. The significance of nitric oxide in poisoning by nitrous gases. Naunyn-Schmiedeberg Arch. Exp. Pathol. Pharmakol. 179:545-547. (German) Cited in NIOSH, 1976. Stavert, D.M. and B.E. Lehnert. 1990. Nitric oxide and nitrogen dioxide as inducers of acute pulmonary injury when inhaled at relatively high concentrations for brief periods. Inhal. Toxicol. 2:53-67. Wilhelm, J.A., P. Veng-Pedersen, P.J. Mihalko, and S.J. Waters. 1998. Pharmacokinetic modeling of methemoglobin concentration-time data in dogs receiving inhaled nitric oxide. Toxicologist 42:213. COMMENTS ON PERCHLOROMETHYL MERCAPTAN At its meeting held on January 17-19, 2007, the committee reviewed the AEGL document on perchloromethylmercaptan. The document was presented by Claudia Troxel of Oak Ridge National Laboratory. General Comments The proposed AEGL values and their derivation appear appropriate, given the very limited database. Time scaling and the use of UFs appear appropriate. Recommendations need to be made for specific additional research to improve the AEGLs, given the paucity of the database. Responses to comments from the committee are considered sufficient unless otherwise noted. The revised document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comments Page 1, Table 1. Include additional vapor pressure value: 3 torr at 20°C (citation is: Shertzer 2001; see reference section below). Additional information for boiling point entry: Decomposition products include chlorine and oxides of chlorine and sulfur (citation is Shertzer 2001). Current citation is ACGIH (1991); however, ACGIH (2006) does not mention decomposition. Pages 3-5, Section 3. There is an unpublished study mentioned in Shertzer (2001) identifying skin absorption as a potential issue: Skin irritation studies in guinea pigs indicated severe skin irritation and absorption of the material through the skin; animals that received 2.5 ml/kg died within 2 days (Eastman Kodak, TSCA Section 8E submission, TSCATS Accession No. 42513, Fiche No. 0533569, 1961). See also the Althoff (1973) reference on pages 1, 3, and 13, which reports that the clothes of the person who died were contaminated with liquid perchloromethyl mercaptan; the clothes of the two survivors apparently were not. Refer also to the editorial comments for the Executive Summary and Sections 2.6 and 7.1. Although this is very limited information, a footnote to Table 7 and/or mention in the discussion in Section 8.1 as potentially affecting the application of the AEGL values should be considered. Alternatively, some statement indicating why possible skin absorption is not addressed should be included. Page 7, lines 32 and 33. When considering the phrase “respiratory nasal epithelial changes,” if available, a more complete description of the nature of these changes should be included. Page 10, lines 23 and 24. Is quoting the SOP in this case sufficient to meet the spelled-out requirement there for a “discussion” of why the mechanism is likely not to differ? 28

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Page 10, lines 28 and 29. Does the text mean that a repeat-exposure study reduces the uncertainty regarding the occurrence of the minor epithelial changes? A clarification of this statement would be helpful. Page 12, line 11. Can the use of the term “reasonable” be better justified? The committee is not disagreeing with the conclusion but wonders why a factor of 3 is any more (or less) reasonable than a factor of 5, for example? This same question applies to the use of this term in the Executive Summary (page viii, line 4) and Appendix B (page 31, line 14). Page 18, line 14. The last sentence is not relevant to this paragraph and can be deleted. Recommendations regarding specific research needs and their priorities are needed. (For example, should reproductive studies be done before dog or monkey studies defining nonlethal effects thresholds?) Editorial Comments Page vii, lines 9 and 10. Change to read “Human data were generally limited to described only in secondary sources; case reports describing respiratory and topical exposures ….” Page vii, line 28. Change to read “the end point is a no-effect level for perchloromethyl mercaptan as a respiratory irritant.” Page viii, lines 4 and 5. Change to read “The divisor of 3 is reasonable based on the steepness of the strong dose-response relationshipcurve for lethality; no rats died following exposure to 9 ppm for 1 hour, while 7/10 died at 18 ppm.” Page viii, lines 35-44. Change to read “1971). Ttherefore, that concentration 9 ppm was selected as …. All exposed animals rats eye developed ocular and mucosal irritation within 5 min after of initial exposure, and; dyspnea, …. Necropsy revealed inflamed mouth oral and nasal … a direct irritant, and is therefore the mechanism is not expected to differ significantly among species … effects of exposure appear to be related to a direct irritant effect tissue irritation at the point of contact, and irritant these effects ….” Page ix, line 2. Change to read “indication of relatively little variation ….” Page