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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17 (2014)

Chapter: 4 Epichlorohydrin Acute Exposure Guideline Levels

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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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Suggested Citation:"4 Epichlorohydrin Acute Exposure Guideline Levels." National Research Council. 2014. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17. Washington, DC: The National Academies Press. doi: 10.17226/18796.
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4 Epichlorohydrin1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 distin- guished 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 1 This document was prepared by the AEGL Development Team composed of Ko- wetha Davidson (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Richard Thomas (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Envi- ronmental Protection Agency). The NAC 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. The NRC committee has concluded that the AEGLs developed in this document are sci- entifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 190

Epichlorohydrin 191 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 sus- ceptible 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 sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and non- disabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a pro- gressive increase in the likelihood of occurrence and the severity of effects de- scribed for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, 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. SUMMARY Epichlorohydrin is a colorless liquid at room temperature; its vapor is ex- plosive when mixed with air. It has a sweet, pungent or chloroform-like odor. Epichlorohydrin has many uses, but it is used primarily in the manufacture of epoxy resins. Most humans would not detect the odor of epichlorohydrin at concentra- tions below 10 ppm. The odor recognition level for epichlorohydrin is about 25 ppm; however, odor detection levels reported in the literature range from 0.08- 25 ppm. The level of distinct odor awareness for epichlorohydrin is 46 ppm. No reports of human deaths from exposure to epichlorohydrin were found. Epichlo- rohydrin is irritating to mucous membranes, causing burning of the eyes, nose, and pharynx in humans. A few breaths or a 30-min exposure at high (unknown) concentrations have caused irritation to eyes, throat, and respiratory tract and gastrointestinal disturbances that may be delayed in onset. Irreversible respirato- ry and hepatic damage, but no renal damage, have been observed in humans. Humans exposed to epichlorohydrin at 20 ppm for 1 h experienced burning of the eyes and nose; 40 ppm for less than 2 h caused throat irritation, 68 ppm for 2 min was irritating to the pharynx, and 100 ppm was reported to be intolerable and potentially associated with pulmonary edema and renal damage. Exposure to epichlorohydrin at 136 ppm for 2 min was irritating to the eyes and pharynx and caused a cooling sensation in the eyes and mouth.

192 Acute Exposure Guideline Levels Inhalation exposure of laboratory animals (rats, mice, and hamsters) to epichlorohydrin causes effects similar to those reported for humans. In acute lethality studies, death was caused by effects on the respiratory center of the central nervous system and severe respiratory irritation manifested as pulmonary hemorrhage and edema. Death usually occurred a few hours or a few days after exposure. Before death, the animals showed signs of cyanosis, muscle relaxation of the extremities, gasping, labored breathing, depressed or increased respira- tion, lethargy, fine tremors, and clonic convulsions. In addition, animals showed degenerative lesions of the nasal epithelium and kidneys and damage to the low- er respiratory tract. Evidence of nasal irritation and renal lesions also were seen after acute inhalation exposure to epichlorohydrin at nonlethal concentrations. AEGL-1 values were derived from the no-effect level (17 ppm) for irrita- tion in four subjects exposed to epichlorohydrin vapor for 2 min (Kobernick et al. 1983). The total uncertainty factor was 10; a factor of 10 was applied to ac- count for intraspecies variability. Although mild irritation experienced by hu- mans would most likely be confined to the nasal passages and eyes, a factor of 10 was used to provide sufficient protection for asthmatic individuals. Adjusting the point-of-departure by 10 yields an AEGL value of 1.7 ppm. That concentra- tions was used for all of the AEGL durations because the irritant effects of epichlorohydrin are not expected to become more severe with time at that con- centration. The AEGL-1 value is below the level of odor recognition (25 ppm) and the level of odor awareness (46 ppm). Therefore, odor is not a factor for early warning of exposure to epichlorohydrin. The available human and animal studies reporting nonlethal effects were not suitable for deriving AEGL-2 values. Therefore, AEGL-2 values were de- rived by reducing the AEGL-3 values by a factor of 3; that approach is used when a steep concentration-response curve is observed. The AEGL-2 value of 53 ppm for a 30-min exposure was also used for the 10-min exposure, because concentrations of 100 ppm or higher may cause pulmonary edema and renal damage. The 10-min, 30-min, and 1-h AEGL-3 values were based on the 1-h rat LC01 (lethal concentration, 1% lethality) of 721 ppm (Dietz et al. 1985). A total uncertainty factor of 10 was applied. A factor of 3 was selected for interspecies differences on the basis of LC50 values for rats, mice, guinea pigs, and rabbits, which showed little variability among species. A factor of 3 was applied for intraspecies variability, on the basis of mechanistic information and information on occupational exposures. Epichlorohydrin is an epoxide and direct alkylating agent. These effects are likely involved in the observed irritation and systemic toxicity, and are not expected to vary considerably in the population. In addition, use of higher total uncertainty factor 30 would result in an 8-h AEGL-3 value of 6.6 ppm. That concentration is inconsistent with occupational data; exposures to epichlorohydrin at 15-54 ppm were apparently not life-threatening (Pet’ko et al. 1966 [as cited in NIOSH 1976]; de Jong et al. 1988). Time scaling was per- formed using the equation Cn × t = k (ten Berge et al. 1986), where n = 0.87. The

Epichlorohydrin 193 value of the exponent n was derived from rat LC50 (lethal concentration, 50% lethality) values for 1-, 4-, 6-, and 8-h exposures. The 4- and 8-h AEGL-3 values were based on the 6-h rat LC01 of 274 ppm (Laskin et al. 1980). The same uncertainty factors and time-scaling method were the same as those used to derive the 10-min, 30-min, and 1-h AEGL-3 values. Two inhalation studies in rats found squamous cell carcinomas of the na- sal cavity after exposure to epichlorohydrin vapor. The studies showed that short-term exposure at high concentrations were more effective in inducing neo- plasms than lifetime exposure at low concentrations. AEGL values calculated from the cancer unit risk for epichlorohydrin are 14,000, 4,500, 2,300, 560, and 280 ppm for 10-min, 30-min, 1-h, and 4-h, to 8-h exposures, respectively. Those values are for risks of 1 in 10,000 (10-4), the level of risk most relevant for emergency exposure and response purposes. The concentrations greatly exceed values for AEGL-2 and AEGL-3. The AEGL values for epichlorohydrin are presented in Table 4-1. 1. INTRODUCTION Epichlorohydrin is a colorless liquid at room temperature that is flamma- ble (Berdasco and Waechter 2012). It is very reactive with metals such as zinc and aluminum, anhydrous metal halides, strong acids and bases, and alcohol- containing materials; it attacks steel in the presence of moisture (WHO 1984). Epichlorohydrin has a sweet, pungent or chloroform-like odor (Berdasco and Waechter 2012). Additional chemical and physical properties of epichlorohydrin are presented in Table 4-2. Epichlorohydrin is manufactured at three sites in Louisiana and Texas. Epichlorohydrin is also manufactured in Thailand (ABC-Thailand, Ltd. 2013), France (Solvay 2011), and China (Alibaba 2013; ZSITC 2013). Epichlorohydrin is primarily used in the manufacture of epoxy and phenoxy resins (ACGIH 2001). It is also used in the synthesis of glycerol, and in the production of sur- face active agents, pharmaceuticals, insecticides, agricultural chemicals, textile chemicals, coatings, adhesives, ion-exchange resins, solvents, plasticizers, glyc- idyl esters, ethynyl-ethylenic alcohols, and fatty-acid derivatives. It is used as a solvent in the rubber and paper industries (Santodonato et al. 1980). Epichlorohydrin is a bifunctional alkylating epoxide (Laskin et al. 1980). It causes severe irritation and sensitization when the liquid comes in contact with the skin (Berdasco and Waechter 2012); contact dermatitis has been report- ed after occupational exposure to epichlorohydrin (HSE 1991). Severe ocular irritation, skin irritation, and delayed contact skin sensitization have been found in animals after topical application of undiluted or diluted epichlorohydrin (Ber- dasco and Waechter 2012). Epichlorohydrin is moderately toxic by the oral route with LD50 (lethal dose, 50% lethality) values of 90-238 mg/kg in rats, guinea pigs, and mice (Berdasco and Waechter 2012).

194 Acute Exposure Guideline Levels The database that can be used to derive AEGL values for epichlorohydrin consists of acute and repeat-exposure inhalation studies in multiple species and a carcinogenicity study in rats. TABLE 4-1 AEGL Values for Epichlorohydrin End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm No-effect level (nondisabling) (6.4 (6.4 (6.4 (6.4 (6.4 for irritation mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Kobernick et al. 1983). AEGL-2 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm Three-fold (disabling) (200 (200 (91 (53 (25 reduction of mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 values, except for 10 min. AEGL-3 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm Lethality threshold (lethal) (2,200 (600 (270 (170 (76 (Dietz et al. 1985; mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Laskin et al. 1980) TABLE 4-2 Physical and Chemical Data on Epichlorohydrin Parameter Value Reference Synonyms 2-(Chloromethyl) oxirane; 1-chloro-2,3- HSDB 2009 epoxypropane; 3-chloro-1,2-epoxypropane; α-epichlorohydrin CAS registry no. 106-89-8 HSDB 2009 Chemical formula C3H5ClO HSDB 2009 Molecular weight 92.53 HSDB 2009 Physical state Colorless liquid HSDB 2009 Melting point -25.6°C HSDB 2009 Boiling point 117.9°C HSDB 2009 Density (vapor) 3.29 HSDB 2009 Solubility 65.9 g/L of water at 25°C; miscible with HSDB 2009 ether, alcohol, chloroform, trichloroethylene, carbon tetrachloride Vapor pressure 16.4 mm Hg at 25°C HSDB 2009 Flammability limits 3.8% volume to 21% volume in air HSDB 2009 Concentration in saturated air 1.7% at 25°C HSDB 2009 Flash point (open cup) 40.6°C Sienel et al. 2000 Log Kow 0.45 HSDB 2009 Henry’s Law constant 3.0 × 10-5 atm-m3/mol at 25°C HSDB 2009 Conversion factors 1ppm = 3.78 mg/m3 NIOSH 2011 1 mg/m3 = 0.265 ppm

Epichlorohydrin 195 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were available on the lethality of inhaled epichlorohydrin in hu- mans. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold AIHA (1989) reported the range of odor threshold values for epichlorohy- drin of 0.08-12 ppm, and Ruth (1986) reported a range of 50-80 mg/m3 (13-21 ppm). Kobernick et al. (1983) reported that four subjects detected an at 17 ppm, and two identified the odor as epichlorohydrin. Amoore and Hautala (1983) re- ported an odor detection level of 0.93 ppm for humans. Berdasco and Waechter (2012) reported a mean odor threshold of 10 ppm and an odor recognition level of 25 ppm. The odor threshold during and after a 5-min exposure of uncondi- tioned personnel to epichlorohydrin was 10-12 ppm for 50% of the subjects and 25 ppm for 100% of the subjects (Shell Oil Co. 1977). Shell Oil Co. (1977) also reported that epichlorohydrin is not detected by its odor at 5 ppm, the permissi- ble exposure limit established by the Occupational Safety and Health Admin- istration (29 CFR 1910.100 [2012]). The level of odor awareness determined by the method of Ruijten et al. (2009) for epichlorohydrin is 46 ppm. 2.2.2. Experimental Studies, Case Reports, and Anecdotal Data Anecdotal information on effects of epichlorohydrin in humans has been reported in various sources. In a toxicology book, a chapter stated that humans exposed to epichlorohydrin vapor at 20 ppm for 1 h experienced burning of the eyes and nasal mucosa, that exposure at 40 ppm caused ocular and throat irrita- tion that lasted about 48 h, and that 100 ppm was intolerable to man, with poten- tial for pulmonary edema and renal lesions (Lefaux 1968). The statements were attributed to an individual (C.U. Dernehl) without a specific reference. Lefaux (1968) also indicated that chronic low-level exposure caused fatigue, gastroin- testinal pain, conjunctivitis, and profuse nasal discharge, citing another individ- ual (I. Sax). The anecdotal information was repeated in later references, includ- ing that of Wexler (1971). In another book chapter, Deichmann and Gerarde (1969) reported that humans exposed to epichlorohydrin at 40 ppm for less than 2 h experienced throat irritation; no data or citation was provided to support the statement. Enterline et al. (1990) reported that during the early years (assumed to be 1948-1955) of epichlorohydrin use and production, concentrations of the chemical at a Shell chemical facility were “sufficiently high to be a source of irritation (10-20 ppm)”; the publication did not specify whether exposure con- centrations were measured in that range or assumed to be in that range on the

196 Acute Exposure Guideline Levels basis of worker reports of irritation. In another book chapter on epoxy com- pounds, Berdasco and Waechter (2012) reported that marked nasal and ocular irritation occurred only at epichlorohydrin concentrations exceeding 100 ppm; no background or reference for this statement was provided. In a toxicity and safety bulletin on epichlorohydrin (prepared in 1977 and submitted to the U.S. Environmental Protection Agency [EPA] under TSCA Section 8ECP in 1992), Shell Oil Co. (1977) reported that overexposure to epichlorohydrin vapor is manifested first by complaints of ocular, nasal, and throat irritation and possibly sneezing and bleeding of the nose in more serious cases. On the basis of indus- trial experience, Shell Oil Co. (1977) noted that no cases of serious pulmonary injury or systemic toxicity had been observed during the manufacture or han- dling of epichlorohydrin, and ocular conditions resulting from exposure to the vapor or contact with liquid epichlorohydrin were not serious and caused no loss of vision. No information on exposure conditions or concentrations was provid- ed. In a summary of warning properties, the bulletin stated that “one report indi- cated eye and nose irritation only at levels exceeding 100 ppm while another stated that 40 ppm at the site of a spill caused immediate eye, nose, and throat irritation”; references were not provided for these statements. Two case reports of accidental human exposure (Schultz 1964; NIOSH 1976) were identified in the available literature; neither included measurement or estimation of exposure concentrations. Schultz (1964) reported a case of irre- versible hepatic and respiratory damage caused by accidental exposure of a worker to epichlorohydrin. A 39-year-old man took several deep breaths of a substance stored in a container under pressure that was later identified as epichlorohydrin. Initial symptoms included slight burning of the eyes and throat that increased in sensation along with a gradual swelling of the face, malaise, vomiting, and severe headache several hours later. He experienced shortness of breath and a feeling of suffocation the following night (probably more than 24 h after the accident). Clinical examination about 2 days after the accident showed inflammation of mucous membranes in the upper respiratory tract and a painful- ly enlarged liver, slight jaundice, increased serum bilirubin, and positive urine urobilinogen. Five and 8 months after the accident, clinical findings included bronchial changes in the right lung, elevated blood pressure, and evidence of abnormal liver function. Two years after the accident, the patient complained of nonspecific epigastric pain; a clinical examination showed pronounced fatty liver, abnormal liver function, and chronic asthmatic bronchitis. The fatty liver and chronic asthma-like bronchitis were attributed to exposure to epichlorohy- drin because there were no preexisting conditions related to these findings. There was no evidence of renal damage. NIOSH (1976) reported on a case of a 53-year-old worker exposed to a high but unknown concentration of epichlorohydrin for 30 min (written commu- nication by Thoburn, May 1976, no additional citation information). Several hours after exposure he experienced burning of the nose and throat, cough, chest congestion, runny nose, eye tenderness, and headache followed by nausea. The man was hospitalized briefly, and the symptoms diminished within 3-4 days;

Epichlorohydrin 197 however, he reported more frequent upper-respiratory-tract infections followed by a productive cough. Clinical tests showed that the residual volume was in- creased by 40% (suggesting air trapping in the lungs) and arterial pO2 of 77 mm Hg instead of 96 mm Hg. The report did not state how long after exposure these symptoms persisted. NIOSH (1976) also reviewed a Russian study (Pet’ko et al. 1966, as cited in NIOSH 1976) of worker health in a facility producing epichlorohydrin. Workers were generally exposed at concentrations of 3.1-5.5 ppm, but concen- trations during a mechanical failure reached about 55 ppm. NIOSH indicated that the study did not report the sampling method, and no further information on the sampling or analyses that resulted in these concentrations was provided by NIOSH (1976). Apart from two cases of dermatitis, Pet’ko et al. (1966, as cited in NIOSH 1976) concluded that medical examination of 49 men and 33 women in the epichlorohydrin-production areas showed no changes attributable to occu- pational exposure. In the single controlled-exposure study, four human subjects were exposed to epichlorohydrin at concentrations of 17, 68, or 136 ppm for 2 min in a 6.5-ft3 chamber (Kobernick et al. 1983). Three subjects exposed at 68 ppm reported no irritating effect, and one reported irritation to the pharynx. Two subjects exposed at 136 ppm reported a cooling sensation in the eyes and mouth and two reported irritation to the eyes or pharynx. 2.2.3. Epidemiologic Studies Epidemiologic studies of epichlorohydrin have involved the analysis of mortality or morbidity data from two cohorts from the Shell Oil Company in its Texas and Louisiana facilities, both of which produced epichlorohydrin (Enter- line et al. 1990; Tsai et al. 1990, 1996). Dow Chemical workers engaged in epichlorohydrin production also have been the subject of mortality studies (Ol- sen et al. 1994). Tsai et al. (1990) conducted a study on the prevalence of morbidity among workers engaged in the manufacture of epichlorohydrin from January 1, 1981, to December 31, 1988. Morbidity included all illnesses resulting in work absence of more than 5 days. The only illness showing a significantly elevated standard- ized morbidity ratio involved skin and subcutaneous tissue, particularly in work- ers classified as having light to moderate exposure to epichlorohydrin. Light- and moderate-exposure categories (defined as the 95% upper confidence limit of the geometric mean of personal air samples) were >0.1 ppm but ≤0.5 ppm, and >0.5 ppm but ≤1.0, respectively. The investigators noted that skin conditions were more often associated with causes unrelated to epichlorohydrin exposure, such as physical trauma and poison ivy. Although a concern existed for a possible association between exposure to epichlorohydrin and heart disease among workers engaged in the manufacture or use of epichlorohydrin, a statistically significant increase in the standard mor-

198 Acute Exposure Guideline Levels tality ratio (SMR) was not observed. However, Enterline et al. (1990) reported an increase in the SMR for heart disease among workers classified as having heavy exposure compared with workers in the low-exposure category. There was no significant increase compared with the reference population (local white males). Epichlorohydrin concentrations for the exposure categories were not reported, but concentrations during the early production years were high enough to cause irritation. In a subsequent study of the same cohort followed for an ad- ditional 10 years, Tsai et al. (1996) found a nonsignificant increase in the SMRs for heart disease among workers with moderate to heavy exposure to epichloro- hydrin compared with those having no to light exposure. Other epidemiologic studies have been conducted on workers with poten- tial exposure to epichlorohydrin, but none demonstrated an association between epichlorohydrin and mortality experience due to any cause (Barbone et al. 1992, 1994; Olsen et al. 1994). Barbone et al. (1992, 1994) did not report exposure concentrations. Olsen et al. (1994) estimated that the 8-h time-weighted average (TWA) concentration of epichlorohydrin was below 1 ppm at an epoxy resin plant, and was 1-5 ppm at a glycerine department between 1957-1969; concen- trations after 1970 were estimated to be less than 1 ppm. The publication did not report how the TWA estimates were derived, but did indicate that industrial hy- giene records were reviewed. 2.3. Developmental and Reproductive Toxicity Milby et al. (1981) investigated the association between fertility, as meas- ured by sperm count and hormone concentrations, and potential exposure to epichlorohydrin at the two Shell chemical plants that produced epichlorohydrin. The control group consisted of workers from the same plant who had no known exposure to epichlorohydrin or any chemical known to be toxic to the testes. The investigators found no association between potential exposure to epichlorohy- drin and sperm count or levels of testosterone, luteinizing hormone, or follicle stimulating hormone. Exposures in one of the plants (sampling for epichlorohy- drin was conducted at only one) were categorized into four groups. Three of the four categories were exposures less than 1.0 ppm, and the fourth was 1.0 ppm or greater; no information on maximum exposure concentration was provided. Venable et al. (1980) compared the fertility status, as measured by several sperm parameters (including sperm count/cc and percent normal forms) and hormone concentrations, in 64 men employed in the three-carbon production units at Dow Chemical (Texas Division) with 63 men who had not worked with chlorinated hydrocarbons for at least 5 years prior to the study. None of the pa- rameters showed statistically significant differences that could be attributed to work environment or exposure to epichlorohydrin. The 8-h TWA exposures to epichlorohydrin were estimated to be less than 1 ppm in all groups; no further exposure information was provided.

