United States Prevention, Pesticides EPA 738-R-06-029
Environmental Protection and Toxic Substances August 2006
Agency (7508P)
Reregistration
Eligibility Decision for
Propylene Oxide
-------
Reregistration Eligibility Decision (RED) Document
for Propylene Oxide
ListB
Case Number 2560
Approved by: Date: July 31,2006
Debra Edwards, Ph. D.
Director
Special Review and Reregistration Division
Page 2 of 192
-------
Table of Contents
Propylene Oxide Reregistration Eligibility Decision Team 5
Glossary of Terms and Abbreviations 6
Abstract 8
I. Introduction 9
II. Chemical Overview 10
A. Chemical Identity 10
B. Use and Usage Profile 11
C. Tolerances 11
III. Propylene Oxide Risk Assessments 12
IV. Risk Management, Reregistration Decision, and Tolerance Reassessment Decisions... 12
A. Determination of Reregistration Eligibility 12
B. Public Comments and Responses 13
C. Regulatory Position 13
1. Food Quality Protection Act Findings 13
a. "Risk Cup" Determination 13
b. Determination of Safety to U.S. Population (Including Infants and Children) .... 14
c. Endocrine Disrupter Effects 14
d. Cumulative Risks 15
2. Tolerance Summary 15
D. Regulatory Rationale 17
1. Human Health Risk Management and Mitigation 17
a. Dietary Risk Mitigation (Food and Drinking Water) 17
b. Residential Risk Mitigation 18
c. Aggregate Risk Mitigation 19
d. Occupational Risk Mitigation 20
2. Ecological Risk Management and Mitigation 21
3. Other Labeling Requirements 22
4. Threatened and Endangered Species Considerations 22
V. What Registrants Need to Do 23
A. Manufacturing-Use Products 23
1. Additional Generic Data Requirements 23
2. Labeling for Manufacturing-Use Products 24
B. End-Use Products 24
1. Additional Product-Specific Data Requirements 24
2. Labeling for End-Use Products 24
VI. Appendices 33
Appendix A. Propylene Oxide Uses and Use-Patterns Eligible for Reregistration 34
Appendix B. Table of Generic Data Requirements and Studies Used to Make the
Reregistration Decision 36
Appendix C. Technical Support Documents 41
Appendix D. Citations Considered to be Part of the Database Supporting the
Reregistration Decision (Bibliography) 44
Appendix E. Generic Data Call-In (GDCI) 49
Appendix F. Product-Specific Data Call-In (PDCI) 50
Page3 of 192
-------
Appendix G. EPA's Batching of Propylene Oxide Products for Meeting Acute Data
Requirements for Reregistration 51
Appendix H. Registrant Sent this Data Call-In Notice 52
Appendix I. List of Available Related Documents and Electronically Available Forms 53
Appendix J. Human Health Risk Assessment 57
Appendix K. Environmental Fate and Effects Risk Assessment 153
Page 4 of 192
-------
Propylene Oxide Reregistration Eligibility Decision Team
EPA Office of Pesticide Programs
Special Review and Reregistration Division
Diane Sherman
Susan Bartow
Veronica Dutch
Eric Olson
Robert McNally
Health Effects Division
Matthew Crowley
William Dykstra
Jerry Stokes
Pramod Terse
Ray Kent
Rebecca Daiss
Environmental Fate and Effects Division
Kevin Costello
Ed Odenkirchen
Nancy Andrews
Biological and Economic Analysis Division
Tara Chandgoyal
David Donaldson
Rafael Prieto
Alan Halvorson
Leonard Yourman
David Widawsky
Arnet (Skee) Jones
Antimicrobials Division
Nader Elkassabany
Registration Division
Tony Kish
Cynthia Giles-Parker
Page 5 of 192
-------
Glossary of Terms and Abbreviations
AGDCI
ai
aPAD
BCF
CFR
cPAD
CSF
CSFII
DCI
DEEM
DFR
DNT
EC
EDWC
EEC
EPA
EUP
FDA
FIFRA
FFDCA
FQPA
GLN
IR
LD5
'50
LOC
LOAEL
MATC
mg/kg/day
mg/L
MOE
MRID
MUP
NOAEL
OPP
Agricultural Data Call-In
Active Ingredient
Acute Population Adjusted Dose
Bioconcentration Factor
Code of Federal Regulations
Chronic Population Adjusted Dose
Confidential Statement of Formulation
USDA Continuing Surveys for Food Intake by Individuals
Data Call-In
Dietary Exposure Evaluation Model
Dislodgeable Foliar Residue
Developmental Neurotoxicity
Emulsifiable Concentrate Formulation
Estimated Drinking Water Concentration
Estimated Environmental Concentration
Environmental Protection Agency
End-Use Product
Food and Drug Administration
Federal Insecticide, Fungicide, and Rodenticide Act
Federal Food, Drug, and Cosmetic Act
Food Quality Protection Act
Guideline Number
Index Reservoir
Median Lethal Concentration. A statistically derived concentration of a
substance that can be expected to cause death in 50% of test animals. It is
usually expressed as the weight of a substance per weight or volume of
water, air, or feed, e.g., mg/1, mg/kg, or ppm.
Median Lethal Dose. A statistically derived single dose that can be
expected to cause death in 50% of the test animals when administered by
the route indicated (oral, dermal, inhalation). It is expressed as a weight
of substance per unit weight of animal, e.g., mg/kg.
Level of Concern
Lowest Observed Adverse Effect Level
Maximum Acceptable Toxicant Concentration
Micrograms Per Gram
Micrograms Per Liter
Milligram Per Kilogram Per Day
Milligram Per Liter
Margin of Exposure
Master Record Identification Number. EPA's system for recording and
tracking studies submitted.
Manufacturing-Use Product
No Observed Adverse Effect Level
EPA Office of Pesticide Programs
Page 6 of 192
-------
OPPTS
PAD
PCA
PDF
PHED
PHI
ppb
PPE
ppm
PRZM/EXAMS
Q*
RAC
RED
REI
RfD
RQ
SCI-GROW2
SAP
SF
SLC
TGAI
USDA
USGS
UF
UV
WPS
EPA Office of Prevention, Pesticides, and Toxic Substances
Population Adjusted Dose
Percent Crop Area
USDA Pesticide Data Program
Pesticide Handler's Exposure Data
Pre-harvest Interval
Parts Per Billion
Personal Protective Equipment
Parts Per Million
Pesticide Root Zone Mode/Exposure Analysis Modeling System, Tier II
Surface Water Computer Model
The Carcinogenic Potential of a Compound, Quantified by the EPA's
Cancer Risk Model
Raw Agriculture Commodity
Reregi strati on Eligibility Decision
Restricted-Entry Interval
Reference Dose
Risk Quotient
Tier I Ground Water Computer Model
Science Advisory Panel
Safety Factor
Single Layer Clothing
Technical Grade Active Ingredient
United States Department of Agriculture
United States Geological Survey
Uncertainty Factor
Ultraviolet
Worker Protection Standard
Page 7 of 192
-------
Abstract
This document presents the Environmental Protection Agency's (EPA or the Agency's)
decision regarding the reregi strati on eligibility of the registered uses of the active ingredient
propylene oxide (PPO). The Agency has conducted human health and environmental fate and
effects risk assessments for PPO and has made tolerance reassessment decisions for existing
tolerances. The Agency has determined that, with label amendments and changes as specified in
this document, there is a reasonable certainty that no harm will result to the general U.S.
population, infants, children, or other major identifiable subgroups of consumers, from the use of
PPO. The Agency has determined that products containing the active ingredient PPO are eligible
for reregistration provided that the risk mitigation measures outlined in this document are
adopted and label amendments are made to reflect these measures.
EPA has identified potential human health risks of concern associated with the current
registered uses of PPO from residential bystander exposure and occupational exposure. To
reduce these exposures and to address current risks of concern, EPA is requiring that all vacuum-
sealed pressurized chambers (also referred to as commercial sterilization chambers) used in PPO
fumigation be equipped with emission reduction technology, that a buffer zone of 180 feet be
maintained around fumigation facilities that are not vacuum-sealed pressurized chambers, and
that an 8-hour time weighted average concentration limit of 2 parts per million for occupational
exposure be satisfied. Additionally, EPA has determined that products containing the active
ingredient PPO meet the criteria for restricted use classification and is requiring that all labels
include language identifying end-use products as restricted use. The Agency is also requiring
appropriate data to confirm the decisions presented in this Reregi strati on Eligibility Decision.
Page 8 of 192
-------
I. Introduction
The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended in 1988
to accelerate the reregistration of products with active ingredients registered prior to November
1, 1984. The amended Act calls for the development and submission of data to support the
reregistration of an active ingredient, as well as a review of all data submitted to the
Environmental Protection Agency (hereafter referred to as EPA or the Agency). Reregistration
involves a thorough review of the scientific database underlying a pesticide's registration. The
purpose of the Agency's review is to reassess the potential hazards arising from the currently
registered uses of a pesticide, to determine the need for additional data on health and
environmental effects, and to determine whether or not the pesticide meets the "no unreasonable
adverse effects" criteria of FIFRA.
On August 3, 1996, the Food Quality Protection Act (FQPA) was signed into law. This
Act amended FIFRA and the Federal Food, Drug, and Cosmetic Act (FFDCA) to require
reassessment of all existing tolerances for pesticides in food by August 3, 2006. EPA decided
that, for those chemicals that have tolerances and are undergoing reregistration, tolerance
reassessment would be accomplished through the reregistration process. Under FQPA, in
reassessing these tolerances, the Agency must consider, among other things, aggregate risks from
non-occupational sources of pesticide exposure, whether there is increased susceptibility among
infants and children, and the cumulative effects of pesticides that have a common mechanism of
toxicity. When the Agency determines that aggregate risks are not of concern and concludes that
there is a reasonable certainty of no harm from aggregate exposure, the tolerances are considered
reassessed.
Risks summarized in this document are for propylene oxide (PPO) only. FQPA requires
EPA to consider available information concerning the cumulative effects of a particular
pesticide's residues and "other substances that have a common mechanism of toxicity" when
considering whether to establish, modify, or revoke a tolerance. Unlike other pesticides for
which EPA has followed a cumulative risk approach based on a common mechanism of toxicity,
EPA has not made a common mechanism of toxicity finding as to PPO, and PPO does not appear
to produce a toxic metabolite produced by other substances. Therefore, for the purposes of this
reregistration decision, EPA has not assumed that PPO shares a common mechanism of toxicity
with other compounds. For information regarding EPA's efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals,
see the policy statements released by EPA's Office of Pesticide Programs (OPP) concerning
common mechanism determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA's website at http://epa.gov/pesticides/cumulative/.
This document presents EPA's revised human health and environmental fate and effects
risk assessments (see Appendices J and K), its progress toward tolerance reassessment, and the
reregistration eligibility decision for PPO. The document consists of six sections. Section I
contains the regulatory framework for reregistration and tolerance reassessment. Section II
provides a description of the chemical and a profile of the use and usage of the chemical.
Section III references the revised human health and environmental fate and effects risk
assessments attached as Appendices to this document. Section IV presents the Agency's risk
Page 9 of 192
-------
management, reregi strati on eligibility, and tolerance reassessment decisions. Section V
summarizes the data requirements necessary to confirm the reregi strati on eligibility decision as
well as specific label changes and language necessary to implement the risk mitigation measures
outlined in Section IV. Section VI, the Appendices, provides related information and supporting
documents. The preliminary and revised risk assessments for PPO are available in the public
docket EPA-HQ-OPP-2005-0253 located on-line in the Federal Docket Management System
(FDMS) at http://www.regulations.gov.
II. Chemical Overview
A. Chemical Identity
Chemical Structure: O
ChL
Empirical Formula:
Common Name:
CAS Name:
CAS Registry Number:
OPP Chemical Code:
Case Number:
Reaction Products:
C3H60
Propylene oxide
Propylene oxide; 1,2-epoxypropane
75-76-9
042501
2560
Technical Registrant: Aberco, Inc.
Propylene chlorohydrin (CsHyCIO) and Propylene bromohydrin
(C3H7BrO)
PPO is a colorless liquid that is highly volatile and flammable at room temperature and
normal atmospheric pressure. There are two reaction products formed during the PPO
sterilization process - propylene chlorohydrin (PCH) and propylene bromohydrin (PBH). In
addition to PPO, PCH is considered to be a residue of concern for dietary risk assessment and
tolerance reassessment purposes because residues persist at high levels and are likely to be
present in treated commodities at the time of consumption. PBH residues are minimal relative to
PCH residues; therefore, PBH is not considered to be a residue of concern.
PPO has been used to treat food products since 1958. PPO was classified as List B
through the FIFRA amendments of 1988. A FIFRA '88 Data Call-In (DCI) was issued for PPO
in October 1989. Subsequent DCIs were issued in 1990, 1991, and 1993.
Page 10 of 192
-------
B. Use and Usage Profile
The following is information on the currently registered uses of PPO. Sections IV and V
include information on those currently registered uses which are not eligible for reregi strati on
and Appendix A provides a detailed table of those uses which are eligible for reregi strati on.
Type of Pesticide:
Formulations:
PPO is an insecticidal fumigant and sterilant used both to control
bacteria contamination, mold contamination, insect infestations, and
microbial spoilage of food products as well as to control insects in
nonfood products.
PPO is formulated as a pressurized liquid and/or gas.
Methods of Application: End-use products containing PPO can be applied indoors or outdoors
as a gas in vacuum-sealed pressurized chambers (also referred to as
commercial sterilization chambers). PPO can also be applied
outdoors as a gas in other types of chambers and in/under loose-fitting
structures such as trailers, rail cars, tents or tarps where gas is
confined and entry is restricted during fumigation.
Use Sites:
Application Rates:
Estimated Usage:
C. Tolerances
PPO is registered for use on several food items such as dried herbs
and spices, dried onions, dried garlic, cacao beans, cocoa powder and
in-shell and processed nutmeats (except peanuts). There are proposed
new uses on figs, prunes, and raisins. PPO also has nonfood uses for
cosmetic articles, gums, ores, packaging, pigments, pharmaceutical
materials, and discarded nutshells prior to disposal. There is an
additional proposed new nonfood use on books.
The maximum application rate (in vapor form) is 2.4 ounces (oz)
active ingredient (ai) per ft3 in vacuum-sealed pressurized chambers
(also referred to as commercial sterilization chambers).
The maximum application rate (in vapor form) is 0.0448 oz ai/ft3 in
other types of chambers and in/under loose-fitting structures such as
trailers, rail cars, tents or tarps that are used in outdoor commodity
fumigation.
Approximately 64.8 million pounds of commodities are treated with
PPO annually. PPO is used mostly on nutmeats (approximately 1.8%
crop treated) and spices (approximately 1% crop treated).
Currently there are four tolerances listed in 40 CFR 180.491 for PPO on raw agricultural
commodities. Tolerances for PPO residues are expressed in terms of the parent compound
(PPO) only. Tolerances for PPO currently exist for spices (processed), nutmeat (processed,
Page 11 of 192
-------
except peanuts), gum (edible), and cocoa bean (bean). Section IV includes a summary of the
tolerance reassessment decision for PPO and lists those tolerances the Agency will propose to
revoke, decrease, increase, maintain, reassign, and establish.
III. Propylene Oxide Risk Assessments
Please refer to Appendices J and K for the human health and environmental fate and
effects risk assessments for PPO, dated July 31, 2006 and May 16, 2006, respectively, for details
on the risks associated with the use of PPO. These documents are also available in the public
docket EPA-HQ-OPP-2005-0253 located on-line at http://www.regulations.gov.
IV. Risk Management, Reregistration, and Tolerance Reassessment Decisions
A. Determination of Reregistration Eligibility
Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after submission of
relevant data concerning an active ingredient, whether or not products containing the active
ingredient are eligible for reregi strati on. The Agency has previously identified and required the
submission of the generic (technical grade) data required to support reregi strati on of products
containing PPO as an active ingredient. The Agency has completed its review of these generic
data, and has determined that the data are sufficient to support reregi strati on of all products
containing PPO provided the registrations are amended in a manner consistent with this
document.
The Agency has completed its review of submitted data and its assessment of the dietary
(both food and drinking water), residential, occupational, and ecological risks associated with the
use of pesticide products containing the active ingredient PPO. Based on these data and public
comments received on the Agency's assessments for the active ingredient PPO, the Agency has
sufficient information on the human health and ecological effects of PPO to make decisions as
part of the tolerance reassessment process under FFDCA and reregi strati on process under
FIFRA, as amended by FQPA. The Agency has determined that products containing the active
ingredient PPO are eligible for reregi strati on provided that the risk mitigation measures outlined
in this document are adopted and label amendments are made to reflect these measures. Specific
label changes and language are presented in Section V. Appendix A provides a detailed table of
those uses eligible for reregi strati on. Appendix B identifies generic data requirements that the
Agency reviewed as part of its determination of reregi strati on eligibility of PPO, and lists the
submitted studies the Agency found acceptable. Data gaps are identified as either outstanding
generic data requirements that have not been satisfied with acceptable data or additional data
requirements necessary to confirm the decision presented here.
Based on its evaluation of PPO, the Agency has determined that products containing the
active ingredient PPO, unless labeled and used as specified in this document, would present risks
inconsistent with FIFRA and FFDCA. Accordingly, should a registrant fail to implement any of
the risk mitigation measures identified in this document, the Agency may take appropriate
Page 12 of 192
-------
regulatory action to address the risk concerns from the use of PPO. If all changes outlined in this
document are incorporated into the product labels, then all current risks for PPO will be
adequately addressed for the purposes of this determination under FIFRA. Once a
comprehensive endangered species assessment is completed, further changes to these
registrations may be necessary as explained in Section IV.D.4 of this document below.
B. Public Comments and Responses
Through the Agency's public participation process, EPA worked with stakeholders and
the public to reach these regulatory decisions for PPO. During the public comment period on the
risk assessments, which closed on January 9, 2006, the Agency received comments from Aberco,
Inc. (the technical registrant), the American Chemistry Council, a number of nut growers
(Navarro Pecan Company, Carriere Family Farms, Frazier Nut Farms, Green Valley Pecan
Company, Blue Diamond Growers, Sun Valley Pecan Company), the Almond Board of
California, and the California Walnut Commission. These comments expressed disagreement
with the Agency's use and interpretation of a number of carcinogenicity studies, contended that
PPO is a threshold carcinogen via the inhalation route with an identifiable threshold or dose
below which the risk of developing cancer is negligible, refuted the Agency's preliminary list of
data requirements, described the process of nutmeat fumigation and supplied usage statistics for
nutmeats, supplied residue data for nutmeats, supplied worker exposure data for the fumigation
of nutmeats, indicated why PPO is important to the nut industry, and suggested potential
mitigation measures.
These comments were reviewed and taken into consideration when the revised risk
assessments and their supporting documents, in addition to this PPO RED, were completed. The
comments are available in their entirety in the public docket EPA-HQ-OPP-2005-0253 located
on-line at http://www.regulations.gov. The Agency's responses to substantive comments are
available in memoranda in the public docket and the revised assessments available in the public
docket reflect these responses.
C. Regulatory Position
1. Food Quality Protection Act Findings
a. "Risk Cup" Determination
As part of the FQPA tolerance reassessment process, EPA assessed the risks associated
with PPO. The Agency has concluded that, with the risk mitigation measures outlined in this
document, the aggregate risk from food, drinking water, and residential exposures to PPO is
within its own "risk cup." The Agency has determined that the human health risks from these
combined exposures are within acceptable levels and that the established tolerances for PPO,
with label amendments and changes as specified in this document, meet the safety standards
under the FQPA amendments to Section 408(b)(2)(C) and 408(b)(2)(D) of the FFDCA. In
reaching these determinations, EPA has considered the available information on the special
sensitivity of infants and children.
Page 13 of 192
-------
b. Determination of Safety to U.S. Population (Including Infants and
Children)
The Agency has determined that there is a reasonable certainty that no harm will result to
the general U.S. population, infants, children, or other major identifiable subgroups of
consumers, from the use of PPO. The safety determination considers factors such as the toxicity,
use practices and exposure scenarios, and environmental behavior of PPO. In determining
whether or not infants and children are particularly susceptible to toxic effects from PPO
residues, the Agency considered the completeness of the hazard database for developmental and
reproductive effects, the nature of the effects observed, and other information.
The Agency determined it was necessary to retain a 10X FQPA database uncertainty
factor for PPO and PCH (its reaction product) in the dietary human health risk assessment
because of the lack of acceptable developmental toxicity studies for PPO and PCH. This lack of
acceptable studies limits the ability to assess the fetal susceptibility effects under FQPA.
However, there are no residual uncertainties for pre- and/or post-natal toxicity if the 10X
database uncertainty factor is retained. The endpoints and corresponding doses selected for
regulatory purposes are considered protective for infants and children and the human health risk
assessment does not underestimate the potential risks for infants and children.
c. Endocrine Disrupter Effects
EPA is required under the FFDCA, as amended by FQPA, to develop a screening
program to determine whether certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect produced by a naturally
occurring estrogen, or other endocrine effects as the Administrator may designate." Following
recommendations of its Endocrine Disrupter Screening and Testing Advisory Committee
(EDSTAC), EPA determined that there was a scientific basis for including, as part of the
program, the androgen and thyroid hormone systems, in addition to the estrogen hormone
system. EPA also adopted EDSTAC's recommendation that EPA include evaluations of
potential effects in wildlife. For pesticides, EPA will use FIFRA and, to the extent that effects in
wildlife may help determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations. As the science develops and resources allow,
screening for additional hormone systems may be added to the Endocrine Disrupter Screening
Program (EDSP).
In the available subchronic and reproduction toxicity studies on PCH (a reaction product
of PPO), there was an observed increase in the percentage of abnormal sperm. This effect was
observed in the same study from which the endpoint and corresponding dose ("lowest observed
adverse effect level" or LOAEL) were selected for regulatory purposes for PCH. The human
health risk assessment is therefore protective of this observed potential endocrine effect. When
the appropriate screening and/or testing protocols being considered under the EDSP have been
developed, PPO may be subject to additional screening and/or testing to better characterize
effects related to endocrine disruption.
Page 14 of 192
-------
d. Cumulative Risks
FQPA stipulates that when determining the safety of a pesticide chemical EPA shall base
its assessment of the risk posed by the chemical on, among other things, available information
concerning the cumulative effects to human health that may result from dietary (both food and
drinking water), residential, or other non-occupational exposure to other substances that have a
common mechanism of toxicity. The reason for consideration of other substances is due to the
possibility that low-level exposures to multiple chemical substances that cause a common toxic
effect by a common mechanism could lead to the same adverse health effect as would a higher
level of exposure to any of the other substances individually. A person exposed to a pesticide at
a level that is considered safe may in fact experience harm if that person is also exposed to other
substances that cause a common toxic effect by a mechanism common with that of the subject
pesticide, even if the individual exposure levels to the other substances are also considered safe.
Unlike other pesticides for which EPA has followed a cumulative risk approach based on
a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding
as to PPO, and PPO does not appear to produce a toxic metabolite produced by other substances.
Therefore, for the purposes of this reregi strati on decision, EPA has not assumed that PPO shares
a common mechanism of toxicity with other compounds. For information regarding EPA's
efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released by OPP concerning
common mechanism determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA's website at http://epa.gov/pesticides/cumulative/.
2. Tolerance Summary
The tolerance summary and tolerance reassessment decision is presented for PPO in
Table 1 below. Currently there are four tolerances listed in 40 CFR 180.491 for residues of PPO
on raw agricultural commodities.
Available residue data support maintaining the existing tolerance for spices (processed),
although the tolerance needs to be clearly defined as herbs and spices (group 19, dried). This
tolerance covers only those commodities in crop group 19 as listed in 40 CRF 180.41(b)(19).
Available residue data for cacao bean (cocoa powder) support establishing a tolerance for PPO
for this commodity and lowering the existing tolerance for cacao bean (bean). Although newly
submitted preliminary residue data from industry representatives show that PPO residues are
lower on nutmeat (processed, except peanuts) than the existing tolerance when typical
application rates are considered, the existing and reassessed tolerance reflects the labeled
maximum application rate allowable for these commodities. Therefore, no change to the current
tolerance is required for nutmeat (processed, except peanuts).
The Agency will propose establishing tolerances for PPO for grape (raisin), fig, and plum
(prune, dried), which are all proposed new uses for PPO for which the Agency has received a
tolerance petition, based on the available residue data. Available residue data also support
establishing tolerances for PPO for the dehydrated vegetables onion (dried), and garlic (dried).
Although the technical registrant considers these commodities to be spices under the existing
Page 15 of 192
-------
tolerance for spices (processed), EPA defines these two commodities in a separate crop group
(crop group 3) so separate tolerances must be established in order to support PPO use on these
commodities. Additional corrections need to be made to some of the existing commodity
definitions as indicated below in Table 1.
Additionally, the Agency will propose to revoke the existing tolerance for gum (edible)
based on the registrant's request for termination of PPO use on all edible gums pursuant to
FIFRA Section 6(f)(l)(A), as announced in a Federal Register Notice published on May 24,
2005, 71 F^ 29957.
Since the Agency has determined that residues of concern in/on raw agricultural
commodities are not only PPO but also its reaction product, PCH, the Agency will propose that
tolerances for PCH also be established for the following raw agricultural commodities: cacao
bean (dried bean), cacao bean (cocoa powder), nut (tree, group 14), herbs and spices, (group 19,
dried, except basil), onion (dried), garlic (dried), grape (raisin), fig, and plum (prune, dried). The
Agency will propose establishing a separate tolerance for PCH for basil (dried) as available
residue data supports establishing a tolerance for basil at a higher level than for other
commodities in crop group 19. The proposed tolerance levels listed below in Table 1 for these
raw agricultural commodities are based on available residue data.
Additionally, in 40 CFR 180.49l(a)(2), (a)(4), and (a)(5) application directions for PPO
are listed, including time and temperature conditions. The Agency will propose that Sections
(a)(2), (a)(4), and (a)(5) be removed so that treatment parameters are not defined in the tolerance
expression. Additionally, the Agency will propose that Sections (a)(3) and (a)(l) be combined
into one Section (a)(l) and revised as indicated in Appendix 8 of the human health risk
assessment (Appendix J). The Agency will propose that a new Section (a)(2) be added as
indicated in the human health risk assessment and that it include tolerances for PCH. Where
labeling revisions are warranted for treatment parameters, label changes and language are
specified in Section V.
In terms of confirmatory data requirements, analytical reference standards for PPO and
PCH need to be supplied to the EPA National Pesticide Standards Repository, as indicated below
in Table 2.
CODEX maximum residue limits (MRLs) and Canadian MRLs do not exist for PPO or
PCH.
Table 1. Tolerance reassessment summary for PPO
Cocoa bean, bean
Gum, edible
Nutmeat, processed,
except peanuts
Spices, processed
300
300
300
300
200
Revoke
300
300
Available residue data supports lowering tolerance.
[Cacao bean, dried bean}
Registrant has requested termination of use.
[Nut, tree, group 14}
[Herbs and spices, group 19, dried}
Page 16 of 192
-------
Existing Commodity
Existing
Tolerance (ppm)
Tolerance
Reassessment
Decision (ppm)
Comments
[Correct Commodity Definition]
Cacao bean, cocoa
powder
Onion, dried
Garlic, dried
Grape, raisin
Fig
Plum, prune, dried
None
None
None
None
None
None
200
300
300
1
o
J
2
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Proposed new use.
Proposed new use.
Proposed new use.
Cacao bean, dried bean
Cacao bean, cocoa
powder
Nut, tree, group 14
Herbs and spices, group
19, dried, except basil
Basil, dried
Onion, dried
Garlic, dried
Grape, raisin
Fig
Plum, prune, dried
None
None
None
None
None
None
None
None
None
None
20
20
10
1500
6000
6000
6000
4
o
J
2
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Available residue data supports establishing a separate
tolerance.
Available residue data supports establishing a tolerance.
Available residue data supports establishing a tolerance.
Proposed new use.
Proposed new use.
Proposed new use.
D. Regulatory Rationale
The Agency has determined that products containing the active ingredient PPO are
eligible for reregi strati on provided that the risk mitigation measures outlined in this document
are adopted and label amendments are made to reflect these measures. The following is a
summary of the risk mitigation measures and EPA's rationale for the decision for managing risks
associated with the use of PPO. Where labeling revisions are warranted, label changes and
language are specified in Section V.
1. Human Health Risk Management and Mitigation
a. Dietary Risk Mitigation (Food and Drinking Water)
As discussed in Section 6.2 of the human health risk assessment (Appendix J), there are
no risk estimates that exceed EPA's level of concern from dietary exposure (from both food and
drinking water) to PPO or PCH. Therefore, no dietary risk mitigation is necessary. Although
there are no risks of concern at the current labeled maximum application rate for PPO, Aberco,
Inc., the technical registrant, proposed lowering the maximum application rate from 2.4 to 2.0 oz
ai/ft3 for tree nuts, herbs, spices, dried onion, dried garlic, cacao beans, and cocoa powder. This
rate reduction will further reduce potential dietary exposure. Label changes and language
necessary to incorporate this rate reduction are specified in Table 3 in Section V.
Page 17 of 192
-------
b. Residential Risk Mitigation
As discussed in Section 7 of the human health risk assessment (Appendix J), there are no
residential uses for PPO but there is the potential for residential bystander exposure through the
inhalation route to emissions from nearby PPO fumigation facilities. In the case of PPO,
residential bystanders are considered to be any person in the vicinity of a fumigation facility
unless he or she is a worker supervising or performing fumigation activities. This includes other
workers, nearby residents, and other bystanders. Residential risks were assessed separately for
exposure to emissions resulting from three methods of fumigation: fumigation with vacuum-
sealed pressurized chambers (also referred to as commercial sterilization chambers) equipped
with emission reduction technology, fumigation with vacuum-sealed pressurized chambers not
equipped with emission reduction technology, and all other commodity fumigation (which
occurs outdoors in chambers and in/under loose-fitting structures such as trailers, rail cars, tents,
or tarps). Maximum application rates vary depending on the type of fumigation facility. The
end-use product labeled for use only in vacuum-sealed pressurized chambers has a maximum
application rate of 2.4 oz ai/ft3 while the end-use product labeled to provide for use in facilities
that are not vacuum-sealed pressurized chambers has a maximum application rate of 0.0448 oz
ai/ft3.
For vacuum-sealed pressurized chambers equipped with emission reduction technology
that achieves a 99% reduction in PPO emissions, potential non-cancer (acute and chronic) risks,
as well as cancer risks, for residential bystanders are not of concern. Therefore, no residential
risk mitigation is needed for vacuum-sealed pressurized chambers equipped with emission
reduction technology.
For fumigation in vacuum-sealed pressurized chambers not equipped with emission
reduction technology, there are potential acute risks of concern to residential bystanders at the
higher rate used in these chambers. The Probabilistic Exposure and Risk Model for FUMigants,
or PERFUM, (V2.1.2) was used to determine distances from these facilities where residential
bystanders would not be exposed to concentrations of PPO that exceed the acute level of concern
during fumigation treatment and aeration. PERFUM is available at
http://www.sciences.com/perfum/index.html and will eventually be placed on the Agency's
website at http://www.epa.gov/opphed01/models/fumigant/. The PERFUM modeling framework
was subjected to a Scientific Advisory Panel (SAP) review in 2004. Please refer to the SAP
background documents and the SAP report at http://www.epa.gov/scipoly/sap/2004/index.htm.
Characterization of the Agency's use of PERFUM in estimating acute bystander exposure to
PPO is included in Section 7.2 of the human health risk assessment (Appendix J).
The distances identified by PERFUM for vacuum-sealed pressurized chambers not
equipped with emissions technology range up to 1440 meters (or 4724 feet), as indicated in
Section 7.2 of the human health risk assessment (Appendix J). EPA understands that the vast
majority of these facilities currently use emission reduction technology, often to comply with air
pollution standards. Therefore, to reduce residential bystander exposure to PPO and address
acute risks of concern associated with fumigations in vacuum-sealed pressurized chambers, the
Agency is requiring that all of these facilities utilize emission reduction technology, such as
scrubbers and acid bubblers, that achieve a performance standard of 99% emission reduction.
Page 18 of 192
-------
EPA has concluded that use of emission reduction technology is protective, practical, and
feasible. As noted above, all risks for residential bystanders are below EPA's level of concern
for vacuum-sealed pressurized chambers equipped with such emission reduction technology.
Therefore, potential risks resulting from exposure from the use of PPO in vacuum-sealed
pressurized chambers will be addressed with addition of this technology requirement. Please
refer to Table 3 in Section V for the specific label changes and language needed.
For all other commodity fumigation (i.e., those with a much lower maximum application
rate), potential acute risks of concern were also identified for residential bystanders. Longer
durations of exposure to bystanders are not expected because these methods of fumigation occur
infrequently and intermittently in non-permanent sources (e.g., temporary or mobile structures
such as rail cars, tents, and tarps as indicated above). Risks were assessed for residential
bystanders during fumigation treatment and aeration at various distances from the fumigation
facility using PERFUM, although the distances needed to mitigate risks of concern were much
smaller than for vacuum-sealed pressurized chambers using the higher application rate. To
reduce residential bystander exposure to PPO and address acute risks of concern associated with
fumigations in facilities other than vacuum-sealed pressurized chambers equipped with emission
reduction technology, EPA is requiring facilities that are not vacuum-sealed pressurized
chambers to maintain a buffer zone of 55 meters (or 180 feet), within which bystanders must be
excluded during fumigation treatment and aeration. This buffer zone must be established and
maintained until PPO concentrations being exhausted from the treated enclosure are less than 10
ppm (although aeration may continue after this concentration threshold is met).
The buffer zone of 180 feet is based on the application rate and size of the fumigation
facility and was calculated for a 5000 ft3 facility to which a maximum of 0.0448 oz ai/ft3 is
applied. Language on the product label that provides for use in facilities that are not vacuum-
sealed pressurized chambers restricts use to small-scale structures, as described above. A higher
application rate or larger fumigation facility would result in a larger buffer zone being necessary
to ensure that risks to residential bystanders are not of concern. Therefore, EPA is requiring that
labels for products that can be used in facilities other than vacuum-sealed pressurized chambers
equipped with emission reduction technology, clearly limit fumigation to a maximum application
rate of 0.0448 oz ai/ft3 in a facility that is at maximum 5000 ft3. The Agency believes that these
restrictions are reasonable and sufficient to allow for all existing and proposed new uses. Please
refer to Table 3 in Section V for the specific label changes and language needed.
c. Aggregate Risk Mitigation
As discussed in Section 8 of the human health risk assessment (Appendix J), a
quantitative aggregate risk assessment was not completed for PPO because the endpoints and
corresponding doses or concentrations selected for dietary and residential (in this case,
residential bystander) exposures are not based on a common effect. As such, mitigation for
specific routes and pathways of exposure will be protective of aggregate risks, including cancer
risks, and no additional risk mitigation is necessary based on aggregate exposure.
Page 19 of 192
-------
d. Occupational Risk Mitigation
As discussed in Section 10 of the human health risk assessment (Appendix J) there are
potential cancer and non-cancer chronic risks of concern to workers, including workers who are
supervising or performing fumigation activities and other on-site personnel who are not involved
in fumigation activities (such as fork-lift drivers), from the use of PPO in vacuum-sealed
pressurized chambers and all other commodity fumigation.
There are no occupational risks of concern from the dermal route of exposure to PPO if
the following personal protective equipment (PPE) is worn, which the Agency has determined
adequately reduces the potential for dermal exposure: chemical-resistant gloves, chemical-
resistant apron, chemical-resistant footwear, face-sealing (vapor-proof) goggles, and a full-face
shield (unless a respirator that covers the entire face is worn). EPA has determined that this PPE
must be worn when there is the potential for contact with liquid PPO due to PPO's classification
as a severe eye and skin irritant. Please refer to Table 3 in Section V for the specific label
language needed.
Potential risks of concern do exist, however, from the inhalation route of exposure to
PPO at the current labeled exposure concentration limit of 20 parts per million (ppm). As
discussed in Section 10 of the human health risk assessment (Appendix J), at an exposure
concentration greater than 2 ppm as an 8-hour time weighted average (TWA), potential non-
cancer risks to workers exceed EPA's level of concern. To reduce occupational exposure to PPO
and address risks of concern for workers, the daily or 8-hour TWA concentration must be limited
to 2 ppm and specified as an 8-hour TWA on PPO labels. Additionally, the Agency is requiring
that respiratory protection, as described below, must be worn when concentrations of PPO are
measured at or above 20 ppm as a direct-read sample in any area a worker may be in.
The Agency has concluded that mitigation for non-cancer risks of concern at an 8-hour
TWA concentration of 2 ppm, which is the recommended worker exposure concentration by the
American Conference of Governmental Industrial Hygienists, is protective of all potential
exposure durations (including acute, short-term, intermediate-term, and chronic). Additionally,
data supporting a threshold carcinogenic mode of action (MO A) for PPO have been provided to
EPA. Initial analysis by the Agency indicates that the proposed MOA is highly plausible.
Therefore, EPA has also concluded that potential cancer risks to workers from inhalation
exposure to PPO should be regulated at this same concentration limit because the non-cancer
chronic endpoint is based on nasal lesions that are considered precursors to the development of
tumors. The Agency has concluded that potential cancer risks will not exceed EPA's level of
concern using the 8-hour TWA concentration limit of 2 ppm.
To ensure that occupational exposure to PPO is below 2 ppm as an 8-hour TWA
concentration, the responsible party supervising the fumigation must determine when appropriate
respiratory PPE, aeration/ventilation, and other mitigation techniques (such as changing work
schedules or fumigation processes) are necessary. Responsible parties supervising fumigations
may use a variety of air monitoring devices to determine when mitigation is needed. These
devices include direct-read instrumentation, passive air monitoring (i.e., badges with activated
carbon adsorbent), and active air monitoring (i.e., calibrated air collection pumps with standard
Page 20 of 192
-------
charcoal filter tubing). Workers who are supervising or performing fumigation activities are the
only workers who may be within the buffer zone described above for bystanders, provided their
exposure to PPO does not exceed an 8-hour TWA of 2 ppm.
If the responsible party determines that respiratory PPE is needed to ensure that PPO
concentrations are not greater than 2 ppm as a TWA for an individual worker, or, concentrations
of PPO are measured at or above 20 ppm as a direct-read sample in any area a worker may be in,
either a supplied air (SA) respirator or self-contained breathing apparatus (SCBA) must be worn.
The Agency has determined that the use of air purifying respirators (APRs) for protection against
PPO exposure is not permissible at this time due to several factors. The National Institute for
Occupational Safety and Health (NIOSH) has not given certification to any cartridge used with
APRs that is specifically for protection against PPO, and NIOSH does not recommend use of
APRs for PPO. In addition, no manufacturer has identified a cartridge for use as protection
against PPO in APRs. If, in the future, a cartridge is certified for protection against PPO, the
Agency may approve use of APRs with the certified cartridge for protection against PPO. Please
refer to Table 3 in Section V for the specific label changes and language needed.
EPA has determined that for PPO a performance standard approach is appropriate for
protecting workers because strict label requirements would not consider site-specific
circumstances. By specifying a performance standard on product labels, the Agency is providing
responsible parties supervising fumigations with the flexibility to identify the best mitigation
practices for each fumigation facility and to adjust the periods during which appropriate
respiratory PPE, aeration/ventilation, and/or other mitigation techniques are necessary for that
facility. By monitoring to determine whether and when respiratory PPE is needed to meet the
performance standard, responsible parties supervising fumigations can ensure workers are
protected without burdening them with unnecessary protective equipment.
2. Ecological Risk Management and Mitigation
As discussed in the environmental fate and effects risk assessment (Appendix K),
ecological risks (direct adverse acute and chronic effects) to non-target aquatic and terrestrial
organisms are not of concern from the use of PPO in indoor vacuum-sealed pressurized
chambers. For all outdoor commodity fumigation with PPO, ecological risks (direct adverse
acute and chronic effects) to non-target aquatic and terrestrial organisms are also not of concern.
Quantitative determinations regarding the potential for acute risks of concern, or direct adverse
acute effects, to non-target aquatic plants from PPO dissolved in surface water, and to non-target
terrestrial plants from contact with PPO in its vapor form, cannot be made due to the lack of
available effects data with which to define suitable toxicity endpoints. However, EPA has
concluded that none of the uses or use patterns of PPO are expected to result in significant
exposure in surface water and that the short durations for which plants can be exposed to PPO in
its vapor form may be insufficient to cause demonstrable adverse effects. The Agency intends to
require confirmatory acute toxicity data for these taxa, and the specific data requirement is listed
below in Table 2 in Section V.
Page 21 of 192
-------
3. Other Labeling Requirements
In order to be eligible for reregi strati on, additional PPO use and user safety information
also needs to be included in the labeling of all end-use products containing PPO. Uses and use
patterns need to be clarified as indicated in Table 3 below to reflect and better describe actual use
patterns for PPO. EPA has determined that products containing the active ingredient PPO meet
the criteria for restricted use classification due to PPO's toxicity (see 40 CFR 152.170). Further,
individuals handling and applying such products need specialized training and equipment and
must perform complex operations or procedures to ensure safe use. As such, all labels must
include language identifying end-use products as restricted use. For the specific label statements
and a list of additional data requirements necessary to confirm this decision, refer to Section V of
this RED document.
4. Threatened and Endangered Species Considerations
The Agency's screening level risk assessment for endangered and threatened species
concluded that use of PPO has no direct adverse effects on listed species in the following
taxonomic groups: terrestrial invertebrates, birds, terrestrial phase amphibians, reptiles,
mammals, freshwater fish, aquatic phase amphibians, freshwater crustaceans, marine/estuarine
fish, and marine/estuarine invertebrates. The Agency's level of concern for direct adverse
effects was exceeded, however, for listed species in the following taxonomic groups: monocot
terrestrial and semi-aquatic plants, dicot terrestrial and semi-aquatic plants, aquatic vascular
plants, and mollusks. There is also the potential for indirect adverse effects for listed species in
multiple taxonomic groups that are dependent upon species that do experience direct adverse
effects. These findings are based solely on EPA's screening level assessment and do not
constitute "may affect" findings under the Endangered Species Act.
The Agency has developed the Endangered Species Protection Program to identify
pesticides whose use may cause adverse impacts on threatened and endangered species and to
implement mitigation measures that address these impacts. The Endangered Species Act
requires federal agencies to ensure that their actions are not likely to jeopardize listed species or
adversely modify designated critical habitat. To analyze the potential of registered pesticide uses
that may affect any particular species, EPA uses basic toxicity and exposure data developed for
REDs and considers it in relation to individual species by evaluating important ecological
parameters, pesticide use information, the geographic relationship between specific pesticide
uses and species locations, and biological requirements and behavioral aspects of the particular
species. When conducted, this species-specific analysis will take into consideration any risk
mitigation measures that are being implemented at the time as a result of this RED.
Following this future species-specific analysis, a determination that there is a likelihood
of potential effects to a listed species or its critical habitat may result in limitations on use of
PPO, other measures to mitigate any potential effects, or consultations with the Fish and Wildlife
Service and/or the National Marine Fisheries as appropriate. If the Agency determines use of
PPO "may affect" listed species or their designated critical habitat, EPA will employ the
provisions in the Services regulations (50 CFR Part 402). Until a species-specific analysis is
completed, the risk mitigation measures being implemented through this RED (e.g., the
Page 22 of 192
-------
requirement for use of 99% emission reduction technology for vacuum-sealed pressurized
chambers) will reduce the likelihood that endangered and threatened species may be exposed to
PPO at levels of concern. EPA is not requiring specific PPO label language at the present time
relative to threatened and endangered species. If, in the future, specific measures are necessary
for the protection of listed species, the Agency will implement them through the Endangered
Species Protection Program.
V. What Registrants Need to Do
The Agency has determined that products containing the active ingredient PPO are
eligible for reregi strati on provided that the risk mitigation measures outlined in this document
are adopted and label amendments are made to reflect these measures. The Agency intends to
issue DCIs for generic (technical grade) data and product-specific data. Generally, registrants
will have 90 days from receipt of a generic DCI to complete and submit response forms or
request time extension and/or waiver requests with a full written justification. The DCIs will
include specific requirements and instructions on how to do so. Table 2 below presents the
additional generic data the Agency intends to require for PPO to confirm the decision that
products containing the active ingredient PPO are eligible for reregi strati on. For product-
specific DCIs, registrants will have eight months from receipt of the DCI to submit data and to
submit amended labels. In order for products containing the active ingredient PPO to be eligible
for reregi strati on, all product labels must be amended to incorporate the specific changes and
language presented in Table 3 below. Table 3 also describes how the required language should
be incorporated.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic database supporting the reregi strati on of PPO has been reviewed and
determined to be substantially complete. However, EPA is requiring the following additional
data to confirm the decisions presented in this RED. The Agency intends to issue a generic DCI
for this data.
Table 2. Data requirements for the reregi strati on of PPO
Submittal of Analytical Reference Standards
Analytical references standards for PPO and PCH are not currently
available in the EPA National Pesticide Standards Repository. Analytical
reference standards of PPO and PCH must be supplied and supplies
replenished as requested by the Repository.
Chronic Toxicitv (nonrodent) (in reserve)
Pending results of further review of the proposed cancer threshold or
MOA for PPO.
Modified Aquatic Plant Toxicitv Studv
Modified Terrestrial Plant Toxicitv Studv
860.1650
870.4 lOOb
Special Study
Special Study
171-13
83-1
N/A
N/A
Page 23 of 192
-------
2. Labeling for Manufacturing-Use Products
To ensure compliance with FIFRA, labeling for all manufacturing-use products (MUPs)
should be revised to comply with all current EPA regulations, PR Notices, and applicable
policies. The MUP labeling should bear the specific language presented in Table 3 below.
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any needed product-specific
data regarding the pesticide after a determination of eligibility has been made. The registrant
must review previous data submissions to ensure they meet current EPA acceptance criteria and
if not, commit to conduct new studies. If a registrant believes that previously submitted data
meet current testing standards, then the study MRID numbers can be cited according to the
instructions in the Requirement Status and Registrations Response Form provided for each
product. The Agency intends to issue a separate product-specific DCI outlining specific data
requirements.
2. Labeling for End-Use Products
To be eligible for reregi strati on, labeling changes are necessary to implement measures
outlined in Section IV above. The specific changes and language are presented in Table 3 below.
Generally, conditions for the distribution and sale of products bearing old labels/labeling will be
established when the label changes are approved. However, specific existing stocks time frames
will be established case-by-case, depending on the number of products involved, the number of
label changes, and other factors.
Page 24 of 192
-------
Table 3. Summary of required labeling changes for PPO products
For all Manufacturing-
Use Products
"Propylene oxide only can be formulated into end-use products containing directions for use that
include acceptable air concentration levels of 2 ppm as an 8-hour time weighted average and
other measures for ensuring that workers and other persons are not exposed to concentrations of
propylene oxide that exceed this level unless appropriate respiratory protection is used."
"Propylene oxide cannot be formulated into end-use products labeled for use on edible gums or
birdseed. End-use product labels must be revised to delete all references to and use directions for
edible gums or birdseed."
"Propylene oxide only can be formulated into end-use products that are classified as and
identified as Restricted Use."
Directions for Use
One of these statements
may be added to a label to
allow reformulation of
the product for a specific
use or use-pattern or all
additional uses supported
by a formulator or user
group
"This product may be used to formulate products for specific use(s) not listed on the MP label if
the formulator, user group, or grower has complied with U.S. EPA submission requirements
regarding support of such use(s)."
"This product may be used to formulate products for any additional use(s) not listed on the MP
label if the formulator, user group, or grower has complied with U.S. EPA submission
requirements regarding support of such use(s)."
Directions for Use
Environmental Hazards
Statements Required by
the RED and Agency
Label Policies
"ENVIRONMENTAL HAZARDS
This pesticide is toxic to birds and mammals. Do not discharge effluent containing this product
into lakes, streams, ponds, estuaries, oceans, or other waters unless in accordance with the
requirements of a National Pollution Discharge Elimination System (NPDES) permit and the
permitting authority has been notified in writing prior to discharge. Do not discharge effluent
containing this product to sewer systems without previously notifying the local sewage treatment
plant authority. For guidance contact your State Water Board or Regional Office of the EPA."