ix, lines 15-20. Change to read “appears to be a direct irritant effect contact irritation, it is … but rather the AEGL-3 concentration represents the a threshold for …. Therefore, the irritation is sufficiently severe enough that continued exposure would result in produce increased and likely irreversible damage … longer to shorter durations of exposure periods, respectively.” Page 3, lines 5-7. Change to read “One fatality f Following exposure to an unknown concentration of pechloromethyl perchloromethyl mercaptan vapors and skin contact with the liquid, one fatality occurred due to resulted from massive hemorrhagic pulmonary edema, accompanied by simultaneous heart, circulatory, and kidney collapse ….” Page 3, line 17. Change to read “When averaged together, the 1-h LC50 for males and females Sprague-Dawley rats (combined) is …” Page 5, line 27. Change to read “Necrospy Necropsy ….” Page 5, line 31. Change to read “included gross findings of mucus ….” Page 6, lines 4 and 5. Change to read “by Gage was confounded compromised by … including: the lack of ….” Page 6, lines 8-21. Change to read “exposed to perchloromethyl mercaptan at a nominal … study should can be used … results section of the study report were mostly … mercaptan to the gassing exposure chamber. The (legible) summary section (which was legible) did not failed to discuss or even mention control animals, leading one to believe suggesting that control animals were not assigned.This was unfortunate because there were questions about the animals’ health. … infestation and had findings … bronchopneumonia,; … septicemia,; and the … not already present prior to or at the start of the exposures … presented together below. Page 6, lines 22-31. Change to read “exposure. Toxicity sSigns … respiration. As already stated, the gGuinea pigs … guinea pig had developed fibrotic … dogs died as a result of their exposure. The dogs 29

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exhibited developed excessive lacrimation … stools.It is reiterated [Note that at least one of the dogs … infection.] … Microscopic examination of their lungs … appearance. I and, in some areas, the alveolar walls had ruptured ….” Page 6, lines 36 and 37. Change to read “… mercaptan tested positive for was mutagenicity in a number of in vitro genotoxicity assays ….” Page 7, lines 3-8. Change to read “kinase locus in cultured L5178Y … mercaptan did not induce failed to increase chromosomal aberrations … in cultured Chinese hamster … activation and did not induce there was no increase in micronuclei … mice in the a micronucleus assay ….” Page 7, lines 21-37. Change to read “mercaptan exposure were extremely are very limited … 1971). Unfortunately, tThe severity of these those signs at this concentration and at the higher concentrations (which resulted in mortality) was not provided;, and a no control group was not included. … Mild nasal epithelial changes were observed in rats … 0.580 ppm, consisting of decreased reduced body weight … 1987). No effects such changes were observed in rats subchronically exposed to that inhaled 0.014 or 0.079 ppm for 70-72 days (Knapp … (1952) are limited in usefulness of little use because the protocols used were confounded fundamentally compromised by several factors.” Page 7, lines 38-40. Change to read “Perchloromethly mercaptan was generally tested positive for mutagenicity in standard in vitro test systems … mercaptan exposure to cause … reproductive effects toxicity or to induce neoplasia increase carcinogenic risk. Page 9, line 3. Change to read “This fact would explains the deeper lung damage after HCl exposure compared with ….” Page 9, lines 7-13. Change to read “were not used for in the derivation … Although there are acute toxicity data are available … the toxicity potency of perchloromethyl mercaptan is much greater than that of the congener as seen when examining lethality data methyl mercaptan. In rats, the 1-hour LC50 the highest nonlethal concentration of perchloromethly mercaptan is 9 ppm for 1 h, and the 1-h LC50 is reported as 11, 13, or 16 ppm, and the highest nonlethal concentration is 9 ppm for 1 hour with the next concentration of 18 ppm for 1 hour resulting in 7/10 rats dying within 24 hours of exposures. By way of comparison, the highest nonlethal concentration of methyl mercaptan in rats is 400 ppm for 4 h ….” Page 10, lines 2-13. Change to read “appropriate for use in deriving … provided, and it was the report stated that dyspnea, gasping, and signs of acute depression … 1.15 ppm resulted in objective clinical signs of intoxication (haircoat … in the nose) (Knapp ….” Page 10, lines 27 and 28. Change to read “(SOP 2.5.3.4.4.) (no deaths … Company, 1971).” Page 10, line 30. Change to read “level for an irritant irritation.” Page 11, line 27. Change to read “by Gage are of limited in usefulness utility.” Page 11, lines 28-36. Change to read “0.13 ppm developed only mild … next higher concentration of (1.15 ppm) developed … rats exposed for 6 h … highest exposure concentration of (0.58 ppm) (Knapp … present until