Fourteenth 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, EPA, several other federal and state agencies, and several private academia organizations convened an advisory committee—the National Advisory Committee on Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances (referred to as the NAC)—to develop, review, and approve AEGLs (similar to CEELs) for up to 400 EHSs. AEGLs developed by the 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, either from accidents or as a result of terrorist activities.

THE CHARGE TO THE COMMITTEE

The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by the 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 developed by the NAC for scientific validity, completeness, 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 the NAC’s draft AEGL documents for 16 chemicals: xylenes (mixtures of ortho, para, and meta xylenes; meta-xylene predominates the mixture constituting 40-70% of the commercial mixture); acetone; acetone cyanohydrin; carbon disulfide; allyl alcohol; acrolein; chloroform; peracetic acid; n,n-dimethylformamide; carbon tetrachloride; 1,2-dichloroethylene; sulfur dioxide; hydrazine; ethylenimine; propylenimine; and trichloroethylene.

COMMENTS ON XYLENES

At its previous meeting, the committee reviewed the AEGL document on xylenes. The presentation was made by Claudia Troxel of Oak Ridge National Laboratory and James Dennison of Century Environmental Hygiene LLC. The committee recommends a number of revisions. A revised draft can be finalized if the recommended revisions are made appropriately.



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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Fourteenth 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, EPA, several other federal and state agencies, and several private academia organizations convened an advisory committee—the National Advisory Committee on Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances (referred to as the NAC)—to develop, review, and approve AEGLs (similar to CEELs) for up to 400 EHSs. AEGLs developed by the 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, either from accidents or as a result of terrorist activities. THE CHARGE TO THE COMMITTEE The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by the 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 developed by the NAC for scientific validity, completeness, 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 the NAC’s draft AEGL documents for 16 chemicals: xylenes (mixtures of ortho, para, and meta xylenes; meta-xylene predominates the mixture constituting 40-70% of the commercial mixture); acetone; acetone cyanohydrin; carbon disulfide; allyl alcohol; acrolein; chloroform; peracetic acid; n,n-dimethylformamide; carbon tetrachloride; 1,2-dichloroethylene; sulfur dioxide; hydrazine; ethylenimine; propylenimine; and trichloroethylene. COMMENTS ON XYLENES At its previous meeting, the committee reviewed the AEGL document on xylenes. The presentation was made by Claudia Troxel of Oak Ridge National Laboratory and James Dennison of Century Environmental Hygiene LLC. The committee recommends a number of revisions. A revised draft can be finalized if the recommended revisions are made appropriately.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels General Comments Based on discussion at the meeting, there was agreement among the committee members to use an interspecies uncertainty factor (UF) of 3 to derive the values for AEGL-2 and -3, because the physiologically based pharmacokinetic (PBPK) model used accounted for the oversensitivity of the animals in the experiment compared to humans. The committee also recommended that a statement and a specific citation to the standard operating procedures (SOP) (including the specific section) should be added to explain why an intraspecies UF of 3 was selected, for both AEGL-2 and -3. The committee recommended that new language should be added to describe why a “correction” factor was used to derive AEGL-2 and -3 values. The committee also agreed with the approach used by the authors for time extrapolation and dose extrapolation and supported their findings and recommendations relative to the modeling. The committee believes that the methods used are accepted in the modeling community. However, since PBPK modeling is notorious for visualizing the uncertainties in dose-response relationships, further clarification is needed regarding how to handle the concept of “adequate fit,” “model validation,” and “poor fit.” In addition, new text needs to be added describing how the specific PBPK model used to derive the AEGL values was evaluated and why it is considered to be a “valid” model for application in the derivation of AEGL values for xylenes. Specific Comments Page 41, lines 13-15. Eye irritation is not a sensory irritation (for example, bad smell is a sensory irritation to the olfactory system and glaring light is a sensory irritation to the vision). Page 44, lines 25-32. Contradiction? Was an exposure of rats to 2,800 parts per million (ppm) xylene for 4 hours (h) a no-observed-effect level (NOEL) for prostration (lines 25-26), or did it produce prostration (line 32)? Or does “NOEL” in line 25 refer to death only and not to “reversible prostration”? Editorial Comments Page 5, line 9. Delete “age” (or “years old”). Page 31, Table 10. Add units (hours) to the Duration column. Page 37, Section 4.3.2. Intraspecies Differences. The discussion of the two- to threefold range in humans is discussed in the SOP, but no references are provided here. Because this is an important point, add a reference to the SOP here so the reader understands that the basis for this statement is documented in the SOP. Add NRC 2001 (SOP manual) as a reference either at the end of the first or second paragraphs. Page 48, line 35. Spell out what “EEL” stands for. Scientific Comments in Response to the Initial Comments on Xylenes Discussion Page 3, lines 12-15. This statement and consequent calculation is not justified. An elderly person being at greater risk for pharmacodynamic reasons (maximal sensitivity in newborn, pregnant, and

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels elderly) may have to run in an emergency situation irrespective of whether he is “the most physically active” or a rather physically inactive person. Thus, a pharmacokinetic component (“physical activity during exposure”) may well add to a pharmacodynamic component (higher sensitivity). Also in the preceding lines (7-12), it is not clear whether “an intraspecies uncertainty factor of 3 includes both the pharmacokinetic and pharmacodynamic components. The corresponding corrections will also have to be made in the Executive Summary (page viii) and in the main text (page 45, lines 1-21). Page 8, lines 14-16. This important point is still not incorporated in the text. Specific/Editorial Comments Page 3, lines 3-7. Unclear sentence. Is it meant to say, “because although it appears that similar central nervous system effects occur …”? (Same for present text on xylenes—for example, page viii, lines 37-39, and page 72, lines 8-10.) When these changes are complete, the amended text of this technical summary document (TSD) should be sent to the committee for their approval. The revised document can be finalized if the revisions recommended by the committee are made appropriately. COMMENTS ON ACETONE At its previous meeting, the committee reviewed the AEGL document on acetone. The document was presented by Jens-Uwe Voss of Germany. General Comment This is a well-documented report. A major issue is that acetone is a nontoxic compound. The fire and explosion hazard is considerably more important than the toxic hazard. Addressing the question of why AEGLs, and especially an AEGL-3, for this substance are needed at all is justified. Specific Comments Page vii, 1st and 7th paragraph. Conflicting data on odor level of 41-86 ppm versus the level of distinct odor awareness (LOA) 160 ppm. Page viii, line 5. It is unlikely that inhalation exposure to high acetone concentrations in air will ever lead to toxicologically relevant blood concentrations. Page 3, lines 5-6. Paint thinner is not acetone, although it may contain some. This case does not prove that oral acetone intake may be lethal. Is it necessary to cite all six reports by Litovitz et al.? Page 3, line 23. Systemic acetone clearance is not rapid. Acetone, because of its relatively high water solubility, has a relatively high blood:air partition coefficient. As a result, its rate of exhalation is limited. The rate of metabolism of acetone is also limited, as is urinary excretion of the parent

