Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460



### MEMORANDUM

Date: September 5, 2013 OFFICE OF
CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Propylene Oxide. Human-Health Assessmen t Scoping Document in Support of Registration Review.

PC Code: 042501 DP Barcode: 414670
Decision No.: 476419 

### Registration No.: NA
Petition No

. : NA Regulatory Acti on: NA

Risk Assessment Type: 

### Scoping Case No. : NA


### TXR No.: NA CAS No: 

### NA

MRID No.: NA 40 CFR: 180.491



## FROM: Thurston G. Morton, Risk Assessor

# -"/~~r Ange l a Howard, Ph.D., DABT

, Toxicot6gist

# __A,~~**v\~** Susan V. Hummel, Ph.D, Senior Chemist

Ivan Nieves

, Chemist

Risk Assessment Branch 4 (RAB4)

Health Effec ts Division (7509P )



### THROUGH: Elissa Reaves, PhD., Branch Chief

# ~)k Risk Assessment Branch 4, Health Effects Div ision

, 7509P



### TO: Garland Waleko, Risk Manager Reviewer

Andrea Mojica, Risk Manager Reviewer

Pesticide Re-evaluation Di vis i on Risk Management and Implementation Branch IV (7508P) 

# -

Attached is HED's human-health risk assessment scoping document for Propy l ene Oxide to support registration review.

Page I of38Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### Executive Summary

Propylene oxide (PPO) is used as an insectic idal fumigant on several food items such as processed spices, cocoa (beans and powder), in-s hell and processed nutmeats (except peanuts). In addition, there is a label claim of aiding in the contro l of microbiological spoilage. PPO also has nonfood uses for cosmetic articles, gums, ores, packaging, pigments, pharmaceutical materials, and discarded nut shells prior to dis posal. The assessment of the food use of PPO as an insecticidal fumigant will cover the antimicro bial use. The Health Effects Division (HED)
has evaluated the status of the human-health assessments for propylene oxide to determine whether sufficient data are available to support Registration Review. HE D has also considered
the most recent human health risk assessments for propylene oxide with respect to toxicity, exposure, and usage databases, and the most upd ated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review.

The Propylene Oxide Reregistration Eligibility Decision (RED) document was signed in July 2006. It was then amended in September 2008 and again in June 2009. No new uses of PPO have been registered since the RED was issue d. An updated dietary e xposure analysis was
conducted in October 2011 to address pine nuts.

Propylene oxide (PPO) is a highly reactive gas and is rapidly take n up via the lungs. It is classified as moderately toxic in acute oral studies and less toxic in acute inhalation toxicity studies (Class III or Class IV). PPO has severe irritant propert ies to eyes and skin and is
classified as Class I for both tissues. PPO has s hown neurotoxicity in rats at high dose levels. PPO causes nasal cavity lesions in both rats and mice and tumors of the nasal cavity (hemangiomas and hemangiosarcomas) were observed in chronically exposed mice. Forestomach tumors were reported in rats in one chronic oral toxicity study with PPO. PPO is mutagenic and forms adducts with proteins a nd DNA and is classified as a probable human carcinogen.

Propylene chlorohydrin (PCH) is a reaction produc t of PPO. It is formed in PPO-fumigated commodities whenever chloride ion is present. PC H is moderately toxic via the oral route. A two-generation reproductive toxici ty study in rats showed syst emic, reproductive and offspring toxicity. PCH showed evidence of mutagenicit y. There was no evidence of carcinogenicity via
the oral route.

The toxicity database for propylene oxide is inad equate for Registration Review. A special acute inhalation toxicity study is n eeded for PPO; and 870.6200a an acute neurotoxicity study and 870.3700a and b developmental toxicity studies in rats and rabbits are needed for (PCH).Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### The following data deficiencies we re identified for propylene oxide:

 Toxicology: a special acute inhalation toxic ity study is required fo r PPO at this time based on current testing policy applicable to all commodity fumigants (Attachment 4: Justification for Special Acute Inhalation Toxicity Study with PPO; Rury K., 5/14/13, TXR No. 0056638)

.

 Residue Chemistry: None

 Dietary Exposure: None

 Occupational/Residen tial Exposure:

o 

### 875.1400 Inhalation Exposure Study for Applicators . These studies are required to assess exposures for applicators involved in fumigating commodities/materials
and/or structural 

### facilities.

o 

### 875.1700 Product Use Information . This study is required to assess product use information parameters by major us e region, frequency, and application equipment.

o 875.2500 Post-Application Inhalatio n Exposure Study - outdoor. This study is required to assess post-app lication exposures for work ers or bystanders near fumigation facilities/operations, or for t hose who work directly with previously
treated commodities/materials.

o Special Study - Monitoring data on fumigated commodities . This study is required to evaluate emission rates for PPO from treated commodities/materials and the potential for occupati onal exposure due to those emissions in the channels of trade after fumigation activities are complete.

o Special Study – Ambient air monitoring. This study is required to assess ambient air concentrations for communities in proximity to treated facilities.

