### Page 2 of 69

Ethylene Oxide Regis tration Review Team

Human Health & Environmental Effects

Antimicrobials Division

Donna Randall

Srinivas Gowda Najm Shamim Siroos Mostaghimi

Tim McMahon Timothy Leighton

William Hazel

Environmental Fate and Effects Division

Ed Odenkirchen Meghan Radtke

H e Zhong Stephen Carey

Gabe Rothman

Health Effects Division Ray Kent Angela Howard

Sue Hummel

Ivan Nieves

Jessica Kidwell

Thurston Morton Jeffrey Dawson

Biological and Economic Analysis Division Sepehr Haddad

Michelle Ranville

L eonard Yourman

Risk Management

Donna Kamarei

Susan Bartow Rose Kyprianou Cathryn Britton

Sandra O’N eil l

Office of General Counsel Philip Ross

### Page 3 of 69



## Table of Contents

1 Introduction

................................ ................................ ................................ ............................. 5

1.1 Statutory and Regulatory Authority

................................ ................................ ................. 5

1.2 Updates to the Workplan

................................ ................................ ................................ .. 6

1.3 Case Overview

................................ ................................ ................................ ................. 7

1.4 Chemical Identification and Properties

................................ ................................ ............ 7

1.5 Use and Usage Profile

................................ ................................ ................................ .... 10

1.5.1 Registrations

................................ ................................ ................................ ........... 10

1.5.2 Summary of Registered Uses

................................ ................................ .................. 10

1.5.3 Usage Information

................................ ................................ ................................ .. 12

1.6 Regulatory History

................................ ................................ ................................ ......... 13

1.6.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 14

1.6.2 Tolerance Information

................................ ................................ ............................ 14

1.7 Incidents

................................ ................................ ................................ ......................... 15

1.7.1 Human Health

................................ ................................ ................................ ......... 15

1.7.2 Ecological

................................ ................................ ................................ ............... 15

2 Anticipate d Data Needs

................................ ................................ ................................ ........ 15

3 Human Health Risk Assessment

................................ ................................ ........................... 17

3.1 Existing Toxicological Endpoints

................................ ................................ .................. 18

3.2 Dietary Exposure

................................ ................................ ................................ ............ 20

3.2.1 Di etary (Food

- Conventional Uses)

................................ ................................ ....... 20

3.2.2 Dietary (Food

- Antimicrobial Uses)

................................ ................................ ...... 21

3.2.3 Dietary (Drinking Water)

................................ ................................ ........................ 21

3.2.4 Residue Chemistry (Conventional and Antimicrobial Uses)

................................ .. 21

3.3 Occupational and Residential Exposures

................................ ................................ ....... 21

3.3.1 Occupational Exposure

................................ ................................ ........................... 21

3.3.2 Residential Exposures

................................ ................................ ............................. 24

3.4 Aggregate and Cumulative Exposure and Risk

................................ .............................. 25

3.4.1 Aggregate Exposures and Risk

................................ ................................ ............... 25

3.4.2 Cumulative Exposure and Risk

................................ ................................ ............... 26

4 Ecological Risk Assessment

................................ ................................ ................................ . 26

4.1 Environmental Fate Assessment

................................ ................................ .................... 27

4.1.1 Clean Water Act

................................ ................................ ................................ ...... 27

4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 27

4.3 Ecological Effects Assessment

................................ ................................ ....................... 28

4.3.1 Mechanism of Action

................................ ................................ .............................. 28

4.3.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 28

4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 30

4.4.1 Wildlife Exposure Estimates

................................ ................................ ................... 30

4.5 Effects Analysis Plan

................................ ................................ ................................ ..... 32

5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 33

6 Next Steps

................................ ................................ ................................ ............................. 33

7 References

................................ ................................ ................................ ............................. 34

### Page 4 of 69

Appendix A T oxicology Profile

................................ ................................ ............................... 36 Appendix B Environmental Fate

................................ ................................ ............................. 40 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 44 Appendix D Product Chemistry

................................ ................................ ............................... 50 Appendix E Modeling Input Based on ETO Release Scenarios for Spices and Herbs

........... 52 Appendix F Output Example of AERSCREEN Estimated Environmental Concentration (EEC) for ETO Release Scenario 2

................................ ................................ .............................. 55 Appendix G Comments Received Concerning the Preliminary Work Plan

............................ 60

List of Tables

Table 1

– Summary of Anticipated Risk Assessments and Data Needs: ETO

............................... 7

Table 2

– Anticipated Registration Review Schedule

................................ ................................ .... 7

Table 3

– Chemical Identification of ETO

................................ ................................ ..................... 8

Table 4

– Physical/Chemical, Fate and Transport Properties of ET O and Major Reaction

Products

................................ ................................ ................................ ................................ ........... 9

Table 5

– Summary of ETO Registered Uses

................................ ................................ ............... 10

Table 6

– Maximum Rates for Registered Agricultural Uses of ETO

................................ .......... 12

Table 7

– Studies Anticipated as Needed for the Registration Review of ETO

........................... 16

Table 8

– Summary of Toxicological Doses and Endpoints for ETO, ECH, and EG Selected for

Use in Past Human Risk Assessments

................................ ................................ .......................... 18

Table 9

– Summary of Medical Facility SIC Codes

................................ ................................ ..... 22

Table 10

– ETO Air Concentrations from IMIS for All Medical SIC Codes

............................... 23

Table 11

– ETO Air Concentrations (ppm) from IMIS for All Available Medical SIC Codes (198 8 to 2007)

................................ ................................ ................................ ............................... 23

Table 12

– ETO Air Concentrations for Contract Sterilization Facilities

................................ .... 24

Table 13

– Selected Ecological Effects Endpoints for Risk Assessment of ETO

........................ 29

Table 14

– AERSCREEN Modeling Scenarios and Data Summary

................................ ............ 31

Table 15

– ETO

– Acute Toxicity

................................ ................................ ................................ . 36

Table 16

– ETO

– Subchronic, Chronic Toxicity Studies

................................ ............................ 36

Table 17

– Environmental Fate Properties of ETO

................................ ................................ ...... 40

Table 18

– Effects D ata on ETO

................................ ................................ ................................ ... 46

Table 19

– ECOSAR v1.11 Results for ETO

................................ ................................ ............... 46

Table 20

– Summary of the Most Sensitive Endpoints from Aquatic Toxicity Studies for EG (Degradate of ETO).

................................ ................................ ................................ ..................... 47

List of Figures Figure 1

– Conceptual Model for Ecological Exposure and Effects of ETO to Aquatic and Terrestrial Organisms

................................ ................................ ................................ .................... 28 Figure 2

– Proposed ETO air exposure scenario for the risk assessment.

................................ .... 32

### Page 5 of 69



# 1 Introduction

This document is the United States Environmental Protection Agency’s ( USEPA, EPA or “the

A gency”) Final Work Plan ( F WP) for ethylene oxide ( ETO ) . The F WP document explains what

EPA’ s Office of Pesticide Programs (OPP) knows about ETO , highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the Agency in conducting the review, and providing an anticipated tim eline for completing ETO ’s

review.

The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intends, by sharing this information in the docket, to inform the public o f what it knows about ETO and what types of new data or other information would be helpful for the Agency to receive as it moves toward a decision on ETO

.



# 1.1 Statutory and Regulatory Authority

The Food Quality Protection Act (FQPA) of 1996 mandated a registr ation review program. All pesticides distributed or sold in the United States generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risks to human health or

the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable

adverse effec ts to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

.
The Agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standa rd for registration. The regulations governing registration review begin at 40 CF R 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for eac h case. The docket is the Agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision.

The ETO Preliminary Work Plan (PWP) was publ ished on September 2 5 , 2013 and the 60

- day comment period ended on November 2 5 , 2013.

Public comments received concerning the PWP and documents associated with this registration

review can be viewed at http://www.regulations.gov in docket EPA

- HQ

- OPP

- 2013

- 0244 . Below is a summary of the issues relevant to this registration review case.

### Page 6 of 69



# 1.2 Updates to the Workplan

Since the publication of the PWP, the A gency has made the following updates:

 Corrected the ti meline in Table 2, the anticipated registration review table.

 Updated Section 6 , Next Steps.

 Added Appendix G, which includes the Agency’s response to comments submitted about

the PWP.

The Agency received 12 submissions from 10 commenters during the public comment period on

the initial docket. See Appendix G for the Agency’s responses to these comments.

Comments received did not result in a modification to the anticipated data needs in the ETO

PWP

. T his document makes final the work plan for the ETO registration review process.

Additionally , after the comment period closed

, the A gency received additional information from The Ethylene Oxide Sterilization Association, Inc. that will be considered in the risk assessment phase of registration review. This additional information can be found in the docket for the ETO

case.

### Page 7 of 69

Table 1

– Summary of Anticipated Risk Assessments and Data Needs : ETO

Risk Assessment Assessment Necessary to Support Registration

Review Date of Most

Recent

Assessment Type of

Assessment Required Data Anticipated

as Needed (See Table 7 for more detail)

Dietary (food /drinking water) No (see 3.2 ) 2008 None None

Occupational Handler Yes 2008 Updated Toxicity Exposure Air monitoring

Residential Handler No (see 3.3.2 ) 2008 None None

Residental Post Application

– Inhalation (bystander) Yes 200 7 Updated Special acute inhalation toxicity study

Aggregate & Cumulative No (see 3.4 ) 2008 None None

Tolerance Review Yes 2006 U pdated None

Ecological Yes 2011 Section 18 Updated Ecotoxicity and air monitoring data

N/A = Not applicable



### Table 2

– Anticipated Registration Review Schedule

Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2013

- 09 2013

- 09

- 2 5

Close Public Comment Period 2013

- 11 2013

- 11

- 2 5 Phase 2: Case Development

Issue Final Work Plan 2014

- 03 2014

- 03

Issue Data Call

- In (DCI) 2015

- 03

Receive Data to be Considered in Risk Assessment 201 9

- 03 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 20 20

- 09

Close Public Comment Period 20 20

- 10 Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 20 21

- 03

Close Public Comment Period 20 21

- 05

Issue Final Decision 20 21

- 09 Begin Post

- Decision Follow

- up 20 21 Total (years) 8

* The anticipated schedule will be revised as necessary ( e.g.
, need arising under the Endocrine Disruptor Screening Program with respect to the active ingredients in this case).



# 1.3 Case Overview

The docket for the ETO Case (Case 2275 ) has been established at http://www.regulations.gov in

docket number EPA

- HQ

- OPP

- 2013

- 0244

.



# 1.4 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in C ase 2275, ETO (PC Code 04 2 3 01 ). ETO

in its natural state is a colorless, highly reactive, and flammable gas at room temperature and ambient pressure

.

### Page 8 of 69

Table 3

– Chemical Identification of ETO

Common Name Ethylene Oxide ( ETO )

Chemical Name Oxirane

Dihydrooxirene Dimethylene oxide Diethylene oxide

Ethene oxide Oxacyclopropane Epoxyethane, 1,2

- Epoxyethane

Oxidoethane

IUPAC/CAS * Name Oxirane

Classification Epoxide

Oxirane Cyclic ether

PC Code 042301

CAS N umber 75

- 21

- 8

Molecular Formula C 2 H 4 O

H 2 COCH 2 Molecular Weight 44.052601 g rams /mol e (g/mole)

Molecular Structure:

* CAS: Chemical Abstracts Service ; IUPAC: International Union of Pure and Applied Chemistry



### The ETO product chemist ry and fate information (source: MRIDs 41531002, 42458502, 42466702, 42811401, 43053201

, and EPI Suite v4.1) relevant to conducting a risk assessment is

summarized in Table 4

. D etails of the environmental fate properties are discussed in Appendix B and product chemistry information in Appendix E. Three reaction products identified in open literature include ethylene bromohydrin (EBH), ethylene chlorohydrin (ECH), and ethylene glycol (EG) (USEPA 2008). Table 4 also presents the chemical identification and chemical properties of these degradat es

. The halogenated reaction products, EBH and ECH

, have been shown to result from fumigation

of foods with ETO due to interaction with natural bromides and chlorides present in the food

items. Residues of EBH and ECH are found in spices. At high steriliz ation concentrations, ETO reacts with moisture to form EG and, in the presence of sugars, glycol derivatives. Therefore,
EBH, ECH, and EG were the chemicals of concern for dietary (oral) exposure and were assessed

in the 2006 tolerance reassessment

. Until 1991, EG was a registered a.i. for use as an air

sanitizer/deodorizer , and is still an inert ingredient in pesticide formulations

.

### Page 9 of 69

Table 4

– Physical/Chemical, Fate and Transport Properties of ETO and M ajor Reaction

P roduct s

Common name Ethylene Oxide

( ETO ) Ethylene chlorohydrin (ECH) Ethylene

bromohydrin (EBH) Ethylene Glycol

(EG)

Chemical structure

Molecular Formula C 2 H 4 O C 2 H 5 ClO C 2 H 5 BrO C 2 H 6 O 2 Molecular Weight

, g rams /mol e 44.053 80.514 124.965 62.068

IUPAC name Oxirane 2

- chloroethanol 2

- bromoethanol Ethane

- 1,2

- diol

CAS name Oxirane 2

- chloroethanol 2

- bromoethanol Ethylene glycol

CAS # 75

- 21

- 8 107

- 07

- 3 540

- 51

- 2 107

- 21

- 1

PC Code 042301 600502 NA 042203, 800009 Melting point, degrees Celsius ( o C ) - 111.6

- 89

- 80

- 1 2.9

Boiling point

, o C 10.4 130 150 (EPISuite v 4.10 ) 195 Density or specific gravity , grams/liter (g/L) at 25 o C 1.80 1.2015

- 1.2025 1.494 at 20 o C 1.1155

Water solubility, at

20°C Not available Not available Not available Not available

Vapor pressure 1255 mm Hg at 25 o C

(EPI Suite, v4.10) 7.18 mm Hg at 25 o C

(EPISuite v 4.10 ) 2.06 mm Hg at 25 o C

(EPI Suite, v 4.10) 0.0609 mm Hg at 25

o C (EPISuite 4.10 ) Henry’s Law Constant

at 25 o C (atm

m 3 /mole) 1.48E

- 04

( Conway et al 1983 ) 7.61E

- 07 ( EPISuite v 4.10 ) 4.1 2E

- 07

(EPISuite v 4.10 ) 1.31E

- 07

(EPISuite v 4.10 )

Dissociation constant

, pKa NA NA NA NA

Soil Adsorption Coefficient (Koc), L/kg 4.662

(EPISuite v 4.10 ) 3.39 (EPISuite v 4.10 ) 4.374

(EPISuite v 4.10 ) 0.2239

(EPISuite v 4.10 )

Sludge Adsorption

, %

removal 1.65

(EPISuite v 4.10 ) 1.76 (EPISuite v 4.10 ) 1.76

(EPISuite v 4.10 ) 1.75

(EPISuite v 4.10 ) Log Octanol/water partition coefficient ( Log K
ow ) at 25 o C - 0.30

( EPISuite v 4.10 ) 0.112 ( EPI Suite, V4.10) 0.23

( EPISuite v 4.10 ) - 1.20

( EPISuite v 4.10 )

Bioaccumulation Factor, L/kg

- ww Not available Not available Not available Not available

UV/ VIS absorption

spectrum Not applicable, non

conjugated molecule Not applicable, non

conjugated molecule Not applicable, non

conjugated molecule Not applicable, non

conjugated molecule

Half

- life in air (days) 39

(EPISuite v4.10) Not available Not available Not available

Activated Sludge Biodegradation, %

removal Not available Not available Not available Not available

CAS = Chemical Abstracts Service; IUPAC = International Union of Pure and Applied Chemistry; NA = not applicable; UV = ultraviolet light; VIS = visible light

### Page 10 of 69



# 1.5 Use and Usage Profile

1.5.1 Registrations

As of March 27, 2014 , there were 2 3 registered Section 3 products and 1 Section 24(c) containing ETO

. ETO is formulated and marketed as a pressurized gas or liquid. The end use formulations are all gas mixtures of ETO and other gases (e.g., carbon dioxide) in varying

concentrations.



## 1.5.2 Summary of Registered Uses

Table 5 presents a su mmary of the registered uses of ETO that will be assessed in this registration review

.
1.5.2.1 Agricultural Uses

ETO is a commodity fumigant/sterilant registered for use to reduce microbials on whole and ground spices or other seasoning materials (40 CFR §180) , and to fumigate beekeeping equipment (e.g., wooden ware, boxes and frames) in North Carolina. Sterilization/fu migation with ETO must be performed only in vacuum or gas tight chambers designed for use with ETO. It is applied by commercial applicators only; there are no residential uses of ETO. It is used in vacuum chambers at full strength (100%) for herbs and spic es. The maximum application rate is 500mg/L (or 31.22 lb a.i./1000 ft 3 

### ) in a sealed chamber ( Table 6 )

.
1.5.2.2 Non

- Ag ricultural (Antimicrobial) Uses

The registered antimicrob ial uses of ETO include the fumigation/ sterilization of medical or laboratory equipment

, pharmaceuticals, and aseptic packaging (21CFR §201) ; or to reduce the microbial load on cosmetics; and to sterilize artifacts, archival material

, library objects, and

mu sical instruments (40 CFR §180).

Table 5

– Summary of ETO Registered Uses

EPA Registration

Number %ai Form Registration Type Use Site

7182

- 1 100 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

36736

- 8 100 Pressurized

gas Technical Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

58779

- 5 100 Pressurized

gas Technical Medical /lab items; pharmaceuticals

67470

- 6 100 Pressurized

gas Technical Medical/lab items; pharmaceuticals; packaging; spices; cosmetics

67470

- 7 100 P ressurized

gas Technical Medical/lab items; pharmaceuticals; packaging; spices; cosmetics

36736

- 2 100 Liquid Technical Industrial and/or medical uses

73711

- 5 100 Pressurized

gas EP Surgical instruments; hospital instruments; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hypodermic needles/syringes; veterinary hospital instruments

89514

- 1 100 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

### Page 11 of 69

EPA Registration

Number %ai Form Registration Type Use Site

69340

- 8 98.06 Pressurized

gas EP Surgical instruments; hospital instruments; o ral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hypodermic needles/syringes; veterinary hospital instruments

69340

- 2 97 Pressurized

gas EP Surgical instruments; heat labile materials; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hospital materials; first aid equipment; human face gear; contact lens

69340

- 7 97 Pressurized

gas EP Surgical instruments; hospital instruments; sterilizers; v eterinary hospital instruments

69340

- 4 96 Pressurized

gas EP Surgical instruments; surgical prosthetic parts; hospital instruments; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hospital materials ; surgical dressings; hypodermic needles/syringes; veterinary hospital

instruments

69340

- 6 96 Pressurized

gas EP Surgical instruments; hospital instruments; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hypodermic needles/syringes; veterinary hospital instruments

69340

- 5 90 Pressurized

gas EP Surgical instruments; hospital instruments; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hypoderm ic needles/syringes; veterinary hospital instruments

69340

- 1 89.4 Pressurized

gas EP Surgical instruments; hospital instruments; hospital critical equipment; heat labile materials; oral and inhalation equipment; diagnostic instruments/equipment; hospital critical rubber/plastic items; hospital materials; first aid equipment; veterinary hospital premises; veterinary hospital instruments; veterinary hospital critical equipment; human face gear; contact lens

36736

- 3 80 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

36736

- 5 20 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

36736

- 6 12 Pressu rized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

67470

- 10 10.4 Pressurized

gas EP Hospital instruments; laboratory instruments; pharmaceutical equipment; pharmaceutical materials

36736

- 4 10 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

67470

- 9 10 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; cosmetics

67470

- 8 8.6 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; cosmetics

36736

- 7 8.5 Pressurized

gas EP Medical/lab items; pharmaceuticals; packaging; spices; seasonings; artifacts, archival material, library objects

NC 070004 8.5 P ressurized

gas EP Bee keeping equipment

### Page 12 of 69

Table 6

– Maximum Rates for Registered Agricultural Uses of ETO

Use Method of

Application Single

Maximum Application

Rate Application

Conditions EPA Reg No.

Indoor Food:

Processed herbs, spices

and dried vegetables Sterilization

chamber / Fumigation

Chamber <500 mg/L

(a.i.) (<8hrs) & <500 mg/L (a.i.) (<16hrs) Evacuate the gas from

the chamber using a sequence of not less than 1) 21 steam washes, 5.0

PSIA at 115oF and 2) 16 steam washes, 5.0 PSIA

at 120oF 36736

- 2 (100% ai)

, 36736

- 3 (80% ai &

20% CO 2 )

, 36736

- 4 (10% ai & 90% CO 2 )

, 36736

- 5 (20% ai & 80% CO 2 )

, 36736

- 6 (12% ai & 88% dischlorodifluormethane)

, 36736

- 7 (8.5% ai & 91.5% CO 2 )

, 36736

- 8 (100% ai) & 67470

- 6 (100% ai)



## 1.5.3 Usage Information

According to the Biological and Economic Analysis Division (BEAD) (USEPA 2013a), agricultural uses for ETO include processed herbs and spices (except basil), and processed vegetables (dried/dehydrated). Sterilization or fumigation with ETO must be performed in

vacuum cham bers with outside venting designed for use with ETO. The Agency estimated about 8.2 million pounds of ETO were used annually in the U.S. for commercial fumigation or sterilization of medical and laboratory items or equipment an d about 800,000 pounds of ETO (approximately 10%) are used annually for fumigation of herbs and spices (USEPA 2008). ETO

treat ed spices account for 40

- 85% of spices consumed in the U.S. (ASTA, 2005). The use for vegetable processing comprises less than 1% of the total annual usage.