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels compound. The elimination of acetone is quite slow when compared to more lipophilic solvents such as toluene (see Figure 4 in Bruckner and Peterson 1981). Page 3, line 24. The word “excretion” should be replaced with “urinary excretion and exhalation.” Page 4, line 5. Comparable concentrations may be observed in diabetics and are not really alarming. Page 4, lines 26-30. Acetylene is the most likely cause of coma in this case, not acetone. Page 5, lines 5-15. These concentrations would be lethal for ethanol; apparently acetone is even less toxic than ethanol. A 6-month (mo) follow-up is too short a time to exclude neurodevelopmental complications. Page 6, lines 24-30. The study of Nakaaki (1974) was poorly done, and its findings are uncertain. Therefore, it and its description should be deleted. Page 9, line 15. What is 23-element clinical chemistry? Which parameters were actually included? Page 9, line 28. The paper of Haggard et al. was published in 1944, not in 1994 (as in the text). Page 13, line 25. Is “30-44” the age of workers or their number of years of acetone exposure? Page 14, lines 39 sqq. Apparently, at a chronic exposure to 1,000 ppm, no excess mortality was observed. This corroborates the conclusion that acetone is nontoxic. See also page 19 where oral LD50s are given in g/kg body weight. Page 15, lines 40-41. It is stated that no reports of acetone-induced lethality were located, but Litovitz et al. (1999, 2001) recorded two such cases (See page 3, lines 6-11). It should be pointed out that each victim was also exposed to a variety of other chemicals present in the commercial products to which they were exposed. Page 16, lines 23-25. Were the workers described by Smith and Mayers (1944) exposed to acetone and butanone (as stated here) or methyl ethyl ketone (MEK) as described in lines 10-16 on page 4 of the current document? MEK is the primary metabolite of 2-butanone. The parent compound and metabolite are more lipophilic than acetone and are thus more-potent CNS depressants. Page 16, lines 36-38. It would be worthwhile to point out that, as expected, LC50s are higher for shorter exposures. Page 17, lines 9-11. The highest acetone exposure concentration (50,600 ppm) was lethal to some, but not all rats. Thus, the calculated 3-h LC50 of 55,700 ppm is reliable. Page 19, line 23. Tanii et al. (1986) is not included in the References. Page 20, line 1. Was this oral exposure? Page 23, lines 6 and 22. Frantik’s initials are given in the References as E.M. and E.L. for the 1994 and 1996 publications, respectively. Which is correct? Page 23, lines 32-35. It is not necessary to include an account of the study by Garcia et al. (1978). The study design was flawed, and the findings were variable and of doubtful value.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Page 24, lines 29-30: The meaning of the latter part of this sentence is unclear. Did the depression in respiratory rate diminish/cease within a few minutes of cessation of acetone exposure? Page 26, lines 14-15: How do fetal “variations” differ from fetal “malformations”? Page 28, line 39: The carcinogenicity study of isopropanol should be included here. Page 29, lines 22-23: Respiratory uptake of acetone is primarily dependent upon three factors: (1) respiratory rate; (2) cardiac output; and (3) blood:air partition coefficient. Acetone is a relatively water-soluble volatile organic chemical (VOC). It is therefore quite soluble in blood and is rapidly absorbed into the pulmonary (blood) circulation and distributed throughout the total body water. The large volume of distribution contributes to acetone’s relatively slow clearance. Page 30, lines 5-7. Blood:air partition coefficient (PC) is an indirect index of the water solubility of a VOC, as blood (especially plasma) is largely aqueous. It is best to avoid equating the terms blood:air and tissue:blood PC here in the text. Most tissues have a high water content, but their lipid content varies significantly. Acetone would, for example, have a relatively low tissue:blood PC for bone marrow, skin, adipose tissue, pancreas, etc. Dills et al. (1994) is not included in the References. Page 30, lines 22-26. The authors should differentiate here between percentage uptake/retention and total systemic uptake of inhaled acetone. The document’s authors’ statements about the relationship between pulmonary ventilation rate and retention/uptake appear contradictory. Page 30, lines 39-43. The low lipophilicity of acetone (relative to many other VOCs) contributes to its relatively slow uptake from blood into fat and other lipid-rich tissues, which in turn delays its pulmonary uptake, because of a high acetone concentration in venous blood returning to the pulmonary circulation. The influence of solubility on the rate of diffusion of acetone across alveolar/endothelial membranes should be minimal because acetone has a balance of lipid and water solubility, is uncharged, and has a low molecular weight. Page 31, lines 3-8. It is right to assume that the 10 and 22 mg/kg values represent total absorbed dose, not venous blood concentration? Page 32 line 7. Acetone monooxygenase is probably the same as CYP2E1 and is just another name for it. Page 34, lines 2, 3, 13-14. Is the metabolic rate 2 mg/kg/h? Page 34, lines 4-6. The meaning of the concluding sentence of the paragraph is not clear. Metabolic saturation is not an “all or none” phenomenon, but a progressively pronounced, dose-dependent process. The findings of Haggard et al. (1944) clearly show lower metabolic efficiency at higher blood acetone concentrations. Page 36, Table 5. This table is confusing and should be replaced by a graphical representation of the data. Page 37, lines 4-5. It should be pointed out here that fasting rats metabolize acetone more rapidly than fed rats because of CYP2E1 induction by fasting. Bruckner et al. (2002), for example, demonstrated that overnight fasting of rats causes lipolysis, which in turn results in increased formation of acetone and other ketone bodies. Acetone markedly induces hepatic CYP2E1 activity by stabilizing the existing isozyme, rather than by enhancing the synthesis of new enzymes.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels CYP2E1, as previously described in the current document, is largely responsible for acetone metabolism. The complete reference to the aforementioned paper is as follows: Bruckner, J.V., R. Ramanathan, K.M. Lee, and S. Muralidhara. 2002. Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity. J. Pharmacol. Exp. Therap. 300:273-281. Page 37, line 23. Acetone should not be characterized as moderately toxic. Extremely high concentrations of this endogenous compound are required to produce central nervous system (CNS) effects. Page 37, lines 23-28. As described above, acetone induces CYP2E1, which is one of the P450s primarily responsible for metabolic activation of short-chain aliphatic halocarbons, including carbon tetrachloride, as shown by Bruckner et al. (2002). Items (ii) and (iii) are not applicable here. Page 38, lines 2-5. Only some ketones is known to cause peripheral neuropathy at chronic exposure; this has no relevance for (acute) acetone exposure. Page 38, lines 26-28. It is logical that neonatal rats would be more susceptible to the CNS depressant effects of the parent compound. Newborn rats’ hepatic CYP2E1 metabolic capacity is much lower than that of human newborns. Page 43, line 24. Were the papers of Geller et al. published in 1978 (as stated here in the text) or in 1979 (as stated in the References)? Page 43, lines 29-35. The AEGL-1 is based on too low a NOAEL. An AEGL-1 is defined as “The airborne concentration above which … individuals could experience notable discomfort, irritation…” Studies (for example, Dick et al. 1988, 1989; Ernstgard et al. 1999) clearly showed that 250 ppm was a NOAEL for mucus membrane irritation in 10 subjects. Inhalation of 300 ppm is said to be slightly irritating by Nelson et al. (1943), although their study results may not be reliable. 500 ppm (for 6 h) produces subjective complaints of mucus membrane irritation by most subjects (Matsushita et al. 1969b; Nelson et al. 1943). A 4- or 8-h 1,000-ppm acetone exposure definitely produces subjective complaints of mucosal irritation, although adaptation occurs (Seebler et al. 1992a, b). Minimal CNS effects require higher exposure concentrations. Most 8-h occupational-exposure limits are 500 or 750 ppm (see page 51). Therefore, 500 ppm would be an appropriate AEGL-1 for each exposure duration (= 3× level of distinct odor awareness (LOA), although 300 ppm could be adopted if a more-conservative threshold were desired. A 500-ppm exposure would be in agreement with the “slight irritation” in the Matsushita paper. Pages 44-49. There needs to be a clear explanation for why an interspecies UF of 1 was chosen for the derivation of AEGL-2 and -3. The current explanation is poorly worded and sounds too much like “the values were too high, and so we lowered the interspecies UF factor.” There needs to be a more scientific basis for reducing the UF. Page 45, lines 21-24. It should be noted that the PBPK model of Clewell et al. (2001) was validated for an extremely wide range (2,110-126,600 ppm) of inhaled acetone vapor concentrations in rats. Metabolic rate constants were determined for a wide range of inhaled acetone concentrations from 5,000 to 45,000 ppm. The model was validated for humans inhaling 100 and 500 ppm. Humans cannot be ethically subjected to high concentrations of acetone or other chemicals to obtain toxicokinetic data for PBPK model validation. Human metabolic rate constants for high acetone concentrations can be determined by in vitro experiments. Use of this PBPK model for time-scaling for humans would be preferable to the rather arbitrary ten Berge et al. (1986) methodology.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels See Bruckner et al. (2004 J. Toxicol. Environ. Health A 67:621-634) for a comparison of the two approaches with trichloroethylene. The key study is based on oral exposure in rats, which has nothing to do with inhalatory exposure in humans. Moreover, an intraspecies UF of 4.2 gives a false impression of precision. Page 45, line 43. A more scientifically sound reason for using an interspecies factor of 1 would be the greater systemic absorption of inhaled VOCs by rats (than by humans). As noted previously, the three primary factors that govern the respiratory uptake of VOCs are (1) respiratory rate; (2) cardiac output; and (3) blood:air PC. (1) and (2) are significantly higher in rats than humans, resulting in the rat receiving a greater systemic dose of acetone (upon equivalent inhalation exposures of rats and humans) and therefore experiencing more-pronounced CNS depression. An interspecies factor would not be necessary if PBPK modeling were utilized. Page 46, lines 1-7. Numerous clinical studies of a variety of inhaled anesthetics have clearly shown that there is modest (that is, two- to threefold) variability in the sensitivity of human subpopulations (including newborns, children, and the elderly). This principle is included in the SOP manual. This committee has consistently recommended the use of an intraspecies UF of 3 for CNS inhibitory effects of VOCs. This factor should be utilized rather than 4.2, a value derived from a single rodent study. Page 47, lines 3-4. A little more information on the patient described by Ramu et al. (1978) should be provided here in the summary. Page 47, lines 34-40. Selection of 12,600 ppm as the starting point for the derivation of AEGL-3 values results in 4- and 8-h values that human experiments (see lines 5-8) have shown produce only mucous membrane irritation and modest CNS depression. Adoption of the intermediate NOAEL or lethality (19,000 ppm) reported by Bruckner and Peterson (1981a) would result in more-reasonable AEGL-3 values. Page 47, lines 41-42. As described above, rats will receive a greater systemic dose upon equivalent inhalation exposures of rats and humans to acetone. Page 48, lines 1-2. There are a limited number of data points in Figure 2 from which to draw a conclusion about interspecies differences in blood acetone concentrations. Nevertheless, two things are clear: (1) Exercise, which produces increases in respiratory rate and cardiac output, substantially increases internal exposure to acetone (that is, blood concentrations)—see comments above about rats’ higher respiratory rate and cardiac output. (2) At the 2,000-ppm exposure concentration, the resting rats have a higher blood acetone concentration than the exercising humans. Page 48, lines 9-15. Again, it is preferable to use a human anesthesiology-based interspecies UF of 3 for CNS depression caused by VOCs. Page 51, Table 12. (1) Remove TEEL 0, 1, 2, and 3 from the table because these concentrations are not documented and should not be used. The 1-h AEGL-2 (3,200 ppm) was based on animal data. The emergency exposure limits (EEL) 8,500 ppm) was based on neurotoxicity studies in humans. Why did the NAC use animal data instead of human data?