The following data deficiencies were identified for PCH:

 Toxicology: 870.6200a An acute neurotoxicity study and 870.3700a and b developmental toxicity studies in rats and rabbits

 Residue Chemistry: None

 Dietary Exposure: None

 Occupational/Residenti al Exposure: None

EPA anticipates conducting the following risk assessment updates during Registration Review:

 Toxicology:

o Reevaluation of the toxicity endpo int/dose selection may be necessary.

 Residue Chemistry: None

 Dietary Exposure:

o New dietary exposure and risk assessme nts may be required during Registration Review to incorporate po tential changes to the pr opylene oxide and/or PCH toxicological PODs. In addition, the assessment should include updated consumption information and utilize the newest version of DEEM-FCID.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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###  Occupational/Residen tial Exposure:

o Revised HED occupational handler risk assessments may be necessary based on the most recent exposure data, Agency policies, or if the toxicological
reevaluation of PPO results in changes to the endpoints.

o Additional or revised HED residential bystander risk assessments may be necessary based on the most recent expos ure data, Agency policies, or if the toxicological reevalua tion results in change s to the endpoints.

1.0 Introduction

Propylene oxide (PPO) is used as an insectic idal fumigant on several food items such as processed spices, cocoa (beans and powder), in-s hell and processed nutmeats (except peanuts). In addition, there is a label claim of aiding in the contro l of microbiological spoilage. PPO also has nonfood uses for cosmetic articles, gums, ores, packaging, pigments, pharmaceutical materials, and discarded nut shells prior to di sposal. Currently, there are three registered products for PPO. Both the technical and an e nd-use product contain 100% a.i. An additional end-use registration product, Propoxide 892, whic h contains 8% PPO a nd 92% carbon dioxide (CO 2 

### ) is being proposed for uses on dried frui ts such as figs, raisins, and prunes.

The Health Effects Division (HED) has evaluated the status of th e human health assessments for
PPO to determine whether sufficient data are avai lable to support Regist ration Review. HED has
also considered the most recent human-health risk assessments for PPO with respect to toxicity, exposure, and usage databases, along with th e most updated Agency science policy and risk assessment methodologies to determine the scop e of work necessary to support Registration
Review. The assessment of the food use of PP O as an insecticidal fumigant will cover the
antimicrobial use.

Propylene oxide is a FIFRA 88 List B reregistration pesticide. A FIFRA 88 Phase VI Data CallIn (DCI) was issued by the Agency in October 1989 that cited numerous deficiencies in the product and residue chemistry databases. A dditional 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 requirement for the series of acute toxicity studies on PPO has been waived in the past based on available information in the literature, cons ideration of PPO as a low volume, minor use
chemical and/or consideration of the irritant properties of the compound.

Dermal and inhalation exposure monitoring data were requested in 1990 (Morris, 1990). However, a waiver was granted in 1993 based on labeling restrictions and risk mitigation measures such as site air monitoring and placarding.

Occupational Safety and Health Administra tion (OSHA) has established the 8-hour timeweighted 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 carc inogens, which includes PPO. The ACGIH (American Conference of Gove rnmental Industrial Hygienis ts) 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 Hea lth (Cal/OSHA) has established an exposure limit value for PPOPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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### as 20 ppm. The current EPA label for PPO require s respiratory protection if PPO concentrations exceed 20 ppm.

2.0 Hazard Identification/Toxicology

The toxicology database for PPO is not comp lete. Based on a weight of evidence (WOE) approach, a special acute inhalati on toxicity study shoul d be required for PPO at this time based on current testing policy applicable to all commodity fumigants (Rury K., 5/14/13, TXR No. 0056638)

. This special acute inhala tion toxicity study should incl ude the evaluation of the following: histopathology of the respiratory tract, including incidence and severity at multiple tested concentrations; GSH measurements (i.e., nose); pharmacokinetics/tissue dosimetry including time course; and sublet hal portal of entry effects (i.e., within the respiratory tract) along with information on dose response, incidence, and severity. The protocol for this special acute inhalation study should be submitted for agency review, prior to study initiation.

The toxicology database for PCH is not complete. Based on the available da ta and the weight of the evidence, the following studi es are required for PCH: 870.6200a an acute neurotoxicity study and 870.3700a and b developmental toxicity studies in rats and rabbits.

The available evidence from the open literatur e suggests that PPO is 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 minut es following inhalation exposure. PPO is metabolized via conjugati on with glutathione and hydrolysis by epoxide hydrolase to 1,2-propanediol (propylene glycol), which is subse quently metabolized to lactic and pyruvic acids.