At the time of the 2008 RED, a pproximately 1,900 hospitals ha d in

- house ETO sterilization chambers. Hospitals tend to have small self

- contained units for ETO sterilization. Bulk sterilization occurs at contract sterilization facilities that handle multiple p allet sterilizations. The scope of materials potentially sterilized within these types of contract sterilization facilities is assumed to include medical devices (representing the majority of use), musical instruments, library and museum artifacts, and cos metic ingredients. There were a pproximately 30 contract sterilization facilities in the United States; 21 of those facilities represent ed 90 percent of the contract medical device sterilization capacity in the United States. In addition, many

manufacturers of medical devices use d ETO in

- house to sterilize their products. ETO’s pesticidal use to reduce microbial loads on cosmetics is minimal (less than 1 percent of total ETO pesticidal use).

At the time of the 2008 RED, t here we re approximately 9 contract sterilization facilities in the United States that treat both medical devices and spices and 6 contract sterilization facilities in the United States that only treat spices; each facility ha d 2 to 3 workers that are actively involved in the ETO treatment p rocess in some capacity.

The beekeeping use of ETO currently is limited to a state

- managed facility in North Carolina. The North Carolina Department of Agriculture and Consumer Affairs (NCDA&CS) uses 2 vacuum tight chambers designed for use with ETO. Both chambers are located outdoors. Approximately a half dozen employees in NC currently are involved with the ETO use for sterilization/fumigation of beekeeping equipment.

### Page 13 of 69



# 1.6 Regulatory Histor y

ETO was first registered as a pesticide in 1966. It has been used to treat food products since

19 57

. ETO is a FIFRA List B 1 

### reregistration pesticide through the FIFRA amendments of 1988

. ETO entered EPA’s Special Review process in 1978 based on concern for potential developmental toxicity, mutagenicity, and neurotoxic effec ts in workers. A Position Document 1 (PD1) was published in the Federal Register of January 27, 1978, to announce the initiation of the Special Review. In the early 1980s, the carcinogenicity of ETO became of concern and was added to the Special Review. On August 3, 2005, EPA opened the public docket with the preliminary risk assessments for ETO. The Agency completed its Reregistration Eligibility

Decision ( RED ) for ETO in 2008 and addressed the major risk s identified at that time due to occupational exposure

, which included the workers who are exposed while they work to sterilize medical instruments and spices. A voluntary request to terminate the u se o f ETO on basil was published in the Federal Register of October, 2008 and the c ancelation order followed on May
20, 2009 2



### . EPA’s Office of Research and Development (ORD), National Center for Env ironmental Assessment (NCEA) is re

- evaluating the carcinogenic potential of ETO as part of the Integrated Risk Information System (IRIS) program review

. The Special Review is still open, pending the

outcome of the IRIS review. The time line and projected dates for this re

- assessment are posted

at: http://cfpub.epa.gov/ncea/iristrac/index.cfm?fuseaction=viewChemical.showChemical&sw_id=1

004

. The Occupational Safety and Health Administration (OSHA) regulates worker exposure to ETO. In 1984, OSHA reduced the permissible exposure limit (PEL ) from 50 ppm to 1 ppm. In 1988,

OSHA established a short

- term exposure limit (STEL) of 5 ppm for exposures up to 15 minutes. In 1996, EPA required pesticide product label improvements to standardize precautionary statements, specify items to be treated wi th ETO, and require all users to adopt OSHA’s risk

reduction measures.

The EPA’s Office of Air and Radiation (OAR) promulgated ETO emission standards for sterilization facilities on December 6, 1994. The rule regulates major commercial sterilization

facili ties and area sources requiring the application of Maximum Achievable Control Technology (MACT) and/or Generally Available Control Technology (GACT). OAR assessed risks from residual ETO emissions after the application of MACT standards to determine if

fur ther control was warranted. After conducting this review, OAR determined that no additional control requirements were warranted. OAR issued a final decision for ETO emissions standards

for sterilization facilities on April 7, 2006 (available at http://www.epa.gov/fedrgstr/EPA

TOX/2006/April/Day

- 07/t3314.htm ). More r ecently, OAR analyzed ETO emissions from hospital sterilizers. OAR issued a final rule for hospital emissions on December 28, 2007 (availa ble at http://www.epa.gov/fedrgstr/EPA

- AIR/2007/December/Day

- 28/a25233.htm ). The final rule required that all hospitals that do not control their e missions of ETO reduce emissions by sterilizing full loads of equipment to the extent possible.

1 http://www.epa.gov/oppsrrd1/registration_review/

2 http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2008

- 0722

- 0001 and http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2008

- 0722

- 0025

### Page 14 of 69

The Food and Drug Administration (FDA) is an important federal partner in ETO regulation. For ETO’s medical uses, FDA reviews the efficacy of ETO in the sterili zation of a wide variety of medical devices and approves ETO sterilizers for medical use. Sterilization methods available in the United States for the sterilization of medical devices and regulated by FDA fall into two categories. The first category includ es sterilization methods used in health care facilities to resterilize devices designed for reuse in patient care. The second general category of sterilization subject to FDA regulation is the sterilization of manufactured medical devices (Murphy, 2006).

F or ETO’s spice uses, FDA is responsible for ensuring that food, including spices, is not adulterated or misbranded. FDA samples imported spice shipments as well as domestic spice commodities for the presence of pathogens. FDA detains spice shipments when p athogens are found. When a spice shipment is detained, a reconditioning proposal can be submitted by the responsible firm to FDA. ETO is often used to recondition the shipment. After the reconditioning, the shipment is tested again to verify that the conta minant load has been reduced. Also, as part of ensuring that foods are not adulterated, FDA is responsible for the enforcement of pesticide tolerances in foods.

The Federal Food, Drug, and Cosmetic Act ( FFDCA ) prohibits the marketing of adulterated or

misb randed cosmetics in interstate commerce and vests FDA with authority in this area. In addition, under the authority of the Fair Packaging and Labeling Act (FPLA), FDA requires an ingredient declaration for finished cosmetic products. ETO and its reaction p roducts (EBH, ECH, and EG) are not considered cosmetic ingredients. They are not listed in the International Cosmetic Ingredient Dictionary, the primary source of cosmetic ingredient nomenclature.

FDA also regulates finished cosmetic products after they are in commercial distribution and have entered interstate commerce. During the manufacturing of cosmetics, ETO is used as an ethoxylating agent for the synthesis of ethoxylated surfactants that are used in cosmetic products. FDA monitors cosmetic products for levels of 1,4

- dioxane, a reaction product of ETO formed during the ethoxylation process. There is a potential for residual ETO to be present in ethoxylated surfactants and cosmetic products containing these ingredients. In addition, there are

many cos metic ingredients that are derivatives of EG. Any unreacted EG present in a cosmetic ingredient, may also be present in a finished cosmetic product (Havery, 2008).



## 1.6.1 Recent/Pending Regulatory Actions

A DCI was issued in November 2007, in conjunction with the 2006 TRED, requiring submission of UV/visible absorption data for ETO (Guideline 830.7050), as well as a prenatal developmental toxicity study (870.3700), and a reproduction and fertility effects study (870.3800) for the reaction product ECH. Waivers were granted for the UV/visible absorption and prenatal developmental toxicity studies. The reproduction and fertility effects study was

submitted to the Agency in 2012 and currently is being reviewed.



## 1.6.2 Tolerance Information

The EPA Tolerance Reassessment Decis ion ( TRED ) for ETO was issued July 24, 2006. The TRED is available in the public docket EPA

- HQ

- OPP

- 2005

- 0203 located in the Federal Dock et Management System (FDMS) at http://www.regulations.gov

. Tolerances for ETO and ECH are

established under 40 CFR 180.151 for herb s and spice s, dried vegetable, and walnuts 3



### .

3 Tolerances for ETO and ECH were added for licorice roots, tops of peppermint and spearmint, and sesame seed in September 2009 . ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2008

- 0834

- 0036 )

### Page 15 of 69

Tolerances for ETO on basil were removed following the use being voluntarily cancelled by the registrant. The tolerance expression for ETO will be reviewed during registration review to ensure that it appropriately covers the metabolites and degradates of ETO and that it specifies the residues to be measured for each commodity.



# 1.7 Incidents

1.7.1 Human Health

The evaluat ion of incidents related to human exposure to ETO w as discussed in a separate memorandum from the Health Effects Division dated May 8, 2013 (D411127). For this evaluation, both OPP Incident Data System (ID S) and the Centers for Disease C ontrol and

Preventi on/National Institute for Occupational Safety and Health (CDC/ NIOSH) and Sentinel

Event Notification S y s tem for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredient ETO (PC Code: 042301). The purpose of the database search is to identify potential patterns in the frequency and severity of

the health effects attributed to ETO exposure.

From the IDE database, one incident was reported from Jan u ar y 2008 to Februar y 2013. This reported incident in volved a worker who attributed his acute promyeloctyic leukemia to ETO in his capacity as a worker at a sterilization facility. In the aggregate IDS database, which reports

hu man incidents of a minor nature, from January 1, 2008 to February 19, 2013 there were three reported incidents involving ETO . These incidents were classified as minor in severity

.

T he SENSOR

- Pestic ides database id e n tified nine cases, stemming from five events involving

ETO from 1998

- 2009 . All cases/ events involved a single active ingredient. One case was classified as moderate in severity and eight cases were classified as lo w in severity. Eight of the

nine cases were work related; s even of nine cases were exposures in a hospital.



## 1.7.2 Ecological

There ar e no reported incidents for ETO in the ecological incident ( EIIS ) or Avian Monitoring System ( AIMS ) databases, as well as no reports of aggregate incidents for the time period from

2005 to 2013

. The absence of reported incidents should not be construed as the absence of incidents. Incident reports for non

- target organisms typically provide information only on mortality events and plant damage. Sublethal effects in organisms such as abnormal behavior, reduced growth and/or impaired reproduction are rarely re ported, except for some phytotoxic effects in terrestrial plants. EPA's changes in the registrant reporting requirements for incidents in 1998 may also account for a reduced number of reported incidents. Registrants are now only required to submit detailed information on ’major’ fish, wildlife, and plant incidents. Minor fish, wildlife, and plant incidents, as well as all other non

- target incidents, are generally reported aggregately and are not included in EIIS. In addition, there have been changes in stat e monitoring efforts due to a lack of resources.



# 2 Anticipated Data Needs

Table 7 presents a summary of the data anticipated as being needed to support this registration

review.

### Docket Number EPA

- HQ

- OPP

- 2013

- 0244

www.regulati ons.gov
Table 7

– Studies Anticipated as Needed for the Registration Review of ETO

GLN Study Name Test

Substance Time Frame

(Measured in

months from DCI Receipt) Risk

Assessment(s)

Data Will Support Use Site(s)

Triggering Anticipated Data Requirement Applicable Exposure Scenario

Studies Anticipated to be Required through the Registration Review DCI

Special Study A cute inhalation toxicity

study 4 ETO 24 Occupational and bystander

inhalation All w orker/bystander acute inhalation exposures

870.4300 Chronic

toxicity/carcinogenicity study ECH 48 Occupational and

Residential Post

- harvest

fumigant use on food

commodities c hronic dietary exposure to ECH

875.1400 Inhalation exposure study

for applicators ETO 12 Occupational All applicator i nhalation exposure

875.1700 Product use information ETO 12 All All All

875.2500 Post

- application inhalation

exposure study ETO 12 P ost

- application (site specific) All emissions from specific facilities

Special study Monitoring data on

fumigated commodities 4 

### 4 ETO 24 Occupational All uses except for

medical items emission from treated commodities/materials and

the potential for occupational exposure due to

those emissions in the channels of trade after fumigation activities are complete Special Study Ambient Air Monitoring

Study ETO 36 Residential All ambient air concentrations for communities in proximity to treated facilities Special Study Avian Acute Inhalation

Toxicity Study 4

, 5 ETO 24 Ecological All

i nhalation of air emissions by non

- target wildlife Special Study Honeybee Acute Vapor

Exposure Toxicity Study 4 ETO 24 Ecological All

850.41 50 Vegetative Vigor 6

, 7 , Gas

Chamber Exposure Study ETO 24 Ecological All c ontact with air emissions by non

- target plants

4 A protocol is expected to be required to be submitted for review prior to conduct of the study.

5 An acute avian inhalation study using the Northern bobwhite quail species is expected to be necessary to satisf y the toxicity profile for ETO.

6 Data from five dicot species of at least three families (excluding soybean ( Glycine max ) which has already been tested) , and four dicot species of at least two families, one species of which is corn ( Zea mays ) are expected to be required

. Additionally of the ten species tested, at least one species should be a root crop (either a monocot such as onion or dicot such as carrot, table beet or sugar beet).

7 S tudies should be modified to accommodate exposure to a volatile substance by using env ironmental chambers that maintain the air concentrations of the gas , see 850.4230.

### Docket Number EPA

- HQ

- OPP

- 2013

- 0244

www.regulati ons.gov



# 3 Human Health Risk Assessment

In 2008, the EPA’s Office of Pesticide Programs (OPP ) published a human health risk assessment in support of the RED for ETO ( http://www.epa.gov/oppsrrd1/REDs/ethylene

- oxide

red.pdf )

. The Agency ’s OPP anticipates conducting a human health risk assessment for ETO as part of the registration review. This will inc lude both a non

- cancer and cancer risk assessment.

Non

- cancer endpoints for ETO and the reaction products of ETO have been previously selected and published by the Agency in the ETO RED. In the 2008 RED, it was recommended that a range of rodent unit risk estimates from 2.22 E

- 02 (mg/m 3 

### )

- 1 

### to 2.67 E

- 03 (mg/m 3 

### )

- 1 

### based on lung adenomas/carcinomas in male B6C3F1 mice at the high end and brain tumors in male F344 rats at the low end be considered for carcinogenicity risk assessment purposes. Since publication of the RED, the carcinogenic potential of ETO is being re

- evaluated by the National Center for Environmental Assessment’s IRIS program. The time line and projected dates for this re

assessment are posted at : http://cfpub.epa.gov/ncea/iristrac/index.cfm?fuseaction=viewChemical.showChemical&sw_id=1

004

.
When this re

- assessment is finalized, any modification to the carcinogenic potency estimate for

ETO will be used by OPP in conducting the carcinogenicity risk assessment for ETO

.

For ETO , the Health Effects Division’s Hazard and Science Policy Council (HASPOC) identified the need for a special acute inhalatio n toxicity study for ETO and additional information on the chronic toxicity and carcinogenicity of the ETO reaction product ECH. A special acute inhalation toxicity study is needed for ETO because as part of the risk assessment

for ETO , the Agency will nee d to conduct an acute worker and acute bystander assessment. This special study has shown to be useful in fumigant risk assessment because it often provides the

most sensitive acute e ndpoint for risk assessment. Inhalation studies with ETO have shown that the nasal cavity is a target organ for ETO

. Therefore, there is a reasonable likelihood that a special acute inhalation toxicity study would identify an endpoint that would be protective of acute effects in workers and bystanders exposed to ETO

.
This special acute inhalation toxicity study should include the evaluation of the following: histopathology of the respiratory tract, including incidence and severity at multiple tested concentrations; GSH measurements ( i.e. , nose); pharmacokinetics/tissue dosi metry including time course; and sublethal portal of entry effects ( i.e. , within the respiratory tract) along with information on dose response, incidence, and severity. The protocol for this special acute inhalation study should be submitted for Agency re view, prior to study initiation.

The HASPOC also concluded that an immunotoxicity study (as required in both the 158 conventional pesticide test rule and the 158 antimicrobial pesticide test rule) would not be

needed for ETO. This decision was made on the basis of several factors, including: (1) The toxicology databases for ETO and ECH do not reveal any evidence of treatment related effects on the immune system. The overall weight of evidence (WOE) suggests that ETO does not directly target the immune syste m; (2) Dietary risk assessments were not conducted for ETO since residues are unlikely to be found in sterilized spices available for consumption; (3) Dietary risk assessments for the reaction product ECH are based on the most sensitive endpoints from

stud ies conducted with the subject chemicals; (4) The dietary risk assessment indicates that for all supported commodities, the acute dietary exposure estimates for ECH indicate no risks of concern for the general population or other population subgroups. The chronic dietary exposure

### Page 18 of 69

estimates for both ECH and EG indicate no risks of concern for the general population or other population sub groups; (5) Points of Departure (POD ) for the most sensitive endpoints (neurotoxicity) seen in the most sensitive species (mouse) from a route

- specific study ( i.e.

, inhalation study) are used for assessing risks from short

- and intermediate term inhalation exposures to ETO; (6) A POD for the most sensitive endpoints in the most sensitive population (offspring) seen in a route

- specific ( i.e. , inhalation) study is used for assessing risks from long

term inhalation exposures to ETO.

The Agency also anticipates requiring additional information on the chronic toxicity and carcinogenicity of ECH. When considering whether the chronic toxicity and/or carcinogen i city studies were needed for ECH, the HASPOC used a weight of evidence ( WOE ) approach including: ( 1) the current use pattern which results in dietary exposure to ECH at up to 940 ppm as a residue on food commodities (ECH is not f ound in drinking water); ( 2) the lack of feeding studies in rodents (mice and rats) that could provide a POD or an endpoint of concern for assessing risk from chronic dietary exposures as well as asses the carcinogenic potential of ECH;

and ( 3) the lack of confidence in the available long

- term study (Johnson et al , 1967) which tested low levels of ECH in drinking water in an inadequate number of animals

.
The HASPOC concludes that data to inform the potential for chronic toxicity and/or carcinogenicity are n eeded for ECH at this time. The rat chronic/carcinogenicity study and/or the carcinogenicity study in mice may be conducted to fill this need. However, if there are additional exposure, pharmacokinetic, or other data/information which could be used to bett er understand the exposure or toxicological profile of ECH, the registrant is encouraged to discuss this

information with the Agency

. 

# 3.1 Existing Toxicological Endpoints

Toxicological endpoints were selected for ETO , ECH, and EG as part of the 2008 RED. The existing endpoints are shown below in Table 8

. All available information including existing guidelines toxicology studies, valid scientific literature, and the studi es that are expected to be required for registration review will be considered in establishing the endpoints to be used in the registration review risk assessment. A detailed description of the toxicity studies is provided in Appendix A

.

Table 8

– Summary of Toxicological Doses and Endpoints for ETO

, ECH

, and EG Selected

for Use in Past Human Risk Assessments

Exposure

Scenario Dose Used in

Risk Assessment,

UF Special FQPA

SF* and Level of

Concern for

Risk Assessment Study and Toxicological Effects

ECH Acute Dietary (General populations) Dose for Risk

Assessment = 100 mg/kg/day

UF = 1000

Acute RfD = 0.1 mg/kg/day FQPA SF = 1X

aPAD = acute RfD FQPA SF

= 0.10 mg/kg/day Developmental Toxicity Study

– CD

- 1 Mice

(Courtney et al ., 1982) At 150 mg/kg/day, 75% mortality of maternal animals

observed after 2

- 4 treatments (days) of dosing. Note:

Th e study NOAEL/LOAEL for this endpoint is

different from the overall study NOAEL/LOAEL.

### Page 19 of 69

Exposure

Scenario Dose Used in

Risk Assessment,

UF Special FQPA

SF* and Level of

Concern for

Risk Assessment Study and Toxicological Effects

Chronic Dietary (All populations) NOAEL= 45

mg/kg/day

UF = 1000

Chronic RfD = 0.045 mg/kg/day FQPA SF = 1X

cPAD = chronic RfD FQPA SF

= 0.045 mg/kg/day Subchronic Toxicity Study

– Albino Rats (Courtney

et al ., 1982). LOAEL: 67.5 mg/kg/day Decreased mean body weight in males (↓34%), poor
survival, i.e. , 32% in males and 24% in females as compared to 100% in control males and 96% in control females, labored breathing and gross effects

such as dark liver a nd lungs and hemorrhagic gastro intestinal tissues and adrenal and pituitary glands. Histopathological effects include subacute myocarditis, colloid depletion in thyroid, thyroid congestion, fatty liver and congestive pulmonary changes.

