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i 1

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## I MMEDIATELY 

## D ANGEROUS TO 

## L IFE OR 

## H EALTH 

## (IDLH) V ALUE 

## P ROFILE 7

8

9

10



## F OR 11

12

13

14



## M ETHYL 

## I SOCYANATE 15

16

17

18



## [CAS N O



## . 624-83-9] 19

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24

25

Department of Health and Human Services 26

Centers for Disease Control and Prevention 27

National Institute for Occupa tional Safety and Health 28

29

30External 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

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iii 

## Foreword 1

2

Chemicals are a ubiquitous component of the modern wo rkplace. Occupational exposures to chemicals have the 3

potential to adversely affect the health and lives of workers. Acute or short-term exposures to high concentrations 4

of some airborne chemicals have the ability to quickly overwhelm workers, resulting in a spectrum of undesirable 5

health outcomes that may inhibit the ability to escape from the exposure envi ronment (e.g., irritation of the eyes 6

and respiratory tract or cognitive impairment), cause severe irreversible effects (e.g., damage to the respiratory 7

tract or reproductive toxicity), and in extreme cases, cause death. Airborne concentrations of chemicals capable 8

of causing such adverse health effects or of impeding escape from high-risk conditions may arise from a variety of 9

non-routine workplace situations , including special wo rk procedures (e.g., in confined spaces), industrial 10

accidents (e.g., chemical spills or explosions), and chemical releases into the community (e.g., during 11

transportation incidents or other uncontrolled-release scenarios). 12

13

The “immediately dangerous to life or health air concen tration values (IDLH values)” developed by the National 14

Institute for Occupational Safety a nd Health (NIOSH) characterize these high-risk exposure concentrations and 15

conditions [NIOSH 2013]. IDLH values are based on a 30-minute exposure duration and have traditionally 16

served as a key component of the decision logic for the selection of respiratory protection devices [NIOSH 2004]. 17

In addition, occupational health professionals have employed these values beyond their initial purpose as a 18

component of the NIOSH Respirator Selection Logic to assist in developing Risk Management Plans for non19

routine work practices governing operations in high -risk environments (e.g., confined spaces) and the 20

development of Emergency Preparedness Plans. 21

22

The approach used to derive IDLH values for high priority chemicals is outlined in the NIOSH Current 23

Intelligence Bulletin (CIB) 66: Derivation of Immediately Da ngerous to Life or Health Values [NIOSH 2013]. 24

CIB 66 provides 1) an update on the scientific basis a nd risk assessment methodology used to derive IDLH 25

values, 2) the rationale and derivati on process for IDLH values, and 3) a demonstration of the derivation of 26

scientifically credible IDLH values using available data resources. 27

28

The purpose of this technical report is to present the IDLH value for methyl isocyanate (CAS # 624-83-9). The 29

scientific basis, toxicologic data and risk assessment appr oach used to derive the ID LH value are summarized to 30

ensure transparency and scientific credibility. 31

32

John Howard, M.D. 33

Director 34

National Institute for Occupa tional Safety and Health 35External Draft

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iv Centers for Disease Control and Prevention 1External Draft

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v 

## Table of Contents 1

FOREWORD

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

ABBREVIATIONS

............................................................................................................................... ........................ VI 3

GLOSSARY

............................................................................................................................... .................................. VII 4

ACKNOWLEDGMENTS

............................................................................................................................... ............... X 5

1.0 INTRODUCTION

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

1.1 IDLH V ALUE FOR M ETHYL I SOCYANATE

................................................................................................................... 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

............................................................................................................................... ................. 11 13

14

15

16

17

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vi 

## 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

GD gestation day 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 recommend 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 Draft

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vii 

## 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 Draft

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viii 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 Draft

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ix 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 38

effects related to occupational chemical exposures expressed as a TWA or ceiling limit. 39External Draft

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x 

## 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

Richard B. Schlesinger, Ph.D., Fellow A.T.S., Senior Associate Dean for Academic Affairs and Research 22

