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i 1

2

3

4

5

6



## I MMEDIATELY 

## D ANGEROUS TO 

## L IFE OR 

## H EALTH 

## (IDLH) V ALUE 

## P ROFILE 7

8

9

10



### FOR 11

12

13

14



## H EXAFLUOROACETONE 

## (HFA) 15

16

17

18



## [CAS N O



## . 684-16-2] 19

20

21

22

23

24

25

26

Department of Health and Human Services 27

Centers for Disease Control and Prevention 28

National Institute for Occupa tional Safety and Health 29External Review Draft

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ii 

## Disclaimer 1

2

Mention of any company or product does not constitute endorsement by the National Institute for Occupational 3

Safety and Health (NIOSH). In add ition, citations to Web sites extern al to NIOSH do not constitute NIOSH 4

endorsement of the sponsoring organizations or thei r programs or products. Furthermore, NIOSH is not 5

responsible for the content of these Web sites. 6

7



## Ordering Information 8

9

To receive this document or information about other o ccupational safety and health topics, contact NIOSH: 10

11

Telephone: 1-800-CDC-INFO (1-800-232-4636) 12

TTY: 1-888-232-6348 13

E-mail: cdcinfo@cdc.gov 14

Or visit the NIOSH Web site: www.cdc.gov/niosh 15

16

For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.gov/niosh/eNews. 17

18

DHHS (NIOSH) Publication No. XXX 19

20

21External Review Draft

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iii 

## Foreword 1

Chemicals are a ubiquitous component of the modern wo rkplace. Occupational exposures to chemicals have the 2

potential to adversely affect the health and lives of workers. Acute or short-term exposures to high concentrations 3

of some airborne chemicals have the ability to quickly overwhelm workers, resulting in a spectrum of undesirable 4

health outcomes that may inhibit the ability to escape from the exposure envi ronment (e.g., irritation of the eyes 5

and respiratory tract or cognitive impairment), cause severe irreversible effects (e.g., damage to the respiratory 6

tract or reproductive toxicity), and in extreme cases, cause death. Airborne concentrations of chemicals capable 7

of causing such adverse health effects or of impeding escape from high-risk conditions may arise from a variety of 8

non-routine workplace situations , including special wo rk procedures (e.g., in confined spaces), industrial 9

accidents (e.g., chemical spills or explosions), and chemical releases into the community (e.g., during 10

transportation incidents or other uncontrolled-release scenarios). 11

12

The “immediately dangerous to life or health air concen tration values (IDLH values)” developed by the National 13

Institute for Occupational Safety a nd Health (NIOSH) characterize these high-risk exposure concentrations and 14

conditions [NIOSH 2013]. IDLH values are based on a 30-minute exposure duration and have traditionally 15

served as a key component of the decision logic for the selection of respiratory protection devices [NIOSH 2004]. 16

Occupational health professionals have employed these values beyond their initial purpose as a component of the 17

NIOSH Respirator Selection Logic to assist in developi ng Risk Management Plans for non-routine work practices 18

governing operations in high-risk envi ronments (e.g., confined spaces) and the development of Emergency 19

Preparedness Plans. 20

21

The approach used to derive IDLH values for high priority chemicals is outlined in the NIOSH Current 22

Intelligence Bulletin (CIB) 66: Derivation of Immediately Da ngerous to Life or Health Values [NIOSH 2013]. 23

CIB 66 provides 1) an update on the scientific basis a nd risk assessment methodology used to derive IDLH 24

values, 2) the rationale and derivati on process for IDLH values, and 3) a demonstration of the derivation of 25

scientifically credible IDLH values using available data resources. 26

27

The purpose of this technical report is to present the IDLH value for hexafluoroacetone (CAS # 684-16-2). . The 28

scientific basis, toxicologic data and risk assessment appr oach used to derive the ID LH value are summarized to 29

ensure transparency and scientific credibility. 30

31

John Howard, M.D. 32

Director 33

National Institute for Occupa tional Safety and Health 34

Centers for Disease Control and Prevention 35External Review Draft

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iv 

## Table of Contents 1

FOREWORD

............................................................................................................................... ................................. III 2

ABBREVIATIONS

............................................................................................................................... ......................... V 3

GLOSSARY

............................................................................................................................... ................................... VI 4

ACKNOWLEDGMENTS

............................................................................................................................... .............. IX 5

1.0 INTRODUCTION

............................................................................................................................... ............... 1 6

1.1 O VERVIEW OF THE IDLH V ALUE FOR H EXAFLUOROACETONE

................................................................................... 1 7

1.2 P URPOSE

............................................................................................................................... ...................................... 1 8

1.3 G ENERAL S UBSTANCE I NFORMATION

......................................................................................................................... 1 9

2.0 ANIMAL TOXICITY DATA

............................................................................................................................. 5 10

