EPA/635/R-06/001 

www.epa.gov/iris 

TOXICOLOGICAL REVIEW

OF

PHOSGENE

(CAS No. 75-44-5) 

In Support of Summary Information on the 

Integrated Risk Information System (IRIS) 

December 2005 

U.S. Environmental Protection Agency 

Washington, DC 
DISCLAIMER 

This document has been reviewed in accordance with U.S. Environmental Protection 

Agency policy and approved for publication. Mention of trade names or commercial products 

does not constitute endorsement or recommendation for use. 

ii 
CONTENTS – TOXICOLOGICAL REVIEW OF PHOSGENE (CAS No. 75-44-5) 

LIST OF TABLES ............................................................. v

LIST OF FIGURES ............................................................ v

LIST OF ABBREVIATIONS AND ACRONYMS ................................... vi

FOREWORD ............................................................... viii

AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................ ix

1. INTRODUCTION .......................................................... 1

2. CHEMICAL AND PHYSICAL INFORMATION .................................. 3

3. TOXICOKINETICS ......................................................... 5

4. HAZARD IDENTIFICATION ................................................. 6

4.1. STUDIES IN HUMANS – EPIDEMIOLOGY, CASE REPORTS .............. 6

4.1.1. Acute Inhalation Exposure ..................................... 6

4.1.2. Subchronic Inhalation Exposures ................................ 7

4.1.3. Occupational Epidemiology Studies .............................. 8 

4.2. ACUTE/SUBCHRONIC AND CHRONIC STUDIES IN ANIMALS ........... 9

4.2.1. Oral Exposures ............................................... 9

4.2.2. Inhalation Exposures .......................................... 9

4.2.2.1. Acute Exposures ..................................... 9

4.2.2.2. Subchronic Exposures ................................ 10

4.3. REPRODUCTIVE/DEVELOPMENTAL TOXICITY STUDIES ............. 17

4.4. OTHER EFFECTS .................................................. 18

4.4.1. Dermal Toxicity ............................................ 18

4.4.2. Ocular Toxicity ............................................. 18

4.4.3. Neurotoxicity .............................................. 18

4.4.4. Genotoxicity ............................................... 18

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS .... 18

4.5.1. Oral ...................................................... 18

4.5.2. Inhalation ................................................. 19

4.5.3. Mode of Action Information ................................... 19

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER

CHARACTERIZATION ........................................... 21

4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES .................... 22

4.7.1. Possible Childhood Susceptibility .............................. 22

4.7.2. Possible Gender Differences ................................... 22

4.7.3. Other ..................................................... 22

5. DOSE-RESPONSE ASSESSMENTS .......................................... 23

5.1. ORAL REFERENCE DOSE (RfD) ..................................... 23

5.2. INHALATION REFERENCE CONCENTRATION (RfC) .................. 23

5.2.1. Choice of Principal Study and Critical Effect(s) ................... 23

iii 
5.2.2. Methods of Analysis for Point of Departure, Including Application of

Models (BMD, NOAEL/LOAEL, and CatReg) ................... 24

5.2.3. BMD Approach ............................................. 25

5.2.4. NOAEL/LOAEL Approach ................................... 31

5.2.5. CatReg Approach ........................................... 31

5.2.6. Comparison of Approaches .................................... 32

5.2.7. RfC Derivation: Application of Uncertainty Factors ................ 34

5.2.8. Previous RfC Assessment ..................................... 37

5.3. CANCER ASSESSMENT ............................................ 37

5.3.1. Oral Slope Factor ........................................... 37

5.3.2. Inhalation Unit Risk ......................................... 37

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF

 HAZARD AND DOSE RESPONSE ....................................... 38

6.1. HUMAN HAZARD POTENTIAL ..................................... 38

6.2. DOSE RESPONSE ................................................. 39

6.2.1. Noncancer/Oral ............................................. 39

6.2.2. Noncancer/Inhalation ........................................ 39

6.2.3. Cancer/Oral and Inhalation .................................... 40

7. REFERENCES ............................................................ 41

APPENDIX A: ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR PHOSGENE A-1

APPENDIX B: BMD AND CATREG ANALYSES ............................... B-1

APPENDIX C: SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC 

COMMENTS AND DISPOSITION ................................. C-1

iv 
LIST OF TABLES

Table 1. Histopathology incidence indicating the number of animals affected following

phosgene exposure (from Kodavanti et al., 1997) ............................ 12

Table 2. Pulmonary histopathology severity score in rats following subchronic phosgene

exposure (from Kodavanti et al., 1997) .................................... 13

Table 3. Benchmark dose results from a subchronic study in rats (Kodavanti et al., 1997) ... 26

Table 4. Results of CatReg analysis of severity-graded lung lesions reported by Kodavanti

et al. (1997). ......................................................... 32

Table 5. Application of uncertainty factors (UFs) for two different approaches for deriving the

RfC ............................................................... 37

LIST OF FIGURES 

Figure 1. Increased collagen staining of terminal bronchiole/peribronchiolar region

(multistage model) .................................................... 28

v 
LIST OF ABBREVIATIONS AND ACRONYMS

AEGL Acute Exposure Guideline Level 

ARE Acute reference exposure 

BAL Bronchio-alveolar lavage 

BMD Benchmark dose 

BMDL Lower-bound confidence limit on the benchmark dose 

BMDS Benchmark Dose Software 

BMR Benchmark response 

C Concentration 

CatReg Categorical regression 

CL Confidence limit 

CO2 Carbon dioxide 

EC Effective concentration 

EPA U.S. Environmental Protection Agency 

ERD Extra risk dose 

FVC Forced vital capacity 

G6PD Glucose 6-phosphate dehydrogenase 

HCl Hydrochloric acid 

HEC Human equivalent concentration 

IRIS Integrated Risk Information System 

LOAEL Lowest-observed-adverse-effect level 

LOEL Lowest-observed-effect level 

MW Molecular weight 

NCTR National Center for Toxicological Research 

NOAEL No-observed-adverse-effect level 

NOEL No-observed-effect level 

NPSH Nonprotein sulfhydryl 

NTP National Toxicology Program 

PBPK Physiologically based pharmacokinetic 

PMN Polymorphonuclear 

POD Point of departure 

RfC Reference concentration 

RfD Reference dose 

RGDR Regional gas-dose ratio 

SAR Structure-activity relationship 

SMR Standard mortality ratio 

T Time 

UF Uncertainty factor 

Units of Measure 

mg/kg Milligrams per kilogram body weight 

mg/m3 Milligrams per cubic meter 

ng/m3 Nanograms per cubic meter 

ppb Parts per billion 

vi 
ppm Parts per million 

ppt Parts per trillion 

vii 
FOREWORD

The purpose of this Toxicological Review is to provide scientific support and rationale 

for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to phosgene. 

It is not intended to be a comprehensive treatise on the chemical or toxicological nature of 

phosgene. 

In Section 6, Major Conclusions in the Characterization of Hazard and Dose Response, 

EPA has characterized its overall confidence in the quantitative and qualitative aspects of hazard 

and dose response by addressing knowledge gaps, uncertainties, quality of data, and scientific 

controversies. The discussion is intended to convey the limitations of the assessment and to aid 

and guide the risk assessor in the ensuing steps of the risk assessment process. 

For other general information about this assessment or other questions relating to IRIS, 

the reader is referred to EPA’s IRIS Hotline at 202-566-1676 (phone), 202-566-1749 (fax), or 

hotline.iris@epa.gov (email address). 

viii 
AUTHORS, CONTRIBUTORS, AND REVIEWERS 

CHEMICAL MANAGER 

Dharm Singh 

National Center for Environmental Assessment–Washington Office 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 20460 

AUTHORS 

Jeff Gift 

National Center for Environmental Assessment 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 

Robert McGaughy 

National Center for Environmental Assessment–Washington Office 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 20460 

Babasaheb Sonawane 

National Center for Environmental Assessment–Washington Office 

Office of Research and Development 

U.S. Environmental Protection Agency 

Washington, DC 20460 

CONTRIBUTOR 

Femi Adeshina, National Center for Environmental Assessment, Washington, DC 

REVIEWERS 

This document and the accompanying IRIS Summary have been peer reviewed by EPA 

scientists and independent scientists external to EPA. Comments from all peer reviewers were 

evaluated carefully and considered by the Agency during the finalization of this assessment. 

During the finalization process, the IRIS Program Director achieved common understanding of 

the assessment among the Office of Research and Development; Office of Air and Radiation; 

Office of Prevention, Pesticides, and Toxic Substances; Office of Solid Waste and Emergency 

Response; Office of Water; Office of Policy, Economics, and Innovation; Office of Children’s 

Health Protection; Office of Environmental Information; and EPA’s regional offices. 

ix 
INTERNAL EPA REVIEWERS 

Robert Bruce, National Center for Environmental Assessment, Cincinnati, OH 

David Chen, Office of Children’s Health Protection, Washington, DC 

James Cogliano, National Center for Environmental Assessment, Washington, DC 

Julie Du, Office of Science and Technology, Office of Water, Washington, DC 

Annie Jarabek, National Center for Environmental Assessment, Research Triangle Park, NC 

Urmila Kodavanti, National Health and Environmental Effects Research Laboratory, Research 

Triangle Park, NC 

Deirdre Murphy, Office of Air Quality Planning and Standards/Office of Air and Radiation, 

Research Triangle Park, NC 

Bruce Rodan, National Center for Environmental Assessment, Immediate Office 

Michel Stevens, National Center for Environmental Assessment, Research Triangle Park, NC 

Paul White, National Center for Environmental Assessment, Washington, DC 

Tracey Woodruff, Office of Policy, Economics and Innovation, Washington, DC 

EXTERNAL PEER REVIEWERS 

Walter Piegorsch, Ph.D., Professor of Statistics, University of South Carolina, Columbia, SC 

Andrew Salmon, D. Phil., Chief, Air and Toxics Risk Assessment, Cal-EPA 

Hanspeter Witschi, MD, Professor emeritus, University of California-Davis 

A.M. Sciuto, Ph.D., U.S. Army Medical Research Institute of Chemical Defense, Aberdeen, MD 

Summaries of the external peer reviewers’ comments and public comments and the 

disposition of their recommendations are provided in Appendix C. 

ACKNOWLEDGMENTS 

A preliminary draft of the document was prepared by Bruce Buxton, Patricia McGinnis, 

and Mark Osier of Battelle Memorial Institute, Columbus, Ohio, under EPA Contract No. 68-C00-122. 

x 
1. INTRODUCTION

This document presents background information and justification for the Integrated Risk 

Information System (IRIS) Summary of the hazard and dose-response assessment of phosgene. 

IRIS Summaries may include an oral reference dose (RfD), an inhalation reference concentration 

(RfC), and a carcinogenicity assessment. 

The RfD and RfC provide quantitative information for use in risk assessments for health 

effects known or assumed to be produced through a nonlinear (possibly threshold) mode of 

action. The RfD (expressed in units of mg/kg-day) is defined as an estimate (with uncertainty 

spanning perhaps an order of magnitude) of a daily exposure to the human population (including 

sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a 

lifetime. The inhalation RfC (expressed in units of mg/m3

) is analogous to the oral RfD, but 

provides a continuous inhalation exposure estimate. The inhalation RfC considers toxic effects 

for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory 

system (extrarespiratory or systemic effects). 

This document does not attempt to develop concentration values protective of acute 

toxicity. For reference purposes, Appendix A presents a summary of the phosgene Acute 

Exposure Guideline Levels (AEGLs) that was prepared by the National Academy of Sciences. 

The carcinogenicity assessment provides information on the carcinogenic hazard 

potential of the substance in question and quantitative estimates of risk from oral and inhalation 

exposure. The information includes a weight-of-evidence judgment of the likelihood that the 

agent is a human carcinogen and the conditions under which the carcinogenic effects may be 

expressed. The quantitative risk estimates are derived from the application of a low-dose 

extrapolation procedure, and are presented in two ways to better facilitate their use. First, routespecific risk values are presented. The “oral slope factor” is an upper bound on the estimate of 

risk per mg/kg-day of oral exposure. Similarly, a “unit risk” is an upper bound on the estimate 

of risk per unit of concentration, either per g/L drinking water or per g/m3

 air breathed. 

Second, the estimated concentration of the chemical substance in drinking water or air when 

associated with cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided. 

Development of these hazard identification and dose-response assessments for phosgene 

has followed the general guidelines for risk assessment as set forth by the National Research 

Council (NRC, 1983). EPA guidelines that were used in the development of this assessment 

may include the following: Guidelines for the Health Risk Assessment of Chemical Mixtures 

(U.S. EPA, 1986a), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Guidelines 

for Developmental Toxicity Risk Assessment (U.S. EPA, 1991), Guidelines for Reproductive 

1
Toxicity Risk Assessment (U.S. EPA, 1996a), Guidelines for Neurotoxicity Risk Assessment (U.S. 

EPA, 1998a), Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), Supplemental 

Guidance for Assessing Susceptibility from Early-Life Exposures to Carcinogens (U.S. EPA, 

2005b), Recommendations for and Documentation of Biological Values for Use in Risk 

Assessment (U.S. EPA, 1988), (proposed) Interim Policy for Particle Size and Limit 

Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of 

Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 

1994b), Use of the Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995), 

Science Policy Council Handbook: Peer Review (1st and 2nd editions) (U.S. EPA, 1998b, 2000a), 

Science Policy Council Handbook: Risk Characterization (U.S. EPA, 2000b), Benchmark Dose 

Technical Guidance Document (U.S. EPA, 2000c), Supplementary Guidance for Conducting 

Health Risk Assessment of Chemical Mixtures (U.S. EPA, 2000d), and A Review of the Reference 

Dose and Reference Concentration Processes (U.S. EPA, 2002). 

The literature search strategy employed for this compound was based on the CASRN and 

at least one common name. Any pertinent scientific information submitted by the public to the 

IRIS Submission Desk was also considered in the development of this document. The relevant 

literature was reviewed through March 2004. 

2
2. CHEMICAL AND PHYSICAL INFORMATION 

Phosgene is also known as carbon dichloride oxide, carbonic dichloride, carbon 

oxychloride, carbonyl chloride, carbonyl dichloride, and chloroformyl chloride. Some relevant 

physical and chemical properties are listed below (NTP, 2001; WHO, 1997): 

CAS number: 75-44-5 

Structural formula: COCl2 

Molecular weight: 98.92 

Vapor pressure: 1,180 mmHg at 20°C 

Water solubility: slight, reacts with water 

Boiling point: 8.2°C 

Odor threshold: 0.4 to 1.5 ppm 

Irritation threshold: 3 ppm 

Conversion factor: 1 ppm = 4.05 mg/m3, 1 mg/m3 = 0.247 ppm (25°C, 760 mmHg) 

Phosgene is primarily used in the polyurethane industry for the production of polymeric 

isocyanates (WHO, 1998, 1997; U.S. EPA, 1986c, 1984). Phosgene is also used in the 

polycarbonate industry and in the manufacture of carbamates and related pesticides, dyes, 

perfumes, pharmaceuticals, and isocyanates. The majority of phosgene for industrial 

applications is made on site by the reaction of carbon monoxide and chlorine gas using an 

activated carbon catalyst. Phosgene may also be produced as a combustion product of carbon 

tetrachloride, methylene chloride, trichloroethylene, or butyl chloroformate, although these 

methods are not utilized industrially. Estimated worldwide production exceeds 5 billion pounds 

(WHO, 1997). Phosgene is a colorless gas at room temperature with an odor ranging from 

strong and stifling when concentrated to hay-like when diluted. Phosgene is slightly soluble in 

aqueous media, but, when dissolved, it is very rapidly hydrolyzed to carbon dioxide (CO2) and 

hydrochloric acid (HCl), with a half-life at 37°C of approximately 0.026 seconds (Schneider and 

Diller, 1989; Manogue and Pigford, 1960). 

Phosgene levels have been measured in ambient air (U.S. EPA, 1983; Singh et al., 1981, 

1977; Singh, 1976). Multiple samples (10–257) were taken from four locations in California 

within a 24-hour period. The average level for three clean-air (rural and coastal) locations was 

87 ng/m3 (21.7 ppt). In the Los Angeles basin, the average was 127.2 ng/m3 (31.8 ppt). These 

values were also cited by the World Health Organization (WHO, 1997). Kelly et al. (1994) also 

reported concentrations and transformations of hazardous air pollutants. They reported that the 

3
phosgene ambient concentration median was 80 ng/m3

. 

Inhalation is the primary exposure route for phosgene. Suspected sources of atmospheric 

phosgene are fugitive emissions, thermal decomposition of chlorinated hydrocarbons, and photooxidation of chloroethylenes. Although the existence of atmospheric sinks for phosgene has 

been questioned, it is postulated that phosgene’s removal from the atmosphere is rather slow 

(Singh et al., 1977). 

The American Conference of Governmental Industrial Hygienists (ACGIH, 2000) 

recommends a time-weighted average of 0.1 ppm (0.4 mg/m3) to protect against irritation, 

anoxia, and pulmonary edema. The National Institute for Occupational Safety and Health 

(NIOSH, 2001) recommended exposure limit is 0.1 ppm, and the Occupational Safety and Health 

Administration (OSHA, 1993) has promulgated an 8-hour permissible exposure limit of 0.1 ppm. 

4
3. TOXICOKINETICS

Phosgene is rapidly hydrolyzed in aqueous solution to CO2 and HCl, which are likely to 

be exhaled (Schneider and Diller, 1989; Diller, 1985; Diller et al., 1979). Consequently, 

phosgene is not expected to leave the pulmonary circulation following inhalation exposure, nor 

is exposure by the oral route likely (WHO, 1998, 1997; U.S. EPA, 1986c, 1984). Data on 

phosgene absorption are not available. Phosgene is electrophilic and undergoes attack by a 

variety of nucleophiles. The predominant reaction is hydrolysis by water yielding carbon 

dioxide and hydrochloric acid. It also reacts with a wide variety of nucleophiles, including 

primary and secondary amines, hydroxy groups, and thiols. In addition, it also reacts with 

macromolecules, such as enzymes, proteins, or other polar phospholipids, resulting in formation 

of covalent adducts that can interfere with molecular functions. The loss of enzyme activity may 

lead to loss of cellular function and cell death (reviewed in WHO, 1998). Studies on the 

distribution and elimination of phosgene in animals or humans were not located in the published 

literature. 

Phosgene is thought to participate directly in acylation reactions with amino, hydroxyl, or 

sulfhydryl groups (WHO, 1998, 1997; Schneider and Diller, 1989; U.S. EPA, 1986c; Diller, 

1985). Formation of phosgene as a metabolite of other compounds has been hypothesized 

(reviewed in U.S. EPA, 2001, 1984) but not directly measured, perhaps owing to the rapid 

reaction of phosgene with tissue molecules or hydrolysis in aqueous solution. Phosgene is 

believed to be the major intermediate metabolite of chloroform (oxidative metabolism) (U.S. 

EPA, 2001a). Despite rapid conversion of phosgene to less “toxic” end products, other systemic 

effects, such as permeability-related edema (Borak and Diller, 2001) and adenosine triphosphaterelated changes (Currie et al., 1987), have been noted. 

5
4. HAZARD IDENTIFICATION 

4.1. STUDIES IN HUMANS – EPIDEMIOLOGY, CASE REPORTS 

As noted in Section 2, phosgene is a gas at room temperature, and aqueous phosgene 

rapidly hydrolyzes to CO2, and HC1; consequently, exposure by the oral route is highly unlikely. 

Diller and Zante (1982) performed an extensive literature review of human effects from 

phosgene inhalation exposure and found that a great majority of data were anecdotal or rough 

estimates and, thus, did not contain reliable exposure concentrations and/or durations. Many 

case reports describe symptomology and postmortem results from human phosgene poisonings; 

however, exposure concentrations were not reported. 

4.1.1. Acute Inhalation Exposure 

The acute toxicity of phosgene inhalation has been well documented in humans (WHO, 

1998, 1997; U.S. EPA, 1986c, 1984; Underhill, 1919). 

Inhalation of phosgene at high concentrations results in a sequence of events, including 

an initial bioprotective phase, a symptom-free latent period, and a terminal phase characterized 

by pulmonary edema (Schneider and Diller, 1989; Diller, 1985). In the initial phase, high 

concentrations (>3 ppm) may result in a vagal reflex action that causes frequent, shallow 

respiration and decreased respiratory vital capacity and volume. This, in turn, leads to a 

decreased arterial CO2 pressure increase and decreased blood pH. After cessation of exposure, 

the reflex syndrome shows a tendency to regress. 

In the second phase, which may last for several hours postexposure, clinical signs and 

symptoms are generally lacking (Schneider and Diller, 1989; Diller, 1985). However, histologic 

examination reveals the beginnings of an edematous swelling, with blood plasma increasingly 

entering the pulmonary interstitium and alveoli. This may result in damage to the alveolar type I 

cells and a rise in hematocrit. In exposed humans, the individual is unaware of these processes; 

thus, this phase is termed the “clinical latent phase.” The length of this phase varies inversely 

with the inhaled dose. 

In the third clinical phase of phosgene toxicity (Schneider and Diller, 1989; Diller, 1985), 

the accumulating fluid in the lung results in the edema becoming apparent both directly and 

indirectly. The severity of the edema increases, potentially resulting in decreased gas exchange 

as the fluid gradually rises from the alveoli to the proximal segments of the respiratory tract. 

Agitated respiration may cause the protein-rich fluid to take on a frothy consistency. A severe 

edema may result in an increased concentration of hemoglobin in the blood and congestion of the 

alveolar capillaries. At sufficiently high exposure levels, the heart also may be affected, 

6
resulting in cardiac failure due to pulmonary congestion. In general, this phase peaks 

approximately 24 hours after an acute exposure and, assuming lethality does not occur, recedes 

over the next 3 to 5 days. 

A case history of phosgene poisoning was reported in a 45-year-old welder who had 

symptoms of dyspnea and weakness (Glass et al., 1971). The authors concluded that phosgene 

poisoning causes reduction of forced vital capacity (FVC), airway obstruction, arterial hypoxia, 

and impaired co-transfer. Some of the pulmonary events precipitated by phosgene exposure, 

such as neutrophil and leukocyte infiltration, edema, and bronchial dilation, are also observed in 

asthmatics in the presence of ozone and nitrous oxide. Although the mechanisms for the 

phosgene-produced effect (acylation) and the ozone and nitrous oxide effect (oxidation) are 

presumed to be different, the resulting health endpoint appears to be similar (Jaskot et al., 1991) 

because phosgene acts as a lung irritant. 

