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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A (2011)

Chapter: Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels

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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels

BACKGROUND

In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) asked the National Research Council (NRC) to provide technical guidance for establishing community emergency exposure levels (CEELs) for extremely hazardous substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects.

NAC was established to identify, review, and interpret relevant toxicologic and other scientific data and to develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a broad array of potential applications for federal, state, and local governments and for the private sector. AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or terrorist activities.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-2 and AEGL-3, and AEGL-1 values as appropriate will be developed for each of five exposure periods (10 and 30 min and 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be susceptible. The three AEGLs have been defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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THE CHARGE TO THE COMMITTEE

The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL documents approved by NAC. The committee members were selected for their expertise in toxicology; medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment.

The charge to the committee is to (1) review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review NAC’s research recommendations and—when appropriate—identify additional priorities for research to fill data gaps; and (3) review periodically the recommended standard procedures for developing AEGLs.

This interim report presents the committee’s conclusions and recommendations for improving the NAC’s AEGL documents for 29 chemicals: chloroacetyl chloride, dichloroacetyl chloride, methanesulfonyl chloride, trimethylacetyl chloride, bromoacetone, butane, BZ (3-quinuclidinyl benzilate), chloroacetone, epichlorohydrin, ethyl phosphorodichloridate, ethylene chlorohydrin (2-chloroethanol), isocyanates (cyclohexyl, ethyl, and phenyl isocyanates), mercaptans (ethyl, methyl, phenyl, and tert-octyl mercaptans), methacrylonitrile, methyl bromide, methyl chloride, methyl isothiocyanate, nitrogen mustards (HN-1, HN-2, and HN-3), perchloryl fluoride, piperidine, tetramethoxysilane, and trimethoxysilane.

ACID CHLORIDES

At its meeting held on April 5-7, 2011 the committee review the technical support documents (TSDs) on chloroacetyl and dichloroacetyl chloride (CAC and DCAC, respectively), methanesulfonyl chloride, and trimethylacetyl chloride. Presentations of the CAC and DCAC and trimethylacetyl chloride TSDs were made by Lisa Ingerman of Syracuse Research Corporation. A presentation of methanesulfonyl chloride was made by Julie Klotzbach of Syracuse Research Corporation. Although CAC and DCAC are combined into a single TSD, AEGL-specific comments below are separated.

Chloroacetyl and Dichloroacetyl Chloride

The following is excerpted from the Executive Summary of the TSD:

Because the database for DCAC was very limited, and the available data indicated that DCAC was less toxic than CAC, all AEGL values developed for CAC were adopted for DCAC…. AEGL-1 values were derived from a multiple-exposure study in which rats, mice, and hamsters received 18-20 exposures for 6 hours/day to nominal concentrations of 0.5, 1, 2.5 or 5 ppm CAC (Dow 1982)…. The AEGL-2 values were derived using a study in which rats inhaled 32, 208, 522, or 747 ppm CAC for 1 hour (Dow 1986)…. The AEGL-3 values were also based on the Dow (1986) 1-hour inhalation rat study in which exposure was to 32, 208, 522, or 747 ppm CAC.

A revised document should be submitted to the committee for review.

AEGL-Specific Comments for Chloroacetyl Chloride

AEGL-1

Page 26, lines 26-28: “AEGL-1 values were derived using a single 6-hour exposure to ~1 ppm (0.84 ± 0.51 ppm) because this is the highest concentration that caused conjunctival redness but no other more serious effects after one exposure.” The authors should revisit the point of departure (POD) for the

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-1 values. As noted by the committee as well as the technical presenter at the April meeting, the lowest exposure level associated with conjunctival redness is 0.5 ppm. AEGL-1 values must be recalculated, and corrections made throughout the text to reflect this lower exposure concentration.

Page 26, lines 28-29: “A modifying factor [MF]of 2 was applied to estimate a no-effect level concentration for conjuctivitis.” Please provide justification for selecting an MF of 2 rather than 3 to estimate the no-effect level. Is a MF of 3 more appropriate considering the potential for respiratory irritation in susceptible subgroups at similar concentrations?

Page 26, lines 29-31: “The same AEGL value is adopted for 10 minutes to 8 hours because mild irritant effects do not vary greatly over time.” The authors should revisit the scaling assumption, taking into consideration the biologic basis as well as consistency (see related comment for the AEGL-2 values). Not only are the concentrations corresponding to mild and significant ocular effects very close to one another, but also CAC is a respiratory irritant. Thus, in the general population, a substantial number of people susceptible to respiratory effects (e.g., those having asthma and chronic obstructive pulmonary disease [COPD]) could potentially incur adverse effects at concentrations corresponding to mild ocular effects, considering the small set of workers (assumed healthy) for which eye irritation data are available. It is also useful to acknowledge that effects may be delayed (e.g., see IPCS [1998]: “The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physical effort.”) Also, see similar comments below for AEGL-2 and AEGL-3.

Page 26, lines 31-33: “A total uncertainty factor [UF]of 10 was applied: 3 for interspecies variability and 3 for intraspecies variability, because the NOEL [no-observed-effect level] for eye conjunctivitis due to local contact irritation is not expected to vary greatly among animals or humans.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with the standing operating procedures (SOP) section 2.5.3.4 (pages 88-91). This factor would produce a combined (total) UF of 30 rather than 10. Note that the UF of 3 reflected in the TSD is not necessarily consistent with the interspecies response differences noted in the Executive Summary, Section 5.2 (page 25, line 42–page 26, line 16).

AEGL-2

Page 27, lines 23-25: “The AEGL-2 end point was the NOEL for impaired ability to escape due to lacrimation and eye squinting, which was estimated by applying a modifying factor of 2 to the lowest concentration tested of 32 ppm.” The authors should consider a lower POD for AEGL-2. As noted in the TSD, a CAC exposure of 0.91 in workers was “painful to the eyes and caused lacrimation” (p. 27, lines 6-7), both effects (in relatively healthy adults) suggesting an impaired ability to escape in the general population. Additional justification should be provided for selecting an MF of 2 to estimate the no-effect level, or consideration should be given to selecting a factor of 3. Selection includes considering the potential for respiratory irritation in susceptible subgroups at similar concentrations.

Page 27, lines 28-30: “To obtain protective AEGL-2 values, scaling across time was performed using n = 3 to extrapolate to exposure times [of] <1 hour (exposure duration in the key study) and n = 1 to extrapolate to exposure times [of] >1 hour.” Please note that it is not clear here what value of n is used for the exposure time of 1 h. Please revisit the assumption for scaling across time, and consider the biologic basis as well as the consistency across the AEGL values. No scaling was applied for the AEGL-1 values, yet scaling was applied to derive AEGL-2 values that are also based on ocular irritation. See the more detailed comment above for AEGL-1.

Page 27, lines 31-33: The authors applied an intraspecies UF of 3 “because the AEGL-2 end point (NOEL for eye irritation sufficient to cause lacrimation and squinting) is a direct surface contact effect that is not likely to vary in severity among animals or humans.” CAC is also a respiratory irritant, and it is possible that sensitive individuals may experience respiratory effects at these levels. Section 2.5.3.3.4 of the SOP (p. 88) states that “a default UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants.… Responses of asthmatics to

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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respiratory irritants may range from mild to severe. A UF of less than 10 might be used when scientific evidence shows that a smaller UF will be protective of health.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with the SOP.

AEGL-3

Page 28, lines 35-38: “An intraspecies uncertainty factor of 3 was applied because the threshold for lethality from direct destruction of respiratory tissue is not expected to vary greatly among humans, based on the steep dose-response seen in the animal studies.” The committee recommends that a UF of 10 be applied for intraspecies variability; 10 is consistent with Section 2.5.3.3.4 of the SOP (p. 88). See the similar comment above for AEGL-2.

AEGL-Specific Comments for Dichloroacetyl Chloride

Page 7, lines 10-12: “Because the database for DCAC was very limited, and the available data indicated that DCAC was less toxic than CAC, all AEGL values developed for CAC were adopted for DCAC.” The authors should reconsider the available information to derive separate AEGL values for DCAC. For example, see DuPont (2004, 2006) and EPA (2008a,b, 2010a,b; 2011a,b,c). EPA (2008b) considers dichloroacetic acid (DCA) as an analog for DCAC and stated that “Acute toxicity of DCAC and/or DCA is low via the oral route, but is moderate via inhalation and dermal exposure.” Such statements suggest that the TSD authors could consider other toxicity information, including information for DCA, as part of a weight-of-evidence approach to support the derivation of AEGL values for DCAC.

To illustrate for information related to the AEGL-3, a male rat LC50 (lethal concentration to 50% of the exposed population) for a 4-h vapor exposure was identified as about 2,000 ppm (not an analytic measurement), and 8 min was indicated as the maximum exposure time to saturated vapor that produced no deaths (as summarized in EPA [2011b], as cited in Smyth et al. [1951], which is included in the TSD, and Smyth and Carpenter [1948], which is not). Note that the information from Smyth and colleagues might reflect a nominal concentration, and actual analytic levels could be quite low; thus, DCAC could be worse than CAC. It would be useful to evaluate additional information to determine if measurements were made for these earlier studies.

Other acute toxicity information highlighted in EPA (2011b) includes data from Yount et al. (1982). This original study is not readily available online; it could be helpful to pursue it and other studies, such as the Ciba-Geigy report (cited as V. Traina et al. [1977] in EPA 2011b) for additional insights regarding relative toxicity. More information regarding relative toxicities is also indicated in Woodard et al. (1941), as cited in WHO (2004), and other sources. Comparisons between the acetyl chlorides and associated fate and metabolic products should also be considered for potential insights, including the corresponding chloroacetic acids, hydrogen chloride, and phosgene.

Other Comments for CAC and DCAC

Multiple pages and sections: Various sections of the TSD reflect outdated or missing information. The TSD authors need to ensure that the literature summaries for the chemicals have been updated for documents that have been in the AEGL-development process for several years. The date of the most recent literature review should be included in the TSD (perhaps the cover page and the executive summary). The TSD should be revised to include current information and additional data potentially useful to the AEGL derivations (particularly DCAC) and supporting material. The following sources contain more recent information (including production and use data): the EPA High Production Volume (HPV) Program, including risk-based prioritization analyses (EPA 2008a,b), the Chemical Assessment

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

and Management Program (EPA 2010a, 2011a), the Inventory Update Reporting (EPA 2010b), and the HPV Information System (HPVIS, EPA 2011b,c) as well as DuPont (2004, 2006).

Page 7, line 43: In light of the potential for respiratory effects, the committee suggests deleting “protective” from “To obtain protective AEGL-2 values….” because data are insufficient to clearly support that statement (here and elsewhere in the document).

Page 8, Table 1, Summary of AEGL Values: In the “End Point (reference)” column, clarify that these entries reflect an estimated NOEL (not a study-reported NOEL), and include the PODs, UFs, and MFs used. The authors should consider providing additional information in the footnote on odor detectability to indicate that lower odor thresholds have been reported and to indicate how close the detectable levels are to the concentration associated with discomfort.

Page 10, Table 2, Chemical and Physical Properties of CAC and DCAC: Please re-evaluate the information presented in this table. Information available via several common sources include many values that differ (in some cases, substantially) from those reported in Table 2. Information sources include the National Library of Medicine Hazardous Substances Data Bank (HSDB) (note EPA [2008b] refers to HSDB [2007], compared to the 2003 HSDB citation in the TSD) and the HPVIS (EPA 2011b) as well as material safety data sheets and the International Program on Chemical Safety (IPCS 1997) (e.g., the latter includes explosive limit information for DCAC).

Page 10, Section 2.1. Acute Lethality (also Section 2.2. Nonlethal Toxicity): It would be helpful to check the current literature to determine if relevant data are available (e.g., Zou et al. 2008) to add to the human data sections.

Page 10, lines 6-8: “Based on the adverse effects of inhalation exposure in humans, it is likely that exposure to sufficiently high concentrations of CAC would result in death.” The authors should consider deleting this statement as it could apply to all chemicals, not only CAC.

Page 10, lines 8-9: “Reported effects include chest tightness, laryngospasm, pulmonary edema, bronchospasm, and bronchopneumonia (HSDB 2003a).” Please clarify who reported these effects. Is it from an occupational exposure or a research study?

Page 10, Section 2.2. Nonlethal Toxicity (also Section 3.2. Nonlethal Toxicity): Consider adding further subsections to address other end points (e.g., cardiovascular for humans and immunotoxicity and hepatotoxicity for animals). Some potential sources are Cai et al. 2006; Khan et al. 1997; and König et al. (2008).

Page 11, line 31 (also page 12, Table 3): “Dahlberg and Myrin (1971) described scenarios in 10 welding shops in which welders were exposed to DCAC….” Please clarify what “scenario” means. Do the authors mean workplace exposures or accidents? The committee suggests using a different word.

Page 13, Section 2.6. Carcinogenicity, lines 41-43: “No studies examining the carcinogenic activity of CAC or DCAC were located.” We suggest checking the current literature for information regarding potential carcinogenicity (notably for DCAC).

Page 13, lines 41-43: “Treatment of male or female Sherman albino rats with 1000 ppm (range of 700-1390 ppm) CAC for 4 hours killed either 2/6, 3/6, or 4/6 animals after 14 days in a range-finding test (Carpenter et al. 1949).” Please check whether additional information might be available (possibly in subsequent studies) regarding the specific concentrations that killed the animals. It is not clear whether the target was 1,000 ppm or whether actual concentrations were in the noted range. These mortality data are not useful in terms of deriving guideline levels unless the specific concentrations resulting in the different percent mortalities are known.

Page 14, lines 7-8; lines 9-10: “It was not specified whether the air concentrations were analytical or nominal (assume nominal).” Please provide the basis for the assumption that the concentration is nominal, or delete “(assume nominal)” from the text (lines 7-8). “Results were not given other than that all animals inhaling ≥16 mg/L (3462 ppm) died on study, and that 5 rats inhaling 2381-6480 ppm died within the first 2-3 minutes of exposure.” Please clarify what is meant by this sentence (lines 11-12). Also, the committee suggests rewording “died on study” to “died during the exposure.” The suggested revision also applies to page 20, line 14, and page 21, line 24.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 16, Table 4, The “Effects, Comments” column is not aligned with the concentration and mortality entries in the other columns. It is difficult to determine which effects are associated with which concentrations; please align the columns in Table 4.

Page 17, Table 5, Chloroacetyl Chloride Multiple-Exposure Animal Studies: For the Dow (1982) summary, please add the statement that death occurred in mice and rats at 2.5 and 5.0 ppm (and include the number of deaths per total number or animals exposed). Please check whether more specific information could be provided regarding effects observed following the initial exposure; some overviews of this study indicate effects at lower concentrations throughout the study period.

Page 18, lines 31-34: “No mice died at ≤649 ppm, all mice inhaling ≥3030 ppm died during the 2-hour exposure, and 18 mice inhaling 2381-6480 ppm died within the first 2-3 minutes of exposure. Over the 5-day period, all mice died at ≥10 mg/L (2164 ppm).” Please clarify this information, as there is some confusion regarding all mice dying at or above 3,030 ppm and then all mice dying at or above 2,164 ppm. Also, please indicate how many mice were included in the 2381-6486 exposure group (i.e. 18 our of how many mice died)?

Page 19, line 2: Please clarify whether “detachment of mucosa” reflects sloughing of mucosa.

Page 19, lines 31-32: The text states that “exposure to ~4 ppm for 5-10 minutes caused ‘respiratory embarrassment’ (i.e. respiratory difficulty or distress) in a range-finding study (Dow 1970a).” This study was not readily available to check how the original authors defined “respiratory embarrassment”; we suggest revising this sentence to use more readily understandable terminology.

Page 20, Section 3.4. Developmental and Reproductive Toxicity: The text states that “No animal studies were located that evaluated developmental and/or reproductive toxicity of CAC or DCAC.” Relevant information is available. The description of a developmental toxicity study was included in the DuPont (2004) submission to EPA for DCAC under the Chemical Right-to-Know Program, as part of the proposed test plan package. Recognizing general route differences, the data indicative of fetal soft tissue malformations, notably the cardiovascular system and ascending aorta and right ventricle, could be relevant to the weight-of evidence evaluation for the AEGL-3. See the subsequent update of that submittal, which included responses to EPA comments regarding use of the analog dichloroacetic acid (DuPont 2006). These reports should be reflected in the TSD. A number of other studies are highlighted in EPA information sources (2008a,b, 2011b) that also warrant consideration in the TSD.

Page 20, Section 3.5. Genotoxicity: The most recent information provided in the TSD is from 1994. Please review the literature for updated information.

Page 23, line 20–page 24, line 21, Section 4. Special Considerations: Please review information in EPA (2011b), EPA TSDs for the Integrated Risk Information System (IRIS) program, Agency for Toxic Substances and Disease Registry (ATSDR) toxicologic profiles for related chemicals, and the primary literature, such as Chiu et al. (2009), to update the appropriate subsections (including analog information considered relevant)—particularly Section 4.1. Metabolism and Disposition; Section 4.2. Mechanisms of Toxicity; and Section 4.3. Structure Activity Relationships.