3.0 HUMAN DATA

............................................................................................................................... .................. 9 11

4.0 SUMMARY

............................................................................................................................... ......................... 9 12

5.0 REFERENCES

............................................................................................................................... ........................ 10 13

14

15

16

17

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v 

## Abbreviations 1

2

ACGIH American Conference of Gove rnmental Industrial Hygienists 3

AEGL Acute Exposure Guideline Levels 4

AIHA American Industrial Hygiene Association 5

BMC benchmark concentration 6

BMCL benchmark concentra tion lower confidence limit 7

C ceiling 8

CAS chemical abstract service 9

ERPG Emergency Response Planning Guidelines 10

HFA hexafluoroacetone 11

IDLH immediately dangerous to life or health 12

LC 50 median lethal concentration 13

LC Lo lowest concentration of a chemical that caused death in humans or animals 14

LEL lower explosive limit 15

LOAEL lowest observed adverse effect level 16

mg/m 3 milligram(s) per cubic meter 17

NAC National Advisory Committee 18

NAS National Academy of Sciences 19

NIOSH National Institute for O ccupational Safety and Health 20

NOAEL no observed adverse effect level 21

OSHA Occupational Safety and Health Administration 22

PEL permissible exposure limit 23

ppm parts per million 24

RD 50 concentration of a chemical in the air that is estimated to cause a 50% decrease in the respiratory 25

rate 26

REL recommended exposure limit 27

SCP Standard Completion Program 28

STEL short term exposure limit 29

TLV threshold limit value 30

TWA time weighted average 31

UEL upper explosive limit 32

WEEL workplace environmental exposure level 33External Review Draft

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vi 

## Glossary 1

2

Acute Exposure : Exposure by the oral, dermal, or inhalation route for 24 hours or less. 3

Acute Exposure Guideline Levels (AEGLs) : Threshold exposure limits for the general public applicable to 4

emergency exposure periods ranging from 10 minutes to 8 hours. AEGL-1, AEGL 2, and AEGL-3 are 5

developed for five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and are distinguished 6

by varying degrees of severity of toxic effects ranging fro m transient, reversible effects to life-threatening 7

effects [NAS 2001]. AEGLs are intended to be guideline le vels used during rare events or single once-in-a8

lifetime exposures to airborne concentrations of acu tely toxic, high-priority chemicals [NAS 2001]. The 9

threshold exposure limits are designed to protect the general population, including the elderly, children or 10

other potentially sensitive groups that are generally not considered in the development of workplace exposure 11

recommendations (additional information av ailable at http://www.epa.gov/oppt/aegl/). 12

Acute Reference Concentration (RfC) : An estimate (with uncertainty spa nning perhaps an order of magnitude) 13

of a continuous inhalation exposure for an acute dur ation (24 hours or less) of the human population 14

(including sensitive subgroups) that is li kely to be without an appreciable risk of deleterious effects during a 15

lifetime. It can be derived from a NOAEL, LOAEL, or benchmark concentration, with uncertainty factors 16

(UFs) generally applied to reflect li mitations of the data used. Generally used in USEPA noncancer health 17

assessments [USEPA 2014]. 18

Acute Toxicity : Any poisonous effect produced within a short period of time following an exposure, usually 24 19

to 96 hours. 20

Adverse Effect : A substance-related biochemical change, functional impairment, or pathologic lesion that affects 21

the performance of an organ or system or alters the ab ility to respond to additional environmental challenges. 22

Benchmark Dose/Concentration (BMD/BMC) : A dose or concentration that produces a predetermined change 23

in response rate of an effect (called the benchmar k response, or BMR) compared to background [USEPA 24

2014] (additional information available at http://www.epa.gov/ncea/bmds/). 25

Benchmark Response (BMR) : A predetermined change in response rate of an effect. Common defaults for the 26

BMR are 10% or 5%, reflecting study design, da ta variability, and sensitivity limits used. 27

BMCL : A statistical lower confidence limit on th e concentration at the BMC [USEPA 2014]. 28

Bolus Exposure : A single, relatively large dose. 29

Ceiling Value (“C”) : U.S. term in occupational exposure indicati ng the airborne concentration of a potentially 30

toxic substance that should never be exceeded in a worker’s breathing zone. 31

Chronic Exposure : Repeated exposure for an extended period of time. Typically exposures are more than 32

approximately 10% of life span for humans and >90 days to 2 years for laboratory species. 33

Critical Study : The study that contributes most significantly to the qualitative and quantitative assessment of risk 34

[USEPA 2014]. 35

36

Dose : The amount of a substance available for interactions with metabolic processes or biologically significant 37

receptors after crossing the outer boundary of an organism [USEPA 2014]. 38

ECt 50 : A combination of the effective concentration of a s ubstance in the air and the exposure duration that is 39

predicted to cause an effect in 50% (one half) of the experimental test subjects. 40External Review Draft