Precautionary Statements
Page 25 of 192
-------
End-Use Products Intended for Occupational Use
Restricted Use Pesticide
"RESTRICTED USE PESTICIDE DUE TO INHALATION TOXICITY
For retail sale to and use only by Certified Applicators or persons under their direct supervision
and only for those uses covered by the Certified Applicator's certification."
Top of Front Panel
Identify as a fumigant all
propylene oxide end-use
products
Prominently identify the end-use product as a "Fumigant"
Insert the word "fumigant"
as part of the product name
or close to the product
name, either as part of the
product-type identification
or as a separate word or
sentence
Add precautionary
language in Spanish on
propylene oxide end-use
products
Add the following Spanish signal word and statement:
"PELIGRO
Si Usted no entiende la etiqueta, busque a alquien para que se la explique a Usted en detalle. (If
you do not understand the label, find someone to explain it to you in detail.)"
On front panel of the label
near the signal word
DANGER.
Add acceptable air
concentration language to
propylene oxide end-use
products
"AIR CONCENTRATION LEVEL
The acceptable air concentration level for persons exposed to propylene oxide is 2 ppm (8 mg/m3)
as a time weighted average."
In the Hazards to Humans
and Domestic Animals
section of the labeling
immediately following the
precautionary statements.
Page 26 of 192
-------
PPE Requirements
Established by the RED
for propylene oxide end-
use products
"PERSONAL PROTECTIVE EQUIPMENT
Some materials that are chemical-resistant to this product are (registrant inserts correct chemical-
resistant material). If you want more options, follow the instructions for category [registrant
inserts
A,B,C,D,E,F,G,orH\ on an EPA chemical-resistance category selection chart.
All handlers opening propylene oxide drums or tanks, cleaning up leaks or spills, or who
otherwise may potentially contact liquid propylene oxide, must wear:
> long-sleeved shirt and long pants,
> chemical-resistant gloves,
> chemical-resistant footwear plus socks,
> chemical-resistant apron.
> face-sealing goggles, and
> full-face shield, unless a respirator that covers the entire face is
worn.
Respirator Requirements: Once propylene oxide has been introduced into an enclosure, the
certified applicator supervising the fumigation must make sure that all persons in the exposure
area (the treatment area and the buffer zone, if applicable) have appropriate respiratory protection
or are removed from the exposure area.
Air Concentrations 20 PPM or Greater from a Direct-Read Device or Air Concentrations
Greater than 2 ppm as an 8-Hour Time Weighted Average: If propylene oxide air
concentration level is measured to be 20 ppm or greater at anytime when measured using a direct
read device or if propylene air concentration exceeds 2 ppm as an 8-hour time weighted average,
each person in the exposure area must wear either
- a supplied-air respirator (MSHA/NIOSH approval number prefix TC-19C), or
- a serf-contained breathing apparatus (SCBA) (MSHA/NIOSH approval number prefix TC-
13F).
Air Concentrations at or below 2 PPM as an 8-hour Time Weighted Average: No respirator
is required if the air concentration level of propylene oxide in the exposure area is measured to be
at or below 2 ppm as an 8-hour time weighted average and the air concentration is lower than 20
ppm using a direct-read device."
Immediately
following/below
Precautionary Statements:
Hazards to Humans and
Domestic Animals
Page 27 of 192
-------
User Safety Requirements
for all propylene oxide
end-use products
"WORK SAFETY REQUIREMENTS
Respirator Requirements: When a respirator is required for use with this product, the certified
applicator supervising the fumigation must make sure that:
a) Respirators must be fit tested and fit checked using a program that conforms with OSHA's
requirements (described in 29 CFR Part 1910.134;
b) Respirator users must be trained using a program that conforms with OSHA's requirements
(described in 29 CFR Part 1910.134;
c) Respirator users must be examined by a qualified medical practitioner to ensure the physical
ability to safely wear the style of respirator to be worn;
d) Respirators must be maintained according to a program that conforms with OSHA's
requirements (described in 29 CFR Part 1910.134.
~ If liquid fumigant splashes or spills on clothing, remove them at once, and place them outdoors
in an isolated place to aerate, because fumes will be an intolerable source of irritation.
~ Immediately after application remove personal protective equipment. Do not reuse the
personal protective equipment until cleaned. Keep and wash the work clothing and personal
protective equipment separately from other laundry.
~ Discard clothing and other absorbent materials that have been drenched or heavily
contaminated with this product. Do not reuse them.
~ Follow manufacturer's instructions for cleaning/maintaining personal protective equipment."
Precautionary Statements:
Hazards to Humans and
Domestic Animals
immediately following
Personal Protective
Equipment Requirements
User Safety
Recommendations
"User Safety Recommendations
Users should wash hands before eating, drinking, chewing gum, using tobacco, or using the toilet.
Users should remove clothing/PPE immediately if pesticide gets inside. Then wash thoroughly
and put on clean clothing.
Users should remove PPE immediately after handling this product. Wash the outside of gloves
before removing. As soon as possible, wash thoroughly and change into clean clothing."
Precautionary Statements
under: Hazards to Humans
and Domestic Animals
immediately following User
Safety Requirements
(Must be placed in a box.)
Page 28 of 192
-------
Restrictions for Vacuum-
Sealed Pressurized
Chambers
"Fumigation in Vacuum-Sealed Pressurized Chambers
All vacuum-sealed pressurized chambers must be fitted with equipment specifically designed to
reduce propylene oxide emissions by 99 percent."
In the Directions for Use
under "Fumigation in
Vacuum-Sealed Pressurized
Chambers"
Restrictions for
Fumigation Not
Contained within a
Vacuum-Sealed
Pressurized Chamber
"Fumigation Not Contained Within a Vacuum-Sealed Pressurized Chamber
For any fumigation that does not take place in a vacuum-sealed pressurized chamber, a 180-foot
buffer zone must be established around the treated enclosure from the time propylene oxide is
introduced into the enclosure and must remain in effect until the air concentration of propylene
oxide being exhausted from the treated enclosure is measured to be 10 ppm or less. Fumigation
that does not take place in a vacuum-sealed pressurized chamber is limited to a maximum
concentration of 0.0448 ounces of propylene oxide per cubic foot of fumigation enclosure and the
enclosure where fumigation is taking place can be no more than 5000 cubic feet.
Buffer Zone Entry Restrictions
Entry by the certified applicator supervising the fumigation, or persons under his/her direct
supervision, is permitted in the 180-foot buffer zone, provided either:
~ the appropriate respirator is worn (see PPE requirements elsewhere in this labeling); OR
— the air concentration level for propylene oxide is at or below 2 ppm for an 8-hour time
weighted average.
The certified applicator supervising the fumigation must ensure that any person, except the
certified applicator or persons under his/her direct supervision, is kept outside the 180-foot buffer
zone surrounding the treated enclosure from the time propylene oxide is introduced into the
enclosure until the air concentration of propylene oxide being exhausted from the treated
enclosure is measured to be 10 ppm or less."
In the Directions for Use
under the heading:
Fumigation Not Contained
Within a Vacuum-Sealed
Pressurized Chamber"
immediately following
"Fumigation in Vacuum-
Sealed Pressurized
Chambers"
Page 29 of 192
-------
Onsite Notification for all
propylene oxide end-use
products
"PLACARDING OF FUMIGATED ENCLOSURES
The certified applicator supervising the fumigation (or person under his/her direct supervision)
must placard all entrances to the fumigation enclosure with signs bearing:
~ skull and crossbones symbol
- "DANGER/PELIGRO,"
- "Area under fumigation, DO NOT ENTER/NO ENTRE,"
~ "Propylene Oxide Fumigant in use,"
~ the date and time of fumigation, and
~ name, address, and telephone number of the certified applicator supervising the fumigation."
"The certified applicator supervising the fumigation must ensure that no person, except the
certified applicator or persons under his/her direct supervision who are wearing appropriate
respiratory protection, enters into the treated enclosure until the signs are removed. Such signs
must only be removed when aeration has occurred and when the air concentration level of
propylene oxide is monitored as described in this labeling and the monitoring indicates that
workers can enter without respiratory protection. Signs must remain legible during entire posting
period.
The warning signs at entrances to fumigation enclosure may only be removed by the certified
applicator supervising the fumigation or person under his/her direct supervision.
Vehicles must be placarded with applicable U.S. Department of Transportation warning signs."
In the Directions for Use
under the heading
"PLACARDING OF
FUMIGATED
ENCLOSURES"
Environmental
Hazards Statements
"ENVIRONMENTAL HAZARDS
This pesticide is toxic to birds and mammals. Do not discharge effluent containing this product
into lakes, streams, ponds, estuaries, oceans or other waters unless in accordance with the
requirements of a National Pollutant Discharge Elimination System (NDPES) permit and the
permitting authority has been notified in writing prior to discharge. Do not discharge effluent
containing this product to sewer systems without previously notifying the local sewage treatment
plants authority. For guidance contact your State Water Board or Regional Office of the EPA."
Precautionary Statements
under Environmental
Hazards
Storage and Disposal
language of for all
propylene oxide end-use
products
"Persons moving, handling, or opening containers must wear the personal protective equipment
(including prescribed respirators when necessary) specified in the Human Hazards section of this
labeling. Store containers in a well-ventilated area."
Storage and Disposal
section of the label
Page 3 Oof 192
-------
Spill and Leak
Procedures of for
propylene oxide end-use
products
"SPILL AND LEAK PROCEDURES
Evacuate everyone from the immediate area of the spill or leak. For entry into affected area to
correct problem, wear the personal protective equipment (including prescribed respirators)
specified in the Hazards to Humans section of this labeling. Move leaking or damaged containers
outdoors or to an isolated location. Observe strict safety precautions. Work upwind, if possible.
Allow spilled fumigant to evaporate. Only correctly trained and PPE-equipped handlers are
permitted to perform such cleanup. Do not permit entry into the spill or leak area by any other
person until the air concentration level of propylene oxide is measured to be at or below 2 ppm as
an 8-hour time weighted average.
Contaminated soil, water, and other cleanup debris is a toxic hazardous waste. Report spill to the
National Response Center (800-424-8802) if the reportable quantity of 1000 Ibs. is exceeded."
In the labeling section titled
"Storage and Disposal" or
by themselves under the
heading "Spill and Leak
Procedures"
General Application
Restrictions
"DIRECTIONS FOR USE
It is a violation of Federal Law to use this product in a manner inconsistent with its labeling.
Do not apply this product in a way that will contact workers or other persons, either directly or
through drift. Only protected handlers may be in the area during application. For any
requirements specific to your State or Tribe, consult the agency responsible for pesticide
regulation."
Place in the Direction for
Use directly below the
heading "Directions for
Use"
Page 31 of 192
-------
Use-Specific Application
Restrictions
(The product label must
list the specified
application rates in
ounces or pounds of
formulated product in
place of ounces of active
ingredient.)
For products with the following uses and use patterns please amend labels to include specified
language and to reflect the following application rates:
If labels refer to "gums", the label language must be changed to "non-edible gums".
If labels refer to "cocoa beans" or "cocoa", the label language must be changed to "cacao
beans" and "cocoa powder". Do not apply more than 2.0 oz ai/ft3 per application when used in
vacuum-sealed pressurized chambers. For all other fumigation methods, do not apply more than
0.0448 oz ai/ft3.
If labels refer to "processed spices", the label language must be changed to "dried or processed
herbs and spices", "dried onions", and "dried garlic". Do not apply more than 2.0 oz ai/ft3 per
application when used in vacuum-sealed pressurized chambers. For all other fumigation
methods, do not apply more than 0.0448 oz ai/ft3.
If labels refer to "in-shell and processed nutmeats (except peanuts)", the label language must
be changed to "raw or processed tree nuts". Do not apply more than 2.0 oz ai/ft3 per application
when used in vacuum-sealed pressurized chambers. For all other fumigation methods, do not
apply more than 0.0448 oz ai/ft3.
Directions for Use
Associated with the
Specific Use Pattern
a PPE that is established on the basis of Acute Toxicity of the end-use product must be compared to the active ingredient PPE in this document. The more
protective PPE must be placed in the product labeling. For guidance on which PPE is considered more protective, see PR Notice 93-7.
Page 32 of 192
-------
VI. Appendices
Page 3 3 of 192
-------
Appendix A. Propylene Oxide Uses and Use-Patterns Eligible for Reregistration
Cosmetic articles and
ingredients
Non-edible gums
Ores
Packaging
Pigments
Pharmaceutical
materials
Discarded nut shells
prior to disposal
Dried or processed
herbs and spices
Dried onion
Dried garlic
0.0448
2.4
0.0448
2.4
0.0448
2.4
0.0448
2.4
0.0448
2.4
0.0448
2.4
0.0448
2.4
0.0448
2.0
0.0448
2.0
0.0448
2.0
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Page 34 of 192
-------
Cacao bean
Cocoa powder
Raw or processed tree
nuts
0.0448
2.0
0.0448
2.0
0.0448
2.0
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Rate allowable only for use in vacuum-
sealed pressurized chambers.
Page 3 5 of 192
-------
Appendix B. Table of Generic Data Requirements and Studies Used to Make the
Reregistration Decision
Guide to Appendix B
Appendix B contains listing of data requirements which support the reregi strati on for active
ingredients within case #2560 (propylene oxide) covered by this RED. It contains generic data
requirements that apply to simazine in all products, including data requirements for which a
"typical formulation" is the test substance.
The data table is organized in the following formats:
1. Data Requirement (Column 1). The data requirements are listed in the order in which
they appear in 40 CFR part 158. The reference numbers accompanying each test refer to
the test protocols set in the Pesticide Assessment Guidance, which are available from the
National technical Information Service, 5285 Port Royal Road, Springfield, VA 22161
(703) 487-4650.
2. Use Pattern (Column 2). This column indicates the use patterns for which the data
requirements apply. The following letter designations are used for the given use patterns.
A. Terrestrial food
B. Terrestrial feed
C. Terrestrial non-food
D. Aquatic food
E. Aquatic non-food outdoor
F. Aquatic non-food industrial
G. Aquatic non-food residential
H. Greenhouse food
I. Greenhouse non-food
J. Forestry
K. Residential
L. Indoor food
M. Indoor non-food
N. Indoor medical
O. Indoor residential
3. Bibliographic Citation (Column 3). If the Agency has acceptable data in its files, this
column list the identify number of each study. This normally is the Master Record
Identification (MIRD) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix (Appendix D) for a complete citation of
the study.
Page 3 6 of 192
-------
830.1550
830.1600
830.1620
830.1670
830.1700
830.1750
830.1800
830.6302
830.6303
830.6304
830.6313
830.7000
830.7050
830.7220
830.7300
830.7550
830.7840
830.7950
61-1
6 1-2 A
61-2B
61-2B
62-1
62-0
62-3
63-2
63-3
63-4
63-13
63-12
None
63-6
63-7
63-11
63-8
63-9
Product Identity and Composition
Description of materials used to
produce the product
Description of production process
Formation of Impurities
Preliminary Analysis
Certification of Limits
Analytical Method
Color
Physical State
Odor
Stability to normal and elevated
temperatures, metals, and metal ions
PH
UV/Visible Absorption
Boiling Point
Density
Partition coefficient, shake flask
method
Solubility
Vapor Pressure
All
All
Al
All
All
All
All
All
All
All
All
All
All
All
All
All
All
All
41011301
43139701
43139701
43139701
43139702
41874103
41874103
41874103
41874103
41874103
44799201
41011301
41011301
41011301
41011301
41011301
41011301
850.4150
(modified)
850.4400 or
850.4500
(modified)
122-1
122-2 123-2
124-2
Special Study: Modified Terrestrial
Plant Toxicity
Special Study: Modified Aquatic Plant
Toxicity
All
All
Data Gap
Data Gap
860.1300
860.1340
860.1360
860.1650
860.1500
171-4A
171-4C
171-4M
171-13
171-4K
Nature of Residue - Plants
Residue Analytical Method - Plants
Multiresidue Method
Analytical Reference Standards
A
A
A
A
45301901 45301902
45499101
44692802
Data Gap
Crop Field Trials - Crop group 19 A: Herbs
Basil, Dried Leaves
Basil, dried leaves - babyfood
Chive
Coriander, leaves
Coriander, leaves - babyfood
Dillweed
Herbs, other
Lemongrass
Marjoram
Marjoram - babyfood
Parsley, dried leaves
Parsley, dried leaves - babyfood
Savory
A
45301901
Page 3 7 of 192
-------
860.1500
860.1500
860.1500
860.1500
171-4K
171-4K
171-4K
171-4K
Crop Field Trials - Crop group 19B: Spices
Cinnamon
Cinnamon - babyfood
Spices, other
Spices, other - babyfood
Coriander, seed
Coriander, seed - babyfood
Dill, seed
Pepper, black and white
Pepper, black white - babyfood
A
45301901
Crop Field Trials - Crop group 3 : Bulb Vegetables
Garlic, dried
Garlic, dried - babyfood
Onion, dry bulb, dried
Onion, dry bulb, dried - babyfood
A,B
45301901
Crop Field Trials - Crop group 14: Tree Nuts
Almond
Almond, babyfood
Almond oil
Almond oil, babyfood
Brazil nut
Butternut
Cashew
Chestnut
Flibert
Filbert oil
Hickory nut
Macadamia nut
Pecan
Walnut
A,B
A,B
46867701
44692801
Crop Field Trials - Crop group O: Other
Cocoa bean, chocolate
Cocoa bean, powder
Fig
Fig, dried
Grape, raison
Plum prune, fresh
Plum prune, fresh, babyfood
Plum prune, dried
Plum prune, dried, babyfood
Plum prune, juice
Plum prune, juice, babyfood
A,B
A,B
45138501
45813601
870.1100
870.1300
870.2400
870.2500
870.3700
870.3800
81-1
81-3
81-4
81-5
83-3A
83-4
Acute Oral Toxicity - Rat
Acute Inhalation Toxicity - Rat
Primary Eye Irritation - Rabbit
Primary Skin Irritation
Developmental Toxicity - Rat
2-Generation Reproduction - Rat
All
All
All
All
All
All
Smyth et al., 1941 and Antonova et
al., 1981 as cited in USEPA, 1987
NTP, 1985
Weil et al., 1963 as cited in WHO,
1985
Rowe et al., 1956 as cited in
USEPA, 1987
41750801
45292701
Page 3 8 of 192
-------
870.4100
870.4100
870.4200
870.4300
870.5100
870.5375
870.5550
870.7485
N/A
N/A
N/A
N/A
N/A
83-1A
83-1B
83-2B
83-5
84-2
84-2B
84-2
85-1
N/A
N/A
N/A
N/A
N/A
Chronic Feeding Toxicity Study - Rat
Chronic Feeding Toxicity Study - Non-
rodent
Carcinogenicity Mice
Combined Chronic
Toxicity /Carcinogenicity - Rats
Bacterial Reverse Gene Mutation
Cytogenetics
Unscheduled DNA Synthesis in
Mammalian Cells in Culture
General Metabolism
24-week Rat Subchronic Inhalation
Subchronic Rat Oral (12- 14 days)
Subchronic Mouse Oral (12- 14 days)
Subchronic Inhalation Toxicity - Rat 13
weeks
Subchronic Inhalation Toxicity -
Mouse 13 weeks
All
All
All
All
All
All
All
All
All
All
All
All
All
Dunkelberg, 1982
Sprinz et al., 1982 as cited in
USEPA, 1994 Setzeratal., 1996
Data Gap
NTP, 1985
41874102 42039901
Kuperetal., 1988
Lynch etal., 1984 NTP, 1985
Multiple references as cited in
I ARC, 1994
WHO, 1985
45292801
NTP, 1998
NTP, 1998
NTP, 1985
NTP, 1985
870.1100
870.1200
870.1300
870.2400
870.2500
870.3100
870.3150
870.3700
870.3800
870.4300
870.4300
870.5100
870.5375
870.5550
870.7485
N/A
81-1
81-2
81-3
81-4
81-5
82-1A
82-1B
83-3A
83-4
83-5
83-5
84-2
84-2B
84-2
85-1
N/A
Acute Oral Toxicity - Rat
Acute Dermal Toxicity - Rabbit/Rat
Acute Inhalation Toxicity - Rat
Primary Eye Irritation - Rabbit
Primary Skin Irritation
Subchronic Oral Toxicity: 90-Day
Study Rodent
Subchronic Oral Toxicity: 90-Day
Study Non-rodent
Developmental Toxicity - Rat
2-Generation Reproduction - Rat
Combined Chronic
Toxicity /Carcinogenicity: Rats
Combined Chronic
Toxicity /Carcinogenicity: Mice
Bacterial Reverse Gene Mutation
Cytogenetics
Unscheduled DNA Synthesis in
Mammalian Cells in Culture
General Metabolism
Subchronic Rat Oral (14 days)
All
All
Al
All
All
All
All
All
All
All
All
All
All
Al
All
All
Smyth etal., 1941 and USFDA,
1969 and Weisbrod, 1981 and
Smyth et al., 1941 and USFDA,
1969 as cited in TNO BIBRA
International, 1994
Smyth et al., 1969 and Weisbrod,
1981 as cited in TNO BIBRA
International, 1994
Smyth and Carpenter, 1969 as
cited in NTP, 1998
Carpenter and Smyth et al., 1946
as cited in NTP, 1998
Smyth et al., 1969 as cited in TNO
BIBRA International, 1994
NTP, 1998
NTP, 1998
Exxon Chemical Company, 1980
as cited in NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
NTP, 1998
Page 3 9 of 192
-------
N/AI N/AI Subchronic Mouse Oral (14 days) [All I NTP, 1998
Page 40 of 192
-------
Appendix C. Technical Support Documents
Additional documentation in support of this RED is maintained in the OPP docket EPA-
HQ-OPP-2005-0253. This docket may be accessed in the OPP docket room located at
Room S-4900, One Potomac Yard, 2777 S. Crystal Drive, Arlington, VA. It is open
Monday through Friday, excluding Federal holidays, from 8:30 a.m. to 4:00 p.m. All
documents may be viewed in the OPP docket room or downloaded or viewed via the
Internet at the following site: http://www.regulations.gov.
The docket initially contained preliminary risk assessments, supporting documents, and
technical (or manufacturing-use) registrant error comments for PPO as of November 9,
2005. After a sixty-day public comment period, EPA considered the public comments
that were submitted to the docket and revised the risk assessments as necessary. The
revised risk assessments, any supporting documents that needed to be revised, an impact
assessment, and memos describing the Health Effects Division (HED) and the Biological
and Economic Assessment Division (BEAD) response to public comments will be added
to the docket on August 9, 2006.
The Agency documents in the docket include:
1. Federal Register Notice: Propylene Oxide Risk Assessment, Notice of
Availability, and Risk Reduction Options
2. PPO Revised Risk Assessment
3. PPO Response to Phase 1 Comments
4. Revised Residue Chemistry Chapter for Propylene Oxide Reregi strati on
Eligibility Decision (RED) Document
5. PPO Dietary Chapter
6. Aberco Phase 1 Comments
7. PPO Incident Report
8. PPO MARC Memo
9. EFED PPO Chapter
10. PPO ORE Chapter
11. PPO MARC Memo dated 8/16/00
12. PPO CARC Memo 3/20/00
13. Federal Register Notice: Propylene Oxide Risk Assessment; Notice of
Availability and Risk Reduction Options; Extension of Comment Period
Page 41 of 192
-------
14. Request for Additional Information and Risk Management Suggestions for the
Reregi strati on of PPO Phase 3 Public Comment Period
15. Federal Register Notice: Propylene Oxide (PPO) Reregi strati on Eligibility
Decision; Notice of Availability
16. Reader's Guide to the Propylene Oxide Docket EPA-HQ-OPP-2005-0253
17. Reregi strati on Eligibility Decision for Propylene Oxide
18. Propylene Oxide - Revised HED Risk Assessment for Reregistration Eligibility
Decision (RED) Document, PC Code: 042501, DP Barcode: D316547
19. Propylene Oxide Acute, Chronic and Revised Cancer Dietary Exposure
Assessments for the Reregistration Eligibility Decision PC Code: 042501, DP
Barcode: D329648
20. Addendum to Revised PPO RED Chemistry Chapter Dated 09/19/05: Additional
Residue Chemistry Data For Fumigation Use of Propylene Oxide In/on Almond
and Walnut Nutmeats and Inshell Almonds. (MRID 46867701)
21. Propylene Oxide: Revised Phase IV Occupational and Residential Exposure
Assessment and Recommendations for the Reregistration Eligibility Decision
(RED) Document (RED Case 2560)
22. Propylene Oxide: Revised Non-Occupational/Residential Risk Assessment for
Commodity Fumigations (RED Case 2560)
23. Appendix I. A.Ventura.4hr 2.81b MSFEV
24. Appendix I. A.Ventura.4hr 2.81b NS
25. Appendix I. A.Ventura.4hr 1501b MSFEV
26. Appendix I. A. Ventura.4hr 751b MSFEV
27. Appendix I. A.Ventura.4hr 43.751b MSFEV
28. Appendix I. A.Venturya.4hr 31.251b MSFEV
29. Impact Assessment of Propylene Oxide and Alternatives on Almonds, Pecans,
Walnuts and Spices (DP# 316567)
30. Propylene Oxide: Response to Public Comments on the HED Risk Assessment
for Propylene Oxide; PC Code 042501; DP Barcode; 329650
31. BEAD Response to Phase 3 Public Comments Concerning the Reregistration of
Propylene Oxide (PPO) for Uses on Almonds, Pecans, and Walnuts
Page 42 of 192
-------
32. EFED RED Chapter for Propylene Oxide (042501) DP Barcode D263366
Page 43 of 192
-------
Appendix D. Citations Considered to be Part of the Database Supporting the
Reregistration Decision (Bibliography)
Guide to Appendix D
1. Contents of Bibliography. This bibliography contains citations of all studies
considered relevant by EPA in arriving at the positions and conclusions stated
elsewhere in the Reregistration Eligibility Document. Primary sources for studies
in this bibliography have been the body of data submitted to EPA and its
predecessor agencies in support of past regulatory decisions. Selections from
other sources including the published literature, in those instances where they
have been considered, are included.
2. Units of Entry. The unit of entry in this bibliography is called a "study." In the
case of published materials, this corresponds closely to an article. In the case of
unpublished materials submitted to the Agency, the Agency has sought to identify
documents at a level parallel to the published article from within the typically
larger volumes in which they were submitted. The resulting "studies" generally
have a distinct title (or at least a single subject), can stand alone for purposes of
review and can be described with a conventional bibliographic citation. The
Agency has also attempted to unite basic documents and commentaries upon
them, treating them as a single study.
3. Identification of Entry. The entries in this bibliography are sorted numerically by
Master Record Identifier, or "MRID" number. This number is unique to the
citation, and should be used whenever a specific reference is required. It is not
related to the six-digit "Accession Number" which has been used to identify
volumes of submitted studies (see paragraph 4(d)(4) below for further
explanation). In a few cases, entries added to the bibliography late in the review
may be preceded by a nine character temporary identifier. These entries are listed
after all MRID entries. This temporary identifying number is also to be used
whenever specific reference is needed.
4. Form of Entry. In addition to the Master Record Identifier (MRID), each entry
consists of a citation containing standard elements followed, in the case of
material submitted to EPA, by a description of the earliest known submission.
Bibliographic conventions used reflect the standard of the American National
Standards Institute (ANSI), expanded to provide for certain special needs.
a. Author. Whenever the author could confidently be identified, the Agency
has chosen to show a personal author. When no individual was identified,
the Agency has shown an identifiable laboratory or testing facility as the
author. When no author or laboratory could be identified, the Agency has
shown the first submitter as the author.
b. Document date. The date of the study is taken directly from the
document. When the date is followed by a question mark, the
bibliographer has deduced the date from the evidence contained in the
Page 44 of 192
-------
document. When the date appears as (1999), the Agency was unable to
determine or estimate the date of the document.
c. Title. In some cases, it has been necessary for the Agency bibliographers
to create or enhance a document title. Any such editorial insertions are
contained between square brackets.
d. Trailing parentheses. For studies submitted to the Agency in the past, the
trailing parentheses include (in addition to any self-explanatory text) the
following elements describing the earliest known submission:
(1) Submission date. The date of the earliest known submission
appears immediately following the word "received."
(2) Administrative number. The next element immediately following
the word "under" is the registration number, experimental use
permit number, petition number, or other administrative number
associated with the earliest known submission.
(3) Submitter. The third element is the submitter. When authorship is
defaulted to the submitter, this element is omitted.
(4) Volume Identification (Accession Numbers). The final element in
the trailing parentheses identifies the EPA accession number of the
volume in which the original submission of the study appears. The
six-digit accession number follows the symbol "CDL," which
stands for "Company Data Library." This accession number is in
turn followed by an alphabetic suffix which shows the relative
position of the study within the volume.
Page 45 of 192
-------
Bibliography
41011301
41874103
43139701
43139702
44799201
Warren, M. (1988) Chemical Identity: 100% Propylene Oxide: Volume #1.
Unpublished compilation prepared by Aberco Inc. 102 p.
Meyland, W.; Papa, L.; DeRossa, C.; et al. (1986) Chemicals of Current Interest -
Propylene Oxide Health and Environmental Effects Profile. Unpublished study prepared
by Syracuse Research Corp. and Environmental Criteria and Assessment. 45 p.
Mandava, N. (1994) Propylene Oxide Product Chemistry Data. Unpublished study
prepared by Science Regulatory Services Int'l. 27 p.
Ellison, F. (1994) Propylene Oxide Product Chemistry Data: Lab Project Number: 780-
01. Unpublished study prepared by Case Consulting Laboratories, Inc. 16 p.
Patil, S. (1999) Determination of Propylene Oxide Stability inUSP Synthetic Human
Gastric Juice and in USP Synthetic Gastric Juice Mixture Modified to the Conditions of
the Rat Forestomach, Using (carbon-14)-Propylene Oxide: Pilot Study: Final Report:
Lab Project Number: 0533-AC-02. Unpublished study prepared by SISTEK Research
Laboratories. 49 p.
N/A
N/A
N/A
N/A
N/A
N/A
Conway, R.A., G.T. Waggy, M.H. Spiegel, R.L. Berglund. 18983. Environmental fate
and effects of ethylene oxide. Environ. Sci. & Technol. 17:107-112.
Crews, R.C. 1974. Effects of propylene Oxide on Selected Species of Fishes.
Technical Report AFATL-TR-74-183. Air Force Armament Laboratory, Eglin Air
Force Base, FL, 13pp.
Hazardous Substances Data Bank (HSDB). 2005. 1,2 Propylene Oxide. Monograph is
available on-line through the National Library of Medicine, http://toxnet.nlm.nih.gov.
Isikber A. A., S. Navarro, S. Finkelman, M. Rindner, A. Azrieli, R. Dias. 2004.
Toxicity of propylene oxide at low pressure against life stages of four species of stored
product insects. Journal of Economic Entomology, 97:281-295.
Navarro S, A. Isikber, S. Finkelman, M. Rindner, A., Azrieli. R., Dias R. 2004.
Effectiveness of short exposures of propylene oxide alone and in Combination with low
pressure or carbon dioxide against Tribolium castaneum (Herbst) (Coleoptera:
Tenebrionidae). Journal of Stored Products Research, 40 : 1 97-205 .
United States Environmental Protection Agency (USEPA). 1993. Wildlife Exposure
Factors Handbook. EPA/600/R-93/187a, Office of Research and Development,
Washington, DC.
44692801
44692802
45138501
45301901
45301902
"Residues of Propylene Oxide, Propylene Chlorohydrin, and Propylene Bromohydrin in
Nutmeats Following Fumigation with Propylene Oxide (PPO)." Authored by L. C.
Schrier and D. A. Koch. (Dated October 9, 1998).
Conrath, B. (1998) Multiresidue Method Testing for Propylene Oxide, Propylene
Chlorohydrin, and Propylene Bromohydrin, According to PAM I, Appendix II, as
Updated January 1994: Lab Project Number: 43508: PS-9204: PS-10319. Unpublished
study prepared by ABC Laboratories. 256 p.{OPPTS 860.1360}
"Magnitude of the Residue in Cocoa Powder Following Fumigation with Propylene
Oxide." Authored by J. E. Blinne. (Dated May 18, 2000).
Blinne, J.; Koch, D. (2001) Magnitude of the Residue in Herbs/Spices Following
Fumigation with Propylene Oxide (PPO): Lab Project Number: 45125. Unpublished
study prepared by ABC Laboratories, Inc. 1862 p. {OPPTS 860.1500}
"Analysis of Propylene Oxide (PPO) and Propylene Chlorohydrin (PCH, including 1-
chloro-2-propanol and 2-chloro-l-propanol) and Propylene Bromohydrin (PBH,
including l-bromo-2-propanol and 2-bromo-l-propanol) in Fumigated Commodities."
Authored by J. E. Blinne and D. A. Koch. (Dated December 19, 2000)
Page 46 of 192
-------
45499101
45813601
46867701
Simons, C.; Lake, R. (2001) Independent Laboratory Validation of Analytical Method
"The Determination of Propylene Oxide (PPO) and Propylene Chlorohydrins (PCH,
including l-chloro-2-propanol and 2-chloro-l-propanol), and Propylene Bromohydrins
(PBH, including l-bromo-2-propanol and 2-bromo-l-propanol) in Fumigated
Commodities: Lab Project Number: 042-001: 01P-042-001. Unpublished study
prepared by Centre Analytical Laboratories, Inc. 152 p. {OPPTS 860.1340}
"Magnitude of the Residue in Dried Fruits Following Fumigation with
Propylene Oxide (PPO)." Authored by J. E. Blinne. (Dated September 20, 2002).
Almond Board of California; California Walnut Commission (2006) Miscellaneous
Information Concerning PPO Residues in Almonds and Walnuts Prepared in Response
to OPP/HED Requests. Unpublished study prepared by U.S. Environmental Protection
Agency. 7 p.
41750801
41874102
42039901
45292701
45292801
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Drummond, J.G., and Keller, K.A. 1988. Inhalation developmental toxicity study in
rats. International Research and Development Corporation, Mattawan, MI 49071.
Unpublished.
Hackett, P.L., Brown, M.G., Buschbom, R.L. (1982). Teratogenic Study of Ethylene
and Propylene Oxide and n-Butyl Acetate. Battelle, Pacific Northwest Laboratories,
Richland, WA, NIOSH Contract # 210-80-0013, May 1982. Unpublished.
Reuzel, P. and C. Kuper 1983. 1,2-Propylene Oxide: Chronic (28-month) Inhalation
Toxicity/Carcinogenicity Study of 1,2-Propylene Oxide. TNO Netherlands
Organization for Applied Scientific Research, P.O. Box 360, 3700 AJ Zeist,
Netherlands. Laboratory project study identification V 82.215/280853, March 2, 1983.
Unpublished.
Hayes, W., T. Gushow, H. Kirk, et al. 1985. Propylene oxide: Two generation
inhalation reproduction study in Fischer 344 rats. Mammalian and Environmental
Toxicology Research Laboratory, Dow Chemical, Midland, MI, Laboratory report
number, D-001784, June 19, 1985. Unpublished
Young, J.T., Mattsson, J.L., Albee, R.R., and Schuetz, DJ. 1985. Propylene oxide:
assessment of neurotoxic potential in male rats. Mammalian and Environmental
Toxicology Research Laboratory, Health & Environmental Sciences, U.S.A., Dow
Chemical U.S.A., Midland, MI 48640. Study No. D1831, October 24, 1985.
Unpublished.
Cal/OSHA. Occupational Safety and Health Standards Board (OSHSB). Public
meeting/public hearing/business meeting of the OSHSB on General Industry Safety
Orders, Section 5155 - Airborne Contaminants. June 17, 2004.
Dunkelberg, H. 1982. Carcinogenicity of ethylene oxide and 1,2-propylene oxide upon
intragastric administration to rats. Br. J. Cancer. 46: 924- 933.
Faulkner, John. Ethylene Oxide Quantitative Usage Analysis. Biological and
Economic Analysis Division, USEPA/OPPTS/OPP.
IARC (International Agency for Research on Cancer) 1994. World Health
Organization, IARC Monographs on the evaluation of carcinogenic risks to humans.
Vol. 60. Some industrial chemicals. pl81-213.
Lynch, D.W., T.R. Lewis, W.J. Moorman et al. 1984. Carcinogenic and toxicologic
effects of inhaled ethylene oxide andpropylene oxide inF344 rats. Toxicol. Appl.
Pharmacol. 76: 69-84.
Morris, Mark. USEPA/OAQPS/ESD. Memorandum to Dave Guinnup,
USEPA/OAQPS/ESD: Residual Risk Assessment for the Ethylene Oxide Commercial
Sterilization Source Category. February 25, 2005.
NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of
propylene oxide (CAS No. 75-56-9) inF344/N rats and B6C3F1 mice (Inhalation
studies). NTP-TR-267.
Kuper, C.F., P.G.J. Reuzel, V.J. Feron et al. 1988. Chronic inhalation toxicity and
carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26: 159-
167.
Page 47 of 192
-------
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
NTP (National Toxicology Program). 1998. Toxicology and carcinogenesis studies of
l-chloro-2-propanol (CAS No. 127-00-4) in F344/N rats and B6C3F1 mice (Drinking
Water Studies). NTP-TR-477.
Ohnishi, A., T. Yamamato, Y. Murai, et al.. 1988. Propylene oxide causes central-
peripheral distal axonopathy in rats. Arch. Environ. Health. 43:353-356.
Setzer, J.V. W. S. Brightwell, J.M. Russo et al. 1996. Neurophysiological and
neuropathological evaluation of primates exposed to ethylene oxide and propylene
oxide. Toxicol. and Indust. Health 12:667-682.
TNO BIBRA International Limited. 1994. Toxicity Profile. Propylene chlorohydrins.
1st edition, pi -6
USEPA (US Environmental Protection Agency), 1987. Summary review of the health
effects associated with propylene oxide. Office of Health and Environmental
Assessment, Washington, DC. EPA/600/8-86/007F
USEPA (US Environmental Protection Agency), 1994. Integrated Risk Information
System, http://www.epa.gov/iris/subst/0403 .htm
USEPA (US Environmental Protection Agency). (2005a) Guidelines for carcinogen risk
assessment. EPA/630/P-03/001F. Available at: www.epa.gov/cancerguidelines.
USEPA (US Environmental Protection Agency). (2005b) Supplemental guidance for
assessing susceptibility from early-life exposure to carcinogens. EPA/630/R-03/003F.
Available at: www.epa.gov/cancerguidelines.
WHO (World Health Organization), 1985. Propylene Oxide. Environmental Health
Criteria, 56, Geneva.
Page 48 of 192
-------
Appendix E. Generic Data Call-In (GDCI)
Note that a complete generic DCI, with all pertinent instructions, will be sent to
registrants under separate cover.
Page 49 of 192
-------
Appendix F. Product-Specific Data Call-In (PDCI)
Note that a complete product-specific DCI, with all pertinent instructions, will be sent to
registrants under separate cover.
Page 50 of 192
-------
Appendix G. EPA's Batching of Propylene Oxide Products for Meeting Acute Data
Requirements for Reregistration
Often products containing an active ingredient are batched in an effort to reduce the time,
resources and number of animals needed to fulfill the acute toxicity data requirements for
reregi strati on of the products. Because of the type and small number of products
containing the active ingredient PPO, the Agency has determined that batching products
which can be considered similar for purposes of acute toxicity is not necessary.
Page 51 of 192
-------
Appendix H. Registrant Sent this Data Call-In Notice
Aberco, Inc.
9430 Lanham Severn Road
Seabrook, MD 20706
Page 52 of 192
-------
Appendix I. List of Available Related Documents and Electronically Available
Forms
Pesticide Registration Forms are available at the following EPA internet site:
http://www.epa.gov/opprd001/fortns/.
Pesticide Registration Forms (These forms are in PDF format and require the Acrobat
reader)
Instructions:
1. Print out and complete the forms. (Note: Form numbers that are bolded can be
filled out on your computer then printed.)
2. The completed form(s) should be submitted in hardcopy in accord with the
existing policy.
3. Mail the forms, along with any additional documents necessary to comply with
EPA regulations covering your request, to the following address for the Document
Processing Desk.:
Document Processing Desk (distribution code)*
Office of Pesticide Programs (7504P)
Environmental Protection Agency
1200 Pennsylvania Ave, NW
Washington, DC 20460-0001
* Distribution Codes are as follows:
(APPL) Application for product registration
(AMEND) Amendment to existing registration
(CAN) Voluntary Cancellation
(EUP) Experimental Use Permit
(DIST) Supplemental Distributor Registration
(SLN) Special Local Need
(NEWCO) Request for new company number
(NOTIF) Notification
(PETN) Petition for Tolerance
(XFER) Product Transfer
DO NOT fax or e-mail any form containing "Confidential Business Information" or
"Sensitive Information."
If you have any problems accessing these forms, please contact Nicole Williams at (703)
308-5551 or by e-mail at williams.nicole@epamail.epa.gov. If you want these forms
mailed or faxed to you, please contact Lois White, white.lois@epa.gov or Floyd Gayles,
gayles.floyd@epa.gov.
If you have any questions concerning how to complete these forms, please contact OPP's
ombudsperson for conventional pesticide products: Linda Arlington, (703) 305-5446
Page 53 of 192
-------
The following Agency Pesticide Registration Forms are currently available via the
Internet at the following locations:
8570-1
8570-4
8570-5
8570-17
8570-25
8570-27
8570-28
8570-30
8570-32
8570-34
8570-35
8570-36
8570-37
Application for Pesticide
Registration/ Amendment
Confidential Statement of Formula
Notice of Supplemental Registration of
Distribution of a Registered Pesticide
Product
Application for an Experimental Use
Permit
Application for/Notification of State
Registration of a Pesticide To Meet a
Special Local Need
Formulator's Exemption Statement
Certification of Compliance with Data
Gap Procedures
Pesticide Registration Maintenance
Fee Filing
Certification of Attempt to Enter into
an Agreement with other Registrants
for Development of Data
Certification with Respect to Citations
of Data (in PR Notice 98-5)
Data Matrix (in PR Notice 98-5)
Summary of the Physical/Chemical
Properties (in PR Notice 98-1)
Self-Certification Statement for the
Physical/Chemical Properties (in PR
Notice 98-1)
http://www.epa.sov/opprd001/forms/8570-l.pdf
http://www.epa.sov/opprd001/forms/8570-4.pdf
http://www.epa.sov/opprd001/forms/8570-5.pdf
http://www.epa.sov/opprd001/forms/8570-17.pdf
http://www.epa.sov/opprd001/forms/8570-25.pdf
http://www.epa.sov/opprd001/forms/8570-27.pdf
http://www.epa.sov/opprd001/forms/8570-28.pdf
http://www.epa.sov/opprd001/forms/8570-30.pdf
http://www.epa.sov/opprd001/forms/8570-32.pdf
http://www.epa.sov/opppmsdl/PR Notices/pr98-
5.pdf
http://www.epa.sov/opppmsdl/PR Notices/pr98-
5.pdf
http://www.epa.sov/opppmsdl/PR Notices/pr98-
l.pdf
http://www.epa.sov/opppmsdl/PR Notices/pr98-
l.pdf
Pesticide Registration Kit http://www.epa.gov/pesticides/resistrationkit/
Dear Registrant:
For your convenience, we have assembled an on-line registration kit which
contains the following pertinent forms and information needed to register a pesticide
product with the U.S. Environmental Protection Agency's Office of Pesticide Programs
(OPP):
Page 54 of 192
-------
1. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal
Food, Drug and Cosmetic Act (FFDCA) as Amended by the Food Quality
Protection Act (FQPA) of 1996.
2. Pesticide Registration (PR) Notices
a. 83-3 Label Improvement Program-Storage and Disposal Statements
b. 84-1 Clarification of Label Improvement Program
c. 86-5 Standard Format for Data Submitted under FIFRA
d. 87-1 Label Improvement Program for Pesticides Applied through Irrigation
Systems (Chemigation)
e. 87-6 Inert Ingredients in Pesticide Products Policy Statement
f. 90-1 Inert Ingredients in Pesticide Products; Revised Policy Statement
g. 95-2 Notifications, Non-notifications, and Minor Formulation Amendments
h. 98-1 Self Certification of Product Chemistry Data with Attachments (This
document is in PDF format and requires the Acrobat reader.)
Other PR Notices can be found at http://www.epa.gov/opppmsdl/PR_Notices.
3. Pesticide Product Registration Application Forms (These forms are in PDF format
and will require the Acrobat reader.)
a. EPA Form No. 8570-1, Application for Pesticide Registration/Amendment
b. EPA Form No. 8570-4, Confidential Statement of Formula
c. EPA Form No. 8570-27, Formulator's Exemption Statement
d. EPA Form No. 8570-34, Certification with Respect to Citations of Data
e. EPA Form No. 8570-35, Data Matrix
4. General Pesticide Information (Some of these forms are in PDF format and will
require the Acrobat reader.)
a. Registration Division Personnel Contact List
b. Biopesticides and Pollution Prevention Division (BPPD) Contacts
c. Antimicrobials Division Organizational Structure/Contact List
d. 53 F.R. 15952, Pesticide Registration Procedures; Pesticide Data
Requirements (PDF format)
e. 40 CFR Part 156, Labeling Requirements for Pesticides and Devices (PDF
format)
f. 40 CFR Part 158, Data Requirements for Registration (PDF format)
g. 50 F.R. 48833, Disclosure of Reviews of Pesticide Data (November 27,
1985)
Before submitting your application for registration, you may wish to consult some
additional sources of information. These include:
1. The Office of Pesticide Programs' Web Site
2. The booklet "General Information on Applying for Registration of Pesticides in
the United States", PB92-221811, available through the National Technical
Information Service (NTIS) at the following address:
National Technical Information Service (NTIS)
5285 Port Royal Road
Page 5 5 of 192
-------
Springfield, VA 22161
The telephone number for NTIS is (703) 605-6000. Please note that EPA is
currently in the process of updating this booklet to reflect the changes in the
registration program resulting from the passage of the FQPA and the
reorganization of the Office of Pesticide Programs. We anticipate that this
publication will become available during the Fall of 1998.
3. The National Pesticide Information Retrieval System (NPIRS) of Purdue
University's Center for Environmental and Regulatory Information Systems. This
service does charge a fee for subscriptions and custom searches. You can contact
NPIRS by telephone at (765) 494-6614 or through their website.
4. The National Pesticide Telecommunications Network (NPTN) can provide
information on active ingredients, uses, toxicology, and chemistry of pesticides.
You can contact NPTN by telephone at (800) 858-7378 or through their website:
http://npic.orst. edu
The Agency will return a notice of receipt of an application for registration or
amended registration, experimental use permit, or amendment to a petition if the
applicant or petitioner encloses with his submission a stamped, self-addressed
postcard. The postcard must contain the following entries to be completed by
OPP:
• Date of receipt
• EPA identifying number
• Product Manager assignment
Other identifying information may be included by the applicant to link the
acknowledgment of receipt to the specific application submitted. EPA will stamp
the date of receipt and provide the EPA identifying File Symbol or petition
number for the new submission. The identifying number should be used whenever
you contact the Agency concerning an application for registration, experimental
use permit, or tolerance petition.
To assist us in ensuring that all data you have submitted for the chemical are
properly coded and assigned to your company, please include a list of all
synonyms, common and trade names, company experimental codes, and other
names which identify the chemical (including "blind" codes used when a sample
was submitted for testing by commercial or academic facilities). Please provide a
CAS number if one has been assigned.