Page 24, line 23–page 25, line 27, Section 4.4. Other Relevant Information: As described in the preceding comment, please review recent information to update Section 4.4.1. Species Variability (much more information is available in the literature than is reflected here; consider adding a concise summary table). This section could be expanded (or a subsection could be added) to address gender variability. The authors should consider adding a further subsection to address potential joint (combined) toxicity from fate products and metabolites that could coexist during the durations of interest, unless this information is added to Section 4.4.4 (Concurrent Exposure Issues). This further subsection would benefit from the inclusion of additional information for atmospheric fate in Section 1 (Introduction). For example, CAC can form when dichloroethylene (DCE) is released to air. The toxicities of each compound could be jointly considered (as well as other fate products) during exposures lasting up to 8 h. Consider that 1,1-DCE in air forms CAC, phosgene, and formaldehyde; certain data indicate that the atmospheric half-life of this parent can be 4 h when hydroxyl radical concentrations are only 20% above average concentrations (e.g., see ATSDR 2004, 2007; Forkert 2001; EPA 2011b). Similarly, trichloroethylene

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

released to air can form DCAC (as well as phosgene). Additional information can be found in the literature (e.g., Ou and Lo 2007; Christiansen and Francisco 2010). This information regarding potential mixture toxicity could help inform emergency-response measures in CAC and DCAC release situations.

Page 24, lines 35-38: “Interspecies variability between mice, rats, and guinea pigs in a 2-hour exposure study (108-6494 ppm CAC) could not be established because mortality for single exposure concentrations was only provided for mice (Herzog 1959). A comparison of the LC100 values, which were provided for all three species, suggests that interspecies variability was not great. All animals died within 5 days of exposure to 3030 ppm (mice), 3462 ppm (rats), or 3462-3895 ppm (guinea pigs).” This study does not appear well-suited to any conclusions regarding interspecies sensitivity differences. It is possible that the exposure concentrations were so high such that it was not possible to make any meaningful interpretation by being above the threshold for all species for a 100% mortality. It is possible that interspecies differences could have been observed at lower levels, but this study does not provide that information.

Page 25, Section 4.4.4. Concurrent Exposure Issues, lines 20-27: “The presence of CAC in the air can also result in inadvertent exposure of the skin, which is capable of absorbing sufficient CAC to result in death (Morris and Bost 2002).” This short section provides brief text for only one compound (CAC) and one (24-h) dermal study. Much more information is available in the literature related to toxicity following dermal exposure (including data for the DCAC analog), which would be valuable to include in this section.

Page 25, line 45–page 26, line 2: Section 5.2 lists animal studies “potentially useful for developing AEGL-1 values.” The Dow (1970b) study should not be included in this list because it involved repeated exposures and the rats were examined only after a recovery period or following re-exposure after such a period. This situation complicates any attempt to determine acute effects from these data. Please delete Dow (1970b) from this list.

Page 30, Section 8.2. Comparison with Other Standards and Guidelines: The proposed 1-h AEGL-2 is more than 3-fold higher than the corresponding Emergency Response Planning Guideline 2 (ERPG-2). The proposed 1-h AEGL-3 is more than 5-fold higher than the corresponding ERPG-3. The authors should include an explanation for these differences in the text (or consider revising the AEGLs, as suggested in preceding comments). This comment is consistent with the SOP, Appendix J (p. 201): “A summary discussion of important comparisons should be presented in the text and the values for recognized standards and guidelines, if available, should be presented in the table.”

References

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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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EPA (U.S. Environmental Protection Agency). 2010a. Chemical Assessment and Management Program (ChAMP). U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/ChAMP/ [accessed May 1, 2011].

EPA (U.S. Environmental Protection Agency). 2010b. Non-confidential 2006 IUR Records by Chemical, Including Manufacturing, Processing and Use Information: CAS (79-36-7) Acetyl Chloride, 2,2-dichloro-Inventory Update Reporting (IUR), U.S. Environmental Protection Agency [online]. Available: http://cfpub.epa.gov/iursearch/2006_iur_companyinfo.cfm?chemid=6372&outchem=both [accessed May 1, 201].

EPA (U.S. Environmental Protection Agency). 2011a. Prioritization for Acetyl Chloride, Dichloro-. Chemical Assessment and Management Program, U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/mpv_hpv_prioritizations.case_detail?caseid=4 [accessed May 1, 2011].

EPA (U.S. Environmental Protection Agency). 2011b. High Production Volume Information System (HPVIS): CAS (79-36-7) Acetyl Chloride, Dichloro-. U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=100841 [accessed May 1, 2011].

EPA (U.S. Environmental Protection Agency). 2011c. High Production Volume Information System (HPVIS): CAS (79-04-9) Acetyl Chloride, Chloro-. U.S. Environmental Protection Agency [online]. Available: http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=100837 [accessed May 16, 2011].

Forkert, P.G. 2001. Mechanisms of 1,1-dichloroethylene-induced cytotoxicity in lung and liver. Drug Metab. Rev. 33(1):49-80.

Herzog, S. 1959. Experimental studies on the toxicity of chloro-acetyl chloride [in Romanian]. Igiena (Bucharest) 8:135-144.

HSDB (Hazardous Substances Data Bank). 2003a. Acetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Sept. 2003].

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

HSDB (Hazardous Substances Data Bank). 2003b. Dichloroacetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Sept. 9, 2003].

HSDB (Hazardous Substances Data Bank). 2007. 2, 2-Dichloroacetyl Chloride. Toxicology Data Network, National Library of Medicine [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed Aug. 2, 2007](as cited in EPA 2008b).

IPCS (International Programme on Chemical Safety). 1997. Dichloroacetyl Chloride. ICSC: 0869. International Programme on Chemical Safety. April 1997 [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics0869.htm [accessed May 16, 2011].

IPCS (International Programme on Chemical Safety). 1998. Chloroacetyl Chloride. ICSC: 0845. International Programme on Chemical Safety. March 1998 [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics0845.htm [accessed May 16, 2011].

Khan, M.F., B.S. Kaphalia, and G.A. Ansari. 1997. Time-dependent autoimmune response of dichloroacetyl chloride in female MRL +/+ mice. Immunopharmacol. Immunotoxicol. 19(2):265-277.

König, R., P. Cai, X. Guo, and G.A. Ansari. 2008. Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride. Chem. Res. Toxicol. 21(3):572-582.

Morris, E.D., and J.C. Bost. 2002. Acetic acid, halogenated derivatives: Chloroacetyl chloride. In Kirk-Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons, Inc.

Ou, H.H., and S.L. Lo. 2007. Photocatalysis of gaseous trichloroethylene (TCE) over TiO2: The effect of oxygen and relative humidity on the generation of dichloroacetyl chloride (DCAC) and phosgene. J. Hazard. Mater. 146(1-2):302-308.

Smyth, H.F., Jr., and C.P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30(1):63-68.

Smyth, H.F., Jr., C.P. Carpenter, and C.S. Weil. 1951. Range-finding toxicity data: List IV. A.M.A. Arch. Ind. Hyg. Occup. Med. 4(2):119-122.

Traina, V. et al. 1977. Ciba-Geigy Pharmaceuticals Unpublished Report No. 7-77, CGS [as cited in EPA 2011b].

WHO (World Health Organization). 2004. Monochloroacetic Acid in Drinking-Water: Background Document for Development of WHO Guidelines for Drinking-Water Quality. WHO/SDE/WSH/03.04/85. Geneva: World Health Organization [online]. Available: http://www.who.int/water_sanitation_health/dwq/chemicals/monochloroaceticacid.pdf [accessed May 17, 2011].

Woodard, G., S.W. Lange, K.W. Nelson, and H.O. Calvery. 1941. The acute oral toxicity of acetic, chloroacetic, dichloroacetic and trichloroacetic acids. J. Ind. Hyg. Toxicol. 23(2):78-82 [as cited in WHO 2004].

Yount, E.A., S.Y. Felten, B.L. O’Connor, R.G. Peterson, R.S. Powell, M.N. Yum, and R.A. Harris. 1982. Comparison of the metabolic and toxic effects of 2 chloroproprionate and dichloroacetate. J. Pharmacol. Exp. Ther. 222(2):501-508.

Zou, J.F., J. Li, and Y.P. Sun. 2008. Three cases of acute chloroacetyl chloride poisoning [in Chinese]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 26(10):600.

Methanesulfonyl Chloride

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient to derive AEGL-1 values for methanesulfonyl chloride. Therefore, AEGL-1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for methanesulfonyl chloride. This approach is justified by the steep concentration-response curve (10% mortality in rats exposed to 20 ppm and 90% mortality at 28 ppm for 4-hr; Pennwalt Corporation, 1987). A 4-hour rat BMCL05 [benchmark concentration with its lower confidence limit at a 5% extra risk] of 15.5 ppm (Pennwalt Corporation, 1987) was used as the point-of-departure (POD) for the AEGL-3 values.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee agrees that there are insufficient data at this time to derive AEGL-1 values for methanesulfonyl chloride

AEGL-2

The AEGL-2 values are derived based on AEGL-3 values. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values.

AEGL-3

Page 12, lines 23-27: “Inter- and intraspecies uncertainty factors of 3 each (total 10) will be applied because methanesulfonyl chloride is irritating, and much of the toxicity is likely caused by a direct chemical effect on the tissue; this type of portal-of-entry effect is not expected to vary greatly between species or among individuals.” Section 2.5.3.2.7 (p. 73) of the SOP states that “The UF for interspecies response adjustment is 10 where there are inadequate data or insufficient information about the chemical or its mechanism of action to justify an alternative UF.” The default intraspecies UF is also 10 “in the absence of data or information to the contrary” (Section 2.5.3.4, p. 89). The authors did not provide data to support reducing the default interspecies and intraspecies UF from 10 to 3. Thus, the overall UF of 100 (= 10 × 10), instead of the factor of 10 (= 3 × 3), should be used to derive AEGL-3.

Other Comments

Page 6, Table 1: Please add MFs to the end point (reference) column in Table 1 for AEGL-3.

Page 9, line 38: “No relevant structure-activity data were located.” The NRC AEGL committee reviewed several acid chlorides together. Although data on direct comparisons may not be available, the authors should consider adding brief toxicity information about similar compounds.

Page 12, lines 19-20: “Although, the model probability was low, the output of the log probit calculation excluded the default n = 3 for scaling from longer to shorter time points….” Please explain what is meant by “model probability was low.”

References

Pennwalt Corporation. 1987. Methanesulfonyl Chloride: Acute Inhalation Toxicity in Rats, 4-Hour Exposure. Report No. PWT 45/861670. Huntingdon Research Centre. February 23, 1987.

Trimethylacetyl Chloride

The following is excerpted from the Executive Summary of the TSD:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Data were insufficient to derive AEGL-1 values for trimethylacetyl chloride. Therefore, AEGL-1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for trimethylacetyl chloride. This approach is justified by the steep concentration-response curve (0% mortality in rats exposed to 78 ppm for 6-hours and 100% mortality at 249 ppm for 3.5-hours (Eastman Kodak, 1992); 25% mortality in mice exposed to 115 ppm and 75% mortality at 180 ppm for 30-minutes (Hardy and Kieran, 1992).An exposure causing no death in rats (78 ppm for 6 hours; Eastman Kodak, 1992) was used as the point-of-departure (POD) for the AEGL-3 values

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee agrees that data are insufficient at this time to derive AEGL-1 values for trimethylacetyl chloride.

AEGL-2

Page 10, lines 38-42: The authors state that the AEGL-2 values are derived from AEGL-3 and offer several justifications for this choice, including the “0% mortality in rats exposed to 78 ppm for 6-hours” (line 40) at the AEGL-3 POD. The authors should also include that the POD was selected because exposure at 78 ppm for 6 h resulted in one AEGL-2 effect.

See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values.

AEGL-3

Page 11, lines 24-26: “An intraspecies uncertainty factor of 3 will be applied because contact irritation is not expected to vary greatly within species.” Section 2.5.3.2.7 (p. 73) of the SOP states that “The UF for interspecies response adjustment is 10 where there are inadequate data or insufficient information about the chemical or its mechanism of action to justify and alternative UF.” The authors did not provide data to support reducing the default intraspecies UF from 10 to 3. Thus, together with the MF of 3 and the interspecies UF of 10 used in the draft TSD, the overall extrapolation factor should be 300 (=3 × 10 × 10).

Other Comments

Page 7, Table 1: Please add the exposure concentration to the end point (reference) column for AEGL-3 in Table 1. Also add the UFs used for estimating AEGL-3 in the same column.

Page 8, lines 18-19: “Groups of three rats were exposed to 78 ppm trimethylacetyl chloride for 3.5 hours or 249 ppm trimethylacetyl chloride for 6-hours….” Please correct the exposure durations. The exposure at 78 ppm should be for 6 h instead of 3.5 h. The exposure at 249 ppm should be for 3.5 h instead of 6 h. These are correctly stated elsewhere in the TSD.

Page 9, line 4: “An LC50 value of 101-182 ppm was estimated by the study authors.” Please specify that the LC50 value of 101-182 ppm is for 30 min.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 9, line 38: “No relevant structure-activity data were located.” Although data on direct comparisons may not be available, the authors should consider adding brief information on similar compounds.

Page 10, lines 39-40: “This approach is justified by the steep concentration-response curve (0% mortality in rats exposed to 78 ppm for 6-hours and 100% mortality at 249 ppm for 3.5-hours…” Please add further clarification regarding the dose-response curve. Steepness is an assumption because the data are not adequate to determine dose-response robustly.

References

Eastman Kodak. 1992. Initial Submission: Acute Inhalation Toxicity Study with Pivaloyl Chloride in Rats with Cover Letter Dated August 10, 1992. Microfiche No. OTS0544099.

Hardy, C.J., and P.C. Kieran. 1992. Initial Submission: Assessment of the Respiratory Tract Irritancy of Trimethyl Acetyl Chloride in the Mouse with Cover Letter Dated November 12, 1992. Prepared by Huntingdon Research Centre, Ltd, Huntingdon, Cambridgeshire, England. Submitted by Shell Oil Company. EPA Document No. 88930000053. Microfiche No. OTS0538315.

BROMOACETONE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on bromoacetone. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 values were based on a concentration causing ocular irritation in 2/6 humans (0.1 ppm) (Dow Chemical, 1968)…. Although the concentration-response relationship for bromoacetone is not particularly steep, the AEGL-3 values were divided by 3 to derive AEGL-2 values for bromoacetone. This approach is utilized because use of the rat irritation data as a point-of-departure yields AEGL-2 values essentially identical to AEGL-3 values calculated from lethality data…. AEGL-3 values were based on rat lethality data of varying exposure concentrations and durations (Dow Chemical (1968).

AEGL-Specific Comments

AEGL-1

The committee approves the derivation of AEGL-1 values for bromoacetone.

Page 10, lines 20-21: “Bromoacetone inhalation data in humans are limited. Bromoacetone caused ocular irritation in 2/6 subjects at 0.1 ppm and 6/6 subjects at 1.0 ppm.” Animal toxicity data demonstrated ocular and respiratory irritation in rats exposed to bromoacetone (p. 10, lines 41-44; p. 11, lines 22-25). Please provide clarifying language or additional information that ocular irritation was not accompanied by respiratory irritation in human exposure to bromoacetone.

AEGL-2

The committee approves the derivation of AEGL-2 values for bromoacetone

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 19, lines 23-27 (Appendix A. Derivation of AEGL-2 Values for Bromoacetone): Please show the calculations of AEGL-2 values based on the rat irritation data (not just the calculated values). The calculations will improve the reader’s ability to compare differences between the derivation using one-third of the AEGL-3 and the derivation using the rat irritation data. It will be helpful to show the dose-response curve to demonstrate the steepness of the response curve.

AEGL-3

The committee approves the derivation of AEGL-3 values for bromoacetone.

Page 20, lines 23-25 (Appendix A. Derivation of AEGL-3 Values for Bromoacetone): Please show the calculations of AEGL-3 instead of the computer output.

Other Comments

Page 21, lines 3-25 (Appendix B. Time Scaling Calculations): The first paragraph details background information about time-scaling. The appendix needs to provide only the time-scaling calculations and appropriate references to the methods. The committee suggests that the TSD authors delete the paragraph. The following should replace the first sentence of the paragraph that begins on line 27: “Using the ten Berge modification to Haber’s law [provide references], an n of 1.3 was obtained following analysis of lethality data in rats (Dow Chemical 1968).”

Page 13, lines 29-20: “This analysis produced an exponent ‘n’ value of 1.3 with confidence limits of 0.800 and 1.713.” The confidence limit values have too many significant figures. Please report them as 0.08 and 1.7, respectively.

Reference

Dow (Dow Chemical Company). 1968. Inhalation Exposure Toxicity of Bromoacetone and a Fumigant Mixture Containing Bromoacetone with cover Letter Dated April 10, 1986. EPA Document No. 86860000027. Microfiche No. OTS0510179.

BUTANE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on butane. A presentation on the TSD was made by Mark Follansbee, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

The AEGL-1 derivation is based on observations in a study with volunteers on the warning properties of short exposures to butane (Patty and Yant 1929). It is concluded that 10,000 ppm (10-min exposure) can be regarded as a boundary for drowsiness…. The AEGL-2 values are based on a study with guinea pigs exposed for 2 hours to a butane concentration varying between 50,000 and 56,000 ppm (Nuckolls 1933)…. The AEGL-3 derivation is based on an acute exposure study with rats and mice (Shugaev 1969).

