Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION
MEMORANDUM
DATE: March 27, 2023
SUBJECT: Ethylene Oxide (EtO). Addendum to "Draft Human Health and Ecological Risk
Assessment in Support of Registration Review" - Inhalation Exposure Risk
Assessment in Support of Registration Review.
Q
%
PRO-**-0
«r
*
P
PC Codes: 042301
DP Barcode: D467242
Decision No.: 590751
Docket Number: EPA-HQ-OPP-2013-0244
Petition No.: NA
Case No.: 2275
Risk Assess Type: Single Chemical Aggregate
CAS No.: 75-21-8
MRU) No.: NA
40 CFR: §180.151
FROM: Timothy Dole, C1H, Senior Scientist ^
Tim McMahon, Ph.D., Senior Science Advisor MP for TM
Chuck Peck, Senior Fate Scientist
Risk Assessment Branches I and II (RAB I and II)
Antimicrobials Division (7510M)
Digitally signed by
MELISSA PANGER
Date: 2023.03.27
14:42:08 -04'00'
THRU:
Kelly Lowe, Environmental Scientist ' *:-- • -
Risk Assessment Branch VII
Health Effects Division (7509T)
ANDREW
Andrew Byro Ph.D., Risk Assessment Process Leader Chief byro
Melissa Panger, Ph.D., Branch Chief
Risk Assessment Branch 1 (RAB1)
Antimicrobials Division (7510M)
Digitally signed by
MELISSA PANGER
Date: 2023.03.27
14:42:32 -04'00'
Michael S. Metzger, Chief
Risk Assessment Branch V/VII
Health Effects Division (7509T)
TO:
Jessica Bailey, Chemical Review Manager
Reevaluation Branch
Antimicrobials Division (7510M)
Susan Bartow, Chemical Review Manager
Risk Management and Implementation Branch IV
Pesticide Re-evaluation Division (7508M)
Page 1 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Table of Contents
Executive Summary 4
1.0 Introduction 11
1.1 Review of the 2020 DRA 11
1.2 Office of Air Rulemaking of EtO Emissions from Commercial Sterilization Facilities. 11
1.3 Rationale for Use of the IRIS Assessment for Risk Assessment 11
1.4 Ethylene Oxide Formulations and Use Patterns 12
1.5 Anticipated Exposures 13
1.6 Label Requirements 14
2.0 Toxicological Effects and Endpoints for Human Health Risk Assessment 15
2.1 Inhalation Unit Risk Estimates for Carcinogenicity 15
2.1.1 Inhalation Unit Risk Estimates for Continuous Environmental Exposures 15
2.1.2 Inhalation Unit Risk Estimates for Occupational Exposures 16
2.2 Levels of Concern for Cancer Risks 18
2.3 Occupational Exposure Limits for Ethylene Oxide (EtO) 19
3.0 Occupational Exposure and Risk Assessment 20
3.1 Occupational Handler Exposures and Cancer Risks 20
3.1.1 Occupational Exposure Data Submitted to EPA 20
3.1.2 Occupational Cancer Risks for Handlers Using EtO 24
3.1.3 Comparison to Occupational Exposure Data Available from OSHA 25
3.2 Occupational Bystander Exposures and Cancer Risks 27
4.0 Non-Occupational Bystander Exposure and Risk Assessment 28
4.1 Commercial Sterilization Facilities (Antimicrobial and Conventional Uses) 28
4.1.1 Commercial Sterilization Facility Emissions 28
4.1.2 Residential Bystander Exposures and Risks 28
4.1.3 Non-Residential Bystander Exposures and Risks (Daycare Centers and Schools).. 28
4.2 Health Care Facility Residential and Non-Residential Bystander Exposures 29
4.3 Beekeeping Equipment Fumigations (Special Local Need) 29
5.0 Ambient Air Monitoring Data and Analytical Uncertainties 31
6.0 Comparison of Bystander Exposures and Risks to OAR Model Results 32
7.0 Risk Summary and Characterization 33
8.0 References 34
Appendix A. Reported Work Activities in Spice Facilities (from MRID 47338301) and the
Work Activity Subset Assumed for Beekeeping Equipment Fumigations 37
Appendix B. Details on the PERFUM modeling for the Bystander Assessment for the
Beekeeping Equipment Fumigation Use 39
Page 2 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
List of Tables
Table 1. Summary of EtO Registered Products and Use Sites 13
Table 2. IRIS Inhalation Unit Risks for Environmental Exposures to EtO 16
Table 3. IRIS Extra Risk Est. for Total Cancer Incidence for Occupational Exposure Levels.... 17
Table 4. Ethylene Oxide Occupational Exposure Limits 20
Table 5. EtO Occupational Air Concentration and Exposure Data Submitted to EPA 23
Table 6. Occupational Handler Cancer Risks for the Antimicrobial Uses 24
Table 7. Occupational Handler Cancer Risks for the Conventional Spice Uses 25
Table 8. Occupational Handler Cancer Risks for the Beekeeping Use 25
Table 9. OSHA EtO Data for EPA Registered Uses (2008 through 2020) 26
Table 10. Occupational Bystander Exposure Associated with Cancer Risk Targets 27
Table 11. Residential Bystander Exposures Associated with a Cancer Risk of 1 x 10"6 28
Table 12. Daycare and School Bystander Exposures Associated with a Cancer Risk of 1 x 10"6 29
Table 13. Cancer Risks at Buffer Distances from the Beekeeping Fumigation Chambers 31
Page 3 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Executive Summary
In November 2020, the Office of Pesticide Programs (OPP) issued a draft human health and
ecological risk assessment (2020 DRA) for the currently registered conventional and
antimicrobial pesticidal uses of ethylene oxide (EtO) in support of Registration Review (US
EPA, 2020). This memorandum updates and revises the aspects of the 2020 DRA that relate to
human health inhalation cancer risk. In the 2020 DRA, OPP conducted a quantitative dietary
risk assessment for exposures from EtO use to sterilize spices and determined there were no
dietary risks of concern for either EtO or the metabolites ethylene glycol (EG) or ethylene
chlorohydrin (ECH). This addendum does not present any revisions to the human health dietary
risk assessment nor does it update the ecological risk assessment. With regard to effects to listed
species, the Agency was not able to make a 'no effect' determination in the 2020 DRA due to
potential exposure to terrestrial species.
The 2020 DRA presented multiple perspectives on cancer evaluations for EtO but did not choose
a single value for risk extrapolation. Inhalation exposures to EtO were qualitatively assessed
based on the variety of cancer dose response evaluations for inhalation exposure, and risks of
concern were expected for the inhalation route based on the qualitative assessment. Since the
publication of the DRA, and in contexts1 other than the registration review of EtO, EPA has
continued to consider the best approach for characterizing the cancer risk associated with
inhalation exposure to EtO. While there are some uncertainties associated with all of the
approaches to characterizing the cancer risk (as discussed in the 2020 DRA), the EPA has
determined that the Integrated Risk Information System (IRIS) assessment of EtO (US EPA,
2016) should be used to characterize the cancer risk associated with inhalation exposure to EtO.
The IRIS assessment (US EPA, 2016) went through "unusually extensive processes for the
consideration of public comment and external peer review," and is considered by EPA's Office
of Research and Development (ORD) to be the "best available scientific information regarding
cancer risks from EtO2." Further, since the publication of the DRA, the EPA has repeatedly
expressed favorable views of the IRIS assessment, including in comparison to the other EtO
cancer inhalation risk characterization approaches cited in the 2020 DRA3'4.
Therefore, the EtO 2020 DRA is being revised here for the human health inhalation risk
assessment using the IRIS Assessment (US EPA, 2016) to characterize the cancer risk from
inhalation exposure.
Registered Uses of EtO
The registered antimicrobial uses of EtO include medical or laboratory equipment,
pharmaceuticals, and aseptic packaging; and artifacts, archival material, library objects, and
musical instruments. EtO is also registered for use on whole and ground spices or other
1 US EPA, 2022. Reconsideration of the 2020 National Emission Standards for Hazardous Air Pollutants: Miscellaneous Organic Chemical
Manufacturing Residual Risk and Technology Review - Final Action. FR Doc. 2022-27522 Filed 12-20-2022
2 US EPA, 2021. Memo from W. Cascio (ORD) to J. Goffman (OAR), ORD Review of Comments on the IRIS Ethylene Oxide Assessment
Contained in the ACC Request for Correction Submitted Regarding EPA's National Air Toxics Assessment, Aug. 25, 2021, Page 1.
3 US EPA, 2022.
4 US EPA, 2021a. EPA Should Conduct New Residual Risk and Technology Reviews for Chloroprene- and Ethylene Oxide-Emitting Source
Categories to Protect Human Health, Report No. 21-P-0129, US EPA Office of Inspector General, May 6, 2021
Page 4 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
seasoning materials. Additionally, a special local need (SLN) registration (North Carolina) is
currently in place for the treatment of beekeeping equipment.
Hazard Assessment
The 2020 DRA (US EPA, 2020) includes a complete toxicological profile of EtO that addresses
non-cancer effects such as neurotoxicity and effects from all exposure routes including oral,
inhalation and dermal. In this document, only the cancer risks from inhalation exposure are
being evaluated. Regulating on the risks from cancer effects is protective of non-cancer effects
such as neurotoxicity because the non-cancer effects occur at much higher exposures in
comparison to cancer effects. The effects from inhalation exposure are also protective of the
other exposure routes.
Because the weight of evidence supports a mutagenic mode of action for EtO carcinogenicity,
and as there are no chemical-specific data from which to assess early-life susceptibility,
increased early-life susceptibility was assumed and age dependent adjustment factors (ADAFs)
were incorporated to calculate lifetime risks, in accordance with the EPA's Supplemental
Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (US EPA,
2005). The total cancer inhalation unit risk estimate for lifetime exposures is 5.0 x 10"3 per
[j,g/m3 (9.15 x 10"3 per ppb). This unit risk already accounts for application of the ADAFs for
early life exposures and, therefore, can be used with exposures that have not been adjusted for
ADAFs to estimate inhalation cancer risk. The total cancer inhalation unit risk estimate for adult
exposure is 3.0 x 10"3 per ug/m3 (5.5 x 10"3 per ppb). This unit risk does not include the ADAF
adjustments. If exposures have already been adjusted using ADAFs for early life exposures, then
this unit risk can also be used with these exposures to estimate the cancer risk.
For occupational exposures, a maximum likelihood estimate (MLE) and an upper-bound estimate
are provided. An upper bound estimate is considered a "higher" value that is still considered
reasonable with regard to its probability of occurring (e.g., a 95th percentile value); whereas a
MLE is the most probable overall, but not the most probable "high" value like the upper bound
estimate.
Under the Federal Insecticide Fungicide and Rodenticide Act, OPP applies a "no unreasonable
risk" standard for both dietary and non-dietary exposures in making a risk management
decisions. To help initially identify chemicals which may pose such unreasonable risks, OPP
considers whether the risks from a chemical exceed a specified level of concern. If a given risk
exceeds this level, OPP decides what further action, if any, is needed. OPP generally seeks to
reduce the risk to 1 x 10"6 (1 in a million) for both occupational and residential exposures. In
some cases, when it is not possible to mitigate to this level of risk and benefits are high, a risk
target of up to 1 x 10"4 (100 in a million) may be used for occupational exposures.
Occupational Safety and Health Administration (OSHA) Exposure Limits
The permissible exposure limits (PELs) for EtO are 1.0 ppm as an eight hour time weighted
average (TWA) and 5.0 ppm as a 15 minute short term excursion limit (STEL) and are
enforceable under 29 CFR 1910.1047. These limits were established in the 1980s and have not
Page 5 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
been updated. They are noted as being outdated and inadequate for ensuring protection of
worker health on the OSHA website at https://www.osha.gov/annotated-pels.
Residential Handler and Post Application Exposure
There are no uses of EtO resulting in direct residential applications; therefore, residential handler
and post-application exposures from residential uses are not expected (see non-occupational
"bystander" exposures).
Aggregate Risk Assessment
An aggregate assessment for EtO was not conducted since there are no food or drinking water
exposures to EtO. For the metabolites of EtO (ECH and EG), there are no water or non-dietary
residential exposures; the only exposure route is through food. Thus, an aggregate assessment
was not conducted for ECH or EG (US EPA, 2020).
Non-Occupational Bystander Exposure (Residential and Non-Residential)
There is the potential for non-occupational bystander exposure for people who live near
sterilization facilities (residential non-occupational bystanders) or who spend significant time in
the area for non-work related activities (e.g., school, daycare, shopping, etc.) near sites where
sterilization or fumigation occurs (non-residential non-occupational bystanders). The exposure
can occur from EtO emissions from commercial sterilizers, hospitals/health care facilities and
beekeeping equipment fumigation chambers.
The Office of Air and Radiation (OAR) is proposing to address non-occupational residential
bystander exposures from commercial sterilization facilities through proposed amendments to
the National Emission Standards for Hazardous Air Pollutants (NESHAP) for the Commercial
Sterilization Facilities source category. Exposures to non-occupational non-residential
bystanders are not addressed by the proposed OAR rulemaking and are included below. These
exposures are represented by children attending day care centers and schools because these
exposures occur more frequently and with a longer duration than other non-work related
activities.
Commercial Sterilization Facilities
The EtO average daily air concentration which corresponds to a cancer risk target of 1 x 10"6
(i.e., one in one million5) was back calculated using the unit risk estimates from the IRIS
Assessment (US EPA, 2016). These air concentrations are as follows:
• Residential Non-Occupational Bystanders Living Near Sterilization Facilities - A lifetime
average daily EtO air concentration of 0.00011 parts per billion (ppb) or 0.11 parts per
trillion (ppt) has a cancer risk of 1 xlO"6 assuming continuous exposure (i.e., 24 hours a
day for seven days a week) for a 70 year lifetime starting at birth. The cancer risk will be
greater than 1 x 10"6 if the lifetime average daily concentration is greater than 0.11 ppt.
5 The cancer risk target of 1 x 10"6 (i.e. one in a million) is normally used by OPP as a risk management goal for non-occupational exposures.
Page 6 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
• Non-Residential Non-Occupational Bystanders (Daycare Centers and Schools) - An
average daily concentration of 0.0012 ppb (1.2 ppt) has a cancer risk of 1 x 10"6 assuming
children attend daycare 8 hours per day for 240 days per year for 6 years and school for 6
hours a day for 180 days per year for 12 years near a sterilization facility. The cancer risk
will be greater than 1 x 10"6 if the average daily concentration is greater than 1.2 ppt.
