UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM			

July 31, 2006								

SUBJECT:	Propylene Oxide – Revised HED Risk Assessment for
Reregistration Eligibility Decision (RED) Document, PC Code: 042501, DP
Barcode: D316547

									

FROM:	Becky Daiss 

		Biologist

Reregistration Branch 4

Health Effects Division (7509C)

THROUGH:	Susan Hummel

		  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)

		

Attached is the revised Health Effect Division’s risk assessment of
the insecticidal fumigant/sterilant, propylene oxide (PPO).  This
document revises the September 26, 2005 Revised Propylene Oxide HED Risk
Assessment to address public comments.  The disciplinary science
chapters have also been revised to address public comments.  These and
other supporting documentation are incorporated into the risk assessment
and/or included as appendices as follows:

Hazard Identification Assessment; William Dykstra - Section 4 and
Appendices 1-6 

	Residue Chemistry Assessment; Jerry Stokes (D316571, 9/22/05; D316573,
6/22/06)

Occupational and Residential Exposure Assessment; Matthew Crowley
(D316545, 7/31/06; D331131, 7/31/06)

	Dietary Exposure and Risk Assessment; Becky Daiss (D329648, 6/30/06)

	Incident Report; Jerry Blondell (  SEQ CHAPTER \h \r 1 D316407,
5/17/05)

Drinking Water Assessment; Kevin Costello (D263366, 3/15/00)

TABLE OF CONTENTS

 				        pg.

1.0 	EXECUTIVE SUMMARY	4

2.0	INGREDIENT PROFILE	9

2.1	Summary of Registered and Proposed Uses	9

2.2  	Structure, Nomenclature and Physical/Chemical Properties	9

3.0	METABOLISM ASSESSMENT	10

3.1	Comparative Metabolic Profile	10

3.2 	Nature of the Residue in Foods 	10

3.2.1	Description of Primary Crop Metabolism	11

3.2.2  	Description of Livestock Metabolism tc \l3 "3.1.2  	Plant
Metabolism 	11

3.3  	Environmental Degradation tc \l2 "3.2  	Environmental Degradation 
	11

3.4  	Summary of Residues for Tolerance Expression and Risk Assessment 
11

	3.4.1    Rationale for Inclusion of Metabolites and Degradates
Assessment	12

4.0	HAZARD CHARACTERIZATION/ASSESSMENT 	13

4.1	Hazard Characterization 	13

4.2	FQPA Hazard Considerations 	24

4.2.1	Adequacy of the Toxicity Data Base tc \l3 "4.2.1	Adequacy of the
Toxicity Data Base  	24

4.2.2	Evidence of Neurotoxicity tc \l3 "4.2.2	Evidence of Neurotoxicity 
	25

4.2.3	Developmental Toxicity Studies tc \l3 "4.2.3	Developmental
Toxicity Studies  	26

4.2.4	Reproduction Toxicity Studies 	31

4.2.5  	Pre-and/or Postnatal Toxicity tc \l3 "4.2.5  	Pre-and/or
Postnatal Toxicity  	34

4.2.6	Recommendation for a Developmental Neurotoxicity Study	35

4.2.7	Rationale for the UFDB	36

4.3	Additional FQPA Safety Factor	36

4.4	Hazard Identification and Toxicity Endpoint Selection	36

4.4.1   	Acute and Chronic Reference Doses for Propylene Oxide tc \l3
"4.4.1   	Acute Reference Dose - General Population 	36

4.4.2	Acute and Chronic Reference Doses for Propylene Chlorohydrin tc
\l3 "4.4.2	 	37

4.4.3   	Incidental Oral Exposure tc \l3 "4.4.1   	Acute Reference Dose
- General Population 	38

4.4.4	 tc \l3 "4.4.3	 Dermal Absorption	38

4.4.5	 tc \l3 "4.4.4	 Dermal Exposure 	38

4.4.6	 tc \l3 "4.4.5	 Inhalation Exposure 	39

4.4.7	 tc \l3 "4.4.6	 Margins of Exposure	40

4.4.8	 tc \l3 "4.4.7	 Recommendation for Aggregate Exposure Risk
Assessments	40

4.4.9	 tc \l3 "4.4.8	 Classification of Carcinogenic Potential	41

4.4.10	Summary of Endpoints Selected for Risk Assessment	49

4.5	Endocrine Disruption	51

5.0	INCIDENT REPORT	51

	

6.0	DIETARY EXPOSURE/RISK PATHWAY	51

6.1	Residue Profile	516.2	Acute and Chronic Dietary Exposure and Risk
53

7.0 	RESIDENTIAL EXPOSURE/RISK PATHWAY	55

7.1 	Emissions from Controlled Commercial Sterilization Chambers	56

7.2	Emissions from Stationary Sources with No Emission Controls and
Commodity Fumigation with Propoxide 892	57

	7.2.1  Modeling Methodology	57

	7.2.2  Exposure Scenarios	58

	7.2.3  PERFUM Model Inputs	58

	7.2.4  Residential Bystander Exposure and Risk Estimates	59

8.0 	AGGREGATE EXPOSURE AND RISK	61

9.0	CUMULATIVE RISK	62

10.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	62

10.1	Exposure Scenarios	62

10.2	Established Exposure Levels	63

	10.2.1  Regulatory/Recommended Exposure Levels	63

	10.2.2  Label Requirements	63

10.3	Exposure Monitoring Data	64

10.4	Exposure Assumptions	65

10.5	Exposure and Risk Estimates	65

	10.5.1  Inhalation Exposure and Risk	65

	10.5.2  Dermal Exposure and Risk	66

	10.5.3  Risk Characterization	66

11.0	DATA NEEDS	67

11.1	Toxicology Data Requirements Residue Chemistry Data Requirements	67

11.2	Residue Chemistry Data Requirements	67

11.3	Occupational and Residential Exposure Data Needs	68

 

APPENDICES

1.0	GUIDELINE TOXICOLOGY DATA SUMMARY	69

2.0	NON-CRITICAL TOXICOLOGY STUDIES	70

3.0	PPO METABOLISM	75

4.0	REFERENCES	76

5.0	ALTERNATE ORAL CANCER SLOPE FACTOR	79

6.0	MODE OF ACTION SUMMARY	83

7.0	BMD ANALYSES	84

	7.1  BMD Analysis Memo – Dunkelberg (1982)	84

	7.2  BMD Analysis Memo – Kuper et al. (1988)	88

8.0	TOLERANCE REASSESSMENT TABLE	94

          EXECUTIVE SUMMARY

Use Profile

PPO is used as an insecticidal fumigant on several food items such as
processed spices, cocoa (beans and powder), in-shell and processed
nutmeats (except peanuts).  PPO also has nonfood uses for cosmetic
articles, gums, ores, packaging, pigments, pharmaceutical materials, and
discarded nut shells prior to disposal.  

Currently, there are three registered products for PPO.  Both technical
and an end-use product contain 100% a.i..  An additional end-use
registration product, Propoxide 892 which contains 8% PPO and 92% carbon
dioxide (CO2) is being proposed for uses on dried fruits such as figs,
raisins, and prunes.

Regulatory History

  SEQ CHAPTER \h \r 1 Propylene oxide is a FIFRA 88 List B
reregistration pesticide.  A FIFRA 88 Phase VI Data Call-In (DCI) was
issued by the Agency in October 1989 which cited numerous deficiencies
in the product and residue chemistry databases.  Additional product and
residue chemistry data received since 1989 have been reviewed by the
Agency.  PPO has a tolerance of 300 ppm for processed spices, cocoa
(beans or powder), edible gums, and processed nutmeats (except peanuts)
under 40 CFR 180.491.

The requirements for the series of acute toxicity studies have been
waived in the past based on available information in the literature,
consideration of PPO as a low volume, minor use chemical and/or irritant
properties of the compound.  The requirements for subchronic and chronic
oral toxicity studies in rodents and non rodents have been reserved
pending dissipation and residue studies (D165449, 9/4/92).  

 

A data call-in for dermal and inhalation exposure monitoring data was
requested in 1990 (Morris, 1990).  However, a waiver request was granted
in 1993 based on labeling restrictions and risk mitigation measures such
as site air monitoring and placarding. 

OSHA (Occupational Safety and Health Administration) has established the
8-hour time-weighted average (8-hour TWA), permissible exposure limit
(PEL) for PPO as 100 ppm.  NIOSH (National Institute for Occupational
Safety and Health) recommends the Lowest Feasible Concentration (LFC)
for occupational carcinogens a group which includes PPO.  The ACGIH
(American Conference of Governmental Industrial Hygienists) recommends a
TLV-TWA (Threshold Limit Value – Time Weighted Average) of 2 ppm for
PPO.  The exposure limits from NIOSH and ACGIH are recommended levels
and are not enforceable.  The California Division of Occupational Safety
and Health (Cal/OSHA) has established an exposure limit value for PPO as
20 ppm.  The current EPA label for PPO requires respiratory protection
if PPO concentrations exceed 20 ppm.  

Hazard Characterization

Propylene oxide:  The database for PPO is incomplete. Based on
information available from the literature, PPO is classified as Category
III by the oral route and Category IV by the inhalation route.  PPO has
severe irritant properties to eyes and skin and is classified as
Category I for both tissues.  

Evidence suggests that PPO, similar to ethylene oxide, is most probably
completely absorbed, distributed throughout the body and rapidly
metabolized following inhalation.  The metabolism occurs predominantly
by conjugation with glutathione and hydrolysis to 1, 2-propanediol by
epoxide hydrolase.

PPO has been shown to cause awkward gait/ataxia and axonal degeneration
of the hindleg nerve in rats at a high dose level (1500 ppm or 3.6
mg/L).  At a similar dose level, PPO also caused decreased survival and
produced clinical symptoms like dyspnea, hypoactivity, and gasping in
rats.  

PPO causes nasal cavity lesions (e.g., hyperplasia of the respiratory
epithelium) in both rats and mice.  Tumors such as hemangiomas and
hemangiosarcomas of the nasal cavity were produced in mice exposed to
PPO for a long term.  Nasal tumor incidences in rats were not
statistically significant.  Forestomach tumors in rats were reported in
one chronic oral toxicity study available in the literature.  PPO is
mutagenic and forms adducts with proteins and DNA.  PPO has been
classified by the Agency as a B2 carcinogen (probable human carcinogen).
 

The PPO database lacks an acceptable rabbit developmental study and a
chronic oral toxicity study in non rodents.  There is no evidence of
increased quantitative or qualitative susceptibility following in utero
exposures in rats.  Also, there are no residual uncertainties found in
existing studies for pre- and post natal toxicity in rats.  

Propylene Chlorohydrin:  PCH exists in two isomers, 1-chloro 2-propanol
and 2-chloro-1-propanol.  Most of the toxicity studies are done with a
mixture of isomers containing predominantly 1-chloro-2-propanol.

There are no guideline studies (acute, subchronic, developmental,
reproduction or chronic toxicity studies) submitted to the Agency and
the database for PCH is inadequate.  The available data from the open
literature indicate PCH is Category II or III  by the oral route and
Category II by the dermal route and the Category is undetermined for the
inhalation route.

One rat developmental toxicity study was identified in the literature as
a secondary source of information and is unacceptable.  There is no
rabbit developmental study available for PCH.  In a rat two generation
reproductive toxicity study identified in the literature, decreased body
weight gain in dams during gestation and lactation, increased percentage
of abnormal sperm and decreased pup weights were reported. No neurotoxic
effects are evident in the available database for PCH.

  

PCH appears to be widely distributed in tissues, metabolized and
excreted following inhalation.  Most of the administered radioactivity
appears to be excreted in urine as glutathione conjugates.  Also,
biliary excretion is reported in rats exposed to PCH by inhalation. 
Following oral exposure, PCH is eliminated as glucuronic acid conjugate
in addition to glutathione conjugate.  

 

In subchronic studies conducted using rats and mice cytoplasmic
alterations and/or degeneration of acinar cells in the pancreas are
reported.  In addition, atrophy of the bone marrow and/or spleen and
hepatocellular vacuolization were reported and these effects were not
reported in the rodent chronic studies.  

Inductions of mutations in bacteria and chromosomal aberrations as well
as sister chromatid exchange in mammalian cells were reported for PCH.  
 

Dose Response Assessment

For PPO, the acute dietary endpoint for females of 13-49 years is
derived from a rat developmental toxicity study.  No endpoint of concern
is found suitable for the acute dietary endpoint for the general
population.  The chronic dietary endpoint for PPO is selected from the
chronic oral carcinogenicity study.  BMD (Bench Mark Dose) modeling was
done to derive the chronic reference dose (cRfD) since the study did not
establish a clear NOAEL.  the chronic cancer risk from the oral route
was derived using a revised concentration based cancer slope factor. 
Since the toxicology database is incomplete, a database uncertainty
factor of 10X was applied in addition to the traditional 100X
uncertainty factor for the dietary risk assessment to address residual
uncertainties.  The short-term and long-term inhalation endpoints for
workers potentially exposed to PPO were derived using the rat
two-generation reproduction study and two-year combined chronic
carcinogenicity study in rats, respectively.  The chronic cancer risk
from the inhalation route for workers was derived using a cancer slope
factor of 3.5x10-6 (µg/m3)-1 for nasal tumors.  This revised assessment
also provides a discussion of use of a margin of exposure (MOE) approach
for assessing inhalation risks based on mode of action (MOA) information
submitted by and on behalf of the registrant.  After an initial
analysis, EPA concludes that the proposed MOA is highly plausible, and
will review the proposed MOA in more depth, both within OPP and in
conjunction other Agency offices. If the proposed MOA is accepted by the
Agency, propylene oxide will not be regulated using a q* approach for
inhalation exposures.  Rather, an MOE analysis will be conducted.

For PCH, no acute dietary endpoint was selected.  The chronic reference
dose for PCH was derived from the two-generation reproduction study in
rats.  A database uncertainty factor of 10X is applied for dietary
assessment to address any residual uncertainties.  

Exposure/Risk Assessment and Risk Characterization

The potential exposures and risk from dietary sources were determined
for PPO as well as for the reactive metabolite, PCH found in significant
amounts in fumigated spices, nuts and other commodities. Occupational
exposure and risk via inhalation for all durations were determined for
the parent only.  Potential occupational exposures via the dermal route
from changing/installing PPO drums and handling treated commodities are
considered negligible.  There are no residential uses for PPO and
therefore, no risk for incidental oral exposures or residential
exposures via inhalation was determined; however, a qualitative
assessment for background exposures to subjects near PPO commercial
fumigation facilities was performed based on the risk estimated by
Office of Air for ethylene oxide.  HED also conducted a quantitative
assessment of potential exposure/risk to bystanders from outdoor
commodity fumigation with Propoxide 892 containers such as railcars,
tents and tarps.   

    

Dietary Exposure and Risk Characterization

  SEQ CHAPTER \h \r 1 Refined acute and chronic dietary risk assessments
were conducted using the Dietary Exposure Evaluation Model
(DEEM-FCID™, Version 2.03), and the Lifeline Model Version 3.0 which
use food consumption data from the USDA’s Continuing Surveys of Food
Intake by Individuals (CSFII) from 1994-1996 and 1998.  Residue data
obtained from studies on propylene oxide sterilization of nutmeats,
cocoa powder, herbs and spices, figs, prunes and raisins were used for
the acute and chronic assessments.  Residue distribution data from PPO
sterilization studies were used for the acute dietary analysis of
propylene oxide.  Average residues from the sterilization study were
used for the chronic and cancer assessments of propylene oxide. 
Tolerance level residues were used for the chronic dietary analysis of
propylene chlorohydrin.  Percent crop treated data provided by BEAD were
used for the acute and chronic analyses.  A drinking water exposure
assessment was not conducted for this assessment because the
Environmental Fate and Effects Division (EFED) expects that uses of
propylene oxide for indoor and outdoor food and nonfood uses will result
in insignificant exposure to drinking water resources. 