Cases of acute phosgene toxicity associated with two large-scale releases of phosgene in 

Germany and Japan have been reported. In Hamburg, Germany, on May 20, 1928, 11 metric 

tons (24,640 pounds) of “pure” phosgene escaped from a storage tank, resulting in a large-scale 

exposure to the airborne gas (Hegler, 1928; Wohlwill, 1928, both cited in U.S. EPA, 1986c). A 

total of 300 people—some located as far as 6 miles from the site—reported illness within a few 

days of the release. Of those, 10 died as a result of the exposure. One hospital reported 

admitting 195 victims on the night of May 20. Of those, 17 were very ill, 15 were moderately ill, 

and the rest were only slightly affected. Autopsy of six of the fatalities revealed abnormalities 

primarily in the lungs. Occasional lesions of the kidney, liver, and heart were observed. 

In November 1966, phosgene was accidentally released from a factory in Japan 

(Sakakibara et al., 1967, cited in WHO, 1997). A total of 382 people were reported poisoned, 12 

of whom were hospitalized. Signs and symptoms of exposure in the 12 hospitalized patients 

included headache, nausea, cough, dyspnea, fatigue, pharyngeal pain, chest tightness, chest pain, 

and fever. Seven patients showed evidence of pulmonary edema, as revealed by chest x-ray 48 

hours postexposure. One patient reported lacrimation and redness of the eyes. 

4.1.2. Subchronic Inhalation Exposures 

Galdston et al. (1947) reported six cases (four women, two men) of phosgene exposure, 

with exposure ranging from 1 to 24 months. Common symptoms included rapid, shallow 

breathing; high minute volume; and low oxygen extraction. The measurable changes in 

pulmonary function that were consistently observed varied in type and severity, but they could 

not be correlated with the severity of phosgene intoxication or with chronic symptoms. 

7
4.1.3. Occupational Epidemiology Studies 

The effect of occupational exposure to phosgene was examined in workers employed 

from 1943 to 1945 at a uranium processing plant in the United States (Polednak and Hollis, 

1985; Polednak, 1980). In the initial report (Polednak, 1980), a comparison was made between a 

group of 699 male workers exposed daily to phosgene and 9,352 male controls employed during 

the same time period but not exposed to phosgene. The duration of exposure was generally 2 

months to 1 year; the followup period was 30 years. Exposure levels were not reported but were 

instead described as “low” (undetectable), with the level exceeding 1 ppm four to five times 

daily. Standard mortality ratios (SMRs) for respiratory diseases were not significantly different 

between controls (SMR = 113, 95% confidence limit [CL] = 98–130) and exposed workers 

(SMR = 78, 95% CL = 31–161) relative to cause- and age-specific death rates for white males in 

the United States. Likewise, no differences in the SMRs for lung cancer were found between 

controls (SMR = 113, 95% CL = 97–131) and exposed workers (SMR = 127, 95% CL = 

66–222). No significant differences were found between controls and exposed workers for any 

other cause of death. 

Interestingly, it should be noted that approximately 30 years after exposure, this cohort 

showed no statistically significant increases in mortality from overall cancer, from cancers at 

specific anatomical sites, or from diseases of the respiratory system or in overall mortality. 

However, the exposure period covered by the study was short, exposed groups were small, and 

exposure levels were not well documented. Consequently, evidence presented in this study is 

inadequate to assess the chronic toxicity or carcinogenicity of phosgene. 

In the followup study (Polednak and Hollis, 1985), the number of subjects had decreased 

to 694 male workers who were exposed daily to phosgene and 9,280 male controls who were 

employed in the same plant but not exposed to phosgene. The SMRs for respiratory diseases 

were not significantly different between controls (SMR = 119, 95% CL = 106–133) and exposed 

workers (SMR = 107, 95% CL = 59–180). Likewise, no differences in the SMRs for lung cancer 

were found between controls (SMR = 118, 95% CL = 105–133) and exposed workers (SMR = 

122, 95% CL = 72–193). No significant differences were found between controls and exposed 

workers for any other cause of death. The authors pointed out, however, that because of the small 

sample sizes, only large differences in mortality rates would have been detected in these studies. 

Polednak and Hollis (Polednak and Hollis, 1985; Polednak, 1980) also examined a 

subgroup of 106 men who were exposed to high levels of phosgene (thought to be 50 ppm-min 

or greater) as a result of accidental workplace exposures. The reported overall SMR for all 

causes for exposed workers was 109 (95% CL = 73–157) in the 1980 study and 121 (95% CL = 

86–165) in 1985 follow-up study. In the respiratory disease category, the SMR increased from 

219 (3 deaths reported, 1.37 expected, 95% CL not reported) in the 1980 study to 266 (95% CL 

= 86–622) in the 1985 study; however, several of these cases reported using tobacco, making the 

8
role of phosgene in the deaths uncertain. None of these values reached statistical significance. 

An attempt was made in the 1985 study to analyze a similar cohort of 91 female workers also 

exposed to approximately 50 ppm-min, but ascertainment of deaths and followup was less 

certain for this group and prevented a full analysis. Approximately 35 years after exposure to 

phosgene, no increase in overall mortality or mortality from cancer or respiratory disease was 

noted in this cohort. 

4.2. ACUTE/SUBCHRONIC AND CHRONIC STUDIES IN ANIMALS 

4.2.1. Oral Exposures 

No animal studies on the toxicity of phosgene following oral exposure were identified. 

4.2.2. Inhalation Exposures 

No chronic studies in experimental animals on the effects of inhaled phosgene were 

located in the published literature. The majority of studies of phosgene are of acute duration, 

spanning from minutes to several hours. However, several studies (Kodavanti et al., 1997; 

Franch and Hatch, 1986; Clay and Rossing, 1964; Rossing, 1964) examined the effects of 

repeated short-term, “acute” exposures over 2 to 12 weeks. These studies are described below. 

4.2.2.1. Acute Exposures 

A number of studies have examined the effects of acute phosgene exposure in animals. A 

similar spectrum of effects was seen across the many species examined. Exposures were limited 

to concentrations between 0.5 and 40 ppm (2 to 160 mg/m3

) for intervals ranging from 5 minutes 

to 8 hours. 

Animals exposed to phosgene for a short duration show changes in breathing, including 

decreased tidal volume and minute volume, increased breathing frequency (Lehnert, 1992), and 

increased heart rate (Meek and Eyster, 1920). Exposed animals also show decreased body 

weight relative to air-exposed animals (Lehnert, 1992). An increase in lung weight also has been 

observed (Sciuto, 1998; Jaskot et al., 1991, 1989). After exposure to phosgene, lungs appear 

voluminous and heavy, contain considerable amounts of pale yellow fluid, and show signs of 

edema and emphysema (Ardran, 1950; Durlacher and Bunting, 1947). Exposure also results in 

changes in bronchio-alveolar lavage (BAL) parameters, including increased protein (Jugg et al., 

1999; Sciuto, 1998; Jaskot et al., 1989; Slade et al., 1989; Hatch et al., 1986), phospholipid 

content (Jugg et al., 1999), and enzyme levels (Lehnert, 1992; Jaskot et al., 1991), as well as 

increases in the numbers of inflammatory cells (Lehnert, 1992). It has been reported that prior 

acute exposure to phosgene is protective against the effects of a later acute exposure (Ghio and 

Hatch, 1996; Box and Cullumbine, 1947). 

9 
Histopathologic examination of the lungs of phosgene-exposed animals reveals exposuredependent edema and a progressive bronchiolar inflammatory response, with an infiltration of 

polymorphonuclear cells and lymphocytes and the presence of extravasated erythrocytes (Jugg et 

al., 1999; Lehnert, 1992; Keeler et al., 1990; Gross et al., 1965; Durlacher and Bunting, 1947; 

Meek and Eyster, 1920). This condition progresses with increasing exposure, causing alveolar 

hyperplasia, a progressive fibrotic response, and the gorging of capillaries with blood cells. 

Following phosgene exposure, an initial increase in blood volume occurs, followed by a 

significant decrease. With the resulting increase in hemoglobin concentration (Meek and Eyster, 

1920), it is thought that the volume decrease is the result of fluid entering the lungs during 

edema formation. 

Acute exposure to phosgene also has been shown to result in a decreased immune 

response in animals, as evidenced by an increased susceptibility to in vivo bacterial and injected 

tumor cells (Selgrade et al., 1989) and viral (Ehrlich and Burleson, 1991) infections as well as a 

decreased in vitro virus-killing and T-cell response (Burleson and Keyes, 1989; Ehrlich et al., 

1989). Selgrade et al. (1989) reported that a single 4-hour exposure to phosgene concentrations 

as low as 0.025 ppm significantly enhanced mortality due to streptococcal infection in mice. 

Furthermore when the exposure time was increased from 4 to 8 hours, a significant increase in 

susceptibility to streptococcus was also seen at an exposure concentration of 0.01 ppm. The 

authors attempted to establish a mechanism for these findings by measuring alveolar macrophage 

activity. With intratracheal administration of bacteria, which delivers a much larger amount of 

bacteria than the inhalation route used in the earlier experiments, phosgene concentrations of 

0.25 ppm and higher, which is 10-fold higher than the lowest observable effect, had little or no 

effect on alveolar macrophage phagocytic activity and little or no effect on total cells recovered, 

viability, or differential cell counts in lavage fluid obtained shortly after exposure. The 

mechanism(s) responsible for increased sensitivity to bacterial infection are unclear. 

4.2.2.2. Subchronic Exposures 

Kodavanti et al. (1997) exposed groups of male F344 rats to phosgene levels designed to 

provide equal products of concentration times time (C × T) for all groups but the lowest 

exposure concentration. Groups of eight rats were exposed to clean air (control) or phosgene for 

6 hours per day as follows: to 0.1 ppm (0.4 mg/m3) for 5 days per week, to 0.2 ppm (0.8 mg/m3) 

for 5 days per week, to 0.5 ppm (2 mg/m3) for 2 days per week, or to 1 ppm (4 mg/m3) for 1 day 

per week for 4 or 12 weeks. Groups of similarly exposed rats were allowed clean air recovery 

for 4 weeks after 12 weeks of exposure. The measured 12-week average concentrations were as 

follows (mean ± SD range): 0.1 ppm group was 0.101 ± 0.002 (0.098–0.113); 0.2 ppm group 

was 0.201 ± 0.002 (0.196–0.207); 0.5 ppm group was 0.505 ± 0.008 (0.495–0.536); 1 ppm group 

10
was 0.976 ± 0.03 (0.912–1.009). At the end of the exposure or recovery period, animals were 

sacrificed, and the lungs were weighed and processed for histologic examination. The 0.5 ppm 

histology samples were inadvertently lost, but other analyses were performed (e.g., BAL, lung 

volume, and biochemical parameters). 

No mortality was reported for any exposure level or time examined. However, small but 

statistically significant decreases in body weight gain were reported in the 0.5 and 1 ppm rats at 

both 4 and 12 weeks of exposure. A concentration-dependent increase in relative lung weight 

was seen following both 4 and 12 weeks of exposure (statistically significant at 0.2 ppm or 

greater). The phosgene concentration at either time point seemed to drive this response rather 

than the C × T product. The effect appeared to be more severe at the end of 4 weeks than after 

12 weeks of exposure. Phosgene also increased the lung displacement volume (an index of total 

lung volume) in all exposed groups at 4 weeks and at 0.2 ppm or greater at 12 weeks of 

exposure. 

Histologic examination of animals exposed for 4 weeks revealed changes in the 

bronchiolar regions, with a small but apparent thickening and mild inflammation seen at 0.1 ppm 

that progressed in severity with concentration to a severe inflammation and thickening of the 

terminal bronchiolar regions and alveolar walls at 1 ppm (Tables 1 and 2). An increase in 

collagen staining, using Masson’s trichrome stain, was seen in the 0.2 and 1 ppm animals, 

although no elevation of pulmonary hydroxyproline, a measure of collagen deposition, was 

observed. 

11
Table 1. Histopathology incidence indicating the number of animals affected following phosgene exposurea 

(from Kodavanti et al., 1997) 

12

4 weeks 12 weeks 16 weeks c 

Phosgene concentration (ppm) 0.0 0.1d 0.2d 1.0e 0.0 0.1d 0.2d 1.0e 0.0 0.1d 0.2d 1.0e 

Number of animals examined (12) (8) (8) (6) (12) (8) (8) (8) (9) (6) (7) (5) 

Alveolar effusion 0 0 0 2 0 0 0 1 2 0 0 0 

Alveolus, interstitial thickening 0 2 5b 6b 0 2 4b 8b 0 0 0 0 

Bronchus, epithelial alteration 0 1 2 3 0 0 0 1 0 0 0 0 

Bronchus, inflammation 1 2 2 3 0 0 0 3 0 0 0 0 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

2 3 8b 6b 1 3 8b 8b 0 0 1 1 

Terminal bronchiole, 

peribronchiolar alveolus, 

epithelial alteration 

2 4 5b 6b 0 1 7b 8b 0 2 3 2 

Terminal bronchiole/ 

peribronchiolar, increased 

collagen staining 

1 1 8b 6b 2 2 8b 8b 2 1 7b 5b 

a

 Number in each column indicates number of animals affected (of total numbers used in analysis). b

 Statistically significant compared with unexposed (0.0 ppm) group, p<0.01 (pairwise Fisher’s exact test). c

 Indicates 12-week exposure, followed by a 4-week recovery period.

d Phosgene exposure was 6 hours per day, 5 days per week.

e

 Phosgene exposure was 6 hours per day, 1 day per week.
Table 2. Pulmonary histopathology severity score in rats following subchronic phosgene exposurea

 (from 

Kodavanti et al., 1997) 

13

4 weeks 12 weeks 16 weeks b 

Phosgene concentration (ppm) 0.0 0.1 0.2 1.0 0.0 0.1 0.2 1.0 0.0 0.1 0.2 1.0 

Number of animals examined (12) (8) (8) (6) (12) (8) (8) (8) (9) (6) (7) (5) 

Alveolar effusion 0 0 0 0.33 0 0 0 0.13 0.4 0 0 0 

Alveolus, interstitial thickening 0 0.25 0.63 1.83 0 0.25 0.5 2.13 0 0 0 0 

Bronchus, epithelial alteration 0 0.13 0.50 0.33 0 0 0.13 0.25 0 0 0 0 

Bronchus, inflammation 0.08 0.25 0.4 0.83 0 0 0 0.13 0 0 0 0 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

0.17 0.38 1.00 3.00 0.08 0.38 1.13 2.13 0 0 0.14 0.16 

Terminal bronchiole, peribronchiolar 

alveolus, epithelial alteration 

0.17 0.5 0.63 2.50 0 0.13 0.88 2.38 0 0.33 0.43 0.60 

Terminal bronchiole/peribronchiolar, 

increased collagen staining 

0.08 0.13 1.00 1.00 0.17 0.25 1.0 2.0 0.2 0.17 1.0 1.0 

a Severity scores given to individual animals from a complete pathological examination are 0, not remarkable; 1, minimal; 2, slight/mild; 3, moderate; 4, 

moderately severe; and 5, severe, based on relative evaluation of lesions. Based on severity scoring, a maximum score of 3 was assigned for some of the lesion 

types at highest phosgene concentrations. Severity scores for each animal within a group were added, and an average score per animal was calculated; this is 

shown in the table. 

b Indicates 12-week exposure, followed by a 4-week recovery period. 
Similar changes were seen following 12 weeks of exposure; the lesions did not appear to 

have progressed beyond those seen at 4 weeks. Both pulmonary prolyl hydroxylase activity and 

pulmonary desmosine were elevated at both 4 and 12 weeks of exposure in the 1 ppm animals 

only. The intensity of collagen staining in the bronchiolar region was elevated (higher than in 

controls) in the 0.2 and 1 ppm groups. The pulmonary hydroxyproline level was significantly 

elevated only in the 1 ppm animals after 12 weeks of exposure. 

Following 4 weeks of clean air recovery, body weights were significantly reduced only in 

the 1 ppm rats, with absolute lung weights also significantly increased only in the 1 ppm 

animals. The displacement volumes returned to control levels regardless of phosgene 

concentration. Histopathology following 4 weeks of recovery showed considerable, although not 

complete, recovery of the bronchiolar lesions and inflammation. Both prolyl hydroxylase 

activity and desmosine levels had returned to normal postrecovery, but hydroxyproline levels in 

the 0.5 and 1 ppm groups were significantly higher than in controls. Collagen staining remained 

at the same level of intensity as seen in the 12-week groups dosed at 0.2 and 1 ppm. Phosgeneinduced changes in collagen staining were not reversible within the 4-week recovery period, and 

the severity of lesions in the 12- week exposure group was dependent on concentration, not on 

the C × T product. 

As a followup to the same study, Hatch et al. (2001) pointed out that hydroxyproline 

content and collagen staining are standard measures of lung fibrosis and can be considered good 

markers of chronic injury. Fibrosis is accompanied by decreased lung compliance and diffusion 

capacity. The critical toxic effect for purposes of defining the point of departure in the RfC 

derivation is collagen staining, which is indicative of irreversible lung fibrosis. As Table 1 

shows, the effect is not statistically significant at 0.1 ppm, but it is significant at 0.2 ppm, not 

only for the 4- and 12-week exposure groups but also for the 16-week recovery group. 

Kodavanti et al. (1997) found that, at 0.1 ppm, the lung displacement volume was statistically 

significantly elevated in the 4-week exposure group but not in the 12-week exposure group or 

the 16-week recovery group. This effect is not considered an adverse effect of chronic exposure 

because it diminished with longer exposure (12 vs. 4 weeks), and it disappeared after the 4-week 

recovery. Taking the pathology incidence findings as indications of chronic toxicity, a lowestobserved-adverse-effect level (LOAEL) of 0.2 ppm (0.8 mg/m3

) for collagen staining, indicative 

of irreversible lung fibrosis, can be identified. The no-observed-adverse-effect level (NOAEL) 

for this effect was 0.1 ppm in this study. 

Rossing (1964) exposed 14 mongrel dogs to phosgene for 30 minutes at concentrations of 

between 24 and 40 ppm (96 and 160 mg/m3); pretest values for each animal served as its control. 

The dogs were exposed three times per week until a definite rise was seen in their airway 

resistance; at that time, the frequency of exposure was reduced to once or twice a week. 

14
Exposures were performed for 10 to 12 weeks. During the fifth and sixth weeks, the 

experimental schedules were disrupted. 

Phosgene exposure resulted in no apparent discomfort to the animals. Seven of the 14 

animals died within the first 3 weeks of exposure, and 3 additional animals were sacrificed at the 

end of 3 weeks. Animals that died during exposure or were sacrificed were autopsied, and their 

lungs were fixed and examined. The dynamic elasticity rose very quickly, reaching a maximum 

mean value of four times the control in the first week of exposure. It fell slightly during the next 

3 weeks but remained significantly elevated above that of controls. After the disruption of 

exposure, elastance returned to the week 4 levels (approximately twice those of controls) until 

the ninth week, when it increased again. Mean lower airway resistance followed a similar 

pattern, with a rise for the first 4 weeks, a recovery period during the disruption of exposure, and 

then another rise once exposure had resumed. 

During the first 2 to 3 weeks, the animals were often tachypneic and breathed with 

reduced tidal volume. After the first 3 weeks, the breathing pattern was similar to that seen in 

patients with obstructive airway disease: the animals had a slow respiratory rate and, frequently, 

active respiratory effort, as suggested by active contraction of the abdominal muscles. In two 

animals that were allowed to survive beyond the exposure period, elastance dropped rapidly to 

normal. Histologic examination revealed bronchiolitis with peribronchiolar edema, hemorrhage, 

and inflammation at earlier time points (3 weeks or less). In animals surviving to the fourth 

week and beyond, the inflammatory reaction was still present but less intense, despite continuing 

exposure. Owing to inadequate reporting of exposure levels, poor experimental design, and 

inadequate number of animals per treatment group, no NOAEL or LOAEL could be identified 

from this study. 

Clay and Rossing (1964) also described lung histopathology for a separate group of dogs 

as described in Rossing (1964). They exposed groups of mongrel dogs (sex not specified) to 

phosgene at levels of between 24 and 40 ppm (96 and 160 mg/m3) for 30 minutes for one to three 

exposures per week. Group 1 animals (n = 2) consisted of unexposed controls; group 2 dogs (n 

= 7) were exposed one or two times and sacrificed 1–2 days postexposure; group 3 animals (n = 

7) were exposed 4–10 times and sacrificed up to 7 days postexposure; group 4 animals (n = 5) 

were exposed 15–25 times and sacrificed immediately or up to 2 weeks postexposure; and group 

5 animals (n = 4) were exposed 30–40 times and sacrificed immediately or up to 12 weeks after 

the final exposure. The lungs of the sacrificed animals were inflated with fixative and dried. 

Both histologic sections and 1-mm-thick macrosections of the dried lungs were examined for all 

groups. 

Both micro- and macroscopic examination revealed progressive pulmonary changes with 

increasing number of exposures. Microscopic changes revealed acute bronchiolitis and 

15 
peribronchiolitis that affected only scattered sections of the lung at the lowest number of 

exposures. With increasing number of exposures, a progression to a chronic obliterative 

bronchiolitis was seen, with fibrotic changes that affected the majority, but not all, of the lung 

tissue. Macrosections similarly revealed little or no changes in animals exposed one or two 

times, with a progressing fibrosis and emphysema seen with increasing number of exposures, 

resulting in severe dilation of the respiratory bronchioles and increased alveolar pore size in 

animals exposed 30–40 times. Owing to the poor design of the study and the inadequate number 

of experimental animals and dose level tested, no NOAEL or LOAEL values could be identified. 