Page 56 of 192
-------
Appendix J. Human Health Risk Assessment
Page 57 of 192
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
OFFICE OF PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
MEMORANDUM
July 31,2006
SUBJECT: Propylene Oxide - Revised HED Risk Assessment for Reregistration Eligibility
Decision (RED) Document, PC Code: 042501, DP Barcode: D316547
FROM: Becky Daiss
Biologist
Reregistration Branch 4
Health Effects Division (7509C)
THROUGH: Susan Hummel
Branch Senior Scientist
Reregistration Branch 4
Health Effects Division (7509C)
TO: Susan Bartow
Chemical Review Manager
Special Review Branch
Special Review and Reregistration Division (7509C)
Attached is the revised Health Effect Division's risk assessment of the insecticidal
fumigant/sterilant, propylene oxide (PPO). This document revises the September 26, 2005
Revised Propylene Oxide HED Risk Assessment to address public comments. The disciplinary
science chapters have also been revised to address public comments. These and other supporting
documentation are incorporated into the risk assessment and/or included as appendices as
follows:
Hazard Identification Assessment; William Dykstra - Section 4 and Appendices 1-6
Residue Chemistry Assessment; Jerry Stokes (D316571, 9/22/05; D316573, 6/22/06)
Occupational and Residential Exposure Assessment; Matthew Crowley (D316545, 7/31/06;
0331131,7/31/06)
Dietary Exposure and Risk Assessment; Becky Daiss (D329648, 6/30/06)
Incident Report; Jerry Blondell (D316407, 5/17/05)
Drinking Water Assessment; Kevin Costello (D263366, 3/15/00)
Page 1 of 95
Page 5 8 of 192
-------
TABLE OF CONTENTS
Pg-
1.0 EXECUTIVE SUMMARY 4
2.0 INGREDIENT PROFILE 9
2.1 Summary of Registered and Proposed Uses 9
2.2 Structure, Nomenclature and Physical/Chemical Properties 9
3.0 METABOLISM ASSESSMENT 10
3.1 Comparative Metabolic Profile 10
3.2 Nature of the Residue in Foods 10
3.2.1 Description of Primary Crop Metabolism 11
3.2.2 Description of Livestock Metabolism 11
3.3 Environmental Degradation 11
3.4 Summary of Residues for Tolerance Expression and Risk Assessment 11
3.4.1 Rationale for Inclusion of Metabolites and Degradates Assessment 12
4.0 HAZARD CHARACTERIZATION/ASSESSMENT 13
4.1 Hazard Characterization 13
4.2 FQPA Hazard Considerations 24
4.2.1 Adequacy of the Toxicity DataBase 24
4.2.2 Evidence of Neurotoxicity 25
4.2.3 Developmental Toxicity Studies 26
4.2.4 Reproduction Toxicity Studies 31
4.2.5 Pre-and/or Postnatal Toxicity 34
4.2.6 Recommendation for a Developmental Neurotoxicity Study 35
4.2.7 Rationale for the UFDB 36
4.3 Additional FQPA Safety Factor 36
4.4 Hazard Identification and Toxicity Endpoint Selection 36
4.4.1 Acute and Chronic Reference Doses for Propylene Oxide 36
4.4.2 Acute and Chronic Reference Doses for Propylene Chlorohydrin 37
4.4.3 Incidental Oral Exposure 38
4.4.4 Dermal Absorption 38
4.4.5 Dermal Exposure 38
4.4.6 Inhalation Exposure 39
4.4.7 Margins of Exposure 40
4.4.8 Recommendation for Aggregate Exposure Risk Assessments 40
4.4.9 Classification of Carcinogenic Potential 41
4.4.10 Summary of Endpoints Selected for Risk Assessment 49
4.5 Endocrine Disruption 51
5.0 INCIDENT REPORT 51
6.0 DIETARY EXPOSURE/RISK PATHWAY 51
6.1 Residue Profile 51
6.2 Acute and Chronic Dietary Exposure and Risk 53
7.0 RESIDENTIAL EXPOSURE/RISK PATHWAY 55
7.1 Emissions from Controlled Commercial Sterilization Chambers 56
Page 2 of 95
Page 59 of 192
-------
7.2 Emissions from Stationary Sources with No Emission Controls and Commodity Fumigation with
Propoxide892 57
7.2.1 Modeling Methodology 57
7.2.2 Exposure Scenarios 58
7.2.3 PERFUM Model Inputs 58
7.2.4 Residential Bystander Exposure and Risk Estimates 59
8.0 AGGREGATE EXPOSURE AND RISK 61
9.0 CUMULATIVE RISK 62
10.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY 62
10.1 Exposure Scenarios 62
10.2 Established Exposure Levels 63
10.2.1 Regulatory/Recommended Exposure Levels 63
10.2.2 Label Requirements 63
10.3 Exposure Monitoring Data 64
10.4 Exposure Assumptions 65
10.5 Exposure and Risk Estimates 65
10.5.1 Inhalation Exposure and Risk 65
10.5.2 Dermal Exposure and Risk 66
10.5.3 Risk Characterization 66
11.0 DATA NEEDS 67
11.1 Toxicology Data Requirements Residue Chemistry Data Requirements 67
11.2 Residue Chemistry Data Requirements 67
11.3 Occupational and Residential Exposure Data Needs 68
APPENDICES
1.0 GUIDELINE TOXICOLOGY DATA SUMMARY 69
2.0 NON-CRITICAL TOXICOLOGY STUDIES 70
3.0 PPO METABOLISM 75
4.0 REFERENCES 76
5.0 ALTERNATE ORAL CANCER SLOPE FACTOR 79
6.0 MODE OF ACTION SUMMARY 83
7.0 BMD ANALYSES 84
7.1 BMD Analysis Memo - Dunkelberg (1982) 84
7.2 BMD Analysis Memo-Kuperetal. (1988) 88
8.0 TOLERANCE REASSESSMENT TABLE 94
Page 3 of 95
Page 60 of 192
-------
1.0 EXECUTIVE SUMMARY
Use Profile
PPO is used as an insecticidal fumigant on several food items such as processed spices,
cocoa (beans and powder), in-shell and processed nutmeats (except peanuts). PPO also
has nonfood uses for cosmetic articles, gums, ores, packaging, pigments, pharmaceutical
materials, and discarded nut shells prior to disposal.
Currently, there are three registered products for PPO. Both technical and an end-use
product contain 100% a.i.. An additional end-use registration product, Propoxide 892
which contains 8% PPO and 92% carbon dioxide (CO2) is being proposed for uses on
dried fruits such as figs, raisins, and prunes.
Regulatory History
Propylene oxide is a FIFRA 88 List B reregi strati on pesticide. A FIFRA 88 Phase VI
Data Call-In (DCI) was issued by the Agency in October 1989 which cited numerous
deficiencies in the product and residue chemistry databases. Additional product and
residue chemistry data received since 1989 have been reviewed by the Agency. PPO has
a tolerance of 300 ppm for processed spices, cocoa (beans or powder), edible gums, and
processed nutmeats (except peanuts) under 40 CFR 180.491.
The requirements for the series of acute toxicity studies have been waived in the past
based on available information in the literature, consideration of PPO as a low volume,
minor use chemical and/or irritant properties of the compound. The requirements for
subchronic and chronic oral toxicity studies in rodents and non rodents have been
reserved pending dissipation and residue studies (D165449, 9/4/92).
A data call-in for dermal and inhalation exposure monitoring data was requested in 1990
(Morris, 1990). However, a waiver request was granted in 1993 based on labeling
restrictions and risk mitigation measures such as site air monitoring and placarding.
OSHA (Occupational Safety and Health Administration) has established the 8-hour time-
weighted average (8-hour TWA), permissible exposure limit (PEL) for PPO as 100 ppm.
NIOSH (National Institute for Occupational Safety and Health) recommends the Lowest
Feasible Concentration (LFC) for occupational carcinogens a group which includes PPO.
The ACGIH (American Conference of Governmental Industrial Hygienists) recommends
a TLV-TWA (Threshold Limit Value - Time Weighted Average) of 2 ppm for PPO. The
exposure limits from NIOSH and ACGIH are recommended levels and are not
enforceable. The California Division of Occupational Safety and Health (Cal/OSHA) has
established an exposure limit value for PPO as 20 ppm. The current EPA label for PPO
requires respiratory protection if PPO concentrations exceed 20 ppm.
Page 4 of 95
Page 61 of 192
-------
Hazard Characterization
Propylene oxide: The database for PPO is incomplete. Based on information available
from the literature, PPO is classified as Category III by the oral route and Category IV by
the inhalation route. PPO has severe irritant properties to eyes and skin and is classified
as Category I for both tissues.
Evidence suggests that PPO, similar to ethylene oxide, is most probably completely
absorbed, distributed throughout the body and rapidly metabolized following inhalation.
The metabolism occurs predominantly by conjugation with glutathione and hydrolysis to
1, 2-propanediol by epoxide hydrolase.
PPO has been shown to cause awkward gait/ataxia and axonal degeneration of the
hindleg nerve in rats at a high dose level (1500 ppm or 3.6 mg/L). At a similar dose
level, PPO also caused decreased survival and produced clinical symptoms like dyspnea,
hypoactivity, and gasping in rats.
PPO causes nasal cavity lesions (e.g., hyperplasia of the respiratory epithelium) in both
rats and mice. Tumors such as hemangiomas and hemangiosarcomas of the nasal cavity
were produced in mice exposed to PPO for a long term. Nasal tumor incidences in rats
were not statistically significant. Forestomach tumors in rats were reported in one
chronic oral toxicity study available in the literature. PPO is mutagenic and forms
adducts with proteins and DNA. PPO has been classified by the Agency as a B2
carcinogen (probable human carcinogen).
The PPO database lacks an acceptable rabbit developmental study and a chronic oral
toxicity study in non rodents. There is no evidence of increased quantitative or
qualitative susceptibility following in utero exposures in rats. Also, there are no residual
uncertainties found in existing studies for pre- and post natal toxicity in rats.
Propylene Chlorohydrin: PCH exists in two isomers, 1-chloro 2-propanol and 2-chloro-
1-propanol. Most of the toxicity studies are done with a mixture of isomers containing
predominantly l-chloro-2-propanol.
There are no guideline studies (acute, subchronic, developmental, reproduction or chronic
toxicity studies) submitted to the Agency and the database for PCH is inadequate. The
available data from the open literature indicate PCH is Category II or III by the oral
route and Category II by the dermal route and the Category is undetermined for the
inhalation route.
One rat developmental toxicity study was identified in the literature as a secondary
source of information and is unacceptable. There is no rabbit developmental study
available for PCH. In a rat two generation reproductive toxicity study identified in the
literature, decreased body weight gain in dams during gestation and lactation, increased
percentage of abnormal sperm and decreased pup weights were reported. No neurotoxic
effects are evident in the available database for PCH.
Page 5 of 95
Page 62 of 192
-------
PCH appears to be widely distributed in tissues, metabolized and excreted following
inhalation. Most of the administered radioactivity appears to be excreted in urine as
glutathione conjugates. Also, biliary excretion is reported in rats exposed to PCH by
inhalation. Following oral exposure, PCH is eliminated as glucuronic acid conjugate in
addition to glutathione conjugate.
In subchronic studies conducted using rats and mice cytoplasmic alterations and/or
degeneration of acinar cells in the pancreas are reported. In addition, atrophy of the bone
marrow and/or spleen and hepatocellular vacuolization were reported and these effects
were not reported in the rodent chronic studies.
Inductions of mutations in bacteria and chromosomal aberrations as well as sister
chromatid exchange in mammalian cells were reported for PCH.
Dose Response Assessment
For PPO, the acute dietary endpoint for females of 13-49 years is derived from a rat
developmental toxicity study. No endpoint of concern is found suitable for the acute
dietary endpoint for the general population. The chronic dietary endpoint for PPO is
selected from the chronic oral carcinogenicity study. BMD (Bench Mark Dose)
modeling was done to derive the chronic reference dose (cRfD) since the study did not
establish a clear NOAEL. the chronic cancer risk from the oral route was derived using a
revised concentration based cancer slope factor. Since the toxicology database is
incomplete, a database uncertainty factor of 10X was applied in addition to the traditional
100X uncertainty factor for the dietary risk assessment to address residual uncertainties.
The short-term and long-term inhalation endpoints for workers potentially exposed to
PPO were derived using the rat two-generation reproduction study and two-year
combined chronic carcinogenicity study in rats, respectively. The chronic cancer risk
from the inhalation route for workers was derived using a cancer slope factor of 3.5x10"6
(jig/m3)"1 for nasal tumors. This revised assessment also provides a discussion of use of a
margin of exposure (MOE) approach for assessing inhalation risks based on mode of
action (MO A) information submitted by and on behalf of the registrant. After an initial
analysis, EPA concludes that the proposed MOA is highly plausible, and will review the
proposed MOA in more depth, both within OPP and in conjunction other Agency offices.
If the proposed MOA is accepted by the Agency, propylene oxide will not be regulated
using a q* approach for inhalation exposures. Rather, an MOE analysis will be
conducted.
For PCH, no acute dietary endpoint was selected. The chronic reference dose for PCH
was derived from the two-generation reproduction study in rats. A database uncertainty
factor of 10X is applied for dietary assessment to address any residual uncertainties.
Page 6 of 95
Page 63 of 192
-------
Exposure/Risk Assessment and Risk Characterization
The potential exposures and risk from dietary sources were determined for PPO as well
as for the reactive metabolite, PCH found in significant amounts in fumigated spices, nuts
and other commodities. Occupational exposure and risk via inhalation for all durations
were determined for the parent only. Potential occupational exposures via the dermal
route from changing/installing PPO drums and handling treated commodities are
considered negligible. There are no residential uses for PPO and therefore, no risk for
incidental oral exposures or residential exposures via inhalation was determined;
however, a qualitative assessment for background exposures to subjects near PPO
commercial fumigation facilities was performed based on the risk estimated by Office of
Air for ethylene oxide. HED also conducted a quantitative assessment of potential
exposure/risk to bystanders from outdoor commodity fumigation with Propoxide 892
containers such as railcars, tents and tarps.
Dietary Exposure and Risk Characterization
Refined acute and chronic dietary risk assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03), and the Lifeline Model
Version 3.0 which use food consumption data from the USDA's Continuing Surveys of
Food Intake by Individuals (CSFII) from 1994-1996 and 1998. Residue data obtained
from studies on propylene oxide sterilization of nutmeats, cocoa powder, herbs and
spices, figs, prunes and raisins were used for the acute and chronic assessments. Residue
distribution data from PPO sterilization studies were used for the acute dietary analysis of
propylene oxide. Average residues from the sterilization study were used for the chronic
and cancer assessments of propylene oxide. Tolerance level residues were used for the
chronic dietary analysis of propylene chlorohydrin. Percent crop treated data provided by
BEAD were used for the acute and chronic analyses. A drinking water exposure
assessment was not conducted for this assessment because the Environmental Fate and
Effects Division (EFED) expects that uses of propylene oxide for indoor and outdoor
food and nonfood uses will result in insignificant exposure to drinking water resources.
This assessment has been updated to include a revised propylene oxide cancer assessment
that incorporates new data on residue levels in treated nutmeats based on actual
maximum application rates, incorporates refined estimates of percent of nutmeats treated
with propylene oxide, and excludes edible gums from the assessment based on the
registrants submission of a voluntary cancellation notice requesting deletion of edible
gums from product labels. Only the cancer dietary exposure assessment has been revised
for this assessment because only that scenario produced risk estimates above EPA's level
of concern. Conservative estimates of acute and chronic dietary risks for PPO are well
below HED's level of concern and incorporation of new data would result in risks <
previously estimated risks.
A refined probabilistic acute dietary exposure assessment for the population subgroup
females 13-49 concludes that for all supported commodities, the acute dietary exposure
estimates for PPO are below HED's level of concern. This assessment also concludes
Page 7 of 95
Page 64 of 192
-------
that for all supported commodities, the chronic dietary exposure estimates for PPO are
below HED's level of concern. The revised cancer dietary risk estimates for propylene
oxide are below HED's level of concern; the revised cancer dietary excess lifetime risk
estimate for the U.S. general population is 4xlO"7. An acute RfD was not established for
propylene chlorohydrin because an endpoint attributable to a single (or few) day exposure
was not identified from the available database. This assessment concludes that for all
supported commodities, the chronic dietary exposure estimates for propylene
chlorohydrin are below HED's level of concern.
Residential Exposure and Risk Characterization
There are no residential uses for PPO. However, exposure to PPO is expected to occur to
the subjects residing near PPO fumigation facilities. PPO emissions monitoring data
necessary to quantitatively estimate exposures and risks from sterilization/fumigation
facilities are unavailable. Therefore, a qualitative assessment was conducted comparing
the risks associated with fugitive emissions from the use of a similar chemical, ethylene
oxide, in similar commercial fumigation scenarios. Risks to bystanders from comparably
controlled commercial sterilization sources are not expected to be of concern based on
HED's qualitative risk analysis. Additionally, HED conducted a quantitative assessment
of residential bystander risk associated with emissions from outdoor commodity
fumigation with the recently registered product Propoxide 892 and from stationary
sources that do not have emission controls comparable to those required for ethylene
oxide. There is potential for exposure and risk to PPO for non-occupational/residential
bystanders as a result of commodity fumigations conducted with the registered product
Propoxide 892 and those conducted in non-emission controlled commercial sterilization
chambers. However, potential bystander risks may be mitigated by requiring buffer areas
at designated distances.
Occupational Exposure and Risk Characterization
The cancer and non-cancer risks from exposure to PPO were determined based on
currently recommended or regulatory concentration levels. The short- (1-30 days),
intermediate- (1-6 months), and long-term (greater than 6 months) inhalation non-cancer
and cancer risks from the use of PPO in commodity sterilization/fumigation are of
concern at 20 ppm the exposure limit value established by Cal/OSHA and is included in
current EPA PPO label. The acute, short-, intermediate- and long-term non-cancer risks
are not of concern at the ACGIH recommended worker exposure concentration of 2 ppm.
As previously noted, EPA has concluded that an MOA is highly plausible, and will
review the proposed MOA in more depth, both within OPP and in conjunction other
Agency offices. If the Agency concurs with the proposed MOA, then cancer and long-
term non-cancer risks would be regulated at the same level, since the long-term non-
cancer endpoint is based on nasal lesions that are considered precursors to the
development of tumors.
The registrant and industry representatives have submitted inhalation monitoring data and
descriptive information on typical workday exposure patterns for outdoor fumigation
Page 8 of 95
Page 65 of 192
-------
facilities. The exposure monitoring data was reviewed and incorporated into the revised
occupational exposure assessment. Potential risk reduction from respiratory protection
has not been quantitatively factored into the risk assessment, however, due to insufficient
data on the daily PPO exposure profile. However, a qualitative discussion of potential
risk reduction provided by use of respirators is included in this assessment i.e.,
respiratory protection during peak PPO exposures could reduce the daily average
exposure to levels that would not be of concern. Additional monitoring data and
information on exposure patterns that may be used to develop effective risk mitigation
measures for both indoor and outdoor facilities is expected from the registrant and
industry representatives.
2.0 INGREDIENT PROFILE
2.1. Summary of Registered/Proposed Uses
Products and Formulations
The two registered products (one technical and one end-use registration) contain 100%
a.i.. An additional end-use registration (8% a.i) is being proposed for use on figs, raisins,
and prunes. PPO is used as a post harvest fumigant in the food commodities. Table 1
provides the summary of current and new uses for PPO.
Table 1. Registered Uses of Propylene Oxide
EPA Reg.
No.
47870-1
47870-2
47870-3
'Product
Name
Propylene
Oxide
Propylene
Oxide
Technical
PROPOXIDE
892
%AI
100
100
8
Formulation
NA
NA
92% CO2
Application
Rate (oz
PPO/ft3)
2.4
2.4
0.05
Uses
Spices, nutmeats (except peanuts), cocoa
beans, cocoa powder and non food uses
Spices, nutmeats (except peanuts), cocoa
beans, cocoa powder and non food uses
Figs, prunes and raisins and other
commodities
Aberco Inc. is the registrant for all the products.
2.2 Structure, Nomenclature and Physical/Chemical Properties
Product Chemistry data for PPO and its reaction products, i.e., chlorohydrins and
bromohydrins are provided in Table 2.
Page 9 of 95
Page 66 of 192
-------
Table 2. Nomenclatures and Physical/Chemical Properties of Propylene Oxide and Reaction
Products
Common name
Chemical
Structure
Molecular
Formula
Molecular Weight
1UPAC Name
CAS Name
CAS#
PC Code
Melting
Point/range °C
Boiling Point °C
Density or
Specific Gravity
at 20 °C (g/cm3)
Water Solubility
(20 °C)
Solvent Solubility
at 25 °C
Vapor Pressure at
20 °C
Dissociation
Constant, pKa
Octanol/Water
Partition
Coefficient (Kow)
25 °C
UV/vis
Absorption
Spectrum
Propylene Oxide
O
/ \ CH,
C3H60
58.080
-
Propylene oxide; 1 ,2-
epoxy propane
75-76-9
042501
-
34.2 °C
0.829-0.831
39.5g/100mL
Miscible with
acetone, benzene.
carbon tetrachloride,
diethyl ether, and
methanol.
440 mm Hg
NA
Kow 0.03
NA
Propylene chlorohydrins
(75% l-Chloro-2-propanol, 25% 2-
Chloro-1-propanol)
OH
Cl
C3H7C10
94.541
-
l-chloro-2-
propanol
127-00-4
NA
-
126-127 °C
1.115
NA
NA
NA
NA
NA
NA
-
2-chloro-l-
propanol
37493-14-4
NA
-
130°C
1.09
NA
NA
NA
NA
NA
NA
Propylene bromohydrins
(80% l-Bromo-2-propanol, 20% 2-
Bromo-1-propanol)
OH
Br^^k
Br
H°^^k
C3H7BrO
138.992
-
l-bromo-2-
propanol
19686-73-8
NA
-
145-148 °C
1.53
NA
NA
NA
NA
NA
NA
-
2-bromo-l-
propanol
NA
NA
-
NA
NA
NA
NA
NA
NA
NA
NA
NA = not available
3.0 METABOLISM ASSESSMENT
3.1 Comparative Metabolic Profile
The available evidence from the open literature suggests that PPO like ethylene oxide is
most probably completely absorbed, distributed throughout the body and rapidly
metabolized following inhalation. The half-life for the elimination from rat tissues was
Page 10 of 95
Page 67 of 192
-------
reported as 40 minutes following inhalation exposure. PPO is metabolized via
conjugation with glutathione and hydrolysis by epoxide hydrolase to 1, 2-propanediol
(propylene glycol), which is subsequently metabolized to lactic and pyruvic acids.
The available evidence from the open literature suggests that PCH is widely distributed to
tissues, metabolized and excreted following inhalation in animals. Most of the
administered radioactivity appears to be excreted in urine as glutathione conjugates.
Also, biliary excretion is reported in rats exposed to PCH by inhalation. Following oral
exposure, PCH is eliminated as glucuronic acid and glutathione conjugates.
3.2 Nature of the Residue in Foods
3.2.1. Description of Primary Crop Metabolism
The qualitative nature of PPO residues in plants is adequately understood. The residues
of propylene glycol, PCHs and PBHs (propylene bromohydrins) are formed upon
postharvest fumigation of cocoa bean, nutmeats (except peanut), and spices. Spices that
contain salt that are treated with PPO react with chloride ion to form PCH. Similarly, any
bromide ion present in the material to be fumigated reacts with PPO to form PBH. In
addition, reaction with water in samples can produce small amounts of propylene glycol
(PPG).
3.2.2 Description of Livestock Metabolism
Based on the post harvest fumigant uses of PPO on commodities of spices and herbs,
nutmeats (except peanut), cocoa bean, fig, prune and raisin, livestock are not exposed to
PPO or PCH residues in any feedstuffs, or from dermal treatments. Data on livestock
metabolism are not collected and are not required.
3.3 Environmental Degradation
EFED expects that exposure to water resources from the exclusive registration of PPO for
indoor food and non food uses will be negligible. EFED has neither required nor
received environmental fate data for propylene oxide. In the November 28, 1990 'List B
Review for Propylene Oxide', EFED wrote of environmental data that there are no
significant issues at this time. EFED maintains that additional environmental data are not
necessary for the reregi strati on of this sterilant. EFED would require this data when PPO
would ever be considered for registration for outdoor uses. EFED determined that there
would be negligible risk for any contamination of surface and ground water for the
current uses of PPO. Therefore, no drinking water assessment was found necessary (K.
Costello, D263366, 3/15/2000).
3.4 Summary of Residues for Tolerance Expression and Risk Assessment
PPO and PCH are considered separately as residues of concern for risk assessment and
tolerance assessment. The commodity sterilization study residue data indicate that these
Page 11 of 95
Page 68 of 192
-------
compounds are consistently present at high levels. The spice sterilization study data
indicate that PBH is also a reaction product of the propylene oxide sterilization process.
However, PBH residues are minimal relative to propylene chlorohydrin residues.
Therefore, PBH is not considered a residue of concern for risk assessment and is not
assessed separately.
Based on current information from the spice industry trade practices, HED concludes that
residues measured at 2 days (in transit) after treatment should be used for setting the
tolerance level, and the residue data at approximately 2 weeks (and after) should be used
in estimating dietary exposure to PPO and PCH only. Because the propylene oxide label
requires that treated nutmeats must be allowed to off-gas for at least 28 days, only residue
data from > 28 days post-fumigation are used in estimating dietary exposure. Based on
the differences in physical chemical properties and toxicological effects, PPO and PCH
are assessed separately and the residues are not combined in this risk assessment. Table 3
provides the residues included in risk assessment and tolerance expression.
Table 3. Compounds to be included in the Risk Assessment and Tolerance Expression
Commodities
Plant
Livestock
Primary Crop
Rotational Crop
Ruminant
Poultry
Drinking Water
Residues included in Risk
Assessment
Propylene oxide
Propylene chlorohydrin
Not Applicable
Not Applicable
Not Applicable
Not Applicable
Residues included in
Tolerance Expression
Propylene oxide
Propylene chlorohydrin
Not Applicable
Not Applicable
Not Applicable
Not Applicable
3.4.1 Rationale for Inclusion of Metabolites and Degradates
HED Metabolism Committee concluded that both halohydrins (PCH and PBH) are
residues of concern and risk assessment and tolerance expression should include both the
parent and the halohydrins pending additional data on residue chemistry and toxicity for
these compounds. (D264138, 8/16/00). Based on the available toxicity data and the
commodity sterilization study residue data, PPO Risk Assessment Team concludes that
propylene oxide and propylene chlorohydrin are residues of concern for dietary exposure
since these residues persist at high levels and are likely to be present in treated
commodities at time of consumption. The spice sterilization study data indicate that
propylene bromohydrin is also a reaction product of the propylene oxide sterilization
process. However, PBH residues are minimal relative to propylene chlorohydrin
residues. Therefore, PBH is not considered a residue of concern for dietary exposure and
is not included in the tolerance expression.
Page 12 of 95
Page 69 of 192
-------
4.0 HAZARD CHARACTERIZATION/ASSESSMENT
4.1 Hazard Characterization
Propylene Oxide
This assessment includes the toxicity assessment of propylene oxide and its reaction
product, PCH (l-chloro-2-propanol and its isomer, 2-chloro-l-propanol) found in
significant quantities in treated spices and nutmeats. For dietary assessment, endpoints
were selected for both parent and the reaction product. For occupational risk assessment
the endpoints were selected for the parent only.
The toxicology database for PPO is not complete. The database includes acceptable
developmental toxicity, reproduction toxicity, subchronic neurotoxicity (non-guideline),
and chronic carcinogenicity studies in rats, all conducted via inhalation. There is one
developmental study in rabbits conducted via inhalation which is not acceptable because
only one dose was used. Also, the database includes one rat chronic carcinogenicity
study conducted via the oral route which provides limited information as the study was
conducted in one sex (females only) and lacked measurements on systemic toxicity (body
weights, food consumption, clinical measurements, organ weight changes etc.) or
carcinogenicity effects in major tissues. Therefore, the PPO database lacks a
developmental toxicity study in rabbits, and subchronic and chronic oral toxicity studies
in non rodents.
Waivers were issued in the past for acute oral (§81-1, 870.1100), dermal (§81-2,
870.1200), eye irritation (§81-4, 870.2400), skin irritation (§81-5, 870.2500) and dermal
sensitization (§81-6, 870.2600) studies based on the corrosive nature of the compound
and the acceptance of the chemical as a low volume minor-use chemical. The
requirement for an acute inhalation study was satisfied based on available information
from the open literature (D165449, dated 9/4/92). PPO is classified as Category III by
the oral route and Category IV by the inhalation route. PPO is a severe eye and skin
irritant and is classified as Category I for both routes of exposure.
Based on the available toxicity data, an additional 10X data base uncertainty factor is
deemed necessary for the dietary assessment to address the inadequate subchronic and
chronic data for the oral route of exposure and the lack of an acceptable rabbit
developmental study. There is no evidence of increased quantitative or qualitative
susceptibility following in utero exposures in rats. Also, there are no susceptibility
effects in pups in the two-generation reproductive toxicity study.
No data on absorption and metabolism of PPO have been submitted. Evidence suggests
that PPO like ethylene oxide is most probably completely absorbed, distributed
throughout the body and rapidly metabolized following inhalation. The half-life for the
elimination from rat tissues was reported as 40 minutes for inhalation exposure.
Metabolism occurs predominantly by conjugation with glutathione and hydrolysis by
Page 13 of 95
Page 70 of 192
-------
epoxide hydrolase to 1,2-propanediol, which is subsequently metabolized to lactic and
pyruvic acids.
PPO has been shown to cause awkward gait/ataxia and axonal degeneration of the
hindleg nerve in rats at a very high dose (3.6 mg/L) in one subchronic toxicity study.
Axonal dystrophy was reported in monkeys exposed to PPO for 2 years, but there was no
dose response effect and the study was conducted with a limited number of animals per
group (n=2). PPO produces nasal cavity lesions in rats and mice in chronic studies. The
lesions include atrophy of the olfactory epithelium, basal cell hyperplasia and nest-like
infolds of the nasal epithelium. Although the mode of action for these non-neoplastic
lesions is not established, irritation of the nasal tissues is considered to contribute to these
extra extrathoracic effects.
Similar to ethylene oxide, PPO is a known mutagen which directly alkylates proteins and
DNA. Numerous published studies have shown that PPO induces mutations in bacteria,
yeast, fungi and insects. Chromosomal damage and aberrations and sister chromatid
exchange were reported in mammalian cells in vitro. PPO tested negative for
micronuclei induction in mice via the oral route and for dominant lethal assays in rats via
the inhalation and in mice via oral route.
PPO induces several types of tumors depending on the route of exposure. PPO
administered by oral gavage to rats produced tumors of the forestomach, which were
mainly squamous-cell carcinomas. This study provides limited information on
carcinogenicity effects in key tissues such as liver, kidney, thyroid etc. Further, it was
conducted only in rats of one sex (females), and any sex specific effects were not
determined.
In the carcinogenicity studies in rats via inhalation, equivocal evidence for mammary
gland tumors (significant fibroadenoma with marginal tubulopapillary adenocarcinoma)
in Wistar rats, and thyroid tumors (dose related increase in thyroid C-cell adenomas and
carcinomas) and adrenal gland tumors (adrenal pheochromocytoma) in F344 rats was
reported. The incidence of tumors in the nasal cavity was not significant in rats.
However, in mice exposed by inhalation, PPO produced hemangiomas and
hemangiosarcomas of the nasal cavity. The doses tested in the carcinogenicity studies
were considered adequate based on inflammatory lesions in the nasal cavity and other
systemic effects.
Although the incidence of forestomach tumors observed in PPO treated rats has a
questionable relevance to humans, these tumors could not be excluded due to 1) evidence
of mutagenicity in different organisms 2) chromosomal damage in mammalian cells in
vitro, and 3) adduct formation in vivo in tissues distant from the site of administration.
PPO has been classified by the Agency as a B2 carcinogen (probable human carcinogen).
The cancer slope factor is determined to be 0.15 (mg/kg/day)"1 for forestomach tumors
for the oral route of exposure. HED has derived an alternative cancer slope factor (Q*)
of 0.000086 (mg/kg diet)"1 using a concentration based approach. Use of an alternative
Page 14 of 95
Page 71 of 192
-------
approach is based on the fact that forestomach tumors in the rat treated by gavage may be
considered a portal of entry response. By analogy to the RfC methodology which
considers the concentration of test material to be the most important determinant of
response in portal of entry tumors, PPO dosage can be expressed as a concentration. The
cancer slope factor for the inhalation route of exposure is 3.5xlO~6 (jig/m3)'1 for nasal
cavity tumors for the inhalation route of exposure (USEPA, 1994). This assessment also
discusses MOA data submitted by, and on behalf of the registrant, which provide the
basis for use of an MOE approach for assessing inhalation cancer risks. After an initial
analysis, EPA concludes that the MOA proposed by the registrant is quite plausible, and
will review the proposed MOA in more depth, both within OPP and in conjunction other
Agency offices. If the proposed MOA is accepted by the Agency, propylene oxide will
not be regulated using a q* approach. Rather an MOE analysis will be conducted.
Propylene chlorohydrin
PCH, a major metabolite identified in spices and nutmeats sterilized with PPO, was
considered separately for dietary risk assessment. The database for PCH is inadequate.
PCH exists in two isomers, 1-chloro 2-propanol and 2-chloro-l-propanol. Most of the
toxicity studies are done with a mixture of isomers containing predominantly l-chloro-2-
propanol.
There are no guideline studies (acute, subchronic, developmental, reproduction or chronic
toxicity studies) submitted to the Agency. A search in the open literature provided a
developmental toxicity study and a few subchronic studies in rats. These studies lacked
sufficient study details or had deficiencies (poor stability of the test compound, studies
conducted before GLPs were established) which precluded gleaning any useful
information. However, the subchronic and chronic toxicity studies in rats and mice and
the reproduction toxicity study in rats conducted by NTP provided minimum information
to assess the dietary risk for PCH.
The available acute toxicity data indicate PCH as the Category II or III compound by the
oral route and a Category II compound by dermal route and Category is undetermined for
the inhalation route. Limited data suggest that PCH is a severe eye irritant but not a skin
irritant. There are no data available on dermal sensitization effects.
The evidence suggests that PCH is widely distributed in tissues, metabolized and
excreted following inhalation. Most of the administered radioactivity appears to be
excreted in urine as glutathione conjugates. Also, biliary excretion is reported in rats
exposed to PCH by inhalation. Following oral exposure, PCH is eliminated as a
glucuronic acid conjugate in addition to glutathione conjugate.
Adequate developmental studies are not available. One reproduction study in rats found
an increased percentage of abnormal sperm at the same dose which produced body
weight changes in dams. The decreased pup weights observed at doses which did not
produce toxic effects in dams indicate pups are more sensitive to the toxic effects of PCH
compared to dams. However, the dose level selected for risk assessment with an
Page 15 of 95
Page 72 of 192
-------
additional database uncertainty factor (10X) to the traditional 100X is considered to
protect any potential increased susceptibility effects in children. No neurotoxic effects
are evident in the available database for PCH.
In subchronic studies in rats and mice PCH produces cytoplasmic alteration and/or
degeneration of acinar cells in the pancreas. In addition, atrophy of the bone marrow and
spleen and hepatocellular vacuolization were reported in subchronic studies in rodents
and these effects were not reported in the chronic studies. The doses used for the chronic
studies are considered inadequate since no endpoints were established for systemic
effects.
Inductions of mutations in bacteria and chromosomal aberrations as well as sister
chromatid exchange in mammalian cells were reported for PCH. No evidence of
carcinogenicity was reported in the chronic studies conducted with inadequate doses in
both rats and mice.
Table 4 and 5 provide the toxicity profile of PPO* and PCH, respectively.
Table 4a- Acute Toxicity Profile of PPO
Study/ Species
870.1100
Acute Oral, Rats
Mice
Guinea pigs
870.1200
Acute Dermal, Rabbits
870.1300
Acute Inhalation, Rats
Mice
870.2400
Primary Eye Irritation, Rabbits
870.2500
Primary Skin Irritation, Rabbits
870.2600
Dermal Sensitization, Guinea Pigs
870.6200
Acute Neurotoxicity, Rats
MRID or Publication
Smyth etal. 1941 and
Antonova et al., 1981
Antonova et al., 1981
Smyth etal. 1941
Antonova et al., 1981
(AscitedinUSEPA,
1987)
No study identified
NTP, 1985
NTP, 1985
Weil etal., 1963
(As cited in WHO,
1985)
Roweetal., 1956
(AscitedinUSEPA,
1987)
No study identified
No study identified
Results
LD50 520-1 140 mg/kg bw
LD50 630 mg/kg bw (males)
LD50 660-690 mg/kg bw
LC50(4h): 7697-8265 mg/m3
(3207-3444 ppm)
LC50(4h): 2420-3540 mg/m3
(1008- 1475 ppm)
Severe eye irritant
Severe skin irritant
-
-
Classification
Category III
Category III
Category III
Category IV
Category IV
Category I
Category I
-
-
Table 4b: Subchronic, Chronic Toxicity Studies -PPO
Study/Species
MRID or
Publication
Doses
Results/Classification
Page 16 of 95
Page 73 of 192
-------
Table 4b: Subchronic, Chronic Toxicity Studies -PPO
Study/Species
MRID or
Publication
Doses
Results/Classification
Developmental/Reproduction Toxicity
Developmental
Toxicity
Fischer 344 Rats
41750801
Doses
(inhalation):
0, 100, 300,
500 ppm
(GD 6-15)
Maternal NOAEL: 300 ppm
Maternal LOAEL: 500 ppm
Decreased body weight gain, food efficiency and food
consumption
Developmental NOAEL: 300 ppm
Developmental LOAEL: 500 ppm
Increased litter incidence of an accessory 7th cervical rib
Acceptable/Guideline
Developmental
Toxicity
Sprague-Dawley Rats
41874102
Doses
(inhalation):
0, 500 ppm
(GD 7-16,
GD1-16,
GDl-16with
3 week
pregesational
exposure)
Maternal NOAEL: <500 ppm
Maternal LOAEL: 500 ppm
Decreased body weight, body weight gain and food
consumption
Developmental NOAEL: <500 ppm
Developmental LOAEL: 500 ppm
Decreased mean fetal weight, decreased crown rump length in
males and females and possibly increased fetal and litter
incidence for the reduced ossification of the vertebra.
Unacceptable/Guideline
Use of one exposure level, and inadequate data reporting
exposure)
Developmental
Toxicity, New Zealand
White Rabbits
41874102
Doses
(inhalation):
0, 500 ppm
GD7-19; GD
1-19
Maternal NOAEL: <500 ppm
Maternal LOAEL: 500 ppm
Increased mortality, reduced food consumption, and
microscopic changes in liver (minimal to mild portal
mononuclear inflammation), lungs (minimal to mild portal
mononuclear inflammation) and kidneys (mineralization of
proximal and renal tubules, subacute/chronic nephritis)
Developmental NOAEL: <500 ppm
Developmental LOAEL: 500 ppm
Increased resorptions, and/or increased incidence of minor
skeletal abnormalities
Unacceptable/Guideline
Study deficiencies included low pregnancy rate, use of one
exposure level, and inadequate data reporting. Complications
by a possible Pasteurella infection.
Two-Generation
Reproduction Study,
Fischer 344 Rats
45292701
Doses
(inhalation):
0, 30, 100,
300 ppm
Parental NOAEL: 100 ppm
Parental LOAEL: 300 ppm
Decreased body weights and weight gain in FO and Fl males
during premating and post mating periods and decreased body
weight and weight gain in FO and Fl females during premating
period
Reproductive NOAEL: 300 ppm
Reproductive LOAEL: >300 ppm
No reproductive effects at HOT
Offspring NOAEL: 300 ppm
Offspring LOAEL: >300 ppm
No offspring effects at HPT Acceptable/Guideline
Subchronic Oral Toxicity
Subchronic Toxicity,
Rats, Strain not
specified, 26-weeks
Antonova et al. 1981
(as cited in WHO,
1985)
Doses
(drinking
water): 0,
NOAEL: 0.0052 mg/kg/day
LOAEL: 0.052 mg/kg/day
Mild hematological abnormalities
Page 17 of 95
Page 74 of 192
-------
Table 4b: Subchronic, Chronic Toxicity Studies -PPO
Study/Species
Subchronic
24 days
Females rats
MRID or
Publication
Roweetal. 1956
(as cited in USEPA,
1987)
Doses
0.00052,
0.0052,
0.052, 0.52
mg/kg/day
Doses (oral):
0, 100, 200,
300 mg/kg
Results/Classification
Unacceptable/Non-Guideline
Secondary source and information could not be verified
NOAEL: 200 mg/kg
LOAEL: 300 mg/kg
Slight decrease in body weight, gastric irritation, and slight liver
damage
Unacceptable/Non-Guideline
Secondary source and information could not be verified
Subchronic Inhalation Toxicity
Subchronic
Neurotoxicity, Fischer
344 male Rats, 24
weeks
Subchronic
Neurotoxicity, Wistar
Rats, 7 weeks
Subchronic Toxicity,
Fischer 344/N Rats, 12-
14 days
Subchronic Toxicity,
B6C3FlMice, 12-14
days
Subchronic Toxicity,
Fischer 344/N Rats, 13
weeks
Subchronic Toxicity,
B6C3FlMice, 13
weeks
45292801
Ohnishietal., 1988
NTP, 1985
NTP, 1985
NTP, 1985
NTP, 1985
Doses
(inhalation):
0, 30, 100,
300 ppm
Doses
(inhalation):
0, 1500 ppm
Doses
(inhalation):
0, 47, 99,
196, 487,
1433 ppm
Doses
(inhalation):
0, 20, 47, 99,
196, 487
ppm
Doses
(inhalation):
0,31,63,
125, 250,
500 ppm
Doses
(inhalation):
0,31,63,
125, 250,
500 ppm
NOAEL: 300 ppm
LOAEL: >300 ppm
No systemic and neurological effects at the HOT
Acceptable/Non-Guideline
NOAEL: Not Established
LOAEL: 1500 ppm
Awkward gait during third and fourth week of exposure and
more ataxia in all rats by 7th week; histo: axonal degeneration of
the hindleg nerve and fasciculus gracilis and myelinated fibers
in the sacral spinal root
Uncceptable/Non-Guideline Only one dose was tested
NOAEL: 487 ppm
LOAEL: 1433 ppm
Decreased body weight gain, dyspnea, hypoactivity, gasping,
ataxia, and diarrhea were observed at the highest dose; 20%
mortality in males Acceptable/Non-Guideline
NOAEL: 99 ppm
LOAEL: 196 ppm
Dyspnea
Acceptable/Non-Guideline
NOAEL: 500 ppm
LOAEL: Not established
Acceptable/Non-Guideline
NOAEL: 250 ppm
LOAEL: 500 ppm
Decreased body weight (12.9% in males and 14.6% in females)
Acceptable/Non-Guideline
Chronic Oral Toxicity
870.4100
Chronic Toxicity-
Female Sprague-
Dawley Rats
2 years
Dunkelberg, 1982
Doses (oral):
0, 0(salad
oil), 15 or 60
mg/kg by
Gavage
NOAEL: Not Established
LOAEL: 15 mg/kg/day
Based on hyperkeratosis, hyperplasia and papillomas
Combined incidences of hyperkeratosis, hyperplasia and
papillomas were 0/50, 7/50, and 17/50
Forestomach tumors-primarily squamous cell carcinoma -
incidence: 0/50 for both controls, 2/50, and 19/50 for low and
high dose groups. Highest dose also had one adenocarcinoma of
the pylorus and carcinoma in situ of the forestomach
Page 18 of 95
Page 75 of 192
-------
Table 4b: Subchronic, Chronic Toxicity Studies -PPO
Study/Species
MRID or
Publication
Doses
Results/Classification
Acceptable/Non-Guideline
Chronic Inhalation Toxicity
870.4300
Combined/
Chronic Toxicity/
Carcinogenicity Study,
Wistar Rats
123 weeks (Females)
124 weeks (Males)
Kuperetal. 1988
and 4203 9901
Doses
(inhalation):
0, 30, 100 or
300 ppm
Systemic NOAEL: 30 ppm
Systemic LOAEL: 100 ppm
BMD/BMDL10:140/120 ppm (moderate to marked effects)
Increased incidences for basal cell hyperplasia, and nest-like
infolds of the respiratory epithelium
Cancer Effects
No statistically significant nasal tumors in nasal cavity.
However, 3 malignant tumors in nasal cavity were reported in
males (one tumor of ameloblastic fibrosarcoma in low dose
male, one squamous cell carcinoma in a low dose male and in a
high dose male). Four males in the HDT had a carcinoma in the
larynx or pharynx, trachea or lungs. Controls had no nasal
tumors.
Incidences of fibroadenomas of the mammary gland tumors are:
32/69(46%), 30/71(42%), 39/69(57%), 47/70 (67%) in control,
low, mid and high dose groups respectively; significant at high
dose (p<0.04). Historical control incidence of benign tumors in
the mammary gland in the lab ranges 19-61%.
Incidences of tubulopapillary adenocarcinoma: 3/69, 6/71, 5/69
8/70 (pO.Ol) 70 in control, low, mid and high dose groups
respectively. Historical control incidence of malignant tumors
in the mammary gland in the lab ranges 0-15%.
Acceptable/Guideline Study
870.4300
Combined
Chronic Toxicity/
Carcinogenicity
Male F344 Rats, 104
weeks
Lynch etal. 1984
Doses
(inhalation):
0, 100, 300
ppm
Systemic NOAEL: Not Established
Systemic LOAEL: 100 ppm
Decreased body weight, increased hemoglobin, organ weights
and extra thoracic (nasal suppurative rhinitis) effects.
Cancer Effects
Adrenal pheochromocytoma at both doses (8/78, 25/78, 22/80 in
control, low and high dose groups, p<0.05)
870.4300
Combined
Chronic Toxicity/
Carcinogenicity
F344 Rats, 103 weeks
NTP, 1985
Doses
(inhalation):
0, 200, 400
ppm
Systemic NOAEL: Not Established
Systemic LOAEL: 200 ppm
extra thoracic respiratory effects
Cancer Effects
At 400 ppm, 2/50 (m) and 3/50 (f) had papillary adenomas of
the respiratory epithelium and submucosal glands of the nasal
turbinates compared to none in low and control groups.
An increase in the thyroid C-cell adenomas and carcinomas
occurred at 400 ppm. In females the combined incidences of C-
cell adenomas and carcinomas of the thyroid were 2/45, 2/35,
7/37 (p=0.023).
NTP concluded that this tumor type does not provide
unequivocal evidence of Carcinogenicity for PPO in rats.
Acceptable/Non-Guideline
870.4200
Combined Chronic
Toxicity/
Carcinogenicity
B6C3FlMice, 103
weeks
NTP, 1985
Doses
(inhalation):
ppm
0, 200, 400
ppm
Systemic NOAEL: Not established
Systemic LOAEL: 200 ppm
extrathoracic respiratory effects
HDT had decreased survival in males and females, decreased
body weights in both sexes, sporadic metaplasia and
hyperplasia and chronic inflammation in the nasal cavity.
Page 19 of 95
Page 76 of 192
-------
Table 4b: Subchronic, Chronic Toxicity Studies -PPO
Study/Species
870.4100
Chronic Toxicity-
cynomolgus Monkeys
2 years
MRID or
Publication
Sprinzetal. 1982
(As cited in EPA,
1994)andSetzerat
al. 1996
Doses
Doses
(inhalation):
0, 100 or 300
ppm
Results/Classification
Cancer Effects
Nasal cavity: The combined incidences of hemangiomas and
hemangiosarcomas in the nasal cavity were: males-0/50, 0/50,
10/50, pO.OOl; females- 0/50, 0/50, 5/50, p=0.028)
one squamous cell carcinoma and one papilloma were induced
in nasal cavity at high dose (1 male each, not significant),
adenocarcinomas in nasal cavity ( 2 females, not significant)
NTP concluded as clear evidence of carcinogenicity for PPO in
mice. Acceptable/Non-Guideline
NOAEL: Not established
LOAEL: 100 ppm
Increased incidence for axonal dystrophy in the medulla
oblongata and in the most distal portions of the fasciculus
gracilus in all treated monkeys (2/2 in each PPO group) as
compared to one (1/2) in controls. No dose related lesions
between the treatments. Acceptable/Non-Guideline Study
Subchronic Dermal Toxicity
21 -Day Dermal
Toxicity (Rats)
Dermal Absorption
No Study identified
No Study identified
Metabolism
WHO, 1985
-No data on absorption of propylene oxide.
-Two metabolic pathways suggested: 1) conjugation with
glutathione via glutathione epoxide transferase 2) hydrolysis by
epoxide hydrolase to 1,2 propanediol (propylene glycol).
Propanediol can be excreted as such or metabolized to lactic and
pyruvic acid
-Propylene oxide is a direct alkylating agent. Forms DNA (N-2-
hydroxypropyl-guanosine, N-2-hydroxypropyl-guanosine) and
protein adducts (hemoglobin alkylation at the cysteine, histidine
orvaline) residues.