This assessment has been updated to include a revised propylene oxide
cancer assessment that incorporates new data on residue levels in
treated nutmeats based on actual maximum application rates, incorporates
refined estimates of percent of nutmeats treated with propylene oxide,
and excludes edible gums from the assessment based on the registrants
submission of a voluntary cancellation notice requesting deletion of
edible gums from product labels.  Only the cancer dietary exposure
assessment has been revised for this assessment because only that
scenario produced risk estimates above EPA’s level of concern. 
Conservative estimates of acute and chronic dietary risks for PPO are
well below HED’s level of concern and incorporation of new data would
result in risks < previously estimated risks.

A refined probabilistic acute dietary exposure assessment for the
population subgroup females 13-49 concludes that for all supported
commodities, the acute dietary exposure estimates for PPO are below
HED’s level of concern.  This assessment also concludes that for all
supported commodities, the chronic dietary exposure estimates for PPO
are below HED’s level of concern.  The revised cancer dietary risk
estimates for propylene oxide are below HED’s level of concern; the
revised cancer dietary excess lifetime risk estimate for the U.S.
general population is 4x10-7.  An acute RfD was not established for
propylene chlorohydrin because an endpoint attributable to a single (or
few) day exposure was not identified from the available database.  This
assessment concludes that for all supported commodities, the chronic
dietary exposure estimates for propylene chlorohydrin are below HED’s
level of concern.  

Residential Exposure and Risk Characterization

There are no residential uses for PPO.  However, exposure to PPO is
expected to occur to the subjects residing near PPO fumigation
facilities.  PPO emissions monitoring data necessary to quantitatively
estimate exposures and risks from sterilization/fumigation facilities
are unavailable.  Therefore, a qualitative assessment was conducted
comparing the risks associated with fugitive emissions from the use of a
similar chemical, ethylene oxide, in similar commercial fumigation
scenarios.  Risks to bystanders from comparably controlled commercial
sterilization sources are not expected to be of concern based on HED’s
qualitative risk analysis.  Additionally, HED conducted a quantitative
assessment of residential bystander risk associated with emissions from
outdoor commodity fumigation with the recently registered product
Propoxide 892 and from stationary sources that do not have emission
controls comparable to those required for ethylene oxide.  There is
potential for exposure and risk to PPO for non-occupational/residential
bystanders as a result of commodity fumigations conducted with the
registered product Propoxide 892 and those conducted in non-emission
controlled commercial sterilization chambers.  However, potential
bystander risks may be mitigated by requiring buffer areas at designated
distances. 

Occupational Exposure and Risk Characterization

The cancer and non-cancer risks from exposure to PPO were determined
based on currently recommended or regulatory concentration levels.  The
short- (1-30 days), intermediate- (1-6 months), and long-term (greater
than 6 months) inhalation non-cancer and cancer risks from the use of
PPO in commodity sterilization/fumigation are of concern at 20 ppm the
exposure limit value established by Cal/OSHA and is included in current
EPA PPO label.  The acute, short-, intermediate- and long-term
non-cancer risks are not of concern at the ACGIH recommended worker
exposure concentration of 2 ppm.  As previously noted, EPA has concluded
that an MOA is highly plausible, and will review the proposed MOA in
more depth, both within OPP and in conjunction other Agency offices.  If
the Agency concurs with the proposed MOA, then cancer and long-term
non-cancer risks would be regulated at the same level, since the
long-term non-cancer endpoint is based on nasal lesions that are
considered precursors to the development of tumors.

The registrant and industry representatives have submitted inhalation
monitoring data and descriptive information on typical workday exposure
patterns for outdoor fumigation facilities.  The exposure monitoring
data was reviewed and incorporated into the revised occupational
exposure assessment.  Potential risk reduction from respiratory
protection has not been quantitatively factored into the risk
assessment, however, due to insufficient data on the daily PPO exposure
profile.  However, a qualitative discussion of potential risk reduction
provided by use of respirators is included in this assessment i.e.,
respiratory protection during peak PPO exposures could reduce the daily
average exposure to levels that would not be of concern.  Additional
monitoring data and information on exposure patterns that may be used to
develop effective risk mitigation measures for both indoor and outdoor
facilities is expected from the registrant and industry representatives.

2.0	Ingredient Profile

2.1.	Summary of Registered/Proposed Uses

Products and Formulations

The two registered products (one technical and one end-use registration)
contain 100% a.i..  An additional end-use registration (8% a.i) is being
proposed for use on figs, raisins, and prunes.  PPO is used as a post
harvest fumigant in the food commodities.  Table 1 provides the summary
of current and new uses for PPO.

  

Table 1. Registered Uses of Propylene Oxide   SEQ CHAPTER \h \r 1 

EPA Reg. No. 	*Product Name	% AI	Formulation	Application Rate (oz
PPO/ft3)	Uses

47870-1	Propylene Oxide	100	NA	2.4	Spices, nutmeats (except peanuts),
cocoa beans, cocoa powder and non food uses

47870-2	Propylene Oxide Technical	100	NA	2.4	Spices, nutmeats (except
peanuts), cocoa beans, cocoa powder and non food uses

47870-3	PROPOXIDE 892	8	92% CO2	0.05	Figs, prunes and raisins and other
commodities

*Aberco Inc. is the registrant for all the products.

2.2	Structure, Nomenclature and Physical/Chemical Properties

  SEQ CHAPTER \h \r 1 Product Chemistry data for PPO and its reaction
products, i.e., chlorohydrins and bromohydrins are provided in Table 2.

	

Table 2. Nomenclatures and Physical/Chemical Properties of Propylene
Oxide and Reaction Products

Common name	Propylene Oxide	Propylene chlorohydrins

(75% 1-Chloro-2-propanol, 25% 2-Chloro-1-propanol)	Propylene
bromohydrins 

(80% 1-Bromo-2-propanol, 20% 2-Bromo-1-propanol)

Chemical Structure				        	       

Molecular Formula	C3H6O	C3H7ClO	C3H7BrO

Molecular Weight	58.080	94.541	138.992

IUPAC Name	-	-	-	-	-

CAS Name	Propylene oxide; 1,2-epoxypropane	1-chloro-2-propanol
2-chloro-1-propanol	1-bromo-2-propanol	2-bromo-1-propanol

CAS #	75-76-9	127-00-4	37493-14-4	19686-73-8	NA

PC Code	042501	NA	NA	NA	NA

Melting Point/range ºC	-	-	-	-	-

Boiling Point ºC	  SEQ CHAPTER \h \r 1 34.2 ºC	126-127 ºC	130 ºC
145-148 ºC	NA

Density or Specific Gravity

at 20 ºC (g/cm3)	0.829- 0.831	1.115	1.09	1.53	NA

Water Solubility  (20 ºC)	39.5 g/100 mL	NA	NA	NA	NA

Solvent Solubility at 25 ºC	Miscible with acetone, benzene. carbon
tetrachloride, diethyl ether, and methanol.	NA	NA	NA	NA

Vapor Pressure at 20 ºC	440 mm Hg	NA	NA	NA	NA

Dissociation Constant, pKa	NA	NA	NA	NA	NA

Octanol/Water Partition Coefficient (Kow) 25 ºC	Kow 0.03	NA	NA	NA	NA

UV/vis  Absorption Spectrum	NA	NA	NA	NA	NA

NA = not available

3.0	Metabolism Assessment

	

3.1 	Comparative Metabolic Profile

The available evidence from the open literature suggests that PPO like
ethylene oxide is most probably completely absorbed, distributed
throughout the body and rapidly metabolized following inhalation.  The
half-life for the elimination from rat tissues was reported as 40
minutes following inhalation exposure.  PPO is metabolized via
conjugation with glutathione and hydrolysis by epoxide hydrolase to 1,
2-propanediol (propylene glycol), which is subsequently metabolized to
lactic and pyruvic acids.

The available evidence from the open literature suggests that PCH is
widely distributed to tissues, metabolized and excreted following
inhalation in animals.  Most of the administered radioactivity appears
to be excreted in urine as glutathione conjugates.  Also, biliary
excretion is reported in rats exposed to PCH by inhalation.  Following
oral exposure, PCH is eliminated as glucuronic acid and glutathione
conjugates.  

	

3.2	Nature of the Residue in Foods

	

	3.2.1.	Description of Primary Crop Metabolism

  SEQ CHAPTER \h \r 1 The qualitative nature of PPO residues in plants
is adequately understood.  The residues of propylene glycol, PCHs and
PBHs (propylene bromohydrins) are formed upon postharvest fumigation of
cocoa bean, nutmeats (except peanut), and spices.  Spices that contain
salt that are treated with PPO react with chloride ion to form PCH. 
Similarly, any bromide ion present in the material to be fumigated
reacts with PPO to form PBH.  In addition, reaction with water in
samples can produce small amounts of propylene glycol (PPG).

	3.2.2	Description of Livestock Metabolism

  SEQ CHAPTER \h \r 1 Based on the post harvest fumigant uses of PPO on
commodities of spices and herbs, nutmeats (except peanut), cocoa bean,
fig, prune and raisin, livestock are not exposed to PPO or PCH residues
in any feedstuffs, or from dermal treatments.  Data on livestock
metabolism are not collected and are not required.

	

3.3 	Environmental Degradation

EFED expects that exposure to water resources from the exclusive
registration of PPO for indoor food and non food uses will be
negligible.  EFED has neither required nor received environmental fate
data for propylene oxide.  In the November 28, 1990 ‘List B Review for
Propylene Oxide’, EFED wrote of environmental data that there are no
significant issues at this time.  EFED maintains that additional
environmental data are not necessary for the reregistration of this
sterilant.  EFED would require this data when PPO would ever be
considered for registration for outdoor uses.  EFED determined that
there would be negligible risk for any contamination of surface and
ground water for the current uses of PPO.  Therefore, no drinking water
assessment was found necessary (K. Costello, D263366, 3/15/2000).

3.4	Summary of Residues for Tolerance Expression and Risk Assessment

  SEQ CHAPTER \h \r 1 PPO and PCH are considered separately as residues
of concern for risk assessment and tolerance assessment.  The commodity
sterilization study residue data indicate that these compounds are
consistently present at high levels.  The spice sterilization study data
indicate that PBH is also a reaction product of the propylene oxide
sterilization process.  However, PBH residues are minimal relative to
propylene chlorohydrin residues.  Therefore, PBH is not considered a
residue of concern for risk assessment and is not assessed separately.  

Based on current information from the spice industry trade practices,
HED concludes that residues measured at 2 days (in transit) after
treatment should be used for setting the tolerance level, and the
residue data at approximately 2 weeks (and after) should be used in
estimating dietary exposure to PPO and PCH only.  Because the propylene
oxide label requires that treated nutmeats must be allowed to off-gas
for at least 28 days, only residue data from > 28 days post-fumigation
are used in estimating dietary exposure.  Based on the differences in
physical chemical properties and toxicological effects, PPO and PCH are
assessed separately and the residues are not combined in this risk
assessment.  Table 3 provides the residues included in risk assessment
and tolerance expression.  

Table 3. Compounds to be included in the Risk Assessment and Tolerance
Expression

Commodities	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plant	Primary Crop	Propylene oxide

Propylene chlorohydrin	Propylene oxide

Propylene chlorohydrin

	Rotational Crop	Not Applicable	Not Applicable

Livestock	Ruminant	Not Applicable	Not Applicable

	Poultry	Not Applicable	Not Applicable

Drinking Water	Not Applicable	Not Applicable



	3.4.1	Rationale for Inclusion of Metabolites and Degradates

  SEQ CHAPTER \h \r 1 HED Metabolism Committee concluded that both
halohydrins (PCH and PBH) are residues of concern and risk assessment
and tolerance expression should include both the parent and the
halohydrins pending additional data on residue chemistry and toxicity
for these compounds. (D264138, 8/16/00).   Based on the available
toxicity data and the commodity sterilization study residue data, PPO
Risk Assessment Team concludes that   SEQ CHAPTER \h \r 1 propylene
oxide and propylene chlorohydrin are residues of concern for dietary
exposure since these residues persist at high levels and are likely to
be present in treated commodities at time of consumption.  The spice
sterilization study data indicate that propylene bromohydrin is also a
reaction product of the propylene oxide sterilization process.  However,
PBH residues are minimal relative to propylene chlorohydrin residues. 
Therefore, PBH is not considered a residue of concern for dietary
exposure and is not included in the tolerance expression. 

4.0	Hazard Characterization/Assessment 

4.1	Hazard Characterization 

Propylene Oxide

This assessment includes the toxicity assessment of propylene oxide and
its reaction product, PCH (1-chloro-2-propanol and its isomer,
2-chloro-1-propanol) found in significant quantities in treated spices
and nutmeats.  For dietary assessment, endpoints were selected for both
parent and the reaction product.  For occupational risk assessment the
endpoints were selected for the parent only.

The toxicology database for PPO is not complete.  The database includes
acceptable developmental toxicity, reproduction toxicity, subchronic
neurotoxicity (non-guideline), and chronic carcinogenicity studies in
rats, all conducted via inhalation. There is one developmental study in
rabbits conducted via inhalation which is not acceptable because only
one dose was used.  Also, the database includes one rat chronic
carcinogenicity study conducted via the oral route which provides
limited information as the study was conducted in one sex (females only)
and lacked measurements on systemic toxicity (body weights, food
consumption, clinical measurements, organ weight changes etc.) or
carcinogenicity effects in major tissues.  Therefore, the PPO database
lacks a developmental toxicity study in rabbits, and subchronic and
chronic oral toxicity studies in non rodents.  

Waivers were issued in the past for acute oral (§81-1, 870.1100),
dermal (§81-2, 870.1200), eye irritation (§81-4, 870.2400), skin
irritation (§81-5, 870.2500) and dermal sensitization (§81-6,
870.2600) studies based on the corrosive nature of the compound and the
acceptance of the chemical as a low volume minor-use chemical.  The
requirement for an acute inhalation study was satisfied based on
available information from the open literature (D165449, dated 9/4/92). 
PPO is classified as Category III by the oral route and Category IV by
the inhalation route.  PPO is a severe eye and skin irritant and is
classified as Category I for both routes of exposure.   

Based on the available toxicity data, an additional 10X data base
uncertainty factor is deemed necessary for the dietary assessment to
address the inadequate subchronic and chronic data for the oral route of
exposure and the lack of an acceptable rabbit developmental study. 
There is no evidence of increased quantitative or qualitative
susceptibility following in utero exposures in rats.  Also, there are no
susceptibility effects in pups in the two-generation reproductive
toxicity study.  

No data on absorption and metabolism of PPO have been submitted. 
Evidence suggests that PPO like ethylene oxide is most probably
completely absorbed, distributed throughout the body and rapidly
metabolized following inhalation.  The half-life for the elimination
from rat tissues was reported as 40 minutes for inhalation exposure. 
Metabolism occurs predominantly by conjugation with glutathione and
hydrolysis by epoxide hydrolase to 1,2-propanediol, which is
subsequently metabolized to lactic and pyruvic acids.

PPO has been shown to cause awkward gait/ataxia and axonal degeneration
of the hindleg nerve in rats at a very high dose (3.6 mg/L) in one
subchronic toxicity study.  Axonal dystrophy was reported in monkeys
exposed to PPO for 2 years, but there was no dose response effect and
the study was conducted with a limited number of animals per group
(n=2).  PPO produces nasal cavity lesions in rats and mice in chronic
studies.  The lesions include atrophy of the olfactory epithelium, basal
cell hyperplasia and nest-like infolds of the nasal epithelium. 
Although the mode of action for these non-neoplastic lesions is not
established, irritation of the nasal tissues is considered to contribute
to these extra extrathoracic effects.   