This document can be finalized provided that the following comments are adequately addressed.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-Specific Comments

The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 for butane

Other Comments

Page 4, lines 29-33 (also Page 12, lines 3-5): “The female child was delivered normally and appeared in good condition. A CT-scan at 7 days post partum revealed an almost complete absence of both cerebral hemispheres in the newborn. The thalamus, brainstem, and cerebellum were preserved. The malformation was considered to be due to intra-uterine anoxia as a result of the butane intoxication of the mother (Fernandèz et al. 1986).” Please check the accuracy of the statement that the effect is “a result of the butane intoxication.” It is possible that the malformation would have occurred due to anoxia from any asphyxiant chemical and is not specific to butane exposure.

Page 5, line 24: “A concentration of 200,000-250,000 ppm was required to produce relaxation in dogs…” Please explain what is meant by “relaxation.”

Page 9, line 40–Page 10, line 2: “Shugaev (1969) determined LC50-values for 2-hour exposures in mice and 4-hour exposures in rats.… Mean brain concentrations of butane in dead rats (7.5 μg/g) and mice (7.8 μg/g) were very similar. However, the tissue butane concentrations in rats were not determined after a 2-hour exposure and the reported brain concentration could already have been reached with a shorter exposure time. It is known that upon exposure to gases that are relatively insoluble in water (like butane) and thus in blood, the blood concentration of the gas will rise quickly toward equilibrium. In that case mice may just be more susceptible than rats toward butane toxicity.” The meaning of the last sentence about relative susceptibilities of the mice and rats is unclear. Please clarify. Also, what is the basis (evidence) for the assertion that mice may be more susceptible than rats towards butane toxicity?

Page 10, lines 36-37: “Further, no noticeable irritation was reported up to a concentration of 100,000 ppm (unknown duration, but probably a few minutes).” Please provide support for the conclusion that the exposure duration was “probably a few minutes,” or delete this phrase from the TSD.

Page 12, lines 12-13: Please correct “56,0000” to read “56,000” in the following phrase: “butane concentration varying between 50,000 and 56,0000 ppm.”

References

Fernàndez, F., A. Pèrez-Higueras, R. Hernàndez, A. Verdú, C. Sánchez, A González, and J. Quero. 1986. Hydranencephaly after maternal butane-gas intoxication during pregnancy. Dev. Med. Child Neurol. 28(3):361-363.

Nuckolls, A.H. 1933. The Comparative Life, Fire, and Explosion Hazards of Common Refrigerants. Miscellanous Hazards No. 2375. Underwriters’ Laboratories, Chicago, IL.

Patty, F.A., and W.P. Yant. 1929. Pp. 1-10 in Odor Intensity and Symptoms Produced by Commercial Propane, Butane, Pentane, Hexane, and Heptane Vapor. Report of Investigation No. 2979. U.S. Department of Commerce, Bureau of Mines, Washington, DC.

Shugaev, B.B. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch. Environ. Health 18(6):878-882.

BZ (3-QUINUCLIDINYL BENZILATE)

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on BZ. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Data in humans did not define no-effect exposures or exposures that would result in effects consistent with the AEGL-1 definition. Therefore, AEGL-1 values for BZ are not recommended. For AEGL-2 development, a 3-fold reduction of the ICt50 value of 60.1 mg-min/m3 (60.1 mg-min/m3 ÷ 3 = 20 mg-min/m3 or 4 mg/m3) was considered an estimate of the threshold for incapacitating effects…. The AEGL-3 values for BZ were derived using 3,700 mg-min/m3 as the point-of-departure. This is a 10-fold reduction of the LCt50 [concentration and time of a substance that is lethal to 50% of an exposed population] value for monkeys; 37,000 mg-min/m3 based upon 6-25 minute exposure data (DA, 1974).

A revised document should be submitted to the committee for review

AEGL-Specific Comments

AEGL-1

Page 17, lines 32-34: The authors state that “data in humans did not define no-effect exposures or exposures that would result in effects consistent with the AEGL-1 definition. Therefore, AEGL-1 values for BZ are not recommended.” However, on page 12, lines 1-2, the authors note that “a maximum no-effect dose of 0.5 to1.0 μg BZ/kg in humans was reported by the NRC (NRC, 1982).…” The authors should consider calculating an airborne concentration corresponding to the maximum no-effect dose reported by the NRC (1982) as a POD for AEGL-1. Specifically, the authors should assume a rapid respiratory rate, and the comparison should be made between AEGL-1 values calculated for children (by using lower body weight and respiratory volume) and AEGL-1 values calculated for adults. The calculation would be as follows: AEGL-1 = (airborne concentration) × (body weight)/(respiratory volume).

AEGL-2

Page 18, lines 31-33: “For AEGL-2 development, a 3-fold reduction of the ICt50 [concentration and time of a substance causing incapacitation in 50% of an exposure population] value of 60.1 mg-min/m3 (60.1 mg-min/m3 ÷ 3 = 20 mg-min/m3 or 4 mg/m3; equivalent to 0.004 mg/L) was considered an estimate of the threshold for incapacitating effects.” Although taking one-third of the ICt50 results in a value below the lowest exposure level causing an AEGL-2 effect, there is no precedent for calculating AEGL-2 in this manner. Section 2.2.2.3.2 (p. 44) states that one-third of the LC50 can be used to develop AEGL-3 values when all concentrations cause death. In risk assessment, there is precedent for use of the highest concentration between the 95% upper confidence limit and lowest measured concentration. In the case of BZ, the 95% lower confidence limit (LCL; 41.3 mg-min/m3) is below the lowest exposure level resulting in an AEGL-2 effect. The committee recommends using the 95% LCL of the ICt50, 41.3 mg-min/m3, as the POD.

Page 19, lines 14-20: “The effects in the human studies are likely due to the anticholinergic properties of BZ; structures of muscarinic receptors are highly conserved in humans and, thus, receptor affinity (and, therefore, toxicodynamics) is not likely to vary among individuals.… The 3 intraspecies uncertainty factor accounts for possible pharmacokinetic differences between individuals.” Although the authors present a good toxicodynamic argument for a UF of 3, the study used as the basis for the POD was conducted in healthy military volunteers, and the authors need to take that into consideration. The SOP section 2.5.3.4.4 states that a UF=3 can be chosen if ‘the response elicited by exposure to the chemical by different subpopulations is unlikely to differ’ and to provide a ‘discussion of why the response to chemical exposure is unlikely to differ.’ The TSD authors should provide rationale for why physiological difference in response in younger people (e.g., deterioration of normal gait) is unlikely to

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

differ from the elderly, who are often encumbered with age-related factors that may already interfere with their ability to move (and hence escape). If data is unavailable to support such a rationale, an intraspecies UF=10 should be used.

Page 19, lines 20-22: “A modifying factor of 3 was applied to account for uncertainties in the overall database, particularly the short exposure duration (5 minutes) of the critical study.” The committee agrees that an MF of 3 is appropriate, but the rationale should state that the MF was added to account for the lack of incidence data (the same as is stated for AEGL-3 on page 20, lines 40-41). The total UF = 10 (intraspecies) × 3 (MF) = 30

AEGL-2 calculations based upon the 95% LCL and the recommended UFs would be as follows:

10-min AEGL-2: (41.3 mg-min/m3 ÷ 10 min) ÷30 = 0.14 mg/m3 30-min AEGL-2: (41.3 mg-min/m3 ÷ 30 min) ÷ 30 = 0.05 mg/m3 1-h AEGL-2: (41.3 mg-min/m3 ÷ 60 min) ÷ 30 = 0.023 mg/m3

AEGL-3

The committee approved the derivation of AEGL-3 values for BZ.

Page 20, lines 30-31: “Intraspecies uncertainty factor (3) application was based upon the same rationale as that for AEGL-2.” The justification for the AEGL-2 is based upon pharmacokinetics related to an escape-impairing end point. As stated above, this justification is insufficient for AEGL-2 because it does not take into consideration age-related differences. The authors should provide an alternative or additional justification for use of a UF of 3 instead of the default UF of 10 in regard to AEGL-3 (lethality).

Other Comments

Page 26, lines 20-24 (also Page 28, lines 20-24): “For AEGL durations within the range of exposure times used for the reported concentration-time products (Ct), a linear relationship was assumed. For extrapolation from the durations of experimental data to longer duration AEGL durations, a linear relationship was also applied (i.e., default value of n = 1 for Cn × t = k was applied….” This statement is misleading. Although using the default of n = 1 has the effect of a linear relationship, the rationale for use of the default was because of the insufficient data to calculate a value for “n” (see SOP, Section 2.7.8 Time Scaling—Guidelines for the NAC/AEGL Committee Approach). The authors of the TSD correctly state this rationale in the Executive Summary (p. 6, lines 47-48). Please revise the text on page 26 and page 28 to match what is written about time-scaling in the Executive Summary.

References

DA (U.S. Department of the Army). 1974. Pp. 109-113 in Chemical Agent Data Sheets, Vol. 1. Edgewood Arsenal Special Report AD0030. U.S. Department of the Army, Edgewood Arsenal, Aberdeen Proving Ground, MD.

NRC (National Research Council). 1982. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents, Vol.1. Washington, DC: National Academy Press.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

CHLOROACETONE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on chloroacetone. A presentation on the TSD was made by Heather Carlson-Lynch, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for chloroacetone. No robust data consistent with the definition of AEGL-2 were available. In addition, the available acute toxicity data demonstrate that effects of chloroacetone exposure exhibit a steep dose-response relationship. Therefore, the AEGL-2 values were based upon a 3-fold reduction in the corresponding AEGL-3 values; this is considered an estimate of a threshold for irreversible effects. A 1-hour male rat BMCL05 (lethality threshold) of 131 ppm was used as the basis of the AEGL-3 values (Arts and Zwart, 1987).

A revised document should be submitted to the committee for review

AEGL-Specific Comments

AEGL-1

Page 9, lines 10-16 (also Page 10, lines 5-9): The authors describe a paper by Sargent et al. (1986) that reported eye and skin irritation (AEGL-1 type effects) in humans exposed to chloroacetone. The TSD (page 18, lines 40-42) also states that the Sargent report lacks sufficient information about exposure concentration and duration to derive an AEGL-1. However, the authors also note that the ACGIH Threshold Limit Value (TLV) ceiling of 1 ppm is based upon the “human exposure data (irritation) reported by Sargent et al. (1986)” (page 21, line 18). Although the TLV ceiling has no clear parallels with AEGL-1 end-point time frames, the committee suggests that the TSD authors make an effort to contact the author of the key reference, Sargent, for additional information.

AEGL-2

The committee approves the derivation of AEGL-2 values for chloroacetone.

AEGL-3

The committee approves the derivation of AEGL-3 values for chloroacetone.

References

Arts, J.H.E., and A. Zwart. 1987. Acute (One-Hour) Inhalation Toxicity Study of Chloroacetone in Rats. TNO Report No. V87.093/261236. CIVO Institutes, Zeist, The Netherlands. EPA Document No. 88870000029. Microfiche No. OTS0513466.

Sargent, E.V., G.D. Kirk, and M. Hite. 1986. Hazard Evaluation of monochloroacetone. Am. Ind. Hyg. Assoc. J. 47(7):375-378.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

EPICHLOROHYDRIN

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on epichlorohydrin. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 values were derived from the no-effect level for irritation in four subjects exposed to epichlorohydrin vapor (UCC, 1983)…. No specific effects consistent with the definition of AEGL-2 were reported in any of the studies on nonlethal effects. Therefore, AEGL-2 values were derived by reducing the AEGL-3 values by a factor of 3…. The 10-min, 30-min, and 1-hr AEGL-3 values were based on the 1-hr rat LC01 of 721 ppm (Dietz et al., 1985).

A revised document should be submitted to the committee for review

AEGL-Specific Comments

AEGL-1

Page 41, lines 35-38: “The default uncertainty factor of 10 was not used because it is intended to account for variability in the dose-response relationship resulting from variability in pharmacokinetics and pharmacodynamics. However, epichlorohydrin is an irritant; mild irritation experienced by humans (e.g., at 17 ppm) would most likely be confined to the nasal passage and eyes.” Section 2.5.3.3.4 of the SOP stated that “a default UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants…responses of asthmatics to respiratory irritants may range from mild to severe. A UF of less than 10 might be used when scientific evidence shows that a smaller UF will be protective.” In addition, the SOP stated that “information about similarities and differences in toxicokinetics and toxicodynamics is used when available to modify the UF used” (p. 88). The TSD authors do not provide sufficient data to support reducing an intraspecies UF to 3. For instance, in the absence of direct data on asthmatics (beyond the one anecdotal report), data that asthmatic reactions are not triggered by naso-pharyngeal irritation combined with indications that low concentrations of epichlorohydrin are removed at this level of the respiratory tract would be supportive. Likewise, data which address the relevance (or lack thereof) to either direct-action irritation or bronchoconstriction receptor activation of genetic polymorphisms in glutathione S-transferase and the degree to which they may affect the effective concentration of epichlorohydrin at the site(s) of action for these effects would be supportive. A UF=10 should be used for AEGL-1 unless adequate data is provided support a lower UF.

AEGL-2

Pages 43-44, Section 6.2: The section begins, “A relatively large animal database was available for evaluating nonlethal toxicity related to AEGL-2 derivation” (lines 31-32), and proceeds to briefly describe many studies. However, the second sentence of Section 6.3 (page 43, lines 40-41) states that “Adequate data were not available for deriving AEGL-2 values from studies with humans or animals.” For some of the studies described in Section 6.2, reasons are given for their not being used to derive AEGL-2 values, but many have no indication regarding their unsuitability. Indicate briefly why these studies are unsuitable.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-3

Page 46, lines 3-5: The authors explain that time-scaling from the 4-h AEGL-3 value (based on the 6-h rat LC01 of 274 ppm) to generate an 8-h AEGL-3 value was not done because the extrapolation “yields an AEGL-3 value of 20 ppm; however, humans exposed to 20 ppm for 1-hour experienced only burning of the eyes and nose.” Why is this reasoning appropriate for the 8-h value and not the 4-hvalue? The 4-h AEGL-3 value is 44ppm. Page 10, lines 25-28 state that humans exposed to epichlorohydrin vapor for 1 h at “40 ppm caused throat irritation that lasted about 48 hours (Lefaux, 1968; Wexler, 1971). Deichmann and Gerarde (1969) reported that humans exposed to 40 ppm epichlorohydrin for less than 2 hours experienced throat irritation.” Additional explanation needs to be provided for the differences in the approach to time-scaling for the 4-h and the 8-h AEGL-3 values.

Other Comments

Page 1, cover page: Add structural formula for epichlorohydrin.

Pages 6-8, Executive Summary: The Executive Summary should be a succinct description of the chemical substance, toxicology, and derivation of the AEGL values, but the summary for epichlorohydrin is more than two pages of text. The target audience for this summary is different from that for the body of the document. For instances, whole paragraphs found in Sections 5.3, 6.3, and 7.3 (the derivations of AEGL-1, AEGL-2, and AEGL-3, respectively) should not be repeated in the summary. The authors should modify the summary text by deleting unnecessary information and reducing the level of detail.

Page 10, Table 1: In the row for “Conversion”, please add the conversion factor for mg/m3

to ppm.

Page 10, lines 19-20: “The level of distinct odor awareness (LOA) for epichlorhydrin determined by the method of Van Doorn et al.(2002) is 46ppm.” The reference is incorrect. As described in Appendix C, the LOA is determined by the method of Ruijten et al. (2009). Please include the correct reference (also see comment below on reference corrections).

Page 12, lines 12-14: “Light 12 and moderate exposure categories (defined as the 95% upper confidence limit of the geometric 13 mean of personal air samples) were ≤0.5 but >1 ppm and ≤1.0 but >0.5 ppm, respectively.” Verify that the concentration ranges shown here for light and moderate exposure groups are expressed properly.

Page 13, lines 9-10: “On the basis of sufficient evidence of carcinogenicity in animals (U.S. EPA, 2006; reviewed in 1986).” The citation is confusing. It seems to state that the 2006 document was reviewed 20 years prior to publication. Please reword to clarify, for example, “review conducted in 1986 and described in EPA 2006.”

Page 14, lines 27-28: “Shell Oil Co. (1994) reported that occupational exposure of workers to epichlorohydrin at 0.11-0.23ppm during 11.15 hours/day and 0.19-2.57 ppm during 3 × 15 minutes/day….” The expressions of exposure duration here are confusing; please clarify.

Page 14, lines 40-41: “NIOSH (1976) reported epichlorohydrin concentrations for 1974 ranging from highs of 0.1-15ppm to lows of 0.1-0.6 ppm (average = 0.1-2.02 ppm) for an epoxy-producing unit.” It is unclear what distinguishes exposure “lows” from exposure “highs”. Please verify that the concentration ranges shown are accurate.

Page 16, line 15-26: “Six young male Carworth Farm-Wistar rats were exposed 5, 10, or 15 minutes to 23,400 ppm of epichlorohydrin vapor….” The exposure concentration cited here seems in conflict with the saturated vapor concentration listed in Table 1 (1.7% at 20oC and 16.4 mmHg at 25oC; about 40% greater). Did the authors provide any explanation for this concentration?

Page 25, Table 4 Summary of Acute Lethality Data in Laboratory Animal Exposure to Epichlorohydrin Atmospheres Generated from Aerosols: Please add a footnote indicating whether exposure-concentration analytic methods were stated explicitly to capture both aerosol and vapor components. Also, please note that the third table entry (960 mg/m3) does not have a footnote indicating

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

whether a solvent was used in the aerosol-generating process. Please add the footnote, as is done with the other six entries.