Epichlorohydrin 199 2.4. Carcinogenicity EPA’s Integrated Risk Information System assessment of carcinogenicity for epichlorohydrin, which was revised in 1994, considered the human data to be inadequate for evaluating the carcinogenicity of epichlorohydrin and classified epichlorohydrin as a B2 carcinogen (probable human carcinogen) on the basis of sufficient evidence of carcinogenicity in animals (EPA 1994). More recent epidemiologic studies than those evaluated by the EPA have been conducted on cohorts with potential exposure to epichlorohydrin during its manufacture or use. Barbone et al. (1994) reported an association between occu- pational exposure to epichlorohydrin, particularly acute exposure, and central nervous system neoplasms (in decedents and living). However, only four cases had potential exposure to epichlorohydrin and three of the four were also poten- tially exposed to anthraquinone dye intermediates or azo dyes. Other epidemio- logic studies produced no convincing evidence of an association between poten- tial occupational exposure to epichlorohydrin and cancer at any site including lung cancer (Enterline et al. 1990; Tsai et al. 1990, 1996; Barbone et al. 1992; Olsen et al. 1994). IARC (1999) reviewed and evaluated the epidemiologic and supporting data on epichlorohydrin and concluded that human data were inadequate for evaluating carcinogenicity of the chemical. It classified epichlorohydrin as 2A, probably carcinogenic in humans, on the basis of adequate evidence of carcino- genicity in animals. 2.5. Genotoxicity Kučerová et al. (1977) analyzed the peripheral lymphocytes of 35 workers occupationally exposed to epichlorohydrin for 1 or 2 years (exposure range was 0.13-1.32 ppm [0.5-5.0 mg/m3]) and compared the frequency of chromosomal aberrations with the preemployment frequency. They observed that the overall percentage of chromosomal aberrations (chromatid and chromosome beaks and exchanges; gaps excluded) were statistically significantly increased after 1 year (1.91/100 cells) and 2 years of employment (2.96/100 cells) compared with the preemployment frequency (1.42/100 cells). The frequency of chromosome breaks in lymphocytes was 2.17/100 cells or 3.26/100 cells after employment for 1 or 2 years, respectively, compared with the preemployment frequency of 1.60/100 cells. The overall percentage of cells with aberrations was 1.91% or 2.69% after employment for 1 or 2 years, respectively, compared with 1.37% before employment. Sram et al. (1980) conducted a follow-up analysis of peripheral lympho- cytes in 28 workers (23 were previously analyzed by Kučerová et al. [1977]) occupationally exposed to epichlorohydrin for an additional 2 years (total expo- sure duration of 4 years). Matching subjects from the working and general popu- lation were analyzed as control groups. Sram et al. (1980) found 3.12% aberrant

200 Acute Exposure Guideline Levels cells (breaks and exchanges; gaps excluded) in exposed workers compared with 2.06% for the matching controls and 1.33% for the general population. All com- parison groups were significantly different from each other including the two controls. The percentage of aberrant cells in the subgroup of 23 workers studied by Kučerová et al. (1977) was 3.02%. Sram et al. (1980) reported that the con- centration of epichlorohydrin in the work environment was about 0.26 ppm (1 mg/m3). Sram et al. (1983) conducted a follow-up study on the workers after an additional 4 years of exposure (total of 8 years); this group consisted of 33 workers and included the 28 previously analyzed by Sram and coworkers. The concentration of epichlorohydrin decreased from 0.26 ppm to 0.10 ppm. The percentage of aberrant cells in exposed workers decreased to 2.00%; the per- centage in the matching controls was 1.68%. Chromatid and chromosome breaks were observed, but not exchanges. Picciano (1979) compared the frequency of chromosome aberrations in peripheral lymphocytes from 93 workers occupationally exposed to epichloro- hydrin with the frequency in 75 preemployment individuals (control). The fre- quencies of chromatid and chromosome breaks, marker chromosomes (rings, dicentrics, and translocations), severely damaged cells, and abnormal cells were increased in exposed workers. The greatest increases were in frequencies of cells with more than 12 chromatid breaks, cells with more than four chromosome breaks, the percent of individuals with more than 12 abnormal cells, and the percent of individuals with severely damaged cells. The investigators did not report the intensity or duration of exposure to epichlorohydrin. de Jong et al. (1988) reported increased chromosome aberrations in the lymphocytes of workers involved in the manufacture of epichlorohydrin, eth- ylene oxide (ETO), and propylene oxide at one plant and epichlorohydrin and allyl chloride at another. They found increases in the percentage of aberrant cells (includes gaps) of 1.46% and 0.93% for the two worker groups, respectively, compared with 0.11% for a control population. The increase in the frequency of aberrations in exposed workers relative to the control population could not be attributed to epichlorohydrin alone. Shell Oil Co. (1994) reported significant increases in the frequencies of sister chromatid exchanges, cells with high frequencies of sister chromatid ex- changes, and chromosome aberrations and aberrant cells in workers exposed to epichlorohydrin. Worker exposures were measured to be 0.11-0.23 ppm for 11.15 h each day and higher concentrations of 0.19-2.57 ppm during three epi- sodes of 15 min each per day (it is presumed that the authors intended to report 11.25, not 11.15 h, for a total duration of 12 h per day). Giri (1997) reviewed data on chromosome aberrations in human cultured cells and noted that epichlorohydrin showed positive evidence of clastogenicity in different types of in vitro test systems.

Epichlorohydrin 201 2.6. Occupational Exposure Concentrations of epichlorohydrin in the work environment of production facilities have ranged from TWA concentration of 0.01 ppm to 15 ppm (0.04 to 57 mg/m3), as reported by WHO (1984). Citing a Dow Chemical Company monitoring report, NIOSH (1976) reported epichlorohydrin concentrations of 0.10-15.0 ppm for an epoxy-producing unit monitored in 1974, and concentra- tions of 0.01-4.69 ppm for a glycerin-producing unit monitored in 1975. de Jong et al. (1988) reported epichlorohydrin concentrations at two plants in a Shell petrochemical complex in the Netherlands. At one plant, the mean 4-8 h TWA concentration in 1977 was 6.6 ppm (25 mg/m3), with a range of <0.03-54 ppm (<0.1-205 mg/m3); in 1978, the mean was 1.3 ppm (5 mg/m3), with a range of <0.03-3.17 ppm (<0.1-12 mg/m3). In the second plant, the mean 4-8 h TWA concentration in 1977 was 1.6 ppm (6 mg/m3), with a range of <0.03-2.9 ppm (<0.1-11 mg/m3); in 1978, mean was 0.3 ppm (1 mg/m3), with a range of <0.03- 0.8 ppm (<0.1-3 mg/m3) (de Jong et al. 1988). According to the National Occu- pational Exposure Survey (NOES), over 95,000 workers were potentially ex- posed to epichlorohydrin between 1981 and 1983 (NIOSH 2003). According to the International Information System on Occupational Exposure to Carcinogens (Carex), almost 48,000 workers in 15 European Union nations were exposed to epichlorohydrin between 1990 and 1993 (Kauppinen et al. 1998). 2.7. Summary No lethality data in humans after acute exposure to epichlorohydrin were available, and data on acute nonlethal effects after acute exposure were limited. The odor detection levels reported in the literature ranged from 0.08 ppm to 25 ppm (Amoore and Hautala, 1983; Kobernick et al. 1983; AIHA 1989; Shell Oil Co. 1977; Berdasco and Waechter 2012). Anecdotal reports suggest that epichlorohydrin may cause ocular and throat irritation at 10-20 ppm, prolonged ocular and throat irritation at 40 ppm, and pulmonary edema and renal lesions at concentrations greater than 100 ppm (Lefaux 1968; Deichmann and Gerarde 1969; Wexler 1971; Enterline et al. 1990). A more definitive study showed that epichlorohydrin at 68 ppm was irri- tating to the pharynx in one of four subjects after 2 min, and 138 ppm caused a cooling sensation in the eyes and mouth and irritation to the eyes and pharynx after 2 min (Kobernick et al. 1983). Exposure to epichlorohydrin may also cause sneezing and nosebleed (Shell Oil Co. 1977). Two case reports of accidental exposure to epichlorohydrin provided evi- dence that exposure at high concentrations for only seconds (few breaths) or for 30 min caused irritation to the eyes, throat, and respiratory tract, gastrointestinal

202 Acute Exposure Guideline Levels disturbances, and irreversible liver damage in one case and irreversible damage to the respiratory tract in both cases (Schultz 1964; NIOSH 1976). Genetic toxicity studies showed that workers exposed to epichlorohydrin at average concentrations of 0.26 ppm had higher frequencies of aberrant cells and chromosome aberrations in peripheral lymphocytes when compared with unexposed workers or the general population (Sram et al. 1980). However, the unexposed workers also had a higher frequency of chromosome aberrations than the general population (Sram et al. 1980). Occupational exposure to epichloro- hydrin had no reproductive effects in human males as determined by sperm count and hormone concentrations (Venable et al. 1980; Milby et al. 1981). Occupational exposure to epichlorohydrin also has not been associated with any other long-term clinical effects. Workers exposed chronically at low concentration of epichlorohydrin for various durations showed no excess in cause-specific morbidity or mortality due to nonneoplastic or neoplastic diseases (Enterline et al. 1990; Tsai et al. 1990, 1996; Barbone et al. 1992, 1994; Olsen et al. 1994). The epidemiologic data are inadequate for evaluating the carcinogen- icity of epichlorohydrin in humans (EPA 1994; IARC 1999). Taken as a whole, the data on human exposures to epichlorohydrin suggest that chronic exposure at concentrations greater than 10 ppm may be associated with irritation, but that concentrations up to 54 ppm over 4-8 h are unlikely to trigger life-threatening effects (Pet’ko et al. 1966, as cited in NIOSH 1976). 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality The literature on the acute and short-term inhalation toxicity of epichloro- hydrin is extensive, consisting of lethality data from studies of rats, mice, guinea pigs, rabbits, dogs, hamsters, and cats. In some studies, animals were exposed to epichlorohydrin vapor, whereas in others they were exposed to an aerosol. Ex- posure conditions were either dynamic or static. Concentrations of epichlorohy- drin in the chamber atmospheres were determined analytically in some studies or were calculated on the basis of the flow rate and quantity of test substance delivered to the chamber in others. Single and repeat-exposure studies were con- sidered in the evaluation. 3.1.1. Rats Berdasco and Waechter (2012) reported 1-h LC50 values for epichlorohy- drin in male and female rats of 2,165 and 3,617 ppm, respectively (geometric mean = 2,798 ppm). They also reported a 4-h LC50 of 500 ppm and 8-h LC50 250 ppm for rats. In an acute inhalation study by Kobernick et al. (1983), groups of six young male Carworth Farm-Wistar rats were exposed for 5, 10, or 15 min to “essentially saturated” vapor of epichlorohydrin in a dynamic 9-L glass chamber

Epichlorohydrin 203 and were observed for 14 days after exposure. The authors calculated the vapor concentration of epichlorohydrin from material loss and flow rate to be 23,400 ppm; analysis of the chamber concentrations was not undertaken. No rats ex- posed for only 5 min died within the specified time; five of six rats exposed for 10 min died within 2 days, and all six exposed for 15 min died within 12 h. Gasping was observed during exposure in all groups, and poor condition (indica- tive of narcosis) was observed in animals exposed for 10 or 15 min. Gross ex- amination showed hemorrhage in the lungs, the severity of which increased with duration of exposure. Dietz et al. (1985) exposed groups of six male and six female Fischer 344 rats to epichlorohydrin vapor at concentrations of 552, 1,008, 1,970, or 3,995 ppm for 1 h; additional groups of six male rats were exposed at 2,865 or 3,275 ppm for 1 h. The animals were exposed in 2.6-m3 stainless-steel and glass Roch- ester-type inhalation chambers operated under dynamic conditions. Chamber concentrations were determined by gas chromatography seven times during each 1-h exposure. The animals were maintained for a 14-day observation period. Body weights were recorded at 2- to 3-day intervals. Necropsies were performed on all animals with special attention given to the eyes and nasal cavities. The mortality response is summarized in Table 4-3. No deaths occurred during expo- sure, but one female each died on days 2 and 3 after exposure at 1,970 ppm and all females exposed at 3,995 ppm died within 1 day of exposure. All males ex- posed at 3,995 ppm died 1-4 days after exposure. The LC50 values were 3,617 ppm for males, 2,165 ppm for females, and 2,369 ppm for the combined sexes. Clinical signs were observed in all exposure groups. During exposure at 552 and 1,008 ppm, the animals huddled in their cages and completely shut their eyes; no other signs were observed. At 1,970 ppm or higher, clinical signs included ocu- lar and nasal irritation, respiratory difficulty, and secretion of a reddish, porphy- rin-like material on the facial area. At 3,275 and 3,995 ppm, hyperactivity was observed during exposure followed by lethargy after exposure, and rats exposed at 3,995 ppm became cyanotic before the end of exposure. TABLE 4-3 Mortality in Fisher 344 Rats Exposed to Epichlorohydrin Vapor by Inhalation Concentration Mortality ppm mg/L Male Female Male + Female 552 2.088 0/6 0/6 0/12 1,008 3.814 0/6 0/6 0/12 1,970 7.453 0/6 2/6 2/12 2,865 10.839 0/6 – 0/6 3,275 12.390 0/6 – 0/6 3,995 15.114 6/6 6/6 12/12 1-h LC50 = 3,617 ppm (male); 2,165 ppm (female); 2,369 ppm (combined sexes) Source: Adapted from Dietz et al. 1985.

204 Acute Exposure Guideline Levels Grigorowa et al. (1974) exposed groups of 20 male albino rats to epichlo- rohydrin vapor at calculated concentrations of 0.190, 0.390, 0.855, 0.915, or 1.680 mg/L (50, 103, 226, 242, or 444 ppm, respectively) for 4 h in a dynamic exposure chamber. After exposure, one-half the rats were subjected to a temper- ature of 35°C and relative air humidity of 35-50% for 45 min and all animals were observed for an additional 72 h. The LC50s for rats exposed to epichloro- hydrin without and with heat treatment were 2.40 mg/L (635 ppm) and 2.20 mg/L (582 ppm), respectively. Marked hepatic damage, which was enhanced by heat, was observed in exposed animals. Microscopic lesions were observed in the kidneys (proximal tubules), adrenal glands (medulla), and thyroid gland (fol- licular epithelium); heat exacerbated the toxicity in the adrenal and thyroid glands. Hemorrhage, hyperemia, and edema were observed in the lungs, but subsequent heat treatment had no effect. The investigators did not report the concentrations at which the effects were observed. Data for other measures of toxicity were not presented in a manner meaningful for derivation of acute tox- icity values. In a study conducted by Kimmerle (1967), groups of 10 rats were exposed in a 400-L test chamber to epichlorohydrin evaporated from a petri dish and distributed around the chamber room with a fan. Complete evaporation of the material produced achieved concentrations (calculated) of 132, 331, 661, or 2,646 ppm (0.50, 1.25, 2.50, or 10.00 mg/L, respectively). Each group was ex- posed for 4 h and observed for 14 days. Five of 10 rats exposed at 661 ppm died within 2-4 days and all 10 rats exposed at 2,646 ppm died within 1-2 days. Symptoms of toxicity (not otherwise described) were observed in all rats at the two highest concentrations, moderate irritation to mucous membranes was ob- served at 661 ppm, and strong irritation occurred at 2,646 ppm. The 4-h LC50 for epichlorohydrin vapor was 741 ppm. Kobernick et al. (1983) reported a study in which groups of six young or mature (not otherwise specified) Carworth Farm-Wistar rats were exposed to epichlorohydrin vapor at 290 or 580 ppm (calculated concentrations) for 4 h in a dynamic 9-L glass chamber and observed for 14 days. No young or mature rats died after exposure at 290 ppm. No signs of irritation were observed at 290 ppm; the mature females lost weight during the observation period, and slight pulmo- nary congestion and hemorrhage were observed in all animals. All rats except four mature females died within the first 24 h after exposure at 580 ppm, and the remaining rats died within 3-12 days. Gasping was observed in females exposed at 580 ppm. The LC50 was 411 ppm. In another experiment by Kobernick et al. (1983), six different animal species including rats were exposed to epichlorohydrin vapor for 4 h and ob- served for 14 days. Male Carworth Farm-Wistar stock rats were exposed at 580 ppm (30 rats) or 1,160 ppm (six rats) in a 193-L hardboard chamber operated under dynamic conditions. Vapor concentrations were calculated from the amount of material used, the flow rate, and the ratio of analytic to nominal con- centrations (1.16) determined from a repeat-exposure study. Fifteen of 30 rats died after exposure at 580 ppm and all six rats died after exposure at 1,160 ppm.