Similar to ethylene oxide, PPO is a known mutagen which directly
alkylates proteins and DNA.  Numerous published studies have shown that
PPO induces mutations in bacteria, yeast, fungi and insects. 
Chromosomal damage and aberrations and sister chromatid exchange were
reported in mammalian cells in vitro.  PPO tested negative for
micronuclei induction in mice via the oral route and for dominant lethal
assays in rats via the inhalation and in mice via oral route.  

PPO induces several types of tumors depending on the route of exposure. 
PPO administered by oral gavage to rats produced tumors of the
forestomach, which were mainly squamous-cell carcinomas.  This study
provides limited information on carcinogenicity effects in key tissues
such as liver, kidney, thyroid etc.  Further, it was conducted only in
rats of one sex (females), and any sex specific effects were not
determined.

In the carcinogenicity studies in rats via inhalation, equivocal
evidence for mammary gland tumors (significant fibroadenoma with
marginal tubulopapillary adenocarcinoma) in Wistar rats, and thyroid
tumors (dose related increase in thyroid C-cell adenomas and carcinomas)
and adrenal gland tumors (adrenal pheochromocytoma) in F344 rats was
reported.  The incidence of tumors in the nasal cavity was not
significant in rats.  However, in mice exposed by inhalation, PPO
produced hemangiomas and hemangiosarcomas of the nasal cavity.  The
doses tested in the carcinogenicity studies were considered adequate
based on inflammatory lesions in the nasal cavity and other systemic
effects.   

Although the incidence of forestomach tumors observed in PPO treated
rats has a questionable relevance to humans, these tumors could not be
excluded due to 1) evidence of mutagenicity in different organisms 2)
chromosomal damage in mammalian cells in vitro, and 3) adduct formation
in vivo in tissues distant from the site of administration. 

PPO has been classified by the Agency as a B2 carcinogen (probable human
carcinogen).  The cancer slope factor is determined to be 0.15
(mg/kg/day)-1 for forestomach tumors for the oral route of exposure. 
HED has derived an alternative cancer slope factor (Q*) of 0.000086
(mg/kg diet)-1 using a concentration based approach.  Use of an
alternative approach is based on the fact that forestomach tumors in the
rat treated by gavage may be considered a portal of entry response.  By
analogy to the RfC methodology which considers the concentration of test
material to be the most important determinant of response in portal of
entry tumors, PPO dosage can be expressed as a concentration.  The
cancer slope factor for the inhalation route of exposure is 3.5x10-6
(μg/m3)-1 for nasal cavity tumors for the inhalation route of exposure
(USEPA, 1994).  This assessment also discusses MOA data submitted by,
and on behalf of the registrant, which provide the basis for use of an
MOE approach for assessing inhalation cancer risks.  After an initial
analysis, EPA concludes that the MOA proposed by the registrant is quite
plausible, and will review the proposed MOA in more depth, both within
OPP and in conjunction other Agency offices. If the proposed MOA is
accepted by the Agency, propylene oxide will not be regulated using a q*
approach.  Rather an MOE analysis will be conducted.

Propylene chlorohydrin

PCH, a major metabolite identified in spices and nutmeats sterilized
with PPO, was considered separately for dietary risk assessment.  The
database for PCH is inadequate.  PCH exists in two isomers, 1-chloro
2-propanol and 2-chloro-1-propanol.  Most of the toxicity studies are
done with a mixture of isomers containing predominantly
1-chloro-2-propanol.  

There are no guideline studies (acute, subchronic, developmental,
reproduction or chronic toxicity studies) submitted to the Agency.  A
search in the open literature provided a developmental toxicity study
and a few subchronic studies in rats.  These studies lacked sufficient
study details or had deficiencies (poor stability of the test compound,
studies conducted before GLPs were established) which precluded gleaning
any useful information.  However, the subchronic and chronic toxicity
studies in rats and mice and the reproduction toxicity study in rats
conducted by NTP provided minimum information to assess the dietary risk
for PCH. 

The available acute toxicity data indicate PCH as the Category II or III
compound by the oral route and a Category II compound by dermal route
and Category is undetermined for the inhalation route.  Limited data
suggest that PCH is a severe eye irritant but not a skin irritant. 
There are no data available on dermal sensitization effects.

The evidence suggests that PCH is widely distributed in tissues,
metabolized and excreted following inhalation.  Most of the administered
radioactivity appears to be excreted in urine as glutathione conjugates.
 Also, biliary excretion is reported in rats exposed to PCH by
inhalation.  Following oral exposure, PCH is eliminated as a glucuronic
acid conjugate in addition to glutathione conjugate.  

  

Adequate developmental studies are not available.  One reproduction
study in rats found an increased percentage of abnormal sperm at the
same dose which produced body weight changes in dams.  The decreased pup
weights observed at doses which did not produce toxic effects in dams
indicate pups are more sensitive to the toxic effects of PCH compared to
dams.  However, the dose level selected for risk assessment with an
additional database uncertainty factor (10X) to the traditional 100X is
considered to protect any potential increased susceptibility effects in
children.  No neurotoxic effects are evident in the available database
for PCH.  

In subchronic studies in rats and mice PCH produces cytoplasmic
alteration and/or degeneration of acinar cells in the pancreas.  In
addition, atrophy of the bone marrow and spleen and hepatocellular
vacuolization were reported in subchronic studies in rodents and these
effects were not reported in the chronic studies.  The doses used for
the chronic studies are considered inadequate since no endpoints were
established for systemic effects.  

Inductions of mutations in bacteria and chromosomal aberrations as well
as sister chromatid exchange in mammalian cells were reported for PCH.  
 No evidence of carcinogenicity was reported in the chronic studies
conducted with inadequate doses in both rats and mice.

Table 4 and 5 provide the toxicity profile of PPO* and PCH,
respectively.

Table 4a- Acute Toxicity Profile of  PPO

Study/ Species	MRID or Publication	Results	Classification

870.1100

Acute Oral, Rats

Mice

Guinea pigs	

Smyth et al. 1941 and 

Antonova et al., 1981

Antonova et al., 1981

Smyth et al. 1941 Antonova et al., 1981

(As cited in USEPA, 1987)		

LD50 520-1140 mg/kg bw 

LD50 630 mg/kg bw (males)

LD50 660-690 mg/kg bw	

Category III

Category III

Category III

870.1200

Acute Dermal, Rabbits	No study identified



870.1300

Acute Inhalation, Rats 

Mice

 	

NTP, 1985

NTP, 1985

	

LC50(4h): 7697-8265 mg/m3 

(3207-3444 ppm)

LC50(4h): 2420-3540 mg/m3

(1008- 1475 ppm)	

Category IV

Category IV

870.2400

Primary Eye Irritation, Rabbits 	Weil et al., 1963

(As cited in WHO, 1985)	Severe eye irritant	Category I

870.2500

Primary Skin Irritation, Rabbits	Rowe et al., 1956

(As cited in USEPA, 1987)	Severe skin irritant	Category I

870.2600

Dermal Sensitization, Guinea Pigs	No study identified	-	-

870.6200

 Acute Neurotoxicity, Rats	No study identified	-	-



Table 4b:  Subchronic, Chronic Toxicity Studies –PPO

Study/Species	MRID or Publication	Doses 	Results/Classification

Developmental/Reproduction Toxicity

Developmental Toxicity

Fischer 344 Rats

	41750801 	Doses (inhalation): 0, 100, 300, 500 ppm

(GD 6-15)

	Maternal NOAEL: 300 ppm

Maternal LOAEL:  500 ppm 

Decreased body weight gain, food efficiency and food consumption

Developmental NOAEL:  300 ppm

Developmental LOAEL:  500 ppm  

Increased litter incidence of an accessory 7th cervical rib

Acceptable/Guideline

Developmental Toxicity

Sprague-Dawley Rats

	41874102 

	Doses (inhalation): 0, 500 ppm

(GD 7-16, GD1-16, GD1-16 with 3 week pregesational exposure)

	Maternal NOAEL:  <500 ppm

Maternal LOAEL:   500 ppm

Decreased body weight, body weight gain and food consumption 

Developmental NOAEL: <500 ppm

Developmental LOAEL: 500 ppm  

Decreased mean fetal weight, decreased crown rump length in males and
females and possibly increased fetal and litter incidence for the
reduced ossification of the vertebra.

Unacceptable/Guideline

Use of one exposure level, and inadequate data reporting exposure)

Developmental Toxicity, New Zealand White Rabbits	41874102 

	Doses (inhalation) : 0, 500 ppm

GD7-19; GD 1-19 	Maternal NOAEL:  <500 ppm

Maternal LOAEL: 500 ppm

Increased mortality, reduced food consumption, and microscopic changes
in liver (minimal to mild portal mononuclear inflammation), lungs
(minimal to mild portal mononuclear inflammation) and kidneys
(mineralization of proximal and renal tubules, subacute/chronic
nephritis)

Developmental NOAEL:  <500 ppm

Developmental LOAEL: 500 ppm

Increased resorptions, and/or increased incidence of minor skeletal
abnormalities

Unacceptable/Guideline

Study deficiencies included low pregnancy rate, use of one exposure
level, and inadequate data reporting.  Complications by a possible
Pasteurella infection.   

Two-Generation Reproduction Study, Fischer 344 Rats

	45292701

	Doses (inhalation): 0, 30, 100, 300 ppm                                
                                                                        
    	Parental NOAEL: 100 ppm

Parental LOAEL: 300 ppm

Decreased body weights and weight gain in F0 and F1 males during
premating and post mating periods and decreased body weight and weight
gain in F0 and F1 females during premating period

Reproductive NOAEL: 300 ppm 

Reproductive LOAEL: >300 ppm

No reproductive effects at HDT

Offspring NOAEL: 300 ppm

Offspring LOAEL: >300 ppm

No offspring effects at HDT  Acceptable/Guideline

Subchronic  Oral Toxicity

Subchronic Toxicity, Rats, Strain not specified, 26-weeks

	Antonova et al. 1981

(as cited in WHO, 1985)	Doses (drinking water): 0, 0.00052, 0.0052,
0.052, 0.52 mg/kg/day	NOAEL: 0.0052 mg/kg/day 

LOAEL:  0.052 mg/kg/day

Mild hematological abnormalities

Unacceptable/Non-Guideline

Secondary source and information could not be verified

Subchronic

24 days

Females rats

	Rowe et al. 1956

(as cited in USEPA, 1987)	Doses (oral): 0, 100, 200, 300 mg/kg

	NOAEL: 200 mg/kg

LOAEL: 300 mg/kg

Slight decrease in body weight, gastric irritation, and slight liver
damage 

Unacceptable/Non-Guideline

Secondary source and information could not be verified

Subchronic Inhalation Toxicity

Subchronic Neurotoxicity, Fischer 344 male Rats, 24 weeks	45292801

	Doses (inhalation): 0, 30, 100, 300 ppm	NOAEL: 300 ppm

LOAEL: >300 ppm

No systemic and neurological effects at the HDT 

Acceptable/Non-Guideline 

Subchronic Neurotoxicity, Wistar Rats, 7 weeks	Ohnishi et al., 1988

	Doses (inhalation): 0, 1500 ppm	NOAEL: Not Established

LOAEL:  1500 ppm

Awkward gait during third and fourth week of exposure and more ataxia in
all rats by 7th week; histo: axonal degeneration of the hindleg nerve
and fasciculus gracilis and myelinated fibers in the sacral spinal root 

Uncceptable/Non-Guideline Only one dose was tested

Subchronic Toxicity, Fischer 344/N Rats, 12-14 days	NTP, 1985 

	Doses (inhalation):

0, 47, 99, 196, 487, 1433 ppm	NOAEL: 487 ppm

LOAEL:  1433  ppm

Decreased body weight gain, dyspnea, hypoactivity, gasping, ataxia, and
diarrhea were observed at the highest dose; 20% mortality in males
Acceptable/Non-Guideline

Subchronic Toxicity, B6C3F1Mice, 12-14 days

	NTP, 1985

 	Doses (inhalation):

0, 20, 47, 99, 196, 487 ppm 	NOAEL: 99 ppm 

LOAEL:  196 ppm

Dyspnea 

Acceptable/Non-Guideline



Subchronic Toxicity, Fischer 344/N Rats, 13 weeks

	NTP, 1985

	Doses (inhalation):

0, 31, 63, 125, 250, 500 ppm	NOAEL: 500 ppm

LOAEL:  Not established

Acceptable/Non-Guideline



Subchronic Toxicity, B6C3F1Mice, 13 weeks

	NTP, 1985

	Doses (inhalation):

0, 31, 63, 125, 250, 500 ppm	NOAEL: 250 ppm 

LOAEL:  500 ppm

Decreased body weight (12.9% in males and 14.6% in females)

Acceptable/Non-Guideline



Chronic Oral Toxicity

870.4100

Chronic Toxicity- Female Sprague-Dawley Rats

2 years	Dunkelberg, 1982

	Doses (oral): 0, 0(salad oil), 15 or 60 mg/kg by

Gavage

	NOAEL: Not Established 

LOAEL: 15 mg/kg/day

Based on hyperkeratosis, hyperplasia and papillomas

Combined incidences of hyperkeratosis, hyperplasia and papillomas were
0/50, 7/50, and 17/50

Forestomach tumors-primarily squamous cell carcinoma –incidence: 0/50
for both controls, 2/50, and 19/50 for low and high dose groups. 
Highest dose also had one adenocarcinoma of the pylorus and carcinoma in
situ of the forestomach

Acceptable/Non-Guideline

Chronic Inhalation Toxicity

870.4300

Combined/

Chronic Toxicity/ Carcinogenicity Study, Wistar Rats

123 weeks (Females)

124 weeks (Males)	Kuper et al. 1988

and 42039901

	Doses  (inhalation): 0, 30, 100 or 300 ppm

	Systemic NOAEL: 30 ppm

Systemic LOAEL: 100 ppm 

BMD/BMDL10:140/120 ppm (moderate to marked effects)

Increased incidences for basal cell hyperplasia, and nest-like infolds
of the respiratory epithelium

Cancer Effects

No statistically significant nasal tumors in nasal cavity.  However, 3
malignant tumors in nasal cavity were reported in males (one tumor of
ameloblastic fibrosarcoma in low dose male, one squamous cell carcinoma
in a low dose male and in a high dose male).  Four males in the HDT had
a carcinoma in the larynx or pharynx, trachea or lungs.  Controls had no
nasal tumors.  

Incidences of fibroadenomas of the mammary gland tumors are: 32/69(46%),
30/71(42%), 39/69(57%), 47/70 (67%) in control, low, mid and high dose
groups respectively; significant at high dose (p<0.04).  Historical
control incidence of benign tumors in the mammary gland in the lab
ranges 19-61%.

Incidences of tubulopapillary adenocarcinoma:  3/69, 6/71, 5/69 8/70
(p<0.01) 70 in control, low, mid and high dose groups respectively. 
Historical control incidence of malignant tumors in the mammary gland in
the lab ranges 0-15%. Acceptable/Guideline  Study 

870.4300

Combined

Chronic Toxicity/ Carcinogenicity

Male F344 Rats, 104 weeks	Lynch et al. 1984

	Doses (inhalation): 0, 100, 300 ppm	Systemic NOAEL: Not Established 

Systemic LOAEL: 100 ppm  

Decreased body weight, increased hemoglobin, organ weights and extra
thoracic (nasal suppurative rhinitis) effects.

Cancer Effects

Adrenal pheochromocytoma at both doses (8/78, 25/78, 22/80 in control,
low and high dose groups, p<0.05)

870.4300

Combined

Chronic Toxicity/ Carcinogenicity

F344 Rats, 103 weeks	NTP, 1985	Doses (inhalation): 0, 200, 400 ppm

	Systemic NOAEL: Not Established 

Systemic LOAEL: 200 ppm 

extra thoracic respiratory effects

Cancer Effects

At 400 ppm, 2/50 (m) and 3/50 (f) had papillary adenomas of the
respiratory epithelium and submucosal glands of the nasal turbinates
compared to none in low and control groups.  