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vii Emergency Response Planning Guidelines (ERPGs) : Maximum airborne concentrations below which nearly all 1

individuals can be exposed without experiencing health effects for 1-hour exposure. ERPGs are presented in a 2

tiered fashion with health effects ranging from mild or transient to serious, irreversible, or life threatening 3

(depending on the tier). ERPGs are developed by the Am erican Industrial Hygiene Association [AIHA 2006]. 4

Endpoint : An observable or measurable biological event or si gn of toxicity ranging from biomarkers of initial 5

response to gross manifestations of clinical toxicity. 6

Exposure : Contact made between a chemical, physical, or biological agent and the outer boundary of an 7

organism. Exposure is quantified as the amount of an agent available at the exchange boundaries of the 8

organism (e.g., skin, lungs, gut). 9

Extrapolation : An estimate of the response at a point outside the range of the experimental data, generally 10

through the use of a mathematical model, although qualitative extrapol ation may also be conducted. The 11

model may then be used to extrapolate to res ponse levels that cannot be directly observed. 12

Hazard : A potential source of harm. Hazard is distinguished from risk, which is the probability of harm under 13

specific exposure conditions. 14

Immediately Dangerous to Life or Health (IDLH) condition : A situation that poses a threat of exposure to 15

airborne contaminants when that exposure is likely to cause death or immediate or delayed permanent adverse 16

health effects or prevent escape from such an environment [NIOSH 2004, 2013]. 17

IDLH value : A maximum (airborne concentration) level above which only a highly reliable breathing apparatus 18

providing maximum worker protection is permitted [NIOSH 2004, 2013]. IDLH values are based on a 30- 19

minute exposure duration. 20

LC 01 : The statistically determined concentra tion of a substance in the air that is estimated to cause death in 1% of 21

the test animals. 22

LC 50 : The statistically determined concentr ation of a substance in the air that is estimated to cause death in 50% 23

(one half) of the test animals; median lethal concentration. 24

LC LO : The lowest lethal concentration of a substance in the air reported to cause death, usually for a small 25

percentage of the test animals. 26

27

LD 50 : The statistically determined lethal dose of a substance that is estimated to cause death in 50% (one half) of 28

the test animals; median lethal concentration. 29

LD LO : The lowest dose of a substance that causes death, usua lly for a small percentage of the test animals. 30

LEL : The minimum concentration of a gas or vapor in air, below which propagation of a flame does not occur in 31

the presence of an ignition source. 32

Lethality : Pertaining to or causing death; fatal; referring to th e deaths resulting from acute toxicity studies. May 33

also be used in lethality threshold to describe the poi nt of sufficient substance concentration to begin to cause 34

death. 35

Lowest Observed Adverse Effect Level (LOAEL) : The lowest tested dose or concentration of a substance that 36

has been reported to cause harmful (adverse) health effects in people or animals. 37

Mode of Action : The sequence of significant events and processes that describes how a substance causes a toxic 38

outcome. Mode of action is distinguished from the more detailed mechanism of action, which implies a more 39

detailed understanding on a molecular level. 40External Review Draft

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viii No Observed Adverse Effect Level (NOAEL) : The highest tested dose or concentration of a substance that has 1

been reported to cause no harmful (adverse) health effects in people or animals. 2

Occupational Exposure Limit (OEL) : Workplace exposure recommendations developed by governmental 3

agencies and non-governmental organizations. OELs are intended to represent the maximum airborne 4

concentrations of a chemical substance below wh ich workplace exposures should not cause adverse health 5

effects. OELs may apply to ceiling, short-term (STELs), or time-weighted average (TWA) limits. 6

Peak Concentration : Highest concentration of a substance record ed during a certain period of observation. 7

Permissible Exposure Limit (PEL) : Occupational exposure limits devel oped by OSHA (29 CFR 1910.1000) or 8

MSHA (30 CFR 57.5001) for allowable occupational air borne exposure concentr ations. PELs are legally 9

enforceable and may be designated as ceiling, STEL, or TWA limits. 10

11

Point of Departure (POD) : The point on the dose–response curve fro m which dose extrapolation is initiated. 12

This point can be the lower bound on dose for an estim ated incidence or a change in response level from a 13

concentration-response model (BMC), or it can be a NOAEL or LOAEL for an observed effect selected from 14

a dose evaluated in a health e ffects or toxicology study. 15

RD 50 : The statistically determined concentr ation of a substance in the air that is estimated to cause a 50% (one 16

half) decrease in the respiratory rate. 17

Recommended Exposure Limit (REL) : Recommended maximum exposure limit to prevent adverse health 18

effects based on human and animal studies and established for occupational (up to 10-hour shift, 40-hour 19

week) inhalation exposure by NIOSH. RELs may be designated as ceiling, STEL, or TWA limits. 20