Beekeeping Equipment Fumigations
For the beekeeping equipment fumigation use in North Carolina, there is the potential for both
residential and non-residential non-occupational bystander exposure. A quantitative residential
non-occupational bystander assessment, assuming someone lives near a fumigation chamber for
a full lifetime (70 years), was conducted using the Probabilistic Exposure and Risk Model for
Fumigants (PERFUM) (US EPA, 2019). This assessment would be protective of any non-
residential exposures which would have a shorter exposure duration (e.g., 35 working years vs
70 lifetime years). Two application rates were modeled as provided on the product label: 28.3 lb
ai/1,000 ft3 and 46.5 lb ai/1,000 ft3. The concentration distribution output from PERFUM for
various percentiles (50th, 75th, 80th, 85th, and 90th) was used to calculate cancer risk estimates
assuming four or eight exposure days (24 hrs/day) per year based on specific use information for
the beekeeping use and 70 years of exposure per lifetime. The IRIS inhalation unit risk for
environmental exposures for a full lifetime [5.0 x 10"3 per [j,g/m3 (9.15 x 10"3 per ppb)] was used
to estimate cancer risks.
The distances from the fumigation chamber at which the cancer risk estimates are less than 1 x
10"6 increase from lower to higher percentiles. For example, at the lower percentiles (e.g., 75th
and 80th), the distance from the fumigation chamber at which the cancer risk is less than 1 x 10"6
is only 10 meters, while at the higher percentiles (e.g., 90th), distances of 300 meters or more are
necessary to reach cancer risk estimates less than 1 x 10"6. Because the model only provides
results at specific distances from the fumigation chamber (e.g., 1, 5, 10, 15 meters, etc) and not at
continuous distances, the distances at which risks are greater than 1 x 10"6 do not change based
on the model results whether assuming four or eight exposure days per year. It is likely that the
exact distances change, but per the model results which are only reported at specific distances,
the distance at which the cancer risk estimate is not of concern does not change between four and
eight exposure days.
Hospitals/Healthcare Facilities
Since 2010, health care sterilization facilities have been required to operate on an all-in-one basis
in accordance with the EtO Reregi strati on Eligibility Decision (US EPA, 2008). These facilities
sterilize material in oven-sized chambers using 4.5 to 170 grams of EtO per load. The exhaust
from the chambers is typically routed to an air pollution control device and the room air is
typically ventilated though an exhaust stack (ANSI/AAMI, 2018). Given this information,
exposures to non-occupational bystanders are expected to be minimal, but the exact air
concentrations are not known and therefore the risks are not quantitatively assessed in this DRA.
It is known, however, that the exposures that would result in a cancer risk of 1 in a million are
the same as those calculated for contract sterilization facilities (i.e., 0.11 ppt for residential areas
and 1.2 ppt for children in schools/daycares. These potential exposures around health care
sterilization facilities can be addressed in the Preliminary Interim Decision (PID) by requiring
control measures that are recommended in ANSI/AAMI (2018).
Page 7 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Occupational Handler Exposure
There is potential for occupational handler inhalation exposure from the registered uses of EtO.
OPP has obtained personal breathing zone (PBZ) air monitoring data from registrant-submitted
studies for commercial sterilization plants, health care facilities and spice treatment facilities
(MRIDs 50231101, 50231102 and 47338301). These PBZ air monitoring data represent
observational monitoring during routine workdays and are expressed as 8-hour TWAs when
compared to the OSHA PEL-TWA of 1.0 ppm or as 15-minute TWAs when compared to the
OSHA PEL-STEL of 5 ppm. It should be noted that workers involved in all various activities
were monitored. Some of these activities did not require the use of a respirator, such as working
with untreated product in receiving areas or in the warehouse.
Antimicrobial Uses: Exposure data for commercial sterilization plant workers were included in a
registrant submission of 1,273 results from 25 facilities (MRID 50231101). The EtO air
concentrations were measured6 in the PBZ outside the respirator and ranged from non-detect to
35 ppm with a mean of 1.3 ppm. The measured air concentrations along with the time that a
respirator was worn were used to calculate 8-hour TWA exposures to EtO. These 8-hour TWAs
of EtO range from 0.002 to 4.6 ppm with an arithmetic mean of 0.23 ppm. The 8-hour TWAs for
workers who wore respirators were calculated by assuming that they wore full face supplied air
respirators. These respirators have an assigned protection factor of 1,000 (OSHA, 2009), which
means that the respirators reduce exposures by a factor l,000x when workers were wearing the
respirators. The 8-hour TWAs for workers involved in activities that did not require a respirator
were not adjusted for use of a respirator.
Air concentration data for EtO in health care facilities were included in a registrant submission
of 647 sample results that were collected in health care facilities in 2012 (MRID 50231102).
The results ranged from 0.0007 ppm (the limit of detection) to 10.1 ppm with an arithmetic mean
of 0.12 ppm and a 90th percentile value of 0.16 ppm. These air concentration data represent
actual exposures and have not been modified to account for respiratory protection because the
use of respirators was not documented in the submission. It is likely that respirators were not
used in most cases because the 90th percentile exposures were less than the PEL.
Based on the exposure data that were provided for the commercial sterilization plant workers and
health care facilities and the IRIS MLE and upper bound unit risks, the cancer risks range from
6 x 10"2 (1 in 17) to 1 x 10"1 (1 in 10) for sterilization facilities and 4 x 10"2 (1 in 25) to 8 x 10"2
(1 in 12) for health care facilities. These risks are greater than the maximum risk target of
1 x 10"4 that OPP normally uses for managing occupational cancer risk.
Conventional Uses: In support of the use of EtO for the sterilization of spices, the American
Spice Trade Association (ASTA) submitted exposure monitoring of two workers at each of two
facilities7. Each worker was monitored for 10 days and indicated what tasks they were doing
throughout the day and whether they were wearing respirators for those tasks. While the study
6 This study is not subject to the requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR part 26) as discussed in
US EPA 2022a.
7 This study was reviewed by OPP's Human Research Ethics Reviewer, who found no barrier in law or regulation to reliance on this study in
EPA actions taken under FIFRA or Section 408 of FFDCA (Arling, M., 2022, "Ethics Review of Ethylene Oxide Worker Exposure Study"). The
study does not involve intentional exposure of human subjects, therefore, the requirement to consult the Human Studies Review Board does not
apply.
Page 8 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
reported that a PF50 respirator was worn, these respirators are no longer available for EtO8;
therefore, when adjusting for the use of respirators, it was assumed that workers would be
wearing self-contained breathing apparatus (SCBA) which are more protective than PF50
respirators. EtO 8-hour time-weighted averages (TWAs) for all activities, including those where
respirators were not worn and those where respirators were worn, ranged from 0.01 to 0.841
ppm, with an overall average of 0.075 ppm. The 8-hr TWAs for only those activities where
respirators were not worn was 0.092 ppm and the 8-hr TWAs for only those activities where
SCBA was worn was 0.00002 ppm, highlighting the fact that exposures while conducting
activities where a respirator was not required were driving overall exposure. The cancer risk
estimate for workers conducting all activities monitored ranged from a maximum likelihood
estimate (MLE) of 3 x 10"2 (1 in 36) to an upper bound of 6 x 10"2 (1 in 16). If the SCBA was
worn for all tasks, the 8-hour TWA of 0.092 ppm for the non-respirator tasks would be reduced
by 10,000; however, it is not likely feasible for workers to wear SCBAs for entire workdays.
For the beekeeping equipment fumigation use, there are no monitoring data specific to this use;
therefore, the spice facility air concentration data were used as a surrogate. In order to account
for the differences in potential exposure between workers in an indoor spice facility and workers
fumigating beekeeping equipment in an outdoor chamber, the activities reported were limited to
include only those that would likely occur during outdoor beekeeping equipment fumigation. A
lifetime average concentration (LAC) was calculated assuming either four or eight exposure days
per year, and then the cancer risks were calculated using the LAC and the adult specific
inhalation unit risk of 5.5 x 10"3 per ppb. Cancer risks range from 2 x 10"4 (1 in 5,000) when
assuming 4 exposure days per year to 4 x 10"4 (1 in 2,500) when assuming 8 exposure days per
year.
OSHA Exposure Data
To provide context for the occupational handler exposures assessed using submitted data, EtO
chemical exposure health data (i.e., PBZ air samples) that were collected during OSHA
inspections were downloaded from the OSHA website9 for the years 2008 through 2020.
Combined TWAs were calculated for each facility rather than for each worker because the
identity of the worker associated with each sample is not included in the chemical exposure
health data. The combined TWAs range from 0.0013 ppm to 1.5 ppm for the medical equipment
production and sterilization facilities, with two facilities above the OSHA PEL of 1 ppm. The
combined TWAs for the health and veterinary care facilities ranged from 0.0061 to 0.022 ppm
and were all below the OSHA PEL. The combined TWA of 0.082 ppm for the spice and extract
manufacturing facility is also below the OSHA PEL. The OSHA data represent exposures that
occur in the breathing zone and do not account for the use of respiratory protection.
Occupational Bystander Exposure
OPP considers the potential for exposure to occupational bystanders who work in non-processing
areas of treatment facilities or who work near sterilization facilities. Occupational bystanders are
estimated to have a cancer risk of 1 x 10"6 if their average daily concentration is 0.002 ppb. This
8 The NIOSH approval for the PF-50 respirators (i.e., gas masks) that were previously used for EtO has been cancelled. There are no air purifying
respirators approved for EtO. Only air supplying respirators can be used.
9 https://www.osha.gov/oDengov/health-samDles
Page 9 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
is based on the assumptions that these workers do not wear respirators and are exposed 8 hours
per day for 240 days per year for 35 years out of a 70-year lifetime. Using the same
assumptions, a cancer risk of 1 x 10"4 corresponds to an average daily concentration of 0.2 ppb.
Page 10 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
1.0 Introduction
This memorandum revises and updates the aspects of the 2020 DRA (US EPA, 2020) that relate
to human health inhalation cancer risk using the inhalation unit risk estimates from the Integrated
Risk Information System (IRIS) Assessment of EtO (US EPA, 2016). This addendum does not
revise the human health dietary risk assessment nor does it update the ecological risk assessment.
1.1 Review of the 2020 DRA
The 2020 Draft Risk Assessment (DRA) for ethylene oxide (EtO) included both antimicrobial
and conventional uses (US EPA, 2020). The antimicrobial uses assessed include sterilization of
medical supplies and equipment in commercial sterilization facilities and health care facilities
and the sterilization of artifacts, archival material, library objects, cosmetics and musical
instruments in commercial sterilization facilities. The conventional uses assessed include
fumigation/sterilization of spices or other seasoning materials and a special local need (SLN)
registration (North Carolina) for the treatment of beekeeping equipment. The 2020 DRA
primarily focused on EtO (for the inhalation route) and the EtO reaction product ethylene
chlorohydrin (ECH) for the dietary route - from the spice sterilization use. A quantitative dietary
assessment was conducted for exposures from the spice sterilization use. Inhalation exposures to
EtO were qualitatively assessed based on a variety of cancer dose response evaluations for
inhalation exposure. There were no dietary risks of concern; however, risks of concern were
expected for the inhalation route based on the qualitative assessment. With regard to effects to
listed species, the Agency was not able to make a 'no effect' determination in the 2020 DRA due
to potential exposure to terrestrial species.
1.2 Office of Air Rulemaking of EtO Emissions from Commercial Sterilization Facilities
EtO is a listed hazardous air pollutant (HAP) under Clean Air Act (CAA) section 112(b). Within
EPA, the responsibility for developing the CAA emission standards and other requirements
applicable to the commercial sterilizer and fumigation operations source category rests with the
Office of Air and Radiation's (OAR) Office of Air Quality Planning and Standards (OAQPS).
The OAR is proposing amendments to the National Emission Standards for Hazardous Air
Pollutants (NESHAP) for the Commercial Sterilization Facilities source category. OAR is
proposing decisions concerning the risk and technology review (RTR), including proposing
amendments pursuant to the technology review for certain point source emissions and proposing
amendments pursuant to the risk review to specifically address ethylene oxide (EtO) emissions
from point source and room air emissions from certain groups of facilities. OPP is collaborating
with OAR in these efforts.
1.3 Rationale for Use of the IRIS Assessment for Risk Assessment
In the 2020 DRA, OPP presented multiple perspectives on cancer evaluations for EtO, including
the IRIS assessment (US EPA, 2016), but did not choose a single value for risk
assessment. Since the publication of the 2020 DRA, and in contexts10 other than the registration
10US EPA, 2022 Reconsideration of the 2020 National Emission Standards for Hazardous Air Pollutants: Miscellaneous Organic Chemical
Manufacturing Residual Risk and Technology Review - Final Action. FR Doc. 2022-27522 Filed 12-20-2022.
Page 11 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
review of EtO, EPA has continued to consider the best approach for characterizing the cancer
risk associated with inhalation exposure to EtO. While there are some uncertainties associated
with all of the approaches in characterizing the cancer risk (as discussed in the 2020 DRA), the
EPA has determined that the IRIS assessment should be used to characterize the cancer risk
associated with inhalation exposure to EtO. Therefore, OPP is using the same inhalation unit
risk estimates from the IRIS assessment that are being used by OAR in their rulemaking of EtO
emissions from commercial sterilization facilities.
The IRIS assessment went through "unusually extensive processes for the consideration of
public comment and external peer review," and is considered by EPA's Office of Research and
Development (ORD) to be the "best available scientific information regarding cancer risks
from EtO11." In developing the IRIS assessment, ORD "utilized extensive advice" from the
Science Advisory Board (SAB) and incorporated recommendations from the SAB into the IRIS
assessment to address uncertainties identified by the SAB12. Further, since the publication of
the DRA, EPA has repeatedly expressed favorable views of the IRIS assessment, including in
relation to the other EtO cancer inhalation risk characterization approaches cited in the 2020
DRA1314
1.4 Ethylene Oxide Formulations and Use Patterns
As of November 29, 2022, there were fifteen Section 3 end use product registrations and one
Section 24(c) Special Local Need registration for EtO as an active ingredient (a.i.). EtO is
formulated as a pressurized gas. The end-use products are all gas mixtures of EtO and other
gases (e.g., carbon dioxide) in varying concentrations that are formulated from EPA Reg No.
36736-8, which is a manufacturing use product. Table 1 presents a summary of the registered
antimicrobial and conventional end use products and uses of EtO.
Antimicrobial Uses: The registered antimicrobial uses of EtO include the fumigation/
sterilization of medical or laboratory equipment, pharmaceuticals, and aseptic packaging
(21 CFR §201.1(d)(5)); and to sterilize artifacts, cosmetics, archival material, library objects, and
musical instruments. The antimicrobial products are packaged in returnable bulk cylinders for
use in tractor trailer sized chambers in commercial sterilization facilities or as single use
cartridges or ampules for use in oven-sized chambers in health care facilities.
The application rates are not generally listed on the labels of EtO products registered for
antimicrobial uses. There are two voluntary consensus standards (ANSI AAMI ISO 11135:2014
and ANSI AAMI ISO 10993-7:2008) that describe how to develop, validate, and control EtO
sterilization processes for medical devices and the acceptable levels of residual EtO and ECH left
on a device after it has undergone EtO sterilization. These standards help ensure levels of EtO on
medical devices are within safe limits since long-term and occupational exposure to EtO has
been linked to cancer. These standards are included in the FDA database of recognized
consensus standards.