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels COMMENTS ON ACETONE CYANOHYDRIN At its previous meeting, the committee reviewed the AEGL document on acetone cyanohydrin. The document was presented by Jens-Uwe Voss of Germany. General Comments The major comments of the committee were addressed. The discussion of the mechanism of action for acetone cyanohydrin was revised. The AEGL-1 value is now based on hydrogen cyanide. All editorial comments were also appropriately addressed. A revised document can be finalized if the committee’s recommended revisions are made appropriately. Revisions Recommended The sentence footnoted on Tables 5, 6, 7, and 8, “Therefore always a mixed cyanide and acetone cyanohydrin exposure will result from acetone cyanohydrine release” should be deleted because it may not be a mixed exposure if all the material is converted to cyanide. Also, this sentence is not necessary; the explanation is adequate without it. The phrase “be measured” should be deleted from the footnote sentence, and it should read “Therefore, both acetone cyanohydrin and hydrogen cyanide concentrations should be considered.” Page 21. The figure is missing the AEGL-1 and -3 labels, and the AEGL-2 designation is misplaced. COMMENTS ON CARBON DISULFIDE At its previous meeting, the committee reviewed the revised AEGL document on carbon disulfide. The document was presented by Jens-Uwe Voss of Germany. A revised document can be finalized if the committee’s recommended revisions are made appropriately. Summary The proposed AEGL values appear appropriate. Time scaling for derivation of the AEGL values appears appropriate. The use of UFs appears appropriate. The document is generally well written. Many reports are reviewed, but the import of the data presented might be clearer if more-concise summaries of the individual reports were used along with summary data tables (for example, Table 4 on page 18). The discussion of developmental effects is quite good but should be condensed (Figure 1 is very helpful in this regard). General Comments This is, in general, a well-written document. It includes much valuable data, including interesting, hard-to-find literature. An adverse effect of this is that the technical support document (TSD) is very long—too long in places. It can be improved greatly by deleting a number of details and repetitions