Short-Term Exposure Limit (STEL) : A worker’s 15-minute time-weighted average exposure concentration that 21

shall not be exceeded at any time during a work day. 22

Target Organ : Organ in which the toxic injury manifests in terms of dysfunction or overt disease. 23

Threshold Limit Values (TLVs®) : Recommended guidelines for occupa tional exposure to airborne 24

contaminants, published by the American Conference of Governmental Industrial Hygienists (ACGIH). TLVs 25

refer to airborne concentrations of chemical substa nces and represent conditions under which it is believed 26

that nearly all workers may be repeatedly exposed, da y after day, over a working lifetime, without adverse 27

effects. TLVs may be designated as ceiling, short-term (STELs), or 8-hr TWA limits. 28

Time-Weighted Average (TWA) : A worker’s 8-hour (or up to 10-hour) time-weighted average exposure 29

concentration that shall not be exceeded during an 8- hour (or up to 10-hour) work shift of a 40-hour week. 30

The average concentration is weighted to take into ac count the duration of different exposure concentrations. 31

Toxicity : The degree to which a substance is able to ca use an adverse effect on an exposed organism. 32

33

Uncertainty Factors (UFs) : Mathematical adjustments applied to th e POD when developing IDLH values. The 34

UFs for IDLH value derivation are determined by consid ering the study and effect used for the POD, with 35

further modification based on the overall database. 36

Workplace Environmental Exposure Levels (WEELs) : Exposure levels developed by the American Industrial 37

Hygiene Association (AIHA) that provide guidance for protecting most workers from adverse health effects 38

related to occupational chemical expos ures expressed as a TWA or ceiling limit. 39External Review Draft

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ix 

## Acknowledgments 1

2

This document was developed by the Education and Info rmation Division (Paul Schulte, Ph.D., Director). G. 3

Scott Dotson, Ph.D., was the project officer and lead NIOS H author for this technical report. The basis for this 4

document was a report contracted by NIOSH and prepar ed by Andrew Maier, Ph.D., Ann Parker, and Lynn 5

Haber, Ph.D. (Toxicology Excellen ce for Risk Assessment [TERA]). 6

7



### Education and Information Division 8

Devin Baker, M.Ed. 9

Charles L. Geraci, Ph.D. 10

Thomas J. Lentz, Ph.D. 11

Richard Niemeier, Ph.D. 12

Chris Sofge, Ph.D. 13

14

NIOSH would like to acknowledge the contribution of th e following subject matter experts for their critical 15

technical review of this report. 16

17

Michael S. Bisesi, Ph.D., R.E.H.S., C.I.H., Senior Asso ciate Dean for Academic Affairs; Director, Center 18

for Public Health Practice; Interim Chair & Asso ciate Professor, Division of Environmental Health 19

Science, College of Public H ealth, Ohio State University 20

21

Mary A. Fox, Ph.D., Assistant Professor; Co-Direct or, Risk Sciences and Public Policy Institute; 22

Department of Health Policy and Management, Bl oomberg School of Public Health, Johns Hopkins 23

University 24External Review Draft

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1 

## 1.0 Introduction 1



### 1.1 Overview of the IDLH Value for Hexafluoroacetone 2

3

IDLH Value: 9 ppm (61 mg/m 3 ) 4

5

Basis for IDLH Value: A rat LC 50 value of 900 ppm for a 30-minute exposure period is the basis of the IDLH 6

value for hexafluoroacetone [Borzelleca and Lester 1965], since it was the lowest value among studies with the 7

most appropriate exposure duration. A composite unc ertainty factor of 100 was applied to account for 8

extrapolation from a lethal concentration in animals, animal to human differe nces, human variability and 9

uncertainties in the database, including uncertainties about the potential for developmental toxicity from acute 10

exposure, as well as the lack of data on female reproduc tive toxicity and functiona l measures of reproductive 11

toxicity; resulting in a recommended IDLH value of 9 ppm

. 12

13



### 1.2 Purpose 14

15

This IDLH Value Profile presents (1) a brief summary of technical data associated with acute inhalation 16

exposures to hexafluoroacetone and (2) th e rationale behind the Immediately Da ngerous to Life or Health (IDLH) 17

value for hexafluoroacetone. IDLH values are developed based on the scientific rationale and logic outlined in the 18

NIOSH Current Intelligence Bulletin (CIB) 66: Derivation of Immediately Dangerous to Life or Health (IDLH) 19

Values [NIOSH 2013]. As described in CIB 66, NIOSH perfo rms in-depth literature searches to ensure that all 20

relevant data from human and animal studies with acute exposures to the substance are identified. Information 21

included in CIB 66 on the literature search includes per tinent databases, key terms, and guides for evaluating data 22

quality and relevance for the establishment of an IDLH value. The information that is identified in the in-depth 23

literature search is evaluated with ge neral considerations that include d escription of studies (i.e., species, study 24

protocol, exposure concentration and duration), health endpoint evaluated, and criti cal effect levels (e.g., 25