"US EPA, 2021. Memo from W. Cascio (ORD) to J. Goffman (OAR), page 1.
12US EPA, 2021. Memo from W. Cascio (ORD) to J. Goffman (OAR), page 4.
"US EPA, 2022.
14US EPA, 2021a. EPA Should Conduct New Residual Risk and Technology Reviews for Chloroprene- and Ethylene Oxide-Emitting Source
Categories to Protect Human Health, Report No. 21-P-0129, US EPA Office of Inspector General, May 6, 2021.
Page 12 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Conventional Uses: EtO is a commodity fumigant/sterilant registered for use to reduce
microbials on whole and ground spices or other seasoning materials (40 CFR §180.151).
Additionally, a special local need registration (North Carolina) is currently in place for the
treatment of beekeeping equipment. The use of EtO for the treatment of spices currently
represents less than 10 percent of the total EtO pesticide use. The American Spice Trade
Association (ASTA) estimates that less than 50% of spices in the U.S. are treated with EtO each
year15. There are eight products currently registered for treatment of spices. These are all
formulated as pressurized gas contained in cylinders. Sterilization/fumigation with EtO must be
performed only in vacuum or gas tight chambers designed for use with EtO. The maximum
application rate is 500 mg/L (or 31.22 lb a.i./l,000 ft3) in a sealed chamber.
Table 1. Summarv of EtO Registered End Use Products and Use Sites
r.PA
Ueii. N«».
•'«» il.l.
I'iickiiuinu
(IK) ( onk'iin
I sc Silo
3o~3o-2
loo
Liu Ik C\ linder
Medical or laboratory items, pharmaceuticals, and aseptic packaging,
(21 CFR 201.1(d)(5)), whole and ground spices or other seasoning
materials (40 CFR 180.151) artifacts, archival material, library
objects, cosmetics and musical instruments.
36736-3
80
Bulk Cylinder
36736-4
10
Bulk Cylinder
36736-5
20
Bulk Cylinder
36736-6
12
Bulk Cylinder
36736-7
8.5
Bulk Cylinder
69340-2
97
Ampule (18.15 g)
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
instruments; veterinary hospital critical equipment; human face gear;
contact lens.
69340-4
96
Cartridge (5 to 14 g)
69340-5
90
Cartridge (4.5 g)
69340-6
96
Cartridge (10.5 g)
69340-7
97
Ampule (17.6 g)
69340-9
97
Cartridge (17.6 g)
7182-1
100
Cartridge
(100 to 170 g)
Medical equipment and supplies, musical instruments,
library /museum artifacts, and cosmetics.
73711-5
100
Ampule
(100 to 170 g)
Medical or laboratory items, pharmaceuticals, and aseptic packaging,
cosmetics, and artifacts, archival material or library objects.
89514-1
100
Bulk Cylinder
Medical or laboratory items, pharmaceuticals, and aseptic packaging,
cosmetics, spices or other seasoning materials, artifacts, archival
material or library objects, musical instruments.
NC140003
8.5
Bulk Cylinder
(parent label)
Special Local Need for beekeeping equipment in North Carolina. The
parent label is 36736-7.
1.5 Anticipated Exposures
As stated previously, the purpose of this document is to quantitatively assess the cancer risks
from inhalation exposures to EtO. In commercial sterilization facilities, where there are separate
treatment chambers and aeration rooms, occupational inhalation exposures primarily occur when
moving treated materials, such as medical equipment, from the treatment chambers to the
aeration rooms and when moving the aerated material out of the aeration rooms to the warehouse
for shipping. These transfers are typically done using forklifts. In some commercial sterilization
facilities, such as those for spices, treatment and aeration is done in the same chamber (all-in-one
treatment) which eliminates the exposure that is associated with moving materials prior to
15ASTA, 2017. Clean, Safe Spices: Guidance from the American Spice Trade Association. 2017 Update, https://www.astaspice.org/food-
safetv/clean-safe-spices-guidance-document/.
Page 13 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
aeration. Exposures also occur in commercial sterilization facilities when changing cylinders
and when repairing leaks.
The all-in-one treatment method is also used on a much smaller scale in health care and
veterinary facilities where the treatment and aeration occur in the same oven-sized chamber
using cartridges and ampules that contain 4.5 to 170 grams of EtO. For the beekeeping use, the
treatment is done in a 126 ft3 chamber that is located at an off-campus research facility of a state
university.
In addition to the occupational exposures that occur within the processing areas of a treatment
facility, health care facility, or beekeeping equipment treatment area, occupational bystander
exposures may occur in non-processing areas of a treatment facility, health care facility, or
beekeeping equipment treatment area, in "downstream" facilities where the treated product is
shipped and stored, or in other businesses or workplaces that are near the treatment facility,
health care facility or beekeeping equipment treatment area.
There are no EtO products that can be purchased by consumers, therefore, there is no potential
for residential handler applications; however, there is the potential for non-occupational/
residential bystander exposures to persons living near commercial sterilization facilities. OAR is
proposing to address residential bystander exposures through amendments to the NESHAP for
the Commercial Sterilization Facilities source category. EtO emissions from hospitals where
EtO is used are addressed in a different NESHAP that OAR promulgated in 2006—the NESHAP
for Hospital Ethylene Oxide Sterilizers— and OAR plans to evaluate the risks from hospital
sterilizers in an upcoming regulatory review. In addition, there is the potential for non-
occupational/non-residential exposure for people who spend significant time for non-work
related activities (e.g., school, daycare, shopping, etc.) in the areas that are between the fence line
of a commercial sterilization facility and the nearest residence. OPP's assessment of risks from
non-occupational/residential bystander and non-occupational/non-residential bystander
exposures are included in this addendum.
1.6 Label Requirements
Currently, all labels indicate the Occupational Safety and Health Administration (OSHA)
permissible exposure limit (PEL) is an 8-hr time weighted average (TWA) of 1 ppm16 and the
short term excursion limit (STEL) for 15 minutes is 5 ppm. All labels require personal
protective equipment (PPE) consisting of a long-sleeved shirt, long pants, shoes plus socks,
chemical-resistant gloves and a respirator. If the worker could have eye or skin contact with EtO
or EtO solutions, they must wear chemical-resistant attire (e.g., apron or footwear) and face-
sealing goggles, a full-face shield, or a full-face respirator. There are no EtO solutions registered,
only gas, and therefore, language relating to EtO solutions is not necessary. Labels for the spice
uses also include language that requires all applications to be made using an EtO sterilization
method that uses a single sterilization chamber to precondition and aerate (i.e., an all-in-one
system).
16Per the Ethylene Oxide Standard 29 CFR 1910.1047.
Page 14 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
2.0 Toxicological Effects and Endpoints for Human Health Risk Assessment
The agency's published 2020 DRA includes a complete toxicological profile of EtO that
characterizes non-cancer effects from all exposure routes including oral, inhalation and dermal.
In this current 2023 DRA addendum, only cancer risks from inhalation exposures to EtO are
being evaluated. Carcinogenic effects of EtO are observed at lower exposures (i.e., ppb and
below) compared to non-carcinogenic effects; thus, any mitigation for carcinogenic effects is
also protective of non-carcinogenic effects, including neurotoxicity, because the non-cancer
effects occur at much higher exposures (i.e., ppm levels). The effects from inhalation exposure
are also protective of the other exposure routes, because EtO is a gas at room temperature, and
inhalation exposure is the predominant route of exposure to gases. In addition, the pulmonary
region of the respiratory tract (i.e. the lungs) for the average adult has a surface area of 54 m2
(US EPA, 1994) which is 27 times greater than the surface area of the skin which is 2.2 m2 for
the average adult (US EPA, 2011).
2.1 Inhalation Unit Risk Estimates for Carcinogenicity
In the 2020 DRA, the Agency cited several data sources that characterized the carcinogenicity of
EtO. The Agency presented multiple perspectives on the carcinogenicity of EtO and summarized
the risks from these perspectives. A single perspective was not chosen at that time.
As discussed in Section 1.0, the Agency has now determined in this 2023 DRA addendum that
the inhalation unit risk estimates published in the IRIS assessment (US EPA, 2016), which was
one of the risk estimates discussed in the 2020 DRA, should be used to characterize the cancer
inhalation risk from EtO for the purpose of this Registration Review.
2.1.1 Inhalation Unit Risk Estimates for Continuous Environmental Exposures
The inhalation unit risk estimates for environmental exposure are listed in Table 2. These unit
risks are the preferred estimates highlighted in bold in Table 1.1 of the IRIS assessment (US
EPA, 2016). These unit risks were developed for use with continuous environmental exposure
(i.e., 24 hours a day for seven days a week for a 70 year lifetime) to EtO where maximum
modeled levels are on the order of 1-2 [j,g/m3 (0.5 to 1.0 ppb) as discussed on page 99 of section
4 of the IRIS assessment. These unit risks are not applicable to higher level exposures, such as
those that may occur occupationally, which appear to have a different exposure-response
relationship.
Because the weight of evidence supports a mutagenic mode of action for EtO carcinogenicity,
and as there are no chemical-specific data from which to assess early-life susceptibility,
increased early-life susceptibility was assumed, in accordance with the EPA's Supplemental
Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (US EPA,
2005). To calculate lifetime risks, the risk associated with each of the three relevant time periods
is calculated using age dependent adjustment factors (ADAFs). The ADAF is 10 for the first 2
years of life, 3 for ages 2 through <16, and 1 for ages 16 and above.
The inhalation unit risk estimate for full lifetime exposures is 5.0 x 10"3 per [ig/m3 (9.15 x 10"3
per ppb) as listed in Table 2. The unit risk accounts for the application of ADAF adjustments for
Page 15 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
the exposures that occur in the first 16 years of life and, therefore, can be used with exposures
that have not been adjusted for ADAFs to estimate inhalation cancer risk. The inhalation unit
risk estimate for adult-based exposures is 3.0 x 10"3 per ug/m3 (5.5 x 10"3 per ppb). This unit
risk does not include the ADAF adjustments because it is intended for use to evaluate exposures
that occur from age 17 to age 70.17 If exposures are available that have already been adjusted
using ADAFs for early life exposures, then this unit risk can also be used for lifetime exposures.
Table 2. IRIS Inhalation Unit Risks for Environmental Exposures to EtO
liiisis
r.\|)ONIMY
Diimlion
liihiiliilion I nil Risk
1-1 Mi m ill i'
( milmcnl
(.iiji/mM 1
(|)|)b) 1
Total cancers based
on human data -
lymphoid cancers
incidence and breast
cancer incidence in
females
Full Lifetime
5.0 xlO"3
9.15 xlO"3
Includes ADAF adjustments for lifetime
exposures. Can be used with exposures that do
not account for the ADAF adjustments.
Adult - Based
3.0 xlO 3
5.5 xlO 3
Requires that ADAF adjustments be applied to
the estimated exposure at each lifestage up to
16 years if used for lifetime exposures.
Note. The unit risks are listed as (ug/m3)1 in Table 1.1 of the IRIS assessment (US EPA, 2016). They were
converted to ppb by multiplying by 1.83 ug/m3 per ppb. \i.e. (ug/m3)1 * 1.83 ug/m3 per ppb = (ppb)1]
Source: Table 1-1 of the IRIS Assessment (US EPA, 2016).
2.1.2 Inhalation Unit Risk Estimates for Occupational Exposures
In the IRIS assessment (US EPA, 2016), cancer risk estimates are provided for occupational
exposures. These exposures are assumed to occur for eight hours a day, 240 days per year for 35
years at a certain concentration. Cancer risk estimates are provided for exposures in the range of
0.1 to 1.0 ppm and for exposures that are less than 0.1 ppm.
Continuous Occupational Exposures from 0.1 ppm to 1.0 ppm
According to IRIS assessment (US EPA, 2016, Section 4, page 99), "The unit risk estimates
derived in the preceding sections were developedfor environmental exposure levels, where
maximum modeled levels are on the order of 1-2 /ug/m3 ... i.e., roughly 0.5 1 ppb, and are not
applicable to higher exposures, including some occupational exposure levels... The occupational
exposure scenarios of interest to the EPA include ...exposure levels in the nonlinear range of
some of the models (i.e., above the maximum exposure level at which the low-dose-linear unit
risk estimates apply). Therefore, extra risk estimates were calculatedfor a number of
occupational exposure scenarios of possible concern. Extra risk estimates are estimates of the
extra cancer risk above background and are the same type of estimate that one gets from
multiplying a unit risk estimate by an exposure level."
The extra cancer risk estimates presented in the IRIS assessment (US EPA, 2016) for total
cancers (lymphoid and breast cancers) are shown in Table 3. The EtO air concentrations used to
illustrate the cancer risks range from 0.1 ppm to a maximum of 1.0 ppm, which is the
Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL). For
occupational exposures, a maximum likelihood estimate (MLE) and an upper-bound estimate are
provided. An upper bound estimate is considered a "higher" value that is still considered
17In page 4-25 of the IRIS assessment (US EPA, 2016), the EPA default average lifespan is listed as 70 years. This value is also listed in the
EPA's Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (US EPA, 2005).
Page 16 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
reasonable with regard to its probability of occurring (e.g., a 95th percentile value); whereas a
MLE is the most probable overall, but not the most probable "high" value like the upper bound
estimate.
Table 3. IRIS Extra Risk Est, for Total Cancer Incidence for Occupational Exposure Levels
X-liour TW A (ppm I'.lO)
Miixiiiiiiin likelihood |risk| csiiniiiio'1'
I ppcr-houiul |risk| osliniiilo'1'
0.1
0.037
0.081
0.2
0.058
0.13
0.3
0.072
0.15
0.4
0.085
0.18
0.5
0.094
0.19
0.6
0.10
0.20
0.7
0.10
0.21
0.8
0.11
0.21
0.9
0.11
0.21
1.0
0.11
0.22
aAssuming a 35-yr exposure between ages 20 and 55 years.
bFrom combining results for lymphoid cancer incidence in both sexes and breast cancer incidence in females.
*Source: Table 4-30 of EPA/635/R-16/350Fa, December 2016 (US EPA 2016).