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels (some phrases appear as many as three times). It could be pruned down to approximately 50% the present size without losing relevant information, which would result in improved readability. Many reports are reviewed, but the import of the data presented might be clearer if more concise summaries of the individual reports were used along with summary data tables (for example, Table 4 on page 18). The discussion of developmental effects is quite good but should be condensed (Figure 1 is very helpful in this regard). There are many spelling and grammatical errors in the report, which need to be corrected. There is inconsistent use of units and a mix-up of generic and trade names. These should be harmonized. The metabolism of ethanol is not correctly described. Although the SOP (pages 124-125) requires concentration to be expressed in the units used in the original text, an application of this would lead to confusion. In this TSD, the blood alcohol concentration is expressed as “0.75 %o (permil).” The Freundt et al. (1976b) paper uses the European convention for the units of blood alcohol concentration (BAC), which is, by the way, not followed in several European countries (g/L is preferred instead). The units in the United States would be expressed as %, mg/dL, or gm/100 mL. Given the target audience for the AEGLs, particularly the Executive Summary, it may be appropriate to insert an alternative unit in parentheses, for example, “level of 0.75 g/L (75 mg/dL).” Similar reasoning applies to other differences in conventions (for example, the use of comma separators in large numbers [see page 1, line 18, where the Anglo-Saxon convention would write the number as 900,000 tons]). In these cases, the comma separator should be used to separate at thousands (that is, at every 103 increment). The proposed AEGL-2 and -3 values appear appropriate. Time scaling for derivation of the AEGL values appears appropriate. The use of UFs for AEGL-2 and -3 appears appropriate. For AEGL-1, see comment at page 52. Specific Comments Page v, lines 8-9. Change to read “A wide range … was reported” (changed word underlined). Page v, line 17. Change to read “toxicokinetic” (changed letter underlined). Make the same change elsewhere in the document for this spelling. Page v, lines 18-19. Change to read “It must also must be taken.” Page v, line 26. Change to read “… may accumulate with repeated …” (changed word underlined). Page v, line 33. Change to read “… on the CNS already led to an ….” Page vi, line 2. Change to read “… lacrimation …” (changed letter underlined). Make the same change elsewhere in the document for this spelling. Page vi, line 4. Change to read “… difficulty in performing tasks …” (changed words underlined). Page vi, line 12. Change to read “… person served as their own …” (changed words underlined). As an alternative to “their,” “his or her” can be used. Page vi, line 23. Change to read “… allele …” (added letter underlined). Make the same change elsewhere in the document for this spelling. Page vi, line 34. Change to read “… derivation of the AEGL-2 …” (added words underlined).

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Page vii, line 31. Change to read “Newark, DE” (changed letter underlined). Page viii, line 22. Change to read “… lipid composition by …” (added letter underlined). Page viii, lines 11, 18, and 27; page ix, line 7. These four references place the first initial of the last-cited author in front of the author’s last name; all the other references place the initial after the last name (compare, for example, page viii, lines 11 and 14). For consistency, use the same format as in the other references cited. Review the references listed on pages 63-73 for similar consistency. Page 1, line 5. Not everyone is familiar with decaying radish and will not recognize its smell. The smell of overcooked cauliflower will be better recognized. Change throughout the document and page 12, line 5. Page 2, line 4. “Toxicity” rather than “lethality.” The human toxicity data should be subdivided in 2.1 acute and 2.2 chronic (mostly occupational) toxicity. A division between lethal and nonlethal is unusual and incorrect. Neurotoxicity (both central and peripheral) is the most well-known effect of CS2 and should be emphasized here. A concise review is Verberk in Vinken & Bruyn’s Handbook of Clinical Neurology, Vol. 64 (1994) pages 23-29, but any recent source of medical toxicology will do (like Dart 2004, pages 1182-1184, which gives a good scheme of CS2 metabolism as well). Page 3. Sections 2.1.1 and 2.2.1 have the same title. Clarify. Also, what is the rationale for including descriptions of noninhalation studies in the TSD? Page 4, line 7. Is the concentration range 400-470,000 ppm, or 400,000-470,000 ppm? Page 4, lines 10-11. The sentence currently reads “… measurement of cerebral flow showed reduced cortical flow in the right hemisphere.” The presumption is that this refers to cerebral blood flow. If this is the case, change the sentence to state that. Page 4, line 13. Remove “during consciousness.” Page 4, line 21. This sentence is unclear. Clarify. Page 5, line 1. What are bloody bowel movements? State more precisely. Pages 6-9. Although the Lehman (1894) paper is very interesting reading from a medico-historical point of view, the dedication of so many pages (with repetitions further in the TSD) is not necessary. One should realize that it is an open study with only two (nonblind) volunteers and no control group, with all the disadvantages linked to this experimental design. Moreover, the air concentrations of CS2 were not monitored. The study is (justly) not used for the derivation of AEGL values and should therefore be condensed into no more than one or two paragraphs. Page 5, line 7 and 14. “Psychic” should be replaced by either “neurologic” or “psychiatric.” Page 9, line 31. “Pharmako” and “toxiko” should read “pharmaco” and “toxico” throughout the document. Page 9, line 32. Define “W.” Page 10, line 27 sqq. Is there anything known about differences in the elimination kinetics of alcohol between exposed and nonexposed workers? This is essential information because it could