Professor of Biology, Dyson College of Arts and Sciences, Pace University 23

24

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1 

## 1.0 Introduction 1



### 1.1 IDLH Value for Methyl Isocyanate 2

3

IDLH Value: 0.12 ppm (0.28 mg/m 3 ) 4

5

Basis for IDLH Value: The IDLH value for methyl isocyanate is based on the LOAEL for severe reproductive 6

and developmental effects, specifically fetal resorption and fetal skeletal malformations. Varma et al. [1987] 7

reported a LOAEL of 2 ppm for these developmental and reproductive effects in dams exposed for 3 hours on 8

gestation day (GD) 8. This represents a one-time acute exposure at a critical developmental time of the dam and 9

fetuses. The LOAEL was adjusted to a 30-minute equivale nt duration concentration of 3.6 ppm. A composite 10

uncertainty factor of 30 was applied to account for extra polation from a concentration that causes severe effects in 11

animals, animal to human differences, human variability, and uncertainty about the threshold for escape-impairing 12

effects, yielding an IDLH value of 0.12 ppm

. 13

14



## 1.2 Purpose 15

16

This IDLH Value Profile presents (1) a brief summary of technical data associated with acute inhalation 17

exposures to acrylonitrile and (2) the rationale behind the Immediately Dangerous to Life or Health (IDLH) value 18

for methyl isocyanate. IDLH values are developed based on the scientific rationale and logic outlined in the 19

NIOSH Current Intelligence Bulletin (CIB) 66: Derivation of Immediately Dangerous to Life or Health (IDLH) 20

values [NIOSH 2013]. As described in CIB 66, NIOSH perfo rms in-depth literature searches to ensure that all 21

relevant data from human and animal studies with acute exposures to the substance are identified. Information 22

included in CIB 66 on the literature search includes per tinent databases, key terms, and guides for evaluating data 23

quality and relevance for the establishment of an IDLH value. The information that is identified in the in-depth 24

literature search is evaluated with ge neral considerations that include d escription of studies (i.e., species, study 25

protocol, exposure concentration and duration), health endpoint evaluated, and criti cal effect levels (e.g., 26

NOAELs, LOAELs, LC 50 values). For methyl isocyanate, the in -depth literature search was conducted through 27

February 2014. 28



### 1.3 General Substance Information 29

30

Chemical: Methyl Isocyanate 31

CAS No: 624-83-9 32External Draft

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2 Synonyms: Methyl ester isocyanic acid; Isocyanato-methane; MIC [Isocyanate] * 1

Chemical category: Organic isocyanates † 2

Structural formula: 3

4

5

6

7

Table 1 highlights selected physiochemical properties of me thyl isocyanate relevant to IDLH conditions. Table 2 8

provides alternative exposure guidelines for methyl isocyanate. Table 3 summarizes the Acute Exposure 9

Guidelines Level (AEGL) values for methyl isocyanate. 10

11

12

Table 1: Physiochemical Properties of Methyl Isocyanate 13

14

Property Value

Molecular weight 57.06 ‡

Chemical formula C 2 H 3 NO

Description Colorless liquid

Odor Sharp, unpleasant

Odor Threshold 2.1 ppm +

UEL 26% †

LEL 5.3% †

Vapor pressure 348 mmHg at 20°C (68°F) ‡

Flash point -7°C (19°F) ‡ - closed cup

Ignition temperature 534°C (994°F) ‡

Solubility Hydrolysis †

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

* NLM [2012] 16

+ AIHA [1989] 17

† IFA [2012] 18

‡ HSDB [2012] 19

§ AIHA [1989] 20

21

22

23

24

25

26

27

28

29

30

31

32 N H 3 C

C OExternal Draft

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3 Table 2: Alternative Exposure Guidelines for Methyl Isocyanate 1

2

Organization Value

Revised (1994) IDLH value * 3 ppm

NIOSH REL [2014] † 0.02 ppm (0.05 mg/m 3 )

OSHA PEL[2014] ^ 0.02 ppm (0.05 mg/m 3 ) [skin]

ACGIH TLV [2014] ‡ TWA 0.02 ppm (0.05 mg/m 3 )

STEL 0.06 ppm (0.14 mg/m 3 )

