COPC/Exposure Limits September 2016

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PNNL-25790

State of Knowledge Assessment: COPC/Exposure Limits September 2016

JN Smith C Timchalk TJ Weber

Prepared for the U.S. Department of Energy under Contract DE-AC05-76RL01830

PNNL-25790

State of Knowledge Assessment: COPC/Exposure Limits

JN Smith C Timchalk TJ Weber

September 2016

Prepared for the U.S. Department of Energy under Contract DE-AC05-76RL01830

Pacific Northwest National Laboratory Richland, Washington 99352

Summary Many chemicals, including volatile organic and inorganic compounds, metals, gases and others, have been identified in the headspaces of tanks used to store mixed chemical and radioactive waste at the U.S. Department of Energy (DOE) Hanford Site. To protect workers from potential exposures to hazardous levels of vapors during tank farm operations, Hanford Tank Farm Occupational Exposure levels (HTFOELs), which were previously termed Acceptable Occupational Exposure Levels (AOELs), have been established (Poet and Timchalk, 2006). The overall process considers human exposure limits for airborne chemicals established in the United States and other countries by governmental and non- governmental agencies. The Occupational Health and Safety Administration (OSHA) of the U.S. Department of Labor and the American Conference of Governmental Industrial Hygienists (ACGIH) have recommended Occupational Exposure Level (OEL) values for protection of workers and individuals from levels of vapors that may harm health.

To establish time weighted average (TWA) HTFOELs for the chemicals in the tank waste headspace, the chemicals were first assessed and a screening level determined to identify chemicals with sufficient concentrations to warrant further concern. A HTFOEL was developed for each chemical agent with headspace concentrations exceeding its screening value. In some cases, OELs were available from other government agencies or international organizations or foreign governments, and these were evaluated for use in assessing tank waste vapors (Table S.1). For many other chemicals identified in the tank waste vapors, no OELs were available. For these chemicals, available epidemiology and toxicology information was reviewed to identify potential hazards, select critical effects, and estimate dose-response to determine exposure levels expected to be safe. In addition, when toxicity information was limited or lacking, a HTFOEL was proposed based on a structurally related chemical (surrogate) for which sufficient data were available. Surrogates with close structural and pharmacological activity with established OELs (ACGIH or OSHA) were preferentially selected. The OEL for a given chemical and/or chemical class that was proposed via this process was submitted to the Exposure Assessment Strategy Review (EASR) Group for peer review and an HTFOEL was established. The current effort determined whether sufficient data exists to warrant re-evaluation of existing OELs and HTFOELs for chemicals of potential concern (COPCs) and surrogate chemicals used to determine HTFOELs (Table S.2). The Code of Federal Regulations, 10 CFR 851 Worker Safety and Health Program specifies that DOE contractors must comply with the 2005 version of the ACGIH TLVs when they are lower than permissible exposure limits in 29 CFR 1910. Therefore, Table S2 also references the 2005 ACGIH guidelines for the chemicals where that information was available. Ongoing OEL development will consider the most recent regulatory guidelines. Based on recent tank headspace sampling results, several new chemicals have been recommended for addition to the COPC list. These chemicals, 2-propenal, N-nitroso-n-butyl-1-butanamine, and dimethyl mercury were included in this study to determine whether existing OEL guidance was available. These efforts parallel ongoing work to continue sampling tank headspace, revise the list of COPCs and provide the foundation to assess health effects of complex mixtures.

Table S.1. OELs for Chemicals with Limits from NIOSH, AIHA, or MAK Chemical CAS Number OEL (ppm) OEL Source Propanenitrile 107-12-0 6 REL(a) 2-ethyl-1-hexanol 104-76-7 20 MAK(b) Butanal 123-72-8 25 WEEL(c) Butanenitrile 109-74-0 8 REL (a) Recommended Exposure Limits, National Institute for Occupational Safety and Health (b) Maximum Arbeitsplatz Konzentration, German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) (c) Workplace Environmental Exposure Limits, American Industrial Hygiene Association

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Table S.2. Current COPC List, Summary of Previously Established HTFOELs, and Suggested Action for Re-evaluation Suggested 2005 ACGIH CAS Current HTFOEL Re-Evaluation TWA/STEL Chemical Number (ppm) (Y/N) (ppm) Halocarbons 2-Fluoropropene 1184-60-7 0.1 Y NA(a) Alcohols 1-Butanol 71-36-3 20 Y 20/- Methanol 67-56-1 200 N 200/250 Aldehydes Acetaldehyde 75-07-0 25 Y -/25 C(b) Butanal 123-72-8 25 Y NA Formaldehyde 50-00-0 0.3 Y -/0.3 C 2-methyl-2butenal 1115-11-3 0.03 Y NA 2-ethylhex-2-enal 645-62-5 0.1 Y NA 2-propenal 107-02-8 0.1 Y -/0.1 C Amines Ethylamine 75-04-7 5 Y 5/15 N-Nitrosodiethylamine 55-18-5 0.001 Y NA N-Nitrosodimethylamine 62-75-9 0.0003 Y NA N-Nitrosomethylethylamine 10595-95-6 0.0003 Y NA N-Nitrosomorpholine 59-89-2 0.0006 Y NA N-nitroso-n-butyl-1-butanamine 924-16-3 NPD NPD NA Ketones 4-Methyl-2-hexanone 105-42-0 0.5 Y NA 2-Hexanone 591-78-6 5 Y 5/10 6-Methyl-2-heptanone 928-68-7 8 Y NA 3-Methyl-3-buten-2-one 814-78-8 0.02 Y NA 3-Buten-2-one 78-94-4 0.2 Y -/0.2 C Esters Dibutyl butylphosphonate 78-46-6 0.02 Y NA Nitriles Acetonitrile 75-05-8 20 Y 20/- Butanenitrile 109-74-0 8 Y NA 2-Methylene butanenitrile 1647-11-6 0.3 Y NA Pentanenitrile 110-59-8 6 Y NA Hexanenitrile 628-73-9 6 Y NA Heptanenitrile 629-08-3 6 Y NA 2,4-Pentadienenitrile 1615-70-9 0.3 Y NA Propanenitrile 107-12-0 6 Y NA Nitrites and Nitrates Methyl nitrite 624-91-9 0.1 N NA Butyl nitrite 544-16-1 0.1 N NA

Suggested 2005 ACGIH CAS Current HTFOEL Re-Evaluation TWA/STEL Chemical Number (ppm) (Y/N) (ppm) Butyl nitrate 928-45-0 8 N NA 1,4-Butanediol, dinitrate 3457-91-8 0.05 Y NA 1,2,3-Propanetriol, 1,3-dinitrate 623-87-0 0.05 Y NA Nitro Compounds 2-methyl-2-nitropropane 594-70-7 0.3 Y NA Heterocyclics Furan 110-00-9 0.001 Y NA 2-Heptylfuran 3777-71-7 0.001 Y NA 2-Octylfuran 4179-38-8 0.001 Y NA 2-Pentylfuran 3777-69-3 0.001 Y NA 2-Methylfuran 534-22-5 0.001 Y NA 2-Propylfuran 4229-91-8 0.001 Y NA 2-Ethyl-5-methylfuran 1703-52-2 0.001 Y NA 2-(2-Methyl-6-oxoheptyl)furan 51595-87-0 0.001 Y NA 2-(3-Oxo-3-phenylprop-1- Y NA 717-21-5 0.001 enyl)furan 2,3-Dihydrofuran 1191-99-7 0.001 Y NA 2,5-Dihydrofuran 1708-29-8 0.001 Y NA 2,5-Dimethylfuran 625-86-5 0.001 Y NA 3-(1,1-dimethylethyl)-2,3- Y NA 34314-82-4 0.001 dihydrofuran 4-(1-Methylpropyl)-2,3- Y NA 34379-54-9 0.001 dihydrofuran 2,4-Dimethylpyridine 108-47-4 0.001 Y NA Pyridine 110-86-1 1 Y 1/- Chlorinated Compounds Chlorinated biphenyls Various 0.003 N NA Biphenyl 92-52-4 0.2 N 0.2/- Dienes 1,3-Butadiene 106-99-0 1 Y 2/- Metals Mercury 7439-97-6 0.003 Y 0.003/- Dimethyl Mercury 593-74-8 0.001 Y NA Phthalate Esters Diethyl phthalate 84-66-2 0.55 Y 0.55/- Miscellaneous Ammonia 7664-41-7 25 Y 25/35 Benzene 71-43-2 0.5 Y 0.5/2.5 Methyl Isocyanate 624-83-9 0.02 Y 0.02/- Nitrous Oxide 10024-97-2 50 Y 50/- Tributyl phosphate 126-73-8 0.2 Y 0.2/- (a)NA – not available. (b)C – ceiling.

The COPC list recommended in this report, and summarized in Table S.2 contains 62 chemicals. Of the 62 chemicals, it is recommended that HTFOELs be re-evaluated for 56 compounds due to 1) changes in regulatory guidelines for individual chemicals, 2) changes in regulatory guidelines for surrogate chemicals upon which current HTFOELs are based or 3) addition of new chemicals to the COPC list (3 total) that were not previously evaluated. No changes were suggested for 6 chemicals. Because many of COPCs have no published regulatory guidelines, a surrogate chemical was previously used to establish HTFOELs. Twenty-six (26) COPCs were identified for re-evaluation because of a change to the regulatory values for the surrogate chemical upon which the current HTFOEL was based. In addition, new acute regulatory guidelines have been established (AEGL and PAC databases) for many COPCs, prompting re- evaluation of chemicals within the context of acute exposure (27 chemicals). Overall, there has been sufficient new regulatory information during the last 10 years to warrant re-evaluation of current HTFOELs.

Acronyms and Abbreviations

AEGL Acute Exposure Guideline Levels ACGIH American Conference of Governmental Industrial Hygienists AIHA American Industrial Hygienist Association AOEL Acceptable Occupational Exposure Limit. OELs developed for Hanford tank farm chemicals without existing regulatory guidelines. BEI Biological Exposure Index BMD Benchmark dose BMDL BMD limit CAS Chemical Abstracts Service CSF cancer slope factor DOE U.S. Department of Energy EPA U.S. Environmental Protection Agency (references to particular U.S. state or foreign country EPAs are so noted) ERPGs Emergency Response Planning Guidelines

HTFOEL Hanford Tank Farm Occupational Exposure Limit. An OEL or AOEL accepted for Hanford tank farm use. HSDB® Hazardous Substances Data Bank IARC International Agency for Research on Cancer IDLH Immediately Dangerous to Life or Health

LC50 lethal concentration for 50% of test population

LD50 lethal dose for 50% of test population

LCLO lethal Concentration low; the lowest concentration at which death occurred MAK 1) German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission), 2) the maximum permissible concentration of a chemical compound present in the air within a working area, which according to current knowledge, does not impair the health of the employee or cause undue annoyance. MF modifying factors NIEHS National Institute of Environmental Health Sciences NIH National Institutes of Health NIOSH National Institute for Occupational Safety and Health NLM National Library of Medicine NOELs No-Observed-Effect Levels NTP National Toxicology Program OEL(s) Occupational Exposure Limit(s). OELs established by government agencies (e.g., OSHA, NIOSH) or recommended by professional occupational and environmental health organizations (e.g., ACGIH).

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OSHA Occupational Safety and Health Administration PAC Protective Action Criteria PCBs polychlorinated biphenyls PEL Permissible Exposure Limit POD point of departure ppm parts per million REL Recommended Exposure Limits RfC reference concentration RfD reference dose RTECS® Registry of Toxic Effects of Chemical Substances SCAPA DOE Subcommittee on Consequence Assessment and Protective Actions STEL short-term exposure limit TCLO lowest published toxic concentration TEEL Temporary Exposure Limit TLV® threshold limit value (ACGIH-specific) TWA time-weighted average TOXNET® The Toxicology Data Network TWINS Tank Waste Information Network System UF Uncertainty factor WEEL Workplace Environmental Exposure Limit WHO World Health Organization

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Contents

Summary ...... iii Acronyms and Abbreviations ...... vii 1.0 Introduction ...... 1.1 1.1 Established Exposure Guidelines ...... 1.1 2.0 Overview of Approach ...... 2.1 2.1 Data Base and Literature Evaluation ...... 2.1 2.1.1 Data Base Searches ...... 2.1 2.1.2 Literature Evaluation of Published Exposure Guidelines ...... 2.2 2.1.3 Use of Surrogate OELs ...... 2.3 2.1.4 Format for Summarizing Chemical Search Information...... 2.3 3.0 Chemical Search Summaries ...... 3.1 3.1 Halocarbons ...... 3.1 3.1.1 Previous Assessment ...... 3.1 3.1.2 Current Search Summary ...... 3.2 3.2 Alcohols ...... 3.4 3.2.1 Previous Assessment ...... 3.4 3.2.2 Current Search Summary ...... 3.6 3.3 Aldehydes ...... 3.9 3.3.1 Previous Assessment ...... 3.9 3.3.2 Current Summary ...... 3.13 3.4 Ketones ...... 3.25 3.4.1 Previous Assessment ...... 3.25 3.4.2 Current Summaries ...... 3.33 3.5 Esters ...... 3.40 3.5.1 Previous Assessment ...... 3.40 3.5.2 Current Summary ...... 3.41 3.6 Alkyl Nitriles and Alkene Nitriles ...... 3.42 3.6.1 Previous Assessment ...... 3.42 3.6.2 Current Summaries ...... 3.48 3.7 Amines and Amides ...... 3.60 3.7.1 Previous Assessment ...... 3.60 3.7.2 Current Summaries ...... 3.63 3.8 Nitrites and Nitrates ...... 3.74 3.8.1 Previous Assessment ...... 3.74 3.8.2 Current Summaries ...... 3.80 3.9 Nitro Compounds ...... 3.87

3.9.1 Previous Assessments ...... 3.87 3.9.2 Current Summary ...... 3.91 3.10 Heterocyclics ...... 3.92 3.10.1 Previous Assessments ...... 3.92 3.10.2 Current Summaries ...... 3.100 3.11 Chlorinated Compounds ...... 3.118 3.11.1 Previous Assessment ...... 3.118 3.11.2 Current Summaries ...... 3.122 3.12 Current Summaries of Chemicals Not Previously Addressed ...... 3.126 3.12.1 Dienes ...... 3.126 3.12.2 Metals ...... 3.128 3.12.3 Phthalate Esters ...... 3.131 3.12.4 Miscellaneous ...... 3.133 4.0 References ...... 4.1

1.0 Introduction

A large number of volatile chemicals have been identified in the headspaces of single- and double-shelled tanks used to store mixed chemical and radioactive waste at the U.S. Department of Energy (DOE) Hanford Site. The Industrial Hygiene Chemical Vapor Technical Basis (RPP-22491, Rev 1, Meacham et al., 2006) is the current guidance by which Chemicals of Potential Concern (COPC) have been identified and managed. This technical basis document includes the current Hanford tank farm Occupational Exposure Limits (OELs) and the source of those OEL values. There have been no formal updates to OELs since this 2006 report.

The identification of COPCs in tank vapor head-space and the development of specific recommended Hanford Tank Farm OELs (HTFOELs) was completed over 10 years ago and the results were published in a number of reports (Burgeson et al., 2004; Poet et al., 2006; Poet and Timchalk, 2006, Meacham et al., 2006). As an initial step, a comprehensive review of these documents and procedures was done with a specific goal of updating the toxicology basis for tank vapor/aerosol chemicals and mixtures of chemicals of concern based upon current available toxicological/exposure data. In addition, a review of available health-related literature dealing with acute, bolus and long-term exposure effects, as well as an assessment of latent health effects related to chemicals identified in the COPC list was performed. A key outcome is the identification of those tank vapor/aerosol chemical constituents that require further evaluation based upon the most recent health data assessment.

This report specifically reviews the available literature relevant to published changes in OELs (i.e. ACGIH/NIOSH etc.) and includes an assessment of newer published literature that could suggest a need to modify any HTFOELs for the current COPC list. The process that was used to assign a HTFOEL to non- carcinogenic chemicals or family of chemicals that had no previously established OELs but were identified in the tank waste headspace at or above preliminary screening values has been previously described (Poet and Timchalk, 2006). In that assessment, a HTFOEL is defined as a level of exposure to a given chemical expected to lead to no adverse health effects that is acceptable to management, professionals, and workers at the Hanford Site. These chemicals are listed and discussed in Section 3.0. The COPC list is considered a living document and will be updated as additional tank farm sampling, analysis and monitoring is performed. Therefore, we have included HTFOELs for tank farm vapor constituents that are not included in the current COPC list, as historical reference to chemicals that were previously detected in tank headspace and evaluated as potential COPCs. Inclusion of this information may be useful to future tank vapor screening efforts if these chemicals are detected in tank vapors at higher concentrations.

1.1 Established Exposure Guidelines

Occupational Exposure Limits are established in the United States by the U.S. Department of Labor - Occupational Safety and Health Administration (OSHA). OSHA regulations are legal obligations for defined industries. The National Institute for Occupational Safety and Health (NIOSH) is an arm of the Centers for Disease Control (CDC) and makes recommendations to OSHA regarding OEL values. The American Conference of Governmental Industrial Hygienists (ACGIH) is a private organization that recommends OEL values to industry for voluntary application. Other human exposure standards have been published, e.g., by the Emergency Response Planning Guidelines (ERPGs) Committee of the American Industrial Hygiene Association (AIHA), the AIHA Workplace Environmental Exposure Levels, the Acute Exposure Guideline Levels (AEGLs) Committee of the U.S. Environmental Protection Agency (EPA), and others. However, their applicability as OEL values must, in each case, be carefully evaluated.

1.1

The DOE mandates the need to comply with the OSHA and ACGIH standards in its contract with the tank operations contractor, Washington River Protection Solutions (WRPS).

1.2

2.0 Overview of Approach

The following approach was utilized to review and update the literature on COPCs. 1. Technical staff reviewed and became familiar with previous PNNL reports (Burgeson et al., 2004; Poet et al., 2006; Poet and Timchalk, 2006) that detailed the process for selecting COPCs and assigning HTFOEL values. 2. The current priority COPC list was obtained from the tank farm contractor (WRPS). This also included additional tank vapor constituents (currently not of COPC list) based upon more recent head space analysis (Hoppe et al., 2016). 3. For those COPCs that had previously set guidelines (ex. ACGIH, OSHA, NIOSH) the assessment was focused on evaluation of published revisions to those OELs. Chemicals for which a HTFOEL was developed by PNNL and adopted by the tank farm contractor, the evaluation focused on the following: a. Has an OEL guideline been established? b. Is there any new/relevant toxicology information that needs to now be considered as part of a revised HTFOEL? c. In those cases where surrogate chemical data/guidelines were utilized to establish a HTFOEL, has there been any changes associated with the surrogate that needs to be considered in the current assessment? 4. The approach also considered new information identified in the EPA (AEGL) and DOE Protective Action Criteria (PAC) databases. 5. For each COPC, the report provides a recommendation as to whether additional review of the current OEL/HTFOEL is warranted based upon the current review and assessment of the literature.

2.1 Data Base and Literature Evaluation

2.1.1 Data Base Searches

It is imperative to consider relevant human exposure, epidemiology, and toxicological information in evaluating HTFOELs. A methodical analysis of the available literature as it relates to hazard identification and quantitative dose-response toxicity evaluation is central to the assessment process. Internet data bases such as The Toxicology Data Network (TOXNET®), PUBMED®, the Comparative Toxicogenomics Database (CTD®), HAZMAP®, Hazardous Substances Data Bank (HSDB®), Integrated Risk Information System (IRIS®), Registry of Toxic Effects of Chemical Substances (RTECS®), Toxicology Literature Online (Toxline®), Acute Exposure Guideline Levels (AEGL®) and Protective Action Criteria (PAC®) were utilized as primary sources for initiating searches, which include both the name and Chemical Abstracts Service (CAS) registry number of the compound of interest. These data bases contain information applicable to toxicological assessment of chemicals, and the information they provide frequently overlapped. Initially chemicals were searched in AEGL, PAC, HAZMAP and HSDB databases which provided numerical OEL values, when available, that were easily identifiable for direct comparison with the current HTFOELs. Subsequently, PUBMED, TOXNET, CTD, IRIS, RTECS, and Toxline databases were searched to identify dose-dependent information on toxicity of chemicals and to identify new information on chemicals for which regulatory information was not available in AEGL, PAC, HAZMAP and HSDB databases. If information was found in one or more of the above sources but was incomplete, conflicting or considered insufficient, other sources such as National Institute of

2.1

Environmental Health Sciences (NIEHS) National Toxicology Program (NTP), IARC, the US EPA and the Agency for Toxic Substances and Disease Registry Monographs (ATSDR) or a google search were undertaken.

Table 2.1. On-Line Data Bases Name Description AEGL® Acute Exposure Guideline Levels, an EPA database describing the human health effects from once-in-a-lifetime, or rare, exposure to airborne chemicals. Used by emergency responders when dealing with chemical spills or other catastrophic exposures, AEGLs are set through a collaborative effort of the public and private sectors worldwide. (https://www.epa.gov/aegl) PAC® The Protective Action Criteria dataset is a hierarchy-based system of the three common public exposure guideline systems: AEGLs, ERPGs, and TEELs. A particular hazardous substance may have values in any—or all—of these systems. (http://response.restoration.noaa.gov/oil-and-chemical-spills/chemical- spills/resources/protective-action-criteria-chemicals-pacs.html) HAZMAP® A remote measuring system for the Mapping of Hazardous environments. An occupational health database designed for health and safety professionals and for consumers seeking information about the adverse effects of workplace exposures to chemical and biological agents. (https://hazmap.nlm.nih.gov/about-us) HSDB® Hazardous Substances Data Bank - accessible through TOXNET. A NLM database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. (https://toxnet.nlm.nih.gov/cgi- bin/sis/htmlgen?HSDB) CTD® Comparative Toxicogenomics Database. A robust, publicly available database that aims to advance understanding about how environmental exposures affect human health. (http://ctdbase.org/) TOXNET® The Toxicology Data Network, a set of data bases covering toxicology, hazardous chemicals, and related areas; it is maintained by the National Library of Medicine (NLM). (http://toxnet.nlm.nih.gov/) HSDB® Hazardous Substances Data Bank. A NLM toxicology database that focuses on the toxicology of potentially hazardous chemicals. Accessible through TOXNET. (https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB) IRIS® Integrated Risk Information System. An EPA database identifying and characterizing the health hazards of chemicals found in the environment. Each IRIS assessment can cover a chemical, a group of related chemicals, or a complex mixture. (https://www.epa.gov/iris) PUBMED® PubMed, provided by the NLM, contains citations for biomedical articles back to the 1950s; sources include MEDLINE and additional life science journals. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed). RTECS® Registry of Toxic Effects of Chemical Substances is a compendium of data extracted from the open scientific literature. Provided by Thomson Micromedex, Inc. Accessed through TOMES®, which has the same provider. (http://www.cdc.gov/niosh/rtecs/default.html)

2.1.2 Literature Evaluation of Published Exposure Guidelines

Initial efforts focused on a comprehensive evaluation of the available literature to identify any published exposure guidelines for the chemical of interest or for a reasonable surrogate.

2.2

2.1.3 Use of Surrogate OELs

If there were no appropriate exposure guidelines for the chemical of interest, the previous approach identified and assigned a HTFOEL based on a structurally related chemical (surrogate). In addition to being structurally related, ideal surrogates also had a similar toxicological profile (i.e., similar target organs and response), although they may display greater or lesser potency than the chemical of concern.

2.1.4 Format for Summarizing Chemical Search Information.

The primary focus of the search strategy was to identify new regulatory information and a focus on respiratory/irritation health effects occurring at exposures nearing current OEL/HTFOEL guidelines to facilitate prioritization of chemicals for re-evaluation. Data was organized into general headings as follows: 1) Previous assessment for individual or classes of chemicals within the COPC list (extracted from PNNL-15736 technical document), 2) current OEL/HTFOEL, 3) Literature search summary, 4) Toxicity, 5) Carcinogenicity, 6) Irritation Indications, 7) Odor Threshold, 8) Mixture Interactions, 9) Recommendations/Conclusions and 10) References. The previous assessment information was included to provide the background information that was used to establish the current HTFOELs. In many cases new information on acute exposure guidelines were identified in AEGL and PAC databases. AEGLS are exposure guidelines designed to help responders deal with emergencies involving chemical spills or other catastrophic events where members of the general public are exposed to a hazardous airborne chemical (Acute exposures are single, non-repetitive exposures that don't exceed 8 hours). PACs are a comprehensive emergency management system supported by AEGLs, ERPGs and TEELs. The definition for specific AEGL and PAC categories used throughout the document is as follows:

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

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

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

• PAC-1 is airborne concentration in which the general population, including susceptible individuals, if exposed to for one hour could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects.

• PAC-2 is the airborne concentration in which the general population, including susceptible individuals, if exposed to for one hour could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

• PAC-3 is the airborne concentration in which the general population, including susceptible individuals, if exposed to for one hour could experience life-threatening health effects or death.

2.3

3.0 Chemical Search Summaries

3.1 Halocarbons

3.1.1 Previous Assessment

3.1.1.1 Fluoropropene (CAS# 1184-60-7)

A HTFOEL is proposed for 2-fluoropropene based on a comprehensive review of the available toxicology and guideline literature. 2-Fluoropropene is a fluorinated propene that is similar in structure to halogenated ethylenes such as fluoroethylene (vinyl fluoride), chloroethylene (vinyl chloride), or bromoethylene (vinyl bromide). As a class of compounds, the halogenated ethylenes have been classified as known (A1) or suspected (A2) human carcinogens. Although there are no ACGIH or OSHA guidelines for 2-fluoropropene, the ACGIH has set TLV-Time Weighted Average (TWA) exposure concentrations for fluoroethylene at 1 ppm (1.9 mg/m3) largely based on analogy to the TLV-TWAs for chloroethylene (vinyl chloride) and bromoethylene (vinyl bromide) (ACGIH 2001bb). Based on the uncertainty associated with chemical differences between 2-fluoropropene and the halogenated ethylenes, a HTFOEL of 0.1 ppm is proposed for 2-fluoropropene.

Methodology

Standard Operating Procedures were used as a guide for developing this HTFOEL. To identify and access available toxicity data on 2-fluoropropene, a number of Internet data bases, including PUBMED, TOXNET, and TOMES, were searched and summary toxicity profiles were obtained, including the identification of primary references. In addition, ACGIH documentation was likewise reviewed for 2- fluoropropene and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and used for the development of the HTFOEL.

Available Guidelines

No OEL for 2-fluoropropene has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogate fluoroethylene (ACGIH 2001n). The ACGIH documentation for fluoroethylene is based upon the structural similarity to the known human carcinogen vinyl chloride and the suspected human carcinogen vinyl bromide. However, it has been suggested that the slower relative metabolism of fluoroethylene vs. vinyl chloride to a similar toxic metabolite supports fluoroethylene being less potent than vinyl chloride (Filser and Bolt 1979). Likewise, a direct comparison of rodent bioassay results between fluoroethylene (Bogdanffy et al. 1995) and vinyl bromide (Benya et al. 1982) suggests that vinyl bromide is more than twice as potent as fluoroethylene. Therefore, ACGIH recommended a 1 ppm TLV-TWA for fluoroethylene, which is twice the recommended TLV-TWA (0.5 ppm) for vinyl bromide.

Toxicology Summary and Data Analysis

There was no available toxicity information for 2-fluoropropene. A search of the RTECS data base found very limited and dated toxicity data on 2-chloropropene but suggested a low acute toxicity with an LC50 in 3 3 mice of 267 g/m and a lowest published concentration (TCLO) in rats of 191 g/m following repeated inhalation exposure. For the structural surrogate vinyl fluoride, the acute toxicity is very low with lethal concentrations in rats reported to be >800,000 ppm for an ~12-hour exposure, and no fatalities were noted

3.1

in rats exposed for 7 hours/day, 5 days/week for 30 days at 100,000 ppm vinyl fluoride (Clayton 1967). A 13-week exposure of rats and mice to vinyl fluoride concentrations ranging from 200 – 20,000 ppm reported a concentration-dependent increase in urinary fluoride excretion (Bogdanffy et al. 1990). The oncogenic potential of vinyl fluoride was evaluated in both rats and mice by inhalation at concentrations of 0, 25, 250 and 2500 ppm, and vinyl fluoride was found to be carcinogenic at the lowest concentration (25 ppm) in both species (Bogdanffy et al. 1995). The tumorigenic response was reported to be similar to that seen with vinyl chloride and vinyl bromide (ACGIH 2001bb; Maltoni et al. 1981; Benya et al. 1982).

Summary and Recommendations

The ACGIH has set the TLV-TWA for vinyl fluoride at 1 ppm (1.9 mg/m3) based primarily by analogy with vinyl chloride and vinyl bromide. Based on the uncertainty associated with chemical differences between 2-fluoropropene and vinyl fluoride, an additional 10-fold factor is applied to the vinyl fluoride OEL to establish a HTFOELof 0.1 ppm for 2-fluoropropene.

3.1.2 Current Search Summary

Based on the uncertainty associated with chemical differences between 2-fluoropropene and the halogenated ethylenes, a HTFOEL of 0.1 ppm was proposed for 2-fluoropropene (see above).

Literature Search

A literature search focusing on new toxicity data for 2-fluoropropene was conducted on May 16, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 2-fluoropropene: HazMap, Toxline, PubMed. No new information on 2-fluoropropene that would be relevant to assessing OELs was identified. Surrogate used to develop the HTFOEL, chloroethylene (vinyl chloride; CAS No. 75-01-4) and bromoethylene (vinyl bromide; CAS No. 593-60- 2) were identified in AEGL and PAC databases. • OSHA guidelines state an OEL of 1 ppm TWA, 0.5 ppm action level for vinyl chloride (https://www.osha.gov/dts/chemicalsampling/data/CH_275395.html). Date Last Revised: 08/05/2003. • No specific guideline for vinyl bromide was identified in the OSHA database. • Vinyl chloride and vinyl bromide have not been updated in ACGIH database since the 2001 publication.

3.2

PAC values for Vinyl Chloride are the same as AEGLs.

Toxicity

Flammable; May cause skin and eye irritation and corneal burns; Ingestion may cause vomiting, diarrhea, loss of consciousness, and convulsions; Inhalation may cause coughing, wheezing, congestion of the lungs, shortness of breath, loss of consciousness, and convulsions; [Apollo Scientific MSDS] See "2- Chloro-1-propene." Other CNS Neurotoxin (HazMap Database).

Carcinogenicity

Surrogate vinyl chloride is known to be a human carcinogen.

Irritation Indications

May cause skin and eye irritation (HazMap Database).

Odor Threshold

Not available.

Mixture Interactions

None identified (PubMed; mixture interaction and 2-fluoropropene or vinyl chloride or vinyl bromide as search terms).

Summary and Recommendations

Acute exposure guidelines identified in AEGL and PAC databases for surrogates (vinyl chloride [70 ppm], vinyl bromide[39 ppm]) are orders of magnitude higher than previous TLV- TWA exposure concentrations for fluoroethylene (1 ppm) set by ACGIH largely based on analogy to the TLV-TWAs for chloroethylene (vinyl chloride) and bromoethylene (vinyl bromide). OSHA guidelines state an OEL of 1 ppm TWA, 0.5 ppm action level for vinyl chloride. Therefore, the stringency of the current HTFOEL for 2-fluoropropene [0.1 ppm] should be re-evaluated. Carcinogenesis indications for the surrogate vinyl chloride will need to be considered.

References

None

3.3

3.2 Alcohols

3.2.1 Previous Assessment

3.2.1.1 1-Hexadecanol (CAS # 36653-82-4), 1-Octadecanol (CAS # 112-92-5)

There are currently no published exposure guidelines for 1-hexadecanol (16-carbon) or 1-octadecanol (C-18). Both these long-chain aliphatic alcohols have relatively low toxicity based on acute toxicity testing. These alcohols are common components of cosmetic compounds. Octadecanol (stearyl alcohol) is found naturally in various mammalian tissues and is readily converted to stearic acid. Stearyl alcohol is an 18-carbon straight chain aliphatic alcohol often used as an emollient to prevent drying and chapping of skin and as a thickener and pearlizing agent in cosmetics. The common use in cosmetics and relatively low toxicity indicate a HTFOEL is not needed for these chemicals at this time. As additional new data become available for these compounds, it would be reasonable to reassess the appropriateness of assigning a HTFOEL.

3.2.1.2 Cyclopentanol (CAS# 96-41-3)

A HTFOEL is proposed for cyclopentanol based on a comprehensive review of the available toxicology and guideline literature. Cyclopentanol is a cyclic (5-carbon) alcohol. Although there are no ACGIH or OSHA guidelines for cyclopentanol, the ACGIH has set TLV-TWA exposure concentrations for cyclohexanol (ACGIH 2001). The TLV-TWA for the cyclohexanol was set at 50 ppm (206 mg/m3) to minimize the potential for eye irritation and possible central nervous system effects including narcosis and incoordination. Based on the uncertainty associated with chemical and toxicological differences between cyclopentanol and cyclohexanol, a HTFOEL of 5 ppm is proposed for cyclopentanol.

Methodology

To identify and access available toxicity data on cyclopentanol, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched and summary toxicity profiles were obtained and primary references identified. ACGIH documentation was also reviewed for cyclohexanol, which is a relevant surrogate chemical. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for cyclopentanol has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the surrogate, cyclohexanol. The ACGIH documentation indicates that a TLV-TWA of 50 ppm will protect from cyclohexanol vapor irritation based on both animal and human data.

Toxicology Summary and Data Analysis

Limited toxicity evaluation has been conducted with cyclopentanol. Acute oral exposure to doses of 0.6 – 1.3 ml/kg of body weight did result in mortality, and toxic response included unsteady gait and convulsion. Gross pathology indicated effects on the liver and kidneys. Acute inhalation exposure to a saturated atmosphere (~1300 ppm) for 1 hour resulted in no mortality; however, a ~3-hour exposure at this same concentration resulted in 100% mortalities.

The surrogate cyclohexanol has a low acute oral toxicity in rats with LD50 s at ~2 g/kg of body weight. Inhalation exposure to ~1000 ppm for 6 hours/day, 5 days/week, for 5 to 11 weeks resulted in intoxication

3.4

and death in 50% of rabbits. Rabbits exposed to concentrations of 145 ppm showed only slight degeneration in the liver and kidneys (Treon et al. 1943). In humans exposed to cyclohexanol (3-5 minutes), an 8-hour acceptable air concentration was calculated as < 100 ppm (Nelson 1943).

Summary and Recommendations The ACGIH has set the TLV-TWA for the cyclohexanol at 50 ppm (206 mg/m3) to minimize the potential for eye irritation and possible central nervous system effects including narcosis and incoordination. Based on the uncertainty associated with chemical and toxicological differences between cyclopentanol and cyclohexanol, an additional 10-fold factor is applied to the cyclohexanol OEL to establish a HTFOEL of 5 ppm for cyclopentanol.

3.2.1.3 2-Ethyl-1-hexanol (CAS# 104-76-7)

A HTFOEL is proposed for 2-ethyl-1-hexanol based on a comprehensive review of the available toxicology and guideline literature. 2-Ethyl-1-hexanol is an aliphatic branched (8-carbon) alcohol. Although there are no ACGIH or OSHA guidelines for 2-ethyl-1-hexanol, the German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) set a MAK of 20 ppm (MAK set in 2005). In addition, the ACGIH has set a TLV-TWA exposure concentration for isooctyl alcohol, which has the same molecular formula but a slightly different structural formula than 2-ethyl-1- hexanol. The TLV-TWA for isooctyl alcohol was set at 50 ppm (266 mg/m3) to minimize the potential for upper respiratory tract irritation (ACGIH 2001p). The German MAK of 20 ppm will be adopted for 2- ethyl-1-hexanol.

Methodology

To identify and access available toxicity data on 2-ethyl-1-hexanol, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was likewise reviewed for isooctyl alcohol as a relevant surrogate chemical. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for 2-ethyl-1-hexanol has been proposed by OSHA or ACGIH, and the German MAK commission has recently updated their OEL for 2-ethyl-1-hexanol from 50 ppm to 20 ppm. There is no available documentation explaining the reasons for the change (MAK set in 2005). In addition, ACGIH has assigned a TLV-TWA for a structural surrogate isooctyl alcohol (ACGIH 2001p). The ACGIH documentation indicates that a TLV-TWA of 50 ppm will minimize the potential for upper respiratory tract irritation.

Toxicology Summary and Data Analysis

There appears to be substantial toxicity data on 2-ethyl-1-hexanol, however no U. S. guidelines have yet been established for occupational exposure. In mice, rats, and guinea pigs, the LC50 for 2-ethyl-1-hexanol was >227 ppm (6-8 hour exposure) (Scala and Burtis 1973; Smyth et al. 1969; Treon 1963). The oral LD50 in rats reported in several studies was ~3 g/kg of body weight (Scala and Burtis 1973; Albro 1975; Treon 1963; NIOSH 1976). In these studies, the animals were observed for 24 hours prior to necropsy, and no deaths occurred during exposure or observation. All animals exhibited central nervous system depression, labored breathing, and one guinea pig had a clonic convulsion. The results of long-term oral carcinogenicity studies in both rats and mice indicate that 2-ethyl-1-hexanol is not carcinogenic (BASF 1991; 1992). Although the German MAK has established an OEL for 2-ethyl-1-hexanol (20 ppm), for comparison isooctyl alcohol was also chosen as a surrogate because it has the same molecular formula as

3.5

2-ethyl-1-hexanol, and an ACGIH TLV-TWA has been established and documented (ACGIH 2001p). An acute oral LD50 for isooctyl alcohol in rats of 1.5 g/kg of body weight has been reported, and the principal signs of effect were central nervous system depression and labored respiration. In addition, mice, rats, and guinea pigs that inhaled 200 ppm isooctyl alcohol for 6 hours showed only moderate local irritation of the upper respiratory tract, but no signs of systemic intoxication were observed (Scala and Burtis 1973). These toxicological responses seen with isooctyl alcohol following either oral or inhalation exposure are reasonably comparable to the response seen with 2-ethyl-1-hexanol. Hence, isooctyl alcohol is a reasonable surrogate based on similar molecular structure and toxicological profile.

Summary and Recommendations

The German MAK commission has set an OEL TWA for 2-ethyl-hexanol at 20 ppm; however, we lack documentation explaining the rational for the selection of the OEL. The ACGIH has set the TLV-TWA for isooctyl alcohol at 50 ppm (266 mg/m3) to minimize the potential for upper respiratory tract irritation. The German MAK of 20 ppm will be adopted for 2-ethyl-hexanol. For perspective, this HTFOEL is 2.5- fold lower than the ACGIH TLV-TWA for the surrogate isooctyl alcohol.