An increase in the thyroid C-cell adenomas and carcinomas occurred at
400 ppm.   In females the combined incidences of C-cell adenomas and
carcinomas of the thyroid were 2/45, 2/35, 7/37 (p=0.023).  

NTP concluded that this tumor type does not provide unequivocal evidence
of carcinogenicity for PPO in rats.  Acceptable/Non-Guideline   

870.4200

Combined Chronic Toxicity/

Carcinogenicity

B6C3F1Mice, 103 weeks	NTP, 1985

	Doses (inhalation): ppm

0, 200, 400 ppm	Systemic NOAEL: Not established

Systemic LOAEL: 200 ppm 

extrathoracic respiratory effects

HDT had decreased survival in males and females, decreased body weights
in both sexes, sporadic  metaplasia and hyperplasia and chronic
inflammation in the nasal cavity. 

Cancer Effects

Nasal cavity:  The combined incidences of hemangiomas and
hemangiosarcomas in the nasal cavity were: males-0/50, 0/50, 10/50,
p<0.001; females- 0/50, 0/50, 5/50, p=0.028)

one squamous cell carcinoma and one papilloma were induced in nasal
cavity at high dose (1 male each, not significant),  adenocarcinomas in
nasal cavity ( 2 females, not significant)

NTP concluded as clear evidence of carcinogenicity for PPO in mice. 
Acceptable/Non-Guideline

870.4100

Chronic Toxicity- cynomolgus Monkeys

2 years

	Sprinz et al. 1982 (As cited in EPA, 1994) and Setzer at al. 1996	Doses
(inhalation): 0, 100 or 300 ppm	NOAEL: Not established 

LOAEL: 100 ppm

Increased incidence for axonal dystrophy in the medulla oblongata and in
the most distal portions of the fasciculus gracilus in all treated
monkeys (2/2 in each PPO group) as compared to one (1/2) in controls. 
No dose related lesions between the treatments. Acceptable/Non-Guideline
Study

Subchronic Dermal Toxicity

21-Day Dermal Toxicity (Rats)	No Study identified

Dermal Absorption	No Study identified



Metabolism

	WHO, 1985	  -	-No data on absorption of propylene oxide.  

-Two metabolic pathways suggested: 1) conjugation with glutathione via
glutathione epoxide transferase 2) hydrolysis by epoxide hydrolase to
1,2 propanediol (propylene glycol).   Propanediol can be excreted as
such or metabolized to lactic and pyruvic acid

-Propylene oxide is a direct alkylating agent.  Forms DNA
(N-2-hydroxypropyl-guanosine, N-2-hydroxypropyl-guanosine) and protein
adducts (hemoglobin alkylation at the cysteine, histidine or valine)
residues.

-Assuming a 100% alveolar absorption and first-order kinetics, a
half-life of 40 minutes was estimated for the elimination of PPO in rats


Under in vitro conditions, the half-life of propylene oxide in stomach
(pH1 and 37°C) is reported approximately one minute.

Mutation/Genotoxicity

	Multiple references as cited in IARC, 1994	-	Mutagenic in bacteria,
fungi and insects; caused DNA damage in rat hepatocytes in vitro; caused
chromosomal aberrations in vitro in mammalian cells; however, no
increase in chromosomal aberrations of peripheral lymphocytes of male
cynomolgus monkeys after long term exposure in vivo (up to 300 ppm for 2
years), inconsistent results in micronuclei formation in mice
erythrocytes in vivo, negative results for dominant lethal assays in
rats and mice. 

*1 ppm = 2.4 mg/m3 or 1 mg/m3 = 0.42 ppm

Table 5a: †Acute Toxicity of Propylene Chlorohydrin
(1-chloro-2-propanol,  2-chloro-1-propanol)

Study/ Species	MRID or Publication	Results	Classification

870.1100

Acute Oral, Rats

Mouse

Guinea pigs

Dogs	

Smyth et al., 1941, US FDA, 1969 

Weisbrod, 1981

Smyth et al., 1941

FDA, 1969

(as cited in TNO BIBRA International, 1994)	

Oral LD50 =   220 mg/kg

Oral LD50 =   580 mg/kg

Oral LD50 =   720 mg/kg

At 200 mg/kg one of seven dogs died while 250 mg/kg or above was lethal
to all six treated dogs	

Category  II

Category  III

Category  III



870.1200

Acute Dermal, Rabbits	

Smyth et al., 1969

Weisbrod, 1981

(as cited in TNO BIBRA International, 1994)	

LD50 =      528 mg/kg

LD50 =      440 mg/kg	

Category II 

Category II



870.1300

Acute Inhalation, Rats

	

Smyth and Carpenter, 1969

(as cited in NTP, 1998)	

LC50 =   Not Determined

Inhalation of 500 ppm (1.94 mg/L) PPO resulted in death of  1/6 animals
after 4 hours.	

Category Undetermined

870.2400

Primary Eye Irritation, Rabbits 	

Carpenter and Smyth et al. 1946?)

(as cited in NTP, 1998)	

Severe injury to the rabbit cornea  following instillation of 0.005 ml
propylene chlorohydrin	-

870.2500

Primary Skin Irritation,

Rabbits	

Smyth et al 1969

(as cited in TNO BIBRA International, 1994)	

Limited data-No irritation 24 hr following application of 0.01 ml
propylene chlorohydrin in a rabbit	-

870.2600

Dermal Sensitization,

Guinea pig	No study identified	-	-

870.6200

Acute Neurotoxicity, Rats	

No study identified	

-	

-

† Note:  The strain of the animals used and type of PCH isomer used in
acute tests are not specified.

Table 5b:  Subchronic, Chronic Toxicity Studies - Propylene Chlorohydrin
(1-chloro-2-propanol,  2-chloro-1-propanol)

Study/Species	MRID or Publication	Doses	Results/Classification

Developmental/Reproduction Toxicity

870.3700

Developmental Toxicity

Rats (Strain not specified)

	Exxon Chemical Company, 1980

(as cited in NTP, 1998)

	Doses: 8, 20, 50 or 125 mg/kg

GD 6-15 (gavage)	Maternal NOAEL/LOAEL:   Could not be determined

Developmental NOAEL/LOAEL: Could not be determined 

Maternal effects:  Slight decrease in embryo survival in the 8 and 125
mg/kg groups

Developmental effects:  Two fetuses showed gross malformation (dose not
specified) 

Unacceptable/Non-Guideline 

Data could not be verified; secondary source of information

870.3700

Developmental Toxicity Rabbits	No study identified

870.3800

Two-Generation Reproduction Study, Rats	NTP, 1998	Doses: 0, 300, 650,
1300 ppm in drinking water

(equivalent to 0, 30, 65, 130, mg/kg/day; determined assuming 30 ml as
daily water consumption and average body weight of dams as 0.3 kg)
Parental NOAEL:65 mg/kg/day 

Parental LOAEL: 130 mg/kg/day

 Decreased body weight of F0 dams during gestation and lactation, and F1
dams during gestation

Reproductive NOAEL: Not determined

Reproductive LOAEL: 130 mg/kg/day 

Increased percentage of abnormal sperm

Offspring NOAEL: 30 mg/kg/day

Offspring LOAEL: 65 mg/kg/day

Decreased F1 male and female pup weights at PND 14 and 21

Acceptable/Non-Guideline 

Subchronic Oral Toxicity

Subchronic (22 weeks)

Rats 

	USFDA, 1969

(as cited in TNO BIBRA Internation

al, 1994)	Doses: 0, 25, 50 or 75  mg/kg/day; Another group with 100-250
mg/kg/day

Gavage	NOAEL: <25 mg/kg/day

LOAEL: 25 mg/kg/day

Increased liver weight in males

100% mortality at 250 mg/kg/day within 3 weeks.

Unacceptable/Non-Guideline

Secondary reference and information could not be verified.

Subchronic (25 weeks)

Rats 

	USFDA, 1969

(as cited in TNO BIBRA Inter

national, 1994)	Doses: 0, 1000, 2500, 5000 or 10000 ppm in diet
(estimated as 0, 100, 250, 500, 1000 mg/kg/day)	NOAEL: 250 mg/kg/day

LOAEL: 500 mg/kg/day

Decreased body weight

Unacceptable/Non-Guideline

Secondary reference and information could not be verified.



Subchronic (14 days)

 F344 Rats	NTP, 1998

	Doses: 0, 100, 330, 1000, 3300, 10,000 ppm in drinking water

(determined by study authors as 0,  15, 45, 140, 260, 265 mg/kg/day)
NOAEL:  45 mg/kg/day

LOAEL:  140 mg/kg/day

cytoplasmic alteration and degeneration of the acinar cells in the
pancreas and atrophy of the bone marrow in females 

Acceptable/Non-Guideline

Subchronic (14 days), B6C3F1 mice

	NTP, 1998

	Doses: 0, 100, 330, 1000, 3300, 10,000 ppm in drinking water

(determined by study authors as 0, 20, 60, 175, 430, or 630 mg/kg/day in
males and 0, 25, 95, 290, 640, or 940 mg/kg/day in females) 	NOAEL: 60
mg/kg/day 

LOAEL: 175 mg/kg/day 

Increased liver weight relative to body weight in females and increased
vacuolization of cytoplasm of hepatocytes in both males and females

Acceptable/Non-Guideline 



Subchronic (14 week)

F344 Rats 	NTP, 1998	Doses: 0, 33, 100, 330, 1000, 3300 ppm in drinking
water

(determined by study authors as 0, 5, 10, 35, 100, 220 mg/kg/day)	NOAEL:
35 mg/kg/day 

LOAEL:  100 mg/kg/day 

Increased incidences of the acinar cell degeneration, and fatty change
of the pancreas in males and females.

Acceptable/Non-Guideline 

Subchronic (14 week)

B6C3F1 mice	NTP, 1998	Doses: 0, 33, 100, 330, 1000, 3300 ppm in drinking
water

(determined by study authors as 5, 15, 50, 170, 340  mg/kg/day in males
and 7, 20, 70, 260 or 420 mg/kg in females)	NOAEL: 50 mg/kg/day 

LOAEL: 170 mg/kg/day 

Increased organ weights and increased incidence of renal tubule
vacuolization in males

Acceptable/Non-Guideline 

Subchronic Dermal Toxicity

Subchronic (21 days or 13 week)	No study identified

Combined Chronic Carcinogenicity

870.4300

Chronic (2 years)

F344 Rats 	NTP, 1998	Doses:  0, 150, 325, or 650 ppm 

in drinking water

(determined by study authors as 0, 15, 30, or 65 mg/kg/day during
beginning months and 0, 8, 17, or 34 mg/kg/day during remainder months) 
	NOAEL: 65 mg/kg/day (HDT)

LOAEL:  Not established

No treatment related cancer or non-cancer effects.

Acceptable/Non-Guideline 



870.4300

Chronic (2 years)

B6C3F1 mice	NTP, 1998	Doses: 0, 250, 500 or 1000 ppm in drinking water

(determined by study authors as 0, 45, 75, or 150 

mg/kg/day in males and 0, 60, 105, or 210 mg/kg/day in females during
first few months and 0, 25, 50, or 100 mg/kg/day for remainder of the
study)	NOAEL: 210 mg/kg/day 

LOAEL: Not established

No effects at any of the doses tested.

No evidence of carcinogenicity.

Acceptable/Non-Guideline 



Mutation/Genotoxicity

	Multiple references (as cited in NTP, 1998)	-	-Weakly mutagenic in
TA100 in the presence of S9

Positive in TA1535 with or without S9.

-No mutagenic activity in TA97, TA98, and TA1537 with or without S9
extract.

-CHO cells- caused high levels of chromatid exchanges and chromosomal
aberration in the presence or absence of S9 extract.  

-No chromosomal aberrations in vivo.  

-Induced sex-linked recessive lethal mutations in Drosophila in
injection but not by feed 

-Negative for germ cell reciprocal translocation in Drosophila

-Negative for micronuclei formation in vivo in mice

Metabolism

	Multiple references (as cited in NTP, 1998)	-	Absorption: No data

Metabolism: Following inhalation, PCH was widely distributed to tissues,
rapidly metabolized and eliminated.

Excretion: Following oral administration of propylene chlorohydrin in
rabbits 11% was excreted in urine as glucuronic acid conjugate.  In rats
dosed orally with PCH the metabolites, 2-hydroxy propylmercapturic acid
(N-acetyl-S-(2-hydroxy propyl)-cysteine) and beta-choloroacetate were
identified in urine.  In rats administered with PCH by inhalation most
of the radioactivity (80%) was excreted in urine and in the expired air.
 Half-lives for elimination were 4 hours for breath and 5 hours for
urine.  Also, biliary excretion was reported as another major route of
elimination (30% of inhaled dose) for PCH administered by inhalation. 
Metabolites related to glutathione conjugates, N-acetyl-S-(2-hydroxy
propyl)-cysteine and/or S-(2-hydroxy propyl)-cysteine were identified in
both liver and urine.               



4.2	FQPA Hazard Considerations

4.2.1	  Adequacy of the Toxicity Database

	

4.2.1.1	  Propylene Oxide

The toxicology database for PPO is considered incomplete.  The database
includes acceptable developmental toxicity and reproduction toxicity,
subchronic neurotoxicity (non-guideline), and chronic carcinogenicity in
rats, all conducted via inhalation.  There is no acceptable
developmental study in rabbits.  Also, the database lacks a chronic
toxicity study in non rodents.  In addition, there is a published study
examining the carcinogenicity effects of PPO by the oral route.  This
chronic toxicity study via the oral route is inadequate since one sex
alone was examined.  Moreover, adequate systemic effects were not
measured, and pathological examination of tissues is not complete.  This
study was the only chronic toxicity study available for the oral route
and was considered for risk assessment.

		4.2.1.2	  Propylene Chlorohydrin

The database for PCH is inadequate.  There are no guideline studies
(acute battery of tests, subchronic, developmental, reproduction or
chronic toxicity studies) submitted to the Agency.  A search in the open
literature provided information on reproductive toxicity and subchronic
and chronic toxicities.  One rat developmental toxicity study identified
in the literature lacked sufficient study details to glean any useful
information.  A few subchronic oral toxicity studies in rats identified
in the literature had deficiencies such as poor stability of the test
compound, and were conducted before GLPs were established.  However, the
subchronic and chronic toxicity studies in rats and mice and the
reproduction toxicity study in rats conducted by NTP provided sufficient
information to assess the dietary risk for PCH. The lack of acceptable
developmental toxicity studies limited the ability to assess the fetal
susceptibility effects under FQPA.   

4.2.2	Evidence of Neurotoxicity

4.2.2.1	  Propylene Oxide

  SEQ CHAPTER \h \r 1 In a subchronic inhalation neurotoxicity study
(MRID 45292801), Fisher-344 male rats exposed to 0, 30, 100, or 300 ppm
of propylene oxide (>99% active ingredient) for 6 hr/day, 5 days/week
for the first 14 weeks and 7 days/week for the remainder of the study up
to 24 weeks.  No treatment-related mortalities or clinical signs of
toxicity were reported.  No treatment-related changes in body weight,
FOB or motor activity or hind limb strength were seen.  No
treatment-related abnormalities were observed during handling and no
gait or locomotor abnormalities were noted in the open field.  Reflex
and sensorimotor responses were similar between the treated and control
groups.  No gross necropsy and neuropathology were observed.  

This study is classified as Acceptable/Non-Guideline and does not
satisfy the requirements for a subchronic inhalation neurotoxicity study
[OPPTS 870.6200 (§82-7)] in rats.  The LOAEL for neurotoxic effects is
not established.  Validation of the laboratory neurotoxicity testing
methods was not included and females were not tested.  However, the
study is sufficient for the purposes for which it was intended to assess
the potential of propylene oxide to induce neurotoxicity in male rats
following subchronic inhalation exposure.