Franch and Hatch (1986) performed a series of experiments examining the effects of 

inhaled phosgene in male Sprague-Dawley rats. In the first exposure regimen, groups of rats 

(4–10 per group) were exposed to 0 or 1 ppm (4.05 mg/m3) of phosgene for 4 hours and then 

sacrificed immediately after exposure or at 1, 2, 7, 14, or 38 days postexposure. Body weights 

were decreased to 13% below those of controls (p<0.01) on the first day postexposure and then 

rose toward control values, reaching 3% below control values on day 14 of recovery. Food 

intake was also significantly decreased in exposed animals on days 1–3 postexposure before 

returning to nearly normal values. Lung wet weights were significantly elevated in exposed rats 

immediately after exposure and remained elevated through day 7 postexposure. No change in 

nonprotein sulfhydryl (NPSH) content was seen immediately postexposure, but it showed an 

upwardly increasing trend thereafter. G6PD activity was elevated over that of controls from 

days 1–14 postexposure. 

 The second regimen consisted of a single 7-hour exposure during which one rat per 

group (control, exposed) was sacrificed each hour; the experiment was replicated three times. 

Lung weights were significantly increased 4 hours into the exposure and beyond, whereas NPSH 

content was decreased. No significant change in G6PD activity was seen. 

In their third exposure regimen, Franch and Hatch (1986) exposed groups of male 

Sprague-Dawley rats to 0.125 (0.5 mg/m3) or 0.25 ppm (1 mg/m3) of phosgene for 4 hours per 

day, 5 days per week, for 17 total exposures over 4 weeks. Lung weight was significantly 

increased at exposure day 7 and later in the 0.25 ppm group and at day 17 in the 0.125 ppm 

group. Pooled over all time points, the 0.25 ppm group had higher NPSH content than did the 

0.125 ppm group, and it was significantly greater than in controls. In animals allowed to recover 

postexposure, lung weights and NPSH levels returned to near control levels. Histology of the 

lungs after 17 days of exposure to 0.25 ppm of phosgene revealed moderate multifocal 

mononuclear-cell accumulations in the walls of the terminal bronchioles and a minimal type-II 

cell hyperplasia; lesions in the 0.125 ppm groups were minimal. 

Selgrade et al. (1995) administered Streptococcus zooepidemicus bacteria via an aerosol 

spray to the lungs of male Fischer 344 rats immediately after phosgene exposure and measured 

16
the subsequent clearance of bacteria. They also evaluated the immune response of uninfected 

rats similarly exposed to phosgene, as measured by an increase in the percentage of 

polymorphonuclear leukocytes (PMN) in lung lavage fluid. The exposure regimen was similar 

to that of Kodavanti et al. (1997); animals inhaled phosgene at concentrations of 0, 0.1, or 0.2 

ppm, 6 hours per day, 5 days per week, and 0.5 ppm, 6 hours per day, 2 days per week, for 4 and 

12 weeks. For each of the 12-week exposure regimen, additional groups of animals were 

assessed for all endpoints at 4 weeks postexposure. 

Within 24 hours after bacterial infection, the lungs of unexposed animals cleared the 

bacteria, but in animals exposed to phosgene for both 4 and 12 weeks at all three concentrations 

the clearance was impaired. After 4 weeks of recovery following 12 weeks of phosgene 

exposure, the bacteria clearance was comparable to that of unexposed animals. In uninfected 

rats, the % PMN cells was statistically significantly higher than in the unexposed group in all 4­

week phosgene exposure groups, and it was also higher at the highest concentration (0.5 ppm) in 

the 12-week exposure group. In the 4-week recovery animals, no difference in % PMN cells was 

observed between the exposed and control groups. This experiment shows that all phosgene 

concentrations from 0.1 to 0.5 ppm impaired resistance to bacterial infection and that the 

immune response is stimulated by phosgene exposure. After 4 weeks following exposure, 

bacterial resistence is back to normal and there is no immune response in excess of unexposed 

controls. 

In an earlier experiment measuring the same effects with a single 6-hour exposure to 

phosgene concentrations of 0.1 and 0.2 ppm, Yang et al. (1995) also reported a decrease in 

bacterial clearance in the lungs at 24 hours post infection, but over a period of 72 hours postinfection it returned to normal in the 0.1 ppm group. In comparison with single exposures, the 

multiple daily exposures extending to 4 and 12 weeks in the Selgrade et al. (1995) report showed 

a slight enhancement of effect in the 0.1 ppm group at 24 hours post-infection, but no 

“adaptation,” or lessening of the effect. Yang et al. (1995) found that if the bacteria are 

administered 18 hours after single phosgene exposures rather than immediately, the clearance is 

normal, indicating that recovery from the toxic effect of phosgene is rapid. Selgrade et al. 

(1995) suggested that in a repeated cycle of intermittent exposures there is an increased chance 

for infection to occur during and immediately after each exposure period. 

4.3. REPRODUCTIVE/DEVELOPMENTAL TOXICITY STUDIES 

No epidemiological studies examining the effects of phosgene on reproduction or 

development for any exposure duration or route in humans were located in the published 

literature. A case report by Gerritsen and Buschmann (1960) describes a 7-months-pregnant 

woman who survived severe phosgene-induced pulmonary edema and subsequently delivered a 

17
normal, full-term infant. No experimental animal studies have been reported on the effects of 

phosgene on reproductive and developmental organ systems. Therefore, the data from which to 

draw any conclusions about potential reproductive/developmental effects of phosgene in humans 

or animals are inadequate. 

4.4. OTHER EFFECTS 

4.4.1. Dermal Toxicity 

Skin contact with phosgene has been known to cause severe skin burns in humans. 

Vapor contact with moist or wet skin can lead to irritation and erythema (WHO, 1997). No 

dermal toxicity studies in experimental animals have been conducted. 

4.4.2. Ocular Toxicity 

In humans, low vapor concentration exposure to phosgene gas can cause conjunctival 

inflammation, and high vapor concentration exposure can lead to corneal opacifications and 

perforation (Grant and Schuman, 1993). 

4.4.3. Neurotoxicity 

Phosgene-induced hypoxia and hypotension may cause anoxic injury to the brain (Borak 

and Diller, 2001). 

4.4.4. Genotoxicity 

The in vivo cytogenetic effects of phosgene inhalation were investigated in mice at 5, 10, 

or 15 ppm for 6 hours. No evidence was found that phosgene is clastogenic, aneuploidogenic, or 

capable of inducing sister chromatid exchanges and micronuclei (Klingerman et al., 1994). 

Furthermore, Reichert et al. (1983) reported that phosgene was negative under the conditions of 

the Ames bacterial mutagenicity assay with and without metabolic activation. The authors 

concluded that the negative result was likely due to phosgene reacting rapidly in the test 

medium. Additional in vitro testing would be subject to similar technical limitations imposed by 

the water reactivity of phosgene. As discussed, the physical and chemical properties of 

phosgene preclude a valid in vivo test of genetic toxicity. 

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS 

4.5.1. Oral 

No published studies on the toxicity of phosgene following oral exposure in animals were 

found. The lack of oral studies reflects the fact that phosgene is a gas at room temperature, and 

that aqueous phosgene rapidly hydrolyzes to CO2 and HCl. 

18 
4.5.2. Inhalation 

No relevant published studies are available with which to evaluate the nonpulmonary 

effects of inhaled phosgene. Therefore, the discussion in this section focuses on pulmonary 

effects. The acute toxicity of phosgene inhalation in humans and animals has been well 

documented (Underhill, 1919, as reviewed in WHO, 1998, 1997; U.S. EPA, 1986c, 1984). 

Acute inhalation of phosgene results in a sequence of events, including an initial bioprotective 

phase, a symptom-free latent period, and a terminal phase characterized by pulmonary edema 

(Schneider and Diller, 1989; Diller, 1985). 

Phosgene is not expected to leave the pulmonary circulation following inhalation 

exposure. The effects of inhaled phosgene reported in human and animal studies have been 

attributed to a direct effect on the respiratory tissues or to secondary consequences resulting from 

damage to the respiratory system. The toxicity of phosgene is thought to result from its ability to 

directly participate in acylation reactions with amino, hydroxyl, or sulfhydryl groups (WHO, 

1998, 1997; Schneider and Diller, 1989, as discussed in U.S. EPA, 1986c; Diller, 1985). 

4.5.3. Mode of Action Information 

Fibrosis is a common consequence of various exogenous insults to a variety of 

parenchymal tissues in the lung. The underlying mechanism of the induction and progression of 

fibrosis—at both the molecular and cellular levels—is not well understood. Fibrosis is 

characterized by a dense, hard mass in the lung; it may be diffuse and interstitial in character 

rather than nodular. Phosgene-induced pulmonary inflammation and fibrosis in the experimental 

animals provides a good model for chronic pulmonary inflammation and fibrosis in humans. 

Connective tissue may develop both interstitial and intra-alveolar fibrosis following short-term 

exposure. Hydroxyproline content and the activities of prolyl hydroxylase and galactosylhydroxy-lysyl glucotransferase were increased in the lungs of rats exposed to phosgene. These 

observations were reported by Kodavanti et al. (1997) and later by Hatch et al. (2001), who also 

indicated that lung fibrosis can be considered a good marker for chronic injury from exposure to 

phosgene. Borak and Diller (2001) reviewed the biochemical mechanisms that lead to adult 

respiratory distress syndrome due to phosgene exposure; they are summarized below. In 

addition, several other postulated biochemical mechanism studies are also reviewed that relate to 

phosgene mode of action. 

Phosgene is a highly reactive gas capable of damaging a variety of biological 

macromolecules in an oxidant-like fashion. This activity potentially results from at least two 

separate chemical reactions: acylation and hydrolysis. 

Acylation, the more important and rapid mechanism, results from the reaction of 

phosgene with nucleophilic moieties, such as the amino, hydroxyl, and sulfhydryl groups of 

19
tissue macromolecules. Acylation causes destruction of proteins and lipids, irreversible 

alterations of membrane structures, and disruption of enzyme and other cell functions. Exposure 

to phosgene depletes lung nucleophiles, particularly glutathione, and restoration of glutathione 

seems to protect against phosgene-induced injury (Sciuto and Moran, 1999; Sciuto et al., 1998, 

1995; Schroeder and Gurtner, 1992; Jaskot et al., 1991; Sciuto and Gurtner, 1989). For several 

days after acute phosgene exposure, tissue levels of antioxidant enzymes, such as glutathione 

reductase and superoxide dismutase, increase as part of the lungs’ response to injury (Jaskot et 

al., 1991). 

In addition to acylation, phosgene is hydrolyzed to HC1 as shown below: 

COC12 + H2O â CO2 + 2HC1 

The formation of HCl occurs on moist membranes and may cause irritation and tissue damage 

(Diller, 1985). Because of the limited water solubility of phosgene, it is unlikely that large 

quantities of HC1 could result from the exposure of biological tissues. However, small amounts 

do form and may contact moist membranes of the eye, nasopharynx, and respiratory tract. 

Hydrolysis to HC1 is the probable cause of immediate inflammation and discomfort after 

phosgene exposure at concentrations greater than 3 ppm (>12 mg/m3). 

Pulmonary cellular glycolysis and oxygen uptake following phosgene exposure are 

depressed and, thus, leads to a corresponding decrease in the levels of intracellular adenosine 

triphosphate and cyclic adenosine monophosphate (Sciuto et al., 1996; Kennedy et al., 1989; 

Currie et al., 1985). This is associated with increased water uptake by epithelial, interstitial, and 

endothelial cells (Helm, 1980). The semipermeability of the blood-air barrier becomes gradually 

compromised as a result of fluid entering the interstitial and alveolar spaces. Later, the blood-air 

barrier disrupts, opening channels for the flooding of alveoli (Diller et al., 1969; Schulz, 1959). 

Compression of pulmonary microvasculature leads to the opening of arteriovenous shunts 

(Schocimerich et al., 1975). The onset of pulmonary edema correlates temporally with the 

decrease in adenosine triphosphate levels (Currie et al., 1985). Interventions that increase 

intracellular cyclic adenosine monophosphate, such as treatment with phosphodiesterase 

inhibitors (e.g., aminophylline), beta-adrenergic agonists (e.g., isoproterenol), or cyclic 

adenosine monophosphate analogs, markedly reduce pulmonary edema formation in animals 

exposed to phosgene (Sciuto et al., 1998, 1997, 1996; Kennedy et al., 1989). 

Phosgene exposure also has been shown to cause lipid peroxidation in lungs. In mice and 

guinea pigs, phosgene exposure of 22 ppm via inhalation for 20 minutes increased levels of lipid 

peroxidation products, such as thiobarbituric acid-reactive substances in tissue and bronchioalveolar lavage fluid (Sciuto et al., 1998). 

20 
The effects of phosgene on pulmonary arachidonic-acid metabolism were studied both in 

vivo and in vitro (Madden et al., 1991). Male Wistar rats were exposed to 0.05, 0.10, 0.25, 0.50, 

or 1 ppm phosgene for 4 hours. Lung lavage fluid total and differential cellularity and viability 

were determined at 0, 4, 20, or 44 hours after exposure. Furthermore, the lavage fluid was 

analyzed for prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4, leukotriene 

D4 plus leukotriene E4 (LTCDE4). Phosgene at 1 ppm significantly decreased lavage fluid cell 

viability at all time points but resulted in transient decrease at 0.1 ppm only at 4 and 20 hours. 

The decreases in PGE2, LTB4, and LTCDE4 induced by the 0.1 and 0.25 ppm exposures 

returned to, or exceeded, the control values at 44 hours postexposure. Phosgene did not affect 

the PGE2 and LTCDE4 formation in rat macrophages. The authors concluded that phosgeneinduced alterations in arachidonic-acid metabolism may be involved in its toxicity. Guo et al. 

(1990) investigated the role of arachidonate mediators in phosgene-induced lung toxicity in male 

New Zealand rabbits. The authors concluded that phosgene stimulated the synthesis of 

lipooxygenase products of arachidonic-acid metabolism, which appear to contribute to 

pulmonary edema. 

Increased thromboxane production occurred in human pulmonary microvascular 

endothelial cells after phosgene exposure in vitro (Cheli et al., 1995). Neutrophils migrated to 

the lung surface in large numbers following phosgene exposure in several animal species 

(Robinson, 1994; Schroeder and Gurtner, 1992). Pre-exposure injections of cyclophosphamide, 

which significantly reduced circulating neutrophil counts, also decreased neutrophil migration to 

the lungs and limited phosgene-induced edema and mortality (Ghio et al., 1991). 

Acyltransferase activity in alveolar type II cell microsomes (which is necessary for the 

synthesis of pulmonary surfactant) was shown to be inhibited in rabbits after edematrogenic 

doses of phosgene (Frosolono and Passarelli, 1978). 

The above studies shed some light on the postulated mechanisms of phosgene toxicity; 

however, they are inadequate to define modes of action at the cellular level. 

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION 

Based on the criteria in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 

2005a), the available toxicity and mode(s) of action data provide inadequate information to 

assess the carcinogenic potential of phosgene. A single epidemiology study of phosgene-exposed 

workers (Polednak and Hollis, 1985; Polednak, 1980) was not considered adequate for 

evaluating carcinogenic potential in humans. Furthermore, no animal cancer bioassays of 

phosgene have been conducted to evaluate carcinogenic potential in experimental animals. 

Phosgene has been identified as a reactive intermediate in the metabolism of a number of 

chemical carcinogens, including chloroform (Pohl et al., 1981, 1977); however, its role in the 

21
carcinogenesis of these compounds is not clearly understood. The reactive metabolites of 

chloroform covalently bind to proteins and lipids but only minimally to DNA and nucleic acids. 

The failure of the reactive species (e.g., phosgene, trichloromethyl free radical, and other 

metabolites) to significantly bind to DNA has been ascribed to their short half-lives and to their 

lack of nuclear penetration (as cited in U.S. EPA, 2001a). 

There is some concern for the carcinogenic potential of phosgene on the basis of SAR 

analysis because the two chlorines (linked to the carbonyl group) are highly reactive; however, 

phosgene rapidly hydrolyzes into CO2 and HCl, such that exposure to phosgene might not result 

in a reaction with nuclear DNA. However, no data exist regarding DNA alkylation as a result of 

exposure to phosgene. Covalent binding of phosgene with cellular macromolecules has been 

proposed as a mechanism of chloroform-induced hepatic and renal toxicity (Pohl et al., 1980a, 

b), and it is generally accepted that the carcinogenic activity of chloroform resides in its highly 

reactive intermediate metabolites, such as phosgene. Irreversible binding of reactive chloroform 

metabolites to cellular macromolecules supports several theoretical concepts as a mechanism for 

possible phosgene’s carcinogenicity (as discussed in the Toxicological Review of Chloroform; 

U.S. EPA, 2001a). 

4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES 

4.7.1. Possible Childhood Susceptibility 

No published studies are available to evaluate the effects of phosgene exposure on 

children or young experimental animals. 

4.7.2. Possible Gender Differences 

No published studies have directly compared the effects of phosgene inhalation exposure 

in males and females. 

4.7.3. Other 

No published experimental animal or human epidemiological studies are available to 

evaluate the effects of phosgene in the geriatric population or in individuals with compromised 

disease conditions, such as asthmatics or those with respiratory impairments. 

22
5. DOSE-RESPONSE ASSESSMENTS

5.1. ORAL REFERENCE DOSE (RfD) 

No published studies on the toxicity of phosgene following oral exposure in humans or 

experimental animals were located. Phosgene is a gas at room temperature, and aqueous 

phosgene rapidly hydrolyzes to CO2 and HCl. Therefore, exposure by the oral route is unlikely 

and the lack of data precludes derivation of an RfD. 

5.2. INHALATION REFERENCE CONCENTRATION (RfC) 

For effects other than cancer, the risk from exposure via the inhalation route is assessed 

by deriving an inhalation RfC. The RfC is an estimate (with uncertainty spanning perhaps an 

order of magnitude) of a daily exposure to the human population (including sensitive subgroups) 

that is likely to be without appreciable risk of deleterious effects during a lifetime. Like the RfD, 

the RfC is based on the assumption that a threshold exists for certain toxic effects. Exposure to 

phosgene for a short period of time can have serious acute effects (NAS, 2002). Therefore, the 

RfC cannot be directly compared to average air concentrations without also examining available 

benchmarks regarding acute effects from the inhalation of phosgene (see Appendix A). 

In this assessment, the RfC was estimated using three different approaches: the standard 

NOAEL/LOAEL approach, which has been used extensively in the past (U.S. EPA, 1994b); the 

benchmark dose (BMD) approach, which is currently being used by the Agency and has several 

advantages over the NOAEL/LOAEL approach (U.S. EPA, 2000c); and a categorical regression 

(CatReg) approach, which is suited to the analysis of severity-graded data and makes use of 

recently developed EPA CatReg software (U.S. EPA, 2000e). Use of these approaches has 

the potential to add multiple dimensions of information that include the slope of the doseresponse curve and the severity of effect. 

5.2.1. Choice of Principal Study and Critical Effect(s) 

In the selection of principal studies for identifying critical endpoints of phosgene toxicity, 

two studies are relevant for deriving the RfC: Selgrade et al. (1995) and Kodavanti et al. (1997). 

These are subchronic inhalation studies with periods of recovery following exposure. Both 

studies have limitations, not being of chronic duration; however, they have similar exposure 

protocols and used the same experimental animal strain (F344 rats) to measure two different 

endpoints (immune response and pulmonary damage). 

The subchronic study in rats reported by Kodavanti et al. (1997) and the followup study 

by Hatch et al. (2001) are considered to be suitable for development of an RfC. Results of the 

23
study are summarized in Tables 1 and 2. The most sensitive target organ following chronic 

inhalation exposure to phosgene appeared to be the lungs. The investigators observed 

statistically nonsignificant terminal bronchiolar changes and interstitial thickening of the 

alveolar walls, inflammatory cell influx, and epithelial alterations of the terminal bronchioles at 

0.1 ppm after 4 and 12 weeks of exposure and a statistically significant increase in lung 

displacement volume in all exposed groups after 4 weeks of exposure. The incidence and 

severity of these effects increased in the 0.2 ppm and 1 ppm exposed groups. These effects were 

not statistically significantly increased after a 4-week recovery period; they may be adverse, but 

they are not persistent. Other effects noted at the 0.2 and 1 ppm exposure levels were as follows: 

a statistically significant increase in collagen staining within thickened terminal bronchioles that 

was more intense at 1 ppm and persisted after a 4-week recovery period; and a statistically 

significantly increase in lung displacement volume and lung/body weight changes, which 

returned to control levels after the 4-week recovery period. 

Collagen staining was considered by Kodavanti et al. (1997) as a marker of chronic lung 

damage, and an increase in lung displacement volume was considered as a sensitive indicator of 

structural changes in the lung. These changes and the other histopathological changes noted in 

Table 1 are considered adverse effects and, consequently, BMD and Cat Reg modeling were 

done, as described in the next section. 

Selgrade et al. (1995) concluded that phosgene exposure at 0.1, 0.2, and 0.5 ppm 

impaired resistance to bacterial infection in rats. However, at the 0.5 ppm concentration, an 

immune response was observed in noninfected animals. Phosgene is toxic to the immune cells 

that are in the lungs, but after phosgene exposure stops, the cells repopulate the lung from 

elsewhere in the body and no permanent damage to immune system cells is evident. It appears 

that concentration rather than exposure duration is the more critical factor for the extent of toxic 

response to phosgene, even at these low concentrations. A concentration of 0.1 ppm is 

considered as a LOAEL for this effect in this study. 

5.2.2. Methods of Analysis for Point of Departure, Including Application of Models (BMD, 

NOAEL/LOAEL, and CatReg) 

This assessment makes use of two dose-response modeling software suites developed by 

EPA, the Benchmark Dose Software (BMDS) (U.S. EPA, 2001b) and CatReg (U.S. EPA, 

2000e). BMD assessment methods (U.S. EPA, 2000c, 1995) and supporting software were 

developed to improve upon the NOAEL/LOAEL approach by taking into account the quality of 

the study and the complete dose-response, and the CatReg software was developed to allow for 

the evaluation of categorically graded responses over time. The following sections describe how 

three assessment methods (BMD, NOAEL/LOAEL, and CatReg) were used to analyze the 

24
critical effects identified from the Kodavanti et al. (1997) rat subchronic inhalation study to 

obtain a point of departure (POD) for use in derivation of an RfC for phosgene. These sections 

also describe attempts to use the BMD approach for the Selgrade et al. (1995) study and the 

decision to use the NOAEL/LOAEL approach instead for that study. 