Continuous Occupational Exposures from less than 0.1 ppm to 0.001 ppm
The cancer risks for occupational exposures that are less than 0.1 ppm can be calculated using
the formulas listed in Section 4, page 111 of the IRIS assessment (US EPA, 2016). There are
formulas for the 95% upper confidence limit (UCL)18 and MLE of extra risk for total cancer
incidence. According to the IRIS assessment: "For total cancer risk, low-exposure linear
extrapolation from the total cancer extra risk estimates for the 0.1 ppm 8-hour TWA exposure
level presented in Table 4-30 of the assessment is recommended. Both of the underlying models
are linear in the low-exposure range (e.g., at the 0.1 ppm TWA and below); thus, their sum is
also linear. For 35-year exposures, the following formulae would apply:"
95% UCL on extra risk for total cancer incidence ~ (8-h TWA occ exp [in ppm]) x (0.081/0.1 ppm)
= (8-h TWA occ exp [in ppm]) x (0.81/ppm)
MLE of extra risk for total cancer incidence = (8-h TWA occ exp [in ppm]) x (0.037/0. lppm)
= (8-h TWA occ exp [in ppm]) x (0.37/ppm)
For the purposes of this assessment, the above formulas have been simplified as follows:
• 95% UCL, Total Cancer Incidence = 8-hour TWA (ppm) x (0.81/ppm)
• MLE, Total Cancer Incidence = 8-hour TWA (ppm) x (0.37/ppm)
18 The sum of the 95% UCLs for the two cancer types is the upper bound shown in Table 4-30 (US EPA, 2016, section 4, page 109).
Page 17 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
Continuous Occupational Exposures less than 0.001 ppm
The cancer risks for occupational exposures that are less than 0.001 ppm (i.e. 1 ppb) are
calculated using the adult specific inhalation unit risk of 5.5xl0"3 per ppb from Table 2. This is
because the inhalation unit risks in Table 2 were developed for environmental exposure levels,
where maximum modeled levels are on the order of roughly 0.5-1 ppb (US EPA, 2016).
Intermittent Occupational Exposures
The beekeeping equipment use, where applications are made on an "as needed" basis instead of
on a daily basis, results in intermittent occupational exposures. The IRIS assessment does not
provide specific cancer risk estimates for these exposures. Normally, these exposures are
assessed by calculating a lifetime average concentration (LAC) and multiplying the LAC by the
continuous exposure unit risk. In the case of EtO, this approach is only valid if the LAC is less
than 0.001 ppm (1 ppb). If the LAC is greater than 1 ppb, then the section 4 formulas should be
used with adjustments made to account for the days of exposure per working year.
As noted in the 2020 DRA (US EPA, 2020), in 2008, information specific to the beekeeping
equipment use was received from North Carolina indicating that use is approximately 40 times
per year (electronic mail correspondence from Dan Hopkins, NC Dept. of Agriculture to Susan
Bartow, EPA/OPP/SRRD; 2/7/2008), as opposed to a potential year-round operation like the
spice treatment facilities. In 2020, updated information was received that there had been eight
treatments for beekeeping equipment between January 2019 and October 2020 (call held with
NCDA-CS on 10/20/20). Therefore, a range of exposure days per year was assumed (four or
eight exposure days) for the cancer assessment for the beekeeping equipment fumigation use.
Worker monitoring data specific to the beekeeping use are not available and it has been assumed
that estimated exposures for the spice industry would be protective of the treatment of
beekeeping equipment with EtO. Therefore, the exposure data for the spice use has been
adjusted for the difference in exposure days per year (i.e., 4 or 8 days/240 days).
2.2 Levels of Concern for Cancer Risks
Levels of concern for cancer risks are typically determined during risk mitigation (rather than
risk assessment), when benefits of the use and feasibility of reducing exposures are also
considered. Under the Federal Insecticide Fungicide and Rodenticide Act, OPP applies a "no
unreasonable risk" standard for both dietary and non-dietary exposures in making a risk
management decisions. To help initially identify chemicals which may pose such unreasonable
risks, OPP considers whether the risks from a chemical exceed a specified level of concern. If a
given risk exceeds this level, OPP decides what further action, if any, is needed. OPP generally
seeks to reduce the risk to 1 x 10"6 (1 in a million) for both occupational and residential
exposures. In some cases, a risk target of up to 1 x 10"4 (100 in a million) may be used for
occupational exposures in consideration of benefits and feasibility of mitigation measures.
Page 18 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
In the OAR assessment of EtO risk from commercial sterilizers, community cancer risks that are
greater than 100 in a million are considered to be elevated19. OAR is proposing to require
emissions controls to reduce the risk to less than 100 in a million.
2.3 Occupational Exposure Limits for Ethylene Oxide (EtO)
Occupational exposure limits have been established for EtO by the Occupational Safety and
Health Administration (OSHA), the National Institute for Occupational Safety and Health
(NIOSH), the American Conference of Governmental Industrial Hygienists (ACGIH) and the
California Division of Occupational Safety and Health (Cal/OSHA). These limits are
summarized in Table 4. The limits are expressed as 8-hour time weighted averages (TWAs),
which represent the average exposure during an 8-hour workday, or as short-term exposure limits
(STELs), which represents the exposure of a 10- or 15-minute period within the workday. The
purpose of these limits is to reduce cancer risks for workers exposed to EtO. In 1984, OSHA
established a permissible exposure limit (PEL) of 1 ppm as an 8-hour TWA and in 1988, OSHA
added a short term excursion limit of 5 ppm as a 15-minute TWA. These values are enforceable
by OSHA under 29 CFR 1910.1047. These values were also adopted by Cal/OSHA in 1985 and
are enforceable under section 5220 of Title 8 of the California Code of Regulations. NIOSH
established the recommended exposure limit (REL) of <0.1 ppm as an 8-hour TWA in 1981 and
added the REL-STEL of 5 ppm as a 10 minute TWA in 1983. ACGIH established a threshold
limit value (TLV) of 1.0 ppm as an 8-hour TWA in 1984. Both the NIOSH RELs and the
ACGIH TLV are recommended values that are not enforceable.
In 2019, the ACGIH adopted the biological exposure indexes (BEIs) for EtO that were proposed
in 2018 (ACGIH, 2018). These include a BEI of 5,000 pmol HEV/g globin for N-(2-hydro-
xy ethy) valine (HEV) hemoglobin adducts in blood and a BEI of 5 ug HEMA/g creatinine for S-
(2-hydroxyethyl)mercapturic acid (HEMA) in urine. The BEI for HEV is set at a level that is
associated with airborne equivalent to the TLV of 1 ppm integrated over the past 120 days. The
BEI for HEMA is based on the upper 95th percentile reported in the 2014 correction of the
2011/2012 National Human and Nutrition Examination study (CDC, 2014 as cited in ACGIH,
2018).
With the exception of the new BEIs adopted by the ACGIH, the above exposure limits have not
been updated since they were established in the 1980s. In a regulatory review of the OSHA EtO
Standard (OSHA, 2005), it was concluded that the EtO Standard should be continued without
change and does not need to be revised or rescinded to minimize economic impacts on small
entities. The OSHA website at https://www.osha.gov/annotated-pels currently indicates that
"OSHA recognizes that many of its permissible exposure limits (PELs) are outdated and
inadequate for ensuring protection of worker health".
19 https://www.epa.gov/hazardous-air-pollutants-ethYlene-oxide/forms/ethYlene-oxide-risk-commercial-sterilizers
Page 19 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
Table 4. Ethylene Oxide Occupational Exposure Limits
Or^iiiii/iilion iind
Yc;ir I sliihlishod
I'1\|)omiiv l.imil l \|)c
X-liour T\\ A
10- or 15-
Minulc S I 111.
Action I.cm'I'
OS11A (l')X4j
IVi'iiiiwble Exposure Limn (I'LL)
1 ppm
5 ppm
0.5 ppm
NIOSH (1981)
Recommended Exposure Limit (REL)
<0.1 ppmd
5 ppme
Not Applicable
ACGIH (1984)
Threshold Limit Value (TLV)
1 ppm
Not Applicable
Not Applicable
Cal OSHA (1985)
Permissible Exposure Limit (PEL)
1 ppm
5 ppm
0.5 ppm
a Action Level: Concentration as an 8-hour TWA, above which the employer must initiate certain compliance activities such as
periodic employee exposure monitoring and medical surveillance.
b The employer shall ensure that no employee is exposed to EtO in excess of the PEL as an 8-hour TWA.
c The employer shall ensure that no employee is exposed to EtO in excess of the STEL as averaged over a period of 15 minutes.
d The REL of <0.1 ppm is based on the limit of detection.
e The NIOSH REL-STEL is based on a sampling period of 10 minutes.
3.0 Occupational Exposure and Risk Assessment
There is potential for occupational handler inhalation exposure from the registered uses of EtO.
Occupational dermal exposures are not expected given the high vapor pressure of EtO and based
on the delivery systems used (which include pressurized cylinders).
In the 2020 DRA (US EPA, 2020), OPP summarized personal breathing zone (PBZ) air
monitoring data from registrant-submitted studies for sterilization plant workers, health care
facilities and workers involved in the treatment of spices. These PBZ air monitoring data
represent observational monitoring during routine workdays and are expressed as 8-hour TWA
air concentrations when compared to the OSHA PEL of 1.0 ppm or as 15-minute TWAs when
compared to the OSHA EL of 5 ppm. No new occupational exposure data have been submitted
since the 2020 DRA.
3.1 Occupational Handler Exposures and Cancer Risks
3.1.1 Occupational Exposure Data Submitted to EPA
A summary of available exposure data included in the 2020 DRA is presented in Table 5.
Antimicrobial Uses - Sterilization Plants: Air concentration data from a sterilization plant
worker study (MRID 50231101) were submitted. The study contains 1,273 PBZ air samples that
were collected using 3M passive sampling badges. These badges are typically fastened to the
workers' lapel and they represent the exposure that occurs outside the respirator.
Only data with a reporting time of 210 minutes or more were used. The study report indicates
that this was done because OSHA defines full-shift sampling ".. .as a minimum of the total time
of the work shift less one hour (e.g., seven hours of an 8-hour work shift or nine hours of a ten-
hour work shift)..and samples from periods of at least half a day (i.e., 420 / 2) were
considered to reflect TWA exposures. The sample times ranged from 210 to 420 minutes for
four samples, 420 to 480 minutes for 1,121 samples and 480 to 772 minutes for 148 samples.
Page 20 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
The reported EtO air concentrations for all 1,273 samples ranged from 0.002 ppm to 35 ppm20.
Of the 1,273 samples, 80 samples (6.3%) were reported as less than the level of detection (LOD).
The reported LOD for a 480-minute sample was 0.026 ppm and one half the LOD (i.e., 0.013
ppm) was used for calculating exposures. This LOD is comparable to the reporting limit of 0.01
ppm21 for an 8-hour sample using a 3M badge that has a sampling rate of 12 ml minute (3M,
2021).
The study report indicates the current industry standard is to use supplied air respiratory
protection with a protection factor of 1,000 or a pressure-demand self-contained breathing
apparatus (SCBA) with a protection factor of 10,000. The protection factor of 1,000 for airline
respirators operated in pressure demand mode (OSHA, 2009) was used to estimate exposure for
the workers that wore respirators. Of the 1,273 samples, respirators were worn at all times for 6
samples and respirators were worn part of the time for 605 samples. For these 611 samples, the
use of respirators was accounted for by dividing the sample result for exposure period when the
respirator was worn by the protection factor of 1,000. Respirators were not worn at any time
during monitoring for 662 samples; therefore, the respirator exposure adjustments were not made
for these samples. As shown in Table 7, the calculated exposures for all 1,273 samples ranges
from 0.002 to 4.6 ppm with an arithmetic mean of 0.23 ppm. The calculated exposures for the
611 samples when workers wore a respirator at any time during sampling ranges from 0.013 to
2.2 ppm with an arithmetic mean of 0.18 ppm. 22.5 percent of these calculated exposures are
below the LOD and are reported as one half the LOD. If the actual calculated exposures are
reported rather than half the LOD, the calculated exposures range from 0.00011 to 2.2 ppm with
an arithmetic mean of 0.18 ppm (US EPA, 2023). The exposures for the 662 workers who did
not wear a respirator at any time during sampling ranges from 0.002 to 4.6 ppm with an
arithmetic mean of 0.27 ppm.
The estimates for the 605 samples when workers wore respirators part of the time is based on 6
different calculation methods that attempted to quantify the EtO air concentrations during the
times respirators were and were not worn during the period that the air samples were collected.
This was done because only one 8 hour air sample is typically collected per worker per day in
accordance with the OSHA standard and because respirators are only required in certain areas
during certain tasks (i.e., moving a load from the treatment cylinder to the aeration cylinder).
These tasks are done at intermittent times and are mixed in with other tasks (such as monitoring
the process in the control room or working in the warehouse) that do not require respiratory
protection. Ideally, a separate air sample would have been taken for each interval when a worker
was in a certain area doing a certain task. The results of these samples in combination with
information on when respirators were worn would allow for a more accurate estimation of the
worker exposure that occurs underneath the respirator.
In addition, when accounting for the use of respirators, only those exposure estimates reflecting
respirator use were adjusted for the protection factors. Exposure estimates not reflective of the
use of a respirator were not adjusted. Because of this, the exposure estimates are driven by
exposures that occur when respirators are not worn and are not significantly different when the
20In the DRA (US EPA 2020), it is stated that "the reported TWA EtO concentrations for all 1,273 workers ranged from 0.002 ppm to 4.6 ppm".
These values are actually the calculated TWAs that included the use of respirators. The reported air concentrations are the values that were
measured and they ranged from 0.002 to 35 ppm.
21In the DRA (US EPA 2020), the LOD was reported to be 0.7 ppb (0.0007 ppm) for an 8 hour sample based on OSHA Method 49 for EtO. This
was based on the 3M badge airflow rate of 49.3 mL/minute and the detection limit of 0.03 ug/sample.
Page 21 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
protection factors are increased from PF-1,000 to PF-10,000 (US EPA, 2023). The arithmetic
mean exposure is 0.22 ppm when the PF is 10,000 which is only slightly less than the arithmetic
mean exposure of 0.23 ppm when the PF is 1,000.
Antimicrobial Uses - Health Care Facilities: The 3M Health Care Facility data from 2012 (MRID
50231102) were presented at a May 15, 2015, meeting at the U.S. Food and Drug Administration
(FDA). The exposures range from 0.026 ppm to 10.2 ppm with an average of 0.12 ppm and a
90th percentile value of 0.16 ppm. The lowest value was not reported in the submission and is
estimated to be 0.026 ppm, which is the LOD for an 8-hour badge sample that was reported for
sterilization worker study. Since the data were provided only as summary as included in the
presentation to show how exposures have decreased since the implementation of the OSHA -
PEL in hospitals, it is not known exactly how many health care facilities were included or what
tasks were associated with the measured exposures. These data are the actual exposures and
have not been modified to account for respiratory protection because respirator use information
was not included in the submission. It is likely that respirators were not used in most cases
because the 90th percentile value of 0.16 ppm is below the OSHA PEL of 1.0 ppm.
Conventional Uses -Spice Sterilization Facilities: In support of the use of EtO for the
sterilization of spices, the ASTA submitted exposure monitoring of two workers at each of two
facilities (MRID 47338301; D347717). Each worker was monitored for 10 days at facilities that
ASTA claims treat the majority of spices in the United States. Activities monitored included
unloading/loading chambers, cleaning chambers, charging the chamber with EtO, receiving
untreated product, shipping treated product, sampling EtO treated product, etc. (see Appendix A
for a full list of activities). For some of these activities, workers wore a respirator (per the label
requirements); however, for some activities workers did not wear a respirator and would not be
required to per the product label. The Agency believes the data - representing a total of 40 EtO
exposure-days - are a reasonable representation of EtO exposure throughout the spice industry.
