This report is the twentieth volume in the series Acute Exposure Guideline Levels for Selected Airborne Chemicals. Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.
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). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are 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.
Airborne concentrations below the AEGL-1 represent exposure concentrations that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of
effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
The contents of this report come from a document that was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Heather Carlson-Lynch (SRC, Inc.), and Chemical Manager Ernest V. Falke (U.S. Environmental Protection Agency). The National Advisory Committee on Acute Exposure Guideline Levels reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. However, during the finalization process it was discovered that the AEGL values for n-propyl chloroformate and isopropyl chloroformate relied on studies performed by Industrial Bio-Test, a company that is now known to have improperly conducted and reported some of its studies. The Department of Defense requested that the National Academies of Sciences, Engineering, and Medicine, convene a new committee to re-evaluate the AEGL values for the chloroformates and determine appropriate values for n-propyl chloroformate and isopropyl chloroformate.
SUMMARY OF REPORT ON GUIDELINES FOR DEVELOPING AEGLs
As described in Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (NRC 1993) and the NRC guidelines report Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (NRC 2001), the first step in establishing AEGLs for a chemical is to collect and review all relevant published and unpublished information. Various types of evidence are assessed in establishing AEGL values for a chemical. These include information from (1) chemical-physical characterizations, (2) structure-activity relationships, (3) in vitro toxicity studies, (4) animal toxicity studies, (5) controlled human studies, (6) observations of humans involved in chemical accidents, and (7) epidemiologic studies. Toxicity data from human studies are most applicable and are used when available in preference to data from animal studies and in vitro studies. Toxicity data from inhalation exposures are most useful for setting AEGLs for airborne chemicals because inhalation is the most likely route of exposure and because extrapolation of data from other routes would lead to additional uncertainty in the AEGL estimate.
For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires both experienced scientific judgment and clear and
transparent criteria. The toxicity data for animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, data from the most sensitive animal species are used. Uncertainty factors are commonly used when animal data are used to estimate risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmacokinetic data on tissue doses are considered for interspecies extrapolation.
For substances that affect several organ systems or have multiple effects, all end points (including reproductive [in both genders], developmental, neurotoxic, respiratory, and other organ-related effects) are evaluated, the most important or most sensitive effect receiving the greatest attention. For carcinogenic chemicals, excess carcinogenic risk is estimated, and the AEGLs corresponding to carcinogenic risks of 1 in 10,000 (1 × 10-4), 1 in 100,000 (1 × 10-5), and 1 in 1,000,000 (1 × 10-6) exposed persons are estimated.
STATEMENT OF TASK
An ad hoc committee will review and update the technical support document on acute exposure guideline levels (AEGLs) for selected chloroformates. The update will focus on establishing AEGL-3 values for n-propyl chloroformate and isopropyl chloroformate, but will also consider whether any new data are available that would affect the proposed values for the other 10 chloroformates.
APPROACH TO THE STUDY
The National Academies convened the Committee on Acute Exposure Guideline Levels for Chloroformates in 2016. Members of the committee have expertise in general toxicology, inhalation toxicology, industrial hygiene, occupational health, and risk assessment. One public meeting was held to familiarize the committee members with the history and importance of AEGLs and to discuss the approach to revising and updating the chloroformate AEGL values.
ORGANIZATION OF THE REPORT
This report is organized into two additional chapters and five appendixes. Chapter 2 is divided into 11 sections, one that provides, general information on selected chloroformates, and then separate sections that discuss the AEGLs for methyl chloroformate (Section 2), ethyl chloroformate (Section 3), isopropyl chloroformate (Section 4), n-propyl chloroformate (Section 5), allyl chloroformate (Section 6), n-butyl chloroformate, isobutyl chloroformate, and sec-butyl
chloroflormate (Section 7), benzyl chloroformate (Section 8), phenyl chloroformate (Section 9), 2-ethylhexyl chloroformate (Section 10), and ethyl chlorothioformate (Section 11). Appendix A provides biographical information on the committee members, Appendix B provides the benchmark calculations, Appendix C provides the derivation summaries, Appendix D provides the category plots.