EG

Chronic Dietary (All populations) NOAEL= 40

mg/kg/day

UF = 100

Chronic RfD = 0.4 mg/kg/day FQPA SF = 1X

cPAD = chronic RfD FQPA SF

= 0.4 mg/kg/day Chronic Oral Toxicity in Rats (DePass et al ., 1986b).

Increased oxalate crystals in urine of both sexes and possible fatty liver changes in females at 200 mg/kg/day. At the HDT, 100% mortality by 12 months, decreased body weight, changes in clinical chemistry and hematological parameters, organ weight changes, and chronic nephritis in males and mild fatty change s in the liver of females.

ETO

Inhalation

Short

- Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL= 7.5

ppm (13.5 mg/m 3 )

Inhalation Absorption Rate =

N/A Residential

MOE =N/A

Occupational

MOE = 30 Subchronic Inhalation Toxicity Study in Mice

(Snellings et al ., 1984a) LOAEL = 37.5 ppm (68 mg/m 3 ) based on neurological effects (altered gait and decreased motor activity) and absolute and relative organ weight changes

Inhalation Long

- Term (> 6 months) NOAEL= 7.5

ppm (13.5 mg/m 3 )

Inhalation Absorption Rate =

N/A Residential

MOE =N/A

Occupational

MOE = 30 Two Generation Reproduction Study, Inhalation

Exposure, Rats (MRID 42788101) Systemic LOAEL = 25 ppm (45 mg/m 3 ) based on decreased mean body weight gains in F0 males and females and F1 males during premating period. Reproductive LOAEL = 25 ppm based on increased postimplantation loss (two

- fold) and decreased live pups per litter in F0 generation were observed. Offspring LOAEL = 25 ppm based on decr eased mean pup body weight gain in both F0 and F1 generations.

Cancer (Inhalation) Studies indicate p ositive evidence for carcinogenicity in animals and humans. The Agency is

currently determining the carcinogenicity classification of ETO

. Unit Risk Factor (CDHS) based on mononuclear leukemia in female rats and analysis by linearized multistage model = 8.8x10

- 5 per μ g/m3 or 0.16 per ppm Unit Risk Factor (ORD, Pending Review) based on lympho hematopoietic cancer in humans and analyzed by linear regress ion = 9.0 x 10

- 4 per μ g/m3 or 1.6 per ppm
UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = referenc e dose, MOE = margin of exposure, LOC = level of concern, N/A = Not Applicable, HDT = highest does tested, CDHS = California Department of Health Services

### Page 20 of 69



# 3.2 Dietary Exposure

In the tolerance reassessment conducted for ETO in 2006, study data from spice ste rilization

indicated that ETO levels declined rapidly after sterilization, but persistent levels of ECH and

EG remained. Therefore, endpoints were selected to assess risks associated with dietary exposure to these reaction products. The assessment in the 2 006 TRED indicated no risks of concern for acute or chronic dietary exposure to ECH or EG

.


## 3.2.1 Dietary ( Food

- Conventional Uses)

The most recent dietary exposure and risk assessment (B. Daiss, 6/30/09, D P 316651) was performed as an addendum to the June 21

, 2006 assessment (conducted for the TRED) of dietary risk from exposures to ECH resulting from use of ETO as a food fumigant using an improved fumigation process (B. Daiss, D P 316677). This addendum revised the dietary exposure

assessment to include the fol lowing commodities: licorice, roots; peppermint, tops, dried; sesame, seed; spearmint, tops, dried. Based on the revised dietary analysis, inclusion of the four listed commodities did not significantly affect the dietary risk assessment. This assessment

co ncluded that for all supported commodities, including those listed, the acute dietary exposure

estimates for ECH were below t he Agency ’s level of concern. The acute dietary exposure (food only) utilized 96% of the aPAD for the highest exposed population su bgroup, children 1

- 2 years of age. It was based on a refined acute dietary risk assessment of exposure to ECH conducted using the Dietary Exposure Evaluation Model (DEEM

- FCID  , Version 2.03) which uses food consumption data from the USDA’s Continuing Surve ys of Food Intakes by Individuals (CSFII)

from 1994

- 1996 and 1998. Residue data for this assessment was provided in 2001 ETO spice sterilization study submitted by the American Spice Trade Association (ASTA) (MRID 46635201). The entire distribution of fumi gated commodity residues was used for the acute

assessment. Since specific residue data are not available for the four additional commodities added to the analysis (licorice roots, peppermint tops, sesame seed, and spearmint tops), existing data for spice commodities were assumed to be representative of those commodities. Maximum percent crop treated (sterilized) was used for the acute assessment.

Refined chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation
Model (DEEM

- FCID  , Version 2.03), and the Lifeline Model Version 2.0 which use food consumption data from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII)

from 1994

- 1996 and 1998. Residue data obtained from an ETO spice sterilization study were used for the chronic assessments. Average residues and average percent crop sterilized were used

for the chronic assessment. Only the ETO reaction products, ECH and EG , were included in the dietary assessment for ETO treated commodities products.

The chronic dieta ry exposure estimates for both ECH and EG were below t he Agency ’s level of

concern. For ECH , the DEEM and Lifeline model chronic dietary exposure estimates for the highest exposed population subgroup, children 1

- 2 years of age, were both 38% of the chronic population adjusted dose ( cPAD ) for treated commodities. For EG , the DEEM and Lifeline model chronic dietary exposure estimates for the highest exposed population subgroup, children

1

- 2 years of age, were 19% and 12% of the cPAD respectively for treated c ommodities.

The dietary exposure database is adequate to support the existing registrations.

### Page 21 of 69



## 3.2.2 Dietary (Food

- Antimicrobial Uses )

There is no anticipated dietary exposure in food from the non

- agricultural (antimicrobial) uses of

ETO (see 1.5.2.2 ) . A dietary assessment will not be needed for the exposures resulting from

antimicrobial uses of ETO

.


## 3.2.3 Dietary ( Drinking Water )

Based on the chemical and ph ysical properties (see 4.1 and Appendix B )

, t here is no drinking

water exposure to ETO residues expected from the currently registered uses of ETO . Therefore, residue chemistry data or assessment of risk associated with drinking water is not expected to be

needed.



## 3.2.4 Residue Chemistry ( C onventional and A ntimicrobial U ses)

ETO residues disappear rapidly after sterilization and are unlikely to be found in spices and other food commodities by the time they are available for consumption. ECH and EBH have been shown to result from fumigation of foods with ETO due to reaction with n atural chlorides and bromides present in the crop. At high sterilization concentrations, ETO reacts with moisture to

form EG and, in the presence of sugars, glycol derivatives. Spice sterilization study data indicate persistent high levels of the reaction products ECH and EG in treated spices and herbs and

walnuts. EBH residues are also found in treated commodities but are minimal relative to ECH

. No residues are expected in livestock commodities as a result of ETO fumigation, as no livestock

feedstuffs are treated (see 1.5.2.1 )

. The qualitative nature of ETO residues in plants is adequately understood. The residues of potential concern in plants are ECH and EG becau se of the high levels of these reaction products present in treated spices and herbs and walnuts. ETO is not considered a residue of concern for dietary exposure because data from an ETO spice sterilization study indicate that it disappears rapidly after s terilization. ECH is a reaction product from sterilization of herbs, spices and walnuts. ECH is not removed by out

- gassing.

The residue chemistry database for ETO is adequate for registration r eview (see Appendix B and Appendix D )

. 

# 3.3 Occupational and Residential Exposures

3.3.1 Occupational Exposure

3.3.1.1 Conventional Uses

In the 2008 RED, c onventional uses for ETO include sterilization in the spice industry and for beekeeping eq uipment in North Carolina

. I nhalation exposure was identified as the route of most

concern

. While there may be potential for dermal exposure to residues of ETO reaction products,

ECH and EG

, durin g post

- sterilization activities; t he Agency concluded that h andling of the actual treated materials is limited, and therefore, dermal exposure is negligible.

In the most recent assessment of ETO occupational exposures (Crowley, M., 3/24/2008, D347717), inhalation exposure was assessed using observational monitoring data submitted by the American Spice Trade Association ( ASTA ) where two workers at two different facilities were monitored for 10 days

. Inhalation exposures were assessed for short

- , intermediate

- , and long

- term durations and it was assumed that worker ex posure for the sterilization process for the spice industry and the beekeeping equipment were substantially similar

. No worker exposure

### Page 22 of 69

frequency data was submitted to the Agency regarding ETO spice sterilization activities; therefore, it was assumed that exposure frequency was 240 days per year. For activities associated with sterilizing beekeeping equipment, it was indicated that ETO can be used approximately 40 times per year (Crowley, M., D347717, 3/24/08; electronic mail correspondence from Dan Hopkins , NC Dept. of Agriculture to Susan Bartow, EPA/OPP/SRRD; 2/7/2008).

The results of the 2008 risk assessment indicate that in some circumstances ETO exposures could occur at levels which are of concern to the Agency ; however, this conclusion is based on

ver y limited information. EPA anticipates requiring data regarding potential worker exposure associated with commodity fumigation as detailed in sections 3.3.1.3 and 3.3.2.3 below.

Further consideration may be given to post

- application exposures pending future evaluation of the air monitoring data submitted. As part of registration review, tasks near fumigat ion

facilities /operations need to be defined to properly assess risks to workers performing p ost

application activities ( i.e.

, aerators, fork

- lift operators, etc. ). Potential exposures due to off

gassing will also be assessed for workers conducting post

- application activities near treat ment operations

.
3.3.1.2 Antimicrobial Uses

Antimicrobial use site s of ETO include m edical d evices

, musical instruments, library and museum artifacts, and cosmetic ingredients

. Two sources of observational information were used

to assess the medical device sterilization in the 2008 RED. Information obtained from OSHA’s Integrated Management Information System (IMIS) was used as the basis for the medical facility treatments (DP339831) and a subm ission by the ETO Sterilization Association, Inc (MRID 47331801, DP348868) was used as the basis for the contract sterilization facility treatments. The scope of materials potentially sterilized within the contract sterilization facilities includes

medical devices (representing the majority of use), musical instruments, library and museum artifacts, and cosmetic ingredients.

The 2008 RED assessment of the medical facility treatments using the IMIS data base covered the years from 1979 to 1987 and from 1988 to 2007 (DP339831). The delineation by years was necessary to reflect the 1988 OSHA Standard. The 2008 RED assessment of the medical facilities was based on the Standard Industrial Classification (SIC) codes and facility descriptions provided in Table 9

. The summaries of the air concentrations associated with the medical

industries listed in Table 9 are provided in Table 10 and Table 11 below. The data used in these analyses were restricted to 8

- hr time weighted averages (TWA) from personal air samplers from

the observational data

. It should be noted that the air samples were not exclusively obtained from

one part icular area in the medical facility ( e.g. , sterilization chamber) rather they were taken from every area that the person entered during his/her 8

- hour work day and averaged over time

to obtain an 8

- hr TWA.

Table 9

– Summary of Medical Facility SIC Codes

SIC Code Description

3841 Surgical, Medical

Instruments and Apparatus Establishments primarily engaged in manufacturing medical, surgical, ophthalmic,

and veterinary instruments and apparatus

### Page 23 of 69

SIC Code Description

3842 Orthopedic,

Prosthetic, and Surgical Appliances and Supplies Establishments primarily engaged in manufacturing orthopedic, prosthetic, and

surgical appliances and supplies, arch supports and other foot appliances; fracture appliances, elastic hosiery, abdominal suppor ters, braces, and trusses; bandages; surgical gauze and dressings; sutures; adhesive tapes and medicated plasters; and personal safety appliances and equipment.

6324 Hospital and

Medical Service

Plans Establishments primarily engaged in providing hospita l, medical, and other health

services to subscribers or members in accordance with prearranged agreements or service plans.

8011 Offices and Clinics

of Doctors of

Medicine Establishments of licensed practitioners having the degree of M.D. and engaged in

the practice of general or specialized medicine and surgery.

8043 Offices and Clinics

of Podiatrists Establishments of licensed practitioners having the degree of D.P. and engaged in

the practice of podiatry.

8051 Skilled Nursing Care

Facilities Establishments primarily engaged in providing inpatient nursing and rehabilitative

services to patients who require continuous health care, but not hospital services.

8062 General Medical and

Surgical Hospitals Establishments primarily engaged in providi ng general medical and surgical

services and other hospital services.

8063 Psychiatric Hospitals Establishments primarily engaged in providing diagnostic medical services and inpatient treatment for the mentally ill.

8069 Specialty Hospitals,

Except Psychiatric Establishments primarily engaged in providing diagnostic services, treatment, and

other hospital services for specialized categories of patients, except mental.

8099 Health and Allied

Services, Not

Elsewhere Classified Establishments primaril y engaged in providing health and allied services, not

elsewhere classified.



### Table 10 illustrates the reduction in air concentrations based on the 1988 OSHA Standard. Only

the air concentrations from 1988 to 2007 were used in the assessment for the 2008 RED to

reflect the curr ent practices as of 2008. Table 11 provides the air concentrations for all medical

SIC codes as well as a delineation of air concentr ations by individual SIC codes.

Table 10

– ETO Air Concentrations from IMIS for All Medical SIC Codes

Statistic 1979 to 1987 (ppm) 1988 to 2007 (ppm)

Arithmetic mean ± std 2.44 ± 24 0.49 ± 2

50 th %tile 0.029 0.026

75 th %tile 0.17 0.21

90 th %tile 0.83 0.83

Maximum 312 22

Number of observations 171 343

Note: 1⁄2 Level of Detection ( LOD ) (where LOD = 52.2 ppb for years prior to 1984 and 3 ppb for years 1984+) was used for all

non

- detects



### Table 11

– ETO Air Concentrations (ppm) from IMIS for All Available Medical SIC Codes (1988 to 2007)

SIC Code All

codes 3841 3842 6324 8011 8043 8051 8062 8063* 8069 8099

Arithmetic mean 0.49 0.43 0.65 0.22 0.20 0.0015 0.57 0.42 NA 0.09 2.02

Std 2.0 0.46 1.91 0.39 0.20 0.0 0.98 2.13 NA 0.20 4.85

50%tile 0.026 0.37 0.16 0.0015 0.20 0.0015 0.0015 0.0015 NA 0.03 0.05

75%tile 0.21 0.52 0.50 0.34 0.20 0.0015 0.85 0.09 NA 0.07 0.51

90%tile 0.83 1.09 1.18 0.54 0.20 0.0015 1.36 0.65 NA 0.17 5.69

M in 0.0015 0.0015 0.0015 0.0015 0.20 0.0015 0.0015 0.0015 NA 0.0015 0.02

M ax 22.0 1.7 13.8 0.67 0.20 0.0015 1.7 22.0 NA 0.83 13.0

Number of observations 343 18 76 3 1 2 3 216 NA 17 7

* No samples were collected after 1988 for SIC Code 8063.

### Page 24 of 69

The 2008 RED assessment of the contract sterilization facilities was based on the ETO Sterilization Association, Inc., submission (MRID 47331801, DP348868). Their submission (2008) is a summary of existing ETO observational air concentration data obtained from 21

contract sterilization facilities. At the time of the submission, the 21 facilities represented 90 percent of the contract sterilization facility capacity in the United States. ETO air concentrations were retrieved from worker activity log sheets a s well as the facility records of the air

concentrations.

The results of the inhalation exposure to workers that were used in the 2008 RED assessment are reported in Table 12

. The average inhalation exposure to workers not wearing respirators ( i.e.

, workers working in areas of the facility not in the aeration/unloading rooms) is 0.30 ± 0.57 ppm (n=271). For the workers involved in the aeration process, hence wearing re spirators for some portion of the work shift, the average inhalation exposure is 0.15 ± 0.10 ppm (n=294) (adjusted for respirator use if appropriate). For a more detailed description of the sampling methodology

the reader is referred to D P 348868.

Table 12

– ETO Air Concentrations for Contract Sterilization Facilities

Statistic Individual Sampling Badge

Results for Workers in Areas Needing No Respirator (ppm) Workers involved in aeration process ( i.e

. , onl y workers who wore respirators) (ppm)

Arithmetic mean ± std 0.30 ± 0.57 0.15 ± 0.10

50 th %tile 0.10 0.13

75 th %tile 0.27 0.21

90 th %tile 0.63 0.27

Maximum 5.30 0.52

Number of observations 271 294

Note: 1⁄2 LOD to the full LOD was used for all non

- detects

.


### The 2008 RED process resulted in additional mitigation measures to further reduce the potential exposure and risks to workers. The upcoming r egistration r eview assessment should be based on the air concentrations post

- mitigation. The reassessment of the air concentrations in both medical facilities and contract sterilization facilities would be better refined by the submission of the most current OSHA data ( available at http://www.osha.gov/opengov /healthsamples.html ). Post

mitigation contract facility observational monitoring data would also help refine the upcoming

r egistration r eview assessment. In lieu of post

- mitigation air concentration data, the above

estimates from the 2008 assessment for th e RED would be used in the reassessment.

3.3.1.3 Occupational Data Anticipated as Needed

The following data are anticipated to be required for ETO:

875.1400

– applicator inhalation data

875.1700

– product use data



## 3.3.2 Residential Exposures

There are no residential handler (applicator) uses for ETO.

3.3.2.1 Conventional U ses

There is a potential for bystander exposures which can occur from emissions during treatment

and aeration of commodities associated with ETO

. In 2005 , the EPA’s Office of Air and Radiation (OAR) conducte d a residential risk assessment for ETO which estimated cancer as

### Page 25 of 69

well as acute and chronic non

- cancer risk to bystanders ( EPA/OAR, Mark Morris, 2005; http://www.epa.gov/ttnatw01/eo/eo_rra.pdf )

. Based on the results, according to the RED, the Agency concluded that potential cancer and non

- cancer risks did not indicate any further regulatory action was necessary at the time for residential inhalation exposure. As a supplement to the 2005 OAR analys is and any future refinements of their analysis, bystander exposures will

be reassessed, for registration review and as per other fumigants, using c omputer modeling ( e.g.
, PERFUM)

. There is sufficient information to complete such analyses for ETO

. However, in the event that the available information suggests that there may be bystander risks of concern, a more refined analysis would be possible if additional data were available . T ypes of information that could be used to refine the bystander assessment incl ude: information on treatment conditions such as

volume s treated

, concentration/time schedules used , release height

, and air exchange rates

. In summary, to the extent that the available data show potential for bystander exposure, updated

residential assess ments will be conducte d during registration review. Additionally, the OAR bystander assessment and any refinements to this analysis will be considered as appropriate.

3.3.2.2 Antimicrobial Uses

P otential residential exposure may result from the use of ETO as a sterilant for musical wind instruments, and from releases from commercial sterilization sources. Based on a qualitative screening

- level risk assessment conducted in the 2008 RED, residues from the use of ETO for

the sterilization of musical wind inst rument are not likely to result in adverse health effects to musicians (D. Smegal, D309124, 2/15/05). No additional information is available to contradict this qualitative screening assessment, thus the Agency is not anticipating quantifying this

scenario during r egistration r eview.

The 2008 residential/bystander assessment of releases resulting from commercial sterilization sources relied on EPA’s Office of Air and Radiation (OAR) residual risk assessment conducted

in 2005 for ETO (DP338729) as cited in se ction 3.3.2.1

. The ambient air assessment was based on the EPA Human Exposure

- Screen (HEM

- Screen). The HEM

- Screen model contained (1) an atmospheric dispersion m odel with meteorological data, and (2) U.S. Bureau of Census population data for 2000 and the census block level. The HEM

- Screen's dispersion model is a

Gaussian model. OAR estimated ambient concentration at census blocks at varying distances

from ETO comm ercial sterilization sources. For details of the assessment the reader is referred to

DP338729. An updated residential assessment will be conducted during registration review.

3.3.2.3 Residential Data Anticipated as Needed

The following data are anticipated to be required for ETO:

875.2500

– Post application bystander inhalation exposure data Special Study

- Monitoring data on fumigated commodities



# 3.4 Aggregate and Cumulative Exposure and Risk

3.4.1 Aggregate Exposures and Risk

As noted in the 2008 RED for ETO , “An aggregate assessment of risk is not required because drinking water exposures are not expected and there is not a common chemical exposure for residential and dietary exposure scenarios ( i.e. , the reaction products ECH and EG are the

### Page 26 of 69

chemicals of concern f

or dietary exposure while ETO is the compound of concern for residential exposure).



## 3.4.2 Cumulative Exposure and Risk

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “ava ilable information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether ETO has a common

mechanism of t oxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to ETO and any other substances and, ETO

does n ot appear to produce a toxic metabolite produced by other substances which have

tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has

not assumed that ETO has a common mechanism of toxicity with other substances

. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/

. 

# 4 E cological Risk Assessment

In accordance with EPA regulations (40 CFR Sections 158. 630

, 660 , and 1300 ), indoor

conventional pesticides involving substances of a gaseous, highly volatile liquid or highly

reactive solid do not typically require submission of environmental fate data, or data on effects to

non

- target terrestrial wildlife, aquatic organisms, or plants. Similarly for the antimicrobial sterilization use, the Agency has not required submission of environmental fate or effects data. Therefore, the i nformation that is currently available on the fate and effects of ETO is based on public literature and fate and effect models.