The available evidence from the open literature suggests that PCH is wi dely distributed to tissues, metabolized and excreted following inhalation in animals. Most of the administered radioactivity appears to be excreted in urine as glutathione conjugates. Al so, biliary excretion is reported in rats exposed to PC H by inhalation. Following oral e xposure, PCH is eliminated as glucuronic acid and gl utathione conjugates.

PPO is of moderate acute toxicity via the oral route (Category III ) and of low acute toxicity via the inhalation route (Category IV). PPO has seve re irritant properties to eyes and skin and is classified as Category I for both tissues. PPO ha s shown neurotoxicity in rats at a high dose level (1500 ppm or 3.6 mg/L) incl uding: awkward gait/ataxia a nd axonal degeneration of the hindleg nerve. Decreased survival in conjuncti on with clinical symptoms such as dyspnea, hypoactivity, and gasping was also observed at this concentration. PPO causes nasal cavity lesions in both rats (2-year inhalation study; 100 ppm) and mi ce (2-year inhalation study; 200 ppm). Tumors of the nasal cavity (hemangiomas and hemang iosarcomas) were observed in chronically exposed mice. Forestomach tumors were reported in rats in on e chronic oral toxicity study (0, 15 or 60 mg/kg/day; 0/50, 2/50, 19/50, respectively). PPO is mutagenic and forms adducts with proteins and DNA. For the pur pose of risk characterization, a low dose extrapolation model was applied to the animal data for the quantifica tion of human risk (Q 1 

### *), based on the total incidence of hemangiomas and hemangiosarcomas in the nasal cavity of male mice (Q 1 

### * = 1.3x10 -2 

### ). PPO is classified as a probable human carcinogen (B2).

Attachment 2 provides a summary of the acute, subc hronic, and chronic toxi city profiles for PPO
and PCH.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### Attachment 3 provides a summary of the relevant toxicological endpoints used in the PPO risk
assessment. In the most recent risk assessm ent (Memo, D316547, B. Daiss et al., 7/31/06), inhalation endpoints were selected for the acute, short/intermediate-term, and long-term exposure scenarios for PPO. Dermal exposure is not likely due to the volatility of PPO; therefore, dermal endpoints were not selected. In the case of the acute inhalation endpoint, an inhalation point of departure (POD) of 500 ppm, was selected based on developmental effects in rabbits (increased resorptions and an accessory 7 th 

### cervical rib) which were obs erved at the LOAEL of 500 ppm (349 mg/kg/day). To assess the short- and inte rmediate-term occupational inhalation scenario, an inhalation POD of 75 ppm (180 mg/m 3 

### ) was selected based on decreased body weight and body weight gain in both F0 and F1 males a nd females during the premating period in a twogeneration reproduction study with PPO in rats . The study NOAEL and LOAEL were adjusted to human equivalent doses for the occupationa l scenario only, e.g., animal NOAEL of 100 ppm (6h/day, 5d/week) was adjusted to a human NOAEL of 75 ppm (8 h/day, 5d/week), assuming the regional gas dose ratio (RGDR) is similar be tween animals and humans for systemic effects (100 ppm x 6h/8h =75 ppm).

To assess the long-term occupational inhalati on scenario, an inhalation POD of 5.2 ppm (12.5 mg/m3) was selected based on decreased surv ival, increased incidences for basal cell hyperplasia, and nest-like infolds of the re spiratory epithelium. The study NOAEL and LOAEL were adjusted to human equivalent doses fo r the occupational scenario only, e.g., animal NOAEL of 30 ppm (6h/day, 5d/week) was adjust ed to a human NOAEL of 5.2 ppm, after correcting for the duration (8 h/day, 5d/week) and regional gas dose ratio (RGDR) of 0.23 for extrathoracic effects in rats (30 ppm x 6h/8h =22.5 ppm; 22.5 ppm x 0.23= 5.2 ppm). The level of concern (LOC) for acute exposure wa s a margin of exposure (MOE) < 300 (UF H 

### =10, a UF A 

### =3
and a UF L 

### =10) 1 

### . The level of concern (LOC) for short- , intermediate- and long-term exposures was a margin of exposure (MOE) < 30 (UF H 

### =10 and a UF A 

### =3). During registration review, HED may assess whether the endpoints need to be updated based on newly requested data and current policies.

No guideline studies (acute, subchronic, de velopmental, reproduction, immunotoxicity or chronic toxicity studies) have been submitted to agency for PCH. The available data from the open literature indicate that PCH is Categor y II or III by the or al route (D316547, 2006).

