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 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.

Table 7. Tolerance Reassessment for Propylene Oxide and Propylene
Chlorohydrin

Tolerances Established Under 40 CFR §180.491

                             Propylene Oxide	Propylene Chlorohydrin

Commodity	Current Tolerance (ppm)	Reassessed Tolerance (ppm)	Current
Tolerance (ppm)	Reassessed Tolerance (ppm)

Basil 	--	--	--	6000

Spices/herbs	300	300	--	1500

Dried onion1	--	--	--

	Dried garlic1	--	--	--

	Processed nutmeats 	300	300	--	10

Figs	--	3	--	3

Prunes	--	2	--	2

Raisins	--	1	--	4

Gum, edible	300	Revoke	--	--

Cacoa bean	300	200	--	20

1 Tolerance based on data given for basil

6.2	Acute and Chronic Dietary Exposure and Risk

sk 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 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.

  SEQ CHAPTER \h \r 1 Table 8.  Acute and Chronic Dietary Exposure and
Risk Estimates for Propylene oxide

Population Subgroup	PAD, mg/kg/day	DEEM-FCID	Lifeline

Exposure, mg/kg/day	% PAD	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	0.0014	0.0001	6	0.0001	7

All infants (< 1 yr)	0.0014	0.0001	3	0.0001	2

Children 1-2 yrs	0.0014	0.0002	16	0.0002	13

Children 3-5 yrs	0.0014	0.0002	15	0.0002	14

Children 6-12 yrs	0.0014	0.0001	10	0.0001	10

Youth 13-19 yrs	0.0014	0.0001	5	0.0001	6

Adults 20-49 yrs	0.0014	0.0001	5	0.0001	6

Adults 50+ yrs	0.0014	0.0001	6	0.0001	7

Females 13-49 yrs	0.0014	0.0001	5	0.0001	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 4x10-7.  The results of the cancer analysis conducted
using the alternative cancer slope factor are provided in Table 9.

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	Slope Factor

(mg/kg diet)	DEEM-FCID Exposure

mg/kg/day	mg PPO/kg Diet 1	Estimated Cancer Risk 2

General U.S. Population	0.000086	0.0001	0.0047	4x10-7

1 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.

  SEQ CHAPTER \h \r 1 Table 10.  Result of Chronic Dietary Exposure and
Risk Estimates for Propylene chlorohydrin

Population Subgroup	cPAD, mg/kg/day	DEEM-FCID	Lifeline

Exposure, mg/kg/day	% PAD	Exposure, mg/kg/day	%PAD

U.S. Population	0.03	0.0018	6	0.0034	11

All infants (< 1 yr)	0.03	0.0017	6	0.0027	9

Children 1-2 yrs	0.03	0.0074	25	0.0087	29

Children 3-5 yrs	0.03	0.0062	21	0.0080	27

Children 6-12 yrs	0.03	0.0037	12	0.0054	18

Youth 13-19 yrs	0.03	0.0015	5	0.0035	11

Adults 20-49 yrs	0.03	0.0010	4	0.0030	10

Adults 50+ yrs	0.03	0.0011	4	0.0030	10

Females 13-49 yrs	0.03	0.0011	4	0.0036	12

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 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.

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 lbs) 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 µg/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 lbs, OAR found no ETO source posing a cancer
risk greater than 100 in a million with a unit risk estimate (Q1* or
cancer slope factor) of 0.16 ppm-1).  The existing cancer slope factor
for PPO (Q1* = 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).  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 µg/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.

Modeling Methodology

The PERFUM (Probabilistic Exposure and Risk model for FUMigants PERFUM V
2.1.2;   HYPERLINK "http://www.sciences.com/perfum/index.html"
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 (    HYPERLINK "(http://www.epa.gov/scram001/)"
http://www.epa.gov/scram001/) .  It incorporates actual weather data,
and links flux profiles to the appropriate time of day when calculating
results.

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.

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 lb lb ai/1000 ft3 (0.0448 oz/ft3) (Propoxide 892)

-	31.25 lb ai/1000 ft3 (0.5 oz/ft3)

-	43.75 lb ai/1000 ft3 (0.7 oz/ft3)

-	75 lb ai/1000 ft3 (1.2 oz/ft3)

-	150 lb 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;

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:  1.7 ppm.

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 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.