Air concentrations were collected utilizing a continuous monitoring instrument (BW
Technologies, Inc. Gas Alert Extreme) set to record EtO exposure throughout the day with a LOD
of 0.1 ppm. Results submitted to the Agency included the following:
• 5-minute instantaneous readings (e.g., 0.2 ppm at 7:05 AM, 0.1 ppm at 7:10 AM, etc.);
• 15-minute rolling averages;
• 8-hour rolling averages;
• Activity specific information corresponding to each 5-minute reading;
• "Yes/No" indication for respiratory protection (a PF50 MSA Ethylene Oxide Gas Mask -
NIOSH Certification TC 14G-0202) worn during time of reading; and,
• 8-hour TWA results from a ChemChip™ Ethylene Oxide Personal Monitor by Assay
Technologies, Inc.
While the study reported that a PF50 respirator was worn, these respirators are no longer
available for EtO22; therefore, it was assumed that workers would be wearing self-contained
breathing apparatus (SCBA) which are more protective than PF50 respirators. A protection
factor of 10,000 was then applied to those 5-minute averages where a respirator was worn, and
daily averages were calculated. For results showing no exposure (i.e., non-detects), half the
22 The NIOSH approval for the PF-50 respirators (i.e., gas masks) that were previously used for EtO has been cancelled. There are no air
purifying respirators approved for EtO. Only air supplying respirators can be used.
Page 22 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
LOD (0.1 ppm) was used as is standard Agency practice; unless EtO was detected, breaks and
lunch were not included. Of note, many of the samples for the workers were less than the LOD
and therefore, many values were included in the calculations as V2 LOD or 0.05 ppm, which
impacted the overall arithmetic mean calculated.
Also of note, MRID 50231101 (mentioned above under the antimicrobial uses) indicates on page
6, "whereas most of the data were obtained from facilities that sterilized medical equipment,
badge data were obtainedfrom two facilities which treat spices exclusively andfrom at least one
other facility which treated both medical equipment and spices on days when badge monitoring
was conducted. " Therefore, some of the data from this study would also be representative of
spice facility fumigations as well.
Conventional Uses - Beekeeping Equipment:
Based on information provided at the time of the EtO RED (US EPA 2008), the beekeeping
equipment use of EtO 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. Monitoring data
specific to the beekeeping equipment fumigation use are not available; however, based on the
label directions and requirements for the SLN beekeeping equipment use (related to EPA Reg. #
36736-7), it is anticipated that the ASTA monitoring data for the spice facilities would be
protective of the beekeeping use and was used as a surrogate. While the exact tasks and
environment (indoor spice facility versus outdoor beekeeping equipment fumigation chamber)
may not be the same between the two uses, the data provide an estimate of potential exposure.
In order to better represent the potential exposures from fumigating beekeeping equipment, the
activities reported were limited to those that would likely occur during outdoor beekeeping
equipment fumigation (see Appendix A).
Previously, information submitted to the Agency for EtO sterilization of beekeeping equipment
in North Carolina indicated that use is approximately 40 times per year (electronic mail
correspondence from Dan Hopkins, NC Dept. of Agriculture to Susan Bartow, EPA/OPP/SRRD;
2/7/2008), as opposed to a potential year round operation like the spice treatment facilities.
However, this number has reportedly decreased even more in recent years; information provided
in 2020 from North Carolina indicated that only eight treatments had been conducted between
January 2019 and October 2020 (i.e., about 4 per year). In order to account for any potential
variation in number of treatments, both four and eight treatments per year were assumed for the
beekeeping equipment fumigation use.
Table 5. EtO Occupational Air Concentration and Exposure Data Submitted to EPA
Diilii Sou i co
Number of liicililks
Monitored
Numhi-r of Air
Siimplos
( oik-clod
I'.lO l.xnosuivs (nnni)
Uiiniic
Arilhmolic
Mo.iii
Sterilization & Spice Plant
Worker Exposure Study
(MRID 5023110If
25
1,273
0.002 to 4.6
0.23
3M Health Care Facility Data
(MRID 50231102)b
More than 34
647
0.026 to 10.1
0.12
ASTA Worker Exposure Study
(MRID 47338301; D347717)c
2 (2 workers at each facility)
40
0.01-0.841
0.075
Page 23 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
aMRID 50231101. Ethylene Oxide Exposures for Ethylene Oxide Sterilization Plant Workers, Acta Group, 3/31/2017. The EtO
expo sures reflect the use of PF 1,000 respiratory protection when it was worn for specific tasks.
b MRID 50231102. Supplemental Information on State Controls Affecting Ethylene Oxide Emissions, Targeted
Monitoring Data near Operating Chambers, and Monitoring Data from Health Care Facilities. Acta Group, 3/31/2017.
Includes data from passive EtO monitors in health care facilities across 33 states and Puerto Rico in 2012. The EtO exposures
are the actual measured air concentrations and do not reflect the use of respiratory protection.
c MRID 47338301. Render, C. 2008. Ethylene Oxide Worker Exposure Study. Sponsored by the American Spice Trade
Association (ASTA). The EtO exposures reflect the use of SCBA respiratory protection for only certain activities when it was
indicated that respirators were worn.
3.1.2 Occupational Cancer Risks for Handlers Using EtO
Antimicrobial Uses - The cancer risks for the antimicrobial uses were calculated using the
arithmetic mean of the submitted exposure data for commercial sterilizer and health care
facilities. Since these facilities operate on a continuous basis, the submitted exposure data were
assumed to represent a 35-year occupational exposure between ages 20 and 55 years. The cancer
risks for the exposure were, therefore, estimated using the table "Extra Risk Est. for Total Cancer
Incidence for Occupational Exposure Levels" which is included as Table 3 in this document and
Table 4-30 of the IRIS assessment (US EPA, 2016). The MLE and upper bound cancer risk
estimates are included in Table 6 and range from 4 x 10"2 (1 in 25) to 1 x 10"1 (1 in 10),
depending upon which facility type and cancer risk estimate is considered. The upper bound
cancer risks are approximately twice the MLE cancer risks.
Table 6. Occupational Handler Cancer Risks for the Antimicrobial Uses
l);il;i Souico
Arilhmolic Menu
X-lir l \\ A (ppm)
( ;iiKvr K
Mil.
isks'
I |)|KT lion 11(1
SkTili/nlion I'lnnl Worker 1 \posure Siud\
(MRID 50231101)
0.23a
(> \ In
(1 in 17)
1 \ lu
(1 in 10)
3M Health Care Facility Data
(MRID 50231102)
0.12b
4 x 10"2
(1 in 25)
8 x 10"2
(1 in 12)
a Air samples were adjusted to account for the use of PF-1,000 Supplied Air Respirators if the worker wore a respirator during the
sampling period. This adjustment was made for 611 of the 1273 samples.
b Air samples were not adjusted to account for respirators since it is not known if respirators were worn.
c Risks are for total cancers and are taken from IRIS Table 4-30. Risks are rounded to one significant figure.
Conventional Uses - Spice Facilities: The cancer risks for the conventional spice uses were
calculated using the arithmetic mean of the submitted exposure data for the spice facilities. Since
these facilities operate on a continuous basis, the submitted exposure data were assumed to
represent a 35-year occupational exposure between ages 20 and 55 years. Since the exposure is
less than 0.1 ppm, however, the cancer risks for the exposure could not be estimated using Table
4-30 of the IRIS assessment (US EPA, 2016) and instead MLE and Upper Bound cancer risks
were calculated using the formulae listed on page 4-111 of the IRIS assessment (as described in
Section 2.1.2 above, for Continuous Occupational Exposures from less than 0.1 ppm to 0.001
ppm).
As noted above, some of the workers did not wear respirators during the time that they were
monitored when they were doing activities for which a respirator was not required. Therefore,
when calculating exposures, respiratory protection factors were only applied to concentrations
measured during activities when a respirator was worn. Concentrations measured during
activities when no respirator was worn (and is not required to be worn according to the product
labels) were not adjusted for any respiratory protection factors. A summary of the cancer risks is
Page 24 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
presented in Table 7. Cancer risks range from 3 x 10"2 (1 in 36) for the MLE to 6 x 10"2 (1 in 16)
for the upper bound.
Table 7. Occupational Handler Cancer Risks for the Conventional Spice Uses
Diilii Source
Arilhmelic Menu
X-lir l\\ A (ppm)
( ;inccr Risks'1
Mil.
I |)|HT lioil 11(1
ASTA Worker Exposure Study
(MRID 47338301; D347717)
0.075
3 x 10"2
(1 in 36)
6 x 10"2
(1 in 16)
a MLE of extra risk for total cancer incidence = (8-h TWA [ppm]) x (0.37/ppm). Upper Bound (95% UCL) on extra risk for total
cancer incidence = (8-h TWA [ppm]) x (0.81/ppm).
Special Local Need -Beekeeping Equipment Fumigations: As noted above, the cancer risks for
the beekeeping equipment use were calculated using the arithmetic mean of the submitted
exposure data for the spice facilities. In order to account for the differences in potential exposure
between workers in an indoor spice facility and workers fumigating beekeeping equipment in an
outdoor chamber, the activities reported were limited to those that would likely occur during
outdoor beekeeping equipment fumigation (see Appendix A). Since the beekeeping fumigation
exposures are considered "intermittent occupational exposures", as noted above in Section 2.1.2,
a lifetime average concentration (LAC) was calculated, assuming either four or eight exposure
days per year, and then the cancer risks were calculated using the LAC and the adult specific
inhalation unit risk of 5.5 x 10"3 per ppb.
A summary of the cancer risks is presented in Table 8. Cancer risks range from 2 x 10"4(1 in
5,000) when assuming four exposure days per year to 4 x 10"4 (1 in 2,500) when assuming eight
exposure days per year.
Table 8. Occupational Handler Cancer Risks for the Beekeeping Use
l);il;i Soui co
Arilhmclic Mc:iir'
X-lir l \\ A
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
202023 were downloaded and screened to eliminate area samples, bulk samples and blank values
leaving only personal breathing zone samples. Data were also deleted for industries, such as
chemical manufacturing, that are not relevant for FIFRA registered uses. The remaining data are
summarized in Table 9 below. Numerical results were calculated for the samples reported as,
non-detect (ND) by dividing the reliable quantitation limit (RQL) of 0.032 |ig/sample for the
method used (OSHA, 2014) by the sample air volume. Given that the OSHA PEL is 1 ppm for
the 8-hour TWA and 5 ppm for the 15-minute short term excursion limit (STEL), the data for
EtO include both samples of up to 480 minutes that were collected for comparison to the PEL
and samples of less than 30 minutes for comparison to the STEL.
The combined sample TWA values reported in Table 9 for each facility inspection are the time
weighted averages (TWAs) for all the samples collected during that inspection. These TWAs
were calculated for each facility rather than for each worker because the identity of the worker
associated with each sample is not included in the chemical exposure health data. Combined
sample durations that are greater than 480 minutes indicate that more than one worker was
sampled during the inspection. For example, the combined sample duration of 3,150 minutes for
the 21 samples collected during Inspection #315303131 suggests that at least seven workers were
sampled. It also is likely that multiple samples were collected on each worker sampled at a
particular facility because the PEL of EtO is expressed both as an 8-hour TWA and as a 15-
minute EL. For some of the inspections listed in Table 9, the upper end of the range of results
includes samples that were collected to evaluate the EL. This is particularly true for Inspection
#1192822 which includes a result of 19.5 ppm. This result of 19.5 ppm and the next highest
result of 4.4 ppm were from 19-minute samples that were taken to evaluate the EL of 5 ppm. The
remaining results are from samples of approximately 240 minutes in duration that were collected
to evaluate the PEL of 1 ppm. The combined TWAs range from 0.0013 ppm to 1.5 ppm for the
medical equipment production and sterilization facilities, with two facilities above the PEL of 1
ppm. The combined TWAs for the health and veterinary care facilities ranged from 0.0061 to
0.022 ppm and were all below the PEL. The combined TWA of 0.082 ppm for the spice and
extract manufacturing facility is also below the PEL. The OSHA data represent exposures that
occur in the breathing zone and do not account for the use of respiratory protection; therefore,
they were not used to calculate cancer risks.
Table 9. OSHA EtO Data for EPA Registered Uses (2008 through 2020)
OSHA
Inspection
Number
Year
Industry
Number
of
Samples
Range of
Results"
(ppm EtO)
Combined
Sample Durationb
(Minutes)
Combined
Sample TWA'
(ppm EtO)
Medical Equipment Production and Sterilization Facilities
315303131
1192822
2011
2017
Medical Equipment
Wholesale
21
15
0.05 to 0.74
0.05 to 19.5
3150
2903
0.22
1.5
1169775
2016
Scientific and Technical
Consulting11
8
0.0008 to 0.03
2074
0.0013
317586501
2014
Surgical Equipment and
Supplies Manufacturing
11
0.0015 to 0.60
1065
0.23
23 The data for 2008 through 2019 were included in the 2020 DRA. The data for 2020 became available in 2021. There are no data for 2021.
Page 26 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
OSHA
Number
Range of
Combined
Combined
Inspection
Year
Industrv
of
Results"
Sample Durationb
Sample TWA'
Number
Samples
(ppm EtO)
(Minutes)
(ppm EtO)
314845975
2011
4
0.005 to 0.18
350
0.11
810881
2013
Surgical and Medical
6
0.005 to 0.85
603
0.43
1013403
2015
Equipment
6
0.02 to 2.4
906
1.4
1400790
2019
Manufacturing
13
0.001 to 0.23
2280
0.15
1428553
2020
16
0.0008 to 0.23
2578
0.063e
Health and Veterinary Care Facilities
312835390
2009
4
0.003 to 0.02
217
0.0061
310770896
2009
4
0.0008 to 0.89f
460
0.031
315129924
2011
Health Care Facilities
3
0.005 to 0.03
99
0.010
1147145
2016
5
0.001 to 0.03
445
0.0040
312226533
2008
6
0.009 to 0.02
150
0.013
1007452
1276007
2015
2017
Veterinary Care Facilities
2
2
0.02, 0.02
0.006, 0.002
30
75
0.024
0.0095
Non-Medical Facilities
1241931
2017
Spice and Extract
Manufacturing
5
0.002 to 0.168
472
0.083
a Results in bold font are based on the air sample volume and the reliable quantitation limit of 0.032 ug/sample.
b The combined sample duration is the duration of all of the samples taken during the inspection.
c The combined TWA is the TWA of all of the samples taken during the inspection.
dThis facility does sterilization protocol development and testing.
e For this inspection it was possible to identify the employees by field number. Five employees were sampled for 458 to 480
minutes each. The average 8 hour TWA is 0.058 ppm for these five employees. An additional employee was sampled for 229
minutes. The combined sample TWA of 0.063 ppm includes all six employees.
f Only one sample was above the RQL. This sample was collected for 15 minutes.
g The highest result of 0.16 ppm is from a 240 minute sample.