later in the study duration increased (salivation … compared with the controls were minimal, and included decreases reductions in ….” Page 12, lines 8-12. Change to read “Insufficient data were are available to derive AEGL-2 values consistent with the AEGL-2 definition. Available sStudies that … concentrations did not report failed to describe adverse health effects consistent with the definition of an AEGL-2 end point … values are were derived … based on the steepness of the steep … lethality: no rats … 18 ppm.” Page 13, lines 10 and 11. Change to read “describing exposures to unquantifiable unquantified concentrations … mercaptan and the likelihood these accidents involved both skin and respiratory tract contact with the material (Althoff ….” Page 13, line 26. Change to read “there was no increase in mortality … Therefore, that concentration 9 ppm was selected ….” Page 13, lines 29-30. Change to read “5 minutes after initial exposure … depression” were also observed ….” Page 14, line 15. Change to read “mechanism of action responsible for death appears to be a direct irritant effect contact irritation in the lung, it is ….” Page 14, line 35. Change to read “are summarized is presented ….” 30

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Page 15, lines 13-18. Change to read “repeat-exposure study, which … This end point represents … the AEGL-2 values are were obtained … for lethality. Also at this concentration At the no-effect level for increased mortality, exposed animals exhibited developed eye and … revealed inflamed mouth oral and nasal mucosa.” Page 15, line 28. Change to read “A useful One way….” Page 15, lines 29-32. Where are these code numbers used in the text? This paragraph refers to the Category Plot on page 16, but these codes do not appear to be used there or elsewhere outside the SOP. The codes 1,2,3 and NL can be left out. Pages 15, line 37, and 16, line 1. Change to read “From this plot, one sees it is evident that AEGL values are below any exposure concentration in animals resulting in any adverse effects, and should therefore be protective of human health. Page 16, Figure 1. Parts per million values less than 1 have been either rounded or truncated to 0. Page 17, line 11. The entry for IDLH should be in the “30 minute” column. It looks like two cells have been joined or combined. Pages 19-21. If a document is available online (other than a journal article), the URL should be provided to improve ease of access. In this reference list, add the following: Page 20, lines 6-9. The NIOSH IDLH database is also online at http://www.cdc.gov/niosh/idlh/idlh-1.html. Page 20, lines 10-12. The NIOSH Pocket Guide to Chemical Hazards is also online at http://www.cdc.gov/niosh/npg/npg.html. Page 20, line 13. The OSHA Air Contaminants list (Table Z-1) is also online at http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9992. Page 21, lines 13 and 14. The EPA AEGLs list is online at http://www.epa.gov/oppt/aegl/pubs/chemlist.htm. If there is a citation of a common secondary source, check to see if there is a more recent version, verify the information being referenced therein, and cite the most recent version that contains the material to be referenced. This is especially appropriate for annually updated sources such as the TLVs, WEELs or ERPGs, which can change and even withdraw certain values or the references used to support them. For exposure limits or guidelines, also ensure that the citation clearly refers to either the value or the documentation. In this reference list, the more recent versions of the secondary sources used are the following: Page 19, lines 2-4. ACGIH, 2006a. Documentation of the Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs). American Conference of Governmental Industrial Hygienists, Inc. (ACGIH), Cincinnati OH. Page 19, lines 5-7. ACGIH, 2006b. 2006 TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Inc. (ACGIH), Cincinnati OH. Page 19, lines 15-17. Shertzer H.G., 2001. Organic Sulfur Compounds. Vol. VII, Ch. 94, § 33, Perchloromethyl Mercaptan. Pp. 681-765 in Bingham E., Cohrssen B., Powell C.H., eds. (2001). Patty's Toxicology (5th Edition) Volumes 1-8. John Wiley & Sons, New York NY. Page 19, lines 10-12. Does this report have a title? How many pages? [N.B.: for reports like this one, and for various unpublished company reports cited below, the standard citation form includes the number of pages, as with the citation for Knapp and Thomassen, 1987] Page 19, lines 20 and 21. Is this the complete report title? Page 23, line 5. Change to read “the effects are those of mild irritation” [alternative choice: minor]. Change recommended based on the discussion on page 14, lines 14-18; using “mild” or “minor” will distinguish irritation at the AEGL-1 concentrations from that at higher concentrations. Page 27. For consistency across documents, application of UFs should be after calculation of the time scaling equation, rather than integrated into it. This is a stylistic recommendation, not an algebraically substantive one. Page 27, line 4. What does “this document” mean here? 31