In a rat two generation reproducti ve toxicity study (oral drin king water) identified in the literature, decreased body weight gain (15%) in dams during gestation and lactation were observed at 130 mg/kg/day, increased percentages of abnormal sperm (F 1 

### 2.4% vs. 0.78% in the controls), decreased absolute testis weight (8 %) and increased relative epididymis weight (8%) were observed at 130 mg/kg/da y and decreased pup weights (F 1 

### 9% and 20%) were observed at

≥ 65 mg/kg/day. The NOAEL for parental system ic toxicity is 65 mg/kg/day, the NOAEL for reproductive toxicity was not established, but th e NOAEL for offspring was 30 mg/kg/day. This study was used to derive a chronic RfD base d on the offspring NOAEL of 30 mg/kg/day and 1000x UF (cRfD = 0.030 mg/kg/day). A suitable e ndpoint was not found to assess the risk to females 13-49 therefore, the aRfD for PCH was not determined.

PCH was weakly mutagenic in S. typhimurium, and induced sister chromatid exchanges and
chromosomal aberrations in CHO cells and in the mouse lymphoma assay (D316547, 2006).
PCH did not induce micronucleated erythrocytes in peripheral blood of male or female mice via

1 UF H – Uncertainty factor intraindividual variability; UF A –Uncertainty factor interspecies variability; UF L – Uncertainty factor LOAEL to NOAEL extrapolationPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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### drinking water following a 14-week exposure. In addition, there are chronic/carcinogenicity studies conducted by the National Toxicology Program (NTP; in rats and mice) using a mixture of PCH isomers (75% 1-chloro-2 -propanol and 25% 2-chloro-1-pr opanol). This was a drinking water study in rats (0, 15, 30, or 65 mg/kg/da y during the beginning months and 0, 8, 17, or 34 mg/kg/day during the remaining months) and mi ce (0, 45, 75, or 150 mg/kg/day in males and 0, 60, 105, or 210 mg/kg/day in females during firs t few months and 0, 25, 50, or 100 mg/kg/day for remainder of the study) and did not report an y treatment-related cance r or non-cancer effects in either species.

Conclusions: The toxicity database for PPO is in adequate for Registration Review. During Registration Review, the Agency will reevaluate the points of departure (PODs) and uncertainty factors (UFs) for the residen tial and occupational exposure as sessments based on current HED policy, recently submitted studies, and any other outstanding data.

The following toxicological study is required for PPO:

 a special acute inhalation toxi city test (Attachment 4: Justification for Special Acute Inhalation Toxicity Study with PPO),

The following toxicological st udies are required for PCH:

 870.6200a an acute neurotoxicity study,

 870.3700a and b developmental toxicity studies in rats and rabbits

3.0 Residue Chemistry

The residue chemistry database for propylene oxid e is adequate for Registration Review. PPO and PCH are considered separately as residues of concern for tolerance assessment. Residue data from the commodity sterili zation study indicates both PPO a nd PCH are consistently present at high levels in foods fumigated with PPO. Residue data from the spice sterilization study
indicates that PBH is also a reaction product of propylene oxide sterilization. However, PBH
residues are minimal relativ e to PCH residues.

Based on current information from the spice in dustry trade practices, HED concluded that residues measured at 2 days (in transit) after treatment are appropriate for setting tolerance levels; therefore tolerances were set at these levels during rere gistration. Tolerances for PPO range from 1 ppm on raisin to 300 ppm on a num ber of commodities including herbs and spices. Tolerances for PCH range from 3 ppm on fi g to 6000 ppm on a number of commodities.

Conclusions: The residue chemistry database for pr opylene oxide is adequate for Registration Review. The tolerance expression for propylen e oxide will be review ed during registration review to ensure that it appr opriately covers the metabolites a nd degradates of propylene oxide and that it specifies the residues to be measur ed for each commodity. Modifications will be

made as needed.

4.0 Dietary Exposure

The most recent dietary exposure and risk asse ssment was performed in conjunction with the October 2011 request from PRD to assess pine nu ts. Refined acute and chronic dietary risk assessments were conducted using the Dietar y Exposure Evaluation Model (DEEM-FCIDTM, Version 2.03), and the Lifeline Model Version 3 .0 which use food consumption data from thePropylene Oxide Registration Review Human-Health Assessment Scoping Document

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### 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 PP O sterilization studies were used for the acute dietary analysis of propylene oxide. Average residues from the st erilization study were us ed for the chronic and cancer assessments of propylene oxide. Toleran ce level residues were used for the chronic dietary analysis of PCH. Per cent crop treated data provided by BEAD were used for the acute and chronic analyses. A dri nking water exposure assessment was not conducted for this
assessment because the Environmental Fate and E ffects Division (EFED) expects that uses of propylene oxide for indoor and outdoor food a nd nonfood uses will result in insignificant exposure to drinking water resources.