3.2.2 Current Search Summary

3.2.2.1 1-Butanol (CAS No. 71-36-3)

1-Butanol was not previously assessed PNNL-15736. Current Regulatory information (HAZMAP): 1. TLV (ACGIH) 20 ppm 2. PEL (OSHA) 100 ppm 3. MAK 100 ppm 4. IDLH 1400 ppm

Literature Search

A literature search focusing on new toxicity data for 1-Butanol was conducted on May 17, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 1-Butanol: CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, and PubMed. 1-Butanol was also identified in PAC, but not AEGL databases.

Toxicity

Neurotoxin at high dose (HAZMAP).

3.6

Carcinogenicity

CLASSIFICATION: D; not classifiable as to human carcinogenicity.(HSDB)

Irritation Indications

A skin, eye, and respiratory tract irritant (HAZMAP).

Odor Threshold

0.12 ppm

Mixture Interactions

None identified (PubMed; mixture interaction and 1-Butanol as search terms).

Summary and Recommendations

Recently established PAC values (PAC-1 60 ppm) are higher than ACGIH TLV guidelines (20 ppm) and could potentially be considered for acute 1-Butanol exposures.

References

None.

3.2.2.2 Methanol (CAS No. 67-56-1)

The OEL for methanol is 200 ppmv based on a Threshold Limit Value (TLV) set by the ACGIH.

Literature Search

A literature search focusing on new toxicity or regulatory data for methanol was conducted May 9, 2016. Using standardized search criteria, the following databases were identified as containing active records on methanol: EPA AEGL, EPA PAC, HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, and CTD.

New regulatory guidelines for methanol were discovered. In 2013, IRIS reevaluated methanol and increased the oral reference dose (RfD) to 2 mg/kg/day based on 43.1 mg/L point of departure (Rogers et al. 1993b), 100 UF, and physiologically based pharmacokinetic (PBPK) model extrapolation (IRIS). The reference concentration for inhalation (RfC) was increased to 2 mg/m3 based on 858 mg×hr/L point of departure (NEDO 1987), 100 UF, and PBPK model extrapolation (IRIS). EPA established interim Acute Exposure Guideline Levels (AEGLs) for methanol. The US DOE has established PAC (Revision 29) for acetaldehyde that was adopted as the 1 hr AEGL values. Occupational Safety and Health Agency (OSHA) maintains an 8 hr time-weighted average (TWA) Permissible Exposure Limit (PEL) of 200 ppm for methanol (HSDB, 29 CFR 1910.1000 2005). ACGIH maintains an 8 hr TWA TLV of 200 ppm and a 15 min short-term exposure limits (STEL) of 250 ppm based on skin (HSDB, ACGIH 2011). ACGIH recommends a 15 mg/L end of shift Biological Exposure Index (BEI) for methanol (HSDB, ACGIH 2011B). National Institute for Occupational Safety and Health (NIOSH) recommends a 10 hr TWA recommended exposure limit (REL) of 200 ppm and 15 min short-term exposure limit of 250 ppm, both based on skin (HSDB, NIOSH 2005). NIOSH also suggests that 6000 ppm is immediately dangerous to life or health (HSDB, NIOSH 2005).

3.7

AEGLs for methanol (EPA 2005).

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 670 670 530 340 270 Batterman 1998; Franzblau 1999; Frederick 1984; NIOSH 1980, 1981 AEGL-2 11000 4000 2100 730 520 Rogers 1993, 1995, 1997, 1999 AEGL-3 40000 14000 7200 2400 1600 AACT 2002

Toxicity

Methanol poisoning can cause blindness and death (HazMap).

Methanol causes clinical effects similar to ethanol intoxication, including central nervous system depression, teratogenic effects, and embryolethal effects (HSDB).

Clinical effects may include visual disturbances, nausea, abdominal and muscle pain, dizziness, weakness and disturbances of consciousness ranging from coma to clonic seizures (HSDB).

Carcinogenicity

Not listed.

Irritation Indications

Moderate irritant to the eye and skin (HSDB).

Odor Threshold

Characteristic pungent odor (HazMap).

The air odor threshold for methanol has been reported as 100 ppm. A level of 2,000 ppm is barely detectable (HSDB).

Low threshold= 13.1150 mg/m3; High threshold= 26840 mg/m3 (HSDB, Ruth 1986).

Mixture Interactions

Methanol is metabolized to formaldehyde. Thus, methanol exposures could increase internal concentrations of formaldehyde.

Effects of methanol may be additive with other alcohols.

Summary and Recommendations

Although many of the TLVs were established based on skin, TLVs recommended by ACGIH, NIOSH, and OSHA remain at 200 ppm, the current OEL for methanol. Acute exposure criteria have also been established (AEGLs, PACs, and STELs) at levels higher than 200 ppm. In either acute or chronic exposure scenarios or dermal or inhaled exposure routes, the current OEL should be protective and reevaluation is not warranted. Consideration of acute-specific criteria or route-specific criteria would necessitate methanol OEL reevaluation.

3.8

References

Rogers, JM; Mole, ML; Chernoff, N; Barbee, BD; Turner, CI; Logsdon, TR; Kavlock, RJ. (1993b). The developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses. Teratology 47: 175-188.

NEDO (New Energy Development Organization). (1987). Toxicological research of methanol as a fuel for power station: summary report on tests with monkeys, rats and mice. Tokyo, Japan.

U.S. EPA (U.S. Environmental Protection Agency). (2013). Toxicological review of Methanol (CASRN 67-56-1) in support of summary information on the Integrated Risk Information System (IRIS). (EPA/635/R-11-001). Washington, DC.

29 CFR 1910.1000; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of June 1, 2005: http://www.gpoaccess.gov/ecfr

American Conference of Governmental Industrial Hygienists; 2011 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH 2011, p. 38

American Conference of Governmental Industrial Hygienists; 2011 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH 2011B, p. 104

Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986)

3.3 Aldehydes

3.3.1 Previous Assessment

3.3.1.1 2-Methylbut-2-enal (CAS# 1115-11-3) and 2-ethylhex-2-enal (CAS# 645-62-5)

2-Methylbut-2-enal and 2-ethylhex-2-enal are alcrolein derivatives, which contain a branched aliphatic sidechain with a double bond and oxygen on the C-1 carbon. The principal toxic effect that stems from exposures to aldehydes and aliphatic hydrocarbons is irritation to mucous membranes. Irritation caused by similar compounds with both a double bond and a double-bonded oxygen can be severe, and the ACGIH has recommended TLV-ceilings of 0.1 and 0.3 ppm for acrolein and crotonaldehyde, respectively. Very little information was found regarding 2-methylbut-2-enal and 2-ethylhex-2-enal, and proposed OELs were based on crotonaldehyde as a surrogate with an UF of 30 (2-methylbut-2-enal) or 100 (2-ethylhex-2- enal), depending on the availability of toxicology data. The recommended OELs for 2-methylbut-2- enal and 2-ethylhex-2-enal are 0.03 and 0.1 ppm, respectively.

Methodology

To identify and access available toxicity data on 2-methylbut-2-enal and 2-ethylhex-2-enal, a number of on-line data bases including PUBMED, TOXNET, and TOMES were searched and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was likewise reviewed for crotonaldehyde, acrolein, and propionaldehyde as potentially relevant surrogate

3.9

chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OELs have been proposed by OSHA or ACGIH for either 2-methylbut-2-enal or 2-ethylhex-2-enal. However, ACGIH has assigned TLV ceilings for the structural surrogates, crotonaldehyde and acrolein, and a TLV-TWA for propionaldehyde. Propionaldehyde lacks the double bond, and the ACGIH TLV- TWA is 20 ppm (ACGIH 2002b). The ACGIH TLV ceilings for crotonaldehyde and acrolein are 0.3 and 0.1 ppm, respectively (ACGIH 2001e; 2001a). The toxicological endpoint of concern for all of these aldehydes is irritation of the eyes and upper respiratory tract. The irritation caused by exposures to crotonaldehyde and acrolein are rapid and can be lethal due to changes in pulmonary function. Crotonaldehyde is an animal carcinogen (hepatocellular carcinomas).

Toxicology Summary

No toxicity data were found for 2-methylbut-2-enal. 2-Methylbut-2-enal is a pheromone released in rabbit milk apparently needed by newborn rabbit pups to find the nipple (Schaal et al. 2003). The structural surrogate of 2-methylbut-2-enal lacking the double-bonded oxygen, 2-methyl-2-butene has a high LC50 (low toxicity), and an inhalation NOEL in a 26-week study was 580 ppm (Olefins Panel 2004).

There are limited toxicity data available for 2-ethylhex-2-enal. The European Commission of the European Chemicals Bureau has collected toxicology data since 2-ethylhex-2-enal is a high-production volume chemical in Europe. All animals exposed acutely to 2-ethylhex-2-enal via inhalation at levels of 2425 ppm died. No animals died or were grossly affected by exposures to 8406 ppm. The oral LD50 for 2- ethylhex-2-enal is 3-4.7 g/kg (Table 3.2). 2-Ethylhex-2-enal was negative in Ames Salmonella tests for genotoxicity.

Aldehydes such as these are generally irritating to mucous membranes, especially of the eyes or upper respiratory tract. The unsaturated aldehydes such as acrolein and crotonaldehyde are much more acutely irritating than the similarly sized aldehydes (compare propionaldehyde to acrolein).

Summary and Recommendations

In reviewing the available toxicity data bases on acrolein derivatives with similar structures to 2-ethylhex- 2-enal and 2-methylbut-2-enal, the most robust data were found for crotonaldehyde and acrolein, which differ in that they lack branching and have smaller carbon chains. The ACGIH-recommended TWA ceilings for crotonaldehyde and acrolein are 0.3 and 0.1 ppm, respectively. An UF of 3 is recommended to extrapolate a recommended OEL for 2-ethylhex-2-enal from crotonaldehyde due to the structural differences inherent with branching of the side-chain, which may result in metabolic or toxicological differences. Thus, the recommended OEL for 2-ethylhex-2-enal is 0.1 ppm. An additional UF of 3 is recommended to extrapolate a recommended OEL for 2-methylbut-2-enal from crotonaldehyde due to the limited toxicological data for 2-methylbut-2-enal. Thus, the recommended OEL for 2-methylbut-2-enal is 0.03 ppm. Based on the LD50 for 2-ethylhex-2-enal (Table 3.3), these OELs are expected to be very conservative.

3.10

Table 3.2. Comparative Toxicity Parameters

1 Chemical NOEL LC50 LD50 Structure

2-Methylbut-2- enal

2-ethylhex-2-enal 3-4.7 g/kg

Surrogates

2-Methylbut-2- 580 ppm 26 weeks ene

Crotonaldehyde 10 ppm/3.3 hr 600- LOEL 1500/30mi n

100/4 hours

Propionaldehyde 150 ppm 26000 ~0.8 - 1.7 ppm/30 g/kg

6 hours/day, 7 min days/week, 52 weeks (reversible nasal lesions)

Acrolein ~4 ppm 6 46 mg/kg hours/day 62 days

3.11

Table 3.3. OEL Summary

HTFOEL Comment

2-Methylbut-2-enal 0.03 ppm UF = 3 for ceiling adjustment, and additional 3 for limited data

2-ethylhex-2-enal 0.1 ppm UF = 3 for ceiling adjustment

Surrogates

2-Methylbut-2-ene NA

Crotonaldehyde 0.3 ppm ACGIH TLV-Ceiling

Propionaldehyde 20 ppm ACGIH TLV-TWA

Acrolein 0.1 ppm ACGIH TLV-Ceiling

3.3.1.2 Butanal (CAS# 123-72-8)

A HTFOEL is proposed for butanal based on a comprehensive review of the available toxicology and guideline literature. Butanal (butyraldehyde) is an aliphatic aldehyde. Aliphatic aldehydes are generally volatile organic compounds that irritate skin, eyes, and the upper respiratory tract. Although there are no ACGIH or OSHA guidelines for butanal, the AIHA has proposed a TWA Workplace Environmental Exposure Limit (WEEL) of 25 ppm. The AIHA procedures for developing WEELs are similar to procedures for developing proposed HTFOELs for the current tank waste headspace analysis and include an assessment of the chemicals by qualified personnel, a review of the toxicological literature, and a committee assessment (http://www.aiha.org/committees/documents/weel_procedures.doc). The proposed HTFOEL for butanal is 25 ppm and is equivalent to the WEEL developed by the AIHA.

Methodology

To identify and access available toxicity data on butanal, a number of Internet data bases including PUBMED, TOXNET, TOMES, and IARC, were searched and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OEL for butanal has been proposed by OSHA or ACGIH. However, the AIHA has assigned a WEEL for butanal at 25 ppm. Several aliphatic aldehydes have had TLVs and WEELS set, and values assigned by these two groups are generally the same. For comparison, basic toxicity/exposure guidelines for butanal and propanal are given in Table 3.4. The Spacecraft Maximum Allowable Concentration for butanal is 41 ppm (CLS 2000), and the Danish EPA (http://www.mst.dk/chemi/01084008.htm) has set a TLV of an average 8-hour mean limit of 25 ppm based on the WEEL.

3.12

Table 3.4. Butanal and Propanal

1 Chemical Structure LC50 (rats, ppm) WEEL TLV

Butanal O 59000 25 n.a.

Propanal O 26000 20 20

1Skog 1950, as reported in CLS 2000.

(http://books.nap.edu/books/0309067952/html/1.html)

Toxicology Summary and Data Analysis

Butanal is used in the production of resins, solvents, and plasticizers. It is metabolized to butyric acid, primarily in the liver. Acids from aliphatic aldehydes can serve as substrates for fatty acid oxidation within the Krebs cycle. The primary toxicological endpoint from butanal exposures is irritation to the skin and eyes. Acute toxicity is low (See Table 5.3). The NOEL following a 1-month inhalation exposure (6 hours/day, 5 days/week) in rats was 320 ppm (EPA 1989). No evidence has been presented that butanal exposures cause cancer. In humans, exposures to 200 ppm for 30 minutes were non-irritating (CLS 2000). The odor threshold for butanal is approximately 3 ppm (Cometto-Muniz et al. 1998).

No guidelines have been established for butanal by either ACGIH or OSHA. The 8-hour TWA WEEL of 25 ppm proposed by the AIHA is within the same range as available ACGIH TLVs given for several related aliphatic aldehydes (ACGIH 2005b), including the closely related propanal (ACGIH 2002b; Table 5.3).

Summary and Recommendations

Based on the high LC50 in rats, the lack of irritation observed in human exposures to 200 ppm, and the 320 ppm NOEL for subchronic inhalation exposures in rats, the 25 ppm WEEL is appropriate. In addition, the WEELs assigned by AIHA that are available for other aliphatic aldehydes generally match the TLVs assigned by ACGIH. Therefore, a HTFOEL of 25 ppm is proposed for butanal.

3.3.2 Current Summary

3.3.2.1 Acetaldehyde (CAS No. 75-07-0)

The OEL for acetaldehyde is 25 ppmv as defined by the ACGIH ceiling limit (ACGIH 2014).

Literature Search

A literature search focusing on new toxicity data for acetaldehyde was conducted May 25, 2016. Using standardized search criteria, the following databases were identified as containing active records on acetaldehyde: EPA AEGL, DOE PAC, IRIS, CCRIS, CTD, GeneTox, HazMap, HSDB, ITER, and RTECS.

3.13

Since exposure guidelines have been established for acetaldehyde, the primary focus of in-depth screening of identified databases was updates to regulatory guidelines as well as new, noteworthy data. ACGIH published an OEL for acetaldehyde in 2014, and it remained unchanged (25 ppmv ceiling). ACGIH has not recommended a short-term exposure limits (STEL) for acetaldehyde. It was identified that in December 2008, the EPA established interim AEGLs for acetaldehyde. The US DOE has established PAC (Revision 28A) for acetaldehyde that was adopted as the 1 hr AEGL values. Additionally, new data was published demonstrating upper respiratory tract irritation in humans after exposure to 125 ppm acetaldehyde for 30 min (ACGIH Conference 2013, HSDB database). It is also noted that toxicity to acetaldehyde may be variable in human populations, as many East Asians have a genetic polymorphism of aldehyde dehydrogenase, an enzyme responsible for detoxification of acetaldehyde.

AEGLs for acetaldehyde (AEGL 2009).

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 45 45 45 45 45 Sim and Pattle 1957 AEGL-2 340 340 270 170 110 Cassee 1996 AEGL-3 1100 1100 840 530 260 Appelman 1982

Toxicity

Prolonged exposure to high concentrations (unspecified) may injure the corneal epithelium, causing persistent lacrymation, photophobia, and foreign body sensation. Fatalities following inhalation are due to anesthesia when prompt and to pulmonary edema when delayed. (AEGL 2009).

Carcinogenicity

Acetaldehyde is Classified as a probable human carcinogen (B2) (IRIS Database). Using the Linearized Multistage Model US-EPA (1991) derived an inhalation unit risk of 2.2×10-6 (risk per 1 µg/m3 of lifetime exposure) (AEGL 2009).

Irritation Indications

Acetaldehyde is an eye, nose, skin, and respiratory irritant (HSDB Database).

Odor Threshold

Odor detection threshold mean: 0.067 ppm (AIHA, HazMap Database)

Odor detection threshold 0.21 ppm (ACGIH, HazMap Database)

Level of distinct odor awareness 0.56 ppm (AEGL 2009)

Mixture Interactions

In vitro screens suggest primarily toxic effects are more important than mixture effects when evaluating acetaldehyde in a mixture using a factorial design (Parvez et al. 2008).

Exposure to chemical mixtures with other aldehydes may have additive effects.

3.14

Other

Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL): 200 ppm 8 hr time-weighted average (TWA), (HazMap & RTECS Databases, Code of Federal Regulations)

Summary and Recommendations

Literature searches of recent toxicity and regulatory data confirm that ACGIH Ceiling TLV of 25 ppmv remains appropriate for acetaldehyde. Recently established AEGLs for acute exposures could potentially be considered for Tank Farm guidelines, although those values are higher than current OEL, thus acute exposures should be protected using the current OEL. In light of newly established AEGLs, we suggest that the OEL for acetaldehyde be reviewed to ensure that current guidelines are appropriate for acute exposures.

References

American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 10

EPA. NAS/COT Subcommittee for AEGLS. Acetaldehyde Interim Acute Exposure Guideline Levels (AEGLs) 2009.

Sim, V.M., and R.E. Pattle (1957) Effect of Possible Smog Irritants on Human Subjects. Journal of American Medical Association 165 (15):1908-1913.

Cassee, F., Groten, J., Feron, V. (1996b) Changes in the nasal epithelium of rats exposed by inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundamental and Applied Toxicology 29 (no. 2) 208-18

Appelman, L.M, R.A.Woutersen, V.J.Feron (1982) Inhalation Toxicity of Acetaldehyde in Rats (I. Acute and Subacute Studies). Toxicology 23: 293-307.

Parvez S, Venkataraman C, Mukherji S. 2008. Toxicity assessment of organic contaminants: Evaluation of mixture effects in model industrial mixtures using 2n full factorial design. Chemosphere 78: 1049- 1055.

Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29,1910.1000, 1994

3.3.2.2 Butanal (CAS No. 123-72-8)

The proposed HTFOEL for butanal is 25 ppm and is equivalent to the WEEL developed by the AIHA. Literature Search

A literature search focusing on new toxicity data for butanal was conducted on June 29, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on Butanal: CCRIS, CTD, HazMap, HSDB, RTECS, Toxline and PubMed. Butanal was also identified in the PAC, but not AEGL database. A closely related compound (propionaldehyde, CAS No. 123-38-6) was identified in AEGL and PAC databases.

3.15

Toxicity

No new information indicating toxicity at concentrations lower than previously evaluated was identified (see Previous Assessment).

Carcinogenicity

Evidence for the carcinogenicity of butanal is inconclusive. Exposure to acetaldehyde has produced nasal tumors in rats and laryngeal tumors in hamsters, and exposure to malonaldehyde has produced thyroid gland and pancreatic islet cell tumors in rats. NIOSH recommends that acetaldehyde and malonaldehyde be considered potential occupational carcinogens in conformance with the OSHA carcinogen policy. Testing has not been completed to determine the carcinogenicity of butanal, a related low-molecular- weight-aldehyde. The limited studies to date indicate that this substance has chemical reactivity and mutagenicity similar to acetaldehyde and malonaldehyde. Therefore, NIOSH recommends that careful consideration be given to reducing butanal exposures (NIOSH 2005).

Irritation Indications

Butanal is a skin, eye and respiratory tract irritant (HazMap Database).

Odor Threshold

0.005 ppm

Mixture Interactions • Rats responded to mixtures of butanal and heptanal in behavioral studies as if only butanal was present, suggesting butanal may have higher mobility to compete more effectively for occupation of shared receptor sites (Sokolic et al., 2007). • Mixture interactions were not identified for propanal or propionaldehyde (PubMed PubMed; mixture interaction and propanal or propionaldehyde as search terms).

Summary and Recommendations

Recently established PAC values for acute exposures to Butanal indicate higher regulatory values (75 ppm PAC1) than the current HTFOEL (25 ppm) established based on the WEEL assessment in previous documentation. Therefore, re-evaluation of the HTFOEL for Butanal is warranted.

3.16

References

Butyraldehyde: 9-Day Repeated Vapor Inhalation Toxicity, Vapor Inhalation By Dogs and Rats for 12 and 13 Weeks Respectively and a 12-Wk Vapor Inhalation Study in Rats, with Cover Letter Dated 02/06/89. EPA/OTS Doc #86-890000097; U.S. EPA: Washington, DC, 1989.

Sokolic L, Laing DG, McGregor IS. Asymmetric suppression of components in binary aldehyde mixtures: behavioral studies in the laboratory rat. Chem Senses. 32(2):191-9, 2007.

3.3.2.3 Formaldehyde (CAS No. 50-00-0)

The OEL for formaldehyde is 0.3 ppmv based on ACGIH ceiling value.

Literature Search

A literature search focusing on new toxicity or regulatory data for formaldehyde was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on formaldehyde: EPA AEGL, DOW PAC, HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, GENETOX, and CTD.

New regulatory and toxicity data for formaldehyde was discovered. The EPA established interim Acute Exposure Guideline Levels (AEGLs) for formaldehyde. The US DOE has established PAC (Revision 29) for formaldehyde that was adopted as the 1 hr AEGL values. Lang et al. (2008) concluded that the no- observed-effect level for subjective and objective eye irritation due to formaldehyde exposure was 0.5 ppm in case of a constant exposure level and 0.3 ppm with peaks of 0.6 ppm in case of short-term peak exposures in humans with co-exposure to ethyl acetate. ACGIH has maintained a ceiling limit of 0.3 ppmv based on dermal and respiratory sensitization (HSDB, ACGIH 2014). NIOSH has recommended an exposure limit of 0.016 ppmv based on a 10 hr TWA with a 15 min ceiling of 0.1 ppm (HSDB, NIOSH 2010). OSHA has established an 8 hr TWA-PEL of 0.75 ppm and a 15 min STEL of 2 ppm (29 CFR 1910.1048 2014).

AEGLs for formaldehyde (EPA 2008).

Interim AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 0.9 0.9 0.9 0.9 0.9 Bender 1983 AEGL-2 14 14 14 14 14 Sim 1957 AEGL-3 100 70 56 35 35 Nagorny 1979

Toxicity

Irritant, especially eye irritant.

Carcinogenicity

Group B1 Probable Human Carcinogen (HSDB, USEPA 2006, IRIS 2014).

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A2; Suspected human carcinogen (HSDB, ACGIH 2014)

Irritation Indications

Formaldehyde is very irritating to the mucous membranes (HSDB, Tomlin 2005)

Eye irritation is the first sign of sensory irritation in nonacclimatized subjects as the formaldehyde concentration is increased. The threshold for slight eye irritation is near 1.0 ppm. This eye response serves as a warning of exposure and helps to prevent upper respiratory tract irritation, which is seen at higher concentrations (HSDB, Sullivan 1999).

Odor Threshold

Pungent, suffocating odor (HSDB, O’Neil 2013)

The odor threshold concentration /of formaldehyde/ is between 60 and 220 µg/m3 (HSDB, Zenz 1994).

1 ppm (HSDB, Fassalari 1978)

0.5-1.0 ppm (HSDB, Environment Canada 1985)

Mixture Interactions

Indication of competitive agonism between acrolein and formaldehyde in mice (HSDB, Kane 1978).

Exposure to chemical mixtures with other aldehydes may have additive effects.

Summary and Recommendations

Due to new regulatory exposure guidelines, it is suggested that the OEL for formaldehyde be reevaluated. The current OEL is based on ACGIH ceiling value, which remains unchanged. However, NIOSH has recommended an exposure limit lower than the ACGIH value (0.016 vs. 0.03 ppmv, respectively). Additionally, EPA has established AEGLs for acute exposure scenarios (albeit at high concentrations than current OELs) that could be of relevance to tank farm personnel. The NIOSH recommendations highlight the need to reevaluate the OEL for formaldehyde.

References

EPA. NAS/COT Subcommittee for AEGLS. Interim Acute Exposure Guideline Levels (AEGLs) for Formaldehyde 2008.

Lang I et al; Regul Toxicol Pharmacol 50 (1): 23-36 (2008)

American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 32

American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 66

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29 CFR 1910.1048(c) (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of December 3, 2014: http://www.ecfr.gov. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from: http://www.cdc.gov/niosh/npg.

Bender, J.R., L.S. Mullin, G.J. Grapel, and W.E. Wilson. 1983. Eye irritation response of humans to formaldehyde. Am. Ind. Hyg. Assoc. J. 44:463-465.

Sim, V.M. and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. J. Amer. Med. Assoc. 165:1908-1913.

Nagorny, P.A., Zh.A. Sudakova and S.M. Schablenko. 1979. On the general toxic and allergic action of formaldehyde. Gig. Tr. Prof. Zabol. 1:27-30.

USEPA Office of Pesticide Programs, Health Effects Division, Science Information Management Branch: "Chemicals Evaluated for Carcinogenic Potential" (April 2006)

U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on Formaldehyde (50-00-0). Available from, as of December 15, 2014: http://www.epa.gov/iris/

American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 32

Tomlin CDS, ed. Formaldehyde (50-00-0). In: The e-Pesticide Manual, 13th Edition Version 3.2 (2005- 06). Surrey UK, British Crop Protection Council.

Sullivan, J.B., Krieger G.R. (eds). Clinical Environmental Health and Toxic Exposures. Second edition. Lippincott Williams and Wilkins, Philadelphia, Pennsylvania 1999., p. 1009

Kane LE, Alarie Y; Am Ind Hyg Assoc J 39 (4): 270-4 (1978)

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 778

Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p. 1069

Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978., p. 95

Environment Canada; Tech Info for Problem Spills: Formaldehyde p.1 (1985)

3.3.2.4 2-Methyl-2-butenal (CAS No. 1115-11-3)

The OEL for 2-Methyl-2-butenal is 0.03 ppm.

Literature Search

A literature search focusing on new toxicity data for 2-Methyl-2-butenal was conducted on June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 2-Methyl-2-butenal: CCRIS, PubMed, Toxline. No new regulatory information on 2-Methyl-

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2-butenal was discovered. Information on surrogates (acrolein, CAS# 107-02-8; crotonaldehyde, CAS# 4170-30-3) were identified in AEGL and PAC databases.

PAC values for acrolein and crotonaldehyde are the same as AEGLs.

Toxicity

Not available.

Carcinogenicity

Not available.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified for 2-Methyl-2-butenal (PubMed; mixture interaction and 2-Methyl-2-butenal as search terms). However, aldehydes exhibit a common MOA, therefore, mixture interactions with other aldehydes present in tank farm vapors is expected.

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Summary and Recommendations

Recently established AEGL and PAC values for surrogates (acrolein, crotonaldehyde) could potentially be considered for acute 2-Methyl-2-butenal exposures.

References

None.

3.3.2.5 2-Ethylhex-2-enal (CAS No. 645-62-5)

The HTFOELfor 2-ethylhex-2-enal (also known as 2-ethyl-3-propylacrolein) is 0.1 ppmv based on a ceiling value of 0.3 ppmv for crotonaldehyde (2-butenal) (CAS No. 4170-30-3; trans-: 123-73-9; cis-: 15798-64- 8) set by the ACGIH with a 3× uncertainty factor.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2-ethylhex-2-enal was conducted May 23, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-ethylhex-2-enal: HazMap, HSDB, RTECS, CCRIS, PubMed, and Toxline.

No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

A brief literature search for crotonaldehyde was conducted using the EPA AEGL, DOE PAC, and HSDB.

Various regulatory values were discovered for crotonaldehyde. Since both trans- and cis- isomers exist (trans is more abundant), both isomers were searched. All regulatory data was either for the trans- isomer or for crotonaldehyde in general. ACGIH has maintained a 0.3 ppm ceiling as a skin basis (HSDB, ACGIH 2008). ACGIH classifies crotonaldehyde as a confirmed animal carcinogen with unknown relevance to humans (A3) (HSDB, ACGIH 2008). NIOSH recommended exposure limit 10 hr time- weighted average (TWA) is 2 ppm (HSDB, NIOSH 2005). NIOSH has established 50 ppm of crotonaldehyde as immediately dangerous to life or health (HSDB, NIOSH 2005). OSHA recommends an 8 hr TWA-PEL of 2 ppm (HSDB, 29 CFR 1910.1000 2009). EPA established AEGLs for crotonaldehyde (NRC 2008). The US DOE adopted 1 hr AEGL values as PAC (Revision 29) for crotonaldehyde.

AEGLs for crotonaldehyde.

AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 0.19 0.19 0.19 0.19 0.19 Fannick 1982 AEGL-2 27 8.9 4.4 1.1 0.56 Rinehart 1967 AEGL-3 44 27 14 2.6 1.5 Rinehart 1967

Toxicity

Symptoms of overexposure may include vomiting, headache, dizziness, and unconsciousness (HazMap).

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May cause 1st degree burns on short contact and 2nd degree burns on prolonged contact (HazMap).

Carcinogenicity

Negative in in vitro mutagenicity assays (CCRIS)

Irritation Indications

2-Ethylhex-2-enal is very irritating to skin and eyes (HazMap).

Personnel will not usually tolerate irritating vapor at medium to high concentrations (HazMap).

Causes lacrimation (HazMap).

Odor Threshold

Sharp, powerful, irritating odor (HSDB, US Coast Guard 1978).

Mixture Interactions

No available data.

Summary and Recommendations

It is recommended that the HTFOEL for 2-ethylhex-2-enal be reevaluated. New toxicity or regulatory data for 2-ethylhex-2-enal was not found using our standard search strategy. New acute exposure guidelines have been established for the surrogate crotonaldehyde. Level 1 AEGLs are lower for all exposure durations compared to the ceiling value established by ACGIH that is utilized for the HTFOEL (0.19 vs. 3 ppm). Thus, the HTFOEL for 2-ethylhex-2-enal should be reevaluated, and acute exposure guidelines should be established.

References

American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 22

National Research Council (NRC), Acute Exposure Guideline Levels for Selected Airborne Chemicals (AEGLs), 2008, Vol 6

U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978.

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3.3.2.6 2-Propenal (CAS No. 107-02-8)

Previously, 2-propenal (also known as acrolein) was not recognized as a COPC. Thus, HTFOEL or OEL has not been determined.

Literature Search

A literature search focusing on toxicity or regulatory data for 2-propenal was conducted August 19, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-propenal: EPA AEGL, DOE PAC, HazMap, HSDB, IRIS, ITER, CCRIS, RTECS, Genetox, CTD, and CPDB.

2-Propenal is a well-studied compound in which several occupation exposure regulatory values have been established. OSHA has established an 8 hr TWA-PEL of 0.1 ppm for 2-propenal (HSDB, 29 CFR 1910.1000 2008). ACGIH has recommended a 0.1 ppm ceiling limit based on skin (HSDB, ACGIH 2008). NIOSH suggests a 10 hr TWA-REL of 0.1 ppm and a 15 min short-term exposure REL of 0.3 ppm (HSDB, NIOSH 2005). NIOSH also suggests that 2 ppm is immediately dangerous to life (HSDB, NIOSH 2005). EPA established AEGLs for 2-propenal. The US DOE has adapted 1 hr AEGLs for PAC (Revision 29) for 2-propenal. IRIS set an oral reference dose (5×10-4 mg/kg/day) and reference inhalation concentration (2×10-5 mg/m3) for 2-propenal (IRIS).

AEGLs for 2-propenal (NRC 2010). AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 0.03 0.03 0.03 0.03 0.03 Weber-Tschop 1977 AEGL-2 0.44 0.18 0.1 0.1 0.1 Weber-Tschop 1977 AEGL-3 6.2 2.5 1.4 0.48 0.27 Ballantyne 1989

Toxicity

May cause pulmonary edema, skin burns, and severe burns to the eyes (HazMap).

Carcinogenicity

Classified as C, possible carcinogen (HSDB, IRIS 2000).

Inadequate evidence in humans for the carcinogenicity of acrolein (HSDB, IARC 1995).

A4: Not classifiable as a human carcinogen (HSDB, ACGIH 2010).

Group C Possible Human Carcinogen (HSDB, USEPA 2006).

Irritation Indications

Highly irritating to mucous membranes, especially upper respiratory tract and eyes (HSDB).

2-Propenal irritates skin, mucous membranes. Vapors cause lacrimation. Weak sensitizer. Inhalation may cause asthmatic reaction (HSDB, Budavari 1989).

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Odor Threshold

Odor threshold is <0.1 ppm (Beauchamp 1985).

0.02-1.8 ppm (HazMap)

Piercing, disagreeable odor (HazMap)

Mixture Interactions

Sensory irritation in rats exposed to mixtures of irritant aldehydes, including acrolein, is more pronounced than that caused by each of the aldehydes separately (Cassee 1996).

Summary and Recommendations

Ample regulatory guidelines are available to establish an OEL for 2-propenal. OSHA, NIOSH, and ACGIH all recommend 0.1 ppm as work-day length TWAs or ceiling values for 2-propenal. AEGL values are more conservative suggesting 0.03 ppm for all exposure durations for an AEGL-1. Although 10-fold higher than AEGL-1 values, additional acute exposure guidance is available from NIOSH as a 15 min short-term exposure REL (0.3 ppm). Both acute and chronic guidelines are available to support OEL establishment for 2-propenal.

References 29 CFR 1910.1000 (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of October 15, 2008: http://www.gpoaccess.gov/ecfr American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 10. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005). National Research Council (NRC) 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Committee on Acute Exposure Guideline Levels. Vol 8. Weber-Tschopp, A., T. Fischer, R. Gierer, and E. Grandjean. 1977. Experimentally induced irritating effects of acrolein on men [in German]. Int. Arch. Occup. Environ. Health 40(2):117-130. Ballantyne, B., D.E. Dodd, I.M. Pritts, D.J. Nachreiner, and E.H. Fowler. 1989. Acute vapour inhalation toxicity of acrolein and its influence as a trace contaminant in 2- methoxy-3,4-dihydro-2H-pyran. Hum. Toxicol. 8(3):229-235. U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on Acrolein (107-02-8). Available from, as of March 15, 2000: http://www.epa.gov/iris/ IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. 63 361 (1995). American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH 2010, p. 10. USEPA Office of Pesticide Programs, Health Effects Division, Science Information Management Branch: "Chemicals Evaluated for Carcinogenic Potential" (April 26, 2006).

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Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989, p. 20 Beauchamp, R.O., D.A. Andjelkovich, A.D. Klingerman, K.T. Morgan, and H.D. Heck. 1985. A critical review of the literature on acrolein toxicity. Crit. Rev. Toxicol. 14(4):309-380. Cassee FR, Arts JHE, Groten JP, Feron VJ. 1996. Sensory irritation to mixtures of formaldehyde, acrolein, and acetaldehyde in rats. Archives of Toxicology 70:6, 329-337.

3.4 Ketones

3.4.1 Previous Assessment

3.4.1.1 4-Methyl-2-hexanone (CAS# 105-42-0)

A HTFOEL is proposed for 4-methyl-2-hexanone based on a comprehensive review of the available toxicology and guideline literature. 4-Methyl-2-hexanone is an aliphatic branched (7-carbon) ketone that is structurally similar to 2-hexanone. Aliphatic ketones are generally volatile organic compounds that can be irritating to the skin, eyes, and upper respiratory tract. Although there are no ACGIH or OSHA guidelines for 4-methyl-2-hexanone, the ACGIH has set TLV-TWA exposure concentrations for 2- hexanone which has extensive animal toxicity and human data available. 2-Hexanone is a known animal and human neurotoxicant in which the mechanism of neurotoxicity has been well studied. The TLV-TWA for 2-hexanone was set at 5 ppm (20 mg/m3) to minimize the potential for distal peripheral neurotoxicity, primarily nerve fiber conduction, with weakness in the hands and feet and loss of coordination. Based on the uncertainty associated with chemical and toxicological differences between 4-methyl-2-hexanone and 2-hexanone, a HTFOEL of 0.5 ppm is proposed for 4-methyl-2-hexanone.

Methodology

To identify and access available toxicity data on 4-methyl-2-hexanone, a number of Internet data bases, including PUBMED, TOXNET, and TOMES, were searched and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was likewise reviewed for 4-methyl-2-hexanone and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for 4-methyl-2-hexanone has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogate 2-hexanone. The ACGIH documentation indicates that a TLV-TWA of 5 ppm was reasonable based on the decrements in rodent and nonhuman primate sciatic- tibial nerve conduction following 9 months of inhalation exposure to 2-hexanone at concentrations equivalent to an 8-hour TWA of 75 ppm (Johnson et al. 1978). The ACGIH indicated that the TLV-TWA of 5 ppm is anticipated to include an adequate margin of safety to minimize the potential for adverse neurotoxicity.

Toxicology Summary and Data Analysis

The toxicity data base for the surrogate 2-hexanone was utilized for the assessment because no substantial information was available on 4-methyl-2-hexanone. In the case of 2-hexanone, there is very robust toxicity information particularly as it relates to neurotoxicity. Subchronic inhalation exposure to 2-

3.25

hexanone at concentrations ranging from 200 ppm to 1600 ppm is associated with the observance of peripheral neuropathy in chickens, rats, cats, and monkeys (Abou-Donia et al. 1985; Mendell et al. 1974; Spencer et al. 1975; Duckett et al. 1974). Johnson et al. (1979) reported that rats and monkeys that inhaled 100 ppm of 2-hexanone for 9 months developed abnormal neurophysiologic indicators, and this exposure was equivalent to a daily 8-hour TWA of 75 ppm. In addition to the observed neurotoxicity, rats that inhaled 700 ppm 2-hexanone for 11 weeks developed testicular atrophy (Katz et al. 1980); however, observed testicular toxicity occurs at doses that are greater than those leading to axonopathy. Extensive pharmacokinetic and metabolism investigations have identified the ultimate neurotoxic metabolite as 2,5- hexanedione, which is a metabolite of both 2-hexanone and hexane. Anthony et al. (1983) evaluated the neurotoxicity of the 3,4-dimethyl-2,5-hexanedione, and it was reported as 20-30 times more potent on a molar basis than 2,5-hexanedione. It was noted that alkyl substitution causes branched-chain compounds to cyclize more rapidly than unbranched analogs, implicating pyrrole formation in the pathogenesis of the axonopathy. Although no data were available on 4-methyl-2-hexanone, it is feasible that the alkyl substitution could likewise enhance pyrrole formation.