Epichlorohydrin 205 The LC50 was 580 ppm. Irritation of mucous membranes was observed in all animals, and increased respiration, lethargy, and labored breathing were ob- served in all animals that died. Gross examination showed hemorrhagic lungs in the animals that died and in a few survivors. The investigators described only a few specific effects for each species. The difference in the mortality response of rats exposed in the 9-L glass chamber and the 193-L hardboard chamber was attributed to the generation of heat by the rats and the smaller surface:volume ratio that prevented adequate heat loss in the smaller chamber. Slott et al. (1990) observed no overt signs of toxicity in 48 male F344 rats during or after exposure to epichlorohydrin vapor at 100 ppm for 4 h. This was a reproduction study that showed a transient effect on sperm motility (see Section 3.3). Groups of 20 Sprague-Dawley rats (8-week old males) were exposed to epichlorohydrin vapor in 128-L or 1.3-m3 dynamic chambers at concentrations of 283, 303, 339, 369, 421, or 445 ppm for 6 h, and were observed for 14 days (Laskin et al. 1980). Chamber atmospheres were sampled every 30 min and ana- lyzed by a spectrophotometric procedure. Acute respiratory irritation with hem- orrhage and severe edema of the lungs along with elevated lung:body weight ratios occurred at concentrations of 339 ppm and higher. Mortality in each expo- sure group was 0/20, 1/20, 1/20, 15/20, 16/20, and 17/20, respectively; the LC50 reported was approximately 360 ppm. Weil et al. (1963) reported that four of six rats (unspecified strain and sex) died after exposure to epichlorohydrin at 250 ppm for 8 h. No additional details were provided. Groups of 20 male Wistar rats were exposed under dynamic conditions to atomized (aerosolized) epichlorohydrin in a mixture of lutrol (ethylene glycol) and alcohol (1:1) at epichlorohydrin concentrations of 296, 638, 1,038, or 1,440 mg/m3 4 h, and were observed for 2 weeks (Kimmerle 1967). The concentra- tions of epichlorohydrin in the chamber atmospheres were determined spectro- photometrically on air samples reacted with hydroxylamine. The number of deaths and time-to-death were concentration related. One rat exposed at 638 mg/m3 died on day 7, nine exposed at 1,038 mg/m3 died on days 1 and 6, and all 20 exposed at 1,440 mg/m3 died on days 1 and 4. Symptoms of toxicity were observed in all rats exposed to concentrations of 638 mg/m3 or higher. The LC50 reported was 960 mg/m3. Groups of 10 or 20 rats inhaled epichlorohydrin aerosols for 1 h in a 2-m3 chamber, and were observed for 14 days (Kimmerle 1967). Chamber concentra- tions were maintained by spraying epichlorohydrin dissolved in a mixture of lutrol (ethylene glycol) and alcohol (1:1) into the chamber every 30 min. Concentrations were analyzed by spectrophotometry of air samples collected through three con- secutive U tubes cooled to -60oC. The average analytic concentrations were 70, 204, 324, 500, and 3,350 mg/m3. The method for analyzing chamber atmospheres was not reported. The chamber also contained three rabbits, five guinea pigs, and 20 mice during each exposure. Eleven of 20 rats exposed at 3,350 mg/m3 died 3-8

206 Acute Exposure Guideline Levels days after exposure. Symptoms of toxicity were observed at 324 and 3,350 mg/m3, but not at 500 mg/m3. The LC50 was 3,073 mg/m3. In the next series of studies, rats were repeatedly exposed to epichlorohy- drin aerosols or vapor for different durations. Groups of 10 rats were exposed by inhalation to epichlorohydrin evaporated from a petri dish at concentrations of 66 and 661 ppm (250 or 2,500 mg/m3, respectively), 4 h/day for 5 days (Kim- merle 1967). No rats died and no symptoms of toxicity were observed at 66 ppm, but nine of 10 rats died and symptoms of toxicity were observed in all rats exposed at 661 ppm. No signs of irritation of mucous membranes were reported. Groups of young sexually mature male and female Carworth Farm-Wistar rats (23-32 per group) were exposed to calculated concentrations of epichloro- hydrin vapor in 550-L hardboard chambers operated under negative pressure (Kobernick et al. 1983). Each group was exposed for 7 h/day, 5 days/week to epichlorohydrin at 0, 68, or 136 ppm for 45 exposures; 0, 17, or 43 ppm for 91 exposures; or 0, 5, or 8 ppm for 90 exposures. The incidences, severity, and types of effects increased as the exposure concentration increased from 5 ppm to 136 ppm. Repeated exposure to epichlorohydrin resulted in death only at 136 ppm (10 rats) and 68 ppm (5 rats). Reduced weight gain, renal toxicity, and uri- nary coproporphyrins were observed at 68 and 136 ppm. No definitive signs of renal toxicity occurred at less than 43 ppm; however, weight gain was depressed and coproporphyrins were found in the urine at 43 ppm. In the another repeat-exposure study submitted by Kimmerle (1967), groups of 20 Wistar rats inhaled atomized epichlorohydrin in a mixture of lutrol (ethylene glycol) and alcohol (1:1) at epichlorohydrin concentrations of 32, 63, or 340 mg/m3 for 4 h/day for 5 days, and were observed for 2 weeks. No animals died at 32 mg/m3; two rats died at 63 mg/m3, and four rats died at 340 mg/m3. Symptoms of toxicity were observed in all rats exposed at 63 and 340 mg/m3. 3.1.2. Mice In 1941, Freuder and Leake reported the effects of inhaled epichlorohydrin on groups of 20-30 white mice exposed to epichlorohydrin vapors in a dynamic glass chamber at calculated concentrations of 8,300 or 16,600 ppm (0.35 or 0.70 mmol/L) for 30 min or at 2,370 ppm (0.10 mmol/L) for 60 min. All concentra- tions caused immediate signs of irritation to the nose and eyes, but the intensity was greater at 16,600 ppm. No additional signs were observed in mice exposed at 2,370 ppm for 1 h. Bristling of the hairs was observed almost immediately at 8,300 and 16,600 ppm and delirium (term not defined) was observed after 3 min at 16,600 ppm and after 14 min at 8,300 ppm. All animals exposed at 2,370 ppm for 60 min survived, but all mice exposed at 8,300 and 16,600 ppm for 30 min died within the first 24 h after exposure. Nno subsequent deaths occurred; how- ever, the duration of the observation period was not reported. Before death, mice exhibited signs of cyanosis followed by muscular relaxation of the extremities, stiffening of the tail, fine tremors, depressed respiration, clonic convulsion, and finally respiratory arrest.

Epichlorohydrin 207 Grigorowa et al. (1974) exposed groups of 20 male albino mice to epichlo- rohydrin vapor at calculated concentrations of 50, 103, 226, 242, and 444 ppm (190, 390, 855, 915, or 1,680 mg/m3, respectively) for 2 h in a dynamic expo- sure chamber as described for rats (see Section 3.1.1). The LC50s for mice ex- posed to epichlorohydrin without and with subsequent heat treatment were 794 ppm and 1,058 ppm, respectively. Marked hepatic damage (enhanced by heat) and renal damage (not affected by heat) was observed in exposed animals. Hemorrhages, hyperemia, and edema were observed in the lungs; subsequent heat treatment had no effect on severity of the pulmonary lesions. The investiga- tors did not report the concentrations at which the effects were observed. In a study reported by Kobernick et al. (1983), groups of 6 or 11 male mice (strain and age not specified) were exposed to epichlorohydrin vapor at calculated concentrations of 290, 580, or 1,160 ppm for 4 h in 193-L hardboard chambers operated under dynamic conditions. The concentrations were verified in a repeat-exposure study and adjusted by the ratio of 1.16 for analytic:nominal concentrations. The mortality response was 0/11, 0/6, and 6/6 at 290, 580, and 1,160 ppm, respectively, resulting in an LC50 of 820 ppm. Irritation of mucous membranes, increased respiration, lethargy, and labored breathing were ob- served in all animals that died, whereas only irritation of mucous membranes was observed in animals that survived. In a study reported by Kimmerle ( 1967), groups of 20 male CF1 mice were exposed for 4 h to epichlorohydrin vapor at 132, 331, 661, or 2,646 ppm. The vapor was generated by evaporation of epichlorohydrin from a petri dish as described for rats (see Section 3.1.1). No deaths, symptoms of toxicity (not oth- erwise described), or irritation of mucous membranes were observed at 132 and 331 ppm, but one death occurred at 661 ppm and 100% died after exposure at 2,646 ppm. Toxicity was observed in all mice exposed at 661 and 2,646 ppm, moderate irritation was observed at 661 ppm, and strong irritation occurred at 2,646 ppm. The LC50 was 1,153 ppm for the 4-h exposure. All mice exposed by inhalation to epichlorohydrin at 687 ppm (10-min RC50, see Section 3.2.3) for 6 h either died or were moribund within 72 h (Buck- ley et al. 1984). Groups of 16-24 (exact number per group not reported) male Swiss-Webster mice were exposed to epichlorohydrin vapor for 6 h. The cham- ber atmosphere was analyzed at least once per hour by infrared spectrophotome- try. The mice were necropsied immediately or 72 h after exposure, and the heads and respiratory tracts were examined microscopically. At necropsy, a serous exudate was observed in the nose, and the abdomen was distended by gas prob- ably caused by attempts to mouth breathe. Microscopic examination of the nasal tissue showed moderate exfoliation, erosion, ulceration, and necrosis along with minimal inflammation of the respiratory epithelium of the nose. Moderate ulcer- ation and necrosis were observed in the olfactory epithelium. Mice exposed to epichlorohydrin vapor at 687 ppm also showed epithelial exfoliation, hyperplas- ia, and squamous metaplasia of the trachea and slight exfoliation of the bron- chial epithelium with diffuse neutrophil infiltration.

208 Acute Exposure Guideline Levels Groups of 20 male CF1 mice were exposed to epichlorohydrin aerosols for 1 h in a 2-m3 chamber containing multiple species as described for rats in Sec- tion 3.1.1 (Kimmerle 1967). Chamber concentrations were maintained by spray- ing epichlorohydrin dissolved in a mixture of lutrol (ethylene glycol) and alco- hol (1:1) into the chamber every 30 min. The average analytic concentrations were 70, 204, 324, 500, and 3,350 mg/m3. One mouse exposed at 324 mg/m3 and one exposed at 3,350 mg/m3 died 7 days and 1 day, respectively, after expo- sure. Symptoms of toxicity were observed in 19 mice exposed at 324 mg/m3 and all 20 mice exposed at 3,350 mg/m3, but in none exposed at 500 mg/m3. Lawrence et al. (1972, 1974) calculated the LT50 (time to 50% lethality) for male ICR mice (number and age not reported) exposed to epichlorohydrin vapor in an 8.75-L glass chamber operated under dynamic conditions. Chamber concentrations of epichlorohydrin were calculated from the amount of material lost and the air flow. The LT50 was 9.13 min at a concentration of 71,890 mg/m3. The study author presented little detail regarding experimental procedures. Groups of 20 male CF1 mice were exposed repeatedly to epichlorohydrin at 66 and 661 ppm (Kimmerle 1967). Epichlorohydrin was evaporated from a petri dish placed in a 400-L chamber as described for rats (see Section 3.1.1). The mice were exposed for 4 h/day for 5 days. No mice died after exposure at 66 ppm but 18 died after exposure at 661 ppm. Symptoms of toxicity were ob- served in all mice exposed at 661 ppm, but signs of irritation to mucous mem- branes were not observed in this group. 3.1.3. Guinea Pigs Groups of four or six male guinea pigs (unspecified strain and age) inhaled epichlorohydrin vapor in a 193-L dynamic chamber at calculated concentrations of 290, 580, or 1,160 ppm for 4 h and were observed for 14 days (Kobernick et al. 1983). No deaths occurred at 290 ppm; two of six guinea pigs exposed at 580 ppm died and all four guinea pigs exposed at 1,160 ppm died. Irritation of mu- cous membranes, increased respiration, lethargy, and labored breathing were observed in all animals that died, whereas only irritation of mucous membranes was observed in surviving animals. The LC50 was 651 ppm for the 4-h exposure. Kimmerle (1967) reported on a study in which groups of five male Purl- bright guinea pigs were exposed for 4 h to epichlorohydrin vapor at 132, 331, 661, or 2,646 ppm. Epichlorohydrin was evaporated from a petri dish as de- scribed for rats (see Section 3.1.1). All guinea pigs died after exposure at 2,646 ppm and four in each group died after exposure at 331 and 661 ppm. Moderate and strong irritation of mucous membranes was observed at 661 and 2,646 ppm, respectively, and symptoms of toxicity were observed at concentrations of 331 ppm and higher. Groups of five male Purlbright guinea pigs were exposed to epichlorohy- drin aerosols at concentrations of 70, 204, 324, 500, and 3,350 mg/m3 for 1 h and at 171 and 498 mg/m3 for 4 h in a 2-m3 chamber containing multiple species as described for rats (see Section 3.1.1) ( Kimmerle 1967). Two guinea pigs died

Epichlorohydrin 209 after exposure at 3,350 mg/m3 for 1 h and three died after exposure at 498 mg/m3 for 4 h. Symptoms of toxicity were observed in all guinea pigs exposed at 324 and 3,350 mg/m3 for 1 h and at 498 mg/m3 for 4 h, but no symptoms of toxicity were observed in the group exposed at 498 mg/m3 for 1 h. In a repeat-exposure study by Kimmerle (1967), groups of five male Purl- bright guinea pigs were exposed by inhalation to epichlorohydrin vapor at con- centrations of 66 and 661 ppm (250 or 2,500 mg/m3) in a 400-L chamber as de- scribed for the single exposure studies. The guinea pigs were exposed for 4 h/day for 5 days. No deaths occurred at 66 ppm, but four deaths occurred at 661 ppm. Symptoms of toxicity or irritation to mucous membranes were observed in all five guinea pigs exposed at 661 ppm, but not those exposed at 66 ppm. 3.1.4. Rabbits Groups of three male rabbits (unspecified strain and age) were exposed by inhalation to epichlorohydrin vapor at 290, 580, or 1,160 ppm for 4 h, as de- scribed for rats in Section 3.1.1 (Kobernick et al. 1983). Three rabbits exposed at 1,160 ppm and two exposed at 580 ppm died during the 14-day observation period. Irritation of mucous membranes, increased respiration, lethargy, and labored breathing were observed in all animals that died, whereas only irritation of the mucous membranes was observed in surviving animals. The LC50 was 516 ppm for the 4-h exposure. One rabbit each was exposed repeatedly to epichlorohydrin vapor at con- centrations of 66 or 661 ppm (250 or 2,500 mg/m3). The vapor was generated by evaporation of epichlorohydrin from a petri dish in a 400-L chamber (Kimmerle 1967). The rabbits were exposed for 4 h/day for 5 days. The rabbit exposed at 66 ppm survived and showed no symptoms of toxicity or irritation of the mucous membranes. The rabbit exposed at 661 ppm showed symptoms of toxicity and died 2 days after exposure. Groups of 10 male New Zealand white rabbits were exposed to epichloro- hydrin vapor at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 10 weeks (John et al. 1983b). The exposure was during the premating period for a reproduction study. Three rabbits died or were killed moribund during the 10-week exposure period, two at 50 ppm and one at 25 ppm. Suppurative rhinitis and diffuse pneu- monia or pleuritis were observed during necropsy of the 50-ppm group and pul- monary abscesses were observed in the 25-ppm group. Surviving animals showed similar gross lesions, as well as microscopic evidence of inflammation and erosion of the nasal epithelium characterized by focal erosion and metaplasia at 50 ppm. 3.1.5. Dogs In an acute inhalation study, one dog (male or female) per group inhaled epichlorohydrin vapor at concentrations of 72, 290, 580, or 1,160 ppm for 4 h, and were observed for 14 days (Kobernick et al. 1983). Two dogs (one male and one female) were exposed similarly at 145 ppm. Exposure conditions were as

210 Acute Exposure Guideline Levels described for rats in Section 3.1.1. The investigators noted that the dogs exposed at 145, 290, 580, or 1,160 ppm regurgitated a small dose of an herbicide (no explanation provided). The dogs exposed at 580 and 1,160 ppm developed a slightly hemorrhagic dura mater and died. Irritation of mucous membranes, in- creased respiration, lethargy, and labored breathing were observed in animals that died (580 and 1,160 ppm) and mucous membrane irritation was observed in surviving animals (290 ppm and higher). Gross examination showed hemorrhag- ic lungs in animals that died. 3.1.6. Cat One cat each was exposed repeatedly to epichlorohydrin vapor at concen- trations of 66 and 661 ppm for 4 h/day for 5 days, and were observed for an un- specified period after the last exposure (Kimmerle 1967). The chamber atmos- pheres were generated by evaporation of the test substance in a 400-L chamber using a fan. The cat exposed at 66 ppm survived treatment and showed no symp- toms of toxicity or irritation of mucous membranes, whereas the cat exposed at 661 ppm showed symptoms of toxicity and died the third day after exposure. 3.1.7. Summary of Lethality Data Lethality data are summarized in Tables 4-4 and 4-5. 3.2. Nonlethal Toxicity 3.2.1. Monkeys One monkey (unspecified species) was exposed to epichlorohydrin at a concentration of 290 ppm for 4 h (Kobernick et al. 1983). The exposure condi- tions were the same as described for rats in Section 3.1.1. This animal survived the 14-day observation period; some mucous membrane irritation was observed. Gross examination revealed a blood clot in the midsagittal section of the brain. The monkey was suspected of having tuberculosis unrelated to treatment. Two rhesus macaque monkeys exposed repeatedly to epichlorohydrin at 21 ppm for 7 h/day, 5 days/week for 90 exposures, had damage in the lungs and kidneys (Kobernick et al. 1983). The animals were exposed in a 550-L hard- board dynamic chamber. The chamber concentrations were determined by tak- ing occasional air samples, analyzing the samples using a spectrophotometric procedure, and averaging all concentrations measured during exposure. Serum enzyme and hematologic parameters were not affected by exposure to epichlo- rohydrin. Microscopic findings in the lungs included bronchial irritation, mu- cous hypersecretion, subacute bronchitis, focal proliferation of alveolar septa, and hemosiderin deposits in the lungs. Microscopic findings in the kidneys in- cluded focal cloudy swelling of proximal convoluted tubules. A control group was not described.