The Agency has not conducted a quantitative ecological risk assessment for the ETO uses

. Previous assessments have presumed indoor uses would not result in exposures of concern to the

environment based on an assumption that exposures to non

- target wildlife, aquatic organisms, and plants from such labeled indoor uses of a gaseous substance are negligible. However, considering the production volume used for fumigation and monitoring data from use fa cilities demonstrating releases of ETO

, a more quantitative assessment of risks will be conducted during registration review. T he ecological risk assessment planned during regi stration review will allow

the Agency to determine potential risks to organisms exposed to ETO transported from treatment

sites into the environment. The risk assessment also will allow the Agency to determine whether

use s of ETO ha ve 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or the ir designated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the Agency will

consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.

### Page 27 of 69



# 4.1 Environmental Fate Assessment

E TO is a gas in its natural state, and is used primarily as a fumigant

. For this use

, ETO enters the

environment primarily when gases are vented during aeration

. ETO released to the air is expected to be persist e nt

. ETO is highly water soluble (1000 g/L at 25 o 

### C, EPI Suite version

4.10 ) but also has a high tendency to volatilize from water (half

- life <1 hour, Conway, 1983;

vapor pressure 1255 millimeters of mercury, EP ISuite v 4.10 ). Additionally ETO is not stable in aqueous medium (fresh water and sea water) under aerobic condition s and in water the concentration of ETO would be further reduced due to hydrolytic degradation. The likely hydrolytic degradates are: EG

, ECH , and possibly EBH

. A st udy by Gomer , and Noyes (1950),

showed that ETO au t ocatalyzes into methane, ethane, hydrogen, and carbon dioxide (MRID 49126104). Since ETO is biodegradable and volatile

, it is not likely to be present in gr ound

water. Based on the chemical and physical properties, ETO is unlikely to accumulate in soils or sediments and it will volatilize as water evaporates, leach through the soil, or be removed by runoff during rainstorms. Also, ETO has a low Log Kow (

- 0.30 , EPISuite v4.10) and is not likely

to bioac c um ulate

.
The potential for risk concerns from ETO use is most likely through the inhalation pathway.



## 4.1.1 Clean Water Act

ETO is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clea n Water Act

. 8 

### In addition, no Total Maximum Daily Loads (TMDL) have been developed for ETO

. 9 

### EG was identified as contributing to the impairment of the Creek

near Iowa Inte r n ational Airport, where the deicing is carried out on planes by using glycol. The

TMDL established a daily maximum for glycol of 125 mg/L and for a thirty

- day average it is 190.0 mg/L. T hese TMDL are not associated with ETO use as a pesticide

. More information on impaired water bodies and TMDLs can be found at EPA’s website

. 10



# 4.2 Conceptual Model s for Environmental Exposure Pathways

Based on the summary of registered uses of ETO presented in Table 5

, physical/chemical properties and environmental fate data presented in Table 4 and Appendix B, the Age ncy has developed a conceptual exposure model diagram for terrestrial and aquatic organisms to ETO

. U nder ambien t environmental conditions, ETO released to air is expected to be persistent resulting in potential inhalation exposure of terrestrial wildlife. There is some indication that scrubbing of ETO from air using water is employed in some facilities. More information is needed to identify if this is a method used to remove ETO from air before venting. However

,

u nder ambient conditions ETO scrubbed from vented air to water is expected, with a half

- life of <1 h, to volatilize along the way to a Waste Water Treatment Plant (WWTP)

. Chemicals that are

released down

- the

- drain can typically take from a few to several hours to reach wastewater treatment plant in takes following their discharge and from several hours to roughly a day following their discharge down

- the

- drain to subsequently be discharged from wastewater treatment plants to surf

ace water. Since uses of ETO are not expected to have a significant

compo nent that is available for runoff or leaching, it will not be considered for aquatic exposure

8 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_de tail_303d?p_cause_group_id=885

9 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_p ollutant_group_id=885&p_pollutant_ group_name=PESTICIDES

10 http://www.epa.gov/owow/tmdl/

### Page 28 of 69

(USEPA 2013b). For the purposes of this risk assessment, terrestrial non

- target organisms are assumed to occupy areas immediately adjacent to treatment sites and aquatic non

- target organisms are assumed to occupy water bodies immediately adjacent to treatment sites. For a gaseous pesticide released from a treatment chamber, the terrestrial exposure pathways considered most likely to occur are those to terrestrial a nimals via inhalation of the gas and to terrestrial plants via contact of the gas to the external layer of plant tissues.

Figure 1

– Conceptual Model for Ecological Exposure and Effects of ETO to Aquatic and Terrestrial Organisms



# 4.3 Ecological Effects Assessment

4.3.1 Mechanism of Action

ETO is a strong alkylating agent that is a universal poison for protoplasm. It causes clotting of proteins, deactivation of enzymes and other biologically important components of a living organism (WHO, 2003)

.


## 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. All available ecotoxicity endpoints in the Agency ’s files from ETO studies submitted by registrants

o r other interested parties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the data requirements and data gaps. Where models could be used to estimate values for missing endpoints, the models and results are also described in Appendix C. The most sensitive values for each receptor group are used for the risk assessment ( Table 13 ).

### Page 29 of 69

These selected endpoints will be updated during the risk assessment phase based on any additional submitted data or data found in the public literature.

Table 13

– Selected Eco logical Effects Endpoints for Risk Assessment of ETO

Receptor Group Surrogate Species Risk

Scenario Toxicity Endpoint Reference (MRID)

Birds 6 Northern bobwhite Acute Oral No data. D ata are not expected to be required since significant concentrations are not expected to reach the receptors via the oral and dietary routes ( ETO is a gas

, and the exposure pathway most likely to occur to birds is

via inhalation )

.

Acute

Inhalation Data gap (Special Study): An acute avian inhalation study

using the Northern bobwhite quail species is necessary to satisfy the toxicity profile for ETO. Without data, risk would be presumed for birds, reptiles, and terrestrial

phase amphibians, including listed species.

Subacute Dietary No data . D ata are not expected to be required because

significant concentrations are not expected to reach the receptors due to the rapid decline of air concentrations of the gas which results in low potential for chronic exposure

and residues are not expected to accumulate or persist in

food items. Chronic

Mammals Laboratory mice Acute

Inhalation LD 50 = 1.5 mg/kg

- bw (820

ppm) IPCS, 2003

Laboratory rat Chronic

Inhalation NOAEL = 10 ppm (0.18

mg/mL) 8 42788101

Freshwater fish 1 Fathead minnow 1

( Pimephales promelas ) Acute 96

- h LC 50 = 84 m g a.i./L Conway et al., 1983

, Supplemental

Chronic No data available, not an anticipated data gap as this is

expected to be a negligible exposure pathway.

Freshwater

invertebrates Waterflea ( Daphnia

magna ) Acute 48

- h EC 50 = 137 mg a.i./L Conway et al., 1983

, Supplemental

Chronic No data available, not a n anticipated data gap as this is

expected to be a negligible exposure pathway.

Freshwater benthic

invertebrates -- Subchronic

or Chronic Data not anticipated to be required: Not expected to be

associated with sediment

Estuarine/marine

fish Striped mullet ( Mugil

cephalus ) Acute 96

- h LC 50 = 89 mg ai/L Crews et al, 1974 Supplemental 4

Chronic No data available, not an anticipated data gap as this is

expected to be a negligible exposure pathway.

Estuarine/marine

invertebrates Eastern oyster (shell

deposition/embryo larval) Acute No data

, but data are not anticipated to be required

because significant concentrations are not expected to reach the receptors due to the rapid decline of water concentrations of the gas which results in low potential for chronic exposure nor is it expected to be in the

sediment. Mysid Acute

Chronic

Estuarine/marine

benthic

invertebrates -- Subchronic

or Chronic

Aquatic Nonvascular plants Freshwater green alga

Pseudokirchneriella subcapitata Non

- listed 2 IC 50 >0.86 mg/L 47921703 Acceptable 4 , 5

Listed 3 NOAEC > 0.86

Aquatic vascular Duckweed ( Lemna

gibba ) Non

- listed 2 IC 50 > 0.87 mg/L 47921702 Acceptable 4 , 5 Listed 3 NOAEC > 0.87 mg/L

### Page 30 of 69

Receptor Group Surrogate Species Risk

Scenario Toxicity Endpoint Reference (MRID)

Aquatic Rooted Macrophytes Seedling Emergence Non

- listed No data available, not a data gap as exposure pathway is not likely. Listed

Terrestrial Plants Vegetative vigor Non

- listed IC 50 > 252 mg a.i./m 3 47921701 Acceptable Data gap for nine species. 7 Listed NOAEC = 252 mg a.i./m 3

Beneficial insects Honey bee Acute

contact No data, not a n anticipated data gap since significant

concentrations are not expected to reach the receptors via the oral and contact routes since the greatest exposure pathway to honeybees is via inhalation because ETO is a

gas

. Acute oral

Acute

vapor

- phase Data gap, Special Study : a honeybee acute vapor

- phase

exposure toxicity study is necessary to satisfy the toxicity profile for ETO. Without data, risk would be presumed for beneficial insects, including listed species.

1 Freshwater fish may be surrogates for aquatic

- phase amphibians.

2 For aquatic plants, the g uideline standard half maximal inhibitory concentration ( IC 50 ) value is used for assessing

risk to non

- target, non

- listed species.

3 For aquatic plants, the g uideline standard NOAEC value is used for assessing risk to non

- target, listed species.

4 The studies were modified to accommodate a volatile substance by using environmental chambers that maintain the air concentrations of the gas.

5 PPO data.

6 Birds represent surrogates for terrestrial

- phase amphibians and reptiles.

7 Only one species out of a battery of ten has been tested , the data for the remaining nine species is a data gap . T he

stud y w as modified to accommodate a volatile substance by using environmental chambers that maintain ed the air

concentrations o f the gas.

8 1 ppm = 1.83 mg a.i./m 3



# 4.4 Exposure Analysis Plan

4.4.1 Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment. Resulting exposure estimates will be compare d to the toxicity endpoints to determine if levels of concern are exceeded for each receptor group.

Stressors of Concern

The stressors of concern for ecological exposure will only be the parent compound, ETO. Three reaction products were identified based on the open literature data as EBH, ECH, and EG (USEPA 2008). There is not any evidence that the residues of these reaction products exist in terrestrial or aquatic environment following fumigant application.

Antimicrobial Uses

Monitoring data collected fr om around facilities for assessment of human health risk will be used to evaluate exposure and risk.

Spice and Herb

AERSCREEN, an air screening model, was used for preliminary estimation of the fumigant

concentration after the sterilization near the treatm ent facility (USEPA 2013b, http://www.epa.gov/scram001/dispersion_screening.htm ). The model estimates the "worst

- case"

of 1

- hour concentrations for a single source, without the need for h ourly meteorological data.

### Page 31 of 69

AERSCREEN is intended to produce concentration estimates that are equal to or greater than the estimates produced by other refined air dispersion model with a fully developed set of meteorological and terrain data, but the degree of conservatism may vary depending on the application. The maximum concentration in the first hour is 0.687 g/m 3 

### according the current

label at 31.22 lb/1000 ft 3 

### (500 mg/L) with 16 steam washes on an estimated treatment facility with 10,000ft 3 

### spaces base d on the second release scenario. The detailed modeling information

can be found in Appendices E and F.

In order to address the risk hypothesis, the potential for adverse effects on the environment will be assessed by estimated air concentration adjacent to the treatment facility through modeling or monitoring (Fig. 1) (USEPA 2013b). The use of ETO fumigant and quantity of air emission, and ecological effects will be characterized and integrated to assess risk. This will be accomplished using a risk quotie nt (ratio of exposure concentration to effects concentration) approach. Although risk is often defined as the likelihood and magnitude of adverse ecological effects, the risk quotient

- based approach does not provide a quantitative estimate of likelihood or magnitude

of an adverse effect. However, as outlined in the Overview Document (USEPA, 2004), the likelihood of effects to individual organisms from particular uses of ETO will be estimated using the probit dose

- response slope and either the level of conce rn or actual calculated risk quotient

value.

The aquatic exposure pathways considered is unlikely to occur to aquatic organisms. In the worst case scenario, ETO is introduced to surface water during precipitation events where the gas

dissolves in t he precipitation. However, exposure to ETO is expected to be limited by its rapid evaporation from water bodies with a one

- hour dissi pation half life (see 4.1 and Appendix B )

.

Table 14

– AERSCREEN Modeling Scenarios and Data Summary

Maximum

1

- Hr Conc (μ g /m 3 ) Scaled 3

- Hr

Conc (μ g /m 3 ) Scaled 8

- Hr

Conc (μ g /m 3 ) Scaled 24

- Hr

Conc (μ g /m 3 ) Scaled Annual

Conc (μ g /m 3 )

Scenario 1 : assume 21 air exchanges per hour 0.6766E+06 0.6766E+06 0.6090E+06 0.4060E+06 0.6766E+05

Scenario 2 : assume 16 air exchanges per hour 0.6871E+06 0.6871E+06 0.6184E+06 0.4123E+06 0.6871E+05

### Page 32 of 69

Figure 2

– Proposed ETO air exposure scenario for the risk assessment.

ETO concentrations in air will be modeled or monitored using the maximum labeled application rates and numbers of applications, the minimum application intervals, and application methods that have the greatest potential for off

- site transport.

ETO Concent

ration in Air near the Treatment Facility

ETO concentrations in air will be initially estimated by a Tier

- I screening model, AERSCREEN (http://www.epa.gov/scram001/dispersion_screening.htm). The Tier

- I model will produce

estimates of "worst

- case" 1

- hour c oncentrations for a single source, without the need for hourly meteorological data. AERSCREEN is intended to produce concentration estimates that are equal to or greater than the estimates produced by more refined models, but the degree of conservatism

wil l vary depending on the application. Air EECs may be refined by the Tier II Probabilistic Exposure and Risk Model for Fumigants (PERFUM). PERFUM is capable of producing a distribution of air EECs from a range of different meteorological conditions.

This an alysis plan may be revisited and revised depending upon a full review of the data available in the open literature and the information submitted by the public in response to the opening of the registration r eview docket.



# 4.5 Effects Analysis Plan

Additional op en literature studies will be identified through EPA’s ECOTOXicology (ECOTOX)

database. The ECOTOX database will be searched during the risk assessment phase of ETO and

t he data reviewed following the Agency ’s policy for reviewing public literature for use in assessing risks from pesticides

. 11 

### Those ecotoxicity values found in the public literature to be more sensitive than those currently in Table 13 and/ or which satisfy an existing data gap(s) will be used during the risk assessment phase of ETO to update Table 13

. ECOTOX was created and is maintained by the USEPA, O ffice of Research and Development, and the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.

11 http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/endangered_species_reregistration_wor kgroup/esa_evaluation_open_literature.htm



### Treat ment

Chamber Release Vent or Stack

### Page 33 of 69



# 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess p otential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in offs pring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision , for ETO, EPA reviewed these data and

s elected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), ETO is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effec ts as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the est rogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which , if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T ef fect.

Under FFDCA section 408(p), the agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 12 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screeni ng battery, please visit our

website. 13



# 6 Next Steps

A DCI will be developed regarding the data needs listed under the “Risk Assessments and Anticipated Data Needs” section of this document. The Agency expects to issue the DCI by

March 2015

.

12 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

13 http://www.epa.gov/endo/

### Page 34 of 69



# 7 References

ASTA (American Spice Trade Association). 2005. Public comments to Phase 3 of the reregistration risk assessment of ethylene oxide. Docket ID: OPP

- 2005

- 0203

- 0032/0034. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2005

- 0203

- 0034 ATSDR (Agency for Toxi c Substances and Disease Registry) 1990, Toxicological Profile for Enthylene Oxide, a report by ATSDR, U.S. Public Health Service. pp122 Bogyo, D.A., Lande, S.S., Meylan, W.M., Howard, P.H. and Santodonato J. 1980. Investigation

of Selected Potential Envi ronmental Contaminants: Epoxides. A final report submitted to USEPA Office of Toxic Substances, Contract No. 68

- 01

- 3920. 216 pp. Conway, R.A., Waggy, G.T., Spiegel, M.H. and Berglund, R.L. (1983) Environmental fate and effects of ethylene oxide. Environ. S ci. Technol., 17,107

- 112. Cupitt, L.T. 1980. Fate of toxic and hazardous materials in the environment, Research Triangle Park, North Carolina, USEPA, Environmental Sciences Laboratory, Office of Research and Development (US EPA 600/3

- 80

- 084, PB 80

- 221948). Gangolli, S, 1999: The Dictionary of Substances and their effects, 2nd ed., The Royal Society of Chemistry. GDCh, BUA: The German Chemical Society

- Advisory Committee on Existing Chemicals of Environmental Relevance, 1995: Ethene Oxide BUA Report No. 141S, Hezl Verlag, Stuttgart. Gennari, M, Negre, M and Ambrosoli, R, 1987: Effects of ETO on Soil and Microbial Content and Some Soil Chemical Characteristics. Plant and Soil, 102:197

- 200. Gomer, R, and Noyes, A. 1950. Photochemical Studies, XLII: ETO. J. Amer. Chem. Soc

. , 72 :1 01

- 108 (MRID 49126104). Hansch, C, and Leo A. 1979. Substituent constants for correlation analysis in chemistry and biology. New York, NY: John Wiley & Sons, Inc., 176. Hazardous Substance Data Bank (HSDB), 1988: National Library of Medici ne, National Toxicological Information Program, Bethesda, MD. Hellman, T.M. & Small, F.H. (1974) Characterization of the odor properties of 101 petrochemicals using sensory methods. J. Air Pollut. Control Assoc., 24: 979

- 982. Howard Philips, 1989: Handbook of Environmental Fate and Exposure Data for Organic Chemicals, Lewis Publishers, Inc., Chelsea, MI, USA.

IPCS. 2003. International Programme on Chemical Safety. Concise International Chemical

Assessment Document 54. (http://www.inchem.org/documents/cicads /cicads/cicad54.htm) (Accessed 2/27/2013). Jacobson, K.H., Hackley, E.B., & Feinsilver, L. (1956) The toxicity of inhaled ethylene oxide and Ethylene oxide vapors. Arch. ind. Health, 13: 237

- 244. Joshi, SB, Dodge, MC, and Bufalani, JJ. 1982

. 2. Reactivitie s of Selected Organic Compounds

and Contamination Effects

. Atmospher ic Environment

, 16: 1301

- 1310: (MRID 49126101). Lyman, WJ, Reehl, WF, and Rosenblatt, DH, 1982: Handbook of Chemical Property Estimation Methods, Chapter 15, McGraw

- Hill, NY (quoted from U S NLM, HSDB, 2003). Public Health Risk Evaluation Database (PHRED), 1988, US EPA, Washington, DC.

USEPA. 1985. Health assessment document for ethylene oxide, Washington DC, US Environmental Protection Agency (EPA 600/8

- 84/009F).

USEPA. 2001. EFED RED Chapter for Ethylene Oxide DP279672. 2pp

### Page 35 of 69

US EPA. 2002. ECOTOX User Guide: ECOTOXicology Database System. Version 3.0. Available: http://www.epa.gov/ecotox/

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Agency. Endangered and Threatened Species

Effects Determinations. Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Washington, D.C. January 23, 2004.

USEPA. 2008. Review of Calculated Ethyle ne Oxide Exposures for Ethylene Oxide Sterilization Plant Workers (MRID 47331801) Submitted in Support of the Occupational Exposure Assessment of the Antimicrobial Uses of Ethylene Oxide for the Reregistration Eligibility Decision (RED). DP 348868.

USEPA. 2008. Reregistration Eligibility Decision for ETO, 2008. Online at http://www.epa.gov/oppsrrd1/REDs/ethylene

- oxide

- red.pdf USEPA. Ecological Structure Activity Relationships (ECOSAR). 2011. Version 1.10, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm

. USEPA. 2013a. BEAD Chemical Profile for Registration Review: Ethylene oxide (042301). 5pp.

USEPA. 2013b. Guidance for Conducting Fumigant Exposure Assessment in Ecological Risk

Assessment

. Interim Divisional Guidance, EFED. 118pp.

WHO. 1985. E nvironmental H ealth C riteria 55: Ethylene oxide, Geneva, Switzerland, World Health Organization, 79 pp.

WHO. 2003. Concise International Chemical Assessment Document 54 . Ethylene oxide, Geneva, Switzerland, World Health Organization, 63 pp.

### Page 36 of 69 

# Appendix A T oxicology Profile

The following tables summarize the toxicity of ETO and ECH . The tables include both the acute toxicity profile and the profile after repe ated dosing for both chemicals.