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels discriminate between increased CNS sensitivity and decreased elimination as the mechanism of CS2. Liver enzyme nomenclature: GOT should be referred to as ASAT and GPT is called ALAT nowadays. Change throughout the document and on page 15, line 23). Page 11, line 15 sqq. Apparently, CS2 inhibits the second step of the ADH oxidative pathway. This should be mentioned because it explains the increased intolerance to alcohol in CS2- exposed workers. Give a scheme of both ethanol oxidative pathways (ADH and CYP2E1) to clarify this. Page 15, line 19. Replace “alcoholized subjects” with “subjects given alcohol.” Page 15, line 30, to page 16, line 8. Reduce quotation of Lehman and expend neurotoxicity data. Page 19, line 36. Change “exsiccator” to “desiccator.” Page 22, Table 5. Some entries describe effects at different exposures or at different times during an exposure (see, for example, Frantik 1970 and McKenna and DiStafano 1977b). In instances like these, it would be much clearer to align the statements in the Effect column with the relevant entry in the Concentration or Exposure column(s). Page 26, line 24. Change “trail” to “trial.” Page 28, line 21. Disulfiram is the generic name of Antabuse; the generic name should be used throughout, with the trade name in brackets when disulfiram is mentioned for the first time. Page 48, line 1; page 49, line 17. Dithiocarbamates (change underlined). “The alcohol inducible isoenzyme”: clarify. What is meant is that the CYP450 isoenzyme that can be induced by ethanol (never use alcohol where ethanol is meant). Here, a short survey of the two known pathways of ethanol metabolism should be given (the noninducible ADH-/AlDH-pathway and the inducible CYP2E1-pathway). Page 48, line 22. P-450 dependent pathway is confusing; the P-450 isoenzyme in dependent on substrates (it is a mixed-function oxidase) and coenzymes, but not on itself. Page 51, lines 3-20. These data are not relevant for the present TSD and should be deleted or condensed. It suffices when the disulfiram syndrome is mentioned only once in the paragraph where ethanol metabolism will be described. Page 52, line 31; page 53, line 12. There is no consensus in the committee about the use of the key studies by Freundt et al. for derivation of the AEGL-1, because it is remarkable that this is based on data obtained in a population under the influence of alcohol. 0.7 g/L (70 mg/dL) cannot be described as “low to at most moderate” concentrations, because this concentration exceeds the legal limit for driving in most states and countries; several countries consider lowering this limit to 0.2 g/L (20 mg/dL) as it is in several European countries. Although the majority of the committee agrees with the use of this “sensitive subpopulation,” more arguments should be given to defend this decision. The UF of 10 is based on the fact that there is a population subgroup with atypical aldehyde dehydrogenase whose members are more sensitive to the disulfiram effect of CS2 than “ordinary” ethanol consumers. In fact, sensitivity is now counted twice: once for alcohol consumption per se

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Page 28, lines 3-6. This new sentence is poorly written. The committee’s comment was in regard to the appropriateness of using chronic studies to derive AEGLs, not to the appropriateness of using chronic exposures to derive cancer-risk estimates. Page 37, line 3. Appendix 3 should be Appendix B. Appendix B. Correct page numbers (listed as C-1, C-2, etc.). Appendix C. Three risk values should be calculated here, not just one. COMMENTS ON 1,2-DICHLOROETHYLENE At its previous meeting, the committee reviewed the AEGL document on 1,2-Dichloroethylene. The document was presented by Cheryl Bast, of Oak Ridge National Laboratory. The revised document can be finalized if the recommended revisions are made appropriately. General Comment Use of the ten Berge et al. (1986) approach and adoption of a value of 1 for the exponent n (as a default) frequently results in underestimation of 4- and 8-h AEGLs (that is, overestimation of risks) for VOCs when extrapolating from shorter exposure periods. See Bruckner et al. (2004 J. Toxicol. Environ. Health A 67:621-634) for an illustration of this phenomenon with trichloroethylene (TCE). For most well-metabolized VOCs, such as TCE, blood concentrations rapidly attain near steady-state during inhalation exposures. As a consequence, adverse effects typically only increase modestly with time for the longer exposure periods (once near steady-state is reached). Cis- and trans-dichloroethylene (DCE) are unique in that they are suicide inhibitors (that is, the epoxide metabolite of each isomer interacts with and inhibits cytochrome P4502E1 [the P450 isozyme that mediates biotransformation of DCE to the epoxide]) (Lilly et al. 1998). Trans-DCE is a more potent suicide inhibitor than cis-DCE. As a result, blood and brain concentrations of DCE should continue to increase during prolonged exposures, rather than reaching near steady-state. The parent compounds are responsible for producing CNS depression, the toxic effect of interest. Thus, the AEGLs should progressively decrease, as is the case with AEGL-2s and -3s in the current document. COMMENTS ON SULFUR DIOXIDE At its previous meeting, the committee reviewed the AEGL document on sulfur dioxide (SO2). The revised document was presented by Cheryl Bast, of Oak Ridge National Laboratory. Overall Comment The NRC committee on AEGLs concluded that this is a well-written document and had only relatively minor suggestions for improvement. A revised document can be finalized if the committee’s recommended revisions are made appropriately.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Specific Comments The committee concurs with comments and responses below unless otherwise noted by additional comments. Page ii, line 34. Have any casualties/anaphylactic reactions been reported in asthmatics at low exposure? Response: No causalities/anaphylactic responses were reported in the referenced literature. Page 1, line 25. Add “co-exposure” before respirable particles at beginning of sentence. Response: Revised as suggested. Page 3, line 32. Because bronchiolar obstruction was still present 4 years (y) after the accident, the airway Response: Text revised (the word “reversible” has been deleted). Page 4, line 1. What is “destructing bronchitis”? Response: Text revised (the word “destructing” has been deleted). Page 5, line 6. In the London case, 1.3 ppm was the peak SO2 concentration at which people died. This could lead to the conclusion that 1.3 ppm is an AEGL-3, whereas this document proposes 16-42 ppm for AEGL-3 and 0.75 ppm for AEGL-2. This discrepancy should be explained. Response: A statement has been added referring the reader to Section 4.4, showing that particulate matter and other pollutants enhance the effects of SO2. The concentration of particulate matter in the London episode was too great to measure. Page 5, lines 8-9. Change sentence to “The excess deaths were attributed to bronchitis or to other impairments of the respiratory tract.” Response: Text revised as suggested. Page 7, lines 8-9. The increase in sensitivity to SO2 odor at the end of exposure is remarkable and opposite to, for example, dioxane and H2S, where the sensitivity of the olfactory system decreases after a certain time. Is this logical? Response: This is not logical. The reference was consulted, and the text has been modified, as follows, to reflect what is actually reported by the study authors. “Unpleasant odor was reported more frequently (p < 0.05) at the end of the exposure to SO2 at 4 ppm than before exposure at the beginning of this exposure period.”