The refined probabilistic acute dietary exposur e assessment for the population subgroup females 13-49 concluded that for all supported commoditie s, the acute dietary exposure estimates for
PPO were below HED’s level of concern. The as sessment also concluded that for all supported commodities, the chronic dietary exposure estimates for PPO were below HED’s level of concern. The cancer dietary risk estimates fo r propylene oxide were below HED’s level of

concern. An acute RfD was not established for PCH b ecause an endpoint attributable to a single (or few) day exposure was not identified from th e available database. The assessment concluded that for all supported commodities, the chronic dietary exposure estimates for PCH were below
HED’s level of concern.

Conclusions: The dietary-exposure database is adequa te to support the exis ting registrations. However, a new dietary exposure and risk as sessment may be required during Registration Review to incorporate potential changes to the propylen e oxide and PCH toxicological PODs. In addition, the assessment should include updated cons umption information and utilize the newest
version of DEEM-FCID.

5.0 Residential Exposure

For most fumigants, the Agency has historica lly assumed that, provided adequate aeration of structures is completed prior to re-entry, exposure to owners of fu migated structures is expected to be negligible; however, there is the potenti al for bystander exposures, which can occur from emissions during treatment and aeration of comm odities and structures. In the most recent exposure/risk assessment for PPO (Memo, M. Cr owley; D337025; 4/26/07), the Probabilistic Exposure and Risk model for Fumigants (PERFUM) was used to assess residential bystander risks, and risks of concern were identifi ed for various fumigation scenarios.

Another set of PERFUM data submitted in 2009 by the registrant, ABERCO, Inc., (MRID 47692001), was reviewed by the Agency (Memo, Crow ley; D316539; 4/9/09), a nd used to refine the bystander assessment. Using these data, the “buffer zones” ranged from 165 meters down to zero meters. Currently, the Agency is in the pr ocess of reviewing a new set of PERFUM data that have been submitted along with other suggest ed modifications to the existing registered product label of Propoxide 892. The proposed labe l amendments would greatly alter the use pattern for PPO because use would be permitted on much larger structures (i.e., 1,000,000 ft 3 

### structure size with a 10 ft buffer zone). Cu rrently the maximum structure size is 10,000 ft 3 

### with
a 200 ft buffer zone.

There is sufficient information to complete registration review for PPO. However, in the event that the available information suggests that there may be bystander risks of concern, a morePropylene Oxide Registration Review Human-Health Assessment Scoping Document

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### refined analysis would be possible if additional data were availabl e. Types of information that could be used to refine the bystander assessm ent include: information on treatment conditions such as building/structure types, volumes treat ed, concentration/time schedules used, release height, air exchange rates, and historical emissions data. In summary, to the extent that the available data show potential for bystander exposure, updated residential assessments will be conducted during registration review.

Conclusions for Residential Bystander Exposure

Revisiting the residential bystander risk assessm ent during registration re view is recommended. Bystander risk from PPO emissions from treated commodities and structures will need to be evaluated based on PPO emissions, the label pres cribed use conditions, and if the points of departure (PODs) or uncertainty factors (UFs) change based on new acute toxicological data being submitted.

6.0 Aggregate-Risk Assessment

Aggregate-risk assessments included only exposur e from food only for PPO during the RED. Residential exposure and dietary exposure from water was not expe cted since PPO is registered for commodity and structure fumigation only. Aggregate risk assessments may be required during Registration Review since residential bystander exposure may be assessed at that time.

7.0 Occupational Exposure

PPO is an insecticidal fumigant and sterilant us ed both to control bacter ial contamination, mold contamination, insect infestations , and microbial spoilage of food products, as well as to control insects in non-food products. PPO is formulated as a pressurized liquid and/or gas. PPO can be applied as a gas in vacuum-sealed pressurized chambers (also referred to as commercial sterilization chambers). PPO can also be applie d in other types of chambers and in spaces such as trailers, rail cars, tents or tarps where gas is confined sufficiently to achieve a viable fumigation.

No data regarding the number of exposure da ys per year for occupational workers were provided. According to the Reregistration El igibility Decision (RED) for PPO, inhalation exposures were assessed for short-, intermediate-, and long-term durations , and potential risks of concern were found. To address these risks, the Agency concluded that an 8-hour Time Weighted Average (TWA) concentration of 2 ppm, as recommended by the American
Conference of Governmental Indus trial Hygienists (ACGIH), wa s protective of all potential exposure durations. Dermal exposure ri sks were considered negligible.

No worker exposure data were submitted to the Agency regarding the fumigation of food commodities. As such, HED is requiring worker exposure data associated with commodity fumigation.