3.2 Occupational Bystander Exposures and Cancer Risks
Occupational bystander exposures may occur in non-processing areas of a treatment facility,
health care facility, or beekeeping equipment treatment area; in downstream facilities where the
treated product is shipped and stored; or in other workplaces that are near the treatment facilities,
health care facilities, or beekeeping equipment treatment areas. To aide in mitigation planning
for these types of exposures where respiratory protection is not used, the EtO concentration at
which the cancer risk equals a certain target level (1 x 10"4 or 1 x 10"6) was back calculated from
the inhalation unit risk for adults as shown in Table 9. This calculation indicates that if the EtO
exposure in these areas does not exceed 0.19 parts per billion (ppb) as an 8-hour TWA, the
cancer risk will not exceed 1 x 10"4 (100 in 1 million). If the EtO exposure does not exceed
0.0019 ppb, the cancer risk will not exceed 1 x 10"6 (1 in 1 million). This calculation is relevant
to both the antimicrobial and conventional uses of EtO.
Table 10. Occupational Bystander Exposure Associated with Cancer Risk Targets
Cancer Risk
Tariiel
8-hr TWA
(ppb)
Hours Per
Day
l);i\s Per
Year
Years Per
l.ifelime
l. \( ,h
(ppb)
Inhalation
I nil Risk'
Cancer
Risk'1
1 x 10"4
0.19
8
240
35
0.021
5.5 xlO"3
per ppb
1 x 10"4
1 x 10"6
0.0019
0.00021
1 x 10"6
a LAC = Lifetime Average Concentration
b LAC = 8-hr TWA (ppb) * (8 hours exposure per day/24 hours) * (240 days exposure per year/365 days) * (35 years/70 years)
Page 27 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
c Adult Inhalation Unit Risk from Table 2.
d Cancer Risk = LAC (ppb) * Inhalation Unit Risk (per ppb)
4.0 Non-Occupational Bystander Exposure and Risk Assessment
4.1 Commercial Sterilization Facilities (Antimicrobial and Conventional Uses)
Non-occupational bystander exposures around commercial sterilization facilities are considered
either "residential" exposure occurring where people live (i.e., their homes) or "non-residential"
meaning exposures occurring at places other than homes where people may spend a significant
amount of time (i.e., daycare centers, schools).
4.1.1 Commercial Sterilization Facility Emissions
In proposing amendments to the NESHAP for the Commercial Sterilization Facilities source
category, OAR is assessing and proposing to regulate only residential exposure (i.e., exposure
where people live). Exposures to workers and non-residential bystanders are not addressed in
this proposed rulemaking.
4.1.2 Residential Bystander Exposures and Risks
There is the potential for EtO exposure to children and adults who live near sterilization
facilities. These exposures are also being addressed by the proposed OAR rulemaking (US EPA,
2022). The EtO average daily concentration at which the cancer risk is 1 x 10"6 was back
calculated from the inhalation unit risk for lifetime exposure as shown in Table 11. This
calculation indicates that if the average daily concentration in these areas does not exceed
0.00011 ppb (0.11 ppt), the cancer risk will not exceed 1 x 10"6 (1 in 1 million). As discussed in
Section 5.0 below, this is below the LOD of 20 to 90 ppt for EtO in ambient air.
Table 11. Residential Bys
tander Exposures Associated with a Cancer Risk of 1 x 10~6
l-'.TO A\er;iiie l);iil\
( oncciilr;ilioii (AI)C)
l-'.TO l.il'climc A\cr;iiic
( uiKTiilriilioir' il..\()
liihiiliilion I nil Risk1'
('.nicer
Risk1
('.nicer
Risk'1
0.00011 ppb (0.11 ppt)
0.00011 ppb
9.15 x 10 3 per ppb
1 x 10"6
1 in 1 million
a LAC = ADC * (24 hour / 24 hours) * (365 days / 365 days) * (70 years / 70 years)
b Full Lifetime Inhalation Unit Risk Estimate from Table 2.
c Cancer Risk (unitless) = LAC (ppb) * Inhalation Unit Risk (9.15 x 10"3 per ppb for lifetime exposures)
d Cancer Risk (in a million) = Cancer Risk (unitless) x 1,000,000
4.1.3 Non-Residential Bystander Exposures and Risks (Daycare Centers and Schools)
Non-residential bystander exposures can occur at a variety of facilities such as retail
establishments, restaurants, gyms, swimming pools, music studios, movie theatres, etc., that are
between the fence line of a sterilization facility and the nearest residence. These exposures are
best represented by children attending day care centers and schools because they occur more
frequently and with a longer daily duration and because EtO is a mutagen that requires the use of
ADAFs to assess childhood exposures. The EtO concentration at which the cancer risk equals
1 x 10"6 was back calculated from the inhalation unit risk as shown in Table 12. These
calculations indicate that the cancer risk is 1 x 10"6 (1 in 1 million) for children who attend
Page 28 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
daycare and school where the average daily EtO concentration is 0.0012 ppb (1.2 ppt). As
discussed in Section 5.0 below, this is below the LOD of 20 to 90 ppt for EtO in ambient air.
Table 12.
Daycare and School
Bystander Exposures Associatec
with a Cancer Risk of 1 x 10"6
IK) AIM '
Alio
Hours Per
l);i\s Per
Years Per
LACbc
A DAP1
liih;il;ilion
('¦nicer
Dsi>
Year
1.ill-lime
(|)|)b)
I nil Risk'
Risk1
0 to 2
8
240
2
7.5 x 10"6
10
4.1 x 10"7
0.0012 ppb
3 to 6
8
240
4
1.5 x 10"5
3
5.5 x 10"3
2.5 x 10"7
7 to 16
6
180
10
2.1 x 10"5
3
per ppb
3.5 x 10"7
(1.2 ppt)
17 to 18
6
180
2
4.2 x 10"6
1
2.3 x 10"8
Oto 18
N/A
N/A
18
N/A
N/A
1 xlO"6
a ADC = Average Daily Concentration (24 hours)
b LAC = Lifetime Average Concentration
c LAC = ADC (ppb) * (hours per day/24 hours) * (days per year/365 days) * (years per lifetime/70 years)
d ADAF = Age Dependent Adjustment Factor
e Adult for Use with ADAFs Inhalation Unit Risk Estimate from Table 3.
f Cancer Risk = LAC (ppb) * ADAF * Inhalation Unit Risk (per ppb)
4.2 Health Care Facility Residential and Non-Residential Bystander Exposures
Since 2010, health care sterilization facilities have been required to operate on an all-in-one basis
in accordance with the EtO Reregi strati on Eligibility Decision (US EPA, 2008). These facilities
sterilize material in oven-sized chambers using 4.5 to 170 grams of EtO per load. The exhaust
from the chambers is typically routed to an air pollution control device and the room air is
typically ventilated though an exhaust stack to minimize exposures as recommended in the
American National Standard Institute/Association for the Advancement of Medical
Instrumentation (ANSI/AAMI) standard ST41 (ANSI/AAMI, 2018). Given this information,
exposures to non-occupational bystanders are expected to be minimal, but the exact air
concentrations are not known and, therefore, the risks are not quantitatively assessed in this
DRA. It is known, however, that the exposures that would result in a cancer risk of 1 in a
million are the same as those calculated for contract sterilization facilities (i.e., 0.11 ppt for
residential areas and 1.2 ppt for children in schools/daycares). The potential exposures around
health care sterilization facilities can be addressed in the Preliminary Interim Decision (PID) by
requiring control measures that are recommended in ANSI/AAMI (2018). In addition, the
NESHAP for Hospital Ethylene Oxide Sterilizers addresses EtO emissions from hospitals where
EtO is used, and OAR plans to evaluate the risks from hospital sterilizers in an upcoming
regulatory review of this NESHAP.
4.3 Beekeeping Equipment Fumigations (Special Local Need)
For the beekeeping equipment use in North Carolina, a quantitative residential bystander
assessment was conducted using the Probabilistic Exposure and Risk Model for Fumigants
(PERFUM). This approach was taken since the use is limited to one area and information was
available on the fumigation chambers and process to allow for the exposure to be modeled.
Details on the PERFUM inputs and a table of the outputs at various percentiles is provided in
Appendix B. A summary of the inputs and outputs is provided below.
EPA reached out to the North Carolina Department of Agriculture and Consumer Affairs
(NCDA&CS) to obtain information about the chamber set up and operations for the beekeeping
Page 29 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
equipment fumigations. Based on the information provided, the approach taken was to model
the beekeeping equipment use as an area source in PERFUM, with passive aeration from the
source, and assuming the mass of EtO in the chamber all comes out during the first hour (first
flushing out of the chamber after fumigation). NCDA&CS indicated that the chamber is flushed
3 times after fumigation and given the size of the chamber (126 ft3), this process would not be
expected to take longer than an hour, and by releasing all the mass in one hour, a conservative air
concentration would be modeled. NCDA&CS also provided information on the chamber and
aeration set up, and based on this information, EPA assumed the source to be a circular area,
with a radius of 15 cm (0.15 m). The emission rate was entered for hour 1 (assumed to be noon
based on the information from NCDA&CS which stated that the treatments start midday and run
until the following midday) and then zero emissions assumed for the rest of the day. The
meteorological data for Raleigh, North Carolina was used as this would be the closest to the
actual location of the fumigation.
Two application rates were modeled as provided on the product label: 450 mg/L (28.3 lb ai/1,000
ft3) and 740 mg/L (46.5 lb ai/1,000 ft3). Information provided by North Carolina indicated the
chamber size to be 126 ft3 (3.57 m3). The mass of EtO released and the corresponding emission
rate modeled were the following:
• For the 28.3 lb ai/1,000 ft3 rate:
o Mass of EtO released: 3.6 lb (1,617,409,181 |ig or 1,617 grams)
o Emission rate: 6,370,963 |ig/(m2-s)
• For the 46.5 lb ai/1,000 ft3 rate:
o Mass of EtO released: 5.9 lb (2,657,600,376 |ig or 2,657 grams)
o Emission rate: 10,468,269 |ig/(m2-s)
The PERFUM output provides distributions of modeled air concentrations at various distances
from the chamber. These air concentrations are then used to estimate inhalation cancer risk
assuming four or eight exposure days per year and 70 years of exposure per lifetime. The IRIS
inhalation unit risk for environmental exposures for a full lifetime [5.0 x 10"3 per [j,g/m3
(9.15 x 10"3 per ppb) from Table 2] was used to estimate cancer risks. For the purposes of this
assessment, a summary of the cancer risk estimates for the 50th, 75th, 80th, 85th, and 90th
percentiles assuming 4 and 8 days (24 hrs/day) per year, based on specific use information for
the beekeeping use, are provided below in Table 12 from 10 to 300 meters from the chamber.
While the cancer risks are twice as high when assuming 8 days per year, the distances at which
risks are greater than 1 x 10"6 (1E-06) do not change. It is likely that the exact distance at which
the cancer risks change from "of concern" to "not of concern" are different when assuming 4
versus 8 exposure days; however, the model results are only reported at specific distances (e.g.,
1, 5, 10, 15 meters, etc) and not at continuous distances from the fumigation chamber.
Therefore, the distance, as reported by the model, at which the cancer risk estimate is not of
concern does not change between four and eight exposure days.
The distances from the fumigation chamber at which the cancer risk estimates are less than
1 x 10"6 increase from lower to higher percentiles. For example, at the lower percentiles (e.g.,
75th and 80th), the distance from the fumigation chamber at which the cancer risk is less than 1 x
10"6 is only 10 meters, while at the higher percentiles (e.g., 90th) distances of 300 meters or more
are necessary to reach cancer risk estimates less than 1 x 10"6. Cancer risk estimates are less than
Page 30 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
1 x 10"6 at all percentiles for both application rates when the distance is equal to or greater than
300 meters.
Table 13. Cancer Risks at Buffer Distances from the Beekeeping Fumigation Chambers
Appliciilion Kiiic
Modeled Air ( cmcoii 1 r;ilion
( iiiKTr Risk ill liulTcr
Disl ;i nces
(II) ii.i./iooo IV1)
Dislrihulion IVivonlilo
10 IlK'kTN
50 inekTs
100 inolcrs
200 niolors
300 mold's
4 Exposure Days Per Year
50
6E-41
5E-41
2E-41
3E-41
3E-41
75
3E-16
1E-12
2E-15
3E-18
2E-21
46.5
80
2E-06
7E-09
4E-11
6E-14
9E-15
85
3E-04
3E-06
1E-07
2E-09
3E-10
90
5E-03
4E-04
4E-05
3E-06
4E-07
50
6E-41
3E-41
2E-41
5E-41
2E-41
75
2E-16
7E-13
9E-16
2E-18
1E-20
28.3
80
1E-06
4E-09
3E-11
4E-14
5E-15
85
2E-04
2E-06
8E-08
1E-09
2E-10
90
3E-03
2E-04
3E-05
2E-06
3E-07
8 Exposure Days Per Year
50
1E-40
1E-40
4E-41
5E-41
6E-41
75
5E-16
2E-12
3E-15
5E-18
4E-21
46.5
80
4E-06
1E-08
9E-11
IE-13
2E-14
85
7E-04
6E-06
3E-07
3E-09
6E-10
90
1E-02
7E-04
9E-05
6E-06
9E-07
50
1E-40
6E-41
5E-41
1E-40
4E-41
75
3E-16
1E-12
2E-15
3E-18
3E-20
28.3
80
3E-06
9E-09
5E-11
8E-14
1E-14
85
4E-04
4E-06
2E-07
2E-09
4E-10
90
6E-03
4E-04
5E-05
4E-06
5E-07
Bolded values are greater than lxlO 6 (1E-06)
5.0 Ambient Air Monitoring Data and Analytical Uncertainties
Ambient air data are normally used to provide context for the exposures and risks that are being
assessed. In the case of EtO; however, there are risks of concern for levels that are below the
levels of detection for the methods that are used to measure EtO in ambient air. To achieve a
residential population cancer risk that is less than 1 x 10"6, for example, the lifetime average EtO
concentration would need to be less than 0.11 ppt. As discussed below, this level is less than the
detection limit of 20 to 90 ppt and this detection limit can only be achieved under optimum
conditions.
EtO has been measured in the outdoor air in areas away from specific sources of EtO.
Monitoring data are available in EPA's Air Quality System (AQS), which houses outdoor air
quality data collected by EPA, state, local, and tribal air pollution control agencies across the
country (see https://www.epa.gov/aqs).