Table 15

– ETO

– Acute Toxicity

Study/ Species MRID or Publication Results Classification

870.1100

Acute Oral

Rats

Mice

Guinea pigs IPCS, 2003 IPCS, 2003

IPCS, 2003 LD 50 = 330 mg/kg (m)

LD 50 = 365 mg/kg (m)

LD 50 = 280 mg/kg (f)

LD 50 = 270 mg/kg (m&f) Category II Category II

Category II

870.1200 Acute Dermal, Rabbits No Study Identified N/A N/A

870.1300 Acute Inhalation, Rats Acute Inhalation, Rats Acute Inhalation, Mice Acute Inhalation, Dogs 42046601

42429201 IPCS, 2003 IPCS, 2003 4h

- LC 50 = 1741 ppm (3.1 mg/L) (m&f)

1h

- LC 50 =5029 ppm (9.2 mg/L) (m&f)

4h

- LC 50 = 820 ppm (1.5 mg/L)

4h

- LC 50 = 983 ppm (1.8 mg/L) Category IV Category IV Category III Category III

870.2400 Primary Eye Irritation,

Rabbits No Study identified

870.2500 Primary Skin Irritation,

Rabbits No Study Identified

870.2600 Dermal Sensitization, Human case study 40087801 Sensitization possible

870.6200 Acute Neurotoxicity 44256402 Doses: 0, 100, 300, 500 ppm NOAEL:100 ppm LOAEL: 300 ppm Drooping eyelids/half

- closed eyes, low arousal, no response to approach Acceptable/Guideline

LD 50 = lethal dose, 50%



### Table 16

– ETO

– Subchronic, Chronic Toxicity Studies

Study/Species MRID or

Publication Doses Results/Classificat ion

Developmental/Reproduction Toxicity
Developmental Toxicity

Rats 42797702 Doses (inhalation): 0,
50, 125, 225

ppm (6h/day, GD 6

- 15) Maternal NOAEL: 50 ppm

Maternal LOAEL: 125 ppm Decreased body weight gain on GDs 6

- 15 and GDs 0

- 21 Developmental NOAEL: 50 ppm Developmental LOAEL: 125 ppm Decreased fetal weight, increased litter incidence of delayed ossification in phalanges, metatarsals, metacarpals and sternebrae #4

- 6 Acceptable/Guideline Developmental Toxicity, Rabbits 41874102 Doses (inhalati on) : 0, 150 ppm

GD7

- 19, GD1

- 19 7h/day Maternal and Developmental NOAEL: 150 ppm

Maternal and Developmental LOAEL: Not Established

Unacceptable/Guideline No dose response effects were determined

### Page 37 of 69

Study/Species MRID or

Publication Doses Results/Classificat ion

Two

- Generation Reproduction Study,

Rats 42788101 Doses (inhalation): 0, 10, 33, 100

ppm 6h/day,

5d/week Parental NOAEL: 10 ppm

Parental LOAEL: 33 ppm Decreased body weight and/or weight gain in F0 and F1 males during premating Reproductive NOAEL: 10 ppm Reproductive LOAEL: 33 ppm Increased post implantation loss in F0 generation Offspring NOAEL: 10 ppm Offspring LOAEL: 33 ppm Decreased mean body weight and weight gain of F1pups on PND 7 and

PND 21 Acceptable/Guideline Subchronic Toxicity

Subchronic Neurotoxicity, Rats,

13 weeks

Subchronic Neurotoxicity, Rats,

4 weeks 44359401

44256401 Doses

(inhalation): 0, 25, 50, 100, 200 ppm

Doses (inhalation): 0, 100, 300, 400, 500 ppm NOAEL: 100 ppm

LOAEL: 200 ppm Decreased body weight gain in both sexes and decreased hindlimb grip strength in females

Note: Cancer incidence in all treated groups during 13 weeks recovery period. Malignant glioma in cerebral cortex at 200 ppm (1 male), mononuclear cell leukemia (1 male at 100 ppm), hemangiosarcoma of skin (1 male at 25 ppm) and basal c ell carcinoma of the skin (1 female at 50 ppm; 1 female at 200 ppm)

5/sex/dose evaluated Acceptable/Guideline NOAEL: 100 ppm

LOAEL: 300 ppm Decreased body weight, body weight gain, hindlimb grip strength Range Finding Study
Subchronic (14 weeks)

B6C3F1 Mice NTP (1987) Doses (inhalation): 0, 50, 100, 200, 400, 800

ppm NOAEL: 50 ppm

LOAEL: 100 ppm Renal tubular degeneration Acceptable/Non

- Guideline

Subchronic (10 weeks)

B6C3F1 Mice Snellings et al

.,

1984 Doses

(inhalation): 0, 10, 50, 100, 250 ppm NOAEL 50 ppm

LOAEL 100 ppm Neurological effects such as altered gait, decreased locomotor activity and abnormal righting reflex and organ weight changes. Acceptable/Non

- Guideline Chronic Toxicity

870.4100 Chronic Toxicity

Monkeys 2 years MRID

42159401, Setzer

et al ., 1996 and IPCS, 2003 Doses

(inhalation):
0, 50, 100

ppm
6

- 7h/day, 5d/wk, 24 months, 12

males/

treatment NOAEL: Not Established

LOAEL: 50 ppm Eye lesions, demyelination of the sciatic nerve, axonal dystrophy in the

nucleus gracilis, decreased sperm counts and motility abnormalities; Decreased mean conduction velocity at 100 ppm

Deficiencies: Age of animals unknown; inadequate dose groups, Incomplete study details with regard to study examination, individual gross or histolog ical data, inadequate hematological and clinical

parameters etc. .); small number of animals tested (only 2 animals were sacrificed after 2 years of exposure). Acceptable/Non

- Guideline Study

### Page 38 of 69

Study/Species MRID or

Publication Doses Results/Classificat ion

Combined Chronic Carcinogenicity

Chronic Carcinogenicity Study, Rats 2 years Snellings et al

.

(1984b)

Garman et al

. (1985), Garman and Snellings, (1986) Doses

(inhalation):
0, 10, 33, 100

ppm (6h/day, 5d/week) Systemic NOAEL: 10 ppm

Systemic LOAEL: 33 ppm Decreased survival and body weight Type of cancer incidence

- 0, 10, 33, 100 ppm: mononuclear cell

leukemia

- 13/97, 9/51, 12/39, 9/30 (m), 11/116, 11/54, 14/48, 15/26 (f); peritoneal mesothelioma

- 2/97, 2/51, 4/39, 4/30 (m), brain tumors which include glioma, malignant reticuloses and granular cell tumors

1/181, 1/92, 5/ 85, 7/87 (m), 1/188, 1/94, 3/92, 4/80 (f) Acceptable/Non

- Guideline Study

Chronic Carcinogenicity Study, Male Rats Lynch et al

(1984) Doses

(inhalation): 0, 50, 100 ppm (males only) (7h/day, 5d/week) Systemic NOAEL: Not Established

Systemic LOAEL: 50 ppm Decreased body weight gain, organ weights and non

- neoplastic lesions in adrenal cortex, spleen and respiratory tract) Type of cancer incidence

- 0, 50, 100 ppm: mononuclear cell leukemia

24/77, 38/79, 30/76; peritoneal mesothelioma

- 3/78, 9/79, 21/79;

mixed cell brain glioma

- 0/76, 2/77, 5/79 Note: No interim clinical and hematological parameters measurements; inadequate clinical parameter measurements at the termination (NIOSH study) Acceptable/Non

- Guideline Study

870.4300

Combined Chronic Toxicity/Carcino geni city

Mice NTP (1987) Doses (inhalation): 0, 50, 100

ppm (6h/day, 5d/week) Systemic NOAEL: 100 ppm

Systemic LOAEL: Not Established (Type of cancer incidence, control, 50, 100 ppm): alveolar/bronchiolar

carcinoma

- 6/50, 10/50, 16/50 (m), 0/49, 1/48, 7/49 (f); harderian gland papillary cystadenoma

- 1/43, 9/44, 8/42 (m), 1/46, 6/46, 8/47 (f); malignant lymphoma of hematopoietic system

- 9/49, 6/48, 22/49 (f);

uterine adenocarcinoma

- 0/49, 1/47, 5/49 (f), mammary gland adenocarcinoma or adenosquamous carcinoma

- 1 /49, 8/48, 6/49 (f) Acceptable/Non

- Guideline Subchronic Dermal Toxicity

21

- Day Dermal Toxicity (Rats) No Study

identified - -

Dermal Absorption No Study

identified - -

Metabolism

Rat Metabolism IPCS, 2003

- Absorption: Very soluble in blood; rapid absorption in several species; limited by the concentration in air and ventilation rate Distribution: In mice greater amount of inhaled ETO is found distributed in liver, kidneys and lungs with small amounts in spl een, testes and brain. In rats, greater amount of inhaled ETO is found in urinary bladder, liver, packed blood cells, adrenal glands and lower

levels in fat Metabolism: Two pathways are identified. 1) ETO is found hydrolyzed

to EG and subsequently to oxalic acid, formic acid and carbon dioxide. This is predominant in larger species such as rabbits and dogs 2) Conjugation with glutathione. This step is predominant in rats and mice.

Excretion: In rats and mice 40

- 80% of the inhaled d ose is eliminated in

urine within 48 hours Large amount of the administered ETO are eliminated in the urine as glutathione conjugates; Small amounts (10%) are eliminated as carbon dioxide and negligible amounts (1%) are eliminated via lungs as the parent c ompound

### Page 39 of 69

Study/Species MRID or

Publication Doses Results/Classificat ion

Mutation/Genotoxicity

IPCS, 2003

- Positive evidence for mutation in bacteria, eukaryotic somatic and germ cells; Increased chromosomal aberrations, sister chromatid exchange and unscheduled DNA synthesis in mammalian cells,, Induction of

dominant lethal mutations and heritable translocatio ns in mice. In humans, increased chromosomal aberrations in peripheral blood leukocytes of workers exposed to ETO

. Human Studies

Steenland et al

.

2003 - Breast cancer incidence studied in a cohort of 7576 women. Breast cancer reported in 319 subjects. The standardized incidence ratio (SIR)

for incident breast cancer in the whole cohort was below the US population. Trend analysis in SIRs, using Poisson regression was positive with increasing exposure (p=0.002). The odds ratios with 15 year lag for cumula tive exposure categories, 0 (lagged out), <647, 647

- 2026, 2026

- 4919, 4919

- 14620, >14620 ppm

- days were 1.00, 1.06, 0.99, 1.24, 1.42, and 1.87, respectively.

Steenland et al

. 2004 - In the mortality analysis of a 1998 follow

- up study of a large cohort of 18235 men and women, 2852 deaths present. The mortality analysis of the overall cohort indicates no excess risk for hematopoietic cancers

combined or of non

- Hodgkin’s lymphoma. However, internal exposure response analyses conducted using a 15 year lag foun d positive trends for hematopoietic cancers in males (p=0.02). The odds ratios with 15 year lag for hematopoietic cancer mortality in males were 1.00, 1.23, 2.52, 3.13, and 3.42 for 0 (lagged out), >0

- 1199, 1200

- 3679, 3680

- 13499, >13500 ppm

- days, respectiv ely. The trend in hematopoietic cancer was driven by lymphoid tumors (non

- Hodgkin’s lymphoma, myeloma, lymphocytic leukemia). Although there is no excess overall risk for breast cancer, internal exposure analyses found positive trend

for breast cancer usin g the log of cumulative exposures with a 20 year lag (p=0.01). The odds ratios with 20 year lag for breast cancer mortality correspond to 1.00, 1.76, 1.77, 1.97, and 3.13 for cumulative exposure categories, 0 (lagged out), >0

- 646, 647

- 2779, 2780

- 12321,

>12 322 ppm

- days, respectively.

### Page 40 of 69 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of ETO

The primary mode of transport of ETO for both the antimicrobial and conventional uses is via air emissions into the atmosphere. ETO enters the environment mainly through vented gases during

use. Because ETO uses fall under the indoor use category for conventional pesticides and historically an indoor use pattern for antimicrobials and is a gaseous substance

, submission of

environmental fate data has not bee n required (40 CFR Sections158. 630

, 660 , and 1300 )

.

Table 17

– Environmental Fate Properties of ETO

Parameter Value 

### Reference

Hydrolysis (t 1⁄2 @ 25oC, pH 7) 13.8 days Bogyo et al., 1980

Aqueous Photolysis (t 1⁄2) N/A

Atmospheric Oxidation (t 1⁄2 @ 25 oC, 12

- hr day) 38.16 days EPI V4.10

Soil Photolysis (t 1⁄2) N/A

Aerobic Soil Metabolism (t 1⁄2) N/A

Anaerobic Aquatic Metabolism (t 1⁄2) N/A

Aerobic Aquatic Metabolism (t 1⁄2) N/A

BCF Estimates 3.162 L/Kg wet

- wt EPI V4.10

Mobility

Koc 4.662 ( mL/g) EPI V4.10

Field Dissipation

Terrestrial Field Dissipation (t 1⁄2) N/A

Volatilization (t 1⁄2 from Model River) 3.30 (hrs) EPI V4.10

Volatilization (t 1⁄2 from Model Lake) 91.68 (hrs) EPI V4.10



### Air

The major removal of ETO from the atmosphere will occur rapidly via oxidation by hydroxyl

radicals. The atmospheric residence time of ETO was calculated to be 5.8 days based on the theoretical rate constant for this reaction (Cupitt, 1980). However, experimental data have shown

the residence time to be 100

- 215 days, depending on the hydroxyl radical concentration and the ambient temperature (US EPA, 1985). Because of its high solubility in water ( 1000 g/L ), ETO

levels in air can also be reduced via washout by rain (Conway et al., 1983).

The photochemical reactivity of ETO ozone

- forming ability is low (Joshi et al., 1982). Joshi et al. 1982 (MRID 49126101) de termined the photolytic reactivity of five oxygen containing hydrocarbons, ETO be ing one of them, in smog chambers specially made for the study. Irradiation was provided through fluorescent lamps consisting of 22 black lights, and 7 sunlamps kept around the smog chamber. Initial concentration of ETO was 4 ppm, and the residual

concentr ation of ETO was monitored by using Porapak Q columns at 100 o 

### C. The photooxidation of ETO is slow in the atmosphere; its half life was measured to be 53 hours. This

is a non

- guideline study. It is classified as supplemental because not all raw data is av ailable for independent review. The information is useable in a risk assessment.

### Page 41 of 69

Gomer and Noyes, 1950 (MRID 49126104) investigated the direct impact of sunlight on the photodecomposition and characterization of photochemical degradates of ultra pure ETO i n the presence or absence of some reactants. The photochemical degradates of ETO with direct sunlight in the absence of any reactants were: methane, ethane, hydrogen and carbon monoxide, and minor quantities of formaldehyde and acetaldehyde. The duration o f the formation of the photodegradates was not determined. The study is a non

- guideline study. It is classified as supplemental.

A German Study concluded that ETO is not degraded by direct sunlight in the a tmosphere (GDCh BUA, 1995 )

.
Water and Sediment

Eva p oration from water is expected to be a significant ETO removal process. Conway et al. (1983) found a half

- life of < 1 h for ETO evaporation from water. ETO degradation in water through ionic reactions and hydrolysis appear to be comparatively slow in the e nvironment.

Volatilization from Water or Water Desorption

Conway et al. 1983 (MRID 49126102) studied the volatilization of ETO from water under no

wind and under a 5 meter/second wind conditions. The study showed that with no wind, the

volatilization half life of ETO is 0.72 hour s and that under a wind flow of 5 meters/second the

half life i s 0.88 hours in neutral conditions. The results under perturbed and non

- perturbed conditions indicate that perturbation is not a required condition for volatilizati on. ETO is broken down in fresh water to form 1,2

- ethanediol with a half

- life of 14 days at 25 °C. In 3% saline water, 77% ETO forms 1,2

- ethanediol and 23% forms 2

- chloroethanol with a half

- life of 9 days (Conway et al., 1983). The results indicate that th e half lives in these three media are quite similar to each other (9 to 14 days), which likely means that presence of biota is not a condition for the degradation of ETO. This study is classified as supplemental because not all raw data is

available for in dependent review. The information is useable in a risk assessment and no additional volatilization data is required.

A study by Gomer, and Noyes (1950), showed that ETO autocatalyzes into methane, ethane, hydrogen, carbondioxide (MRID# 49126104)

. Hydrolysi

s

ETO degradation in water through ionic reactions and hydrolysis appear to be comparatively

slow in the environment.

In 1999, Gangolli reported a 12

- 14 day hydrolytic half life f or ETO in fresh water, with 9

- 11 day hydrolytic half

- life in seawater. Thus this study indicates that under biotic conditions, ETO hydrolyzes, and is not considered as persistent in biotic conditi ons (MRID 49126105)

. Conway et al. , 1983 (MRID 49126102) conducted a hydrolysis study with ETO in three different

media sources : distilled water , natural fresh water, and salt water

. Natural fresh water samples

were made f

r o m th e water collected from Kanawha R iver (South Carolina). Salt water was created by adding sodium chloride at 0%, 1%, and 3%, mixing dipotassium hydrogen phosph ate, and sodium dihydrogen phosphate, and then a known quantity of ETO was dissolved in the

solution

. Hydrolysis half life in natural water was determined to be 14 days; in salt water it was about 9 days (in the presence of 3% sodium chloride ); and in dist illed wat er it was measured to

be about 12 days. Chemical degradates in these media included e thylene glycol (or simply

### Page 42 of 69

glycol), chlorohydrin, and in sea water bromohydrin. The study is a non

- guideline study and was published as a research paper. This stud y is classified as supplemental because not all raw data is available for independent review. The information is useable in a risk assessment and no additional hydrolysis data are expected to be required.

Virtanen (1963) reported that ETO’s half

- life is 30 9 days at 0 °C, and the reaction is acid

- and

base

- catalyzed. Bogyo et al., (1980) reported that ETO hydrolyzes under neutral conditions with a half life of 13.8 days at 25°C.

Octanol

- Water Partition Coefficient

ETO is a very polar chemical with a logarith m of the octanol/water partition coefficient (K
ow 

### ) of

- 0.30 ( EPI Suite, version 4.10)

Biotic Metabolism

- Aquatic

Microorganisms were found to degrade ETO very slowly with biological oxygen demand varying from between 3

- 5% and 52% of the theoretical oxygen after 5 and 20 days, respectively (Bridié et al., 1979; Conway et al., 1983).

Soil

The log K
oc 

### value of ETO is 0.325 which indicates a highly mobility through soil. Thus if ETO has not degraded while migrating through soils, it might contaminate ground w ater.

Fate and Transport in WWTP

Conway et al.

, 1983 (MRID 49126102) conducted a b iodegradation study using a n American

Public Health Association method as outlines in the Standard Methods for the Examination of

Water and Waste water Method ( APHA , 14 th 

### Edit ion, Washington, DC)

. The results showed that

ETO was degraded 5% by day 5, 22% by day 10, and by day 20, it had degraded by 52% . This

stu dy indicates that ETO is degradable, but cannot be classified as ready biodegradable. This study is classified as supp lemental because not all raw data is available for independent review.

The information is useable in a risk assessment and no additional activated sludge biodegradation data are expected to be required.

Bioaccumulation

The l og Kow of ETO (

- 0.30 ) is very small, and thus it is not likely to bioaccumulate in aquatic organisms. There are no published reports of measured bioconcentration in any aquatic organisms. A b ioconcentration factor can be estimated using the log Kow:

Log BCF = ( 0.76 )( log K
ow )



### - 0.23

With a log K
ow 

### of

- 0.45, then the log BCF is 0.167

, which indicates that the likelihood

bioaccumulation of ETO into aquatic organism is low.

Analytical Method(s)

ETO in environmental samples is most commonly determined after derivatization to stable,

volat ile halogenated species, particularly 2

- bromoethanol followed by GC/ECD (Cummins et al. 1987), or by GC/MS (Farmer et al. 1986). ETO in air samples can be directly analyzed by a portable gas chromatograph using clean air as a carrier gas and a photoionizat ion detector (PID) for detection (Bond and Dumas 1982; Collins and Barker 1983). A method for the determination

### Page 43 of 69

of ETO in water and soil samples by partition infrared spectrophotometry has been reported (APHA 1985; Environment Canada 1985).

References Appendix B

Conway, RA, Waggy, GT , Spiegel, MH, and Berglund, RL. 1983

. Environmental Fate and Effects of Ethylene Oxide. Environmental Sci. Technol

. , 1 7 ( 2 ): 107

- 112 (MRID 49126102)

. Gangolli, S, 1999: The Dictionary of Substances and their effects, 2nd ed ., The Royal Society of Chemistry. GDCh, BUA: The German Chemical Society

- Advisory Committee on Existing Chemicals of Environmental Relevance, 1995: Ethene Oxide BUA Report No. 141S, Hezl Verlag, Stuttgart. Gennari, M, Negre, M and Ambrosoli, R, 1987: Effe cts of ETO on Soil and Microbial Content and Some Soil Chemical Characteristics. Plant and Soil, 102, pp 197

- 200. Gomer, R, and Noyes, A. 1950. Photochemical Studies, XLII: ETO

. J. Amer. Chem. Soc

. , 72 :1 01

- 108 (MRID 49126104).