TABLE 4-4 Summary of Acute Lethality Data in Laboratory Animals Exposed to Epichlorohydrin Vapor Exposure LC50 Species/Strain/Sex Duration (Exposure Range) Comments Reference Rats/F344/males and females 1h 3,617 ppm (males) No deaths in males at ≤3,275 ppm or in females at ≤1,008 ppm. Dietz et al. 1985 2,165 ppm (females) (552-3,995 ppm) Rats/Sprague-Dawley/males 6h 360 ppm LCLo = 303 ppm (1/20); respiratory irritation and severe Laskin et al. 1980 (283-445 ppm) lung edema at ≥339 ppm. Rats/Carworth Farm-Wistar/males 4h 441 ppm Pulmonary irritation, but no deaths at 290 ppm; deaths at Kobernick et al. 1983 and females (290-580 ppm) 580 ppm. Rats/Carworth Farm-Wistar/males 4h 580 ppm Deaths at both concentrations; irritation of mucous membranes Kobernick et al. 1983 (580-1,160 ppm) (all animals) and lethargy, labored breathing, and hemorrhagic lungs in animals that died. Rats/albino/males 4h 635 ppm Toxicity in the liver, kidney, lungs, adrenal glands, thyroid Grigorowa et al. 1974 (50-444 ppm) gland (concentration not reported) Rats/Wistar/males 4h 741 ppm Irritation at 661 and 2,646 ppm, other symptoms of toxicity Kimmerle 1967 (132-2,646 ppm) not described. Rats/Carworth Farm-Wistar/males 5, 10, or 15 min NA No deaths after 5 min; 5/6 after 10 min and 6/6 after 15 min; Kobernick et al. 1983 (23,400 ppm) gasping in all groups; hemorrhagic lungs after 10 and 15 min. Mouse/Swiss-Webster/males 6h (RC50 = 687 ppm) All animals dead or moribund within 72 h; moderate Buckley et al. 1984 degeneration of nasal epithelium (respiratory and olfactory). Mouse/?/males 4h 820 ppm Deaths only at 1,160 ppm; mucous membrane irritation at all Kobernick et al. 1983 (290-1,160 ppm) concentrations, lethargy and labored breathing at 1,160 ppm. Mouse/CF1/male 4h 1,153 ppm LClo = 661 ppm (1/20); moderate mucous membrane irritation, Kimmerle 1967 (132-2,646 ppm) and symptoms of toxicity at ≥661 ppm. Mouse/albino/males 2h 794 ppm Toxicity in the liver, kidneys, and lungs (concentration Grigorowa et al. 1974 (50-444 ppm) not reported). 211 (Continued)

212 TABLE 4-4 Continued Exposure LC50 Species/Strain/Sex Duration (Exposure Range) Comments Reference Mouse/albino/? 1h (2,370 ppm) Signs of irritation, no deaths (observation period not reported). Freuder and Leake 1941 Mouse/albino/? 30 min (8,300, 16,000 ppm) 8,300 ppm: 100% mortality (20/20) in 24 h. Freuder and Leake 1941 Guinea pigs/?/males 4h 651 ppm LClo = 580 ppm (2/6); mucous membrane irritation at all Kobernick et al. 1983 (290-1,160 ppm) concentrations; labored breathing and lethargy in non-survivors. Guinea pigs/ Purlbright/males 4h 275 ppm Deaths and symptoms of toxicity at ≥331 ppm; moderate to Kimmerle 1967 (132-2,646 ppm) strong irritation at ≥661 ppm. Dogs/males and females 4h (72-1,160 ppm) Death at 580 and 1,160 ppm. Kobernick et al. 1983 Rabbit/?/males 4h 516 ppm Deaths at 580 (2/3) and 1,160 ppm (3/3); mucous membrane Kobernick et al. 1983 (290-1,160 ppm) irritation at all concentrations; labored breathing and lethargy in non-survivors.

Epichlorohydrin 213 TABLE 4-5 Summary of Acute Lethality Data in Laboratory Animals Exposed to Epichlorohydrin Atmospheres Generated from Aerosols Exposure LC50 Species/Strain/Sex Duration (Exposure Range) Comments Rats/Wistar/males 1h 3,073 mg/m3 No deaths at ≤500 mg/m3; signs (70-3,350 mg/m3)a of toxicity at ≥324 and 3,350 mg/m3. Rats/Wistar/males 1h ND No deaths; signs of toxicity at (825 or 1,375 mg/m3)a 1,375 mg/m3. Rats/Wistar/males 4h 960 mg/m3 No deaths at 296 mg/m3; signs (296-1,440 mg/m3)a of toxicity at ≥638 mg/m3. Rats/Wistar/males 4h ND No deaths or signs of toxicity. (171 or 498 mg/m3)b Mouse/CF1/males 1h ND 1 death (1/20) at 324 and (70-,350 mg/m3)a 3,350 mg/m3; signs of toxicity at ≥324 and 3,350 mg/m3. Guinea pig/males 1h ND 2 deaths (2/6) at 3,350 mg/m3; signs (70-3,350 mg/m3)a of toxicity at 324 and 3,350 mg/m3. Guinea pig/males 4h ND 4 deaths (4/6) at 498 mg/m3; signs (171 or 498 mg/m3)a of toxicity at 498 mg/m3. a Exposures generated by aerosolizing epichlorohydrin dissolved in a mixture of ethylene glycol and water (1:1, v:v). Concentrations analyzed by spectrophotometry of air samples collected through three consecutive U tubes cooled to -60°C. b Exposures generated by aerosolizing epichlorohydrin without a solvent. Concentrations analyzed as described above. Abbreviations: LD50, lethal concentration, 50% lethality; ND, not determined. Source: Data from Kimmerle 1967. 3.2.2. Rats Gardner et al. (1985) determined the concentration of inhaled epichloro- hydrin that caused a 50% decrease in the respiratory rate (RD50) of rats exposed to epichlorohydrin vapor; the study also was reported by Haskell Laboratory (1980). The RD50 model is based on stimulation of the trigeminal nerve upon contact with an airborne irritant followed by inhibition of respiration (Kane et al. 1979). Groups of four 8-week old male Crl-CD® rats were exposed head-only to epichlorohydrin vapor for 15 min, and time respiratory rates were determined using a plethysmograph. Exposure concentrations were 101.6, 363.2, 394.1, 642.7, 662.9, 913.7, and 1,963 ppm. Chamber atmospheres were sampled every 2-3 min and analyzed by gas chromatography. The maximum decrease in the respiratory rate occurred after the 15-min exposure; partial recovery was noted during the first 5 min postexposure. A clear nasal discharge was produced in rats

214 Acute Exposure Guideline Levels exposed at the highest concentration (1,963 ppm), and a slight weight loss oc- curred in all groups during the first 24 h postexposure. The authors did not re- port the duration of the postexposure observation period. The calculated RD50 for rats was 1,342 ppm. The maximum decrease in the respiratory rate at each concentration is presented in Table 4-6. A clear dose-response was not observed. Robinson et al. (1995) found no histopathologic evidence of hepatic or re- nal damage in rats exposed to epichlorohydrin vapor at a concentration of 100 ppm for 4 h. Groups of male Fischer 344 rats were exposed to epichlorohydrin vapor in 422-L dynamic flow through inhalation chambers. The rats were either young adults (about 65 or 73 days old; six per group) or adults (96 days old; 11 per group). At least 14 grab samples per 4-h exposure period were taken from a single point near the geometric center of the chamber and analyzed for epichlo- rohydrin by infrared spectrophotometry. Controls were sham exposed. The study focused on various parameters of hepatic and renal damage on days 1, 2, and 3 postexposure. There was no evidence of hepatic damage in young rats as deter- mined by organ weight, serum chemistry, or histopathologic examination. The only statistically significant change potentially relevant to renal toxicity was a 5% increase in relative kidney weight in exposed young adult rats on day 1 after exposure, which was not observed on days 2 or 3 after exposure, or at any time in adult rats. Furthermore, serum creatinine levels were unaffected by epichloro- hydrin exposure in young or adult rats and blood urea nitrogen (BUN) levels decreased (15%) in adult rats on the day of exposure, but not at any other time (an increase in BUN would be indicative of possible renal toxicity). Collective- ly, the observations provide no consistent evidence of renal toxicity in young or adult rats. Robinson et al. (1995) did not conduct clinical observations of the rats during or after exposure. Groups of 60 male white rats were exposed to epichlorohydrin vapors at concentrations of 1.9, 5.3, or 93 ppm (7, 20, or 350 mg/m3) for 4 h, and they were evaluated on day 0 or 1 after exposure (Shumskaya et al. 1971). Exposure conditions (chamber size and mode of operation) and duration of the observation period were not reported by the investigators. The results showed increased he- patic and renal weights and decreased lung and spleen weights. Evaluation of urine showed increased production, decreased specific gravity, increased output of chlorides, and elevated excretion of protein at all concentrations. Bromosul- fophthalein (BSP) removal from the blood was decreased at all three concentra- tions on the day of exposure. BSP was used to assess liver function, particularly biliary function, at the time this study was conducted. TABLE 4-6 Reduction in Respiratory Rate of Rats Exposed to Epichlorohydrin Concentration (ppm) 101 363.2 394.1 642.7 662.9 913.7 1,963 Decease in respiratory rate, % 6 ± 15 33 ± 9 32 ± 7 52 ± 7 36 ± 19 54 ± 8 52 ± 21

Epichlorohydrin 215 In a 14-day inhalation toxicity study, groups or five male and five female Fischer rats were exposed to epichlorohydrin vapor at concentrations of 0, 10, 25, 50, 100, or 200 ppm for 6 h/day, 5 days/week, in an 8-m3 stainless-steel and glass inhalation chamber operated under dynamic conditions (Industrial Bio- Test Laboratories 1977a). The analytic concentrations were 0, 9.7, 23.0, 48.8, 97.3, and 209.8 ppm. Clinical signs observed after the first exposure are summa- rized in Table 4-7. No clinical signs attributed to epichlorohydrin exposure were observed at 10 and 25 ppm. Clinical signs at 50 ppm and higher involved pri- marily the eyes and respiratory tract. The number of different clinical signs in- creased as the exposure concentration increased from 50 ppm to 200 ppm. One male and three females died after repeated exposure at 200 ppm for 4-11 days. Gross findings at the end of the study included areas of consolidation in the lungs of two males, pale kidneys in three males and two females, extreme intes- tinal bloating in one male, and red oral and nasal discharge in one female at 200 ppm. Groups of 20 male Wistar rats exposed to aerosolized epichlorohydrin (in a 1:1 mixture of alcohol and lutrol) at concentrations of 825 or 1,375 mg/m3 for 1 h exhibited no symptoms of toxicity at 825 mg/3, but symptoms of toxicity were observed in all rats exposed at 1,375 mg/m3 (Kimmerle 1967). Symptoms of toxicity were not observed in groups of 10 male Wistar rats exposed to aero- solized epichlorohydrin (without alcohol and lutrol) at concentrations of 171 or 498 mg/m3 for 4 h. Ito et al. (1995) conducted a study to determine the biochemical and histo- pathologic effects of inhaled epichlorohydrin on the kidneys of Wistar rats (10 weeks old rats; sex and number per group not specified). Rats were exposed to epichlorohydrin vapor at 150 ppm for 1 h or 5 ppm for 2 h/day, 6 days/week for a total of 20 exposures. Chamber concentrations were monitored by gas chroma- tography (no other details provided). The effects in the experimental groups were compared with those of a control group. Body weight in the rat exposed repeatedly at 5 ppm was reduced throughout the exposure period. Pathologic lesions were observed in the kidney after single and repeat exposures. Exposure at 150 ppm caused severe damage to the proximal tubular epithelium of the kid- neys. Severe microscopic changes also were observed in epithelial cells (apopto- sis) in distal tubules in the kidneys of rats exposed at 150 ppm. Similar but less severe damage occurred after repeat exposures at 5 ppm. Quast et al. (1979b) conducted a 12-day inhalation study using Fischer 344 and Sprague-Dawley rats (five males and five females per group) exposed to epichlorohydrin vapor at a concentration of 100 ppm for 7 h/day, 5 days/week for a total of nine exposures. The animals were exposed under dynamic condi- tions in a 4.3-m3 Rochester-type chamber. Exposure concentrations were deter- mined 3-7 times per day by gas chromatography. Control groups were not placed in a chamber. No signs of significant ocular or nasal irritation were ob- served during exposure; the animals, however, tended to huddle together and sleep. Transient moist nasal discharge, discoloration around the nasal orifice,

216 Acute Exposure Guideline Levels TABLE 4-7 Clinical Signs, Mortality, and Time of Onset in Fischer 344 Rats Exposed by Inhalation to Epichlorohydrin for 6 Hours/Day, 5 Days/Week for 14 Days Concentration (ppm) Clinical Signs 10 and 25 50 100 200 Squinting – + (82 min) + (28 min) + (66 min) Hypoactivity – + (82 min) + (78 min) + (66 min) Head shaking – – + (178 min) – Drooping eyelids – – + (223 min) + (126 min) Irritated eyes – – – + (136 min) Gasping, intermittent – – – + (171 min) Red nasal discharge – – – + (266 min) Lacrimation – – – + (336 min) Mortality (earliest) – – – 4/10 (4-11 d) + clinical signs observed; – no clinical signs observed Source: Data from Industrial Bio-Test Laboratories 1977a. sneezing, and rubbing of the nose were observed after each exposure and disap- peared before the next exposure. Decreased body size (due to less filled ab- dominal region), food consumption, and fecal production observed after repeat- ed exposures recovered somewhat over the weekend in the absence of exposures, but reappeared when another round of exposures was initiated. Ef- fects at study termination attributed to epichlorohydrin included gross and histo- pathologic evidence of damage to nasal turbinates (degeneration, inflammation, hyperplasia, and squamous metaplasia), kidneys (increased weight and slight degeneration), and epididymis (slight change in contents). The kidneys were more affected in males than in females, and Sprague-Dawley rats were more affected than Fischer rats. Groups of four male and four female albino Wistar rats were exposed un- der dynamic conditions to atomized epichlorohydrin (in propanol) diluted with air to achieve concentrations of 9, 17, 27, or 56 ppm (Gage 1959). Exposures were for 6 h/day, 5 days/week for 18 or 19 exposures or at 120 ppm repeatedly for 11 exposures. Labored breathing was observed 3 h after initiating the first exposure at 120 ppm. Profuse nasal discharge was observed at 120 ppm, lethar- gy and weight loss at 56 and 120 ppm, respiratory distress and nasal discharge at 56 ppm, poor general condition at 27-120 ppm, and signs of mild nasal irritation at 27 ppm. Gross and histopathologic evidence of leucocytosis and toxicity were observed in the lung, kidneys, and liver of rats exposed at 120 ppm and evidence of toxicity was found in the lungs at 27 ppm but not at 56 ppm. No rats died after only one exposure, but one rat died after 11 exposures at 120 ppm. Groups of 30 male and 30 female Sprague-Dawley rats were exposed to epichlorohydrin at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 10 weeks (John et al. 1983b). Weight gain was decreased slightly in male and female rats

Epichlorohydrin 217 exposed at 50 ppm. A slight potentiation of spontaneous renal damage and de- generative changes (inflammation, hyperplasia, and metaplasia) in the respirato- ry epithelium of the nasal cavity were observed at 25 and 50 ppm. The damage was minimal to moderate at 25 ppm and moderate to severe at 50 ppm. All nasal and renal damage was reversed during the 10-week postexposure period. The study was a reproduction study that showed marked transient decreases in fertili- ty in male rats exposed at 25 and 50 ppm. Groups of 20 male and 20 female Sprague-Dawley and Fischer 344 rats were exposed to epichlorohydrin at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 3 months (Quast et al. 1979a). No effects were observed that could be at- tributed to a single exposure to epichlorohydrin. The most notable microscopic changes observed at the end of the study were inflammatory, degenerative, and reactive changes in the nasal turbinates of male and female rats of both strains exposed at 25 and 50 ppm. Other microscopic changes were observed in the liver and kidneys of males and females of both strains at 50 ppm and in the ad- renal gland of males at 50 ppm. 3.2.3. Mice Kane et al. (1979) determined the RD50 in groups of four specific patho- gen free Swiss-Webster mice exposed to aerosolized epichlorohydrin head-only for 10 min at different concentrations. The respiratory rate was measured using a plethysmograph. Epichlorohydrin concentrations were determined spectropho- tometrically after oxidation of epichlorohydrin with periodic acid. The RD50 was 687 ppm (95% confidence limits: 633-748 ppm). The concentrations were re- ported as ppm, although the exposure atmospheres were generated by aerosoliz- ing epichlorohydrin. Presumably, the animals were actually exposed to vapor produced from the epichlorohydrin aerosol; however, that could not be con- firmed from the report. TABLE 4-8 Clinical Signs, Mortality, and Time of Onset in B6C3F1 Mice Exposed by Inhalation to Epichlorohydrin for up to 6 Hours/Day, 5 Days/Week for 14 Days Concentration (ppm) Clinical Signs 10 and 25 50 100 200 Squinting – + (66 min) + (78 min) + (66 min) Hypoactivity – + (217 min) + (178 min) + (126 min) Drooping eyelids – – + (223 min) + (126 min) Ruffed fur – – – + (306 min) Gasping – – – + (381 min) Mortality (earliest) – – – 7/10 (6-12 d) + clinical signs observed; – no clinical signs observed. Source: Data from Industrial Bio-Test Laboratories 1977b.