The ACGIH documentation provides numerous examples of occupational exposure to 2-hexanone that have led to peripheral neuropathy, and the ACGIH has established a Biological Exposure Index of 0.4 mg/L for 2,5-hexanedione in urine taken at the end of a work shift (ACGIH 2003).

Summary and Recommendations

The ACGIH has set the TLV-TWA for 2-hexanone at 5 ppm (20 mg/m3) to minimize the potential for neurotoxic effects. Based on uncertainty associated with chemical and toxicological differences between 2-hexanone and 4-methyl-2-hexanone, an additional 10-fold factor is applied to the 2-hexanone OEL to establish a HTFOEL of 0.5 ppm for 4-methyl-2-hexanone.

3.4.1.2 3-Hexanone (CAS# 589-38-8)

A HTFOEL is proposed for 3-hexanone based on a comprehensive review of the available toxicology and guideline literature. 3-Hexanone is an aliphatic (6-carbon) ketone. Aliphatic ketones are generally volatile organic compounds that can be irritating to the skin, eyes, and the upper respiratory tract. Although there are no ACGIH or OSHA guidelines for 3-hexanone, the ACGIH has set TLV-TWA exposure concentrations for 2-pentanone and 3-pentanone (ACGIH 2001h; 2001r) with 2-pentanone having the more robust data set. The TLV-TWA for the pentanones was set at 200 ppm (705 mg/m3) to minimize the potential objectionable narcotic effects and significant irritation. Based on the uncertainty associated with chemical differences between 3-hexanone and 2- or 3-pentanone, a HTFOEL of 67 ppm is proposed for 3- hexanone.

Methodology

To identify and access available toxicity data on 3-hexanone, a number of Internet data bases, including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. ACGIH documentation was likewise reviewed for 3-hexanone and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for 3-hexanone has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV- TWA for the structural surrogates 2- and 3-pentanone. The ACGIH documentation indicates that occupational exposure to 1500 ppm 2-pentanone has been associated with complaints of ocular and

3.26

mucous membrane irritation in humans, and high-dose exposure to 2-pentanone was associated with narcosis in animals. Therefore, a 200 ppm TLV-TWA was recommended by ACGIH and is believed to be low enough to protect from narcotic and irritation effects.

Toxicology Summary and Data Analysis

The lowest published lethal concentration for 3-hexanone was reported as a 4-hour inhalation exposure to 4000 ppm in rats. No other relevant information was obtained for 3-hexanone. However, for the surrogate 2-pentanone, occupational exposure to 1500 ppm was associated with a strong odor and ocular and upper respiratory tract irritation in humans. Inhalation exposure of guinea pigs to 5000 ppm for 8 hours resulted in narcosis, but obvious ocular and upper respiratory tract irritation was likewise noted. The 4-hour LC50 in rats was >2000 ppm.

Summary and Recommendations

The ACGIH has set the TLV-TWA for the pentanones at 200 ppm (705 mg/m3) to minimize the potential objectionable narcotic effects and significant irritation. Based on the uncertainty associated with chemical differences between 3-hexanone and 2- or 3-pentanone, an additional 3-fold factor is applied to the pentanone OEL to establish a HTFOEL of 67 ppm for 3-hexanone.

3.4.1.3 6-Methyl-2-heptanone (CAS# 928-68-7)

A HTFOEL is proposed for 6-methyl-2-heptanone based on a comprehensive review of the available toxicology and guideline literature. 6-methyl-2-heptanone is an aliphatic branched (8-carbon) ketone. Aliphatic ketones are generally volatile organic compounds that can be irritating to the skin, eyes, and the upper respiratory tract. Although there are no ACGIH or OSHA guidelines for 6-methyl-2-heptanone, the ACGIH has set TLV-TWA exposure concentrations for 5-methyl-3-heptanone and 2-heptanone (ACGIH 2001i; 2001q) with 5-methyl-3-heptanone having available human data. The TLV-TWA for 5-methyl-3- heptanone was set at 25 ppm (131 mg/m3) as a comfort level in unconditioned workers. Based on the uncertainty associated with chemical differences between 6-methyl-2-heptanone, 5-methyl-3-heptanone, and 2-heptanone a HTFOEL of 8 ppm is proposed for 6-methyl-2-heptanone.

Methodology

To identify and access available toxicity data on 3-hexanone, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. ACGIH documentation was likewise reviewed for 6-methyl-2-heptanone and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for 6-methyl-2-heptanone has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogates 5-methyl-3-heptanone and 2-heptanone. The ACGIH documentation indicates that humans are sensitive to 5-methyl-3-heptanone vapor exposures at concentrations of >25 ppm, which results in both eye and respiratory irritation. Therefore, a 25 ppm TLV- TWA was recommended by ACGIH as a comfort level for unconditioned workers. Data for 2-heptanone was limited to animal studies, and a TLV-TWA of 50 ppm was recommended to minimize the potential for irritant effects.

3.27

Toxicology Summary and Data Analysis

The ACGIH documentation indicates that unconditioned human occupational exposure to 50 ppm 5- methyl-3-heptanone was the threshold for eye and nose irritation in 50% of the exposed subjects, while 6 ppm was an odor threshold. A 100-ppm exposure was reported to be irritating to the mucous membranes and produced headache and nausea that was too intense to tolerate for more than a few minutes. In rats and mice, 4-hour exposure to a saturated atmosphere (3000 ppm) rapidly resulted in signs of eye and respiratory system irritation. Oral LD50s ranged from 2.5- to 3.8 g/kg in rats, mice, and guinea pigs. There were no reported human data with 2-heptanone, although NIOSH reported that ~67,000 workers are potentially exposed. Exposure to 1500 ppm 2-heptanone produced irritation, while 2000 ppm was strongly narcotic, and 4800 ppm caused narcosis and death in 4-8 hours in rats. The oral LD50 is ~1.7g/kg in rats. A subchronic study conducted in both rats and monkeys found no clinical evidence of toxicity or neurological impairment following a 9-month exposure to either 131 or 1025 ppm 2-heptanone (Johnson et al. 1978). The TLV-TWA of 50 ppm was recommended by ACGIH to minimize any potential for irritant effects.

Summary and Recommendations

The ACGIH has set the TLV-TWA for 5-methyl-3-heptanone and 2-heptanone at 25 ppm (131 mg/m3) and 50 ppm (233 mg/m3), respectively, to minimize the potential irritation effects. The results observed in humans with 5-methyl-3-heptanone are the most relevant and will be the primary surrogate for establishing a HTFOEL for 5-methyl-2-heptanone. Based on minimal uncertainty associated with chemical differences between 5-methyl-3-heptanone and 6-methyl-2-heptanone, an additional 3-fold factor is applied to the 5-methyl-3-heptanone OEL to establish a HTFOEL of 8 ppm for 6-methyl-2-heptanone.

3.4.1.4 2-Nonanone (CAS# 821-55-6), 3-Dodecanone (CAS#1534-27-6), 2-Tridecanone (CAS#593-08-8), 3-Tridecanone (CAS#1534-26-5)

A HTFOEL is proposed for 2-nonanone, 3-dodecanone, 2-tridecanone, and 3-tridecanone based on a comprehensive review of the available toxicology and guideline literature. These long-chained aliphatic ketones range from 9-carbon to 13-carbon in length with the ketone present on either the 2nd or 3rd carbon. Aliphatic ketones can be irritating to the skin, eyes and the upper respiratory tract. Although there are no ACGIH or OSHA guidelines for these long chained aliphatic ketones, the ACGIH has set TLV-TWA exposure concentrations for the structural isomers of heptanone (2-heptanone, 3-heptanone and 4- 3 heptanone [molecular formula: C7H14O]) at 50 ppm (233 mg/m ) to minimize the potential for eye and skin irritation (ACGIH 2001i; 2001b; 2001q). Based on the uncertainty associated with chemical differences between 2-nonanone, 3-dodecanone, 2-tridecanone, and 3-tridecanone, and the isomers of heptanone, a HTFOEL of 17 ppm is proposed for these long (C-9 to C-13) chained aliphatic ketones.

Methodology

To identify and access available toxicity data on 2-nonanone, 3-dodecanone, 2-tridecanone, and 3- tridecanone a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for 2-heptanone, 3-heptanone, 4-heptanone, and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profiles and develop the HTFOEL.

3.28

Available Guidelines

No OELs for 2-nonanone, 3-dodecanone, 2-tridecanone, and 3-tridecanone have been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogate isomers 2-heptanone, 3-heptanone, and 4-heptanone. The ACGIH documentation recommends a 50-ppm TLV-TWA to minimize the potential for ocular, dermal, and mucus membrane irritation.

Toxicology Summary and Data Analysis

These higher molecular weight ketones generally have low volatility; therefore, toxicity information is more available from oral and dermal exposures. Acute oral LD50 s are high (greater than 5 g/kg), indicating low toxicity. For 2- nonanone, the LD50 is greater than 5 and 7 g/kg in rats and mice, respectively (Tanii 1986). The ACGIH documentation for 2-heptanone, 3-heptanone, and 4-heptanone ketone isomers was based upon the similar toxicological response. Exposure to 1500 ppm 2-heptanone produced irritation, while 2000 ppm was strongly narcotic, and 4800 ppm caused narcosis and death in 4- 8 hours in rats. The oral LD50 in rats is ~1.7g/kg (ACGIH 2001i). A report suggested that irritation potency might increase with increasing ketone carbon chain length (Specht et al. 1940). A subchronic study conducted in both rats and monkeys found no clinical evidence of toxicity or neurological impairment following a 9-month exposure to either 131 or 1025 ppm 2-heptanone (Johnson et al. 1978). Likewise, limited inhalation toxicity studies (4-hour acute exposure) with 3-heptanone resulted in no fatalities at 2000 ppm, but all animals died at 4000 ppm (Smyth et al. 1949). Rats exposed to 700 ppm for 24-weeks exhibited no signs of neurotoxic effects (Katz et al. 1980), even though the neurotoxic 2,5- heptanedione metabolite was detected. Katz et al (1980) concluded that even though the neurotoxic metabolite was detectable, the systemic concentration achieved was insufficient to elicit a neurotoxic response. Limited toxicity studies have also been conducted with the 4-heptanone isomer. Following a 6- hour inhalation exposure, the LC50 for 4-heptanone was 2690 ppm, with narcosis occurring at 1600 ppm, and three out of four rats killed at 3200 ppm (Krasavage et al. 1982). A 6-hours/day exposure to 1200 ppm of 4-heptanone resulted in a slightly decreased response to stimulation during exposure, and marginal liver enlargement but no changes in clinical chemistry or pathology (Krasavage et al. 1982). Hence, for these structurally related heptanone compounds, the ACGIH recommended a TLV-TWA of 50 ppm primarily to minimize any potential for irritant effects.

Summary and Recommendations

The ACGIH has set the TLV-TWA for 2-heptanone, 3-heptanone, and 4-heptanone ketone isomers at 50 ppm (233 mg/m3). Based on the uncertainty associated with chemical differences between 2-nonanone, 3- dodecanone, 2-tridecanone, 3-tridecanone, and the isomers of heptanone, an additional 3-fold factor is applied to the OEL to establish a HTFOEL of 17 ppm for these long (C-9 to C-13) chained aliphatic ketones.

3.4.1.5 5-Methyl-2-(1-methyethenyl)cyclohexanone (CAS# 89-82-7)

A HTFOEL is proposed for 5-methyl-2-(1-methyethenyl) cyclohexanone, which is also known as Pulegone, based on a comprehensive review of the available toxicology and guideline literature. This methyl and isopropyl substituted cyclohexanone is structurally similar to cyclohexanone. Although there are no ACGIH or OSHA guidelines for pulegone, the ACGIH has set TLV-TWA exposure concentrations for cyclohexanone at 25 ppm (100 mg/m3) to minimize the potential for eye, skin, and throat irritation (ACGIH 2001j). Based on the uncertainty associated with chemical differences between cyclohexanone and 5-methyl-2-(1-methyethenyl) cyclohexdanone, a HTFOEL of 2.5 ppm is proposed.

3.29

Methodology

To identify and access available toxicity data on 5-methyl-2-(1-methyethenyl) cyclohexanone, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for 5-methyl-2-(1-methyethenyl) cyclohexanone and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profiles and develop the HTFOEL.

Available Guidelines

No OELs for 5-methyl-2-(1-methyethenyl) cyclohexanone have been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogate cyclohexanone at 25 ppm to minimize the potential for eye, nose, and throat irritation.

Toxicology Summary and Data Analysis

5-Methyl-2-(1-methyethenyl) cyclohexanone, commonly known as pulegone, is a major component of oil of pennyroyal, which has been used for flavoring foods and drinks. Pennyroyal oil has also been used as a fragrance agent and as an herbal medicine. Tice (1998) prepared a detailed review of the toxicology literature on pulegone and one of its metabolites, menthofuran, in support of pulegone and its metabolite being nominated by the NTP for additional chronic testing. The rational for further testing was based on the potential for human exposure and the absence of any carcinogenicity data. Human exposure to pulegone is primarily through ingestion of food products, and human acute toxicity has been associated with the ingestion of high doses of pennyroyal oil. There are no available animal inhalation studies with pulegone; however, the LD50 values for subcutaneous or intraperitoneal routes ranged from 150 – 1700 mg/kg in mice and rats. In a 28-day oral gavage study in rats, pulegone was administered at doses of 0 20, 60 and 160 mg/kg/day. The NOEL for pulegone was 20 mg/kg/day (Thorup et al. 1983). In experimental animals, pulegone is metabolically transformed (CYP450 involvement) to methofuran and other metabolites. The primary toxic response at high doses is associated with hepatic effects. There are currently no published data found on chronic exposure, teratogenicity, embryotoxicity, or carcinogenicity of pulegone.

Cyclohexanone (CAS 108-94-1) is a structural surrogate for pulegone, and ACGIH (2001j) has established a TLV-TWA of 25 ppm (100 mg/m3) for occupational exposure, which is intended to minimize the potential for eye, nose, and throat irritation. The acute toxicity of cyclohexanone is low; the intraperitoneal and subcutaneous LD 50 values ranged from 1130 – 1535 mg/kg (Smyth et al. 1969; Gupta et al. 1979; Deichman and LeBlanc 1943). A 6-hour exposure to 4000 ppm in guinea pigs resulted in narcosis, hypothermia, and decreased respiration (Specht et al. 1940). Rabbits were exposed to 190 to 1414 ppm cyclohexanone for 6 hours/day for 50 days. The 190-ppm exposure showed only minor degenerative changes in liver and kidney (Treon et al. 1943). A 2-year carcinogenicity study was conducted in both rats and mice, and the neoplasms in the treated groups did not differ significantly from controls (Lijinsky and Kovatch 1986). The major metabolite of cyclohexanone is a reduction to cyclohexanol and subsequent conjugation with glucuronic acid. In humans, exposure to 25 ppm cyclohexanone was not uncomfortable for most subjects; 50 ppm was irritating to the throat, while exposure to 75 ppm for 3-5 minutes resulted in more pronounced irritation of the eyes, nose, and throat (Nelson et al. 1943).

3.30

Summary and Recommendations

The ACGIH has set the TLV-TWA for cyclohexanone at 25 ppm (100 mg/m3). Based on the uncertainty associated with chemical, metabolic, and toxicological differences between cyclohexanone and 5-methyl- 2-(1-methyethenyl) cyclohexanone, an additional 10-fold factor is applied to the cyclohexanone OEL to establish a HTFOEL of 2.5 ppm for 5-methyl-2-(1-methyethenyl) cyclohexanone.

3.4.1.6 4,7,7-Trimethyl-bicyclo[4.1.0]heptan-3-one (CAS# 4176-04-9)

A HTFOEL is proposed for 4,7,7-trimethyl-bicyclo[4.1.0]heptane-3-one, which is also known as caranone, based on a comprehensive review of the available toxicology and guideline literature. This cyclo ketone is structurally similar to camphor (1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one). Although there are no ACGIH or OSHA guidelines for caranone, the ACGIH has set TLV-TWA exposure concentrations for the structurally similar camphor at 2 ppm (12 mg/m3) to minimize the potential for eye and nose irritation and loss of sense of smell (ACGIH 2001b). Based on the uncertainty associated with chemical differences between camphor and caranone, a HTFOEL of 0.7 ppm is proposed.

Methodology

To identify and access available toxicity data on 4,7,7-trimethyl-bicyclo[4.1.0]heptane-3-one (caranone), a number of Internet data bases, including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for camphor (1,7,7-tricmethyl-bicyclo[2.2.1]heptan-2-one), which is a relevant surrogate chemical. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profiles and develop the HTFOEL.

Available Guidelines

No OELs for 4,7,7-trimethyl-bicyclo[4.1.0]heptane-3-one have been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogate camphor (1,7,7-tricmethyl- bicyclo[2.2.1]heptan-2-one) at 2 ppm to minimize the potential for eye and nose irritation and loss of sense of smell.

Toxicology Summary and Data Analysis

4,7,7-Trimethyl-bicyclo[4.1.0]heptane-3-one is commonly known as caranone. There are no available animal inhalation studies with caraonone. Camphor (CAS 76-22-2) is a structural surrogate for caranone, and ACGIH (2001b) has established a TLV-TWA of 2 ppm (12 mg/m3) for occupational exposure, which is intended to minimize the potential for eye and nose irritation and loss of sense of smell. The acute inhalation toxicity of camphor was evaluated; the LC50 in mice was reported as 75 ppm, and the TCLO in mice was 18 ppm for a repeated (7-week) exposure. No tumorigenic response was reported in mice following subcutaneous or topical treatment with camphor. In humans, exposure at or below 2 ppm over a 5-day work week showed that irritation to the eyes and nose and loss of sense of smell did not occur (Gronka et al. 1969). In addition, physical examination of exposed workers failed to reveal any significant findings apart from nose and throat inflammation, with the longest exposures lasting ~10 months. High- level exposures (concentration not specified) are reported to cause nausea, anxiety, dizziness, confusion, headache, and twitching of facial muscles (Gronka et al. 1969; Proctor et al. 1988; Gosselin et al. 1984; Arnow 1976).

3.31

Summary and Recommendations

The ACGIH has set the TLV-TWA for camphor at 2 ppm (12 mg/m3). Based on the uncertainty associated with chemical and toxicological differences between caranone and camphor, an additional 3- fold factor is applied to the camphor OEL to establish a HTFOEL of 0.7 ppm for 4,7,7-trimethyl- bicyclo[4.1.0]heptane-3-one.

3.4.1.7 3-Methyl-3-buten-2-one (CAS# 814-78-8)

A HTFOEL is proposed for 3-methyl-3-buten-2-one, based on a comprehensive review of the available toxicology and guideline literature. This ketone is structurally similar to 3-butene-2-one. Although there are no ACGIH or OSHA guidelines for 3-methyl-3-buten-2-one, the ACGIH has set TLV-Ceiling exposure concentrations for 3-butene-2-one at 0.2 ppm (0.6 mg/m3) to minimize the potential for irritation of the skin, eyes and respiratory tract and the risk of dermal sensitization or allergic type reaction (ACGIH 2001s). Based on the uncertainty associated with chemical and toxicological differences between 3-buten-2-one and 3-methyl-3-buten-2-one a HTFOEL of 0.02 ppm is proposed.

Methodology

To identify and access available toxicity data on 3-methyl-3-buten-2-one, a number of Internet data bases, including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for 3-buten-2-one, which is a relevant surrogate chemical. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profiles and develop the HTFOEL.

Available Guidelines

No OELs for 3-methyl-3-buten-2-one have been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-ceiling for the structural surrogate 3-buten-2-one at 0.2 ppm to minimize the potential for irritation of the skin, eyes, and respiratory tract and the risk of dermal sensitization or allergic reaction. The German MAK commission has reported 3-methyl-3-buten-2-one as a skin sensitizing substance based on animal tests (MAK 2000).

Toxicology Summary and Data Analysis

For 3-methyl-3-buten-2-one, the lowest published lethal concentration in rats and guinea pigs ranged from 125 – 250 ppm for 4 hours. A 30 ppm, 7 hours/day exposure to rats, guinea pigs, and rabbits for a total of 20 exposures in 28 days resulted in ocular and nasal irritation in all species, death and weight loss in rats, and decreased growth in guinea pigs. In addition, 100 7 hours/day exposures of 15 ppm over 140 days resulted in ocular and nasal irritation in all animals (Clayton and Clayton 1982). In humans, 3-methyl-3- buten-2-one is reported to produce skin irritation upon contact. Vapors have also been reported to be highly irritating to the respiratory tract (Clayton and Clayton 1982).

The surrogate 3-buten-2-one has an odor threshold of ~0.2 ppm, which corresponds to the current ACGIH TLV-ceiling. The 4-hour LC50 values for 3-buten-2-one ranged from 2.4 to 2.8 ppm in rats and mice, and a 50% respiratory depression of 5.3 ppm was reported for mice (Schaper 1993). These acute results with 3-buten-2-one suggest that this surrogate may be acutely more toxic than 3-methyl-3-buten-2-one. In humans, 3-buten-2-one is a severe skin, eye, and respiratory tract irritant.

3.32

Summary and Recommendations

The ACGIH has set the TLV-ceiling for 3-buten-2-one at 0.2 ppm (0.6 mg/m3). Based on the uncertainty associated with chemical and toxicological differences between 3-methyl-3-buten-2-one and 3-buten-2- one, an additional 3-fold factor is applied; in addition, a 3-fold factor is applied for extrapolation from the TLV-ceiling to a TWA. Hence, a net 9-fold factor is applied to the 3-buten-2-one OEL to establish a HTFOEL of 0.02 ppm for 3-methyl-3-buten-2-one.

3.4.2 Current Summaries

3.4.2.1 4-Methyl-2-hexanone (CAS No. 105-42-0)

The HTFOEL for 4-methyl-2-hexanone is 0.5 ppmv based on a Threshold Limit Value (TLV) of 5 ppmv for 2-hexanone (CAS No. 591-78-6) with a 10× uncertainty factor.

Literature Search

A literature search focusing on new toxicity data for 4-methyl-2-hexanone was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 4-methyl-2-hexanone: HazMap, PubMed, and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

A brief literature search for 2-hexanone (CAS No. 591-78-6) was conducted using the HSDB. ACGIH has maintained a 5 ppm TLV for 8 hr TWA and 15 min STEL of 10 ppm for skin (HSDB, ACGIH, 2008). NIOSH recommended exposure limit 10 hr TWA is 1 ppm (HSDB, NIOSH 2005).

Toxicity

4-Methyl-2-hexanone is known to cause CNS Solvent Syndrome (HazMap Database).

Carcinogenicity

No available data.

Irritation Indications

4-Methyl-2-hexanone is an eye and skin irritant (HazMap Database).

Odor Threshold

No available data.

Mixture Interactions

No available data.

Summary and Recommendations

3.33

Due to NIOSH recommending a different OEL than ACGIH for the surrogate 2-hexanone, the HTFOELfor 4-methyl-2-hexanone should be reevaluated to determine if it is adequate.

References

3.4.2.2 2-Hexanone (CAS No. 591-78-6)

The OEL for 2-Hexanone is 5 ppm based on an ACGIH Threshold Limit Value (TLV).

Literature Search

A literature search focusing on new toxicity data for 2-Hexanone was conducted on June 21, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases all of which contained active records on 2-Hexanone. ACGIH has maintained a 5 ppm TLV-TWA and 15 min STEL of 10 ppm for skin (HSDB, ACGIH, 2008). NIOSH recommended exposure limit 10 hr TWA is 1 ppm (HSDB, NIOSH 2005). 2-Hexanone was identified in the PAC database.

Toxicity

2-Hexanone is known to cause peripheral neuropathy due to the toxic intermediary metabolite, gamma- diketone 2,5-hexanedione. (HazMap Database).

Carcinogenicity

Not available.

Irritation Indications

2-Hexanone is an eye irritant (1000 ppm) (HazMap Database and CDC).

Odor Threshold

0.06 ppm (HazMap database)

3.34

Mixture Interactions • Clinical tests demonstrated a threshold for a structurally similar compound (Methyl Isobutyl Ketone)-induced irritation of the lungs at 0.03 to 0.1 mg/L after 1 min of respiration. PMID: 15162837 (mg/L = ppm) • MEK (2-butanone) when combined with MBK (2-hexanone) markedly enhanced MBK neurotoxicity. AM IND HYG ASSOC J; 37 (2). 1976 95-102

2-Hexanone methyl isobutyl ketone

Summary and Recommendations

Due to NIOSH recommending a different OEL than ACGIH for 2-hexanone, it should be revaluated to determine if current OEL is adequate.

References American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 39 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005).

3.4.2.3 6-Methyl-2-heptanone (CAS No. 928-68-7)

The ACGIH has set the TLV-TWA for 5-methyl-3-heptanone and 2-heptanone at 25 ppm (131 mg/m3) and 50 ppm (233 mg/m3), respectively, to minimize the potential irritation effects. The results observed in humans with 5-methyl-3-heptanone (CAS # 541-85-5) are the most relevant and will be the primary surrogate for establishing a HTFOEL for 6-methyl-2-heptanone. Based on minimal uncertainty associated with chemical differences between 5-methyl-3-heptanone and 6-methyl-2-heptanone, an additional 3-fold factor was applied to the 5-methyl-3-heptanone OEL to establish a HTFOEL of 8 ppm for 6-methyl-2- heptanone.

Literature Search

A literature search focusing on new toxicity data for 6-Methyl-2-heptanone was conducted on June 29, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 6-Methyl-2-heptanone: HazMap, Toxline, PubMed. Information on 6-methyl-2-heptanone and the surrogate 5-methyl-3-heptanone was identified in the PAC database.

3.35

Surrogate • CDC website lists a 10 ppm TLV for the surrogate 5-methyl-3-heptanone (ACGIH 2008) which is lower than previous guidelines for 5-methyl-3-heptanone (25 ppm) used to establish a HTFOEL for 6- methyl-2-heptanone (http://www.cdc.gov/niosh/npg/npgd0418.html). • CDC website lists 100 ppm (NIOSH REL, OSHA PEL) for 2-Heptanone (https://www.cdc.gov/niosh/npg/npgd0399.html).

Toxicity

Not available.

Carcinogenicity

Not available.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified for 6-Methyl-2-heptanone (PubMed; mixture interaction and 6-Methyl-2-heptanone, 5- methyl-3-heptanone or 2-Heptanone as search terms).

3.36

Summary and Recommendations

Recently established PAC values for 6-Methyl-2-heptanone were identified that were not available in the previous review. A surrogate (5-methyl-3-heptanone) used in the original evaluation has shown a change in TLV from 25 ppm to 10 ppm. This new information suggests that re-evaluaton of the HTFOEL for acute 6-Methyl-2-heptanone exposures is warranted.

References

None.

3.4.2.4 3-methyl-3-butene-2-one (CAS No. 814-78-8)

A HTFOEL is proposed for 3-methyl-3-buten-2-one, based on a comprehensive review of the available toxicology and guideline literature. This ketone is structurally similar to 3-butene-2-one (CAS# 78-94-4). Although there are no ACGIH or OSHA guidelines for 3-methyl-3-buten-2-one, the ACGIH has set TLV- Ceiling) exposure concentrations for 3-butene-2-one at 0.2 ppm (0.6 mg/m3) to minimize the potential for irritation of the skin, eyes and respiratory tract and the risk of dermal sensitization or allergic type reaction. Based on the uncertainty associated with chemical and toxicological differences between 3- buten-2-one and 3-methyl-3-buten-2-one a HTFOEL of 0.02 ppm was proposed..

Literature Search

A literature search focusing on new toxicity data for 3-methyl-3-butene-2-one was conducted on June 29, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 3-methyl-3-butene-2-one: CCRIS, HazMap, HSDB, RTECS and Toxline databases. Information on the surrogate 3-butene-2-one (synonym, methyl vinyl ketone) (CAS# 78-94-4) was identified in AEGL and PAC databases.

PAC values for methyl vinyl ketone are the same as AEGLs.

Toxicity

3-methyl-3-buten-2-one has been identified as highly toxic by inhalation, skin absorption, and ingestion; A skin, eye, and respiratory tract irritant; Strong lacrymator (HazMap Database).

3.37

Carcinogenicity

Not available.

Irritation Indications

skin, eye, and respiratory tract irritant (HazMap Database).

Odor Threshold

Not available.

Mixture Interactions

None identified for 3-methyl-3-buten-2-one (PubMed; mixture interaction and 3-methyl-3-buten-2-one or 3-butene-2-one as search terms).

Summary and Recommendations

Recently established AEGL and PAC values for 3-butene-2-one (0.17 ppm) are slightly lower than the previous HTFOEL (0.2 ppm), suggesting that the HTFOEL for 3-methyl-3-buten-2-one be re-evaluated. This interpretation is based solely on a change in AEGL or PAC values relative to the previously established HTFOEL and it is feasible that this marginal change could also be sufficient to move re-evaluation efforts to a lower priority status.

References

None

3.4.2.5 3-Buten-2-one (CAS No. 78-94-4)

The OEL for 3-buten-2-one (also known as methyl vinyl ketone) is 0.2 ppmv adapted from ACGIH ceiling limit.

Literature Search

A literature search focusing on new toxicity or regulatory data for 3-buten-2-one was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 3-buten-2-one: EPA AEGL, DOE PAC, HazMap, HSDB, CCRIS, RTECS, Toxline, PubMed, and CTD.

Regulatory values have been developed or reviewed for 3-buten-2-one. ACGIH has maintained a 0.2 ppmv ceiling limit for 3-buten-2-one (HSDB, ACGIH 2008) based on skin sensitization. In 2008, the EPA established AEGL for 3-buten-2-one. These values were set primarily based on results of a chronic inhalation experiment with Fischer-344 rats and B6C3F1 mice (Morgan 2000). The US DOE adapted the 1 hr AEGL for PAC (Revision 29).

AEGL values for 3-buten-2-one.

3.38

Interim AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 0.17 0.17 0.17 0.17 0.17 Morgan 2000 AEGL-2 1.5 1.5 1.2 0.76 0.5 Morgan 2000 AEGL-3 3.1 3.1 2.4 1.5 1 Eastman Kodak 1992, Morgan 2000

Toxicity

Exposure to 3-buten-2-one may cause contact burns to the skin and eyes, tachycardia, nausea, shortness of breath, headache, dizziness, fainting, coma, and death (HSDB)

Carcinogenicity

Numerous Ames Assays have demonstrated mutagenicity with and without metabolic activation (CCRIS, RTECS).

Irritation Indications

3-Buten-2-one is highly irritating to mucous membranes, especially the upper respiratory tract and eyes. (3-Buten-2-one AEGL 2008). May cause skin sensitization (HazMap).

Odor Threshold

Detectable odor concentrations have been reported at 0.5720 mg/m3 (HSBD, Ruth 1986) and 0.5 mg/m3 (HSDB, Verschueren 2001)

Mixture Interactions

No available data. Since 3-buten-2-one is expected to sensitize skin, it may increase the potency of other skin irritants in chronic exposures.

Summary and Recommendations

Due to EPA setting interim acute (10 min) AEGL values (0.17 ppm) lower than the ACGIH ceiling limit used for the OEL (0.2 ppm), it is suggested that the OEL be reevaluated for 3-buten-2-one. This interpretation is based solely on a change in AEGL or PAC values relative to the previously established OEL and it is feasible that this marginal change could also be sufficient to move re-evaluation efforts to a lower priority status. Since the AEGL values are based on inhalation effects and the ACGIH is based on skin sensitization, route of exposure may influence potential OEL modification during revaluation.

References Morgan, D.L., H.C. Price, R.W. O’Conner et al. 2000. Upper respiratory tract toxicity of inhaled methylvinyl ketone in F-344 rats and B6C3F1 mice. Toxicol. Sci 58:182-194. Eastman Kodak. 1992. Initial submission: Letter from Eastman Kodak to USEPA regarding toxicity studies of 3-buten-2-one with attachments and cover letter dated 9/02/92. Doc #88- 920008988. American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 42 Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986)

3.39

Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 1547

3.5 Esters

3.5.1 Previous Assessment

3.5.1.1 Methylethyl tetradecanoate (Cas # 110-27-0), Butyl tetradecanoate (Cas # 110- 36-1), and 1-Methylethyl hexadecanoate (CAS # 142-91-6)

The screening value for these decanoic acids was obtained from a Swedish TWA of 5 mg/m3 for the related butyl stearate (butyl octadecanoate, CAS # 123-95-5). The ACGIH also has established a TLV- TWA for stearates of 10 mg/m3 (~ 0.72 ppm), and OSHA has set a nuisance dust level for stearates of 5 mg/m3. These values are for total particulates or nuisance dusts and do not apply to vapors. These decanoic acids are common components of cosmetic compounds. They break down into innocuous metabolic products and are non-toxic, similar to the related fatty acids. The common use in cosmetics and the known and expected metabolic breakdown to non-toxic products indicates a HTFOEL is not needed for these chemicals at this time. As additional new data become available for these compounds, it would be reasonable to reassess the appropriateness of assigning a HTFOEL.

3.5.1.2 Dibutyl butylphosphonate (CAS# 78-46-6)

A HTFOEL is proposed for dibutyl butylphosphonate based on a comprehensive review of the available toxicology and guideline literature. Dibutyl butylphosphonate is a phosphoric acid similar in structure to dibutyl phosphate (DBP, CAS# 107-66-4) and tributyl phosphate (TBP, CAS# 126-73-8). Although there are no ACGIH or OSHA guidelines for dibutyl butylphosphonate, the ACGIH has set TLV-TWA exposure concentrations for TBP at 0.2 ppm (2.2 mg/m3) and for DBP at 1 ppm (8.6 mg/m3) (ACGIH 2001aa; 2001g). Based on the uncertainty associated with chemical and toxicological differences between dibutyl butylphosphonate and DBP or TBP, a HTFOELof 0.007 ppm is proposed for dibutyl butylphosphonate by adding additional uncertainty factors to the TBP TLV-TWA.

Methodology

To identify and access available toxicity data on dibutyl butylphosphonate, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for dibutyl phosphate and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for dibutyl butylphosphonate has been proposed by OSHA or ACGIH. However, ACGIH has assigned a TLV-TWA for the structural surrogates DBP and TBP (ACGIH 2001aa; 2001g). The ACGIH documentation for DBP and TBP are based upon very limited toxicity information (primarily sensory irritation), and in the case of TBP, by structural analogy with triphenyl phosphate. The current TLV-TWA for TBP and DBP are 0.2 ppm (2.2 mg/m3) and 1 ppm (8.6 mg/m3), respectively.

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Toxicology Summary and Data Analysis

A search of the RTECS data base found very limited toxicity data on dibutyl butylphosphonate. The LD50 following intraperitoneal and intravenous dosing in the mouse were 125 mg/kg and 56 mg/kg, respectively. For the structural surrogate DBP there is very limited information supporting the TLV- TWA, with some indication of respiratory tract irritation and headache in some workers exposed to DBP (unknown concentration/time) (ACGIH 2001g). In contrast, there are slightly more toxicity data available for TBP (ACGIH 2001aa). A 6-hour inhalation exposure of rats to TBP resulted in an LC50 of 123 ppm, and a 4- to 5-hour inhalation LC50 of 227 ppm (as determined by the World Health Organization [WHO] in 1991). Workers exposed to 1.4 ppm TBP have complained of nausea and headaches (ACGIH 2001aa); hence, the ACGIH recommended a TLV-TWA of 0.2 ppm for TBP because it was less than the concentration reported to be associated with worker complaints.

Summary and Recommendations

The ACGIH has set the TLV-TWA for tributyl phosphate at 0.2 ppm (2.29 mg/m3) based primarily by analogy with triphenyl phosphate and reports of worker complaints at 1.4 ppm exposure. Based on the uncertainty associated with chemical and toxicological differences between dibutyl butylphosphonate and TBP, a 30-fold factor is applied to the TBP TLV-TWA to establish a HTFOEL of 0.007 ppm for dibutyl butylphosphonate. A 10-fold factor was used to account for the lack of a robust toxicity data set, and an additional 3-fold factor used to account for structural differences between dibutyl butylphosphonate and TBP.

3.5.2 Current Summary

3.5.2.1 Dibutyl butylphosphonate (CAS No. 78-46-6)

The HTFOEL for dibutyl butylphosphonate is 0.007 ppmv based on a ACGIH TLV of 0.2 ppmv for tributyl phosphate (CAS No. 126-73-8) with a 30× uncertainty factor (10× for lack of robust data and 3× for structural differences.

Literature Search

A literature search focusing on new toxicity data for dibutyl butylphosphonate was conducted May 25, 2016. Using standardized search criteria, the following databases were identified as containing active records on 4-methyl-2-hexanone: HazMap, HDSB, RTECS, Toxline, PubMed, and DOE PAC.

The US DOE has established Protective Action Criteria (PAC) (Revision 29) for dibutyl butylphosphonate. No other new toxicity data or regulatory values were found.

PAC for dibutyl butylphosphonate.

Classification Protective Action Critera (PAC) (ppm) PAC-1 0.018 PAC-2 0.2 PAC-3 1.2

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Surrogate Literatures Search

Tributyl phosphate is used as a surrogate for dibutyl butylphosphonate. Updated TLV and Permissible Exposure Limit (PEL) values exist for tributyl phosphate (adjusted from 0.2 ppmv to 0.46 ppmv). See tributyl phosphate literature review for more details.

Toxicity

Dibutyl butylphosphonate is known to cause respiratory tract irritation, if severe, can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases (HSDB).

Carcinogenicity

No available data.

Irritation Indications

Dibutyl butylphosphonate is known to cause respiratory tract irritation (HSDB).

Odor Threshold

No available data.

Mixture Interactions

No available data.

Summary and Recommendations

Due to new regulatory criteria for both dibutyl butylphosphonate and tributyl phosphate (the surrogate currently used for dibutyl butylphosphonate HTFOEL derivation), it is suggested the dibutyl butylphosphonate HTFOEL be reevaluated. US DOE has established PACs for acute exposure scenarios, where previously, no criteria existed. Additionally, regulatory values for tributyl phosphate have become less stringent (8 hr TWA TLV and PEL values adjusted to 5 mg/m3 (0.46 ppmv = 5 mg/m3 × 24.45 L/mol / 266.32 g/mol) from 0.2 ppmv by ACGIH and OSHA). In aggregate, these new criteria support dibutyl butylphosphonate HTFOEL revaluation.