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Responses to Committee’s Comments on the Previous Document Page 1. “The NAC did not feel a modifying factor was needed.” Is there a justification for this position, rather than just a feeling? Page 2. The committee concurs that the two chemicals are sufficiently different to warrant no SAR comparison. A statement to that effect in the TSD would be useful. Page 3. The committee concurs with the response to the committee’s comment about odor and ocular and respiratory tract irritation. However, the point raised regarding highlighting the intensity and nociceptive properties of the odor remain valid. This point should be presented as a footnote to Table 7. Page 7, Section 5.2. The committee concurs; however, the rationale for selecting the Knapp et al. (1987) study has not been explicitly stated in the response to the committee’s comment. COMMENTS ON PHOSPHORUS OXYCHLORIDE At its meeting held on January 17-19, 2007, the committee reviewed the AEGL document on phosphorus oxychloride. The document was presented by Robert Young of Oak Ridge National Laboratory. General Comments The committee finds that this document is good and has convincing reasons not to propose AEGL-1 and AEGL-2 values. Previously, there was concern about the high interspecies UF of 10 and a proposal for lowering it to 3. The author has convinced the committee that the interspecies UF of 10 should be retained. A total UF of 30 is justified. After taking the comments shown below into account, the document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comments Pages 11, line 39, and 12, line 2. The only concern that remains is a statement on page 11 in Section 7.3 that contact irritation as a toxic mechanism would not vary greatly among individuals, and, therefore, the UF of 3 for intraspecies differences was used. For other chemicals, there are data that justify a UF of 10. For sulfur dioxide, e.g., there is a factor 10 difference in concentration for response between nonasthmatic and asthmatic individuals. Thus, the statement made in the TSD might not be universally true and might depend on the specific chemical. In the case of phosphorous oxychloride, the intraspecies UF of 3 appears to result in a reasonable value for the AEGL-3, which seems in line with other published standards. COMMENTS ON PHOSPHORUS TRICHLORIDE At its meeting held on January 17-19, 2007, the committee reviewed the AEGL document on phosphorus trichloride. The document was presented by Robert Young of Oak Ridge National Laboratory. 32

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General Comments The committee finds that this revision is responsive to the comments made on the original submission. The major difference with the first submission is that time scaling for the AEGL-1 value has now been skipped for reasons mentioned on page 9. The committee agrees with this decision. After taking the comments shown below into account, the document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comments Page 9, lines 17-20. A point on page 9 that needs some clarification is the rationale for intraspecies UF of 3. The authors state that the UF was ‘limited’ to a value of 3 because the main effect of the chemical appears to be due to hydrogen chloride and phosphonic acid resulting from dissociation. Please indicate why this chemical reaction should limit the UF. Page 9, lines 20 and 21. This indicates that effects from direct contact of dissociation products are likely to be similar for any epithelial surface. This is, however, unlikely to be true if skin is compared with the eye or bronchial epithelium, for example. Possibly, mucosa is meant instead of epithelium. COMMENTS ON PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING (PBPK) At its meeting held on January 17-19, 2007, the committee reviewed the document on physiologically based pharmacokinetic modeling (PBPK). The document was presented by James Dennison of Century Environmental Hygiene, LLC. General Comments PBPK models have gained acceptance over the last decade for use in dose-response assessments and risk assessments. This timely white paper lays out how PBPK models can be used in the AEGL development process. The report is generally well written and should be useful in implementing the application of these models to derive AEGLs, where feasible. After taking the comments shown below into account, the document can be finalized if the committee’s recommended revisions are made appropriately. The concerns of the reviewers are as follows. A more basic introduction on PBPK modeling is needed. Particularly, it would be helpful if the document could include 1. A basic (and brief) discussion about drug (maybe anesthesia) kinetics and how the practice of medicine and drugs is based on understanding the blood levels or tissue levels. This shows that other established disciplines use pharmacokinetic information to estimate effects. 2. Basic physiology of the body. What happens when a chemical is inhaled, and how does it get to tissues? What governs the rate of uptake, distribution, and elimination? Focus discussion, so the structure of a PBPK model can be understood. 3. State and restate that the intended purpose is to estimate the concentrations in blood or tissues associated with exposures to chemicals and that the estimated internal concentration is thought to be a better representation of exposure than air concentration (C). Perhaps show an example of calculated AEGL values with a PBPK model using Cn × T = k and point out which physiological 33