218 Acute Exposure Guideline Levels In a 14-day inhalation toxicity study, groups or five male and five female B6C3F1 mice were exposed to epichlorohydrin vapor at concentrations of 0, 10, 25, 50, 100, or 200 ppm for 6 h/day, 5 days/week. The animals were exposed in an 8-m3 stainless-steel and glass inhalation chamber operated under dynamic conditions (Industrial Bio-Test Laboratories 1977b). The procedure for analysis of chamber atmospheres was not reported. The analytic concentrations were 0, 9.7, 23.0, 48.8, 97.3, and 209.8 ppm. Clinical signs observed after the first expo- sure are summarized in Table 4-8. No clinical signs attributed to epichlorohydrin were observed in the 10- and 25-ppm groups. The number of different clinical signs increased as the exposure concentration increased from 50 ppm to 200 ppm. A total of seven deaths occurred (all five females and two males) in the 200-ppm group after day 6. Gross findings were observed only at 200 ppm, and consisted of consolidation in the lungs of one male and two female mice. Quast et al. (1979b) conducted a 12-day inhalation study using B6C3F1 mice (five males) exposed to epichlorohydrin vapor at a concentration of 100 ppm for 7 h/day, 5 days/week for a total of nine exposures. The animals were exposed under dynamic conditions in a 4.3-m3 Rochester-type chamber. Expo- sure concentrations were determined by gas chromatography 3-7 times each day. Five males serving as the control group were not placed in a chamber. No signs of significant ocular or nasal irritation were observed during exposure; the ani- mals, however, tended to huddle together and sleep. Transient moist nasal dis- charge, sneezing, and rubbing of the nose were observed after exposure; the signs disappeared before the next exposure. Decreases in body size, food con- sumption, and fecal production observed during the weekday exposures showed recovery over the weekend (no exposures), but the same effects became readily apparent upon initiation of another round of exposures. Effects at study termina- tion attributed directly to epichlorohydrin included gross and histopathologic damage to nasal turbinates (degeneration, inflammation, hyperplasia, and squa- mous metaplasia) but not to the kidneys or epididymis as observed in rats. Groups of 20 male and 20 female B6C3F1 mice were exposed to epichlo- rohydrin at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 3 months (Quast et al. 1979a). No effects were observed that could be attributed to a single expo- sure to epichlorohydrin. The male and female mice, like the rats, had inflamma- tory, degenerative, and reactive changes in the nasal turbinates at 25 and 50 ppm. Other microscopic changes occurred only in the liver of males and females at 50 ppm. In a continuous inhalation study, Formin (1966) exposed groups of 15 mice to epichlorohydrin at 0, 0.05, 0.53, or 5.3 ppm (0, 0.2, 2, or 20 mg/m3) for 98 days. No details were provided regarding the exposure system or analysis of chamber atmospheres. Mice exposed at 0.05 ppm showed no adverse effects. On the first day of exposure, mice exposed at 5.3 ppm were noticeably excited, rest- less, and fairly active, and then became sluggish and somnolent before showing a gradual improvement. Body weight was 14-19% lower than that of controls by the end of exposure. Additional effects observed after repeated exposure to epichlorohydrin included increased latent reaction period of the motor defense

Epichlorohydrin 219 response to electrical stimulation (central nervous system effect) at 5.3 ppm, transient increase in the number of leukocytes with altered fluorescence at 0.53 and 5.3 ppm, decreased nucleic acids in blood at 0.53 and 5.3 ppm, and in- creased excretion of coproporphyrin in the urine at 5.3 ppm. Mice exposed at 5.3 ppm also had emphysema, bronchopneumonia, small edematous areas, and loos- ening and swelling of the adventitia of blood vessels in the lungs; foci of inter- stitial hemorrhages and venous congestion of the heart; cloudy swelling of the convoluted tubular epithelium of the kidney; and severe neuronal lesions in the medulla oblongata, cornu ammonis (hippocampus), and cerebellum of the cen- tral nervous system. No morphologic effects were seen in mice exposed at 0.05 and 0.53 ppm. 3.2.4. Hamsters In a 14-day inhalation toxicity study, groups or five male and five female Syrian hamsters were exposed to epichlorohydrin vapor at concentrations of 0, 25, 50, 100, 200, or 400 ppm for 6 h/day, 5 days/week, in a 8-m3 stainless-steel and glass inhalation chamber operated under dynamic conditions (Industrial Bio-Test Laboratories 1977c). The procedure for analysis of chamber atmos- pheres was not reported. The analytic concentrations were 0, 23.0, 48.8, 97.3, 209.8, and 364.3 ppm. Clinical signs observed after the first exposure are sum- marized in Table 4-9. The number of different clinical signs observed in each group increased as the exposure concentration increased from 50 ppm to 400 ppm. Salivation was observed before exposure was initiated. A total of four males and all five females exposed at 200 ppm died between day 4 and termina- tion of the study; all males and females exposed at 400 ppm died between day 3 and 6 of the study. Gross findings included areas of lung consolidation in four male hamsters and one female hamster, intestinal bloating in three females, and pale kidneys in one female. 3.2.5. Rabbits Groups of three male and female rabbits were exposed under static condi- tions to atomized epichlorohydrin sprayed every 30 min into a 2-m3 chamber for a single exposure of 1 or 4 h; the animals were observed for 14 days (Kimmerle 1967). Average exposure concentrations determined analytically were 70, 204, 324, 500, and 3,350 mg/m3 for 1 h or 171 and 498 mg/m3 for 4 h. Other species were housed in the same chamber. Symptoms of toxicity were observed only at 3,350 mg/m3. Gage (1959) exposed two New Zealand white rabbits to epichlorohydrin at 35 ppm or at 16 ppm reduced to 9 ppm after the second day. The animals were exposed daily for 6 h/day, 5 days/week for a total of 20 exposures. Signs of na- sal irritation were observed at 35 and 16 ppm, but not at 9 ppm. Gross and histo- pathologic examinations showed no signs of toxicity.

220 Acute Exposure Guideline Levels TABLE 4-9 Clinical Signs, Mortality, and Time of Onset in Syrian Hamsters Exposed by Inhalation to Epichlorohydrin for up to 6 Hours/Day, 5 Days/Week for 14 Days Concentration (ppm) Clinical Signs 25 50 100 200 400 Squinting – + (82 min) + (78 min) + 66 (min) + (40 min) Hypoactivity – + (262 min) + (178 min) + (126 min) + (100 min) Drooping eyelids – – + (223 min) + (126 min) + (100 min) Salivation – – + (268 min) + (126 min) + (-20 min) Excitation, intermittent – – – + (216 min) + (-30 min) Gasping, intermittent – – – + (381 min) – Gasping, not intermittent – – – + (426 min) + (145 min) Mouth pouches full or full of saliva – – – + (306 min) + (240 min) Very heavy labored breathing – – – – + (240 min) Mortality (earliest) – – – 9/10 (7-14 d) 2/10 (3-6 d) + clinical signs observed; – no clinical signs observed Source: Data from Industrial Bio-Test Laboratories 1977c. 3.2.6. Dogs Two dogs were exposed to epichlorohydrin vapor at a concentration of 21 ppm for 7 h/day, 5 days/week for 90 exposures (Kobernick et al 1983). The an- imals were exposed in 550-L hardboard chambers operated under dynamic con- ditions. The chamber atmosphere was sampled occasionally and analyzed using a spectrophotometric procedure. One dog lost a small amount of weight. Micro- scopic examination showed hemosiderin deposits and diffuse congestion of al- veolar capillaries in both dogs, bronchial hypersecretion of mucus in one dog, focal interstitial nephritis in both dogs, diffuse cloudy swelling of the proximal convoluted tubules in one, and centrilobular cloudy swelling in the liver of one dog. 3.3. Developmental and Reproductive Toxicity In developmental toxicity range finding studies, groups of five or six pre- sumed pregnant rats and groups of five presumed pregnant rabbits were exposed to epichlorohydrin vapor under dynamic conditions at concentrations of 0, 25, 50, or 100 ppm for 7 h/day (Pilny et al. 1979). The rats were exposed on gesta- tion days 6-15 and then killed on day 16, and the rabbits were exposed on gesta- tion days 6-18 and then killed on day 19. At 50 and 100 ppm, female rats gained less weight and had decreased intraabdominal adipose tissue, decreased thymus size, and an increased incidence of pale liver. At 100 ppm, three of six rats had 100% resorptions, one had normal fetuses, and two had no evidence of being

Epichlorohydrin 221 pregnant (no implantation sites). Three rabbits exposed at 100 ppm and one ex- posed at 50 ppm died at an unknown time. Decreased body weight gain, respira- tory tract irritation, pneumonia, and suppurative rhinitis were observed in all rabbits at 50 and 100 ppm. Severe pneumonia was confirmed at necropsy at 50 and 100 ppm and focal pneumonia in one rabbit at 25 ppm. No maternal or developmental effects attributed to epichlorohydrin were observed in groups of 43-46 pregnant Sprague-Dawley rats exposed to epichlo- rohydrin vapor at concentrations of 0, 2.5, or 25 ppm for 7 h/day on gestation days 6-15 (John et al. 1983a). The animals were exposed in a 14.3-m3 dynamic stainless-steel and glass chamber. Chamber atmospheres were sampled two to seven times per day and analyzed by gas chromatography. Analytic concentra- tions of epichlorohydrin were 2.5 and 24.6 ppm. Fetuses were harvested by Ce- sarean section on gestation day 21. Groups of 20-25 New Zealand white rabbits exposed on gestation days 6-18 under the same conditions as the rats and evalu- ated on gestation day 29 also had no maternal or developmental effects attribut- ed to epichlorohydrin (John et al. 1983a). John et al. (1983b) examined the effects of inhaled epichlorohydrin on fer- tility in groups of 30 male and 30 female Sprague-Dawley rats exposed to epichlorohydrin at 0, 5, 25, or 50 ppm for 6 h/day, 5 days/week for 10 weeks (about one spermatogenic cycle), followed by a 10-week postexposure period. A sialodacryadenitis infection (sialoacryadenitis virus is a coronavirus affecting the lacrimal and salivary glands, as well as upper and lower respiratory tracts, of rats) affected both control and exposed groups during weeks 1 and 2. Fertility was assessed during exposure (weeks 2, 4, 7, and 10) and postexposure (weeks 2, 5, and 10) in male rats mated with unexposed females. Fertility in the males of the 25- and 50-ppm groups was significantly reduced during exposure weeks 2-10, as assessed by the number of implantations per unexposed females mated with the exposed males, but was reduced only in the 50-ppm group, as assessed by the percentage of the exposed males impregnating unexposed females. Epichlorohydrin had no effect on the weight or histology of male reproductive organs. Fertility in exposed females was assessed by the ability of the females to produce viable litters after mating with unexposed males. Exposure to epichlo- rohydrin had no adverse effect on the estrous cycle, pregnancy rate, parturition, litter size, or pup viability. Renal damage and degenerative lesions in the nasal cavity were observed at 25 and 50 ppm (see Section 3.2.2). Fertility and testicular function were evaluated in groups of 10 male New Zealand white rabbits exposed to epichlorohydrin at 0, 5, 25, or 50 ppm, as de- scribed for rats (John et al. 1983b). Semen evaluated prior to exposure, at week- ly intervals from week 2 to termination of exposure, and biweekly during the postexposure period showed no effects on sperm motility, viability, concentra- tion, or morphology. No adverse effects were observed on fertility assessed in unexposed does mated with the exposed males. Light microscopic examination of spermatozoa revealed no abnormalities. Death, pulmonary lesions, and nasal lesions occurred at 25 and 50 ppm (see Section 3.1.4).

222 Acute Exposure Guideline Levels Slott et al. (1990) evaluated the effect of inhaled epichlorohydrin on sperm motility and testicular function in male Fischer-344 rats. Groups of 48 rats (90 days old) were exposed to epichlorohydrin at 0 or 100 ppm for 4 h, and sperm motility and other parameters were evaluated immediately after exposure and on days 1, 2, 6, and 14 postexposure. The exposed rats showed no overt signs of toxicity. No adverse effects were observed on testicular or epididymal weight, caudal epididymal sperm counts, or testicular spermatid counts in rats exposed to epichlorohydrin. Evaluation of sperm motility showed transient decreases (- 14% to -20% of control values) in progressive (straight line) and path (smoothed curvilinear) velocities of caudal epididymal sperm on day 1 postexposure only. The authors stated that the transient nature of the decrease and the small magni- tude of the effect suggested that epichlorohydrin vapor at 100 ppm did not have a significant adverse effect on reproductive parameters. 3.4. Carcinogenicity Only two inhalation carcinogenicity studies were found. Laskin et al. (1980) reported on studies in rats exposed to epichlorohydrin vapor for a total of 30 exposures or for their entire lifetime. In the first study, two groups of male Sprague-Dawley rats were exposed to epichlorohydrin vapor at 100 ppm for 6 h/day, 5 days/week for 30 exposures, and observed until death. One group had 40 rats and the other had 100 rats. In the second study, groups of 100 male Spra- gue-Dawley rats were exposed to epichlorohydrin vapor at 10 or 30 ppm for 6 h/day, 5 days/week until death. A total of 150 male rats served as controls; 100 were sham-exposed and 50 were untreated. It was unclear whether each study had separate control groups. Among the 140 animals exposed at 100 ppm for 30 days, 15 developed squamous cell carcinomas in the nasal cavity, two developed a nasal papilloma, and one developed a bronchial papilloma. The first tumor to appear was a carcinoma on day 330. After a lifetime exposure to epichlorohy- drin at 30 ppm, one animal had a squamous cell carcinoma of the nasal cavity (at 752 days) and one had a nasal papilloma (at 402 days). No nasal neoplasms de- veloped in animals exposed at 10 ppm. Nonneoplastic respiratory lesions in the 100-ppm group consisted of severe inflammation, suppuration, destruction of the mucous membrane, and mucosal metaplasia of the nasal cavity; severe in- flammation in the larynx and trachea; and pulmonary edema, congestion, and pneumonia. Tubular degenerative changes in the kidney were also observed at 100 ppm. Rats exposed at 10 or 30 ppm over a lifetime developed pulmonary congestion, bronchiectasis, pneumonia, a very low incidence of mucosal meta- plasia of the nasal cavity, and tubular degenerative changes in the kidney. These studies showed that: (1) epichlorohydrin is carcinogenic in rats; (2) the neo- plastic response to inhaled epichlorohydrin occurs only at the site of contact; and (3) short-term intense exposure to epichlorohydrin is much more effective in inducing a neoplastic response than low-level long-term exposures (a dose-rate effect was observed [3,000 ppm-days [100 ppm × 30 days] vs. 8,700 ppm-days [30 ppm for lifetime] and 2,500 ppm-days [10 ppm for lifetime]).

Epichlorohydrin 223 Carcinogenicity studies have been conducted in rats exposed orally and topically to epichlorohydrin. Oral exposure to epichlorohydrin resulted in a dose-related increase in forestomach neoplasms (primarily squamous cell carci- nomas) after gavage administration, and in papillomas after administration in drinking water. Skin tumors have been induced in mice receiving a single appli- cation of epichlorohydrin followed by repeated applications of phorbol myristate acetate (initiation/promotion protocol) (HSE 1991). A quantitative assessment of single-exposure estimates for epichlorohy- drin is presented in Appendix B. 3.5. Genotoxicity In a review of the genetic toxicology of epichlorohydrin, Giri (1997) con- cluded that epichlorohydrin is a direct-acting mutagen in Salmonella typhimuri- um, Escherichia coli, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Klebisella pneumoniae. It is more effective as a mutagen in the absence of an exogenous metabolizing system. There is a reduction in mutagenic activity in the presence of an activation system. In vitro cytogenetic assays showed con- sistent positive clastogenic effects (chromosome aberrations) and sister chroma- tid exchanges in test systems using cultured animal cells. In a study of mice and rats exposed to epichlorohydrin at concentrations of 1.3, 6.6, and 33 ppm (5, 25, or 125 mg/m3) for 120 h, Sram et al. (1981) showed increased frequencies of chromosome aberrations in mouse bone marrow and spermatogonia and increased abnormal sperm in mice (unspecified strain) ex- posed by inhalation to concentrations of epichlorohydrin as low as 1.3 ppm. The abstract did not state whether the animals were exposed continuously or inter- mittently for 120 h The frequency of sister chromatid exchanges was not in- creased in bone marrow cells of mice, and the frequencies of chromosome aber- rations in bone marrow cells and peripheral lymphocytes were not increased or were only slightly increased in rats after inhalation exposure to epichlorohydrin. Another inhalation study showed a significant increase in the frequency of chromosome aberrations in spleen lymphocytes in CD-1 Swiss mice exposed to mixtures containing benzene, chloroprene, xylene, and epichlorohydrin at con- centrations of 0, 0.1, 1.0, or 10 ppm (epichlorohydrin concentration was one-half that of the other components) for 3 or 6 weeks (Au et al. 1988). Exposure condi- tions are assumed to have been continuous. The effect could not be attributed to epichlorohydrin. Mixed results have been observed in oral and parenteral studies (Giri 1997). 3.6. Summary Inhalation exposure to epichlorohydrin causes varying degrees of irritation of the mucous membranes of contact organs and effects on the central nervous system, kidneys, and liver. Acute lethality data are summarized in Table 4-3. LC50 values varied considerably depending on the exposure condition (dynamic

224 Acute Exposure Guideline Levels or static chambers) and the physical state (aerosol or vapor) of the epichlorohy- drin (see discussion in Section 4.5). Acute LC50 values for epichlorohydrin va- por in rats were 2,165-3,617 ppm for a 1-h exposure, 471-635 ppm for a 4-h exposure, and 360 ppm for a 6-h exposure. LC50 values in other species were 794 ppm for a 2-h exposure and 820-1,153 ppm for a 4-h exposure in mice, 275- 651 ppm for a 4-h exposure in guinea pigs; and 516 ppm for a 4-h exposure in rabbits. Deaths were due to effects on the respiratory center of the central nerv- ous system and severe respiratory irritation manifested as pulmonary hemor- rhage and edema. Before death occurred, the animals showed signs of cyanosis, muscle relaxation of the extremities, gasping, labored breathing, depressed or increased respiration, lethargy, fine tremors, and clonic convulsions. In addition, the animals had degenerative lesions of the nasal epithelium and kidneys and damage to the lower respiratory tract. Inhalation exposure to nonlethal concentrations of epichlorohydrin result- ed in systemic but mainly portal-of-entry effects. Data are summarized in Table 4-10. The RD50 is 1,342 ppm for a 15-min exposure of rats and 687 ppm (aero- sol) for a 10-min exposure of mice. Clinical signs indicative of nasal irritation and sometimes ocular irritation have been observed in rats, mice, guinea pigs, hamsters, and rabbits exposed at nonlethal concentrations of epichlorohydrin. The nasal epithelium shows signs of degeneration similar to that described for lethal concentrations. Severe renal damage in rats exposed to epichlorohydrin vapor at 150 ppm for 1 h has been observed by light and electron microscopy (Ito et al. 1995) and functional changes in the kidney were noted after exposure at 93 ppm for 4 h (Shumskaya et al. 1971); however, no microscopic evidence of renal damage was found after exposure at 100 ppm for 4 h (Robinson et al. 1995). Renal damage was seen in rats, but not mice, exposed repeatedly to epichlorohydrin. Sprague-Dawley rats appeared to be more sensitive than Fisch- er 344 rats, and males were more severely affected than females (Quast et al. 1979a,b). Damage to the nasal epithelium was seen in both strains of rats and in mice, but the effect may be less severe in mice. No developmental effects were observed in rats or rabbits exposed to epichlorohydrin at concentrations up to 25 ppm for 7 h/day during organogene- sis (John et al. 1983a). A transient decrease in fertility was observed in male rats but not females exposed repeatedly to epichlorohydrin vapor at 25 or 50 ppm for 6 h/day for 2-10 weeks. Studies in rabbits exposed at concentrations up to 50 ppm for 6 h/day for up to 10 weeks showed no effects on sperm parameters (John et al. 1983b). However, decreases in sperm motility were observed in rats exposed at 100 ppm for 4 h (Slott et al. 1990). Genetic toxicity studies showed that epichlorohydrin is mutagenic in bac- teria and yeast without metabolic activation. In vivo studies in mice showed chromosome aberrations after exposure at concentrations as low as 1.3 ppm for 120 h (Sram et al. 1981). Carcinogenicity studies showed that 30 exposures (6-h exposures for 5 days/week) to epichlorohydrin vapor at 100 ppm followed by

TABLE 4-10 Nonlethal Effects in Animals Exposed to Epichlorohydrin by Inhalation Species/Strain/Sex Exposure Protocol Effects Reference Single Exposures Rat/Crl-CD®/males 101-1,963 ppm × 15 min 6-54% decrease in respiration; RD50 = 1,342 ppm (50% decrease Gardner et al. 1985 in respiratory rate). Rat/Wistar 150 ppm × 1 h Severe renal damage. Ito et al. 1995 Rat/F344 100 ppm × 4 h Slight increase in renal weight in young rats; slight decrease in Robinson et al. 1995 BUN in adult rats; no microscopic evidence of hepatic or renal damage. Rats 1.9, 5.3, or 93 ppm × 4 h Increased hepatic and renal weight; decreased pulmonary and Shumskaya et al. 1971 spleen weight; increased urinary protein and chlorides; decreased specific gravity and BSP removal from blood. Rat/F344/males and females 10 or 25 ppm × 6 h No effect. Industrial Bio-Test Laboratories 1977 50 or 100 ppm × 28-223 min Squinting, hypoactivity, head shaking, drooping eyelids. 200 ppm × 136-336 min Same as at 100 ppm; plus irritated eyes, gasping, red nasal discharge, lacrimation. Mice/Swiss Webster 687 ppm × 10 min RD50 (50% decrease in respiratory rate) Kane et al. 1979 Mouse/B6C3F1/males and females 10 or 25 ppm × 6 h No effect. Industrial Bio-Test Laboratories 1977b 50, 100, or 200 ppm × 66-381 min Squinting, hypoactivity, drooping eyelids, ruffed fur, gasping. Mouse 5.3 ppm × 24 h Transient excitation, restlessness, sluggishness, somnolence. Formin 1966 Hamster/Syrian/males and females 25 ppm × 6 h No effects. Industrial Bio-Test Laboratories 1977c 50 or 100 ppm × 78-262 min Salivation, hypoactivity, squinting, drooping eyelids. 200 ppm × 66-381 min Same as at 100 ppm; plus excitation, gasping, full mouth pouch. 400 ppm × 20-240 min Same as at 200 ppm; plus labored breathing. (Continued) 225

226 TABLE 4-10 Continued Species/Strain/Sex Exposure Protocol Effects Reference Repeated Exposures Rat/Wistar 150 ppm × 1 h or 5 ppm × 2 h/day Less severe renal damage than single 1-h exposure at Ito et al. 1995 for 6 days/week for 20 exposures 150 ppm. Rats/Sprague-Dawley, F344/males 100 ppm × 7 h/day for 5 days/week Signs of nasal irritation after each exposure (discharge, Quast et al. 1979b and females for 9 exposures sneezing, rubbing); nasal epithelial and renal degeneration after repeated exposures. Mouse/B6C3F1/males 100 ppm ×7 h/day for 5 days/week Signs of nasal irritation after each exposure (discharge, Quast et al. 1979b for 9 exposures sneezing, rubbing); nasal epithelial degeneration after repeated exposures.