AIHA ERPG [2010] + ERPG 1: 0.025 ppm

ERPG 2: 0.5 ppm

ERPG 3: 5 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 Progr am; STEL - short term exposur e limit; TWA - time weighted 6

average; WEEL – workplace environmental exposure level 7

References : *NIOSH [1994]; ^OSHA [2014]; †NIOSH [2014]; ‡ ACGIH [2014]; AIHA [2010a]+; §AIHA [2010b] 8External DraftMarch 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 Methyl Isocyanate12Classification 10-min 30-min 1-hour 4-hour 8-hour End Point [reference]AEGL-1 NR NR NR NR NR Insufficient dataAEGL-2 0.40 ppm0.94 mg/m30.13 ppm0.32 mg/m30.067 ppm0.16 mg/m30.017 ppm0.034 mg/m30.008 ppm0.02 mg/m3Decreased fetal body weights[Varma 1987];Cardiac arrhythmias[Tepper et al. 1987]AEGL-3 1.2 ppm2.8 mg/m30.40 ppm0.95 mg/m30.20 ppm0.47 mg/m30.05 ppm0.12 mg/m30.025 ppm0.06 mg/m3Decreased pup survival duringlactation[Schwetz et al. 1987]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 [2003]4External Draft

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5 

## 2.0 Animal Toxicity Data 1

2

Methyl isocyanate is one of the most reactive isocyana tes and rapidly degrades in water [Varma and Guest 1993; 3

NAS 2003]. The reactive nature of methyl isocyanate c ontributes to its toxicological potential and ability to cause 4

irritation and cytotoxicity in the respiratory tract. The da tabase for acute lethality in animals consists of multiple 5

studies in rabbits [Pant et al. 1987; Dow Chemical 1990] , guinea pigs [Mellon Institute 1966, 1970; Dodd et al. 6

1985, 1986, 1987; Kolb et al. 1987; Tro up et al. 1987; Ferguson and Alarie 1991], rats [Mellon Institute 1963b, 7

1970; IRDC 1964; Kimmerle and Eben 1964; Eastman Kodak 1966; Fait and Dodd 1981; Dodd et al. 1985, 1986, 8

1987; Nemery et al. 1985a; Salmon et al. 1985; Bucher et al. 1987a,b; Dinsdale et al. 1987; Pant et al. 1987; 9

Vijayaraghavan and Kaushik 19 87; Dutta et al. 1988; Sethi et al. 1989; Dow Chemical 1990; Jeevaratnam et al. 10

1990; Man Tech Environmental 1992; Jeevaratnam and Srir amachari 1994; Sriramachari and Jeevaratnam 1994], 11

and mice [Dodd et al. 1985, 1986; Boorman et al. 1987a,b; Bucher et al. 1987a; Vijayaraghavan and Kaushik 12

1987; Varma et al. 1988]. Based on histopathology and necropsy reports, lethality appears to be primarily caused 13

by damage to the respiratory system. 14

15

Multiple studies have reported varied no n-lethal effects following acute exposure to methyl isocyanate. Studies in 16

guinea pigs indicate that exposure to methyl isocyana te for 15 minutes causes hypoxia and metabolic acidosis at 17

concentrations as low as 240 ppm [Fedde et al. 1987; Ma ginniss et al. 1987]. Rats acutely exposed to methyl 18

isocyanate developed severe inflamma tion and erosion of the respiratory tract [Mitsumori et al. 1987] and 19

hypoxia [Troup et al. 1987]. Studies that observed acute ly exposed rats for extended periods of time reported 20

evidence of pulmonary obstruction [Stevens et al. 1987; Bucher and Uriah 1989]. Tepper et al. [1987] reported an 21

increase in cardiac arrhythmia in rats at 4-6 months post-exposure to a 2 hour exposure to 3 ppm methyl 22

isocyanate. In mice, an RD 50 value of 1.3 – 2.9 ppm and an RD 50TC of 1.9 ppm have been estimated [Ferguson et 23

al. 1986; James et al. 1987]. 24

25

Developmental and reproductive studies ha ve determined that acute exposure to methyl isocyanate significantly 26

decreases maternal body, fetal, and placental weight a nd significantly increases the total number of resorptions 27

and skeletal malformations in both rats and mice [Varma 1987; Varma et al. 1990; Singh et al. 1994]. Varma et al. 28