NOAELs, LOAELs, LC 50 values). For hexafluoroacetone, the in-d epth literature search was conducted through 26

February 2014. 27



### 1.3 General Substance Information 28

29

Chemical: Hexafluoroacetone 30

CAS No: 684-16-2 31External Review Draft

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2 Synonyms: HFA; 1,1,1,3,3,3-Hexafluoro-2-propanon e; Hexafluoro-2-propanone; Perfluoroacetone * 1

Chemical category: Substituted ketones oxo compounds; Or ganic fluorine compounds; Organic gases † 2

3

Structural formula: 4

5

6

7

8

Table 1 highlights selected physiochemical properties of hexafluoroacetone relevant to IDLH conditions. Table 2 9

provides alternative exposure guidelines for hexafl uoroacetone. Table 3 summarizes the Acute Exposure 10

Guidelines Level (AEGL) values for hexafluoroacetone. 11

12

Table 1: Physiochemical Properties of Hexafluoroacetone 13

14

Property Value

Molecular weight 166.03 ‡

Chemical formula C 3 F 6 O

Description Colorless gas

Odor Disagreeable, musty

Odor Threshold Not available

UEL Not applicable *

LEL Not applicable *

Vapor pressure 5.0 mmHg at 25°C (77°F) ‡

Flash point Noncombustible †

Ignition temperature Noncombustible †

Solubility Soluble in water; hydrolyses †

Abbreviation: °C – Celsius; °F – Fahrenheit; mmHg – millimeter mercury; LEL – lower explosive limit; UEL – upper explosive limit 15

* OSHA [2014] 16

† IFA [2014] 17

‡ HSDB [2014] 18

19

20

21

22

23

24

25

26

27

28 F F F

F F

F OExternal Review Draft

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3 Table 2: Alternative Exposure Gu idelines for Hexafluoroacetone 1

2

Organization Value

Original (SCP) IDLH value None

NIOSH REL Not available

OSHA PEL [2014] 0.1 ppm TWA [skin]

ACGIH TLV [2014] Not available

AIHA ERPG [2010] ERPG-1: not derived; ERPG-2: 1 ppm; ERPG-3: 50 ppm

AIHA WEEL [2010] Not available

Abbreviation: ACGIH – American Conference of Governmental I ndustrial Hygienists; AIHA – Am erican Industrial Hygiene 3

Association; ERPG – Emergency Re sponse Preparedness Guidelines; IDLH – immediatel y dangerous to life or health; NIOSH – Nationa l 4

Institute for Occupational Safety and Hea lth; OSHA – Occupational Safety and Health Administration; PEL – permissible exposure limit; 5

REL – recommended exposure limit; SCP – Standards Completion Program; WEEL – workplace e nvironmental exposure level 6External Review DraftMay 2015This information is distributed solely for the purpose of predissemination peer review under applicable information quality guidelines. It has not beenformally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent anyagency determination or policy.4Table 3: AEGL Values for Hexafluoroacetone12Classification 10-min 30-min 1-hour4-hour 8-hour Endpoint [reference]AEGL-1 NR NR NR NR NR Insufficient dataAEGL-2 0.40 ppm2.7 mg/m30.40 ppm2.7 mg/m30.20 ppm1.4 mg/m30.050 ppm0.34 mg/m30.025 ppm0.17 mg/m3NOAEL for developmental effects in rat[E. I. du Pont de Nemours and Co. 1989]AEGL-3 160.0 ppm1,100.0 mg/m3160.0 ppm1,100.0 mg/m380.0 ppm540.0 mg/m320.0 ppm140.0 mg/m310.0 ppm68.0 mg/m3Lethality threshold estimated from rat LC50data[E. I. du Pont de Nemours and Co. 1962a,b]Abbreviation: AEGL – acute exposure guideline levels; mg/m3– milligrams per cubic meter; min – minute; NR – not recommended due to insufficient data; ppm – parts per million3*References: NAS [2012]4External Review Draft

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5 

## 2.0 Animal Toxicity Data 1

2

Several acute inhalation studies were id entified for hexafluoroacetone. Borzelleca and Lester [1965] exposed rats 3

to a series of concentrati ons (range not repor ted) for 0.5, 3 or 6 hours. LC 50 values of 900 ppm and 275 ppm were 4

reported for 30-minute and 3-hour exposures, respectively; 6-hour values were not reported. Minor to no lung 5

effects were reported for all the concentrations. The author also reported that postmortem exam revealed 6

pulmonary hemorrhage and edema in dogs exposed to 5,000 and 10,000 ppm for either 30 or 45 minutes. E.I. du 7