  SEQ CHAPTER \h \r 1 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	2000 Cubic Feet	5000 Cubic Feet

95% Mass Release	75% Mass Release	95% Mass Release	75% Mass Release	95%
Mass Release	75% Mass Release

During Aeration

Maximum Buffer Distances

Minimum Stack

(4 xch/hr)	90	10	0	35	30	40	30

	95	15	10	40	30	45	35

	99	20	15	50	40	50	40

	99.9	20	15	55	40	55	45

No Stack	90	40	30	75	60	150	130

	95	45	35	85	70	170	145

	99	55	40	100	80	185	160

	99.9	60	45	105	85	195	165

Whole Field Buffer Distances

Minimum Stack

(4 xch/hr)	90	0	0	0	0	0	0

	95	0	0	0	0	0	0

	99	0	0	0	0	20	0

	99.9	15	10	35	30	40	35

No Stack	90	0	0	0	0	0	0

	95	0	0	0	0	5	0

	99	10	0	25	20	55	45

	99.9	40	30	80	65	160	135

During Treatment

Maximum Buffer Distances

No Stack	95	0	0	0	0	0	0

	99	0	0	0	0	0	0

	99.9	0	0	0	0	0	0

Whole Field Buffer Distances

No Stack	95	0	0	0	0	0	0

	99	0	0	0	0	0	0

	99.9	0	0	0	0	0	0

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	1440	1410

	95	1440	1440

	99	1440	1440

	99.9	1440	1440

Whole Field Buffer Distances

Minimum Stack (4 xch/hr)	90	0	0

	95	45	40

	99	545	470

	99.9	1440	1440

Application Rate 75 lb/1000 ft3

Maximum Buffer Distances

Minimum Stack (4 xch/hr)	90	1015	180

	95	1155	965

	99	1330	1120

	99.9	1370	1150

Whole Field Buffer Distances

Minimum Stack

(4 xch/hr)	90	0	0

	95	35	30

	99	350	300

	99.9	1085	915

Application Rate 43.75 lb/1000 ft3

Maximum Buffer Distances

Minimum Stack(4 xch/hr)	90	680	560

	95	775	645

	99	870	735

	99.9	920	770

Whole Field Buffer Distances

Minimum Stack

(4 xch/hr)	90	0	0

	95	25	25

	99	245	205

	99.9	720	600

Application Rate 31.25 lb/1000 ft3

Maximum Buffer Distances

Minimum Stack

(4 xch/hr)	90	515	425

	95	590	490

	99	685	565

	99.9	710	590

Whole Field Buffer Distances

Minimum Stack

(4 xch/hr)	90	0	0

	95	25	20

	99	195	165

	99.9	555	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 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

  SEQ CHAPTER \h \r 1 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   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/"
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
1x10-6.  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.

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	Concentration (ppm)	Nomenclature

Occupational Safety and Health Administration (OSHA)	100	PEL1

National Institute for Occupational Safety and Health (NIOSH)	LFC2	REL3

American Conference of Governmental Industrial Hygienists (ACGIH)	2
TLV-TWA4

California Division of Occupational Safety and Health (Cal/OSHA)	205	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-1 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).

3 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,
Subchapter 7, Group 16, Article 107, Section 5155 Airborne Contaminants.
 Note:  The Cal/OSHA Standards Board had proposed lowering this level to
1.0 ppm, 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.

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	Activity	# Samples	Avg Hrs Sampled	TWA (ppm)

Mean	Median	Geometric Mean	Max

All Data	Non-Specific (Daily TWA)	19	8.1	0.94	0.55	0.58	6.6

	Combined Non-Specific & Adjusted Chamber Unloading TWA	22	8.1	1.2	0.64
0.71	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.

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)	Cancer Risk	Exposure Concentration

(ppm)

240	1.0 x 10-4	0.11

240	1.0 x 10-6	0.0011

Non-Cancer Risk

Exposure Duration	LOC for MOE	Exposure Concentration (ppm)

Acute	300	1.7

Short/Intermed- term	30	2.5

Long-term	30	3

Q1* = 3.5x10-6 (μg/m3) -1 or 0.0084 ppm-1;  Short-/Intermediate-term
NOAEL = 75 ppm;  Long-term BMDL10 = 90 ppm (HEC)

Table 16:  Non-Cancer and Cancer Risk Estimates at Regulatory Levels

Organization	Concentration

(μg/m3) -1 or 0.0084 ppm-1

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	Activity	Daily TWA1

(ppm)	Non-Cancer MOE	Cancer Risk4

	ST/IT2	LT3

LOC for MOE = 30

	Mean	Non-Specific (Daily TWA)	0.94	80	96	8.7E-04

	Combined Non-Specific & Adjusted Chamber Unloading TWA	1.21	62	74
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.