For most of the sites included in the AQS, the EtO air concentrations were measured as 24-hour
air samples using 6 liter evacuated stainless steel canisters. The air collected in the canisters was
then analyzed using gas chromatography and mass spectrometry. When the method was initially
developed, it had a detection limit of 0.25 ppb using EPA's traditional approach of seven
Page 31 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
replicate analyses of a low-level standard and 0.20 ppb using a novel probabilistic approach
(Eklund et al., 2004). Since that time, the method has been incorporated into EPA Method TO-
15, which has recently been updated to EPA Method TO-15A (US EPA, 2019a). The method
now has an analytical method detection limit (MDL) of approximately 0.020 to 0.09 ppb (20 to
90 ppt). The overall method MDL will be higher than the analytical MDL ranges noted above
when sampling media and sampling handling are taken into consideration (US EPA, 2021b).
The interior surfaces of the stainless-steel air sampling canisters are typically electropolished or
coated with a silicon-ceramic film (US EPA, 2019a). There are concerns that if electropolished
canisters are used, the EtO concentration in the canister will increase after sample collection due
to interaction with canister wall surfaces (i.e., the canister wall effect). In a preliminary study
conducted by ORD (Gitipour, 2022), initial one-week results showed EtO concentrations in the
samples stored in the silicon ceramic-lined canisters were below the method detection limit
(MDL) for all samples, whereas EtO was measured at detectable concentrations in all of the
samples stored in electropolished canisters. After the 4 - 5 week holding period, the background
EtO concentrations observed in the silicon-ceramic canisters were below the MDL for the
majority of the samples. However, the EtO concentrations in the electropolished canisters had
increased over the 4 - 5 week hold time by a factor of 7 to 10 times from the initial one-week
values. These concentrations were substantially higher than typical ambient EtO concentrations.
The type of canister that was used is not listed in the AQS dataset.
In addition to the effects of the canister lining, there are concerns regarding the cleaning and
preparation of the canisters for air sampling. If cleaning is not done thoroughly, even silicon-
ceramic lined canisters can yield results that are biased due to contamination and wall effects.
Due to the uncertainties associated with the currently available ambient air sampling results,
many of the results reported in the AQS are biased high and do not reflect actual ambient EtO air
concentrations. In addition, the working limits of detection achieved by the commercial
laboratories that analyze ambient air samples are typically greater than the MDL of 20 to 90 ppt.
For these reasons, it cannot be concluded that measured ambient air concentrations of EtO are
less than the level (0.11 ppt) which corresponds to a cancer risk of 1 x 10"6. ORD is actively
working in this area to improve sampling methods for ambient levels of EtO24.
6.0 Comparison of Bystander Exposures and Risks to OAR Model Results
To get a better understanding of how the back-calculated concentrations that exceed risks of
concern for non-residential bystanders (e.g., children who attend school) and occupational
bystanders (adults who work near sterilization facilities) relate to concentrations around
facilities, the air concentrations developed by the Office of Air and Radiation (OAR) in their
recent proposed rulemaking were considered25. Air concentrations for polar receptor rings
around each sterilizing facility were modeled and annual average air concentrations were derived
by OAR. The model results indicate that there is a potential for EtO concentrations to exceed the
level of 1.2 ppt that corresponds to a cancer risk of 1 x 10"6 for children in schools/daycares that
are in non-residential areas near sterilization facilities. The model results also indicate that EtO
concentrations in the non-residential areas modeled by OAR could exceed the level of 0.0019
24 See https://www.epa.gov/hazardous-air-pollutants-ethvlene-oxide/epas-work-understand-background-levels-ethvlene-oxide
25 See OAR's residual risk assessment for the commercial sterilization facilities source category document in support of the 2022 Risk and
Technology Review Proposed Rule. This document is currently an internal draft and will be posted to Regulations.Gov for Docket Number:
EPA-HQ-OAR-2019-0178 when it is finalized.
Page 32 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
ppb (1.9 ppt) that corresponds to cancer risk of 1 x 10"6 for adults who work near facilities
modeled by OAR.
7.0 Risk Summary and Characterization
The inhalation cancer risks are likely of concern for all of the scenarios considered in this 2023
DRA addendum. These risks are driven by the high inhalation unit risk estimates which suggest
that EtO is a potent carcinogen. Based on these unit risks, the EtO exposures that are associated
with the risk targets that OPP normally uses for cancer risks (i.e., 1 x 10"4 for occupational
exposure and 1 xlO"6 for non-occupational exposure) are so low that they cannot be measured
using existing air monitoring technologies and analytical methods. For example, to achieve the
risk target of 1 x 10"6 for continuous residential exposures, the EtO air concentration must not
exceed 0.11 parts per trillion (ppt). This level is over one hundred times less than the analytical
MDL of 20 to 90 ppt for the 24-hour canister method that is used for ambient air sampling. For
worker exposures, to achieve the target risk level of 1 x 10"4, the average EtO air concentration
should not exceed 0.2 ppb. This level is 5,000 times less than the OSHA PEL of 1.0 ppm. The
level of 0.2 ppb is also 100 times lower than the LOD of 0.026 ppm (26 ppb) for the passive
badge method that is most commonly used by employers to measure EtO and 7.5 times less than
the reliable quantification limit of 1.5 ppb for the sampling tube and pump method (OSHA,
2014) that OSHA inspectors use to measure EtO.
Page 33 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
8.0 References
ACGIH, 2018. Documentation for Ethylene Oxide Biological Exposure Index. Proposed 2018,
Adopted 2019.
ANSI/AAMI, 2018. American National Standard: Ethylene Oxide Sterilization in Health Care
Facilities: Safety and Effectiveness. ANSI/AAMI ST41:2008/(R)2018. American National
Standards Institute/Association for the Advancement of Medical Instrumentation (ANSI/AAMI).
2018.
ASTA, 2017. Clean, Safe Spices: Guidance from the American Spice Trade Association. 2017
Update, https://www.astaspice.org/food-safetv/clean-safe-spices-guidance-document.
Eklund, 2004. Development and Validation of a Canister Method for Measuring Ethylene Oxide
in Ambient Air. Eklund, B. M., Williams, H.C., Bontempo, L.W., Isbell, M., Loos, K.R.,
Environmental Science and Technology. Volume 38, Number 15, pp 4200-4205, 2004.
Gitipour, 2022. Intercomparison of Ethylene Oxide Measurement Methods Under Controlled
and Relevant Atmospheric Conditions. Gitipour, A., George, I., Yelverton, T., Lewandowski,
M., Thomas, E., Loftis, K., Nwia, J., Sieffert, M., Queiroz, G., Burnette, P., Singer, C., ME45,
Air and Waste Management Association (AWMA) Air Quality Measurement Methods and
Technology Conference, San Diego, CA, March 9, 2022.
Master Record Identification (MRID) 47338301. Ethylene Oxide Worker Exposure Study: Final
Study Report. Project Number: 2007/001/EO. Render, C. (2008) Unpublished study prepared by
ETO Sterilization and Baltimore Quality Assurance. 478 p.
MRID 50231101. Ethylene Oxide Exposures for Ethylene Oxide Sterilization Plant Workers.
Project Number: 1296/001/05. Johnston, J. (2017) Unpublished study prepared by Acta Group,
L L C. 59p.
MRID 50231102. Supplemental Information on State Controls Affecting Ethylene Oxide
Emissions, Targeted Monitoring Data Near Operating Chambers, and Monitoring Data from
Health Care Facilities. Project Number: 1296/001/06. Johnston, J. (2017) Unpublished study
prepared by Acta Group, L.L.C. 15p.
OSHA, 2005. Regulatory Review of the Occupational Safety and Health Administration's
Ethylene Oxide Standard [29 CFR 1910.1047] Pursuant to Section 610 of the Regulatory
Flexibility Act and Section 5 of Executive Order 12866. Office of Evaluations and Audit
Analysis Directorate of Evaluation and Analysis, Occupational Safety and Health
Administration, Washington, D.C. March 2005
OSHA, 2009. Assigned Protection Factors for the Revised Respiratory Protection Standard,
3352-02, Occupational and Safety and Health Administration, U.S. Department of Labor, 2009.
OSHA, 2014. Ethylene Oxide Method Number 1010, Version 2, Methods Development Team
Industrial Hygiene Chemistry Division, OSHA Salt Lake Technical Center, March 2014.
Page 34 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
US EPA, 1994. Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry, EPA/600/8-90/066F, Office of Research and Development (ORD), U.S.
Environmental Protection Agency (US EPA), Washington DC, October 1994
US EPA, 2005. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure
to Carcinogens. Risk Assessment Forum, US EPA, Washington, DC. EPA/630/R-03/003F.
March 2005.
US EPA, 2008. Registration Eligibility Decision for Ethylene Oxide. Office of Pesticide
Programs (OPP), US EPA, March 31, 2008.
US EPA, 2011. Exposure Factors Handbook, 2001 Edition, EPA/600/R-09/052F, National
Center for Environmental Assessment (NCEA), US EPA, Washington, DC; September 2011.
US EPA, 2016. Evaluation of the Inhalation Carcinogenicity of Ethylene Oxide, (CASRN 75-21-
8), In Support of Summary Information on the Integrated Risk Information System (IRIS).
EPA/635/R-l6/350Fa. NCEA, ORD, US EPA, Washington, DC. December 2016.
US EPA, 2019. User's Guide for the Probabilistic Exposure and Risk model for FUMigants
PERFUM Version 3.0. Prepared by Exponent, 1800 Diagonal Road, Suite 500
Alexandria, VA 22314. Sponsored by US EPA, OPP, Health Effects Division (HED). October
28, 2019
US EPA, 2019a. Method TO-15A. Determination of Volatile Organic Compounds (VOCs) in
Air Collected in Specially Prepared Canisters and Analyzed by Gas Chromatography-Mass
Spectrometry (GC-MS), National Exposure Research Laboratory, OAQPS, Air Quality
Assessment Division, ORD, US EPA. September 2019.
US EPA, 2020. Draft Human Health and Ecological Risk Assessment in Support of Registration
Review. D458706, November 2, 2020.
US EPA, 2021. ORD review of comments on the IRIS Ethylene Oxide assessment contained in
the ACC Request for Correction submitted regarding EPA's National Air Toxics
Assessment. Memo from W. Cascio (ORD) to J. Goffman (OAR), August 25, 2021
US EPA, 2021a. EPA Should Conduct New Residual Risk and Technology Reviews for
Chloroprene- and Ethylene Oxide-Emitting Source Categories to Protect Human Health, Report
No. 21-P-0129, US EPA Office of Inspector General, May 6, 2021
U.S. EPA, 2021b. Ethylene Oxide Measurements Method TO-15/TO-15A Overview,
Challenges, Resources and Next Steps. Office of Air and Radiation (OAR), Office of Air Quality
Planning and Standards (OAQPS)/Air Quality Assessment Division (AQAD)/Ambient Air
Monitoring Group (AAMG). 4/15/2021.
Page 35 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
US EPA, 2022. Reconsideration of the 2020 National Emission Standards for Hazardous Air
Pollutants: Miscellaneous Organic Chemical Manufacturing Residual Risk and Technology
Review-Final Action. FRDoc. 2022-27522, Filed: 12/20/2022.
US EPA, 2022a. Ethics Review of Ethylene Oxide Plant Worker Exposure Study, Memorandum
from Michelle Arling, OPP Human Research Ethics Review Officer to Tim Dole of the
Antimicrobials Division, October 21, 2022
US EPA, 2023. Review of MRID 50231101. Ethylene Oxide Exposures for Ethylene Oxide
Sterilization Plant Workers Submitted in Response to the Registration Review GDCI for ETO.
D440254.
Page 36 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
Appendix A. Reported Work Activities in Spice Facilities (from MRID 47338301) and the Work Activity Subset Assumed for
Beekeeping Equipment Fumigations
Worker Activities Lisial in
ASTA Study Proincnl
Worker Activities Li sled in
\ST \ Snid> Submission
kespnaloi'
Worn''
1 ncluded in Spice Facilii>
()ccupational Handler
Exposure Assessment
Included in Beekeepi nu
1 Equipment Occupational
1 landler Exposure Assessment
Reason for including/noi
including for Beekeepinu
Equipment Fumigation
Forklift Checklist
Forklift Checklist
N
X
Beekeeping equipment
fumigation chamber not inside
Working Control
(Computer) Room
Computer room
N
X
Beekeeping equipment
fumigation chamber not inside
- would not be in same
facility/space as office
Shipping Treated Product
Shipping
N
X
Beekeeping equipment
fumigation chamber not inside
- would not be in same
facility/space as shipping area
Present in another building
Office for tickets, Office,
Warehouse
N
X
Beekeeping equipment
fumigation chamber not inside
- would not be in same
facility/space as office
Paperwork
Chamber Sheet, Paperwork
N
X
Beekeeping equipment
fumigation chamber not inside
- would not be in same
facility/space as office
Empty Trash
Empty Trash, Cleaning
N
X
Beekeeping equipment
fumigation chamber not inside
- would not be in same
facility/space as office
not listed
Sampling
N
X
Assumed to be sampling of
untreated product; specific to
spices
not listed
Control H20 chamber
N
X
Assumed specific to indoor
spice facility
Receiving Untreated Product
Ticket/Tag/Labels on
Product, Untreated Product,
Restack/working with
spices, Pull untreated
product for chamber,
Receiving, Moving Product
N
X
Activities assumed to occur
inside spice treatment facility;
not applicable to beekeeping
equipment fumigation
Page 37 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Worker Activities Lisial m
ASTA Study Protocol
Worker Activities Listed in
\ST \ Sludv Submission
Respirator
Worn?
Included in Spice Facilils
Occupational Handler
Exposure Assessment
Included in Beekeeping
1 Equipment Occupational
1 laudler Exposure Assessment
Reason for including/noi
i ncluding for Beekeepinu
Lquipment Fumigation
Clean mask
Clean mask, Clean
N
X
X
respirator, Clean SCUBA
not listed
Receipt of EtO Gas
N
X
X
Vacuum down EtO cylinders
for shipment
Vacuum
N
X
X
not listed
Start, Start up Chamber,
Heat Chamber, Heat
Product
N
X
X
Unloading Chamber
Open Chamber, Unload
Chamber
Y
X
X
Assumed to occur regardless of
Loading Chamber
Load Chamber
Y
X
X
product being treated
Charging Chamber with EtO
Chamber "X", Gassing
Chamber "X"
Y
X
X
Cleaning (sweeping)
chamber
Clean chamber room,
Sweep Chamber
Y
X
X
Sampling EtO Treated
Product
Work with Treated Product,
Sampling
Y
X
X
Draining empty gas cylinder
Drain cylinder
Y
X
X
not listed
New EtO Cylinder
Y
X
X
not listed
Remove EtO Cylinder
Y
X
X
not listed
Caps in EtO Cylinders
Y
X
X
Page 38 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
Appendix B. Details on the PERFUM modeling for the Bystander Assessment for the
Beekeeping Equipment Fumigation Use
The Special Local Need beekeeping equipment fumigation use is not a typical
fumigation/warehouse type use as these chambers are smaller and the aeration configuration is
somewhat unique. According to information provided by North Carolina, the chamber is vented
through a pipe into a bucket located approximately 40 feet from the chamber. The set up was
described as something akin to this:
Bucket filled with water
The approach taken to model bystander exposure was to assume an area source, with the bucket
as the "source," with passive aeration from the source, and assuming the mass of EtO in the
chamber all comes out during the first hour (first flushing out of the chamber after fumigation).