Epichlorohydrin 227 lifetime observation was very effective in inducing squamous cell carcinomas in the nasal cavity of rats, whereas lifetime exposure at 30 ppm (6 h/day, 5 days/week) was almost ineffective (Laskin et al. 1980). The study demonstrated that short-term exposure at high concentrations of epichlorohydrin are more effective than long-term exposure at low concentrations for nasal tumor induc- tion; therefore, dose fractionation may not be effective for epichlorohydrin ex- posure. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism, Disposition, and Kinetics In a pharmacokinetic study, groups of three or four male Fischer 344 rats were exposed (head-only) to epichlorohydrin-1,3–14C vapor at 1 or 100 ppm of for 6 h. About 72% of the dose was excreted in the first 24 h and about 83% was excreted within 72 h regardless of the concentration (Smith et al. 1979). About 46% and 54% of the radioactivity was recovered from urine, 34% and 27% in expired air, and 3% from feces after exposure at 1 and 100 ppm, respectively. Excretion of epichlorohydrin was biphasic; the half-life for the slower fraction was about 24 h. The half-life for elimination from plasma was 26 h, which was comparable to that for excretion. The uptake rates at 1 and 100 ppm were 15.48 and 1,394 µg/h and the total systemic doses were 0.37 and 33 mg/kg. The vol- ume of distribution was 385 and 350 mL/kg, and was equivalent to 38.5 and 35% of the body weight. The investigators concluded that epichlorohydrin is not extensively sequestered in a deep compartment. Six metabolites were identified by chromatography of urine; the major metabolites recovered after exposure at 1 and 100 ppm were similar in type and proportion. The parent compound was not identified as a constituent of urine, indicating complete metabolic conversion of epichlorohydrin. Tissue distribution of radioactivity immediately after exposure showed that nasal turbinates (target organ) contained the largest fraction of epichlorohydrin when calculated on the basis of grams of tissue, followed by the lacrimal glands, large intestines, kidneys, liver, adrenal glands, erythrocytes, pancreas, and lungs. Except for the lacrimal glands, radioactivity decreased in all tissues over the first 24 h. Stott and McKenna (1984) studied the absorption of epichlorohydrin in the isolated upper and isolated lower respiratory tract and the intact animal (male Fischer 344 rats). The animals were anesthetized and exposed to epichlorohy- drin at 100 ppm by nose-only inhalation or via a one-way cephalad (upper res- piratory tract) or endotracheal tube (lower respiratory tract, bypassing the nose) for about 2 h. Absorption reached a plateau in about 10-20 min and remained constant for the remaining exposure period. Absorption was 61% of available compound by the upper respiratory tract at a flow rate approximating the intact

228 Acute Exposure Guideline Levels breathing rate, 73% by the lower respiratory tract, and 51% by the intact respira- tory tract. The authors explained some of the discrepancies in the percentages of absorption in the isolated upper and lower respiratory tract compared with the intact animal. Air flow through the isolated upper respiratory was unidirectional, which circumvented the loss of absorbed chemical due to significant back pres- sure during exhalation; the lower relative humidity may have altered blood flow and consequently chemical absorption by the isolated organ; and stimulation of the trigeminal nerve may have altered uptake by the lower respiratory tract. The authors further noted that absorption by the intact animal may have been under- estimated because of unavoidable rebreathing of exhaled air, the effective dead- space in the upper respiratory tract causing less effective uptake, and fluctuating airflow during normal breathing patterns in the intact animals. Doubling the flow rate decreased the absorption fraction in the upper respiratory tract by about 17%. When absorption was calculated based on surface area, the dose received by the upper respiratory tract was estimated to be 5,000-6,000 times greater than that of the lower respiratory tract. 4.2. Mechanism of Toxicity The mechanism by which epichlorohydrin causes toxicity is not known. Epichlorohydrin is a direct alkylating agent, which may account for some of its irritant properties. Itoh et al. (1994) examined biochemical and histologic parameters in Wistar rats. Rats given a single inhalation exposure to epichlorohydrin at 20 ppm for 90 min or were exposed repeatedly to at 5 ppm for 6 h/day for a total of 30 exposures. Findings from the treatment groups were compared the results from those of a control group. The single exposure at 20 ppm caused an increase in urinary N-acetyl glucosaminidase activity, but had no effect on serum chemis- try values. The erythrocyte count also was increased after a single exposure at 20 ppm. Glutathione (GSH) concentrations, along with glutathione peroxidase (GSH-Px) and glutathione-S-transferase activities, were decreased in the kidney. Ito et al. (1995) reported that renal damage after exposure at a single to epichlorohydrin at 150 ppm for 1 h was accompanied by a pronounced reduction in GSH and a moderate reduction in GSH-Px. GSH showed greater than a three- fold increase (attributed to induction of tolerance to epichlorohydrin) and GSH- Px only a slight decrease after repeated exposure. The liver does not appear to be a primary target for epichlorohydrin in rodents, but there was a pronounced reduction in GSH in the liver after a single low-level exposure and no effect after repeated low-level exposures. GSH depletion is probably related to the extent of damage in the kidney. The authors stated that GSH caused cellular dysfunction because of the reduced capacity to process activated oxygen. The extent of damage was greater in the kidneys than in the liver, because of higher intracellular concentrations of epichlorohydrin in the kidney.

Epichlorohydrin 229 4.3. Structure-Activity Relationships Structurally, epichlorohydrin can be related to either ETO or propylene oxide (either as chloromethyl ethylene oxide or as chlorinated propylene oxide) All three compounds are direct alkylating agents; however, the toxicity of epichlorohydrin is more like that of propylene oxide than ETO. Both epichloro- hydrin and propylene oxide caused lesions in the upper respiratory tract after a single exposure and nasal tumors after repeated exposures. Unlike ETO, neither epichlorohydrin nor propylene oxide has been found to be a developmental toxi- cant. Both compounds produce similar clinical signs. The 4-h LC50 values for epichlorohydrin and propylene oxide are 441-635 ppm and 4,000 ppm, respec- tively, in the rat, and 820-1,153 and 1,740 ppm, respectively, in the mouse. Val- ues for propylene oxide were obtained from Berdasco and Waechter (2012). The data suggest that the rat is 5-10 times more sensitive to epichlorohydrin than propylene oxide, and the mouse is less than two times more sensitive to epichlo- rohydrin. Although the clinical signs were similar, the test concentrations elicit- ing clinical signs were much lower for epichlorohydrin than for propylene oxide. Therefore, epichlorohydrin is qualitatively similar but quantitatively different from propylene oxide. 4.4. Other Relevant Information 4.4.1. Species Variability The range of LC50 values for inhalation exposure to epichlorohydrin vapor showed that the mouse is the least sensitive species, but that the values for the rat, guinea pig, and rabbit are within the same range. For nonlethal effects, the Industrial Bio-Test Laboratories (1977a,b,c) studies showed no difference in the lowest concentration eliciting clinical signs (50 ppm) and the type of sign ob- served (squinting, hypoactivity, and/or salivation) and very little difference in the time of onset. Humans exposed to epichlorohydrin experience effects similar to those observed in experimental animals: ocular and upper respiratory tract irritation. In a controlled exposure study (Kobernick et al. 1983), three of four human subjects experienced no irritation after exposure at 68 ppm for 2 min and two of four reported irritation of the eyes and pharynx after exposure at 136 ppm for 2 min. The data suggest that humans are slightly more sensitive than ani- mals. 4.4.2. Susceptible Subpopulations No data were available to identify populations more susceptible to epichlorohydrin. One report on exposure to ETO noted that an asthmatic worker experienced no effects after exposure for 4 h/day for 4 days at concentrations

230 Accute Exposure Guideline Levels detectaable by its odorr. Epichlorohyydrin and ETO have similar sstructures. Direect alkylatiion may be inv volved in the irrritant effects oon the eyes andd upper respiratto- ry tractt; this mechaniism is not expeected to vary coonsiderably wiith individualss in the poppulation. Systeemic effects off epichlorohyddrin may be m modulated by m me- tabolismm (deactivatio on), which invo olves glutathioone conjugatioon. Genetic poly- morphiism of the gluttathione-S-tran nsferase enzym mes (Finell 19996) may result in some variations v in hu uman sensitivitty within the ppopulation duee to the slow ver- sus rap pid deactivation n of epichlorohhydrin. 4.4.3. Concentration C n-Exposure Du uration Relatiionship The T concentrattion-time relattionship for m many irritant an and systemicallly- acting vapors v and gasses may be desscribed by the equation Cn × t = k, where tthe exponeent n ranges fro om 0.8 to 3.5 (tten Berge et all. 1986). LC50 ddata from studies of the rat can be useed to determin ne the relationnship between concentration of orohydrin and exposure duraation. LC50 vallues for the ratt are: 2,798 pppm epichlo (geomeetric mean of 3,617 3 ppm for males and 2,1165 ppm for feemales) for a 11-h exposuure, 580 and 6335 ppm for 4-hh exposures, 3660 ppm for a 66-h exposure, aand 250 pppm for an 8-h exposure. A liinear log-log rrelationship waas observed ovver the 1- to t 8-h exposurre durations. The T calculated value of n waas 0.87. The daata are presented in Figurre 4-1 (the LC50 on the plot ffor the 4-h diraatopm is the mid- point [6 608 ppm] betwween the reported values of 5880 and 635 ppm m). FIGUR RE 4-1 Concentraation-time curvee of LC50 values for epichlorohyydrin in the rat.

Epichlorohydrin 231 4.5. Vapor and Aerosol Exposures AEGL values were derived for epichlorohydrin on the basis of studies in which animals were exposed only to vapor for several reasons. First, epichloro- hydrin will produce vapor when liquid epichlorohydrin or aerosolized epichlo- rohydrin is exposed to air (vapor pressure = 13 mm Hg at 20°C). Thus, in stud- ies that exposed animals to epichlorohydrin aerosols, animals would have inhaled epichlorohydrin both as an aerosol and as a vapor. Second, studies using aerosols generally did not indicate whether exposure concentrations were meas- ured and were reported as total epichlorohydrin (the sum of aerosol and vapor); thus, the nature of the actual exposure in these studies is not known. Third, aero- sol studies frequently used a solvent or other stabilizing agent for which control exposures are not reported; the role of these coexposures in the observed toxicity cannot be evaluated. Finally, there are adequate data available from studies in which animals were exposed to epichlorohydrin vapor, so the aerosol data are not needed to fill any data gaps. In summary, given the uncertainties in the aero- sol studies and the availability of adequate studies of epichlorohydrin adminis- tered as a vapor, aerosol studies were not used in the derivation of AEGL values. 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 Epichlorohydrin has a sweet, pungent or chloroform-like odor. Odor per- ception of epichlorohydrin by human subjects occurs in the range of 0.08-25 ppm (Amoore and Hautala 1983; Kobernick et al. 1983; AIHA 1989; Shell Oil Co. 1977; Berdasco and Waechter 2012). Kobernick et al. (1983) reported that two of four subjects exposed at 17 ppm for 2 min noted the odor of epichlorohy- drin but experienced no irritation, one of four subjects exposed at 68 ppm for 2 min experienced pharyngeal irritation, and two of four subjects exposed at 135 ppm for 2 min experienced ocular and pharyngeal irritation. The odor of epichlorohydrin was detected but irritation was not reported by subjects exposed at 25 ppm for 5 min (Shell Oil Co. 1977). Lefaux (1968) and Wexler (1971) reported that humans exposed at 20 ppm for an extended period experienced burning of the eyes and nasal mucosa and that those exposed at 40 ppm for 1 h experienced throat irritation; however, no direct evidence for this conclusion was provided. 5.2. Animal Data Relevant to AEGL-1 Several datasets are relevant for deriving AEGL-1 values from animal studies. Studies of animals exposed under static conditions are considered infe- rior to studies in which exposures were under dynamic conditions, and were not used as basis for AEGL values. As discussed in Section 4.5, AEGL values were

232 Acute Exposure Guideline Levels derived for epichlorohydrin vapor on the basis of studies in which animals were exposed to vapor, and aerosol studies were not used. Exposure to epichlorohy- drin at 101 ppm for 15 min caused a 6% decrease in the respiratory rate in rats (Gardner et al. 1985). The only evidence of possible hepatic or renal toxicity in male rats exposed to epichlorohydrin vapor at 100 ppm for 4 h was a transient 5% increase in renal weight 1 day after exposure and a transient 15% decrease in blood urea nitrogen (BUN) on the day of exposure, which were not consistently observed in young adult and adult rats (Robinson et al. 1995); neither parameter is considered sufficient evidence of toxicity. The investigators did not indicate whether they observed the animals for clinical signs. In the studies by Industrial Bio-Test Laboratories (1977a,b,c), rats, mice, and hamsters showed clinical signs, such as squinting, hypoactivity, and salivation, after a single exposure to epichlorohydrin at 50 ppm for 66-217 min. Squinting of the eyes was considered separately from ocular irritation, which occurred in rats exposed at 200 ppm for 136 min. In addition, drooping eyelids or head shaking was observed in rats, mice, and hamsters exposed at 100 ppm for at least 178 min. In a repeat inhala- tion study, Quast et al. (1979b) reported no clinical signs in two strains of rats and one strain of mice during exposure to epichlorohydrin vapor at 100 ppm for 7 h, but after exposure the animals showed signs of nasal irritation that disap- peared before the next exposure. John et al. (1983b) reported no clinical signs of toxicity after the first exposure of rats to epichlorohydrin vapor at 5-50 ppm for 6 h. 5.3. Derivation of AEGL-1 Values Because irritation is the most sensitive effect experienced by humans ex- posed to epichlorohydrin at low concentrations, that end point was used to de- rive AEGL-1 values. The point-of-departure was a no-effect level for irritation of 17 ppm for a 2 min exposure (Kobernick et al. 1983). The total uncertainty factor of 10 was applied, which represented uncertainties associated with intra- species variability. Mild irritation experienced by humans (e.g., at 17 ppm) would most likely be confined to the nasal passage and eyes. Variability in pharmacokinetics would not be expected to contribute to variability in dose- response relationships for chemicals acting at the portal of entry. However, to provide sufficient protection for asthmatic individuals, a factor of 10 was used. Applying the total uncertainty factor of 10 to the point-of-departure yields an AEGL value of 1.7 ppm. That value was applied to all the AEGL exposure dura- tions because epichlorohydrin is an irritant and the irritation is not expected to become more severe with increasing exposure duration at that concentration. The AEGL-1 values for epichlorohydrin are presented in Table 4-11. The AEGL-1 values are below the level of odor recognition (25 ppm) and the level of odor awareness (46 ppm). Therefore, odor is not a factor for early warning of exposure to epichlorohydrin.

Epichlorohydrin 233 TABLE 4-11 AEGL-1 Values for Epichlorohydrin 10 min 30 min 1h 4h 8h 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 There are few human data relevant to AEGL-2 derivation. Irreversible he- patic and respiratory-tract damage occurred in a worker who took a few breaths of epichlorohydrin at a very high (unknown) concentration (Shultz 1964). Anec- dotal information (Lefaux 1968; Deichmann and Gerarde 1969; Wexler 1971; Enterline et al. 1990; Berdasco and Waechter 2012) has suggested that exposure to epichlorohydrin at 20 ppm for 1 h caused burning to the eyes and nose, 40 ppm caused throat irritation lasting for about 48 h, and 100 ppm could not be tolerated and may be associated with pulmonary edema and renal damage. No data were provided to support these conclusions. A report by Kobernick et al. (1983) stated that one of four subjects experienced irritation of the pharynx after a 2-min exposure to epichlorohydrin vapor at 68 ppm, and two subjects experi- enced eye or pharyngeal irritation after a 2-min exposure at 136 ppm. Epidemio- logic studies did not provide evidence of a causal association between exposure to epichlorohydrin and morbidity, including skin diseases (Tsai et al. 1990). 6.2. Animal Data Relevant to AEGL-2 A relatively large animal database was available for evaluating nonlethal toxicity of epichlorohydrin (see Table 4-9). However, the available data were not suitable for defining a point-of-departure for AEGL-2 derivation, as dis- cussed below. The study using the monkey is not adequate because the animals had tu- berculosis, only one animal was exposed, and no other primate data were availa- ble (Kobernick et al. 1983). Two RD50 studies were available in rodents. One study showed that the respiration rate in rats was decreased by 33-36% during a 150-min inhalation exposures to epichlorohydrin vapor at 363, 394, and 663 ppm and by about 50% at 643, 914, and 1,963 ppm; the RD50 was 1,332 ppm (Gardner et al. 1985). In an aerosol study, the RD50 for male Swiss-Webster mice was 687 ppm for a 10-min exposure (Kane et al. 1979). The mouse RD50 has been used for AEGL-2 derivation (see NRC 2004) on the basis of its correla- tion with a human irritation threshold (Schaper 1993). However, the mouse RD50 data for epichlorohydrin are not suitable for AEGL-2 derivation because the data are from an aerosol study. In addition, there are no data supporting an associa- tion between rat RD50 values and human irritation.