Pont de Nemours & Co. [1965] found that exposure to 3,600 ppm for 30 minutes was not lethal to rats (0/4 died), 8

but 3/4 rats died after exposure to 4,800 ppm for 30 minutes. Rats in all groups down to the lowest concentration 9

of 2,400 ppm exhibited signs of irritation, including lacr imation, salivation, nasal discharge, and intermittent 10

gasping. 11

12

Acute exposure to hexafluoroacetone also causes testicul ar damage. Rats exposed to 100 ppm for 4 hours 13

exhibited slight to moderate testic ular damage [E.I. du Pont de Nemour s & Co. 1962]. More severe damage, 14

including aspermatogenesis and inters titial damage, were observed at 200 pp m and higher. E.I. du Pont de 15

Nemours & Co. [1965] exposed rats to 200 ppm hexafluoro acetone for 4 hours, and sacrificed the rats at 7-57 16

days post-exposure. The observed testicular degenerati on and decreased testicular weight were only slowly (or 17

partially) reversible. At 57 days, there was some r ecovery, but some spermatogenic tubules still contained no 18

germinal cells. 19

20

Effects of hexafluoroacetone appear to be systemically mediated, with pulmonary damage in rats occurring only 21

at air concentrations exceeding minimal lethality levels . Contact irritation also occurs. Gillies and Lee [1983] 22

suggested that the testicular effects of hexafluoroacetone are due to its alterations of lipid metabolism and the 23

resulting inhibition of sterol synthesis. This hypoth esized pathway for male repr oductive effects suggests that 24

hexafluoroacetone may also affect female reproductive horm ones, and thus female repr oductive function, but no 25

data investigating this hypothesis were located. 26

27

These possibly hormonally-mediated effects may also be related to the developmental toxicity of 28

hexafluoroacetone. Exposure of pregnant rats to 6.9 ppm for 6 hours/day on gestation days (GD) 7-16 resulted in 29

increased resorptions, malformations, and variations [E.I . du Pont de Nemours & Co. 1969]. Exposure to 1 ppm 30

in the same study resulted in increased variations (no st atistical test information available) and decreased body 31

weight, while the only effect in the mothers was increased liver weight. The study authors considered the fetal 32External Review Draft

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6 effects to be more severe than the concurrent maternal e ffects. This repeated exposure study is not appropriate as 1

the basis for the IDLH value, but it does raise the ques tion of whether acute hexafluoroacetone exposure during a 2

key developmental window could cause developmental e ffects. For a single 6-hour exposure period at the 3

LOAEL for severe effects of 6.9 ppm from this study, the equivalent 30-minute duration-adjusted concentration is 4

83 ppm. 5

6

Table 4 summarizes the LC data identified in animal st udies and provides 30-minute equivalent derived values for 7

hexafluoroacetone. Table 5 provides non- lethal data reported in animal studi es with 30-minute equivalent derived 8

values. Information in these tables includes species of test animals, toxicological metrics (i.e., LC, NOAEL, 9

LOAEL), adjusted 30-minute concentration, and the justifi cation for the composite uncertainty factors applied to 10