[1987] reported a LOAEL of 2 ppm for developmental and reproductive effects, including increased fetal 29

resorptions and increased skeletal malformations, in da ms exposed for 3 hours on GD 8. This represents a one30

time acute exposure at a critical devel opmental time of the dam and fetuses. 31

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

6 Table 4 summarizes the LC data identified in animal st udies and provides 30-minute equivalent derived values for 1

methyl isocyanate. Table 5 provides non-lethal data repor ted in animal studies with 30-minute equivalent derived 2

values. Information in these tables in cludes species of test animals, toxicological metrics (i.e., LC, NOAEL, 3

LOAEL), adjusted 30-minute concentration, and the justifi cation for the composite uncertainty factors applied to 4

calculate the derived values. 5

6External DraftMarch 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 Methyl Isocyanate12Reference SpeciesLC50(ppm)LCLo(ppm)Time(min)Adjusted30-minConcentration*(ppm)CompositeUncertaintyFactorDerivedValue(ppm)†Dodd et al. [1985, 1986] Guinea Pig 5.4 -- 360 12.4 10‡0.12Ferguson and Alarie [1991] Guinea Pig 26.5 -- 180 48.2 10‡0.48Vijayaraghavan and Kaushik [1987] Mouse 112.4 -- 30 112.4 10‡1.1Kimmerle and Eben [1964] Rat 5.0 -- 240 10.0 10‡0.01ManTech Environmental [1992] Rat 45.0 -- 60 56.7 10‡0.573Abbreviation:LC – lethal concentration; LC50– median lethal concentration; LCLo– lowest concentration of a chemical that caused death in humans or animals; min – minute; ppm – parts4per million5*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 were6available, therefore the default values were used, n = 3 for exposures greater than 30 minutes and n = 1 for exposures less than 30 minutes.7†The derived value is the result of the adjusted 30-minute concentration divided by the composite uncertainty factor.8‡Composite uncertainty factor to account for adjustment of LC50values to LC01values in animals, interspeciesdifferences and human variability.910External DraftMarch 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 Methyl Isocyanate12Reference Species(reference)NOAEL(ppm)LOAEL(ppm)Time(min)Adjusted30-minConcentration*(ppm)CompositeUncertaintyFactorDerivedValue(ppm)†Mellon Institute [1970] Human 0.5 -- 10 0.2 3‡0.07Mellon Institute [1963a] Human -- 1 10 0.3 10±0.03Kimmerle and Eben [1964] Human -- 4 5 0.7 10±0.07Tepper et al. [1987] Rats -- 3 120 4.8 30^0.16Fedde et al. [1987] Guinea Pig -- 240 15 120 30^4.00Varma [1987]+Mouse -- 2 180 3.6 30^0.12Varma et al. [1990] Rat -- 9 180 16.4 30^0.55Abbreviation:NOAEL – no observed adverse effect level;min – minute; LOAEL – lowest observed adverse effect level; ppm– parts per million3*For exposures other than 30 minutes the ten Berge et al. [1986] relationship is used for duration adjustment (Cnx t = k), with n=3 for exposures greater than 30 minutes and n = 1 for4exposures less than 30 minutes.5†The derived value is the result of the adjusted 0.5-hour valuedivided by the composite uncertainty factor. The composite uncertainty factor used varies foreach study based on the nature6and severity of the endpoint observed.7‡Composite uncertainty factor assigned to account for interspecies differences and human variability.8±Composite uncertainty factor assigned to account for adjusting from a LOAEL to NOAEL, interspecies differences and human variability.9^Composite uncertainty factor assigned to account for adjusting from a LOAEL to NOAEL, severe effects, interspecies differences,human variability, and uncertainty about the threshold for10escape-impairing effects11+Identified study is the primary basis ofthe IDLH value for methyl isocyanate.12External Draft

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9 

## 3.0 Human Data 1

2

An accidental release in Bhopal, India is the source of most information on human exposures to methyl 3

isocyanate. Although actual exposure concentrations are unknown, Karlsson et al. [1985] estimated a 4

concentration range of 10 to 3,000 ppm , with higher concentrations occurring closer to the site of release, based 5

on dispersion calculations. Although multiple deaths were reported, most occurred 8-72 hours post-release 6