2 Short-/Intermediate-term NOAEL = 75 ppm

3 Long-term BMDL10 = 90 ppm (HEC)

4 Q1* = 3.5x10-6 (μg/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 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.
SEQ CHAPTER \h \r 1 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)(1)(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
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.

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

	Technical

	Required	Satisfied

870.1100	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		yes

no¶

yes

no¶

no¶

no¶	yes*

-

yes*

-

-

-

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		yes

yes

no¶

no¶

yes	yes

yes

-

-

yes*

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800	Reproduction		yes

yes

yes	yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

reserved#

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5xxx	Mutagenicity—Structural Chromosomal Aberrations

870.5xxx	Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes*

yes*

yes*

yes*

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		no

no

no

no

no	-

-

no

no

-

870.7485	General Metabolism

870.7600	Dermal Penetration		yes

no¶	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)		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

2.0	NON-CRITICAl TOXICOLOGY STUDIES

Subchronic Neurotoxicity Study - Propylene Oxide

Subchronic Neurotoxicity Study (MRID 45292801)

  SEQ CHAPTER \h \r 1 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 observational 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;
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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.

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 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 toxicologically
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 ↓14.6% 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%
1-chloro-2-propanol and 25% 2-chloro-1-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 1-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 1-chloro-2-propanol (75%
1-chloro-2-propanol and 25% 2-chloro-1-propanol) at concentrations of 0,
33, 100, 330, 1,000, or 3,300 ppm in 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% 1-chloro-2-propanol and 27% 2-chloro-1-propanol) immediately after
mixing and 838 ppm (68% 1-chloro-2-propanol and 32% 2-chloro-1-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
B6C3F1 mice were administered 1-chloro-2-propanol (75%
1-chloro-2-propanol and 25% 2-chloro-1-propanol) in drinking water at
concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days.
The average 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 1-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
B6C3F1 mice were administered 1-chloro-2-propanol (75%
1-chloro-2-propanol and 25% 2-chloro-1-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).

3.0	Propylene Oxide Metabolism

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/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.

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, D.J.  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. p181-213.

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.

Lynch, D.W., T.R. Lewis, W.J. 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, p1-6

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.   HYPERLINK "http://www.epa.gov/iris/subst/0403.htm"
 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:   HYPERLINK
"http://www.epa.gov/cancerguidelines"  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.

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

  SEQ CHAPTER \h \r 1 MEMORANDUM

June 27, 2006

SUBJECT:	  SEQ CHAPTER \h \r 1 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

Reregistration Branch 4

Health Effects Division (7509C)

THROUGH:	Susan Hummel

		  SEQ CHAPTER \h \r 1 Branch Senior Scientist

		Reregistration Branch 4

		Health Effects Division (7509C)

TO:		  SEQ CHAPTER \h \r 1 Susan Bartow

Chemical Review Manager

Special Review Branch

		Special Review and Reregistration Division  (7509C)

		Rebecca Daiss

		Risk Assessor

		Reregistration 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 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	Human Gastric Juice	Rat Fore-stomach Juice

pH	1.46	4.8

Overall hydrolysis Rate for PPO	0.364 min -1	0.0020 min-1

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 week x 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/BMDL10 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 BMDL10  is 0.1/1160 mg/kg salad oil= 0.000086
(mg/kg dosing solution)-1  (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 of 4 x 10-7.

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.

====================================================================

   	  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 conc (mg/L) x 0.92 x 219 /(150 wk x 7 d/w)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

   The form of the probability function is:

   P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)]

   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: 1e-008

 Parameter Convergence has been set to: 1e-008

                  Default Initial Parameter Values

                     Background =            0

                        Beta(1) =  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(1)      Beta(2)

   Beta(1)            1        -0.98

   Beta(2)        -0.98            1

                          Parameter Estimates

       Variable           Estimate             Std. Err.