5.2.3. BMD Approach 

Kodavanti et al., 1997 

Following subchronic inhalation exposure of phosgene, Kodavanti et al. (1997) found 

that the most sensitive target organ in rats is the lung, as discussed in Section 5.2.1. Lung 

hydroxyproline content and trichrome staining for collagen are standard methods for measuring 

lung fibrosis and can be considered reliable chronic injury markers. Support for this is found in 

the present study, which showed lack of reversibility of the collagen accumulation and possibly 

even a progression during the 4-week recovery period, terminal bronchiolar thickening and 

inflammatory cell influx, and an increase in the lung displacement volume. Measurements of 

hydroxyproline in the whole lung, which is considered to be a chemical manifestation of fibrosis, 

were statistically increased in the high-dose group (1 ppm) only and were persistent after the 

recovery period. Concentration seems to be more important than duration in determining this 

pathology response. Collagen staining increased slightly at 4 weeks and increased markedly at 

12 weeks in both the 0.2 and 1 ppm groups, the effect at 1 ppm being more intense. For the 

BMD approach taken in this assessment, it is assumed that the administered concentration is an 

appropriate dose-metric. Although this assumption is uncertain (see discussion in paragraph 2 

below), there is no reasonable alternative assumption. The Kodavanti et al. (1997) data at 1.0 

ppm is not used for the BMD modeling because the exposure duration (once per week) differs 

markedly from the 0.1 and 0.2 ppm groups (5 times per week) and from continuous exposure. 

The BMD approach attempts to fit curves to the dose-response data for a given endpoint. It has 

the advantage of taking most of the dose-response data into account when determining the POD 

as well as estimating the lowest dose for which an adverse effect may have a specific probability 

of occurring. This approach is used when a biologically based dose-response model cannot be 

formulated. 

A benchmark analysis was performed for lung effects considered to be adverse, as 

discussed in Sections 4.2.2 and 5.2.1. An overall summary of this analysis is provided in 

Appendix B, Table B-1. A summary of the results most relevant to the development of a POD 

for quantification of phosgene noncancer risk is provided in Table 3 for 4- and 12-week 

exposures. The lower-bound confidence limit values reported in Table 3 represent the 95% 

BMDL (lower-bound confidence limit on the benchmark dose) on the estimated ppm exposure 

associated with a 10% extra risk (dichotomous endpoints) or a one-standard-deviation change 

25
from the estimated control mean (continuous endpoints, lung volume change).1 The 10% 

response level was chosen as the point of departure (POD) for several reasons: (1) The small size 

of the treated and control animals (only eight were exposed) does not allow the detection of 

statistically significant effects below 10%. (2) A POD of larger than 10% cannot be justified 

because the collagen staining is considered to be a toxicological significant finding of fibrosis. 

(3) A POD of 10% is the default assumption used in the RfC methodology. Although 4-week 

data are not used to derive the POD for an RfC, they are provided in Table 3 for comparison 

purposes. 

Table 3. Benchmark dose results from a subchronic study in rats (Kodavanti 

et al., 1997) 

Effectsa 

BMD/BMDLb (ppm) 

12-week 

exposure 

4-week 

exposure 

Interstitial thickening of the alveolus 0.044/0.025 0.026/0.015 

Inflammatory cell influx to terminal bronchiole/alveolus 0.083/0.031 0.087/0.031 

Epithelial alteration of terminal bronchiole/peribronchiolar alveolus 0.078/0.026 0.031/0.017 

Increased collagen staining of terminal bronchiole/peribronchiolar 0.10/0.018 0.11/0.053 

Displacement volume, left lung (mL/kg body weight × 100) 0.081/0.059c 0.083/0.060c 

a Only endpoints for which a dose-response could be modeled are listed. b EPA’s Benchmark Dose Software (BMDS), versions 1.3 and 1.4 were used to estimate the BMDLs. For 

dichotomous endpoints, BMDLs are the 95% BMDL on the ppm exposure for a 10% extra risk. More details on 

the BMD analysis, including data analyzed, models used, and options employed, are presented in Appendix B. c For this continuous endpoint, the BMDL represents a one-standard-deviation change from the estimated control 

mean. The means and standard deviations for this endpoint were obtained in an e-mail dated October 22, 2001, 

from Dr. Urmila Kodavanti, U.S. EPA/NHEERL, to Dr. Jeff Gift, U.S. EPA/NCEA. 

An element of the BMD approach is the use of several models to determine which one 

best fits the data.2 The model that best fits the experimental data is used when the mode of 

1

BMD analyses at 15, 5, and 1% were also performed and are reported in Appendix B for the 4- and 

12-week exposure durations. However, the exposure group size of eight rats per exposure group is not conducive to 

obtaining response estimates below 10%. One indication of this is the fact that as the BMR% goes down (i.e., x = 

15%, 10% to 5% to 1%) the BMDx/BMDLx ratio goes up (i.e., 3.9, 5.6 to 10.5 to 44.1) for the collagen staining, 

multistage model. This ratio indicates that although the BMDLx’s are all 95% confidence intervals, in a certain 

sense the “variability and/or reliability” of the models is considerably worse at BMRs below 10%. 

2

EPA’s BMD Software (BMDS), versions 1.3 and 1.4, were used for this effort. BMDS can be 

downloaded from the Internet at www.epa.gov/ncea/bmds.htm. BMDS facilitates the application of BMD methods 

by providing simple data-management tools and an easy-to-use interface to run multiple models on the same 

dose-response data set. At this time, BMDS offers nine different models appropriate for the analysis of dichotomous 

(quantal) data (Gamma, Logistic, Log-Logistic, Multistage, Probit, Log-Probit, Quantal-Linear, Quantal-Quadratic, 

26
action is not known and, consequently, there is no theoretical basis for choosing a particular 

model. As described in EPA’s BMD technical guidance (U.S. EPA, 2000c), this is done by 

measures of fit. In this case, the multistage model provided the best fit of all the dichotomous 

models (see Appendix B) to the endpoint characterized as increased collagen staining of terminal 

bronchioles. The dose-response data for the incidence of collagen staining and the multistage 

model fitting these data are shown in Figure 1, which graphically shows the BMD10 and the 

BMDL10. The BMDL10 for this effect is 0.018 ppm. 

Weibull), continuous data (Linear, Polynomial, Power, Hill), and four nested models appropriate for developmental 

toxicology data (NLogistic, NCTR, Rai, and Van Ryzin). Results from all models include a reiteration of the model 

formula and model run options chosen by the user, goodness-of-fit information, the benchmark concentration, and 

the BMDL. 

27 
Multistage Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 

Multistage 

BMDL BMD 

0 0.05 0.1 0.15 0.2 

dose 

Figure 1. Increased collagen staining of terminal bronchiole/peribronchiolar region 

(multistage model) 

In the absence of a relevant physiologically based pharmacokinetic (PBPK) model, RfC 

default methods for lung toxicity caused by gaseous exposures (U.S. EPA, 1994a, b) were used 

to derive human equivalent concentrations (HECs) from the 12-week BMDLs reported in 

Appendix B-1. This was done in three steps by (1) converting the exposure from ppm to mg/m3, 

(2) adjusting from intermittent to continuous exposure, and (3) extrapolating from rats to humans 

using the rat-to-human regional gas-dose ratio (RGDR): 

1. Converting from ppm to mg/m3 . The molecular weight (MW) of phosgene is 98.92. 

Assuming 25°C and 760 mmHg, the NOAEL (mg/m3) = 0.018 ppm × 98.92/24.45 = 0.0728 

mg/m3. 

2. Adjusting from intermittent to continuous exposure. The default method (U.S. EPA, 

1994b) is based on an assumption that the total dose is the proper dose-metric for the effect. 

Total dose is equal to the concentration (C), which is proportional to the rate at which the agent 

is delivered to the cells, multiplied by duration of exposure (T) (i.e., Haber’s Law). However, 

Kodavanti et al. (1997) found that the severity of the collagen-staining lesions and the 

concentration of hydroxyproline, both irreversible after a 4-week recovery period following 

28
dosing with phosgene, were dependent on concentration and not on the product of C × T. The 

hydroxyproline data for this experiment are given in Hatch et al. (2001); Kodavanti et al. (1997) 

show the same data in graphical form. A more detailed examination of these data reveals that 

hydroxyproline concentration in the 12-week study increased with both C (at fixed T) and T (at 

fixed C), and it also increased with the product of C × T. Therefore, the proper dose-metric is a 

combination of these factors; perhaps it is C × Ta

, where “a” is a fractional power of duration. 

The experimental data are not definitive enough to derive a numerical description of the doseresponse surface. There are no data for collagen staining or for hydroxyproline resulting from 

daily exposures in the range from 1 hour per day to 24 hours per day. However, two studies 

employing continuous exposure show that toxic effects are proportional to the C × T product. In 

the range of 0.5 minutes to 2 hours (5 to 500 mg/m3

 [0.74 to 74 ppm], C × T = 37.5 to 563 ppm ­

min), the lethality to cats of phosgene poisoning is proportional to C × T (Flury, 1921, as cited in 

U.S. EPA, 1986c). In the range of 5 minutes to 8 hours (2 to 16 mg/m3 [0.5 to 4 ppm], C × T = 

12 to 360 ppm-min), a measure of pulmonary gas exchange in rats was proportional to C × T 

(Rinehart and Hatch, 1964, as cited in U.S. EPA, 1986c). Therefore, it is likely that collagen 

staining would also follow the C × T product for exposures of fractions of a day. The study of 

Kodavanti et al. (1997) directly implies that intermittent exposures to a certain concentration for 

7 days per week would have the same effect as intermittent exposure for 5 days per week. As 

pointed out by Hatch et al. (2001), the repair events following a continuous exposure are not well 

understood, so the transition from daily (intermittent) exposure to continuous exposure cannot be 

made with any certainty. However, the assumption is made here that continuous exposures for 7 

days per week would have the same effect as intermittent exposures for 7 days per week. 

Therefore, in the standard default method for adjusting for continuous exposures, the traditional 

5/7 factor is not needed. 

The Selgrade et al. (1995) data supply independent evidence that, in the intermittent 

exposure range of 2 to 5 days per week, concentration rather than the C × T product determines 

toxicity. In that study, 0.5 ppm for 2 days per week had a much greater effect on impairment of 

bacterial resistance than 0.2 ppm for 5 days per week, even though the C × T product was 

identical. 

In view of these considerations, the BMDL from the Kodavanti et al. (1997) study, 

adjusted for continuous exposure, is as follows: 

BMDLADJ = 0.0728 mg/m3 × 6/24 = 0.0182 mg/m3 

3. Extrapolating from rats to humans. The HEC corresponding to the BMDLADJ 

(BMDLHEC) was calculated for a gas:respiratory tract effect in the thoracic region, taking into 

29
account volume breathed per day and the surface area of the thoracic region of the rat lung 

versus the human lung. This is the standard procedure for dose conversions from animals to 

humans for Category 1 gases, which are completely and irreversibly absorbed by the lung (U.S. 

EPA, 1994b). The thoracic region, which consists of both the pulmonary and tracheobronchial 

regions of the lungs, was chosen for three reasons. First, some of these lesions have been 

classified as pulmonary lesions. Second, some of the assays measured would not make a 

distinction between the two lung regions (e.g., whole-lung prolyl hydroxylase and 

hydroxyproline as an index of collagen synthesis, volume displacement measurements). Third, 

some lesions appear to occur in both regions (bronchus inflammation, alveolar interstitial 

thickening). 

The RGDR for the thoracic region of the respiratory tract (RGDRTH) is used to adjust for 

differences between rat and human ventilation rates and thoracic surface areas and is calculated 

as follows (values used in this derivation were taken from U.S. EPA, 1988): 

RGDRTH = (MVa/Sa)/(MVh/Sh) = 1.51 

where: 

MVa (minute ventilation for F344 rats) = 0.19 m3/day, 

Sa (thoracic surface area for F344 rats) = 3,423 cm2, 

MVh (minute ventilation for humans) = 20 m3/day, and 

Sh (thoracic surface area for humans) = 543,200 cm2. 

The BMDL HEC was calculated by multiplying the BMDLADJ by the RGDRTH: 

BMDLHEC = 0.0182 mg/m 3 × 1.51 = 0.0275 mg/m3 

Selgrade et al. (1995) 

Application of the benchmark dose approach to the Selgrade et al. (1995) data is 

problematic because of the difficulties establishing what level of bacterial resistance adversely 

affects the overall health and survival of the animals. The extent, duration, and health 

consequences of impaired bacterial resistance from phosgene exposure is highly dependent on 

secondary factors such as the exposure scenario involved, the health status of the exposed 

individual, and the type of infection. Since the quantitative relevance of the rat model of 

bacterial resistance to humans is unknown, it would be inappropriate to use these results in a 

benchmark dose determination of the RfC. 

30
5.2.4. NOAEL/LOAEL Approach 

The impairment of bacterial resistance observed by Selgrade et al. (1995) occurred at a 

lower concentration (0.1 ppm) than the morphological lung damage observed by Kodavanti et al. 

(1997). Therefore, the POD for the NOAEL/LOAEL approach for deriving an RfC is 0.1 ppm. 

As was done for the BMD approach described above, RfC default methods for lung toxicity 

caused by gaseous exposures (U.S. EPA, 1994a, b), in the absence of a relevant PBPK model, 

were used to derive the HEC corresponding to the LOAEL of 0.1 ppm. Using the same default 

procedures described in Section 5.2.3, a LOAELHEC of 0.15 mg/m3 is estimated (0.1 ppm × 4.05 

= 0.405 mg/m3; 0.405 × 6/24 = 0.101 mg/m3; 0.101 × 1.51 = 0.153 mg/m3). 

5.2.5. CatReg Approach 

As described in Appendix B-2, a CatReg analysis was performed using the individual 

animal scores3 that resulted in the severity grade averages reported in Table 2. For purposes of 

the CatReg analysis, and to ensure that the scores assigned by Kodavanti were appropriately 

weighted according to the severity of the various endpoints, the scores assigned to endpoints that 

did not significantly regress or disappear during the 4-week recovery period (epithelial alteration 

and collagen staining of the terminal bronchioles) were increased by 1 severity grade, and the 

scores of endpoints deemed to have recognized and serious long-term consequences (collagen 

staining) were increased by an additional severity grade (see Table B-2a). Thus, reversible 

lesions scored as “minimal” received a severity grade of 1, reversible lesions scored as 

“slight/mild” and potentially irreversible lesions scored as “minimal” received a severity grade 

of 2, and potentially irreversible lesions scored as “slight/mild” or any occurrence of a lesion 

considered to have long-term consequences (collagen staining) received a severity grade of 3. 

The data at 1.0 ppm is not used in the CatReg analysis because the exposure duration (once per 

week) differs markedly from the 0.1 and 0.2 ppm groups (5 times per week) and from continuous 

exposure. CatReg analysis was used to approximate ppm exposure levels that would result in a 

10, 20, and 30% extra risk4 of attaining a severity grade 1, 2, or 3 level of lung effect. As 

discussed in Appendix B-2, the analysis did not indicate that time was an explanatory variable, 

so the results presented in Table 4 are for the 4- and 12-week data combined. The combined 

analysis is preferred because time does not appear to be a significant factor for most of the 

endpoints reported and because of the small number of animals involved in this study. 

The CatReg analysis cannot be compared directly to the NOAEL and BMDL analyses at 

this time and is not appropriate for use in the derivation of an RfC because EPA has not 

3

Personal communication between Dr. Jeff Gift and Dr. U.P. Kodavanti. 

4

As described in Appendix B-2, extra risk is what is generally used in a BMD analysis and is defined as the 

estimated increased risk over background (Pd-P0) divided by the maximum risk with background excluded (1-P0). 

31
published guidance for the application of CatReg to Agency risk assessments and because the 

CatReg software does not provide an estimate of the lower bound confidence limit on the extra 

risk dose (ERD) that would be comparable to the BMDL.5 However, CatReg does provide a 

maximum likelihood estimate, the ERD, that is comparable to the BMD and, because all of the 

observations from the critical study can be severity graded and used in CatReg, it provides an 

estimate of the ERD that is informed by more of the response data. Therefore, the ERD10 

estimate of 0.05 ppm for a severity grade 3 effect (Table 4), which would include collagen 

staining, can be compared to the BMD10 estimates for collagen staining in Table B-1d of 

Appendix B-1. This comparison reveals that the CatReg ERD10 estimate for severity grade 3 is 

similar to the BMD10 estimate of 0.1 ppm for collagen staining alone and falls between the 

BMD10 and the BMDL10 estimate of 0.018 ppm. 

Table 4. Results of CatReg analysis of severity-graded lung lesions reported 

by Kodavanti et al. (1997) [estimates of the exposures that would cause a 10, 20, 

and 30% probability of an effect equal to or greater than severity grade 1, 2, and 3 

(ERD10, ERD20, and ERD30] 

Severity 

grade 

ERD10 

(ppm) 

ERD20 

(ppm) 

ERD30 

(ppm) Model Link function

 1 0.021 0.038 0.051 Cumulative Odds CLogLog

 2 0.031 0.052 0.068 

model 

3 0.050 0.077 0.096 

5.2.6. Comparison of Approaches 

Each approach considered for determining the POD has strengths and limitations; 

however, combining the three approaches yields a consistent and more robust determination of 

the POD for the phosgene RfC. The NOAEL/LOAEL approach allows for a crude comparison 

of results between multiple species and the target species. This approach is less dependent on 

having the same experimental paradigms and results for comparison (e.g., a NOAEL/LOAEL 

can be determined experimentally with less dependence on characterization of other points on 

the dose-response curve). Using the NOAEL/LOAEL approach, the LOAEL for impairment of 

host defenses against bacterial infection of the lung is 0.1 ppm for male rats (Selgrade et al., 

1995). This value was converted to a LOAELHEC of 0.15 mg/m3, about fivefold higher than the 

5

In particular, CatReg does not provide an estimate of the standard error associated with its estimate of 

background risk, which is used in derivation of the ERD (see Appendix B-2 for details). 

32 
BMDLHEC estimate of 0.03 mg/m3

. 

A major disadvantage of the NOAEL approach is that NOAELs and LOAELs are 

restricted to the set of doses used. BMD estimates are the results of interpolation using sound 

statistical principles and so can take on any value in a range of doses. This results in the BMD 

approach having the following advantages over NOAELs for dose-response assessment: 

• BMDs can be more consistent among different studies. 

• BMDs, because they are based on interpolation, do not depend on sample size, 

whereas NOAELs, because they are essentially based on statistical testing, depend on 

sample size, such that, for the same dose-response, smaller sample sizes yield larger 

potential NOAELs. 

• The statistical uncertainty of a BMD estimate can be calculated and weighed in a risk 

assessment, whereas the uncertainty of a NOAEL calculation cannot. 

CatReg requires the user to classify each effect within a study, or combination of effects, 

into severity levels. Duration of exposure, as well as concentration, is included in CatReg 

because it affects the probability of achieving the various severity levels. “Duration” can be 

omitted, however, which is convenient when all subjects are exposed for the same duration or, as 

is the case for this assessment, when duration is not an important explanatory variable. 

CatReg fits a cumulative probability distribution to the combined data from all treatment 

groups using the method of maximum likelihood estimation. From the probability distribution, 

with parameters replaced by their estimates (i.e., the fitted model), the estimated probability of 

any specified severity level or worse (e.g., mild adverse or worse) can be determined at any 

specified concentration and duration. Viewed as an “exposure-response curve” (or “exposureresponse relationship”), an “exposure” is a combination of concentration and duration and 

“response” is the probability of an adverse effect (of specified severity or worse) occurring at 

that exposure. 

Although the BMD approach has several advantages over the NOAEL approach, neither 

it nor the NOAEL approach is capable of incorporating severity grades into a quantitative 

assessment. In this case, for certain endpoints, such as inflammatory cell influx to terminal 

bronchiole/alveolus and increased collagen staining of terminal bronchiole/peribronchiolar, 

incidence data did not indicate a response at the low dose that was significantly different from 

that of controls (Kodavanti et al., 1997) (Table 1), yet severity score data (see Table 2) indicate 

that there may be some level of response at the low dose. This illustrates how BMD and 

NOAEL analyses are sometimes not reflective of a changing profile of severity of response and 

emphasizes the usefulness of a CatReg analysis that does account for differences in severity of 

33
response. Hence, a CatReg analysis that can explicitly account for severity-graded lung effects 

was performed to supplement the BMD analysis (Appendix B-2). 

As mentioned above, when the dose-response data for all severity grade effects are 

considered together in a CatReg analysis, the ERD10 estimate for a severity grade 3 effect of 0.05 

ppm is similar to, but about half that of, the BMD10 estimates obtained from the application of 

several models to the collagen staining data of Kodavanti et al. (1997) (Table B-1d of Appendix 

B-1). The multistage model used in the derivation of the 0.018 ppm BMDL10 point of departure 

discussed above was the only model whose 95% lower bound confidence interval encompassed 

(is lower than) the 0.05 ppm ERD10 estimate. This provides additional justification for the 

choice of a relatively flexible multistage model for derivation of the BMDL point of departure. 

5.2.7. RfC Derivation: Application of Uncertainty Factors 

Uncertainty factors6 (UFs) are applied to account for recognized uncertainties in 

extrapolation from experimental conditions to the assumed human scenario (i.e., chronic 

exposure over a lifetime). Historically, UFs are applied as values of 10 in a multiplicative 

fashion (Dourson and Stara, 1983). Recent EPA practice, however, also includes use of a partial 

UF of 101/2 (3.162) (U.S. EPA, 2002) on the assumption that the actual values for the UFs are 

6

RfDs apply to lifetime human environmental exposure and include sensitive subgroups. Differences 

between study conditions and conditions of human environmental exposure may make a dose that appears to be safe 

in an experiment not safe in the environment. UFs account for differences between study conditions and conditions 

of human environmental exposure. These differences include the following: 

a. Variation from average humans to sensitive humans: RfDs apply to the human population, including 

sensitive subgroups, but studies rarely target sensitive humans. Sensitive humans could be adversely 

affected at doses lower than those in a general study population; consequently, general-population 

NOAELs are reduced to cover sensitive humans. 

b. Uncertainty in extrapolating from animals to humans: If an RfD is developed from animal studies, the 

animal NOAEL is reduced to reflect pharmacokinetic and pharmacodynamic factors that may make 

humans more sensitive than animals. 

c. Uncertainty in extrapolating from subchronic NOAELs to chronic NOAELs: RfDs apply to lifetime 

exposure, but sometimes the best data come from shorter studies. Lifetime exposure can have effects 

that do not appear in a shorter study; consequently, a safe dose for lifetime exposure can be less than 

the safe dose for a shorter period. If an RfD is developed from less-than-lifetime studies, the less-thanlifetime NOAEL is adjusted to estimate a lifetime NOAEL. 

d. Uncertainty in extrapolating from LOAELS to NOAELs: RfDs estimate a dose that is without 

appreciable risks, but sometimes adverse effects are observed at all study doses. If an RfD is 

developed from a dose where there are adverse effects, that dose is adjusted to estimate a NOAEL. 

e. Other factors reflecting professional assessment of scientific uncertainties not explicitly treated above, 

including completeness of the overall database, minimal sample size, or poor exposure 

characterization. 