As part of registration review, tasks for workers near fumigation facilities/ operations need to be defined to properly assess post-application activi ties (i.e. aerators, fork-l ift operators, etc.). Potential exposures due to off-gassing will al so be assessed for workers conducting postapplication activities ne ar treatment operations.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### Conclusions for Occupational Exposure

The Agency believes that most applicator exposures are likely to be of a shorter duration (i.e., acute or short-term by agency definition). A much smaller percentage of the overall user population is expected to have longer duration expos ures (i.e., intermediate-term or chronic). A new occupational handler risk reassessment may be completed during registration review to incorporate recently submitted data that have not yet been reviewed as well as data requested under the data call-in process, a nd to the extent that they are available, policies currently under development regarding assessment of fumigant chemicals. The existing data for workers’ exposure to PPO are limited in term s of the variety of post-applica tion activities (i.e., for tasks where data do not exist). 2 

### Emission-rate data for potential exposures due to off-gassing from
treated facilities/commodities for workers condu cting post-application ac tivities need to be submitted to the Agency (i.e., aeration conditi ons, flux, and off gassing from representative commodities). 2

o 

### 875.1400 Inhalation Exposure Study for Applicators . These studies are required to assess exposures for applicators involved in fumigating commodities/materials
and/or structural 

### facilities.

o 

### 875.1700 Product Use Information . This study is required to assess product use information parameters by major us e region, frequency, and application equipment.

o 875.2500 Post-Application Inhalatio n Exposure Study - outdoor. This study is required to assess post-app lication exposures for work ers or bystanders near fumigation facilities/operations, or for t hose who work directly with previously
treated commodities/materials.

o Special Study - Monitoring data on fumigated commodities . This study is required to evaluate emission rates for PPO from treated commodities/materials and the potential for occupati onal exposure due to those emissions in the channels of trade after fumigation activities are complete.

o Special Study – Ambient air monitoring. This study is required to assess ambient air concentrations for communities in proximity to treated facilities.

8.0 Public Health and Pesticide Epidemiology Data

No cases involving propylene oxide were iden tified in IDS(January 1, 2008 to February 19, 2013) or SENSOR (1998-2009)-Pesticid es. For this reason there does not appear to be a concern at this time that would warrant further investig ation. The Agency will co ntinue to monitor the incident information; and, if a concern is tri ggered, additional analysis will be included in the
risk assessment.

2 Details to be determined based on protocol discussion with Agency.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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### 9.0 Tolerance Assessment and International Harmonization

Tolerances are established for residues of the fumigant propylene oxide, including its metabolites and degradates, in 40 CFR §180.491. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring on ly propylene oxide, when used as a postharvest fumigant, in or on the commodity. Tolerances range from 1 ppm on raisin to 300 ppm on a number of commodities including herbs and spices.

Tolerances are established for residues of the reaction product, propylene chlorohydrin, including its metabolites and degr adates. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring on ly the sum of propylene chlorohydrin (1-chloro-2- propanol), and its isomer 2-chloro -1-propanol, calculated as the stoichiometric equivalent of propylene chlorohydrin (1-chloro-2- propanol), that results from th e use of propylene oxide as a postharvest fumigant, in or on the commodity. Tolerances range from 3 ppm on fig to 6000 ppm
on a number of commodities.

The tolerance expression for propylene oxide will be reviewed during registration review to ensure that it appropriately c overs the metabolites and degradat es of propylene oxide and that it specifies the residues to be measured for each commodity. Modifications will be made as

needed.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 12 of 38 

### International Residue Limits

PPO (PC Code 042501; Date of Request 05/13/13) 

### Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 

### Codex 3



### 40 CFR 180.491 Plant: propylene oxide and separately, propylene chlorohydrin (2-chloroethanol) PPO Plant:



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US 4 

### Canada Mexico 2 

### Codex 3

Basil –, 6000
Herb and spice, group 19, dried, except basil 300, 1500

Cocoa bean, cocoa powder 200, 20

Cocoa bean, dried bean 200, 20
Fig 3,3
Garlic, dried 300, 6000
Grape, raisin 1, 4
Nut, pine 300, 10
Nut, tree, group 14 300, 10 

### 300, --
Nutmeat, processed, except peanuts 300, 10
Onion, dried 300, 6000
Pistachio 300, 10
Plum, prune, dried 2, 2



### Completed: M. Negussie;

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated co mmodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

4 First number represents PPO tolerance values, se cond number represents PCH tolerance value.



### At the present time, there are no CODEX MRLs. The United States is harmonized with Canada on the MRL for PPO in/on Tree Nuts, group 14. There are no other Canadian MRLs for U.S. registered commodities.