3.6 Alkyl Nitriles and Alkene Nitriles

3.6.1 Previous Assessment

5.7.1 Propanenitrile (CAS #107-12-0), Butanenitrile (CAS # 109-74-0), 2-Methylene butanenitrile (CAS#1647-11-6), Pentanenitrile (CAS# 110-59-8), Hexanenitrile (CAS # 628-73-9), Heptanenitrile (CAS# 629-08-3), Octanenitrile (CAS # 124-12-9), Nonanenitrile (CAS #2243-27-8), Decanenitrile (CAS # 1975-78-6)and 3-Butenenitrile (CAS# 109-75-1), and 2,-4-Pentadienenitrile (CAS# 1615-70-9)

HTFOELs are proposed for a family of saturated alkyl nitriles with two to nine carbon alkyl side-chains and unsaturated alkenes with three to four carbon side-chains, based on a comprehensive review of the available toxicology literature. The principal toxic effects of these nitriles have been proposed to be

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mediated by metabolically released cyanide. The chemical in this family with the most robust toxicological data set is propanenitrile. The proposed HTFOELs for these compounds range from 0.3 to 8 ppm and are based on toxicity information and pre-existing exposure guidelines from acceptable private and government agencies for the nitriles of interest and structurally similar compounds. An additional margin of safety was added, where appropriate, for the compounds in this class without pre-existing guidelines.

Methodology

To identify and access available toxicity data on alkyl and alkene nitriles, a number of Internet data bases, including PUBMED, TOXNET, TOMES, EPA-IRIS, and the IARC were searched, and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and for the development of the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

Guidelines have been proposed for propanenitrile and butanenitrile (see Table 3.5). Guidelines have also been proposed for related alkyl nitriles and alkene nitriles (see Tables 3.5 and 3.6). For many of these nitrile compounds, skin notations, but no classifications as carcinogens, have also been recommended.

Table 3.5. Exposure Limit Values Alkyl Nitriles

Nitrile Agency Description Limit (ppm)

Acetonitrile ACGIH® TLV®-TWA 20

EPA AEGL3 (8-hr) 100

Butanenitrile NIOSH REL 8

Propanenitrile NIOSH REL 6

EPA AEGL3 (8-hr) 1.4

REL = Recommended exposure limit

TLV = Threshold limit value

TWA = Time-weighted average

AEGL1 = Acute Exposure Guideline Levels, once-in-a-lifetime, or rare, exposure to airborne chemicals. The AEGLs for acetonitrile and propanenitrile are under review and do not have technical support documentation available at this time.

1 AEGL Levels 1-3. AEGL Level 1 is an exposure at which an individual may have some discomfort. Level 3 is the level at which an individual could experience life-threatening effects. Level 2 is the action level, the level at which an individual may experience long-lasting effects.

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Table 3.6. Acute or Subchronic LD50 s and OELs for Alkene Nitriles

1 Nitrile C # Species LD50 Exposure Limit: Agency (mmol/kg)

Acrylonitrile 2 Mouse 0.73 2 ppm: OSHA PEL

1 ppm: NIOSH REL

Methacrylonitrile 3 Mouse 0.26 1 ppm: NIOSH REL

3-Butenenitrile 3 Mouse 1.0 --

OSHA = Occupational Health and Safety Administration

PEL = Permissible exposure limit

1. All LD50 values are from Tanii and Hashimoto (1984a).

Toxicology Summary

The LC50s for butanenitrile and propanenitrile are similar (see Table 3.7). The endpoint of concern for developing a HTFOEL based on animal toxicity studies is likely to be developmental effects. At high exposure concentrations, embryolethality was observed; at lower concentrations, fetotoxicity was observed (Saillenfait et al. 1993). The NOELs for developmental effects are very similar between butanenitrile propanenitrile and pentanenitrile (see Table 3.7).

Acetonitrile, pentanenitrile, and propanenitrile were all negative in genotoxicity assays conducted by the NTP of the NIEHS1. Lifetime inhalation exposures to the structurally related acetonitrile did not result in increased incidences of cancers in rats (NTP 1996).

Toxicity of these saturated alkyl nitriles and unsaturated alkene nitriles is most likely mediated through metabolically released cyanide (Willhite and Smith 1981; Tanii and Hashimoto 1984b). All of these nitriles contain alkyl or alkene chains with nine carbons or less and a nitrile functional group (R-C≡N). The EPA Office of Pollution Prevention and Toxics has accepted a proposal from Eastman Kodak Co. and Solutia, Inc. to combine alkyl nitriles with up to three carbons (C-3) for the purposes of addressing 2 data gaps . For the purpose of developing HTFOELs, nitriles with longer side-chains are also considered within this family.

Toxicity data for most of these chemicals are limited. The decision to include the alkyl and alkene nitriles as a family was driven by the comparable available data, the similarity of the compounds, and the common active group (C≡N). The research reported by Tanii and Hashimoto (1984a 1984b) found cyanide metabolism in all the tested members of this family. The LD50 values determined by Tanii and Hashimoto (1984a) formed the basis for the proposed HTFOELs for chemicals in this family that currently lack HTFOELs (see Figure 3.1).

1 Assay information can be found online: http://ntp.niehs.nih.gov/ntpweb/index.cfm?objectid=123DED4A-F1F6- 975E-7CB19C212F28F788. 2. See EPA’s comments to the proposal online: http://www.epa.gov/chemrtk/alkyntrl/c14860ct.htm.

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Table 3.7. Acute or Subchronic NOELs and LC50s for Alkyl Nitriles

1 2 Nitrile C # Species LC50 LD50 NOEL Reference

Acetonitrile 1 Rat/Developmental -- -- 190 Johannsen et mg/kg al. 1986 Mouse 2673 6.6 -- Willhite et al. 1981

Propanenitrile 2 Rat/Developmental -- -- 50 ppm Saillenfait et al. 1993 Rat/Developmental -- -- 20 mg/kg Johannsen et Mouse 163 0.65 -- al. 1986

Willhite et al. 1981

Butanenitrile 3 Mouse 249 0.56 -- Willhite et al. 1981 Rat/Developmental -- -- 50 ppm Saillenfait et al. 1993

Pentanenitrile 4 Rat/Developmental -- -- 30 mg/kg Munley et al. 2001 Mouse 2.3

Hexanenitrile 5 Mouse -- 4.8 --

Heptanenitrile 6 NA ------

Octanenitrile 7 Mouse -- 14.1 --

Nonanenitrile 8 Mouse -- 14.8 --

Decanenitrile 9 NA ------

-- = Not applicable

1. Sidechain carbon number

2. All LD50 values are from Tanii and Hashimoto (1984a).

Data Analysis

NIOSH has set exposure guidelines for two of the four short-chain nitriles of interest (i.e., butanenitrile and pentanenitrile) and ACGIH has set exposure guidelines for the structurally similar acetonitrile (see

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Table 3.5). The TLV for acetonitrile is about three-fold higher than the NIOSH-recommended exposure limits (RELs) for the other nitriles. Likewise, the NOELs for developmental effects are about eight-fold higher for acetonitrile than propanenitrile and pentanenitrile (see Table 3.6). The LD50 values follow a similar trend, indicating toxicity of acetonitrile is less than alkyl and alkene nitriles with C-2 to C-5 chains. Alkyl nitriles with chains longer than seven carbons have increased LD50 values (decreased toxicity) compared to the shorter-chain nitriles (see Tables 3.5-3.7).

To determine reasonable HTFOELs, the guidelines for propanenitrile (6 ppm: NIOSH REL) and butanenitrile (8 ppm: NIOSH REL) have been compared to the toxicity data available for the family of compounds in the literature. For alkyl nitriles with toxicity data below those of propanenitrile, a HTFOEL of 6 ppm is proposed. NIOSH has recommended RELs for the structurally similar acrylonitrile and methacrylonitrile. The toxicity data indicate similar LD50 s for the alkene nitriles (see Table 3.6) and a HTFOEL of 1 ppm is proposed for 3-butenenitrile, for which toxicity data are available, and 0.3 ppm for 2,- 4-pentadienenitrile and for 2-methylene butanenitrile, which lack toxicity data. Table 3.8 summarizes the HTFOELs for each nitrile in this family.

It is unclear why the EPA AEGL3 for propanenitrile is lower than the NIOSH REL (see Table 3.5). At this time, no documentation is available to assess the derivation of the AEGL3. As additional new data become available for nitriles, it would be reasonable to reassess the appropriateness of this proposed HTFOEL.

14 No Data 12 10 8

6 Alkenes

LD50 (mmol/kg) 4 2 0 1 2 3 4 5 6 7 8 9 3 4 Carbon Sidechain Length

Figure 3.1. Comparison of Mice LD50 Values (Tanii and Hashimoto 1984a) based on carbon sidechain length.

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Table 3.8. Proposed HTFOELS

Carbon OEL Nitrile HTF Basis # (ppm)

Propanenitrile 2 6 NIOSH (CAS #107-12-0)

Butanenitrile 3 8 NIOSH (CAS # 109-74-0)

3-Butenenitrile Methacrylonitrile Surrogate: NIOSH REL, 3 1 ACGIH TLV (CAS# 109-75-1)

2-Methylene Methacylonitrile Surrogate: NIOSH REL, butanenitrile 3 0.3 ACGIH TLV, with UF of 3 due to lack of (CAS#1647-11-6) toxicity data

Pentanenitrile 4 6 Propanenitrile (CAS# 110-59-8)

Hexanenitrile 5 6 Propanenitrile (CAS # 628-73-9)

Heptanenitrile 6 6 Propanenitrile (CAS# 629-08-3)

Octanenitrile 7 6 Propanenitrile (CAS # 124-12-9)

Nonanenitrile 8 6 Propanenitrile (CAS #2243-27-8)

Decanenitrile 9 6 Propanenitrile (CAS # 1975-78-6)

Methacylonitrile Surrogate: NIOSH REL, 2,-4-Pentadienenitrile 4 0.3 ACGIH TLV, with UF of 3 due to lack of (CAS# 1615-70-9) toxicity data

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Summary and Recommendations

The nitriles are structurally similar and consist of an alkyl or alkene side-chain and a nitrile functional group. Toxicity is most likely mediated though the cyanide metabolite. The known NOELs for developmental effects and LD50s are similar for this class of chemicals. The proposed HTFOELs for this family of nitriles are based on the NIOSH RELs for nitriles, with an additional safety factor when toxicity data are not available. The proposed HTFOELs of 0.3 to 8 ppm are comparable to the NIOSH RELs for propanenitrile and butanenitrile.

3.6.2 Current Summaries

3.6.2.1 Acetonitrile (CAS No. 75-05-8)

The OEL for Acetonitrile is 20 ppm based on a TLV-TWA set by ACGIH. Previous EPA guidelines for AEGL3 (8 Hr) category are 100 ppm.

Literature Search

A literature search focusing on new toxicity data for Acetonitrile was conducted on June 29, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on Acetonitrile: CCRIS, CTD, HazMap, HSDB, IRIS, ITER and RTECS databases. Information on acetonitrile was also identified in AEGL and PAC databases. Acetonitrile TLV has not been updated in the ACGIH database since the original 2002 publication.

PAC values for acetonitrile are the same as AEGLs.

Toxicity

Exposures to 160 ppm for 4 hours has caused flushing of the face and a feeling of constriction in the chest; exposures to 500 ppm for brief (undefined) time periods has resulted in only irritation to the nose and throat (HazMap Database). Central nervous system dysfunction (Pharmacol Toxicol.1992 May;70(5 Pt 1):322-30. Studies on the mechanism of acetonitrile toxicity. I: Whole body autoradiographic distribution and macromolecular interaction of 2-14C-acetonitrile in mice. Ahmed AE, Loh JP, Ghanayem B, Hussein GI.)

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Carcinogenicity

Not carcinogenic from previous documentation. No indications of positive carcinogenicity in the Carcinogenic Potency Project (https://toxnet.nlm.nih.gov/cpdb/chempages/ACETONITRILE.html)

Irritation Indications

Respiratory irritant (HazMap Database).

Odor Threshold

40 ppm

Mixture Interactions

Acetone interaction with acute acetonitrile toxicity in rats. (Freeman JJ, Hayes EP., J Toxicol Environ Health. 1985;15(5):609-21. Acetone potentiation of acute acetonitrile toxicity in rats.)

Summary and Recommendations

Recently established AEGL and PAC values for acetonitrile (13 ppm) are lower than the previous OEL established by ACGIH (20 ppm) warranting re-evaluation of the OEL for acute acetonitrile exposures.

References Ahmed AE, Loh JP, Ghanayem B, Hussein GI. Studies on the mechanism of acetonitrile toxicity. I: Whole body autoradiographic distribution and macromolecular interaction of 2-14C acetonitrile in mice. Pharmacol Toxicol. 70(5 Pt 1):322-30, 1992. Freeman JJ, Hayes EP. Acetone potentiation of acute acetonitrile toxicity in rats. J Toxicol Environ Health. 15(5):609-21, 1985.

3.6.2.2 Butanenitrile (CAS No. 109-74-0)

The HTFOEL for butanenitrile (also known as n-butyronitrile) is 8 ppmv based on a REL set by NIOSH.

Literature Search

A literature search focusing on new toxicity or regulatory data for butanenitrile was conducted May 25, 2016. Using standardized search criteria, the following databases were identified as containing active records on butanenitrile: US DOE PAC, HazMap, HSDB, PubMed, RTECS, and Toxline.

The US DOE has established PAC (Revision 29) for butanenitrile. No other new toxicity or regulatory data was discovered.

Protective Action Criteria (PAC) for butanenitrile.

Classification Protective Action Critera (PAC) (ppm) PAC-1 0.76 PAC-2 8.3 PAC-3 50

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Toxicity

Forms cyanide in the body (HSDB, NIOSH)

Carcinogenicity

No available data.

Irritation Indications

A skin irritant (HSDB, Lewis 1996).

Upper respiratory tract irritation has been reported after chronic occupational exposure (HSDB).

Odor Threshold

A sharp, suffocating odor (HazMap).

Mixture Interactions

P-Aminopropiophenone protected mice against lethal doses of potassium cyanide and many organothiocyanates (HSDB, Ohkawa 1974).

Summary and Recommendations

It is recommended that the HTFOEL for butanenitrile be revaluated. The chronic REL set by NIOSH has not changed and remains at 8 ppmv. However, acute guidelines have been established by US DOE, and PAC-1 guidelines are roughly an order of magnitude lower than the REL. Thus, we recommend that the exposure limits for butanenitrile be revaluated for acute exposures.

References

Ohkawa et al; Bull Soc Pharm Lille ISS (4): 161 (1974)

Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 609

3.6.2.3 2-methylene butanenitrile (CAS No. 1647-11-6)

The OEL for 2-methylene butanenitrile is 0.3 ppm based upon surrogate data.

Literature Search

A literature search focusing on new toxicity data for 2-methylene butanenitrile was conducted on June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 2-methylene butanenitrile: HazMap. No new regulatory information on 2-methylene butanenitrile was discovered. 2-methylene butanenitrile was not identified in AEGL or PAC databases. Surrogate chemicals propanenitrile (CAS #107-12-0) and butanenitrile (CAS # 109-74-0) were identified in the PAC database.

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Toxicity

Not available.

Carcinogenicity

Not available.

Irritation Indications

Not available.

Odor Threshold

Not available.

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Mixture Interactions

None identified for 2-methylene butanenitrile (PubMed; mixture interaction and 2-methylene butanenitrile or propanenitrile or butanenitrile as search terms).

Recommendations/Conclusions

Recently established PAC values for surrogates propanenitrile and butanenitrile are slightly lower (0.27 ppm) than surrogate HTFOELused previously (0.3 ppm) and could potentially be considered for acute 2- methylene butanenitrile exposures.

References

None.

3.6.2.4 Pentanenitrile (CAS No. 110-59-8)

The HTFOEL for Pentanenitrile is 6 ppmv based on a REL set by NIOSH using propanenitrile and butanenitrile as surrogates.

Literature Search

A literature search focusing on new toxicity data for Pentanenitrile was conducted on July 26, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on Pentanenitrile: CCRIS, HazMap, RTECS, Toxline and PubMed. Surrogate chemicals propanenitrile (CAS #107-12-0) and butanenitrile (CAS # 109-74-0) were identified in the PAC database.

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Toxicity

Not available.

Carcinogenicity

Not available.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified (PubMed; mixture interaction and Pentanenitrile or propanenitrile or butanenitrile as search terms).

Summary and Recommendations

It is recommended that the HTFOEL for Pentanenitrile be revaluated. Acute guidelines for the surrogates butanenitrile and propanenitrile have been established by US DOE, and PAC-1 guidelines are roughly an order of magnitude lower than the REL. Thus, we recommend that the exposure limits for heptanenitrile be revaluated for acute exposures.

References

Not available.

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3.6.2.5 Hexanenitrile (CAS No. 628-73-9)

The HTFOEL for hexanenitrile is 6 ppmv based the OEL for propanenitrile (6 ppmv) recommended by ACGIH as an 8 hr TWA-TLV.

Literature Search

A literature search focusing on new toxicity or regulatory data for hexanenitrile was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on hexanenitrile: DOE PAC, HazMap, PubMed, RTECS, and Toxline.

The US DOE has established PAC (Revision 29) for hexanenitrile. No other novel regulatory values or data were discovered.

PAC (Revision 29) for hexanenitrile.

Classification Protective Action Critera (PAC) (ppm) PAC-1 0.19 PAC-2 2.1 PAC-3 13

Surrogate Literatures Search

Propanenitrile, a COPC, was used as a surrogate chemical. See Propanenitrile Review.

Toxicity

Chemical asphyxiant (HazMap).

Carcinogenicity

No available data.

Irritation Indications

An irritant (HazMap)

Odor Threshold

No available data.

Mixture Interactions

Possible mixture interaction with ethanol (Tanii 1986).

Summary and Recommendations

It is recommended that the HTFOEL for hexanenitrile be reevaluated. Previously, no toxicity or regulatory data was available to set an OEL, so propanenitrile was used as a surrogate compound. NIOSH maintains REL of 6 ppmv for propanenitrile. US DOE established PAC values for hexanenitrile, in which PAC-1 and PAC-2 criteria are lower than the current hexanenitrile HTFOEL questioning its validity. PAC values

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could be utilized to establish acute exposure guidelines or to extrapolate an updated hexanenitrile HTFOEL. Overall, the current HTFOEL for hexanenitrile may not be adequate and should be reevaluated.

References

Tanii H, Hashimoto K. 1986. Influence of Ethanol on the In Vivo and In Vivo Metabolism of Nitriles in Mice. ARCH TOXICOL; 58 (3) 171-176.

3.6.2.6 Heptanenitrile (CAS No. 629-08-3)

The HTFOEL for heptanenitrile is 6 ppmv based on a REL set by NIOSH using propanenitrile and butanenitrile as surrogates.

Literature Search

A literature search focusing on new toxicity or regulatory data for heptanenitrile was conducted August 9, 2016. Using standardized search criteria, the following databases were identified as containing active records on heptanenitrile: HazMap, PubMed and Toxline. No new regulatory information on heptanenitrile was discovered.

Information on surrogates propanenitrile and butanenitrile was identified in PAC databases.

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Toxicity

Not available.

Carcinogenicity

Not available.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified (PubMed; mixture interaction and heptanenitrile or propanenitrile or butanenitrile as search terms).

Summary and Recommendations

It is recommended that the HTFOEL for heptanenitrile be revaluated. The chronic REL set by NIOSH has not changed and remains at 8 ppmv. However, acute guidelines for the surrogates butanenitrile and propanenitrile have been established by US DOE, and PAC-1 guidelines are roughly an order of magnitude lower than the REL. Thus, we recommend that the exposure limits for heptanenitrile be revaluated for acute exposures.

References

None

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3.6.2.7 2,4-Pentadienenitrile (CAS No. 1615-70-9)

The HTFOEL for 2,4-pentadienenitrile is 0.3 ppmv based on methacylonitrile (CAS No. 126-98-7) as a surrogate. ACGIH recommends an 8 hr TLV-TWA of 1 ppmv for methacylonitrile. NIOSH also set a REL of 1 ppmv for methacylonitrile. The HTFOEL for 2,4-pentadienenitrile was calculated using a 3× uncertainty factor of methacylonitrile OELs.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2,4-pentadienenitrile was conducted May 23, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2,4-pentadienenitrile: HazMap and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

A brief literature search for methacylonitrile was conducted using EPA AEGL, US DOE PAC, and HSDB. ACGIH continues to recommend an 8 hr TLV-TWA of 1 ppm using skin as the basis (HSDB, ACGIH 2008a). ACGIH further recommends an Excursion Limit Recommendation: Excursions in worker exposure levels may exceed 3 times the TLV-TWA for no more than a total of 30 minutes during a work day, and under no circumstances should they exceed 5 times the TLV-TWA, provided that the TLV-TWA is not exceeded (HSDB, ACGIH 2008b). NIOSH continues to employ a 10 hr TWA REL of 1 ppmv (HSDB, NIOSH 1997). EPA established interim Acute Exposure Guideline Levels (AEGLs) for methacylonitrile (NRC 2014). The US DOE has established Protective Action Criteria (PAC) (Revision 29) for methacylonitrile that was adopted as the 1 hr AEGL values. Since EPA did not recommend an AEGL-1 value, US DOE suggests 0.091 ppm for the PAC-1 value. AEGLs for methacylonitrile (NRC 2014)

AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 NR NR NR NR NR AEGL-2 1.3 1.3 1 0.67 0.33 3× reduction of AEGL-3 AEGL-3 3.9 3.9 3.1 2 0.99 Pozzani 1968 Not recommended (NR)

Toxicity

Chemical asphyxiant (HazMap).

Carcinogenicity

No available data.

Irritation Indications

No available data.

Odor Threshold

No available data.

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Mixture Interactions

No available data.

Summary and Recommendations

It is recommended that the HTFOEL for 2,4-pentadienenitrile be revaluated. Little data is available for 2,4- pentadienenitrile, and methacylonitrile is used as a surrogate compound. NIOSH and ACGIH continue to maintain 1 ppmv as the OEL for methacylonitrile. However, AEGL and PAC values have recently been established further providing acute and chronic guidelines. Various PAC-1 (0.091 ppm), AEGL-2 (4 hr: 0.67 ppm & 8 hr: 0.33 ppm), and AEGL-3 (8 hr: 0.99 ppm) values are lower than NIOSH and ACGIH OELs, questioning the adequacy of the OEL for methacylonitrile. Thus, we recommend that the HTFOEL for 2,4-pentadienenitrile be revaluated.

3.6.2.8 Propanenitrile (CAS No. 107-12-0)

The HTFOEL for Propanenitrile is 6 ppmv based on a REL set by NIOSH.

Literature Search

A literature search focusing on new toxicity data for Propanenitrile was conducted on July 26, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on Pentanenitrile: CCRIS, HazMap, HSDB, RTECS, Toxline and PubMed. Propanenitrile was also identified in the PAC database.

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Toxicity

Developmental toxin in animal studies (HazMap).

Carcinogenicity

Not available.

Irritation Indications

Irritant at high dose (RTECs).

Odor Threshold pleasant, sweetish, ethereal odor (HazMap).

Mixture Interactions

None identified (PubMed; mixture interaction and propanenitrile as search terms).

Summary and Recommendations

Acute guidelines for propanenitrile have been established by US DOE, and PAC-1 guidelines are roughly an order of magnitude lower than the previously established REL. Thus, we recommend that the exposure limits for propanenitrile be revaluated for acute exposures.

References

None.

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3.7 Amines and Amides

3.7.1 Previous Assessment

3.7.1.1 Acetamide (CAS #60-35-5)

In the interest of protecting the health of tank farm workers at DOE’s Hanford Site, chemicals found within tank headspaces that the IARC lists as “possibly carcinogenic to humans” (2B) are being evaluated. The evaluation process will determine if there is a need to establish a HTFOEL for worker exposure based on a review of all available exposure and toxicological data as described in Sections 2.0 - 4.0. IARC assigned acetamide a 2B carcinogen classifications based on a paper by Fleischman et al. (1980) in which a diet of 2.36% acetamide resulted in hepatocarcinomas in male and female rats, and diets of 1.18 and 2.36% resulted in malignant lymphomas in male mice (Table 3.9). Only IARC and California EPA have assigned a carcinogen classification for acetamide; neither the EPA nor OSHA has made such a designation. The NTP investigated the mutagenic potential of acetamide in drosophila and salmonella and the results were negative. The bioassay results from the NTP were “inconclusive and not reportable” (http://ntp.niehs.nih.gov/index.cfm?objectid=07058954-ED59-D6FE- 5E91CDDBC78C556E).

There are more data available for the related chemicals N,N-dimethylacetamide and formamide (Figure 3.2). N,N-Dimethylacetamide is metabolized to acetamide in the liver. Acetamide and formamide are very similar, but acetamide is metabolized more slowly. The ACGIH, OSHA, and NIOSH have all set exposure limits for N,N-dimethylacetamide at 10 ppm TWA. The ACGIH recommended HTFOEL for formamide is also 10 ppm. Neither formamide nor dimethylacetamide have been assigned possible human carcinogen status.

Acetamide, dimethylacetamide, formamide, and dimethylformamide all cause progressive hepatotoxicity (Kennedy 1986). The hepatocellular carcinomas observed by Fleischman et al. (1980) may have been due to hepatocellular cytotoxicity and concomitant compensatory cellular regeneration, which would have a threshold effect. Also, the ACGIH TLV of 10 ppm for demethylacetamide should provide a good estimate for an acetamide TLV, and even after application of a 10x safety factor, the margin of exposure for acetamide (and related compounds, see Table 3.10) should be sufficient (estimated OEL of 1 ppm compared to tank headspace concentration of 0.0032 ppm). Therefore, no OEL is proposed for acetamide at this time. As additional new data become available for acetamide, it would be reasonable to reassess the appropriateness of not assigning an OEL based on the potential carcinogenicity.

Table 3.9. Incidence of Cancers in Rats and Mice Fed Diets Containing Acetamide.

Species Acetamide (%) Endpoint Incidence Control

Rat (male)1 2.36 Hepatocellular 41/47 0/50 Carcinomas

Mouse (male) 1.18 Malignant 7/50 0/79 lymphoma

Mouse (male) 2.36 Malignant 7/46 0/79 lymphoma

1 Male and female rats were dosed, with similar outcomes, but male rats had slightly higher incidence and quicker time to tumor development Fleischman et al. (1980).

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Table 3.10. Acetamide and Related Chemicals.

CAS or Chemical Max. Surrogate Surrogate Safety Screening TWINS Conc. OEL Factor Value Number (ppm) Source (ppm)

60-35-5 Acetamide 0.0032 N,N- TLV 1000 0.01 Dimethylacetamide

79-16-3 N-Methylacetamide 0.00037 N,N- TLV 100 0.1 Dimethylacetamide

541-35-5 Butanamide 0.020 N,N- TLV 100 0.1 Dimethylacetamide

10264- N-Hexylbutanamide 0.000052 N,N- TLV 100 0.1 17-2 Dimethylacetamide

O O

CH3 HC NH 3HC N 3 2 CH3 Acetamide N,N Dimethylacetamide

O O

CH3 H NH2 H N

CH3 Formamide N,N Dimethylformamide Figure 3.2. Acetamide and related compounds.

3.7.1.2 N-Methylaziridine (CAS# 1072-44-2)

A HTFOELis proposed for N-methylaziridine. Aziridines are 3 membered heterocyclic compounds with an amine group. N-Methylaziridine has a methyl group bound to the ring nitrogen. Aziridines have high- angle strains due to the tight nature of the 3-member ring compared to larger ring structures. No toxicological data were found for N-methylaziridine, but it is similar to ethylenimine and propyleneimine, which have ACGIH-recommended TLVs of 0.5 and 2 ppm, respectively. These ACGIH TLVs are intended to minimize respiratory tract irritation. Ethylenimine and propyleneimine are confirmed animal carcinogens. The proposed HTFOEL for N-methylaziridine is 0.05 ppm based on the ACGIH TLVs for the closely relate compound ethylenimine with an uncertainty factor of 10.

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Methodology

To identify and access available toxicity data on N-methylaziridine, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OEL for N-methylaziridine has been proposed by the OSHA or ACGIH. The ACGIH has proposed TLVs of 0.5 and 2 ppm for ethylenimine and propylenimine, structurally similar compounds. In addition, OSHA has assigned a PEL of 2 ppm, and NIOSH has assigned an Immediately Dangerous to Life or Health (IDLH) of 100 ppm for propylenimine. Skin notations have been recommended for these aziridines.

Toxicology Summary

Aziridines are reactive due to the ring strain, and they interact readily with nucleophiles. The substituted polyethylenimine is not mutagenic in salmonella strains. Aziridine and aziridines with smaller substitutions (i.e., propylenimine) are mutagenic and carcinogenic in laboratory animals. Aziridines are irritating to mucous membranes, skin, eyes, and lungs. Acute exposures of laboratory animals have resulted in congestion of the respiratory tract, edema, hemorrhage, and kidney damage. The 10-minute LC50 for aziridine is 2200 ppm, but exposures of 4 or more hours to as low as 25 ppm has resulted in death in rats and guinea pigs. Embryotoxicity (decreased body weights, hematomas, decreased live births) have been observed with inhalation exposure concentrations as low as 0.6 ppm (NTP). Although animal studies to low concentrations result in serious effects, exposures in humans have resulted in less notable outcomes. Vapor exposures in human studies have resulted in no ill-effects for up to 3 hours. After 3 hours, vomiting and eye and nose irritation was reported. Acute dermal or inhalation exposures have resulted in central nervous system effects, fluid in the lungs, and damage to liver and kidneys (ACGIH 2001l).

Propylenimine has less potent toxicity than aziridine. The physiological action of propylenimine, however, resembles that of aziridine (ACGIH 2001z). The LCL0 for rats is 500 ppm for a 4-hour exposure. N-Aziridineethanol is an N-substituted aziridine with an ethanol group. Like the other azeridines, N-aziridineethanol is an eye and skin irritant that also has limited data indicating it is an animal carcinogen (HAZMAP).

Data Analysis

The most data were available for the unsubstituted aziridine. The ACGIH has recommended TLV-TWAs of 0.5 and 2 ppm for aziridine and propylenimine, respectively. The toxicity and carcinogenicity of aziridines with substitutions smaller than three carbons is similar. Due to the ring strain, these compounds are reactive. The primary endpoint of concern is irritation of skin, eyes, and lungs, and, for some aziridines, kidney damage. The ACGIH TLV for aziridine is four-times lower than for propylenimine due to the decreased toxicity for that substituted aziridine over the unsubstituted ring. The N-substitute aziridine is not likely to result in significant decrease in ring strain.

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Summary and Recommendations

Based on the lack of toxicological data for N-methylaziridine, it is proposed that the ACGIH TLV of 0.5 ppm be used with an UF of 10 to propose an OEL for N-methylaziridine of 0.05 ppm. As additional new data become available for the N-methylaziridine, it would be reasonable to reassess the appropriateness of basing the HTFOEL upon the WEEL for substituted pyridines.

3.7.2 Current Summaries

3.7.2.1 Ethylamine (CAS No. 75-04-7)

The OEL for ethylamine is 5 ppmv adapted from an 8 hr TWA-TLV set by ACGIH.

Literature Search

A literature search focusing on new toxicity or regulatory data for ethylamine was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on ethylamine: EPA AEGL, US DOE PAC, HazMap, HSDB, CCRIS, RTECS, PubMed, and Toxline.

New regulatory criteria were discovered for ethylamine. OSHA maintains an 8 hr TWA-PEL of 10 ppm for ethylamine (HSDB, 29 CFR 1910.1000 2015). ACGIH maintains a 5 ppm 8 hr TWA-TLV and recommends a 15 ppm for a 15 min STEL based on skin (HSDB, ACGIH 2014). NIOSH set a 10 hr TWA-REL of 10 ppm and a 600 ppm Immediately Dangerous to Life or Health level (HSDB, NIOSH 2010). EPA established interim AEGLs for ethylamine. The US DOE has established PAC (Revision 29) for ethylamine that was adopted as the 1 hr AEGL values.

AEGLs for ethylamine.

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 7.5 7.5 7.5 7.5 7.5 Kinney 1990; Sriramachari 1994 AEGL-2 150 76 49 22 14 AEGL-3 810 420 270 120 76 IRDC 1993

Toxicity

Liquid causes first degree burns on short exposure (HazMap).

Corrosive to skin (Hazmap).

Inhalation of 70% aqueous solution can cause chemical pneumonitis (HazMap).

Rabbits with inhalation exposure to 50 ppm have lung and corneal injury, while exposure to 100 ppm causes kidney injury (HazMap).

4-Methyl-2-hexanone is known to cause CNS Solvent Syndrome (HazMap Database).

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Carcinogenicity

Negative in vitro mutagen assays (CCRIS).

Irritation Indications

Irritating to eyes and respiratory tract (HazMap). Aliphatic amines exposure usually causes eye, nose, and throat irritation (HSDB, BASF 1998). Irritating to skin, mucous membranes, and respiratory tract (HSDB, O’Neil 2006). Becomes irritating at 180 mg/m3 (HSDB, Bingham 2001) Acute Exposure/ Ethylamine is irritating to both the skin and eyes of test animals. When applied to the skin of a rabbit, a small amount of redness was produced, indicating the material to be only mildly irritating to the skin. However, severe skin irritation with extensive necrosis and deep scarring was produced by 0,1 mL of a 70% ethylamine formulation held in contact with guinea pig skin for 24 hr. Prompt necrotic skin burns were produced from a 70% solution dropped on the skin of guinea pigs (HSDB, ACGIH 2013)

Odor Threshold

Ammonia-like odor (HazMap).

0.27 ppm odor threshold (HazMap, HSDB, Fazzalari 1978).

Odor recognition in air: 0.83 ppm (purity not specified) (HSDB, Fazzalari 1978).

The odor threshold reportedly ranges from 0.027 to 3.5 ppm, having a sharp fishy, ammonia-like odor, which becomes irritating at 180 mg/m3 (HSDB, Bingham 2001)

Mixture Interactions

One Russian study evaluated the effects of aliphatic amines in mixtures (Tkachev 1974). Results available in Russian.

Summary and Recommendations

It is recommended that the OEL for ethylamine does not need to be reevaluated; however, acute exposure guidelines may need to be developed. ACGIH maintains the same TLV as was previously utilized for ethylamine OEL determination (5 ppm). TLVs recommended by NIOSH and OSHA are higher (10 ppm), thus the current OEL is probably appropriate for chronic exposures. Recently, EPA established interim AEGL values that could be adapted for acute exposure guidelines. Acute level 1 AEGL values are higher than the current OEL (7.5 vs 5 ppm), thus the current OEL is protective of acute exposures. However, it may be prudent to develop acute exposure guidelines for ethylamine.

References 29 CFR 1910.1000 (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 4, 2015: http://www.ecfr.gov American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 29 NIOSH. NIOSH Pocket Guide to Chemical Hazards. Department of Health & Human Services, Centers for Disease Control & Prevention. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from: http://www.cdc.gov/niosh/npg

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BASF; Chemical Emergency Medical Guidelines Aliphatic amines. Information and recommendations for doctors at hospitals/emergency departments (November 1998). Available from, as of July 28, 2007: http://www.corporate.basf.com/en/?id=V00-3.JgyAphUbcp2cv O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006, p. 646 Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001), p. V4 714 American Conference of Governmental Industrial Hygienists. Documentation of the TLVs and BEIs with Other World Wide Occupational Exposure Values. 7th Ed. CD-ROM Cincinnati, OH 45240-1634 2013, p. 2 Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978, p. 64 Tkachev P.G.; Kosiborod N.R., 1974: Combined and complex action of certain low aliphatic amines. Gigiena I Sanitariya(8): 7-10

3.7.2.2 N-Nitrosodiethylamine (CAS No. 55-18-5)

The HTFOEL for N-nitrosodiethylamine (also known as diethylnitrosamine) is 0.1 ppbv based on a MAK value set by Germany and the Netherlands for N-nitrosodimethylamine adjusted by a relative carcinogenic potency ranking.

Literature Search

A literature search focusing on new toxicity or regulatory data for N-nitrosodiethylamine was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on N-nitrosodiethylamine: HazMap, IRIS, HSDB, ITER, RTECS, GeneTox, CTD, and MAK values.

No new toxicity data was discovered; however, relevant changes were made to German MAK values for N-nitrosamines. German MAK values were used to establish HTFOELsfor N-nitrosamines within the COPC list. In recent documentation (2015), German MAK values for N-nitrosamines have been removed, and instead, documentation suggests that exposure should be minimized due to carcinogenicity concerns (Deutsche Forschungsgemeinschaft 2015). This is consistent with ACGIH and OSHA guidelines of “as low as reasonably achievable”. The State of Florida has set a drinking water concentration of 4 µg/L for N-nitrosodiethylamine (HSDB, EPA 1993).

Toxicity

Effects in high-dose animal studies include fatty liver degeneration (HazMap).

Carcinogenicity

Classified as B2, probable human carcinogen (HSDB, IRIS 1994)

Within group 2A, probably carcinogenic to humans (HSDB, IARC 1987)

Oral slope factor: 150 (mg/kg/day)-1 (IRIS)

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Drinking water unit risk: 4.3×10-3 (µg/L)-1 (IRIS)

Inhalation unit risk: 4.3×10-2 (µg/m3)-1. Note: inhalation risk were calculated from the oral exposure data (IRIS).

Toxicology Excellence for Risk Assessment (TERA) calculated a risk specific dose (RSD) for N- nitrosodiethylamine. TERA utilized a 1 in 100,000 (E-5) risk level and the EPA oral slope factor to derive the RSD of 6.7×10-8 mg/kg/day (1×10-5 / 150= 6.7×10-8) (ITER).

TERA also calculated at risk specific concentration (RSC) for N-nitrosodiethylamine. TERA again utilized a 1 in 100,000 (E-5) risk level and the EPA Inhalation unit risk to derive the RSC of 2.3×10-7 mg/m3 (1×10-5 / 4.3×10-2 × 1000 µg/mg = 2.3×10-7). The EPA inhalation unit risk was extrapolated using the oral exposure data (ITER).

Irritation Indications

Contact can irritate the skin and eyes. Vapors cause respiratory tract irritation (HSDB, Pohanish 2008).

Odor Threshold

No available data.

Mixture Interactions

May have additive effects with other N-nitrosamines.

Summary and Recommendations

It is recommended that the HTFOEL for N-nitrosodiethylamine be reevaluated due to changes in MAK values used in previous HTFOEL determination. Previously, other methods utilizing the cancer oral slope value were evaluated and considered for HTFOEL determination for all N-nitrosamines in the COPC list using a similar approach used by TERA for RSD and RSC calculations. Former approaches resulted in similar HTFOEL values as previous MAK values. As such, these approaches may be worth revisiting. A major decision point within this approach is the level of risk acceptable for HTFOEL determination. Alternatively, “as low as reasonably achievable” may also be considered. Regardless, all HTFOELvalues for N-nitrosamines may need revaluation.