-Assuming a 100% alveolar absorption and first-order kinetics, a
half-life of 40 minutes was estimated for the elimination of PPO
in rats
Under in vitro conditions, the half-life of propylene oxide in
stomach (pHl and 37°C) is reported approximately one minute.
Mutation/Genotoxicity
Multiple references
as cited in IARC,
1994
Mutagenic in bacteria, fungi and insects; caused DNA damage
in rat hepatocytes in vitro; caused chromosomal aberrations in
vitro in mammalian cells; however, no increase in chromosomal
aberrations of peripheral lymphocytes of male cynomolgus
monkeys after long term exposure in vivo (up to 300 ppm for 2
years), inconsistent results in micronuclei formation in mice
erythrocytes in vivo, negative results for dominant lethal assays
in rats and mice.
1 ppm =
Table 5a: f Acute
Toxicity
of Propylene
Chlorohydrin (l-chloro-2-propanol,
Study/ Species
MRID or Publication
2-chloro-l-propanol)
Results
Classification
Page 20 of 95
Page 77 of 192
-------
Table 5a: f Acute Toxicity of Propylene Chlorohydrin (l-chloro-2-propanol, 2-chloro-l-propanol)
Study/ Species
870.1100
Acute Oral, Rats
Mouse
Guinea pigs
Dogs
870.1200
Acute Dermal, Rabbits
870.1300
Acute Inhalation, Rats
870.2400
Primary Eye Irritation, Rabbits
870.2500
Primary Skin Irritation,
Rabbits
870.2600
Dermal Sensitization,
Guinea pig
870.6200
Acute Neurotoxicity, Rats
MRID or Publication
Smyth etal., 1941, US
FDA, 1969
Weisbrod, 1981
Smyth etal., 1941
FDA, 1969
(as cited in TNO
BIBRA International,
1994)
Smyth etal., 1969
Weisbrod, 1981
(as cited in TNO
BIBRA International,
1994)
Smyth and Carpenter,
1969
(as cited in NTP, 1998)
Carpenter and Smyth
et al. 1946?)
(as cited in NTP, 1998)
Smyth etal 1969
(as cited in TNO
BIBRA International,
1994)
No study identified
No study identified
Results
OralLD50= 220 mg/kg
OralLD50= 580 mg/kg
OralLD50= 720 mg/kg
At 200 mg/kg one of seven dogs
died while 250 mg/kg or above
was lethal to all six treated dogs
LD50 = 528 mg/kg
LD50 = 440 mg/kg
LC50 = Not Determined
Inhalation of 500 ppm (1.94
mg/L) PPO resulted in death of
1/6 animals after 4 hours.
Severe injury to the rabbit cornea
following instillation of 0.005 ml
propylene chlorohydrin
Limited data-No irritation 24 hr
following application of 0.01 ml
propylene chlorohydrin in a
rabbit
-
Classification
Category II
Category III
Category III
Category II
Category II
Category Undetermined
-
f Note: The strain of the animals used and type of PCH isomer used in acute tests are not specified.
Table 5b: Subchronic, Chronic Toxicity Studies - Propylene Chlorohydrin (l-chloro-2-propanol, 2-chloro-l-propanol)
Study/Species
MRID or
Publication
Doses
Results/Classification
Developmental/Reproduction Toxicity
870.3700
Developmental Toxicity
Rats (Strain not specified)
Exxon
Chemical
Company,
1980
(as cited in
NTP, 1998)
Doses: 8, 20, 50 or 125
mg/kg
GD 6-15 (gavage)
Maternal NOAEL/LOAEL: Could not be
determined
Developmental NOAEL/LOAEL: Could not
be determined
Maternal effects: Slight decrease in embryo
survival in the 8 and 125 mg/kg groups
Developmental effects: Two fetuses showed
gross malformation (dose not specified)
Unacceptable/Non-Guideline
Data could not be verified; secondary source of
Page 21 of 95
Page 78 of 192
-------
Table 5b: Subchronic, Chronic Toxicity Studies - Propylene Chlorohydrin (l-chloro-2-propanol, 2-chloro-l-propanol)
Study/Species
870.3700
Developmental Toxicity Rabbits
870.3800
Two-Generation Reproduction
Study, Rats
MRIDor
Publication
Doses
Results/Classification
information
No study identified
NTP, 1998
Doses: 0, 300, 650, 1300
ppm in drinking water
(equivalent to 0, 30, 65,
130, mg/kg/day;
determined assuming 30 ml
as daily water consumption
and average body weight of
dams as 0.3 kg)
Parental NOAEL:65 mg/kg/day
Parental LOAEL: 130 mg/kg/day
Decreased body weight of F0 dams during
gestation and lactation, and FI dams during
gestation
Reproductive NOAEL: Not determined
Reproductive LOAEL: 130 mg/kg/day
Increased percentage of abnormal sperm
Offspring NOAEL: 30 mg/kg/day
Offspring LOAEL: 65 mg/kg/day
Decreased FI male and female pup weights at
PND 14 and 21
Acceptable/Non-Guideline
Subchronic Oral Toxicity
Subchronic (22 weeks)
Rats
Subchronic (25 weeks)
Rats
Subchronic (14 days)
F344 Rats
Subchronic (14 days), B6C3F1
mice
Subchronic (14 week)
F344 Rats
USFDA,
1969
(as cited in
TNO
BIBRA
Internation
al, 1994)
USFDA,
1969
(as cited in
TNO
BIBRA
Inter
national,
1994)
NTP, 1998
NTP, 1998
NTP, 1998
Doses: 0, 25, 50 or 75
mg/kg/day; Another group
with 100-250 mg/kg/day
Gavage
Doses: 0, 1000, 2500, 5000
or 10000 ppm in diet
(estimated as 0, 100, 250,
500, 1000 mg/kg/day)
Doses: 0, 100, 330, 1000,
3300, 10,000 ppm in
drinking water
(determined by study
authors as 0, 15, 45, 140,
260, 265 mg/kg/day)
Doses: 0, 100, 330, 1000,
3300, 10,000 ppm in
drinking water
(determined by study
authors as 0, 20, 60, 175,
430, or 630 mg/kg/day in
males and 0, 25, 95, 290,
640, or 940 mg/kg/day in
females)
Doses: 0, 33, 100, 330,
1000, 3300 ppm in drinking
water
NOAEL: <25 mg/kg/day
LOAEL: 25 mg/kg/day
Increased liver weight in males
100% mortality at 250 mg/kg/day within 3
weeks.
Unacceptable/Non-Guideline
Secondary reference and information could not
be verified.
NOAEL: 250 mg/kg/day
LOAEL: 500 mg/kg/day
Decreased body weight
Unacceptable/Non-Guideline
Secondary reference and information could not
be verified.
NOAEL: 45 mg/kg/day
LOAEL: 140 mg/kg/day
cytoplasmic alteration and degeneration of the
acinar cells in the pancreas and atrophy of the
bone marrow in females
Acceptable/Non-Guideline
NOAEL: 60 mg/kg/day
LOAEL: 175 mg/kg/day
Increased liver weight relative to body weight in
females and increased vacuolization of
cytoplasm of hepatocytes in both males and
females
Acceptable/Non-Guideline
NOAEL: 35 mg/kg/day
LOAEL: 100 mg/kg/day
Increased incidences of the acinar cell
Page 22 of 95
Page 79 of 192
-------
Table 5b: Subchronic, Chronic Toxicity Studies - Propylene Chlorohydrin (l-chloro-2-propanol, 2-chloro-l-propanol)
Study/Species
Subchronic (14 week)
B6C3F1 mice
MRIDor
Publication
NTP, 1998
Doses
(determined by study
authors as 0, 5, 10, 35, 100,
220 mg/kg/day)
Doses: 0, 33, 100, 330,
1000, 3300 ppm in drinking
water
(determined by study
authors as 5, 15, 50, 170,
340 mg/kg/day in males
and 7, 20, 70, 260 or 420
mg/kg in females)
Results/Classification
degeneration, and fatty change of the pancreas in
males and females.
Acceptable/Non-Guideline
NOAEL: 50 mg/kg/day
LOAEL: 170 mg/kg/day
Increased organ weights and increased incidence
of renal tubule vacuolization in males
Acceptable/Non-Guideline
Subchronic Dermal Toxicity
Subchronic (21 days or 13 week)
No study identified
Combined Chronic Carcinogenicity
870.4300
Chronic (2 years)
F344 Rats
870.4300
Chronic (2 years)
B6C3F1 mice
NTP, 1998
NTP, 1998
Doses: 0, 150, 325, or 650
ppm
in drinking water
(determined by study
authors as 0, 15, 30, or 65
mg/kg/day during
beginning months and 0, 8,
17, or 34 mg/kg/day during
remainder months)
Doses: 0, 250, 500 or 1000
ppm in drinking water
(determined by study
authors as 0, 45, 75, or 150
mg/kg/day in males and 0,
60, 105, or 2 10 mg/kg/day
in females during first few
months and 0, 25, 50, or
100 mg/kg/day for
remainder of the study)
NOAEL: 65 mg/kg/day (HOT)
LOAEL: Not established
No treatment related cancer or non-cancer
effects.
Acceptable/Non-Guideline
NOAEL: 210 mg/kg/day
LOAEL: Not established
No effects at any of the doses tested.
No evidence of carcinogenicity.
Acceptable/Non-Guideline
Mutation/Genotoxicity
Multiple
references
(as cited in
NTP, 1998)
-Weakly mutagenic in TA100 in the presence of
S9
Positive in TA1535 with or without S9.
-No mutagenic activity in TA97, TA98, and
TA1537 with or without S9 extract.
-CHO cells- caused high levels of chromatid
exchanges and chromosomal aberration in the
presence or absence of S9 extract.
-No chromosomal aberrations in vivo.
-Induced sex-linked recessive lethal mutations in
Drosophila in injection but not by feed
-Negative for germ cell reciprocal translocation
in Drosophila
-Negative for micronuclei formation in vivo in
mice
Metabolism
Multiple
-
Absorption: No data
Page 23 of 95
Page 80 of 192
-------
Table 5b: Subchronic, Chronic Toxicity Studies - Propylene Chlorohydrin (l-chloro-2-propanol, 2-chloro-l-propanol)
Study/Species
MRIDor
Publication
references
(as cited in
NTP, 1998)
Doses
Results/Classification
Metabolism: Following inhalation, PCH was
widely distributed to tissues, rapidly
metabolized and eliminated.
Excretion: Following oral administration of
propylene chlorohydrin in rabbits 1 1% was
excreted in urine as glucuronic acid conjugate.
In rats dosed orally with PCH the metabolites, 2-
hydroxy propylmercapturic acid (N-acetyl-S-(2-
hydroxy propyl)-cysteine) and beta-
choloroacetate were identified in urine. In rats
administered with PCH by inhalation most of
the radioactivity (80%) was excreted in urine
and in the expired air. Half-lives for elimination
were 4 hours for breath and 5 hours for urine.
Also, biliary excretion was reported as another
major route of elimination (30% of inhaled
dose) for PCH administered by inhalation.
Metabolites related to glutathione conjugates, N-
acetyl-S-(2-hydroxy propyl)-cysteine and/or S-
(2-hydroxy propyl)-cysteine were identified in
both liver and urine.
4.2 FQPA Hazard Considerations
4.2.1 Adequacy of the Toxicity Database
4.2.1.1 Propylene Oxide
The toxicology database for PPO is considered incomplete. The database includes
acceptable developmental toxicity and reproduction toxicity, subchronic neurotoxicity
(non-guideline), and chronic carcinogenicity in rats, all conducted via inhalation. There
is no acceptable developmental study in rabbits. Also, the database lacks a chronic
toxicity study in non rodents. In addition, there is a published study examining the
carcinogenicity effects of PPO by the oral route. This chronic toxicity study via the oral
route is inadequate since one sex alone was examined. Moreover, adequate systemic
effects were not measured, and pathological examination of tissues is not complete. This
study was the only chronic toxicity study available for the oral route and was considered
for risk assessment.
4.2.1.2 Propylene Chlorohydrin
The database for PCH is inadequate. There are no guideline studies (acute battery of
tests, subchronic, developmental, reproduction or chronic toxicity studies) submitted to
the Agency. A search in the open literature provided information on reproductive
toxicity and subchronic and chronic toxicities. One rat developmental toxicity study
identified in the literature lacked sufficient study details to glean any useful information.
A few subchronic oral toxicity studies in rats identified in the literature had deficiencies
Page 24 of 95
Page 81 of 192
-------
such as poor stability of the test compound, and were conducted before GLPs were
established. However, the subchronic and chronic toxicity studies in rats and mice and
the reproduction toxicity study in rats conducted by NTP provided sufficient information
to assess the dietary risk for PCH. The lack of acceptable developmental toxicity studies
limited the ability to assess the fetal susceptibility effects under FQPA.
4.2.2 Evidence of Neurotoxicity
4.2.2.1 Propylene Oxide
In a subchronic inhalation neurotoxicity study (MRID 45292801), Fisher-344 male rats
exposed to 0, 30, 100, or 300 ppm of propylene oxide (>99% active ingredient) for 6
hr/day, 5 days/week for the first 14 weeks and 7 days/week for the remainder of the study
up to 24 weeks. No treatment-related mortalities or clinical signs of toxicity were
reported. No treatment-related changes in body weight, FOB or motor activity or hind
limb strength were seen. No treatment-related abnormalities were observed during
handling and no gait or locomotor abnormalities were noted in the open field. Reflex and
sensorimotor responses were similar between the treated and control groups. No gross
necropsy and neuropathology were observed.
This study is classified as Acceptable/Non-Guideline and does not satisfy the
requirements for a subchronic inhalation neurotoxicity study [OPPTS 870.6200 (§82-7)]
in rats. The LOAEL for neurotoxic effects is not established. Validation of the
laboratory neurotoxicity testing methods was not included and females were not tested.
However, the study is sufficient for the purposes for which it was intended to assess the
potential of propylene oxide to induce neurotoxicity in male rats following subchronic
inhalation exposure.
Studies from the Open Literature
Wistar rats were exposed to 1500 ppm propylene oxide for 6 hours/day, 5 days/week for
7 weeks (Ohnishi et al., 1988). Awkward gait was apparent in exposed rats by the third to
fourth week of exposure and all rats exhibited obvious ataxia by the seventh week.
Histopathological examination revealed axonal degeneration of the hindleg nerve and
fasciculus gracilis myelinated fibers, and myelinated fibers in the sacral spinal root. The
LOAEL for this study was determined as 1500 ppm, the only dose tested. This study is
classified as Unacceptable-Non-Guideline.
Sprinz et al. (1982; as cited in US EPA, 1994) treated male cynomolgus monkeys
(2/group) at 0, 100, or 300 ppm propylene oxide, 7h/day, 5 days/week for 2 years. Nerve
conduction velocity was measured throughout the exposure and at the termination of
exposure; sections of peripheral nerves, spinal cord, and brain (19 regions) were
examined. No exposure-related changes were observed in the peripheral nerves or the
spinal cord. Axonal dystrophy was observed in the medulla oblongata and in the most
distal portions of the fasciculus gracilus in one control monkey and in all four exposed
monkeys. The extent of the lesion was similar in all affected monkeys and was not dose-
Page 25 of 95
Page 82 of 192
-------
related. These findings are also reported in the publication by Setzer et al. (1996). This
study is classified as Acceptable-Non-Guideline.
4.2.2.2 Propylene Chlorohydrin
There are no neurotoxicity studies available for PCH. Clinical signs of neurotoxicity are
not evident in the available database.
4.2.3 Developmental Toxicity Studies
4.2.3.1 Propylene Oxide
Rats
In an inhalation developmental toxicity study (MRTD 41750801), 25 pregnant Fischer
344 rats per group were administered propylene oxide (>99% a.i.; Lot: IRDC Nos.
8863C and 8863D) by whole body exposure to atmospheric concentrations of 0, 100,
300, or 500 ppm for 6 hours/day on gestation days (GD) 6-15, inclusive. On GD 20,
dams were sacrificed, subjected to gross necropsy, and all fetuses examined externally.
One-half of the fetuses were examined viscerally, and the remaining fetuses were
examined for skeletal malformations/variations.
All animals survived to scheduled sacrifice. No treatment-related clinical signs of
toxicity were observed in any treated animals during the study, nor were any treatment-
related gross abnormalities observed at maternal necropsy. Maternal toxicity in the 500
ppm exposure group was evidenced by statistically significant decreases (p < 0.05; 0.01)
in body weight gain (40% of control on GD 6-15), and food consumption (88-91% of
controls during the various exposure intervals). In addition, food efficiency was
substantially decreased during the exposure interval, GD6-16 (45% of controls), further
indicating maternal toxicity. Absolute body weights in the 500 ppm group showed
statistically significant decreases (p < 0.01), but these values represented only 95-96% of
control values. No treatment-related differences in body weight, body weight gain, or
food consumption were observed in animals exposed to 300 ppm propylene oxide or less.
Therefore, the maternal toxicity LOAEL is 500 ppm based on decreased body
weight gains, food efficiency and food consumption and the maternal toxicity
NOAEL is 300 ppm.
There were no differences between treated and control groups for number of corpora
lutea/dam, implantation sites/dam, pre- or post-implantation loss, resorptions/dam,
fetuses/litter, fetal sex ratios, gravid uterine or fetal body weights, or number of dead
fetuses.
Page 26 of 95
Page 83 of 192
-------
There were no statistically significant or treatment-related differences between control
and treated groups regarding the number of external, soft-tissue, or skeletal
malformations/variations with the exception of an increased litter incidence of an
accessory 7th cervical rib in the 500 ppm group compared to the controls (p < 0.01)
(2/17, 4/20, 3/22, and 11/21 for 0, 100, 300 or 500 ppm groups, respectively).
Therefore, the developmental toxicity LOAEL is 500 ppm based on an increased
litter incidence of an accessory cervical rib and the developmental toxicity NOAEL
is 300 ppm.
This study is classified as Acceptable-Guideline and satisfies the requirement for an
inhalation developmental toxicity study in rats (§83-3; OPPTS 870.3700).
COMPLIANCE: Signed and dated Quality Assurance, Good Laboratory Practice
Statements, Data Confidentiality and Flagging statements were included.
In a developmental toxicity NIOSH sponsored study (MRTD 41874102), Sprague-Dawley
rats were whole-body exposed to filtered air (groups 1-3, 170 rats) or 500 ppm propylene
oxide (>99% a.i.; group 4 = 50 rats) for 7 hours/day by inhalation for a 3 week
pregestation (pregestation day = PGD) period. Following this exposure interval, the
group 1-3 animals were reallocated (45-48/exposure interval) and were exposed
according to one of the following regimes: i) control group received filtered air from
gestation days (GDs) 1-16; ii) group 2 received filtered air from GDs 1-6 and test
chemical from GDs 7-16; and iii) group 3 received the test chemical from GDs 1-16.
Group 4 continued to receive the test chemical from GDs 1-16 (in addition to the 3 week
pregestational exposure). All dams were sacrificed on GD 21. No unscheduled deaths
were reported.
When compared to controls, decreases (p<0.05) were observed in group 4 body weights
from GDs 6-21 (xllO-12%). Overall gestation body weight gain (GD 1-21), as calculated
by reviewers and not analyzed for statistical significance, was reduced in all treated
groups when compared to controls (group 2, xll8%; group 3, xll3%; group 4, xll6%).
Further, overall study body weight gain (PGD 3-GD 21) was reduced in all treated groups
when compared to controls (group 2, -Il7%; group 3, >ll2%; group 4, xl<27%, calculated
by reviewers).
When compared to concurrent controls, variations (p<0.05) in absolute (g/rat/day) food
consumption were observed in groups 2, 3, and 4, respectively, as follows: during
pregestation week 2 (tl, ±1, and ^14%); GDs 7-11 (^33, ^29, and ^29%); GDs 12-16
(Il4, ^15, ^8%); and GDs 17-21 (tl2, T18, and
It was unconfirmed on page 10 of the evaluative summary of the study report that the
animals were checked daily for clinical signs of toxicity; the study report does not
indicate that nor any clinical signs data were provided. No gross pathology data were
Page 27 of 95
Page 84 of 192
-------
provided. No treatment-related changes in organ weight or histopathological findings
were noted at any exposure interval tested. Percent pre- and post-implantation losses
were not reported and could not be calculated by reviewers due to the lack of total
numbers of corpora lutea and implantation sites.
The maternal LOAEL is 500 ppm (only dose selected) on PGD 3-GD 21, based on
decreased body weight, body weight gains, and food consumption.
Developmental effects were significant (p<0.05) decrease in mean fetal weights and
decrease in crown-rump lengths in males and females at all exposure regimens in
comparison to concurrent controls. The fetal as well as the litter incidence for the
reduced ossification of the vertebra was significant (p<0.01) compared to controls in
dams exposed to propylene oxide during GD1-16.
The developmental LOAEL based on the decreased mean fetal weights and crown-
rump length in males and females and possibly reduced ossification of the vertebra
is 500 ppm (only dose selected).
Study deficiencies included possible dermal absorption due to whole body exposure, use
of one exposure level, inadequate data reporting and animal husbandry and no historical
control data. Individual animal data were not reported. Therefore, this developmental
toxicity study is classified as Unacceptable/Guideline and does not satisfy the guideline
requirement for a developmental toxicity study in the rat. An acceptable rat
developmental study (MRID 41750801) for inhalation of propylene oxide does exist.
COMPLIANCE: Signed and dated GLP, Data Confidentiality, Flagging, and Quality
Assurance statements were provided.
Rabbits
In a developmental toxicity NIOSH sponsored study (MRID 41874102), New Zealand
White rabbits (30/exposure interval) were whole-body exposed to 500 ppm propylene
oxide (>99% a.i.) for 7 hours/day by inhalation according to one of the following
regimes: i) control group received filtered air from gestation days (GDs) 1-19; ii) group 2
received filtered air from GDs 1-6 and test chemical from GDs 7-19; and iii) group 3
received the test chemical from GDs 1-19. All does received filtered air from GDs 20-29
and were sacrificed on GD 30. All control animals survived to scheduled sacrifice.
In group 2, four rabbits died of pneumonia on GDs 19, 23, or 26. Decreases (p<0.05) in
absolute (g/rabbit/day) food consumption were observed during GDs 11-15 (~l\ 1%) and
GDs 16-20 (xll3%). Regarding histopathological findings, the following minimal to mild
findings were observed: portal mononuclear inflammation in the liver in 10/26 animals
vs. 8/30 controls; sub acute/chronic nephritis in 9/26 animals vs. 3/30 controls; and focal
mononuclear inflammation of the lung in 11/26 animals vs. 5/30 controls.
Page 28 of 95
Page 85 of 192
-------
In group 3, three rabbits died of pneumonia on GDs 15, 17, or 18. Overall body weight
gain was reduced (>l34%, GDs 1-30) as was the gravid uterine weight (*ll9%) when
compared to the controls; both were calculated by reviewers and not analyzed for
statistical significance. Decreases (p<0.05) in absolute food consumption were observed
during GDs 11-15 (^38%) and GDs 16-20 (^21%); additionally, food consumption in
group 3 was different (p<0.05) from group 2 during GDs 1-5 (j.22%) and GDs 11-15
(-130%). The following minimal to mild findings were observed: portal mononuclear
inflammation in the liver in 11/26 animals vs. 8/30 controls; mineralization of the
proximal and distal renal tubules in 10/26 animals vs. 7/30 controls; sub acute/chronic
nephritis in 10/26 animals vs. 3/30 controls; and focal mononuclear inflammation of the
lung in 10/26 animals vs. 5/30 controls.
It was unconfirmed on page 10 of the evaluative summary of the study report that the
animals were checked daily for clinical signs of toxicity; however, no clinical signs data
were provided. No treatment-related differences in maternal body weights or organ
weights (absolute and relative to body) were observed. No gross pathology data were
provided. An insufficient number of females (< 20 females) with implantation sites at
necropsy in the control and group 2 (17 and 14 animals, respectively) and low pregnancy
rates in all groups (47-67%) were observed. The number of implantations/doe, percent
male, and fetal weights were similar between control and treated groups. Percent pre-
and postimplantation losses were not reported and could not be calculated by reviewers
due to the lack of total numbers of corpora lutea and implantation sites.
The maternal LOAEL is 500 ppm (only dose tested) on GDs 7-19, based on
increased mortality, reduced food consumption, and microscopic changes in the
liver, lungs, and kidneys.
In group 3, increases (not statistically significant) in the number of resorptions/doe
(Tl23%), number of early resorptions/doe (T250%), and number of late resorptions/doe
(T34%) were observed. The following minor skeletal abnormalities were observed in the
group 3 fetuses [% fetal incidence (% litter incidence)]: misaligned sternebrae [4.2
(23.5)]; fused sternebrae [2.5 (17.6)]; and forelimb flexures [2.5 (17.6)]. None of these
findings were observed in the control animals. Bipartite sternebrae was observed in the
group 3 fetuses [2.5 (17.6)] vs. controls [0.79 (6.7)].
The developmental LOAEL is 500 ppm (only dose tested) on GDs 7-19, based on
increased resorptions and increased incidence of minor skeletal abnormalities.
Study deficiencies included low pregnancy rate, possible dermal absorption due to whole
body exposure, use of one exposure level, inadequate data reporting and animal
husbandry and no historical control data. Individual animal data was not reported.
Further, the results of the study were complicated by a possible Pasteurella infection.
Therefore, this developmental toxicity study is classified as Unacceptable/Non-
Guideline and does not satisfy the guideline requirement for a developmental toxicity
study in the rabbit.
Page 29 of 95
Page 86 of 192
-------
COMPLIANCE: Signed and dated GLP, Data Confidentiality, Flagging, and Quality
Assurance statements were provided.
Page 3 Oof 95
Page 87 of 192
-------
4.2.3.2 Propylene Chlorohydrin
Rats
There is no guideline developmental toxicity study conducted using rats. However, there
is minimal information found from one rat developmental study was identified from the
open literature.
Exxon Chemical Company, 1980 (as cited inNTP, 1998)
In the developmental study, rats (strain unspecified) were gavaged with PCH at 8, 20, 50
or 125 mg/kg during GD6-15. There was a slight decrease in the embryo survival in the
8 and 125 mg/kg groups. Two fetuses showed gross malformation at unspecified doses.
No information on controls provided.
This study is classified as Unacceptable/Non-Guideline Study and does not satisfy the
requirement for a developmental toxicity study in rats (§83-3, OPPTS 870.3700).
Rabbits
There is no guideline developmental toxicity study available for rabbits.
4.2.4 Reproduction Toxicity Studies
4.2 A A Propylene Oxide
In a two-generation reproduction study (MRID 45292701), propylene oxide (30215 III,
>99%, a.i.) vapor was administered to groups of 30 male and 30 female F0 and FI Fischer
344 rats by inhalation at chamber concentrations of 0, 30, 100, or 300 ppm. Each group
was exposed to room air (controls) or propylene oxide vapor for 6 hours/day,
5 days/week for 14 weeks (Fo) or 17 weeks (Fi) during the premating period and for
6 hour/day, 7 days/week during the mating, gestation, and lactation periods. The FI pups
selected to parent the F2 generation were exposed to room air or the same concentrations
of propylene oxide vapor as their parents.
No treatment-related deaths, clinical signs, or gross lesions were observed in rats exposed
to any concentration of propylene oxide vapor during premating and postmating periods
for adult FO or FI males or during the premating period for adult FO or FI females. Adult
FO and FI males exposed to 300 ppm of propylene oxide vapor weighed 4-10% (p<0.05)
and 7-18% (p<0.05), respectively, less than controls for almost all the study including the
premating and post mating periods. Both generations gained 13% less weight than
controls during the entire study duration. FO males exposed to 30 and 100 ppm and FI
males exposed to 30 ppm weighed significantly less (3-7%) than controls during the
study, but these small differences are not considered lexicologically significant. F0
females in the 300-ppm group weighed 3-6% (p<0.05) less than controls and FI females
weighed 7-10% (p<0.05) less than controls during the premating period; weight gain was
Page 31 of 95
Page 88 of 192
-------
12% and 18% less than controls for the F0 and FI generations, respectively. No
lexicologically significant effect was observed on body weights of F0 or FI females
exposed to any concentration of propylene oxide during the gestation or lactation periods;
statistically significant differences were observed at 300 ppm but did not exceed 8%
during gestation and 9% during lactation periods.
Exposure to concentrations up to 300 ppm had no exposure-related effect on reproductive
performance (mating, fertility or gestation indices) of the adults or on offspring
parameters [clinical signs, mean liter size at any time during lactation, survival indices
(live birth, viability, or lactation), pup weights or gross and microscopic findings in
weanlings].
The parental systemic LOAEL is 300 ppm, based on decreased body weights and
weight gain in F0 and FI males during premating and post mating periods and
decreased body weights and weight gain in F0 and FI females during premating
period. The parental NOAEL is 100 ppm.
The reproductive NOAEL is 300 ppm, HDT. The reproductive LOAEL is not
established.
The offspring NOAEL is 300 ppm, HDT. The offspring LOAEL is not established.
The animals were adequately exposed to assess the reproductive toxicity of propylene
oxide based on reduced body weights of adult males and females in the FI generation.
Estrous cycle, sexual maturation, and sperm parameters were not evaluated in this study.
However, other reproductive parameters were not affected by exposure to propylene
oxide.
The reproductive study in the rat is classified as Acceptable/Guideline and does satisfy
the guideline requirement for a two-generation reproductive study [OPPTS 870.3800,
(§83-4)] in the rat. Deficiencies were noted but they did not impact the overall evaluation
of this study.
COMPLIANCE: A signed and dated Quality Assurance was provided; GLP, Data
Confidentiality, and Flagging statements were not provided.
4.2.4.2 Propylene Chlorohydrin
In a two-generation reproduction study (NTP, 1998), PCH (approximately 75% 1-chloro-
2-propanol and 25% 2-chloro-l-propanol) was administered to Sprague-Dawley rats
(20/sex/group except controls 40/sex) at 0, 300, 650 and 1300 ppm in drinking water.
Assuming 30 ml as daily drinking water consumption, and the average body weight as
0.3 kg, the daily intake values were estimated as 0, 30, 65 and 130 mg/kg/day
respectively. F0 adults were continued for five litters and the last litter was selected for
FI adults. For F2 generation, control and high dose animals from FI parents alone were
treated and continued for one litter. Clinical observations, water consumption, pregnancy
Page 32 of 95
Page 89 of 192
-------
index, litters per pair, cumulative number of days to litter, dam body weights, live pups
per litter, proportion of pups born alive, sex of live pups, and pup body weights were
recorded. Also, selected organ weights, epididymal spermatozoal measurements and
estrous cycle parameters were measured.
At delivery of each litter, the mean body weights of F0 dams in the MDT (except for the
second litter) and the HDT were significantly less than those of the controls (p<0.05; |4-
8% for MDT and p<0.01; 110-15% for HDT). Mean body weights of litter 5 F0 dams in
the MDT were significantly less than those of the controls from lactation days 0 to 14
(p<0.05; |4-8%), and the mean body weights of F0 dams in the FIDT were significantly
less than those of the controls throughout lactation, PND 0 to 21 (p<0.05; 115-16%). The
body weight changes in F0 dams of MDT although statistically significant, was not
considered biologically significant (<10% decrease). The mean body weight of FI dams
of 1300 ppm, only dose tested, were significantly less (p<0.01; [11%) at delivery,
compared to controls.
Mating, fertility and pregnancy indices in the l-chloro-2-propanol treated groups were
similar to controls. The average numbers of litters per pair of all exposed groups were
not affected as compared to controls. The cumulative days to deliver were slightly higher
in the HDT as compared to controls (116.7 days in controls to 118.7 days in HDT) for
litter 5 but this was not affected in the other four litters. The days to litter in FI dams
were not affected.
The survival of the final litters of exposed FI pups was similar to that of the controls
throughout lactation. Male and female FI pup weights of HDT were significantly less
than those of the controls on days 7, 14, and 21 (p<0.05; [ 10-23%) and of MDT on days
14 and 21 (p<0.05; |7-34%). The organ weights of the FI rats at HDT were similar to
controls. The percentage of abnormal sperm was significantly greater in FI male rats of
HDT compared to controls (1210%; 0.78±0.11 in controls vs. 2.4±0.53 in HDT, p<0.05).
There were no significant differences in estrous cycle parameters between control and FI
females of HDT. The effects on sperm abnormalities and other reproductive measures at
doses below HDT were not determined. Exposure of FI adults to HDT did not affect the
sex ratio, or pup or organ weights.
The parental systemic LOAEL is 1300 ppm (130 mg/kg/day), based on decreased
body weights of FO dams during delivery and lactation and FI dams during delivery.
The parental NOAEL is 650 ppm (65 mg/kg/day).
The reproductive LOAEL is 1300 ppm (130 mg/kg/day) based on increased
percentage of abnormal sperm in FI rats. The reproductive NOAEL is not
established.
The offspring LOAEL is 650 ppm (65 mg/kg/day) based on decreased FI pups
weights for males and females during PND 14 and 21. The offspring NOAEL is 300
ppm (30 mg/kg/day).
Page 33 of 95
Page 90 of 192
-------
The study is classified as Acceptable/Non-Guideline
4.2.5. Pre-and/or Postnatal Toxicity
4.2.5.1 Propylene Oxide
Determination of Susceptibility
There is no quantitative susceptibility between the rat fetuses and the dams from the rat
developmental study (MRID 41750801). The study indicated a possible qualitative
susceptibility since the skeletal variations (increased litter incidence for the accessory 7th
cervical rib) were observed at the same dose which produced maternal toxic effects
(decreased body weight gain, food consumption and food efficiency).
Susceptibility in rabbits could not be adequately ascertained due to the absence of an
acceptable rabbit developmental study.
In the two-generation reproduction study, there is no evidence for quantitative or
qualitative susceptibility in pups exposed to PPO since no offspring effects were seen at
doses which produced significant systemic toxicity in parents.
Degree of Concern Analysis and Residual Uncertainties for Pre and/or Post-natal
Susceptibility
The degree of concern for the qualitative susceptibility effects seen after in utero
exposures in rats was low since the effects (increased incidence of the7th cervical rib) are
1) skeletal variations and not malformations 2) they were seen in the presence of maternal
toxicity and 3) this endpoint is used for assessing potential acute dietary risk to the
population of concern (Females 13-49).
The concern for the lack of an acceptable developmental toxicity study in rabbits is
addressed with the retaining of the 10X database uncertainty factor for risk assessments.
The database uncertainty factor is considered an FQPA factor.
4.2.5.2 Propylene Chlorohydrin
Determination of Susceptibility
There is no adequate data to determine the fetal susceptibility following in utero
exposures in rats or rabbits for PCH.
In the reproduction study (NTP, 1998), quantitative susceptibility effects were evident
since decreased pup weights were seen at dose which had no systemic toxicity in dams.
Page 34 of 95
Page 91 of 192
-------
Degree of Concern Analysis and Residual Uncertainties for Pre and/or
Post-natal Susceptibility
The degree of concern is low for the quantitative susceptibility seen in the reproduction
study since the dose and the endpoint of this study is used for assessing chronic dietary
risk in conjunction with the retaining of the 10X database uncertainty factor. The
database uncertainty factor is considered to be an FQPA factor.
4.2.6 Recommendation for a Developmental Neurotoxicity Study
4.2.6.1 Propylene Oxide
Evidence that supports requiring a Developmental Neurotoxicity Study
In a subchronic study identified in the open literature, Wistar rats exposed to PPO at 1500
ppm for 7 weeks exhibited awkward gait during third and fourth week of exposure and
more ataxia in all rats by 7th week. Also, histopathological evidence such as axonal
degeneration of the hindleg nerve and fasciculus gracilis and myelinated fibers in the
sacral spinal root were observed.
In a chronic study axonal dystrophy in the nucleus gracilis was reported in monkeys
exposed to PPO for 2 years.
Evidence that supports not requiring a Developmental Neurotoxicity Study
No evidence of neurotoxicity was reported in the subchronic neurotoxicity conducted up
to 300 ppm and no evidence neurotoxicity signs were observed in developmental,
reproductive, subchronic or chronic toxicity studies. Since the nasal epithelial effects
(e.g., hyperplasia) occur at low dose level (100 ppm) compared to the developmental,
reproductive effects or neurotoxic effects (> 300 ppm), it is unlikely that the data that
would be derived from the developmental neurotoxicity study would be helpful for risk
assessment. Therefore, the requirement for a developmental neurotoxicity study is not
recommended.
4.2.6.2 Propylene Chlorohydrin
Evidence that supports requiring a Developmental Neurotoxicity Study
None.
Evidence that supports not requiring a Developmental Neurotoxicity Study
No neurotoxic effects found from the available database.
Page 3 5 of 95
Page 92 of 192
-------
4.2.7 Rationale for the UFDB
4.2.7.1 Propylene Oxide
There is a data gap in the toxicology database for PPO (developmental toxicity study in
rabbits and chronic study in non-rodents by oral route). This necessitates the use of 10X
database uncertainty factor (UFoe) for PPO dietary risk assessment. The UFoB is
considered an FQPA factor.
4.2.7.2 Propylene Chlorohydrin
The database for PCH is incomplete. There is a need for developmental toxicity study in
rats and rabbits and chronic toxicity study in nonrodents. In addition, there is a need for
the chronic carcinogenicity studies in rats and mice since the doses used in the existing
studies found in the literature are inadequate. A 10X database uncertainty factor (UFoe)
is applied for PCH dietary risk assessment.
4.3 Additional FQPA Safety Factor
Based on the discussion in 4.2.5., no additional FQPA Safety Factor (i.e., IX) is required
for PPO or PCH since there are no residual uncertainties for pre and/or post-natal toxicity
for PPO and the doses selected for PCH are considered to protect the effects for children.
It is assumed that the exposure databases are complete and the risk assessment does not
underestimate the potential risks for infants and children. The FQPA SF has been
retained as a data base uncertainty factor.
4.4 Hazard Identification and Toxicity Endpoint Selection
4.4.1 Acute and Chronic Reference Doses for Propylene Oxide
4.4.1.1 Acute Reference Dose (aRfD) - Females 13-49 Years
Study Selected: Developmental Toxicity Study in Rats § 83-3; OPPTS 870.3700
Executive Summary: MRTD 41750801 (See section 4.2.3.1)
Dose and Endpoint Selected for Establishing Acute RfD (Gen Population): The NOAEL
of 300 ppm (Wai equivalent to 209 mg/kg/day) based on the increased litter incidence of
an accessory 7th cervical rib.
Uncertainty Factor (UF): 1000X (10X interspecies extrapolation, 10X intraspecies
variation and 10X database uncertainty factor for the data gaps in toxicity studies).
Extrapolation from inhalation to oral route: mg/kg/day = (mg/L x absorption factor x respiratory volume in L/hr x
duration of daily animal exposure x activity factor) /mean body weight in kg; The oral equivalent dose for 300 ppm =[
(300x 58.08/24.4x1000) mg/L x Ix 6.06 L/hr x 6 h/day x 1 / (0.124 kg)] = 209 mg/kg/day.
Page 36 of 95
Page 93 of 192
-------
Comments about Study/Endpoint/Uncertainty Factor:
The study is considered appropriate for the population of concern. The developmental
effects could be attributed to a single dose. In addition to the developmental effects, the
same dose level also caused maternal toxic effects.
Acute RfD (Females 13-49 years) = 209 mg/kg/dav (NOAEL) = 0.21 mg/kg/day
1000 (UF)
4.4.1.2 Acute Reference Dose (aRfD) - General Population
No endpoint of concern is found suitable to assess risk for this population.
4.4.1.3 Chronic Reference Dose (cRfD) - General Population
Study Selected: Chronic Carcinogenicity Study in Rats- Oral §83-5; OPPTS
870.3700
Executive Summary: Dunkelberg, 1982 (See Section 4.4.10.1)
Dose and Endpoint Selected for Establishing Chronic RfD (Gen Population): BMDm of
1.4 mg/kg/day based on the increased incidence for the hyperkeratosis, hyperplasia and
papillomas in forestomach in PPO administered rats.
Uncertainty Factor (UF): 1000X (10X interspecies extrapolation, 10X intraspecies
variation and 10X database uncertainty factor for the data gaps in toxicity studies).
Comments about Study/Endpoint/Uncertainty Factor: The study selected is appropriate
for the duration and route of exposure. This was the only chronic study available for PPO
by oral route. Since the study did not establish a clear NOAEL, bench mark dose
modeling (BMD) was used. Although the data fitted well for several dichotomous
models, the BMDLio (the lower confidence limit on the dose that produced 10% effects)
from the log logistic model was used to derive cRfD since it provided the conservative
dose as compared to other dichotomous models.
Chronic RfD (General Population) = 1.4 mg/kg/dav (BMDL) = 0.001 mg/kg/day
1000 (UF)
4.4.2 Acute and Chronic Reference Doses for Propylene Chlorohydrin
4.4.2.1 Acute Reference Dose (aRfD) - Females 13-49 Years and
General Population
No endpoint of concern is found suitable to assess risk for this population.
Page 37 of 95
Page 94 of 192
-------
4.4.2.2 Chronic Reference Dose (cRfD) - General Population
Study Selected: Two-generation Reproduction Study, Rats § 83-4; OPPTS
870.3800
Executive Summary: NTP. 1998 (See Section 4.2.4.2)
Dose and Endpoint Selected for Establishing Chronic RfD (Gen Population): The
offspring NOAEL of 30 mg/kg/day based on decreased FI pup weights in males and
females during PND 14 and 21 at 65 mg/kg/day.
Uncertainty Factor (UF): 1000X (10X interspecies extrapolation, 10X intraspecies
variation and 10X database uncertainty factor for the data gaps in toxicity studies).
Comments about Study/Endpoint/Uncertainty Factor: The study selected is appropriate
for the route and duration of the exposure. The doses selected are comparable to the
NOAELs established for pathological changes in pancreas, spleen or bone marrow in
subchronic studies conducted using adult rats and mice (NOAEL of 35 to 45 mg/kg/day
in rats and 50-60 mg/kg/day in mice) and conservative to the endpoints observed in the
chronic studies (NOAEL of 65 mg/kg/day, HOT for rats and NOAEL of 210 mg/kg/day,
HDT for mice. The discrepancy in the pathological changes reported between the
subchronic and chronic exposures using the same strain of animals and identical test
compound is not understood (NTP, 1998). However, the potential for any such
pathological changes in the offspring could be protected by the dose selected and the
application of 10X database uncertainty factor.
Chronic RfD (General Population) = 30 mg/kg/dav (NOAEL) = 0.03 mg/kg/day
1000 (UF)
4.4.3 Incidental Oral Exposure (Short-Term, 1-30 days and
Intermediate -Term, 1-6 months)
There are no residential uses for propylene oxide and therefore, the endpoints for the
incidental oral exposure are not derived.
4.4.4 Dermal Absorption
Studies on dermal absorption are unavailable.
4.4.5 Dermal Exposure Short-Term (1-30 days) and Intermediate-
Term (1-6 months), Long -Term (>6 months)
Dermal exposure was not assessed.
Page 3 8 of 95
Page 95 of 192
-------
4.4.6 Inhalation Exposure
4.4.6.1 Acute (1-day)
Study Selected: Rabbit Developmental Study § 83-4, OPPTS
870.3700
Executive Summary: MRID 41874102 (See Section 4.2.3.1)
COMPLIANCE: Signed and dated GLP, Data Confidentiality, Flagging, and Quality
Assurance statements were provided.
Dose and Endpoint Selected: The LOAEL of 500 ppm based on increased resorptions,
and/or increased incidence of minor skeletal abnormalities.
Comments about Study/Endpoint: Although there are concerns for this study, primarily
because it is a single dose study with no NOAEL, the study is appropriate for the route
and duration of exposure, and the study is considered adequate for assessment of acute
inhalation risk if an additional uncertainty factor of 10X is included in the derivation of a
concern level. The rat developmental inhalation study is also appropriate to assess acute
inhalation risks; however, the rabbit study provides a more conservative point of
departure when the additional uncertainty factor is included.
4.4.6.2 Short-Term (1-30 days) and Intermediate-Term (1-6 months)
Study Selected: Two generation Reproduction Study in Rats § 83-4, OPPTS
870.3800
Executive Summary: MRID 45292701 (See Section 4.2.4.1)
COMPLIANCE: A signed and dated Quality Assurance was provided; GLP, Data
Confidentiality, and Flagging statements were not provided.
Dose and Endpoint Selected: The NOAEL of 75 ppm based on decreased body weight
and weight gain in both F0 and FI males and females during premating periods at 225
ppm.
Comments about Study/Endpoint:
The study selected is appropriate for the route of exposure. It must be noted that the study
NOAEL/LOAEL of 100/300 ppm is converted to human equivalent concentrations of
75/225 ppm for occupational scenarios. For example, the human equivalent NOAEL of
75 ppm is derived after adjusting the 6 hour exposure per day in the animal study to 8
hours per day for humans (100 ppm x 6h/8h = 75 ppm). Similarly, 225 ppm is derived
from the animal LOAEL of 300 ppm (300 ppm x 6h/8h = 225 ppm).
Page 39 of 95
Page 96 of 192
-------
4.4.6.3 Inhalation Exposure Long -Term (>6 months)
Study Selected: Two year combined carcinogenicity study § 83-5; OPPTS 870.4300
Executive Summary: MRID 42039901 (See Section 4.4.10.1)
Dose and Endpoint Selected: The NOAEL of 30 ppm based on increased incidences of
basal cell hyperplasia, and nest-like infolds of the respiratory epithelium at 100 ppm. A
Benchmark Dose analysis was performed on the data, and the most appropriate point of
departure was determined to be a BMD of 140 ppm based on moderate to marked nest-
like infolds of the respiratory epithelium in male rats. The corresponding BMDLio is 120
ppm.
Comments about Study/Endpoint:
The study selected is appropriate for the route of exposure and duration. The BMDLio of
120 ppm is converted to a human equivalent concentration of 90 ppm to reflect an
occupational scenario, i.e., the difference between the study duration of 6 hours and an 8-
hour workday for typical workers. The previous version of this risk assessment had
included an additional dosimetric adjustment factor, the regional gas dose ratio (RGDR),
of 0.23 to further reduce the human equivalent concentration; however, in its review of
the RfD and RfC processes, the Agency has questioned whether the default RGDR
calculation for the extrathoracic region is appropriate, and indicates that the interspecies
dosimetric adjustment factor for extrathoracic effects may be closer to 1 (EPA, 2002,
page 4-33).
4.4.7 Margins of Exposure
Summary of target Margins of Exposure (MOEs) for risk assessment.
Route
Duration
Acute
(1-day)
Short-Term
(1-30 days)
Intermediate Term
(1-6 months)
Long Term
(>6 Months)
Occupational & Residential Exposure
Dermal
Inhalation
N/A
300
N/A
30
N/A
30
N/A
30
The occupational and residential MOE for short, intermediate and long term for
occupational exposure is based on a combined uncertainty factor of 30X (3X interspecies
factor and 10X intraspecies factor). The MOE for acute inhalation exposure includes an
extra lOx factor for database uncertainties. The traditional interspecies factor of 10X is
reduced to 3X since the animal doses are converted to human equivalent concentrations.
4.4.8 Recommendation for Aggregate Exposure Risk Assessments
As per FQPA, when there are potential residential exposures to the pesticide, aggregate
risk assessment must consider exposures from residues in food commodities and drinking
Page 40 of 95
Page 97 of 192
-------
water as well as exposures arising from non-dietary sources (e.g., incidental oral, dermal
and inhalation routes). The residues from drinking water are negligible since PPO is used
only indoors. PPO has no direct residential uses; however residential bystanders may be
exposed to emissions from fumigation facilities or structures. Dietary and bystander
exposure cannot be combined for this assessment, however, because the endpoints
selected for these exposures are not based on a common effect. Therefore, the
aggregation of risk from dietary and inhalation routes is not performed.