calculate the derived values. 11External Review DraftMay 2015This information is distributed solely for the purpose of predissemination peer review under applicable information quality guidelines. It has not beenformally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent anyagency determination or policy.7Table 4: Lethal Concentration Data for Hexafluoroacetone12Reference Species(reference)LC50(ppm)LCLo(ppm)Time(min)Adjusted30-minConcentration*(ppm)CompositeUncertaintyFactorDerivedValue(ppm)†Borzelleca and Lester [1965] Dog 5,000‡-- 45 5,724 100±57E.I. du Pont de Nemours & Co. [1962] Rat 300§-- 240 2,400 100±24E.I. du Pont de Nemours & Co. [1965] Rat -- 3,600^30 3,600 30‡120Borzelleca and Lester [1965]+Rat 900 -- 30 900 100±9Borzelleca and Lester [1965] Rat 275 -- 180 1,650 100±173Abbreviation:LC – lethal concentration; LC50– median lethal concentration; LCLo– lowest concentration of a chemical that caused death in humans or animals; min – minute; ppm – parts4per million56*For exposures other than 30 minutes the ten Berge et al. [1986]relationship is used for duration adjustment (Cn x t = k); no empirically estimated n values were available, therefore the7default values were used, n = 3 for exposures greater than 30 minutes and n = 1 for exposures less than 30 minutes.8†The derived value is the result of the adjusted 30-minute LC value divided by the composite uncertainty factor.9‡1 of 2 dogs died10±Composite uncertainty factor to account for the use of lethal concentration threshold in animals,interspecies differences, human variability and uncertainties in the11database that focus on issues pertaining to developmental toxicity from acute exposure, absence of data on female reproductivetoxicity and functional measures of12reproductive toxicity.13‡Composite uncertainty factor to account for the use of a lethalconcentration threshold in animals, interspecies differences and human variability.14§2 of 4 rats died15^No lethality16+Identified study is the primary basis ofthe IDLH value for hexafluoroacetone.171819202122External Review DraftMay 2015This information is distributed solely for the purpose of predissemination peer review under applicable information quality guidelines. It has not beenformally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent anyagency determination or policy.8Table 5: Non-lethal Concentration Data for Hexafluoroacetone12Reference SpeciesNOAEL(ppm)LOAEL(ppm)Time(min)Adjusted30-minConcentration*CompositeUncertaintyFactorDerivedValue(ppm)†E.I. du Pont de Nemours & Co. [1962a] rat 200 240 1,600 30^53E.I. du Pont de Nemours & Co. [1962b]rat 100 240 800 30^2727E.I. du Pont de Nemours & Co. [1989]rat 6.9 360 82.8 10±8Abbreviation:NOAEL – no observed adverse effect level;min – minute; LOAEL – lowest observed adverse effect level; ppm– parts per million34*For exposures other than 30 minutes the ten Berge et al. [1986] relationship is used for duration adjustment (Cnx t = k); no empirically estimated n values were available, therefore the5default values were used, n = 3 for exposures greater than 30 minutes and n = 1 for exposures less than 30 minutes.6†The derived value is the result of the adjusted 30-min valuedivided by the composite uncertainty factor. The composite uncertainty factor used varies for each study based on the nature7and severity of the endpoint observed.8‡The cardiac sensitization response is a concentration-dependent threshold effect; dogsexposed to similar chemicals for longerdurations responded in a similar manner, so no time9adjustment was applied.10^Composite uncertainty factor assigned to account for adjusting from a LOAEL to NOAEL, severe effects, interspecies differences,human variability, and uncertainty about the threshold for11escape-impairing effects.12±Composite uncertainty factor assigned to account for adjusting from a LOAEL to NOAEL, interspecies differences and human variability.13141516External Review Draft

May 2015

This information is distributed solely for the purpose of pre dissemination peer review under applicable information

quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and

Health. It does not represent and should not be construed to represent any agency determination or policy.

9 

## 3.0 Human Data 1

2

There are no acute lethality data available for humans. Kutznetsova [1972] reported that exposure to 3

hexafluoroacetone at 4 ppm is irritating to the respirator y tract, but specific descriptions were not provided on the 4

exposure conditions that induce irritation or on the severity of the observed effects. 5



## 4.0 Summary 6

7

Among the acute lethality studies, the rat LC 50 value of 900 ppm for a 30-minute exposure period [Borzelleca and 8

Lester 1965] was chosen as the basis for the IDLH va lue for hexafluoroacetone since it was the lowest value 9

among studies with the most appropriate exposure duration. A composite uncertainty factor of 100 was applied to 10

account for extrapolation from a lethal concentration in animals, animal to human differences, human variability 11

and uncertainties in the database, including uncertainties a bout the potential for developmental toxicity from acute 12

exposure, as well as the lack of data on female reproduc tive toxicity and functiona l measures of reproductive 13

toxicity; resulting in an IDLH value of 9 ppm

. 14

15

It should be noted that the IDLH value for hexafluoroacetone differs by more than an order of magnitude from the 16

AEGL-2 30-minute value, which is intended to represent an airborne concentration of a substance above which it 17

is predicted that the general population, including suscep tible individuals, could experi ence irreversible or other 18

serious, long-lasting adverse health effects or an impa ired ability to escape [NAS 2001]. The AEGL-2 value for 19

hexafluoroacetone is based on a NOAEL for developmental ef fects in rats [NAS 2012]. NIOSH based the IDLH 20

value for hexafluoroacetone on lethality data from a rat study [Borzelleca and Lester 1965 ] . More precisely, the 21

point of departure was a LC 50 value of 900 ppm for a 30-minute exposure period. The use of differing studies and 22

endpoints results in the order of magnitude differe nt between the AEGL-2 and IDLH value. 23External Review Draft

May 2015

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quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and

Health. It does not represent and should not be construed to represent any agency determination or policy.