References U.S. Environment Protection Agency's Integrated Risk Information System (IRIS) on N- Nitrosodiethylamine (55-18-5) from the National Library of Medicine's TOXNET System, November 1, 1994 IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. S7 67 (1987) Pohanish, R.P. (ed). Sittig's Handbook of Toxic and Hazardous Chemical Carcinogens 5th Edition Volume 1: A-H,Volume 2: I-Z. William Andrew, Norwich, NY 2008, p. 1887 USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) To Present

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3.7.2.3 N-Nitrosodimethylamine (CAS No. 62-75-9)

The HTFOEL for N-nitrosodimethylamine (also known as dimethylnitrosamine) is 0.3 ppbv based on a MAK value set by Germany and the Netherlands.

Literature Search

A literature search focusing on new toxicity or regulatory data for N-nitrosodimethylamine was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on N-nitrosodimethylamine: DOE PAC, HazMap, IRIS, HSDB, ITER, RTECS, CCRIS, GeneTox, CTD, and MAK values.

No new toxicity data was discovered; however, relevant changes were made to German MAK values for N-nitrosamines. German MAK values were used to establish HTFOELs for N-nitrosamines within the COPC list. In recent documentation (2015), German MAK values for N-nitrosamines have been removed, and instead, documentation suggests that exposure should be minimized due to carcinogenicity concerns (Deutsche Forschungsgemeinschaft 2015). This is consistent with ACGIH and OSHA guidelines of “as low as reasonably achievable” (ACGIH 2012, NIOSH 2005). The US DOE has established PAC (Revision 29) for N-nitrosodimethylamine. The State of Florida has set a drinking water concentration of 7.5 µg/L for N-nitrosodiethylamine (HSDB). California and Massachusetts have adopted 0.01 µg/L for drinking water criteria (HSDB).

PAC for N-nitrosodimethylamine.

Classification Protective Action Critera (PAC) (mg/m3) PAC-1 0.082 PAC-2 0.9 PAC-3 10

Toxicity

Hepatotoxin. May cause liver injury and jaundice (ICSC, HazMap).

Potential symptoms of overexposure are nausea, vomiting, diarrhea and abdominal cramps; headache; fever; enlarged liver, jaundice; reduced function of liver, kidneys and lungs (O’Neil, 2006).

In persons with acute NDMA poisoning due to systemic exposure, headaches, a feeling of generalized malaise, fever, and weakness often occur. Gastrointestinal effects are frequent and include abdominal cramping and nausea. Vomiting and diarrhea occur within hours of absorption. Liver enlargement and jaundice may follow (Haddad, 1998).

Carcinogenicity

Classified as B2, probable human carcinogen (IRIS 1994)

Group 2A, probably carcinogenic to humans (IARC 1987)

A3 Confirmed animal carcinogen with unknown relevance to humans (ACGIH 2012)

N-Nitrosodimethylamine: reasonably anticipated to be a human carcinogen (US Health and Human Services, 2012)

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Oral slope factor: 51 (mg/kg/day)-1 (IRIS)

Drinking water unit risk: 1.4×10-3 (µg/L)-1 (IRIS)

Inhalation Unit Risk: 1.4×10-3 (µg/m3)-1 (IRIS)

Irritation Indications

A skin, eye, and, respiratory tract irritant (ICSC, HazMap).

Odor Threshold

A faint, characteristic odor (NIOSH, 2010)

Threshold low: 0.0079 ppm (AIHA, HazMap)

Threshold low: 0.01 ppm (AIHA, HazMap)

Mixture Interactions

May have additive effects with other N-nitrosamines.

Co-exposure to ethanol has been demonstrated to reduce N-nitrosodimethylamine carcinogenic toxicity (Teschke, 1983; Swann 1984)

Summary and Recommendations

It is recommended that the HTFOEL for N-nitrosodimethylamine be reevaluated due to changes in MAK values used in previous HTFOEL determination. Previously, other methods utilizing the cancer oral slope value were evaluated and considered for HTFOEL determination for all N-nitrosamines in the COPC list using a similar approach used by Toxicology Excellence for Risk Assessment (TERA) for risk specific dose (RSD) and risk specific concentration (RSC) calculations of N-nitrosodiethylamine (see N- nitrosodiethylamine). Former approaches resulted in similar HTFOEL values as previous MAK values. As such, these approaches may be worth revisiting. A major decision point within this approach is the level of risk acceptable for HTFOELdetermination. Alternatively, “as low as reasonably achievable” may also be considered. PAC values have been established for acute exposures should be considered. All HTFOELvalues for N-nitrosamines may need revaluation.

References Deutsche Forschungsgemeinschaft. List of MAK and BAT Values 2015. Maximum Concentrations and Biological Tolerance Values at the Workplace. Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Report No. 51 American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2012, p. 45 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005) O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1147

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Haddad, L.M. (Ed). Clinical Management of Poisoning and Drug Overdose 3rd Edition. Saunders, Philadelphia, PA. 1998., p. 1277 IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. S7 67 (1987) U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on N- Nitrosodimethylamine (62-75-9) from the National Library of Medicine's TOXNET System, November 1, 1994 American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2012, p. 45 U.S. Department of Health & Human Services/National Toxicology Program; Twelfth Report on Carcinogens (2011); N-Nitrosodimethylamine (62-75-9). Available from, as of August 4, 2012: http://ntp.niehs.nih.gov/ NIOSH. NIOSH Pocket Guide to Chemical Hazards. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from, as of May 29, 2012: http://www.cdc.gov/niosh/npg/ Teschke R et al; J Cancer Res Clin Oncol 106 (1): 58-64 (1983) Swann PF; IARC Sci Publ 57: 501-12 (1984)

3.7.2.4 N-Nitrosomethylethylamine (CAS No. 10595-95-6)

The HTFOELfor N-nitrosomethylethylamine (also known as methylethylnitrosamine) is 0.3 ppbv based on MAK values set by Germany and the Netherlands.

Literature Search

A literature search focusing on new toxicity or regulatory data for n-nitrosomethylethylamine was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on n-nitrosomethylethylamine: HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, Toxline, PubMed, and MAK values.

No new toxicity data was discovered; however, relevant changes were made to German MAK values for N-nitrosamines. German MAK values were used to establish HTFOELsfor N-nitrosamines within the COPC list. In recent documentation (2015), German MAK values for N-nitrosamines have been removed, and instead, documentation suggests that exposure should be minimized due to carcinogenicity concerns (Deutsche Forschungsgemeinschaft 2015). This is consistent with ACGIH and OSHA guidelines of “as low as reasonably achievable”. The State of Florida has set a drinking water concentration of 7.5 µg/L for N-nitrosomethylethylamine (HSDB, EPA 1993).

Toxicity

Causes liver injury in high-dose animal studies (HazMap).

Carcinogenicity

Classified as B2, probable human carcinogen (HSDB, IRIS 2000)

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Oral slope factor is 22 (mg/kg/day)-1 (IRIS 2000)

Group 2B, possibly carcinogenic to humans (HSDB, IARC 1987)

Toxicology Excellence for Risk Assessment (TERA) calculated a risk specific dose (RSD) for N- nitrosomethylethylamine. TERA utilized a 1 in 100,000 (E-5) risk level and the EPA oral slope factor to derive the RSD of 4.5×10-7 mg/kg/day (1×10-5 / 22 = 4.5×10-7) (ITER).

Irritation Indications

An irritant (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive effects with other N-nitrosamines.

Summary and Recommendations

It is recommended that the HTFOELfor N-nitrosomethylethylamine be reevaluated due to changes in MAK values used in previous HTFOELdetermination. Previously, other methods utilizing the cancer oral slope value were evaluated and considered for HTFOELdetermination for all N-nitrosamines in the COPC list using a similar approach used by TERA for RSD calculations. Former approaches resulted in similar HTFOELvalues as previous MAK values. As such, these approaches may be worth revisiting. A major decision point within this approach is the level of risk acceptable for HTFOELdetermination. Alternatively, “as low as reasonably achievable” may also be considered. Regardless, all HTFOELvalues for N- nitrosamines may need revaluation.

References

Deutsche Forschungsgemeinschaft. List of MAK and BAT Values 2015. Maximum Concentrations and Biological Tolerance Values at the Workplace. Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area. Report No. 51

USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) To Present

U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on N- Nitroso-N-methylethylamine (10595-95-6) Available from, as of March 15, 2000: http://www.epa.gov/iris/

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. S7 68 (1987)

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3.7.2.5 N-Nitrosomorpholine (CAS No. 59-89-2)

The HTFOELfor N-nitrosomorpholine is 0.6 ppbv based on a maximum workplace concentrations (MAK) value set by Germany and the Netherlands for N-nitrosodimethylamine adjusted by a relative carcinogenic potency ranking (See Industrial Hygiene Chemical Vapor Technical Basis Rev. 1).

Literature Search

A literature search focusing on new toxicity or regulatory data for N-nitrosomorpholine was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on N-nitrosomorpholine: DOE PAC, HazMap, HSDB, RTECS, CCRIS, GeneTox, Toxline, PubMed, CTD, and MAK values.

No new toxicity data was discovered; however, relevant changes were made to German MAK values for N-nitrosamines. German MAK values were used to establish HTFOELsfor N-nitrosamines within the COPC list. In recent documentation (2015), German MAK values for N-nitrosamines have been removed, and instead, documentation suggests that exposure should be minimized due to carcinogenicity concerns (Deutsche Forschungsgemeinschaft 2015). This is consistent with ACGIH and OSHA guidelines of “as low as reasonably achievable”. The US DOE has established PAC (Revision 29) for N- nitrosomorpholine.

PAC for N-nitrosomorpholine.

Classification Protective Action Critera (PAC) (mg/m3) PAC-1 0.85 PAC-2 9.3 PAC-3 56

Toxicity

Causes kidney, liver, and lung injury in high-dose animal studies (HazMap).

Carcinogenicity

Group 2B, possibly carcinogenic to humans (IARC 1987)

N-Nitrosomorpholine: reasonably anticipated to be a human carcinogen (US Health and Human Services, 2012)

Irritation Indications

May cause irritation (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive effects with other N-nitrosamines.

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Summary and Recommendations

It is recommended that the HTFOELfor N-nitrosomorpholine be reevaluated due to changes in MAK values used in previous HTFOELdetermination. Previously, other methods utilizing the cancer oral slope value were evaluated and considered for HTFOELdetermination for all N-nitrosamines in the COPC list using a similar approach used by Toxicology Excellence for Risk Assessment (TERA) for risk specific dose (RSD) and risk specific concentration (RSC) calculations of N-nitrosodiethylamine (see N- nitrosodiethylamine). Former approaches resulted in similar HTFOELvalues as previous MAK values. As such, these approaches may be worth revisiting. One potential drawback of that method for N- nitrosomorpholine is that oral slope values have not been established. A major decision point within this approach is the level of risk acceptable for HTFOELdetermination. Alternatively, “as low as reasonably achievable” may also be considered. PAC values have been established for acute exposures should be considered. All HTFOELvalues for N-nitrosamines may need revaluation.

References

U.S. Department of Health & Human Services/National Toxicology Program; Twelfth Report on Carcinogens (2011); N-Nitrosomorpholine (59-89-2). Available from, as of August 4, 2012: http://ntp.niehs.nih.gov/

3.7.2.6 N-Nitroso-n-butyl-1-butanamine (CAS No. 924-16-3)

Previously, N-nitroso-n-butyl-1-butanamine (also known as N-Nitrosodibutylamine or dibutyl nitrosamine) was not previously recognized as a COPC. Thus, HTFOELor OEL has not been determined. Other N-nitrosoamine compounds have been assigned a HTFOELof 0.1 ppv based on a MAK value set by Germany and the Netherlands for N-nitrosodimethylamine.

Literature Search

A literature search focusing on toxicity and regulatory data for N-nitroso-n-butyl-1-butanamine was conducted August 19, 2016. Using standardized search criteria, the following databases were identified as containing active records on N-nitroso-n-butyl-1-butanamine: HazMap, HSDB, IRIS, ITER, CCRIS, RTECS, Genetox, CTD, and CPDB.

A good amount of toxicity data was identified for N-nitroso-n-butyl-1-butanamine. The primary toxicity concern appears to be cancer, where the compound is either labeled as a possible or potential carcinogen (see Carcinogenicity). No regulatory data for occupational exposure was found.

Toxicity

Effects in high-dose animal studies include acute tubular necrosis and cardiomyopathy (HazMap).

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Carcinogenicity

Classified as B2; probable human carcinogen (HSDB, IRIS 1994).

Group 2B: The agent is possibly carcinogenic to humans (HSDB, IARC 1987).

N-Nitrosodi-n-butylamine: reasonably anticipated to be a human carcinogen (HSDB, NTP 2009).

Oral slope factor is 5.4 per (mg/kg)/day (IRIS).

Inhalation unit risk is 1.6×10-3 per (µg/m3) (IRIS).

Irritation Indications

May cause irritation (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive effects with other N-nitrosamines.

Summary and Recommendations

It is recommended that the HTFOELfor N-nitroso-n-butyl-1-butanamine be established using similar criteria as other N-nitrosamines. We have recommended that other N-nitrosamines undergo reevaluation due to changes in MAK values, which were used as the basis in previous HTFOELdetermination. Utilizing IRIS-derived inhalation unit risk and oral slope factors may be prudent for determining an HTFOEL. These risk factors have been established for N-nitroso-n-butyl-1-butanamine. By utilizing this approach, an acceptable level of risk will need to also be determined for HTFOELcalculation. Alternatively, “as low as reasonably achievable” may also be considered as is a common guideline for occupational exposure to carcinogens. Regardless, all HTFOELvalues for N-nitrosamines need revaluation.

References

U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on N-Nitroso-di-n- butylamine (924-16-3) from the National Library of Medicine's TOXNET System, November 1, 1994.

DHHS/National Toxicology Program; Eleventh Report on Carcinogens: N-Nitrosodi-n-butylamine (924- 16-3) (January 2005). Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s125nitr.pdf

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3.8 Nitrites and Nitrates

3.8.1 Previous Assessment

3.8.1.1 Short-Chain Alkyl Nitrites: n-Butyl nitrite (CAS# 544-16-9), Ethyl nitrite (CAS# 109-95-5), and Methyl nitrite (CAS# 624-91-1)

The principal toxic effect of exposures to volatile organic nitrites results from methemoglobinemia. Evidence indicates that the methemoglobinemia is mediated by the nitrite ion after the organic nitrite is oxidized; therefore, it should be possible to set an HTFOELfor the family of organic nitrites of interest. The ACGIH has suggested a TLV of 1 ppm for the related organic volatile nitrite, isobutyl nitrite. Using the TLV for isobutyl nitrite and applying a safety margin for chemical differences, the proposed HTFOELfor the nitrite family is 0.1 ppm (100 ppb).

Toxicology Summary

- 2+ Nitrate (NO2 ) is a naturally occurring inorganic ion. Nitrites react with the iron (Fe ) of deoxyhemoglobin and form methemoglobin, resulting in iron incapable of transporting oxygen (Fe3+). The principal toxicology of nitrite exposures stems from methemoglobinemia and includes cyanosis, cardiac dysrhythmias, hemolytic anemia, circulatory failure, and progressive central nervous system effects. Children are especially at risk from oral exposures.

Volatile organic nitrites (e.g., butyl and amyl nitrite) are in medications and drugs of abuse. Production of nitric oxide from exposures to several nitrites has been observed (Cederqvist et al. 1994), and is likely to represent a common mechanism between chemicals of this class. Cyanosis is the major effect seen in animals following inhalation exposures to butyl nitrite. In rats, the LC50s for the primary three nitrites of interest were 176, 160, and 420 ppm/4 hours for methyl, ethyl, and butyl nitrite, respectively (Klonne et al. 1987). No reports on chronic effects from nitrite exposures were found.

The potential of nitrites to cause cancer in humans is unknown. Isobutyl nitrite vapor was mutagenic in the Ames assay (Mirvish et al. 1993) and in salmonella tests (NTP 1996). Several nitrites have been shown to be mutagenic in vitro, including n-butyl, isobutyl, iso-amyl, sec-butyl, and n-propyl in mice lymphoma cells (Dunkel et al. 1989), and methyl nitrite (with and without an S9 activating system) in Salmonella (Tornqvist et al. 1983).

Although no in vivo animal carcinogenicity studies were identified for n-butyl, ethyl, or methyl nitrites, a two-year bioassay with the structurally similar isobutyl nitrite was reported (NTP 1996). In the two-year inhalation studies, there was “clear evidence” of increased incidences of alveolar and bronchiolar adenomas and carcinomas in rats, and some evidence of carcinogenic activity in B6C3F1 mice (NTP 1996). Based on the results of this study, ACGIH has recommended that isobutyl nitrite be given the notation of Confirmed Animal Carcinogen with Unknown Relevance to Humans (A3).

Summary and Recommendations

The most robust set of toxicological data were for butyl nitrite. A single study did show that the LC50 for nitrites was lowest, with the smaller side chains (methyl ≈ ethyl < butyl). In reviewing the available exposure guidelines for organic nitrites, only an ACGIH guideline for isobutyl nitrite was found. An additional safety factor of 10 is proposed to account for chemical differences between isobutyl nitrite and methyl- or ethyl- nitrite. Since the TLV for isobutyl nitrite has been set by ACGIH at 1 ppm, a proposed HTFOELfor the family of short-chain alkyl nitrites (such as methyl, ethyl, and butyl) is 0.1 ppm. As

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additional and appropriate new data become available for nitrites, it would be reasonable to reassess the appropriateness of basing the alkyl nitrite’s HTFOELupon isobutyl nitrite.

3.8.1.2 Short-Chain Alkyl Nitrates Methyl Nitrate (CAS #598-58-3), Ethyl Nitrate (CAS # 625-58-1), Butyl Nitrate (CAS # 120-92-3), and Propyl Nitrate (CAS # 627-13-4)

A HTFOELis proposed for the short-chain alkyl nitrates (methyl, ethyl, and butyl) based on a comprehensive review of the available toxicology literature. These four nitrates are structurally similar and consist of a one- to four-carbon alkyl side-chain and a nitrite functional group. The principal toxic effects of exposures to volatile short-chain alkyl nitrates result from methemoglobinemia. Nitrates are converted to nitrites, and the toxicity is mediated by the nitrite ion after the organic nitrite is oxidized; therefore, it should be possible to set a HTFOELfor the family of short-chain alkyl nitrates of interest. Although the organic nitrate identified with the most available data is propyl nitrate, the nitrates of interest are methyl and ethyl nitrate. A TLV of 25 ppm has been assigned by ACGIH for n-propyl nitrate. Based on the uncertainty associated with chemical differences between propyl nitrate and methyl and ethyl nitrate, a HTFOELof 8 ppm is proposed for these nitrates.

Methodology

To identify and access available toxicity data on organic nitrates, a number of Internet data bases including PUBMED, TOXNET, TOMES, the EPA-IRIS, and IARC were searched, and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile to develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OEL for ethyl, methyl, or butyl nitrate has been proposed by OSHA or ACGIH. However, NIOSH, OSHA, and ACGIH have all set OELs for propyl nitrate (see Table 3.11). From 1971 to 2001, the TLVs have not changed and are 25 or 40 ppm, depending on the length of exposure, for all agencies.

Table 3.11. Exposure Limit Values for Propyl Nitrate

Agency Description Value (ppm) Date1

ACGIH TLV-STEL 40 2001

ACGIH TLV-STEL 25 2001

CDC2 IDLH 500 1994

NIOSH STEL 40 1994

NIOSH REL 25 1994

OSHA PEL-STEL 40 1989

OSHA PEL-TWA 25 1994

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1The date listed is the most recent found; in some cases an earlier OEL had been proposed.

2See NTIS (1995).

IDLH = Immediately dangerous to life or health

PEL = Permissible exposure limit

REL = Recommended exposure limit

STEL = Short-term Exposure Limit

TWA = Time-weighted Average

Toxicology Summary

Organic nitrates are used in the synthesis of other compounds as a room deodorizer propellant and in rocket propellants. Butyl nitrate and the related amyl nitrate are in the inhalant drugs of abuse known as Poppers and, therefore, exposures to these nitrates can be high. Butyl nitrate is a degradation product of tributyl phosphate (Tashiro et al. 2000). Environmental contamination with nitrates often stems from nitrogen-containing fertilizers. In the environment, organic nitrogen is converted to nitrite and nitrate by microbes, and nitrite is oxidized to nitrate so nitrate is found in high levels in groundwater. Worldwide, nitrate-contaminated groundwater is common, especially around farming communities where nitrogen- containing fertilizers are used. Epidemiological studies indicate that nitrate contamination of water supplies may be associated with risk of Type I diabetes, but only at concentrations greater than 10 to 25 mg/L (Van Maanen et al. 2000).

- - Nitrate (NO3 ) and nitrite (NO2 ) are naturally occurring inorganic ions. Nitrates are converted to nitrites by intestinal bacteria. Nitrites, in turn, react with the iron (Fe2+) of deoxyhemoglobin and form methemoglobin, resulting in iron incapable of transporting oxygen (Fe3+). The principal toxicity of nitrate exposures stems from methemoglobinemia and includes cyanosis, cardiac dysrhythmias, hemolytic anemia, circulatory failure, and progressive central nervous system effects. Children are especially at risk from oral exposures. The EPA has derived a reference dose (RfD) of 1.6 mg/kg/day for inorganic nitrate (IRIS 2002); a RfC has not been derived.

Orally, nitrates are rapidly absorbed from the small intestine. Regardless of exposure route, nitrates are delivered to the intestine via blood circulation and converted, primarily by bacterial oxidation, to the more reactive nitrites; therefore, nitrites are expected to have lower LD50 and LC50 values than nitrates (Bruning-Fann and Kaneene 1993). The LC50 value for methyl nitrate in rats is 1275 ppm/4 hr; the LC50 for the corresponding nitrite is seven times lower (176 ppm/4 hr)1. Organic nitrites are rapidly converted in the liver to inorganic nitrite. The toxic mechanism of action leading to methemoglobinemia proceeds through either direct oxidation of the heme iron by the nitrite, or through production of NO from the nitrite (Cederqvist et al. 1994). Production of nitric oxide from exposures to several nitrites and nitrates has been observed (Cederqvist et al. 1994) and is likely to represent a common mechanism among chemicals of this class. The risk of methemoglobinemia from exposure of nitrate depends on the dose of nitrate and on the number and type of enteric bacteria.

1 Refer to the Hazardous Substances Data Bank online: http://csi.micromedex.com/assm.asp?HS7197.

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The potential of nitrates to cause cancer in humans is unknown. Nitrates can react with amino acids to form nitrosamines, which can cause cancer in animals. An epidemiological study in workers exposed to nitrate fertilizers has shown a slight increase in stomach cancer incidence, but no increase in total cancer (Zandjani et al. 1994). Other studies have shown no relationship between occupation exposures to nitrate containing dust and any cancers (Fraser et al. 1982, 1989).

Data Analysis

No guidelines have been established for methyl, ethyl, or butyl nitrate (C-1, C-2, and C-4 side-chains, respectively). Exposure-level guidelines have been established by several agencies for propyl nitrate (see Table 3.11). The ACGIH TLVs were recommended based on acute and subchronic animal studies. Propyl nitrate causes sensory irritation at exposure levels much lower than needed to produce measurable methemoglobinemia (Rinehart et al. 1958). Therefore, there were no relevant human studies identified by the ACGIH. The TLV was based on the acute inhalation exposure LC50 in dogs (2000 to 2500 ppm) with a “reasonable uncertainty” factor. The LD50 for methyl nitrate in rats is about two times lower than the LC50 value reported for propyl nitrate in dogs. Due to the potential increase in toxicity of the shorter-chain nitrates and the uncertainty associated with chemical differences, an additional uncertainty factor of 10 is recommended for the proposed HTFOELfor propyl nitrate, which results in an HTFOELof 2.5 ppm. The ACGIH also concluded that there is insufficient data to warrant skin or carcinogenicity notations for propyl nitrate.

Summary and Recommendations

The most robust set of toxicological data were for propyl nitrate. The LC50 for acute inhalation of methyl nitrate in rats is 1275 ppm/4 hours, the acute LC50 for propyl nitrate in dogs is 2000 to 2500 ppm/4 hours. Several agencies have established OELs for propyl nitrate, and these values were used to propose an HTFOELfor methyl and ethyl nitrate. An additional safety factor of 3 is proposed to account for chemical differences between propyl nitrate and the shorter-chain nitrates. Since the TLV for propyl nitrate has been set by ACGIH, OSHA, and NIOSH at 25 ppm (TWA), a proposed HTFOELfor the family of short- chain alkyl nitrates (methyl and ethyl) is 8 ppm. As additional new data become available for nitrates, it would be reasonable to reassess the appropriateness of basing the alkyl nitrate’s HTFOELupon propyl nitrate.

3.8.1.3 Dinitrates: 1,3-Propanediol, dinitrate (CAS # 3457-90-7), 1,4-Butanediol, dinitrate (CAS # 3457-91-8), 1,5-Pentanediol, dinitrate (CAS # 3457-92-9), and 1,2,3-Propantriol, 1,3-dinitrate (CAS # 623-87-0)

A HTFOELis proposed for the dinitrates, based on a comprehensive review of the available toxicology literature. The principal toxic effects of exposures to nitrates result from methemoglobinemia. Dinitrates are also vasodilators, but the mechanism of action is incompletely understood. The development of proposed HTFOELsfor the dinitrates are based on short-chain aliphatic nitrites, propylene glycol dinitrate, and nitroglycerine. Nitrates are converted to nitrites, and the methemoglobinemia is mediated by the nitrite ion after the organic nitrite is oxidized. The ACGIH has assigned TLVs of 0.05 ppm for ethylene glycol dinitrate, propylene glycol dinitrate, and nitroglycerine. The ACGIH TLV has already considered the incomplete understanding of the mechanism of action and the use of surrogate chemicals, therefore, a HTFOELof 0.05 ppm is proposed for these dinitrates.

Methodology

To identify and access available toxicity data on dinitrates, a number of Internet data bases, including PUBMED, TOXNET, TOMES, the EPA-IRIS, and IARC were searched, and summary toxicity profiles

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were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OELs are available for the dinitrates found in the tank waste headspace. The ACGIH has set TLVs of 0.05 ppm for the related dinitrates propylene glycol dinitrate, (ACGIH 2001y), ethylene glycol dinitrate (ACGIH 2001k) and the trinitrate, nitroglycerine (ACGIH 2001t). The TLVs for all of these compounds are based on assessment of propylene glycol dinitrate (ACGIH 2001y). OSHA and NIOSH have also set REL and PELs for propylene glycol at a TWA of 0.05 ppm, respectively.

Toxicology Summary

Very little data were found concerning the toxicity of these dinitrates. By analogy with propylene glycol dinitrate, and other nitrates, a probable toxicity profile can be estimated. When ingested orally, nitrates are rapidly absorbed from the small intestine. Regardless of exposure route, nitrates are delivered to the intestine via blood circulation and converted, primarily by bacterial oxidation, to more reactive nitrites. Organic nitrites are rapidly converted in the liver to inorganic nitrite. The toxic mechanism of action leading to methemoglobinemia proceeds through either direct oxidation of the heme iron by the nitrite or through production of NO from the nitrite (Cederqvist et al. 1994). Production of nitric oxide from exposures to several nitrites and nitrates has been observed (Cederqvist et al. 1994) and is likely to represent a common mechanism among chemicals of this class. The risk of methemoglobinemia from exposure of nitrate depends on the dose of nitrate and on the number and type of enteric bacteria.

The related compound with the most available toxicological information is propylene glycol dinitrate (CAS# 6423-43-4). The primary toxicological endpoints of concern for propylene glycol dinitrate exposures are its effects on the cardiovascular and central nervous systems. Human exposures have led to symptoms of dizziness, eye irritation, nasal congestion, heart palpitations, and chest pain. Dizziness has been reported for inhalation exposures as low as 1.5 ppm, and the threshold for mild headache was 0.5 ppm (reviewed in: National Research Council 2001).

Data Analysis

No guidelines have been established for the dinitrates within the tank waste headspace. The ACGIH has set TWA-TLV of 0.05 ppm for related dinitrates based primarily on the data available for propylene glycol dinitrate. This TLV is 500-fold lower than the ACGIH TWA for n-propyl nitrate (see Section 5.9.2). Due to the vasodilation effects from exposures to dinitrates and potential increase in toxicity of the dinitrates over the nitrates, it is proposed that the HTFOELof 0.05 ppm set by ACGIH for propyl glycol dinitrate, ethyl glycol dinitrate, and nitroglycerine be applied to the dinitrates within the tank waste headspace.

Summary and Recommendations

The most robust set of toxicological data were for propylene glycol dinitrate. The ACGIH has used this dataset to base HTFOELsfor other di- and tri-nitrates. By analogy with the short-chain aliphatic mono- nitrates, this HTFOELof 0.05 ppm is conservative for these dinitrates. As additional new data become available for dinitrates, it would be reasonable to reassess the proposed HTFOEL.

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3.8.1.4 1-Nitrate 1,2,3-propanetriol (CAS # 624-43-1)

A HTFOELis proposed for 1-nitrate 1,2,3-propanetriol based on a comprehensive review of the available toxicology literature. 1-Nitrate 1,2,3-propanetriol consists of a nitrate functional group and a glycerol sidechain. The principal toxic effects of exposures to nitrates result from methemoglobinemia. Nitrates are converted to nitrites, and the methemoglobinemia is mediated by the nitrite ion after the organic nitrite is oxidized. Very high exposures to glycerol mist may result in hemolysis, hemoglobinuria, and renal failure. The ACGIH has assigned TLVs of 2.65 and 25 ppm for glycerin mist and n-propyl nitrate vapor, respectively. Following metabolism in the intestine and liver, the likely metabolites will be inorganic nitrite and propylene glycol. Since propylene glycol is relatively non-toxic, the proposed HTFOELfor 1- nitrate 1,2,3-propanetriol is based on the 25 ppm OEL for n-propyl nitrate with a safety factor of 3 for uncertainties between chemical differences. The proposed HTFOELfor 1-nitrate 1,2,3-propanetriol is 8 ppm.

Methodology

To identify and access available toxicity data on 1-nitrate 1,2,3-propanetriol, a number of On-Line data bases, including PUBMED, TOXNET, TOMES, and IARC were searched, and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OEL for 1-nitrate 1,2,3-propanetriol has been proposed by either OSHA or ACGIH. NIOSH, OSHA, and ACGIH have all set 25 ppm TWA OELs for propyl nitrate. Likewise, OSHA and ACGIH have both set an OEL of 10 mg/m3 (2.65 ppm) for glycerin particulate exposures.

Toxicology Summary

Very little data were found concerning the toxicity of 1-nitrate 1,2,3-propanetriol. By analogies with propyl nitrate, nitroglycerine, glycerin, and propylene glycol, a probable toxicity profile can be estimated. When ingested orally, nitrates are rapidly absorbed from the small intestine. Regardless of exposure route, nitrates are delivered to the intestine via blood circulation and converted, primarily by bacterial oxidation, to more reactive nitrites. Organic nitrites are rapidly converted in the liver to inorganic nitrite. The toxic mechanism of action leading to methemoglobinemia proceeds through either direct oxidation of the heme iron by the nitrite, or through production of NO from the nitrite (Cederqvist et al. 1994). Production of nitric oxide from exposures to several nitrites and nitrates has been observed (Cederqvist et al. 1994) and is likely to represent a common mechanism among chemicals of this class. The risk of methemoglobinemia from exposure of nitrate depends on the dose of nitrate and on the number and type of enteric bacteria.

Data Analysis

No guidelines have been established for 1-nitrate 1,2,3-propanetriol. Exposure level guidelines have been established by several agencies for propyl nitrate (see alkyl nitrates HTFOEL). The ACGIH TLVs were recommended based on acute and subchronic animal studies. Propyl nitrate causes sensory irritation at exposure levels much lower than needed to produce measurable methemoglobinemia (Rinehart et al. 1958). Propylene glycol is relatively non-toxic, and human ingestion of up to 100 ml primarily leads to gastrointestinal upset. Due to the uncertainty associated with chemical differences, an additional uncertainty factor of 3 is recommended for the proposed HTFOELfor 1-nitrate 1,2,3-propanetriol, which

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results in an HTFOELof 8 ppm. The proposed HTFOELfor glycerol is based on mist exposures, rather than vapor, and is therefore not applicable for vapors in the tank waste headspace.

Summary and Recommendations

The most likely active moiety of 1-nitrate 1,2,3-propanetriol will be the nitrite following metabolism in the gastrointestinal tract and liver and leaving inorganic nitrite and propylene glycol. Alternative metabolism may lead to the production of glycerin. Inorganic nitrite and glycerin have more toxicity associated with exposures than does propylene glycol. Based on the supposition that the metabolism will follow that typical for alkyl nitrates, an HTFOELof 8 ppm, based on n-propyl nitrate is proposed. As additional new data become available for 1-nitrate 1,2,3-propanetriol, it would be reasonable to reassess the proposed HTFOEL.

3.8.2 Current Summaries

3.8.2.1 Methyl nitrite (CAS No. 624-91-9)

The HTFOELfor methyl nitrite is 0.1 ppmv based on a point of departure OEL of 1 ppmv for isobutyl nitrite (CAS number: 542-56-3) with an uncertainty factor of 10× (3× for unbranched and 3× for short- chain alkyl nitrites). OEL for isobutyl nitrite was set by OSHA, ACGIH and NIOSH.

Literature Search

A literature search focusing on new toxicity or regulatory data for methyl nitrite was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on methyl nitrite: HazMap, HSDB, PubMed, RTECS, and Toxline.

No new regulatory data was discovered. A recent case report and rat toxicity study was available.

Case report: Methyl nitrite was found to be a potent cyanosing agent for workers synthesizing a rubber antioxidant. Six cases of methyl nitrite intoxication are described, consisting initially of dizziness and later headache and palpitation, the last more pronounced in two workers who consumed alcohol after exposure at work. All men responded satisfactorily to bed rest for 12 hr and inhaling of oxygen for about 2 hr. Atmospheric concentrations in the plants where the men had been affected, simulating the conditions at the time of intoxications, indicated that "50 ppm is the uppermost limit of safety". Another incident, when it was estimated that workers were exposed to 50-100 ppm, caused cyanosis, dizziness, and nausea but complete recovery after exposure ceased. (HSDB, Wax 1994)

Rats demonstrated a median acute lethal concentration (LC50) at 176 ppm for 4 hr (HSDB, Bingham 2001).

Surrogate Literatures Search

A brief literature search for isobutyl nitrite was conducted using the HSDB and RTECS. ACGIH maintains a 1 ppm ceiling concentration TLV based on inhalation for isobutyl nitrite (RTECS, ACGIH 2013).

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Toxicity

Methyl nitrite caused methemoglobinemia in two workers at a phenylpropanolamine production plant (HazMap, Wax 1994).

Evaporating liquid can cause frostbite (HazMap).

Alkyl nitrites relax smooth muscles and cause vasodilation, increased heart rate, and decreased blood pressure.

Carcinogenicity

Mutagenic in the Ames test (HSDB, Bingham 2001)

Irritation Indications

No available data.

Odor Threshold

Alkyl nitrites have a distinctive fruity odor.

Mixture Interactions

Potential carcinogenetic mixture effects with N-nitroso compounds. (Toxline, Montesano 2008).

Alkyl nitrites interact with other vasodilators and can lead to rapid decrease in blood pressure.

Summary and Recommendations

There has been no new regulatory or toxicity data discovered that would necessitate HTFOELreevaluation for methyl nitrite or isobutyl nitrite (chemical surrogate). Therefore, it is recommended that the methyl nitrite HTFOELremain unchanged.

References

Wax PM, Hoffman RS. 1994. Methemoglobinemia: an occupational hazard of phenylpropanolamine production. J Toxicol Clin Toxicol. 32(3):299-303.

Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001), p. V4 619

American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2013.

Montesano R. Systemic Carcinogens (N-Nitroso Compounds) And Synergistic Or Additive Effects In Respiratory Carcinogenesis. Tumori, Vol. 56, pages 335-344, 59 references, 19701970.

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3.8.2.2 Butyl nitrite (CAS No. 544-16-1)

The HTFOELfor Butyl nitrite is 0.1 ppmv based on a point of departure OEL of 1 ppmv for isobutyl nitrite (CAS number: 542-56-3) with an uncertainty factor of 10× (3× for unbranched and 3× for short-chain alkyl nitrites) . OEL for isobutyl nitrite was set by OSHA, ACGIH and NIOSH.

Literature Search

A literature search focusing on new toxicity or regulatory data for Butyl nitrite was conducted June 30, 2016. Using standardized search criteria, the following databases were identified as containing active records on Butyl nitrite: CCRIS, HazMap, PubMed, RTECS and Toxline. No information on Butyl nitrite was identified in AEGL or PAC databases. No new regulatory data was discovered.

Case report

Neurotoxicity induced by alkyl nitrites (including butyl nitrite): Impairment in learning/memory and motor coordination. Effects observed at 5 ppm – 7 days. Lower doses not tested. (Cha et al. 2016).

Surrogate Literatures Search

A brief literature search for isobutyl nitrite was conducted using the HSDB and RTECS. ACGIH maintains a 1 ppm ceiling concentration TLV based on inhalation for isobutyl nitrite (RTECS, ACGIH 2013).

Toxicity

Butyl nitrite can induce methemoglobinemia and is a vasodilator (HazMap).

Carcinogenicity

Not available.

Irritation Indications

Irritant (Hazmap).

Odor Threshold

Alkyl nitrites have a distinctive fruity odor.

Mixture Interactions

Potential carcinogenetic mixture effects with N-nitroso compounds. (Toxline, Montesano 2008).

Alkyl nitrites interact with other vasodilators and can lead to rapid decrease in blood pressure.

Summary and Recommendations

There has been no new regulatory or toxicity data discovered that would necessitate HTFOELreevaluation for butyl nitrite or isobutyl nitrite (chemical surrogate). Therefore, it is recommended that the butyl nitrite HTFOELremain unchanged.

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References

American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2013.

Cha HJ, Kim YJ, Jeon SY, Kim YH, Shin J, Yun J, Han K, Park HK, Kim HS. Neurotoxicity induced by alkyl nitrites: Impairment in learning/memory and motor coordination. Neurosci Lett. 619:79-85, 2016.

Montesano R. Systemic Carcinogens (N-Nitroso Compounds) And Synergistic Or Additive Effects In Respiratory Carcinogenesis. Tumori, Vol. 56, pages 335-344, 59 references, 19701970.

3.8.2.3 Butyl Nitrate (CAS No. 928-45-0)

The HTFOELfor butyl nitrate is 8 ppmv based on a 8 hr time-weighted average (TWA)

TLV of 25 ppmv for propyl nitrate (CAS No. 627-13-4) set by OSHA, NIOSH and ACGIH with a 3× uncertainty factor.