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processes are accounted for in the PBPK model that were not accounted for in the air concentration extrapolation methodology. The use of the term standard operating procedure (SOP) appears overstated. The document provides general guidance and uses toluene as an example for how PBPK models could be used. SOP infers more refined step-by-step procedures than are outlined in this document. This is a guidance document, not an SOP for PBPK modeling and AEGL derivation. The white paper should make clear that only peer-reviewed PBPK models are to be used in the process. If modification to the model structure or description is made, then it should undergo peer review before being used for AEGL derivation. This document also should make it clear from the outset that the use of PBPK models is only intended for AEGLs associated with systemic effects. Reevaluate the emphasis on the inclusion of exercise physiology in these models. Changes in physiological parameters relevant to exposure (e.g., breathing rate) are not accounted for currently in setting the AEGLs. Therefore, the proposed consideration of exercise physiology in PBPK models intended for AEGL application (e.g., of different levels of physical activity at different AEGLs) would appear to be inconsistent with the current practice of guideline setting. PBK models should be executed under the conditions of light-to-moderate level of human activity; sedentary conditions should not be used. A plot of the dosimetrics as a function of time and dose might be useful. If the dosimetrics for each chemical are plotted in this way, readers can readily grasp the relationships between exposure or administered dose and internal dose. Some guidance should also be provided on the choice of dose surrogates, particularly for acute effects. The use of interspecies UFs to adjust dosimetrics other than administered dose should be clarified. The authors should clearly indicate that application of UF to the internal dose is the scientifically defensible approach—particularly, given that the AEGL development probably deals with nonlinear kinetics in several situations. In addition, provide guidance on the use of intraspecies UFs. How well do the simulations have to fit the data points to be a good fit (variability)? A discussion of current practices would be helpful. Should any statistical procedures be implemented to address this? For example if 10 infants, 10 teenagers, 10 adult males, and 10 pregnant females are all exposed for 10 min to chemical X, what is the expected range of blood concentrations? If unknown, what UF should be applied and what is the basis for this factor? Specific Comments Page 13, lines 7-10. It is the other way around. Metabolism is often dominated by more than one enzyme; their relative impact depends on the concentration of the substance to be metabolized. For example, enzyme X might dominate at relatively low concentrations (e.g., AEGL-2 concentrations), and enzyme Y might dominate at relatively high concentrations (e.g., AEGL-3 concentrations). Their relative abundance across species is often drastically different. Therefore, modeling of just one enzyme may lead to grossly wrong values in either the low concentration or the high concentration range. Editorial Comments Page 12, lines 10-21. This sentence is unclear. Page 22, line 14: Unclear what “the present order” is. To facilitate reading, state which sequence is meant here. 34

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COMMENTS ON TRIMETHYLCHLOROSILANE At its meeting held on January 17-19, 2007, the committee reviewed the document on trimethylchlorosilane. The document was presented by Cheryl Bast of Oak Ridge National Laboratory. General Comments The proposed AEGL values and support for their derivation appear appropriate given the limited database. Given the proposed mode or mechanism of action, reliance on the HCl database and the AEGLs derived from it is appropriate. Appendix E and the discussion of molar ratios in Sections 4.3, 6.3, and 7.3 are helpful. Time scaling and the use of uncertainty and modifying factors appear appropriate. A revised document should be submitted to the committee for review. As was mentioned in the comments on the TSD for methyltrichlorosilane earlier in this report, the revised TSD for trimethylchlorosilane, should explain why toxic intermediates are not considered. A total UF of 100 for AEGL-3 seems high; please provide some justification. Recommendations