Studies from the Open Literature

Wistar rats were exposed to 1500 ppm propylene oxide for 6 hours/day, 5
days/week for 7 weeks (Ohnishi et al., 1988). Awkward gait was apparent
in exposed rats by the third to fourth week of exposure and all rats
exhibited obvious ataxia by the seventh week. Histopathological
examination revealed axonal degeneration of the hindleg nerve and
fasciculus gracilis myelinated fibers, and myelinated fibers in the
sacral spinal root. The LOAEL for this study was determined as 1500 ppm,
the only dose tested.  This study is classified as
Unacceptable-Non-Guideline.

Sprinz et al. (1982; as cited in US EPA, 1994) treated male cynomolgus
monkeys (2/group) at 0, 100, or 300 ppm propylene oxide, 7h/day, 5
days/week for 2 years.  Nerve conduction velocity was measured
throughout the exposure and at the termination of exposure; sections of
peripheral nerves, spinal cord, and brain (19 regions) were examined. No
exposure-related changes were observed in the peripheral nerves or the
spinal cord. Axonal dystrophy was observed in the medulla oblongata and
in the most distal portions of the fasciculus gracilus in one control
monkey and in all four exposed monkeys. The extent of the lesion was
similar in all affected monkeys and was not dose-related.  These
findings are also reported in the publication by Setzer et al. (1996). 
This study is classified as Acceptable-Non-Guideline.

	4.2.2.2	  Propylene Chlorohydrin

	

There are no neurotoxicity studies available for PCH.  Clinical signs of
neurotoxicity are not evident in the available database.   

	4.2.3	Developmental Toxicity Studies 

4.2.3.1	  Propylene Oxide

Rats

Study1

In an inhalation developmental toxicity study (MRID 41750801), 25
pregnant Fischer 344 rats per group were administered propylene oxide
(>99% a.i.; Lot : IRDC Nos. 8863C and 8863D) by whole body exposure to
atmospheric concentrations of 0, 100, 300, or 500 ppm for 6 hours/day on
gestation days (GD) 6-15, inclusive.  On GD 20, dams were sacrificed,
subjected to gross necropsy, and all fetuses examined externally. 
One-half of the fetuses were examined viscerally, and the remaining
fetuses were examined for skeletal malformations/variations. 

All animals survived to scheduled sacrifice.  No treatment-related
clinical signs of toxicity were observed in any treated animals during
the study, nor were any treatment-related gross abnormalities observed
at maternal necropsy.  Maternal toxicity in the 500 ppm exposure group
was evidenced by statistically significant decreases (p < 0.05; 0.01) in
body weight gain (40% of control on GD 6-15), and food consumption
(88-91% of controls during the various exposure intervals).  In
addition, food efficiency was substantially decreased during the
exposure interval, GD6-16 (45% of controls), further indicating maternal
toxicity.  Absolute body weights in the 500 ppm group showed
statistically significant decreases (p < 0.01), but these values
represented only 95-96% of control values.  No treatment-related
differences in body weight, body weight gain, or food consumption were
observed in animals exposed to 300 ppm propylene oxide or less.

Therefore, the maternal toxicity LOAEL is 500 ppm based on decreased
body weight gains, food efficiency and food consumption and the maternal
toxicity NOAEL is 300 ppm.

There were no differences between treated and control groups for number
of corpora lutea/dam, implantation sites/dam, pre- or post-implantation
loss, resorptions/dam, fetuses/litter, fetal sex ratios, gravid uterine
or fetal body weights, or number of dead fetuses.

There were no statistically significant or treatment-related differences
between control and treated groups regarding the number of external,
soft-tissue, or skeletal  malformations/variations with the exception of
an increased litter incidence of an accessory 7th cervical rib in the
500 ppm group compared to the controls (p < 0.01) (2/17, 4/20, 3/22, and
11/21 for 0, 100, 300 or 500 ppm groups, respectively).

Therefore, the developmental toxicity LOAEL is 500 ppm based on an
increased litter incidence of an accessory cervical rib and the
developmental toxicity NOAEL is 300 ppm. 

This study is classified as Acceptable-Guideline and satisfies the
requirement for an inhalation developmental toxicity study in rats
(§83-3; OPPTS 870.3700).

COMPLIANCE: Signed and dated Quality Assurance, Good Laboratory Practice
Statements, Data Confidentiality and Flagging statements were included.

Study 2

In a developmental toxicity NIOSH sponsored study (MRID 41874102),
Sprague-Dawley rats were whole-body exposed to filtered air (groups 1-3,
170 rats) or 500 ppm propylene oxide (99% a.i.; group 4 = 50 rats)
for 7 hours/day by inhalation for a 3 week pregestation (pregestation
day = PGD) period.  Following this exposure interval, the group 1-3
animals were reallocated (45-48/exposure interval) and were exposed
according to one of the following regimes: i) control group received
filtered air from gestation days (GDs) 1-16; ii) group 2 received
filtered air from GDs 1-6 and test chemical from GDs 7-16; and iii)
group 3 received the test chemical from GDs 1-16.  Group 4 continued to
receive the test chemical from GDs 1-16 (in addition to the 3 week
pregestational exposure).  All dams were sacrificed on GD 21.  No
unscheduled deaths were reported.  

0.05) were observed in group 4 body weights from GDs 6-21
(10-12%).  Overall gestation body weight gain (GD 1-21), as
calculated by reviewers and not analyzed for statistical significance,
was reduced in all treated groups when compared to controls (group 2,
18%; group 3, 13%; group 4, 16%).  Further, overall study body
weight gain (PGD 3-GD 21) was reduced in all treated groups when
compared to controls (group 2, 17%; group 3, 12%; group 4, 27%,
calculated by reviewers).

When compared to concurrent controls, variations (p0.05) in absolute
(g/rat/day) food consumption were observed in groups 2, 3, and 4,
respectively, as follows: during pregestation week 2 (1, 1, and
14%); GDs 7-11 (33, 29, and 29%); GDs 12-16 (14, 15,
8%); and GDs 17-21 (12, 18, and 2%). 

It was unconfirmed on page 10 of the evaluative summary of the study
report that the animals were checked daily for clinical signs of
toxicity; the study report does not indicate that nor any clinical signs
data were provided.  No gross pathology data were provided.  No
treatment-related changes in organ weight or histopathological findings
were noted at any exposure interval tested.  Percent pre- and
post-implantation losses were not reported and could not be calculated
by reviewers due to the lack of total numbers of corpora lutea and
implantation sites.  

The maternal LOAEL is 500 ppm (only dose selected) on PGD 3-GD 21, based
on decreased body weight, body weight gains, and food consumption.  

Developmental effects were significant (p<0.05) decrease in mean fetal
weights and decrease in crown-rump lengths in males and females at all
exposure regimens in comparison to concurrent controls.  The fetal as
well as the litter incidence for the reduced ossification of the
vertebra was significant (p<0.01) compared to controls in dams exposed
to propylene oxide during GD1-16.

The developmental LOAEL based on the decreased mean fetal weights and
crown-rump length in males and females and possibly reduced ossification
of the vertebra is 500 ppm (only dose selected).

Study deficiencies included possible dermal absorption due to whole body
exposure, use of one exposure level, inadequate data reporting and
animal husbandry and no historical control data.  Individual animal data
were not reported.   Therefore, this developmental toxicity study is
classified as Unacceptable/Guideline and does not satisfy the guideline
requirement for a developmental toxicity study in the rat.  An
acceptable rat developmental study (MRID 41750801) for inhalation of
propylene oxide does exist.  

COMPLIANCE:  Signed and dated GLP, Data Confidentiality, Flagging, and
Quality Assurance statements were provided.

 

Rabbits

99% a.i.) for 7 hours/day by inhalation according to one of the
following regimes: i) control group received filtered air from gestation
days (GDs) 1-19; ii) group 2 received filtered air from GDs 1-6 and test
chemical from GDs 7-19; and iii) group 3 received the test chemical from
GDs 1-19.  All does received filtered air from GDs 20-29 and were
sacrificed on GD 30.  All control animals survived to scheduled
sacrifice.  

In group 2, four rabbits died of pneumonia on GDs 19, 23, or 26. 
Decreases (p0.05) in absolute (g/rabbit/day) food consumption were
observed during GDs 11-15 (11%) and GDs 16-20 (13%).  Regarding
histopathological findings, the following minimal to mild findings were
observed: portal mononuclear inflammation in the liver in 10/26 animals
vs. 8/30 controls; subacute/chronic nephritis in 9/26 animals vs. 3/30
controls; and focal mononuclear inflammation of the lung in 11/26
animals vs. 5/30 controls.  

34%, GDs 1-30) as was the gravid uterine weight (19%) when
compared to the controls; both were calculated by reviewers and not
analyzed for statistical significance.  Decreases (p0.05) in absolute
food consumption were observed during GDs 11-15 (38%) and GDs 16-20
(21%); additionally, food consumption in group 3 was different
(p0.05) from group 2 during GDs 1-5 (22%) and GDs 11-15 (30%). 
The following minimal to mild findings were observed: portal mononuclear
inflammation in the liver in 11/26 animals vs. 8/30 controls;
mineralization of the proximal and distal renal tubules in 10/26 animals
vs. 7/30 controls; subacute/chronic nephritis in 10/26 animals vs. 3/30
controls; and focal mononuclear inflammation of the lung in 10/26
animals vs. 5/30 controls. 

It was unconfirmed on page 10 of the evaluative summary of the study
report that the animals were checked daily for clinical signs of
toxicity; however, no clinical signs data were provided.  No
treatment-related differences in maternal body weights or organ weights
(absolute and relative to body) were observed.  No gross pathology data
were provided.  An insufficient number of females (< 20 females) with
implantation sites at necropsy in the control and group 2 (17 and 14
animals, respectively) and low pregnancy rates in all groups (47-67%)
were observed.  The number of implantations/doe, percent male, and fetal
weights were similar between control and treated groups.  Percent pre-
and postimplantation losses were not reported and could not be
calculated by reviewers due to the lack of total numbers of corpora
lutea and implantation sites. 

123%), number of early resorptions/doe (250%), and number of late
resorptions/doe (34%) were observed.  The following minor skeletal
abnormalities were observed in the group 3 fetuses [% fetal incidence (%
litter incidence)]: misaligned sternebrae [4.2 (23.5)]; fused sternebrae
[2.5 (17.6)]; and forelimb flexures [2.5 (17.6)].  None of these
findings were observed in the control animals.  Bipartite sternebrae was
observed in the group 3 fetuses [2.5 (17.6)] vs. controls [0.79 (6.7)].

The developmental LOAEL is 500 ppm (only dose tested) on GDs 7-19, based
on increased resorptions and increased incidence of minor skeletal
abnormalities.  

Study deficiencies included low pregnancy rate, possible dermal
absorption due to whole body exposure, use of one exposure level,
inadequate data reporting and animal husbandry and no historical control
data.  Individual animal data was not reported.  Further, the results of
the study were complicated by a possible Pasteurella infection.   

Therefore, this developmental toxicity study is classified as
Unacceptable/Non-Guideline and does not satisfy the guideline
requirement for a developmental toxicity study in the rabbit. 

COMPLIANCE:  Signed and dated GLP, Data Confidentiality, Flagging, and
Quality Assurance statements were provided.

	4.2.3.2   Propylene Chlorohydrin

Rats

There is no guideline developmental toxicity study conducted using rats.
 However, there is minimal information found from one rat developmental
study was identified from the open literature.    

Exxon Chemical Company, 1980 (as cited in NTP, 1998)

In the developmental study, rats (strain unspecified) were gavaged with
PCH at 8, 20, 50 or 125 mg/kg during GD6-15.  There was a slight
decrease in the embryo survival in the 8 and 125 mg/kg groups. Two
fetuses showed gross malformation at unspecified doses.  No information
on controls provided.

This study is classified as Unacceptable/Non-Guideline Study and does
not satisfy the requirement for a developmental toxicity study in rats
(§83-3, OPPTS 870.3700).

Rabbits

There is no guideline developmental toxicity study available for
rabbits.

  

	4.2.4	Reproduction Toxicity Studies 

4.2.4.1	Propylene Oxide

In a two-generation reproduction study (MRID 45292701), propylene oxide
(30215 III, >99%, a.i.) vapor was administered to groups of 30 male and
30 female F0 and F1 Fischer 344 rats by inhalation at chamber
concentrations of 0, 30, 100, or 300 ppm.  Each group was exposed to
room air (controls) or propylene oxide vapor for 6 hours/day,
5 days/week for 14 weeks (F0) or 17 weeks (F1) during the premating
period and for 6 hour/day, 7 days/week during the mating, gestation,
and lactation periods.  The F1 pups selected to parent the F2 generation
were exposed to room air or the same concentrations of propylene oxide
vapor as their parents.

0.05) and 7-18% (p0.05), respectively, less than controls for
almost all the study including the premating and post mating periods. 
Both generations gained 13% less weight than controls during the entire
study duration.  F0 males exposed to 30 and 100 ppm and F1 males exposed
to 30 ppm weighed significantly less (3-7%) than controls during the
study, but these small differences are not considered toxicologically
significant.  F0 females in the 300-ppm group weighed 3-6% (p0.05)
less than controls and F1 females weighed 7-10% (p0.05) less than
controls during the premating period; weight gain was 12% and 18% less
than controls for the F0 and F1 generations, respectively.  No
toxicologically significant effect was observed on body weights of F0 or
F1 females exposed to any concentration of propylene oxide during the
gestation or lactation periods; statistically significant differences
were observed at 300 ppm but did not exceed 8% during gestation and 9%
during lactation periods.

Exposure to concentrations up to 300 ppm had no exposure-related effect
on reproductive performance (mating, fertility or gestation indices) of
the adults or on offspring parameters [clinical signs, mean liter size
at any time during lactation, survival indices (live birth, viability,
or lactation), pup weights or gross and microscopic findings in
weanlings].

  SEQ CHAPTER \h \r 1 The parental systemic LOAEL is 300 ppm, based on
decreased body weights and weight gain in F0 and F1 males during
premating and post mating periods and decreased body weights and weight
gain in F0 and F1 females during premating period.  The parental NOAEL
is 100 ppm.  

  SEQ CHAPTER \h \r 1 The reproductive NOAEL is 300 ppm, HDT.  The
reproductive LOAEL is not established.  

  SEQ CHAPTER \h \r 1 The offspring NOAEL is 300 ppm, HDT.  The
offspring LOAEL is not established.

The animals were adequately exposed to assess the reproductive toxicity
of propylene oxide based on reduced body weights of adult males and
females in the F1 generation.  Estrous cycle, sexual maturation, and
sperm parameters were not evaluated in this study.  However, other
reproductive parameters were not affected by exposure to propylene
oxide. 

 

The reproductive study in the rat is classified as Acceptable/Guideline
and does satisfy the guideline requirement for a two-generation
reproductive study [OPPTS 870.3800, (§83-4)] in the rat.  Deficiencies
were noted but they did not impact the overall evaluation of this study.

COMPLIANCE: A signed and dated Quality Assurance was provided; GLP, Data
Confidentiality, and Flagging statements were not provided.