4.4.9 Classification of Carcinogenic Potential
4.4.9.1 Propylene Oxide
Animal Studies
Rats - Oral
Study 1 (Dunkelbers. 1982)
In a chronic carcinogenicity study (Dunkelberg, 1982), female Sprague-Dawley rats
(50/group) were administered with 0, 0 (salad oil as vehicle control), 15 or 60 mg/kg bw
propylene oxide (99.7% pure) by gavage twice a week for 109.5 weeks (determined from
219 times of dosing) and observed for 150 weeks. The average total doses in the low and
high propylene oxide treated groups were reported as 2714 or 10798 mg/kg bw,
respectively. Adjusting the doses to the whole study period of 150 weeks, the average
daily doses are estimated as 2.58 and 10.28 mg/kg/day, respectively. Between the 79th
and 82nd week several rats in the various groups were affected with pneumonia and
during which time the administration was interrupted. Survival rates were not affected by
propylene oxide treatment. The first tumor was observed in the 79th week of the
treatment. A dose dependent increase in the incidence of forestomach tumors (mainly
squamous-cell carcinomas) were observed in the propylene oxide treated animals (0/50,
0/50, 2/50, 19/50 in the control, vehicle control, low and high propylene oxide treatment
groups, respectively). Further, one animal in the high dose group had a carcinoma in situ
and another animal in the high dose group had an adenocarcinoma of the glandular
stomach. In addition to the neoplastic lesions, a dose dependent increase in the combined
incidences of papilloma, hyperplasia and hyperkeratosis of the stomach (0/50, 0/50, 7/50,
17/50 in control, vehicle, low dose and high dose, respectively) was reported.
The LOAEL is determined as 2.58 mg/kg/day based on increased combined
incidences for hyperkeratosis, hyperplasia and papillomas. The NOAEL is not
established.
The carcinogenicity study is limited by inadequate pathological data because pathological
examination in several tissues including lung, liver, kidney and thyroid tissues were not
reported. The study examined only female rats and any sex specific effects were not
determined. It must be noted this is the only chronic study available for PPO by oral
route and used for chronic reference dose and chronic cancer risk determination. The
Page 41 of 95
Page 98 of 192
-------
lack of adequate measurements on systemic effects such as body weights, food
consumption, clinical measurements, organ weights etc. along with the inadequate
pathological examinations and lack of determination of any sex specific effects limit to
classify this study as combined chronic toxicity/carcinogenicity guideline study (OPPTS
No. 870.4300). Therefore, the study is classified as Acceptable/Non-Guideline.
Rats - Inhalation
Study 1 (MRID 42039901)
In a chronic inhalation toxicity study (MRID 42039901), 100 Wistar rats/sex/exposure
group were exposed to 1,2-propylene oxide gas (technical grade, 99.9903% a.i.; Lot Nos.
- not provided) at target exposure concentrations of 0, 30, 100, or 300 ppm for 6
hours/day, 5 days/week for up to 28 months. Seventy rats/sex/exposure group were in the
main group, and 10 rats/sex/exposure group were in each of three satellite groups killed
after 12, 18, or 24 months to provide interim toxicological data.
The mortality rate was statistically increased at the end of the study in 300 ppm group
males (79% vs. 46% for controls) and 100 and 300 ppm group females (61 and 79%,
respectively, vs. 43% for controls) as compared to controls. It appears that the decreased
survival in high dose females is evidence that the MTD was exceeded in the study.
Statistically significant decreases in absolute body weights in 300 ppm males during
weeks 1-71 and 99-111 and 300 ppm females during weeks 1-67, with the body weight
means ranging from 90-97% of controls for males, and 92-98% of controls for females,
were reported. Mean body weight gains in the high dose level males (>I^16%) and females
(^22%) during the first four weeks and in 300 ppm males during weeks 13-59 (*ll2%)
were decreased as compared to respective controls. During weeks 59-99, 100 and 300
ppm males and 300 ppm females had an increased body weight gain, suggestive of a
compensatory effect. Food consumption was marginally decreased during the first two
weeks of the study (p < 0.02) in high level males (94%) and during the first week in high
dose level females (89%).
There were no treatment-related changes observed in hematology and clinical chemistry
parameters or in organ weights. Macroscopic evaluation revealed that females in the 300
ppm group had an increased incidence of adrenal enlargement, which may be related to
treatment.
Microscopic examination revealed an increased incidence of degenerative and
hyperplastic changes in the nasal mucosa of exposed rats as compared to controls. The
300 ppm male and female satellite groups had statistically significant (p < 0.05; 0.01)
increase in the incidences of olfactory epithelium atrophy at 12 months (males: 4/10 vs.
0/10 controls; females: 5/9 vs. 0/10 controls) and basal cell hyperplasia of the olfactory
epithelium at 12 months (males: 5/10 vs. 0/10 controls; females: 7/9 vs. 0/10 controls), 18
months (males: 6/10 vs. 1/10 controls; females: 6/10 vs. 0/10 controls), and 24 months
(males: 4/10 vs. 0/10; females: 5/9 vs. 0/9 controls) compared to controls. The
incidences of nest-like infolds of respiratory epithelium were increased (p < 0.05; 0.01) in
Page 42 of 95
Page 99 of 192
-------
300 ppm males at 12 months (9/10 vs. 1/10 controls), 18 months (9/10 vs. 0/10 controls)
and 24 months (7/10 vs. 0/10 controls); and 300 ppm females at 12 months (9/9 vs. 0/10
controls), 18 months (10/10 vs. 0/10 controls), and 24 months (7/9 vs. 0/9 controls). The
incidences of these nasal lesions were similar in animals from the main study (28
months). Atrophy of the olfactory epithelium was increased (p < 0.01) in 300 ppm males
(21/63 vs. 5/66 controls) and females (26/65 vs. 7/64). Both 100 and 300 ppm males and
females had increased incidences (p < 0.05; 0.01) of basal cell hyperplasia (males: 10/62
and 24/63 vs. 4/66 controls; females: 9/62 and 33/65 vs. 0/64 controls) and nest-like
infolds of the respiratory epithelium (males: 29/62 and 47/63 vs. 5/66 controls; females:
20/62 and 43/65 vs. 4/64 controls). The nest-like infolds showed a clear concentration-
response relationship. Other microscopic changes that may be related to exposure to 300
ppm 1,2-propylene oxide include increased incidence of thrombi in the heart in males,
and myocardial degeneration in females.
The LOAEL is 100 ppm based on increased incidences for basal cell hyperplasia, and nest-
like infolds of the respiratory epithelium. The NOAEL is determined as 30 ppm.
There were incidences of fibroadenomas (control, 32/69; low dose, 30/71; mid dose,
39/69; high-dose 47/70, p<0.05) and tubulopapillary carcinomas (control, 3/69; low dose,
6/71; mid dose, 5/69; high-dose 8/70, p<0.05) in the mammary glands of females.
Multiplicity of fibroadenomas was significantly increased at all doses (p<0.01).
However, the study was conducted for 28 months and the high dose incidence of 67%,
although exceeding the historical control range 19-61%, is of questionable usefulness,
since the usual proliferation of mammary gland fibroadenomas, the most common type of
female tumor, is expected to be significantly enhanced at this point in the study. These
facts, in part, support the conclusion that the fibroadenoma data do not provide
unequivocal evidence that PPO is a systemic carcinogen.
Three malignant tumors were found in the nasal cavity of treated males: one tumor
described as 'ameloblastic fibrosarcoma' in a low dose male, one squamous cell
carcinoma in a low dose male and one in a high dose male. Four males in the high dose
group had a carcinoma in the larynx or pharynx, trachea or lungs with none in controls or
low-dose males.
Dosing was considered adequate based on increased mortality and decreased body weight
in males and females at the highest concentration and increased incidences of nasal
lesions at all exposure concentrations.
This combined chronic/oncogenicity toxicity study is Acceptable/Guideline (§83-5;
OPPTS 870.4300) and does satisfy the guideline requirement for a combined
chronic/oncogenicity study in rats.
COMPLIANCE: Signed and dated GLP, Quality Assurance, Data Confidentiality, and
Flagging statements were provided.
Study 2 (NTP, 1985)
Page 43 of 95
Page 100 of 192
-------
In a chronic carcinogen!city study (NTP, 1985), F344 rats (50/sex/group) were exposed
via inhalation to 99.9% pure propylene oxide at concentrations of 0, 200, and 400 ppm
for 6 hours/day, 5 days/week for 103 weeks. Hematology, serum chemistry, urinalysis,
and histopathology were performed. Survival in the rats was unaffected by exposure to
propylene oxide, and terminal body weights were slightly depressed in the high-dose
male (8%) and female (9%) rats. The respiratory epithelium of the nasal turbinates was
the primary tissue affected by propylene oxide exposure in rats. Exposure-related
increases in suppurative inflammation of the nasal cavity (7/50, 19/50, and 33/50 in the
control, 200, and 400 ppm males, respectively, and 3/50, 5/50, and 20/50 in the control,
200, and 400 ppm females, respectively) in addition to exposure-related increases in
epithelial hyperplasia (0/50, 1/50, and 11/50 in males; 0/50, 0/48, and 5/48 in females in
respective dose groups) and squamous metaplasia (1/50, 3/50, and 21/50 in males; 1/50,
2/48, and 11/48 in females in respective dose groups) were reported at the end of the
treatment.
The LOAEL is determined as 200 ppm based on the extrathoracic effects. The
NOAEL is not established.
Papillary adenomas of the nasal cavity occurred in 0/50 control, 0/50 low dose and 3/50
high dose females, and in 0/50 control, 0/50 low dose and 2/50 high dose males. In
historical controls from five different laboratories for the same strain of rats, the
incidences for nasal cavity tumors were reported as 3/1523 for females and 1/1477 for
males. However, although the incidence of papillary adenomas of the nasal cavity
occurred at increased frequency, the occurrence of these tumors was not statistically
significant by pair wise comparison with the controls, and are not considered treatment
related. A increase in thyroid C-cell adenoma and carcinoma (p=0.023) occurred in
females and the incidences are 2/45, 2/35, 7/37 in control, low dose and high dose
groups, respectively. Since these tumors are relatively common in female F334/N rats,
the combined incidence of C-cell adenomas and carcinomas in this study is considered to
be unrelated to the administration of propylene oxide. The incidences in historical
control females for C-cell adenoma or carcinoma ranged from 1/49 (2%) to 9/50 (18%)
and the total incidence corresponded to 122/1472 (8.3%±4.3%) based on the data
collected from five different laboratories. The incidence in the 400 ppm PPO group was
similar to that observed for the historical controls at the high end (19%) but greater than
the overall or total incidence for thyroid gland tumors.
The doses tested are considered adequate based on the extrathoracic effects in propylene
oxide treated groups.
The study is classified as Acceptable/Non-Guideline
Study 3 (Lynch et al. 1984)
In a chronic carcinogenicity study male F344 rats were exposed via inhalation to
propylene oxide (80/group) at 0, 100, or 300 ppm propylene oxide for an average of 6.9
hours/day, 5 days/week for 104 weeks. A statistically significant (p<0.01) increase in
Page 44 of 95
Page 101 of 192
-------
mortality was observed at the high dose compared to controls. The median survival time
was 720, 705, and 675 days for control and 100 and 300 ppm groups, respectively. The
mean body weights were significantly (p<0.05) reduced in both 100 and 300 ppm
treatment groups, compared to controls. Hemoglobin concentrations were increased
significantly in both groups of propylene oxide-treated rats (p<0.025) compared to
controls. Absolute and/or relative weights to the body weights were reported increased
for lungs and adrenal glands and decreased for testes, in both treatment groups. The
incidences for complex epithelial hyperplasia (0/76, 2/77, 11/78 in control, 100 and 300
ppm groups; significant only in 300 ppm group, p<0.05) and suppurative rhinitis in the
nasal cavity (12/76, 21/77, 44/78 in control, 100 and 300 ppm groups; significant in both
groups, p<0.05) were higher in treated groups compared to controls. The skeletal muscle
atrophy in the absence of sciatic nerve neuropathology was noticed in 300 ppm group
compared to controls.
The only noticeable neoplastic lesion was adrenal pheochromocytomas and the
incidences were 8/78, 25/78, 22/80 in control, 100 and 300 ppm groups, respectively.
The LOAEL is determined as 100 ppm based on decreased survival, decreased body
weights, increased hemoglobin, extra thoracic effects (nasal suppurative rhinitis)
and systemic effects such as decreased body weight, increased hemoglobin, and
organ weight changes. The NOAEL is not established.
The study is classified as Acceptable/Non-Guideline. The study was conducted using
only one sex and with two doses only. No individual animal data or interim sacrifice
data were provided. Also, limited clinical parameters were measured. The findings of
this study are complicated by the outbreaks of Mycoplasma pneumonia infection which
occurred at 8, 16, and 20 months of the study.
Mice - Inhalation
NTP (1985)
In a chronic carcinogenicity study (NTP, 1985), B6C3F1 mice (50/sex/treatment) were
exposed to 99.9% pure propylene oxide at concentrations of 0, 200, and 400 ppm for 6
hours/day, 5 days/week for 103 weeks. Survival tended to be adversely affected in all
treated groups (males: controls, 42/50; low-dose, 34/50; high dose, 29/50 and females:
controls, 38/50; low-dose, 29/50; high dose, 10/50), but the decrease was statistically
significant only for male and female mice in the 400 ppm group. Terminal body weights
were 10% below control values for the high-dose female mice and 22% below control
values for the high-dose male mice. Chronic inflammation of the nasal cavity was
observed in 1/50, 13/50, and 38/50 of the male mice and in 0/50, 13/50, and 17/50 of the
female mice exposed to 0, 200 ppm, and 400 ppm, respectively. Hyperplasia and
metaplasia were also observed sporadically in mice exposed to 400 ppm propylene oxide.
These lesions were most pronounced in the anterior portion of the nasal cavity and on the
greater curvatures of the nasal maxillary turbinates. No consistent effect was observed in
Page 45 of 95
Page 102 of 192
-------
the tracheobronchiolar or pulmonary region of the respiratory tract, or in skeletal muscle,
bronchial lymph nodes, or central nervous system.
The LOAEL is determined as 200 ppm based on extra thoracic effects. The NOAEL
is not established.
The combined incidences of hemangiomas and hemangiosarcomas in the nasal cavity
were significantly elevated in the high dose group (males: controls, 0/50; low-dose, 0/50;
high dose, 10/50, p<0.001 and females: controls, 0/50; low-dose, 0/50; high dose, 5/50,
p=0.03). One squamous cell carcinoma and one papilloma were induced in nasal cavity
of high dose males and adenocarcinomas in two high dose females, but these effects were
not statistically significant. Doses tested were considered adequate based on the extra
thoracic effects.
The study is classified as Acceptable/Non-Guideline.
Mutagenicity Studies
No mutagenicity studies were submitted to the Agency. However, there are several
reports published in the literature. The following summary provides a brief over view of
the studies available in the open literature.
Propylene oxide induced reverse mutations in Salmonella typhimurium TA100, TA1535
strains consistently in the absence of S9 activation (S9 was not included in most of the
tests). Mutations were also induced in E.coli (WP2, WP2 wvrA), yeast (Saccharamyces
cerevisiae and Schizosaccharomyces pombe), and fungi (Neurospora crassa). PPO
caused sex-linked recessive lethal mutations in Drosophila melanogaster. Propylene
oxide induced DNA single strand breaks in rat hepatocytes, and caused gene mutations in
Chinese hamster ovary cells and mouse L5178Y cells, in vitro. Propylene oxide induced
sister chromatid exchange in Chinese hamster ovary cells, rat liver cells and human
lymphocytes and chromosomal aberrations in cultured human lymphocytes (as reviewed
inlARC, 1994).
Chromosomal aberrations and sister chromatid exchange were induced in mouse bone-
marrow cells after intraperitoneal injection. In one chronic study, no significant increase
in sister chromatid exchange or chromosomal aberrations in peripheral blood
lymphocytes was reported in cynomolgus monkeys exposed to 300 ppm PPO for 7h/day,
5days/week for two years. Micronuclei were not induced in bone-marrow cells of mice
administered PPO by gavage but were induced in mice receiving PPO by intraperitoneal
injection. Dominant lethal mutations were not induced in mice exposed to PPO orally or
rats exposed to PPO by inhalation (as reviewed in IARC, 1994).
DNA adducts were reported in vitro when calf thymus DNA was incubated with
propylene oxide. Increased DNA adducts (7-(2-hydroxy propyl)guanine) in DNA
hydrolysates of various organs were formed in male mice 3h and lOh after intraperitoneal
injection of 14C-propylene oxide. In mice, rats and dogs, the levels of DNA adducts in
Page 46 of 95
Page 103 of 192
-------
liver were greater after intraperitoneal or intravenous injection as compared to inhalation.
Male Fischer rats exposed to tritiated propylene oxide via inhalation at 46 ppm for 2
hours had 17, 5.8, 3.3 adducts/106 base in nasal cavities, trachea and lungs, respectively.
The persistence of the radiolabel was seen in trachea and lungs as compared to nasal
cavities. The elimination of the radiolabel from nasal cavities appears to be biphasic with
half-lives of 8h and 5.3 days (as reviewed in IARC, 1994).
Cancer Classification
Oral
PPO has been classified by the Agency as a B2 carcinogen (probable human carcinogen).
The cancer slope factor for the oral route is 0.15 (mg/kg/day)"1 based on the Dunkelberg
study which showed forestomach tumors in rats.
HED has derived an alternative cancer slope factor (Q*) of 0.00086 (mg/kg dose)"1 using
a concentration based approach. Use of an alternative approach is based on the fact that
forestomach tumors in the rat treated by gavage may be considered a portal of entry
response. By analogy to the RfC methodology which considers the concentration of test
material to be the most important determinant of response in portal of entry tumors, PPO
dosage may be expressed as a concentration. A detailed description of the derivation of
the alternate slope factor is provided in Appendix 5.0. The Agency is considering mode
of action data relevant to both oral and inhalation routes of exposure. If the proposed
MOA is adopted, characterization of cancer risks is likely to change from a low-dose
linearity approach to a threshold approach.
Inhalation
The cancer slope factor based on nasal tumors in mice for the inhalation route is 3.5xlO~6
(jig/m3)"1 using RfC methodology and assuming linearity at low doses.
As previously noted, the registrant and consultants to the registrant have submitted a
large amount of information supporting a threshold carcinogenic mode of action (MOA)
of PPO. The Agency has done an initial review of the data supporting the proposed
MOA and finds it highly plausible. The key points of the proposed MOA are described
in Appendix 6.0
4.4.9.2 Propylene Chlorohydrin
Animal Studies
Rats Oral
In a chronic carcinogenicity study (NTP, 1998), groups of 50 male and 50 female
F344/N rats were administered drinking water containing 0, 150, 325, or 650 ppm PCH
(75% l-chloro-2-propanol and 25% 2-chloro-l-propanol; equivalent to average daily
Page 47 of 95
Page 104 of 192
-------
doses of approximately 15, 30, or 65 mg/kg during the first several months of the study
and 8, 17, or 34 mg/kg for the remainder of the 2-year study) for up to 105 weeks.
Survival of all exposed groups was similar to that of the controls. Mean body weights of
exposed rats were generally similar to those of the controls throughout most of the study.
Water consumption by all exposed groups was similar to that by the controls. No
treatment-related neoplasms or nonneoplastic lesions were observed in this study. The
NOAEL is determined as 65 mg/kg/day (HDT) and the LOAEL is not established.
The study is classified as Acceptable/Non-Guideline. The NTP concluded that there
was no evidence of carcinogenicity.
Mice - Oral
In a chronic carcinogenicity study (NTP, 1998), groups of 50 male and 50 female B6C3F
mice were administered drinking water containing 0, 250, 500, or 1,000 ppm PCH (75%
l-chloro-2-propanol and 25% 2-chloro-l-propanol) (equivalent to average daily doses of
approximately 45, 75, or 150 mg/kg to males and 60, 105, or 210 mg/kg to females
during the first several months of the study and 25, 50, or 100 mg/kg for the remainder of
the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that
of the controls. The mean body weights of all exposed mice were generally similar to
those of the controls throughout the study. Water consumption by all exposed groups was
similar to that by the controls. No treatment-related neoplasms or nonneoplastic lesions
were observed in this study.
The NOAEL is determined as 210 mg/kg/day (HDT) and the LOAEL is not
established.
The study is classified as Acceptable/No n-Guideline. No evidence of carcinogenicity
was reported. The doses used in the study are inadequate. Consequently, no conclusions
can be made as to the carcinogenicity of PCH.
Mutagenicity Studies
PCH (l-Chloro-2-propanol) is a demonstrated mutagen in vitro. It was weakly
mutagenic in Salmonella typhimurium strain, TA100 in the presence of hamster or rat
liver S9 activation enzymes and was positive, with and without S9, in TA1535. No
mutagenic activity was detected in strains TA97, TA98, and TA1537, with or without S9.
PCH was positive in E.colipolA assay for DNA damage (as reviewed in NTP, 1998).
In cytogenetic tests with Chinese hamster ovary cells, PCH induced high levels of sister
chromatid exchanges and chromosomal aberrations in the presence and the absence of
S9. Positive results were reported when PCH was tested in L5178Y mouse lymphoma
cells with and without S9 (as reviewed in NTP, 1998).
PCH induced sex-linked recessive lethal mutations in germ cells of male Drosophila
melanogaster when administered via injection; however, negative results were obtained
Page 48 of 95
Page 105 of 192
-------
when males were administered PCH in feed. A subsequent germ cell reciprocal
translocation test in D. melanogaster yielded negative results. Further, no induction of
micronucleated erythrocytes was observed in peripheral blood of male and female mice
administered PCH via drinking water for 14 weeks (as reviewed in NTP, 1998).
4.4.10 Summary of Endpoints Selected for Risk Assessment
Table 6: Summary of Toxicological Doses and Endpoints Use in Human Risk Assessments
Exposure
Scenario
Dose Used in
Risk
Assessment, UF
Additional FQPA
SF* and Level of
Concern for Risk
Assessment
Study and Toxicological Effects
Propylene Oxide
Acute Dietary
(Females, 13-49
years)
Acute Dietary
(General
populations)
Chronic Dietary
(All populations)
Incidental Oral
Exposure, Short-
Term(l - 30 days)
Intermediate-Term
(1-6 months)
Dermal, Short-
Term, Intermediate-
Term, and Long-
Term (> 6 months)
Inhalation - acute
(1-day)
Residential
Inhalation - acute
(1-day)
Occupational
Inhalation
Short-Term (1-30
days) and
Intermediate-Term
(1-6 months)
NOAEL =
#209
mg/kg/day
(300 ppm)
UF =1000
Acute RfD =
0.21 mg/kg/day
FQPA SF = IX
aPAD =
acute RfD
FQPA SF
= 0.21 mg/kg/day
Developmental Toxicity, Rats (MRID 41750801)
Developmental LOAEL: #349 mg/kg/day (500 ppm)
Increased litter incidence of an accessory 7th cervical
rib
No endpoint of concern is found suitable to assess risk for this population
fBMDL10=
1.4 mg/kg/day
UF = 1000
Chronic RfD =
0.001
mg/kg/day
FQPA SF = IX
cPAD =
chronic RfD
FQPA SF
= 0.001
mg/kg/day
Chronic carcinogenicity study, Rats (Dunkelberg,
1982)
f Systemic LOAEL = 2.6 mg/kg/day
Increased combined incidence for hyperkeratosis,
hyperplasia and papillomas.
No hand to mouth exposure is expected for children. Therefore, this scenario is not
applicable.
Propylene oxide is a severe skin irritant and therefore, care must be taken to avoid direct
contact with the skin.
LOAEL = 500
ppm
UF = 30
LOAEL = 500
ppm
UF = 30
UFL=10
If NOAEL= 75
ppm (180
mg/m3)
Inhalation
Absorption
Rate = N/A
FQPA SF = lOx
(UFL)
Residential
MOE = 300
FQPA SF = Ix
Occupational
MOE = 300
Residential
MOE =N/A
Occupational
MOE = 30
Developmental toxicity in rabbits (MRID 41874102).
Increased resorptions, and/or increased incidence of
minor skeletal abnormalities.
Two-generation Reproduction Study in Rats (MRID
45292701)
If LOAEL = 225 ppm (540 mg/m3)
Decreased body weight and body weight gain in both
FO and Fl males and females during premating periods
Page 49 of 95
Page 106 of 192
-------
Table 6: Summary of Toxicological Doses and Endpoints Use in Human Risk Assessments
Exposure
Scenario
Inhalation
Long-Term
(> 6 months)
Cancer (Oral)
Cancer (Inhalation)
Dose Used in
Risk
Assessment, UF
§BMDL10 =
120 ppm (90
ppmHEC)
Inhalation
Absorption
Rate = N/A
Additional FQPA
SF* and Level of
Concern for Risk
Assessment
Residential
MOE =N/A
Occupational
MOE = 30
Study and Toxicological Effects
Two year combined chronic carcinogenicity study,
Rats (MRID 4203 9901)
Increased incidences of basal cell hyperplasia, and
nest-like infolds of the respiratory epithelium
Traditional cancer slope factor (oral- forestomach tumors in rats) = 0.15 (mg/kg/day)-l;
Alternate cancer slope factor using concentration based approach = 0.000086 (mg/kg diet)-l
**
Traditional cancer slope factor (inhalation - hemangioma and hemangiocarcinoma in mice) =
3.5x10-6 (ug/m3)'1
Note: if a proposed MOA is accepted, inhalation cancer risks will be likely equal to non-
cancer risks.
Propylene chlorohydrin
Acute Dietary
(Females, 13-49
years) and (General
populations)
Chronic Dietary
(All populations)
Cancer (Oral and
Inhalation)
No endpoint of concern is found suitable to assess risk for these populations
NOAEL= 30
mg/kg/day
UF = 1000
Chronic RfD =
0.030
mg/kg/day
FQPA SF = IX
cPAD =
chronic RfD
FQPA SF
= 0.030
mg/kg/day
Two-Generation Reproduction Study, Rats (NTP,
1998)
Offspring LOAEL: 65 mg/kg/day
Decreased Fl male and female pup weights at PND 14
and 21.
Data is inadequate to determine the carcinogenic effects.
UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL =
lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose,
MOE = margin of exposure, LOG = level of concern, NA = Not Applicable
"Extrapolation from inhalation to oral route: mg/kg/day = (mg/L x absorption factor x respiratory volume in L/hr x
duration of daily animal exposure x activity factor) /mean body weight in kg; Lhe oral equivalent dose for 500 ppm =[
(500x (58.08/24.4)xlOOO) mg/L x Ix 6.06 L/hr x 6 h/day x 1 / (0.124 kg)] = 349 mg/kg/day; similarly 300 ppm
corresponds to 209 mg/kg/day. In the equation the default value of 1 is used for both absorption factor and animal
activity factor.
t Study gavage doses of 15 and 60 mg/kg/day administered twice a week (corresponding average total doses are 2714
and 10798 mg/kg bw) are adjusted for experimental duration of 150 weeks to 2.58 and 10.28 mg/kg/day, respectively.
Lhese adjusted doses were used for bench mark dose modeling (BMDL10; Log Logistic Model had a good fit of the
data).
£Study LOAEL of 500 ppm needs no adjustment to a human equivalent dose for residential bystander scenario, since
the study duration of 7 hrs is assumed to be equivalent to the human exposure interval.
'Study NOAEL and LOAEL are adjusted to human equivalent doses for occupational scenario only, e.g., animal
NOAEL of 100 ppm (6h/day, 5d/week) is adjusted to human NOAEL of 75 ppm (8 h/day, 5d/week), assuming the
regional gas dose ratio (RGDR) is similar between animals and humans for systemic effects (100 ppm x 6h/8h =75
ppm);
§ Study POD is adjusted to human equivalent dose for occupational scenario only; ie., animal BMDL10 of 120 ppm is
adjusted to human NOAEL of 90 ppm, by correcting for differences in study (6 h/day, 5 d/week) and exposure (8
h/day, Sd/week) durations. (120 ppm x 6h/8h = 90 ppm).
* Refer to Section 4.3
** Slope factor used for dietary exposure assessment
Page 50 of 95
Page 107 of 192
-------
4.5 Endocrine Disruption
EPA is required under the FFDCA, as amended by FQPA, to develop a screening
program to determine whether certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect produced by a
naturally occurring estrogen, or other such endocrine effects as the Administrator may
designate." Following recommendations of its Endocrine Disrupter and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as part of the program, the androgen and thyroid hormone systems, in addition
to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the
Program include evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to require the
wildlife evaluations. As the science develops and resources allow, screening of
additional hormone systems may be added to the Endocrine Disrupter Screening Program
(EDSP).
In the available toxicity studies on the reaction product of propylene oxide, PCH, there
was increased percentage of abnormal sperm in the subchronic and reproduction toxicity
studies. When additional appropriate screening and/or testing protocols being considered
under the Agency's EDSP have been developed, PCH may be subjected to further
screening and/or testing to better characterize effects related to endocrine disruption.
5.0 INCIDENT REPORT
Scientific literature reports a few cases of contact dermatitis from exposure in workplace
settings, although these occurrences were in laboratories, not sterilization/fumigation
facilities or food processing facilities. Information from the Poison Control Center
showed evidence of throat and skin irritation. One reported case in California described
an almond fumigator experiencing lightheadedness, coughing, and skin sores from
changing cylinders.
6.0 DIETARY EXPOSURE/RISK PATHWAY
6.1 Residue Profile
Residue data are adequate to support the fumigant uses on spices and herbs (as defined by
the Agency's crop groups), cocoa bean, and nutmeats (except peanut). The existing 300
ppm PPO tolerances for "spices processed" should be clearly defined in regard to what
spice/herb commodities are fumigated. The proposed PPO tolerances in/on spices are
based on residue data collected 2 days after treatment. A 1500 ppm tolerance should be
established for residues of PCHs in/on spices and herbs (dried) (except basil) based on
residues at 2 day sampling. A 6000 ppm PCH tolerance should be established for basil.
A 6000 ppm PCH tolerance should be established for dried onion and dried garlic
powders. Magnitude of the residue studies found minimal PBHs levels in cocoa powder,
nutmeats (almond, pecan, walnut), spices (black pepper, chili powder, celery seed), dried
Page 51 of 95
Page 108 of 192
-------
basil, dried onion powder, and dried garlic powder. Therefore, HED suggests that a
tolerance be established based on PCHs residue levels which should cover any expected
PBHs residues.
The existing 300 ppm PPO tolerance for nutmeats is adequate based on existing and
newly submitted residue data. New data on anticipated residues of PPO in nutmeats has
been submitted to and evaluated by HED for this revised assessment. According to the
registrant and industry representatives, actual application rates for nutmeats are
significantly lower than the maximum allowable label rate of 2.4 oz PPO/ft3. The new
residue data for nutmeats reflect actual maximum application rates (0.5-0.7 oz PPO/ft3),
as well as actual fumigation parameters (e.g., temperature, duration) which also differ
from those provided in the current label. Tolerances in/on nutmeats for residues of PCHs
are proposed at a 10 ppm level.
The tolerance levels for PPO and PCHs in/on cocoa bean should be established at 200
ppm and 20 ppm, respectively. The existing 300 ppm tolerance for vegetable gums
should be revoked based on the registrant's submission of request for voluntary
cancellation of PPO use on edible gums pursuant to FIFRA Section 6(f). PPO tolerances
should be established for fig, prune, and raisin at 3 ppm, 2 ppm, and 1 ppm, respectively.
PCHs tolerances should be established for fig, prune, and raisin at 3 ppm, 2 ppm, and 4
ppm, respectively.
Presently in 40 CFR §180.491(a)(2), application directions are listed including time and
temperature conditions. This section (a)(2) should be removed. All treatment
parameters should be on the label only. The Registration Division should request
revised labels from the registrant of PPO formulations to reflect the proposed lower
maximum rate tree nuts as well as any other proposed changes to fumigation
parameters. All labels must be amended to match the conditions of the study.
The PPO tolerance for nutmeats should remain at 300 ppm until the maximum label rate
is lowered from 2.4 oz PPO/ft3 to 0.5-0.7 oz PPO/ft3 for treatment of tree nuts. At such
time, it may be possible to decrease the existing tolerance. However, since the newly
submitted data are only preliminary, HED will require additional adequate confirmatory
residue data (with adequate sampling) to support any change to the existing 300 ppm
tolerance. Any study submitted must be run under GLP conditions. Residue chemistry
requirements are provided in more detail in the residue chemistry assessments. (J. Stokes,
D316571, 9/22/05; D316573, 6/22/06)
Table 7 provides the summary of the tolerances assessments or reassessments for PPO
and the PCH.
Page 52 of 95
Page 109 of 192
-------
Table 7. Tolerance Reassessment for Propylene Oxide and Propylene Chlorohydrin
Tolerances Established Under 40 CFR §180.491
Propylene Oxide
Commodity
Basil
Spices/herbs
Dried onion1
Dried garlic1
Processed nutmeats
Figs
Prunes
Raisins
Gum, edible
Cacoa bean
Current Tolerance
(ppm)
-
300
~
-
300
-
-
-
300
300
Reassessed
Tolerance (ppm)
-
300
~
-
300
3
2
1
Revoke
200
Propylene Chlorohydrin
Current Tolerance
(ppm)
-
-
~
-
-
-
-
-
~
-
Reassessed
Tolerance (ppm)
6000
1500
10
3
2
4
~
20
1 Tolerance based on data given for basil
6.2 Acute and Chronic Dietary Exposure and Risk
Refined acute and chronic dietary risk assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03), and the Lifeline Model
Version 3.0 which use food consumption data from the USDA's Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The dietary exposure
and risk assessment for cancer has been revised to incorporate new residue and percent
crop sterilized data and to exclude edible gums as a fumigated commodity. Only the
dietary cancer assessment has been revised for this analysis because only that scenario
produced risk estimates above EPA's level of concern based previous dietary
assessments. Other acute and chronic dietary exposure assessments resulted in risks well
below HED's level of concern and incorporation of new data would result in risks <
previously estimated risks.
Residue data obtained from studies on propylene oxide sterilization of nutmeats, cocoa
powder, herbs and spices, figs, prunes and raisins were used for the acute and chronic
assessments. Residue distribution data from PPO sterilization studies were used for the
acute dietary analysis of propylene oxide. Tolerance level residues were used for the
chronic dietary analysis of propylene Chlorohydrin. Average residues from the
sterilization study data were used for the chronic and cancer assessments of propylene
oxide. Percent crop treated data provided by BEAD were used for the acute and
chronic/cancer analyses. EPA concluded that a drinking water exposure assessment was
not necessary because based on use patterns and physical-chemical properties of PPO,
none of the uses of PPO are expected to result in significant exposure from drinking
water.
An acute dietary assessment was conducted for PPO only. A refined probabilistic acute
dietary exposure assessment was conducted for all supported propylene oxide food uses
Page 53 of 95
Page 110 of 192
-------
for the population subgroup females 13-49. This assessment concludes that for all
supported commodities, the acute dietary exposure estimates for propylene oxide are
below HED's level of concern. The DEEM and LifeLine acute dietary exposure
estimates for a single treatment for females 13-49, the only population subgroup assessed
for acute dietary exposure, were 6% and 7 % of the aPAD respectively.
Refined chronic dietary exposure assessments were conducted for all supported
propylene oxide food uses for the general U.S. population and various population
subgroups. This assessment concludes that for all supported commodities, the chronic
dietary exposure estimates for propylene oxide are below HED's level of concern. The
DEEM and Lifeline model chronic dietary exposure estimate for the highest exposed
population subgroup, children 1-2 years of age were 16% and 13% of the cPAD
respectively. The results of the DEEM and Lifeline acute and chronic non cancer dietary
exposure analyses and risk estimates for PPO are reported in Table 8.
Table 8. Acute and Chronic Dietary Exposure and Risk Estimates for Propylene oxide
Population Subgroup
PAD,
mg/kg/day
DEEM-FCID
Exposure,
mg/kg/day
% PAD
Lifeline
Exposure,
mg/kg/day
%PAD
Acute Dietary Estimates (99.9th Percentile of Exposure)
Females 13-49 years old
0.21
0.0131
6
0.0141
7
Chronic Dietary Estimates
General U.S. Population
All infants (< 1 yr)
Children 1-2 yrs
Children 3 -5 yrs
Children 6- 12 yrs
Youth 13-19 yrs
Adults 20-49 yrs
Adults 50+ yrs
Females 13-49 yrs
0.0014
0.0014
0.0014
0.0014
0.0014
0.0014
0.0014
0.0014
0.0014
0.0001
0.0001
0.0002
0.0002
0.0001
0.0001
0.0001
0.0001
0.0001
6
3
16
15
10
5
5
6
5
0.0001
0.0001
0.0002
0.0002
0.0001
0.0001
0.0001
0.0001
0.0001
7
2
13
14
10
6
6
7
7
The cancer assessment for PPO has been revised to incorporate new residue and percent
crop treated data for nutmeats and to omit guar (edible gums) as a fumigated commodity.
Revisions to the cancer analysis resulted in a DEEM chronic exposure estimate for the
general population of 0.0001 mg/kg/day. Cancer risks for dietary exposure to PPO were
estimated using this revised chronic exposure estimate and the alternative cancer slope
factor derived using a PBPK or concentration based approach. The revised chronic
dietary exposure assessments conducted for all supported propylene oxide food uses for
the general U.S. population concludes that the cancer dietary risk estimates for propylene
oxide are below HED's level of concern. Based on the revised assessment, excess
lifetime risk estimates for the U.S. general population are 4xlO"7. The results of the
cancer analysis conducted using the alternative cancer slope factor are provided in Table
9.
Page 54 of 95
Page 111 of 192
-------
Conclusions of the cancer dietary risk assessment only are based on residue data supplied
by Aberco, Inc. and industry representatives that reflect typical application rates.
Although the typical application rates are lower than the agreed-upon maximum
application rate of 2.0 oz ai/ft3, the conclusion of the dietary risk assessment will not
change if the maximum rate for nuts is 2.0 oz ai/ft3. In other words, cancer risk estimates
would not exceed EPA's level of concern. In addition, the registrant has proposed
reducing the maximum application rate from 2.4 to 2.0 oz ai/ft3 for herbs, spices, dried
onion, dried garlic, cocoa beans, and cocoa powder.
Table 9. Cancer Dietary Exposure and Risk Estimates for Propylene oxide
Population Group
General U.S. Population
Slope Factor
(mg/kg diet)
0.000086
DEEM-FCID Exposure
mg/kg/day
0.0001
mg PPO/kg Diet l
0.0047
Estimated
Cancer Risk 2
4xlO'7
mg PPO/kg Diet = 0.0001 mg/kg/day chronic dietary exposure x 70 kg bw -=-1.5 avg kg food consumed/day*
2 Estimated Cancer Risk = slope factor 0.000086 (mg/kg diet)'1 x 0.0047 mg PPO/kg diet
* American Industrial Health Council (AIHC), 1994 Exposure Factors Sourcebook Washington DC., AIHC
An acute RfD was not established for propylene chlorohydrin because an endpoint
attributable to a single (or few) day exposure was not identified from the available
database. The results of both the DEEM and Lifeline chronic dietary exposure analyses
for propylene chlorohydrin are reported in the Table 10. These assessments for PCH
conclude that for all supported commodities, the chronic dietary exposure estimates are
below HED's level of concern. The DEEM and Lifeline chronic dietary exposure
estimates for the highest exposed population subgroup, children 1-2 years of age, are
25% and 29% of the cPAD respectively.
Table 10. Result of Chronic Dietary Exposure and Risk Estimates for Propylene chlorohydrin
Population Subgroup
U.S. Population
All infants (< 1 yr)
Children 1-2 yrs
Children 3 -5 yrs
Children 6- 12 yrs
Youth 13-19 yrs
Adults 20-49 yrs
Adults 50+ yrs
Females 13-49 yrs
cPAD,
mg/kg/day
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
DEEM-FCID
Exposure,
mg/kg/day
0.0018
0.0017
0.0074
0.0062
0.0037
0.0015
0.0010
0.0011
0.0011
% PAD
6
6
25
21
12
5
4
4
4
Lifeline
Exposure,
mg/kg/day
0.0034
0.0027
0.0087
0.0080
0.0054
0.0035
0.0030
0.0030
0.0036
%PAD
11
9
29
27
18
11
10
10
12
7.0 RESIDENTIAL EXPOSURE/RISK PATHWAY
There are no residential uses for PPO. However, exposure to PPO is expected to occur to
the subjects residing near the PPO fumigation facilities. PPO emissions monitoring data
Page 55 of 95
Page 112 of 192
-------
necessary to quantitatively estimate exposures and risks from sterilization/fumigation
facilities are unavailable. Therefore, a qualitative assessment was conducted comparing
the risks associated with emissions from the use of a similar chemical, ethylene oxide
(ETO), in similar commercial sterilization/fumigation scenarios. Additionally, a
quantitative assessment of residential bystander risk associated with emissions from
outdoor commodity fumigation in stationary commercial sterilization chambers which
have no emission controls and in temporary structures with the recently registered
product Propoxide 892.
7.1 Emissions from Commercial Sterilization Chambers with Emission Controls
EPA's Office of Air Quality Planning and Standards (OAQPS) has recently conducted a
residual risk assessment for fugitive and point source emissions of ETO in the
commercial sterilization source category (Mark Morris, OAR, 2/25/05). OAR's
residential risk assessment estimated cancer as well as short and long term non-cancer
risk to the general population. The results of OAR's assessment were included in HED's
ETO risk assessment (D316794, May 18, 2005). Based on the results of its residential
exposure assessment, OAR concluded that potential cancer and non-cancer (acute and
chronic) risk indicate that no further regulatory action is necessary at this time.
Because of the similarity in chemical characteristics (e.g., vapor pressure) and usage
scenarios, the results and conclusions from the ETO assessment can be compared,
qualitatively, with PPO use in commercial sterilization facilities that have emission
controls comparable to those required for ETO. To further refine or attempt a
quantitative assessment specific for PPO, use of similar air modeling techniques and
emissions monitoring data would be required.
Using various data sources, including EPA's Toxic Release Inventory (TRI) and the
National Emissions Inventory (NEI) point source database, OAR estimated that the
facility with the highest annual ETO usage (500 tons) would have total annual emissions
of 10 tons (20,000 Ibs) and these emissions are further corroborated by a 2003 TRI
report. Using modeling techniques, OAR concluded that no source poses a lifetime
cancer risk greater than 100 in a million and that chronic non-cancer effects are unlikely
to occur because no source emitted ETO in quantities that resulted in exposures that
approached the inhalation reference concentration of 30 |ig/m3.
A qualitative comparison with the results from the residual risk assessment for ETO
concludes that the residual cancer risks for PPO emissions would be significantly less
than those reported by OAR for ETO due to the difference in the chemicals' risk factors
and the less annual usage for PPO compared to ETO. Assuming the source with the
highest emissions, 20,000 Ibs, OAR found no ETO source posing a cancer risk greater
than 100 in a million with a unit risk estimate (Qi* or cancer slope factor) of 0.16 ppm"1).
The existing cancer slope factor for PPO (Qi* = 0.0084 ppm"1) is approximately 20-fold
less compared to that for ETO. In addition to the reduction in cancer slope factors, the
annual usage for PPO is found approximately 14 times less compared to ETO usage
(4000 tons versus 285 tons) (J. Faulkner, EPA/OPP/BEAD Quantitative Usage Analysis).
Page 56 of 95
Page 113 of 192
-------
Based on the reduction in usage and cancer slope factors, the cancer risk for PPO
exposure is significantly less than ETO.
For acute risk, OAR conducted a screening assessment of potential risk from short-term
emissions from ethylene oxide commercial sterilization sources using three acute
endpoints, the Acute Exposure Guideline Level-2 (AEGL) of 81 mg/m3(45 ppm), the
Emergency Response Planning Guideline (ERPG) of of 90 mg/m3 (50 ppm), and the
OSHA Immediately Dangerous to Life and Health (IDLH/10) Level of 140 mg/m3 (78
ppm). OAR concluded that results of the acute exposure assessment indicate that
estimated acute exposures are not of concern. The level of concern (daily TWA) for
acute risks from both ETO and PPO is 1.7 ppm. Therefore, risks from PPO for the acute
exposure scenario would be similar to those for ETO. For non cancer risk, OAQPS used
a Reference Exposure Level (REL) developed by California EPA of 30 |ig/m3 or 0.02
ppm and determined that potential for non cancer risks are also not of concern. Since the
chronic reference concentration for PPO is higher than the ETO RfC and the annual
usage is less for PPO, chronic non-cancer risks are not expected to be of concern.
7.2 Emissions from Stationary Sources with No Emission Controls and Outdoor
Commodity Fumigation with Propoxide 892
This assessment addresses residential bystander risk from commodity fumigations
conducted in stationary fumigation chambers that do not have emission controls and from
commodity fumigation scenarios outlined in the registered product Propoxide 892 (EPA
Reg. No. 47870-3). (M. Crowley, D316545, 7/31/06) Fumigation with Propoxide 892
differs from fumigation with other PPO products in that the Propoxide 892 label allows
for fumigation of commodities in a variety of outdoor containment structures. These
structures include trailers, air/sea containers, railcars, tents, and tarps. The use pattern for
Propoxide 892 closely follows that of methyl bromide for which a quantitative
commodity fumigation bystander risk assessment has been conducted (J. Dawson,
D304623, 3/10/06). Therefore, due to the similarities in use pattern, the bystander
assessment for propylene oxide fumigation is generally consistent with the methodologies
used to assess residential bystander risk for methyl bromide - although certain aspects
and assumptions differ.
7.2.1 Modeling Methodology
The PERFUM (Probabilistic Exposure and Risk model for FUMigants PERFUM V 2.1.2;
http://www.sciences.com/perfum/index.html) was used to assess potential risk to
residential bystanders from two additional fumigation scenarios; 1) commodity
fumigations in commercial sterilization chambers that do not have emission controls and
2) commodity fumigations with Propoxide 892. The PERFUM model was used for this
assessment because HED believes it provides the most refined, scientifically defensible
approach for calculating and characterizing risks. PERFUM uses as its core processor the
proven technology of ISCST3 (Industrial Source Complex: Short-Term Model
(http://www.epa.gov/scram001/). It incorporates actual weather data, and links flux
profiles to the appropriate time of day when calculating results.
Page 57 of 95
Page 114 of 192
-------
7.2.2 Exposure Scenarios
The scenarios modeled are assumed to represent typical PPO use scenarios and are
similar to those modeled for methyl bromide. The exposure scenario evaluated for this
assessment were developed based on a set of critical factors including the nature of the
buildings, chambers, or structures being treated; application rates and treatment
durations; and emission rates and factors. Based on the available information regarding
likely use patterns for Propoxide 892, the most conservative scenario in which no stack is
assumed (e.g., opening doors to railcars for aeration) was modeled for this assessment.
This scenario represents leakage from a structure during treatment as it is assumed for
certain structures (i.e., railcars or air/sea containers) that fugitive emissions are possible.
Based on likely use patterns, PPO fumigation conducted in non-stationary sources (e.g.,
temporary structures such as railcars, tents, tarps) is expected to be infrequent and
intermittent. Therefore, long term exposures to bystanders from this scenario are not
expected. Emission controls are not required for sterilization conducted with PPO.
Therefore, HED also evaluated residual risk to bystanders from fumigations conducted in
commercial sterilization chambers without emission controls. Only acute exposures were
assessed for this scenario because protecting for acute effects at the acute daily TWA
level of concern of 1.7 ppm will also protect against effects from chronic exposure.
7.2.3 PERFUM Model Inputs
In order to assess the potential levels of exposures that could be associated with the
exposure scenarios described above, HED has developed a series of input parameters for
the PERFUM modeling that is meant to bracket the range of possible exposures
associated with PPO treatment of commodities under various common use practices.
Again, these conditions are generally modeled after the MeBr commodity fumigation
assessment. The factors which have been used include:
• Treatment Concentration
- 2.8 Ib Ib ai/1000 ft3 (0.0448 oz/ft3) (Propoxide 892)
- 31.25 Ib ai/1000 ft3 (0.5 oz/ft3)
- 43.75 Ib ai/1000 ft3 (0.7 oz/ft3)
- 751bai/1000ft3(1.2oz/ft3)
- 150 Ib ai/1000 ft3 (2.4 oz/ft3)
• Retention and Emission Rates (expressed as % of treatment concentrations)
- During Treatment (Scenario 1): 1, 5, 10, 25, and 50% of treatment concentration;
Aeration (Scenarios 2-3): 50, 75, 90, 95, 99, and 100% of treatment concentration
is released and varies based on how airtight the chamber is and/or how much is
absorbed.