34
log-normally distributed. In the assessments, when a single partial UF is applied, the factor is 

rounded to 3, such that the total factor for a UF of 3 and 10, for example, would be 30 (3 × 10). 

When two partial UFs are evoked, however, they are not rounded, such that a UF of 3, 3, and 10 

would result in total uncertainty of 100 (actually 101/2 × 101/2 × 10). UFs applied for this RfC 

assessment and the justification for their use are as follows: 

1. Human variation: UFH = 10. This factor is used to account for the variation in 

susceptibility within the human population and for the possibility that the data 

available are not representative of sensitive subgroups and lifestages, including 

children (U.S. EPA, 2002). For phosgene, two studies are suitable for derivation of 

the RfC, and, because they are in animals, they cannot be regarded as representative 

of sensitive humans. Therefore the default value of 10 is appropriate. 

2. Animal-to-human uncertainty: UFA = 3. Use of an RGDR to estimate an HEC is 

deemed to largely account for the pharmacokinetic portion of this uncertainty. A 

threefold UF is retained to account for uncertainties regarding pharmacodynamic 

differences between animals and humans. 

3. Subchronic-to-chronic uncertainty: UFS = 3. The PODs are based on adverse 

effects in two subchronic inhalation studies. The full factor of 10 is not appropriate 

because the lung damage observed by Kodavanti et al. (1997) and the impairment in 

bacterial resistence observed by Selgrade et al. (1995) are not likely to progress 

significantly with further exposure. However, a partial factor of 3 is still necessary 

because of the remaining uncertainty in predicting full lifetime effects from both 12­

week studies. 

4. LOAEL-to-NOAEL uncertainty: UFL = 3 in the NOAEL/LOAEL approach; UFL 

= 1 in the BMD approach. A partial uncertainty factor of 3 rather than the full factor 

of 10 is used in the NOAEL/LOAEL approach because the impairment of lung 

immunological function in the Selgrade et al. (1995) study at the LOAEL of 0.1 ppm 

is considered to be a minimal effect. The effect is local to the lung, resulting in the 

impairment of the bacterial clearance process; the impairment occurs only during the 

exposure and it does not persist after phosgene exposure stops. No uncertainty factor 

is applied to the 0.018 ppm BMDL derived from collagen staining in the Kodavanti et 

35
al. (1997) study because this POD is consistent with the NOAEL7

 of 0.1 ppm given 

the small group sizes in this study and because it represents minimal severity of lung 

damage. 

5. Database: UFD = 1. In general, a database UF is needed to account for the potential 

for deriving an underprotective RfC as a result of an incomplete characterization of 

the toxicity (U.S. EPA, 2002). This includes areas where there is a complete lack of 

information as well as areas where existing data indicate that further information on a 

particular subject has the potential for demonstrating effects at lower exposures. 

Because phosgene is a chemically reactive agent with an extremely short half-life in 

water and in lung tissue, its effects when inhaled are not likely to be observed outside 

the lung, and no such effects have been observed to date. While it is recognized that 

the investigation of systemic effects following phosgene exposure has not been the 

focus of existing studies, there is no reason to expect that reproductive, 

developmental, or other systemic effects would occur, and no UF is needed for the 

absence of data on these effects. In view of the Selgrade et al. (1989) finding of 

increased sensitivity to bacterial infection in mice due to short-term (4 and 8 hour) 

phosgene exposures (section 4.2.2.1) at lower concentrations than in the sub-chronic 

rat experiments (Selgrade et al., 1995), there is a possibility that a longer-term study 

in mice might show effects at a lower concentration than in rats. That possibility 

would be a rationale for a data base uncertainty factor of greater than one. However, 

the species difference between the response in mice and rats is small and adequately 

accounted for in the subchronic-to-chronic factor of 3 and the animal-to-human factor 

of 3, and a separate data base uncertainty factor is not necessary. 

The PODs derived using the NOAEL/LOAEL and BMD approaches are compared in 

Table 5. A POD of 0.03 mg/m3

, derived from the BMD analysis of collagen-staining lesions in 

terminal bronchioles, is chosen for derivation of the RfC. The BMD approach is preferred 

because it is based on the entire dose-response data. Using the BMD approach, the RfC is 

calculated as follows: 

RfC = 0.03 mg/m3 ÷ 100 = 3E-4 mg/m3 

7

This does not mean that the 0.1 ppm level is deemed to be a true no-effect level. It is recognized that 

responses at putative NOAELs can be as high as 20% (U.S. EPA, 2000c). 

36 
Table 5. Application of uncertainty factors (UFs) for two different 

approaches for deriving the RfC 

Factor 

NOAEL/LOAELa 

Approach 

BMDLb 

Approach

 POD (mg/m3

) 0.15 0.03 

UFH 

UFA 

UFS 

UFL 

UFD

 10

 3

 3

 3

 1

 10 

3 

3 

1 

1 

UF(Total) 300 100 

RfC (mg/m3

) 5E–4 3E–4 

a The LOAELHEC, based on impairment of resistance to bacterial infection in the Selgrade et al. (1995) study, was the 

point of departure (POD). It is shown for comparison purposes only. b The BMDLHEC, based on collagen staining in the Kodavanti et al. (1997) study, was the POD used to derive the 

RfC. 

5.2.8. Previous RfC Assessment 

The health effects data for phosgene were evaluated in the IRIS database in 1990 and 

were determined to be inadequate for derivation of an inhalation RfC. 

5.3. CANCER ASSESSMENT 

5.3.1. Oral Slope Factor 

No studies on the carcinogenicity of phosgene following oral exposure in humans or 

animals were located. Therefore, the lack of data precludes the derivation of an oral slope factor 

for phosgene. 

5.3.2. Inhalation Unit Risk 

No studies on the carcinogenicity of phosgene in animals and no carcinogenicity studies 

which adequately characterized inhalation exposure in humans were located. The Polednak 

(1980) study of mortality among men occupationally exposed to phosgene was considered 

inadequate to derive cancer unit risk. Thus, the lack of relevant data precludes the derivation of 

an inhalation unit risk for phosgene. 

37
6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF

 HAZARD AND DOSE RESPONSE 

6.1. HUMAN HAZARD POTENTIAL 

Phosgene (CAS No. 75-44-5) has a chemical formula of COCl2 and a molecular weight 

of 98.92. At room temperature, it is a colorless gas with an aroma of moldy hay that may be 

stifling at high concentrations. Phosgene is poorly soluble in water and is rapidly hydrolyzed to 

CO2 and HCl in aqueous solution. Industrially, phosgene is used as a chemical intermediate, 

primarily in the polyurethane industry. The majority of phosgene used industrially is produced 

by the reaction of carbon monoxide and chlorine gas using an activated charcoal catalyst, and it 

is used at the production site. 

Data on the effects of phosgene following exposure by the oral route are lacking. 

Because phosgene is a gas at room temperature and because it is highly reactive and hydrolyzes 

rapidly in water to CO2 and HCl, exposure to phosgene by the oral route is unlikely to occur. 

The acute effects of phosgene inhalation have been well studied. Short-term exposure 

results in the development of pulmonary edema and an increased concentration of hemoglobin in 

the blood resulting from a decreased blood volume. At relatively high concentrations (>3 ppm, 

or 12 mg/m3), irritation of the eyes and alterations in respiratory parameters may occur. 

Symptoms of acute exposure (>0.5 ppm, or 2 mg/m3) increase in severity with both 

concentration (C) and time (T), as described by Haber’s Law. At sufficiently high C × T levels, 

death may occur as a result of hypoxia or cardiac failure, both believed to be secondary 

responses resulting from the severe pulmonary edema associated with high levels of inhaled 

phosgene. 

Inhalation of phosgene for subchronic or chronic durations is less well studied; there are 

limited human data and very few animal studies. Available studies point to the respiratory tract 

as the target for subchronic phosgene toxicity. The lungs are identified as the primary target 

organ in all species. In addition, immunotoxicity has been observed in a few animal studies; the 

importance of these findings to human hazard cannot be addressed at this time. U.S. and 

international health and safety institutions have determined that 0.1 ppm (0.4 mg/m3

) phosgene is 

an exposure limit that offers some protection in occupational settings. According to the 

Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), there is inadequate information 

to assess the carcinogenic potential of phosgene. 

38
6.2. DOSE RESPONSE 

6.2.1. Noncancer/Oral 

Phosgene is a gas at room temperature and rapidly hydrolyzes to CO2 and HCl in aqueous 

solution; exposure by the oral route is unlikely. Available data for humans and animals are 

inadequate to assess the potential chronic toxicity of phosgene following oral exposure. Data on 

the effects of phosgene on reproductive function or on the developing organism are not 

available. 

6.2.2. Noncancer/Inhalation 

The RfC was derived using the BMD approach to estimate a lower confidence limit on 

the toxic lung effects observed in the 12-week study by Kodavanti et al. (1997). Five measures 

of toxicity were modeled at doses of 0.1 and 0.2 ppm (0.4 and 0.8 mg/m3): (1) epithelial 

alteration of terminal bronchioles and peribronchiolar alveoli, (2) increased collagen staining of 

terminal bronchioles, (3) interstitial thickening of alveoli, (4) influx of inflammatory cells into 

the terminal bronchioles and alveoli, and (5) lung volume. The BMD and BMDL values for 

various benchmark response levels (15, 10, 5, and 1%) were calculated for each of the five 

responses using seven different dose-response models. The 10% response level was chosen as 

the lowest level of response that can be reliably modeled. The results giving the lowest value of 

the BMD10 for each response were selected, and the lowest collagen-staining data were chosen to 

characterize the BMD10 and BMDL10 for the entire study. Using this procedure, a BMDL10 of 

0.018 ppm was derived. This value from the rat data was adjusted for continuous human 

exposure by using the RGDR and exposure duration data. The resulting POD is 0.03 mg/m3. 

The RfC was derived by dividing by a composite UF of 100 (10 for human variability and 3 each 

for animal-to-human uncertainty in pharmacodynamics and subchronic-to-chronic animal data). 

UFs of 3 are actually 101⁄2, so when two factors of 3 are present, the combined UF is 10. 

Therefore, the RfC is 0.03/100 = 3E-4 mg/m3. 

Two additional alternative approaches were considered (the LOAEL/NOAEL approach 

and the CatReg approach). The NOAEL/LOAEL approach uses the LOAEL of 0.1 ppm in the 

Selgrade et al. (1995) study as the POD. This was adjusted for continuous human exposure by 

using the exposure duration and RGDR to give a POD of 0.15 mg/m3. The total UF was 300 (10 

for human variation and 3 each for animal-to-human, subchronic-to-chronic and LOAEL-toNOAEL). The resulting RfC using this approach is 0.15/300 = 5E–4 mg/m3

. 

The CatReg approach uses the EPA CatReg model applied to graded severity of lung 

responses. The model estimated from the Kodavanti et al. (1997) study that the exposure 

concentration associated with a 10% extra risk of attaining a severity grade 3 effect in rats 

(e.g.,“minimal” or more severe collagen staining) would be 0.05 ppm. This result cannot be 

39
compared directly to the BMDL10 or NOAEL but provides justification for the choice of the 

Multistage model for derivation of the BMDL point of departure. The BMDL10 POD of 0.018 

ppm obtained from the Multistage model is well below the CatReg ERD10 estimate and the 0.05 

to 0.07 ppm range of BMDL10 estimates provided by the other BMDS models. 

6.2.3. Cancer/Oral and Inhalation 

Available data in humans are inadequate to assess the potential carcinogenicity of 

phosgene. In addition, chronic animal bioassays are not available. 

40
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U.S. EPA. (1986c) Health assessment document for phosgene. Draft. Office of Health and Environmental 

Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8–86/022A. 

U.S. EPA. (1988) Recommendations for and documentation of biological values for use in risk assessment. EPA 

600/6–87/008. Available from: National Technical Information Service, Springfield, VA. NTIS PB88–179874/AS, 

February 1988. 

U.S. EPA. (1991) Guidelines for developmental toxicity risk assessment. Federal Register 56(234):63798–63826. 

Available from: <http://www.epa.gov/ncea/raf/rafguid.htm>. 

45 
U.S. EPA. (1994a) Interim policy for particle size and limit concentration issues in inhalation toxicity: notice of 

availability. Federal Register 59(206):53799. 

U.S. EPA. (1994b) Methods for derivation of inhalation reference concentrations and application of inhalation 

dosimetry. EPA/600/8–90/066F. 

U.S. EPA. (1995) Use of the benchmark dose approach in health risk assessment. National Center for Environmental 

Assessment, Washington, DC. EPA/630/R–94/007. 

U.S. EPA. (1996a) Guidelines for reproductive toxicity risk assessment. Federal Register 61(212):56274–56322. 

Available from: <http://www.epa.gov/ncea/raf/rafguid.htm>. 

U.S. EPA. (1996b) Air quality criteria for ozone and related photochemical oxidants. ORDEPA/600/P–93/004CF. 

U.S. EPA. (1998a) Guidelines for neurotoxicity risk assessment. Federal Register 63(93):26926–26954. Available 

from: <http://www.epa.gov/ncea/raf/rafguid.htm>. 

U.S. EPA. (1998b) Science policy council handbook: peer review. First edition. Prepared by the Office of Science 

Policy, Office of Research and Development, Washington, DC. EPA–100–B–98–001. 

U.S. EPA. (2000a) Science policy council handbook: peer review. Second edition. Prepared by the Office of 

Science Policy, Office of Research and Development, Washington, DC. EPA 100–B–00–001. 

U.S. EPA. (2000b) Science policy council handbook: risk characterization. Prepared by the Office of Science Policy, 

Office of Research and Development, Washington, DC. EPA 100–B–00–002. 

U.S. EPA. (2000c) Benchmark dose technical guidance document [external review draft]. Office of Research and 

Development, Risk Assessment Forum, Washington, DC. EPA/630/R–00/001. Available from: 

<http://www.epa.gov/bnchmrk/ncea/bmds_peer.htm>. 

U.S. EPA. (2000d) Supplementary guidance for conducting health risk assessment of chemical mixtures. Office of 

Research and Development, Risk Assessment Forum, Washington, DC. EPA/630/R–00/002. 

U.S. EPA. (2000e) CatReg software documentation. Office of Research and Development, Washington, DC. 

EPA/600/R–98/053F. Available from: <http://cfpub2.epa.gov/ncea/cfm/recordisplay.cfm?deid=18162>. 

U.S. EPA. (2001a) Toxicological review of chloroform. Integrated Risk Information System (IRIS), National Center 

for Environmental Assessment, Washington, DC; EPA/635/R-01/001. Available from: National Technical 

Information Service, Springfield, VA, and <http:// www.epa.gov/iris>. 

U.S. EPA. (2001b) Help manual for benchmark dose software version 1.3. National Center for Environmental 

Assessment. EPA/600/R–00/014F. Available from: <http://www.epa.gov/ncea/bmds.htm>. 

U.S. EPA. (2002) A review of the reference dose concentration and reference concentration processes [final report]. 

Risk Assessment Forum, Washington, DC. Available from: <http://www.epa.gov/iris/backgr-d.htm>. 

U.S. EPA. (2005a) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; 

EPA/630/P-03/001B. Available from: <http://www.epa.gov/iris/backgr-d.htm>. 

U.S. EPA. (2005b) Supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. Risk 

Assessment Forum, Washington, DC; EPA/630/R-03/003F. Available from:<http://www.epa.gov/iris/backgrd.htm>. 

WHO (World Health Organization). (1997) Environmental health criteria monograph on phosgene. Monograph 193. 

International Programme on Chemical Safety. Geneva, Switzerland. 

46 
WHO. (1998) Phosgene health and safety guide. Health and Safety Guide No. 106. International Programme on 

Chemical Safety. Geneva, Switzerland. 

Wohlwill, F. (1928) II. Zur pathologischen anatomie der phosgenvergiftung [II. Pathological findings of phosgene 

poisoning]. Dtsch Med Wochenschr 54:1153-1157. (Cited in U.S. EPA, 1986c.) 

Yang, YG; Gilmore, MI; Lange, R; et al. (1995) Effects of acute exposure to phosgene on pulmonary host defenses 

and resistance to infection. Inhal Toxicol 7:393–404. 

Zwart, A; Arts, JHE; Klokman-Houweling, JM; et al. (1990) Determination of concentration-time-mortality 

relationship to replace LC50 values. Inhal Toxicol 2:105–117. 

47
APPENDIX A: ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

FOR PHOSGENE 

The development and application of AEGLs was first described in NAS (2002). They 

represent threshold exposure limits for the general public and are applicable to emergency 

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

levels as appropriate, are developed for each of five exposure periods (10 minutes, 30 minutes, 1 

hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

It is believed that the recommended exposure levels are applicable to the general population, 

including infants and children and other individuals who may be susceptible. The three AEGLs 

are defined as follows. 

AEGL-1 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 notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, 

the effects are not disabling and are transient and reversible upon cessation of exposure. 

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 

which it is predicted that the general population, including susceptible individuals, could 

experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

to escape. 

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 

which it is predicted that the general population, including susceptible individuals, could 

experience life-threatening health effects or death. 

Airborne concentration below AEGL-1 represent exposure levels that could produce mild 

and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or 

certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each 

AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects 

described for each corresponding AEGL. Although the AEGL values represent threshold levels 

for the general public, including susceptible subpopulations such as infants, children, the elderly, 

persons with asthma, and those with other illnesses, it is recognized that individuals subject to 

unique or idiosyncratic responses could experience the effects described at concentrations below 

the corresponding AEGL. 

Appropriate data were not available for deriving AEGL-1 values for phosgene. Odor 

cannot be used as a warning for potential exposure. The odor threshold is reported to be between 

0.5 and 1.5 ppm, a value above or approaching AEGL-2 and AEGL-3 values, and tolerance to 

the pleasant odor of phosgene occurs rapidly. Furthermore, following odor detection and minor 

irritation, serious effects may occur after a clinical latency period of 24 hours. 

A-1 
AEGL-2 values were based on chemical pneumonia in rats (2 ppm for 90 min) (Gross et 

al., 1965). An uncertainty factor (UF) of 3 was applied for interspecies extrapolation because 

little species variability is observed with both lethal and nonlethal endpoints after exposure to 

phosgene. A UF of 3 was applied to account for sensitive human subpopulations because of the 

steep concentration-response curve and because the mechanism of phosgene toxicity (binding 

to macromolecules and irritation) is not expected to vary greatly between individuals. Therefore, 

the total UF is 10. The 1.5-hour value was then scaled to the 30-minute value and the 1-, 4-, and 

8-hour AEGL exposure periods using Cn × T = k, where n = 1 (Haber’s Law), because Haber’s 

Law has been shown to be valid for phosgene within certain limits. Haber’s Law was originally 

derived from phosgene data (Haber, 1924). The 30-minute value is also adopted as the 10­

minute value because extrapolation would yield a 10-minute AEGL-2 value approaching 

concentrations producing alveolar edema in rats; Diller et al. (1985) observed alveolar 

pulmonary edema in rats exposed to 5 ppm phosgene for 10 minutes. Applying a total of UF of 

10 to this data point yields a supporting 10-minute value of 0.5 ppm. 

The 30-minute and 1-, 4-, and 8-hour AEGL-3 values were based on the highest 

concentration causing no mortality in the rat after a 30-minute exposure (15 ppm) (Zwart et al., 

1990). A UF of 3 was applied for interspecies extrapolation because little species variability is 

observed with both lethal and nonlethal endpoints after exposure to phosgene. A UF of 3 was 

applied to account for sensitivity of phosgene toxicity (binding to macromolecules and 

irritation), which is not expected to vary greatly between individuals. Therefore, the total UF is 

10. The value was then scaled to the 1-, 4-, and 8-hour AEGL periods using Cn × T = k, where n 

= 1 (Haber’s Law), because Haber’s Law has been shown to be valid for phosgene within certain 

limits. Haber’s Law was originally derived from phosgene data (Haber, 1924). The 10-minute 

AEGL-3 value was based on the highest concentration causing no mortality in the rat or mouse 

(36 ppm) after a 10-minute exposure (Zwart et al., 1990). A UF of 3 was applied for interspecies 

extrapolation because little species variability is observed with both lethal and nonlethal 

endpoints after exposure to phosgene. A UF of 3 was applied to account for sensitive human 

subpopulations because of the steep concentration-response curve and because the mechanism of 

phosgene toxicity (binding to macromolecules and irritation) is not expected to vary greatly 

between individuals (total UF = 10). The calculated values are listed in Table A-1. 

A-2
Table A-1. Summary of AEGL values for phosgene [ppm (mg/m3

)] 

10-minute 30-minute 1-hour 4-hour 8-hour 

Classification value value value value value Endpoint (reference) 

AEGL-1 NA NA NA NA NA NA 

Nondisabling 

AEGL-2 

Disabling 

0.60

 (2.5)

 0.60

 (2.5)

 0.30

 (1.2)

 0.08

 (0.33)

 0.04 

(0.16) 

Chemical pneumonia 

rats (Gross et al., 

1965) 

AEGL-3 

Lethal

 3.6

 (15)

 1.5

 (6.2)

 0.75

 (3.1)

 0.20

 (0.82)

 0.09

 (0.34) 

Highest concentration 

causing no mortality 

in the rat after a 30­

minute or 10-minute 

exposure (Zwart et al., 

1990) 

Source: NAS (2002).