[Varma 1989; Varma and Guest 1993]. Symptoms reported w ith the most frequency were ocular irritation, 7

coughing, respiratory distress, pulmonary congestion, na usea, vomiting, muscle weakness, and hypoxia resulting 8

in CNS involvement [Kamat et al. 1985; Misra et al. 1987; Lorin and Kulling 1986; Andersson et al. 1988; Weill 9

1988; Kamat et al. 1992]. Most of these symptoms resolved within 2 weeks post-release, but many of those 10

exposed, including adults and children, reported c ontinued restrictive respiratory, ophthalmological, 11

neuromuscular, and gastrointestinal symptoms for years after the accident [Andersson et al. 1984, 1985; Kamat et 12

al. 1985; Irani and Mahashur 1986; Maskati 1986; Naik et al. 1986; Khurrum and Ahmad 1987; Andersson et al. 13

1990; Kamat et al. 1992; Cullinan et al. 1997; Misra and Kalita 1997]. 14

15

In addition to information from the Bhopal release, a case report and multiple experimental studies on human 16

volunteers exist. Skin irritation and respiratory irr itation were reported in workers exposed to unknown 17

concentrations of methyl isocyanate for unknown durations [Union Carbide 1973]. In one experimental study, 18

four volunteers were exposed to 0.4 to 21 ppm methyl isocyanate for 1-5 minutes [Kimmerle and Eben 1964]; 19

minor irritation of the mucous membranes was reported at 2 ppm with more pronounced ocular irritation at 4 20

ppm. Volunteers reported that exposure to 21 ppm was inst antaneously intolerable. A nother experimental study 21

exposed 8 volunteers to 1.75 ppm for 1 minute and then re-exposed 6 of the 8 to 0.5 ppm for 10 minutes [Mellon 22

Institute 1970]. All volunteers reported ocular irritation and multiple volunteers reported nose and throat irritation 23

in both exposures. A third study exposed 7 male volunteers to 0.3 to 5.0 ppm for 1 minute or to 1 ppm for 10 24

minutes [Mellon Institute 1963a]. Exposure to 2.5 and 5. 0 ppm for 1 minute resulted in eye and nose irritation. 25

One volunteer exposed to 5.0 ppm also reported throat irritation. Volunteers exposed to 1 ppm for 10 minutes 26

reported eye, nose, and throat irritation. 27



## 4.0 Summary 28

29

Methyl isocyanate is one of the most reactive isocyana tes and rapidly degrades in water [Varma and Guest 1993; 30

NAS 2003]. The reactive nature of methyl isocyanate c ontributes to its toxicological potential and ability to cause 31External Draft

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10 irritation and cytotoxicity in the respiratory tract. The IDLH value for methyl isocyanate is based on a LOAEL, 1

which corresponds to severe reproductive and development effects in animal s. Tepper et al. [1987] reported 2

cardiac arrhythmia in rats at 4-6 m onths post-exposure to a 2-hour exposure to 3 ppm methyl isocyanate. Varma 3

et al. [1987] reported a LOAEL of 2 ppm for developm ental and reproductive effects, including increased fetal 4

resorptions and increased skeletal malformations, in da ms exposed for 3 hours on GD 8. This represents a one5

time acute exposure at a critical developmental time of the dam and fetuses. The re productive and developmental 6

effects occurred at lower concentrati ons than the cardiac effects and are id entified as the most sensitive health 7

endpoint. The LOAEL of 2 ppm when adjusted to a 30- minute equivalent duration concentration is 3.6 ppm. A 8

composite uncertainty factor of 30 was applied to acc ount for extrapolation from a concentration that causes 9

severe effects in animals, animal to human differences, human variability, and uncertainty about the threshold for 10

escape-impairing effects, yielding an IDLH value of 0.12 ppm for methyl isocyanate. This IDLH value should be 11

protective against the reproductive, developmental and cardiac effects associated with methyl isocyanate 12

exposure. Additionally, it is suppor ted by duration-adjusted estimates of the irritation threshold in humans 13

[Mellon Institute 1963a; Kimmerle and Eben 1964]. 14External Draft

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11 

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