Hazardous Substance Data Bank (HSDB), 1988: National Library of Medicine, National Toxicological Information Program, Bethesda, MD. Howard Philips, 1989: Handbook of Environmental Fate and Exposure Data for Organic Chemicals, Lewis Publishers, Inc., Chelsea, MI, USA. Joshi, SB, Dodge, MC, and Bufalani, JJ. 1982

. 2. Reactivities of Selected Organic Compounds

and Contamination Effects

. Atmospher ic Environment

, 16: 1301

- 1310: (MRID 49126101). Lyman, WJ, Reehl, WF, and Rosenblatt, DH, 1982: Handbook of Chemical Property Estimation Methods, Chapter 15, McGraw

- Hill, NY (quoted from US NLM, HSDB, 2003). Public Health Risk Evaluation Database (PHRED), 1988, US EPA, Washington, DC. USEPA, 1982b: US EPA Federal Register, # 47, 26992

- 27008 USEPA, 1988: US EPA, Part V, Federal Register; # 53: 38642

- 38654 WHO, 1985: Environmental Health criteria 55: Ethylene oxide, Geneva, Switzerland, pp 2

- 79

### Page 44 of 69 

# Appendix C Ecotoxicology Profile

Toxicity of ETO to Terrestrial Receptors

Mammals

There is acute oral information for three mammalian species: laboratory rats, mice, and guinea pigs. Selected endpoints for these species are provided in the Appendix A Toxicology Profile for

human health. The median lethal dose (LD 50 

### ) ranges from 270 mg/kg

- bw for guinea pigs (male and female, combined) to 365 mg/kg

- bw for male rats (IPCS, 2 003). These results categorize

ETO as moderately toxic to mammalian wildlife on an acute oral basis.

There is acute inhalation data for three mammalian species: laboratory rats, mice, and dogs. Selected endpoints for these species are provided in the Appen dix A Toxicology Profile for

human health (MRIDs 42046601 and 42429201; IPCS, 2003)

. The four hour median lethal concentration (4

- h LC 50 

### ) values range from 820 ppm (1.5 mg/L) for mice (males and females, combined) to 1741 ppm (3.1 mg/L) for r ats (male and femal, combined); the 1

- hr LC 50 

### value

available for rats (males and females, combined) is 5029 ppm (9.2 mg/L)

. There is also an inhalation exposure, two

- generation rat study (MRID 42788101)

. The parental, reproductive and offspring no obse rved adverse eff ect concentration (NOAEC ) from the study is 10 ppm ( 0.018 mg/L )

.
Birds

There is no ETO acute or chronic toxicity data for birds. Inhalation data for birds are anticipated

as needed to determine risk from ETO use patterns. ETO has fumigant uses that may res ult in exposure to birds. The acute effects to birds exposed to ETO are unknown. Avian acute inhalation toxicity data were not submitted for birds exposed to ETO; however, the study anticipated to be required is a non

- guideline study under the 40 CFR Part 158 data requirements. Typically, the Agency asks for avian acute oral and dietary studies with an upland game bird, a passerine bird and a waterfowl to assess the acute effects to birds via the oral and dietary routes; however, because ETO is a gas, which is released to the atmosphere after aeration of the

treat ment chamber , the terrestrial animal exposure route considered most likely to occur is through inhalation of the gas. Therefore, the Agency expect s to require a non

- guideline inhalation study with b irds instead of the oral and dietary studies. Since this inhalation study is a

non

- guideline study, a study protocol would need to be submitted for review by the Agency prior to test initiation. The preferred bird species is the Northern bobwhite quail. Un til an acute inhalation endpoint to evaluate acute risk to birds is available, the acute risk to birds exposed to ETO cannot be precluded and will be presumed.

Beneficial Insects

ETO has fumigant uses that may result in exposure to honeybees. The toxicity of ETO to honeybees is unknown. Honeybee acute vapor

- phase exposure toxicity data were not submitted for beneficial insects exposed to ETO; however, the study anticipated to be requi red is a non

guideline study under the 40 CFR Part 158 data requirements. ETO is an insecticide which is formulated to kill insects, some effects to insects are expected (as observed in other terrestrial invertebrate studies), the Agency expects to require a non

- guideline vapor

- phase exposure toxicity study with bees to assess whether the effects seen in bees are similar to those observed in

### Page 45 of 69

other terrestrial invertebrates. Since this vapor

- phase exposure study is a non

- guideline study, a study protocol tha t calculates a vapor

- phase exposure LD 50 

### for adult bees would need to be submitted for review by the Agency prior to initiation of the study. Until an acute vapor

- phase exposure endpoint to evaluate the toxicity to honeybees is available, the acute risk to beneficial insects exposed to ETO cannot be precluded and will be presumed.

Terrestrial Plants

ETO has fumigant uses that may result in exposure to terrestrial plants. Typically, the Agency requires seedling emergence and vegetative vigor studies to assess the effects to terrestrial plants exposed to a pesticide as a result of surface water runoff or/and off

- site spray drift, respectively; however, because ETO will be released from t reatment chambers as a gas, the terrestrial plant exposure pathway co nsidered most likely to occur is through contact of the external layer of plant tissues as a result of spray drift. Instead of needing both seedling emergence and vegetative vigor studies, the Agency only expects to need vegetative vigor data with actively growing plants to assess the effects of ETO when the gas penetrates the plants. The Agency uses a battery of ten species 14 

### representing at least six different families to evaluate potential effects to all flora. There is one vegetative vigor study with a d icot species (soybean) exposed to ETO as a gas (MRID 47921701). At the highest exposure concentration of 252 mg ai/m 3 

### , no effects to vegetative vigor were observed (i.e., IC 25 

### >252 mg ai/m 3 

### , NOAEC > 252 mg ai/m 3 

### ). The Agency expects to

requ ire vegetative vigor data with ETO for the remaining nine species in the battery.



## Toxicity of ETO to Aquatic Receptors

No aquatic toxicity data has been submitted for ETO

. Conaway et al., 1983 tested ETO with several aquatic species; they are provided in Table 18

. These studies were conducted under static conditions and results are based on nominal, not measured exposure concentrations. Given the

known fate characteri stics of ETO in water, the concentration of ETO in these studies was not likely stable throughout the duration of the test due to volatilization, hydrolysis to EG , and biodegradation. ECOSAR version 1.10 was used to estimate aquatic toxicity results for th e green algae, and acute and chronic results for a generic freshwater fish and a freshwater daphnia (see the following ECOSAR version 1.10 results page). ETO is a member of the mono epoxides group, which was used in ECOSAR version 1.10 to model toxicity re sults. There is a footnote in the ECOSAR version 1.10 results output that empirical ETO data, a fish 96

- h LC 50 

### value and a

48

- h EC 50 

### value for a daphnid (Conaway et al ., 1983), are included in the structure activity model for the mono epoxides group. Curre nt guideline standards call for flow through tests and measured concentrations for such test substances to ensure stable exposure concentrations for t he duration of the study (USEPA 1986 ).

Since ETO ’s vapor pressure and experimental half

- life <1 hr indicat es it will rapidly volatilize out of water, exposure of aquatic organisms is not considered a significant exposure pathway and additional aquatic toxicity data is not anticipated as being needed to conduct the risk assessment for the sterilization and spic e fumigation use patterns.

14 Battery of species consists of s ix dicot species of at least four families, one species of which is soybean ( Glycine

max ) , and f

our dicot species of at least two families, one species of which is corn ( Zea mays ) . Additionally of the ten species tested, at least one species should be a root crop (either a monocot such as onion or dicot such as carrot, table beet or sugar beet)

.

### Page 46 of 69

Table 18

– Effects Data on ETO

Data Requirement Test Species, Test

Type Value Submitted Studies (MRID or Citation) Study Classifications /

Toxicity

Classification

Freshwater fish, acute toxicity Fathead minnow

( Pimephales promelas ), static,

nominal 96

- h LC 50 = 85 mg

a.i./L Conway et al.,

1983 Supplemental /

Slightly toxic

Freshwater

invertebrate acute toxicity Waterflea ( Daphnia

magna ), static, nominal 48

- h EC 50 = 137 mg

a.i./L Conway et al, 1983 Supplemental / Practically non

- toxic

Estuarine/Marine

fish Acute toxicity Striped mullet ( Mugil

cephalus ) 96

- h LC 50 = 89 mg

a.i./L Crews et al., 1974 Supplemental/ Slightly oxic

A cute toxicity Brine shrimp 1

Artemia sp. EC 50 = 490 mg a.i./L Conway et al, 1983 Supplemental / Not surrogate for

estuarine/marine

Aquatic plant growth:

Tier I vascular plants Duckweed ( Lemna

gibba ) IC 50 >0.87 mg/L

NOAEC > 0.87 47921702 Acceptable /

-- 2

Aquatic plant growth: Tier I algae Freshwater green alga

( Pseudokirchneriella subcapitata ), static IC 50 >0.86 mg/L

NOAEC > 0.86 47921703 Acceptable /

-- 2

1 Brine shrimp, which are found in specialized habitat, are not used as a surrogate for estuarine/marine species.

2 Toxicity categories have not been assigned for aquatic plants.



### Table 19

– ECOSAR v1.11 Results for ETO
Organism Endpoints Fish, Freshwater generic 96

- h LC 50 = 57.7 mg/L ChV = 0.015 mg/L Daphnia, Freshwater Invertebrate, generic 48

- h EC 50 = 278 mg/L ChV = 27.8 mg/L

Green algae, generic 96

- h IC 50 = 501 mg/L ChV = 168 mg/L

ChV = geometric mean of the NOEC and LOEC, also referred to as the MATC



## Effects of ETO on Soil Microbes

Gennari et al. 1987 (MRID 49126103) investigated the effects of ETO on soil microflora in a west German soil sample with specifications similar to the US sandy loam soil. Suspensions were prepared by adding 100 grams of soil in 100 ml of water. Effects on the following microorganisms were monitored: fungi, actinomycetes, aerobic and anaerobic nitrogen fixers, ammonifiers, n itrifying, denitrifying, proteeolytic, ammololytic, pectinolytic, aerobic and anaerobic cellulolytic.

The exposure with ETO was carried out for four hours and eight hours. The study was conducted by taking 10% ETO in a chamber containing carbon dioxide (CO 2 

### ) atmosphere (3375 mm Hg pressure), where 65% relative humidity was maintained and temperature was kept at 40 o 

### C. After 3 days, desorption process was carried out. Microbial analysis on the 4 hour

- treated soil did not show any degree of sterilization; how ever, 8 hour treated soil showed complete elimination of all microorganisms. Slight changes in soil characteristics were observed for the ETO

- treated soil. These changes were: a slight increase in pH, an increase in organic matter, and an increase in

### Page 47 of 69

available phase iron (Fe) and manganese (Mn). These metals were extractable by ethylene diamine tetraacetate ( EDTA ) analysis. A slight decrease in cation exchange capacity and total nitrogen (N) content was also observed with ETO

- treated soil. This study i ndicated a strong pesticidal effect of ETO on the soil microorganisms. The study is a non

- guideline study. It is classified as supplemental and useable for characterizing effects to soil microflora and function from exposure to ETO

. 

## Aquatic Toxicity of Deg radate EG

There is an acute freshwater fish and invertebrate value for EG ( Table 20 )

. Both results indicate this degradate is significantly less toxic than the parent ETO.

Table 20

– Summary of the Most Sensitive Endpoints from Aquatic Toxicity Studies for

EG (Degradate of ETO).

Receptor Group Surrogate

Species Risk

Scenario Toxicity

Endpoint Reference (MRID)

Freshwater fish 1 Fathead minnow 1

( Pimephales promelas ) Acute 96

- h LC 50 > 100,000 mg a.i./L Conway et al.,

1983

Freshwater

invertebrates Waterflea ( Daphnia

magna ) Acute 48

- h EC 50 >100,000 mg a.i./L Conway et al.,

1983



### References Appendix C

ASTA (American Spice Trade Association). 2005. Public comments to Phase 3 of the reregistration risk assessment of ethylene oxide. Docket ID: OPP

- 2005

- 0203

- 0032/0034. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2005

- 0203

- 0034 ATSDR (Agency for Toxic Substances and Disease Registry) 1990, T oxicological Profile for Enthylene Oxide, a report by ATSDR, U.S. Public Health Service. pp122 Bogyo, D.A., Lande, S.S., Meylan, W.M., Howard, P.H. and Santodonato J. 1980. Investigation of Selected Potential Environmental Contaminants: Epoxides. A final report submitted to USEPA Office of Toxic Substances, Contract No. 68

- 01

- 3920. 216 pp. Conway, R.A., Waggy, G.T., Spiegel, M.H. and Berglund, R.L. (1983) Environmental fate and effects of ethylene oxide. Environ. Sci. Technol., 17,107

- 112. Cupitt, L.T. 198 0. Fate of toxic and hazardous materials in the environment, Research Triangle Park, North Carolina, USEPA, Environmental Sciences Laboratory, Office of Research and Development (US EPA 600/3

- 80

- 084, PB 80

- 221948). Gennari, M, Negre, M, Ambrosoli, R. 1987. Effects of Ethylene Oxide on Soil Microbial Content and Some Soil Chemical Characteristics Plant ands Soil, 102 : 197

- 200

. Hansch, C, and Leo A. 1979. Substituent constants for correlation analysis in chemistry and biology. New York, NY: John Wiley & Sons, Inc., 176. Hellman, T.M. & Small, F.H. (1974) Characterization of the odor properties of 101 petrochemicals using sensory methods. J. Air Pollut. Control Assoc., 24: 979

- 982.

IPCS. 2003. International Programme on Chemical Safety. Concise International Che mical

Assessment Document 54. (http://www.inchem.org/documents/cicads/cicads/cicad54.htm) (Accessed 2/27/2013).

### Page 48 of 69

Jacobson, K.H., Hackley, E.B., & Feinsilver, L. (1956) The toxicity of inhaled ethylene oxide and Ethylene oxide vapors. Arch. ind. Health, 13: 237

- 244. United States Environmental Protection Agency (USEPA). 1985. Health assessment document for ethylene oxide, Washington DC, US Environmental Protection Agency (EPA 600/8

- 84/009F).

USEPA. 2001. EFED RED Chapter for Ethylene Oxide DP279672. 2pp

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Agency. Endangered and Threatened Species

Effects Determinations. Office of Prevention, Pesticides and Toxic Substances, Offi ce of Pesticide Programs, Washington, D.C. January 23, 2004.

USEPA. 2008. Reregistration Eligibility Decision for ETO, 2008. Online at http://www.epa.gov/oppsrrd1/REDs/ethylene

- oxide

- red.pdf USEPA. Ecological Structure Activity Relationships (ECOSAR). 2011

. Version 1.10, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm

. USEPA. 2013a. BEAD Chemical Profile for Registration Review: Ethylene oxide (042301). 5pp.

USEPA. 2013b. Guidance for Conducting Fumigant Exposure Assessment in Ecological Risk

Assessment. Interim Divisional Guidance, EFED. 118pp.

WHO. 1985. EHC 55: Ethylene oxide, Geneva, World Health Organization, 79 pp.



## ECOSAR Version 1.10 Results Page

SMILES : O(C1)C1

CHEM : Oxirane

C AS Num: 000075

- 21

- 8

ChemID1:

MOL FOR: C2 H4 O1

MOL WT : 44.05

Log Kow:

- 0.045 (EPISuite Kowwin v1.68 Estimate)

Log Kow: (User Entered)
Log Kow:

- 0.30 (PhysProp DB exp value

- for comparison only)

Melt Pt: (User Entered for Wat Sol estimate)

Melt Pt:

- 111.70 (deg C, PhysProp DB exp value for Wat Sol est) Wat Sol: 3.067E+005 (mg/L, EPISuite WSKowwin v1.43 Estimate)

Wat Sol: (User Entered)

Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

-------------------------------------- Values used to Generate ECO SAR Profile

-------------------------------------- Log Kow:

- 0.045 (EPISuite Kowwin v1.68 Estimate)

Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

------------------------------------------------ Available Measured Data from ECOSAR Training Set

--------- ---------------------------------------

Measured

CAS No Organism Duration End Pt mg/L (ppm) Ecosar Class Reference

=========== ========== ========== ====== ========== ============== =================== 000075

- 21

- 8 Daphnid 48

- hr LC50 137 Epoxides, mono Conway et al., 1983

000075

- 21

- 8 Fish 96

- hr LC50 84 Epoxides, mono Conway et al., 1983

-------------------------------------- ECOSAR v1.1 Class

- specific Estimations

--------------------------------------

### Page 49 of 69

Epoxides, mono

Predicted

ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================== ======== ====== ========== Epoxides, mono : Fish 96

- hr LC50 57.672 Epoxides, mono : Fish 14

- day LC50 31.003 Epoxides, mono : Daphnid 48

- hr LC50 277.857 Epoxides, mono : Green Algae 96

- hr EC50 501.535 Epoxides, mono : Fish ChV 0.015 Epoxides, mono : Daphnid ChV 27.803 ! Epoxides, mono : Green Algae ChV 168.525

=========================== ================== ======== ====== ========== Neutral Organic SAR : Fish 96

- hr LC50 2486.310
(Bas eline Toxicity) : Daphnid 48

- hr LC50 892.307
: Green Algae 96

- hr EC50 817.901

: Fish ChV 194.495 : Daphnid ChV 67.386
: Green Algae ChV 68.573

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES)
are reported.

NOTE: ! = exclamation designates: The toxicity value was estimated through application of acute

- to

- chronic ratios per methods outlined in

the ECOSAR Methodology Document provided in the ECOSAR Help Menu.

------------------------------ Class Specific LogKow Cut

- Offs

------------------------------ If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, th en no effects at saturation are expected for those endpoints.

Epoxides, mono:

-------------- Maximum LogKow: 5.0 (Fish 96

- h LC50, Daphnid LC50) Maximum LogKow: 6.0 (Fish 14

- day) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

--------------------------------- Maximum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)

### Page 50 of 69 

# Appendix D Product Chemistry

The ETO product chemist ry information is summarized in Table D 1 (source : MRIDs 41531002, 42458502, 42466702, 42811401, 43053201

, and EPI Suite v4.1)

.

Table D 1

– Product Chemistry of ETO

Guideline

Number Physical and Chemical Properties Value

830.1550 Product identity and composition Refer to Table 3.

830.1600 Description of materials used to

produce the product Confidential Business Information (CBI)

830.1620 Description of production process CBI

830.1650 Description of Formulation Process CBI

830.1670 Discussion of formulation of

impurities CBI

830.1700 Preliminary analysis CBI

830.1750 Certified limits CBI

830.1650 Description of Formulation Process CBI

830.1800 Enforcement analytical method Gas chromatography (GC).

830.1900 Submittal of samples CBI

830.6302 Color ETO is a colorless gas or liquid.

830.6303 Physical State ETO is a colorless gas at 25 °C and is a mobile liquid at 0 °C.

830.6304 Odor The gas has a characteristic sweet odor of ether.

830.6313 Stability to normal and elevated

temperature, metals/metal ions ETO is stable at ordinary conditions of temperature and pressure and in ordinary use, handling and storage.

ETO is a reactive molecule. Its ability to chemically combine with itself and other molecules (and the necessary conditions) is reported.

Protect from sunlight. Store in a well

- ventilated place.

830.6314 Oxidation/Reduction:

Chemical Incompatibility: Highly reactive. It is reactive in both the liquid and vapor phases.

Materials to avoid: Alcohols, alkali metals, ammonia, oxidizing agents, chemically active metals and its salts.

830.6315 Flammability

- Flash point Flammable gas. It is extremely flammable and explosive, therefore, it is commonly handled and shipped as a refrigerated liquid. Flash point −20.0 °C − closed cup Flash point <−18.0 °C

– tag op en cup
830.6316 Explodability It is extremely flammable and explosive; therefore, it is commonly handled and shipped as a refrigerated liquid.

830.7000 pH This requirement does not apply to ETO because it is not an acid or base. It is a gas.

830.7050 UV/Visible Absorption Not applicable.

830.7100 Viscosity 0 °C

– 0.325 cP

20°C

– 0.260 cP Viscosity of liquid ETO at 0 °C is about 5.5 times lower than

that of water.

830.7200 Melting point:

Freezing point: − 111.7 °C

− 112.778 °C

830.7220 Boiling point 10.6 °C at 760 mmHg

830.7300 Density 0.995 g/cm 3 0.882 g/cm3 at 25 °C 0.8697 g/ml 20 °C

### Page 51 of 69

Guideline

Number Physical and Chemical Properties Value

830.7370 Dissociation Constant in water (pKa) ETO is a covalently bonded organic molecule (an alkyl epoxide) and does not dissociate.