Page 26, lines 12-16: “Gardner al. (1985) determined the concentration of inhaled epichlorohydrin that caused a 50% decrease in the respiratory rate (RC50) of rat exposure to epichlorohydrin vapor…. The RC50 model is based upon stimulation of the trigeminal nerve upon contact with an airborne irritant followed by inhibition of respiration (Kane et al., 1979).” Both the Gardner study and the Kane study calculated a “RD50”, which is more commonly used in scientific literature. Why are the results of these studies being reported as “RC50”? Unless RC50 is used in some way in the original articles, the TSD authors should change “RC50” to “RD50” wherever the former occurs in the TSD (see also page 16, line 24; page 29, line 25; and elsewhere). Otherwise, the authors should provide an explanation or footnote about the relationship between RC50 and RD50.

Page 33, line 10: “A sialodacryadenitis infection affected both control and exposed groups….” Please define the term “sialodacryadenitis”.

Page 35, lines 23-25: “LC50 values varied considerably depending upon the exposure condition (dynamic or static chambers) and the physical state (aerosol or vapor) of the epichlorohydrin.” The authors should provide a cross-reference to the new subsection within 4.4 described in the following two comments (see below).

Page 39, Section 4.4. Other Relevant Information: Using the language from page 41, lines 4-10 (see comment below), create a new subsection describing the rationale for using vapor-only exposure studies to derive AEGL values. Expand the phrasing to make clear the issue of exposure uncertainty as follows:

Given (1) that the exposure would have been to a mixture of aerosol and vapor of undetermined composition; (2) that studies using aerosols generally do not indicate whether exposure concentrations were measured and reported as total epichlorohydrin, that is, the sum of both aerosol and vapor; and (3) that aerosol studies frequently use a solvent or other stabilizing agent for which control exposures are not reported; and (4) that adequate data were available from studies in which animals were exposed to epichlorohydrin vapor, AEGLs were….

Page 41, lines 4-10 (also Page 42, lines 32-28, and Page 44, lines 16-22): “Epichlorohydrin will produce vapor when liquid epichlorohydrin or aerosolized epichlorohydrin is exposed to air (vapor pressure = 13 mmHg at 20ºC). In studies that exposed animals to epichlorohydrin aerosols, animals would have actually inhaled epichlorohydrin vapor as well as aerosol. Given that the exposure would have been to a mixture of aerosol and vapor of undetermined composition, and given the availability of adequate data from studies in which animals were exposed to epichlorohydrin vapor, AEGL values were derived for epichlorohydrin vapor based on studies in which animals were exposed to vapor.” The material discussing the aerosol-vs.-vapor question adequately justifies the use of only the vapor exposure studies. This material, however, is repeated verbatim in each of the AEGL derivation sections (5.2, 6.2, and 7.2). Remove this discussion from the derivation sections and insert it in a new subsection of Section 4.4 “Other Relevant Information” (also see comment above about expanding the discussion). These revisions will simplify the document and allow for cross-referencing from other sections of the TSD.

Page 41, Figure 1: The time curve for LC50 values is incomplete. Extend the line to the final data point on the graph.

Page 41, Section 5.3 Derivation of AEGL-1: The source study for the POD of AEGL-1 is not cited. Please provide the citation.

Page 46, Section 8.2 Comparison of AEGLs with Other Standards and Criteria: Additional discussion should be added to Section 8.2 regarding ERPG, TLV, and other relevant standards. The SOP, Appendix J, List of Extant Standards and Guidelines in a Technical Support Document (p. 201) states that “A summary discussion of important comparisons should be presented in the text….” The following issues warrant some discussion (beyond the mere statement of differences) in Section 8.2:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

1. The proposed AEGL-1 values exceed other general public and occupational guidelines, specifically the American Industrial Hygienist Association (AIHA) ERPG-1 for a 1-h exposure (by more than a factor of 2.5), and the ACGIH TLV–time-weighted average (TWA) for an 8-h exposure (by more than a factor of 10). Please provide an explanation for this difference. 2. Page 46, lines 28-29: “The AEGL-1 value is higher than the ERPG-1 value of 2 ppm but is the same as the OSHA PEL [Occupational Safety and Health Administration permissible exposure limit].” Note that while the OSHA PEL may be legally binding, the more appropriate comparisons are with the ACGIH TLV, the AIHA ERPGs, and with various European occupational exposure limits (OELs), all of which are reviewed periodically and updated as new data become available. OSHA adopted the 1968 ACGIH TLV as the PEL; however, in 1980 ACGIH reduced the TLV to 2 ppm and further reduced it to 0.5 ppm in 1997. It is also worth noting in this context that OSHA attempted to update the PELs in 1988 and proposed to adopt the then-extant ACGIH TLV of 2 ppm, but the courts remanded the proposed rule.

Page 46, lines 28-30: “The AEGL-2 value of 24 ppm for 1 hour is similar to the ERPG-2 value of 20 ppm for 1 hour… [and] the AEGL-1 value is higher than the ERPG-1 value of 2 ppm but is the same as the OSHA PEL.” Please verify that the comparison between the values for the AEGLs and ERPGs are correct (see comment below). Also, please include the OSHA PEL value (5 ppm) in the text.

Page 46, line 50 (see also Page 48, Table 14): The ERPG values for epichlorohydrin were updated in 2008. The value for the ERPG-1 is 5 ppm, not 2 ppm. Please correct the value in the text and table.

Page 47, line 3: “Epichlorohydrin is classified in category 2 by the DFG (2002) based on animal data.” Please assess whether this statement is needed. If the authors keep the sentence, please provide a brief definition of what “category 2” is.

Page 48, Table 14: Extant Standards and Guidelines for Epichlorohydrin: Please make certain that all values are up-to-date (see note about ERPG-1). Also, place the PEL, TLV, and immediately dangerous to life or health (IDLH) values in the appropriate time columns. As listed, these values appear to represent the same exposure durations. Also, please move the notations (skin, carcinogen, etc.) into the footnotes.

Page 49, Section 9 References: The authors should carefully review the reference section for errors and missing information and confirm accessibility of listed references. If an online database or document is cited, the authors should confirm that the URL is still active and provide the last-accessed date. In addition, the authors should provide the URL for publicly accessible federal documents (e.g., NIOSH and EPA). For unpublished documents, the authors should report sources and identifiers (that is, report or publication numbers, TSCA submission document numbers, etc.) sufficient to enable easy identification and access. The following list provides specific examples of reference issues that need to be addressed:

• Page 51, line 8: The URL provided for Finnish Institute of Occupational Health is no longer active. Please confirm the URL, and provide the last-accessed date.

• Page 52, line 44, to Page 8, line 9: Please list the URL for documents that have publicly accessible online counterparts (e.g., the NIOSH citations).

• Page 50, line 28 (also Page 51, line 30): The Dietz et al. (1985) reference does not include a report number or any identifier other than the laboratory. Likewise, the Health and Safety Executive (p. 51, line 30) does not include a report or publication number. Ensure that these documents have reported sources and identifiers sufficient to enable easy identification and access.

• Page 52, lines 29-20: It appears that the document identification number for the Mobay citation is similar to those for the Monsanto citations (lines 32-40). However, the Mobay citation does not include EPA in the citation. Please confirm that the Mobay citation is complete.

• Page 53, line 24: Why was the date 1999 chosen for the citation of 29 CFR 1910.1000?

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

• Page 53, lines 44-46. The Van Doorn et al. reference is superseded by Ruijten et al. (2009). Delete Van Doorn from the reference list (also see comment above).

• Page 54, lines 11-12: Please provide the URL for the Registry of Toxic Effects of Chemical Substances (RTECS) online database. Also please provide a note that a subscription is required to access.

Page 60, Appendix B Carcinogenicity Assessment: The table presenting AEGL values associated with cancer risks should be rearranged. The standard table of AEGL values shows toxicity and risk increasing from top to bottom (AEGL-1, AEGL-2, AEGL-3). Rearrange the cancer risk table by increasing risk value, and include the AEGL values to demonstrate where AEGL and cancer risk values fall relative to one another.

Page 65, Appendix E Category Plot for Epichlorohydrin: The plot appears to show a small rectangle at 20 ppm for 60 minutes, indicating a “human-disabling” effect. To which study does this refer?

References

Deichmann, W.B., and H.W. Gerarde, eds. 1969. Epichlorohydrin. P. 241 in Toxicology of Drugs and Chemicals. New York: Academic Press.

DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002. Maximum Concentrations and Biological Tolerance Values at the Workplace Report No. 38. Weinheim: Wiley-VCH.

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.

EPA (U.S. Environmental Protection Agency). 2006. Epichlorohydrin (CASRN 106-89-8). Integrated Risk Information System (IRIS), U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/iris/subst/0050.htm [accessed Oct. 30, 2006].

Gardner, R.J., B.A. Burgess, and G.L. Kennedy, Jr. 1985. Sensory irritation potential of selected nasal tumorigens in the rat. Food Chem. Toxicol. 23(1):87-92.

Kane, L.E., C.S. Barrow, and Y. Alarie. 1979. A short-term test to predict acceptable levels of exposure to airborne sensory irritants. Am. Ind. Hyg. Assoc. J. 40(3):207-229.

Lefaux, R. 1968. P. 108 in Practical Toxicology of Plastics, P.P. Hopf, ed. Cleveland, OH: CRC Press.

NIOSH (National Institute for Occupational Safety and Health). 1976. Criteria for a Recommended Standard….Occupational Exposure to Epichlorohydrin. HEW (NIOSH) 76-206. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/pdfs/76-206a.pdf [accessed May 19, 2011].

Ruijten, M.W.M.M., R. van Doorn, and A.P. van Harreveld. 2009. Assessment of Odour Annoyance in Chemical Emergency Management. RIVM Report 609200001/2009. RIVM, Bithoven, The Netherlands.

Shell Oil Co. 1994. Initial Submission: Letter to EPA Regarding Genotoxicity Studies of Ethylene Oxide, Epichlorohydrin and 1,3-Butadiene with Attachments Dated May 6, 1994. EPA Document No. 88940000277.

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. EPA Document No. 87820012138. Microfiche OTS 0206066.

Van Doorn, R., M. Ruijten, and T. van Harreveld. 2002. Guidance for the Application of Odor in Chemical Emergency Response. Unpublished Report.

Wexler, B. 1971. Determination of epichlorohydrin contamination in an industrial facility for the manufacturing of epoxy resins [in Romanian]. Mater. Plast. (Bucharest) 8:322-323.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

ETHYL PHOSPHORODICHLORIDATE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on ethyl phosphorodichloridate. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values. Therefore, AEGL-1 values are not recommended for ethyl phosphorodichloridate. In the absence of appropriate chemical-specific data, a fractional reduction of the AEGL-3 values may be used to derive AEGL-2 values (NRC, 2001). The AEGL-3 values were divided by 10 to derive AEGL-2 values for ethyl phosphorodichloridate…. A combined male and female rat 4-hour BMCL05 of 38.0 ppm (Bayer, 1983) was used as the point-of departure (POD) for AEGL-3 values.

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee agrees that there are insufficient data at this time to derive AEGL-1 values for ethylphosphorochloridate.

AEGL-2

Page 15, lines 5-11: “In cases of a steep-concentration-response curve, AEGL-3 values may be divided by 3 to estimate AEGL-2 values (NRC, 2001). However, rat lethality data for ethyl phosphorodichloridate suggest that the concentration-response curve is not steep (4-hour exposure: 0% mortality at 37 ppm, 20% mortality at 61 ppm; 20% mortality at 75 ppm; 60% mortality at 90 ppm; 85% mortality at 143 ppm,; and 100% mortality at 355 ppm; Bayer, 1983). Therefore, the factor of 3 is not considered sufficient, and AEGL-2 values will be estimated by dividing AEGL-3 values by 10.” The data appears to be contrary to the statement “the concentration-response curve is not steep.” The authors should remove this statement from the TSD. AEGL-2 should be recalculated by dividing AEGL-3 values by 3, as recommended in SOP section 2.2.2.2.3 (page 43). The authors should consider including a plot of the concentration-response curve in the TSD to add clarity.

The AEGL-2 values are derived based on AEGL-3 values. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values.

AEGL-3

Page 16, lines 8-15: “Inter- and intra-species uncertainty factors of 3 each will be applied (total UF = 10). Ethyl phosphorodichloridate appears to be a primary contact irritant. Rat studies suggest that vapors are irritating to the eyes and nose, and that pulmonary edema increases as concentration increases (Rhone Poulenc, Inc., 1990; Bayer, 1983). The liquid was corrosive to the skin and eyes of rabbits (Rhone Poulenc, Inc., 1990). It also reportedly reacts with water to produce hydrogen chloride, which supports a mechanism of primary irritation. These types of portal of entry effects are not expected to vary greatly within or between species. Therefore, the total UF of 10 is considered sufficient.” Section 2.5.3.3.4 of the SOP states that “a default [intraspecies] UF of 10 is generally used to account for the

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

differences in the potential broad range of human susceptibility to respiratory irritants… [and] responses of asthmatics to respiratory irritants may range from mild to severe. A UF of less than 10 might be used when scientific evidence shows that a smaller UF will be protective.” The TSD authors did not provide sufficient scientific evidence that a UF of 3 will be protective. Unless such evidence is available, the intraspecies UF must be changed to 10.

Other Comments

Page 8, Table S-1: Add MFs to the end-point (Reference) column in the AEGL values table in the summary.

Page 9, Table 1: Add vapor pressure data to Table 1 on chemical and physical data for ethyl phosphorodichloridate

Page 10, line 20, to Page 11, line 12: Please summarize the acute lethality data for 1-h exposure in a table—similar to the table provided for the 4-h exposure data (Page 12, Table 3). A table summary will facilitate comparisons across exposure regimes and the lethality results.

Page 15, lines 32-33: “The smaller chamber size used in the 4-hr study (10 L) likely allowed for better mixing of the test atmosphere than the 40 L and 100 L chambers used in the 1-hr study.” This statement is speculative and should be deleted from the TSD.

Page 13, Section 4.2 Mechanisms of Toxicity: Expand narrative to include information on the reactivity and potential for aerosol formation, as the latter may result in deeper airway injury, which could be delayed. In addition, the authors should expand this section to include toxicity comparisons between ethyl phosphorodichloridate and its decomposition products.

References

Bayer. 1983. Letter from Mobay Corp. to EPA Submitting Toxicology Study on Ethylesterdichloride [in German] with Attachment. EPA Document No. 86910000570 and 86910000571. Microfihe No. OTS0530306 and OTS0530307.

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

Rhone Poulenc, Inc. 1990. Letter from Rhone Poulenc, Inc. to EPA Submitting Enclosed Toxicological Test on MOCAP Chloridate and an Acute Inhalation Toxicity Study of EDCP in Rats with Attachments. EPA Document No. 86910000587. Microfihe No. OTS0528775.

ETHYLENE CHLOROHYDRIN (2-CHLOROETHANOL)

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on ethylene chlorohydrin. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for deriving AEGL-1 values. There were neither human nor animal data on AEGL-1 severity effects following exposure to ethylene chlorohydrin vapor…. Consistent with NRC (2001) guidance, the AEGL-2 values have been estimated as a three-fold reduction of the AEGL-3 values…. Analysis of the mouse data from the Goldblatt (1944) revealed both nonlethal and lethal exposures for durations of 120 minutes. Specifically, a 120-minute exposure to 280 ppm was not lethal while exposure to 1090 ppm for the same duration resulted in 100% lethality.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee agrees that at this time there are insufficient data to derive AEGL-1 values for ethylene chlorohydrin.

AEGL-2

The AEGL-2 values are derived based on AEGL-3 values. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values.

AEGL-3

Pages 17, line 43 to Page 18, line 6: “Limited data in guinea pigs suggested this species to be less sensitive than the rats and mice. Based upon the differences in the lethal response between the more sensitive rats and mice, an interspecies uncertainty factor of 3 was considered appropriate.” Section 2.5.3.2.4 of the SOP stated that when “insufficient data on differences between species are available…, an interspecies UF of 10 is applied.” Similarly, Section 2.5.3.2.7 states that “the UF for interspecies response adjustment is 10 when there are inadequate data or insufficient information about the chemical or its mechanism of action to justify and alternative UF.” Although the Goldblatt (1944) data do show little variation between species with regard to lethality, the data set is scant—it is in effect a limited, not-very-systematic dose-ranging study where only a single animal per exposure group was used except for rats and mice and where only three animals were used per exposure group. The interspecies UF for ethylene chlorohydrin should be increased to 10.

Other Comments

Page 7, Executive Summary: “The data in animals are limited….” As noted in the text, the data available are sparse, yet the summary text is longer than one full page. Determine whether there is material that is not necessary in a summary and that can be in the body of the document. For example, the general discussion on the concentration-exposure duration (lines 46-48) could be deleted without effect.

Page 7, line 2: The full title should be “Executive Summary”.

Page 9, Table 1: The authors should address the following items:

• Please review the listed synonyms. There is no “nitro” group in ethylene chlorohydrin, yet “nitrotrichloromethane”, “aquinite”, “trichloronitromethane”, and “mictrochloroform” are listed as synonyms.

• Add the saturated vapor concentration.

• Although the Merck Index (Budavari et al 1996) is a good reference for the chemical and physical data, it is less accessible than other references. Consider using more readily available references, especially those publicly available online.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 9, line 13, to Page 10, line 13: The three human exposure case studies—Goldblatt and Chiesman (1944), Dierker and Brown (1944), and Bush et al. (1949)—are not well-described. For example, the descriptions do not include whether any protective measures were used to limit exposures. Is there additional information to describe in more detail the exposures reported by these three studies and how the exposure levels were estimated?