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Page 13, lines 40-41. If changes were shown to be statistically significant, how can it be difficult to ascertain the exact magnitude of the effect? Response: The data are reported graphically, and it is difficult to read the exact magnitude (percent change) from the graphs. A statement to this effect has been added to the text. Page19, line 6. Insert “ambient” before “air pollution.” Response: Text revised as suggested Section 3.1. Do we really need all these animal data when there are so many human data available? Response: These data are included for completeness and are useful because animal data are used for derivation of AEGL-3 values. Section 4.4. This section does not seem to have a place in the document, because the data described is not used for derivation of AEGLs. Response: Section 4.4 has been retained because this section explains that concurrent exposures to other pollutants or particulate matter enhance the effects of SO2. It is important to retain this information to help explain the apparent discrepancy of the peak SO2 concentration noted in the London case and AEGL-2 and -3 values. The committee agrees with the response and would further note that this information is of value to the end users of the AEGLs because it alerts them to additional factors to consider as they apply the SO2 AEGLs. Section 4.5. Delete from text as explained below. Response: Section 4.5 has been deleted as suggested. Derivation of AEGL-1 It must be realised that effective concentrations in asthmatics are highly dependent upon the severity of the disease in the subjects being tested, the extent of medication use, etc. Thus, one study may show an effect at a concentration showing no effect in another study merely because of differences in subjects. Asthmatics are a highly variable group in terms of response to exposure to irritants, much more so than normal individuals exposed to the same atmospheres. Furthermore, most controlled clinical studies generally use subjects who are not the most severe. Based upon all this, the committee concludes that the value for AEGL-1 of 0.25 ppm is too high and should be reduced to account for susceptibility differences in the most sensitive population, namely asthmatics. The committee suggests a value of 0.2 ppm at the highest. The committee agrees that the time should be held constant for all the time points. This comment also applies to page 19, line 16. The committee agrees with the response and would further note that this information is of value to the end users of the AEGLs because it alerts them to additional factors to consider as they apply the SO2 AEGLs.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Response: The AEGL-1 values have been revised to 0.20 ppm for all time points. The justification in the appropriate text and tables in the technical support document (TSD) have been revised as follows: “AEGL-1 values were based on the weight of evidence from human asthmatic data suggesting that 0.25 0.20 ppm may be a threshold NOEL for bronchoconstriction in exercising asthmatics. No treatment-related effects were noted in asthmatics exposed to 0.2 ppm for 5 min (Linn et al. 1983b), 0.25 ppm for 10-40 min (Schacter et al. 1984), 0.25 ppm for 75 min (Roger et al. 1985), 0.5 ppm for 10-40 min (Schacter et al. 1984), or 0.5 ppm for 30 min (Jorres and Magnussen 1990). However, an increase in airway resistance (SRaw) of 134-139% was observed in exercising asthmatics exposed to 0.25 ppm for 5 min (Bethel et al. 1985); the increase in SRaw in this study, but not in the other studies, may be attributed to the lower relative humidity (36%) in the Bethel et al. (1985) study compared to the other studies (70-85%). No uncertainty factors were applied because the weight-of-evidence approach utilized studies from a sensitive human population, exercising asthmatics. At relatively low concentrations, the role of exposure duration to the magnitude of SO2-induced bronchoconstriction in asthmatics appears to decrease with extended exposure. For example, asthmatics exposed to SO2 at 0.75 ppm for 3 h exhibited increases in SRaw of 322% 10 min into exposure, 233% 20 min into the exposure, 26% 1 h into exposure, 5% 2 h into exposure, and a decrease of 12% at the end of the 3-h exposure period. These data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10 min and increases minimally or resolves beyond 10 min of exposure. Therefore, AEGL-1 values for SO2 were held constant across all time points. Exposure to concentrations at the level of derived AEGL-1 values is expected to have no effect in healthy individuals but are consistent with the definition of AEGL-1 for asthmatic individuals.” Furthermore, the committee recommends that the Comparative Indices table (Table 6) not be included in the document. This table could be misleading. For example, while an increase in SRaw of 200% may not be of concern in normals, it would surely be of concern in someone with pre-existing respiratory disease. Thus, the comment on page 28, line 2, that a change of 134-139% is mild to moderate should be deleted from the text. Response: Table 6 and Section 4.5 have been deleted as suggested. Derivation of AEGL-2 The argument above for AEGL-1 applies here as well. Changes in airway resistance of almost 600% are not necessarily of little consequence to an asthmatic. Response: The AEGL-2 values have been revised to 0.75 ppm for all time points. The justification in the appropriate text and tables in the TSD have been revised as follows: “AEGL-2 values were based on the weight of evidence from human asthmatic data suggesting that 1.0 0.75 ppm induces moderate, but reversible, respiratory response in exercising asthmatics for exposure durations of 10 min to 3 h 5- to 75-minutes. The same response was observed at 0.75 ppm for 10-minutes to 3-hours. Asthmatics developed increased airway resistance of 102% to 580% after exposure to 1.0 ppm SO2 (Roger et al. 1985; Balmes et al. 1987; Kehrl et al.1987 ). No uncertainty factors were applied, because the weight-of-evidence approach utilized studies from a sensitive human population, exercising asthmatics. At relatively low concentrations, the role of exposure duration to the magnitude of SO2-induced bronchoconstriction in asthmatics appears to decrease with extended exposure. For example, asthmatics exposed to SO2 at 0.75 ppm for 3 h exhibited increases in SRaw of 322% 10 min into exposure, 233% 20 min into the exposure, 26% 1