10.0 Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the most recent PPO human health risk assessment, in accordance with U.S. Executive Order 12898,
“Federal Actions to Address Environmental Ju stice in Minority Populations and Low-Income Populations,” ( http://www.hss.energy.gov/nuc learsafety/env/guidance /justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human-health risk assessments , including, but not limited to, people who obtain drinking water from sources near agricultural areas, the va riability of diets within the U.S., and people who may be exposed when harv esting crops. Should th ese highest exposures indicate potential risks of concern, OPP will further refine the risk assessments to ensure that the
risk estimates are based on the best available information.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 13 of 38 

### 11.0 Cumulative

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to PPO and any other substances. For the purpose s of this assessment, therefore, EPA has not
assumed that PPO has a common mechanism of toxi city with other substa nces. For information regarding EPA’s efforts to determine which ch emicals have a common me chanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concer ning common mechanism determinations and procedures for cumulating effects from subs tances found to have a common mechanism on
EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

12.0 Endocrine Disruption

As required by the Federal Insecticide, Fungicide , and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA re views numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,
subchronic and chronic toxici ty, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or syst emic toxicity. These studies include endpoints which may be susceptible to endocrine influenc e, including effects on endocrine target organ histopathology, organ weights, es trus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard asse ssments, EPA evaluates
acute tests and chronic studies that assess growth, developmen tal and reproductive effects in different taxonomic groups. As part of its most recent reregistration decision, EPA reviewed these data and selected the most sensitive endpoint s for relevant risk assessment scenarios from the existing hazard database. However, as re quired by FFDCA section 408(p), propylene oxide is subject to the endocrine scre ening part of the Endocrine Disr uptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required
determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active in gredients and 9 inert ingredients. Propylene oxide is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of Regi stration Review, EPA w ill issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for propylene oxide. For further information on the status of the EDSP, the policies and procedur es, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening batt ery, please visit our website: http://www.epa.gov/endo/

.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 14 of 38 

### 13.0 Human Studies

Past PPO risk assessments rely in part on data from studies in which a dult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Databa se. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databa ses, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevai ling at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subj ects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on
these studies.

14.0 Risk Assessment Updates, Data Deficiencies, and Label Revisions

The following data deficiencies were identified for Propylene Oxide:

 Toxicology:

o PPO - Special acute inhalation toxicity study (Attachment 4: Justification for Special Acute Inhalation Toxicity Study with PPO)

o PCH- 870.6200a Acute neurotoxicity st udy and 870.3700a and b Developmental toxicity studies in rats and rabbits

 Residue Chemistry: None

 Dietary Exposure: None

 Occupational/Residen tial Exposure:

o 

### 875.1400 Inhalation Exposure Study for Applicators . These studies are required to assess exposures for applicators involved in fumigating commodities/materials
and/or structural 

### facilities.

o 

### 875.1700 Product Use Information . This study is required to assess product use information parameters by major us e region, frequency, and application equipment.

o 875.2500 Post-Application Inhalatio n Exposure Study - outdoor. This study is required to assess post-app lication exposures for work ers or bystanders near fumigation facilities/operations, or for t hose who work directly with previously
treated commodities/materials.

o Special Study - Monitoring data on fumigated commodities . This study is required to evaluate emission rates for PPO from treated commodities/materials and the potential for occupati onal exposure due to those emissions in the channels of trade after fumigation activities are complete.

o Special Study – Ambient air monitoring. This study is required to assess ambient air concentrations for communities in proximity to treated facilities.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 15 of 38 

### EPA anticipates conducting the following risk assessment updates during Registration Review:

 Toxicology:

o Reevaluation of the toxicity endpoint/dos e selection may be necessary based on the recently submitted toxicological data.

 Residue Chemistry: None

 Dietary Exposure: New dietary exposure and risk assessments may be required during Registration Review to incorporate potentia l changes to the propylene oxide and/or PCH toxicological PODs. In addition, the a ssessment should include updated consumption
information and utilize the ne west version of DEEM-FCID.

 Occupational/Residen tial Exposure:

o Revised HED occupational handler risk assessments may be necessary based on the most recent exposure data, Agency policies, or if the toxicological
reevaluation results in changes to the endpoints.

o Additional or revised HED residential bystander risk assessments may be necessary based on the most recent expos ure data, Agency policies, or if the toxicological reevaluatio n of results in changes to the endpoints.

15.0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title

J. Stokes D316573 6/22/2006 Addendum to Revised PPO RED Chemistry Chapter Dated 09/19/05: Additional Residue Chemistry Data For Fumigation Use of Propylene Oxide In/on Almond and
Walnut Nutmeats and Inshell Almonds.