Page 9, line 9-13: “Bush et al. (1949) also reported several nonfatal exposures to ethylene chlorohydrin (400-500 ppm) but no exposure duration was provided although it was noted that this level was likely constant for up to 140 hours with a peak concentration of 3300 ppm being attained at about 4 hours.” In the description of Bush et al (1949), there seems to be some confusion in matching concentrations, durations, and effects. A constant exposure of 140 h would be more than 5 continuous, 24-h days. Is this correct? Did the concentration peak (3,300 ppm) at 4 h into the exposure duration of 140 h? The authors should review the original source and determine whether the information can be more clearly described or indicate in the TSD that the reported exposure conditions are unclear.

Page 9, lines 32-33: “An odor threshold of 0.4 ppm has been reported (Semenova et al., 1980). Data are unavailable with which to calculate an LOA.” The LOA is referred to here, but the appropriate reference (Ruijten et al 2009) is not cited. The Semenova citation is listed in the references as “cited in ACGIH 1991.” The text of the TLV documentation (ACGIH 2001) does not list an odor threshold sourced to the Semenova reference. Please confirm the reference or cite another authority (e.g., ACGIH 2001 cites the ninth edition of Sax).

Page 10, Section 3.1 Acute Lethality (also Page 14, Section 3.2. Nonlethal Toxicity): The lethality and nonlethality data from the Ambrose (1950) study are significantly different from the rest of the animal toxicity data presented in the TSD. For example, Ambrose reports lethality in rats exposed to ethylene chlorohydrin for 1-h at 7.5 ppm. All other discussed studies report lethality concentrations greater than 600 ppm for the same exposure duration. Is there any information that might account for this difference? This is of significant concern when comparing the results reported by Ambrose with the proposed AEGL values. To reject the Ambrose results, the authors need to provide some explanation either in Sections 3.1. and 3.2 or in the AEGL derivation sections.

Page 11, lines 14-18 (see also Page 11, Table 2; Page 12, Table 3 and Table 4; Page 13, Table 5; and Page 14, lines 15-16): Please carefully review the ppm equivalents of the g/L values. Different values are given for the ppm equivalent of the same g/L values. Please address the following errors and check for others:

• Page 11, lines 15-16: Two different values are given for the ppm equivalent of 0.001 g/L.

• Page 11, Table 2: Two different values are given for the ppm equivalent of 0.003 g/L.

• Page 12: The same ppm equivalent value is used for both 0.005 g/L in Table 4 and for 0.0052 g/L in Table 3, and these are also repeated in Table 5.

• Page 13, Table 5: Three different values are given for the ppm equivalent of 0.003 g/L.

• Page 14, line 16: The ppm equivalent for 0.005 g/L is a different value than is listed in Tables 4 and 5.

Page 11, Table (see also Page 12, Table 3 and Table 4): A footnote “a” is shown beneath the table, but no entry in the table is so footnoted.

Page 11, line 25: “bConversion from g/L to ppm based upon data reported by investigator.” Please clarify this footnote. Is the investigator the author of the TSD or same reference that is cited in the first footnote (line 24)?

Page 11, lines 27-28: “Goldblatt (1944) also reported on a repeated-exposure experiment in which groups of 3 rats (strain and gender not specified) were exposed….” Please revise this statement. Only a single group of three rats (reference text pp. 216-217) was exposed.

Page 11, lines 34-35: “Browning (1965) cites a four-hour LC50 value of 32 ppm for rats. Semenova et al. (1971) cited an LC50 of 88 ppm with no exposure duration.” Please address the following:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

• Browning (1965) was a review text. Was there a primary source document cited for the LC50? If not, please add a statement that no primary reference was cited.

• Please correct the in-text citation for Semonova et al. The study was published in 1980 not 1971. Also, Semonva et al (1980) is listed in the references (p. 23, line 16) as “cited in ACGIH, 1991.” The authors are citing 20-year-old documentation (ACGIH) that is updated on a regular basis. The 2001 ACGIH documentation does not use Semenova as a source for the LC50. Was the LC50 information obtained elsewhere? If Semenova was used in the1991 ACGIH documentation, it may have been an error that was removed during an update. The authors should revise the text based on the most recent version of the ACGIH documentation.

• Page 13, Table 5: It appears that the Browing and Semenova LC50 values are listed in Table 5, but the Semenova value has been changed from 88 ppm to 33 ppm. In addition, Table 5 includes an exposure duration, but the text indicates “88 ppm with no exposure duration.” Which is correct?

Page 13, Table 5: Table 5 is summary information contained in Tables 2, 3, and 4. To simplify the presentation and facilitate ready comparison and evaluation of the data, the TSD authors should delete Tables 2, 3, and 4. Move the footnotes from Tables 2, 3, and 4 to Table 5. Move the two stand-alone LC50 values to the beginning, footnote the sources of the LC50 values, and identify the source of the rest of the data. As noted above, please carefully review the ppm equivalents of the g/L values

Page 14, lines 26-28: The paragraph describing data in rabbits is worded awkwardly. The authors should consider revising the paragraph as follows (that is, in the same manner as the previous paragraph on cats, lines 19-23): “Goldblatt (1944) reported that rabbits [no details provided regarding gender and breed] inhaling ethylene chlorohydrin at concentrations of 10-15 mg/L…showed no effects on blood pressure or respiration.”

Page 15, line 15: Section 3.6. Summary (weight-of-evidence approach) is missing from the TSD.

Page 15, Section 4 Special Considerations: The authors should consider adding cautionary notes regarding issues related to the toxicity of 2-chloroethanol, which lack supporting data. For example, in both the human and animal toxicity sections, the TSD authors note that in some cases, symptoms did not occur until after exposure to ethylene chlorohydrin had ceased; that is, there were no warning properties of exposure (see p. 10, lines 25-30; p. 11, lines 3-5). There were some indications that some people were more susceptible and that possibly women were more susceptible than men.

Page 15, lines 42-43: “There are no structure activity data with which to develop AEGL values for ethylene chlorohydrin.” Goldblatt (1944) addressed structure-activity relationships, and both chloroacetaldehyde and chloroacetone seem to provide useful structural analogs. It may also be worth noting that 2-chloroethanol and the latter two chemicals all have TLVs of 1 ppm as a ceiling value and that the proposed AEGL values for 2-chloroethanol and chloroacetaldehyde are similar. Supporting data for the 2-chloroethanol AEGL values may be available in this information.

Page 17, lines 43-44: “Limited data in guinea pigs suggested this species to be less sensitive than the rats and mice…. based upon the differences in the lethal response between the more sensitive rats and mice….” Please state this information more clearly. The authors should revise as follows (revisions italicized): “On the basis of the differences in the lethal response between the guinea pigs and the more sensitive rats and mice….”

Page 18, Section 8.1 AEGL Values and Toxicity End Points: The authors should consider revising this section. Because data were insufficient to derive AEGL-1 values and because AEGL-2 is derived from AEGL-3, the summary section should not include information about toxic end points unrelated to AEGL-3. The unrelated toxicity information provided would be more appropriate in Section 3.6. Animal Toxicity Summary, and Section 8.3. Data Adequacy and Research Needs. Please also include specific details about reported effects. The quotation “animals exhibited a wide range of effects during exposure but the effects were not characterized as typical narcosis” (lines 20-21) is vague. What are the effects? What is “typical narcosis”? The next sentence (lines 23-24) mentions “signs and toxicity” findings without providing details. What are the signs?

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 18, Section 8.2 Comparisons with Other Standards and Guidelines: “A summary of currently available standards and guidelines is shown in Table 10. The AEGL values are consistent with currently available guidelines and standards.” As noted in Appendix J of the SOP (p. 201), a summary discussion of important comparisons between AEGL values and other standards and guidelines should be presented. The fact that the OSHA, NIOSH and ACGIH values are all ceiling values is noteworthy and would warrant some discussion. The proximity of short-duration AEGL values with the NIOSH IDLH also warrants some discussion.

Page 19, Table 10, Extant Standards and Guidelines for Ethylene Chlorohydrin: Please address the following:

• Three of the standards or guidelines shown (PEL, recommended exposure limit [REL], and TLV) are ceiling values that should not be exceeded for any time period. These values would be more accurately presented in Table 10 as the same number in each of the exposure duration columns, similar to the way AEGL-1 values for many irritants are presented.

• The IDLH value was revised in May 1994 from 10 ppm to 7 ppm (see http://www.cdc.gov/niosh/idlh/107073.html).

• The last two rows in Table 10 (MAK Spitzenbegrenzung and Einsaztoleranzwert) are blank. If values are available, please add them to the table. If values are not available, please delete these rows and delete the associated footnote definitions (p. 20, lines 26-33).

Pages 19-20, footnotes c, d, f, g, h, and i: The definitions provided for OSHA, NIOSH, and ACGIH do not apply. Please replace these definitions with the relevant definitions for ceiling values from the respective organizations or agencies.

Page 20, Section 8.3 Data Adequacy and Research Needs: “Data defining the exposure-response relationship for nonlethal effects of ethylene chlorohydrin vapor exposure are insufficient…. Descriptions of effects (in any) occurring at the nonlethal exposures are lacking. Additional data are needed with respect to the exposure-response relationship and mode action….” The discussion presented here addresses research needs but not data adequacy. Although the state of the 2-chloroethanol database does not warrant the depth of data-adequacy assessment detailed in the SOP (pp. 53-57), some evaluation of the quality of the data and the deficiencies in the data is required in this section.

Page 21, Section 9, References: Please address the following:

• If an online database or document is cited, list the URL along with the last-accessed date (see p. 23, lines 9 and 21).

• Confirm that all cited URLs are still accessible.

• Please list the URLs for documents that have publicly accessible online counterparts (e.g., the NIOSH citations)

• Page 21, lines 39-40 (also Page 22, lines 7-8): The International Uniform Chemical Information Database (IUCLID) document and the Litchfield paper are not cited in the text. Please add the appropriate in-text citations or delete them from the reference list.

• Page 22, lines 23-26: For the NRC (1985) citation, please indicate which compound in Volume 5 is being referenced.

• Page 23, lines 9-10: For the OSHA Table Z-1 Limits for Air Contaminants reference, how was the 2007 date determined? No date is provided on the OSHA Web site.

Page 34, Table AEGL-3 Values for Ethylene Chlorohydrin: Please delete the 1960-ppm data from “Exposure Route/Concentrations/Durations.” These data were not used in the AEGL-3 derivation.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

References

ACGIH (American Conference of Governmental Industrial Hygeinists). 2001. Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed . Publication #0100Doc. American Conference of Governmental Industrial Hygienists, Inc., Cincinnati OH.

Ambrose, A.M. 1950. Toxicological studies of compounds investigated for use as inhibitors of biological processes. II. Toxicity of ethylene chlorohydrin. A.M.A. Arch. Ind. Hyg. Occup. Med. 2(5):591-597.

Browning, E. 1965. P. 399 in Toxicity and Metabolism of Industrial Solvents. New York: Elsevier.

Budavari, S., M.J. O’Neil, A. Smith, P.E. Heckelman, and J.F. Kennedy, eds. 1996. The Merck Index, 11th Ed. Whitehouse, NJ: Merck.

Bush, A.F., H.K. Abrams, and H.V. Brown. 1949. Fatality and illness caused by ethylene chlorohydrin in an agricultural occupation. J. Ind. Hyg. Toxicol. 31:352-358.

Dierker, H., and P.G. Brown. 1944. Study of a fatal case of ethylene chlorohydrin poisoning. J. Ind. Hyg. Toxicol. 26:277-279.

Goldblatt, M.W. 1944. Toxic effects of ethylene chlorohydrin, Part II. Experimental. Br. J. Ind. Med. 1:213-223.

Goldblatt, M.W., and W.E. Chiesman. 1944. Toxic effects of ethylene chlorohydrin, Part I. Clinical. Br. J. Ind. Med. 1:207-213.

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

Ruijten, M.W.M.M., R. von Doorn, and A.P. van Harreveld. 2009. Assessment of Odour Annoyance in Chemical Emergency Management. RIVM Report 609200001. National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Semenova, V.N., O.V. Sadovnik, V.N. Fedianina, E.V. Kreslina, and V.A. Kopanev. 1980. Biological effects of ethylene chlorohydrin as an atmospheric pollutant [in Russian]. Gig. Sanit. 1:84-85.

ISOCYANATES

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs) on cyclohexyl, ethyl, n-butyl, and phenyl isocyanates. Presentations on the TSDs were made by Heather Carlson-Lynch, of Syracuse Research Corporation.

AEGL-Specific Comments are provided for each individual isocyanate. Specific Comments for n-butyl isocyanate are published in Part B of the twentieth interim report. Comments pertaining to all isocyanates are combined in General Comments for Isocyanates.

n-Butyl Isocyanate

Comments for n-butyl isocyanate are provided in the Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part B. The note provided here only serves as a reminder for the TSD authors to consider the comments in Part B together with the comments provided below for the other isocyanates.

Cyclohexyl Isocyanate

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 and -2 values are not recommended because no data with the appropriate end points were found in either the human or animal studies. Limited animal data were available for calculation of AEGL-3. The 6-hour exposure studies by Eastman Kodak Co. (1990, 1992) were the only studies available that used more than one concentration.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee agrees that there are insufficient data at this time to derive an AEGL-1 value for cyclohexyl isocyanate.

AEGL-2

Page 11, lines 16-17: “AEGL-2 values are not recommended because no data with the appropriate end points were found in either the human or animal studies.” Section 2.2.2.2.3 (p. 43) of the SOP stated that “In the absence of specific data used to determine an AEGL-2 value, one third of the AEGL-3 value has been used to establish the AEGL-2 value. This approach can only be used if the data indicate a steep exposure-based relationship based on data for effects below the AEGL-2 value and the lethal-effect value.” The authors should derive AEGL-2 based on AEGL-3 or provide adequate justification for not deriving an AEGL-2.

AEGL-3

Page 12: lines 1-2: “The lethality data from Eastman Kodak Co. (1990, 1992) were used to calculate a 6-hour BMCL05 value by a log-probit analysis using EPA benchmark dose (BMD) software….” As is noted in Section 7.2 data (p. 11, lines 32-42), the Eastman Kodak studies evaluated toxicity at a low (27.79 ppm) and a higher (53.2 ppm) exposure (three animals per exposure group). At the low exposure, one animal died and the other two animals were killed. At the high exposure, all three animals died. A BMD cannot be calculated from two 100% lethality groups. The TSD authors need to consider whether an AEGL-3 value can be calculated from these data.

Other Comments

Page 9, Table 2 Acute Lethality in Rats Exposed to Cyclohexyl Isocyanate: Please clarify how the studies by Mobay were able to get saturated exposure concentrations and please include the saturated concentrations in the table (if available). The authors should add some discussion to this issue in the supporting text as well.

The vapor pressure is not included in the document. With these very toxic materials, it is important for emergency responders to understand how volatile they are. Please evaluate available sources for potential vapor pressures. For example, Cole-Parmer and Sigma-Aldrich include vapor pressure for cyclohexyl isocyanate on their respective material safety and data sheets (MSDs). As a check, it is possible to estimate vapor pressure using Trouton’s rule.

Ethyl isocyanate

The following is excerpted from the Executive Summary of the TSD:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Data are insufficient for derivation of AEGL-1 values for ethyl isocyanate. Therefore, AEGL-1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for ethyl isocyanate. This approach is justified by the steep concentration-response curve (0% mortality in rats exposed to 27 ppm and 100% mortality at 82 ppm for 6-hr; Eastman Kodak, 1964).The concentration causing no deaths in rats (27 ppm for 6-hours; Eastman Kodak, 1964) was used as the point-of-departure for AEGL-3 derivation.

AEGL-Specific Comments

AEGL-1

The committee agrees that the data are insufficient at this time to derive AEGL-1 values for ethyl isocyanate.

AEGL-2

The committee approves the derivation of AEGL-2 values for ethyl isocyanate.

AEGL-3

The committee approves the derivation of AEGL-3 values for ethyl isocyanate.

Page 14, lines 3-10: “Clinical signs are consistent with contact irritation; this mode of action is not likely to vary considerably across individuals although dosimetric factors may vary. To account for possible dosimetric variability, the intraspecies uncertainty factor is 3. The intraspecies uncertainty factor of 3 is also supported by the steep concentration-response…. A modifying factor of 10 was applied to account for the sparse database; data are available from only one study using a limited number of animals of only one species (3 rats/group).” The rationale for the intraspecies UF is inconsistent with the SOP, Section 2.5.3.3.4, which states that “a default [intraspecies] UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants” unless “scientific evidence shows that a smaller UF will be protective.” The rational for an MF of 10 because of a sparse database is also inconsistent with the rational provided for other isocyanates. Of the four isocyanates presented to the committee, ethyl isocyanate had the best data for AEGL-3 development. An MF of 3 seems more appropriate. Please note that the suggested UF and MF changes do not change the derived AEGL-3 values.

Phenyl isocyanate

The following is excerpted from the Executive Summary of the TSD:

The AEGL-1 values are based upon a 45-minute exposure of rats to 1.1 mg/m3 (0.2 ppm). This exposure was considered to be a threshold for respiratory tract irritation (Pauluhn et al., 1995)…. For AEGL-2 derivation, the exposure of rats to 0.8 ppm over a 2-week period was considered a no-effect level for AEGL-2 severity effects (Pauluhn et al., 1995)…. A toxicity bioassay in rats conducted by Bayer AG (1991a) served as the key study for AEGL-3 development.