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels h into exposure, 5% 2 h into exposure, and a decrease of 12% at the end of the 3-h exposure period. These data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10 min and increases minimally or resolves beyond 10 min of exposure. Therefore, AEGL-2 values for SO2 were held constant across all time points. time for the 10-min, 30-min, and 1-hr values. Because the maximum duration for a 1.0 ppm exposure of asthmatics was 75-minutes, and data were available at 0.75 ppm for up to 3 hours, the 4- and 8-hour AEGL-2 values were held constant at 0.75 ppm. Exposure to concentrations at the level of derived AEGL-2 values is expected to have no effect in healthy individuals but are consistent with the definition of AEGL-2 for asthmatic individuals.” With the change in the AEGL-2 value from 1.0 ppm to 0.75 ppm, the references cited also have to be changed. Is the phrasing in the response above “0.75 ppm induces moderate, but reversible, respiratory response in exercising asthmatics for exposure durations of 10 min to 3 h … consistent with the definition of AEGL-2 for asthmatic individuals” consistent with the phrasing on page 19, lines 15-18? Table 2: The AEGL-3 is almost twice the level of the emergency response planning guideline (ERPG) 3. Thus, the latter seems to be more conservative. Some comment on this should be made. Similarly, the IDLH is more than twice the ERPG-3 value. In this case, the latter seems to be much more conservative. Page 30. The AEGL-3 is extremely high in comparison to AEGL-2. Are there any examples of other substances the committee reviewed where such a high AEGL-3-to-AEGL-2 ratio exists? At first sight, the ERPG-3 seems to be more reasonable. Response: The approximate 30-fold difference between AEGL-2 and AEGL-3 values (at 1 h) is a function of the availability of an extremely sensitive AEGL-2 end point (asthmatic human data) and utilization of animal data for AEGL-3 values. (AEGL-3 values were derived using a lower 95% confidence limit, per the SOP manual.) Also, the data-derived time scaling exponent n is 4, suggesting a flat concentration-response curve. In cases where the concentration-response curve is steep, the AEGL-2 and AEGL-3 values are often very close together. Therefore, it follows that in cases where the curve is flat, values may be further apart. The ratio of 1-h AEGL-3-to-AEGL-2 values for sulfur mustard (published in Vol. 3) is 16. This large difference is also a function of the use of a sensitive human end point for AEGL-2 and of mouse lethality data for AEGL-3 values. The ratio of 1-h AEGL-3-to-AEGL-2 values for chloroform is approximately 80. This large difference is also a function of the use of an exceptionally sensitive AEGL-2 end point, that of developmental toxicity. Several ERPG values also have relatively large ERPG-3-to-ERPG-2 ratios (5/100 chemicals have ratios between 17-100). This is also a function of an exceptionally sensitive ERPG-2 end point. For example, the ratio of chloroform ERPG-3-to-ERPG-2 values is 100, a result of use of developmental toxicity data for ERPG-2 derivation. Conclusions of the Committee The AEGL-1 should be 0.2 ppm across the time scale. The AEGL-2 should be 0.75 ppm throughout.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels The AEGL-3 remains as proposed provided a good justification for these values can be given. Given the discussion during the committee meeting on the final day of the meeting and the rationale developed as a result, the committee is in concurrence with the values for the AEGLs that emerged. Editorial Comments Page 1, line 22. Bronchiolitis is misspelled. Page 1, line 25. Add “of the respiratory cycle” after expiratory phase. Page 3, lines 28-29. The terms do not have to be capitalized, only the initials. Page 4, line 2. What is emphysema of the mediastinum or skin? Page 5, lines 31-32. Are these concentrations correct? Page 7, lines 9-10. This does not seem to make sense. Page 7, line 19. What specific activity of the macrophage was altered? Page 8, line 41. Is the 20% an increase? Page 13, line 9. Exercised is misspelled. Page 14, lines 23-24. This sentence is unclear. Page 14, line 34. Bronchodilator is misspelled. Page 15, lines 3 and 21. Sraw should be SRaw. Page 15, line 15. Effects peak within 10 min of what? AEGL-3. There is a large differential between AEGLs-2 and -3 because of the use of human data for one and animal data for the other. However, it does appear that the animals are not as sensitive as humans to pulmonary functional effects from exposure. Thus, if this is extrapolated to lethal concentrations, then a higher concentration would result in death in animals compared to humans, and the AEGL-3 may have been set too high. COMMENTS ON HYDRAZINE At its previous meeting, the committee reviewed the AEGL document on hydrazine. The revised document was presented by Robert Young, of Oak Ridge National Laboratories. Overall, the committee agrees the AEGL values are appropriate and supported by the data, but the explanations for UFs and MFs are confusing and inconsistent. UFs are used for inter- and intraspecies variability. MFs are for data-quality issues, including suspect concentrations such as those associated