4.2.4.2	  Propylene Chlorohydrin

In a two-generation reproduction study (NTP, 1998), PCH (approximately
75% 1-chloro-2-propanol and 25% 2-chloro-1-propanol) was administered to
Sprague-Dawley rats (20/sex/group except controls 40/sex) at 0, 300, 650
and 1300 ppm in drinking water.  Assuming 30 ml as daily drinking water
consumption, and the average body weight as 0.3 kg, the daily intake
values were estimated as 0, 30, 65 and 130 mg/kg/day respectively.  F0
adults were continued for five litters and the last litter was selected
for F1 adults.  For F2 generation, control and high dose animals from F1
parents alone were treated and continued for one litter.  Clinical
observations, water consumption, pregnancy index, litters per pair,
cumulative number of days to litter, dam body weights, live pups per
litter, proportion of pups born alive, sex of live pups, and pup body
weights were recorded. Also, selected organ weights, epididymal
spermatozoal measurements and estrous cycle parameters were measured.

 those of the controls (p<0.05; ↓4-8% for MDT and p<0.01; ↓10-15%
for HDT).  Mean body weights of litter 5 F0 dams in the MDT were
significantly less than those of the controls from lactation days 0 to
14 (p<0.05; ↓4-8%), and the mean body weights of F0 dams in the HDT
were significantly less than those of the controls throughout lactation,
PND 0 to 21 (p<0.05; ↓15-16%).  The body weight changes in F0 dams of
MDT although statistically significant, was not considered biologically
significant (<10% decrease).  The mean body weight of F1 dams of 1300
ppm, only dose tested, were significantly less (p<0.01; ↓17%) at
delivery, compared to controls.    

Mating, fertility and pregnancy indices in the 1-chloro-2-propanol
treated groups were similar to controls.  The average numbers of litters
per pair of all exposed groups were not affected as compared to
controls.  The cumulative days to deliver were slightly higher in the
HDT as compared to controls (116.7 days in controls to 118.7 days in
HDT) for litter 5 but this was not affected in the other four litters. 
The days to litter in F1 dams were not affected.  

The survival of the final litters of exposed F1 pups was similar to that
of the controls throughout lactation. Male and female F1 pup weights of
HDT were significantly less than those of the controls on days 7, 14,
and 21 (p<0.05; ↓10-23%) and of MDT on days 14 and 21 (p<0.05;
↓7-34%).  The organ weights of the F1 rats at HDT were similar to
controls.  The percentage of abnormal sperm was significantly greater in
F1 male rats of HDT compared to controls (↑210%; 0.78±0.11 in
controls vs. 2.4±0.53 in HDT, p<0.05).  There were no significant
differences in estrous cycle parameters between control and F1 females
of HDT.  The effects on sperm abnormalities and other reproductive
measures at doses below HDT were not determined.  Exposure of F1 adults
to HDT did not affect the sex ratio, or pup or organ weights. 

  SEQ CHAPTER \h \r 1 The parental systemic LOAEL is 1300 ppm (130
mg/kg/day), based on decreased body weights of F0 dams during delivery
and lactation and F1 dams during delivery.  The parental NOAEL is 650
ppm (65 mg/kg/day).  

  SEQ CHAPTER \h \r 1 The reproductive LOAEL is 1300 ppm (130 mg/kg/day)
based on increased percentage of abnormal sperm in F1 rats.  The
reproductive NOAEL is not established.

  SEQ CHAPTER \h \r 1 The offspring LOAEL is 650 ppm (65 mg/kg/day)
based on decreased F1 pups weights for males and females during PND 14
and 21.  The offspring NOAEL is 300 ppm (30 mg/kg/day).

The study is classified as Acceptable/Non-Guideline.

4.2.5.	Pre-and/or Postnatal Toxicity

4.2.5.1	  Propylene Oxide

	

Determination of Susceptibility

There is no quantitative susceptibility between the rat fetuses and the
dams from the rat developmental study (MRID 41750801).  The study
indicated a possible qualitative susceptibility since the skeletal
variations (increased litter incidence for the accessory 7th cervical
rib) were observed at the same dose which produced maternal toxic
effects (decreased body weight gain, food consumption and food
efficiency).

Susceptibility in rabbits could not be adequately ascertained due to the
absence of an acceptable rabbit developmental study.

In the two-generation reproduction study, there is no evidence for
quantitative or qualitative susceptibility in pups exposed to PPO since
no offspring effects were seen at doses which produced significant
systemic toxicity in parents.

Degree of Concern Analysis and Residual Uncertainties for Pre and/or
Post-natal Susceptibility

The degree of concern for the qualitative susceptibility effects seen
after in utero exposures in rats was low since the effects (increased
incidence of the7th cervical rib) are 1) skeletal variations and not
malformations 2) they were seen in the presence of maternal toxicity and
3) this endpoint is used for assessing potential acute dietary risk to
the population of concern (Females 13-49).

The concern for the lack of an acceptable developmental toxicity study
in rabbits is addressed with the retaining of the 10X database
uncertainty factor for risk assessments.  The database uncertainty
factor is considered an FQPA factor.

4.2.5.2	  Propylene Chlorohydrin

Determination of Susceptibility

There is no adequate data to determine the fetal susceptibility
following in utero exposures in rats or rabbits for PCH.

In the reproduction study (NTP, 1998), quantitative susceptibility
effects were evident since decreased pup weights were seen at dose which
had no systemic toxicity in dams. 

	Degree of Concern Analysis and Residual Uncertainties for Pre and/or 	
	Post-natal Susceptibility

The degree of concern is low for the quantitative susceptibility seen in
the reproduction study since the dose and the endpoint of this study is
used for assessing chronic dietary risk in conjunction with the
retaining of the 10X database uncertainty factor.  The database
uncertainty factor is considered to be an FQPA factor.

4.2.6	Recommendation for a Developmental Neurotoxicity Study

	

4.2.6.1	  Propylene Oxide

Evidence that supports requiring a Developmental Neurotoxicity Study

In a subchronic study identified in the open literature, Wistar rats
exposed to PPO at 1500 ppm for 7 weeks exhibited awkward gait during
third and fourth week of exposure and more ataxia in all rats by 7th
week.  Also, histopathological evidence such as axonal degeneration of
the hindleg nerve and fasciculus gracilis and myelinated fibers in the
sacral spinal root were observed.  

In a chronic study axonal dystrophy in the nucleus gracilis was reported
in monkeys exposed to PPO for 2 years.  

Evidence that supports not requiring a Developmental Neurotoxicity Study

No evidence of neurotoxicity was reported in the subchronic
neurotoxicity conducted up to 300 ppm and no evidence neurotoxicity
signs were observed in developmental, reproductive, subchronic or
chronic toxicity studies.  Since the nasal epithelial effects (e.g.,
hyperplasia) occur at low dose level (100 ppm) compared to the
developmental, reproductive effects or neurotoxic effects (≥ 300 ppm),
it is unlikely that the data that would be derived from the
developmental neurotoxicity study would be helpful for risk assessment. 
Therefore, the requirement for a developmental neurotoxicity study is
not recommended.

4.2.6.2  Propylene Chlorohydrin

Evidence that supports requiring a Developmental Neurotoxicity Study

None.

Evidence that supports not requiring a Developmental Neurotoxicity Study

No neurotoxic effects found from the available database.

4.2.7	Rationale for the UFDB

	

4.2.7.1	 Propylene Oxide

There is a data gap in the toxicology database for PPO (developmental
toxicity study in rabbits and chronic study in non-rodents by oral
route).  This necessitates the use of 10X database uncertainty factor
(UFDB) for PPO dietary risk assessment.   The UFDB is considered an FQPA
factor.

4.2.7.2	 Propylene Chlorohydrin

The database for PCH is incomplete.  There is a need for developmental
toxicity study in rats and rabbits and chronic toxicity study in
nonrodents.  In addition, there is a need for the chronic
carcinogenicity studies in rats and mice since the doses used in the
existing studies found in the literature are inadequate.  A 10X database
uncertainty factor (UFDB) is applied for PCH dietary risk assessment.   

4.3	Additional FQPA Safety Factor

Based on the discussion in 4.2.5., no additional FQPA Safety Factor
(i.e., 1X) is required for PPO or PCH since there are no residual
uncertainties for pre and/or post-natal toxicity for PPO and the doses
selected for PCH are considered to protect the effects for children.  It
is assumed that the exposure databases are complete and the risk
assessment does not underestimate the potential risks for infants and
children.  The FQPA SF has been retained as a data base uncertainty
factor.

4.4	Hazard Identification and Toxicity Endpoint Selection

4.4.1	Acute and Chronic Reference Doses for Propylene Oxide

	4.4.1.1  Acute Reference Dose (aRfD) – Females 13-49 Years 

Study Selected:  Developmental Toxicity Study in Rats	§ 83-3; OPPTS
870.3700

Executive Summary:  MRID 41750801 (See section 4.2.3.1)

Dose and Endpoint Selected for Establishing Acute RfD (Gen Population):
The NOAEL of 300 ppm (oral equivalent to 209 mg/kg/day) based on the
increased litter incidence of an accessory 7th cervical rib.

Uncertainty Factor (UF): 1000X (10X interspecies extrapolation, 10X
intraspecies variation and 10X database uncertainty factor for the data
gaps in toxicity studies).

Comments about Study/Endpoint/Uncertainty Factor:  

The study is considered appropriate for the population of concern.  The
developmental effects could be attributed to a single dose.  In addition
to the developmental effects, the same dose level also caused maternal
toxic effects.

4.4.1.2	  Acute Reference Dose (aRfD) – General Population

No endpoint of concern is found suitable to assess risk for this
population.  

4.4.1.3  Chronic Reference Dose (cRfD) – General Population

Study Selected:  Chronic Carcinogenicity Study in Rats- Oral 	§83-5;
OPPTS 870.3700

Executive Summary:   Dunkelberg, 1982 (See Section 4.4.10.1) 

Dose and Endpoint Selected for Establishing Chronic RfD (Gen
Population): BMD10 of 1.4 mg/kg/day based on the increased incidence for
the hyperkeratosis, hyperplasia and papillomas in forestomach in PPO
administered rats.

Uncertainty Factor (UF):  1000X (10X interspecies extrapolation, 10X
intraspecies variation and 10X database uncertainty factor for the data
gaps in toxicity studies).  

Comments about Study/Endpoint/Uncertainty Factor: The study selected is
appropriate for the duration and route of exposure. This was the only
chronic study available for PPO by oral route.  Since the study did not
establish a clear NOAEL, bench mark dose modeling (BMD) was used. 
Although the data fitted well for several dichotomous models, the BMDL10
(the lower confidence limit on the dose that produced 10% effects) from
the log logistic model was used to derive cRfD since it provided the
conservative dose as compared to other dichotomous models.

4.4.2	Acute and Chronic Reference Doses for Propylene Chlorohydrin

	4.4.2.1  Acute Reference Dose (aRfD) – Females 13-49 Years and 				  
 General Population 

No endpoint of concern is found suitable to assess risk for this
population.

4.4.2.2   Chronic Reference Dose (cRfD) – General Population

Study Selected:  Two-generation Reproduction Study, Rats 		§ 83-4;
OPPTS 870.3800

Executive Summary:  NTP, 1998 (See Section 4.2.4.2)

Dose and Endpoint Selected for Establishing Chronic RfD (Gen
Population): The offspring NOAEL of 30 mg/kg/day based on decreased F1
pup weights in males and females during PND 14 and 21 at 65 mg/kg/day.  

Uncertainty Factor (UF):  1000X (10X interspecies extrapolation, 10X
intraspecies variation and 10X database uncertainty factor for the data
gaps in toxicity studies).  

Comments about Study/Endpoint/Uncertainty Factor:  The study selected is
appropriate for the route and duration of the exposure. The doses
selected are comparable to the NOAELs established for pathological
changes in pancreas, spleen or bone marrow in subchronic studies
conducted using adult rats and mice (NOAEL of 35 to 45 mg/kg/day in rats
and 50-60 mg/kg/day in mice) and conservative to the endpoints observed
in the chronic studies (NOAEL of 65 mg/kg/day, HDT for rats and NOAEL of
210 mg/kg/day, HDT for mice. The discrepancy in the pathological changes
reported between the subchronic and chronic exposures using the same
strain of animals and identical test compound is not understood (NTP,
1998).  However, the potential for any such pathological changes in the
offspring could be protected by the dose selected and the application of
10X database uncertainty factor.     

4.4.3	Incidental Oral Exposure (Short-Term, 1-30 days and 			
Intermediate -Term, 1-6 months) 

There are no residential uses for propylene oxide and therefore, the
endpoints for the incidental oral exposure are not derived.

	4.4.4	Dermal Absorption 

Studies on dermal absorption are unavailable.  

	4.4.5	Dermal Exposure Short-Term (1-30 days) and Intermediate-			Term
(1-6 months), Long -Term (>6 months)

Dermal exposure was not assessed.



Inhalation Exposure 

 Acute (1-day)

Study Selected:  Rabbit Developmental Study			§ 83-4; OPPTS 870.3700

		 	

Executive Summary:  MRID 41874102 (See Section 4.2.3.1)

COMPLIANCE:  Signed and dated GLP, Data Confidentiality, Flagging, and
Quality Assurance statements were provided.

Dose and Endpoint Selected:  The LOAEL of 500 ppm based on increased
resorptions, and/or increased incidence of minor skeletal abnormalities.


Comments about Study/Endpoint:  Although there are concerns for this
study, primarily because it is a single dose study with no NOAEL, the
study is appropriate for the route and duration of exposure, and the
study is considered adequate for assessment of acute inhalation risk if
an additional uncertainty factor of 10X is included in the derivation of
a concern level.  The rat developmental inhalation study is also
appropriate to assess acute inhalation risks; however, the rabbit study
provides a more conservative point of departure when the additional
uncertainty factor is included.

Short-Term (1-30 days) and Intermediate-Term (1-6 months)

Study Selected:  Two generation Reproduction Study in Rats	§ 83-4;
OPPTS 870.3800

		 	

Executive Summary:  MRID 45292701 (See Section 4.2.4.1)

COMPLIANCE: A signed and dated Quality Assurance was provided; GLP, Data
Confidentiality, and Flagging statements were not provided.

Dose and Endpoint Selected:  The NOAEL of 75 ppm based on decreased body
weight and weight gain in both F0 and F1 males and females during
premating periods at 225 ppm. 

Comments about Study/Endpoint: 

The study selected is appropriate for the route of exposure. It must be
noted that the study NOAEL/LOAEL of 100/300 ppm is converted to human
equivalent concentrations of 75/225 ppm for occupational scenarios.  For
example, the human equivalent NOAEL of 75 ppm is derived after adjusting
the 6 hour exposure per day in the animal study to 8 hours per day for
humans (100 ppm x 6h/8h = 75 ppm).  Similarly, 225 ppm is derived from
the animal LOAEL of 300 ppm (300 ppm x 6h/8h = 225 ppm).  

4.4.6.3 Inhalation Exposure Long -Term (>6 months)

Study Selected:  Two year combined carcinogenicity study 	§ 83-5; OPPTS
870.4300

		 	

Executive Summary:  MRID 42039901 (See Section 4.4.10.1)

Dose and Endpoint Selected:  The NOAEL of 30 ppm based on increased
incidences of basal cell hyperplasia, and nest-like infolds of the
respiratory epithelium at 100 ppm.  A Benchmark Dose analysis was
performed on the data, and the most appropriate point of departure was
determined to be a BMD of 140 ppm based on moderate to marked nest-like
infolds of the respiratory epithelium in male rats.  The corresponding
BMDL10 is 120 ppm.

Comments about Study/Endpoint: 

The study selected is appropriate for the route of exposure and
duration.  The BMDL10 of 120 ppm is converted to a human equivalent
concentration of 90 ppm to reflect an occupational scenario, i.e., the
difference between the study duration of 6 hours and an 8-hour workday
for typical workers.  The previous version of this risk assessment had
included an additional dosimetric adjustment factor, the regional gas
dose ratio (RGDR), of 0.23 to further reduce the human equivalent
concentration; however, in its review of the RfD and RfC processes, the
Agency has questioned whether the default RGDR calculation for the
extrathoracic region is appropriate, and indicates that the interspecies
dosimetric adjustment factor for extrathoracic effects may be closer to
1 (EPA, 2002, page 4-33).

4.4.7	  Margins of Exposure

Summary of target Margins of Exposure (MOEs) for risk assessment.