A revised document should be submitted to the committee for review.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-Specific Comments

The committee agrees with the derivation of AEG-1, AEGL-2 and AEGL-3 values for phenyl isocyanate. See Other Comments below for suggested revisions to the TSD.

Other Comments

The authors should include a precautionary statement that AEGL values are very close, but the data solidly support the derived AEGLs.

Page 13, lines 23-43: Figure 1 in the Pauluhn (1995) study allows a rat RD50 estimate of approximately 2.7 ppm. The authors should consider adding this value to the summary description of the Pauluhn study; this value would allow a comparison with RD50 of other isocyanates.

Page 14, lines 3-6: “Multiple exposures up to 0.1 ppm appeared to be without discernable effect and exposures up to 0.8 ppm did not result in histological changes in respiratory tract tissue although investigators in one study reported a slightly decreased respiratory rate in rats at exposures above 0.2 ppm for 45 minutes.” Please provide the appropriate citation for this information.

General Comments for All Isocyanates

Because data are relatively sparse for an individual isocyanate and isocyanates have many similarities, the authors should consider consolidating these documents into a single TSD. A comparative table for the four isocyanates and any other related chemicals (such as methyl isocyanate) should be added to the TSD to facilitate comparisons.

The isocyanate documents need to be revised to improve consistency in presentation and evaluation of data. Particular attention needs to be given to the cyclohexyl isocyanate document, as it was written 2 years before the other isocyanates and has major inconsistencies. The documents should be edited for misspellings and word usage.

Use of UFs and MFs are inconsistent across the isocyanate documents. Often there is insufficient rationale supporting the choice of UFs or MFs. The SOP guidance must be followed for selecting UFs and MFs, and doing so will improve consistency.

The chemical structure or formula needs to be provided on the cover page for all isocyanates.

References

Bayer, AG. 1991a. Phenyl Isocyanate; Untersuchungen zur akuten Inhalationstoxizität an der Ratte. Report No. 20354. Study No. T7037386. Bayer AG Institute for Toxicology.

Eastman Kodak Co. 1964. Toxicity and Health Hazard Summary: Ethyl Isocyanate. Laboratory of Industrial Medicine, Eastman Kodak Co., Rochester, NY. EPA Document No. 86910000051. Microfiche No. OTS0528345.

Eastman Kodak Co. 1990. Letter from Eastman Kodak Company to EPA Submitting Enclosed Health and Safety Study on Cyclohexyl Isocyanate with Attachments. EPA Document No. 86910000052. Microfiche No. OTS0528346.

Eastman Kodak Co. 1992. Initial Submission: Acute Inhalation Toxicity Test with Cyclohexyl Isocyanate in Rats with Cover Letter Dated August 10, 1992. EPA Document No. 889200005123.

Pauluhn, J., W. Rüngeler, and U. Mohl. 1995. Phenyl isocyanate-induced asthma in rats following a 2-week exposure period. Fundam. Appl. Toxicol. 24(2):217-228.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

MERCAPTANS

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs) on ethyl, methyl, phenyl, and tert-octyl mercaptans. Presentations on the TSDs were made by Mark Follansbee, of Syracuse Research Corporation. AEGL-specific and other TSD-specific comments are provided for each mercaptan. Comments pertaining to all four mercaptan documents are provided below in General Comments for Mercaptans.

Ethyl Mercaptan

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 values were based on a no effect level of 10 ppm for respiratory changes associated with odor avoidance in rabbits exposed for 20 minutes (Shibata, 1966b)…. No robust data consistent with the definition of AEGL-2 were available. Therefore, the AEGL-2 values for ethyl mercaptan were based upon a 3-fold reduction in the AEGL-3 values; this is considered an estimate of a threshold for irreversible effects and is appropriate because of the steep concentration-response curve for ethyl mercaptan toxicity.AEGL-3 derivation is based on a calculated LC01 (2250 ppm) in mice exposed to ethyl mercaptan for 4 hours (Fairchild and Stokinger, 1958).

This document can be finalized if the following comments are adequately addressed.

AEGL-Specific Comments

The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 for ethyl mercaptan.

Page 18, line 42, to Page 19, line 2 (also Page 6, line 46): “Furthermore, use of a total UF of 30 would yield a 30-minute AEGL-3 of 150 ppm, which is inconsistent with available human data. Humans exposed to 112 ppm ethyl mercaptan for 20 minutes exhibited only a slightly irregular and decreased breathing rate (Shibata, 1966a).” Support of the 30-min AEGL-3 value using the Shibata (1966a) study is appropriate, but the description used could be more precise. The “available human data” in this case is a single subject exposed at 112 ppm and not “humans exposed to 112 ppm….” Rephrase to read “with available quantitative human data, where a single subject exposed at…” or a similar formulation.

Other Comments

Page 8, Table 1 Physical and Chemical Values of Ethyl Mercaptan: Please add the saturated vapor concentration.

Page 20, Section 8.2. Comparisons with Other Standards and Guidelines: Section 8.2. includes a table of occupational exposure limits for ethyl mercaptan. Appendix J of the SOP, p. 201, stated that “A summary discussion of important comparisons should be presented in the text….” AEGL-1 values exceed longstanding occupational guidelines (e.g., the current TLV was established in 1970 and reviewed and confirmed in 2004, and the NIOSH REL was established in 1978). Modest discussion should be added to Section 8.2 to acknowledge and explain the differences. The discussion could address divergent data requirements for the different guidelines, different target populations, and other considerations that may affect these differences.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 20, lines 9-10, and Table 10 Extant Standards and Guidelines for Ethyl Mercaptan: there is an apparent discrepancy in the listing of the REL for ethyl mercaptan in the NIOSH Pocket Guide to Chemical Hazards (at http://www.cdc.gov/niosh/npg/npgd0425.html) compared with the definitions listed in its introduction: Is the REL a ceiling value (“C”) or a short-term value (“15 min”)? If it is a short-term exposure limit (STEL), it typically would be accompanied by an 8-h TWA. If it is a ceiling value, then it is an 8-h value not to be exceeded for any short period (unlike a TWA), so the value would be the same in each AEGL time period column. Determine the correct exposure criterion, use the appropriate definition, and place the value in the correct column(s) in Table 10.

Methyl Mercaptan

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for methyl mercaptan…. AEGL-2 values were based on shallow breathing and hypoactivity in mice exposed to 258 ppm methyl mercaptan for 6 hours (Elf Atcohem, 1996)…. AEGL-3 values were based on the calculated LC01 (430 ppm) for rats exposed for four hours (Tansy et al., 1981).

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

Page 19, line 15: “Animal data consistent with the definition of AEGL-1 were not available.” Review of Section 3.2. Nonlethal Toxicity (pp. 15-16) indicates that three studies (identified below) provide data that might permit either derivation of or support for AEGL-1 values. Reassess the data from these studies to determine whether AEGL-1 values can be derived. If AEGL-1 values cannot be derived from the available data, the rationale for not using these studies should be briefly and clearly stated (e.g., the DuPont study was not used because concentrations were “nominal” rather than measured). Note that the following data may have an impact on the POD for AEGL-2 values:

Elf Atochem (1996). The end points “shallow breathing and hypoactivity” at 258 ppm, at least in the absence of any other descriptors, might meet the definition of AEGL-1 effects, as the severity of these effects is not otherwise described and they were not seen the day after exposure. More notable, no effects were seen at 114 ppm. Thus, 114 ppm appears to meet the criterion for highest experimental exposure without an AEGL-1 effect (SOP, Section 2.2.2.1.3., p. 42).

Tansy et al. (1981). Exposures at 2 and 17 ppm noted no significant effects and only a decrease in body weight at 57 ppm after 3 months of exposure. Thus, 57 ppm would also meet the criterion for highest experimental exposure without an AEGL-1 effect (SOP, Section 2.2.2.1.3., p. 42).

DuPont (acute and subchronic) (1992). Effects seen at exposure concentrations in both the acute and subchronic phases appear consistent with AEGL-1 values: acutely at 250 ppm and subchronically at 100 ppm. These exposures might meet the criterion of an effect level for an AEGL-1 response (SOP, Section 2.2.2.1.4., p. 42).

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-2

The committee approves the derivation of the AEGL-2 values for methyl mercaptan. Please note that potential derivation of AEGL-1 values may have an impact on the chosen POD for AEGL-2 (see comments above).

AEGL-3

The committee approves the derivation of the AEGL-3 values for methyl mercaptan.

Other Comments

Page 10, Table 1 Physical and Chemical Values of Methyl Mercaptan: Please add the saturated vapor concentration to this table.

Page 18, Table 6 Comparative Toxicity of Mercaptans: Add the mouse 4-h LC50 value from the Horiguchi (1960) study (p. 13, line 4) to the methyl mercaptan row.

Pages 24-25, Section 8.2. Comparisons with Other Standards and Guidelines: Appendix J of the SOP, p. 201, states that “A summary discussion of important comparisons should be presented in the text.” Please add a brief discussion for the following discrepancies: (1) the 8-h AEGL-2 value is less than a factor of 2 above the OSHA PEL; (2) no AEGL-1 values are proposed, but there are NIOSH REL and ACGIH TLV-TWA values (as well as Swedish, German, and Dutch OELs); and (3) the 1-h AEGL-2 values is almost a factor of 2 greater than the AIHA ERPG-2 value. The discussion could address divergent data requirements for the different guidelines, different target populations, and other considerations that may affect these differences.

There is a discrepancy in the actual listing of the REL for methyl mercaptan in the Pocket Guide (at http://www.cdc.gov/niosh/npg/npgd0425.html) compared with the definitions listed in its introduction: Is the REL a ceiling value (“C”) or a short-term value (“15 min”)? If it is a STEL, it typically would be accompanied by an 8-h TWA value. If it is a ceiling value, then it is an 8-h value not to be exceeded for any short period (unlike a TWA), so the value would be the same in each AEGL time period column. For use on this line in the TSD, determine the correct exposure criterion, use the appropriate definition and term in the definition (REL TWA, REL STEL, or REL), and place in the correct column in Table 11.

Page 25, line 7: “NIOSH (2003) STEL is a 15-minute TWA exposure that should not be exceeded at any time during a workday.” It is not clear that the NIOSH valued cited in Table 11 is a STEL. See related comment above.

Phenyl Mercaptan

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 values are not recommended for phenyl mercaptan due to insufficient data. No robust data consistent with the definition of AEGL-2 were available. Therefore, the AEGL-2 values for phenyl mercaptan were based upon a 3-fold reduction in the AEGL-3 values; this is considered an estimate of a threshold for irreversible effects and is appropriate because of the steep concentration-response curve for phenyl mercaptan toxicity…. AEGL-3 values were based on a calculated LC01 (10.3 ppm) in rats exposed to phenyl mercaptan for 4 hours (Fairchild and Stokinger, 1958).

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

This document should be returned to the committee for review.

AEGL-Specific Comments

The committee is concerned about discrepancies between derived AEGL values and other exposure standards. Approval of the derivation of AEGL-1, AEGL-2, and AEGL-3 for phenyl mercaptan is contingent upon adequate explanations for the differences. Of particular concern is the similarity between the 8-h AEGL-3 and a chronic occupational exposure standard (see detailed comments below).

Other Comments

Pages 17, Section 8.2. Comparisons with Other Standards and Guidelines: Appendix J of the SOP, p, 201, stated that “A summary discussion of important comparisons should be presented in the text….” Additional discussion is needed for several differences. The discussion could address divergent data requirements for the different guidelines, different target populations, and other considerations that may affect these differences. Please add discussion regarding the following discrepancies:

• AEGL-1 values are “not recommended”, yet there are existing occupational standards for chronic exposure to phenyl mercaptan.

• The 8-h AEGL-2 value (0.17 ppm) is nearly a factor of 2 greater than the ACGIH 8-h ACGIDH TLV-TWA (0.1 ppm).

• The 8-h AEGL-3 value is equivalent to the MAC 8-h TWA, the latter being the same as the ACGIH 8-h TLV-TWA until 2004.

Page 17, line 31: “NIOSH REL-STEL (recommended exposure limits) (NIOSH 2006) is defined analogous to the ACGIH TLV-TWA.” Although the definition given here is technically correct, it would be more precise to use the definition of the NIOSH REL found in the introduction to the NIOSH Pocket Guide to Chemical Hazards at http://www.cdc.gov/niosh/npg/pgintrod.html#exposure. It is not clear, however, that the NIOSH value is a STEL. See the comment below.

There is a discrepancy in the actual listing of the REL for phenyl mercaptan in the Pocket Guide compared with the definitions listed in its introduction: Is the REL a ceiling value (“C”) or a short-term value (“15 min”)? If it is a STEL, it typically would be accompanied by an 8-h TWA value. If it is a ceiling value, then it is an 8-h value not to be exceeded for any short period (unlike a TWA), so the value would be the same in each AEGL time period column. For use on this line in the TSD, determine the correct exposure criterion, use the appropriate definition and term (REL TWA, REL STEL, or REL), and place in the correct column in Table 9. Also please add “NIOSH, 2006” to the reference list.

tert-Octyl Mercaptan

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for tert-octyl mercaptan. Therefore, AEGL-1 values are not recommended. In the absence of appropriate chemical-specific data, the AEGL-3 values were divided by 3 to derive AEGL-2 values for tert-octyl mercaptan. This approach is justified by the steep concentration-response curve for lethality in rats. AEGL-3 values were based on a 4-hour BMCL05 value of 11.5 ppm calculated from combined female rat data (Atochem, 1982).

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

This document can be finalized if the following comments are adequately addressed.

AEGL-Specific Comments

The committee agrees that there are insufficient data at the time to derive AEGL-1. The committee approves the derivations of AEGL-2 and AEGL-3 for tert-octyl mercaptan.

Other Comments

Page 6. Table 1. Physical and Chemical Values for tert-Octyl Mercaptan: Please add the saturated vapor concentration.

Pages 12, Section 4. Special Considerations: Please add a brief note that, at least in rats, females were significantly more susceptible than males to the toxic effects of tert-octyl mercaptan. This information could be added to Section 4.4, Species Variability or as a stand-alone statement in a new subsection for gender differences.

General Comments for All Mercaptans

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data and establishing scientifically-based AEGL values. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately.

When the AEGL values are finalized, the committee recommends that the mercaptans be published in a single volume. Introductory material to the mercaptans should include the AEGL values for hydrogen sulfide (published in Volume 9 of Acute Exposure Guideline Levels for Selected Airborne Chemicals).

References

Atochem. 1982. Initial Submission: Final Report on a Study to Establish an LC50 Concentration of t-Octyl Mercaptan in Adult Sprague-Dawley Rats of Both Sexes (Final) with Attachments and Letter. Microfiche No. OTS0534952.

DuPont. 1992. Toxicity of Methyl Mercaptan. Medical Research Project No. 287. Haskell Laboratory for Toxicology and Industrial Medicine. June 24, 1992.

Elf Atochem. 1996. Bone Marrow Micronucleus Assay in Male and Female Swiss-Webster Mice Following Acute Nose-Only Inhalation Exposure to Methyl Mercaptan. SRI International Study No. M020-95. Elf Atochem North America, Philadelphia, PA.

Fairchild, E.J., and H.E. Stokinger. 1958. Toxicologic studies on organic sulfur compounds. I. Acute toxicity of some aliphatic and aromatic thiols (mercaptans). Am. Ind. Hyg. Assoc. J. 19(3):171-189.

Horiguchi, M. 1960. An experimental study on the toxicity of methyl mercaptan in comparison with hydrosulfide [in Japanese]. J. Osaka City Med Cent. 9:5257-5293

Shibata, Y. 1966a. Studies on the influence of ethyl mercaptan upon the living body: III. Inhalation experiment of ethyl mercaptan gas in the human body [in Japanese]. Shikoku Acta Med. 22:844-850.

Shibata, Y. 1966b. Studies on the influence of ethyl mercaptan upon the living body: II. On the respiratory function and clinical findings in rabbits which inhaled ethyl mercaptan gas [in Japanese]. Shikoku Acta Med. 12:136-145.

Tansy, M.F., F.M. Kendall, J. Fantasia, W.E. Landin, R. Oberly, and W. Sherman. 1981. Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercaptan and other reduced-sulfur compounds. J. Toxicol. Environ. Health 8(1-2):71-88.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

METHACRYLONITRILE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on methacrylonitrile. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

The AEGL-1 was based on transitory nasal, throat or ocular irritation in humans exposed to 2 ppm methacrylonitrile for 10 minutes (Pozzani et al., 1968)…. No inhalation data consistent with the definition of AEGL-2 were available. Therefore, the AEGL-2 values for methacrylonitrile were based upon a 2-fold reduction in the AEGL-3 values…. The loss of consciousness, with no mortality noted, in rats exposed to 176 ppm for 3 hours was used as the basis of AEGL-3 (Pozzani et al., 1968).

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The committee approves the derivation of AEGL-1 values for methacrylonitrile.

AEGL-2

The AEGL-2 values are derived on the basis of the AEGL-3 values. See comments for AEGL-3 regarding UFs and MFs. A change in the AEGL-3 values will affect the final AEGL-2 values.

AEGL-3

The POD of 176 ppm for a 3-h exposure in rats is used to derive the AEGL-3 values. The exponent (n) for the concentration in the time-dose scaling (Cn × t) is 3 to extrapolate down to 30-min and 1-hr AEGLs, and is 1 to scale up to 4-hr AEGL. The 8-h AEGL is assumed to be the same as the 4-h AEGL. However, the available data as presented in Table 6 (p.18) showed that the resultant 8-h AEGL-3 is not protective against death.