Available from: http://www.epa.gov/oppt/aegl/results7.htm

A-3
APPENDIX B: BMD AND CATREG ANALYSES 

APPENDIX B-1: SUMMARY OF BENCHMARK DOSE (BMD) ANALYSIS 

EPA’s Benchmark Dose Software (BMDS), versions 1.3 and 1.4, were used to perform a 

benchmark analysis of lung effects reported in the subchronic study by Kodavanti et al. (1997). 

The BMD approach involves the use of several models to determine which one best fits the data. 

As described in EPA’s BMD technical guidance (U.S. EPA, 2000c), this is done by comparing 

both the graphical fit and the statistical measures of fit. Tables B-1a through B-1e summarize 

the textual output of the model runs, including AIC and p value measures of statistical fit. 

Following the tables, complete output files, including graphical plots, are included for model 

runs used in the derivation of each endpoint BMDL10 value. 

B-1
c 

Table B-1a. Kodavanti et al. (1997): Interstitial thickening of the alveolus in male rats 

ppm n 4-week exposure 12-week exposure 

0 12 

0.1 8 

0.2 8 

0 

2 

5 

0 

2 

4 

NOAEL (ppm) 

NOAEL(HEC) (mg/m3

)

a 

0.1 

0.15 

0.1 

0.15 

BMDs and BMDLsb 

Model AIC P BMD BMDL 

BMD/ 

BMDL AIC P BMD BMDL 

BMD/ 

BMDL 

Multistagec 10% 

15% 

5% 

1% 

Weibulld 10% 

15% 

5% 

1% 

Gammae 10% 

15% 

5% 

1% 

Logistic 10% 

15% 

5% 

1% 

Log-Logisticf 10% 

15% 

5% 

1% 

Probit 10% 

15% 

5% 

1% 

Log-Probitf 10% 

15% 

5% 

1% 

22.00 

23.58 

23.58 

24.46 

23.58 

24.16 

23.58 

0.82 0.026 0.015 1.73333 

1.0 0.056 0.015 3.73333 

1.0 0.06 0.015 4 

0.43 0.079 0.046 1.71739 

1.0 0.062 0.010 6.2 

0.51 0.075 0.043 1.74419 

1.0 0.065 0.028 2.32143 

22.13 

24.09 

24.09 

25.29 

24.09 

25.00 

22.09 

0.98 0.033 0.018 1.8333 

0.050 0.027 1.8519 

0.016 0.0086 1.8605 

0.0031 0.00168 1.8452 

1.0 0.045 0.018 2.5 

0.064 0.027 2.3704 

0.026 0.0086 3.0233 

0.0071 0.0017 4.1765 

1.0 0.05 0.018 2.7778 

0.065 0.027 2.4074 

0.027 0.0086 3.1395 

0.0085 0.0017 5 

0.34 0.085 0.05 1.7 

0.11 0.068 1.6176 

0.056 0.028 2 

0.016 0.0063 2.5397 

1.0 0.05 0.012 4.1667 

0.067 0.019 3.5263 

0.031 0.0055 5.6364 

0.011 0.0011 10 

0.40 0.08 0.047 1.7021 

0.10 0.065 1.5385 

0.052 0.026 2 

0.016 0.0059 2.7119 

1.0 0.055 0.032 1.7188 

0.070 0.041 1.7073 

0.038 0.022 1.7273 

0.019 0.011 1.7273 

Selected BMD/BMDL10value (ppm)g 

BMDL10(HEC) (mg/m3)

a 

0.026 0.015 

0.016 

0.044 0.025 

0.038 a Human equivalent concentration (HEC) calculated via EPA methods (U.S. EPA, 1994b). The regional gas-dose ratio for the 

thoracic region of the respiratory tract (RGDRTH ) was used (see details in Section 5.2.3 of the main text). b BMDL estimates are 95% lower confidence limits on the dose that would elicit 10, 15, 5, or 1% extra risk. Betas restricted to 0 in multistage/polynomial models; parsimony used to select polynomial order. d Power always restricted to 1 in Weibull and Power models. e Power always restricted to 1 in Gamma and Hill models. f Slope always restricted to 1 in Log-Logistic and Log-Probit models. g Selected models (results in bold) were chosen based on statistical (AIC, p, scaled residual values) and visual assessment per 

BMD guidance (U.S. EPA, 2000c). May represent an average of more than one BMDL if model fits are similar. 

NOAEL = no-observed-adverse-effect level determined via statistical comparison with control response; NA = not applicable or

not applied; ZD = zero degrees of freedom; p value could not be calculated. 

B-2
Table B-1b. Kodavanti et al. (1997): Inflammatory cell influx to terminal

bronchiole/alveolus in male rats 

ppm n 4-week exposure 12-week exposure 

0 12 

0.1 8 

0.2 8 

2 

3 

8 

1 

3 

8 

NOAEL (ppm) 

NOAEL(HEC) (mg/m3

)

a 

0.1 

0.15 

0.1 

0.15 

BMDs and BMDLsb

 Model AIC 

BMD/ 

P BMD BMDL BMDL AIC 

BMD/ 

P BMD BMDL BMDL 

Multistagec 10% 

15% 

5% 

1% 

Weibulld 10% 

15% 

5% 

1% 

Gammae 10% 

15% 

5% 

1% 

Logistic 10% 

15% 

5% 

1% 

Log-Logisticf 10% 

15% 

5% 

1% 

Probit 10% 

15% 

5% 

1% 

Log-Probitf 10% 

15% 

5% 

1% 

25.40 

27.40 

25.49 

28.00 

25.40 

27.88 

27.40 

0.98 0.082 0.013 6.30769 

ZD 0.084 0.033 2.54545 

0.83 0.084 0.040 2.1 

0.16 0.031 0.018 1.72222 

0.99 0.094 0.050 1.88 

0.16 0.028 0.017 1.64706 

ZD 0.093 0.050 1.86 

21.47 

23.47 

21.52 

23.02 

21.47 

23.03 

23.47 

1.0 0.077 0.012 6.4167 

0.084 0.018 4.6667 

0.067 0.0057 11.754 

0.048 0.0011 43.636 

ZD 0.079 0.029 2.7241 

0.085 0.037 2.2973 

0.069 0.019 3.6316 

0.051 0.0069 7.3913 

0.87 0.081 0.035 2.3143 

0.086 0.043 2 

0.073 0.025 2.92 

0.061 0.012 5.0833 

0.28 0.041 0.022 1.8636 

0.053 0.031 1.7097 

0.025 0.012 2.0833 

0.0066 0.0026 2.5385 

0.99 0.092 0.046 2 

0.095 0.054 1.7593 

0.089 0.036 2.4722 

0.081 0.021 3.8571 

0.27 0.035 0.020 1.75 

0.047 0.029 1.6207 

0.021 0.011 1.9091 

0.0051 0.0023 2.2174 

ZD 0.091 0.046 1.9783 

0.094 0.053 1.7736 

0.087 0.037 2.3514 

0.081 0.025 3.24 

Selected BMD/BMDL10 value (ppm)g 

BMDL10(HEC) (mg/m3)

a 

0.087 0.027 

0.041 

0.079 0.024 

0.037 a Human equivalent concentration (HEC) calculated via EPA methods (U.S. EPA, 1994b). The regional gas-dose ratio for the 

thoracic region of the respiratory tract (RGDRTH ) was used (see details in Section 5.2.3 of the main text). b BMDL estimates are 95% lower confidence limits on the dose that would elicit 10, 15, 5, or 1% extra risk. 

Betas restricted to 0 in multistage/polynomial models; parsimony used to select polynomial order. d Power always restricted to 1 in Weibull and Power models. e Power always restricted to 1 in Gamma and Hill models. f Slope always restricted to 1 in Log-Logistic and Log-Probit models. The Log-logistic model was deemed to be inappropriate 

for this endpoint because of the large impact that a maximum high-dose response has on its shape in the low-dose region. g Selected models (results in bold) were chosen based on statistical (AIC, p, scaled residual values) and visual assessment per 

BMD guidance (U.S. EPA, 2000c). May represent an average of BMDLs from selected models. 

NOAEL = no-observed-adverse-effect level determined via statistical comparison with control response; NA = not applicable or 

not applied; ZD = zero degrees of freedom; p value could not be calculated. 

B-3

 c 
Table B-1c. Kodavanti et al. (1997): Epithelial alteration of terminal bronchiole/peribronchiolar alveolus, male rat 

ppm n 4-week exposure 12-week exposure 

0 12 

0.1 8 

0.2 8 

2 

4 

5 

0 

1 

7 

NOAEL (ppm) 

NOAEL(HEC) (mg/m3

)

a 

0.1 

0.15 

0.1 

0.15 

BMDs and BMDLsb 

Model AIC P BMD BMDL 

BMD/

BMDL AIC P BMD BMDL 

BMD/

BMDL 

Multistagec 10% 

15% 

5% 

1% 

Weibulld 10% 

15% 

5% 

1% 

Gammae 

10% 

15% 

5% 

1% 

Logistic 10% 

15% 

5% 

1% 

Log-Logisticf 10% 

15% 

5% 

1% 

Probit 10% 

15% 

5% 

1% 

Log-Probitf 

10% 

15% 

5% 

1% 

36.56 

36.56 

36.56 

36.87 

36.49 

36.85 

36.66 

0.79 0.024 0.012 2 

0.79 0.024 0.012 2 

0.79 0.024 0.012 2 

0.53 0.042 0.026 1.61538 

0.94 0.017 0.0064 2.65625 

0.55 0.041 0.026 1.57692 

0.69 0.043 0.023 1.86957 

14.48 

16.06 

16.06 

16.12 

16.06 

16.06 

16.06 

0.82 0.078 0.026 3 

0.090 0.039 2.3077 

0.061 0.013 4.6923 

0.035 0.0025 14 

1.0 0.094 0.044 2.1364 

0.11 0.056 1.9643 

0.079 0.030 2.6333 

0.052 0.012 4.3333 

1.0 0.096 0.050 1.92 

0.10 0.061 1.6393 

0.084 0.036 2.3333 

0.065 0.018 3.6111 

0.85 0.096 0.054 1.7778 

0.11 0.068 1.6176 

0.078 0.034 2.2941 

0.041 0.0091 4.5055 

1.0 0.096 0.055 1.7455 

0.10 0.065 1.5385 

0.084 0.041 2.0488 

0.062 0.021 2.9524 

0.95 0.095 0.050 1.9 

0.11 0.64 0.1719 

0.079 0.032 2.4688 

0.050 0.0084 5.9524 

1.0 0.096 0.057 1.6842 

0.10 0.066 1.5152 

0.086 0.046 1.8696 

0.070 0.030 2.3333 

Selected BMD/BMDL10 value (ppm)g 0.031 0.017 0.078 0.026 

BMDL10(HEC) (mg/m3)

a 0.026 0.040

 a Human equivalent concentration (HEC) calculated via EPA methods (U.S. EPA, 1994b). The regional gas-dose ratio for the 

thoracic region of the respiratory tract (RGDRTH ) was used (see details in Section 5.2.3 of the main text). b BMDL estimates are 95% lower confidence limits on the dose that would elicit 10, 15, 5, or 1% extra risk. 

Betas restricted to 0 in multistage/polynomial models; parsimony used to select polynomial order. d Power always restricted to 1 in Weibull and Power models. e Power always restricted to 1 in Gamma and Hill models. f Slope always restricted to 1 in Log-Logistic and Log-Probit models. g Selected models (results in bold) were chosen based on statistical (AIC, p, scaled residual values) and visual assessment per 

BMD guidance (U.S. EPA, 2000c). May represent an average of BMDLs from selected models. 

NOAEL = no-observed-adverse-effect level determined via statistical comparison with control response; NA = not applicable or 

not applied; ZD = zero degrees of freedom; p value could not be calculated. 

B-4

 c 
Table B-1d. Kodavanti et al. (1997): Increased collagen staining of terminal 

bronchiole/peribronchiolar, male rats 

ppm n 4-week exposure 12-week exposure 

0 12 

0.1 8 

0.2 8 

1 

1 

8 

2 

2 

8 

NOAEL (ppm) 

NOAEL(HEC) (mg/m3

)

a 

0.1 

0.15 

0.1 

0.15 

BMDs and BMDLsb 

Model AIC 

BMD/ 

P BMD BMDL BMDL AIC 

BMD/ 

P BMD BMDL BMDL 

Multistagec 10% 

15% 

5% 

1% 

Weibulld 10% 

15% 

5% 

1% 

Gammae 

10% 

15% 

5% 

1% 

Logistic 10% 

5% 

1% 

Log-Logisticf 10% 

15% 

5% 

1% 

Probit 10% 

5% 

1% 

Log-Probitf 

10% 

15% 

5% 

1% 

16.91 

18.91 

17.66 

16.91 

18.91 

0.99 0.11 0.027 4.07407 

ZD 0.11 0.068 1.61765 

0.48 0.096 0.071 1.35211 

indeterminateg 

0.98 0.1 0.079 1.26582 

indeterminateg 

ZD 0.10 0.079 1.26582 

23.81 

25.81 

24.17 

23.81 

25.81 

1.0 0.10 0.018 5.5556 

0.11 0.028 3.9286 

0.091 0.0087 10.46 

0.075 0.0017 44.118 

ZD 0.10 0.053 1.8868 

0.11 0.062 1.7742 

0.091 0.040 2.275 

0.073 0.021 3.4762 

0.63 0.092 0.059 1.5593 

0.098 0.067 1.4627 

0.083 0.048 1.7292 

0.069 0.031 2.2258 

indeterminateg 

0.99 0.10 0.068 1.4706 

0.10 0.075 1.3333 

0.096 0.057 1.6842 

0.088 0.038 2.3158 

indeterminateg 

ZD 0.10 0.068 1.4706 

0.10 0.74 0.1351 

0.096 0.059 1.6271 

0.090 0.045 2 

Selected BMD/BMDL10 value (ppm)h 

BMDL10(HEC) (mg/m3)

a 

0.11 0.027 

0.041 

0.10 0.018 

0.028 a Human equivalent concentration (HEC) calculated via EPA methods (U.S. EPA, 1994b). The regional gas-dose ratio for the 

thoracic region of the respiratory tract (RGDRTH ) was used (see details in Section 5.2.3 of the main text). b BMDL estimates are 95% lower confidence limits on the dose that would elicit 10, 15, 5, or 1% extra risk. 

Betas restricted to 0 in multistage/polynomial models; parsimony used to select polynomial order. d Power always restricted to 1 in Weibull and Power models. e Power always restricted to 1 in Gamma and Hill models. f Slope always restricted to 1 in Log-Logistic and Log-Probit models. The Log-logistic model was deemed to be inappropriate 

for this endpoint because of the large impact that a maximum high-dose response has on its shape in the low-dose region. g Inadequate model fit, p<0.1. h Selected models (results in bold) were chosen based on statistical (AIC, p, scaled residual values) and visual assessment per 

BMD guidance (U.S. EPA, 2000c). May represent an average of BMDLs from selected models. 

NOAEL = no-observed-adverse-effect level determined via statistical comparison with control response; NA = not applicable or 

not applied; ZD = zero degrees of freedom; p value could not be calculated. 

B-5

 c 
 c 

Table B-1e. Kodavanti et al. (1997): Volume displaced, left lung 

(mL/kg body weight × 100) 

ppm 4-week exposure n S.D. 12-week exposure n S.D. 

0 

0.1 

0.2 

1.0715 12 0.12 

1.21687 8 0.1614 

1.3531 8 0.0767 

1.03736 11 0.0937 

1.13614 7 0.0725 

1.2882 8 0.1428 

NOAELs 

NOAEL (ppm) 

NOAEL(HEC) (mg/m3

)

a 

0.1 

0.15 

0.1 

0.15 

BMDs and BMDLsb 

Model STD 

4-week exposure 

BMD/ 

AIC P BMD BMDL BMDL 

12-week exposure 

BMD/ 

AIC P BMD BMDL BMDL 

Polynomialc 1 

1.5 

0.5 

0.1 

Powerd 1 

1.5 

0.5 

0.1 

Hille 1 

1.5 

0.5 

0.1 

-86.24 0.93 0.083 0.060 1.38333 

-84.24 ZD 0.083 0.060 1.38333 

indeterminatef 

-87.16 0.55 0.081 0.059 1.3729 

0.12 0.88 0.1364 

0.041 0.029 1.4138 

0.0081 0.0059 1.3729 

-85.52 ZD 0.10 0.060 1.6667 

0.14 0.090 1.5556 

0.060 0.030 2 

0.018 0.0060 3 

indeterminatef 

Selected BMD/BMDL10 value (ppm)g 

BMDL10(HEC) (mg/m3)

a 

0.083 0.060 

0.092 

0.081 0.059 

0.090

 a Human equivalent concentration (HEC) calculated via EPA methods (U.S. EPA, 1994b). The regional gas-dose ratio for the 

thoracic region of the respiratory tract (RGDRTH ) was used (see details in Section 5.2.3 of the main text). b BMDL estimates are 95% lower confidence limits on the dose that would result in a response equal to 1, 1.5, 0.5, or 0.1 

standard deviations from the control mean. 

Betas restricted to 0 in multistage/polynomial models; parsimony used to select polynomial order. d Power always restricted to 1 in Weibull and Power models. e Power always restricted to 1 in Gamma and Hill models. f Inadequate model fit, p<0.1. g Selected models (results in bold) were chosen based on statistical (AIC, p, scaled residual values) and visual assessment per 

BMD guidance (U.S. EPA, 2000c). May represent an average of BMDLs from selected models. 

NOAEL = no-observed-adverse-effect level determined via statistical comparison with control response; NA = not applicable or 

not applied; ZD = zero degrees of freedom; p value could not be calculated. 

B-6
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Interstitial Thickening of the Alveolus in Male Rats (12 Weeks) – Multistage Model 

Multistage Model with 0.95 Confidence Level 

Fraction Affected 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

BMDL BMD

Multistage 

0 0.05 0.1 0.15 0.2 

dose 

15:41 08/03 2004

 ==================================================================== 

 Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $ 

Input Data File: F:\BMDS\DATA\PHOSGENE\AIT-12WK-MUL.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\AIT-12WK-MUL.plt 

Thu Oct 25 15:31:04 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP(-beta1*dose^1)]

 The parameter betas are restricted to be positive

 Dependent variable = AIT-12wk

 Independent variable = Dose

 Total number of observations = 3

 Total number of records with missing values = 0

 Total number of parameters in model = 2

 Total number of specified parameters = 0

 Degree of polynomial = 1

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 Default Initial Parameter Values 

B-7 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Interstitial Thickening of the Alveolus in Male Rats (12 Weeks) – Multistage Model 

 Background = 0

 Beta(1) = 3.46574

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Background

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

 Beta(1)

 Beta(1) 1

 Parameter Estimates

Variable Estimate Std. Err. 

Background 0 NA

Beta(1) 3.24026 2.09548

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

 Model Log(likelihood) Deviance Test DF P-value

 Full model -10.0439

 Fitted model -10.067 0.0462843 2 0.9771

 Reduced model -14.5482 9.00875 2 0.01106

 AIC: 22.134

 Goodness of Fit

 Dose Est._Prob. Expected Observed Size Chi^2 Res.

 ----------------------------------------------------------------------­

i: 1

 0.0000 0.0000 0.000 0 12 0.000 

i: 2

 0.1000 0.2768 2.214 2 8 -0.134 

i: 3

 0.2000 0.4769 3.815 4 8 0.092

 Chi-square = 0.05 DF = 2 P-value = 0.9774

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.0325161

 BMDL = 0.0175799 

B-8
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Interstitial Thickening of the Alveolus in Male Rats (12 Weeks) – Log Probit Model 

Probit Model with 0.95 Confidence Level 

0 

0.1 

0.2 

0.3 

0.4 

0.5 

0.6 

0.7 

0.8 

0.9 

Fraction Affected 

BMDL BMD 

Probit 

0 0.05 0.1 0.15 0.2 

dose 

15:48 08/03 2004 

====================================================================

 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 

 Input Data File: F:\BMDS\DATA\PHOSGENE\AIT-12WK-LOG-PRO.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\AIT-12WK-LOG-PRO.plt 

Thu Oct 25 15:31:28 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the probability function is: 

P[response] = Background

 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),

 where CumNorm(.) is the cumulative normal distribution function

 Dependent variable = AIT-12wk

 Independent variable = Dose

 Slope parameter is restricted as slope >= 1

 Total number of observations = 3

 Total number of records with missing values = 0

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 User has chosen the log transformed model

 Default Initial (and Specified) Parameter Values 

B-9 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Interstitial Thickening of the Alveolus in Male Rats (12 Weeks) – Log Probit Model 

 Background = 0

 Intercept = 1.6281

 Slope = 1

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -background -slope

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

intercept 

intercept 1

 Parameter Estimates

Variable Estimate Std. Err. 

Background 0 NA

Intercept 1.61798 0.326388

Slope 1 NA

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

Model Log(likelihood) Deviance Test DF P-value

Full model -10.0439

Fitted model -10.0443 0.000811983 2 0.9996

Reduced model -14.5482 9.00875 2 0.01106

 AIC: 22.0885

 Goodness of Fit

Scaled

 Dose Est._Prob. Expected Observed Size Residual

 -----------------------------------------------------------------------­

 0.0000 0.0000 0.000 0 12 0

 0.1000 0.2468 1.974 2 8 0.02101

 0.2000 0.5034 4.027 4 8 -0.01928

 Chi-square = 0.00 DF = 2 P-value = 0.9996

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.055049

 BMDL = 0.0323742 

B-10
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

Multistage Model 

Multistage Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 BMDL BMD

Multistage 

0 0.05 0.1 0.15 0.2 

dose 

15:52 08/03 2004

 ==================================================================== 

 Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $ 

Input Data File: F:\BMDS\DATA\PHOSGENE\INF-12WK-MUL.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\INF-12WK-MUL.plt 

Thu Oct 25 16:17:32 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP(-beta1*dose^1-beta2*dose^2-beta3*dose^3-beta4*dose^4-beta5*dose^5)]

 The parameter betas are restricted to be positive

 Dependent variable = INF-12wk

 Independent variable = Dose

 Total number of observations = 3

 Total number of records with missing values = 0

 Total number of parameters in model = 6

 Total number of specified parameters = 0

 Degree of polynomial = 5 

B-11 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

Multistage Model 

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 Default Initial Parameter Values

 Background = 1

 Beta(1) = 5e+020

 Beta(2) = 2.5e+021

 Beta(3) = 1.25e+022

 Beta(4) = 6.25e+022

 Beta(5) = 3.125e+023

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Beta(1) -Beta(2) -Beta(3) -Beta(4)

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

 Background Beta(5) 

Background 1 -0.56

 Beta(5) -0.56 1

 Parameter Estimates

 Variable Estimate Std. Err. 