830.7550 Partition coefficient ( n

octanol/water) Log Kow − 0.30 (Log P)

830.7840 Solubility in water Infinitely soluble.

830.7860 Solubility in organic solvents Readily soluble in water, ethanol, diethyl ether, acetone, benzene and many organic solvents.

830.7950 Vapor pressure 1255 mm Hg at 25°C

### Page 52 of 69 

# Appendix E Modeling Input Based on ETO Release Scenarios for Spices and Herbs

ETO is used to treat spices, dried vegetables, and seasonings in fumigation chambers. Labels specify maximum application rates, or indoor concentrations of ETO, which are maintained over periods of time for treatments inside the chambers. Fumigation chambers have a maximum size of 10,000 cubic feet

. 15 

### Labels all require mechanical, or forced, aeration following a treatment of

the commodities. Mechanical aeration releases the fumigant outdoors from the treat ment
chamber through a stack or vent. Product labels particularly specify that ETO is to be evacuated from chambers through the use of steam scavenging techniques, and specifies the number o f washes that are to be applied during aeration. Labels also specify the temperature of the steam which renders the aeration as a buoyant release. ETO labels specify the following mechanical release parameters given the following maximum application rates:

First Release Scenario

 Maximum Application Rate (per chamber) = 500 mg/L = 31.22 lbs./1,000 ft. 3



###  Flow Rate = 21 steam washes specified

 Chamber/Stack Temperature: 115°F

Second Release Scenario

 Maximum Application Rate (per chamber) = 500 mg/L = 31.22 lbs./ 1,000 ft. 3



###  Flow Rate = 16 steam washes specified

 Chamber/Stack Temperature: 120°F

It is important to note that it is possible that more than one ETO treatment inside fumigation

chambers can occur at a time at the same location. The labels do not specify a maximum amount of simultaneous fumigation chamber treatments.

AERSCREEN Description

The Agency’s recommended screening dispersion model for the near field, the American Meteorological Society/EPA Regulatory Screening Model (AERSCREEN), will be used to

gene rate screening EECs for the various release scenarios. The Tier I analysis will consider the emission rates and release flow rates and stack parameters for the various mechanical release

scenarios for ETO. Worst

- case meteorological conditions (light winds and stagnant conditions)

and downwash 16 

### parameters are assumed to calculate peak air EECs, representing one

- hour average concentrations. Documentation on the AERSCREEN model is available at http://www.epa.gov/scram001/dispersion_screening.htm

. A schematic of release scenarios from

treatment chambers and the related conceptual model for ground

- level exposure is shown in Figure E 1

. For purposes of this screening analysis, all ecological receptors of concern will assumed to be present directly downwind from the building at ground level.

15 Fumigation chambers are assumed to possess similar size to railcars. Citation: http://www.csx.c om/index.cfm/customers/equipment/railroad

- equipment/

16 Downwash is defined as the downward flow often observed on the leeside of buildings induced by wake turbulence. Pollutants released from buildings can often become embedded in downwash flows and wake c avities.

### Page 53 of 69

Figure E 1

. Schematic illustrating fumigation releases from treat ment chambers and conceptual model for ground

- level exposure.

AERSCREEN Release Scenarios

Each release scenario from the ETO label described above will be modeled to capture all possible combinations of release parameters. Either release scenario may result in the upper

bound air EEC at ground

- level based upon individual contributions between the flow rate and temperature of the steam. Scenario 1 of the AERSCREEN evaluation represents the first aeration scenario specified on the label described above. Scenario 2 represents the second aeration scenario specified on the label described above. Eac h modeled release scenarios conservatively assumes that aeration is complete after one hour which results in maximized peak (one

- hour average) concentrations.

The input parameter values used in AERSCREEN for the screening analysis of ETO air exposure

is sh own in Table E 1 below. The AERSCREEN modeling captures the upper

- bound air exposure from release scenarios consolidated above from information on the ETO product label.

Table E 1. AESCREEN input parameter values capturing the upper

- bound combination of

rele ase scenarios identified on the ETO label.

Input Parameter Option/Value Notes

Scenario 1 Scenario 2 English or Metric Units E (English) Source Type P (Point) S tack releases

Emission Rate (lbs./hr) 312.2 All mass from labeled specified application rate inside 10,000 ft. 3 chamber released in one

- hour

period 1

Stack or Release Height Above Ground (ft.) 5 Not specified on label Default for 10,000 ft. 3 building size based on methyl bromide assessment 2

Stack Diameter (in.) 39.6 Default for 10,000 ft. 3 building size based on methyl bromide assessment (1 meter) 2

Stack Temperature (°F) 115 120 Based on stack temperatures provided on the

labels Option for Flow Rate or Flow

Velocity 3 (Flow Rate ACFM)

Stack Exit Stream

Flow Rate (f

3 /min.) 3,500 2,667 Scenario 1: Based on 21 steam washes specified on label

– assume 21 air exchanges per hour for hourly

release 3

Scenario 2: Based on 16 steam washes specified on label

– assume 16 air exchanges per hour for hourly

### Page 54 of 69 Input Parameter Option/Value Notes

Scenario 1 Scenario 2

release 3

Urban or Rural? R (Rural) Conservative default

Minimum Distance to Ambient

Air (ft.) 3.3 Conservative default

NO 2 Chemistry 1 (No chemistry/pollutant

is not NO 2 ) Tracer gas NO

x emissions not modeled

Include Building Downwash? Y (Yes) Downwash is feasible downward transport mechanism for plume in release scenarios

Use Pre

- Existing BPIPPRM

File? N (No) Downwash parameters to be input manually

Building Height (ft.) 5 Equivalent to stack height Maximum Horizontal Building Dimension (ft.) 44.72 Square chamber footprint consistent with building heights specified above Minimum Horizontal Building Dimension (ft.) 44.72 Square chamber footprint consistent with building heights specified above Maximum Building Dimension Angle to True North (degrees) 0

Conservative parameterization of building

downwash

– stack located on the leeward edge of

the building Direction of Stack from Building Center (degrees) 0

Distance Between Stack and Building Center (ft.) 22.3

Terrain Heights? N (No) Only flat terrain considered Maximum Distance to Probe (m) 5,000 Default

- maximum feasible distance for screen Include Discrete Receptors N (No) Automated receptors sufficient Flagpole Receptors N (No) Ground

- level concentrations assumed Source Elevation (ft.) 0 Stack base from gr ound release assumed Minimum Temperature (°F)

- 10 Default

– typical national temperature range Maximum Temperature (°F) 100 Default

– typical national temperature range Minimum Wind Speed (m/s) 0.5 Minimum in model: conservative default

Anemometer Height (ft.) 33 Typical boundary layer reference height (10 meters)

Surface Characteristics Option 1 (Single User Specified Values)

Albedo 0.6 Bare surface assumed around source 4

Bowen Ratio 3.0 Bare surface assumed around source 4
Surface Roughness Length (m) 0.001 Bare surface assumed around source 4

1 Scenario 1 and 2 Emission Rate (lbs./hr) = [ Application Rate (lbs./ft. 3 ) x Chamber Size (ft. 3 ) / Duration of Release (hr.) ]

2 Methyl bromide risk assessment citation: Dawson, J. 2008. Second Addenda to the 2006 (DP Barcode 304623) Phase 5 Human Health Risk Assessment for Commodity Uses. Office of Pesticide Programs. Washington, DC. (November 26, 2008) (EPA DP Barcode 304612).

3 Flow rate (ft. 3 /min) = Air exchange rate (air exchanges/hr.) x Chamber Size (ft. 3 ) x ( hours / 60 minutes )

4 Default values for bare soil assumed. Please refer to, “User’s Guide for the AERMOD Meteorological Preprocessor (AERMET)”, (EPA, 2004) for further details.

### Page 55 of 69 

# Appendix F Output Example of

AERSCREEN Estimated Environmental Concentration (EEC) for ETO Release

Scenario 2

AERSCREEN 11126 / AERMOD 1234 04/19/13

15:56:35

TITLE: ETO

- 16

-----------------------------------------------------------------------------

***************************** STACK PARAMETERS *********** *****************

-----------------------------------------------------------------------------

SOURCE EMISSION RATE: 39.3372 g/s 312.200 lb/hr

STACK HEIGHT: 1.52 meters 5.00 feet

STACK INNER DIAMETER: 1.006 meters 39.60 inches

PLUME EXIT TEMPERATURE : 322.0 K 120.0 Deg F

PLUME EXIT VELOCITY: 1.584 m/s 5.20 ft/s

STACK AIR FLOW RATE: 2667 ACFM

RURAL OR URBAN: RURAL

INITIAL PROBE DISTANCE = 5000. meters 16404. feet

-----------------------------------------------------------------------------

*********************** BUILDING DOWNWASH PARAMETERS **********************

-----------------------------------------------------------------------------

BUILDING HEIGHT: 1.5 meters 5.0 feet

MAX BUILDING DIMENSION: 13.6 meters 44.7 feet

MIN BUILDING DIMENSION: 13.6 meters 44.7 feet

BUILDING ORIENTATION TO NORTH: 0. degrees

STACK DIRECTION FROM CENTER: 0. degrees

STACK DISTANCE FROM CENTER: 6.8 meters 22.3 feet

-----------------------------------------------------------------------------

****** ******************** FLOW SECTOR ANALYSIS *************************** 25 meter receptor spacing: 1. meters

- 5000. meters

-----------------------------------------------------------------------------

FLOW BUILD BUILD MAX 1

- HR DIST TEMPORAL

### Page 56 of 69

SECTOR WI DTH LENGTH XBADJ YBADJ CONC (m) PERIOD

----------------------------------------------------------------------------- 10 15.80 15.79

- 14.59

- 1.18 0.2151E+06 1.0 ANN

20 17.48 17.47

- 15.12

- 2.32 0.2694E+06 1.0 ANN

30 18.63 18.62

- 15.20

- 3.40 0.3072E+06 1.0 ANN

40 19.21 19.21

- 14.81

- 4.37 0.3252E+06 1.0 ANN

50 19.21 19.21

- 13.97

- 5.21 0.2594E+06 1.0 ANN

60 18.62 18.63

- 12.71

- 5.88 0.2600E+06 1.0 ANN

70 17.47 17.48

- 11.06

- 6.39 0.2554E+06 25.0 ANN

80 15.79 15.80

- 9.08

- 6.69 0.2702E+06 25.0 ANN

90 13.63 13.64

- 6.82

- 6.80 0.2830E+06 25.0 ANN

100 15.79 15.80

- 6.72

- 6.69 0.3118E+06 25.0 ANN

110 17.47 17.48

- 6.42

- 6.39 0.3058E+06 25.0 ANN

120 18.62 18.63

- 5.92

- 5.88 0.3136E+06 25.0 ANN

130 19.21 19.21

- 5.24

- 5.21 0.3241E+06 25.0 ANN

140 19.21 19.21

- 4.40

- 4.37 0.3431E+06 25.0 ANN

150 18.63 18.62

- 3.43

- 3.40 0.3424E+06 25.0 ANN

160* 17.48 17.47

- 2.35

- 2.32 0.3483E+06 25.0 ANN

170 15.80 15.79

- 1.20

- 1.18 0.3428E+06 25.0 ANN

180 13.64 13.63

- 0.02 0.00 0.3241E+06 25.0 ANN

190 15.80 15.79

- 1.20 1.18 0.3428E+06 25.0 ANN

200 17.48 17.47

- 2.35 2.32 0.3483E+06 25.0 ANN

210 18.63 18.62

- 3.43 3.40 0.3424E+06 25.0 ANN

220 19.21 19.21

- 4.40 4.37 0.3431E+06 25.0 ANN

230 19.21 19.21

- 5.24 5.21 0.3241E+06 25.0 ANN

240 18.62 18.63

- 5.92 5.88 0.3136E+06 25.0 ANN

250 17.47 17.48

- 6.42 6.39 0.3058E+06 25.0 ANN

260 15.79 15.80

- 6.72 6.69 0.3118E+06 25.0 ANN

270 13.63 13.64

- 6.82 6.80 0.2830E+06 25.0 ANN

280 15.79 15.80

- 9.08 6.69 0.2702E+06 25.0 ANN

290 17.47 17.48

- 11.06 6.39 0.2554E+06 25.0 ANN

300 18.62 18.63

- 12.71 5.88 0.2600E+06 1.0 ANN

310 19.21 19.21

- 13.97 5.21 0.2594E+06 1.0 ANN

320 19.21 19.21

- 14.81 4.37 0.3252E+06 1.0 ANN

330 18.63 18.62

- 15.20 3.40 0.3072E+06 1.0 ANN

340 17.48 17.47

- 15.12 2.32 0.2694E+06 1.0 ANN

350 15.80 15.79

- 14.59 1.18 0.2151E+06 1.0 ANN

360 13.64 13.63

- 13.61 0.00 0.1402E+06 25.0 ANN

* = worst case flow sector

-----------------------------------------------------------------------------

********************** MAKEMET METEOROLOGY PARAMETERS ****************** ***

-----------------------------------------------------------------------------

MIN/MAX TEMPERATURE: 249.8 / 310.9 (K)

MINIMUM WIND SPEED: 0.5 m/s

ANEMOMETER HEIGHT: 10.000 meters

SURFACE CHARACTERISTICS INPUT: USER ENTERED

ALBEDO: 0.60

BOWEN RATIO: 3.00

### Page 57 of 69

ROUGHNESS LENGTH: 0.001 (meters)

METEOROLOGY CONDITIONS USED TO PREDICT OVERALL MAXIMUM IMPACT

-------------------------------------------------------------

YR MO DY JDY HR

-- -- -- --- -- 10 06 01 1 01

H0 U* W* DT/DZ ZICNV ZIMCH M

- O LEN Z0 BOWEN ALBEDO REF WS

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- 4.06 0.054

- 9.000 0.020

- 999. 291. 3.8 0.001 3.00 0.60 2.50

HT REF TA HT

- - - - - - - - - - - 10.0 310.9 2.0

ESTIMATED FINAL PLUME HEIGHT ( non

- downwash): 5.3 meters

METEOROLOGY CONDITIONS USED TO PREDICT AMBIENT BOUNDARY IMPACT

--------------------------------------------------------------

YR MO DY JDY HR

-- -- -- --- -- 10 06 28 1 01

H0 U* W* DT/DZ ZICNV ZIMCH M

- O LEN Z0 BOWEN ALBE DO REF WS

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- 13.42 0.124

- 9.000 0.020

- 999. 101. 13.7 0.001 3.00 0.60 4.00

HT REF TA HT

- - - - - - - - - - - 10.0 310.9 2.0

ESTIMATED FINAL PLUME HEIGHT (non

- downwash): 2.6 meters

----------------------------------------------------------------------------- ************************ AERSCREEN AUTOMATED DISTANCES **********************

OVERALL MAXIMUM CONCENTRATIONS BY DISTANCE

------------------------------------------- ----------------------------------

MAXIMUM MAXIMUM

DIST 1

- HR CONC DIST 1

- HR CONC (m) (ug/m3) (m) (ug/m3)

--------------------- --------------------- 1.01 0.3252E+06 2525.00 8586.

25.00 0.3483E+06 2550.00 8512.

50.00 0.2898E+06 2575.00 8439.

75 .00 0.2450E+06 2600.00 8367.

100.00 0.2128E+06 2625.00 8296.

125.00 0.1890E+06 2650.00 8226.

### Page 58 of 69

150.00 0.1706E+06 2675.00 8156.

175.00 0.1550E+06 2700.00 8088.

200.00 0.1387E+06 2725.00 8020.

225.00 0.1222E+06 2750.00 7953.

250.00 0.1056E+06 2775.00 7887.

275.00 0.8956E+05 2800.00 7821.

300.00 0.7444E+05 2825.00 7757.

325.00 0.6068E+05 2850.00 7693.

350.00 0.4852E+05 2875.00 7630.

375.00 0.4011E+05 2900.00 7568.

400.00 0.3704E+05 2925.00 7506.

425.00 0.3435E+05 2950.00 7445.

450.00 0.3197E+05 2975.00 7386.

475.00 0.2986E+05 3000.00 7326.

500.00 0.2906E+05 3025.00 7268.

525.00 0.2880E+05 3050.00 7210.

550.00 0.2848E+05 3075.00 7153.

575.00 0.2812E+05 3100.00 7096.

600.00 0.2771E+05 3125.00 7041.

625.00 0.2728E+05 3150.00 6986.

650.00 0.2683E+05 3175.00 6931.

675.00 0.2637E+05 3200.00 6877.

700.00 0.2589E+05 3225.00 6824.

725.00 0.2541E+05 3250.00 6771.

750.00 0.2493E+05 3275.00 6726.

775.00 0.2445E+05 3300.00 6687.

800.00 0.2398E+05 3325.00 6649.

82 5.00 0.2350E+05 3350.00 6611.

850.00 0.2304E+05 3375.00 6573.

875.00 0.2258E+05 3400.00 6535.

900.00 0.2213E+05 3425.00 6498.

925.00 0.2169E+05 3450.00 6461.

950.00 0.2126E+05 3475.00 6424.

975.00 0.2083E+05 3500.00 6387.

1000.00 0.2042E+05 3525.00 6351.

1025.00 0.2002E+05 3550.00 6315.

1050.00 0.1963E+05 3575.00 6279.

1075.00 0.1924E+05 3600.00 6244.

1100.00 0.1887E+05 3625.00 6208.

1125.00 0.1851E+05 3650.00 6173.

1150.00 0.1815E+05 3675.00 6142.

1175.00 0.1781E+05 3700.00 6112.

1200.00 0.1747E+05 3725.00 6081.

1225.00 0.1715E+05 3750.00 6051.

1250.00 0.1683E+05 3775.00 6022.

1275.00 0.1652E+05 3800.00 5992.

1300.00 0.1622E+05 3825.00 5962.

1325.00 0.1593E+05 3850.00 5933.

1350.00 0.1564E+05 3875.00 5904.

1375.00 0.1537E+05 3900.00 5877.

1400.00 0.1510E+05 3925.00 5849.

1425.00 0.1484E+05 3950.00 5822.

1450.00 0.1458E+05 3975.00 5795.

1475.00 0.1433E+05 4000.00 5768.

1500.00 0.1409E+05 4025.00 5741.

1525.00 0.1387E+05 4050.00 5714.

### Page 59 of 69

1550.00 0.1 366E+05 4075.00 5687.

1575.00 0.1346E+05 4100.00 5661.

1600.00 0.1326E+05 4125.00 5634.

1625.00 0.1307E+05 4150.00 5608.

1650.00 0.1288E+05 4175.00 5582.

1675.00 0.1269E+05 4200.00 5556.

1700.00 0.1251E+05 4225.00 5530.

1725.00 0.1233E+05 4250.00 5505.

1750.00 0.1216E+05 4275.00 5479.

1775.00 0.1199E+05 4300.00 5454.

1800.00 0.1182E+05 4325.00 5428.

1825.00 0.1166E+05 4350.00 5403.

1850.00 0.1150E+05 4375.00 5378.

1875.00 0.1135E+05 4400.00 5354.

1900.00 0.1120E+05 4425.00 5329.

1925.00 0.1105E+05 4450.00 5305.

1950.00 0.1090E+05 4475.00 5280.

1975.00 0.1076E+05 4500.00 5256.

2000.00 0.1062E+05 4525.00 5232.

2025.00 0.1048E+05 4550.00 5208.

2050.00 0.1034E+05 4575.00 5184.

2075.00 0.1021E+05 4600.00 5161.

2100.00 0.1008E+05 4625.00 5137.

2125.00 9957. 4650.00 5114.

2150.00 9833. 4675.00 5091.

2175.00 9715. 4700.00 5068.

2200.00 9628. 4725.00 5045.

2225.00 9542. 4750.00 5022.

2250.00 9458. 4775.00 4999.

2275.00 9374. 4800.00 4977.

2300.00 9291. 4825.00 4954.

2325.00 9209. 4850.00 4932.

2350.00 9128. 4875.00 4910.

2375.00 9048. 4900.00 4888.

2400.00 8968. 4925.00 4866.

2425.00 8890. 4950.00 4845.

2450.00 8813. 4975.00 4823.

2475.00 8736. 5000.00 4802.

2500.00 8661.

-----------------------------------------------------------------------------

********************** AERSCREEN MAXIMUM IMPACT SUMMARY *********************

-----------------------------------------------------------------------------

MAXIMUM SCALED SC ALED SCALED SCALED

1

- HOUR 3

- HOUR 8

- HOUR 24

- HOUR ANNUAL

CALCULATION CONC CONC CONC CONC CONC

PROCEDURE (ug/m3) (ug/m3) (ug/m3) (ug/m3) (ug/m3)

--------------- ---------- ---------- ---------- ---------- ---------- FLAT TERRAIN 0.6871E+06 0.6871E+06 0.6 184E+06 0.4123E+06 0.6871E+05

DISTANCE FROM SOURCE 16.00 meters directed toward 160 degrees

IMPACT AT THE

AMBIENT BOUNDARY 0.3252E+06 0.3252E+06 0.2927E+06 0.1951E+06 0.3252E+05

DISTANCE FROM SOURCE 1.01 meters directed toward 40 degrees

### Page 60 of 69 

# Appendix G C omments Received Concerning the Preliminary Work Plan

On September 25, 2013

, EPA opened a 60

- day public comment period on the preliminary work plan (PWP) for the registration review of e thylene o xide. The comment period ended on November 25, 2013. During the public comment period the Agency received 12 submissions

from 10 commenters . Table 1 below lists the submitters.