Table 6 presents the following two sets of data in rats by Pozzani et al (1968) showing a C × t significantly lower than the C × t of 528 ppm-h (p. 32, line 29) used for deriving the 4-h AEGL-3:

1. In a 9 day exposure study, a 17% death in male and female rats (or 2 of 6 = 33% death in the males) occurred on day 1 of a 7-h exposure at 110 ppm. The 1-day NOEL for the end point of death is 50 ppm.

2. In a 91-day exposure study, a 29% death in male and female rats (or 7 of 12 = 58% death in the males) occurred on day 1 of a 7-h exposure at 110 ppm. The 1-day NOEL for the end point of death is 52.6 ppm. One of 12 male rats died at 52.6 ppm on day 2 of exposure.

The C × t of 368 ppm-h (52.6 ppm for 7 h) based on the higher of the two NOELs above is substantially lower than the 528-ppm-h used for deriving the 8-h AEGL-3. Using the 7-h POD of 52.6 ppm and retaining the current default n = 1 in the Cn × t equation, as well as the total interspecies and intraspecies

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

uncertainty factor of 10, the 8-h AEGL-3 would be 4.6 ppm (see equation below). The 8-hAEGL-2 would be 2.3 ppm (= 4.6/2).

images

The rationale for using a separate POD for the 8-h AEGLs should be discussed in the context of the entire toxicity database and the significance of exposure duration to the HCN mode of action.

Reference

Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacrylonitrile. Am. Ind. Hyg. Assoc. J. 29(3):202-210.

METHYL BROMIDE

At is meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on methyl bromide. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Methyl bromide has no odor or irritation properties at concentrations below those that define the AEGL-2. Therefore, an AEGL-1 was not established. The AEGL-2 values are based on the NOAEL for neurotoxicity, as evidenced by a lack of clinical signs, in several studies with rats and dogs…. The AEGL-3 values were based on the BMCL05 of 701 ppm in a 4-hour exposure of rats (Kato et al. 1986).

This document can be finalized.

AEGL-Specific Comments

The committee agrees that the data are insufficient at this time to derive AEGL-1 values. The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 for methyl bromide.

Other Comments

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately.

References

Kato, N., S. Morinobu, and S. Ishizu. 1986. Subacute inhalation experiment for methyl bromide in rats. Ind. Health 24(2):87-103.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

METHYL CHLORIDE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on methyl chloride. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD:

Because methyl chloride has no clearly defined odor or warning properties at concentrations that may be neurotoxic, an AEGL-1 is not recommended. The AEGL-2 values were based on several studies with rats; a monitoring study was used as support. The basis for the AEGL-2 was the absence of clinical signs in rats exposed to 1500 ppm for 6 hours/day for one day (Dodd et al. 1982) or 90 days (Mitchell et al. 1981)…. Data on lethality are limited to LC50 values for the mouse, a particularly sensitive species. Two studies reported no deaths in rats during the first 4 days of 5- and 12-day exposures to 5000 ppm for 6 hours/day (Morgan et al. 1982; Chellman et al. 1986a).

This document can be finalized.

AEGL-Specific Comments

The committee agrees that AEGL-1 values can not be derived at this time. The committee approves the derivation of AEGL-2 and AEGL-3 for methyl bromide.

Other Comments

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately

Mitchell et al. 1981 is missing from the reference list. Please add this citation to the reference list.

References

Chellman, G.J., K.T. Morgan, J.S. Bus, and P.K. Working. 1986a. Inhibition of methyl chloride toxicity in male F-344 rats by the anti-inflammatory agent BW755C. Toxicol. Appl. Pharmacol. 85(3):367-379.

Dodd, D.E., J.S. Bus, and C.S. Barrow. 1982. Nonprotein sulfhydryl alterations in F-344 rats following acute methyl chloride inhalation. Toxicol. Appl. Pharmacol. 62(2):228-236.

Morgan, K.T., J.A. Swenberg, T.E. Hamm, Jr., R. Wolkowski-Tyl, and M. Phelps. 1982. Histopathology of acute toxic response in rats and mice exposed to methyl chloride by inhalation. Fundam. Appl. Toxicol. 2(6):293-299.

METHYLISOTHIOCYANATE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on methylisothiocyanate (MITC). A presentation on the TSD was made by Heather Carlson-Lynch, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

The AEGL-1 values are based on a study with human volunteers. The study reported NOELs and LOELs for eye irritation, considered the most sensitive irritant response to MITC (Russell and Rush 1996)…. In the absence of data that address AEGL-2 end points and with evidence of a steep concentration-response curve, the AEGL-3 values were divided by 3 to derive the respective AEGL-2 values (NRC 2001).The points of departure for the AEGL-3 were the 1-hour and 4-hour highest non-lethal concentrations of 210 and 80 ppm, respectively, in studies with the rat (Clark and Jackson 1977; Jackson et al. 1981).

A revised document should be submitted to the committee for review.

AEGL-Specific Comments

AEGL-1

The key study for deriving AEGL-1 values is Russell and Rush (1996). However, the TSD notes that data from this study was taken from summaries (p. 25, line 40) in a California EPA document (Rubin et al 2003) and an EPA document. Section 2.3.2 (p. 51) states that “only toxicity data obtained directly from a primary reference source are used as the basis for “key” toxicity studies from which the AEGL values are derived. Additionally, all supporting data and information important to the derivation of an AEGL value are obtained solely from the primary references.” Every effort must be made to obtain the original document for review.

Page 20, lines 11-13: “The study with human volunteers is the most appropriate for derivation of AEGL-1 values. The study reported NOELs and LOELs for eye irritation, considered the most sensitive irritant response to MITC (Russell and Rush 1996).” The committee disagrees that the NOEL reported by Russel and Rush (1996) is a true NOEL for AEGL-1. The odor threshold for MITC (0.2 ppm) is lower than the NOEL for eye irritation across all exposure durations. Section 2.2.2.1 of the SOP (page 40) states that “below the AEGL-1 values, there may be specific effects, such as the perception of a disagreeable odor, taste, or other sensations (mild sensory irritation). In some people, that exposure level could result in mild lacrimation or coughing.” The TSD authors should use these data as a lowest observed adverse effect (LOAEL) for AEGL-1.

Page 20, lines 21-23: “An intraspecies uncertainty factor of unity is appropriate for a no-effect concentration for this sensitive end point….” The committee does not agree that the chosen POD is a NOEL. If the authors choose to use this POD, the committee recommends an intraspecies UF of 3. In addition, the human exposure to MITC was delivered through goggles. As a result, the study could not determine whether there were respiratory effects (the inhalation exposure route was eliminated). This factor is an additional reason to raise the intraspecies UF to 3.

AEGL-2

It is unclear why the eye irritation data from Russell and Rush (1996) was considered insufficient to derive AEGL-2 values. Eye irritation may impair an individuals’ ability to escape—an AEGL-2 effect. This possibility is suggested by a comparison of (1) data from Russell and Rush (1996), as described in the draft TSD (p. 11, lines 1-8, and Table 2); (2) data from Klimisch (1987) and Rosskamp et al. (1978) (p. 13-14, Table 4); (3) and the proposed AEGL values (p. 22, Table 9). This potential is worth noting in the derivation section, with reference to the signs and symptoms noted in Section 4.2. Mechanisms of Toxicity.

Although acute studies that address the AEGL-2 end points are unavailable, repeat-exposure studies support the AEGL-2 values. Rats exposed at 6.8 ppm for 6 h/d, 5 d/wk for 28 days showed signs of eye irritation and general discomfort during the third exposure day (Klimisch 1987). These signs were

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

reversible between exposures. Rats exposed at 10 ppm for 4 h/d, 5 d/wk for 12-13 weeks did not show clinical signs (Rosskamp et al. 1978). These concentrations are close to the derived 4- and 8-h AEGL-2 values. No clinical signs were seen at 1 or 1.7 ppm in the studies. The TSD should be modified to reflect the supporting data from the repeat-exposure studies.

AEGL-3

The data for key studies for deriving AEGL-3 values is from Russell and Rush (1996) and were taken from summaries (p. 23, line 31, and p. 24, line 19). SOP Section 2.3.2 (p. 51) stated that “only toxicity data obtained directly from a primary reference source are used as the basis for “key” toxicity studies from which the AEGL values are derived. Additionally, all supporting data and information important to the derivation of an AEGL value are obtained solely from the primary references.” Every effort must be made to obtain the original document for review.

Page 21, line 42, to page 22, line 7: “Interspecies and intraspecies uncertainty factors of 3 each for a total of 10 are generally applied to chemicals for which the mode of action is that of a direct-acting irritant (NRC 2001). However, application of a total uncertainty factor of 10 to the 4-hour study (80 ppm/10 = 8 ppm) results in values inconsistent with the repeat-exposure studies of Klimisch (1987) and Rosskamp et al. (1978). In those studies, clinical signs were either not observed or were not life-threatening in spite of 4-6 hour daily exposures to 6.8-10 ppm. Therefore, interspecies and intraspecies uncertainty factors of 1 and 3, respectively, were applied. An intraspecies uncertainty factor of 3 is considered sufficient to protect the sensitive population with respiratory disease (NRC 2001).” The material being referenced from the SOP (NRC 2001) is taken from p. 90, Section 2.5.3.4.4. This guidance (a UF of 3 for direct acting irritants) is true in general, but in the case of respiratory irritants, specific guidance is found in the SOP on p. 87, Section 2.5.3.3.4. “Therefore, a default [intraspecies] UF of 10 is generally used to account for the differences in the potential broad range of human susceptibility to respiratory irritants.” Where the weight of the evidence indicates that the UFs applied would result in proposed AEGL values at odds with human data, modification is required, as it appears to be here. Please modify the references to the SOP to use the appropriate guidance. This comment also applies to the material on p. 19, lines 10-16 of the draft TSD.

Other Comments

Page 6-7, Executive Summary: The level of detail presented is excessive for a summary. The paragraphs on derivation of the AEGL-1 and AEGL-3 values should be condensed. The paragraph on the derivation of the AEGL-2 values should be reduced to the first and last sentences (suitably modified).

Because human volunteers were used in the key study for AEGL-1, the TSD authors should state that the volunteers met the criteria for using human subjects.

Page 8, lines 7-8: “Metam sodium (active ingredient MITC) is the third most commonly used agricultural pesticide….” Please correct this sentence. MITC is not an ingredient of metam sodium. Metam sodium decomposes to MITC in the soil.

Page 9, Table 1 Chemical and Physical Properties: Insert the saturated vapor concentration.

Page 9, line 15: “MITC is marketed as a propesticide….” Please define propesticide.

Page 13, lines 24: “Histopathological examination revealed….” Please clarify for which exposure groups the histopathology results apply.

Page 21, lines 19-22: “Rats exposed to 6.8 ppm for 6 hours/day, 5days/week for 28 days showed signs of eye irritation and general discomfort during the third exposure day (Klimisch 1987). These signs were reversible between exposures. Rats exposed to 10 ppm for 4 hours/day, 5 days/week for 12-13 weeks did not show clinical signs.” The phrasing on page 21 to describe the time period when eye irritation was noted is slightly different from that used in a previous section of the TSD. On p. 13, lines

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

18-23 state, “By the third exposure day, rats that inhaled 6.8 or 34 ppm developed clinical signs including eyelid closure, somnolence, and ruffled fur.” Was the irritation not looked for until the third day, was irritation noted progressively among more of the animals until, “by the third day,” all showed signs of irritation, or was irritation undeveloped until the third day?

Page 23, Table 10: Delete Table 10. It is unnecessary since there are no other extant standards aside from AEGLs.

Page 23, Section 8.3. Data Adequacy and Research Needs: This section only notes that adequate data were available to develop AEGL values. The SOP (p. 53-57) provides specific guidance on the material to be presented in Section 8.3. The two sentences in the draft TSD do not seem sufficient to address the guidance in the SOP. The need for additional research to assess the impact of ocular and respiratory irritation on escape impairment could be noted here.

References

Clark, G.C., and G.C. Jackson. 1977. Methylisothiocyanate Acute Inhalation Toxicity: 1 Hour LC50 in Rats. Schering AG Study SHG 132/77372, Schering Report T6. Huntingdon Research Centre, UK.

Jackson, G.C., G.C. Clark, D.E. Prentice, R.M. Read, C. Gopinath, and C. Cherry. 1981. Methyl Isothiocyanate Acute Inhalation Toxicity in Rats: 4 Hour Exposure. RZ No. 81/082. Huntingdon Research Centre, UK.

Klimisch, H.J. 1987. Study of the Subchronic Inhalation Toxicity of Methyl Isothiocyanate in Wistar Rats (4 Weeks Study). BASF No. 87/0244. Department of Toxicology, BASF AG, Germany.

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

Rosskamp, G., G. Schobel, A. Bhargava, et al. 1978. Methyl Isothiocyanate. ZK 3.318: A 12-13 Week Inhalation Study in the Rat. Project ID 374/77. Schering AG.

Rubin, A.L., M. Silva, J. Gee, T. Moore, and T. Thongsinthusak. 2003. Risk Characterization Document: Methyl Isothiocyanate (MITC) Following the Agricultural Use of Metam Sodium. California Environmental Protection Agency, Sacramento, CA [online]. Available: http://www.cdpr.ca.gov/docs/risk/rcd/mitc_sb950.pdf [accessed May 24, 2011].

Russell, M.J., and T.I. Rush. 1996. Methyl Isothiocyanate: Determination of Human Olfactory Detection Threshold and Human no Observable Effect Level for Eye Irritation. Report No. RR96-049B. Sensory Testing Laboratory, University of California, Davis, CA.

NITROGEN MUSTARDS (HN1, HN2, and HN3)

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSD) on nitrogen mustards. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation. Please note that line numbers were not added to the TSD; hence, comments below will refer to page and section numbers.

The following is excerpted from the Executive Summary of the TSD:

No exposure-response data were available regarding AEGL-1 type effects following exposure of human or animals to nitrogen mustard vapors… [and] no AEGL-1 values have been recommended…. The AEGL-2 values for HN1, HN2, and HN3 were developed based upon the lower limits of the previously noted eye injury thresholds from studies with human volunteer subjects; 37, 40, and 20 mg-min/m3, respectively, for HN1, HN2, and HN3.… Lethality thresholds (LCt50) for rats were used as the basis for AEGL-3 values; 860, 2000, and 670 mg-min/m3 for HN1, HN2, and HN3, respectively.

A revised document should be submitted to the committee for review.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-Specific Comments

Page 8, Executive Summary, Paragraph 3: “By consensus, the National Advisory Committee for Acute Exposure Guideline Levels chose the more conservative AEGL-2 values for HN2 as the AEGL-2 values for all of the reviewed nitrogen mustards and the more conservative AEGL-3 values for HN3 as the AEGL-3 values for all of the reviewed nitrogen mustards. Individual AEGL-2 and AEGL-3 values for HN1, HN2, and HN3 are, however, presented in the text body.” Common AEGL values for all three HNs should be considered, as the data suggest (see Appendix D, Category Plots for Nitrogen Mustards, pp. 56-58). If separate values are retained a better justification is needed because the category plots appear to indicate commonality. The TSD authors should consider how likely the individual HNs would be encountered in the environment. Will people be exposed to mixtures or the separate chemicals?

The key studies used to derive AEGL values report nitrogen mustard concentrations as mg·min/m3, which is different from the ppm or mg/m3 units usually discussed in chemical TSDs. If possible, the TSD authors should evaluate and compare the range of exposure durations (that is, convert the mg·min/m3to mg/m3) for HN1, HN2, and HN3. It appears that the maximum exposure concentration for HN2 (~ 55 mg/m3) is almost 10-fold greater than the highest exposure concentrations for either HN1 or HN3. How does this comparison affect the data analysis and calculations for AEGLs?

Page 16, Section 2.6. Summary: “All of the toxic effects of nitrogen mustard appear to involve a latency period; several hours for ocular responses and several days for dermal blistering.” The purpose of setting exposure limits to facilitate emergency response and recovery is at odds with AEGL-2 concentrations that prevent escape-impairing effects but lead to adverse delayed effects (that is,10-24 h post-exposure). Note the ocular effects of HN2 exposure (p. 15—“At 6 to 10 hours post exposure additional effects developed (e.g., photophobia, blepharospasm, pain severe enough to prevent sleep). At 24 hours, these effects continued but pain decreased.” It is insufficient to say people will escape but end up in hospital emergency rooms later. Please add discussion on exposures to nitrogen mustards resulting in delayed adverse health effects. Are the proposed AEGL values sufficiently protective?

The time-scaling used for the AEGL derivations should be revisited. The TSD text and appendixes indicate that time PODs are different for each HN and AEGL because the LCt and ECt (effective dose) cover different time spans. However, a quick comparison of numerical AEGL values (as well as the shape of the AEGL curves in the category plots) suggests that the same time POD was used for all.

AEGL-1

Page 24, Section 5.3: “AEGL-1 values for nitrogen mustards are not recommended (Table 11) due to insufficient data and because adverse effects are reported to occur in the absence of detection of the agents.” The authors should search for AEGL-1-relevant data from treatment protocols or related documentation. For example, Section 2.2 (p. 11) reports that HN2 at 0.036 mg/m3 was used as a treatment for mycosis fungoides. It seems that there must have been some subclinical effects even if they are not adverse. Just because there are no clinical effects does not mean we should not recommend an AEGL-1.