Literature Search

A literature search focusing on new toxicity or regulatory data for butyl nitrate was conducted on May 25, 2016. Using standardized search criteria, the following databases were identified as containing active records for butyl nitrate: HazMap, PubMed, and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

A brief literature search for propyl nitrate was conducted using EPA PAC and HSDB. The US DOE has established PAC (Revision 29) for propyl nitrate. ACGIH maintains an 8 hr TWA-TLV of 25 ppm and 15 minSTEL of 40 ppm (HSDB, ACGIH 2008). NIOSH recommends an exposure limit 10 hr TWA 25 ppm (HSDB, NIOSH 2005) and a 15 min STEL of 40 ppm (HSDB, NIOSH 2001). OSHA recommends a PEL of 25 ppm (HSDB, 29 CFR 2004).

PAC for propyl nitrate.

Classification Protective Action Critera (PAC) (ppm) PAC-1 40 PAC-2 330 PAC-3 2000

Toxicity

Butyl nitrate causes hemolytic anemia and methemoglobinemia (HazMap).

Carcinogenicity

No available data.

Irritation Indications

No available data.

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Odor Threshold

No available data.

Mixture Interactions

No available data.

Summary and Recommendations

It is recommended that the HTFOELfor butyl nitrate remain unchanged. No new data or regulatory values were found for butyl nitrate. For the surrogate propyl nitrate, regulatory 8 and 10 hr TLVs remain at 25 ppm, and acute guidelines (STEL and PAC) remain at 40 ppm.

References American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 50 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases. U.S. Department of Health & Human Services, Public Health Service, Center for Disease Control & Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001. 29 CFR 1910.1000; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 10, 2004: http://www.gpoaccess.gov/ecfr

3.8.2.4 1,4-Butanediol dinitrate (CAS No. 3457-91-8)

The OEL for 1,4-Butanediol, dinitrate is 0.05 ppm based on a TLV of 0.05 ppm for propylene glycol dinitrate (6423-43-4) used as surrogate based on close structural similarity.

Literature Search

A literature search focusing on new toxicity data for 1,4-Butanediol dinitrate was conducted June 21, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on 1,4-Butanediol, dinitrate: HazMap, Toxline. No new information on 1,4-Butanediol, dinitrate for assessing OELs was identified. The surrogate propylene glycol dinitrate was identified in AEGL and PAC databases. OSHA and ACGIH websites indicate a TLV value of 0.05 ppm for propylene glycol dinitrate which is the same as used in the previous assessment of 1,4-Butanediol, dinitrate.

AEGL for propylene glycol dinitrate.

10 min 30 min 60 min 4 hr 8 hr

ppm

AEGL 1 0.33 0.33 0.17 0.050 0.030

AEGL 2 2.0 2.0 1.0 0.25 0.13

AEGL 3 16 16 13 8.0 5.3

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PAC values for propylene glycol dinitrate are the same as AEGLs.

Toxicity

1,4-Butanediol, dinitrate is associated with methemoglobinemia, anemia and hemolytic effects (HazMap Database).

Carcinogenicity

Irritation Indications

Odor Threshold

Mixture Interactions

None identified for surrogate (PubMed; mixture interaction and propylene glycol dinitrate as search terms).

Summary and Recommendations

Recently established AEGL1 values for an 8 hr exposure to the surrogate propylene glycol dinitrate indicate a lowered value (0.03 ppm) as compared with the original TLV of 0.05 for propylene glycol used in the previous assessment of toxicity. This new information should be considered for acute 1,4- Butanediol dinitrate exposures.

References

None.

3.8.2.5 1,2,3-Propanetriol, 1,3-dinitrate (CAS No. 623-87-0)

The HTFOELfor 1,2,3-propanetriol, 1,3-dinitrate is 0.05 ppmv based similarity to three other dinitrate compounds: ethylene glycol dinitrate (CAS No. 628-96-6), propylene glycol dinitrate (CAS No. 6423-43- 4), and nitroglycerine (CAS No. 55-63-0). For all three surrogate compounds, the ACGIH set an 8 hr TWA-TLV at 0.05 ppmv. Since all compounds are structurally similar, 0.05 ppmv was adopted as the HTFOELfor 1,2,3-propanetriol, 1,3-dinitrate.

Literature Search

A literature search focusing on new toxicity or regulatory data for 1,2,3-propanetriol, 1,3-dinitrate was conducted on May 23, 2016. Using standardized search criteria, the following databases were identified as containing active records on 1,2,3-propanetriol, 1,3-dinitrate: HazMap, RTECS, and Toxline.

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No new toxicity or regulatory data was discovered from this search.

Surrogate Literatures Search

A brief literature search for ethylene glycol dinitrate, propylene glycol dinitrate, and nitroglycerine was conducted using the HSDB, US DOE PAC, and EPA AEGL. ACGIH has maintained 0.05 ppmv as an 8 hr TWA TLV skin designation for all compounds (HSDB, ACGIH 2008 & 2010). NIOSH set the Recommended Exposure Limit, 15 min Short Term Exposure Limit at 0.1 mg/m3, skin designation, for nitroglycerine and ethylene glycol dinitrate (HSDB, NIOSH 2001 & 2005). For propylene glycol dinitrate, NIOSH set the Recommended Exposure Limit for 10 hr TWA at 0.05 ppm (0.3 mg/m3), skin designation (HSDB, NIOSH 2001). EPA has finalized AEGL values for propylene glycol dinitrate (NRC 2002). The US DOE established PAC for all three surrogate compounds. The PAC for propylene glycol dinitrate were adapted from the 1 hr AEGL values.

AEGL values for propylene glycol dinitrate

Final AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 0.33 0.33 0.17 0.05 0.03 Stewart 1974 AEGL-2 2 2 1 0.25 0.13 Stewart 1974 AEGL-3 16 16 13 8 5.3 Jones 1972 PAC for ethylene glycol dinitrate, propylene glycol dinitrate, and nitroglycerine.

Protective Action Critera (PAC) (ppm) Classification Ethylene Glycol Dinitrate Propylene Glycol Dinitrate Nitroglycerin PAC-1 0.016 0.17 0.011 PAC-2 0.2 1 0.22 PAC-3 80 13 8.1

Toxicity

1,2,3-Propanetriol, 1,3-dinitrate is known to cause methemoglobinemia and hemolytic anemia (HazMap Database). Propylene glycol dinitrate was reported to be an irritant and cause cardiovascular and central nervous system effects in humans (NRC 2002).

Carcinogenicity

No available data.

Irritation Indications

No available data.

Odor Threshold

No available data.

Mixture Interactions

No available data.

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Summary and Recommendations

Due to new acute guidelines (AEGLs and PACs) for surrogate compounds, it is suggested that the HTFOELfor 1,2,3-propanetriol, 1,3-dinitrate be reevaluated. Acute guidelines for surrogate compounds are different compared to each other, and the 8 hr AEGL-1 for propylene glycol dinitrate is lower than the current HTFOELvalue for 1,2,3-propanetriol, 1,3-dinitrate (0.03 vs. 0.05 ppm). Since it is unknown how structural differences between surrogates and 1,2,3-propanetriol, 1,3-dinitrate will relate to toxicity, reevaluation of 1,2,3-propanetriol, 1,3-dinitrate HTFOELis recommended.

References American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 50 American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH 2010, p. 30 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases. U.S. Department of Health & Human Services, Public Health Service, Center for Disease Control & Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005) NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases. U.S. Department of Health & Human Services, Public Health Service, Center for Disease Control & Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001. Stewart, R.D., J.E. Peterson, P.E. Newton, C.L. Hake, M.J. Hosko, A. J. Lebrun, and G.M. Lawton. 1974. Experimental human exposure to propylene glycol dinitrate. Toxicol. Appl. Pharmacol. 30:377-395. Jones, R.A., J.A. Strickland, and J. Siegel. 1972. Toxicity of propylene glycol 1,2-dinitrate in experimental animals. Toxicol. Appl. Pharmacol. 22:128-137. National Research Council (NRC), Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol 2, 2002.

3.9 Nitro Compounds

3.9.1 Previous Assessments

3.9.1.1 2-Nitro-1-propanol (CAS# 2902-96-7), 2-nitro-methylpropane (CAS# 594-70-7), and 1-nitrobutane (CAS# 627-05-4)

The principal toxic effects that stem from exposures to nitro compounds are irritation of eyes and respiratory tract and liver damage. Because no OELs are available for the nitro compounds of concern, 2- nitropropane (branched) and 1-nitropropane (unbranched) were chosen as surrogates with the most data and available OELs. The branched surrogate nitro compounds are more potent hepatotoxicants than the non-branched. Likewise, 2-nitropropane is an animal hepatocarcinogen, probably due to cellular damage and compensatory proliferation. The ACGIH has recommended TLVs of 10 and 25 ppm for 2- nitropropane (branched) and 1-nitropropane, respectively. 1-Nitrobutane is an unbranched nitro compound with a longer side chain than 1-nitropropane, the recommended OEL for 1-nitrobutane is 2.5

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ppm and was based on the OEL for 1-nitropropane with an uncertainty factor of 10 for minor structural differences and limited data. 2-Nitro-methylpropane is a branched nitro compound, with 1 more methyl group than 2-nitropropane, the recommended OEL for 2-nitro-methylpropane is 0.3 ppm and was based on the OEL for 2-nitropropane with an uncertainty factor of 10 for structural differences and 3 for limited toxicity data. 2-Nitro-1-propanol has an OH group that the other two chemicals of concern do not have. The recommended OEL for 2-nitro-1-propanol is 0.8 ppm based on the OEL for 1-nitropropane with an uncertainty factor of 10 for structural differences and an additional UF of 3 for limited data.

Methodology

To identify and access available toxicity data on 2-nitro-1-propanol, 2-nitro-methylpropane, and 1- nitrobutane, a number of Internet data bases including PUBMED, TOXNET, and TOMES were searched, and summary toxicity profiles were obtained and primary references identified. In addition, ACGIH documentation was reviewed for nitroethane, 2-nitropropane, and 1-nitropropane and relevant surrogate chemicals. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL.

Available Guidelines

No OELs have been proposed by OSHA or ACGIH for 2-nitro-1-propanol, 2-nitro-methylpropane, or 1- nitrobutane. However, ACGIH has assigned a TLV-TWA for the structural surrogates, nitroethane, 2- nitropropane, and 1-nitropropane. 1-Nitropropane is structurally very similar to 1-nitrobutane, differing only in one carbon. Likewise, 2-nitropropane is comparable to 2-nitro-methylpropane, differing in the side-chains; the former is secondary and the latter is a tertiary structure (Table 3.12). The ACGIH documentation for 1-nitropropane indicates that human exposures to 100 ppm or more caused irritation to the eyes and recommended a TLV of 25 ppm to minimize the potential of irritation to eyes and respiratory tract (ACGIH 2001u). The branched 2-nitropropane causes liver damage in laboratory animals, and hepatocellular carcinomas were noted in rats necropsied after 6 months of exposures to 207 ppm. For shorter exposure durations, progressive liver damage was observed, suggesting that the hepatocellular carcinomas were a consequence of cellular regeneration and proliferation secondary to damage. ACGIH recommended a TLV of 10 ppm for 2-nitropropane (ACGIH 2001v).

Table 3.12 Structure and Proposed OELS for Nitro compounds

OEL/proposed Basis OEL

1-Nitropropane 25 ACGIH

2-Nitropropane 10 ACGIH

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Nitroethane 100 ACGIH

2-Nitro-1-propanol 0.8 1-Nitropropane, UF 3 for limited data, UF 10 for structural differences

2-Nitro-methylpropane 0.3 2-Nitropropane, UF 30 for structural differences and limited data

1-Nitrobutane 2.5 1-Nitropropane UF 10 for lack of data

Table 3.13 Comparative toxicity parameters for nitro compound surrogates

NOEL1 LC50 LD50 Other (ppm) (mg/kg)

Surrogates

2-methyl-2-nitro-1-propanol 844-1480

1-nitropropane 101 ppm 250-500 LC1o =5000 ppm/3 hr

LClo = 714-4622 ppm/4.5 hr

2-nitropropane1 27 ppm 400 500-750

nitroethane 500 ppm

1 See text for exposures conditions.

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Toxicology Summary

No toxicity data were found for any of these nitro compounds, necessitating analysis based solely on structurally similar surrogates. For 2-nitro-methylpropane and 1-nitrobutane, the structural similarities to 2-nitropropane and 1-nitropropane, respectively, results in a reasonable level of confidence in using these surrogates. Structural differences for 2-nitro-1-propanol compared to the surrogates are more extensive (discussed in more detail below).

The surrogate for 1-nitrobutane, 1-nitropropane was not mutagenic in Salmonella tester strains. The primary endpoint of concern for 1-nitropropane exposures is irritation of the eyes and respiratory tract (ACGIH 2001u). Acute (1-3 hours) inhalation exposures in rats to 10,000 ppm resulted in conjuntival irritation, lacrimation, and slowed respiration. Rats exposed via inhalation for 7 hours/day, 5 days/week for ~22 months showed no gross or histopathological effects of the liver upon necropsy, and there was also no effect of exposure on organ or body weights or hematology (Table 3.13).

The endpoint of concern for 2-nitropropane is liver damage. The acute lethality of 2-nitropropane was less than the non-branched 1-nitropropane (See Table 3.13). Rats exposed to 2-nitropropane at 207 ppm for 7 hours/day, 5 days/week, for 6 months developed hepatocellular carcinomas. 2-Nitropropane was also positive for genotoxicity in the Ames test but not in other in vitro genotoxicity studies (i.e., Drosophilia recessive assay). Worker exposures to 20-45 ppm resulted in nausea, vomiting, diarrhea, anorexia, and headache.

2-Nitro-1-propanol is a branched nitro compound with a hydroxyl (-OH) group; no surrogate with these structural features and an OEL proposed by ACGIH or OSHA was identified. Some acute toxicity data for a structural analogue, 2-methyl-2-nitro-1-propanol (CAS# 76-39-1) was identified (See structure in Table 3.12). 2-Methyl-2-nitro-1-propanol is produced by the reaction of nitroparaffin with formaldehyde and is used in the production of other alkanolamines. The Dow Chemical Company has assessed the acute toxicity of 2-methyl-2-nitro-1-propanol as a part of its High Production Volume Chemical Challenge Test Plan and reported an LD50 of 845-1480 mg/kg in rats. 2-Methyl-2-nitro-1-propanol was not genotoxic in the Ames assay. The primary toxicological effects seen in laboratory animals following exposures to 2- methyl-2-nitro-1-propanol is eye irritation.

Summary and Recommendations

In reviewing the available toxicity data bases on nitro compounds with similar structures to 2-nitro-1- propanol, 2-nitro-methylpropane, and 1-nitrobutane the most robust data were found for 2-nitropropane and 1-nitropropane, which differ from 2-nitro-methylpropane and 1-nitrobutane by the addition of an extra carbon group, respectively. The ACGIH-recommended TWA-TLVs for 2-nitropropane and 1- nitropropane are 10 and 25 ppm, respectively. An UF of 10 is recommended to extrapolate a recommended OEL for 2 nitro-methylpropane from 2-nitropropane due to the structural differences inherent with the 3° branching of the sidechain compared to the 2° branching of the surrogate, which may result in metabolic and/or toxicological differences. Thus, the recommended OEL for 2-nitro- methylpropane is 0.3 ppm. An UF of 10 is recommended to extrapolate a recommended OEL for 1- nitrobutane from 1-nitropropane due to the lack of data for 1-nitrobutane. The structural differences between the non-branched compounds are less extreme than for the branched nitro compounds. Thus, the recommended OEL for 1-nitrobutane is 2.5 ppm.

2-Nitro-1-propanol is a nitro alcohol and therefore structurally different from the surrogates. Several nitro alcohols are used in high quantities in the manufacture of alkanolamines (The Dow Chemical Company 2002). The acute LD50 for 2-methyl-2-nitro-1-propanal is higher than the acute LD50 for the 2- nitropropane and 1-nitropropane surrogates. The recommended OEL for 2-nitro-1-propanol is 0.8ppm

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based on the TLV-TWA for 1-nitropropane with an UF of 10 for structural differences and an additional UF of 3 for limited data. 1-Nitropropane was used as the surrogate due to the listed toxicological endpoint of concern for the surrogate, 2-methyl-2-nitro-1-propanal, of sensory irritation, which was more similar to 1-nitropropane than 2-nitropropane.

3.9.2 Current Summary

3.9.2.1 2-Methyl-2-Nitropropane (CAS No. 594-70-7)

The HTFOELfor 2-methyl-2-nitropropane is 0.3 ppmv based on an 8 hr TWA-TLV of 1 ppmv for 2- nitropropane (CAS No. 79-46-9) recommended by ACGIH with a 30× uncertainty factor (10× lack of data and 3× for compound extrapolation).

Literature Search

A literature search focusing on new toxicity or regulatory data for 2-methyl-2-nitropropane was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-methyl-2-nitropropane: HazMap, CCRIS, PubMed, and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

A brief literature search for 2-nitropropane was conducted using the DOE PAC and HSDB.

Several regulatory values are published for 2-nitropropane. ACGIH has maintained a 10 ppm TLV for 8 hr TWA (HSDB, ACGIH 2008). ACGIH set Excursion Limit Recommendation: exposure to 3× of the TLV should occur for no more than 30 min and under no circumstances should exposures exceed 5× the TLV (HSDB, ACGIH 2008). ACGIH classifies 2-nitropropane as a confirmed animal carcinogen with unknown relevance to humans (A3) (HSDB, ACGIH 2008). OSHA has established a PEL of 25 ppm as an 8 hr TWA (HSDB, 29 CFR 1910.1000 2005). NIOSH considers 2-nitropropane to be a potential occupational carcinogen and recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration (HSDB, NIOSH 2003). NIOSH suggests medical monitoring with special emphasis on liver function tests (HSDB, NIOSH/CDC 1988). NIOSH suggests that 100 ppm 2- nitropropane is immediately dangerous to life or health (HSDB, NIOSH 2003). The US DOE has established PAC (Revision 29) for 2-nitropropane.

PAC for 2-nitropropane.

Classification Protective Action Critera (PAC) (ppm) PAC-1 30 PAC-2 380 PAC-3 2300

Toxicity

May cause central nervous system depression and cardiac disturbances (HazMap).

Hepatotoxin (HazMap).

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Carcinogenicity

Negative in in vitro mutagen assays (CCRIS).

Irritation Indications

May cause irritation (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive effects with other nitroalkanes.

Summary and Recommendations

The HTFOELfor 2-methyl-2-nitropropane remains appropriate using 2-nitropropane as a surrogate compound. Acute exposure guidelines for 2-methyl-2-nitropropane does not exist and could be established based on recently developed acute exposure guidelines for 2-nitropropane (PACs). Thus we suggest that the acute guidelines for 2-methyl-2-nitropropane be considered.

References American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 44 29 CFR 1910.1000; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of June 1, 2005: http://www.gpoaccess.gov/ecfr NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety& Health. DHHS (NIOSH) Publication No. 2004-103 (2003). NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988, p. V37 (5-7) 22

3.10 Heterocyclics

3.10.1 Previous Assessments

3.10.1.1 Furan (CAS # 110-00-9)

A HTFOELis proposed for furan based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan is the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. Based on the available experimental data, the dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL. The results from the 13-week sub-chronic study were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01%

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-4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis is ~4 µg/m3 or 1 ppb.

Methodology

To identify and access available toxicity data on furan, a number of Internet data bases including PUBMED, TOXNET, TOMES, EPA-developed IRIS, and one by IARC were searched, and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and to help identify or establish NOEL that could be used to develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

A review of the literature indicates that no documented OELs have been established by ACGIH, OSHA, or state regulatory agencies. In reviewing the Registry of Toxic Effects of Chemical Substances, in was noted that Russia had set a short-term exposure limit (STEL) of 0.5 mg/m3 with a skin notation in January 1993; however, specific documentation was unavailable to evaluate how this STEL was established. In 1989, EPA established an oral reference dose (RfD) of 0.001 mg/kg/day based on sub-chronic studies in mice using a NOEL of 1.4 mg/kg/day for hepatic lesions (cellular necrosis), with a 1000-fold uncertainty factor applied (10x extrapolation sub-chronic to chronic; 10x interspecies; 10x for added protection sensitive subpopulation). This EPA assessment did not consider the results obtained from NTP chronic bioassay for furan (NTP 1993).

Toxicology Summary

Furan is the parent compound for a broad class of structurally related compounds. IARC has classified furan as a possible carcinogen to humans (Group 2B), and it is a known animal carcinogen based on the observed carcinogenic response following oral administration in both mice and rats (NTP 1993). In rats, sub-chronic exposure to furan produced a high incidence of hepatic billiary tract hyperplasia and cholangiofibrosis in both male and females. In rats, chronic furan exposure produced hepatocellular adenomas in both male and female rats, and hepatocellular carcinomas in males. A very high incidence (~100%) of cholangiocarcinomas was also observed in both genders. The incidence of mononuclear-cell leukemia was also increased. Mice, likewise, showed an increased incidence of hepatocellular adenomas and carcinomas in both genders. The cholangiocarcinomas showed the steepest dose-response. There is some suggestion that furan is bioactivated to a reactive metabolite that can readily alkylate proteins, resulting in significant cytotoxicity.

Data Analysis

The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan is the observed carcinogenicity following oral administration in rats and mice. In assessing the carcinogenic dose- response, the observed cholangiocarcinoma response in both male and female rats demonstrated the steepest dose-response and represents the most conservative data set for extrapolation. However, the data for this effect lacked an adequate dose-response to fully evaluate. Therefore, the most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan is the observed hepatic billiary tract hyperplasia leading to carcinogenicity following oral administration in rats and mice. The non-neoplastic hepatic hyperplasia response in male and female rats following oral sub-chronic exposure to furan is presented in Table 3.14. In assessing the hepatic non-neoplastic dose-response in rats the billiary tract hyperplasia response in the females is the most sensitive, with a 70% compared to a 40% response in

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males at the lowest dose (4 mg/kg/day). In assessing the carcinogenic dose-response, the observed cholangiocarcinoma response in both male and female rats demonstrated the steepest dose-response. The observed tumor incidence is presented in Table 3.15. Both genders demonstrated reasonably comparable responses; females had slightly more tumors at the low dose (2 mg/kg/day) than males (49 vs. 43, respectively).

Table 3.14 Hepatic Non-Neoplastic Response: Number of Animals with Lesion/Total Number of Animals (NTP 1993)

Billiary Tract Hyperplasia

Dose (mg/kg/day) Male Female

(w/Hyperplasia/Total) (w/ Hyperplasia /Total)

0 0/10 0/10

4 4/10 7/10

8 9/10 10/10

15 10/10 10/10

30 10/10 10/10

60 10/10 10/10

Table 3.15 Tumor Response: Number of Animals with Tumors/Total Number of Animals (NTP 1993).

Cholangiocarcinoma

Dose (mg/kg/day) Male Female

(w/Tumors/Total) (w/Tumors/Total)

0 0/50 0/50

2 43/50 49/50

4 48/50 50/50

8 49/50 49/50

The steep dose-response curves for both the pre-neoplastic and carcinogenic responses are very comparable and consistent with a non-genotoxic mode of carcinogenic action (i.e., tumors are secondary to cytotoxicity). The lack of observable tumors in the control groups also indicates that this response in the Fisher 344 (F344) rat is of a low spontaneous frequency; yet, a near-maximum tumor response is

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observed in both genders following chronic exposure to the low 2 mg/kg/day dose level. The lack of a clearly definable NOEL for either the pre-neoplastic or carcinogenic response does makes it difficult to establish with confidence a point of departure for calculating a HTFOELfor furan.

Data Analysis

Initial evaluation of the data was done with the hope of applying a BMD calculation to establish an appropriate NOEL as a POD for calculating a cancer slope factor (CSF) for furan. Benchmark dose software developed by EPA was used (http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=20167). This software was developed as a tool to facilitate the application of BMD methods to EPA hazardous pollutant risk assessments. However, due to the lack of a clear dose-response for the chronic bioassay (Table 3.15) there was some concern about using a BMD approach since there was substantial uncertainty concerning the calculated POD. A second approach attempted to conduct a similar evaluation of the dose- response for the non-neoplastic hepatic response (Table 3.14); however, these results likewise demonstrated a poor dose-response over the range evaluated. Hence, it was decided that since it was not satisfying to apply the BMD model to the 13-week or chronic experimental data, a simple linear extrapolation approach would be utilized.

This extrapolation was based on the observed dose-response in female rats for billiary tract hyperplasia, where a 70% response (7 out of 10 animals) was observed following 13-weeks of oral exposure to 4 mg/kg/day. Based on this dose-response ratio, it was possible to calculate the dose associated with a 0.01% response as noted in equation 1.

(0.01% ∗ 4mg / kg / day) dose(mg / kg / day) = (1) 70%

The calculated oral dose for a 0.01% response (1 x 10-4) was 5.71 x 10-4 mg/kg/day or 0.571 µg/kg/day. Assuming a human weighed 65 kg, the daily oral equivalent dose would be ~37 µg/day. To convert the oral dose (µg/kg) to an equivalent inhalation dose (µg/m3), it was assumed that an average human would inhale ~10 m3/day of air, using equation 2.

mg / day mg / m3 = (2) 10m3/ day

These calculations also assumed that 100% of the inhaled furan would be absorbed systemically through the respiratory system. Using these assumptions, the proposed HTFOELfor furan based on this analysis is 3 ~4 µg/m or 1 ppb. A HTFOELof 1 ppb inhalation (equivalent to ~0.5 µg/kg/day oral) is reasonably comparable to the 1 µg/kg/day proposed as an oral RfD for furan.

3.10.1.2 Furan Family: Substituted Furans 2-methylfuran (CAS# 534-22-5), 2-5- dihydrofuran and 2-propylfuran (CAS# 4229-91-8) and Others

For the broad class of furan-based chemicals, there is strong experimental evidence suggesting that observed toxicity in several target organs, including the lung and liver, involves the formation of a chemically reactive metabolite. The weight of evidence suggests there is a high probability that a broad range of chemicals containing the unsaturated furan nucleus will be metabolized in animals and humans to a highly reactive and toxic furan epoxide metabolite. For these reactive furans, toxicity is observed in organ systems like the liver and lung, which are capable of CYP450 metabolic activation. In the absence of any substantial toxicity data to fully evaluate the range of substituted furans, the most rational and defensible approach is to set a HTFOELfor all unsubstituted furans based upon the results obtained with

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3 furan itself. Therefore, the proposed HTFOELfor the substituted furans based on this analysis is ~4 µg/m or 1 ppb.

Toxicology Summary

The furans are a class of chemicals that have as their core a common 5-member, oxygen-containing, unsaturated heterocyclic ring. A number of chemicals that contain the furan heterocyclic ring structure have been identified as occurring naturally or being used as industrial intermediates. For the broad class of furan-based chemicals, there is strong experimental evidence suggesting that observed toxicity in several target organs, including the lung and liver, involves the formation of a chemically reactive metabolite. Boyd (1980) has published several reviews on the role of metabolic activation and chemical- induced lung injury and has reviewed a number of furan-based derivatives including furan, 2- methylfuran, 3-methylfuran, and other substituted furans such as 4-ipomeanol. The review provides strong evidence that CYP450 metabolism in microsomes prepared from both the liver and lung of rats and humans appears to mediate the in vitro and in vivo formation of reactive chemical species that were shown to alkylate microsomal proteins. Through the use of metabolic inhibitors, it has also been shown that in the absence of metabolism, there was insufficient reactivity of the parent furan to alkylate tissue proteins. Additional support for the important role of metabolism was gleaned by showing that alkylation was not observed in non-metabolically active tissues (e.g., blood, heart, skeletal muscle) following exposure to 4-ipomeanol.

Important to the assessment of the potential toxicological significance for the broad range of furan chemistry was the observation that when the furan ring of 4-ipomeanol was replaced by phenyl or methyl, there was no evidence of covalent binding in the rat lung or liver microsomes in vitro (Boyd et al. 1978a). In addition, neither of these analogs became covalently bound to the rat lung or liver in vivo, and they were relatively non-toxic at doses >800 mg/kg (Boyd and Burka 1978). As noted by Boyd (1980), data from several other laboratories have suggested that a highly reactive and toxic furan epoxide metabolite can be formed due to the metabolism of the unsaturated furan ring. Evidence for this pathway was shown with the formation of an epoxide of the dihydrofuran moiety of aflatoxin B1 and the metabolic activation of the furan ring of the diuretic, furosemide (Swenson et al. 1974; Mitchell et al. 1976; McMurtry and Mitchell 1977). The importance of the unsaturated furan ring as a prerequisite for toxicity was demonstrated by Wirth et al. (1976), who reported that a furosemide analog that had a fully saturated tetrahydrofuran group could not be metabolized to a reactive epoxide and did not become covalently bound to liver microsomes. There is evidence that both 3-methy and 2-methylfuran are also converted by CYP450 metabolism to highly reactive metabolites that are covalently bound to protein (Ravindranath et al. 1986; Boyd et al. 1978b). Boyd (1980) noted that a number of other furan derivatives, including 1- ipomeanol, 1,4-ipomeanol, ipomeanine, 2-methylfuran, and 2-furamide, as well as furan have been reported to cause pulmonary and/or hepatic necrosis in mice. In all cases, each of these chemicals contained an unsaturated furan ring. Further, while studies have not been conducted with all these substituted furans to determine whether they are metabolized to reactive metabolites, it is reasonable to speculate that they have the potential for such metabolism.

The weight of evidence suggests that a broad range of chemicals containing the unsaturated furan nucleus have a high probability to be metabolized in animals and humans to a highly reactive and toxic furan epoxide metabolite. For these reactive furans, toxicity is observed in organ systems like the liver and lung, which are capable of CYP450 metabolic activation.

Summary and Recommendations

In reviewing the available toxicity data bases on furan and substituted furans, the most robust data were found for the parent furan and includes a 2-year oral gavage bioassay conducted in rats and mice (NTP

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1993). In rats, sub-chronic exposure to furan produced a high incidence of hepatic billiary tract hyperplasia and cholangiofibrosis in both males and females, and chronic furan exposure produced hepatocellular adenomas in both males and females, and hepatocellular carcinomas in males. A very high incidence (~100%) of cholangiocarcinomas was also observed in both genders. There is some suggestion that furan is bioactivated to a reactive metabolite that can readily alkylate proteins, resulting in significant cytotoxicity. (See Section 3.10.1). Hence, there is some suggestion that furan’s mode of carcinogenic action is non-genotoxic (i.e., tumors are secondary to cytotoxicity). In the absence of any substantial toxicity data to fully evaluate the range of substituted furans, the most rationale and defensible approach is to set the HTFOELfor all unsubstituted furans based upon the results obtained with furan itself. As additional and appropriate new data become available for substituted furans, it would be reasonable to reassess the appropriateness of basing that chemical’s HTFOELupon furan.

3.10.1.3 2,4-Dimethylpyridine (CAS# 108-47-4)

A HTFOELis proposed for 2,4-dimethylpyridine. Toxicological data for 2,4-dimethylpyridine are minimal, but it is structurally similar to pyridine, 3-picoline, and 5-ethyl-2-picoline, for which more data are available. 2,4-Dimethylpyridine is a food additive recognized as having “no safety concern” by the WHO. Repeated exposure to high concentrations of a mixture of pyridine derivatives can cause central nervous system and gastrointestinal disturbances, facial paralysis, ataxia, and anisocoria (unequal pupils). A TEEL of 0.5 ppm has been recommended by DOE for 2,4-dimethylpyridine, ACGIH has recommended TLVs of 1 ppm for pyridine, and the AIHA has recommended WEELs of 2 ppm for 2-methylpyridine, 3- methylpyridine, and 4-methylpyridine. The proposed HTFOEL for 2,4-Dimethylpyridine is 0.5 ppm, based on the DOE TEEL-1 and consistent with ACGIH TLVs and AIHA WEELs for closely related compounds.

Methodology

To identify and access available toxicity data on 2,4-dimethylpyridine, a number of Internet data bases including PUBMED, TOXNET, TOMES, EPA-IRIS, and the IARC were searched, and summary toxicity profiles were obtained, and primary references were identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OEL for 2,4-dimethylpyridine has been proposed by the OSHA or ACGIH. A TLV of 1 ppm has been proposed by the ACGIH for pyridine, a structurally similar compound. The AIHA has proposed WEELs of 2 ppm for 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine.

Other available guidelines include the DOE Subcommittee on Consequence Assessment and Protective Actions (SCAPA) TEELs. The TEELs are designed to serve as temporary guidance for chemicals needing guidelines for hazard assessment and safety analysis for DOE personnel and general public adjacent to DOE sites. These TEELs are assigned to chemicals on a temporary basis until they can be replaced with AEGLs or emergency response planning guidelines, which require additional documentation and assessment. The protocol used to consider available OEL and toxicological data in the development of TEELs has been published (Craig et al. 2000). Three levels of TEELs (TEEL-1, TEEL-2, TEEL-3) are calculated as fractions based on set criteria. TEEL-1 is defined as “the maximum airborne concentration below which it is believed that nearly all individuals could be exposed without experiencing other than mild transient adverse health effects or perceiving a clearly defined, objectionable odor.” When a PEL- STEL or TLV-STEL is available, TEEL-1 should be lower (more protective) than the STEL. Although

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not specifically stated, TEEL-1 is usually based on a 1-hour TWA. The DOE SCAPA-recommended TEEL-1 for 2,4-dimethylpyridine is 0.5 ppm. TEEL-3, defined as “the maximum airborne concentration below which it is believed that nearly all individuals could be exposed without experiencing or developing life-threatening health effects,” is 20 ppm.

Toxicology Summary

Repeated industrial exposure to mixtures of pyridine derivatives, which include 2,4-dimethylpyridine, have resulted in central nervous system and gastrointestinal disturbances, facial paralysis, ataxia, and anisocoria. Short-term exposures to high levels of pyridine mixes can cause a burning sensation, coughing, dizziness, drowsiness, headache, labored breathing, nausea and sore throat. The LD50 for 2,4- dimethylpyridine in rats was 200 mg/kg. The WHO has commented that there is no safety concern with 2,4-dimethylpyridine as a food additive (WHO 2005).

Exposures to the surrogate, pyridine, result in irritation. Repeated exposures can also result in kidney and liver damage. The acute LD50 for pyridine in rats and mice ranges from 900-1500 mg/kg (ACGIH 2004). The NOEL in rats and mice in 28-day drinking water exposures was 7-15 mg/kg/day. Pyridine is not mutagenic in bacteria or CHO cells. Human exposure assessment in a chemical plant indicated that repeated exposures to 6-12 ppm resulted in headache, temporary vertigo, nervousness, and sleeplessness. The recommended ACGIH TLV for pyridine is 1 ppm based on minimizing the potential for nasal irritation and liver and kidney toxicity.

2,4-Dimethylpyridine is a substituted pyridine, with slightly higher acute toxicity than pyridine; therefore, a substituted pyridine surrogate was sought to assess the potential for higher toxicity in substituted pyridines. 5-Ethyl-2-picoline was the closest surrogate with sufficient toxicity data identified. The NOEL for 5-ethyl-2-picoline was 30 mg/kg/day in a 28-day oral study in mice.

Data Analysis

2,4-Dimethylpyridine and mixed pyridine exposures occur in industrial settings. The most data were available for the unsubstituted pyridine. The ACGIH first assigned an OEL of 10 ppm for pyridine in 1956; this value has been changed twice and is 1 ppm as of 2004. A comparison of acute toxicity between pyridine, methylpyridine, and 5-ethyl-2-picoline suggests that the substitutions do not result in increased toxicity. The primary endpoint of concern for 5-ethyl-2-picoline is likely due to its corrosive properties and therefore nasal irritation. The HTFOELof 1 ppm for pyridine, and the TEEL-1 for 2,4-dimethylpyridine of 0.5 ppm are similar.

Summary and Recommendations

Based on the comparison of acute and subchronic effects of 5-ethyl-2-picoline, pyridine, and 2,4- dimethylpyridine in laboratory animals and the effects from human exposures to pyridine mixtures, it is proposed that the DOE TEEL-1 of 0.5 ppm be adopted as the HTFOELfor 2,4-dimethylpyridine. TEEL-1 is similar to the ACGIH TLV of 1 ppm for pyridine and the AIHA WEEL of 2 ppm for 2- methylpyridine, 3-methylpyridine, and 4-methylpyridine. Based on the WHO’s recognition of 2,4- dimethylpyridine as having “no safety concern” for oral exposures, this is a very conservative TLV, and TEEL-1 may be based on route-dependent irritation. As additional new data become available for the 2,4- dimethylpyridine, it would be reasonable to reassess the appropriateness of basing the HTFOELupon the DOE SCAPA TEEL-1.

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3.10.1.4 1,2,3,6-Tetrahydropyridine (CAS# 694-05-3)

A HTFOELis proposed for 1,2,3,6-tetrahydropyridine. No toxicological data were found for 1,2,3,6- tetrahydropyridine but it is structurally similar to both pyridine or piperidine, for which more data are available. Repeated exposures to high concentrations of a mixture of pyridine derivatives can cause central nervous system and gastrointestinal disturbances, facial paralysis, ataxia, and anisocoria. ACGIH has recommended TLVs of 1 ppm for pyridine, and the AIHA has recommended WEELs of 2 ppm for 2- methylpyridine, 3-methylpyridine, and 4-methylpyridine. Piperidines are used as nonsedating antihistamines since they do not readily cross the blood-brain barrier. The AIHA has recommended a WEEL of 1 ppm for piperidine. The proposed HTFOELfor 1,2,3,6-tetrahydropyridine is 0.1 ppm based on the AIHA WEEL for surrogate piperidine with an UF of 10 for the lack of data and structural differences. This proposed OEL is also consistent with the ACGIH TLVs of 1 ppm for pyridine and 0.1 for the piperidine derivative, phenylhydrazine.

Methodology

To identify and access available toxicity data on 1,2,3,6-tetrahydropyridine, a number of Internet data bases, including PUBMED, TOXNET, TOMES, EPA-IRIS, and the IARC, were searched and summary toxicity profiles were obtained, including the identification of primary references. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and used for the development of the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

No OEL for 1,2,3,6-tetrahydropyridine has been proposed by the OSHA or ACGIH. A TLV of 1 ppm has been proposed by the ACGIH for pyridine and 0.1 ppm for phenylhydrazine, which are structurally similar compounds. The AIHA has proposed WEELs of 2 ppm for 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine. The structurally similar piperidine has an AIHA-recommended WEEL of 1 ppm with a skin notation.

Toxicology Summary

Repeated industrial exposure to mixtures of pyridine derivatives have resulted in central nervous system and gastrointestinal disturbances, facial paralysis, ataxia, and anisocoria (unequal pupils). Short-term exposures to high levels of pyridine mixes can cause a burning sensation, coughing, dizziness, drowsiness, headache, labored breathing, nausea and sore throat. Piperidines are nasal and dermal irritants. 1,2,3,6-Tetrahydropyridine is also explosive.