 Background 0.0833264 0.275955

 Beta(1) 0 NA

 Beta(2) 0 NA

 Beta(3) 0 NA

 Beta(4) 0 NA

 Beta(5) 38308.2 53667

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

 Model Log(likelihood) Deviance Test DF P-value

Full model -8.73454

Fitted model -8.73457 6.96773e-005 1 0.9933

Reduced model -19.1214 20.7738 2 <.0001

 AIC: 21.4691

 Goodness of Fit

 Dose Est._Prob. Expected Observed Size Chi^2 Res.

 ----------------------------------------------------------------------­

i: 1

 0.0000 0.0833 1.000 1 12 0.000 

i: 2

 0.1000 0.3751 3.000 3 8 -0.000 

i: 3

 0.2000 1.0000 8.000 8 8 1.000

 Chi-square = 0.00 DF = 1 P-value = 0.9953 

B-12
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

Multistage Model 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 0.0772462

BMDL = 0.0117632

B-13
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

Gamma Model 

Gamma Multi-Hit Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 

BMDL BMD 

Gamma Multi-Hit 

0 0.05 0.1 0.15 0.2 

dose 

15:53 08/03 2004

 ==================================================================== 

 $Revision: 2.2 $ $Date: 2001/03/14 01:17:00 $ 

 Input Data File: F:\BMDS\DATA\PHOSGENE\INF-12WK-GAM.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\INF-12WK-GAM.plt 

Thu Oct 25 16:33:03 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power],

 where CumGamma(.) is the cumulative Gamma distribution function

 Dependent variable = INF-12wk

 Independent variable = Dose

 Power parameter is restricted as power >=1

 Total number of observations = 3

 Total number of records with missing values = 0

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 Default Initial (and Specified) Parameter Values 

Background = 0.115385

 Slope = 7.44381

 Power = 1.3

B-14 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

Gamma Model 

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Power

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

 Background Slope 

Background 1 -0.28 

Slope -0.28 1

 Parameter Estimates

Variable Estimate Std. Err. 

Background 0.0823419 0.0785952

Slope 158.604 20.2326

Power 18 NA

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

 Model Log(likelihood) Deviance Test DF P-value

 Full model -8.73454

Fitted model -8.75909 0.049106 1 0.8246

Reduced model -19.1214 20.7738 2 <.0001

 AIC: 21.5182

 Goodness of Fit

Scaled

 Dose Est._Prob. Expected Observed Size Residual

 -----------------------------------------------------------------------­

 0.0000 0.0823 0.988 1 12 0.01249

 0.1000 0.3830 3.064 3 8 -0.04677

 0.2000 0.9971 7.977 8 8 0.153

 Chi-square = 0.03 DF = 1 P-value = 0.8725

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.0808407

 BMDL = 0.0352477 

B-15
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

LogLogistic Model 

Log-Logistic Model with 0.95 Confidence Level 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 

BMDL BMD 

Log-Logistic 

0 0.05 0.1 0.15 0.2 

dose 

15:55 08/03 2004

 ==================================================================== 

Logistic Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:20 $ 

 Input Data File: F:\BMDS\DATA\PHOSGENE\INF-12WK-LOG-LOG.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\INF-12WK-LOG-LOG.plt 

Thu Oct 25 16:29:08 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

 Dependent variable = INF-12wk

 Independent variable = Dose

 Slope parameter is restricted as slope >= 1

 Total number of observations = 3

 Total number of records with missing values = 0

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 User has chosen the log transformed model

 Default Initial Parameter Values

Background = 0.0833333

Intercept = 11.1814

B-16 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Inflammatory Cell Influx to Terminal Bronchiole/Alveolus, Male Rats (12 Weeks) – 

LogLogistic Model 

Slope = 5.187

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -slope

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

Background Intercept

Background 1 -0.3

Intercept -0.3 1

 Parameter Estimates

 Variable Estimate Std. Err. 

 Background 0.0833321 0.0797846

 Intercept 40.6845 0.903084

 Slope 18 NA

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

Model Log(likelihood) Deviance Test DF P-value

Full model -8.73454

Fitted model -8.7346 0.000119887 1 0.9913

Reduced model -19.1214 20.7738 2 <.0001

 AIC: 21.4692

 Goodness of Fit

Scaled

 Dose Est._Prob. Expected Observed Size Residual

 -----------------------------------------------------------------------­

 0.0000 0.0833 1.000 1 12 1.567e-005

 0.1000 0.3750 3.000 3 8 -6.786e-005

 0.2000 1.0000 8.000 8 8 0.007742

 Chi-square = 0.00 DF = 1 P-value = 0.9938

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.0923365

 BMDL = 0.0464352 

B-17
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Epithelial Alteration of Terminal Bronchiole/Peribronchial Alveolus (12 Weeks) – 

Multistage Model 

Multistage Model with 0.95 Confidence Level 

0 

0.2 

0.4 

0.6 

0.8 

1 

Fraction Affected 

BMDL BMD

Multistage 

0 0.05 0.1 0.15 0.2 

dose 

16:00 08/03 2004

 ==================================================================== 

 Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $ 

Input Data File: F:\BMDS\DATA\PHOSGENE\EPI-12WK-MUL.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\EPI-12WK-MUL.plt 

Fri Oct 26 10:22:13 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP(-beta1*dose^1-beta2*dose^2-beta3*dose^3)]

 The parameter betas are restricted to be positive

 Dependent variable = EPI-12wk

 Independent variable = Dose

 Total number of observations = 3

 Total number of records with missing values = 0

 Total number of parameters in model = 4

 Total number of specified parameters = 0

 Degree of polynomial = 3

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008 

B-18 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Epithelial Alteration of Terminal Bronchiole/Peribronchial Alveolus (12 Weeks) – 

Multistage Model 

 Default Initial Parameter Values

 Background = 0

 Beta(1) = 0

 Beta(2) = 100

 Beta(3) = 250

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Background -Beta(1) -Beta(2)

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

 Beta(3)

 Beta(3) 1

 Parameter Estimates

 Variable Estimate Std. Err. 

 Background 0 NA

 Beta(1) 0 NA

 Beta(2) 0 NA

 Beta(3) 225.422 104.079

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

Model Log(likelihood) Deviance Test DF P-value

Full model -6.02832

Fitted model -6.24181 0.426967 2 0.8078

Reduced model -16.7515 21.4465 2 <.0001

 AIC: 14.4836

 Goodness of Fit

 Dose Est._Prob. Expected Observed Size Chi^2 Res.

 ----------------------------------------------------------------------­

i: 1

 0.0000 0.0000 0.000 0 12 0.000 

i: 2

 0.1000 0.2018 1.615 1 8 -0.477 

i: 3

 0.2000 0.8353 6.682 7 8 0.289

 Chi-square = 0.38 DF = 2 P-value = 0.8249

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.0776057

 BMDL = 0.0261034 

B-19 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Increased Collagen Staining of Terminal Bronchiole/Peribronchiolar (12 Weeks) – 

Multistage Model 

Multistage Model with 0.95 Confidence Level 

Multistage 

BMDL BMD 

0 0.05 0.1 0.15 0.2 

dose 

16:52 08/03 2004

 ==================================================================== 

 Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $ 

Input Data File: F:\BMDS\DATA\PHOSGENE\STA-12WK-MUL.(d)

 Gnuplot Plotting File: F:\BMDS\DATA\PHOSGENE\STA-12WK-MUL.plt 

Tue Oct 30 17:17:48 2001

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

 The form of the probability function is: 

 P[response] = background + 

(1-background)*[1-EXP(-beta1*dose^1-beta2*dose^2-beta3*dose^3-beta4*dose^4-beta5*dose^5-beta6*dose^6-beta7*dose^7)]

 The parameter betas are restricted to be positive

 Dependent variable = STA-12wk

 Independent variable = Dose

 Total number of observations = 3

 Total number of records with missing values = 0

 Total number of parameters in model = 8

 Total number of specified parameters = 0

 Degree of polynomial = 7

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008 

B-20 

Fraction Affected 

1 

0.8 

0.6 

0.4 

0.2 

0 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Increased Collagen Staining of Terminal Bronchiole/Peribronchiolar (12 Weeks) – 

Multistage Model 

 Default Initial Parameter Values

 Background = 1

 Beta(1) = 5e+020

 Beta(2) = 2.5e+021

 Beta(3) = 1.25e+022

 Beta(4) = 6.25e+022

 Beta(5) = 3.125e+023

 Beta(6) = 1.5625e+024

 Beta(7) = 7.8125e+024

 Asymptotic Correlation Matrix of Parameter Estimates

 ( *** The model parameter(s) -Beta(1) -Beta(2) -Beta(3) -Beta(4) -Beta(5) -Beta(6)

 have been estimated at a boundary point, or have been specified by the user,

 and do not appear in the correlation matrix )

Background Beta(7) 

Background 1 -0.6 

Beta(7) -0.6 1

 Parameter Estimates

 Variable Estimate Std. Err. 

 Background 0.166651 0.261628

 Beta(1) 0 NA

 Beta(2) 0 NA

 Beta(3) 0 NA

 Beta(4) 0 NA

 Beta(5) 0 NA

 Beta(6) 0 NA

 Beta(7) 1.05428e+006 5.06411e+006

NA - Indicates that this parameter has hit a bound

 implied by some inequality constraint and thus

 has no standard error.

 Analysis of Deviance Table

Model Log(likelihood) Deviance Test DF P-value

Full model -9.90542

Fitted model -9.90542 1.84535e-005 1 0.9966

Reduced model -19.1214 18.432 2 <.0001

 AIC: 23.8108

 Goodness of Fit

 Dose Est._Prob. Expected Observed Size Chi^2 Res.

 ----------------------------------------------------------------------­

i: 1

 0.0000 0.1667 2.000 2 12 0.000 

i: 2

 0.1000 0.2500 2.000 2 8 -0.000 

i: 3

 0.2000 1.0000 8.000 8 8 1.000

 Chi-square = 0.00 DF = 1 P-value = 0.9976 

B-21
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Increased Collagen Staining of Terminal Bronchiole/Peribronchiolar (12 Weeks) – 

Multistage Model 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.0999908

 BMDL = 0.018414

B-22
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Volume Displaced, Left Lung (mL/kg body weight × 100) (12 Weeks) – Polynomial Model 

Linear Model with 0.95 Confidence Level 

1 

1.1 

1.2 

1.3 

1.4 

Mean Response 

BMDL BMD

Linear 

0 0.05 0.1 0.15 0.2 

dose 

08:16 08/04 2004

 ==================================================================== 

 Polynomial Model. Revision: 2.3 Date: 09/08/2003 

 Input Data File: U:\BMDS\DATA\PHOSGENE\10%OUTFILES\LVD-12WK-POLY.(d)

 Gnuplot Plotting File: U:\BMDS\DATA\PHOSGENE\10%OUTFILES\LVD-12WK-POLY.plt 

Mon Aug 02 09:28:17 2004

 ==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 The form of the response function is: 

 Y[dose] = beta_0 + beta_1*dose + beta_2*dose^2 + ...

 Dependent variable = MEAN

 Independent variable = Dose

 rho is set to 0

 The polynomial coefficients are restricted to be positive

 A constant variance model is fit

 Total number of dose groups = 3

 Total number of records with missing values = 0

 Maximum number of iterations = 250

 Relative Function Convergence has been set to: 1e-008

 Parameter Convergence has been set to: 1e-008

 Default Initial Parameter Values

alpha = 0.0113983

rho = 0 Specified

beta_0 = 1.02848

beta_1 = 1.2542

B-23 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Volume Displaced, Left Lung (mL/kg body weight × 100) (12 Weeks) – Polynomial Model 

 Parameter Estimates

 95.0% Wald Confidence Interval

Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit

 alpha 0.0102218 0.002835 0.00466525 0.0157783

 beta_0 1.03121 0.0286698 0.975016 1.0874

 beta_1 1.24267 0.234088 0.783862 1.70147

 Asymptotic Correlation Matrix of Parameter Estimates

 alpha beta_0 beta_1

 alpha 1 5.1e-008 -9.7e-008

 beta_0 5.1e-008 1 -0.72

 beta_1 -9.7e-008 -0.72 1

 Table of Data and Estimated Values of Interest

 Dose N Obs Mean Obs Std Dev Est Mean Est Std Dev Chi^2 Res. 

------ — -------- ----------- -------- ----------- ---------­

0 11 1.04 0.0937 1.03 0.101 0.202

 0.1 7 1.14 0.0725 1.16 0.101 -0.506

 0.2 8 1.29 0.143 1.28 0.101 0.237

 Model Descriptions for Likelihoods Calculated

 Model A1: Yij = Mu(I) + e(ij)

 Var{e(ij)} = Sigma^2

 Model A2: Yij = Mu(I) + e(ij)

 Var{e(ij)} = Sigma(I)^2

 Model R: Yi = Mu + e(I)

 Var{e(I)} = Sigma^2

 Likelihoods of Interest 

Model Log(likelihood) d.f. AIC

A1 46.759659 4 -85.519318

A2 48.576042 6 -85.152085

fitted 46.582087 3 -87.164174

R 36.527257 2 -69.054514

 Test 1: Does response and/or variances differ among dose levels (A2 vs. R)

 Test 2: Are Variances Homogeneous (A1 vs A2)

 Test 3: Does the Model for the Mean Fit (A1 vs. fitted)

 Tests of Interest

 Test -2*log(Likelihood Ratio) Test df p-value

 Test 1 24.0976 4 <.0001

 Test 2 3.63277 2 0.1626

 Test 3 0.355144 1 0.5512

The p-value for Test 1 is less than .05. There appears to be a difference between response and/or variances among the dose levels. It seems 

appropriate to model the data 

The p-value for Test 2 is greater than .05. A homogeneous variance model appears to be appropriate here 

The p-value for Test 3 is greater than .05. The model chosen appears to adequately describe the data

 Benchmark Dose Computation 

Specified effect = 1 

Risk Type = Estimated standard deviations from the control mean 

B-24 
Model Runs Used in the Derivation of Table B-1 Selected BMDL10 Values 

Volume Displaced, Left Lung (mL/kg body weight × 100) (12 Weeks) – Polynomial Model 

Confidence level = 0.95

 BMD = 0.0813596

 BMDL = 0.058627 

B-25
APPENDIX B-2: EXPLANATION OF CATREG ANALYSIS

CatReg is a computer program developed to support toxicologists and health scientists in 

the conduct of exposure-response analyses. Prior to performing categorical regression using 

CatReg, effects observed in toxicological studies must be assigned to ordinal severity categories 

(e.g., no effect, adverse effect, severe effect) and associated with the exposure conditions (e.g., 

concentration and duration) under which the effects occurred. CatReg executes a regression 

analysis of the severity scores and exposure parameters. The categorization of observed 

responses allows expression of dichotomous, continuous, and descriptive data in terms of effect 

severity and supports the analysis of the data from single studies or a combination of similar 

studies. CatReg is designed to work with S-PLUS® Professional version 3 or higher, and the 

user must have access to this software to execute the CatReg program.

1

 Although familiarity 

with S-PLUS® may assist the user, an understanding of the S-PLUS® programming language is 

not required. 

In the case of dichotomous data for phosgene, the lung is assessed in terms of presence or 

absence of an effect, such as the collagen-staining effect observed following phosgene exposure 

(Table B-1d, Appendix B-1). The mathematical form of the models that were used to compute 

the benchmark dose-probability relationship is a function that is nondecreasing as x increases 

and takes only values between 0 and 1 (properties required of a cumulative probability function). 

As is the case in the Kodavanti et al. (1997) report, experimental effects may be reported 

in more detail than simply “absence” or “presence,” which allows for more detailed data analysis 

using CatReg. For example, the number of animals in each treatment group and the number with 

varying degrees of inflammation may be classified into severity levels, such as “no adverse 

effect,” “mild adverse effect,” or “moderate/severe effect.” After classifying the observations 

into the severity levels (which are now the “data” to be input to CatReg), the data are ordinal 

(ranked in terms of severity) and categorical (each animal in each treatment group is in a 

severity category or a range of severity categories). Duration of exposure, as well as 

concentration, is included in CatReg because it affects the probability of achieving the various 

severity levels. “Duration” can be omitted, however, which is convenient when all subjects were 

exposed for the same duration, or if duration is not considered to be an explanatory variable (as 

has been determined to be the case for this analysis). 

In the CatReg analysis of data from Kodavanti et al. (1997), the scores assigned by the 

1

A version of CatReg that will run in the freely distributable R statistical platform is 

under development, but has not been released to date. 

B-26 
study authors were weighted according to the severity of the various endpoints as follows for 

endpoints that did not significantly regress or disappear during the 4-week recovery period 

(epithelial alteration and collagen staining of the terminal bronchioles) were increased by 1 

severity grade, and the scores of endpoints deemed to have recognized and serious long-term 

consequences (collagen staining) were increased by an additional severity grade (see Tables B2a-1 and B-2a-2). Thus, the absence of a lesion was scored as a severity grade of 0, reversible 

lesions scored as “minimal” by the study authors received a severity grade of 1, reversible 

lesions scored as “slight/mild” and potentially irreversible lesions scored as “minimal” by the 

study authors received a severity grade of 2, and potentially irreversible lesions scored by study 

authors as “slight/mild” or any occurrence of a lesion considered to have long-term 

consequences (collagen staining) received a severity grade of 3. Table B-2b is the input file for 

CatReg that was generated from the data for the 4-week, 12-week, and combined exposure 

periods. 

B-27
Table B-2a-1. Adjusted severity grades for CatReg analysis of lung lesions in 

rats exposed to phosgene for 4 weeks (Kodavanti et al., 1997) 

4-Week Controls 1 2 3 4 5 6 7 8 9 10 11 12 

Alveolar effusion 

Alveolus, interstitial thickening 

Bronchus, epithelial alteration 

Bronchus, inflammation 1 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 1 

Alveolus, epithelial alteration 2 2 

Increased collagen staining 3 

Assigned Severity Grade 1 0 0 0 0 2 1 0 0 0 0 3 

0.1 ppm Exposure Group 1 2 3 4 5 6 7 8 

Alveolar effusion 

Alveolus, interstitial thickening 1 1 

Bronchus, epithelial alteration 1 

Bronchus, inflammation 1 1 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 1 1 

Alveolus, epithelial alteration 2 2 2 2 

Increased collagen staining 3 

Assigned Severity Grade 2 2 1 0 2 0 3 2 

0.2 ppm Exposure Group 1 2 3 4 5 6 7 8 

Alveolar effusion 

Alveolus, interstitial thickening 1 1 1 1 1 

Bronchus, epithelial alteration 2 2 

Bronchus, inflammation 1 1 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 1 1 1 1 1 1 1 

Alveolus, epithelial alteration 2 2 2 2 2 

Increased collagen staining 3 3 3 3 3 3 3 3 

Assigned Severity Grade 3 3 3 3 3 3 3 3 

B-28
Table B-2a-2. Adjusted severity grades for CatReg analysis of lung lesions in 

rats exposed to phosgene for 12 weeks (Kodavanti et al., 1997) 

12-Week Controls 1 2 3 4 5 6 7 8 9 10 11 12 

Alveolar effusion 

Alveolus, interstitial thickening 

Bronchus, epithelial alteration 

Bronchus, inflammation 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 

Alveolus, epithelial alteration 

Increased collagen staining 3 3 

Assigned Severity Grade 0 3 0 3 0 0 0 0 0 0 0 0 

0.1 ppm Exposure Group 1 2 3 4 5 6 7 8 

Alveolar effusion 

Alveolus, interstitial thickening 1 1 

Bronchus, epithelial alteration 

Bronchus, inflammation 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 1 1 

Alveolus, epithelial alteration 2 

Increased collagen staining 3 3 

Assigned Severity Grade 0 2 3 1 1 3 0 0 

0.2 ppm Exposure Group 1 2 3 4 5 6 7 8 

Alveolar effusion 

Alveolus, interstitial thickening 1 1 1 1 

Bronchus, epithelial alteration 1 

Bronchus, inflammation 

Terminal bronchiole/alveolus, 

inflammatory cell influx 

1 1 1 2 1 1 1 1 

Alveolus, epithelial alteration 2 2 2 2 2 2 2 

Increased collagen staining 3 3 3 3 3 3 3 3 

Assigned Severity Grade 3 3 3 3 3 3 3 3 

B-29
Table B-2b. CatReg input data file for 4-week, 12-week, and combined 

analysis 

ppm Weeks Target Nsub GpSize Incid SevLo SevHi 

0 4 Lung 12 1 8 0 0 

0 4 Lung 12 1 2 1 1 

0 4 Lung 12 1 1 2 2 

0 4 Lung 12 1 1 3 3 

0.1 4 Lung 8 1 2 0 0 

0.1 4 Lung 8 1 1 1 1 

0.1 4 Lung 8 1 4 2 2 

0.1 4 Lung 8 1 1 3 3 

0.2 4 Lung 8 1 8 3 3 

0 12 Lung 12 1 10 0 0 

0 12 Lung 12 1 2 3 3 

0.1 12 Lung 8 1 3 0 0 

0.1 12 Lung 8 1 2 1 1 

0.1 12 Lung 8 1 1 2 2 

0.1 12 Lung 8 1 2 3 3 

0.2 12 Lung 8 1 8 3 3 

0 Combined Lung 24 1 18 0 0 

0 Combined Lung 24 1 2 1 1 

0 Combined Lung 24 1 1 2 2 

0 Combined Lung 24 1 3 3 3 

0.1 Combined Lung 16 1 5 0 0 

0.1 Combined Lung 16 1 3 1 1 

0.1 Combined Lung 16 1 5 2 2 

0.1 Combined Lung 16 1 3 3 3 

0.2 Combined Lung 16 1 16 3 3 

CatReg was used to fit a cumulative probability distribution to the 4-week and 12-week 

data and the 4-week and 12-week data combined. Given a concentration C and duration T, 

CatReg models the distribution of Y as 

Pr(Y $s | C,T ) = H[(as + b1* f1(C) + b2*f2(T)] 

for ordinal scores s = 1,...,S. This is the probability of attaining a severity score of 1 or higher 

B-30
at some specified concentration and duration of exposure. The parameter a1 is the intercept 

for severity equals 1, and as is an increment in the intercept for severity equals s versus severity 

equals 1, for s = 2,...,S. b1 and b2 determine the relationship between the response and 

concentration and duration, respectively; unrestricted odds models can be chosen such that b's 

may depend on the severity level of interest. CatReg can restrict the slopes so that they are the 

same across all severity levels; thus, the slopes are simply b1 and b2.