10 

## 5.0 References 1

2

ACGIH (American Conference of Gove rnmental Industrial Hygienists) [ 2014]. Annual TLVs® (Threshold Limit 3

Values) and BEIs® (Biological Exposure Indices) booklet . Cincinnati, OH: ACGIH Signature Publications. 4

5

AIHA (American Industrial Hygiene Association) [2009]. AIHA Emergency Response Planning (ERP) 6

Committee procedures and responsibilities. Fairfax, VA: American Industrial Hygiene Association. 7

8

AIHA (American Industrial Hygiene Association) [2010] . Emergency response planning guidelines (ERPG) and 9

workplace environmental exposure levels (WEEL) handbo ok. Fairfax, VA: American Industrial Hygiene 10

Association Press. 11

12

Borzelleca JF, Lester D [1965]. Acute toxicity of some perhalogenated acetones. Toxicol Appl Pharmacol 7 :592– 13

597. 14

15

E. I. du Pont de Nemours & Co. [1962]. Inhalation toxi city of hexafluoroacetone compound in rats. Newark, DE: 16

E. I. du Pont de Nemours & Co., Haskell Laboratory for Toxicology and Industrial Hygiene. Haskell Laboratory 17

report No. 46-62. Unpublished. 18

19

E. I. du Pont de Nemours & Co. [1965]. Inhalation studies on hexafluoroacetone. Part II. A. The lethality of short 20

(<1 hr.). B. The persistence of tissue effects. Newark, DE : E. I. du Pont de Nemours & Co., Haskell Laboratory 21

for Toxicology and Industrial Hygiene. Haskell Laboratory report No. 6-65. Unpublished. 22

23

Gillies PJ, Lee KiP [1983]. Effects of hexafluoroacetone on testicular morphology and lip id metabolism in the rat. 24

Toxicol Appl Pharmacol 68 :188–197. 25

26

HSDB (Hazardous Substances Data Bank) [ 2014]. Hexafluoroacetone (CAS No. 684-16-2) 27

[http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp /~EQMABS:1] . Date accessed: March 21, 2104. 28

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IFA (Institut für Arbeitsschutz der Deutschen Gesetzli chen Unfallversicherung) [2014]. GESTIS: database on 30

hazardous substances [http://www.dguv.de/ifa/en/gestis/sto ffdb/index.jsp]. Date accessed: March 21, 2014. 31

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Kutznestova EE [1972]. Hygienic standardization of perfl uoroacetone dihydrate in air of working zones. Nauch. 33

Tr. Irkutsk Med Inst 115 :54–56 (abstract). 34

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NAS (National Academy of Science) [2001]. Standing operating procedures for developing Acute Exposure 36

Guidelines Levels for hazardous chemicals. NAS, National Research Council (NRC), Committee on Toxicology, 37

Subcommittee on Acute Exposure Gu ideline Levels. National Academy Press: Washington, DC. IBSN: 0-309- 38

07553-X. [http://www.epa.gov/oppt/aegl/pubs/sop. pdf]. Date accessed : March 17, 2014. 39

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NAS (National Academy of Sciences) [2012]. Acute Exposur e Guideline Levels (AEGLs) for Selected Airborne 41

Chemicals - volume 13: Chapter 4 - hexafluoroacetone, CAS No. 684-16-2. NAS, National Research Council, 42

Committee on Toxicology, Subcommittee on Acute Expos ure Guideline Levels National Academy Press: 43

Washington, DC. [http://www.epa.gov/oppt/aegl/pubs/ hexafluoroacetone_final_vol ume_13_2013.pdf]. Data 44

accessed: August 1, 2014 45

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NIOSH (National Institute for Occupational Safety an d Health) [2004]. NIOSH respirator selection logic. 47

Cincinnati, OH: U.S. Department of Health and Huma n Services, Centers for Disease Control and Prevention, 48External Review Draft

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This information is distributed solely for the purpose of pre dissemination peer review under applicable information

quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and

Health. It does not represent and should not be construed to represent any agency determination or policy.

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[http://www.cdc.gov/niosh/docs/2005-100/pdfs/2005-100. pdf]. Date accessed: March 17, 2014. 2

3

NIOSH [2013]. NIOSH Current Intelligence Bulletin 66: Deri vation of Immediately Dangero us to Life or Health 4

(IDLH) Values. Cincinnati, OH: U.S. Department of H ealth and Human Services, Centers for Disease Control 5

and Prevention, National Institute fo r Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014- 6

100. 7

[http://www.cdc.gov/niosh/docs/2014-100/pdfs/2014- 100.pdf]. Date accessed : March 17, 2014. 8

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Health, DHHS (NIOSH) Publication No. 2005-149. [http://www.cdc.gov/niosh/npg/]. Date accessed: March 17, 12

2014. 13

14

OSHA [2014]. OSHA occupational chemical data base: Hexafluoroacetone (Cas No. 684-16-2). 15

[https://www.osha.gov/chemicaldata/chemResult.ht ml?recNo=483]. Date accessed: March 21, 2014. 16

17

ten Berge WF, Zwart A, Appelman LM [1986]. Concentra tion-time mortality response relationship of irritant and 18

systematically acting vapors and gases. J Haz Mat 13 :301–309. 19

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[http://www.epa.gov/iris/]. Date accessed: March 17, 2014. 22

23