• Structure Volume
- Small scale: 1000, 2000, 5000 cubic feet;
• Structure Height
- Small scale: 1000 cu. ft = 10 feet tall, 2000 cu. ft. = 12 feet tall, 5000 cu. ft. = 17
feet tall;
Page 58 of 95
Page 115 of 192
-------
• Stack and Release Heights
All fixed stack heights =10 feet stack affixed to chambers or structures [Note:
absolute release height then varies when added with specific building height]
• Active Air Exchange Rates
4 air exchanges/hour representing full ventilation or exit velocity [Note: this is
based on the Propoxide 892 label whose aeration instructions include 4 chamber
volumes of fresh air and an aeration time of one hour for atmospheric and vacuum
fumigation.]
2 air exchanges/hour representing 50% of full exit velocity;
0.2 air exchanges/hour representing 5% of full exit velocity.
• Stack Diameters
PERFUM can only accommodate a single stack so the diameters are varied to
achieve the proper cross sectional ventilation areas for each combination of
chamber/structure size and air exchange value. The results for larger chambers or
high concentration treatments, therefore, may be based on very large diameter
stacks which would not occur in reality to achieve proper ventilation (i.e., 0.2 m
to 5 m). Under actual conditions, multiple stacks would be used in order to
achieve target air exchange rates. This approach is not expected to be a negative
bias in the results. In fact, this approach is likely a conservative method because
all emitted PPO is forced out at one location making the predicted distances
higher.
• Hazard Concerns
Threshold Level of Concern: 1.7ppm.
• Treatment Frequency and Emission Profiles
- A number of frequency and emission profiles were considered in order to simulate
the practices associated with PPO commodity use. Only those emission profiles
that are assumed to represent current PPO use in commodity fumigations are
presented below. In most applications the active application duration is 16-48
hours followed by aeration on the order of 1 hour. Based on this information,
HED considered 2 frequency and emission profiles in the assessment:
— 1-hour single emission: based on a single application and short-lived emission
period such as 15 minutes, actual modeling of a 15 minute emission profile
was not done since PERFUM accepts emission terms in 1 hour intervals and
the concentration that it is compared to is 8 hours so the 1-hour time-frame is
a better comparison;
— 4-hour single emission: based on a single application and short-lived
emission period such as 15 minutes as the 1-hour emission described above
but 3 additional hours of no emissions were also included (i.e., a 4-hour time-
weighted average) in order to develop a better comparison to the human
equivalent concentration.
7.2.4 Residential Bystander Exposure and Risk Estimates
There is potential for exposure and risk to propylene oxide (PPO) for non-
occupational/residential bystanders as a result of both commodity fumigations conducted
in non-emission controlled commercial sterilization chambers and in those conducted
Page 59 of 95
Page 116 of 192
-------
with the registered product Propoxide 892. The PERFUM results are generated in the
form of buffer distances. The range of buffer zones corresponds to a range of
assumptions regarding key input parameters including, structure size, emission rate, and
ventilation rate. The "Maximum Buffer" distribution is based on the maximum distance
needed to reach the threshold level of concern for each of 1825 days (i.e., a distribution
of the farthest single points on the irregular line as seen in Figure 1 for each of 1825
days). The "Whole Field Buffer" distribution is also based on values from each day,
except the distances on which the distribution is based includes those on each spoke
where the threshold concentration or level of concern is achieved for each day. For both
types of buffer distances, results from selected percentiles from the distribution have been
reported. PERFUM results for aeration of structures (i.e., chamber, tarp, or railcar) using
Propoxide 892 are presented in Table 11. PERFUM results for commercial sterilization
chambers with no emission controls are presented in Table 12. Buffer distances (in
meters) are presented from the 90th percentile to the 99.9th percentile and are based on
95% and 75% of the application rate emitted upon aeration.
Table 11. Propoxide 892 - PERFUM Buffer Distances (meters) 4 hour Exposure Duration, 2.8 lb/1000 cubic feet Application Rate
Aeration Type
Percentile
1000 Cubic Feet
95% Mass
Release
75% Mass
Release
2000 Cubic Feet
95% Mass
Release
75% Mass
Release
5000 Cubic Feet
95% Mass
Release
75% Mass
Release
During Aeration
Maximum Buffer Distances
Minimum
Stack
(4 xch/hr)
No Stack
90
95
99
99.9
90
95
99
99.9
10
15
20
20
40
45
55
60
0
10
15
15
30
35
40
45
35
40
50
55
75
85
100
105
30
30
40
40
60
70
80
85
40
45
50
55
150
170
185
195
30
35
40
45
130
145
160
165
Whole Field Buffer Distances
Minimum
Stack
(4 xch/hr)
No Stack
90
95
99
99.9
90
95
99
99.9
0
0
0
15
0
0
10
40
0
0
0
10
0
0
0
30
0
0
0
35
0
0
25
80
0
0
0
30
0
0
20
65
0
0
20
40
0
5
55
160
0
0
0
35
0
0
45
135
During Treatment
Maximum Buffer Distances
No Stack
95
99
99.9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Whole Field Buffer Distances
No Stack
95
99
99.9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Page 60 of 95
Page 117 of 192
-------
Table 12. Commercial Sterilization w/o Emission Control - PERFUM Buffer Distances (meters) 4 hour
Exposure Duration, 5000 ft3 Treated Volume
Aeration Type
Percentile
95% Mass Release
75% Mass Release
Application Rate 150 lb/1000 ft3
Maximum Buffer Distances
Minimum Stack (4 xch/hr)
90
95
99
99.9
1440
1440
1440
1440
1410
1440
1440
1440
Whole Field Buffer Distances
Minimum Stack (4 xch/hr)
90
95
99
99.9
0
45
545
1440
0
40
470
1440
Application Rate 75 lb/1000 ft3
Maximum Buffer Distances
Minimum Stack (4 xch/hr)
90
95
99
99.9
1015
1155
1330
1370
180
965
1120
1150
Whole Field Buffer Distances
Minimum Stack
(4 xch/hr)
90
95
99
99.9
0
35
350
1085
0
30
300
915
Application Rate 43.75 lb/1000 ft3
Maximum Buffer Distances
Minimum Stack(4 xch/hr)
90
95
99
99.9
680
775
870
920
560
645
735
770
Whole Field Buffer Distances
Minimum Stack
(4 xch/hr)
90
95
99
99.9
0
25
245
720
0
25
205
600
Application Rate 31.25 lb/1000 ft3
Maximum Buffer Distances
Minimum Stack
(4 xch/hr)
90
95
99
99.9
515
590
685
710
425
490
565
590
Whole Field Buffer Distances
Minimum Stack
(4 xch/hr)
90
95
99
99.9
0
25
195
555
0
20
165
460
8.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION
As per FQPA, when there are potential residential exposures to the pesticide, aggregate
risk assessment must consider exposures from residues in food commodities and drinking
water as well as exposures arising from non-dietary sources (e.g., incidental oral, dermal
and inhalation routes). The residue from drinking water is expected to be negligible since
PPO is used only indoors. PPO has no direct residential uses; however residential
Page 61 of 95
Page 118 of 192
-------
bystanders may be exposed to emissions from fumigation facilities or structures. Dietary
and bystander exposure cannot be combined for this assessment, however, because the
endpoints selected for these exposures are not based on a common effect. Therefore, risk
from dietary and inhalation routes are not aggregated for this assessment.
9.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT
Unlike other pesticides for which EPA has followed a cumulative risk approach based on
a common mechanism of toxicity, EPA has not made a common mechanism of toxicity
finding as to propylene oxide and any other substances and propylene oxide does not
appear to produce a toxic metabolite produced by other substances. For the purposes of
this tolerance action, therefore, EPA has not assumed that propylene oxide has a common
mechanism of toxicity with other substances. For information regarding EPA's efforts to
determine which chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released by EPA's Office
of Pesticide Programs concerning common mechanism determinations and procedures for
cumulating effects from substances found to have a common mechanism on EPA's
website at http://www.epa.gov/pesticides/cumulative/.
10.0 OCCUPATIONAL EXPOSURE/RISK
Occupational exposures and risks are assessed for propylene oxide and propylene
chlorohydrin (M. Crowley, D316545, 7/31/06). PPO exposures occur only after PPO
application and thus are considered post application exposures. The "post application"
activities can be broken down into "sterilization activities", including loading/unloading
the sterilization chambers (opening chamber and chamber re-entry) and
replacing/installing drums, and "post-sterilization activities", including transporting
boxes/drums/bags and bagging/containerizing treated commodities. A target level of
concern or margin of exposure (MOE) of 30 is considered adequate for short-,
intermediate- and long-term occupational inhalation exposure to PPO, the primary
exposure route of concern. OPP's goal is to reduce occupational exposures to reflect
cancer risks no greater than IxlO"6. If the proposed cancer MOA is accepted by the
Agency, inhalation exposure to PPO will not be regulated using a q* approach. Rather, a
MOE analysis will be conducted. If the Agency concurs with the proposed MOA, then
cancer and long-term non-cancer risks would be regulated at the same level, since the
long-term non-cancer endpoint is based on nasal lesions that are considered precursors to
the development of tumors.
10.1 Exposure Scenarios
HED anticipates the following activities to result in potential worker exposure to PPO.
• Inhalation exposure to PPO during sterilization activities.
• Dermal exposure to PPO during sterilization activities.
Inhalation exposure to off-gassed PPO from treated commodities during post-
sterilization activities.
Page 62 of 95
Page 119 of 192
-------
• Dermal exposure to PPO residues during post-sterilization activities.
10.2 Established Exposure Levels
The regulatory levels or recommendations for exposure to propylene oxide from various
organizations and the precautionary exposure limit levels mentioned in the EPA label are
used for the estimation of exposure levels.
10.2.1 Regulatory/Recommended Exposure Levels
Table 13 lists various organizations and their regulatory levels or recommendations for
exposure to propylene oxide.
Table 13: Propylene Oxide Regulatory Levels
Organization
Occupational Safety and Health Administration (OSHA)
National Institute for Occupational Safety and Health (NIOSH)
American Conference of Governmental Industrial Hygienists (ACGIH)
California Division of Occupational Safety and Health (Cal/OSHA)
Concentration (ppm)
100
LFC2
2
205
Nomenclature
PEL1
REL3
TLV-TWA4
PEL
1 Permissible Exposure Limit (PEL): The employer shall ensure that no employee is exposed to an airborne
concentration of PPO in excess of the PEL as an 8-hour time-weighted average (8-hour TWA). 100 ppm PEL from 29
CFR 1910.1000 Z-l Table.
2 LFC = Lowest Feasible Concentration. NIOSH policy recommends potential occupational carcinogens without a
quantitative REL to be at the lowest feasible concentrations. (Appendix A to NIOSH Pocket Guide to Chemical
Hazards).
Recommended Exposure Limit (REL): NIOSH-recommended exposure limit for an 8- or 10-h TWA and/or ceiling.
4 Threshold Limit Value - Time Weighted Average (TLV-TWA): Expressed as a TWA for a conventional 8-hour
workday and a 40-hour workweek, to which it is believed that nearly all workers may be repeatedly exposed, day after
day, for a working lifetime without adverse effect. This is a recommended level and is not enforceable. 2 ppm TLV
adopted in 2001.
5 From Table AC-1 of California Code of Regulations Title 8, Chapter 4, SubchapterV, Group 16, Article 107, Section
5155 Airborne Contaminants. Note: The Cal/OSHA Standards Board had proposed lowering this level to l.Oppm,
however the proposal was not adopted due to further review requirements under Executive Order S-2-03 (Cal/OSHA,
2004).
10.2.2 Label Requirements
The current end-use label (EPA Reg. No. 47870-1) requires the following regarding
exposure and worker protection.
• Where there is potential for dermal contact, full body personal protective
equipment (PPE) must be worn. This includes solvent-proof gloves, clothing, hat,
apron, and boots. Vapor-proof goggles are also required.
• Where PPO air concentrations are 20 ppm or greater a full face self-contained
breathing apparatus (SCBA) is required. This is for all work areas including the
chambers and off-gassing holding areas.
• Areas where PPO air concentrations are 20 ppm or greater must be placarded to
indicate the presence of PPO.
Page 63 of 95
Page 120 of 192
-------
10.3 Exposure Monitoring Data
PPO inhalation worker exposure data reflecting outdoor fumigation activities was
submitted during Phase III of the RED process. The majority of monitoring data,
measured using personal badges, was submitted as daily time weighted averages
(TWAs), although some "task-specific" data for unloading sterilization chambers was
submitted as well. For risk assessment purposes, task-specific data was adjusted to
represent a daily average.
The Almond Board of California and the California Walnut Commission submitted
exposure data for workers exposed to PPO while fumigating almonds and walnuts. PPO
concentrations in air (all reported as time-weighted averages) were measured using
Propylene Oxide Vapor Monitor badges analyzed by gas chromatography with flame
ionization detection (GC FID). The reference analysis method was NIOSH Method
1612. The analysis laboratory indicated the limit of quantification is 0.1 ppm for an 8-
hour sample. Most of the data collected represent entire workdays (i.e., approximately 8
hours), although some samples document exposure during specific activities of shorter
duration (i.e., chamber unloading and transportation of commodity to degassing room).
Additional "area" concentrations were submitted for non-work areas and degassing
rooms. Newly submitted worker exposure monitoring data is summarized in Table 13.
Table 14: Combined Almond and Walnut Fumigation Worker Exposure Data Summary
Data Source
All Data
Activity
Non-Specific (Daily TWA)
Combined Non-Specific & Adjusted
Chamber Unloading TWA
#
Samples
19
22
Avg Hrs
Sampled
8.1
8.1
TWA (ppm)
Mean
0.94
1.2
Median
0.55
0.64
Geometric Mean
0.58
0.71
Max
6.6
6.6
It is important to reiterate that all of the newly submitted data represent outdoor
fumigations i.e., situations in which natural ventilation is provided by outdoor air. It is
reasonable to assume that the daily exposure profile indicated by the newly submitted
data are representative of all outdoor sterilization/fumigation operations i.e., that for
outdoor fumigations, daily average exposure comprises sporadic, peak PPO exposures
during certain sterilization/fumigation activities and negligible exposure for the
remainder of the day.
However, the data cannot be assumed to be representative of fumigations conducted in
indoor commercial sterilization facilities. An exposure survey performed for fumigations
done using chambers housed inside large warehouses which are not open to the outside
air could potentially exhibit a different exposure profile. It is reasonable to assume that,
for indoor facilities, shortened periods of heightened PPO exposure would be similar to
the outdoor facilities, however background PPO concentrations and exposure could be
different due to differences in ventilation. Therefore, this data set and any risk estimates
and recommendations should be considered only relevant to outdoor fumigation facilities.
Page 64 of 95
Page 121 of 192
-------
10.4 Exposure Assumptions
It is assumed that there is potential for PPO exposure for short- (1-30 days)/intermediate-
(1-6 months)/ and long- (> 6 months) term durations. For cancer risk calculations,
exposure frequency (the amount of days per year workers are exposed to propylene
oxide) is assumed to be 240 days per year and occupational exposure to be 35 years over
a 70 year lifespan - both standard HED assumptions.
10.5 Exposure and Risk Estimates
10.5.1 Inhalation Exposure and Risk
The cancer and non-cancer risks from exposure to PPO were determined based on
currently recommended or regulatory concentration levels. Concentrations at which risks
are not of concern for cancer and non-cancer effects are provided in Table 14. Non-
cancer and cancer risk estimates at regulatory and or recommended levels established by
various organizations and regulatory agencies are provided in Table 15. HED also
estimated risks based on recently submitted PPO inhalation worker exposure monitoring
data. Task-specific monitoring data was adjusted to represent a daily average for risk
assessment purposes. Results of that assessment are provided in Table 16. The short- (1-
30 days), intermediate- (1-6 months), and long-term (greater than 6 months) inhalation
non-cancer and cancer risks from the use of PPO in commodity sterilization/fumigation
are of concern at 20 ppm the exposure limit value established by Cal/OSHA and included
in current EPA PPO label. The acute, short-, intermediate- and long-term non-cancer
risks are not of concern at the ACGIH recommended worker exposure concentration of 2
ppm. As previously noted, EPA has concluded that a proposed MOA is highly plausible,
and EPA will review the proposed MOA in more depth, both within OPP and in
conjunction other Agency offices. If the Agency concurs with the proposed MOA, then
cancer and long-term non-cancer risks would be regulated at the same level, since the
long-term non-cancer endpoint is based on nasal lesions that are considered precursors to
the development of tumors.
Table 15: Exposure Levels at which Cancer and Non-Cancer Risks are Not of Concern
Cancer Risk
Exposure Frequency
(days/year)
240
240
Cancer Risk
l.OxlO'4
LOxlO'6
Exposure Concentration
(ppm)
0.11
0.0011
Non-Cancer Risk
Exposure Duration
Acute
Short/Intermed- term
Long-term
LOC for MOE
300
30
30
Exposure Concentration (ppm)
1.7
2.5
o
3
(HEC)
' or 0.0084 ppm", Short-/mtermediate-term NOAEL = 75 ppm; Long-term BMDL10 = 90 ppm
Page 65 of 95
Page 122 of 192
-------
Table 16: Non-Cancer and Cancer Risk Estimates at Regulatory Levels
Organization
OSHA (PEL)
Cal/OSHA & EPA Label Levels (8-hour TWA)
ACGIH (TLV-TWA)
Concentration
(ppm)
100
20
2
Non-Cancer MOE
ST/IT
LT
LOC for MOE = 30
0.8
3.8
38
0.9
4.5
45
Cancer Risk
9.2 x 10"2
l.SxlO"2
l.SxlO"3
Short-/Intermediate-term NOAEL = 75 ppm; Long-term BMDL10 = 90 ppm (HEC); Qj = 3.5x10"" (|xg/mj) "' or 0.0084
MOE = Inhalation NOAEL or BMDL + Inhalation dose at regulatory level
Table 17: Non-Cancer and Cancer Risk Estimates - Almond/Walnut Exposure Monitoring Data
Combined
Data
Mean
Activity
Non-Specific (Daily TWA)
Combined Non-Specific & Adjusted Chamber Unloading TWA
Daily
TWA1
(ppm)
0.94
1.21
Non-Cancer MOE
ST/IT2
LT3
LOC for MOE = 30
80
62
96
74
Cancer
Risk4
8.7E-04
1.1E-03
1 All almond and walnut fumigation data are combined. "Combined Non-Specific & Adjusted Chamber Unloading
TWA" refers to the combination of all almond/walnut "non-specific" daily TWAs with the daily adjusted TWAs for
chamber unloading during walnut fumigations.
Short-/Intermediate-term NOAEL = 75 ppm
3 Long-term BMDL10 = 90 ppm (HEC)
4Qi*= S.SxlO^dxg/m3)"1 or 0.0084 ppm'1
10.5.2 Dermal Exposure and Risk
Dermal exposure to liquid PPO while changing drums is negligible as the exposure
pattern is likely episodic and changing drums typically involves disconnecting and re-
connecting valves while wearing full body protection including gloves, face shield, and
goggles as required by the product labels. The registrant has indicated that commodities
are fumigated in packaging which is sealed prior to shipping, and commodity processing
is largely automated (Brooks, 2005). Therefore, dermal exposure to the treated
commodities themselves is also likely negligible. Therefore a quantitative dermal
exposure assessment is not considered necessary.
10.5.3 Risk Characterization
Because of a scarcity of monitoring data, HED has indirectly characterized inhalation
risks for PPO by comparison to the OSHA PEL of 100 ppm, or to recommended air
concentration limits, such as ACGIH's TLV of 2 ppm. During Phase III of the RED
process, HED received data associated with the outdoor use of PPO on almonds and
walnuts. The submissions provide exposure monitoring data (i.e., air concentrations),
and descriptions of daily activities, including duration and, in some instances, PPE (i.e.,
respiratory protection) worn. Due to data limitations, primarily lack of data associating
peak concentrations with specific tasks, HED could not use this information to
quantitatively adjust daily average exposure based on PPE usage. Nevertheless, the
submitted information and data clearly suggests that daily average PPO exposure is
influenced by sporadic instances of peak PPO concentrations during certain activities
during the day. Given this likely exposure pattern, HED believes that steps can be taken
to mitigate risks. For example, respiratory protection during peak PPO exposures could
Page 66 of 95
Page 123 of 192
-------
reduce the daily average exposure to levels that would not be of concern. Additional
monitoring data and/or an exposure survey that "breaks down" activities throughout the
day using separate monitoring badges for each activity or one that uses direct read
instrumentation to obtain measurements throughout the course of the workday is
expected from the registrant and industry representatives.
It is important to reiterate that the submitted data for outdoor fumigation facilities cannot
be assumed to be representative of fumigations conducted in indoor commercial
sterilization facilities. It is reasonable to assume that, for indoor facilities, shortened
periods of heightened PPO exposure would be similar to the outdoor facilities, however
background PPO concentrations and exposure could be different due to differences in
ventilation. Therefore, additional monitoring data specific to indoor activities would be
necessary to determine an appropriate mitigation strategy for indoor uses of PPO.
11.0 DATA NEEDS
11.1 Toxicology
Outstanding toxicology data requirements for PPO are reserved. The requirement for a
nonrodent oral chronic toxicity study (870.4100b) is reserved pending further
consideration of PPO's mode of action.
The toxicology database for PCH is considered complete.
11.2 Residue Chemistry and Label Requirements
Directions for use must be clearly defined on all labels that are allowed for the
fumigation of cocoa bean, nutmeats (except peanut) and spices. Labels of all PPO
formulations that are used to treat these commodities must include postharvest directions
stating exposure time, temperature and percent humidity, amount of active ingredient
PPO, aeration time in treatment chamber, additional storage conditions before treated
commodities are released to market for consumption, and any other parameters (i.e.,
equipment type, capacity, that are necessary to insure consistency in each treatment.
These parameters are needed so the established tolerances will always adequately cover
potential residues of concern from PPO fumigation of the listed commodities. According
to the registrant, items such as dried onions, dried garlic, and dehydrated vegetables are
included in ASTA definition of spices. As these foods are in other crops groups as
defined by the Agency, tolerances have to be established for these items.
The existing 300 ppm tolerance for vegetable gums should be revoked based on the
registrant's request for voluntary cancellation of PPO use on all edible gums pursuant to
FIFRA Section 6(f)(l)(A).
Labels of all PPO formulations that are used to treat tree nuts must mimic the application
conditions used (one rate if for all tree nuts, and list of all rates if slightly different within
the tree nut group) in the residue data trials to include postharvest directions stating
Page 67 of 95
Page 124 of 192
-------
exposure time, temperature and percent humidity, maximum amount of active ingredient
PPO allowed for treatment, aeration time in treatment chamber, additional storage
conditions before treated commodities are released to market for consumption, and any
other parameters (i.e., equipment type, capacity, etc.) that are necessary to insure
consistency in each treatment. These parameters are needed so the established tolerances
will always adequately cover potential residues of concern from the PPO fumigation of
nutmeats.
Analytical reference standards for PPO and PCH are not currently available in the EPA
National Pesticide Standards Repository. Analytical reference standards of PPO and
PCH must be supplied and supplies replenished by the Repository.
Presently in 40 CFR §180.491 application directions are listed including time and
temperature conditions. Sections listing application directions should be removed. All
treatment parameters should be on the label only, and not in the tolerance expression.
Recommended changes to the tolerance expression in 40 CFR §180.491 are provided in
Appendix 8.0.
Newly submitted residue data clearly show that PPO residue are much lower than the
existing 300 ppm tolerance much sooner that the label 28-day limitation. The newly
submitted data is considered preliminary, however. Therefore, HED will require
additional and adequate confirmatory residue data (with adequate sampling) to support
any change to the existing 300 ppm tolerance. Any study submitted must be run under
GLP conditions. Currently, the tolerance should remain at 300 ppm, but if the maximum
label rate is lowered for treatment of tree nuts, and adequate confirmatory data is
submitted, the tolerance may be decreased.
11.3 Occupational and Residential Exposure
Additional information regarding the sterilization activities and exposure monitoring data
from the sterilization and commodity processing industries would help refine the
assessment.
Page 68 of 95
Page 125 of 192
-------
APPENDICES
1.0 GUIDELINE TOXICOLOGY DATA SUMMARY
Data requirements (40 CFR 158.340) for propylene oxide^ are provided in the following
table. Use of the new guideline numbers does not imply that new (1998) guideline
protocols were used.
Data Requirements for Propylene Oxide
Test
870. 11 00 Acute Oral Toxicity
870. 1200 Acute Dermal Toxicity
870 1300 Acute Inhalation Toxicity
870.2400 Primary Eye Irritation
870 2500 Primary Dermal Irritation
870.2600 Dermal Sensitization
870 3100 Oral Subchronic (rodent)
870.3150 Oral Subchronic (nonrodent)
870 3200 21 -Day Dermal
870.3250 90-Day Dermal
870 3465 90-Day Inhalation
870 3700a Developmental Toxicity (rodent)
870 3700b Developmental Toxicity (nonrodent)
870.3800 Reproduction
870.4100a Chronic Toxicity (rodent)
870 4100b Chronic Toxicity (nonrodent)
870.4200a Oncogenicity (rat)
870 4200b Oncogenicity (mouse)
870.4300 Chronic/Oncogenicity
870.5100 Mutagenicity — Gene Mutation - bacterial
870 5300 Mutagenicity — Gene Mutation - mammalian
870. 5xxx Mutagenicity — Structural Chromosomal Aberrations
870. 5xxx Mutagenicity — Other Genotoxic Effects
870.6100a Acute Delayed Neurotoxicity. (hen)
870.6100b 90-Day Neurotoxicity (hen)
870 6200a Acute Neurotoxicity Screening Battery (rat)
870.6200b 90 Day Neurotoxicity. Screening Battery (rat)
870 6300 Develop Neurotoxicity
870 7485 General Metabolism
870.7600 Dermal Penetration
Special Studies for Ocular Effects
Acute Oral (rat)
Subchronic Oral (rat)
Six-month Oral (dog)
Technical
Required
yes
no1
yes
no1
no
no1
yes
yes
no
no1
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
no
no
no
no
no
no
yes
Satisfied
yes*
_
yes*
yes
yes
ves*
yes
yes
yes
yes
reserved
yes
yes
yes
yes*
yes*
yes*
yes*
_
_
no
no
yes
_
yes
Data gap exists for the metabolite of propylene oxide, propylene chlorohydrin; Refer to the Data Needs Section
^Study not required based on the severe irritant properties of the compound.
*Study reserved pending consideration of PPO mode of action.
* No study submitted but information from the open literature is sufficient to satisfy the guideline studies
Page 69 of 95
Page 126 of 192
-------
2.0 NON-CRITICA1 TOXICOLOGY STUDIES
Subchronic Neurotoxicity Study - Propylene Oxide
Subchronic Neurotoxicity Study (MRID 45292801)
In a Subchronic inhalation neurotoxicity study (MRID 45292801), groups of 30 Fisher-
344 male rats were exposed to 0, 30, 100, or 300 ppm of propylene oxide (Lot No. 30215
III; >99% active ingredient) for 24 weeks. Exposures were for 6 hr/day, 5 days/week for
the first 14 weeks and 7 days/week for the remainder of the study. Functional observa-
tional battery (FOB) testing was performed after 8, 16, and 24 weeks of exposure; motor
activity measurements were assessed once for each animal at the end of the study. Body
weights were recorded weekly for each animal. Neuropathologic examinations were
performed on 10 animals from each of the control and high-concentration groups; brain
weights were not reported.
No treatment-related mortalities or clinical signs of toxicity were observed in any rat.
Gross necropsy and neuropathology were unremarkable.
Absolute body weights were significantly (p < 0.05) less than the control group levels
beginning on day 11 for the high-concentration group (90-96% of controls) and on day 39
for the mid-concentration group (92-97% of controls). Body weights of the low-
concentration group were consistently less (96-97% of controls) than those of the controls
after the third week of treatment, but statistical significance was only attained
occasionally and the magnitude was not considered to be biologically significant.
No treatment-related or statistically significant differences in mean hindlimb grip
strengths were found for the treated groups as compared to the controls. No treatment-
related abnormalities were observed during handling and no gait or locomotor
abnormalities were noted in the open field. Reflex and sensorimotor responses were
similar between the treated and control groups. Motor activity was not affected by
treatment.
This study is classified as Acceptable/Non-Guideline and does not satisfy the
requirements for a Subchronic inhalation neurotoxicity study [OPPTS 870.6200 (§82-7)]
in rats. The LOAEL for neurotoxic effects are not established. Validation of the
laboratory neurotoxicity testing methods was not included and females were not tested.
However, the study is sufficient for the purposes for which it was intended to assess the
potential of propylene oxide to induce neurotoxicity in male rats following Subchronic
inhalation exposure.
COMPLIANCE: A signed and dated Quality Assurance statement was included. Data
Confidentiality, Good Laboratory Practice Compliance, and Flagging statements were not
provided.
Page 70 of 95
Page 127 of 192
-------
Subchronic Toxicity Studies -Propylene oxide
Oral Exposure
There were two subchronic reports identified in the literature examining the toxic effects
of PPO by oral route and these are either old (Rowe et al., 1956) or in a foreign journal
(Antonova et al., 1981) and original information could not be verified. The studies cited
below are not from original sources, and provide limited data and are cited as they are the
only subchronic studies identified for the oral exposure. Therefore, these studies were
not considered for the end point selection.
PPO was administered in drinking water to rats (strain unspecified, number of animals
per group not known) at 0, 0.00052, 0.0052, 0.052 and 0.52 mg/kg/day for 26 weeks. At
the highest dose level, polyuria, hematological abnormalities, decreased serum albumin,
increased serum-beta globulin and increased activities of gastrointestinal mucosal
enzymes were reported. Mild hematological abnormalities were reported at 0.052
mg/kg/day The NOAEL was identified as 0.0052 mg/kg/day and the LOAEL was
identified as 0.052 mg/kg/day (Antonova et al., 1981 as cited in WHO, 1985).
The study is classified as Unacceptable /Non-Guideline
In a subchronic oral toxicity study, females rats (strain not specified, number of animals
per treatment not known) were administered 0, 100, 200 or 300 mg/kg for 5d/week for 24
days (18 doses). It is assumed these doses were administered by gavage. The HDT has
slightly lowered body weight, evidence of gastric irritation and slight liver damage. The
NOAEL was identified as 200 mg/kg/day and the LOAEL was identified as 300
mg/kg/day based on decreased body weight, liver damage, and gastric irritation.
(Rowe et al., 1956, as cited in Meylan et al., 1986).
The study is classified as Unacceptable/Non-Guideline.
Inhalation Exposure
In a range-finding test for a carcinogenicity study (NTP, 1985), groups of 5 male and 5
female Fischer 344/N rats were exposed to 0, 47, 99, 196, 487, 1433 ppm propylene
oxide for 5 days per week, and 6 h per day, for two weeks. No gross or pathological
effects were observed. Dyspnea, hypoactivity, gasping, ataxia, and diarrhea were
observed at the HDT. Also, one male died at the HDT. Both males and females at the
HDT had decreased body weight gain as compared to controls. The NOAEL is
determined as 487 ppm and LOAEL is determined as 1433 ppm based on mortality,
decreased body weight gain, dyspnea, hypoactivity, gasping, ataxia, and diarrhea.
In range-finding test for a carcinogenicity study (NTP, 1985), groups of 5 male and 5
female B6C3F1 mice were exposed to 0, 20, 47, 99, 196, 487 ppm propylene oxide for 5
days per week, and 6 h per day, for two weeks. No pathological effects were observed.
Dyspnea was noticed at 196 and 487 ppm and mice at 487 ppm were also less active. No
Page 71 of 95
Page 128 of 192
-------
significant changes in body weights were reported. The NOAEL is determined as 99
ppm and LOAEL is determined as 196 ppm based on dyspnea effects.
In range-finding test for a carcinogenicity study (NTP, 1985), groups of 5 male and 5
female Fischer 344/N rats were exposed to 0, 31, 63, 125, 250, 500 ppm propylene oxide
for 5 days per week, and 6 h per day, for 13 weeks. No rats died. Final mean body
weights relative to those of controls were 7.4% lower in males and
5.3% lower in females exposed to air containing 500 ppm propylene oxide. The changes
in body weights were not considered as lexicologically significant. The NOAEL is
determined as 500 ppm and LOAEL is not established.
In range-finding test for a carcinogenicity study (NTP, 1985), groups of 5 male and 5
female B6C3F1 mice were exposed to 0, 31, 63, 125, 250, 500 ppm propylene oxide for 5
days per week, and 6 h per day, for 13 weeks. Decreased body weights (| 12.9% in males
and 114.6% in females) were reported at HDT as compared to controls. No gross or
microscopic changes were observed. The NOAEL is determined as 250 ppm and
LOAEL is determined as 500 ppm based on decreased body weights.
Propylene Chlorohydrin
Subchronic Toxicity Studies
Rats
In a sub chronic study (NTP, 1988), designed as a range finding study for chronic
carcinogenicity study, groups of 10 male and 10 female F344/N rats were administered 1-
chloro-2-propanol (75% l-chloro-2-propanol and 25% 2-chloro-l-propanol) in drinking
water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. The
daily doses determined by study authors correspond to 0, 15, 45, 140, 260, 265
mg/kg/day, respectively. Two 10,000 ppm females died before the end of the study (20%
mortality). The final mean body weights and body weight gains and water consumption
of 3,300 and 10,000 ppm rats were significantly less than those of the controls. The
absolute thymus weight and relative thymus weight to body weight of 10,000 ppm rats
were significantly less compared to controls. Exposure to l-chloro-2-propanol at 3300
and 10000 ppm caused cytoplasmic alteration and degeneration of the acinar cells in
pancreas, atrophy of the bone marrow in both sexes compared to respective controls. The
females at 1000 ppm, also exhibited cytoplasmic alteration and degeneration of the acinar
cells in pancreas, and atrophy of the bone marrow. Diffuse atrophy of the spleen was
reported in both sexes at 10,000 ppm. The LOAEL is determined as 1000 ppm (140
mg/kg/day) based on the histopathological changes in pancreas and bone marrow of
females. The NOAEL is determined as 330 ppm (45 mg/kg/day).
In a sub chronic study designed as a range finding study for the chronic
carcinogenicity study (NTP, 1998), groups of 10 male and 10 female F344/N rats
were administered l-chloro-2-propanol (75% l-chloro-2-propanol and 25% 2-
chloro-1-propanol) at concentrations of 0, 33,100, 330,1,000, or 3,300 ppm in
Page 72 of 95
Page 129 of 192
-------
drinking water for 14 weeks. The average daily doses as determined by study
authors correspond to 0, 5,10, 35,100, or 220 mg/kg, respectively. All rats survived
to the end of the study. Mean body weight gains of 3,300 ppm rats were
significantly less than those of the controls. Water consumption by the 3,300 ppm
male and female rats was significantly less than that by the controls. A minimal to
mild anemia was observed in exposed female rats at 3300 ppm. The cauda
epididymis and epididymis weights of 3,300 ppm males were significantly less than
those of the controls. The percentage of abnormal sperm in 3,300 ppm males were
significantly increased compared to the controls. The incidences of acinar cell
degeneration and fatty change of the pancreas in 1,000 and 3,300 ppm rats, focal
metaplasia of the pancreatic islets in 3,300 ppm females, cytoplasmic vacuolization
of the liver in 3,300 ppm males, and renal tubule epithelium regeneration in 3,300
ppm females were increased compared to the controls. The LOAEL is determined
as 1000 ppm (100 mg/kg/day) based on increased incidences of the acinar cell
degeneration, fatty change in the pancreas of both sexes. The NOAEL is
determined as 330 ppm (35 mg/kg/day).
In a subchronic oral toxicity study (USFDA, 1969 as cited in TNO BIBRA International,
1994), groups of rats (strain not specified; 10/sex/group) were given PCH in diets at 0,
1000, 2500, 5000 and 10,000 ppm for 25 weeks. Analysis of the 10,000 ppm diet
revealed 3568 ppm (73% l-chloro-2-propanol and 27% 2-chloro-l-propanol)
immediately after mixing and 838 ppm (68% l-chloro-2-propanol and 32% 2-chloro-l-
propanol) after 7 days. The reviewer determined the daily doses as 0, 100, 250, 500,
1000 mg/kg/day prior to the correction for the stability of the diet. There was no
information how often the diets were prepared. There were no effects on survival,
hematological and clinical parameters or gross or pathological changes. At 5000 ppm
and above body weights were decreased. The LOAEL is determined as 5000 ppm (500
mg/kg/day) based on decreased body weight. The NOAEL is determined as 2500
ppm (250 mg/kg/day).
In a subchronic oral toxicity study (USFDA, 1969 as cited in TNO BIBRA International,
1994), groups of rats (strain not specified; 10/sex/group) were administered PCH by
gavage at 0, 25, 50, or 75 mg/kg/day for 22 weeks. Increased liver weights were seen in
males at 25 mg/kg/day and in both sexes at 75 mg/kg/day. No effects on survival, the
clinical parameters, organ weights, gross or microscopic changes. A fifth group was
given doses increasing from 100 to 250 mg/kg/day over a 19 week period. Decreased
body weights were reported at 200 mg/kg/day and 100% mortality was reported at 250
mg/kg/day within 3 weeks of treatment. The LOAEL is determined as 25 mg/kg/day
based on increased liver weight in males. The NOAEL is not established.
Mice
In a subchronic study designed as a range finding study for the carcinogenicity study
(NTP, 1998), groups of 10 male and 10 female B6C3Fi mice were administered l-chloro-
2-propanol (75% l-chloro-2-propanol and 25% 2-chloro-l-propanol) in drinking water at
concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. The average
Page 73 of 95
Page 130 of 192
-------
daily doses determined by the study authors correspond to 0, 20, 60, 175, 430 or 630
mg/kg/day in males and 0, 25, 95, 290, 640 or 940 mg/kg/day in females. One male
mouse in the 10,000 ppm group died before the end of the study. Mean body weight
gains of 10,000 ppm mice were significantly less than those of the controls. Water
consumption by 3,300 and 10,000 ppm males and females was significantly less than that
by the controls throughout the study. Liver weights of 1,000, 3,300, or 10,000 ppm males
and females were significantly greater and thymus weights of 10,000 ppm mice were
significantly less than those of the controls. Exposure to l-chloro-2-propanol caused
hepatocellular vacuolization in males and females at 1000 ppm and above, cytoplasmic
alteration and degeneration of the pancreas acinar cells at 3300 ppm and above, and
atrophy of the spleen at 10000 ppm in both sexes. The LOAEL is determined as 1000
ppm (175 mg/kg/day) based on increased liver weight relative to body weight and
increased vacuolization of cytoplasm of hepatocytes in both males and females. The
NOAEL is determined as 330 ppm (60 mg/kg/day).
In a subchronic study designed as a range finding study for a carcinogenicity study (NTP,
1998), groups of 10 male and 10 female B6C3Fi mice were administered l-chloro-2-
propanol (75% l-chloro-2-propanol and 25% 2-chloro-l-propanol) in drinking water at
concentrations of 0, 33, 100, 330, 1,000, or 3,300 ppm for 14 weeks. The average daily
doses were determined by the study authors as 0, 5, 15, 50, 170, or 340 mg/kg in males
and 7, 20, 70, 260, or 420 mg/kg in females. One 330 ppm male died before the end of
the study. Mean body weight gains of exposed groups were similar to those of the
controls. A minimal anemia was observed in 3,300 ppm males. The right epididymis
weight of 3,300 ppm males was significantly greater than that of the controls. Kidney
weights of 3,300 ppm mice, liver weights of 1,000 ppm males and of all exposed groups
of females, and thymus weights of 1,000 and 3,300 ppm females were greater than those
of the controls. The changes in liver weights in females of all treatment groups did not
exhibit a clear dose response effect. The incidences of acinar cell degeneration and fatty
change in the pancreas increased in 3,300 ppm males and females as compared to
controls. The cytoplasmic vacuolization of the liver were increased in all groups of
exposed females but the incidences were not dose dependent. The severities of renal
tubule cytoplasmic vacuolization were greater in 1,000 and 3,300 ppm males than in the
controls. The LOAEL is determined as 1000 ppm (170 mg/kg/day) based on
increased organ weights and increased incidence of the renal tubule cytoplasmic
vacuolization in males. The NOAEL is determined as 330 ppm (50 mg/kg/day).
Page 74 of 95
Page 131 of 192
-------
3.0 Propylene Oxide Metabolism
CH3CHOHCH2-GS ^
(Glutathione Transferase)
\
(Epoxide hydrolase?)
S-2-(hydroxy-l-propyl)-glutathione Glutathione CH3-CH2 CH2 Water
Propylene Oxide
CH3CHOHCH2OH
1,2-Propanediol
CH3CHOHCH2SCH2NH2CHCOOH
S-2-(hydroxy-l-propyl)-cysteine
CH3CHOHCH2SCH2NHRCHCOOH
N-acetyl-S-(2-hydroxy-l-propyl)-cysteine
S-(2-hydroxy-l-propyl) mercapturic acid
Urine
CH3CHOHCOOH
Lactic Acid
CH3COCOOH
Pyruvic Acid
Propylene Oxide Metabolism (WHO, 1985)
Glycolysis
Tricarboxylic
Acid Cycle
Page 75 of 95
Page 132 of 192
-------
4.0 REFERENCES
MRID 41750801.
Drummond, J.G., and Keller, K.A. 1988. Inhalation developmental toxicity study in rats.
International Research and Development Corporation, Mattawan, MI 49071.
Unpublished.
MRID 41874102.
Hackett, P.L., Brown, M.G., Buschbom, R.L. (1982). Teratogenic Study of Ethylene
and Propylene Oxide and n-Butyl Acetate. Battelle, Pacific Northwest Laboratories,
Richland, WA, NIOSH Contract # 210-80-0013, May 1982. Unpublished.
MRID 42039901
Reuzel, P. and C. Kuper 1983. 1,2-Propylene Oxide: Chronic (28-month) Inhalation
Toxicity /Carcinogen! city Study of 1,2-Propylene Oxide. TNO Netherlands Organization
for Applied Scientific Research, P.O. Box 360, 3700 AJ Zeist, Netherlands. Laboratory
project study identification V 82.215/280853, March 2, 1983.. Unpublished.
MRID 45292701
Hayes, W., T. Gushow, H. Kirk, et al. 1985. Propylene oxide: Two generation inhalation
reproduction study in Fischer 344 rats. Mammalian and Environmental Toxicology
Research Laboratory, Dow Chemical, Midland, MI, Laboratory report number, D-
001784, June 19, 1985. Unpublished
MRID 45292801
Young, J.T., Mattsson, J.L., Albee, R.R., and Schuetz, DJ. 1985. Propylene oxide:
assessment of neurotoxic potential in male rats. Mammalian and Environmental
Toxicology Research Laboratory, Health & Environmental Sciences, U.S.A., Dow
Chemical U.S.A., Midland, MI 48640. Study No. D1831, October 24, 1985.
Unpublished.
Cal/OSHA. Occupational Safety and Health Standards Board (OSHSB). Public
meeting/public hearing/business meeting of the OSHSB on General Industry Safety
Orders, Section 5155 - Airborne Contaminants. June 17, 2004.
Dunkelberg, H. 1982. Carcinogenicity of ethylene oxide and 1,2-propylene oxide upon
intragastric administration to rats. Br. J. Cancer. 46: 924- 933.
Faulkner, John. Ethylene Oxide Quantitative Usage Analysis. Biological and Economic
Analysis Division, USEPA/OPPTS/OPP.
IARC (International Agency for Research on Cancer) 1994. World Health Organization,
IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 60. Some
industrial chemicals, pi81-213.
Page 76 of 95
Page 133 of 192
-------
Kuper, C.F., P.G.J. Reuzel, VJ. Feron et al. 1988. Chronic inhalation toxicity and
carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26: 159-
167.
Lynch, D.W., T.R. Lewis, WJ. Moorman et al. 1984. Carcinogenic and toxicologic
effects of inhaled ethylene oxide and propylene oxide in F344 rats. Toxicol. Appl.
Pharmacol. 76: 69-84.
Morris, Mark. USEPA/OAQPS/ESD. Memorandum to Dave Guinnup,
USEPA/OAQPS/ESD: Residual Risk Assessment for the Ethylene Oxide Commercial
Sterilization Source Category. February 25, 2005.
NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of
propylene oxide (CAS No. 75-56-9) in F344/N rats and B6C3F1 mice (Inhalation
studies). NTP-TR-267.
NTP (National Toxicology Program). 1998. Toxicology and carcinogenesis studies of 1-
chloro-2-propanol (CAS No. 127-00-4) in F344/N rats and B6C3F1 mice (Drinking
Water Studies). NTP-TR-477.
Ohnishi, A., T. Yamamato, Y. Murai, et al.. 1988. Propylene oxide causes central-
peripheral distal axonopathy in rats. Arch. Environ. Health. 43:353-356.
Setzer, J.V. W. S. Brightwell, J.M. Russo et al. 1996. Neurophysiological and
neuropathological evaluation of primates exposed to ethylene oxide and propylene oxide.
Toxicol. and Indust. Health 12:667-682.
TNO BIBRA International Limited. 1994. Toxicity Profile. Propylene chlorohydrins.
1st edition, pi-6
USEPA (US Environmental Protection Agency), 1987. Summary review of the health
effects associated with propylene oxide. Office of Health and Environmental
Assessment, Washington, DC. EPA/600/8-86/007F
USEPA (US Environmental Protection Agency), 1994. Integrated Risk Information
System, http://www.epa.gov/iris/subst/0403.htm
U.S. EPA (Environmental Protection Agency). (2005a) Guidelines for carcinogen risk
assessment. EPA/630/P-03/001F. Available at: www.epa.gov/cancerguidelines.
U.S. EPA (Environmental Protection Agency). (2005b) Supplemental guidance for
assessing susceptibility from early-life exposure to carcinogens. EPA/630/R-03/003F.
Available at: www.epa.gov/cancerguidelines.
WHO (World Health Organization), 1985. Propylene Oxide. Environmental Health
Criteria, 56, Geneva.
Page 77 of 95
Page 134 of 192
-------
5.0 ALTERNATE ORAL CANCER SLOPE FACTOR DERIVATION
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
ATTACHMENT 5
MEMORANDUM
June 27, 2006
SUBJECT: Propylene Oxide (PPO): Qualitative/Quantitative Evaluation of Dietary
Risk Assessment; PC Code 042501; D329650; Decision#:360739; RED-
2560-1921
FROM: William Dykstra, Ph.D.
Toxicologist
Reregi strati on Branch 4
Health Effects Division (7509C)
THROUGH: Susan Hummel
Branch Senior Scientist
Reregi strati on Branch 4
Health Effects Division (7509C)
TO: Susan Bartow
Chemical Review Manager
Special Review Branch
Special Review and Reregi strati on Division (7509C)
Rebecca Daiss
Risk Assessor
Reregi strati on Branch 4
Health Effects Division (7509C)
Based on the submitted registrant's risk assessments, plus supporting documentation,
HED has evaluated the qualitative/quantitative rationale for the further toxicological
analysis of dietary risks from consumption of PPO residues in the diet.
REVIEW:
In the Dunkelberg Gavage study (1982), treated groups of 50 female Sprague-Dawley
rats were orally gavaged with 0, 15, or 60 mg/kg of PPO in one mL volumes of 'Livio"
salad oil twice weekly for 150 weeks (a total of 219 treatments). Controls consisted of
Page 78 of 95
Page 135 of 192
-------
both vehicle-treated and untreated groups. Fore-stomach tumors, primarily squamous cell
carcinomas, were observed in treated animals for PPO. For PPO, the incidence of
squamous cell carcinomas was 2/50 (low dose) and 19/50 (high dose). No other tumors
were produced at biologically significant levels.
As to the question of what becomes of PPO in the stomach, the stomach juice degradation
rates for PPO were measured and it was found that PPO is hydrolyzed in the rat and
human gastric compartments exclusively to PPG (propylene glycol). Even though there
is a reasonable amount of chloride ion in the stomach (from the stomach acid) propylene
chlorohydrin has been shown not to form as a degradation product in either the human
stomach or the rat stomach .