 H is a probability function that takes values between 0 and 1. The inverse of H is 

called the link function, which is used to obtain the parameter estimates. There are several 

possible choices for the inverse of H: logit, probit, and log-log functions (see U.S. EPA, 2000e, 

p. 4). Transformation functions, f1 and f2, transform D and T to another scale, usually a base-10 

logarithm. 

The intercept term at a specified severity level determines the probability of occurrence 

when concentration and duration are both zero (i.e., the probability of a “background” response 

at that severity level). The coefficients of concentration and duration (along with the model 

used) determine how rapidly the probability of response (at a specified severity level) increases 

as concentration and duration increase. The larger the coefficient of concentration, the more 

rapidly the probability increases as concentration increases, and similarly for duration; the 

smaller the coefficient of a variable, the less sensitive the probability is to a change in the 

variable. The coefficient of duration for all model runs of the 4-week and 12-week data was a 

very small number, approximately 0.04 (SE = 0.05). In addition, a Z-test of the null hypothesis 

that there is no time effect yielded a p value of 0.425, well above the p value of 0.05 that would 

cause us to reject the hypothesis. For these reasons, the results of the CatReg analyses of the 

combined 4-week and 12-week data are used. 

The primary goal of this analysis is to determine the CatReg estimate that is most 

comparable to the BMD10 estimates for collagen staining that are presented in Appendix B-1 

(Table B-1d). This was determined to be the 10% extra risk dose (ERD10) for a severity score 

equal to 3, using the combined 4-week and 12-week data.2 The ERD10 for a severity score of 3 is 

defined as the dose d* that satisfies 

Pr(Y $3 | D = d*) - Pr(Y $3 | D = 0) = 0.1 

1 - Pr(Y $3 | D = 0) 

Thus, the ERD10 is the dose that is associated with a 10% relative change from the 

background response at severity level 3 or greater. If the probability of a severity level 3 

2

Other extra risk values and severity grades were evaluated and are presented for comparison purposes. 

B-31 
response or greater were 0 at 0 concentration, the ERD10 would be equal to the 10% 

effective concentration (EC10), a value that the currently released version of CatReg can estimate 

directly. Because this probability is not 0 at 0 in this case, additional calculations are necessary.3 

To determine the best model for finding the extra risk doses, the appropriate link function 

and model had to be identified.4 Next, the data needed to be evaluated to determine whether the 

slopes of the response curves associated with each severity level could be assumed to be parallel, 

allowing for the use of a simplified model. The more complex, unrestricted model, in which the 

severity levels are assumed to have individual slopes, was run first. The CatReg parallel test 

(partest) was then used to determine whether slope parameters estimated in a model run for each 

severity level are equivalent. When the slopes were found to not significantly differ from each 

other, the simpler model that assumes a common slope (parallel curves) was employed. The test 

was insignificant (simpler model was justified) for most endpoints. 

Table B-2c shows the results of the model test. The cumulative odds model (cloglog link 

function) was chosen because it resulted in the lowest deviance values. The unrestricted form of 

this model was not deemed necessary because the parallel test of CatReg did not find that the 

loss of 2 degrees of freedom that this would require was justified. The results for the application 

of this model to the combined 4-week and 12-week severity graded data are shown in Table B2d. The ERD10 for a severity score equal to 3, using the combined 4-week and 12-week data, is 

estimated to be approximately 0.05 ppm. 

3

The current Splus version of CatReg does not give extra risk doses directly at this time; however, it does 

provide the information needed to derive them. To calculate the background risk (Pr(Y 3 | D = 0 in the above 

equation) one must use the severity 3 intercept parameter estimate (Ds) provided by CatReg to solve the function of 

interest (e.g., the logit function, Pr(Y  3| D) = exp[Ds + E 1*D]/(1+ exp[Ds + E 1*D])), where D = 0. Then solve: 

Pr(Y 3 | D = d*) = 0.1*(1 - Pr(Y 3 | D = 0)) + Pr(Y 3 | D = 0) 

CatReg can then be used to calculate the dose (EC) associated with Pr(Y 3 | D = d*). This is the desired d*, the 

10% extra risk dose for a severity 3 effect. 

4

See Section 2.2 of the CatReg documentation (U.S. EPA, 2000e) for the method for determining the best 

link function. 

B-32 
Table B-2c. Selection of model for use in derivation of ERD values 

Scale Link Model Deviance df 

Chisquare df p-value Parallel test result 

None Probit Cumulative Odds 

model 

92.5099 5 0.5952022 2 0.74260 This is generally 

considered not 

significant, indicating 

that it would be more 

appropriate to use the 

simpler restricted 

cumulative model. 

None Probit Unrestricted 

Cumulative model 

91.98678 3 

None CLogLog Cumulative Odds 

model 

87.81308 5 0.3337553 2 0.84630 This is generally 

considered not 

significant, indicating 

that it would be more 

appropriate to use the 

simpler restricted 

cumulative model. 

None CLogLog Unrestricted 

Cumulative model 

87.42469 3 

Log Logit Cumulative Odds 

model 

109.2512 5 0.588963 2 0.74492 This is generally 

considered not 

significant, indicating 

that it would be more 

appropriate to use the 

simpler restricted 

cumulative model. 

Log Logit Unrestricted 

Cumulative model 

108.7628 3 

Log Probit Cumulative Odds 

model 

109.6004 5 0.9155587 2 0.63269 This is generally 

considered not 

significant, indicating 

that it would be more 

appropriate to use the 

simpler restricted 

cumulative model. 

Log Probit Unrestricted 

Cumulative model 

108.8286 3 

Log CLogLog Cumulative Odds 

model 

108.7272 5 0.3245027 2 0.85023 This is generally 

considered not 

significant, indicating 

that it would be more 

appropriate to use the 

simpler restricted 

cumulative model. 

Log CLogLog Unrestricted 

Cumulative model 

108.348 3 

ERD = Extra risk dose. 

B-33 
Table B-2d. Results of CatReg analysis of severity-graded lung lesions reported by 

Kodavanti et al. (1997) [estimates of the exposures that would cause a 10, 20, and 30% 

extra risk of an effect equal to or greater than severity grade 1, 2, and 3 (ERD10, ERD20, 

and ERD30)] 

Severity 

grade Model Link function 

ERD10 

(ppm) 

ERD20 

(ppm) 

ERD30 

(ppm)

 1 Cumulative 

Odds model 

CLogLog 0.02122672 0.03756418 0.05128771

 2 0.03084543 0.05159007 0.0678657

 3 0.04991843 0.07659892 0.09580849

 ERD = Extra risk dose. 

B-34
APPENDIX C: SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC 

COMMENTS AND DISPOSITION 

The Toxicological Review and IRIS summary for phosgene have undergone both internal 

peer review performed by scientists within EPA and a more formal external peer review 

performed by scientists in accordance with EPA guidance on peer review (U.S. EPA, 1998b, 

2000a). Comments made by the internal reviewers were addressed prior to submitting the 

documents for external peer review and are not part of this appendix. Three external peer 

reviewers were tasked with providing written answers to general questions on the overall 

assessment and on chemical-specific questions in areas of scientific controversy or uncertainty. 

A summary of significant comments made by the external reviewers and EPA’s response to these 

comments follows. EPA also received scientific comments from the public. These comments 

and EPA’s response are included in a separate section of this appendix. 

The reviewers considered the overall quality of the Toxicological Review and IRIS 

summary to be good. A number of editorial suggestions were offered. These included 

identification of typographical errors, insufficiently clear text, incomplete descriptions of 

complex calculations, and use of inconsistent concentration units. Revisions and corrections 

were incorporated in the document as appropriate. 

Comments from External Peer Review 

A. RfC Derivation 

1. Principal Study 

Comment: All three reviewers agreed with the Agency’s selection of Kodavanti et al. (1997) as 

the principal study for the derivation of the RfC. One reviewer suggested that the Franch and 

Hatch (1986) study be used to support the findings of the Kodavanti et al. study. 

Response: The Agency disagrees that the findings of Franch and Hatch (1986) should be used as 

support for the derivation of the RfC based on Kodavanti et al. (1997). Although the doses were 

similar in the two studies, different lung effects were observed. 

C-1
2. Methods of Analysis 

Comment 1: The reviewers generally supported the Agency’s use of three methods for derivation 

of the RfC (LOAEL/NOAEL, BMD and categorical regression). Two reviewers expressed the 

least preference for the LOAEL/NOAEL approach, considering it to be the least statistically 

robust method. One of these reviewers expressed more confidence in the BMD method than the 

other two methods. The second reviewer considered the decision to use the benchmark dose 

analysis with the categorical regression analysis in a supporting role to be appropriate. 

Response 1: The Toxicological Review provides a comparison of the three approaches, including 

a discussion of the strengths and limitations of each. The Agency believes that the use of three 

approaches yields a more robust determination of the point of departure for the phosgene RfC. 

Comment 2: Two reviewers offered comments on the BMD approach. One reviewer 

recommended a 5% response level as the point of departure for quantal endpoints in the BMD 

approach rather than a 10% level because the former was considered a closer approximation of 

the NOAEL. A second reviewer observed that for continuous data, the Agency used one 

standard deviation to define the benchmark response, but recommended that EPA consider two 

or more standard deviations from the mean based on Kodell and West (Risk Analysis, 1993). 

One reviewer recommended that the appendix with documentation of the BMD approach include 

a complete description of the actual source data and the methods and assumptions used, and that 

this appendix be appended to the IRIS summary as well as the Toxicological Review. 

Response 2: A 5% level of response was rejected because a group size of only eight rats did not 

provide sufficient statistical power to derive a 5% response level. The second reviewer referred 

to the continuous lung displacement volume data; the BMR selected for this continuous endpoint 

was one standard deviation. The Agency notes that the use of one standard deviation for 

continuous data is standard Agency practice as described in the Benchmark Dose Technical 

Guidance Document (U.S. EPA, 2000c). The Toxicological Review and IRIS summary were 

revised to provide a better description and interpretation of the principal study (Kodavanti et al., 

1997); citations for the published references, which provide the source data, are included in the 

appendix. It is not current practice to include detailed data in the IRIS summary; the 

Toxicological Review for phosgene now contains a complete description of the actual source 

data and detailed assumptions for the BMD modeling. 

Comment 3: One reviewer recommended modifying the calculation in the categorical regression 

analysis to include the lower 95% confidence bound on the CatReg point of departure. 

C-2 
Response 3: EPA has not published guidance for the use of CatReg for the determination of a 

point of departure for use in Agency risk assessments. The primary purpose of the CatReg 

analysis in this assessment is to show how a categorical regression analysis that takes into 

account the different severity grades of responses reported by Kodavanti et al. (1997) compares 

with the BMD analysis. The maximum likelihood estimate, ERD, reported by CatReg is 

comparable to the BMD estimate reported by BMDS. The lower bound confidence limit on the 

ERD is not reported because the existing version of the Agency’s CatReg software does not 

provide an estimate of the lower bound confidence limit on the ERD that is comparable to the 

BMDL reported by BMDS. 

3. NOAEL/LOAEL Approach 

Comment: Three reviewers commented on the C × T assumption (Haber’s Law) used to adjust 

from the intermittent exposure received by animals in the Kodavanti et al. (1997) study 

(6 hours/day, 5 days/week) to continuous exposure. All three acknowledged the complexity of 

the issues associated with application of the C × T assumption to the Kodavanti et al. data for 

phosgene. One reviewer agreed with the Agency’s use of the default C × T procedure given 

insufficient evidence to justify departure from the default. A second reviewer recommended not 

leaving the concentration unadjusted, and offered no suggestions for a better approach. The third 

reviewer indicated he was not opposed to the C × T approach as presented, but recommended 

that a more thorough discussion of the default assumption be provided. 

Response: A discussion of the applicability of Haber’s Law in making the exposure adjustment 

from intermittent dosing in the animal experiments to continuous exposures has been added. It 

says essentially that although Haber’s Law applies to acute exposures lasting on the order of 

minutes to several hours, it does not apply to intermittent exposures where there is a daily 

recovery period. In the latter situation, the data indicate that concentration is the appropriate 

dose metric. In the absence of data on continuous exposure for longer than several hours, the 

document assumes that continuous dosing for periods ranging from 6 to 24 hours would cause a 

progressive increase in lung damage; therefore, the C × T dose metric is appropriate for that 

period of time. 

4. Uncertainty Factors 

Comment 1: One reviewer noted that the appropriate uncertainty factors were applied and 

adequately explained. Two other reviewers agreed with the uncertainty factors applied by the 

EPA for variation in human susceptibility (UFH), animal to human extrapolation, and subchronic 

to chronic extrapolation. One reviewer commented that the uncertainty factor for subchronic to 

C-3
chronic extrapolation appeared reasonable, but that the evidence advanced to support the choice 

of uncertainty factors was not adequate. 

Response 1: The justifications for the uncertainty factors were expanded. 

Comment 2: One reviewer questioned whether a LOAEL to NOAEL uncertainty factor (UFL) as 

large as 10 was supported by the dose-response data. A second reviewer considered the UFL, 

which was applied to the LOAEL/NOAEL and categorical regression approaches to be 

reasonable, but further noted that this uncertainty factor was not applied in the benchmark dose 

approach. This reviewer recommended that an UFL of 10 be applied in the benchmark dose 

approach because he did not consider a BMDL10 as similar to an unqualified NOAEL. This 

reviewer offered as an alternative but less desirable option to use the BMDL10 with a UFL of 3. 

Response 2: The subchronic study by Selgrade et al. (1995) was used for the NOAEL/LOAEL 

analysis in place of the Kodavanti et al. (1997) study because it identified a lower LOAEL. A 

partial uncertainty factor of 3 rather than the full factor of 10 was used in the NOAEL/LOAEL 

approach because the impairment of lung immunological function in the Selgrade et al. (1995) 

study at the LOAEL of 0.1 ppm was considered to be a minimal effect. The effect was local to 

the lung, resulting in the impairment of the bacterial clearance process; the impairment occurred 

only during the exposure and it was not persistent after phosgene exposure stopped. EPA 

disagrees with the recommendation to include a UFL for the BMD method. Because the data on 

collagen staining were considered to represent minimal severity of lung damage, the BMDL10 

associated with a 10% response was considered an appropriate point of departure. Further, it is 

current Agency practice not to apply an additional uncertainty factor for LOAEL to NOAEL 

extrapolation when using the BMD approach. Accordingly, no additional uncertainty factor for 

LOAEL to NOAEL extrapolation was included in the BMD approach. 

Comment 3: Two reviewers questioned the inclusion of a database uncertainty factor of 3 for 

lack of chronic reproductive and developmental studies, noting the lack of consistency with 

statements elsewhere in the assessment that, due to the reactivity of phosgene, the primary toxic 

impacts are expected to occur at the point of first contact. One of the two reviewers supported 

removing the uncertainty factor based on lack of reproductive/developmental studies. The 

second reviewer observed that any effects on reproduction or development secondary to 

respiratory impairment of mothers or newborn offspring would be avoided where the healthprotective level was low enough to avoid such damage to the respiratory system. This reviewer 

raised the possible concern that impacts on the respiratory system might exacerbate or even 

C-4
cause asthma in some individuals, including children, although no evidence was presented to 

imply that such differential impacts would exceed the default UFH of 10. The reviewer 

recommended that further consideration be given to whether additional uncertainty factors are 

needed specifically to protect children from this or other health impacts. 

Response 3: The database uncertainty factor was changed from 3 to 1. As noted by the external 

reviewers, effects outside the respiratory system are not expected because of the short half-life of 

phosgene in the respiratory system, and it would not be expected that phosgene will migrate to 

the systemic circulation in concentrations large enough to cause reproductive or developmental 

effects. Justification for a database uncertainty factor of 1 was provided. 

B. Cancer Weight of Evidence 

Comment: Two reviewers agreed with the Agency conclusion that the available evidence for 

phosgene are inadequate to draw conclusions about the carcinogenicity of the chemical. The third 

reviewer offered no comments on cancer weight of evidence. 

Response: No response is required. 

C. Other Comments 

Comment 1: One reviewer observed that the characterization of the exposure duration in the 

Kodavanti et al. (1997) study on page 9 of the Toxicological Review as a “repeated acute 

exposure” was inaccurate, and that it was more correctly characterized as a subchronic study. 

Response 1: EPA recognizes that a 12-week exposure is not an acute study. The Toxicological 

Review (Section 4.2.2.1) referred to “acute” exposures (in quotes) as the characterization that the 

authors used in the description of their study. 

Comment 2: One reviewer recommended that consistent concentration units be used throughout 

the document. 

Response 2: The assessment was revised to provide equivalent concentration units to facilitate the 

conversion between units (e.g., from ppm to mg/m3). 

Comment 3: One reviewer observed that the CatReg point estimate of 0.088 ppm is sometimes 

C-5
expressed as 0.09 and sometimes as 0.1, but this value should be consistent throughout the 

document. 

Response 3: For the calculation of the HEC at the bottom of page 26 of the external review draft 

of the Toxicological Review, the CatReg value of 0.088 ppm, which reflects the unadjusted 

exposure concentration from the animal study, was rounded to 0.09 ppm. The human equivalent 

concentration (HEC) was calculated as 0.098 mg/m3, which was rounded to 0.1 mg/m3. Therefore, 

the two values are correct as presented in the assessment. 

Comments from the Public 

Comment 1: A reviewer commented that the application of Haber’s Law to chronic effects of a 

non-cumulative substance like phosgene is not well-founded. The sharp dose-response in the 

Kodavanti et al. (1997) study indicates the critical importance of exposure intensity rather than 

exposure duration, as illustrated by the results of Henderson et al. (1993) on effects of ozone 

exposure. 

Response 1: The Agency agrees that it is inappropriate to use Haber’s Law as the sole rationale 

for extrapolating the intermittent animal exposures to continuous animal dosing, as was done in 

the draft document. This is the default assumption used in most EPA evaluations. Since 

Kodavanti et al. (1997) found that variation in intermittent phosgene exposure durations in the 

range of 1 to 5 days per week had little influence on the events leading to lung fibrosis, the 

revised document deletes the 5/7 factor used in the default procedure. However, the 6/24 factor 

for partial day exposure was retained on the assumption that Haber’s Law is valid for continuous 

exposures in the range of a few hours to one day, as shown by earlier continuous acute exposures 

of phosgene. Henderson’s paper dealt with continuous exposures from 3 to 24 hours, and 

therefore, does not contribute to understanding the effect of intermittent phosgene exposures. 

Comment 2: A reviewer observed that exposure intensity, in addition to incidence, should be 

taken into account in the agency’s analysis. The agency should address not only whether the 

chronic effects are driven by (repeated) acute effects, but also that the acute threshold may be 

valid for chronic exposure. This suggested approach would be based on exposure intensity. 

Response 2: In agreement with the commentor, the EPA did consider phosgene concentration 

(which is equivalent to exposure intensity) to be the dose metric critical for lung damage leading 

C-6
to fibrosis. Acute phosgene experiments do not show a threshold, but do show a response 

dependent on C × T . The threshold as analyzed in the Henderson et al. (1993) paper was actually 

what EPA would call a “point of departure,” which is a response level that exceeds that of the 

controls, rather than a threshold dose below which there is no response. 

Comment 3: A reviewer commented that the draft review did not describe in sufficient detail the 

anatomical location of the lung lesions leading to fibrosis, the stains used to identify collagen 

deposition or the scoring criteria used for the pathological analysis. 

Response 3: The information on the stain used and a better description of the criteria that were 

used to judge the severity of the lesions was added to the document. 

Comment 4: A reviewer stated that the uncertainty factor for the CatReg analysis (x10) is not 

sufficiently justified and is overly conservative. 

Response 4: The CatReg analysis has been rewritten (see above discussions regarding the 

relation of CatReg to the BMD and NOAEL approaches). 

Comment 5: A reviewer commented that the draft does not distinguish between measured and 

nominal concentrations used in the various experiments and does not state the temperature and 

humidity conditions under which the experiments were carried out, nor the analytical procedures 

used. 

Response 5: The major studies used in the evaluation (Kodavanti et al., 1997; Hatch et al., 2001; 

Selgrade et al., 1995) were conducted in the same laboratory under the same temperature and 

humidity conditions, and the measured concentrations closely matched the targeted concentration. 

Therefore, there is no need to make concentration adjustments before comparing results between 

the major studies. The measured concentrations for the Kodavanti et al. (1997) study were added 

to the document. The deviation from targeted values was generally within 10% of the mean. 

Comment 6: A reviewer considered the derived RfC to be overly conservative from two points of 

view: (1) the BMD approach results in a lower RfC than the NOAEL approach, and although it is 

preferred, a better understanding of the role of exposure intensity and duration is likely to lead to 

a less conservative RfC, and (2) the RfC may be in the range of rural levels (non-anthropogenic 

sources) of phosgene. 

C-7 
Response 6: The agency agrees that the BMD approach is more valid because it uses more of the 

experimental data than the NOAEL approach, and has stated preference for that approach. 

However the agency is unwilling to speculate about whether better understanding of the role of 

exposure intensity and duration would eventually lead to a higher or lower RfC. 

The RfC derived in this assessment is 3E-4 mg/m3

 = 75 ppt. The current ambient levels of 

phosgene are not known with any degree of confidence but the 1977 phosgene concentration in 

clean air (rural and seacoast) locations averaged 22 ppt, which is about 0.3 times the RfC. Since 

the main precursors of phosgene in air are tetrachloroethylene and trichloroethylene, which have 

steadily decreased over the last 15 years, the current ambient air levels of phosgene are probably 

much less than 0.3 times the RfC. There is an obvious need for current ambient air measurements 

in order to answer this comment. 

C-8