Exposures to the surrogate, pyridine, result in irritation. Repeated exposures can also result in kidney and liver damage. The acute LD50 for pyridine in rats and mice ranges from 900-1500 mg/kg (ACGIH 2004). The NOEL in rats and mice in 28-day drinking water exposures was 7-15 mg/kg/day. Pyridine is not mutagenic in bacteria or CHO cells. Human exposure assessment in a chemical plant indicated that repeated exposures to 6-12 ppm resulted in headache, temporary vertigo, nervousness, and sleeplessness. The recommended ACHGIH TLV for pyridine is 1 ppm based on minimizing the potential for nasal irritation and liver and kidney toxicity.

Data Analysis

The most data were available for the unsubstituted pyridine. The ACGIH first assigned an OEL of 10 ppm for pyridine in 1956; this value has been changed twice and is 1 ppm as of 2004. The primary endpoint of

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concern is likely due to corrosive properties and therefore nasal irritation. The HTFOELof 1 ppm for pyridine, and the WEELs for other pyridines of 2 ppm are similar.

Summary and Recommendations

Based on the lack of toxicological data for 1,2,3,6-tetrahydropyridine, it is proposed that the AIHA WEEL of 1 ppm for piperidine be used with an UF of 10 to propose an OEL for 1,2,3,6- tetrahydropyridine of 0.1 ppm. As additional new data become available for the 1,2,3,6- tetrahydropyridine, it would be reasonable to reassess the appropriateness of basing the HTFOELupon the WEEL for substituted pyridines.

3.10.2 Current Summaries

3.10.2.1 Furan (CAS No. 110-00-9)

The HTFOELfor furan is 0.001 ppmv calculated in-house from rat toxicity data.

Literature Search

A literature search focusing on new toxicity or regulatory data for furan was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on furan: EPA AEGL, DOE PAC, HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, and CTD.

New regulatory values were discovered for furan. Worker exposure by all routes should be minimized to the fullest extent possible (HSDB, AIHA 2010). EPA established AEGLs for furan. EPA did not recommended AEGL-1 values for furan due to insufficient data. The US DOE developed 1 hr AEGL values as PAC (Revision 29) for furan. Since EPA did not recommend AEGL-1 values for furan, US DOE adopted 0.62 ppm for a PAC-1. PAC-1 is airborne concentration in which the general population, including susceptible individuals, if exposed to for one hour could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. Biomonitoring equivalent (BE) values have been derived using physiologically based pharmacokinetic modeling (Aylward 2010).

AEGLs for furan (NRC 2010).

AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 NR NR NR NR NR AEGL-2 12 8.5 6.8 1.7 0.85 Terrill 1989 AEGL-3 35 24 19 4.8 2.4 Terrill 1989 NR: Not Recommended.

Toxicity

Furan vapors are central nervous system depressants (HSDB, Phohanish 2008), and inhalation can cause anesthesia (HazMap).

Corrosive to the mouth and gastrointestinal tract (HazMap).

Causes narcosis (HazMap).

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Exposure can cause headache, dizziness, shortness of breath; unconsciousness and suffocation are among the symptoms (HSDB, Phohanish 2008).

Higher exposures can cause pulmonary edema, a medical emergency that can be delayed for several hours (HSDB, Phohanish 2008).

Can cause severe injury to liver and kidneys (HazMap).

Can cause burns to skin (HazMap).

Carcinogenicity

Furan is possibly carcinogenic to humans (Group 2B) (HSDB, IARC 1995).

Furan is reasonably anticipated to be a human carcinogen (HSDB, DHHS 2009)

Irritation Indications

Contact can irritate or burn skin and eyes (HazMap).

Respiratory tract irritant (HazMap).

May cause skin allergy (HSDB, Phohanish 2008).

Odor Threshold

Ethereal (HSDB, Flick 1985)

Mixture Interactions

May have additive toxic effects with other furans.

Summary and Recommendations

The HTFOELfor furan needs to be reevaluated due to new available regulatory values. The current HTFOELfor furan was derived in-house based on available rat toxicity data and was applied to other substituted furans.

Regulatory values based on non-cancer endpoints have recently been established for furan (AEGLs and PACs). Acute level 1 criteria (e.g., AEGL-1 and PAC-1) is available, but more chronic (e.g. 8 hr) level 1 criteria does not exist. Level 2 criteria (e.g. AEGL-2 and PAC-2) exist for both acute and chronic exposure scenarios. Thus extrapolation from regulatory values may be necessary for a chronic HTFOEL.

EPA has not evaluated furan in terms of carcinogenicity (i.e. categorization or derived slope factors), and furan has been classified as possibly carcinogenic to humans by International Agency for Research on Cancer (IARC). Rodent carcinogenicity data is available for furan and may be applicable to cancer slope value derivations (see Previous Assessment).

Overall, we suggest that the HTFOELfor furan and substituted furans be reevaluated. In that reevaluation, determination of cancer vs. non-cancer endpoints will need to be addressed along with chronic and acute guidelines. Due to level of existing data, further regulatory action could be on the horizon and should continue to be monitored.

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References American Industrial Hygiene Association. 2010 Emergency Response Planning Guidelines (ERPG) Workplace Environmental Exposure Level (WEEL). American Industrial Hygiene Association Guideline Foundation. Fairfax, VA 2010, p. 42 National Research Council (NRC). 2010. Acute Exposure Guideline Levels for Selected Airborne Chemicals (Vol 9). Aylward L.L., Kirman C.R., Blount B.C., Hays S.M. 2010. Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs) application of steady-state PBPK model solutions. Regul Toxicol Pharmacol. 2010 Oct;58(1):33-44. Pohanish, R.P. (ed). Sittig's Handbook of Toxic and Hazardous Chemical Carcinogens 5th Edition Volume 1: A-H,Volume 2: I-Z. William Andrew, Norwich, NY 2008, p. 1297 IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. 63 404 (1995) DHHS/National Toxicology Program; Eleventh Report on Carcinogens: Furan (110-00-9) (January 2005). Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s090fura.pdf Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985., p. 404.

3.10.2.2 2-Heptylfuran (CAS No. 3777-71-7)

The HTFOELfor 2-heptylfuran is 1 ppbv based on a HTFOELestablished for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2-heptylfuran was conducted May 2, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-heptylfuran: HazMap, PubMed, Toxline, RTECS, and CCRIS.

No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

No available data.

Carcinogenicity

Not mutagenic in vitro (CCRIS).

Irritation Indications

May cause irritation (HazMap).

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Odor Threshold

No available data.

Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2-heptylfuran needs to be reevaluated due to new available regulatory values for furan. Due to a lack of regulatory and toxicity data available for substituted furans, HTFOELswere previously based on furan. No new data was discovered for 2-heptylfuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan, we suggest that the HTFOELacute exposure guidelines for furan and substituted furans be reevaluated.

References

None

3.10.2.3 2-Octylfuran (CAS No. 4179-38-8)

The HTFOELfor 2-octylfuran is 1 ppbv based on a HTFOELestablished for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2-octylfuran was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-octylfuran: HazMap. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

No available data.

Carcinogenicity

No available data.

Irritation Indications

No available data.

Odor Threshold

No available data.

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Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2-octylfuran needs to be reevaluated due to new available regulatory values for furan. Due to a dearth of regulatory and toxicity data available for substituted furans, HTFOELswere previously based on furan. No relevant data was discovered for 2-octylfuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan, we suggest that the HTFOELand acute exposure guidelines for furan and substituted furans be reevaluated.

References

None

3.10.2.4 2-pentylfuran (CAS No. 3777-69-3)

The HTFOEL for 2-pentylfuran is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). An HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing an HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 2-pentylfuran was conducted June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 2- pentylfuran. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

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Odor Threshold

Not available.

Mixture Interactions

None identified for surrogate (PubMed; mixture interaction and 2-methylfuran as search terms). Based upon our previous assessment that all Furan and substituted furans may have a common MOA, toxic interactions between furans is plausible.

Summary and Recommendations

HTFOELfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 2- pentylfuran exposures. US DOE developed 0.62 ppm Furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 2-pentylfuran, be re-evaluated in the context of the updated HTFOELfor Furan.

References

Not available.

3.10.2.5 2-methylfuran (CAS No. 534-22-5)

The HTFOELfor 2-methylfuran is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). An HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing an HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 2-(2-Methyl-6-oxoheptyl)furan was conducted June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 2- methylfuran. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

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Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 2- methylfuran exposures. US DOE developed 0.62 ppm Furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 2-methylfuran, be re-evaluated in the context of the updated HTFOELfor Furan.

References

Not available.

3.10.2.6 2-Propylfuran (CAS No. 4229-91-8)

The HTFOELfor 2-propylfuran is 1 ppbv based on a HTFOEL established for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2-propylfuran was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2-propylfuran: HazMap, PubMed, and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

2-Propylfuran is known to cause CNS Solvent Syndrome (HazMap).

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Hepatotoxic (HazMap).

Carcinogenicity

No available data.

Irritation Indications

An irritant (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2-propylfuran needs to be reevaluated due to new available regulatory values for furan. Due to a lack of regulatory and toxicity data available for substituted furans, HTFOELswere previously based on furan. No relevant data was discovered for 2-propylfuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan, we suggest that the HTFOELand acute exposure guidelines for furan and substituted furans be reevaluated.

References

None

3.10.2.7 2-Ethyl-5-methylfuran (CAS No. 1703-52-2)

The HTFOELfor 2-Ethyl-5-methylfuran is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). A HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing anHTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 2-Ethyl-5-methylfuran was conducted June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 2-Ethyl- 5-methylfuran. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

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Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified for surrogate (PubMed; mixture interaction and furan as search terms). Based upon our previous assessment that all Furan and substituted furans may have a common MOA, toxic interactions between furans is plausible.

Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 2-Ethyl- 5-methylfuran exposures. US DOE developed 0.62 ppm furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 2-Ethyl-5-methylfuran, be re-evaluated in the context of the updated HTFOELfor Furan.

References

Not available.

3.10.2.8 2-(2-Methyl-6-oxoheptyl)furan (CAS No. 51595-87-0)

The HTFOELfor 2-(2-methyl-6-oxoheptyl)furan is 1 ppb based on data available for Furan (CAS # 110-00- 9) and substituted furans as surrogates (See Previous Assessment). A HTFOEL for furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

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Literature Search

A literature search focusing on new toxicity data for 2-(2-methyl-6-oxoheptyl)furan was conducted June 21, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 2- (2-methyl-6-oxoheptyl)furan. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 2-(2- methyl-6-oxoheptyl)furan exposures. US DOE adopted 0.62 ppm Furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 2-(2-methyl-6-oxoheptyl)furan, be re-evaluated in the context of the updated HTFOELfor Furan.

References

Not available.

3.10.2.9 2-(3-Oxo-3-phenylprop-1-enyl)furan (CAS No. 717-21-5)

The HTFOELfor 2-(3-oxo-3-phenylprop-1-enyl)furan is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). A HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near

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maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 2-(3-oxo-3-phenylprop-1-enyl)furan was conducted June 21, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 2-(3-oxo-3-phenylprop-1-enyl)furan. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 2-(3-oxo- 3-phenylprop-1-enyl)furan exposures. US DOE developed 0.62 ppm Furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 2-(3-oxo-3-phenylprop-1-enyl)furan, be re-evaluated in the context of the updated HTFOELfor Furan.

References

Not available.

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3.10.2.10 2,3-Dihydrofuran (CAS No. 1191-99-7)

The HTFOELfor 2,3-dihydrofuran is 1 ppbv based on a HTFOELestablished for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2,3-dihydrofuran was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2,3-dihydrofuran: HazMap, PubMed, and Toxline. No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

2,3 Dihydrofuran causes central nervous system solvent syndrome (HazMap).

Carcinogenicity

No available data.

Irritation Indications

An irritant (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2,3-dihydrofuran needs to be reevaluated due to new available regulatory values for furan. Due to a dearth of regulatory and toxicity data available for substituted furans, HTFOELswere previously based on furan. No relevant data was discovered for 2,3-dihydrofuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan, we suggest that the HTFOELand acute exposure guidelines for furan and substituted furans be reevaluated.

References

None

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3.10.2.11 2,5-Dihydrofuran (CAS No. 1708-29-8)

The HTFOELfor 2,5-dihydrofuran is 1 ppbv based on a HTFOELestablished for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2,5-dihydrofuran was conducted May 23, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2,5-dihydrofuran: HazMap, PubMed, Toxline, and RTECS.

New toxicity data was discovered for 2,5-dihydrofuran. Inhaled 2,5-dihydrofuran caused tremors, reduced muscle tone, abnormal gait, histopathological changes in the nasal passages, and significantly reduced body weight observed in 4-week inhalation study of rats at 1,250 ppm for 6 hr/day for 4 weeks and 1686 ppm for 6 hr/day for 5 days (HazMap, RTECS, National Technical Information Service).

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

2,5-Dihydrofuran caused tremors, reduced muscle tone, abnormal gait, histopathological changes in the nasal passages, and significantly reduced body weight (HazMap, RTECS).

2,5-Dihydrofuran causes central nervous system solvent syndrome (HazMap).

Carcinogenicity

No available data.

Irritation Indications

May cause irritation (HazMap).

Odor Threshold

No available data.

Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2,5-dihydrofuran needs to be reevaluated due to new available regulatory values for furan. Due to a dearth of regulatory and toxicity data available for substituted furans, HTFOELswere previously based on furan. A small amount of toxicity data was discovered for 2,5-dihydrofuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan, we suggest that the HTFOELand acute exposure guidelines for furan and substituted furans be reevaluated.

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References

National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0556295-1

3.10.2.12 2,5-Dimethylfuran (CAS No. 625-86-5)

The HTFOELfor 2,5-dimethylfuran is 1 ppbv based on a HTFOELestablished for furan adapted to all substituted furans.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2,5-dimethylfuran was conducted May 24, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2,5-dimethylfuran: HazMap, PubMed, Toxline, RTECS, and CCRIS.

No new toxicity or regulatory data was discovered.

Surrogate Literatures Search

AEGLs and PAC have been established for furan (See Furan).

Toxicity

2,5-Dimethylfuran causes central nervous system solvent syndrome (HazMap).

Lethal concentration low (LClo): 500 ppm for 4 hr in rat (HazMap).

Carcinogenicity

Not mutagenic in vitro (HazMap, CCRIS).

Irritation Indications

May cause irritation (HazMap).

Odor Threshold

An aromatic, caustic odor (HazMap)

Mixture Interactions

May have additive toxic effects with similar substituted furans.

Summary and Recommendations

The HTFOELfor 2,5-dimethylfuran needs to be reevaluated due to new available regulatory values for furan. Due to a lack of regulatory and toxicity data for 2,5-dimethylfuran and other substituted furans, HTFOELswere previously based on furan. No new data was discovered for 2,5-dimethylfuran, and new regulatory criteria has been established for furan. Due to recently established regulatory criteria for furan,

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we suggest that the HTFOELfor furan and substituted furans be reevaluated and that acute exposure guidelines be developed.

References

None

3.10.2.13 3-(1,1-dimethylethyl)-2,3-dihydrofuran (CAS No. 34314-82-4)

The HTFOELfor 3-(1,1-dimethylethyl)-2,3-dihydrfuran is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). A HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 3-(1,1-dimethylethyl)-2,3-dihydrofuran was conducted June 24, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 3-(1,1-dimethylethyl)-2,3-dihydrofuran. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

Mixture Interactions

None identified for surrogate (PubMed; mixture interaction and 3-(1,1-dimethylethyl)-2,3-dihydrfuran as search terms).

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Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 3-(1,1- dimethylethyl)-2,3-dihydrofuran exposures. US DOE developed 0.62 ppm furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 3-(1,1-dimethylethyl)-2,3-dihydrofuran, be reevaluated in the context of the updated HTFOELfor Furan.

References

None.

3.10.2.14 4-(1-Methylpropyl)-2,3-dihydrofuran (CAS# 34379-54-9)

The HTFOELfor 4-(1-Methylpropyl)-2,3-dihydrofuran is 1 ppb based on data available for Furan (CAS # 110-00-9) and substituted furans as surrogates (See Previous Assessment). A HTFOELfor furan was established based on a comprehensive review of the available toxicology literature. The most sensitive and relevant toxicological endpoint for establishing a HTFOELfor furan was the observed hepatic billiary tract hyperplasia (13-week sub-chronic study) leading to carcinogenicity following oral administration in rats and mice. The dose-response for both the hyperplasia and tumor response was very steep (i.e., near maximal response at all dose levels) with no experimentally determined NOEL and were used to extrapolate from an observed 70% incidence at 4 mg/kg/day to a dose that would produce a 0.01% -4 3 incidence (1x10 ). The HTFOELcalculated for furan assumed a human inhalation rate of 10 m /day, and 100% of the inhaled furan was absorbed systemically. The proposed HTFOELfor furan based on this analysis was ~4 μg/m3 or 1 ppb.

Literature Search

A literature search focusing on new toxicity data for 4-(1-Methylpropyl)-2,3-dihydrofuran was conducted June 29, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. No new toxicity or regulatory data was discovered for 4-(1-Methylpropyl)-2,3-dihydrofuran. Information on Furan as a surrogate was identified in the AEGL and PAC databases (see Furan summary).

Toxicity

Not available.

Carcinogenicity

See Previous Documentation.

Irritation Indications

Not available.

Odor Threshold

Not available.

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Mixture Interactions

None identified for surrogate (PubMed; mixture interaction and 4-(1-Methylpropyl)-2,3-dihydrofuran as search terms). Based upon our previous assessment that all Furan and substituted furans may have a common MOA, toxic interactions between furans is plausible.

Summary and Recommendations

HTFOELsfor substituted Furans have considered toxicological information for Furan as a surrogate. Recently established AEGL and PAC values for Furan could potentially be considered for acute 4-(1- Methylpropyl)-2,3-dihydrofuran exposures. US DOE developed 0.62 ppm Furan for a PAC-1 which is higher than the previous HTFOELfor Furan derived in house (0.001 ppm). Therefore, it is recommended that the HTFOELfor all substituted Furans, including 4-(1-Methylpropyl)-2,3-dihydrofuran, be re-evaluated in the context of the updated HTFOELfor Furan.

References

None.

3.10.2.15 Pyridine (CAS No. 110-86-1)

The recommended ACGIH TLV for pyridine was 1 ppm based on minimizing the potential for nasal irritation and liver and kidney toxicity. Pyridine was used as a surrogate to establish HTFOELsfor substituted pyridines.

Literature Search

A literature search focusing on new toxicity data for pyridine was conducted on August 11, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on pyridine: CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS. Pyridine was also identified in PAC, but not AEGL databases. Additional regulatory information: 1. TLV (ACGIH) 1 ppm (HAZMAP). 2. PEL (OSHA) 5 ppm (HAZMAP). 3. MAK 5 ppm (HAZMAP). 4. IDLH (NIOSH) 1000 ppm (HAZMAP).

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Toxicity

Nephrotoxin, skin sensitizer, neurotoxin, hepatotoxin, dermatotoxin (HazMap Database).

Carcinogenicity

IARC (not classifiable); ACGIH (confirmed animal)(HAZMAP).

A3: Confirmed animal carcinogen with unknown relevance to humans.(HSDB)

Irritation Indications

Skin burns (HazMap).

Odor Threshold

0.23 ppm

Mixture Interactions

None identified (PubMed; mixture interaction and pyridine as search terms).

Summary and Recommendations

The ACGIH maintains a TLV of 1 ppm for pyridine. Recently established PAC values for pyridine are slightly higher (3 ppm PAC1) and could potentially be considered for acute exposures.

References

None.

3.10.2.16 2,4-Dimethylpyridine (CAS No. 108-47-4)

The HTFOELfor 2,4-dimethylpyridine (also commonly known as 2,4-lutidine) is 0.5 ppmv based on a DOE assigned TEEL category 1 (general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects) of 0.5 ppmv.

Literature Search

A literature search focusing on new toxicity or regulatory data for 2,4-dimethylpyridine was conducted May 23, 2016. Using standardized search criteria, the following databases were identified as containing active records on 2,4-dimethylpyridine: DOE PAC, HazMap, RTECS, Toxline, and Pubmed.

New regulatory values were established for 2,4-dimethylpyridine. The US DOE has developedPAC (Revision 29) for 2,4-dimethylpyridine. No other new toxicity or regulatory data was discovered.

PAC for 2,4-dimethylpyridine.

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Classification Protective Action Critera (PAC) (ppm) PAC-1 0.14 PAC-2 1.5 PAC-3 9

Toxicity

2,4-Dimethylpyridine has a reported oral medial lethal dose (LD50) of 200 mg/kg (NTIS 1984)

Carcinogenicity

Mutagen (RTECS) by chromosome loss and nondisjunction in Ames Assay (Zimmermann 1986).

Irritation Indications

2,4-Dimethylpyridine is a skin, respiratory tract, and strong eye irritant (HazMap Database).

Odor Threshold

No available data.

Mixture Interactions

No available data.

Summary and Recommendations

The US DOE has developed new PAC for acute exposures to 2,4-dimethylpyridine. The PAC-1 is lower than the current HTFOEL, and it is suggested that the HTFOELbe reevaluated to consider these acute exposure guidelines.

References

National Technical Information Service. Vol. PB85-143766, 1984.

3.11 Chlorinated Compounds

3.11.1 Previous Assessment

3.11.1.1 Polychlorinated biphenyls (PCBs)

A HTFOELis proposed for a family of polychlorinated biphenyls (PCBs). There are 209 different congeners of PCBs that vary in the extent and position of chlorination on the aromatic rings. They are not naturally occurring and primarily come from industrial manufacture of such items as capacitors and transformers. They persist in the environment and fat stores in the body. Exposures to high concentrations can lead to skin lesions (rashes and acne). High chronic concentrations can lead to liver damage, anemia, and potentially to adverse reproductive effects. The toxic potential of PCBs is dependent upon the extent and location of chlorine substation on the aromatic rings. The PCB congeners found in the tank waste headspace are much more similar to the PCBs with lower percentages of chlorine, and the proposed 3 HTFOELfor these PCBs is 0.03 mg/m (~0.003 ppm) based on the ACGIH TLV for 42% chlorinated

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PCBs with an UF of 3 to account for uncertainty associated with the exact mixture of PCBs in the tank and the potential for chloracne.

Methodology

To identify and access available toxicity data on polychlorinated biphenols, a number of Internet data bases, including PUBMED, TOXNET, TOMES, EPA-IRIS, and IARC were searched, and summary toxicity profiles were obtained and primary references identified. These toxicology summaries were then reviewed to identify the most critical data sets that could be used to establish the toxicity profile and develop the HTFOEL. Primary references for the most relevant toxicology endpoints were obtained for review.

Available Guidelines

ACGIH has proposed guidelines for PCBs with 42% (Aroclor 1242®) or 54% (Aroclor 1254®) chlorine. Aroclor 1242 and 1254 are mixtures of different congeners of chlorobiphenyl. The environmental fate, potential carcinogenicity, and toxicity of PCBs is dependant upon the degree of chlorination (ACGIH 2001c; ACGIH 2001d; Chana et al. 2002). The ACGIH assigned an A3 - Confirmed Animal Carcinogen with Unknown Relevance to Humans notation for the mixture of PCBs containing 54% chlorine, but stated there are insufficient data to assign cancer or skin notations for Aroclor 1242 (42% chlorine).

Other available guidelines include the OSHA PEL, which matches the ACGIH TLV of 1 or 0.5 mg/m3 depending on the level of chlorination; the NIOSH REL, which is 1 µg/m3; and the NIOSH IDLH, which is 5 mg/m3. The IDLH is based on acute inhalation toxicity data of PCBs in humans and animals and is not specific for the chlorine content. The 1 µg/m3 NIOSH REL is based on potential carcinogenicity and is not specific for chlorine content. The IARC has given PCBs a 2A Carcinogens status irrespective of the amount of chlorine substitution.

The EPA has calculated CSFs for different mixtures of PCBs based on their associated risks and persistence. For PCBs with the lowest risk and persistence (congeners with more than four chlorines on less than one-half of the total PCBs in the mixture, which includes the PCBs in the tank waste headspace) the upper-bound CSF is 0.07 per mg/kg/day, and the central estimate CSF is 0.04 per mg/kg/day).

Toxicology Summary

The endpoint of concern for the guideline set by the ACGIH for 42% chlorine PCBs is hepatoxicity. The toxicity of a PCB is dependent not only upon the number of chlorines present on the biphenyl structures but also the positions of the chlorines. Table 3.16 shows the general rules for relative toxicity of congeners based on chlorine number and position. It has been theorized that the ability or inability of the aromatic rings to become coplanar is linked to the toxicity and or carcinogenicity of the PCB congeners (Chana et al. 2002).

Exposures of laboratory animals (cats, rabbits, guinea pigs, rats, and mice) to 1.9 to 8.6 mg/m3 42% chlorine PCB for up to 7 months at 7 hours/day on intermittent days resulted in no obvious adverse affects (ACGIH 2001c). Human exposures to 42% chlorine PCB resulted in acne, respiratory irritation, and liver injury (ACGIH 2001c).

The carcinogenic effects of PCBs have been shown to be dependent on chlorine content in mice and rats fed diets containing 30-60% chlorine PCBs (Ito et al. 1974; Ito et al. 1973, reported in ACGIH 2001). In mice, no tumors occurred in groups fed less than 54% chlorine PCB.

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Table 3.16 Relative Toxicities of PCB Congeners in the Tank Waste Head Space

Relative Toxicity1 PCB Congener Description Comments2

5-6 Chlorines None in Head Space

“Dioxin-like” 4, 4' and 3 or 3', or 5 or 5' None in Head Space

4 and 4' 2 Congeners in Head Space

none in ortho (2,or 2’ or 6 or 6’ position) 3 Congeners in Head Space

1 ortho (2,or 2’ or 6 or 6’ position) 10 Congeners in Head Space

2 ortho (2,or 2’ or 6 or 6’ position) 6 Congeners in Head Space

1 PCBs with 5-6 chlorines are the most toxic (Chana et al. 2002), congeners with chlorines in both para positions (4 and 4') and at least 2 chlorines at the meta positions (3, 5, 3', 5') are considered to be "dioxin like" and are “particularly toxic” (U.S. EPA, http://www.epa.gov/toxteam/pcbid/table.htm). Congeners with ortho-substituted chlorines (2,2’,6,6’ positions) are less toxic than those without ortho-substituted chlorines

2 There were insufficient data to rank the additional five congeners or isomers present in the headspace on this chart.

Data Analysis

The PCBs in the headspaces of tanks used to store high-level radioactive waste at DOE sites are almost entirely congeners with less than 42% chlorine. There are only three tetrachloro isomers (49% chlorine). The ACGIH TLVs are based on mixtures of PCBs, and the tetrachloro isomers in the headspace within mixtures containing the PCBs with lower percentages of chlorine will still result in mixtures of less than 42% chlorine. In addition, the congeners in the tank waste headspace generally have chlorine substitutions at positions suggesting relatively lower toxicity (Table 3.16). Therefore, the appropriate guideline comparison is to PCB 1242, which has a TLV-TWA of 1 mg/m3. However, this TLV may not protect exposed individuals from chloracne. Applying the EPA slope factors for upper and central estimate slope factors for PCBs of the type found in the tank waste headspace, estimated OELs are 26 and 45 µg/m3, respectively.

Summary and Recommendations

The use of the ACGIH TLV-TWA of 1 mg/m3 based on exposures to 42% chlorine PCB to propose an HTFOELfor the tank waste PCB headspace content results in a conservative guideline (Table 3.17). The PCB congeners in this population are generally predicted to have relatively low toxicities based on the number and location of chlorine substitutions (See Table 3.17), and the percentage of chlorine in the tank waste headspace will be lower than the 42% in the ACGIH assessment. The proposed HTFOELfor the PCBs in the tank waste headspace is therefore 0.03 mg/m3 and includes an UF of 30 to account for uncertainty associated with the precise composition of the tank waste PCBs and to protect against chloracne. In addition, 0.03 mg/m3 also approximates the OEL achieved using the EPA cancer slope

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factor calculation. As additional new data become available for these PCBs, it would be reasonable to reassess the appropriateness of basing the HTFOELupon Aroclor 1242.

Table 3.17. PCBs in Tank Waste

Tank Name Chemical Name Molecular Chemical Id Conc. Conc. TLV/ Weight (mg/m3) (ppm) Max HS1

241-AX- 1,1`-Biphenyl, 2-chloro- 188.7 2051-60-7 0.0063 0.0008 158 102

241-B-103 1,1`-Biphenyl, 3-chloro- 188.7 2051-61-8 0.033 0.0043 30

241-BY- 1,1`-Biphenyl, 2-chloro- 188.7 2051-60-7 0.0078 0.0010 128 103

241-BY- 1,1`-Biphenyl, 2,6-dichloro and 223.1 MRHUSI0-01 0.0092 0.0010 109 104 siloxane

241-BY- 1,1`-Biphenyl, 2,2`-dichloro- 223.1 13029-08-8 0.0057 0.0006 176 112

241-S-105 Chloro-1,1`-Biphenyl 188.7 URH000-03 0.023 0.0030 44

241-S-111 1,1`-Biphenyl, 2-chloro- 188.7 2051-60-7 0.0016 0.0002 641

241-TX- 1,1`-Biphenyl, 2,3,4`,6-tetrachloro- 292.0 52663-58-8 0.0023 0.0002 442 105

Tanks with More than 1 PCB Detected

241-TX- 1,1`-Biphenyl, 3,3`-dichloro- 223.1 2050-67-1 0.0069 0.0008 118

241-TX- 1,1`-Biphenyl, 3-chloro- 188.7 2051-61-8 0.0064 0.0008 118

Total 0.013 75

241-TY- 1,1`-Biphenyl, 2,3,3`,5`-tetrachloro- 292.0 41464-49-7 0.0045 0.0004 101

241-TY- 1,1`-Biphenyl, 2-chloro- 188.7 2051-60-7 0.035 0.0045 103

Total 0.039 25

241-TY- 1,1`-Biphenyl, 2,2`-dichloro- 223.1 13029-08-8 0.0011 0.0001 104

241-TY- 1,1`-Biphenyl, 2,3-dichloro- 223.1 16605-91-7 0.0010 0.0001 104

241-TY- 1,1`-Biphenyl, 2,4`,5-trichloro- 257.5 16606-02-3 0.0035 0.0003 104

241-TY- 1,1`-Biphenyl, 4,4`-dichloro- 223.1 2050-68-2 0.0037 0.0004 104

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Tank Name Chemical Name Molecular Chemical Id Conc. Conc. TLV/ Weight (mg/m3) (ppm) Max HS1

241-TY- 1,1`-Biphenyl, 2-chloro- 188.7 2051-60-7 0.0037 0.0005 104

241-TY- 1,1`-Biphenyl, 4-chloro- 188.7 2051-62-9 0.0026 0.0003 104

241-TY- 1,1`-Biphenyl, trichloro- 257.5 25323-68-6 0.0032 0.0003 104

241-TY- 1,1`-Biphenyl, 2,6-dichloro- 223.1 33146-45-1 0.0032 0.0004 104

241-TY- 1,1`-Biphenyl, 2,5-dichloro- 223.1 34883-39-1 0.0009 0.0001 104

241-TY- 1,1`-Biphenyl, 2,3,3`,5`-tetrachloro- 292.0 41464-49-7 0.0026 0.0002 104

241-TY- 1,1`-Biphenyl, 2,3,4`,6-tetrachloro- 292.0 52663-58-8 0.0006 0.00005 104

1 The total concentration of PCBs in the Headspace (mg/m3) compared to the ACGIH TLV of 1 mg/m3. Only 3 tanks had headspace concentrations with a margin of exposure less than 50 (in bold).

3.11.2 Current Summaries

3.11.2.1 Chlorinated biphenyls (CAS No. congener-specific)

A HTFOELwas proposed for a family of polychlorinated biphenyls (PCBs). There are 209 different congeners of PCBs and their toxic potential is dependent upon the extent and location of chlorine substituents on the aromatic rings. The PCB congeners found in the tank waste headspace are much more similar to the PCBs with lower percentages of chlorine, and the proposed HTFOELfor these PCBs is 0.03 mg/m3 (~0.003 ppm) based on the ACGIH TLV for 42% chlorinated PCBs with an UF of 3 to account for uncertainty associated with the exact mixture of PCBs in the tank and the potential for chloracne.

Literature Search

A literature search focusing on new toxicity data for chlorinated biphenyls was conducted on July 26, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on chlorinated biphenyls: CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS and PubMed. Several PCB congeners were identified in the PAC database, which may serve as reference surrogates for PCBs detected in tank waste.

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Toxicity • Chloracne, reproductive toxin, probable human carcinogen, endocrine disruption (HazMap)

Carcinogenicity

PCBs are classified as B2 probable human carcinogens by the EPA. Quantitative estimates of carcinogenic risk from oral and inhalation exposures by the EPA have not been updated since the original 1996 publication.

Irritation Indications

People exposed directly to high levels of PCBs, either via the skin, by consumption, or in the air, have experienced irritation of the nose and lungs, skin irritations such as severe acne (chloracne) and rashes, and eye problems. (Johnson et al 1999)

Odor Threshold

None

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Mixture Interactions

A PubMed search using the terms mixture interaction and PCBs results in 84 citations. Many citations were unrelated to health effects or described chemical interactions at high doses whose relevance is questionable. Some citations described interactions in in vitro model systems that are difficult to interpret at present. Because PCB toxicity is highly congener dependent, the specific congeners identified in COPCs should be re-evaluated for mixture effects individually.

Summary and Recommendations

Risk assessment of PCBs is driven by carcinogenesis data which has not changed since the last report, therefore, the proposed HTFOELfor PCB congeners detected in tank farm waste are still valid. As new PCB congeners are identified, their relative toxic potentials and contribution to total PCB levels in head space should be re-evaluated to determine if the current HTFOELis adequate.

References Johnson, B. L. et al (1999). Public Health Implications of Exposure to Polychlorinated Biphenyls (PCBs). Agency for Toxic Substances and Disease Registry. Online at http://www.atsdr.cdc.gov/DT/pcb007.html

3.11.2.2 Biphenyl (CAS No. 92-52-4)

The OEL for biphenyl (also known as diphenyl) is 0.2 ppmv adapted from an 8 hr TWA-TLV set by ACGIH.

Literature Search

A literature search focusing on new toxicity or regulatory data for biphenyl was conducted May 9, 2016. Using standardized search criteria, the following databases were identified as containing active records on biphenyl: EPA AEGL, DOE PAC, HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, and Genetox.

The search identified various regulatory guidelines have been updated. OSHA maintains an 8 hr TWA- PEL PEL of 0.2 ppm (HSDB, 29 CFR 1910.1000 2004). ACGIH maintain a recommendation of an 8 hr TWA TLV of 0.2 ppm (HSDB, ACGIH 2008). ACGIH has an Excursion Limit Recommendation of 3 times the TLV for no more than 30 min during a work day and under no circumstances exceed 5 times TLV (HSDB, ACGIH 2008). NIOSH recommends a 10 hr TWA-REL of 0.2 ppm. NIOSH has established an Immediately Dangerous to Life or Health at 100 mg/m3 (HSDB, NIOSH 2003). EPA established interim AEGLs for biphenyl (EPA 2007). The US DOE has established PAC values for biphenyl, and the PAC-2 was adopted from the 1 hr AEGL-2.

Acute Exposure Guideline Levels (AEGLs) for biphenyl.

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 NR NR NR NR NR AEGL-2 12 12 9.6 6 4.4 Cannon Laboratories 1977 AEGL-3 NR NR NR NR NR Not recommended (NR)

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Protective Action Criteria (PAC) for biphenyl.

Classification Protective Action Critera (PAC) (ppm) PAC-1 0.87 PAC-2 9.6 PAC-3 300

Toxicity

Hepatotoxin and central nervous system toxin (HazMap).

Carcinogenicity

Classified Group D, Not Classifiable as to Human Carcinogenicity. (HSDB, IRIS 2000).

Irritation Indications

Causes irritation of the throat and eyes (HazMap)

In acute exposure, diphenyl causes eye and skin irritation (HSDB, Bingham 2001).

Causes irritation to eyes, skin, and mucous membrane and upper respiratory tract. (HSDB, Prager 1995).

Odor Threshold

0.01-0.05 ppm Odor threshold (HazMap).

Pleasant, peculiar odor (HSDB, O’Neil 2001).

Pleasant, butter-like odor (HSDB, Cain 1993).

Mixture Interactions

It is possible that biphenyl could act additively with chlorinated biphenyl congeners.

Summary and Recommendations

We do not recommend revaluation of the OEL for biphenyl. The OEL is consistent with current guidelines for ACGIH, OSHA, and NIOSH. Acute exposure guidelines have been established by EPA and DOE, and internal acute exposure guidelines could be adapted from those values. Thus we suggest maintaining the current OEL and establishment of acute exposure guidelines for biphenyl.

References 29 CFR 1910.1000; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of November 1, 2004: http://www.gpoaccess.gov/ecfr American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 14 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety& Health. DHHS (NIOSH) Publication No. 2004-103 (2003).

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EPA, Acute Exposure Guideline Levels (AEGLs) for Biphenyl, Interim 2007. Cannon Laboratories, Inc. 1977. Final report: 90-day inhalation toxicity study of biphenyl (99+% purity) in CD-1 mice. Sponsored by Sun Company Lab. EPA Doc. No. 878213532; Fiche No. OTS0206401 U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on 1,1- Biphenyl (92-52-4). Available from, as of March 15, 2000: http://www.epa.gov/iris Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001), p. V4 328 Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995, p. 326 O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001, p. 584 Cain WS et al; Reference Guide to Odor Thresholds for Hazardous Air Pollutants Listed in the Clean Air Act Amendments of 1990. Washington,DC: Off Health Environ Assess, Environ Protect Agency, Report 1992, ECAO-R-0397, USEPA/600/R-92/047 (NTIS PB92-239516) (1993)

3.12 Current Summaries of Chemicals Not Previously Addressed

3.12.1 Dienes

3.12.1.1 1,3-Butadiene (CAS No. 106-99-0)

The OEL for 1,3-butadiene is 1 ppmv based on an 8 hr TWA-PELset by OSHA.

Literature Search

A literature search focusing on new toxicity or regulatory data for 1,3-butadiene was conducted May 9, 2016. Using standardized search criteria, the following databases were identified as containing active records on 1,3-butadiene: EPA AEGL, DOE PAC, HazMap, HSDB, IRIS, ITER, RTECS, and Toxline.

New regulatory data was discovered for 1,3-butadiene. OSHA maintains a 1 ppmv 8 hr TWA PEL, and suggests a 5 ppmv STEL (HSDB, 29 CFR 1910.1051 2015). ACGIH recommends an 8 hr TWA-TLV of 2 ppmv (HSDB, ACIGH 2014). NIOSH considers 1,3-butadiene to be a potential occupational carcinogen (HSDB, NIOSH 2010). EPA proposed interim AEGLs for 1,3-butadiene. The US DOE adopted 1 hr AEGL values as PAC for 1,3-butadiene.

