Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels Part A (2011) / Chapter Skim
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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels
Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels
Pages 1-51
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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.
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, 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)
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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?
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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)
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." Please clarify who reported these effects. Is it from an occupational exposure or a research study?
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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)
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2006. Autoimmune response in MRL +/+ mice following treatment with dichloroacetyl chloride or dichloroacetic anhydride.
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1982. Dow Chemical Company Initial Submission: Chloroacetyl Chloride: A Four-Week Inhalation Toxicity Study in Rats, Mice, and Hamsters with Cover Sheet and Letter Dated 04/21/92 (Sanitized)
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2008. Transcriptomic analysis reveals early signs of liver toxicity in female MRL +/+ mice exposed to the acylating chemicals dichloroacetyl chloride and dichloroacetic anhydride.
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1987. Methanesulfonyl Chloride: Acute Inhalation Toxicity in Rats, 4-Hour Exposure.
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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 6hours" (line 40)
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OTS0538315. BROMOACETONE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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OTS0510179. BUTANE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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BZ (3-QUINUCLIDINYL BENZILATE) At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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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 15
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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)
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. 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.
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. The TSD authors do not provide sufficient data to support reducing an intraspecies UF to 3.
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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)
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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)
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values in the appropriate time columns. As listed, these values appear to represent the same exposure durations.
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. Page 54, lines 11-12: Please provide the URL for the Registry of Toxic Effects of Chemical Substances (RTECS)
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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)
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ETHYLENE CHLOROHYDRIN (2-CHLOROETHANOL) At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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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-verysystematic 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.
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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.
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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.
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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]
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1:84-85. ISOCYANATES At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs)
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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)
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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.
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1992. Initial Submission: Acute Inhalation Toxicity Test with Cyclohexyl Isocyanate in Rats with Cover Letter Dated August 10, 1992.
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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.
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AEGL-2 values were based on shallow breathing and hypoactivity in mice exposed to 258 ppm methyl mercaptan for 6 hours (Elf Atcohem, 1996)
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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)
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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)
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Table 1. Physical and Chemical Values for tert-Octyl Mercaptan: Please add the saturated vapor concentration.
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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.
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:202-210. METHYL BROMIDE At is meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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:293-299. METHYLISOTHIOCYANATE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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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)
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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)
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NITROGEN MUSTARDS (HN1, HN2, and HN3) At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSD)
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Please add discussion on exposures to nitrogen mustards resulting in delayed adverse health effects. Are the proposed AEGL values sufficiently protective?
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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.
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. 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.
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:565-574. PERCHLORYL FLUORIDE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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Washington, DC: National Academy Press. PIPERIDINE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support document (TSD)
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:265-279. TRIMETHOXYSILANE AND TETRAMETHOXYSILANE At its meeting held on April 5-7, 2011, the committee reviewed the AEGL technical support documents (TSDs)
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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]
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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