Route

Duration	Acute

(1-day)	Short-Term

(1-30 days)	Intermediate Term

(1-6 months)	Long Term

 (>6 Months)

Occupational & Residential Exposure

Dermal	N/A	N/A	N/A	N/A

Inhalation	300	30	30	30



The occupational and residential MOE for short, intermediate and long
term for occupational exposure is based on a combined uncertainty factor
of 30X (3X interspecies factor and 10X intraspecies factor).  The MOE
for acute inhalation exposure includes an extra 10x factor for database
uncertainties.  The traditional interspecies factor of 10X is reduced to
3X since the animal doses are converted to human equivalent
concentrations.  

	4.4.8	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from
residues in food commodities and drinking water as well as exposures
arising from non-dietary sources (e.g., incidental oral, dermal and
inhalation routes).  The residues from drinking water are negligible
since PPO is used only indoors.  PPO has no direct residential uses;
however residential bystanders may be exposed to emissions from
fumigation facilities or structures.  Dietary and bystander exposure
cannot be combined for this assessment, however, because the endpoints
selected for these exposures are not based on a common effect. 
Therefore, the aggregation of risk from dietary and inhalation routes is
not performed. 

4.4.9   Classification of Carcinogenic Potential

4.4.9.1  Propylene Oxide

Animal Studies

Rats – Oral 

Study 1 (Dunkelberg, 1982)	

In a chronic carcinogenicity study (Dunkelberg, 1982), female
Sprague-Dawley rats (50/group) were administered with 0, 0 (salad oil as
vehicle control), 15 or 60 mg/kg bw propylene oxide (99.7% pure) by
gavage twice a week for 109.5 weeks (determined from 219 times of
dosing) and observed for 150 weeks.  The average total doses in the low
and high propylene oxide treated groups were reported as 2714 or 10798
mg/kg bw, respectively.  Adjusting the doses to the whole study period
of 150 weeks, the average daily doses are estimated as 2.58 and 10.28
mg/kg/day, respectively.  Between the 79th and 82nd week several rats in
the various groups were affected with pneumonia and during which time
the administration was interrupted.  Survival rates were not affected by
propylene oxide treatment.  The first tumor was observed in the 79th
week of the treatment.  A dose dependent increase in the incidence of
forestomach tumors (mainly squamous-cell carcinomas) were observed in
the propylene oxide treated animals (0/50, 0/50, 2/50, 19/50 in the
control, vehicle control, low and high propylene oxide treatment groups,
respectively).  Further, one animal in the high dose group had a
carcinoma in situ and another animal in the high dose group had an
adenocarcinoma of the glandular stomach.  In addition to the neoplastic
lesions, a dose dependent increase in the combined incidences of
papilloma, hyperplasia and hyperkeratosis of the stomach (0/50, 0/50,
7/50, 17/50 in control, vehicle, low dose and high dose, respectively)
was reported.

The LOAEL is determined as 2.58 mg/kg/day based on increased combined
incidences for hyperkeratosis, hyperplasia and papillomas.  The NOAEL is
not established.   

The carcinogenicity study is limited by inadequate pathological data
because pathological examination in several tissues including lung,
liver, kidney and thyroid tissues were not reported.  The study examined
only female rats and any sex specific effects were not determined.  It
must be noted this is the only chronic study available for PPO by oral
route and used for chronic reference dose and chronic cancer risk
determination.  The lack of adequate measurements on systemic effects
such as body weights, food consumption, clinical measurements, organ
weights etc. along with the inadequate pathological examinations and
lack of determination of any sex specific effects limit to classify this
study as combined chronic toxicity/carcinogenicity guideline study
(OPPTS No. 870.4300).  Therefore, the study is classified as
Acceptable/Non-Guideline.                

Rats – Inhalation

Study 1 (MRID 42039901) 

In a chronic inhalation toxicity study (MRID 42039901), 100 Wistar
rats/sex/exposure group were exposed to 1,2-propylene oxide gas
(technical grade, 99.9903% a.i.; Lot Nos. - not provided) at target
exposure concentrations of 0, 30, 100, or 300 ppm for 6 hours/day, 5
days/week for up to 28 months.  Seventy rats/sex/exposure group were in
the main group, and 10 rats/sex/exposure group were in each of three
satellite groups killed after 12, 18, or 24 months to provide interim
toxicological data.

The mortality rate was statistically increased at the end of the study
in 300 ppm group males (79% vs. 46% for controls) and 100 and 300 ppm
group females (61 and 79%, respectively, vs. 43% for controls) as
compared to controls.  It appears that the decreased survival in high
dose females is evidence that the MTD was exceeded in the study. 
Statistically significant decreases in absolute body weights in 300 ppm
males during weeks 1-71 and 99-111 and 300 ppm females during weeks
1-67, with the body weight means ranging from 90-97% of controls for
males, and 92-98% of controls for females, were reported.  Mean body
weight gains in the high dose level males ((16%) and females ((22%)
during the first four weeks and in 300 ppm males during weeks 13-59
((12%) were decreased as compared to respective controls.  During weeks
59-99, 100 and 300 ppm males and 300 ppm females had an increased body
weight gain, suggestive of a compensatory effect.  Food consumption was
marginally decreased during the first two weeks of the study (p < 0.02)
in high level males (94%) and during the first week in high dose level
females (89%).

There were no treatment-related changes observed in hematology and
clinical chemistry parameters or in organ weights.  Macroscopic
evaluation revealed that females in the 300 ppm group had an increased
incidence of adrenal enlargement, which may be related to treatment.

Microscopic examination revealed an increased incidence of degenerative
and hyperplastic changes in the nasal mucosa of exposed rats as compared
to controls.  The 300 ppm male and female satellite groups had
statistically significant (p < 0.05; 0.01) increase in the  incidences
of olfactory epithelium atrophy at 12 months (males: 4/10 vs. 0/10
controls; females: 5/9 vs. 0/10 controls) and basal cell hyperplasia of
the olfactory epithelium at 12 months (males: 5/10 vs. 0/10 controls;
females: 7/9 vs. 0/10 controls), 18 months  (males: 6/10 vs. 1/10
controls; females: 6/10 vs. 0/10 controls), and 24 months (males: 4/10
vs. 0/10; females: 5/9 vs. 0/9 controls) compared to controls.  The
incidences of nest-like infolds of respiratory epithelium were increased
(p < 0.05; 0.01) in 300 ppm males at 12 months (9/10 vs. 1/10 controls),
18 months (9/10 vs. 0/10 controls) and 24 months (7/10 vs. 0/10
controls); and 300 ppm females at 12 months (9/9 vs. 0/10 controls), 18
months (10/10 vs. 0/10 controls), and 24 months (7/9 vs. 0/9 controls). 
The incidences of these nasal lesions were similar in animals from the
main study (28 months).  Atrophy of the olfactory epithelium was
increased (p < 0.01) in 300 ppm males (21/63 vs. 5/66 controls) and
females (26/65 vs. 7/64).  Both 100 and 300 ppm males and females had
increased incidences (p < 0.05; 0.01) of basal cell hyperplasia (males:
10/62 and 24/63 vs. 4/66 controls; females: 9/62 and 33/65 vs. 0/64
controls) and nest-like infolds of the respiratory epithelium (males:
29/62 and 47/63 vs. 5/66 controls; females: 20/62 and 43/65 vs. 4/64
controls).  The nest-like infolds showed a clear concentration-response
relationship.  Other microscopic changes that may be related to exposure
to 300 ppm 1,2-propylene oxide include increased incidence of thrombi in
the heart in males, and myocardial degeneration in females.

The LOAEL is 100 ppm based on increased incidences for basal cell
hyperplasia, and nest-like infolds of the respiratory epithelium.  The
NOAEL is determined as 30 ppm.

There were incidences of fibroadenomas (control, 32/69; low dose, 30/71;
mid dose, 39/69; high-dose 47/70, p<0.05) and tubulopapillary carcinomas
(control, 3/69; low dose, 6/71; mid dose, 5/69; high-dose 8/70, p<0.05)
in the mammary glands of females.  Multiplicity of fibroadenomas was
significantly increased at all doses (p<0.01).  However, the study was
conducted for 28 months and the high dose incidence of 67%, although
exceeding the historical control range 19-61%, is of questionable
usefulness, since the usual proliferation of mammary gland
fibroadenomas, the most common type of female tumor, is expected to be
significantly enhanced at this point in the study.  These facts, in
part, support the conclusion that the fibroadenoma data do not provide
unequivocal evidence that PPO is a systemic carcinogen.  

Three malignant tumors were found in the nasal cavity of treated males: 
one tumor described as ‘ameloblastic fibrosarcoma’ in a low dose
male, one squamous cell carcinoma in a low dose male and one in a high
dose male.  Four males in the high dose group had a carcinoma in the
larynx or pharynx, trachea or lungs with none in controls or low-dose
males.  

Dosing was considered adequate based on increased mortality and
decreased body weight in males and females at the highest concentration
and increased incidences of nasal lesions at all exposure
concentrations.

This combined chronic/oncogenicity toxicity study is
Acceptable/Guideline (§83-5; OPPTS 870.4300) and does satisfy the
guideline requirement for a combined chronic/oncogenicity study in rats.

COMPLIANCE:  Signed and dated GLP, Quality Assurance, Data
Confidentiality, and Flagging statements were provided.

 

		Study 2 (NTP, 1985)

In a chronic carcinogenicity study (NTP, 1985), F344 rats (50/sex/group)
were exposed via inhalation to 99.9% pure propylene oxide at
concentrations of 0, 200, and 400 ppm for 6 hours/day, 5 days/week for
103 weeks. Hematology, serum chemistry, urinalysis, and histopathology
were performed. Survival in the rats was unaffected by exposure to
propylene oxide, and terminal body weights were slightly depressed in
the high-dose male (8%) and female (9%) rats.  The respiratory
epithelium of the nasal turbinates was the primary tissue affected by
propylene oxide exposure in rats. Exposure-related increases in
suppurative inflammation of the nasal cavity (7/50, 19/50, and 33/50 in
the control, 200, and 400 ppm males, respectively, and 3/50, 5/50, and
20/50 in the control, 200, and 400 ppm females, respectively) in
addition to exposure-related increases in epithelial hyperplasia (0/50,
1/50, and 11/50 in males; 0/50, 0/48, and 5/48 in females in respective
dose groups) and squamous metaplasia (1/50, 3/50, and 21/50 in males;
1/50, 2/48, and 11/48 in females in respective dose groups) were
reported at the end of the treatment.

The LOAEL is determined as 200 ppm based on the extrathoracic effects. 
The NOAEL is not established. 

Papillary adenomas of the nasal cavity occurred in 0/50 control, 0/50
low dose and 3/50 high dose females, and in 0/50 control, 0/50 low dose
and 2/50 high dose males.  In historical controls from five different
laboratories for the same strain of rats, the incidences for nasal
cavity tumors were reported as 3/1523 for females and 1/1477 for males. 
However, although the incidence of papillary adenomas of the nasal
cavity occurred at increased frequency, the occurrence of these tumors
was not statistically significant by pair wise comparison with the
controls, and are not considered treatment related.  A increase in
thyroid C-cell adenoma and carcinoma (p=0.023) occurred in females and
the incidences are 2/45, 2/35, 7/37 in control, low dose and high dose
groups, respectively.  Since these tumors are relatively common in
female F334/N rats, the combined incidence of C-cell adenomas and
carcinomas in this study is considered to be unrelated to the
administration of propylene oxide.  The incidences in historical control
females for C-cell adenoma or carcinoma ranged from 1/49 (2%) to 9/50
(18%) and the total incidence corresponded to 122/1472 (8.3%±4.3%)
based on the data collected from five different laboratories.  The
incidence in the 400 ppm PPO group was similar to that observed for the
historical controls at the high end (19%) but greater than the overall
or total incidence for thyroid gland tumors.      

The doses tested are considered adequate based on the extrathoracic
effects in propylene oxide treated groups.  

 

The study is classified as Acceptable/Non-Guideline.

		Study 3 (Lynch et al. 1984)

In a chronic carcinogenicity study male F344 rats were exposed via
inhalation to propylene oxide (80/group) at 0, 100, or 300 ppm propylene
oxide for an average of 6.9 hours/day, 5 days/week for 104 weeks.  A
statistically significant (p<0.01) increase in mortality was observed at
the high dose compared to controls.  The median survival time was 720,
705, and 675 days for control and 100 and 300 ppm groups, respectively. 
The mean body weights were significantly (p<0.05) reduced in both 100
and 300 ppm treatment groups, compared to controls.  Hemoglobin
concentrations were increased significantly in both groups of propylene
oxide-treated rats (p<0.025) compared to controls.  Absolute and/or
relative weights to the body weights were reported increased for lungs
and adrenal glands and decreased for testes, in both treatment groups. 
The incidences for complex epithelial hyperplasia (0/76, 2/77, 11/78 in
control, 100 and 300 ppm groups; significant only in 300 ppm group,
p<0.05) and suppurative rhinitis in the nasal cavity (12/76, 21/77,
44/78 in control, 100 and 300 ppm groups; significant in both groups,
p<0.05) were higher in treated groups compared to controls.  The
skeletal muscle atrophy in the absence of sciatic nerve neuropathology
was noticed in 300 ppm group compared to controls.  

The only noticeable neoplastic lesion was adrenal pheochromocytomas and
the incidences were 8/78, 25/78, 22/80 in control, 100 and 300 ppm
groups, respectively.

The LOAEL is determined as 100 ppm based on decreased survival,
decreased body weights, increased hemoglobin, extra thoracic effects
(nasal suppurative rhinitis) and systemic effects such as decreased body
weight, increased hemoglobin, and organ weight changes.  The NOAEL is
not established.      

The study is classified as Acceptable/Non-Guideline.  The study was
conducted using only one sex and with two doses only.   No individual
animal data or interim sacrifice data were provided.  Also, limited
clinical parameters were measured.  The findings of this study are
complicated by the outbreaks of Mycoplasma pneumonia infection which
occurred at 8, 16, and 20 months of the study.    

		Mice – Inhalation

		NTP (1985)

In a chronic carcinogenicity study (NTP, 1985), B6C3F1 mice
(50/sex/treatment) were exposed to 99.9% pure propylene oxide at
concentrations of 0, 200, and 400 ppm for 6 hours/day, 5 days/week for
103 weeks.  Survival tended to be adversely affected in all treated
groups (males:  controls, 42/50; low-dose, 34/50; high dose, 29/50 and
females: controls, 38/50; low-dose, 29/50; high dose, 10/50), but the
decrease was statistically significant only for male and female mice in
the 400 ppm group. Terminal body weights were 10% below control values
for the high-dose female mice and 22% below control values for the
high-dose male mice. Chronic inflammation of the nasal cavity was
observed in 1/50, 13/50, and 38/50 of the male mice and in 0/50, 13/50,
and 17/50 of the female mice exposed to 0, 200 ppm, and 400 ppm,
respectively. Hyperplasia and metaplasia were also observed sporadically
in mice exposed to 400 ppm propylene oxide. These lesions were most
pronounced in the anterior portion of the nasal cavity and on the
greater curvatures of the nasal maxillary turbinates. No consistent
effect was observed in the tracheobronchiolar or pulmonary region of the
respiratory tract, or in skeletal muscle, bronchial lymph nodes, or
central nervous system.

The LOAEL is determined as 200 ppm based on extra thoracic effects.  The
NOAEL is not established.      

 

The combined incidences of hemangiomas and hemangiosarcomas in the nasal
cavity were significantly elevated in the high dose group (males: 
controls, 0/50; low-dose, 0/50; high dose, 10/50, p<0.001 and females:
controls, 0/50; low-dose, 0/50; high dose, 5/50, p=0.03).  One squamous
cell carcinoma and one papilloma were induced in nasal cavity of high
dose males and adenocarcinomas in two high dose females, but these
effects were not statistically significant.   Doses tested were
considered adequate based on the extra thoracic effects.  