     Background                   0               NA

        Beta(1)         1.2263e-005         0.000162211

        Beta(2)         1.8522e-008        3.55814e-008

NA - Indicates that this parameter has hit a bound

     implied by some inequality constraint and thus

     has no standard error.

                        Analysis of Deviance Table

       Model      Log(likelihood)  Deviance  Test DF     P-value

     Full model        -41.6004

   Fitted model        -41.6004   3.7943e-012      1               1

  Reduced model        -67.1864       51.1721      2         <.0001

           AIC:         87.2008

                     Goodness  of  Fit

     Dose     Est._Prob.    Expected    Observed     Size     Chi^2 res.

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

i: 1

    0.0000     0.0000         0.000         0         100       0.000

i: 2

 1190.0000     0.0400         2.000         2          50      -0.000

i: 3

 4760.0000     0.3800        19.000        19          50      -0.000

 Chi-square =       0.00     DF = 1        P-value = 1.0000

   Benchmark Dose Computation

Specified effect =            0.1

Risk Type        =      Extra risk

Confidence level =           0.95

             BMD =        2076.86

            BMDL =        1159.24

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.

7.0	BMD ANALYSES

7.1	BMD Analysis Memo – Dunkelberg 1982

  SEQ CHAPTER \h \r 1 MEMORANDUM

June 28, 2005

SUBJECT:	Benchmark Dose Analysis of Propylene Oxide - Combined
Incidences of Papillomas, Hyperplasia and Hyperkeratosis in Rat
Forestomach

FROM:	Becky Daiss

		Environmental Health Scientist

Reregistration Branch 4

Health Effects Division (7509C)

TO:		Santhini Ramasamy

		Toxicologist

		Reregistration 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 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 BMD10, 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 BMD10 (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)	N	Incidences

0	100	0

2.58	50	7

10.28	50	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.

      SEQ CHAPTER \h \r 1

  SEQ CHAPTER \h \r 1 PPO - Rat Carcinogenicity - Combined Incidence -
Papillomas, Hyperplasia, Hyperkeratosis

Model (95% CL)	BMD Extra Risk	BMD	BMDL	x2	P-Value	AIC

Gamma 1

10%

Multistage2 3

2.4	1.7	0.7	0.4	107.2

Log Probit 2

NA	NA	7	<0.05	112

Quantal Linear 1

2.4	1.7	0.7	0.7	107.2

Quantal Quadratic 4

NA	NA	13	<0.005	119

Weibull 1

2.4	1.7	0.7	0.7	107.2

1 The model parameter(s) Background and Power have been estimated at a
boundary point and do not appear in the correlation matrix

2 The model parameter(s) Background and Slope have been estimated at a
boundary point and do not appear in the correlation matrix

3 The model parameter(s) Background and Beta 2 have been estimated at a
boundary point and do not appear in the correlation matrix

4 The model parameter(s) Power have been estimated at a boundary point
and do not appear in the correlation matrix.4  The model parameter(s)
Power have been estimated at a boundary point and do not appear in the
correlation matrix

  SEQ CHAPTER \h \r 1

Attachment

=1

Quantal Quadratic

=2

Weibull

 - background;  - power;  - slope;

7.2	BMD Analysis Memo – Kuper et al. (1988)

  SEQ CHAPTER \h \r 1 MEMORANDUM

July 30, 2006

SUBJECT:	Benchmark Dose Analysis of Propylene Oxide – Nasal Lesions
Associated with  Long-Term Inhalation Exposure

FROM:	      Ray Kent, Chief

	      Reregistration Branch 4

	      Health Effects Division

TO:	      Becky Daiss

	      Environmental Health Scientist

      Reregistration 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.

Study Selected for BMD Analysis

The following study was selected for BMD analysis.

MRID 42039901

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.

This study was subsequently published as:

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.

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

<IP_ADDRESS> (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.

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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.