Table 1. Submitters of Comments on the “Ethylene Oxide Preliminary Workplan”

3M Health Care (2 submissions)

American Farm Bureau Federation (AFBF)

ARC Specialty Products, Balchem Corporation (ARC)

McDermott Will & Emery

– on behalf of the American Spice Trade Association (ASTA)

Minor Crop Farmer Alliance (MCFA)

Physicians Committee for Responsible Medicine

Sterigenics International, LLC (Sterigenics) (2 submissions)

STERIS Corporation

The Ethylene Oxide Sterilization Association, Inc. (EOSA)

University of Florida

This appendix is divided into three sections. Section I includes general comments to the PWP.

Section II offers all comments related to the h uman h ealth assessment

. Section III offers all

comments related to the e nvironmental f ate and e ffects assessment

.

### Page 61 of 69 

# I. General Comments

(Agency response to comments 1

- 4 is below comment 4)

1. Usage Information EOSA, ARC, ASTA: The usage information on page 11 of the PWP may no longer be accurate. EOSA requests the opportunity to review these industry data and provide current reliable usage information. Due to the time and resources necessary to comp ile these data, they will not be available for the November 25, 2013, comment period deadline. ETO has been used for sterilization and fumigation purposes for decades. Approximately 98% of the total pounds of ETO sold for pesticidal purposes are used for

t he sterilization of medical devices by contract sterilizers and medical device manufacturers. The number of hospitals performing in

- house sterilization has declined since the 2008 Reregistration Eligibility Decision (RED), and will continue to decline

subs tantially. The industry now estimates that less than 1% of the total pounds of ETO used for pesticide purposes will be used in hospitals or other medical facilities. Additionally, the use for spice treatment has also declined since the 2008 RED. The

indust ry now estimates that less than 1% of total pounds of ETO sold for pesticidal purposes are used for fumigation of herbs and spices. Therefore, the typical usage of ETO is by large contract sterilization companies or

medical device manufacturers. All of th ese companies comply with EPA’s National Emission Standards for Hazardous Air Pollutants (NESHAP) for Commercial Sterilization Facilities (Subpart O of 40 C.F.R. Part 63). This ETO usage is different than the typical agricultural field pesticide use, as th e process is performed in vacuum chambers. The extent of its use is different from what was published in the 2008 RED.

2. Use or Potential Use Distribution

EOSA: Products containing ETO are currently being used at over 80 contract sterilization facilities, m edical device manufacturing facilities, and spice treatment facilities in 31 states and Puerto Rico. According to the 2008 RED, there are approximately 1,900 hospitals and other medical facilities in nearly all states where treatment with ETO takes place. EOSA believes, however, the number of hospital facilities has significantly decreased since the 2008 RED was released. Additional time will be required to obtain current information.

3. Typical Application Interval

EOSA: There are no “typical” application in tervals for medical device sterilization. Spice

treatment paramete rs are specified on the label.

4. Confirmation of Label Information

EOSA & ARC : The PWP requests additional information and confirmation on label information. The following comments provide additional label information regarding sites of application; formulations; application methods and equipment; maximum application rates; frequency of application, application intervals, and maximum number of applications; and geographic limitations on use.

### Page 62 of 69

Application sites : ETO may be used only to sterilize medical or laboratory items, pharmaceuticals, and aseptic packaging (21 C.F.R. § 201.1(d)(5)) or to reduce microbial load on cosmetics, whole and ground spices, or other seasoning materials (40 C.F.R. § 180.151), and artifacts, archival materials, or library objects. The use of ETO is only approved for industrial and hospital use.

Formulations : Currently, there are 23 active Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) registrations for products containing ETO as the active ingredient. Of those products, eight contain 100% ETO. The remaining 15 products contain ETO in various percentages from 8.5% up to 98.06%; all are blended with inert ingredients, not other actives. Application method s and equipment : ETO may only be used in vacuum or gas

- tight

chambers. Maximum application rates : For sterilization of medical devices, the concentration of ETO is determined by the process used to validate the sterilization cycle in accordance

with FDA re quirements. For the treatment of spices and other seasoning materials, the method described on the label specifies a maximum ETO concentration of 500 mg/L. Frequency of application, application intervals, and maximum number of applications:

ETO treatment facilities typically operate seven days per week, however, application intervals and the number of applications vary from site to site depending on the products needing to be treated. The maximum number of treatments for medical device

sterilization is con trolled by FDA requirements. Geographic limitations on use : Products containing ETO are registered in all 50 states and Puerto Rico. EOSA is not aware of any geographic limitations on use in the United

States. EPA

- registered products containing ETO are al so shipped to other countries.

Response to 1

- 4 : The Agency thanks the submitters for these comments and welcomes the submission of any additional data commenters have on hand related to use, usage, application details, and /or benefits of ethylene oxide. Th e Agency is lacking current information regarding the uses for spice (e.g., rates, spice types, etc.) including the availability, efficacy, and use patterns of alternatives. Similarly, the Agency does not have the latest information on any alternatives th at overlap ETO efficacy for medical devices, especially those that might be available for hospital use sites. During the registration review of ETO, additional use and usage information and details about alternatives may be needed.

5. AFBF: AFBF has been actively engaged for years as a member of the agency’s Pesticide Policy Dialogue Committee (PPDC) and values its membership on that committee. At the same time, AFBF has longstanding policy, adopted by our national membership, that

reflects the views of our agricultural producers on how EPA should utilize its authority in regulating agricultural chemicals. AFBF strongly recommends that EPA:

 Base its implementation of FIFRA on credible scientific information;

 Test pesticides based on realis tic levels of exposure or consumption;

 Consider the risks and benefits when determining whether to cancel or restrict pesticides or chemicals used in agricultural production; and

### Page 63 of 69  Consider actual use data in the risk assessment process and not make decisions

based on worst

- case assumptions.

Response: The Agency thanks AFB for its comment on the registration review process. The Agency uses the best available data in making its decisions, which may include actual use and usage information, field st udies, monitoring data, modeling, and information from incidents. The Agency considered both the risks and benefits of the fumigants during the reregistration process, and those decisions were issued in 2008. During registration review of the fumigants, t he Agency is looking at what has changed since the last assessments, how significant these changes are, if there is a need for any new information or studies to conduct updated risk assessments, and if the Agency’s regulatory position is likely to change a s a result of any new information.

6. ASTA: McDermott, Will & Emery submitted comments on behalf of the ASTA,
emphasizing the importance of ETO for the prevention of pests and microbial
contaminants in spices; expressing concern regarding the potential impa ct of data
requirements on the continued availability of ETO for this use; and stating the intention
of ASTA to be involved in the registration r e view process, including a suggestion to have
a focus meeting to identify issues that will be considered in the review and to confirm use
practices.

Response: The Agency thanks ASTA for their comment on the spice uses of ETO. EPA

hosted a focus meeting on January 29, 2014 with the ETO registrants and stakeholders to discuss comments submitted by the stakeholders p ertaining to the ETO Preliminary Work Plan (PWP). The stakeholders presented an overview on ETO usage and industrial and hospital ETO sterilization (typical ETO sterilization processes, emission controls and worker exposure control measures). Participants also discussed anticipated data needs

and areas where the risk assessment could be refined with data from ETO stakeholders. A summary of the meeting and presentation materials will be available in the docket at

EPA

- HQ

- OPP

- 2013

- 0244. Additional focus meet ings will be held during the registration review process as needed.

7. University of Florida : University of Florida is concerned about further increases in regulatory costs’, or the loss of chemical fumigants’, impact on the fruit and vegetable

industries of Florida and other support industries. A summary of some UF fumigant
research was provided.

Response : This comment pertains to the fumigants used for pre

- plant soil treatment, not

ETO. The comment was placed in the relevant soil fumigant dockets and is a ddressed in

those dockets.

8. MCFA : The MCFA is anticipating the need to move forward with interim changes to
the most current product labels to address problems that users are experiencing.

### Page 64 of 69

Response: The Agency is committed to discussing progress on post

- RED label implementation for the fumigants whenever questions or issues arise. Please contact the active ingredient chemical review manager in the Pesticide Re

- evaluation Division or the Antimicrobials Division who will consult with the fumigant review te am on the appropriate path forward for any issues with labeling specified by the RED. For other label changes, please contact the appropriate Product Manager in the Antimicrobials

Division.

9. MCFA : The MCFA would appreciate periodic updates regarding the progress being
made, and any information needs that could be supplied by its members.

Response: The Agency appreciates the offer for assistance with information, and will keep this in mind moving forward in the registration review process.



# II. Human Healt h Comments

1. Acute inhalation toxicity study
EOSA & Sterigenics : EOSA requests clarification and detail regarding the acute inhalation toxicity study (special study). EPA notes that this might be an update to the 2008 occupational handler risk assessment (Table 1). It is not clear whether EPA is requesting an update to the 2008 study or if review and subsequent determination by the industry that the study accurately reflects current worker exposure will be sufficient. A complete new study, as indicated in Table 7, does not appear to be necessary. Additionally, we believe the worker exposure scenario assessment would be the “worst case” and the industry’s segregation, control of visitors, and area monitoring is sufficient to maintain the safety of “bystanders.”

3M : The concern for bystander exposure through inhalation is acknowledged. Nevertheless, there are questions surrounding the endpoints and study design for the proposed study that would benefit from a face

- to

- face discussion to resolve. Acute inhalation toxicity studies are typically conducted after 4 hour or 8 hou r exposure. However, the changes may be so subtle that requested pathological endpoints may not provide any meaningful information given the short exposure. The requested pharmacokinetic/tissue dosimetry data may require a different dosing regimen as well. A more detailed outline of study objectives would be appropriate. As noted by EPA in Table 8 of the Preliminary Work Plan, short

- term inhalation toxicity data (1

- 30 days) already exists.

PCRM: It appears that data is available for the acute inhalation st udy: Ethylene oxide was tested on groups of rats for either 4

- hour or 1

- hour inhalation exposure, followed by 14 days of observation. Groups of five Sprague

- Dawley rats/sex were exposed, and clinical signs and mortality were recorded. Clinical signs noted included irregular breathing, absence of certain reflexes, and tremors. Rats that died had moderate to severe pulmonary congestion. The calculated LC50 values, reported as ppm by volume (with 95% confidence limits), were as follows. 4

- hour LC50 values wer e 1972

### Page 65 of 69

(1887 to 2061) ppm for males; 1537 (1391 to 1698) ppm for females; 1741 (1655 to 1831) ppm for the combined sexes. The 1

- hour LC50 values were 5748 (5276 to 6262) ppm for males; 4439 (4034 to 4884) ppm for females; 5029 (4634 to 5459) ppm for the

co mbined sexes. Furthermore, please see our comments for Propylene Oxide, as there we provide

information on in vitro methods, additional existing data, and structure

- activity relationships (SAR) that may pr ove helpful for this endpoint.

Response: The Agency thanks the submitters for these comments. The anticipated requirement of a special acute inhalation study was based on a weight of evidence (WOE) approach due to the lack of currently available hazard and exposure information for ETO.

Inhalatio n is the primary route of exposure and there is a lack of non

- lethal histopathology data (respiratory tract). Therefore, the special acute inhalation study would include respiratory tract histology, glutathione (GSH) measurements (i.e., nose)

and kinetics /tissue dosimetry (time course) that would directly inform the acute occupational and residential bystander assessments. T he registrant will have the option of submitting to the Agency and the HED Hazard and Science Policy Council (HASPOC)

an alternative a pproach/method that would specifically address all of the acute inhalation study data requirements.

To clarify, the special acute inhalation toxicity study is different from the standard acute inhalation toxicity study which measures lethality (LC 50 

### ). Sp ecial acute inhalation studies have been required of all the commodity and soil fumigants. The parameters that are expected to be requested for the special acute inhalation toxicity study are not included as measurements in any of the current acute inhala tion toxicity studies on ETO. The study mentioned in Table 8, as mentioned in the comment above, is a subchronic repeated dose inhalation study, which is different from the special acute (single exposure) inhalation study which is the study anticipated as being requested for ETO. Once the data are required, i f the registrant wishes to submit a formal waiver request with all pertinent worker and bystander exposure information, then the HASPOC would consider this additional information for a weight

- of

- evidenc e determination.

2. Inhalation exposure study

EOSA : We also request additional detail on the inhalation exposure study for applicators (875.1400). This study appears redundant to the acute inhalation toxicity special study for workers/bystanders.

The post

- application (site

- specific) inhalation exposure study (875.2500) and ambient air monitoring study (special study) appear to have similar objectives. EOSA requests

additional information and clarification on the need for each.

3M : Inhalation exposure study for applicators EPA Guideline Number 875.1400 The exposure data for individual hospital users are kept at the hospital site as required by OSHA. [4] This information is difficult to obtain by 3M due to confidentiality concerns.

When the 3M Steri

- VacTM Sterilizer is installed and operated per manufacturer’s instructions, user exposure is below OSHA permissible limits.

### Page 66 of 69

Sterigenics : We also request more detail on the inhalation exposure study for applicators (875.1700). This study seems redundant to the Special Study for the acute inhalation toxicity study for the worker/ bystander exposures.

Response : These data are worker exposure data, not to be confused with the acute inhalation toxicity study. The inhalation exposure data are anticipated as being r equired to provide EPA with the most accurate measurements of ETO air concentrations for workers and ambient air (residential exposures) based on the current industry practices. For example, Section 3.3.1.2 of the PWP lists the air concentrations availabl e in OSHA’s Integrated Management Information System (IMIS) for the medical facilities (e.g., hospitals). These measurements are based on air concentrations collected u ntil 2007. Subsequently, the medical facilities have switched to single chambers for E TO sterilization. It is anticipated that the air concentrations that workers are exposed to in

medical facilities have been reduced based on the use of single chambers. EPA anticipates requiring the new representative exposure data (i.e., air concentratio ns) to refine the inhalation exposures to be used in the risk assessment. EPA recommends searching the new version of the IMIS database and gauge its representativeness and seek additional information from individual hospitals as necessary. EPA/OPP will wo rk with EPA/OAR to model ambient ETO concentrations in order to better define what potential bystander exposure data are needed. Stakeholders are encouraged to work with EPA to supply data to refine the ambient modeling results (e.g., effectiveness and pr evalence of ETO scrubbers and aeration methods). The level of concern for workers and bystanders (residential areas/ambient) is yet undetermined and will focus on the results of the EPA/ORD IRIS reassessment once peer reviewed.

3. Chronic toxicity/carcinoge nicity study

- 870.4300

PCRM: ETO, contrary to many other chemicals and as the Agency is aware, has a large body of existing evidence, including in humans, as to its carcinogenicity: “Ethylene oxide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans, including epidemiological studies and studies on mechanisms of carcinogenesis. Ethylene oxide was first listed in the Fourth Annual Report on Carcinogens in 1985 as reasonably anticipa ted to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans and sufficient evidence of carcinogenicity from studies in experimental animals. The listing was revised to known to be a human carcinogen in the Ninth Report on Carcinogens in 2000.” Furthermore, the EPA has indicated, in the documents for this docket and in previous guidance, that it is willing to accept information obtained using QSAR, weight

- of

evidence, and other “non

- testing” approaches in lieu of new in vivo data in some cases. We believe that ETO may be a case where these approaches can help to avoid additional testing. We refer the registrant to the OECD QSAR Toolbox, where one will find several data entries for the carcinogenicity endpoint for ETO. Th ese data points include tests in rats and mice by both inhalation and oral route, and in rats via dosed feed.

### Page 67 of 69

Response: The information anticipated to be requested is for the ETO reaction product epichlorhydrin (ECH) and not ETO. The agency is aware of the database on carcinogenicity of ETO and the curre nt IRIS document under review.

4. Availability of Scrubber Technology for ETO, Prevalence of Use, and Efficiency

EOSA: Facilities using products containing ETO are required to operate in compliance

with the requirements of either the NESHAP for Commercial Sterilization Facilities (Subpart O of 40 C.F.R. Part 63) or the NESHAP for Hospital Ethylene Oxide Sterilizers (Subpart WWWWW of 40 C.F.R. Part 63). Many sterilization companies use acid scrubbers, cata lytic oxidizers, absorbent systems, or a combination of these systems to meet the NESHAP requirements.

Response: Sources which use greater than 10 tons of ETO annually are required under the Clean Air Act (42 U.S.C. 7401 et seq.) to have scrubbers which reduce emissions by a

factor of 99%. The prevalence of sites which use enough ETO to be required to use scrubbers is important to EPA to accurately assess and characterize ambient exposure/risk. It is also important to establish how the efficacy of the sc rubbing systems is ensured by determining how compliance with the 99 percent emission reduction

criteria is assured. It is also important to consider that the national emissions standards for ethylene oxide (40 CFR § 63.362 Subpart O) indicates no control is required for sources less than 1 ton which means more ETO could be emitted from a facility compared to a facility which used 10 tons of ETO and greater that were equipped with

scrubbers. In summary, EPA needs to accurately characterize how ETO use is distributed amongst user facilities and to better understand surety around scrubber performance in order to best characterize potential emissions that could result in exposures to ambient air

levels of ETO.

5. Monitoring data on fumigated commodities

EOSA : EOSA also requests further clarification of the requirement for monitoring data on fumigated commodities (special study). FDA regulates the residual levels in sterilized pharmaceutical and medical device products. As it relates to the use on spices, EPA

al ready possesses monitoring data. EOSA requests clarification of why the existing monitoring data are not sufficient.

Response: EPA is not requiring monitoring data for residues on fumigated spices and

related commodities. The commenter is correct in stat ing that those data are adequate. EPA anticipates requiring monitoring data for the off

- gassing of the fumigant from the commodity after the fumigation process, and after the initial aeration has been completed. Since FDA regulates the residual levels in sterilized pharmaceutical and medical device products, the requirement is only anticipated for the other uses of ETO, such as those on spices, and musical instruments.

### Page 68 of 69



# III. Environmental Fate and Effect Comments

1. Ecological toxicity studies

EOSA & Sterigenics : EOSA and Sterigenics request additional detail on the types of ecological and air monitoring data required for the avian acute inhalation toxicity (special study), honeybee acute vapor exposure toxicity (special study), and vegetative vigor (8 50.4150) studies. As discussed below, we believe that the ETO emissions from the typical ETO usage process are significantly lower than what is presented in the PWP. Due to the reduced quantities of ETO emissions and the rapid dilution anticipated, many

of the studies outlined in Table 7 of the PWP, including the post

- application, residential, and ecological risk assessments would be of limited value. EOSA believes these studies are unnecessary if EPA considers the emission controls from sterilization facil ities.

3M : Ecological toxicity studies

– Special Study for Avian and Honeybee vapor exposure and Vegetative Vigor (EPA Guideline Number 850.4150). Due to the low quantities of emissions from the hospital setting, the breakdown of ETO within the venting pi pe and rapid dilution anticipated at release, this study would be of limited value. There have been no reports of ecological incidents due to hospital

emissions.

Response: The Agency reiterates the importance of generating the anticipated data needs for ecological risk assessment regardless of the emission control. The directions on obtaining the above toxicity studies are listed in Appendix C in ETO Preliminary Work Plan (Docket Number EPA

- HO

- OPP

- 2013

- 0244). ETO has fumigant uses that may result

in e xposure to birds, honeybees and plants. The acute effects to birds, honeybees, and plants exposed to ETO gas are unknown. Without the knowledge of the ETO vapor concentration in air and toxicity levels for birds, honeybees and plants, the Agency is

unable to determine the ecological risk associated with ETO daily emission (or reduced emission as stated above) adjacent to the treatment facility. In the absence of data , the ecological risk to these taxa from ETO vapor exposure will be assumed because of the

u ncertainties in what levels elicit toxic responses of concern.

2. Guidance for Commenters

-- Water Quality EOSA, ARC, Sterigenics : In Section 6.1.2 of the PWP, EPA requests further information on the water quality data for this pesticide. There are no water e missions from the typical ETO sterilization process. Therefore, there does not appear to be any need for additional water quality data associated with ETO sterilization.

Response: The Agency concurs that the water quality data will not be needed for ETO.

3. Environmental Exposure Modeling

EOSA: Prior to requiring the development of field data, it is suggested that modeling of the environmental exposure could be done using revised common site configurations that better reflect current ETO usage with the requ ired emission controls, similar to what is described for spices and herbs in Appendices E and F of the PWP.

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Response: The Agency will consider this approach at the risk assessment stage in the registration review process. Also see response to comment “2 . I nhalation exposure study ” starting on page 6 6

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