 

The study is classified as Acceptable/Non-Guideline.

Mutagenicity Studies

No mutagenicity studies were submitted to the Agency.  However, there
are several reports published in the literature.  The following summary
provides a brief over view of the studies available in the open
literature.

Propylene oxide induced reverse mutations in Salmonella typhimurium
TA100, TA1535 strains consistently in the absence of S9 activation (S9
was not included in most of the tests).  Mutations were also induced in
E.coli (WP2, WP2 uvrA), yeast (Saccharamyces cerevisiae and
Schizosaccharomyces pombe), and fungi (Neurospora crassa).  PPO caused
sex-linked recessive lethal mutations in Drosophila melanogaster. 
Propylene oxide induced DNA single strand breaks in rat hepatocytes, and
caused gene mutations in Chinese hamster ovary cells and mouse L5178Y
cells, in vitro.  Propylene oxide induced sister chromatid exchange in
Chinese hamster ovary cells, rat liver cells and human lymphocytes and
chromosomal aberrations in cultured human lymphocytes (as reviewed in
IARC, 1994).

Chromosomal aberrations and sister chromatid exchange were induced in
mouse bone-marrow cells after intraperitoneal injection.  In one chronic
study, no significant increase in sister chromatid exchange or
chromosomal aberrations in peripheral blood lymphocytes was reported in
cynomolgus monkeys exposed to 300 ppm PPO for 7h/day, 5days/week for two
years.  Micronuclei were not induced in bone-marrow cells of mice
administered PPO by gavage but were induced in mice receiving PPO by
intraperitoneal injection.  Dominant lethal mutations were not induced
in mice exposed to PPO orally or rats exposed to PPO by inhalation (as
reviewed in IARC, 1994).

DNA adducts were reported in vitro when calf thymus DNA was incubated
with propylene oxide.  Increased DNA adducts (7-(2-hydroxy
propyl)guanine) in DNA hydrolysates of various organs were formed in
male mice 3h and 10h after intraperitoneal injection of 14C-propylene
oxide.  In mice, rats and dogs, the levels of DNA adducts in liver were
greater after intraperitoneal or intravenous injection as compared to
inhalation.  Male Fischer rats exposed to tritiated propylene oxide via
inhalation at 46 ppm for 2 hours had 17, 5.8, 3.3 adducts/106 base in
nasal cavities, trachea and lungs, respectively.  The persistence of the
radiolabel was seen in trachea and lungs as compared to nasal cavities. 
The elimination of the radiolabel from nasal cavities appears to be
biphasic with half-lives of 8h and 5.3 days (as reviewed in IARC, 1994).


		Cancer Classification

		Oral

PPO has been classified by the Agency as a B2 carcinogen (probable human
carcinogen).  The cancer slope factor for the oral route is 0.15
(mg/kg/day)-1 based on the Dunkelberg study which showed forestomach
tumors in rats. 

HED has derived an alternative cancer slope factor (Q*) of 0.00086
(mg/kg dose)-1 using a concentration based approach.  Use of an
alternative approach is based on the fact that forestomach tumors in the
rat treated by gavage may be considered a portal of entry response.  By
analogy to the RfC methodology which considers the concentration of test
material to be the most important determinant of response in portal of
entry tumors, PPO dosage may be expressed as a concentration.  A
detailed description of the derivation of the alternate slope factor is
provided in Appendix 5.0.  The Agency is considering mode of action data
relevant to both oral and inhalation routes of exposure.  If the
proposed MOA is adopted, characterization of cancer risks is likely to
change from a low-dose linearity approach to a threshold approach.

	Inhalation

The cancer slope factor based on nasal tumors in mice for the inhalation
route is 3.5x10-6 (µg/m3)-1 using RfC methodology and assuming
linearity at low doses.  

As previously noted, the registrant and consultants to the registrant
have submitted a large amount of information supporting a threshold
carcinogenic mode of action (MOA) of PPO.  The Agency has done an
initial review of the data supporting the proposed MOA and finds it
highly plausible.  The key points of the proposed MOA are described in
Appendix 6.0 

                  

4.4.9.2	Propylene Chlorohydrin

Animal Studies 

Rats – Oral

In a chronic carcinogenicity study (NTP, 1998),  groups of 50 male and
50 female F344/N rats were administered drinking water containing 0,
150, 325, or 650 ppm PCH (75% 1-chloro-2-propanol and 25%
2-chloro-1-propanol; equivalent to average daily doses of approximately
15, 30, or 65 mg/kg during the first several months of the study and 8,
17, or 34 mg/kg for the remainder of the 2-year study) for up to 105
weeks.  Survival of all exposed groups was similar to that of the
controls.  Mean body weights of exposed rats were generally similar to
those of the controls throughout most of the study.  Water consumption
by all exposed groups was similar to that by the controls.  No
treatment-related neoplasms or nonneoplastic lesions were observed in
this study.  The NOAEL is determined as 65 mg/kg/day (HDT) and the LOAEL
is not established.  

The study is classified as Acceptable/Non-Guideline.  The NTP concluded
that there was no evidence of carcinogenicity.  

	Mice – Oral

In a chronic carcinogenicity study (NTP, 1998),  groups of 50 male and
50 female B6C3F mice were administered drinking water containing 0, 250,
500, or 1,000 ppm PCH (75% 1-chloro-2-propanol and 25%
2-chloro-1-propanol) (equivalent to average daily doses of approximately
45, 75, or 150 mg/kg to males and 60, 105, or 210 mg/kg to females
during the first several months of the study and 25, 50, or 100 mg/kg
for the remainder of the 2-year study) for up to 105 weeks. Survival of
all exposed groups was similar to that of the controls. The mean body
weights of all exposed mice were generally similar to those of the
controls throughout the study. Water consumption by all exposed groups
was similar to that by the controls. No treatment-related neoplasms or
nonneoplastic lesions were observed in this study.  

The NOAEL is determined as 210 mg/kg/day (HDT) and the LOAEL is not
established.  

The study is classified as Acceptable/Non-Guideline.  No evidence of
carcinogenicity was reported.  The doses used in the study are
inadequate.  Consequently, no conclusions can be made as to the
carcinogenicity of PCH.

Mutagenicity Studies

PCH (1-Chloro-2-propanol) is a demonstrated mutagen in vitro.  It was
weakly mutagenic in Salmonella typhimurium strain, TA100 in the presence
of hamster or rat liver S9 activation enzymes and was positive, with and
without S9, in TA1535.  No mutagenic activity was detected in strains
TA97, TA98, and TA1537, with or without S9.  PCH was positive in E.coli
polA assay for DNA damage (as reviewed in NTP, 1998).  

In cytogenetic tests with Chinese hamster ovary cells, PCH induced high
levels of sister chromatid exchanges and chromosomal aberrations in the
presence and the absence of S9.   Positive results were reported when
PCH was tested in L5178Y mouse lymphoma cells with and without S9 (as
reviewed in NTP, 1998).  

PCH induced sex-linked recessive lethal mutations in germ cells of male
Drosophila melanogaster when administered via injection; however,
negative results were obtained when males were administered PCH in feed.
 A subsequent germ cell reciprocal translocation test in D. melanogaster
yielded negative results.  Further, no induction of micronucleated
erythrocytes was observed in peripheral blood of male and female mice
administered PCH via drinking water for 14 weeks (as reviewed in NTP,
1998). 

4.4.10 	Summary of Endpoints Selected for Risk Assessment

Table 6:  Summary of Toxicological Doses and Endpoints Use in Human Risk
Assessments

Exposure

Scenario	Dose Used in Risk Assessment, UF 	Additional FQPA SF* and Level
of Concern for Risk Assessment	Study and Toxicological Effects

Propylene Oxide

Acute Dietary

(Females, 13-49 years)	NOAEL =  #209 mg/kg/day

(300 ppm)

UF =1000

Acute RfD = 

0.21 mg/kg/day	FQPA SF = 1X

aPAD = 

acute RfD

 FQPA SF

= 0.21mg/kg/day	Developmental Toxicity, Rats (MRID 41750801)

Developmental LOAEL: #349 mg/kg/day (500 ppm)

Increased litter incidence of an accessory 7th cervical rib

	

Acute Dietary

(General populations)	No endpoint of concern is found suitable to assess
risk for this population

Chronic Dietary

(All populations)	†BMDL10= 1.4 mg/kg/day

UF = 1000

Chronic RfD = 0.001 mg/kg/day	FQPA SF = 1X

cPAD = 

chronic RfD

 FQPA SF

= 0.001 mg/kg/day	Chronic carcinogenicity study, Rats (Dunkelberg, 1982)

 †Systemic LOAEL = 2.6 mg/kg/day 

Increased combined incidence for hyperkeratosis, hyperplasia and
papillomas.

Incidental Oral Exposure, Short-Term (1 - 30 days) Intermediate-Term (1
- 6 months) 	No hand to mouth exposure is expected for children. 
Therefore, this scenario is not applicable.

Dermal, Short-Term, Intermediate-Term, and Long-Term (> 6 months)
Propylene oxide is a severe skin irritant and therefore, care must be
taken to avoid direct contact with the skin.

Inhalation – acute (1-day)

Residential	LOAEL = 500 ppm 

UF = 30

	FQPA SF = 10x (UFL)

Residential MOE = 300	Developmental toxicity in rabbits (MRID 41874102).
 Increased resorptions, and/or increased incidence of minor skeletal
abnormalities.



Inhalation – acute (1-day)

Occupational	LOAEL = 500 ppm 

UF = 30

UFL = 10	FQPA SF = 1x 

Occupational MOE = 300

	Inhalation 

Short-Term (1 - 30 days) and Intermediate-Term

(1 - 6 months)	¶ NOAEL= 75 ppm (180 mg/m3)

Inhalation Absorption Rate = N/A	Residential MOE =N/A

Occupational MOE = 30	Two-generation Reproduction Study in Rats (MRID
45292701)

¶ LOAEL = 225 ppm (540 mg/m3) 

Decreased body weight and body weight gain in both F0 and F1 males and
females during premating periods

Inhalation 

Long-Term

(> 6 months)

	§ BMDL10 = 120 ppm (90 ppm HEC)

Inhalation Absorption Rate = N/A	Residential MOE =N/A

Occupational MOE = 30	Two year combined chronic carcinogenicity study,
Rats (MRID 42039901)

Increased incidences of basal cell hyperplasia, and nest-like infolds of
the respiratory epithelium

Cancer (Oral) 	Traditional cancer slope factor (oral- forestomach tumors
in rats) = 0.15 (mg/kg/day)-1; 

Alternate cancer slope factor using concentration based approach =
0.000086 (mg/kg diet)-1 ** 

Cancer (Inhalation)	Traditional cancer slope factor (inhalation -
hemangioma and hemangiocarcinoma in mice) = 3.5x10-6  (μg/m3)-1  

Note: if a proposed MOA is accepted, inhalation cancer risks will be
likely equal to non-cancer risks.  

Propylene chlorohydrin

Acute Dietary

(Females, 13-49 years) and (General populations)	No endpoint of concern
is found suitable to assess risk for these populations

Chronic Dietary

(All populations)	NOAEL= 30 mg/kg/day

UF = 1000

Chronic RfD = 0.030 mg/kg/day	FQPA SF = 1X

cPAD = 

chronic RfD

 FQPA SF

= 0.030 mg/kg/day	Two-Generation Reproduction Study, Rats (NTP, 1998)

Offspring LOAEL: 65 mg/kg/day

Decreased F1 male and female pup weights at PND 14 and 21.



Cancer (Oral and Inhalation)	Data is inadequate to determine the
carcinogenic effects.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect  level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

#Extrapolation from inhalation to oral route:  mg/kg/day = (mg/L x
absorption factor x respiratory volume in L/hr x duration of daily
animal exposure x activity factor) /mean body weight in kg; The oral
equivalent dose for 500 ppm =[ (500x (58.08/24.4)x1000) mg/L x 1x 6.06
L/hr x 6 h/day x 1 / (0.124 kg)] = 349 mg/kg/day; similarly 300 ppm
corresponds to 209 mg/kg/day.  In the equation the default value of 1 is
used for both absorption factor and animal activity factor. 

† Study gavage doses of 15 and 60 mg/kg/day administered twice a week
(corresponding average total doses are 2714 and 10798 mg/kg bw) are
adjusted for experimental duration of 150 weeks to 2.58 and 10.28
mg/kg/day, respectively.  These adjusted doses were used for bench mark
dose modeling (BMDL10; Log Logistic Model had a good fit of the data).

£Study LOAEL of 500 ppm needs no adjustment to a human equivalent dose
for residential bystander scenario, since the study duration of 7 hrs is
assumed to be equivalent to the human exposure interval.

¶Study NOAEL and LOAEL are adjusted to human equivalent doses for
occupational scenario only.  e.g., animal NOAEL of 100 ppm (6h/day,
5d/week) is adjusted to human NOAEL of 75 ppm  (8 h/day, 5d/week),
assuming the regional gas dose ratio (RGDR) is similar between animals
and humans for systemic effects (100 ppm x 6h/8h =75 ppm); 

§ Study POD is adjusted to human equivalent dose for occupational
scenario only;  ie., animal BMDL10 of 120 ppm is adjusted to human NOAEL
of 90 ppm, by correcting for differences in study (6 h/day, 5 d/week)
and exposure (8 h/day, 5d/week) durations. (120 ppm x 6h/8h = 90 ppm).

* Refer to Section 4.3

** Slope factor used for dietary exposure assessment

4.5	Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate." 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC's recommendation that the Program include evaluations of
potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

	In the available toxicity studies on the reaction product of propylene
oxide, PCH, there was increased percentage of abnormal sperm in the
subchronic and reproduction toxicity studies.  When additional
appropriate screening and/or testing protocols being considered under
the Agency's EDSP have been developed, PCH may be subjected to further
screening and/or testing to better characterize effects related to
endocrine disruption.   

5.0	INCIDENT REPORT	

	

Scientific literature reports a few cases of contact dermatitis from
exposure in workplace settings, although these occurrences were in
laboratories, not sterilization/fumigation facilities or food processing
facilities.  Information from the Poison Control Center showed evidence
of throat and skin irritation.  One reported case in California
described an almond fumigator experiencing lightheadedness, coughing,
and skin sores from changing cylinders.

6.0  	DIETARY EXPOSURE/RISK PATHWAY 

	

6.1	Residue Profile

	

Residue data are adequate to support the fumigant uses on spices and
herbs (as defined by the Agency’s crop groups), cocoa bean, and
nutmeats (except peanut).  The existing 300 ppm PPO tolerances for
“spices processed” should be clearly defined in regard to what
spice/herb commodities are fumigated.  The proposed PPO tolerances in/on
spices are based on residue data collected 2 days after treatment.  A
1500 ppm tolerance should be established for residues of PCHs in/on
spices and herbs (dried) (except basil) based on residues at 2 day
sampling.   A 6000 ppm PCH tolerance should be established for basil.  
A 6000 ppm PCH tolerance should be established for dried onion and dried
garlic powders.  Magnitude of the residue studies found minimal PBHs
levels in cocoa powder, nutmeats (almond, pecan, walnut), spices (black
pepper, chili powder, celery seed), dried 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 

4.4.9.1 (study 1) of this risk assessment.

Selection of Endpoints to be Modeled

The study describes three nasal lesions that were associated with
long-term exposure to PPO:  atrophy of the olfactory epithelium,
basal-cell hyperplasia of the olfactory epithelium and nest-like infolds
of the respiratory epithelium.  This latter lesion is considered a
hyperplastic response of the respiratory epithelium.  The lesions were
graded as slight, moderate or marked, although for reporting purposes,
the moderate and marked categories were sometimes combined. 

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approach is to sum the moderate and marked responses for each lesion. 
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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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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)