AEGL-2

Pages 25-27, Section 6.3: For HN1 and HN3, an MF of 3 was applied “to account for possible latent effects on the respiratory tract.” For HN2, an MF of 10 was used to account for “a deficient database…to estimate an AEGL-2 NOEL” and for “uncertainties regarding the number of test subjects.” The authors should re-evaluate the use and selection of MFs or provide better justifications for their use. For AEGL-2, the observed effect is eye irritation. Although it was stated that a respirator was used for HN2 studies (the highest exposure concentrations were for HN2), there were no statements regarding respirator use in the HN1 or HN3 studies.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Page 25, Section 6.3: “The threshold values were based upon reversible effects following vapor exposures of relatively short maximum durations (7-67 minutes) but included post exposure observation up to 24 days.” Please clarify how the listed exposure range was chosen, or adjust the range. The exposure durations listed on pp. 14-15 for the HN1 and HN2 studies are 5-67 min and 0.5-10 min, respectively, and one of the cited HN3 studies had an exposure duration of 7 min.

AEGL-3

Page 28, Section 7.2: For HN1 “Adjustment regarding individual variability was also limited to 3 because of the action of nitrogen mustards on cellular components would not be expected to greatly differ, and because additional downward adjustment would result in AEGL-3 values inconsistent with AEGL-2 values and available human data.” Use of the intraspecies UF of 3 is justified by proximity of AEGL-2 values; however, the statement that the intraspecies UF of 3 is justified as the default for similar action across species is not correct (see SOP, p. 87, top) because these compounds are, presumably, respiratory irritants. Use the correct SOP citation for this justification—adjustment for weight of evidence (see SOP, Section 2.5.3.3.4., p. 88). Note that changes need to be made in Appendixes A and C to match.

Page 28, Section 7.3: Citing the SOP—presumably Section 2.2.2.3.2. (p. 44)—the TSD states that the estimation of the lethality threshold was done by dividing the LCt50 by 3,. The TSD should note that this section requires information on the slope of the dose-response curve; in its absence, using 3 as the divisor is the acceptable default, but the lack of data should be noted. In addition, this paragraph should note that the rat is the most sensitive to HN1 and HN2, and the mouse is more sensitive to HN3.

Other Comments

Because most if not all PODs are LCt50 values and because the n value in the ten Berge equation depends on the direction of the time-scaling, the time chosen for each POD should be clearly indicated in a consistent manner. For example, on p. 43 (AEGL-2 derivation), “time = 120 min” is given in “calculations,” but on p. 46 (AEGL-3 derivation), the only time information is given as a range: “experimental exposure durations of 10-100 minutes.”

Cover Page: Please insert structure diagrams or chemical formula for the nitrogen mustards.

Pages 6-9, Executive Summary: The summary is lengthy. Consider whether some material can be shortened or left out, provided that essential background information remains.

Page 7, Executive Summary, Paragraph 3: “The identified thresholds represent a response consistent with the overall continuum of nitrogen mustard toxicity.…” If there is a continuum, are data available to calculate n?

Page 7, Executive Summary, Paragraph 3: “(The modifying factor was increased to 10 for HN2 AEGL-2 derivation due to more severed effects (NOAEL-to-LOAEL adjustment).” Why is this a parenthetical statement? It is important information for the AEGL derivation. Justify why an MF is used instead of an alternative UF. Onset of symptoms was delayed. Also note that “severed effects” should be “severe effects”

Page 8, Executive Summary, Footnote B: “By consensus vote.…” It is more important to provide the rationale for selecting AEGL values rather than the “vote”. Please provide the rationale.

Pages 10-11, Tables 1, 2, and 3: Please insert the saturated vapor concentrations.

Page 11, Table 2: Two additional synonyms for HN2 should be added to Table 2: chlormethine and mustine.

Page 12, Section 2.2.1: “The container with vesicant was kept in a water bath to maintain constant temperature.” What was the temperature?

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Pages 15-16, Section 2.6. Summary: Please add a statement that there are no inhalation data to assess respiratory tract effects in humans, although it can reasonably be expected based on the mechanism of action and on notations in the studies cited that exposed subjects were protected from inhaling the test materials.

Pages 16-22, Section 3.1. Animal Lethality: State explicitly in this section that dose-response data were not available, as this is important in the AEGL-3 derivation section. In addition, although there is a wealth of LCt50 values, there is no mention of pathology of any sort. Is there any information on what caused all the animals to die? The presumption seems to be that death was probably due to respiratory tract irritation and its sequelae, given the presumption that a direct-acting irritant and vesicant would have similar effects on the mucosa of the respiratory tract and given the references to some people using oronasal masks, precluding respiratory tract exposure during some controlled exposures used to derive AEGL-2 values.

Page 23, Section 2.4. Genotoxicity: “The genotoxicity of nitrogen mustards has been extensively reviewed (Fox and Scott, 1980).” The authors should consider adding information from more recent reviews, e.g., Povirk 1994.

Page 23, Section 3.5. Carcinogenicity: “No studies are available regarding carcinogenicity in animals following inhalation exposure to nitrogen mustards. A high incidence of spindle-cell sarcomas was observed in male and female rats given subcutaneous injections of HN3 (0.1 or 0.25 mg/kg/day or 1.0 mg/kg/wk for 6 months) but no such tumors were detected in controls (Sýkora et al. 1981).” This sentence is not informative. Nitrogen mustards should be viewed in the light of what is known about mutagens and carcinogens of this type. There is literature on skin cancers associated with exposure to nitrogen mustards. There is also developing literature on the role of anti-cancer alkylating agents on induction of a different type of cancer. The cancers most frequently seen are leukemias. Also, are there assessments from the International Agency for Research on Cancer or the National Toxicology Program? If not, please explicitly state so.

Page 23, Section 4.1. Metabolism and Disposition: This section describes results of several vapor penetration studies and notes that the immonium ion is excreted in urine. Was the immonium ion excretion measured in these experiments?

Page 24, Section 4.2. Mechanisms of Toxicity: “A key reaction that is likely important to the biological activity of nitrogen mustard is the formation of a cyclic onium cation (immonium for nitrogen mustards) in the presence of polar solvents such as water (Somani, 1992). The immonium ion can react with nucleophiles such as nitrogen in the base components of nucleic acids and sulfur in SH-groups in proteins and peptides.” Please address the following:

  • The TSD text identifies a “cyclic onium cation.” To clarify, please provide the structural formula for the immonium ion (and for the sulfonium ion mentioned in Section 4.3. Structure-Activity Relationships
  • Is the immonium ion linked to vesicant properties?
  • Note that some sources identify “immonium” as a nonstandard term, preferring “iminium” or perhaps “aziridinium”. Perhaps all of these terms should be included in the discussion.

Page 24, Section 4.3. Structure-Activity Relationships: If possible, add a comparison table of reactivity or reaction rates of the three HNs (e.g., alkylation rate). Note that similar rates would support the use of common AEGL values.

Page 25, Section 6.1. Human Data Relevant to AEGL-2: “The ocular effects…are reversible and appear to develop post exposure.” Because the duration of this latency period could be critical to escape impairment, some discussion is needed on the length of time required after exposure to manifest effects. The cited studies had short exposure periods lasting from 0.5 to 67 min. The HN2 study noted that effects were reported 8-15 min post-exposure, and the HN1 study reported an average latency of 12 h (with no range given). AEGL exposure periods of 4 to 8 h are well outside this data set and present the

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

potential for effects to develop during the long exposure periods. Discussion should include the possibility that effects might occur during the long duration exposures (4-h and 8-h AEGL time periods) because there are no data to assess the effect of long-term continuous exposure.

Page 29, Section 8.1. AEGL Values and Toxicity End Points: “The AEGL-2 value took into consideration sensitive responders and possible respiratory effects.” Although the derivation described in Section 6.3., pp. 25-27, is quite thorough, it is not clear that “sensitive responders” are either identified or addressed in the process. The intraspecies UF was set at 3 to account for the expected range of human variability (the default value for direct-acting irritants) and the possibility of respiratory irritation (where the default value for this UF would normally be 10). However, no “sensitive responders” were identified in the AEGL-2 derivation section. The authors should consider changing the TSD wording from “sensitive responders” to “the expected range of human variability” or something similar.

Page 29, Section 8.1. AEGL Values and Toxicity End Points: A statement should be added on the lack of data to assess respiratory tract effects. A related statement should also be added to Section 8.3. Data Adequacy and Research Needs (page 31).

Page 43, Derivation of AEGL-3 for Nitrogen Mustards: Please check the calculation for 1-h AEGL-3 “C3 × 60 min.” Why is C3 used instead of C1, as was done for the other time-points?

References

Fox, M., and D. Scott. 1980. The genetic toxicology of nitrogen and sulphur mustard. Mutat. Res. 75(2):131-168.

Povirk, L.F., and D.E. Shuker. 1994. DNA damage and mutagenesis induced by nitrogen mustards. Mutat. Res. 318(3):205-206.Somani, S.M. 1992. Toxicokinetics and toxicodynamics of mustard. Pp. 13-50 in Chemical Warfare Agents. New York: Academic Press.

Sýkora, I., V. Vortel, O. Marhan, and A. Dynterova. 1981. Carcinogenicity of thichloromethine hydrochloride (TS-160 Spofa) and morphological damage after its intraamniotic injection. Neoplasma 28(5):565-574.

PERCHLORYL FLUORIDE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on perchloryl fluoride. A presentation on the TSD was made by Lisa Ingerman, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

The AEGL-1 values were derived from the concentration, 24 ppm, at which dogs and rats were exposed for 6 hours/day, 5 days/week for 26 weeks. At this concentration, all animals survived, exhibited no clinical signs, no signs of irritation and the only long-term effect observed was increased fluoride deposition in the bone and urine over the course of the 26 weeks…. In the absence of appropriate chemical-specific data, AEGL 2 values were set at one-third of the AEGL-3 values (NRC 2001)…. The AEGL-3 values were based on a concentration of 224 ppm which induced moderate cyanosis and hyperpnea in dogs during a 4-hour exposure.

This document can be finalized if the following comments are adequately addressed.

AEGL-Specific Comments

The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 for perchloryl fluoride.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

Other Comments

Cover Page: Please add the structural diagram for perchloryl fluoride.

Page 12, lines 32-22: “In some of the guinea pigs, Bordetella bronchoseptica was isolated, thus making all of the results of this study questionable.” Please explicitly state in the TSD that these data were not considered for derivation of the AEGLs. Also please make correct the spelling of bronchiseptica.

References

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

PIPERIDINE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD) on piperidine. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

The AEGL-1 values were based on the no-effect-level (20 ppm for 6 hours) for nasal irritation in rats…. The AEGL-2 values were based on exposure of rats to piperidine at 200-ppm for 6 hours, which caused nasal irritation without salivation or evidence of eye irritation…. The AEGL-3 values were based on the LC01 calculated from a 4-hour acute inhalation study in rats.

This document can be finalized

AEGL-Specific Comments

The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 values for piperidine.

Other Comments

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately.

PROPANE

At is meeting held on April 5-7, 211, the committee reviewed the AEGL technical support document (TSD) on propane. A presentation on the TSD was made by Mark Follansbee, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

The AEGL-1 derivation is based on observations in a study with volunteers on the warning properties of short exposures to propane (Patty and Yant 1929).… The AEGL-2 derivation is based on cardiac sensitization. In a well-performed cardiac sensitization test beagle dogs were exposed to a propane concentration of 50,000, 100,000, or 200,000 ppm (Reinhardt et al. 1971)…. The same study as for AEGL-2 is used as starting point for AEGL-3.

This document can be finalized

AEGL-Specific Comments

The committee approves the derivation of AEGL-1, AEGL-2, and AEGL-3 values for propane.

Other Comments

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately.

References

Patty, F.A., and W.P. Yant. 1929. Odor Intensity and Symptoms Produced by Commercial Propane, Butane, Pentane, Hexane, and Heptane Vapor. Report of Investigation No 2979. Washington, DC: U.S. Department of Commerce, Bureau of Mines.

Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, Jr., and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol “sniffing”. Arch. Environ. Health 22(2):265-279.

TRIMETHOXYSILANE AND TETRAMETHOXYSILANE

At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs) on trimethoxysilane and tetramethoxysilane. The presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation.

The following is excerpted from the Executive Summary of the TSD:

AEGL-1 values were not derived for either trimethoxysilane or tetramethoxysilane because of limited data. AEGL-2 values for trimethoxysilane were derived by taking 1/3 of AEGL-3 values…. AEGL-3 values were determined by using mortality data from 1 and 4 hour LC50 rat inhalation studies (Nachreiner and Dodd 1988)…. AEGL-2 values for tetramethoxysilane were derived from a repeat dose inhalation study in which rats were exposed for 6 hours/day, 5 days/week for 28 days at concentrations up to 45 ppm (Kolesar et al 1989)…. AEGL-3 values were derived from an LC50 4-hour rat inhalation study (Dow Corning Corp., 1992).

This document can be finalized.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

AEGL-Specific Comments

The committee approves the derivations of AEGL-1, AEGL-2, and AEGL-3 for trimethoxysilane and tetramethoxysilane.

Other Comments

The authors can be complimented for their excellent and critical review of the literature, their analysis of the data, and their establishment of scientifically defensible AEGLs. A number of revisions have been made to this document in response to previous reviewers. The authors have responded to these comments adequately.

References

Dow Corning Corporation. 1992. Initial Submission: The Acute Vapor Inhalation Toxicity of Tetramethoxysilane and Trimethoxysilane with Rats (Final Report) with Cover Letter Dated April 9, 1992. Document ID No. 88920001842. Microfiche No. OTS0539103.

Kolesar, G.B., W.H. Siddiqui, R.G. Geil, R.M. Malczewski, and E.J. Hobbs. 1989. Subchronic inhalation toxicity of tetramethoxysilane in rats. Fundam. Appl. Toxicol. 13(2):285-295.

Nachreiner, D.J., and D.E. Dodd. 1988. Trimethoxysilane: Acute Vapor Inhalation Toxicity Study in Rats. Project Report No. 50-147. Union Carbide- Bushy Run Research Center.

COMMENTS PERTAINING TO ALL TECHNICAL SUPPORT DOCUMENTS

The chemical structure of the compounds should be included on the title page of every TSD.

Whenever substantial discrepancies are found between AEGL values and other guideline values (e.g., IDLHs, STELs, and workplace environmental exposure limits [WEELs]), the possible reasons should be explored and discussed in the text. The SOP, Appendix J, p. 201, of the NRC (2001) report stated that “A summary discussion of important comparisons should be presented in the text and the values for recognized standards and guidelines, if available, should be presented in the table.”

The authors need to ensure that the literature on the chemicals have been updated for documents that have been several years in the AEGL-development process. The date of the most recent literature review should be included in the TSD.

For citations to the SOP (NRC 2001), it would be helpful if the TSD authors included a page number or section number as part of the citation. The SOP is a 200-page document, and it may not be readily apparent to target emergency response and preparedness audiences to which section the TSD authors may be referring.

For the “Summary of AEGL Values” table included in each TSD (located in the Executive Summary), please make certain that any applied UF or MF are listed in the “End Point (Reference)” column of the summary table.

For the “Chemical and Physical Data” table included in each TSD (located in Section 1. Introduction), please include the vapor pressure (if available) and (calculated) saturated vapor concentration.

For the “Extant Standards and Guidelines” table included in each TSD (located in Section 8.2. Comparisons with Other Standards and Guidelines), please make certain the reported guidelines are the most updated available values. A number of the TSDs include out-of-date values.

Please make certain that all listed URLs in the references are still active, and add the date that the Web site was accessed.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×

References

NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.

STANDING OPERATIONING PROCEDURES

For many chemicals, the data are insufficient to develop AEGL-1 values. The AEGL SOP should offer some guidance on appropriate statements on how to communicate with (or what to communicate to) emergency responders and the public in the absence of AEGL-1 values.

Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
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Page 32
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 33
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 34
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 35
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 36
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 37
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 38
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 39
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 40
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 41
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 42
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 43
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 44
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 45
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 46
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 47
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 48
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 49
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 50
Suggested Citation:"Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels." National Research Council. 2011. Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington, DC: The National Academies Press. doi: 10.17226/13197.
×
Page 51
Next: Abbreviations »
Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A Get This Book
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Extremely hazardous substances (EHSs) can be released accidentally as a result of chemical spills, industrial explosions, fires, or accidents involving railroad cars or trucks transporting EHSs. They can also be released intentionally through terrorist activities, or inadvertently by improper storage or handling. Workers and residents in communities surrounding industrial facilities where EHSs are manufactured, used or stored, and in communities along the nation's railways and highways, are potentially at risk of being exposed to airborne EHSs during accidental or intentional releases.

The Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A presents conclusions and recommendations for improving the National Advisory Committee (NCA) on Acute Exposure Guideline Levels (AEGL) documents for the various twenty-nine chemicals and chemical classes, among them being chloroacetyl chloride, butane, ethyl, and nitrogen mustards. In addition to providing advisory data, the interim report reviews the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to prior National Research Council guideline reports. The report reviews NAC's research recommendations and-when appropriate-identifies additional priorities for research to fill data gaps. Moreover, this all-inclusive report provides updated technical guidance for establishing community emergency exposure levels for extremely hazardous substances pursuant to the Superfund Amendments and Reauthorization Act of 1986.

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