In humans, in contrast to rodents, PPO which is ingested in the diet is rapidly detoxified
by three mechanisms. The first of these three mechanisms is acid catalyzed hydrolysis.
This operates effectively in the human stomach but not in the rat fore-stomach or
glandular stomach due to the higher gastric acidity in humans in comparison to rodents.
The second mechanism is enzyme catalyzed ring opening (via epoxide hydratase) This
mechanism functions both in rats and humans. While this enzyme is typically more
concentrated in the liver, studies have shown its active presence in other tissues such as
the nasal and lung epithelium. The net effect of these first two mechanisms in the human
is expected to be that PPO consumed in the diet will be functionally equivalent to
propylene glycol (PPG), a substance which is GRAS for many uses. The third mechanism
is the glutathione conjugation of PPO by GSH-S-transferase and excretion via the
kidneys.
The net effect of all three of these mechanisms working together in humans is that gastric
exposures to PPO consumed in the diet are essentially converted to PPG.
It is seen from an analysis of the PPO rodent studies that an increased tumor incidence is
not seen at PPO doses/exposures which do not also cause an increase in inflammatory
changes/restorative hyperplasia at the local site of administration in response to local
tissue toxicity produced by high local concentrations of PPO.
However, in view of the fact that a gavage dose not resulting in a tumor response was not
identified in the Dunkelberg study, a potential oral carcinogenic risk assessment is
needed to be performed for PPO. Although the Dunkelberg gavage study can be
extrapolated to calculate an oral NOAEL, the present reviewer cannot concur with this
speculative method presented by the registrant's consultant, Dr. John Todhunter. In
contrast, the present reviewer considers the use of the identified modifying factors and
underlying scientific principles which help to characterize the possible, if any,
carcinogenic risks of ingested PPO to be more justified than an RfD approach.
Experimentally Determined Constants for the Conversion of PPO to PPG in Human
Gastric Juice and in Rat Fore-stomach Juice
Parameter
pH
Overall hydrolysis Rate for PPO
Human Gastric Juice
1.46
0.364 min -1
Rat Fore-stomach Juice
4.8
0.0020 min-1
Page 79 of 95
Page 136 of 192
-------
Half-life of PPO | 1.90 min | 347 min
A Concentration-based Approach for Oral Cancer Risk Assessment
Fore stomach tumors in the rat treated by gavage may be considered a portal of entry
response. By analogy to the RfC methodology which considers the concentration of test
material to be the most important determinant of response in portal of entry tumors, PPO
dosage may be expressed as a concentration.
The oral Q*, determined in the usual way, is 0.15 (mg/kg bw/day)-1'. Doses in the
Dunkelberg study were 0, 15 and 60 mg/kg bw/day. There were 219 administrations of
the test material over the 150 week duration of the study. For a standard 0.35 kg rat, the
administered doses in mg/rat were 0, 5.25, and 21 mg. (e.g., 15 mg/kg bw/day x 0.35 kg
= 5.25 mg/rat). Since the volume of administration was 1 mL/rat, the administered
concentrations were 0, 5.25, and 21 mg/mL in the gavage study. To adjust the
concentration to a continuous basis, the mg/mL concentrations are multiplied by 219 -^-
(150 weeks x 7days/week). The adjusted concentrations are 0, 1.10 and 4.38 mg/mL
(e.g., 5.25 mg/mL x 219 + (150 weekx 7 days/week) = 1.10 mg/mL).
The administered PPO was dissolved in salad oil which has a density of 0.92 g/cc. The
adjusted dosage in terms of mg PPO/g salad oil (dosing solution) is 1.19 and 4.76 mg/g or
0, 1190, and 4760 mg/kg dosing solution (e.g., 1.10 mg/mL + 0.92 g/cc. = 1.19 mg
PPO/g salad oil or dosing solution).
The BMD/BMDLio for the cancer dose-response in terms of mg/kg administered gavage
solutions is 2,080/1,160 mg/kg dosing solution. The slope factor using the BMDLio is
0.1/1160 mg/kg salad oil= 0.000086 (mg/kg dosing solution) * (Attached). EPA
assumes that kg dosing solution is a measurable surrogate for kg diet.
The chronic dietary exposure to PPO in the general population is estimated to be 0.0001
mg PPO/kg body weight. Since a 70 kg person eats an average of 1.5 kg of food per day,
the average concentration of PPO in the diet is 0.0001 mg/kg bw x 70 kg + 1.5 kg diet =
0.0047 mg PPO/kg diet.
Multiplying the slope factor of 0.000086 (mg/kg dosing solution) -1 by the PPO chronic
dietary exposure in the general population (0.0047 mg/kg diet) results in a risk estimate
of4x!07.
Quantitative cancer assessments using the RfC methodology include an adjustment for
interspecies differences (the RGDR). In this example of alternative assessment for PPO
using concentrations instead of doses in mg/kg bw, no interspecies adjustments have been
made. If they were made, the adjustment would result in an even lower risk estimate,
since the retention time of material in the rat fore-stomach is far greater than the
residence time of food in the human esophagus.
Page 80 of 95
Page 137 of 192
-------
Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $
Input Data File: C:\BMDS\DATA\PPO_ADJUSTED_DIETARY.(d)
Gnuplot Plotting File: C:\BMDS\DATA\PPO_ADJUSTED_DIETARY.plt
Wed Jun 21 07:03:24 2006
Gavage cone (mg/L) x 0.92 x 219 /(ISO wk x 7 d/w)
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl-beta2*doseA2)]
The parameter betas are restricted to be positive
Dependent variable = Incidence
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(l) = 1.2263e-005
Beta(2) = 1.8522e-008
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
Beta(l) Beta(2)
Beta(l) 1 -0.98
Beta(2) -0.98 1
Parameter Estimates
Variable Estimate Std. Err.
Background 0 NA
Beta(l) 1.2263e-005 0.000162211
Beta(2) 1.8522e-008 3.55814e-008
NA - Indicates that this parameter has hit a bound
Page 81 of 95
Page 138 of 192
-------
implied by some inequality constraint and thus
has no standard error.
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood) Deviance Test DF
-41.6004
-41.6004 3.7943e-012 1
-67.1864 51.1721 2
P-value
1
<.0001
AIC: 87.2008
Goodness of Fit
Dose Est. Prob. Expected Observed
Size
ChiA2
i: 1
0.0000
i: 2
1190.0000
i: 3
4760.0000
Chi-square =
0.0000
0.0400
0.3800
0.00
0.
2.
19.
DF
000
000
000
= 1
0
2
19
P-value
100
50
50
= 1.0000
0.
-0.
-0.
000
000
000
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 2076.86
BMDL = 1159.24
0.5
0.4
0.3
0.2
0.1
0
Multistage
Multistage Model with 0.95 Confidence Level
BMPL
BMD
0 1000
07:03 06/21 2006
2000 3000
dose
Page 82 of 95
4000
5000
Page 139 of 192
-------
6.0 MODE OF ACTION SUMMARY
The registrant and consultants to the registrant have submitted a large amount of
information relevant to the carcinogenic mode of action (MOA) of PPO. Much of the
submitted data are journal articles concerning formation of DNA or hemoglobin adducts
of PPO. Other submissions focus on the genotoxic response of PPO in various
mutagenicity test systems, and still others study the association between PPO
concentration and cytotoxicity and cell proliferation at the site of tumor formation.
Particularly informative articles compare the pattern of adduct formation with
cytotoxicity, regenerative cell proliferation and tumor response. In addition to the journal
articles, we have received a number of presentations that summarize the published
information, and lay out the proposed MOA.
Briefly summarizing the key points of the proposed MOA, exposure to PPO in animals
via the inhalation route results in a linear response with respect to blood concentration of
PPO and the formation of hemoglobin and DNA adducts, but a highly sublinear response
with respect to cytotoxicity and regenerative cell proliferation and tumor formation. The
cytotoxicity/cell proliferation response appears to precede tumor response with respect to
PPO concentration.
After an initial analysis, EPA concludes that the proposed MOA is plausible, and will
review the proposed MOA in more depth, both within OPP and in conjunction other
Agency offices.
If the proposed MOA is accepted by the Agency, propylene oxide will not be regulated
using a q* approach. Rather, a Margin of Exposure analysis will be done. Currently, the
long-term inhalation endpoint for propylene oxide is derived from the Kuper et al. (1988)
(submitted as MRID 42039901) study with a point of departure of 5.2 ppm for nasal
lesions (calculated from the NOAEC of 30 ppm - 30 ppm x 6 hr toxicity study/8 hr
workday x 0.23 (RGDR)). This study and point of departure are reasonable choices to
use to assess PPO cancer risks using an MOE approach, since they are based on basal cell
hyperplasia and nest-like infolds of the nasal epithelium, effects that are likely to be
among the continuum of events leading to cancer.
Page 83 of 95
Page 140 of 192
-------
7.0 BMD ANALYSES
7.1 BMD Analysis Memo - Dunkelberg 1982
• •"• 1
US2W
UNITED STATES ENVIRONM ENTALPROTECTION AGENCY
WASHINGTON,D.C. 20460
OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES
MEMORANDUM
June 28, 2005
SUBJECT:
FROM:
TO:
Benchmark Dose Analysis of Propylene Oxide - Combined Incidences of
Papillomas, Hyperplasia and Hyperkeratosis in Rat Forestomach
Becky Daiss
Environmental Health Scientist
Reregi strati on Branch 4
Health Effects Division (7509C)
Santhini Ramasamy
Toxicologist
Reregi strati on Branch 4
Health Effects Division (7509C)
This memorandum provides benchmark dose analyses of combined incidences of
papillomas, hyperplasia and hyperkeratosis carcinogenicity study of intragastric
administration of ethylene oxide and 1,2-propylene oxide to rats.
BMD Analysis
A benchmark dose (BMD) approach was used to estimate a toxicity endpoint (as a basis
for deriving an RfD) for combined incidences of papillomas, hyperplasia and
hyperkeratosis in rats from chronic exposure to propylene oxide. A BMD is defined as
Page 84 of 95
Page 141 of 192
-------
an exposure due to a dose of a substance associated with a specified low incidence of
risk, generally in the range of 1% to 10%, of a health effect; or the dose associated with a
specified measure or change of a biological effect. This dose is estimated using statistical
methods for fitting curves to experimental data.
EPA's Benchmark Dose Software (BMDS version 1.3.2) was used for the BMD analyses
of propylene oxide incidence data. Since the data are quantal (i.e., incidences of
papillomas, hyperplasia and hyperkeratosis), the BMDS dichotomous models were used
to derive estimated BMDs. Models used for the BMD analyses include gamma, log
logistic, multistage, log probit, quantal linear, quantal quadratic, and Weibull. Model
formulas are provided in the attached table.
BMDS dichotomous models were used to derive the BMDio, the dose estimated to
produce an excess risk of 10% (from incidences of papillomas, hyperplasia and
hyperkeratosis), and the BMDL, the lower limit of a one-sided 95% confidence interval
on the BMDio (i.e., the lower confidence limit on the dose that would result in a 10%
response). The following default initial parameters were used for the BMDS
dichotomous model runs for this analysis: risk type = extra risk; benchmark response
(BMR) = 0.1; power and/or slope restrictions > 1; beta restriction > 0.
Study Selected for BMD Analysis
The following study was selected for BMD analysis. The study was selected based on
relevance, quality, potential for quantification, and significance of the dose-response
results.
Dunkelberg, H. Carcinogenicity of Ethylene Oxide and 1,2-Propylene Oxide Upon
Intragastric Administration to Rats; Br. J Cancer, 46, 924-933, 1982
Dose/Response Input Data
Incidence of Papillomas, Hyperplasia and Hyperkeratosis in Rat Forestomach
Dose (mg/kg/day)
0
2.58
10.28
N
100
50
50
Incidences
0
7
50
Summary of Results
Results of the BMD analysis and representative dose-response graphs are provided
below. Since it is particularly important that the data be adequately modeled for BMD
calculation, it is recommended that p=0.1 be used to compute the value of goodness of fit.
PPO - Rat Carcinogenicity - Combined Incidence - Papillomas, Hyperplasia, Hyperkeratosis
Model (95% CL)
BMD Extra Risk
BMD
BMDL
P-Value
AIC
Page 85 of 95
Page 142 of 192
-------
PPO - Rat Carcinogenicity - Combined Incidence - Papillomas, Hyperplasia, Hyperkeratosis
Model (95% CL)
Gamma1
Log Logistic 2
Multistage2D 3
Log Probit 2
Quanta! Linear :
Quanta! Quadratic 4
Weibull 1
BMD Extra Risk
10%
BMD
2.4
2.0
2.4
NA
2.4
NA
2.4
BMDL
1.7
1.4
1.7
NA
1.7
NA
1.7
x2
0.7
0.2
0.7
7
0.7
13
0.7
P-Value
0.7
0.9
0.4
O.05
0.7
0.005
0.7
AIC
107.2
106.8
107.2
112
107.2
119
107.2
The model parameter(s) Background and Power have been estimated at a boundary point and do not appear in the correlation matrix
2The model parameters) Background and Slope have been estimated at a boundary point and do not appear in the correlation matrix
The model parameter(s) Background and Beta 2 have been estimated at a boundary point and do not appear in the correlation matrix
4 4
The model parameter(s) Power have been estimated at a boundary point and do not appear in the correlation matrix. The model
parameter(s) Power have been estimated at a boundary point and do not appear in the correlation matrix
Gamma Multi-Hit Model with 0.95 Confidence Level
Log-Logistic Model with 0.95 Confidence Level
°-%
0.4
o>
1 0.3
5
c
us 0.2
ro
u_
0.1
0
Gamma Multi-Hit
\J\D Lower Bound —
^*"
4- ^-""'^
^^
, BMDL ,
^ ^^"^
•^ ^^^
-f ^*^^
'•'^^
3MD . . . .
0.5g
0.4
| 0.3
5
§ r
B C
ro
u_
0 1
0 2 4 6 8 10
^
0
Log-Log stic
MD Lower Bound —
-+ ^^^^^
T -^^' ^-^^^^'^
^ ^^^^
-^~ ^^'^
x ^y*^^
^
. BMDL ,3MD
02468
dose
(
10
__
09:5606/072005 10:0406/072005
Multistage Model with 0.95 Confidence Level
0.5
B
0.4
1 °'3
o 0.2
•B
e
"~ 01
0
Multistage
\J\D Lower Bound — T
4- ^^^
, BMDL , E
-K ^^
'^^
JMD
Probit Model with 0.95 Confidence Level
°-%
0.4
•S 02
t3
0 1
0
0 2 4 6 8 10
dose
Probit
yiD Lower Bound —
,+ x/"^
^/ //
" ^s/
L^^^
BMDL 3MD
-^
0 2 4 6 8 10
dose
1 0: 07 06/07 2005 10:10 06/07 2005
Quantal L near Model with 0.95 Confidence Level
O-SE
0.4
£ O-3
§ 02
t3
2
LJ_
0.1
0
Quantal Linear
VID Lower Bound — T
^
^+ ^^^^^'
^
l^
, BMDL ,
/+'^^"^ '
•>^^
MD
0.5
0.4
I 0.3
<
|°-2
LL
0.1
0
0 2 4 6 8 10
dose
Quantal Quadratic Mode with 0.95 Confidence Level
Quantal Quadratic
BMD Lower Bound —
,+ ,/ '
* /-^
- ^^
^-^^^
BMDL, BMD ,
0 2 4 6 8 10
dnsp
10:15 06/07 2005 10:18 06/07 2005
Page 86 of 95
Page 143 of 192
-------
Weibull Model with 0.95 Confidence Level
n K Weibull
u'% JD Lower Bound —
I 0.3
0 2 4 6 8 10
dose
10:21 06/072005
Attachment
BMDS Model
Gamma
Log Logistic
Multistage
Probit
Quantal Linear
Quantal Quadratic
Weibull
Model Formula
1 ffdose
P( rl\ T I H v^ " t r fit
I
1 + &
y " Pjdose1
P(d) = r+(l-/)x (l-e J=' J )
P(d) = y + (y - l)O(or + fi\n(dose}}
P(d} - Y + ( 1 - y}(\ - p-pdosea \
r\aj /i-^i /AI e ) y=1
PC//^ = v + r 1 - v Yl - e~^osea }
A. \ \/V 1 / 1 1 J. / II J. t' I i / ~
V ^^ / / 1 l-l- yll-L (^ 1
(- background; V - power; 3 - slope;
Page 87 of 95
Page 144 of 192
-------
7.2 BMD Analysis Memo - Kuper et al. (1988)
UNITED STATES ENVIRONM ENTALPROTECTION AGENCY
WASHINGTON,D.C. 20460
OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES
MEMORANDUM
July 30, 2006
SUBJECT: Benchmark Dose Analysis of Propylene Oxide - Nasal Lesions Associated
with Long-Term Inhalation Exposure
FROM: Ray Kent, Chief
Reregi strati on Branch 4
Health Effects Division
TO: Becky Daiss
Environmental Health Scientist
Reregi strati on Branch 4
Health Effects Division (7509C)
This memorandum provides benchmark dose analyses of nasal lesions associated with long-
term administration of 1,2-propylene oxide (PPO) to rats.
Background
A benchmark dose (BMD) approach was used to select an endpoint for assessing long-term
non-cancer occupational risks. The study selected for analysis had been used in a prior
version of the PPO risk assessment, but because of the complexity of the study, the risk
assessment team for PPO decided that a BMD analysis should be considered for establishing a
point of departure for long-term scenario. EPA's Benchmark Dose Software (BMDS version
1.3.2) was used for the BMD analysis of propylene oxide incidence data. Since the data are
quantal (i.e., incidences of various nasal lesions) the BMDS dichotomous models were used
to derive estimated BMDs. Models used for the BMD analyses include gamma, log logistic,
multistage, log probit, quantal quadratic, and Weibull. The models are listed in a table
attached to the end of this assessment.
Page 88 of 95
Page 145 of 192
-------
Study Selected for BMP Analysis
The following study was selected for BMD analysis.
MRID 4203 9901
Reuzel, P. and C. Kuper 1983. 1,2-Propylene Oxide: Chronic (28-month) Inhalation
Toxicity/Carcinogen!city Study of 1,2-Propylene Oxide. TNO Netherlands Organization for
Applied Scientific Research, P.O. Box 360, 3700 AJ Zeist, Netherlands. Laboratory project
study identification V 82.215/280853, March 2, 1983.
This study was subsequently published as:
Kuper, C.F., P.G.J. Reuzel, VJ. Feron et al. 1988. Chronic inhalation toxicity and
carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26: 159-167.
A NOAEL of 30 ppm from the study based on increased incidence of basal cell hyperplasia,
and nest-like infolds of the respiratory epithelium was initially selected as the point of
departure for assessment of long-term non-cancer inhalation risks to workers. The study is
complex. There were a number of nasal lesions observed in the study and the responses were
graded with respect to severity. There were a number of intermediate sacrifices in addition to
the terminal sacrifice at 28 months. The NOAEL inadequately captures the variety of effects
and the range of responses of the study whereas a benchmark analysis of the various nasal
lesion was expected to provide more useful information for selection of endpoints and
assessment of risk.
The executive summary of the Data Evaluation Record for the study may be found in Section
4.4.9.1 (study 1) of this risk assessment.
Selection of Endpoints to be Modeled
The study describes three nasal lesions that were associated with long-term exposure to PPO:
atrophy of the olfactory epithelium, basal-cell hyperplasia of the olfactory epithelium and
nest-like infolds of the respiratory epithelium. This latter lesion is considered a hyperplastic
response of the respiratory epithelium. The lesions were graded as slight, moderate or
marked, although for reporting purposes, the moderate and marked categories were sometimes
combined.
Two options were considered for combining the data on the nasal lesions for analysis: The
first approach is to sum all rats exhibiting a nasal lesion. This is the more conservative
approach and involves summing all rats with any particular lesion, slight, moderate or
marked. The second approach is to sum the moderate and marked responses for each lesion.
Because the lesions did not progress over the course of the 28-month study (4 months longer
than the usual chronic study in rats), the second approach was selected. The incidence data
for the three lesions under consideration are shown in Table 1.
Page 89 of 95
Page 146 of 192
-------
Table 1. Incidence of Nasal Lesions* in Male and Female Rats Exposed to Propylene Oxide
Dose (ppm)
Animals Examined
Nasal Lesions in Male Rats
0 30 100 300
66 61 62 63
Nasal Lesions in Female Rats
0 30 100 300
64 64 62 65
Atrophy of the olfactory epithelium
Slight response 5 8 7 10
Moderate response 0 0 3 11
Total (slight + moderate) 5 8 10 21
Basal-cell hyperplasia of the olfactory epithelium
Slight response
Moderate response
Marked response
Moderate + marked response
Total responders
7
0
7
9
0
9
6
1
7
21
5
26
3
1
0
1
4
1
1
0
1
2
5
5
0
5
10
10
9
5
14
24
0
0
0
0
0
0
0
0
0
0
8
1
0
1
9
17
8
8
16
33
4
1
0
1
5
11
0
0
0
11
27
2
0
2
29
21
17
9
26
47
4
0
4
7
1
8
19
1
20
29
14
43
Nest-like infolds of the respiratory
epithelium
Slight response
Moderate response
Marked response
Moderate + marked response
Total responders
* the bold response rows indicate the datasets that were modeled.
Selection of the Benchmark Response
The default BMR for dichotomous data is 10% response. In addition, for the study under
consideration, with 61 -66 animals examined for potential responses, 10% is approximately
the level of statistical significance at the p<.05 level, and therefore 10% was chosen as the
BMR.
Summary of Results
Six dichotomous models were fit to the incidence data for each of the three lesions in both
male and female rats. For each set of models, the results were ordered (Table 2) by increasing
AIC (Akaike's Information Critierion, a measure of model fit particularly useful for selecting
among competing models.). When the models were ordered in this way, the endpoint with the
lowest BMDLio was selected - 120 ppm for male rats exhibiting a moderate to marked
response of nest-like infolds of the respiratory epithelium. There was one other reasonable
endpoint that could have been selected - atrophy of the olfactory epithelium in male rats. The
BMDLio associated with the model with the lowest AIC is 131 ppm, but the AIC's for the six
models analyzed for this lesion did not differ by much (127.3 to 128.6), and the mean of the
model BMDLioS is 112 ppm, which is lower than the endpoint and model selected. The
difference between the BMDLioS is not considered meaningful. The BMDLio of 120 ppm
was chosen as the point of departure for long-term noncancer risk assessment.
Page 90 of 95
Page 147 of 192
-------
Table 2 summarizes the benchmark dose analysis and Figure 1 shows graphically all of the
model runs for nest-like infolds of the respiratory epithelium in male rats. The model
printouts and graphs are available as appendices to this document.
Table 2. Results of Benchmark Dose Modeling of Nasal Lesions in Rats
Model AIC P BMD10 BMDL10
Atrophy of olfactory epithelium - females
Quantal quadratic 47.87 0.95 332 246
Probit 48.14 0.85 321 234
Gamma 49.75 0.92 350 242
Logistic 49.76 0.92 350 242
Weibull 49.76 0.92 348 244
Multistage 49.83 0.89 340 246
Atrophy of olfactory epithelium - males
Probit 85.70 0.69 192 149
Quantal quadratic 86.06 0.59 209 170
Gamma 87.27 0.74 196 139
Logistic 87.29 0.74 195 136
Weibull 87.34 0.73 198 139
Multistage 87.60 0.67 204 136
Basal-cell hyperplasia - olfactory epithelium - females
Quantal quadratic 85.62 0.90 189 157
Probit 86.80 1.00 192 146
Gamma 86.84 0.99 200 154
Logistic 86.86 0.98 204 154
Weibull 86.87 0.98 207 157
Multistage 86.90 0.97 210 161
Basal-cell hyperplasia - olfactory epithelium - males
Probit 127.28 0.52 173 131
Quantal quadratic 127.65 0.41 194 156
Logistic 128.40 0.58 153 94
Gamma 128.41 0.57 155 99
Weibull 128.44 0.56 156 98
Multistage 128.57 0.50 160 98
Nest-like infolds - respiratory epithelium - females
Multistage 93.01 0.65 223 148
Quantal quadratic 93.87 0.47 203 165
Weibull 95.63 0.31 226 137
Logistic 95.63 0.31 224 136
Gamma 95.65 0.31 222 136
Probit 95.66 0.31 216 154
Nest-like infolds - respiratory epithelium - males
Quantal quadratic 120.47 0.30 140 120
Probit 120.76 0.33 155 116
Gamma 120.80 0.33 162 122
Logistic 120.83 0.33 166 122
Weibull 120.85 0.33 171 125
Multistage 120.87 0.33 174 126
Page 91 of 95
Page 148 of 192
-------
Figure 1. Nest-like infolds of the respiratory epithelium in male rats - "moderate+marked"
response
Gamma Multi-Hit Model
I 0.3
Gamma Multi-Hit -
50 100 150 200 250 300
17:2807/302006
Log-Logistic Model with 0.95 Confidence Level
I 0.3
17:2907/302006
BMDL BMP
50 100 150 200 250 300
Probit Model with 0.95 Confidence Level
Multistage Model win 0.95 Confidence Level
Multistage
/
/
/
^^^
,BMDL , BMD ,
0.5
I °'4
if 0-3
1 0.2
0.1
Probit
./
//
//
^-"
BMDL BMD
50 100 150 200 250 300
0 50 100 150 200 250 300
17:2907/302006
17:3007/302006
Quantal Quadratic Model with 0.95 Confidence Level
Quanta! Quadratic
50 100 150 200 250 300
17:31 07/302006
Weibull Model with 0.95 Confidence Level
,BMDL BMP ,
0 50
17:3207/302006
100 150 200 250 300
Page 92 of 95
Page 149 of 192
-------
Attachment
BMDS Model
Model Formula
Gamma
| ffidose
'(r*\ Jo
Log Logistic
Multistage
Probit
P(d} =
Quantal Linear
Quantal Quadratic
Weibull
y- background; a - power;, p - slope;
Page 93 of 95
Page 150 of 192
-------
8.0 TOLERANCE REASSESSMENT TABLE
Tolerance Reassessment Summary for Propylene oxide
Commodity
Current Tolerance
(ppm)
Residues
(ppm)
Tolerance
Reassessment
(ppm)1
Comment/[Correct Commodity
Definition]
Tolerances Listed Under 40 CFR §180.491 For Propylene Oxide
Cacao bean, bean
Gum, edible
Nutmeat, processed (except
peanut)
Spices, processed
300
300
300
300
<137
NA
<300
<164
200
revoke
300
300
change to Cacao bean, dried bean
Use has been voluntarily cancelled
change to Nut, tree, group 14
[Herbs and spices, group 19, dried]
Tolerances to Be Recommended under 40 CFR 180.491 For Propylene Oxide
Cacao bean, cocoa powder
Garlic, dried
Onion, dried
Grape, raisin
Fig
Plum, prune, dried
none
none
none
none
none
none
<137
none
none
<1.0
<3.0
<2.0
200
3002
3002
1.0
3.0
2.0
Tolerances to Be Recommended under 40 CFR 180.491 For Propylene chlorohydrins:
Cacao bean, dried bean
Cacao bean, cocoa powder
Nut, tree, group 14
[Herbs and spices, group 19,
dried], except basil
Basil, dried leaves
Garlic, dried
Onion, dried
Grape, raisin
Fig
Plum, prune, dried
none
none
none
none
none
none
none
none
none
none
<13
<20
<6
<1500
<6000
NA
NA
<4.0
<3.0
<2.0
20
20
10
15003
6000
60002
60002
4.0
3.0
2.0
Reassessed tolerances are based on residues measured or estimated at 2 days (spices and cacao bean), 27/28 days (nutmeats), and 0 days
(grape, fig, and prune) after treatment.
2Tolerance based on data given for basil. Data were not given for dried onion or dried garlic.
3 Tolerance based on spice. Data not given for herbs other than basil.
NA: not available
Tolerance Expression in 40 CFR §180.491
The tolerance expression in the CFR should be revised to reflect the following changes:
180.491 Propylene oxide; tolerances for residues.
Remove all of current Section (a) (1),
Add a new Section (a)(l),
(a) General (1) Tolerances are established for the residues of propylene oxide when used as a
postharvest fumigant in or on the following food commodities:
Page 94 of 95
Page 151 of 192
-------
Commodity
Parts per million
Tolerances to be Listed Under 40 CFR 180.491(a)(l) for propylene oxide
Cacao bean, bean
Gum, edible
Nutmeat, processed (except peanut)
Spices, processed
200
revoke
300
300
Tolerances to be Proposed Under 40 CFR 180.491(a)(l) for propylene oxide
Cacao bean, cocoa powder
Garlic, dried
Onion, dried
Grape, raisin
Fig
Plum, prune, dried
200
300
300
1.0
3.0
2.0
Remove all of current Section (a)(2), (a)(3), (a)(4), and (a)(5)
Add a new Section (a)(2):
Tolerances are also established for residues of the propylene oxide reaction products l-chloro-2-
propanol and 2-chloro-l-propanol, commonly referred to as propylene chlorohydrin, when
propylene oxide is used as a post-harvest fumigant in or on the following food commodities.
Commodity
Parts per million
Tolerances to be Proposed Under 40 CFR 180.491(a)(2) for propylene chlorohydrin
Cacao bean, dried bean
Cacao bean, cocoa powder
Nut, tree, group 14
[Herbs and spices, group 19, dried], except basil
Basil, dried leaves
Garlic, dried
Onion, dried
Grape, raisin
Fig
Plum, prune, dried
20
20
10
1500
6000
6000
6000
4.0
3.0
2.0
Page 95 of 95
Page 152 of 192
-------
Appendix K. Environmental Fate and Effects Risk Assessment
Page 153 of 192
-------
,
I" | UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES
May 16, 2006
MEMORANDUM
SUBJECT: EFED RED Chapter for Propylene Oxide (042501)
DP Barcode D263366
TO: Susan Bartow
Special Review and Reregi strati on Division (7508W)
FROM: Edward Odenkirchen, Ph.D., Senior Biologist
Environmental Risk Branch I
Environmental Fate and Effects Division (7507P)
THROUGH: Nancy Andrews, Ph.D., Chief
Environmental Risk Branch I
Environmental Fate and Effects Division (7507P)
The following document comprises the Environmental Fate and Ecological Effects Division's
(EFED) Science Chapter for the Reregi strati on Eligibility Document for propylene oxide. This
risk assessment has not changed from the previous draft with respect to risk conclusions for
indoor uses. Indoor uses are not of concern with respect to risks to non-target terrestrial and
aquatic organisms. However, as requested by the Special Review and Reregi strati on Division,
this version of the assessment also includes labeled uses associated with the Propoxide 892
product. This label has a number of uses which do not entirely fall within the indoor uses
category. These uses include rail cars, tented areas, tarped materials, and in-field treatment
chambers. The bulk of the ecological risk assessment addresses risks associated with the
Propoxide 892 uses. It should be noted that the entire suite of fate and effects studies described
under the 40 CFR data requirements have not been submitted by the registrant.
Conclusions of the Risk Assessment
Indoor Uses of propylene Oxide
Indoor uses of propylene oxide are not of concern with respect to risks to non-target terrestrial
and aquatic organisms because environmental exposure is assumed to be insignificant.
Page 1 of 39 Page 154 of 192
-------
Taxonomic Groups for Which Risks are Not a Concern for Propoxide 892
The results of the risk assessment indicate that there are likely no concerns for acute lethality or
reproduction impairment in terrestrial mammals. This no-concern finding for acute risk to
mammals can be extended to birds and reptiles because of other lines of evidence, including
relative inhalation rates for birds, reptiles and terrestrial phase amphibians, suggests that gas
exposure and thus acute lethal risks for birds and reptiles would not be any greater than those
predicted for mammals. Extrapolating the no concern finding for reproduction effects in
mammals to other terrestrial vertebrates (e.g. birds) is not without uncertainty. There are
physiological differences between mammalian reproduction and other terrestrial vertebrates.
The avian reproduction data gap evident for propylene oxide represents a possible significant
source of uncertainty. Similarly, the reactive alkylating nature of propylene oxide, the potential
for tissue damage from this alkylation, and the importance of amphibian skin as a respiratory
organ not encountered in other terrestrial vertebrates, suggests that extrapolation of mammalian
and avian risk conclusions to terrestrial phase amphibians for propylene oxide is uncertain.
The Agency has not established levels of concern for interpreting risk quotients for terrestrial
invertebrate risk assessment. However, the exposure modeling conducted in the risk assessment
shows air concentrations of propylene oxide to be well below effects levels determined for
terrestrial arthropods. Consequently, the risk assessment concludes no risks of concern for
terrestrial invertebrates.
Acute risks to fish and aquatic invertebrates do not appear to be of concern based on a first
approximation analysis of possible water concentrations compared with available acute toxicity
data. Estimations of propylene oxide concentrations in water used in the risk assessment are
based on very conservative exposure assumptions. The conservative nature of these exposure
predictions enhances the confidence of the no risk conclusion. There is a lack of chronic effects
data for propylene oxide to aquatic animals. However, the physical/chemical properties of the
gas suggest that little opportunity of anything but short term exposures exist in the aquatic
environment. Therefore, chronic effects to fish and aquatic invertebrates are not expected.
Taxonomic Groups for which Risk is Assumed to be of Concern from Propoxide 892 Because
of a Lack of Information
Propylene oxide is a highly reactive compound with the potential to alkylate bio-molecules on
contact. Little can be said for risk conclusions regarding acute effects to aquatic and terrestrial
plants beyond this statement, because no data are available to establish effects measures for these
taxa. In the absence of such data, and given the reactivity of propylene oxide with a variety of
bio-molecules, risks to plants cannot be precluded. The data gaps regarding effects of propylene
oxide on terrestrial and aquatic are therefore significant from a risk assessment standpoint.
Page 2 of 39 Page 155 of 192
-------
Environmental Fate and Effects Data Requirements
It should be noted that the entire suite of fate and effects studies described under the 40
CFR data requirements have not been submitted by the registrant (see tables below). This was
presumably the result of consideration of only the indoor use patterns. To bring the risk
assessment to its present state of completion, EFED has turned to publicly available
physical/chemical property and effects information. The result of the lack of this environmental
fate and effects information is a diminished confidence in the conclusions of the ecological risk
assessment for propylene oxide as labeled for the Propoxide 892 product. The significance of a
lack of reproduction effects testing with birds and any effects testing with terrestrial and aquatic
plants is noted in the risk assessment.
Environmental Fate Data Requirements
835.2120
835.2240
835.2410
835.4100
835.4200
835.4400
835.4300
835.1240
835.1410
835.6100
161-1
161-2
161-3
162-1
162-2
162-3
162-4
163-1
163-2
164-1
165-4
Hydrolysis
Phot ode gradation
- Water
Phot ode gradation
- Soil
Aerobic Soil
Metabolism
Anaerobic Soil
Metabolism
Anaerobic
Aquatic
Metabolism
Aerobic Aquatic
Metabolism
Leaching &
Adsorption/
Desorption
Laboratory
Volatilization
Terrestrial
Field
Dissipation
Bioaccumulation
in Fish
No
No
No
No
No
No
No
No
No
No
No
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
Page3 of 3 9
Page 156 of 192
-------
Ecological Effects Data Requirements
850.2100
850.2200
850.2300
850.1075
850.1010
850.1075
850.1400
850.1400
850.4100
850.4150
850.4400
850.3020
71-1
71-2
71-3
71-4
72-1
72-2
72-3
72-4
72-5
122-la
122-lb
122-2
141-1
Avian Acute
Oral Toxicity
Avian Dietary
Toxicity
Wild Mammal
Toxicity
Avian
Reproduction
Fish Toxicity
Invertebrate
Acute Daphnid
Toxicity
Estuarine/Mari
ne Toxicity
Aquatic
Organism Early
Life Stage
Life Cycle
Fish
Seedling
Emergence
Vegetative
Vigor
Aquatic Plant
Growth
Honey Bee
Acute Contact
No
No
No
No
No
No
No
No
No
No
No
No
No
No Data
No Data
No Data
No Data
No
Data
No Data
No data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
No Data
Page 4 of 39
Page 157 of 192
-------
Office of Prevention, Pesticides,
C( and Toxic Substances
United States
Environmental Protection
Agency
Environmental Fate and Ecological Risk
Assessment for the Reregistration of Propylene
Oxide
CH,
Page 5 of 39 Page 158 of 192
-------
Table of Contents
I . EXECUTIVE SUMMARY 7
A. Stressors and Use Characterization 7
B. Fate 7
C. Effects 8
D. Risk Conclusions 8
Taxonomic Groups for Which Risks are Not a Concern for Propoxide 892
8
Taxonomic Groups for which Risk is Assumed to be of Concern from
Propoxide 892 Because of a Lack of Information 9
Endangered Species Conclusions for Propoxide 892 9
II. PROBLEM FORMULATION 10
A. Chemical Stressors Considered in the Risk Assessment 10
B. Use Characterization 10
C. Ecological Receptors Considered in this Risk Assessment 11
D. Exposure Pathways Considered for Terrestrial Organisms 11
E. Exposure Pathways Considered for Aquatic Organisms 12
F. Conceptual Model 12
Risk Hypothesis 12
Conceptual Diagram 12
G. Analysis Plan 13
Preliminary Identification of Data Gaps and Methods 13
Assessment Endpoints 13
Exposure Measures 14
Effects Measures 15
IV. ANALYSIS 15
A. Environmental Fate and Transport Assessment 15
B. Terrestrial Exposure Assessment 16
C. Effects Assessment 16
Mammalian Effects 16
Terrestrial Invertebrate Effects 17
Terrestrial Plant Effects 18
Fish Effects 18
Aquatic Invertebrate Effects 18
V. RISK CHARACTERIZATION 19
A. Terrestrial Vertebrate Risk Estimation 19
Results of the PERFUM Model for Terrestrial Vertebrates 20
B. Qualitative Discussion of Risks to Terrestrial Invertebrates .... 20
D. Uncertainties and Limitations in the Risk Assessment 21
Avian and Other Non-Mammalian Terrestrial Vertebrate Risks 21
Assumptions of Significance for Dermal Exposure to Terrestrial
Wildlife 22
E. Conclusions of Risk Assessment 23
Terrestrial Vertebrate Risks 23
Terrestrial Invertebrate Risks 23
Fish and Aquatic Invertebrate Risks 24
F. Risks to Federally Listed Threatened and Endangered Species 24
Action Area 24
Taxonomic Groups Potentially at Risk 25
VII . REFERENCES 25
Appendix A 27
Page 6 of 39 Page 159 of 192
-------
I EXECUTIVE SUMMARY
A. Stressors and Use Characterization
This risk assessment comprises the Environmental Fate and Ecological Effects Division's
science chapter for the Reregi strati on Eligibility Document for Propylene Oxide.
Propylene oxide, a gas, is commonly used as a fumigant for the control of microbial and
arthropod pests in stored commodities. The majority of use sites are considered to be
indoors such as large warehouses. For these indoor uses, propylene oxide exposure to the
environment has been considered to be inconsequential and no environmental fate or
effects data have been required. There is no concern for adverse effects to terrestrial
or aquatic organisms from these indoor uses.
The Special Review and Reregistration Division requested that the risk assessment
include a consideration of the Propoxide 892 labeled product. Propoxide 892 is an 8
percent propylene oxide product that includes a number of commodity uses on cosmetic
articles, gums, ores, packaging, pigments, pharmaceutical materials, discarded nut shells
prior to disposal, shipping containers, processed species, cocoa, cocoa beans, and in shell
processed nutmeats (excluding peanuts). Dried fruit (figs, prunes, and raisins) are
potential new uses for the product as well and though not currently on the label, they
have been included as part the overall assessment of risks for propylene oxide. The label
for Propoxide 892 indicates that application may be made to trailers, containers, rail cars,
tarped materials and tents. These uses as described on the Propoxide 892 label, unlike
those traditionally associated with propylene oxide use, do not involve permanent
structures and are not "indoor" in the usual interpretation for pesticide uses. It is believed
that fugitive emissions of propylene oxide from these non-indoor uses of Propoxide 892
may potentially be of environmental significance and the analysis of the potential risks of
these releases is the principal subject of the risk assessment.
B. Fate
As late as 1990, environmental fate and effects data were not required for propylene
oxide because the uses of the gas at that time were considered to be indoor uses.
However, in light of the Propoxide 892 label and its indicated non-indoor use sites, a re-
evaluation of available information suggests a number of environmental fate and effects
data gaps. For example, no registrant submitted data are available for any of the 40 CFR
Section 158 requirements for environmental fate and effects. The limited information on
propylene oxide suggests that the gas is highly soluble in water, is of low affinity for
organic carbon, and is not likely to bioconcentrate in biota. While substantial
environmental fate data gaps exist, the physical chemical properties of the gas that are
available from other information sources have been useful in evaluating, to a limited
extent, the exposure of terrestrial and aquatic organisms to release of the gas to the
atmosphere.
Page 7 of 3 9 Page 160 of 192
-------
C. Effects
Available propylene oxide effects data are limited for many taxa. Adequate effects data
are available for non-target mammals and that information has been applied to the
evaluation of acute effects to other terrestrial vertebrates (birds, reptiles and terrestrial
amphibians). ECOTOX has provided additional information on acute effects to fish and
terrestrial invertebrates. There is a complete lack of effects data for aquatic invertebrates,
though data are available for the close chemical analog, ethylene oxide (data used as a
surrogate for propylene oxide). No data are available for aquatic and terrestrial plants.
The strong alkylating nature of propylene oxide suggests that exposure to the gas can
produce effects at the bio-molecular level and this may be as applicable to plants as well
as other organisms. Available data cannot preclude the potential concern that propylene
oxide may pose risks to terrestrial and aquatic plants.
D. Risk Conclusions
Taxonomic Groups for Which Risks are Not a Concern for Propoxide 892
The results of the risk assessment indicate that there are likely no concerns for acute
lethality or reproduction impairment in terrestrial mammals. Fugitive emissions of
propylene oxide to air surrounding a treated area, as predicted using the Health Effects
Division modeling tool PERFUM, are well below acute lethal and reproduction concern
levels for mammals. Analysis of other lines of evidence, including relative inhalation
rates for birds and reptiles, suggest that gas exposure and so acute lethal inhalation risks
for birds, reptiles, and terrestrial phase amphibians would not be any greater than those
predicted for mammals. While the risk assessment has used mammalian risk results to
conclude no risks for other terrestrial vertebrates (birds and reptiles), this conclusion is
made with considerable uncertainty because of obvious differences between reproduction
in mammals and other terrestrial vertebrates. The avian reproduction data gap evident for
propylene oxide represents a possible significant source of uncertainly. Similarly, given
the reactive alkylating nature of propylene oxide, the potential for tissue damage from
this alkylation, and the importance of amphibian skin as a respiratory organ not
encountered in other terrestrial vertebrates, suggests that extrapolation of mammalian and
avian risk conclusions to terrestrial phase amphibians in this particular situation is
uncertain.
No Agency-established level of concern for interpretation of risk quotients is available
for terrestrial invertebrate risk assessment. However, the exposure modeling conducted
in the risk assessment shows air concentrations of propylene oxide to be well below
effects levels measured in terrestrial arthropods.
Acute risks to fish and aquatic invertebrates do not appear to be of concern based on a
first approximation analysis of possible water concentrations compared with available
acute toxicity data. The fact that estimations of propylene oxide in water are based on
very conservative exposure assumptions enhances the confidence of this conclusion.
Although there is a lack of chronic effects data for propylene oxide, the
Page 8 of 39 Page 161 of 192
-------
physical/chemical properties of the gas suggest that little opportunity for anything but
short term exposures exist in the aquatic environment. Therefore, chronic effects to fish
and aquatic invertebrates are not expected.
Taxonomic Groups for which Risk is Assumed to be of Concern from Propoxide 892
Because of a Lack of Information
Propylene oxide is a highly reactive compound with the potential to alkylate bio-
molecules on contact. Little can be said for risk conclusions regarding acute effects to
aquatic and terrestrial plants beyond this statement. No effects data are available to
establish effects measures for the taxa. There is insufficient information to preclude a
presumption of acute risk to these organisms. The data gaps associated with propylene
oxide effects on terrestrial and aquatic plants is significant in this regard.
Endangered Species Conclusions for Propoxide 892
The following table summarizes the potential concerns for direct and indirect adverse
effects to federally-listed threatened or endangered plants and animals (listed species).
Listed Taxon
Terrestrial and semi-aquatic plants
- monocots
Terrestrial and semi-aquatic plants
- dicots
Terrestrial invertebrates
Birds
Terrestrial phase amphibians
Reptiles
Mammals
Aquatic vascular plants
Freshwater fish
Aquatic phase amphibians
Freshwater crustaceans
Mollusks
Marine/estuarine fish
Marine/estuarine invertebrates
Direct Effects
Yes1
Yes1
No2
No2
No2
No2
No2
Yes1
No2
No2
No2
No2
No2
No2
Indirect Effects
No
No
Yes3
Yes3'4
Yes3'4
Yes3
Yes3'4
No
Yes3'4
Yes3'4
Yes3'4
Yes3'4
Yes4
Yes3'4
1 The alkylating nature of propylene oxide suggests that adverse effects to organism tissues are possible.
No data are available to quantify at what level of exposure such effects would be expressed. Therefore this
conclusion is the product of a data limitation and could change if effects data were made available.
2 Environmental releases of propylene oxide are expected to be below levels known to cause adverse
effects.
3 There is a potential for direct effects on terrestrial plants (conclusion based on data limitations), which is a
concern for indirect effects on animal species dependent upon plants.
4 There is a potential for direct effects on aquatic plants (conclusion based on data limitations), which is a
concern for indirect effects on animal species dependent upon these plants.
Unlike crop applications of pesticides, there is a paucity of information available to the
risk assessor concerning locations of propylene use consistent with the Propoxide 892
label. Rail cars, infield chambers, tarped materials, and treatment tents may be located
Page 9 of 39
Page 162 of 192
-------
anywhere. Before a list of potentially affected listed species can be assembled, additional
information regarding potential locations of Propoxide 892 use would be necessary.
II. PROBLEM FORMULATION
A. Chemical Stressors Considered in the Risk Assessment
This risk assessment considers propylene oxide gas. Propylene oxide is a highly reactive
alkylating agent and electrophilic substance. The epoxide moiety reacts with cellular
macromolecules such as RNA, DNA and proteins.
The structure of propylene oxide is as follows:
CH,
B. Use Characterization
In accordance with Office of Pesticide Programs Policy (40 CFR Sections 158.290, 490,
and 540), indoor pesticides involving substances of a gaseous, highly volatile liquid or
highly reactive solid do not require submission of environmental fate data, or data on
effects to non-target terrestrial wildlife, aquatic organisms, or plants. Presumably these
data requirement exclusions are based on an assumption that exposures to non-target
wildlife, aquatic organisms, and plants from such labeled indoor uses of such materials
are negligible. Propylene Oxide is a gaseous material. The Agency has maintained that
exposure to wildlife and water resources from the exclusive registration of propylene
oxide for indoor food and nonfood uses would be negligible. Up to now, the Agency has
not required or received environmental fate and ecological effects data for propylene
oxide. In the November 28, 1990 "List B Review for Propylene Oxide," EFED wrote of
environmental fate data that "(t)here are no significant issues at this time. The only
required information, chemical identity (160-5), will be submitted sometime in the future
and reviewed during Phase V." The chemical identity study is not reviewed by EFED. In
regard to the ecological effects data, EFED wrote in 1990 that "(d)ata is (sic) not required
for this chemical because it is a highly volatile liquid used indoors." These uses are not
considered to have complete exposure pathways to ecological receptors and are not
analyzed in this risk assessment
Propoxide 892 is a propylene oxide product for which a label has been submitted to the
Agency for consideration. This product has proposed uses that potentially are not
consistent with indoor permanent structures. This product can be used on cosmetic
articles, gums, ores, packaging, pigments, pharmaceutical materials, discarded nut shells
prior to disposal, shipping containers, processed species, cocoa, cocoa beans, and in shell
processed nutmeats (excluding peanuts). Dried fruit (figs, prunes, and raisins) are
potential new uses for the produce and though not currently on the label, they have been
included as part the overall assessment of risks for propylene oxide. Importantly, many
of these uses involve application of up to 2.8 Ibs of propylene oxide per 100 ft3 to trailers,
Page 10 of 39 Page 163 of 192
-------
containers, rail cars, tarped materials and tents. These uses, unlike those traditionally
ascribed to propylene oxide use, do not involve permanent structures and are not "indoor"
in the classical interpretation for pesticide use. Consequently, fugitive emissions of
propylene from these non-permanent structure uses may potentially be significant and are
the primary subject of this risk assessment.