AEGLs for 1,3-butadiene.

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 670 670 670 670 670 Carpenter 1944 AEGL-2 6700 6700 5300 3400 2700 Carpenter 1944 AEGL-3 27000 27000 22000 14000 6800 Shugaev 1969

Toxicity

Causes central nervous system depression at high concentrations (HazMap).

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1,3-butadiene causes testicular damage (HazMap).

Headache, drowsiness, and eye, nose, or throat irritation may occur in humans that breathe high doses of 1,3-butadiene over a short period of time (HSDB).

Carcinogenicity

Leukemia has been reported in workers exposed to 1,3-butadiene (HSDB).

Classified as a probable human carcinogen (B2) (HSDB, IRIS 2000).

Classified as a suspected human carcinogen (A2) (HSDB, ACGIH 2014).

Classified as a known human carcinogen (HSDB, DHHS/National Toxicology Program 2015).

Irritation Indications

May cause eye, nose, or throat irritation (HSDB).

Irritation of the human respiratory system: 10,000 ppm for 1 min; Slight irritation of the eyes and upper respiratory tract, no other effects: 8,000 ppm/8 hr (HSDB, Verschueren 1983).

Odor Threshold

Mild aromatic or gasoline-like odor (HazMap).

0.35 mg/m3 (odor low) 2.86 mg/m3 (odor high) (HSDB, Ruth 1986).

Mixture Interactions

The mechanism of action for 1,3-butadiene involves metabolic activation to a reactive epoxide compound (HSDB, DHHS/National Toxicology Program 2015). Thus exposure to other compounds that induce cytochrome P450 activities could increase the potential of toxicity due to 1,3-butadiene exposure.

Summary and Recommendations

It is recommended that the OEL for1,3-butadiene does not need to be reevaluated; however, acute exposure guidelines may need to be developed. The OSHA PEL was adopted as the OEL for the Tank Farm. OSHA maintains the most conservative occupational exposure limit (1 ppm), with the exception of NIOSH. NIOSH supports “as low as possible” criteria due to carcinogenic potential. In-house acute exposure guidance has not been developed for 1,3-butadiene, and STEL, AEGL, and PAC guidelines are available to support acute exposure guidance development. We recommend that the OEL does not require reevaluation; however, acute exposure guidance is needed.

References 29 CFR 1910.1051(c) (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 25, 2015: http://www.ecfr.gov American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 15

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NIOSH. NIOSH Pocket Guide to Chemical Hazards. Department of Health & Human Services, Centers for Disease Control & Prevention. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from: http://www.cdc.gov/niosh/npg U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on 1,3- Butadiene (106-99-0). Available from, as of March 15, 2000: http://www.epa.gov/iris/ American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 15 DHHS/National Toxicology Program; Report on Carcinogens, Thirteenth Edition: 1,3-Butadiene (106-99- 0) (2014). Available from, as of February 12, 2015: http://ntp.niehs.nih.gov/go/roc13 Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983, p. 297 Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986)

3.12.2 Metals

3.12.2.1 Mercury (CAS No. 7439-97-6)

Mercury was not previously evaluated in PNNL-15736. Current PAC values for mercury were identified. No information on Mercury in the AEGL database was identified. Additional regulatory information:

1. TLV (ACGIH) 0.02 mg/m3 (HAZMAP). 2. PEL (OSHA) 0.1 mg/m3 (HAZMAP). 3. MAK 0.1 mg/m3 (HAZMAP). 4. IDLH (NIOSH) 10 mg/m3 (HAZMAP). 5. RfC (EPA) 0.025 mg/m3 (IRIS) a. UF — An uncertainty factor of 10 was used for the protection of sensitive human subpopulations (including concern for acrodynia together with the use of a LOAEL. An uncertainty factor of 3 was used for lack of database, particularly developmental and reproductive studies.

Primary supporting references: Fawer et al., 1983; Piikivi and Tolonen, 1989; Piikivi and Hanninen, 1989; Piikivi, 1989; Ngim et al., 1992; Liang et al., 1993

Literature Search

A literature search focusing on data indicating toxic effects of mercury in range of current Pac values was conducted on August 10, 2016. Standardized search criteria evaluated information in CCRIS, CTD,

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HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases, all of which contained active records on mercury. 1. Six of 75 workers exposed to 0.05 to 0.1 mg mercury vapor/m3 in a glass manufacturing plant reported insomnia, and one had tremors. Hyperexcitability was observed in 33 percent of the workers exposed to mercury vapor at concentrations above 0.05 mg mercury vapor/m3, whereas only 8 percent of the workers exposed below this concentration were hyperexcitable. Tremors were observed in 20 percent of the workers in both groups. Occupational mercury exposures resulting in tremors are associated with urinary mercury concentrations ranging from 50 to 200 μg/g creatinine. (Patty’s Industrial Hygiene and Toxicology, 1993-1994). 2. Forty one male mercury exposed workers were examined for serum concentration levels of immunoglobulins (IgG, IgA, IgM), alpha-1-antitrypsin (AIAT), alpha-2-macroglobulin (A2M), ceruloplasmin (CPL), and orosomucoid (ORO). In the period preceding this investigation the mercury concentrations in workplace air ranged from 0.106 to 0.783 mg/cu m; the range of urinary mercury concentrations was from 0.029 to 0.545 mg/l. All but two (IgG and AIAT) of the immune parameters tested were at levels much higher than those found in a control group of 55 workers matched by age to the exposed workers and who lived in a relatively clean area. Almost 80% of the workers in the control group demonstrated no value out of the range of normal physiological limits, but only 36.6% of the exposed workers showed normal values. (Patty’s Industrial Hygiene and Toxicology, 1993-1994).

Toxicity

Nephrotoxin, reproductive toxin, neurotoxin. (HazMap Database). Mercury is readily absorbed through the skin.

Carcinogenicity

CLASSIFICATION: D; not classifiable as to human carcinogenicity. (HSDB)

BASIS FOR CLASSIFICATION: Based on inadequate human and animal data. Epidemiologic studies failed to show a correlation between exposure to elemental mercury vapor and carcinogenicity; the findings in these studies were confounded by possible or known concurrent exposures to other chemicals, including human carcinogens, as well as lifestyle factors (e.g., smoking). Findings from genotoxicity tests are severely limited and provide equivocal evidence that mercury adversely affects the number or structure of chromosomes in human somatic cells. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Inadequate. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on Mercury (Inorganic ) (7439-97-6). Available from, as of March 15, 2000: http://www.epa.gov/iris/

Irritation Indications

Skin and eye irritant (CDC).

Odor Threshold

No odor.

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Mixture Interactions Exposure to low dose metal mixtures affects homeostasis of toxic and essential metals in tissues of mice. Low concentrations were defined as: Pb (0.01 mg L−1), Hg (0.001 mg L−1), Cd (0.005 mg L−1) and As (0.01 mg L−1). (Cobbina et al., 2015).

Summary and Recommendations

Adoption of an OEL set by ACGIH (0.02 mg/m3) is recommended which is consistent with inclusion of uncertainty factors for susceptible individual and database deficiencies.

References Cobbina SJ, Chen Y, Zhou Z, Wu X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wu X, Yang L. Low concentration toxic metal mixture interactions: Effects on essential and non-essential metals in brain, liver, and kidneys of mice on sub-chronic exposure. Chemosphere. 132:79-86, 2015. Fawer, R.F., U. DeRibaupierre, M.P. Guillemin, M. Berode and M. Lobe. 1983.Measurement of hand tremor induced by industrial exposure to metallic mercury. J. Ind. Med. 40: 204-208. Liang, Y-X., R-K. Sun, Y. Sun, Z-Q. Chen and L-H. Li. 1993. Psychological effects of low exposure to mercury vapor: Application of a computer-administered neurobehavioral evaluation system. Environ. Res. 60: 320-327. Ngim, C.H., S.C. Foo, K.W. Boey and J. Jeyaratnam. 1992. Chronic neurobehavioral effects of elemental mercury in dentists. Br. J. Ind. Med. 49: 782-790. Patty's Industrial Hygiene and Toxicology. Clayton, G.D., F.E. Clayton (eds.). Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. Piikivi, L. 1989. Cardiovascular reflexes and low long-term exposure to mercury vapor. Int. Arch. Occup. Environ. Health. 61: 391-395. Piikivi, L. and H. Hanninen. 1989. Subjective symptoms and psychological performance of chlorine- alkali workers. Scand. J. Work Environ. Health. 15: 69-74. Piikivi, L. and U. Tolonen. 1989. EEG findings in chlor-alkali workers subjected to low long term exposure to mercury vapor. Br. J. Ind. Med. 46: 370-375.

3.12.2.2 Dimethyl Mercury (CAS No. 593-74-8)

Dimethyl Mercury was not previously evaluated in PNNL-15736. No information on Dimethyl Mercury was identified in PAC or AEGL databases. Additional regulatory information: 1. TLV (ACGIH) 0.01 mg/m3 (HAZMAP). 2. STEL (ACGIH) 0.03 mg/m3 (HAZMAP). 3. PEL (OSHA) 0.01 mg/m3 (HAZMAP). 4. IDLH (NIOSH) 2 mg/m3 (HAZMAP).

Literature Search

A literature search focusing on data indicating toxic effects of dimethyl mercury on August 10, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. Databases with active documents on dimethyl mercury included: CCRIS, HazMap, RTECS and PubMed. No new regulatory information was discovered.

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Toxicity

Nephrotoxin, reproductive toxin, neurotoxin. (HazMap Database). Dimethyl mercury is readily absorbed through the skin.

Carcinogenicity

Possible carcinogen (HAZMAP).

Irritation Indications

A skin, eye, and respiratory tract irritant (HAZMAP).

Odor Threshold

Mild sweet odor.

Mixture Interactions

None identified (PubMed search using terms mixture interaction and dimethyl mercury.

Summary and Recommendations

Adoption of an OEL set by ACGIH (0.01 mg/m3) is recommended.

References

None

3.12.3 Phthalate Esters

3.12.3.1 Diethyl phthalate (CAS No. 84-66-2)

OEL

The OEL for diethyl phthalate is 5 mg/m3 based on a TLV set by ACGIH.

Literature Search

A literature search focusing on new toxicity or regulatory data for diethyl phthalate was conducted May 26, 2016. Using standardized search criteria, the following databases were identified as containing active records on diethyl phthalate: DOE PAC, HazMap, IRIS, HSDB, ITIER, CCRIS, RTECS, Toxline, PubMed, and CTD.

Updated regulatory values were identified for diethyl phthalate. ACGIH has maintained an 8 hr TWA- TLV at 5 mg/m3 for diethyl phthalate (HSDB, ACGIH 2007). ACGIH has made an Excursion Limit Recommendation where 3× the TLV may be exceeded for no more than 30 total min during a work day, and under no circumstances should exposure exceed 5× the TLV. IRIS released a Preliminary Assessment for diethyl phthalate on 3/2014 and had a public meeting on 4/2014. The updated IRIS assessment for diethyl phthalate is currently in Draft Development. NIOSH recommended an exposure limit of 5 mg/m3

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for diethyl phthalate based on a 10 hr TWA (HSDB, NIOSH 2005). The US DOE established PAC (Revision 29) for diethyl phthalate.

PAC for diethyl phthalate.

Classification Protective Action Critera (PAC) (ppm) PAC-1 15 PAC-2 300 PAC-3 1800

Toxicity

Symptoms include headache, dizziness, and nausea; lacrimation (discharge of tears); possible polyneuropathy, vestibular dysfunction; pain, numbness, weakness, spasms in arms and legs. Sensitive individuals may develop an allergic reaction similar to asthma. Repeated exposure may cause nerve damage (HSDB, Sittig 2002).

Carcinogenicity

Classification D; not classifiable as a human carcinogen (HSDB, IRIS 2000)

A4; Not classifiable as a human carcinogen. (HSDB, ACGIH 2010)

Irritation Indications

Diethyl phthalate is slightly irritating to eye and skin (HSDB, Bingham 2001).

Odor Threshold

Diethyl phthalate has been described as practically odorless to very slight aromatic odor (HSDB, O’Neil 2006, Lewis 2001, NIOSH 2005)

Mixture Interactions

Combined administration of Clophen A60 and diethyl phthalate shows an enhanced toxic effect on adrenal glands of F1-generation male and female rats (Pereira 2007).

Summary and Recommendations

TLVs have been recently reviewed by both ACGIH and NIOSH and remain at 5 mg/m3, the current OEL for diethyl phthalate. PACs for acute exposures have been established at higher concentrations than the current OEL. Thus, utilization of current OEL should protect against acute exposures but may be conservative. Thus, evaluation of acute exposure guidelines may be prudent. Since IRIS is actively assessing diethyl phthalate, it may be diligent to periodically monitor for potentially revised regulatory values.

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NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005) Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 2002. 4th ed.Vol 1 A-H Norwich, NY: Noyes Publications, 2002., p. 881 U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on Diethyl phthalate (84-66-2). Available from, as of March 15, 2000: http://www.epa.gov/iris/ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH 2010, p. 26 Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V6 824 O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1270 Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 377 NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005) Pereira C, Mapuskar K, Rao CV. 2007. A two-generation chronic mixture toxicity study of Clophen A60 and diethyl phthalate on histology of adrenal cortex and thyroid of rats. Acta histochemica 109: 29-36.

3.12.4 Miscellaneous

3.12.4.1 Ammonia (CAS No. 7664-41-7)

TLV for ammonia set by ACGIH at 25 ppm.

Literature Search

A literature search focusing on toxicity data for ammonia was conducted on May 17, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on ammonia: CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS. Information on ammonia was identified in AEGL and PAC databases. The ACGIH has not updated the TLV for ammonia (25 ppm) since the original 2001 publication.

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PAC values for ammonia are the same as AEGLs.

Toxicity 1. HUMAN EXPOSURE STUDIES/ A group of 6 healthy volunteers, not previously accustomed to working in an ammonia environment, were exposed 5 days/week to 25 ppm (2 hr/day), 50 ppm (4 hr/day), or 100 ppm (6 hr/day) of ammonia, or to 50 ppm of ammonia 6 hr/day for 6 weeks. Exposure to ammonia had no significant effect on the measures of respiratory function or in the neurological tests conducted. The results of the evaluations of irritation conducted by the physician showed no significant differences between the exposure groups, including the 0 ppm exposure group (preexposure). All subjects experienced some watering of the eyes and a sensation of dryness in the nose and throat, and there was one observation of definite redness in the mucosa of the nose after a 6-hour exposure to 100 ppm during which time, there was an excursion to 200 ppm ammonia. No redness was observed in this subject the following morning. Throughout the study, the physician observed 6 cases of eye irritation, 20 of nose irritation, and 9 of throat irritation, and most cases appeared to have occurred the first week of the study during exposure to 50 ppm. It is difficult to determine in this study a no-observed adverse- effect level (NOAEL) or LOAEL for irritation due to the different exposure durations experienced by the subjects. – HSDB document - U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Ammonia pp.18-19 (2004) TP126. 2. HUMAN EXPOSURE STUDIES/ Groups of four healthy human volunteers were exposed weekly (5 days/week) to 25 (2 hr/day), 50 (4 hr/day) or 100 (6 hr/day) ppm ammonia (1.0, 4.1, or 12.1 mg/cu m) for 6 weeks; or to 50 ppm (6.2 mg/cu m) 6 hr/day for 6 weeks. Subjective and objective indications of eye and respiratory tract irritation, pulse rate, respiration rate, FVC [Forced Expiratory Vital Capacity], FEV [Forced Expiratory] and difficulty in performing simple cognitive tasks were used to assess toxicity. No abnormalities of the chest, heart, vital organs, neurological response, apparent motor function, or significant weight changes were observed during weekly medical examinations. Transient irritation of the nose and throat was observed at 50 ppm (duration-adjusted to 4.1 mg/m3) or greater. [U.S. Environmental Protection Agency's

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Integrated Risk Information System (IRIS) on Ammonia (CAS #7664-41-7). Available from, as of May 11, 2010: (http://www.epa.gov/iris/subst/index.html) 3. HUMAN EXPOSURE STUDIES/ Eight human volunteers were exposed to 50, 80, 110, and 140 ppm ammonia (35, 56, 76, and 97 mg/cu m, respectively) for 2 hr, with a 1 week interval between exposures. The subjects tolerated a concentration of 76 mg/cu m, although they rated the throat irritation as a nuisance. An ammonia concentration of 97 mg/cu m was intolerable, and all of the subjects left the exposure chamber prematurely. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Ammonia (CAS #7664-41-7). Available from, as of May 11, 2010: (http://www.epa.gov/iris/subst/index.html). 4. Toxnet lists many additional human exposure studies with little/no toxicity or respiratory irritation at concentrations below 50 ppm. 5. HUMAN EXPOSURE STUDIES/ ... Forty-three healthy male volunteers were exposed to ammonia vapors in concentrations of 0, 10, 20, 20/40, and 50 ppm on five consecutive days. To explore a possible influence of habituation on the perception of symptoms, the study group was divided into 30 men who were not familiar with the smell of ammonia, and ten participants regularly exposed to ammonia at the workplace. The perceived intensity of health symptoms and annoyance increased with the concentration of ammonia, while the self-reported dimensions of well-being decreased. Workers familiar with the smell of ammonia vapors reported less symptoms compared to naive subjects. (Ihrig A et al., 2006). 6. HUMAN EXPOSURE STUDIES/ ... Twelve healthy persons underwent sham or ammonia (5 and 25 ppm) exposure randomly in an exposure chamber on three occasions. The exposure duration was 3 hours, 1.5 hr resting (seated) and 1.5 hr exercising (50 W on a bicycle ergonometer). Symptoms were registered repeatedly before, during, and after the exposure on visual analogue scales. Bronchial responsiveness to methacholine, lung function, and exhaled nitric oxide (NO) were measured before and 7 hr after the exposure. In addition, nasal lavage was performed, and peripheral blood samples were drawn before and 7 hr after the exposure. All the symptom ratings increased significantly during 25 ppm ammonia exposure as compared with the control exposure. The cumulative dose of methacholine causing a 20% decrease in forced expiratory volume in 1 second was lower (< 1 concentration step of methacholine) for the exposure than for a pretrial control challenge. However, no difference was found between the control and ammonia exposures (P = 0.33). The ammonia exposure did not significantly influence lung function or the exhaled NO levels. The total cell or interleukin-8 concentration in nasal lavage fluid did not change. The total leucocyte concentration in peripheral blood increased significantly (P < 0.001) after both the sham and ammonia exposure, mainly due to an increase in neutrophils (P < 0.001). Ammonia exposure did not significantly alter complement factor 3b in plasma. Conclusion: During ammonia exposure in an

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exposure chamber, symptoms related to irritation and central nervous effects increase and are constant with no signs of adaptation. Ammonia inhalation does not cause detectable upper-airway inflammation or increased bronchial responsiveness to methacholine in healthy persons. (Sundblad B-M et al., 2004) 7. CASE REPORTS/ A man exposed occupationally for 5 months to low levels of ammonia gas (8-15 ppm) from ammonia-containing silver polish developed asthma-like symptoms. Separate specific bronchial provocation tests to the silver polish and to 12 ppm ammonia produced asthmatic reactions, implicating the ammonia in the silver polish as the cause. Another study reported hyposmia (partial loss of the sense of smell) in a man following acute inhalation exposure (for several hours) to an unknown concentration of ammonia gas; the hyposmia had not resolved 30 months after exposure. (U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Ammonia p.48 (2004) TP126. Available from, as of May 6, 2010: (http://www.atsdr.cdc.gov/toxpro2.html] 8. EPIDEMIOLOGY STUDIES/ A number of occupational cohort studies that examined farmers who worked in enclosed livestock buildings have been conducted. These studies all included measurements of ammonia in the livestock confinement buildings, as well as measurements of one or more of the following: total dust, respirable dust, carbon dioxide, total endotoxins, respirable endotoxins, fungi, bacteria, and molds. Of the pollutants measured, ammonia and dust were most frequently associated with respiratory effects, many of which were temporary and disappeared with cessation of exposure. Ammonia levels ranged from 2.3 to 20.7 ppm and total dust levels from 0.04 to 5.64 mg/cu m. Most of these studies reported an association between exposure to pollutants, including ammonia, in livestock confinement buildings and an increase in respiratory symptoms (such as bronchial reactivity/hyperresponsiveness, inflammation, cough, wheezing, or shortness of breath) and/or a decrease in pulmonary function (such as forced expiratory volume in the first second [FEV1.0], maximum expiratory flow rates [MEF50 and MEF75], and maximal mid-expiratory flow rate [MMEF]). One study, however, reported correlations only between total dust, fungal spore, and endotoxin mean exposure levels and task-specific prevalences. Another study reported no significant correlations between lung function or chronic respiratory symptoms and dust or ammonia levels, but suggested that endotoxins and bacteria levels may play a role. Most studies adjusted for confounding factors, such as smoking and number of years worked on a farm, in their statistical analyses. All of the studies concluded that prevalence of respiratory symptoms of some type was higher in the farmer cohort than in the respective control group. It is not clear from these studies what the contribution of ammonia is to the respiratory changes, but the cumulative data indicate that ammonia may contribute to transient respiratory distress in farmers working in enclosed livestock facilities. (U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for

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Ammonia p.46 (2004) TP126). Available from, as of May 6, 2010: (http://www.atsdr.cdc.gov/toxpro2.html] 9. EPIDEMIOLOGY STUDIES/ A cross-sectional study of male workers at two fertilizer factories in Saudi Arabia showed a significant association between exposure to ammonia gas and respiratory symptoms including bronchial asthma. Workers in factory one were exposed to air ammonia levels of 2.82-183.86 ppm (2.0-130.4 mg/cu m), and workers in factory two were exposed to 0.03-9.87 ppm (0.02-7.0 mg/cu m). However, continuous exposure levels for workers could not be calculated because the number of days worked per week was not provided by the study authors. Logistic regression analysis showed that ammonia concentration was significantly related to cough, phlegm, wheezing (with and without shortness of breath), and asthma, whereas smoking was only a factor for wheezing and phlegm. Additionally, those workers exposed to ammonia levels above ... 25.4 ppm (18 mg/cu m) had significantly higher relative risks for cough, phlegm, wheezing, dyspnea, and asthma ... . Incidence of wheezing was also elevated in workers exposed to ammonia levels below /25.4 ppm/. Cumulative ammonia concentration (CAC) of > 50 mg/cu m - years also showed a significantly increased relative risk for all of the above symptoms compared to workers with a CAC of < or = 50 mg/cu m - years. None of the relative risks for workers in the second factory (ammonia levels < 25.4 ppm) were significant. [U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Ammonia pp.46-7 (2004) TP126. Available from, as of May 6, 2010 http://www.atsdr.cdc.gov/toxpro2.html] 10. Based on the lack of subjective symptomatology and changes in spirometry, this study establishes a free-standing TWA NOAEL of 9.2 ppm (6.4 mg/cu m). Adjustment for the TWA occupational scenario results in a NOAEL(HEC) of 2.3 mg/cu m. [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Ammonia (CAS #7664-41-7). Available from, as of May 11, 2010: (http://www.epa.gov/iris/subst/index.html).

Carcinogenicity

Stomach cancer – oral – 0.01% in drinking water – CCRIS document

Irritation Indications

Listed as one of "major irritant airborne toxicants" (HazMap Database).

Odor Threshold

0.04 ppm

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Mixture Interactions

Synergistic toxicity associated with ammonia and cytokines in vitro (Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. (Alvarez et al., 2011).

Summary and Recommendations

Recently established AEGL and PAC values for ammonia (30 ppm) are higher than the previously established TLV set by ACGIH (25 ppm). However, a number of recent epidemiological studies indicate respiratory toxicity at concentrations below 25 ppm, with a TWA NOAEL of 9.2 ppm. Cytokines have shown synergistic toxicity with ammonia and cytokines are a highly variable and dynamic biological feature at the individual level. These observations collectively suggest that the OEL for ammonia be reevaluated.

References Alvarez VM, Rama Rao KV, Brahmbhatt M, Norenberg MD. Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res. 89(12):2028-40, 2011. Ihrig A, Hoffmann J, Triebig G. Examination of the influence of personal traits and habituation on the reporting of complaints at experimental exposure to ammonia. Int Arch Occup Environ Health. 79(4):332-8, 2006. Sundblad BM, Larsson BM, Acevedo F, Ernstgård L, Johanson G, Larsson K, Palmberg L. Acute respiratory effects of exposure to ammonia on healthy persons. Scand J Work Environ Health. 30(4):313-21, 2004. U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Ammonia pp.18-19 (2004) TP126. Available from, as of May 6, 2010: (http://www.atsdr.cdc.gov/toxpro2.html) [U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Ammonia (CAS #7664-41-7). Available from, as of May 11, 2010: (http://www.epa.gov/iris/subst/index.html)

3.12.4.2 Benzene (CAS No. 71-43-2)

The OEL for benzene is 0.5 ppmv based on a TLV established by ACGIH.

Literature Search

A literature search focusing on new toxicity or regulatory data for benzene was conducted May 9, 2016. Using standardized search criteria, the following databases were identified as containing active records on benzene: EPA AEGL, US DOE PAC, HazMap, IRIS, HSDB, ITER, CCRIS, RTECS, Genetox, and CTD.

Numerous regulatory guidelines have recently been updated for benzene. In 2003, IRIS revised the oral reference dose (RfD) to 4.0×10-3 mg/kg/day based on 1.2 mg/kg/day point of departure (Rothman 1996) and 300 UF (IRIS). The reference concentration for inhalation (RfC) was also revised to 3.0×10-2 mg/m3 based on 8.2 mg/m3 point of departure (Rothman 1996) and 300 UF (IRIS).

ACGIH maintains a 0.5 ppm 8 hr TWA-TLV and a 2.5 ppm STEL for benzene using skin as the basis (HSDB, ACGIH 2014).

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OSHA has set a 1 ppm 8 hr TWA-PEL and a 5 ppm 15 min STEL for benzene (HSDB, 29 CFR 1910.1028 2014). For some exempt industries, these values have been increased to 10 and 50 ppm for an 8 hr TWA and 10 min STEL, respectively (HSDB, 29 CFR 1910.1000 2014). For some exempt industries, OSHA has also set an Acceptable Ceiling Concentration of 25 ppm for an 8 hr TWA (HSDB, 29 CFR 1910.1000 2014).

NIOSH recommends a 0.1 ppm 10 hr TWA-REL and a 1 ppm 15 min STEL (HSDB, NIOSH 2010). NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration (HSDB, NIOSH 2010).

EPA established interim AEGLs for benzene. The US DOE has established PAC (Revision 29) for benzene that was adopted as the 1 hr AEGL values.

AEGLs for benzene.

Proposed AEGL Values (ppm) Classification 10 min 30 min 1 hr 4 hr 8 hr Reference AEGL-1 130 73 52 18 9 Srbova 1950 AEGL-2 2000 1100 800 400 200 Molnar 1986 AEGL-3 9700 5600 4000 2000 990 Molnar 1986

Toxicity

Benzene can induce narcosis and anesthesia acutely. After chronic exposure, it can cause aplastic anemia and leukemia (HazMap). Benzene causes central nervous system Solvent Syndrome (HazMap). Direct exposure of the eyes, skin, or lungs to benzene can cause tissue injury and irritation (HSDB, CDC 2014). Benzene causes harmful effects on the bone marrow and can cause a decrease in red blood cells, leading to anemia. It can also cause excessive bleeding and can affect the immune system, increasing the chance for infection (HSDB, CDC 2014). People who breathe in high levels of benzene may develop the following signs and symptoms within minutes to several hours: drowsiness, dizziness, rapid or irregular heartbeat, headaches, tremors, confusion, unconsciousness, or death (at very high levels) (HSDB, CDC 2014).

Carcinogenicity

A1; Confirmed human carcinogen. (HSDB, ACGIH 2014)

Carcinogenic to humans (HSDB, USEPA 2006)

Category A, known human carcinogen (HSDB, IRIS 2014)

Irritation Indications

Direct exposure of the eyes, skin, or lungs to benzene can cause tissue injury and irritation (HSDB, CDC 2014).

A severe eye and moderate skin irritant. (HSDB, Lewis 2004).

Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks (HSDB, US DHHS/ATSDR 2014).

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Odor Threshold

Aromatic odor (HazMap)

The odor threshold is 1.5 to 4.7 ppm (HSDB, Rumack 2016)

Gasoline-like odor; rather pleasant aromatic odor. Odor threshold = 4.68 ppm (HSDB, Sax 1984)

Human odor perception: 3.0 mg/cu m=1 ppm (HSDB, Verschueren 2001)

Mixture Interactions

Metabolism of benzene may be induced or inhibited based on exposure to various chemicals. For example, benzene, phenobarbital, 3-methylcholanthrene and dimethyl sulfoxide are all microsomal stimulants for the metabolism of benzene. Benzene metabolism in vitro can be inhibited by carbon monoxide, aniline, metyrapone, SKF-525A (proadifen), aminopyrine, cytochrome c, aminotriazole, or toluene (HSDB, USEPA 1980)

Summary and Recommendations

It is suggested that the OEL for benzene be reevaluated. ACGIH continues to maintain a 0.5 ppm TLV OEL the current basis; however, NIOSH is now recommending a 0.1 ppm TLV OEL. Additionally, acute and chronic guidelines exist that could be applied to different benzene exposure durations. Thus reevaluation of the benzene OEL is prudent.

References Rothman, N., G.L. Li, M. Dosemeci, W.E. Bechtold, G.E. Marti, Y.Z. Wang, M. Linet, L.Q. Xi, W. Lu, M.T. Smith, N. Titenko-Holland, L.P. Zhang, W. Blot, S.N. Yin, and R.B. Hayes. 1996. Hematotoxicity among Chinese workers heavily exposed to benzene. Am. J. Ind. Med. 29: 236-246. American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 13 29 CFR 1910.1028(c) (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of January 28, 2014: http://www.ecfr.gov/cgi- bin/ECFR?page=browse 9 CFR 1910.1000 (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of January 28, 2014: http://www.ecfr.gov/cgi- bin/ECFR?page=browse NIOSH. NIOSH Pocket Guide to Chemical Hazards. Department of Health & Human Services, Centers for Disease Control & Prevention. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from: http://www.cdc.gov/niosh/npg NAS/COT Subcommittee for AEGLS. 2009. Interim Acute Exposure Guideline Levels (AEGLs), Benzene CDC; Emergency Preparedness and Response: Facts about Benzene; Available from, as of February 21, 2014: http://www.bt.cdc.gov/agent/benzene/basics/facts.asp American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 13

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USEPA Office of Pesticide Programs, Health Effects Division, Science Information Management Branch: "Chemicals Evaluated for Carcinogenic Potential" (April 2006) U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS). Summary on Benzene (71-43-2). Available from, as of February 21, 2014: http://www.epa.gov/IRIS/subst/0276.htm Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004, p. 360 U.S. Dept Health & Human Services/Agency for Toxic Substances & Disease Registry; Toxicological Profile for Benzene p.83 PB2008-100004 (2007). Available from, as of August 12, 2014: http://www.atsdr.cdc.gov/toxprofiles/index.asp Rumack BH POISINDEX(R) Information System Micromedex, Inc., Englewood, CO, 2016; CCIS Volume 169, edition expires Aug, 2016. Hall AH & Rumack BH (Eds): TOMES(R) Information System Micromedex, Inc., Englewood, CO, 2016; CCIS Volume 169, edition expires Aug, 2016. Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984, p. 152 Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 256 USEPA; Ambient Water Quality Criteria: Benzene p.C-12 (1980) EPA 440/5-80-018

3.12.4.3 Methyl Isocyanate (CAS No. 624-83-9)

Methyl Isocyanate was not previously evaluated in PNNL-15736. Information on Methyl Isocyanate was identified in AEGL and PAC databases. Additional regulatory information: 1. TLV (ACGIH) 0.02 ppm (HAZMAP). 2. PEL (OSHA) 0.02 ppm (HAZMAP). 3. MAK 0.01 ppm (HAZMAP). 4. IDLH (NIOSH) 3 ppm (HAZMAP). 5. STEL (ACGIH) 0.06 ppm (HAZMAP)

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Literature Search

A literature search focusing on new toxicity data for Methyl Isocyanate was conducted on August 10, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases, all of which contained active records on methyl isocyanate.

HUMAN EXPOSURE STUDIES/ Acute experiments of 1- to 5-minute duration were performed on four human volunteers. At 0.4 ppm, volunteers could not perceive odor and experienced no irritation of the eyes, nose, or throat. At 2 ppm, no odor was detected, but the subjects experienced irritation and lacrimation. At 4 ppm, the symptoms of irritation were more marked. Exposure was unbearable at 21 ppm.[American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2005., p. 2]

Toxicity

Reproductive toxin, skin sensitizor, lacrimator, asthma, toxic, pneumonitis, fibrogenic, dermatotoxin (HazMap).

Carcinogenicity

Inconclusive (Senthilkumar et al., 2012).

Irritation Indications

Causes skin chemical burns (HazMap Database).

Odor Threshold

2.1 ppm. Colorless liquid with a sharp, pungent odor; [NIOSH]

Mixture Interactions

None identified (PubMed; mixture interaction and methyl isocyanate as search terms).

Summary and Recommendations

Adequate regulatory information exists on methyl isocyanate to establish an OEL. Acute exposure guidelines identify concentrations lower than proposed TLV values and should be considered in final decisions.

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References

Senthilkumar CS, Sah NK, Ganesh N. Methyl isocyanate and carcinogenesis: bridgeable gaps in scientific knowledge. Asian Pac J Cancer Prev. 13(6):2429-35. 2012. [Asian Pacific journal of cancer prevention : APJCP]

3.12.4.4 Nitrous Oxide (CAS No. 10024-97-2)

Nitrous oxide was not previously evaluated in PNNL-15736. Information on nitrous oxide was identified in PAC, but not AEGL databases. Additional regulatory information: 1. TLV (ACGIH) 50 ppm (HAZMAP). 2. MAK 100 ppm (HAZMAP).

Literature Search

A literature search focusing on new toxicity data for nitrous oxide was conducted on August 10, 2016. Standardized search criteria evaluated information in CCRIS, CTD, HazMap, HSDB, IRIS, ITER, RTECS, Toxline and PubMed databases. The following databases were identified as containing active records on nitrous oxide: CCRIS, CTD, HazMap, HSDB, RTECS. No new regulatory information was discovered.

Toxicity

Reproductive toxin, neurotoxin, asphyxiant (HazMap Database).

Carcinogenicity

A4; Not classifiable as a human carcinogen.(HSDB) Irritation Indications

Non-irritating (HSDB).

Odor Threshold

Not available. Slightly sweetish odor and taste. (HSDB)

Mixture Interactions

None identified (PubMed; mixture interaction and nitrous oxide as search terms).

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Summary and Recommendations

Adequate regulatory information exists to guide OEL standards.

References

None.

3.12.4.5 Tributyl phosphate (CAS No. 126-73-8)

The OEL for tributyl phosphate is 0.2 ppmv based on TLV established by the ACGIH.

Literature Search

A literature search focusing on new toxicity data for tributyl phosphate was conducted May 26 and June 30, 2016. Using standardized search criteria, the following databases were identified as containing active records on 4-methyl-2-hexanone: DOE PAC, HazMap, HSDB, ITER, CCRIS, RTECS, Toxline, PubMed, and CTD.

Several regulatory values were recently reviewed and updated by various government agencies. NIOSH suggests that 30 ppm tributyl phosphate is Immediately Dangerous to Life or Health (HSDB, NIOSH 2010). ACGIH set an 8 hr TWA-TLV of 5 mg/m3 inhalable fraction and vapor (HSDB, ACGIH 2014). ACGIH set an Excursion Limit Recommendation: Excursions in worker exposure levels may exceed 3 times the TLV-TWA for no more than a total of 30 minutes during a work day, and under no circumstances should they exceed 5 times the TLV-TWA, provided that the TLV-TWA is not exceeded (HSDB, ACGIH 2014). OSHA set a PEL at 5 mg/m3 based on a 8 hr TWA (HSDB, 29 CFR 1910.1000 2006). The US DOE has established PAC (Revision 28A) for tributyl phosphate.

PAC for tributyl phosphate.

Classification Protective Action Critera (PAC) (ppm) PAC-1 1.4 PAC-2 8.3 PAC-3 125

Toxicity

Nausea and headache have been reported in workers exposed to 15 mg/m3 (1.4 ppm) tributyl phosphate (Mastromatteo 1964). Tributyl phosphate inhibits cholinesterase activity (HazMap Database).

Carcinogenicity

ACGIH classified Tributyl phosphate is a Confirmed Animal Carcinogen with Unknown Relevance to Humans (HSDB, ACGIH 2008).

Irritation Indications

Tributyl phosphate causes bladder, eye, and upper respiratory tract irritation (HazMap Database). Tributyl phosphate is a skin, eye, and mucous membrane irritant (HSDB, Lews et al. 2004). Tributyl phosphate was found to be non-sensitizing after dermal application to guinea pigs (Toxline, GRA&I 2008).

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Odor Threshold

Odor perception threshold 0.014 mg/L (HSDB, Sheftel et al. 2000).

Mixture Interactions

Since tributyl phosphate inhibits cholinesterase activity, toxic effects may be additive with other cholinesterase inhibitors in a mixture.

Summary and Recommendations

ACGIH and OSHA recently updated 8 hr TWA TLV and PEL to 5 mg/m3 (0.46 ppmv = 5 mg/m3 × 24.45 L/mol / 266.32 g/mol). Considering the new value is higher than the previous OEL (0.2 ppmv), it is suggested that the OEL for tributyl phosphate be reevaluated along with the HTFOELfor dibuty butylphophonate (which utilizes tributyl phosphate as a surrogate compound) to ensure that these OELs are appropriate. Additionally, establishment of PACs by EPA could provide additional guidance for acute exposures.

References NIOSH. NIOSH Pocket Guide to Chemical Hazards. Department of Health & Human Services, Centers for Disease Control & Prevention. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2010-168 (2010). Available from: http://www.cdc.gov/niosh/npg American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 58 American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH 2014, p. 5 29 CFR 1910.1000; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 3, 2006: http://www.gpoaccess.gov/ecfr Mastromatteo E [1964]. Personal communication to TLV Committee. [From ACGIH [1991]. Tributyl phosphate. In: Documentation of the threshold limit values and biological exposure indices. 6th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, pp. 1600-1601. ACGIH Documentation of the Threshold Limit Values and Biological Exposure Indices. 7th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 2008 Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3514 Govt Reports Announcements & Index (GRA&I), Issue 22, 2008, Tributyl Phosphate: Skin Sensitization Study in Guinea Pifs (Final Report). Sheftel, V.O.; Indirect Food Additives and Polymers. Migration and Toxicology. Lewis Publishers, Boca Raton, FL. 2000, p. 225

Previous Documentation None.

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4.1

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