The area source was modeled as a circular area source, with a radius of 15 cm (0.15 m). The
emission rate was entered for hour 1 (assumed to be noon) and then zero emissions assumed for
the rest of the day. The meteorological data for Raleigh, North Carolina was used as this would be
the closest to the actual location of the fumigation.
App rates: two app rates
• 28.3 lb ai/1,000 ft3 (treatment time =16 hours)
• 46.5 lb ai/1,000 ft3 (treatment time = 8 hours)
Chamber size: 126 ft3 (3.57 m3)
The emission rate has been calculated based on the bucket being the source as follows:
Radius = 0.15 m
Area = nr2 = 0.0705 m2
Mass of EtO released:
(1) for 28.3 lb ai/1,000 ft3 rate =
28.3 — x 453.59 x 35.315 = 453.32 x 3.57 m3 x 1,000,000 — = 1,617,409,181 ug
1,000 ft3 lb m3 m3 9
(2) for 46.5 lb ai/1,000 ft3 rate =
46.5 „ 'k a' x 453 59 £. x 35.315 = 744.86 x 3.57 m3 x 1,000,000 — = 2,657,600,376 ug
1,000 ft3 lb m3 m3 g
Page 39 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review D467242
• Emission rates:
(1) for 28.3 lb ai/1,000 ft3 rate =
1,617,409,181 ug -h 0.0705 m2 -h 3600 seconds = 6,370,963
ml —s
(2) for 46.5 lb ai/1,000 ft3 rate =
2,657,600,376 ug -h 0.0705 m2 -h 3600 seconds = 10,468,269
mz — 5
Page 40 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Table 151. ( anc
Percentile
¦r Risks al Modeled liu
Statistic
M'er Dislaiu
1
es I'll ml llle Heel
>
teeming I'limigal
10
ion Chambers a
15
a rale of 2S.3 II
Distance (meters
2S
ai/l and
)
S()
in Assumpl
I ()()
ion ol'4 l!\
150
losure Day
20()
per ^ ear
)()
50
Concentration (ug/m3)
3.40L-37
5.10E-37
1.10E-36
5.30E-37
8.20E-37
5.80E-37
4.30E-37
3.80E-37
1.00E-36
4.10E-37
Lifetime Average
Concentration (LAC)
(ug/m3)
3.7E-39
5.6E-39
1.2E-38
5.8E-39
9.0E-39
6.4E-39
4.7E-39
4.2E-39
1.1E-38
4.5E-39
Cancer risk
2E-41
3E-41
6E-41
3E-41
4E-41
3E-41
2E-41
2E-41
5E-41
2E-41
75
Concentration (ug/m3)
9.60E-21
5.50E-09
3.00E-12
1.90E-13
1.30E-12
1.20E-08
1.70E-11
2.00E-13
3.00E-14
2.30E-16
LAC (ug/m3)
1.1E-22
6.0E-11
3.3E-14
2.1E-15
1.4E-14
1.3E-10
1.9E-13
2.2E-15
3.3E-16
2.5E-18
Cancer risk
5E-25
3E-13
2E-16
1E-17
7E-17
7E-13
9E-16
1E-17
2E-18
1E-20
80
Concentration (ug/m3)
2.90E-17
1.80E-03
2.30E-02
1.50E-03
1.70E-04
8.00E-05
4.90E-07
1.80E-08
7.20E-10
1.00E-10
LAC (ug/m3)
3.2E-19
2.0E-05
2.5E-04
1.6E-05
1.9E-06
8.8E-07
5.4E-09
2.0E-10
7.9E-12
1.1E-12
Cancer risk
2E-21
1E-07
1E-06
8E-08
9E-09
4E-09
3E-11
1E-12
4E-14
5E-15
85
Concentration (ug/m3)
1.10E-13
3.10E-01
3.80E+00
2.90E+00
7.60E-01
3.40E-02
1.50E-03
6.90E-05
1.80E-05
3.50E-06
LAC (ug/m3)
1.2E-15
3.4E-03
4.2E-02
3.2E-02
8.3E-03
3.7E-04
1.6E-05
7.6E-07
2.0E-07
3.8E-08
Cancer risk
6E-18
2E-05
2E-04
2E-04
4E-05
2E-06
8E-08
4E-09
1E-09
2E-10
90
Concentration (ug/m3)
7.10E-11
8.60E+00
5.90E+01
5.00E+01
2.20E+01
4.10E+00
4.80E-01
1.10E-01
3.20E-02
4.80E-03
LAC (ug/m3)
7.8E-13
9.4E-02
6.5E-01
5.5E-01
2.4E-01
4.5E-02
5.3E-03
1.2E-03
3.5E-04
5.3E-05
Cancer risk
4E-15
5E-04
3E-03
3E-03
1E-03
2E-04
3E-05
6E-06
2E-06
3E-07
Bolded values are greater than lxlO 6
Tahle 152. Cane
Percentile
t Risks al Modeled liu
Statistic
I'ler Dislaiu
1
es from 1 he Heel
>
a-eping I'limigal
10
ion Chambers a
15
a rale of 46.5 II
Distance (metei>
2S
ai/l000 ll1 and
)
so
in Assumpl
I 00
ion ol'4 l'.\
150
)osure Day
2()()
per ^ear
300
50
Concentration (ug/m3)
3.40E-37
1.00E-36
1.10E-36
9.30E-37
4.60E-37
9.20E-37
3.70E-37
4.50E-37
5.00E-37
5.80E-37
LAC (ug/m3)
3.7E-39
1.1E-38
1.2E-38
1.0E-38
5.0E-39
1.0E-38
4.1E-39
4.9E-39
5.5E-39
6.4E-39
Cancer risk
2E-41
5E-41
6E-41
5E-41
3E-41
5E-41
2E-41
2E-41
3E-41
3E-41
75
Concentration (ug/m3)
1.60E-20
9.30E-09
4.70E-12
3.20E-13
2.20E-12
1.90E-08
2.80E-11
3.50E-13
4.60E-14
3.40E-17
LAC (ug/m3)
1.8E-22
1.0E-10
5.2E-14
3.5E-15
2.4E-14
2.1E-10
3.1E-13
3.8E-15
5.0E-16
3.7E-19
Cancer risk
9E-25
5E-13
3E-16
2E-17
1E-16
1E-12
2E-15
2E-17
3E-18
2E-21
80
Concentration (ug/m3)
4.70E-17
2.90E-03
3.70E-02
2.60E-03
2.80E-04
1.30E-04
8.00E-07
3.00E-08
1.10E-09
1.70E-10
LAC (ug/m3)
5.2E-19
3.2E-05
4.1E-04
2.8E-05
3.1E-06
1.4E-06
8.8E-09
3.3E-10
1.2E-11
1.9E-12
Cancer risk
3E-21
2E-07
2E-06
1E-07
2E-08
7E-09
4E-11
2E-12
6E-14
9E-15
85
Concentration (ug/m3)
1.80E-13
5.00E-01
6.30E+00
4.70E+00
1.20E+00
5.60E-02
2.50E-03
1.10E-04
3.00E-05
5.80E-06
LAC (ug/m3)
2.0E-15
5.5E-03
6.9E-02
5.2E-02
1.3E-02
6.1E-04
2.7E-05
1.2E-06
3.3E-07
6.4E-08
Cancer risk
1E-17
3E-05
3E-04
3E-04
7E-05
3E-06
1E-07
6E-09
2E-09
3E-10
90
Concentration (ug/m3)
1.20E-10
1.40E+01
9.70E+01
8.20E+01
3.60E+01
6.80E+00
8.00E-01
1.90E-01
5.20E-02
8.00E-03
LAC (ug/m3)
1.3E-12
1.5E-01
1.1E+00
9.0E-01
3.9E-01
7.5E-02
8.8E-03
2.1E-03
5.7E-04
8.8E-05
Cancer risk
7E-15
8E-04
5E-03
4E-03
2E-03
4E-04
4E-05
1E-05
3E-06
4E-07
Bolded values are greater than the cancer target risk of lxlO 6
Page 41 of 42
-------
Ethylene Oxide (EtO). Addendum to the Draft Risk Assessment in Support of Registration Review
D467242
Tahle IJ3. Cane
Percentile
¦r Risk al Modeled Bill
Statistic
'er Dislanu
1
¦s I'll nil lilt.- IJeek
>
i-epiii» I'liinigali
10
in ('haml)ers al
15
a rale nl' 2S.3 II)
Distance (metei>
25
ai/l and a
)
50
l assumplii
1 00
n id's
150
sure l)a\s ]
200
>er ^ ear.
300
50
Concentration (ug/m3)
3.40E-37
5.10E-37
1.10E-36
5.30E-37
8.20E-37
5.80E-37
4.30E-37
3.80E-37
1.00E-36
4.10E-37
LAC (ug/m3)
7.5E-39
1.1E-38
2.4E-38
1.2E-38
1.8E-38
1.3E-38
9.4E-39
8.3E-39
2.2E-38
9.0E-39
Cancer risk
4E-41
6E-41
1E-40
6E-41
9E-41
6E-41
5E-41
4E-41
1E-40
4E-41
75
Concentration (ug/m3)
9.60E-21
5.50E-09
3.00E-12
1.90E-13
1.30E-12
1.20E-08
1.70E-11
2.00E-13
3.00E-14
2.30E-16
LAC (ug/m3)
2.1E-22
1.2E-10
6.6E-14
4.2E-15
2.8E-14
2.6E-10
3.7E-13
4.4E-15
6.6E-16
5.0E-18
Cancer risk
1E-24
6E-13
3E-16
2E-17
1E-16
1E-12
2E-15
2E-17
3E-18
3E-20
80
Concentration (ug/m3)
2.90E-17
1.80E-03
2.30E-02
1.50E-03
1.70E-04
8.00E-05
4.90E-07
1.80E-08
7.20E-10
1.00E-10
LAC (ug/m3)
6.4E-19
3.9E-05
5.0E-04
3.3E-05
3.7E-06
1.8E-06
1.1E-08
3.9E-10
1.6E-11
2.2E-12
Cancer risk
3E-21
2E-07
3E-06
2E-07
2E-08
9E-09
5E-11
2E-12
8E-14
1E-14
85
Concentration (ug/m3)
1.10E-13
3.10E-01
3.80E+00
2.90E+00
7.60E-01
3.40E-02
1.50E-03
6.90E-05
1.80E-05
3.50E-06
LAC (ug/m3)
2.4E-15
6.8E-03
8.3E-02
6.4E-02
1.7E-02
7.5E-04
3.3E-05
1.5E-06
3.9E-07
7.7E-08
Cancer risk
1E-17
3E-05
4E-04
3E-04
8E-05
4E-06
2E-07
8E-09
2E-09
4E-10
90
Concentration (ug/m3)
7.10E-11
8.60E+00
5.90E+01
5.00E+01
2.20E+01
4.10E+00
4.80E-01
1.10E-01
3.20E-02
4.80E-03
LAC (ug/m3)
1.6E-12
1.9E-01
1.3E+00
1.1E+00
4.8E-01
9.0E-02
1.1E-02
2.4E-03
7.0E-04
1.1E-04
Cancer risk
8E-15
9E-04
6E-03
5E-03
2E-03
4E-04
5E-05
1E-05
4E-06
5E-07
Bolded values are greater than lxlO 6
la hie 154. (a nc
Percentile
t Risk al Modeled Bill
Statistic
er Dislanu
1
¦s I'll!Ill Ihe lieek
i-epiii» I'liniigali
10
ill ('hanil)ers al
15
a rale of 46.5 II)
1 )istance (meters
25
ai/l000 I'l-1 and a
)
50
l assumplii
100
n iil'S l!\pi
150
sure l)a\s ]
200
)er ^ ear.
300
50
Concentration (ug/m3)
3.40E-37
1.00E-36
1.10E-36
9.30E-37
4.60E-37
9.20E-37
3.70E-37
4.50E-37
5.00E-37
5.80E-37
LAC (ug/m3)
7.5E-39
2.2E-38
2.4E-38
2.0E-38
1.0E-38
2.0E-38
8.1E-39
9.9E-39
1.1E-38
1.3E-38
Cancer risk
4E-41
1E-40
1E-40
1E-40
5E-41
1E-40
4E-41
5E-41
5E-41
6E-41
75
Concentration (ug/m3)
1.60E-20
9.30E-09
4.70E-12
3.20E-13
2.20E-12
1.90E-08
2.80E-11
3.50E-13
4.60E-14
3.40E-17
LAC (ug/m3)
3.5E-22
2.0E-10
1.0E-13
7.0E-15
4.8E-14
4.2E-10
6.1E-13
7.7E-15
1.0E-15
7.5E-19
Cancer risk
2E-24
1E-12
5E-16
4E-17
2E-16
2E-12
3E-15
4E-17
5E-18
4E-21
80
Concentration (ug/m3)
4.70E-17
2.90E-03
3.70E-02
2.60E-03
2.80E-04
1.30E-04
8.00E-07
3.00E-08
1.10E-09
1.70E-10
LAC (ug/m3)
1.0E-18
6.4E-05
8.1E-04
5.7E-05
6.1E-06
2.8E-06
1.8E-08
6.6E-10
2.4E-11
3.7E-12
Cancer risk
5E-21
3E-07
4E-06
3E-07
3E-08
1E-08
9E-11
3E-12
1E-13
2E-14
85
Concentration (ug/m3)
1.80E-13
5.00E-01
6.30E+00
4.70E+00
1.20E+00
5.60E-02
2.50E-03
1.10E-04
3.00E-05
5.80E-06
LAC (ug/m3)
3.9E-15
1.1E-02
1.4E-01
1.0E-01
2.6E-02
1.2E-03
5.5E-05
2.4E-06
6.6E-07
1.3E-07
Cancer risk
2E-17
5E-05
7E-04
5E-04
1E-04
6E-06
3E-07
1E-08
3E-09
6E-10
90
Concentration (ug/m3)
1.20E-10
1.40E+01
9.70E+01
8.20E+01
3.60E+01
6.80E+00
8.00E-01
1.90E-01
5.20E-02
8.00E-03
LAC (ug/m3)
2.6E-12
3.1E-01
2.1E+00
1.8E+00
7.9E-01
1.5E-01
1.8E-02
4.2E-03
1.1E-03
1.8E-04
Cancer risk
1E-14
2E-03
1E-02
9E-03
4E-03
7E-04
9E-05
2E-05
6E-06
9E-07
Bolded values are greater than lxlO 6
Page 42 of 42
------- |