One final use appearing on the Propoxide 892 label is a birdseed use. This use would
appear to present a possible exposure to wildlife through propylene oxide resides in the
birdseed. However, the Special Review and Reregi strati on Division (SRRD) has
indicated that this will no longer be a supported use (personal communication Susan
Bartow, SRRD, January 27, 2006). Therefore the birdseed use is not a subject of this risk
assessment.
C. Ecological Receptors Considered in this Risk Assessment
The screening level risk assessment approaches the analysis for adverse effects through
the use of broad plant and animal taxonomic groups including:
• Birds (also used as surrogate for terrestrial-phase amphibians and reptiles),
Mammals,
Terrestrial plants,
• Freshwater fish (also used as a surrogate for aquatic phase amphibians),
• Freshwater invertebrates (including sediment-dwelling species),
Algae and vascular aquatic plants
Because of known effects of propylene oxide to arthropods pests, the risks of the gas to
non-target terrestrial invertebrates will also be evaluated, but without the benefit of
Agency established concern thresholds to aid in interpretation of assessment results.
It should be noted that data limitations in this risk assessment preclude a fully
quantitative analysis offish and aquatic invertebrates, and prevent quantitative analysis of
risks to plants.
D. Exposure Pathways Considered for Terrestrial Organisms
For the purposes of this risk assessment, terrestrial non-target organisms are assumed to
occupy areas immediately adjacent to treatment sites. For a gaseous pesticide released
from a treatment chamber, tarped material, or rail car the terrestrial animal exposure
pathways considered most likely to occur include inhalation of gas and dermal absorption
of the gas. Given the low octanol/water partitioning coefficient of propylene oxide (Kow
0.03 from Hazardous Substances Databank, HSDB 2005, http://toxnet.nlm.nih.gov) it is
unlikely that dermal absorption is a significant pathway for most terrestrial animals
(possible exceptions are amphibians, see Risk Characterization). Similarly, the low
octanol water partitioning coefficient and high vapor pressure (538 mm Hg HSDB 2005,
http://toxnet.nlm.nih.gov) suggest that propylene oxide contamination of dietary
materials for terrestrial wildlife is very unlikely. On that basis this risk assessment for
terrestrial animals will focus on the inhalation pathway.
Page 11 of 39 Page 164 of 192
-------
For terrestrial plants, contact with propylene oxide gas is assumed to be capable of
producing effects to the external layer of plant tissues, to react with the cuticle, and,
through penetration of the plant through the spiracles, produce effects to internal plant
tissues. Because there are no quantitative effects data available to the Agency,
quantification of exposure levels of propylene oxide to plants are not included in this risk
assessment.
E. Exposure Pathways Considered for Aquatic Organisms
The most likely pathways for propylene oxide to enter aquatic systems may include gas
in solution as it contacts surface waters and introduction of propylene oxide to surface
waters during precipitation events where the gas dissolves in the precipitation. The
estimated Henry's Law constant for propylene oxide is 6.96 X 10"5 atm-cu m/mole
(HSDB 2005, http://toxnet.nlm.nih.gov ) suggesting that the gas may dissolve in water
from the atmospheric phase.
The low octanol water partitioning coefficient and high vapor pressure suggest that
adsorption to soil surfaces and subsequent transport to surface waters with runoff would
be very limited.
F. Conceptual Model
Risk Hypothesis
The risk hypothesis for this screening-level risk assessment is as follows:
Propylene oxide, used in accordance with the Propoxide 892 label, results in adverse
effects upon survival and reproduction of non-target terrestrial and aquatic organisms.
Testable elements of this hypothesis are confined by effects data and exposure methods
to inhalation risks to terrestrial vertebrates (quantitatively evaluated), terrestrial
invertebrates (quantitatively evaluated but without the aid of Agency policy concern
levels) and fish (qualitatively evaluated).
Because of a lack of effects data, it is not possible to use available techniques to evaluate
the risk potential of propylene oxide to plants or aquatic invertebrates. Therefore,
available methods and information cannot be used to refute the above hypothesis for
these taxa.
Conceptual Diagram
The following is a conceptual plan diagram depicting sources of exposure, potential
receptors and adverse effects from the supported uses of propylene associated with
Propoxide 892
Page 12 of 39 Page 165 of 192
-------
Atmospheric release of propylene oxide gas from treatment site (rail cars, tarped
materials, tents, infield treatment chambers)
Inhalation of gas
by terrestrial
Animals
Acute lethal and
reproduction effects in
terrestrial vertebrates
and invertebrates
(effects data
unavailable for
invertebrates)
Contact of terrestrial
plants with gaseous
propylene oxide
Growth effects in
terrestrial plants
(effects data
unavailable1)
Solution in surface
waters (direct and
by precipitation)
Uptake in aquatic
organism via gill, or
integument
I
Acute lethal and
reproduction effects
fish and invertebrates
(reproduction effects
data unavailable)
Growth effects in
aquatic plants
(effects data
unavailable1)
G. Analysis Plan
Preliminary Identification of Data Gaps and Methods
No environmental fate or effects data consistent with studies outlined in 40 CFR have been
submitted for propylene oxide.
The Agency has conducted an ECOTOX search, which yielded effects data for terrestrial
arthropods and fish. Effects data for mammals are available through submissions in
compliance with human health risk assessment data requirements. For the purposes of
this risk assessment and the exposure routes evaluated, available effects data for
propylene oxide in mammals are used as a surrogate for all terrestrial vertebrates. Risks
to terrestrial invertebrates are assessed using the target arthropod pest effects data, though
the Agency has no policy for establishing thresholds of concern at this time. Available
fish effects data address acute lethal responses and are used to assess risk to fish and
aquatic phase amphibians. The gaseous nature of propylene oxide, coupled with its
potential to rapidly volatilize from water, suggests that chronic effects would not be an
issue for aquatic systems. The lack of any effects data on aquatic invertebrates and plants
precludes even a qualitative discussion of risks to these taxa.
The Agency has turned to other sources of physical chemical data to obtain information
on likely properties important to an analysis of propylene oxide gas environmental fate
and transport.
Assessment Endpoints
Assessment endpoints for this screening-level ecological risk assessment are reduced
survival, reproductive output, and growth of individual organisms. These assessment
endpoints, while measured at the individual level, provide insight about risks at higher
Page 13 of 39
Page 166 of 192
-------
levels of biological organization (e.g., populations). It is assumed that toxicants do not
affect populations or communities except through the impact on the individuals
comprising the population or community and the demographics of birth, growth, and
death that govern population dynamics. The number of individuals within a population
change (intrinsic rate of increase) primarily because of births (fecundity) and deaths
(survival) and secondarily from migration in and out of a specific area. If effects on the
survival and reproduction of individuals are limited, it is assumed that risks at the
population level from such effects will be of minor consequence. However, as the risk of
reductions in survival and/or reproduction rates increases, so does the potential risk to
populations.
Exposure Measures
Exposures estimated in the screening-level risk assessment for non-target organisms are
not species specific.. Because of the inhalation pathway of concern for this risk
assessment and the lack of a standard peer reviewed gaseous exposure model in EFED,
inhalation exposure for terrestrial animals was evaluated using a method developed by
the Health Effects Division (HED). The HED approach for evaluating the human by-
stander risks of fugitive emissions of propylene oxide makes use of the PERFUM model.
OPP is coordinating with EPA's Office of Air, the CDPR, and others to evaluate and
implement the PERFUM modeling approach based on Industrial Source Complex Short
Term model (ISCST3), which incorporates actual meteorological data and refined flux
inputs that are based on available data and other information. PERFUM allows users to
develop an understanding of the distributions of potential exposures around the perimeter
of a treatment facility or structure and thus more fully characterize the range of risks
impacting organisms from commodity treatments. PERFUM V2.1.2 is available at
http://www.sciences.com/perfum/index.html. For comparative purposes, PERFUM VI. 1
is available at http://www.epa.gov/opphed01/models/fumigant/. ISCST3 is an integral
part of the PERFUM model (for further details see
http://www.epa.gov/scipoly/sap/2004/index.htm). The basic physics and code of ISCST3
remain unchanged. PERFUM essentially provides ISCST3 with daily meteorological
data over the selected 5 years as well as user defined flux inputs. PERFUM then uses this
information to create distributional outputs for receptor locations around the treated
structure. For the purposes of this risk assessment, EFED relied on the conservative 99.9
percentile estimate of propylene concentration with distance over a four hour averaging
time. Further discussion of the PERFUM model inputs and scenario are described in the
Exposure Assessment portion of this document.
The Agency does not have a standard peer-reviewed method to estimate aquatic
exposures for gaseous materials released to the atmosphere, or a model to estimate such
water concentrations with any certainty. Instead, the risk assessment makes use of
available physical/chemical data for propylene oxide and estimates a maximum
theoretical dissolved water concentration of the gas based on assumptions of a two equal
compartment equilibrium model. The 99.9 percentile four hour averaged air emissions
information from PERFUM serve as the source of air concentration in this approach.
Page 14 of 39 Page 167 of 192
-------
Effects Measures
The screening-level risk assessment typically relies on a suite of toxicity studies
performed on a limited number of organisms from broad taxonomic groups. As indicated
earlier, effects data were only available for mammals, some terrestrial invertebrates, and
fish. Mammalian inhalation toxicity endpoints were available and applicable to the
performance of an inhalation exposure pathway risk assessment for mammals. Also
indicated earlier, mammalian effects endpoints (acute lethality and chronic reproduction
impairment) are being used as surrogates for all terrestrial vertebrates because there are
no effects data (confirmed by a search of the ECOTOX database) for other forms of
terrestrial vertebrate wildlife (e.g., birds, reptiles, and terrestrial phase amphibians). The
effects measures employed for terrestrial vertebrates for this risk assessment include the
most sensitive acute inhalation median lethal concentration (LCso) and the rat no
observed adverse effect concentration (NOAEC) for reproduction effects.
The ECOTOX database provides a number of studies of propylene oxide effects on
terrestrial invertebrates. While these data are for target arthropod pests, the lowest four
hour LCso from these species is used as the effect measurement endpoint for terrestrial
invertebrates.
Limited data are available for propylene oxide effects on aquatic organisms and are
confined to effects data on fish as confirmed from a search of the ECOTOX database.
The acute effects measure for fish, and as a surrogate for aquatic phase amphibians, is the
median lethal concentration (LCso) for the most sensitive fish species tested.
Measures of effects have not been quantified for plants and aquatic invertebrates and are
not included in this risk assessment because there are no effects data available to the
Agency. Given the potential for propylene oxide to react with bio-molecules, the
potential for propylene oxide to produce adverse effects in these taxa cannot be
dismissed.
IV. ANALYSIS
A. Environmental Fate and Transport Assessment
No guideline data have been submitted to the Agency that allow for an assessment of the
biotic and abiotic degradation processes for propylene oxide. Available data from the
Hazardous Substances Databank (HSDB 2005, http://toxnet.nlm.nih.gov ) include water
solubility (590g/l), vapor pressure (538 mm Hg), octanol/water partitioning coefficient
(Kow 0.03), and Henry's Law constant (estimated 6.96 X 10"5 atm-cu m/mole). The data
suggest that propylene oxide predominates in a gaseous state and is highly soluble in
water. The low octanol/water partition coefficient suggests little affinity for organic
carbon in soils or sediment and a low potential for bioconcentration in organisms. HSDB
(2005, http://toxnet.nlm.nih.gov) also reports that propylene oxide, present at 100 mg/1,
Page 15 of 39 Page 168 of 192
-------
reached 95% of its theoretical BOD in 3 weeks using an activated sludge at 30 mg/1 by
the Japanese MITI test, suggesting that biodegradation is possible.
B. Terrestrial Exposure Assessment
Terrestrial wildlife exposure estimates, in terms of air concentration associated with
fugitive emissions for treated rail cars, in-field treatment chambers, and tarped materials
were calculated using the HED PERFUM Model. HED maintains that the PERFUM
provides the most refined, scientifically defensible approach for calculating and
characterizing risks associated with bystanders to commodity fumigation operations
because it incorporates actual weather data and links flux profiles to the appropriate time
of day. It also uses as its core processor the proven technology of ISCST3.
The PERFUM model was run for a 5000 ft3 treatment chamber (the maximum size
considered in the HED risk assessment and believed consistent with the in-field
chambers, rail cars and tarped operations specified on the Propoxide 892 label).
Propylene treatment rate was modeled as 2.8 lbs/100 ft3. One hundred percent of the
treatment material was conservatively assumed available for release from the treatment
enclosure, and that release was conservatively assumed to occur without an emission
stack, essentially a simple open door. Three meteorological files encompassing 5 years
of data provided the necessary wind inputs for the model runs. These included Ventura,
California (1995-1999); Flint, Michigan (1987-1991); and Tallahassee, Florida (1988-
1992). The model was run to simulate six release periods each modeling day with the air
concentration estimate being a four-hour average for each period based on a highly
conservative assumption of a release occurring each hour of each release period.
The PERFUM model calculates a distribution of daily isopleths of air concentration
radiating out from the propylene oxide treatment source for each of the six daily
treatment periods. These are then compared with effects thresholds expressed in terms of
air concentration ("air concentrations of concern"). The model output is the percentile
distances at which air concentrations reach the defined effects thresholds. As a
consequence, PERFUM model outputs for air concentration are not specifically presented
in this section of the risk assessment but are internal to the computations of the PERFUM
model.
C. Effects Assessment
An ECOTOX database search has been conducted for propylene oxide. No toxicity data
are available from either this database search or from registrant submissions for birds,
aquatic invertebrates, and aquatic and terrestrial plants. Data are available for mammals,
terrestrial invertebrates and fish. These are summarized below.
Mammalian Effects
Data on inhalation exposure effects to mammals are available from HED. These include
a rat 4-hour acute LD50 (7697 mg/m3) and a mouse 4-hour acute LD50 (2420 mg/m3). In
Page 16 of 39 Page 169 of 192
-------
keeping with the screening-level risk assessment approach to use the most sensitive
species tested, the mouse LD50 serves as the acute toxicity threshold for terrestrial
vertebrates in this risk assessment.
In a two-generation reproduction study (MRID 45292701), propylene oxide (30215 III,
>99%, a.i.) vapor was administered to groups of 30 male and 30 female FO and Fl
Fischer 344 rats by inhalation at chamber concentrations of 0, 30, 100, or 300 ppm. Each
group was exposed to room air (controls) or propylene oxide vapor for 6 hours/day, 5
days/week for 14 weeks (FO) or 17 weeks (Fl) during the pre-mating period and for 6
hour/day, 7 days/week during the mating, gestation, and lactation periods. The Fl pups
selected to parent the F2 generation were exposed to room air or the same concentrations
of propylene oxide vapor as their parents. No treatment-related deaths, clinical signs, or
gross lesions were observed in rats exposed to any concentration of propylene oxide
vapor during pre-mating and post-mating periods for adult FO or Fl males or during the
pre-mating period for adult FO or Fl females. Exposure to concentrations up to 300 ppm
had no exposure-related effect on reproductive performance (mating, fertility or gestation
indices) of the adults or on offspring parameters [clinical signs, mean liter size at any
time during lactation, survival indices (live birth, viability, or lactation), pup weights or
gross and microscopic findings in weanlings. The reproductive NOAEL is 300 ppm or
720 mg/m3. The reproductive LOAEL is not established. The NOAEL from this study
served as the reproduction effects threshold for terrestrial vertebrates for this risk
assessment.
Terrestrial Invertebrate Effects
The ECOTOX database provides information on a number of propylene oxide acute
lethal endpoints for arthropod pest species. The toxicity data are available for the four
hour exposure interval modeled in this risk assessment.
Species 4-hour LD50 (mg/m3 air) Reference
Rust-red flour beetle 44055 Navarro et al (2004)
Tribolium castaneum
Flat bark beetle 2100-5700* Isikber et al. (2004)
Oryzaephilus surinamemis
Rust-red flour beetle 5100-9800* Isikber et al. (2004)
Tribolium castaneum
Indian meal moth 1900-7700* Isikber et al. (2004)
Plodia interpunctella
Almond moth 1600-7200* Isikber et al. (2004)
Ephistia cautella
Page 17 of 39 Page 170 of 192
-------
* The range of values is based on test organism life stages
The most sensitive LC50 from the list (1600 mg/m3) serves as the effects measure for
terrestrial invertebrates for the risk assessment.
Terrestrial Plant Effects
No data for airborne propylene oxide effects associated with terrestrial plants are
available.
Fish Effects
No data are available for propylene oxide from registrant submissions. However, the
following data for acute effects are available from a search of the ECOTOX database.
Species 96-hour LC^n (mg/L) Reference
bluegill 215 Crews 1974
Lepomis macrochirus
mosquitofish 141 Crews 1974
Gambusia affinis
striped mullet 89 Crews 1974
Mugil cephalus
The most sensitive freshwater fish (mosquitofish) and estuarine/marine fish (striped
mullet) yield the most sensitive effects endpoints for these taxa. Because there is no
established screening-level risk assessment method to derive estimated environmental
concentrations from atmospheric releases of gases, risks to fish are discussed in
qualitative terms in the risk characterization based on first approximations of exposure.
Aquatic Invertebrate Effects
No data for propylene oxide are available for aquatic invertebrates. However, ECOTOX
does have data for the close chemical analogue ethylene oxide. These are summarized
below.
Species 48-hour LC^n (mg/L) Reference
Brine shrimp 490-1000 Conway et al.(1983)
Artemia sp.
Daphnia magna 137 - 300 Conway et al.(1983)
Page 18 of 39 Page 171 of 192
-------
In the absence of other available data, the lowest values for the above endpoints are the
effects measures for acute effects to freshwater (Daphnia magna 137 mg/L) and
estuarine/marine invertebrates (Brine shrimp 490 mg/L)
V. RISK CHARACTERIZATION
A. Terrestrial Vertebrate Risk Estimation
Normally, the exposure assessment conducted for the screening-level risk assessment
produces a suite of expected environmental concentrations (EECs, the exposure
measurement endpoint). The ratio of EECs to the acute and chronic effects thresholds
constitute the risk quotients. These risk quotients serve as the integration of exposure and
effects measurement endpoints and are then compared to the Agency's stated levels of
concern (LOCs), which are the policy interpretation of risk quotients.
Contrary to this normal risk quotient process for risk estimation routinely performed in
screening-level risk assessments, this risk assessment uses a modified approach dictated
by the computational environment associated with the PERFUM model. In this modified
approach, "air concentrations of concern" serve as in input to the PERFUM model. The
model then compares these concentrations of concern to the calculated distributions of
estimated air concentrations to estimate a distance from the pesticide release source
where estimated air concentrations are equal to the "air concentration of concern".
To establish the "air concentrations of concern", this risk assessment uses the effects
measurement endpoints (acute and chronic) established for terrestrial vertebrate wildlife
and modifies them by multiplying the endpoints by the acute and chronic LOCs
established by the Agency for non-listed and Federally-listed threatened and endangered
species (listed species). In this manner, the PERFUM model can be run to establish the
distance for propylene oxide use to which estimated propylene oxide concentrations in air
meet or exceed concentrations of concern. The following table presents the acute and
chronic air concentrations of concern for the PERFUM model.
Establishing Propylene Oxide Air Concentrations of Concern for Use in PERFUM
Model
Risk Concern Level
Acute non-listed species
Acute listed species
Chronic all species
Toxicity endpoint (mg/m3)
2420
2420
720
LOC
0.5
0.1
1
Air Concentration of Concern
(mg/m3)*
1210
242
720
*air concentration of concern = (toxicity endpoint)(LOC)
Because the acute listed species air concentration of concern is much lower than non-
listed species acute concentration of concern and the chronic effects concentration of
concern for all species, it was assumed that screening with the PERFUM model for the
acute listed species air concentration of concern would provide a protective initial
evaluation. If the PERFUM model predicted that air concentrations above this concern
Page 19 of 39 Page 172 of 192
-------
level extended beyond the point of propylene oxide treatment, further analysis for the
other air concentration concern levels would be performed.
Results of the PERFUM Model for Terrestrial Vertebrates
Results of the PERFUM model runs are presented in Appendix A for comparisons with
the 242 mg/m3 air concentration of concern. Because the model output for all scenarios
predicts that 4-hour average air concentrations will be below 242 mg/m3 at all distances
from the point of release , all other air concentration of concern (720 and 1210 mg/m3)
will not be exceeded either. Therefore, no air concentrations beyond the treatment point
are expected to exceed levels of concern for inhalation by any listed or non-listed
terrestrial vertebrates.
B. Qualitative Discussion of Risks to Terrestrial Invertebrates
The PERFUM modeling conducted for terrestrial vertebrate exposure indicated that air
concentrations at the release point of propylene oxide use will not exceed 242 mg/m3.
Although the Agency has not established RQ levels of concern for terrestrial
invertebrates, it is reasonable to expect that all air concentrations are well below the most
sensitive terrestrial invertebrate LC50 (1600 mg/m3) by close to if not more than an order
of magnitude.
C. Qualitative Discussion of Risks to Aquatic Organisms
While toxicity data are available for freshwater and estuarine/marine fish, no other effects
data are available for aquatic invertebrates or plants. Additionally, a reviewed method
for quantitatively estimating water concentrations of gases associated with atmospheric
relies is unavailable. Consequently, definitive calculations of risk quotients for aquatic
organisms cannot be made at this time. However, using a simplifying assumption of
equal environmental compartment volumes (air and water) and a condition of
equilibrium, it is possible to make some inferences on the likelihood that propylene oxide
would be of toxicological concern.
Using the Henry's Law constant, vapor pressure, and water solubility of propylene oxide
it is possible to provide a coarse approximation of a water concentration for any given
estimate of air concentration. To do so, it is necessary to assume that water and air
compartments are in equilibrium and those compartments are finite and equivalent in
volume. To investigate how such estimates inform conclusions regarding aquatic risk,
EFED used the lowest air concentration of concern (242 mg/m3) used in the PERFUM
model predictions for wildlife inhalation exposure as follows:
(1) (242 mg/m3 )(m3/1000 L) = 0.242 mg/L
(2) (0.242 mg/L)( 22.4 _L molar volume of atmosphere at standard temperature and pressure)= 5.4208 mg
(3) 5.4208 mg/58,058 mg/mole MWof propylene oxide = 9.33687E-05 moles
Page 20 of 3 9 Page 173 of 192
-------
(4) P = nRT/V = ((9.33687 E-05 moles)(0.08314 bars L/moles K)(298 K))/22.4 L
= 1.0327128 E-04 bars
= 1.01928 E-04 atmospheres
(5) Estimated Water Concentration = Vapor Pressure/Henry's constant
= 1.01928 E-04 atm/6.96E-03 atm-m3/mole
= 0.0146448 mole/m3
= (0.0146448 mole/m3)(m3/1000L)
= 1.46448 E-5moles/L
= (1.46448E-5 moles/L)(58,058 mg/mole)
= 0.8502 mg/L
The resulting water concentration pf 0.8502 mg/L would be below both the lowest
freshwater and estuarine/marine fish LCso values available (141 mg/L for mosquitofish
and 89 mg/L for striped mullet). The same water concentration would also be well (two
or more orders of magnitude) below the lowest freshwater and estuarine/marine LC50
values available (Daphnia magna 137 mg/L, Brine shrimp 490 mg/L). Given that all the
available PERFUM model run scenarios predict that air concentrations fall well below
242 mg/m3 at any distance from the propylene oxide release point, it is reasonable to
expect that propylene oxide use will not produce associated water concentrations adjacent
to treatment areas in excess of the most sensitive fish and invertebrate acute toxicity
endpoints. Furthermore, the water concentration estimate is very conservatively based on
assumptions of equilibrium (a condition not likely to occur given the finite sources of
propylene oxide and the changing wind conditions modeled in PERFUM) and
finite/equivalent environmental compartments (in reality the atmosphere is effectively an
infinite compartment). It is reasonable to expect that water concentrations will likely be
orders of magnitude lower than predicted, suggesting no concern for effects on listed or
non-listed fish.
Propylene oxide is a highly reactive compound with the potential to alkylate bio-
molecules on contact. Little beyond this statement can be said for conclusions regarding
the risk for effects to aquatic plants. No effects data are available to establish effects
measures for this taxa. Therefore no comparisons of even first approximations of water
concentrations of propylene oxide to effects measures can be made. There is insufficient
information to preclude a presumption of acute risk to aquatic plants.
The physical/chemical properties of propylene oxide suggest that residence times in
water will be short. Consequently, it is not likely that propylene oxide will remain in
water long enough to raise concerns for chronic effects in aquatic organisms.
D. Uncertainties and Limitations in the Risk Assessment
Avian and Other Non-Mammalian Terrestrial Vertebrate Risks
The risk assessment for terrestrial mammals is used as a surrogate for assessing risks to
birds, reptiles and terrestrial phase amphibians. It is likely that the risk assessment is
Page 21 of 39 Page 174 of 192
-------
adequate to describe the external exposure (i.e., air concentrations) of each of these taxa
to atmospheric propylene oxide. However reliance on mammalian toxicity endpoints for
the effects portion of the assessment is not without uncertainty. Because respiration rates
for each of the untested taxa differ from mammals, this may be manifested in differing
patterns of sensitivity to a given air concentration of propylene oxide.
An allometric equation is available to estimate inhalation rates of non-passerine birds
(USEPA 1993):
Inhalation Rate (ml/min) = 284(body weight kg)0'77
This equation can be compared to the allometric rate for inhalation in mammals (USEPA
1993):
Inhalation Rate (ml/min) = 379(body weight kg)0'80
The results of such a comparison is summarized in the table below for body weights of 20
50 500 and 1000 g animals.
Comparison of Inhalation Rates for Birds and Mammals
Body weight g
20
50
500
1000
Avian Inhalation
ml/min
13.97
28.28
166.5
284
Mammal Inhalation
ml/min
16.58
34.50
217.68
379
Ratio of Birds to
Mammals
0.84
0.82
0.76
0.75
The comparison indicates that avian inhalation rates are lower than corresponding size
mammals. This would suggest that for any given air concentration of propylene oxide,
the amount inhaled over any given time would be greater for mammals than for birds. It
is likely that propylene oxide, a strong alkylating agent, exerts acute through respiratory
epithelium damage. If one assumes that the amount of damage is related to the mass of
propylene oxide gas available for reaction with the epithelium then it would follow that
mammals may be at a slightly greater risk for acute damage than birds. Therefore the
mammal risk assessment for inhalation would be protective of acute effects in birds as
well. A similar argument can be made for reptile inhalation risks as it is highly likely that
the lower metabolic rates of cold-blooded taxa correspond to lower inhalation rates and
therefore lower exposures at modeled air concentrations. The mechanism of action
associated with reproduction effects in mammals is not likely linked to respiratory
epithelium damage. It is likely a result of actual testing of avian species for either acute
or reproduction effects would provide additional lines of evidence to address the
uncertainty regarding equivalent propylene oxide sensitivity between mammals and birds.
Assumptions of Significance for Dermal Exposure to Terrestrial Wildlife
This risk assessment has assumed that dermal contact with gaseous propylene oxide does
not constitute a significant source of exposure in birds and mammals. The logic for this
Page 22 of 3 9
Page 175 of 192
-------
assumption is that the low Kow suggests limited penetration across the skin of these
organisms. For amphibians, this assumption is highly uncertain. The skin of amphibians
is gas permeable and serves as a adjunct respiratory organ. The extent to which
propylene oxide will either penetrate or adversely impact amphibian skin function for
gaseous exchange is unknown.
E. Conclusions of Risk Assessment
Terrestrial Vertebrate Risks
As indicated in the results of the PERFUM model runs, no estimated air concentrations
exceed the most sensitive air concentration of concern established for terrestrial
vertebrates. Because this air concentration of concern was selected to be below acute and
chronic LOCs for both listed and non-listed terrestrial vertebrates, it is concluded that
risks to terrestrial vertebrates, from fugitive air emissions of propylene oxide from the
non-indoor use sites of commodity treatment will not be of concern for either acute or
chronic effects. There are adequate lines of evidence to refute the hypothesis that
propylene oxide poses acute and chronic risk concerns to terrestrial mammals.
The risk assessment has relied upon toxicity endpoints derived from mammal testing as a
surrogate for effects in other terrestrial vertebrates (birds, reptiles, and terrestrial phase
amphibians). Analysis of other lines of evidence, including relative inhalation rates for
birds and reptiles, suggest that a conclusion of no acute risk to mammals would be
protective of birds and reptiles. There is a potential for propylene oxide to produce tissue
damage from alkylation upon chemical contact with amphibian skin. Amphibian skin is
an important respiratory organ not encountered in other terrestrial vertebrates. This
suggests that extrapolation of mammal, bird, and reptile risk conclusions to terrestrial
phase amphibians, is not without some uncertainty in this particular situation,.
It is uncertain whether risk findings for reproduction effects in mammals are applicable to
other terrestrial vertebrates with any certainty because of differences between the
mammalian reproduction and other terrestrial vertebrates. The avian reproduction data
gap evident for propylene oxide represents a possible significant source of uncertainty.
Terrestrial Invertebrate Risks
The Agency currently does not have a policy tool such as an LOG for interpreting
exposure/effects ratios for terrestrial invertebrates. Because the PERFUM modeling
performed for vertebrate risk assessment shows that release concentrations of propylene
oxide from Propoxide 892 use are well below the most sensitive toxicity value for
terrestrial invertebrates by at least a factor of 8x and more likely at least an order of
magnitude it is reasonable to expect that terrestrial invertebrate risks are not a concern. If
one were to use the terrestrial animal LOCs already established for wildlife taxa, it is
likely that the comparisons of estimated air concentrations with terrestrial invertebrate
effects thresholds (the RQ) would be below the accepted 0.1 value for listed species.
Page 23 of 3 9 Page 176 of 192
-------
Fish and Aquatic Invertebrate Risks
There appears to be adequate information to refute the hypothesis of propylene oxide
risks to fish.
Available information suggests that risks to freshwater and estuarine/marine fish and
invertebrates are not of concern. The first approximation water concentration, associated
with the limits of estimated air concentrations at the point of release from the propylene
oxide use site are below the most sensitive effects endpoints for fish. Furthermore, the
modeled water concentrations are very conservative, perhaps by orders of magnitude,
because they are based on assumptions of equilibrium and equal volume for all
environmental compartments. Considering all lines of information, propylene oxide
concentrations in water from the Propoxide 892 use are not expected to be of acute or
chronic concern for listed and non-listed fish and aquatic phase amphibians.
Chronic risks to fish and invertebrates, though not quantitatively assessed in this risk
assessment, are not likely to be of concern. The physical/chemical properties of
propylene oxide suggest that water concentrations of the gas will quickly decline after the
four hour release period modeled. This decline is assumed not to afford adequate
exposure periods to elicit chronic effects.
F. Risks to Federally Listed Threatened and Endangered Species
Action Area
For listed species assessment purposes, the action area is considered to be the area
affected directly or indirectly by the Federal action and not merely the immediate area
involved in the action. At the initial screening-level, the risk assessment considers
broadly described taxonomic groups and conservatively assumes that listed species
within those broad groups are located on or adjacent to the treated site and aquatic
organisms are assumed to be located in a surface water body adjacent to the treated site.
The assessment also assumes that the listed species are located within an assumed area
which has the relatively highest potential exposure to the pesticide, and that exposures are
likely to decrease with distance from the treatment area.
If the assumptions associated with the screening-level action area result in RQs that are
below the listed species LOCs, a "no effect" determination conclusion is made with
respect to listed species in that taxa, and no further refinement of the action area is
necessary. Furthermore, RQs below the listed species LOCs for a given taxonomic group
indicate no concern for indirect effects upon listed species that depend upon the
taxonomic group covered by the RQ as a resource. However, in situations where the
screening assumptions lead to RQs in excess of the listed species LOCs for a given
taxonomic group, a potential for a "may affect" conclusion exists and may be associated
with direct effects on listed species belonging to that taxonomic group or may extend to
indirect effects upon listed species that depend upon that taxonomic group as a resource.
Page 24 of 3 9 Page 177 of 192
-------
In such cases, additional information on the biology of listed species, the locations of
these species, and the locations of use sites could be considered to determine the extent to
which screening assumptions regarding an action area apply to a particular listed
organism. These subsequent refinement steps could consider how this information would
impact the action area for a particular listed organism and may potentially include areas
of exposure that are downwind and downstream of the pesticide use site.
Taxonomic Groups Potentially at Risk
The Level I screening assessment process for listed species uses the generic taxonomic
group-based process to make inferences on direct effect concerns for listed species. The
first iteration of reporting the results of the Level I screening is a listing of pesticide use
sites and taxonomic groups for which RQ calculations reveal values that meet or exceed
the listed species LOCs. An evaluation of risk conclusions for each taxonomic group is
presented below.
Listed Taxon
Terrestrial and semi-aquatic plants - monocots
Terrestrial and semi-aquatic plants - dicots
Terrestrial invertebrates
Birds
Terrestrial phase amphibians
Reptiles
Mammals
Aquatic vascular plants
Freshwater fish
Aquatic phase amphibians
Freshwater crustaceans
Mollusks
Marine/esruarine fish
Marine/esruarine invertebrates
Direct Effects
Yes1
Yes1
No2
No2
No2
No2
No2
Yes1
No2
No2
No2
Yes1
No2
No2
Indirect Effects
No
No
Yes3
Yes3'4
Yes3'4
Yes3
Yes3'4
No
Yes3'4
Yes3'4
Yes3'4
Yes3'4
Yes4
Yes3'4
1 The alkylating nature of propylene oxide suggests that adverse effects to organism tissues are possible.
No data are available to quantify at what level of exposure such effects would be expressed. Therefore this
conclusion is the product of a data limitation and could change if effects data were made available.
2 Environmental releases of propylene oxide are expected to be below levels known to cause adverse
effects.
3 There is a potential for direct effects on terrestrial plants (conclusion based on data limitations), which is a
concern for indirect effects on animal species dependent upon plants.
4 There is a potential for direct effects on aquatic plants (conclusion based on data limitations), which is a
concern for indirect effects on animal species dependent upon these plants.
VII. REFERENCES
Conway, R.A., G.T. Waggy, M.H. Spiegel, R.L. Berglund. 18983. Environmental fate
and effects of ethylene oxide. Environ.Sci.& Technol. 17:107-112.
Crews, R.C. 1974. Effects of propylene Oxide on Selected Species of Fishes. Technical
Report AFATL-TR-74-183. Air Force Armament Laboratory, Eglin Air Force Base, FL,
13pp.
Page 25 of 39
Page 178 of 192
-------
Hazardous Substances Data Bank (HSDB). 2005. 1,2 Propylene Oxide. Monograph is
available on-line through the National Library of Medicine, http://toxnet.nlm.nih.gov.
Isikber A.A., S. Navarro, S. Finkelman, M. Rindner, A. Azrieli, R. Dias. 2004. Toxicity
of propylene oxide at low pressure against life stages of four species of stored product
insects. Journal of Economic Entomology, 97:281-295.
Navarro S, A. Isikber, S. Finkelman, M. Rindner, A., Azrieli. R., Dias R. 2004.
Effectiveness of short exposures of propylene oxide alone and in Combination with low
pressure or carbon dioxide against Tribolium castaneum (Herbst) (Coleoptera:
Tenebrionidae). Journal of Stored Products Research, 40:197-205.
United States Environmental Protection Agency (USEPA). 1993. Wildlife Exposure
Factors Handbook. EPA/600/R-93/187a, Office of Research and Development,
Washington, DC.
Page 26 of 3 9 Page 179 of 192
-------
Appendix A
Propylene Oxide PERFUM Model Runs
Page 27 of 39 Page 180 of 192
-------
README File from Contractor Regarding Propylene Oxide Modeling Runs
This CD contains the results of the PERFUM2 runs that were done for propylene oxide
for three meteorological areas: Ventura, CA, Tallahassee, FL, and Flint, MI.
Under each met region, you will find two directories, one for each endpoint EFED
desired analyzed: 1,210 mg/m3 and 242 mg/m3.
Under each of these directories, you will find two directories, one for 4-hour estimates
where an emission occurred once every 4 hours and one for 4-hour estimates where an
emission occurred every hour.
Under each of these directories, you will find 10 directories, one for each scenario
modeled. These directories include: treatment and aeration from a building w/o a stack
(treatment aeration no stack); aeration from a building with a stack 10 feet above the roof
top (aeration min stack @ full exit velocity, !/2 exit velocity, and 5% exit velocity);
aeration from a building w/ a 50 foot portable stack attached (aeration portable stack @
full exit velocity, /^ exit velocity, and 5% exit velocity); and aeration from a building w/
a ventilation hose hooked to it (aeration ppq @ full exit velocity, /^ exit velocity, and 5%
exit velocity). These are the same scenarios we used in prior modeling commodity
fumigations for PPO.(EFED comment: building w/o stack represents the most
conservative scenario)
Under each of these directories you will find 44 PERFUM2 files and 1 batch file that was
used to automate the process. Each PERFUM2 run consists of 4 files with the following
extensions:
.per is the input file for PERFUM2
.out is the output file from PERFUM2 (this will be the file you'll focus on mostly)
.ctr is a contour file generated by PERFUM2 (nice for making figures)
.pit is a file that has the same results as in the output file, but can imported easily
into Excel or Lotus
PERFUM2 runs were done for the following building volumes: 1000, 2000, 5000, 10000,
25000, 50000, 100000, 250000, 500000, 750000, and 1000000 cu ft. (EFED comment:
5000 cuft was selected as maximum for Propoxide 892 label applications for the
ecological and human health risk assessments)
In each output file (.out) you will find results for different release rates (labeled
application rates in the output file) for whole field and maximum distance analysis. The
results are profiles of distances to the concentration of concern. Do not be alarmed by the
application rates that are depicted in the output files; these are values that were used to
make it easier for someone to visualize the percent applied that is being released; it does
not actually indicate the amount applied or released - this information is reflected
as the hourly flux values. The amount applied values should appear as: 100, 99, 95, 90,
75, 50, 25, 10, 5, and 1 lbs/1000 cu ft. For the portable stack and PPQ, because we are
Page 28 of 39 Page 181 of 192
-------
minimizing the effects of the buildings, we had to use the following values: 100,000,
990,000, 95,000, 90,000, 75,000, 50,000, 25,000, 10,000, 5,000, and 1,000 lbs/1000 cu ft.
Page 29 of 3 9 Page 182 of 192
-------
Tallahassee Florida PERFUM Model run for 5000 cubic foot chamber
treated with 2.8 Ib propylene oxide/ 100 cubic feet. Model assumes a
conservative no-stack emission scenario. The run is for hourly
emissions, with 4 hour averaging times. Air concentration of Concern is
242 mg/m3 (the lowest/most conservative endpoint evaluated)
******************************************************
** PERFUM Output File
******************************************************
Version 2.1.1 - compiled on 12/19/2005
Run finished on: 03/09/2006 at 01:23
******************************************************
** Basic information about the model run
******************************************************
Scenario Type: CRN
Source of flux data: CDPR Commodity Permit Conditions
Source of meteorological data: Tallahassee, FL
ISCST3 meteorological file: ..\PERFUM2\MET\tl.MET
Field size (acres): 0.007
Length in x-direction (m): 5.20
Length in y-direction (m): 5.20
Grid density: FINE
******************************************************
** Toxicity Inputs
******************************************************
Human Equivalent Cone (ug/m3) : 242000.0 (EFED Note; This is the Mammalian
Acute LC%) multiplied by the Endangered Species LOG of 0.1)
Uncertainty factor: 1.0
Threshold (ug/m3): *******
******************************************************
** Exposure Assumptions
******************************************************
Exposure averaging period (hours): 4
Distribution averaging time (hours): 4
******************************************************
** Time Assumptions
******************************************************
Starting year: 1988
Ending year: 1992
Application Start Hour: 3
******************************************************
** Additional assumptions for greenhouse scenario
******************************************************
Greenhouse source type: Area
Page 30 of 39 Page 183 of 192
-------
Height of greenhouse (m): 5.2
Adjusted greenhouse height (m): 0.9
Source of flux data: Manually entered by user (EFED Note treatment was 2.i
lb/100 cubic feet)
** Fumigant Flux Profiles
******************************************************
Flux rates for day number: 1
HOUR Flux Rate
1 64558.000
2 64558.000
3 64558.000
4 64558.000
5 64558.000
6 64558.000
7 64558.000
8 64558.000
9 64558.000
10 64558.000
11 64558.000
12 64558.000
13 64558.000
14 64558.000
15 64558.000
16 64558.000
17 64558.000
18 64558.000
19 64558.000
20 64558.000
21 64558.000
22 64558.000
23 64558.000
24 64558.000
** All flux rates in micrograms per meter squared per second
Number of Periods with Buffer Length Estimates
Period Valid Periods Calm Periods
1
2
3
4
5
6
Period
Period
Period
Period
Period
Period
1186 640
1802 24
1826 0
1826 0
1626 200
1281 545
Definition of Flux Averaging Periods
1
2
3
4
5
6
Hours
Hours
Hours
Hours
Hours
Hours
3
7
11
15
19
23
to
to
to
to
to
to
6
10
14
18
22
2
Page 31 of 39 Page 184 of 192
-------
PERFUM Model Results
Whole field buffer percentiles for an application rate of 100.0 for
Flux Profile Day No. 1
Percentile Perl Per2 Per3 Per4 Per5 Per6
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
99
99.9
99.99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Maximum concentration
100.0 for Flux
Percentile
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
Profile
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
buffer
Day
Perl Per2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
No.
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
percentiles
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
for
Per3 Per4 Per5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
an
Per6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
application rate of
Page 32 of 39 Page 185 of 192
-------
99
99.9
99.99
Page 33 of 39
Page 186 of 192
-------
Flint Michigan PERFUM Model run for 5000 cubic foot chamber treated
with 2.8 Ib propylene oxide/ 100 cubic feet. Model assumes a
conservative no-stack emission scenario. The run is for hourly
emissions, with 4 hour averaging times. Air concentration of Concern is
242 mg/m3(the lowest/most conservative endpoint evaluated)
******************************************************
** PERFUM Output File
******************************************************
Version 2.1.1 - compiled on 12/19/2005
Run finished on: 03/09/2006 at 04:37
******************************************************
** Basic information about the model run
******************************************************
Scenario Type: CRN
Source of flux data: CDPR Commodity Permit Conditions
Source of meteorological data: Flint, MI
ISCST3 meterological file: ..\PERFUM2\MET\flint.MET
Field size (acres): 0.007
Length in x-direction (m): 5.20
Length in y-direction (m): 5.20
Grid density: FINE
******************************************************
** Toxicity Inputs
******************************************************
Human Equivalent Cone (ug/m3) : 242000 . 0 (EFED Note; This is the Mammalian
Acute LC%) multiplied by the Endangered Species LOG of 0.1)
Uncertainty factor: 1.0
Threshold (ug/m3): *******
******************************************************
** Exposure Assumptions
******************************************************
Exposure averaging period (hours): 4
Distribution averaging time (hours): 4
******************************************************
** Time Assumptions
******************************************************
Starting year: 1987
Ending year: 1991
Application Start Hour: 3
******************************************************
** Additional assumptions for greenhouse scenario
******************************************************
Greenhouse source type: Area
Height of greenhouse (m): 5.2
Adjusted greenhouse height (m): 0.9
Source of flux data: Manually entered by user (EFED Note treatment was 2.8
lb/100 cubic feet)
******************************************************
** Fumigant Flux Profiles
******************************************************
Page 34 of 39 Page 187 of 192
-------
Flux rates for day number: 1
HOUR Flux Rate
164558.000
2 64558.000
3 64558.000
4 64558.000
5 64558.000
6 64558.000
7 64558.000
8 64558.000
9 64558.000
10 64558.000
11 64558.000
12 64558.000
13 64558.000
14 64558.000
15 64558.000
16 64558.000
17 64558.000
18 64558.000
19 64558.000
20 64558.000
21 64558.000
22 64558.000
23 64558.000
24 64558.000
** All flux rates in micrograms per meter squared per second
Number of Periods with Buffer Length Estimates
Period Valid Periods Calm Periods
1
2
3
4
5
6
1786
1821
1824
1822
1822
1809
39
4
1
3
3
16
Definition of Flux Averaging Periods
Period 1 Hours 3 to 6
Period 2 Hours 7 to 10
Period 3 Hours 11 to 14
Period 4 Hours 15 to 18
Period 5 Hours 19 to 22
Period 6 Hours 23 to 2
PERFUM Model Results
Whole field buffer percentiles for an application rate of 100.0 for
Flux Profile Day No. 1
Percentile Perl Per2 Per3 Per4 Per5 Per6
Page 35 of 39 Page 188 of 192
-------
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
99
99.9
99.99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Maximum concentration buffer percentiles for an application rate of
100.0 for Flux Profile Day No. 1
Percentile Perl Per2 Per3 Per4 Per5 Per6
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
99
99.9
99.99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Page 36 of 39 Page 189 of 192
-------
Ventura California PERFUM Model run for 5000 cubic foot chamber treated
with 2.8 Ib propylene oxide/ 100 cubic feet. Model assumes a
conservative no-stack emission scenario. The run is for hourly
emissions, with 4 hour averaging times. Air concentration of Concern is
242 mg/m3(the lowest/most conservative endpoint evaluated)
******************************************************
** PERFUM Output File
******************************************************
Version 2.1.1 - compiled on 12/19/2005
Run finished on: 03/09/2006 at 02:39
******************************************************
** Basic information about the model run
******************************************************
Scenario Type: CRN
Source of flux data: CDPR Commodity Permit Conditions
Source of meteorological data: Ventura, California
ISCST3 meterological file: ..\PERFUM2\MET\vt.MET
Field size (acres): 0.007
Length in x-direction (m): 5.20
Length in y-direction (m): 5.20
Grid density: FINE
******************************************************
** Toxicity Inputs
******************************************************
Human Equivalent Cone (ug/m3) : 242000.0
Uncertainty factor: 1.0
Threshold (ug/m3): *******
******************************************************
** Exposure Assumptions
******************************************************
Exposure averaging period (hours): 4
Distribution averaging time (hours): 4
******************************************************
** Time Assumptions
******************************************************
Starting year: 1995
Ending year: 1999
Application Start Hour: 3
******************************************************
** Additional assumptions for greenhouse scenario
******************************************************
Greenhouse source type: Area
Height of greenhouse (m): 5.2
Adjusted greenhouse height (m): 0.9
Source of flux data: Manually entered by user(EFED Note treatment was 2.8
lb/100 cubic feet)
******************************************************
** Fumigant Flux Profiles
******************************************************
Page 37 of 39 Page 190 of 192
-------
Flux rates for day number: 1
HOUR Flux Rate
164558.000
2 64558.000
3 64558.000
4 64558.000
5 64558.000
6 64558.000
7 64558.000
8 64558.000
9 64558.000
10 64558.000
11 64558.000
12 64558.000
13 64558.000
14 64558.000
15 64558.000
16 64558.000
17 64558.000
18 64558.000
19 64558.000
20 64558.000
21 64558.000
22 64558.000
23 64558.000
24 64558.000
** All flux rates in micrograms per meter squared per second
Number of Periods with Buffer Length Estimates
Period Valid Periods Calm Periods
1 1438 357
2 1773 22
3 1792 3
4 1791 4
5 1717 78
6 1306 489
Definition of Flux Averaging Periods
Period 1
Period 2
Period 3
Period 4
Period 5
Period 6
Hours 3 to 6
Hours 7 to 10
Hours 11 to 14
Hours 15 to 18
Hours 19 to 22
Hours 23 to 2
PERFUM Model Results
Whole field buffer percentiles for an application rate of 100.0 for
Flux Profile Day No. 1
Percentile Perl Per2 Per3 Per4 Per5 Per6
Page 38 of 39 Page 191 of 192
-------
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
99
99.9
99.99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Maximum concentration buffer percentiles for an application rate of
100.0 for Flux Profile Day No. 1
Percentile Perl Per2 Per3 Per4 Per5 Per6
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
97
99
99.9
99.99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Page 39 of 39 Page 192 of 192
------- |