need to be made for specific additional research to improve the AEGLs, given the paucity of the database. Specific Comments Page. iii, line 9. There are two 1-h LC50 rat studies—Dow (1999a) and Kolesar et al. (1987). Page iii, lines 23 and 24. In table on page v, effects of “reversible lacrimation, corneal opacity, rales, gasping and nasal discharge” is not an AEGL-2 effect. Page 4, Summary. Explain why the Dow (1999a) LC50 = 4,257 was selected rather than that of Kolesar et al (LC50 = 2,928). Pages 6, line 41-44, and 7, lines 1-5. “Comparison of human vs rodent and differences in breathing.” The authors need to cite papers to support the concluding statement on lines 5 and 6, that humans are more sensitive than rodents to HC1 or irritants. Page 6, lines 35-37. The mice data reported should be vetted to justify not using this species for AEGL development and perhaps guinea pigs (lines 38 and 39). Only the data sets for rats are presented and then used by the authors. A reader would need to obtain these mice papers to determine their relevance. The critical studies have been selected, but the process of getting there should be provided. Page 9, lines 6 and 7. The ratio of HCl to trimethylcholorsilane needs to be rewritten so that it is easier to understand. Were the two AEGL values simply compared (after assumptions about UF values) to derive the ratio? This is important because it shows the relationship between the HCl values and this chemical, which is primarily based on HC1. If this is correct, rewrite text to state clearly the intent to use HCl values as guideline values. Page 8, Section 6.3. The language seems convoluted. Perhaps, the text should state the assumptions that were used to be consistent with the database on HCl and show the results. More detailed discussion of the calculations and their inconsistency could be shown in a table and discussed in an appendix. Page 7. Derivation of AEGL-1. If the AEGL-1 and the ERPG (stated on page 11) are all based on HCl, why are the numbers not the same. Page. 8, line 20. Clinical effects observed are reversible and not an AEGL-2 effect. Page iii, line 23, lists lacrimation, corneal opacity, rales, gasping, and nasal discharge. Page 9, lines 11 and 12. Intraspecies UF of 3. Can the underlying rationale for 3 vs 10 be explained more clearly? Page 10, line 17. The rationale for setting the 8-h AEGL-3 value equal to the 4-h value is not provided and must be presented here. 35

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Page 11, Section 8.3. No specific research needs for trimethylchlorosilane are identified. Is the last sentence intended to indicate that no further research is needed? Editorial Comments Pages iii-iv. Much of the material in the paragraphs on the AEGL-2 and AEGL-3 values is there to explain the rationale for selecting specific values for UFs and illustrating the consequences of using other values. This is all explained in the text; for the purposes of a summary, it could be left out. Page 1. Insert a molecular structure diagram here (or wherever appropriate) for comparison purposes with the other silanes for which AEGLs are being developed. Page 3, line 20. The term “fiducial limits” should be replaced with the more commonly used “confidence limits.” Page 9, line 25. Change “subjective” to “were not quantified.” Page 11, lines 8-11. In Table 7, the lines demarking the cells for ERPG values are missing. While these values are by definition for exposures up to 1 h, the lack of the lines could be inferred to indicate that the values are valid for longer time periods as well. For the WEEL ceiling value, either no cell lines should be used (as is), or the same value should be in each cell (as with the AEGL-1 value). Pages 12 and 13, Section 9. If a document is available online (other than a journal article), the URL should be provided to improve ease of access: — EPA EHS Chemical Profiles are online at http://yosemite.epa.gov/oswer/ceppoehs.nsf/EHS_Profile?openform. — NLM TOXNET databases, including the HSDB, are online at http://toxnet.nlm.nih.gov/. If there is a citation of a common secondary source, check to see if there is a recently updated version, verify the information being referenced there, and cite the most recent version that contains the material to be referenced. This is especially appropriate for annually updated sources such as the TLVs, WEELs, or ERPGs, which can change and even withdraw certain values. For exposure limits and guidelines, also ensure that the citation clearly refers to either the value or the documentation (see Bingham et al. 2001). Pages A1-A3. This material is redundant with the paragraph on the derivation of AEGL-1 values on page 7, line 30, which does not refer to Appendix A. It seems the appendix is redundant, and it can be dropped. Page C-2, line 17. Change “insufficient data” to “not relevant.” Page D2. The category plot is missing an axis. Comment Reference Bingham, E., Cohrssen, B., Powell, C.H. (2001). Patty’s Toxicology (5th Edition) Volumes 1-8. John Wiley & Sons, New York NY. 36