Table 1.  Incidence of Nasal Lesions* in Male and Female Rats Exposed
to Propylene Oxide

	Nasal Lesions in Male Rats	 	   Nasal Lesions in Female Rats

Dose (ppm)	0	30	100	300	 	0	30	100	300

Animals Examined	66	61	62	63	 	64	64	62	65

Atrophy of the olfactory epithelium

Slight response	5	8	7	10	 	7	9	6	21

Moderate response	0	0	3	11	 	0	0	1	5

Total (slight + moderate)	5	8	10	21	 	7	9	7	26

Basal-cell hyperplasia of the olfactory epithelium

Slight response	3	1	5	10	 	0	0	8	17

Moderate response	1	1	5	9	 	0	0	1	8

Marked response	0	0	0	5	 	0	0	0	8

Moderate + marked response	1	1	5	14	 	0	0	1	16

Total responders	4	2	10	24	 	0	0	9	33

Nest-like infolds of the respiratory epithelium

Slight response	4	11	27	21	 	4	7	19	29

Moderate response	1	0	2	17

Marked response	0	0	0	9

Moderate + marked response	1	0	2	26	 	0	1	1	14

Total responders	5	11	29	47	 	4	8	20	43

*  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 BMDL10 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 BMDL10 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 BMDL10s is
112 ppm, which is lower than the endpoint and model selected.  The
difference between the BMDL10s is not considered meaningful. The  BMDL10
of 120 ppm was chosen as the point of departure for long-term noncancer
risk assessment.

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

Figure 1. Nest-like infolds of the respiratory epithelium in male rats
- "moderate+marked" response

Attachment

Quantal Linear

   α =1

Quantal Quadratic

 α =2

Weibull

 γ- background; α - power;  β - slope;

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	300	<137	200	change to Cacao bean, dried bean

Gum, edible	300	NA	revoke	Use has been voluntarily cancelled

Nutmeat, processed (except peanut)	300	<300	300	change to Nut, tree,
group 14

Spices, processed	300	<164	300	[Herbs and spices, group 19, dried]

Tolerances to Be Recommended under 40 CFR 180.491 For Propylene Oxide

Cacao bean, cocoa powder	none	<137	200

	Garlic, dried	none	none	3002

	Onion, dried  	none	none	3002

	Grape, raisin	none	<1.0	1.0

	Fig	none	<3.0	3.0

	Plum, prune, dried	none	<2.0	2.0

	Tolerances to Be Recommended under 40 CFR 180.491 For Propylene
chlorohydrins:

Cacao bean, dried bean	none	<13	20

	Cacao bean, cocoa  powder	none	<20	20

	Nut, tree, group 14	none	<6	10

	[Herbs and spices, group 19, dried], except basil

none

<1500

15003

	Basil, dried leaves	none	<6000	6000

	Garlic, dried	none	NA	60002

	Onion, dried  	none	NA	60002

	Grape, raisin	none	<4.0 	4.0

	Fig	none	<3.0	3.0

	Plum, prune, dried	none	<2.0	2.0

	1 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:

1  Propylene oxide; tolerances for residues.

Remove all of current Section (a) (1),

Add a new Section (a)(1),

General (1) Tolerances are established for the residues of propylene
oxide when used as a postharvest fumigant in or on the following food
commodities:

Commodity	Parts per million

Tolerances to be Listed Under 40 CFR 180.491(a)(1) for propylene oxide

Cacao bean, bean	200

Gum, edible	revoke

Nutmeat, processed (except peanut)	300

Spices, processed	300

Tolerances to be Proposed Under 40 CFR 180.491(a)(1) for propylene oxide

Cacao bean, cocoa powder	200

Garlic, dried	300

Onion, dried  	300

Grape, raisin	1.0

Fig	3.0

Plum, prune, dried	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 1-chloro-2-propanol and 2-chloro-1-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	20

Cacao bean, cocoa  powder	20

Nut, tree, group 14	10

[Herbs and spices, group 19, dried], except basil	1500

Basil, dried leaves	6000

Garlic, dried	6000

Onion, dried  	6000

Grape, raisin	4.0

Fig	3.0

Plum, prune, dried	2.0

 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 1x 6.06
L/hr x 6 h/day x 1 / (0.124 kg)] =  209 mg/kg/day.

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Page   PAGE  95  of   NUMPAGES  95

Acute RfD (Females 13-49 years)  =         209 mg/kg/day (NOAEL)    =
    0.21 mg/kg/day
                         						1000 (UF)

Chronic RfD (General Population)  =          1.4 mg/kg/day (BMDL)    =
  0.001 mg/kg/day
                        						  1000 (UF)

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  =      0.03 mg/kg/day
                              						 1000 (UF)