234 Acute Exposure Guideline Levels Ito et al. (1995) observed severe renal toxicity in rats exposed to epichlo- rohydrin vapor at 150 ppm for 1 h. This effect exceeds the threshold for an AEGL-2 effect, and no other exposure concentrations were tested; therefore, a no-effect level could not be determined. Robinson et al. (1995) reported no his- topathologic evidence of hepatic or renal damage in F344 rats exposed to epichlorohydrin at 100 ppm for 4 h; the result appears to conflict with infor- mation reported by Ito et al. (1995). In a series of studies using rats, mice, and hamsters exposed repeatedly to epichlorohydrin at concentrations ranging from 10 to 400 ppm for 6 h/day for 14 days, the investigators provided detailed information on clinical signs after each exposure (Industrial Bio-Test Laboratories 1977a,b,c). Clinical signs related to AEGL-2 derivation included gasping, irritated eyes, excitation, and labored breathing. Signs were not seen at 100 ppm in any species, but were observed at 200 ppm in rats and mice and 200 and 400 ppm in hamsters. The concentration of 100 ppm may be a no-observed-effect level for clinical effects that may im- pair escape; however, mortality was seen in all three species at 200 ppm, and evaluation of the kidneys was limited to gross examination at study termination (findings included lung consolidation and/or intestinal bloating and pale kidneys at 200 ppm and higher in all species). In a repeated inhalation study using two strains of rats (Fischer 344 and Sprague-Dawley) and B6C3F1 mice (Quast et al. 1979b), the animals huddled together and slept during exposure to epichlorohy- drin at 100 ppm for 7 h/day. Transient signs of nasal irritation were the only clinical findings seen after each individual exposure. Exposure to epichlorohy- drin for 5 days/week for 9 days resulted in histopathologic evidence of damage to nasal turbinates, kidneys, and epididymis; the findings are considered to be above the threshold for AEGL-2 effects. On the first day of a continuous-exposure study, mice showed excitation and restlessness followed by sluggishness and somnolence and gradual recovery at 5.3 ppm (Formin 1966). The study provided no information on exposure con- ditions or analytic measurements and was not considered for use in deriving AEGL-2 values. The study in rabbits exposed to epichlorohydrin at 19-886 ppm for 1 h or at 45 and 132 ppm for 4 h was conducted using a static chamber (Kimmerle 1967) and atomized epichlorohydrin, and is not considered reliable for purposes of AEGL derivation. Several developmental and reproductive toxicity studies were available; inhalation exposure to epichlorohydrin at concentrations of 2.5 or 25 ppm did not induce developmental effects in rats or rabbits exposed during organogenesis (John et al. 1983a). Transient infertility was induced in male rats exposed to epichlorohydrin at concentrations of 25 or 50 ppm for 6 h/day, 5 days/week for 2-10 weeks (one spermatogenic cycle), but no effects were observed on fertility when exposed females were mated with unexposed males (John et al. 1983b). No reproductive effects were observed in male rabbits exposed under conditions similar to those used for the rats (John et al. 1983b). Slott et al. (1990) reported altered sperm motility in male rabbits exposed to epichlorohydrin at 100 ppm for

Epichlorohydrin 235 4 h; the effect is not considered to be irreversible nor of sufficient severity to reflect an AEGL-2 effect. Finally, as discussed in Section 4.5, AEGL values were derived for epichlorohydrin vapor based on studies in which animals were exposed to vapor. Aerosol studies (e.g., Gage 1959; Kane et al. 1979; Kimmerle 1967) were not used to derive AEGL values. 6.3. Derivation of AEGL-2 Values The human and animal data showed that exposure to epichlorohydrin is associated with various degrees of ocular and respiratory-tract irritation. Ade- quate data were not available for deriving AEGL-2 values from studies with humans or animals, as discussed above in Sections 6.1 and 6.2. Therefore, AEGL-2 values were estimated by reducing the AEGL-3 values by a factor of 3. That approach is used in cases of a steep-concentration-response curve (NRC 2001); the steep concentration-response curve is seen in a 1-h study of rats in which no deaths occurred among six rats exposed to epichlorohydrin at 3,275 ppm epichlorohydrin, and all 12 rats exposed at 3,995 ppm died (Dietz et al. 1985). Reducing the 10-min AEGL-3 value by a factor of 3 yields a10-min AEGL-2 value of 188 ppm. Anecdotal information provided by Lefaux (1968) suggested that concentrations greater than 100 ppm for short intervals might result in pulmonary edema and renal damage. Although the information is anec- dotal, support for the effects comes from a study of rats exposed to epichlorohy- drin at 150 ppm for 1 h that exhibited evidence of severe renal damage (Ito et al. 1995). Therefore, t The 30-min AEGL-2 value of 53 ppm was applied to the 10-min exposure to be protective of the lungs and kidneys. AEGL-2 values are presented in Table 4-12. 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data are available on the lethal effects of single inhalation ex- posures to epichlorohydrin. 7.2. Animal Data Relevant to AEGL-3 A large number of lethality studies are available for deriving AEGL-3 val- ues. Studies of animals exposed under static conditions are considered inferior to studies in which exposures were under dynamic conditions, and were not used as basis for AEGL values. As discussed in Section 4.5, AEGLs were derived for epichlorohydrin vapor on the basis of studies in which animals were exposed to vapor, and aerosol studies were not used.

236 Acute Exposure Guideline Levels TABLE 4-12 AEGL-2 Values for Epichlorohydrin 10 min 30 min 1h 4h 8h 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm (200 mg/m3) (200 mg/m3) 91 (mg/m3) (53 mg/m3) (25 mg/m3) Animals exposed at lethal concentrations of epichlorohydrin vapor showed signs of cyanosis, muscle relaxation, lethargy, tremors, increased or decreased respiration, labored breathing, clonic convulsions, and respiratory arrest. Micro- scopic examination of the respiratory tract showed exfoliation, erosion, ulcera- tion, and necrosis of the nasal epithelium and hemorrhage, congestion, edema, or pneumonia in the lower respiratory tract. Systemic effects may include severe renal or hepatic damage. Six studies provided data that could be used to derive AEGL-3 values; they include rat studies by Dietz et al. (1985), Kobernick et al. (1983), and Laskin et al. (1980) and mouse, guinea pig, and rabbit studies by Kobernick et al. (1983). The studies were conducted using dynamic chambers, whereas in the other lethality studies, the animals were exposed to vapor in static chambers or they were exposed to aerosolized epichlorohydrin as discussed in Section 3.1. 7.3. Derivation of AEGL-3 Values The LC50 values, and the corresponding estimates for the threshold for le- thality (LC01 values), derived by probit analysis of the mortality data from five studies are presented in Table 4-13. The best datasets are obtained from the rat studies by Laskin et al. (1980) and Dietz et al. (1985). Although all the studies were conducted in dynamic chambers, Laskin et al. (1980) and Dietz et al. (1985) measured chamber concentrations analytically, whereas Kobernick et al. (1983) calculated the nominal chamber concentrations. Therefore, AEGL-3 val- ues are calculated from the Laskin et al. (1980) and Dietz et al. (1985) data. The 10-min, 30-min, and 1-h AEGL-3 values are based on the 1-h rat LC01 of 721 ppm (Dietz et al. 1985). A total uncertainty factor of 10 was applied. A factor of 3 was used to account for interspecies differences. The 4-h LC50 values for rats, mice, guinea pigs, and rabbits ranged from 573 to 820 ppm; thus, show- ing very little variability among the species. Although limited, the data suggest humans are more sensitive than animals to inhaled epichlorohydrin but are with- in a factor of about 2.5. Epichlorohydrin at 50 ppm for 66-262 min caused squinting, hypoactivity, and salivation in animals, whereas 20 ppm for 1 h caused burning of eyes and nose in humans. In addition, epichlorohydrin is an epoxide and direct alkylating agent, similar in structure to ETO; a factor of 3 was also used for ETO (NRC 2010). A factor of 3 was applied for intraspecies variability. Epichlorohydrin is an epoxide and direct alkylating agent. The irrita- tion and systemic toxicity caused by epichlorohydrin are likely to involve its alkylating activity. Therefore, the concentrations causing severe pulmonary irri-

Epichlorohydrin 237 tation are not expected to vary considerably in the population. The systemic tox- icity may be modulated by the detoxification enzymes, most likely epoxide hy- drolase and glutathione-S-transferase activity. The structural similarity of epichlorohydrin to ETO suggests that metabolism involving the glutathione-S- transferase enzyme system, which is genetically polymorphic in human, may be similar. This similarity in structure provides additional support for an intraspe- cies factor of 3. A factor of 3 is also supported by human data. Use of higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value of 6.6 ppm; however, occupational exposures as high as 15-54 ppm have occurred (Pet’ko et al. 1966 [as cited in NIOSH 1976]; de Jong et al. 1988) and were apparently not life-threatening. Time scaling was performed using he equation Cn × t = k (ten Berge et al. 1986), where n = 0.87. An empirical value for the exponent n was derived from rat LC50 values for 1-, 4-, 6-, and 8-h exposures. The 4- and 8-h AEGL-3 values were based on the 6-h rat LC01 of 274 ppm (Laskin et al. 1980). The uncertainty factors and time-scaling method were the same as those used to derive the AEGL-3 values for the 10-min, 30-min, and 1-h durations. The 8-h AEGL-3 of 20 ppm is supported by a chronic exposure study in rats, in which exposure to epichlorohydrin at 30 ppm for 6 h/day for a lifetime did not result in any mortality. AEGL-3 values for epichlorohydrin are presented in Table 4-14. TABLE 4-13 LC50 Values and Lethality Thresholds (LC01) for Animals Exposed to Epichlorohydrin Vapor Exposure Species/Sex Duration (min) LC50a (ppm) LC01a (ppm) Reference Rat/male 360 373 274 ± 13.1b Laskin et al. 1980 Rat/male 240 580 182 ± 125 Kobernick et al. 1983 Rat/male, female 60 2,369 721 ± 225 Dietz et al. 1985 combined Mouse/male 240 820 468 ± 116 Kobernick et al. 1983 Guinea pig/male 240 666 170 ± 115 Kobernick et al. 1983 Rabbit/male 240 573 100 ±112 Kobernick et al. 1983 a Values derived by probit analysis (Number Cruncher Statistical System: Survival Analy- sis, Version 5.5). b ±Standard error. TABLE 4-14 AEGL-3 Values for Epichlorohydrin 10 min 30 min 1h 4h 8h 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm (2,200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3)

238 Acute Exposure Guideline Levels 8. SUMMARY OF AEGL VALUES 8.1. AEGL Values and Toxicity End Points AEGL values for epichlorohydrin are presented in Table 4-15. The AEGL-1 value was derived from a no-effect level for irritation in humans. The AEGL-2 values were derived by reducing the AEGL-3 values by a factor of 3 and retaining the 30-min value for the 10-min value. AEGL-3 values for the 10-min, 30-min, and 1-h exposures were derived from a 1-h lethality study in rats; the 4- and 8-h values were derived from a 6-h lethality study in rats. 8.2. Other Standards and Guidelines for Epichlorohydrin Standards and guidelines established for epichlorohydrin are presented in Table 4-16. The AEGL-1 value of 1.7 ppm is lower than the emergency re- sponse planning guideline 1 (ERPG-1) value of 5 ppm. The ERPG-1 value is based on an irritation threshold of 10 ppm (AIHA 2013). The ERPG documenta- tion cites Diechmann and Gerarde (1969) as the source of the threshold, but the citation appears to be in error because that publication makes no mention of ef- fects or lack of effects at 10 ppm. The AEGL-2 value of 24 ppm for 1 h is similar to the ERPG-2 value of 20 ppm for 1 h. The ERPG-2 value (AIHA 2013 ) was based on the observation that epichlorohydrin at 20 ppm for 1 h resulted in burning of eyes and nose that was not expected to impair escape; it appears that this observation is based on the anecdotal information in Wexler (1971 [originally reported by Lefaux 1968]). As noted in Section 2.2.2, data supporting these anecdotal statements were not found in the available literature, so this information was not considered adequate to serve as the basis for AEGL values. TABLE 4-15 AEGL Values for Epichlorohydrin Classification 10 min 30 min 1h 4h 8h AEGL-1 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm (nondisabling) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) AEGL-2 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm (disabling) (200 mg/m3) (200 mg/m3) (91 mg/m3) (53 mg/m3) (25 mg/m3) AEGL-3 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm (lethal) (2,200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3)

Epichlorohydrin 239 TABLE 4-16 Standards and Guidelines for Epichlorohydrin Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) AEGL-2 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm (200 mg/m3) (200 mg/m3) (91 mg/m3) (53 mg/m3) (25 mg/m3) AEGL-3 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm (2,200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3) ERPG-1 (AIHA)a – – 5.0 ppm – – (7.6 mg/m3) ERPG-2 (AIHA) – – 20 ppm – – (76 mg/m3) ERPG-3 (AIHA) – – 100 ppm – – (380 mg/m3) IDLH (NIOSH)b – 75 ppm – – – (280 mg/m3) TLV-TWA (ACGIH)c – – – – 0.5 ppm (1.9 mg/m3) PEL-TWA (OSHA)d – – – – 5 ppm (19 mg/m3) MAC-TGG (The – – – – 0.5 ppm Netherlands)e (1.9 mg/m3) a ERPG (emergency response planning guidelines, American Industrial Hygiene Associa- tion) (AIHA 2013). The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor. The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversi- ble or other serious health effects or symptoms that could impair an individual’s ability to take protective action. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life- threatening health effects. b IDLH (immediately dangerous to life or health, National Institute for Occupational Safe- ty and Health) (NIOSH 1994) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects. NIOSH considers epichlorohydrin to be a potential occupational carcino- gen. c TLV-TWA (threshold limit value – time-weighted average, American Conference of Governmental Industrial Hygienists ) (ACGIH 2001, 2012) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all work- ers may be repeatedly exposed, day after day, without adverse effect. The TLV for epichlorohydrin includes a skin notation.

240 Acute Exposure Guideline Levels d PEL-TWA (permissible exposure limit – time-weighted average, Occupational Health and Safety Administration) (29CFR Part 1910.1000 [2012]) is defined analogous to the ACGIH TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week. The PEL for epichlorohydrin includes a skin designation. e MAC (maximaal aanvaaarde concentratie [maximal accepted concentration], Dutch Expert Committee for Occupational Standards, The Hague, The Netherlands) (MSZW 2004) is defined analogous to the ACGIH TLV-TWA. The 1-h AEGL-3 value of 72 ppm is in the same range as the ERPG-3 value of 100 ppm. The ERPG-3 derivation used an LC50 estimate of about 2,000 ppm in multiple species (citing Gage 1959; Kimmerle 1967; and Dietz et al. 1985) as the starting point to derive the guideline of 100 ppm; no further infor- mation was given on how the guideline was derived. The immediately dangerous to life for health (IDLH) value of 75 ppm (NIOSH 1994) is based in part on the statements of Lefaux (1968 [repeated by NIOSH 1976]) that 100 ppm is intolerable and potentially causes pulmonary edema and renal lesions, and on a Russian study (Pet’ko et al. 1966 [cited in NIOSH 1976]) reporting no apparent adverse effects in workers exposed to epichlorohydrin at 4.9-54.9 ppm. Animal data were also referenced to support the IDLH value. The AEGL-1 value of 1.7 ppm is higher than the American Conference of Governmental Industrial Hygienists threshold limit value–time-weighted aver- age (TLV-TWA) of 0.5 ppm (ACGIH 2001). That value is based on a NOAEL of 5 ppm for fertility in male rats exposed for 10 weeks (John et al. 1983b), as well as a NOAEL of 9 ppm for upper respiratory tract irritation (the LOAEL was 16 ppm in rabbits and 17 ppm in rats) in a repeated exposure study (Gage 1959). The 8-h AEGL-1 of 1.7 ppm is intended to protect against discomfort from a single exposure. The Occupation Safety and Health Administration permissible exposure limit–time-weighted average (PEL-TWA) for epichlorohydrin is 5 ppm. The Netherlands has established a maximal accepted concentration of 0.5 ppm for epichlorohydrin. German MAK values have not been established for epichloro- hydrin; however, Germany has a skin designation for this compound. 8.3. Data Quality and Research Needs A robust animal toxicity database was available for deriving AEGL values for epichlorohydrin. However, many animal studies were conducted in a static environment using epichlorohydrin aerosols generated with the use of other sub- stances (alcohol and lutrol). Data were not available for corroborating the nonle- thal effects observed in humans. Only studies conducted with epichlorohydrin vapor in which animals were exposed in a dynamic chamber were considered suitable for deriving AEGL values. There are a number of uncertainties concern- ing some of the AEGL values derived, particularly the 8-h value for AEGL-3.

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248 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR EPICHLOROHYDRIN Derivation of AEGL-1 Values Key study: Kobernick J.H., Nair, III., U.C. Pozzani, L.D. Roger, Jr., and J.S. West1983. Epichlorohydrin Repeated Inhalation, Preliminary Metabolic Studies, Revision of Acute Toxicity Data, and Human Sensory Response. Special Report 33-41. Mellon Institute, January 28, 1983. Submitted to EPA, Washington, DC, by Union Carbide Corporation, Danbury, CT with Cover Letter Dated December 9, 1983.EPA Document No. 878212138. Microfiche No. OTS0206066. Toxicity end point: Irritation in humans; no-effect level was 17 ppm for 2 min; exposure at 68 ppm for 2 min was associated with irritation of the pharynx, and exposure at 136 ppm for 2 min was associated with irritation to the eyes and pharynx. Time scaling: Not applicable Uncertainty factors: 10 for intraspecies variability Calculations: For all AEGL-1 durations: 17 ppm ÷ 10 = 1.7 ppm Derivation of AEGL-2 Values Data on epichlorohydrin were inadequate for deriving AEGL-2 values. Because epichlorohydrin has been shown to have a steep concentration-response curve, AEGL-2 values were estimated by dividing the AEGL-3 values by 3. Calculations: 1/3 AEGL-3 values (30-min, 1-, 4-, and 8-h) 10-min AEGL-2: 53 ppm; set equal to the 30-min value, because reducing the 10-min AEGL-3 value by a factor of 3 yields an AEGL value of 188 ppm for a 10-min exposure. Anecdotal information provided by Lefaux (1968) suggested that concentrations greater than 100 ppm for short intervals might result in pulmonary edema and renal damage.