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels with hydrazine at low concentrations. A revised document can be finalized if the committee’s recommended revisions are made appropriately. Major Issues Page 5, line 45 to end of paragraph. Note the paragraph below. The 0.1 ppm value was correctly applied to all durations, not just 1 h, 30 min, and 10 min, because it is a direct-acting irritant. If a total UF of 10 was applied to 0.4, wouldn’t that yield a value of 0.04? Did the NAC apply a factor of 3—not 3 × 3? Also, does the “variability in acetylation phenotypes among humans and the subsequent effect on at least one aspect of hydrazine metabolism” impact direct-acting irritation? If not, then this seems to be irrelevant. Because hydrazine is extremely reactive and the sensory-irritation effects are considered to be concentration dependent rather than time dependent, the 0.1 ppm AEGL-1 value derived for the 8-h duration was applied to the 1-h, 30-min, and 10-min durations. A total UF of 10 was applied to the 0.4 ppm concentration to derive the AEGL-1 values. A UF of 3 was applied for interspecies variability because the surface-contact irritation by the highly reactive hydrazine is not likely to vary greatly among species and because a nonhuman primate was the test species. A UF of 3 was applied for intraspecies variability because the contact irritation from the highly reactive hydrazine is not expected to vary greatly among individuals, including susceptible individuals. Additionally, variability in acetylation phenotypes among humans and the subsequent effect on at least one aspect of hydrazine metabolism has been shown to vary approximately twofold. Page 6, lines13-15 and lines 27-30. Here is the response to this same issue. Variability in the data is not a reason for a UF. It should be an MF. Comment: The presentation of the UF remains a problem. For irritants and direct-acting chemicals (and the case is made for hydrazine-induced irritation as the primary basis for AEGL-1 and - 2), inter- and intraspecies UF adjustments generally need a factor of 3 for each, for a total of 10. This was done for AEGL-1. However, for AEGL-2, “an uncertainty factor of 10 for interspecies variability was applied to account for the high degree of variability in the data due to the extreme reactivity of hydrazine that compromised exposure concentration measurements.” What does this have to do with interspecies variability, especially when hydrazine appears to be a direct-acting material? Although an interspecies UF of 10 may be reasonable, the rationale of uncertainty of the data is not a UF issue. Uncertainty in the data should be addressed with an MF. The response provided to the comment in Section 6.3 that the nasopharyngeal area of rats and humans are different should be discussed here. This concept is very helpful in distinguishing hydrazine from a simple irritant. Response: As noted, an interspecies UF of 3 is more appropriate and is typically used for direct-contact irritants such as hydrazine. Although the uncertainties regarding species variability may be indirectly the result of uncertainties inherent in exposure measurements of early studies, such deficiencies are more appropriately data-quality issues. Therefore, the AEGL-2 and -3 values are now derived using an interspecies UF of 3 and an MF of 3 for data inadequacies resulting from difficulties in accurately measuring exposure concentrations in older studies. Although newer studies (Health Research Council [HRC] and Latendresse et al.’s work) apparently resolved this issue (both studies used rats), older data in other species are still compromised by possibly inaccurate exposure data. Additionally, an MF of 2 has been retained for AEGL-2 development because of the paucity of data on AEGL-2-specific critical effects. Page 29, lines 17-21. Same issue.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels Editorial Page 5, line 3. Add “of” between “pressure” and “14.4.” Page 5, lines 16-20. Delete this paragraph because it addresses methylated hydrazines, which have their own technical support documents, and the information is irrelevant. Page 5, lines 24-27. The following is stating hydrazine is a direct-acting irritant because it is highly reactive. Why not simply state this? “The role of metabolism and absorption/excretion kinetics is uncertain regarding immediate port-of-entry toxic effects from acute inhalation exposures. The highly reactive nature of hydrazine per se is a plausible determinant of acute port-of-entry toxic effects.” Page 5, lines 32-35. Recommend restating the following paragraph as follows: “Because there were no data to empirically derive the chemical-specific exponent, the default values of n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points were used in the Cn × t = k equation in accordance with the SOP manual.” This is better than the following: “To obtain AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.” COMMENTS ON ETHYLENIMINE At its previous meeting, the committee reviewed the AEGL document on ethylenimine. The revised document was presented by Kowetha Davidson, of Oak Ridge National Laboratory. The document can be finalized if the committee’s recommended revisions are made appropriately. Scientific Comments Page 4, item 25. The logic for why the 4-h value is taken as the point of departure for the derivation of the AEGL-2 (NOAEL or respiratory difficulties in the guinea pig) although after 8 h no respiratory difficulties were observed has to be explained. For example, “The logical point of departure for derivation of the AEGL-2 would be the NOAEL for respiratory difficulties after exposure of guinea pigs for 8 h. However, this would lead to values irresponsibly close to life-threatening AEGL-3 concentrations, at some time points even surpassing the AEGL-3 values. It was therefore decided to take the next-shorter exposure duration of 4 h because this was also a clear NOEL for respiratory difficulties in the guinea pig”). Page 3, Section 2.2.1. Odor Threshold – This section defines the odor threshold for ethylenimine as being 2.0 ppm. This value is repeated in the executive summary, and on page 6, line 1. Yet the Level of Distinct Odor Awareness (LOA) is derived based on an odor threshold of 0.6980. However, there is no discussion in the text to explain why the odor threshold used to derive the LOA is not 2.0 ppm as defined in section 2.2.1 or why it is 0.698. There needs to be some discussion here to address this apparent discrepancy. Perhaps the easiest way to do this would be to include 0.698 in a range of reported odor thresholds and to provide a rationale for why this number was selected for the derivation of the LOA.

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels There are several similar statements regarding the potential carcinogenicity of ethylenimine in the Executive Summary, page vi, line 35-36, in the footnote to the Summary table, and in the text on page 22, lines 27-28; page 34, lines 38-39; and page 35, lines 35-36. These statements, generally expressed as “AEGL values do not account for the carcinogenic potential of ethylenimine,” are open-ended and can be interpreted in different ways (and are likely to be). Suggest adding the reason why the AEGLs values (2 and 3) do not take into account the potential carcinogenicity of ethylenimine—for example, “because no adequate data were available for the derivation of quantitative carcinogenicity potencies.” Editorial Comments Page 3, line 26; page 32, lines 12-24. The use of four decimals suggests an accuracy of the odor threshold (OT50) determination that is not realistic (at least drop the last zero?). Page 3, lines 20-27; page 32. The method for how the level of distinct odor awareness was derived from the OT50 is quoted as the guidance provided by van Doorn et al. (2002). However, the list of references gives no indication where the reader can find this article. Page 4, line 6. Place comma after “nausea.” The reasoning for the selection of the intra- and interspecies UFs used to derive the AEGL-3 values is discussed in several places in the text. In every instance, the text simply states that the reasoning for the selection of the UFs is “based on the same rationale described for AEGL-2 derivation.” In the Executive Summary (page vi), this shorthand is acceptable because the discussion of the reasoning for the selection of the UF for the AGEL-2 values is spelled out on the same page (in the prior paragraph). However, in the text (pages 21-22) and in the Appendix (page 35), where the derivation of the AEGL-3 values is described in detail, it is recommended that the entire rationale be repeated so that the reader does not have to go hunting for the reasoning behind the selection of the UFs for AEGL- 2. This shorthand is not appropriate in this instance. COMMENTS ON PROPYLENIMINE At its previous meeting, the committee reviewed the AEGL document on propylenimine. The revised document was presented by Kowetha Davidson, of Oak Ridge National Laboratory. The document can be finalized if the committee’s recommended revisions are made appropriately. Specific Comment Page 4, lines 27-37; response to comments, item 6. Because the NAC believes that values based on AEGL-2 NOAELs were unreasonably low, it used a relative-potency approach compared to ethylenimine with appropriate MFs to develop AEGL-2 values. While seemingly valid, the explanation needs to be more straightforward as provided in response to comments. The explanation in Section 6.3 is more clear and consistent. The confusing point is the sentence describing the calculations from the NOAEL. The committee recommends deleting this. But still unanswered is why was the geometric mean used rather than the arithmetic mean?

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Fourteenth Interim Report of the Committee on Acute Exposure Guideline Levels COMMENTS ON TRICHLOROETHYLENE The committee’s preliminary comments on pharmacokinetic modeling of TCE are attached. The TCE AEGL document was withdrawn from review by the NAC at the meeting. A basic (and brief) discussion about drug (maybe anesthesia) kinetics and how the practice of medicine and drugs is based on understanding the blood or tissue concentrations is needed to show that other established disciplines use pharmacokinetic information to predict effects. Some basic explanation of the physiology of the body—what happens when a chemical is inhaled and how it gets to tissues—is needed. What governs the rate of uptake, distribution, and elimination? Slant discussion so it helps to explain the structure of a PBPK model. State and restate that the intended purpose is to predict the blood or tissues concentrations associated with exposures to chemicals and that the predicted internal exposure 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 and, using Cn × T = k, point out which physiologic processes are accounted for in the PBPK model that were not accounted for in the air-concentration-extrapolation methodology. UFs remain a great concern. What is the NAC guidance on the use of intra- and interspecies 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 would be applied, and what is the basis for this factor?

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