Epichlorohydrin 249 Support for those effects comes from a study of rats exposed to epichlorohydrin at 150 ppm for 1 h that exhibited evidence of severe renal damage (Ito et al. 1995). Thus, the 10-min value was set equal to the 30-min value to protect against pulmonary and renal effects. 30-min AEGL-2: 160 ppm ÷ 3 = 53 ppm 60-min AEGL-2: 72 ppm ÷ 3 = 24 ppm 4-h AEGL-2: 44 ppm ÷ 3 = 14 ppm 8-h AEGL-2: 20 ppm ÷ 3 = 6.7 ppm Derivation of AEGL-3 Values 10-min, 30-min, 1-h AEGL-3: Key study: Dietz, F.K., M. Grandjean, and J.T. Young. 1985. Epichlorohydrin: 1-Hour LC50 Determination in Fischer-344 Rats. Lake Jackson Research Center, Health & Environmental Sciences - Texas, Dow Chemical, Freeport, TX. . Toxicity end point: 1-h rat LC01 of 721 ppm Time scaling: Cn × k = t; n = 0.87, based on regression analysis of rat lethality data (1-, 4-, 6-, and 8-h LC50 values); C = 721 ppm ÷ 10 = 72.1 ppm; t = 60 min, n = 0.87 k = 72.10.87 ppm × 60 min = 2,480.6 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 10- min AEGL-3: C = (k/t)1/0.87 = (2,480.6 ppm-min ÷ 10)1/0.87 C = 570 30-min AEGL-3: C = (k/t)1/0.87 = (2,480.6 ppm-min ÷ 30)1/0.87 C = 160 1-h AEGL-3: 721 ppm ÷ 10 = 72.1 ppm (rounded to 72 ppm)

250 Acute Exposure Guideline Levels 4- and 8-h AEGL-3: Key study: Laskin, S., A.R. Sellakumar, M. Kuschner, N. Nelson, S. La Mendola, G.M. Rusch, G.V. Katz, N.C. Dulak, and R.E. Albert. 1980. Inhalation carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley rats. J. Natl. Cancer Inst. 65(4):751-757. Toxicity end point: 6-h rat LC01 of 274 ppm Time scaling: Cn × k = t; n = 0.87; C = 274 ppm ÷ 10 = 27.4 ppm; t = 360 min k = 27.40.87 ppm × 360 min = 6,414.2 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 4-h AEGL-3: C = (k/t)1/0.87 = (6,414.2 ppm-min ÷ 240 min)1/0.87 C = 44 ppm 8-h AEGL-3: C = (k/t)1/0.87 = (6,414.2 ppm-min ÷ 480 min)1/0.87 C = 20 ppm

Epichlorohydrin 251 APPENDIX B CARCINOGENICITY ASSESSMENT FOR EPICHLOROHYDRIN The unit risk or q1* for inhalation exposure to epichlorohydrin is 1.2 × 10-6 3 -1 (μg/m ) (EPA 1994). That value was derived from a carcinogenicity study in which rats developed nasal tumors after exposure to epichlorohydrin at 0, 10, or 30 ppm for 6 h/day, 5 days/week for a lifetime (Laskin et al. 1980). This study was summarized in Section 3.4. Data summary: Groups of 100 male Sprague-Dawley rats were exposed to epichlorohydrin at 10 or 30 ppm for 6 h/day, 5 days/week for a lifetime. A total of 150 sham-exposed or untreated animals served as controls. One of 100 rats in the 30- ppm group developed squamous cell carcinomas of the nasal cavity; none of the 10- ppm or control animals developed nasal tumors. The unit risk (q1*) derived from the linearized multistage model is (1.2 × 10-6 μg/m3)-1. The calculations for AEGL values following the method presented by NRC (1986) are presented below. To calculate a virtually safe dose (VSD of d) at a cancer risk of 10-6: d = 10-6 ÷ (1.2 × 10-6 µg/m3)-1 = 8.3 × 101 g/m3 To calculate the total cumulative dose for a total lifetime exposure of 70 years, which is equivalent to 25,600 days: total d = d × 25,600 = (8.33 × 101 µg/m3) × 25,600 = 2.13 × 106 µg/m3. Adjustment to allow for uncertainties in assessing potential cancer risks due to short-term exposure under the multistage model (Crump and Howe 1984), the total dose is divided by a factor of 6: 2.13 × 106 µg/m3 ÷ 6 = 3.56 × 105 µg/m3 = 3.56 × 102 mg/m3 = 94 ppm Therefore, a 24-h exposure concentration associated with a 10-4 risk is 94 ppm. The 10-4 cancer risk associated with exposures for 10, 30, 60, 240, and 480 min can be calculated from the following equation: PC × t = k, where c = concentration, t = time, and k is a constant. The AEGL values are compared with cancer risk-based values associated with risks of 10-4, 10-5, and 10-6 below:

252 Acute Exposure Guideline Levels Risk 10 min 30 min 1h 4h 8h AEGL values (ppm) AEGL-1 1.7 1.7 1.7 1.7 1.7 AEGL-2 53 53 24 14 6.7 AEGL-3 570 160 72 44 20 Cancer risk-based values (ppm) 10-6 140 45 23 5.6 2.8 -5 10 1,400 450 230 56 28 10-4 14,000 4,500 2,300 560 280

Epichlorohydrin 253 APPENDIX C DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS FOR EPICHLOROHYDRIN The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than one-half of the exposed population will experience at least a distinct odor intensity and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emer- gency responders in assessing the public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by Ruijten et al. (2009). The odor detection threshold (OT50) for epichlorohydrin is calculated from the odor threshold of 10 ppm (50% of unconditioned personnel) reported by Shell Oil Co. (1977) and adjusted by Ruijten et al. (2009): 10 ppm × 40 ppm ÷ 100 ppm = 4.0 ppm The concentration (C) leading to an odor intensity (I) of distinct odor de- tection (I = 3) is derived using the Fechner function: I = kw x log(C ÷ OT50) + 0.5 For the Fechner coefficient, the default kw = 2.33 will be used because of the lack of chemical specific data. 3 = 2.33 × log (C ÷ 4.0) + 0.5, which can be rearranged to log (C/4.0) = (3 - 0.5) ÷ 2.33 = 1.07, and results in C = (101.07) × 4.0 = 34.4 ppm The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in everyday life factors, such as sex, age, sleep, smoking, upper airway infections, and allergy, as well as distractions, may in- crease the odor detection threshold by a factor of 4. In addition, it takes into ac- count that odor perception is very fast (about 5 seconds), which leads to the per- ception of concentration peaks. On the basis of current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustments for distraction and peak exposure lead to a correction factor of 4/3 = 1.33. LOA = C × 1.33 = 34.4 ppm × 1.33 = 46 ppm (Ruijten et al. [2009]) Therefore, the LOA for epichlorohydrin is 46 ppm.

254 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR EPICHLOROHYDRIN Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) Key reference: Kobernick, J.L., J.H. Nair, III., U.C. Pozzani, L.D. Roger, Jr., and J.S. West. 1983. 1983. Epichlorohydrin Repeated Inhalation, Preliminary Metabolic Studies, Revision of Acute Toxicity Data, and Human Sensory Response. Special Report 33-41. Mellon Institute, January 28, 1983. Submitted to EPA, Washington, DC, by Union Carbide Corporation, Danbury, CT with Cover Letter Dated December 9, 1983 EPA Document No. 878212138, Microfiche No. OTS0206066. Test species/Strain/Number: Humans Exposure route/Concentration/Durations: Inhalation; 17, 68, or 136 ppm for 2 min. Effects: 17 ppm: 2/4 detected odor, 0/4 experienced irritation 68 ppm: 2/4 had pharyngeal irritation; 4/4 detected odor 136 ppm: 2/4 had pharyngeal irritation and ocular irritation End point/Concentration/Rationale: Irritation (no-effect level); none of the four subjects experienced irritation. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 1, human study Intraspecies: 10, although irritation would likely be confined to the eyes and nasal passage (portal of entry), and variability in this response is expected to be limited to variability in pharmacodynamics, a factor of 10 was applied to provide sufficient protection for asthmatic persons. Modifying factor: 1 Animal-to-human dosimetric adjustment: Not applicable Time scaling: Not applicable Data adequacy: The subjects were exposed for only 2 min; however, the irritating properties of epichlorohydrin are not expected to vary considerably in an exposed human population.

Epichlorohydrin 255 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm (200 mg/m3) (200 mg/m3) (91 mg/m3) (53 mg/m3) (25 mg/m3) Data adequacy: The animal and human data on epichlorohydrin pertaining to nonlethal end points were not adequate. for deriving AEGL-2 values. Therefore, AEGL-3 values were divided by a factor of 3 to estimate the AEGL-2 values. Because of the steepness of the dose-response curve, this method should provide a reasonable estimate of the values and provide an adequate margin of safety relative to lethality and adequate protection against pulmonary edema. Further, long-term studies showed that high concentrations for shorter durations are more effective than lower concentrations for longer durations; therefore, the 3-fold reduction should provide adequate protection against disabling or serious effects. The 10-min value was set equal to the 30-min AEGL-2 value because human and animal data suggested that pulmonary edema and renal damage could occur at concentrations greater than 100 ppm for short intervals. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm (2,200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3) Key reference: Dietz, F.K., M. Key reference: Laskin, S., A.R. Sellakumar, Grandjean, and J.T. Young. 1985. M. Kuschner, N. Nelson, S. La Mendola, Epichlorohydrin: 1-Hour LC50 G.M. Rusch, G.V. Katz, N.C. Dulak, and Determination in Fischer-344 Rats. R.E. Albert. 1980. Inhalation carcinogenicity Lake Jackson Research Center, Health of epichlorohydrin in noninbred Sprague- & Environmental Sciences - Texas, Dawley rats. J. Natl. Cancer Inst. 65(4): Dow Chemical, Freeport, TX. 751-757. Test species/Strain/Sex/Number: Rats; Test species/Strain/Sex/Number: Rats; Fischer-344; males and females; Sprague-Dawley; male; 20/group. 6/group. Exposure route/Concentration/Duration: Exposure route/Concentration/Duration: Inhalation; 552, 1,008, 1,970, or 3,995 Inhalation; 283, 303, 339, 369, 421, or ppm (male and female) and 2,865 and 445 ppm for 6 h. 3,275 ppm (male only) for 1 h. Effects: Weight loss (all concentrations); Effects: Acute respiratory irritation; ocular and nasal irritation, respiratory pulmonary hemorrhage and edema; difficulty, and secretion of porphyrin-like elevated lung:body weight at ~339 ppm; material, corneal cloudiness (~1,970 mortality: 0/20, 1/20, 1/20, 15/20, 16/20, ppm); central nervous system effects and and 17/20, respectively. cyanosis (~3,275 ppm); mortality: 0/12, 0/12, 2/12, 0/6, 0/6, 12/12, respectively. Point of departure: 1-h rat LC01 of Point of departure: 6-h rat LC01 of 274 ppm. 721 ppm. (Continued)

256 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Uncertainty factors: Total uncertainty factor: 10 Interspecies: 3, LC50 values for rats, mice, guinea pigs, and rabbits were 573-820 ppm for a 4-h exposure. Humans appear to be more sensitive than rats but are within a factor of about 2.5. A concentration of 50 ppm for 66-262 min caused squinting, hypoactivity, and salivation in animals; 20 ppm for 1 h caused burning of eyes and nose in humans. Epichlorohydrin is an epoxide and direct alkylating agent and effects are not expected to differ by more than a factor of 3. Intraspecies: 3, the irritation and systemic toxicity caused by epichlorohydrin are likely to involve its alkylating activity. Therefore, the concentrations causing severe pulmonary irritation are not expected to vary considerably in the population. The systemic toxicity may be modulated by the detoxification enzymes, most likely epoxide hydrolase or glutathione-S-transferase. The structural similarity of epichlorohydrin to ETO suggests that metabolism involves glutathione-S-transferase, which is genetically polymorphic in human. This similarity in structure provides additional support for a factor of 3. The use of an intraspecies uncertainty factor of 3 is also supported by data on human exposures to epichlorohydrin. Use of higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value of 6.6 ppm; however, occupational exposures as high as 15-54 ppm have occurred (Pet’ko et al. 1966 [cited in NIOSH 1976]; de Jong et al. 1988) and were apparently not life-threatening. Time scaling: Cn × t = k, where n = 0.87 (derived from LC50 data for the rat exposed for 1, 4, 6, or 8 h).

Epichlo orohydrin 2257 AP PPENDIX E GORY PLOT FOR EPICH CATEG HLOROHYDR RIN FIGUR RE E-1 Category y plot of toxicity data and AEGL L values for epichhlorohydrin.

258 TABLE E-1 Data Used in Category Plot for Epichlorohydrin Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 1.7 10 AEGL AEGL-1 1.7 30 AEGL AEGL-1 1.7 60 AEGL AEGL-1 1.7 240 AEGL AEGL-1 1.7 480 AEGL AEGL-2 53 10 AEGL AEGL-2 53 30 AEGL AEGL-2 24 60 AEGL AEGL-2 14 240 AEGL AEGL-2 6.7 480 AEGL AEGL-3 570 10 AEGL AEGL-3 160 30 AEGL AEGL-3 72 60 AEGL AEGL-3 44 240 AEGL AEGL-3 20 480 AEGL Kobernick et al. 1983 Human 1 17 2 0 Human 1 68 2 1 Throat irritation. Human 1 136 2 1 Ocular, throat and nasal irritation. Berdasco and Waechter 2012 Rat Males 1 2,165 60 SL LC50 Rat Females 1 3,617 60 SL LC50 Rat 1 500 240 SL LC50 Rat 1 250 480 SL LC50

Dietz et al. 1985 Rat Both 1 552 60 1 Rat Both 1 1,008 60 1 Rat Both 1 1,970 60 SL Mortality (2/12) Rat Both 1 3,995 60 3 Mortality (12/12) Grigorowa et al. 1974 Rat Males 1 635 240 SL LC50 Rat Males 1 582 240 SL LC50 Kimmerle 1967 Rat 1 132 240 0 Rat 1 331 240 0 Rat 1 661 240 SL Mortality (5/10), moderate irritation to mucus membranes. Rat 1 2,646 240 3 Mortality (10/10) Kobernick et al. 1983 Rat Both 1 580 240 3 Mortality (12/12) Rat Both 1 580 240 SL Mortality (15/30) Slott et al. 1990 Rat Both 1 1,160 240 3 Mortality (6/6) Laskin et al. 1980 Rat Males 1 100 240 0 Rat Males 1 303 360 SL Mortality (1/20) Rat Males 1 339 360 SL Mortality (1/20), acute respiratory irritation with hemorrhage and severe edema. Rat Males 1 369 360 SL Mortality (15/20), acute respiratory irritation with hemorrhage and severe edema. Rat Males 1 421 360 SL Mortality (16/20), acute respiratory irritation with hemorrhage and severe edema. (Continued) 259

260 TABLE E-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Rat Males 1 445 360 SL Mortality (17/20), acute respiratory irritation with hemorrhage and severe edema. Weil et al. 1963 Rat 1 250 480 SL Mortality (4/6) Freuder and Leake 1941 Mouse 1 8,300 30 3 100% mortality Mouse 1 16,600 30 3 100% mortality Grigorowa et al. 1974 Mouse Males 1 794 120 SL LC50 Kobernick et al. 1983 Mouse Males 1 1,160 240 3 Irritation of mucous membranes, increased respiration, lethargy, and labored breathing. Kimmerle 1967 Mouse Males 1 132 240 0 Mouse Males 1 331 240 0 Mouse Males 1 661 240 SL Mortality (1/20) Mouse Males 1 2,646 240 3 Mortality (20/20) Buckley et al. 1984 Mouse 1 687 360 SL Kobernick et al. 1983 Guinea pig Males 1 290 240 1 Irritation of mucous membranes. Guinea pig Males 1 580 240 SL Mortality (2/6), irritation of mucous membranes. Guinea pig Males 1 1,160 240 3 Mortality (4/4) Kimmerle 1967 Guinea pig Males 1 132 240 0 Guinea pig Males 1 331 240 SL Mortality (4/5) Guinea pig Males 1 661 240 SL Mortality (4/5)

Guinea pig Males 1 2,646 240 3 Mortality (5/5) Kobernick et al. 1983 Rabbit Males 1 290 240 1 Irritation of mucous membranes. Rabbit Males 1 580 240 SL Mortality (2/3), irritation of mucous membranes. Rabbit Males 1 1,160 240 3 Mortality (3/3) Kobernick et al. 1983 Dog 1 290 240 1 Irritation of mucous membranes. Dog 1 580 240 3 Mortality (1/1) Dog 1 1,160 240 3 Mortality (1/1) Monkey 1 290 240 1 Irritation of mucous membranes. Industrial Bio-Test Rat Both 1 9.7 360 0 Laboratories 1977a Rat Both 1 23 360 0 Rat Both 1 48.8 360 1 Rat Both 1 97.3 360 1 Rat Both 1 209.8 360 2 Gardner et al. 1985 Rat 1 101 15 0 For category 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 261

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 17 Get This Book
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Extremely hazardous substances can be released accidentally as a result of chemical spills, industrial explosions, fires, or accidents involving railroad cars and trucks transporting EHSs. Workers and residents in communities surrounding industrial facilities where these substances 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 releases or intentional releases by terrorists. Pursuant to the Superfund Amendments and Reauthorization Act of 1986, the U.S. Environmental Protection Agency (EPA) has identified approximately 400 EHSs on the basis of acute lethality data in rodents.

Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 17 identifies, reviews, and interprets relevant toxicologic and other scientific data for selected AEGL documents for acrylonitrile, carbon tetrachloride, cyanogen, epichlorohydrin, ethylene chlorohydrin, toluene, trimethylacetyl chloride, hydrogen bromide, and boron tribromide in order to develop acute exposure guideline levels (AEGLs) for these high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits (exposure levels below which adverse health effects are not likely to occur) for the general public and are applicable to emergency exposures ranging from 10 minutes (min) to 8 h. Three levels - AEGL-1, AEGL-2, and AEGL-3 - are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. This report will inform planning, response, and prevention in the community, the workplace, transportation, the military, and the remediation of Superfund sites.

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