J. Stokes D316571 9/22/05 Revised Residue Chemistry Chapter For Propylene Oxide Reregistration Eligibility

B. Daiss D316568 10/13/2011 Propylene Oxide – Acute and Chronic Dietary Exposure
and Risk Estimates for Use on Pinenuts

B. Daiss D329648 6/6/2006 Propylene Oxide Acute, Ch ronic and Revised Cancer Dietary Exposure Assessments for the Reregistration Eligibility Decision

B. Daiss D316547 7/30/2006 Propylene Oxide – Revised HED Risk Assessment for Reregistration Eligibility Decision (RED) Document
M. Crowley D316539 4/9/2009 Propylene Oxide: Review of Submitted PERFUM Results

M. Crowley D337025 4/26/2007 Propylene Oxide: Revision to the NonOccupational/Residential Risk Assessment for Commodity Fumigations

M. Crowley D316545 7/31/2006 Propylene Oxide: Revised Non-Occupational/Residential Risk Assessment for Commodity Fumigations



### Attachments:

Attachment 1: Chemical Identity Table. Attachment 2: PPO and PCH Acute, Subchronic, and Chronic Toxicity Profile Attachment 3: Propylene Oxide Endpoint Selection Tables
Attachment 4: Justification for Studies with PPO Attachment 5: Propylene Oxide Literature Study ReferencesPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 16 of 38 

### Attachment 1: Chemic al Identity Table.

Table 2. Nomenclatures and Physic al/Chemical Properties of Prop ylene Oxide and the Metabolites

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 C 3 H 6 O C 3 H 7 ClO C 3 H 7 BrO

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 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 (K

ow ) 25 oC K
ow 0.03 NA NA NA NA

UV/vis Absorption Spectrum NA NA NA NA NA

NA = not available 

### O

CH 3 OH

Cl Cl

O H OH

Br Br

O HPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 17 of 38 

### Attachment 2: PPO and PCH Acute, Subchronic, and Chronic Toxicity Profile

PPO Acute Toxicity Studies

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 EPA, 1987) LD 50 520-1140 mg/kg bw

LD 50 630 mg/kg bw (males)

LD 50 660-690 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 LC 50 (4h): 7697-8265 mg/m 3 (3207-3444 ppm)

LC 50 (4h): 2420-3540 mg/m 3 (1008- 1475 ppm) Category IV

Category IV

870.2400 Primary Eye Irritation, Rabbits Weil et al., 1963 (As cited in WHO, 1985) 5 ul pf PPO applied once to the cornea produced severe burn resulting in necrosis. Severe eye irritant Category I

870.2500 Primary Skin Irritation, Rabbits Rowe et al., 1956 (As cited in EPA, 1987) 10 or 20% PPO aqueous solution produced hyperaemia, edema and
final scars after 6 or more minutes. The intensity proportional to the exposure
time.
Severe skin irritant Category I

870.2600 Dermal Sensitization, Guinea Pigs No study identified

870.6200 Acute Neurotoxicity, Rats No study identified

PPO Subchronic, Chronic Toxicity Studies

Study/Species MRID or
Publication Doses Results/Classification

Developmental/Reproduction Toxicity Developmental Toxicity
Fischer 344

Rats 41750801 (or
Drummond and Keller, 1988) Doses (inhalation): 0, 100, 300, 500 ppm (GD 6-15) Maternal NOAEL: 300 ppm Maternal LOAEL: 500 ppm Decreased body weight gain and food consumption Developmental NOAEL: 300 ppm Developmental LOAEL: 500 ppm Increased litter incidence of an accessory 7th cervical
rib Acceptable/Guideline

- 6h/day 25 rats/group Developmental Toxicity 41874102 (Hackett et al. 1982) Doses (inhalation): Maternal NOAEL: <500 ppm Maternal LOAEL: 500 ppmPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 18 of 38SpragueDawley Rats 0, 500 ppm (GD 7-16, GD1-16,
GD1-16 with
3 week pregesational exposure) Decreased body weight, body weight gain and food consumption Developmental NOAEL: <500 ppm Developmental LOAEL: 500 ppm Decreased mean fetal weig ht, decreased crown rump length in males and females and possibly increased
fetal and litter incidence for the reduced ossification
of the vertebra. Unacceptable/Guideline 45-48 rats/group 7h/day Developmental Toxicity, New
Zealand White
Rabbits 41874102 (Hackett et al. 1982) 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, lungs and kidneys GD7-19: Decrease in absolute food consumption, histo- minimal to mild portal mononuclear inflammation of the lung GD1-19- Decreased body weight, gravid uterine weight, histo. includes minimal to mild portal mononuclear inflammation in the liver, mineralization of proximal and renal tubules, subacute/chronic nephritis and focal mono nuclear inflammation Developmental NOAEL: <500 ppm Developmental LOAEL: 500 ppm Increased resorptions, and/or increased incidence of
minor skeletal abnormalities Unacceptable/Guideline
30/treatment 7h/day

TwoGeneration Reproduction Study, Fischer

344 Rats 45292701 Hayes et al. 1985 Doses (inhalation): 0, 30, 100, 300 ppm 6h/day,
5d/week 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 30/sex/group 6h/d, 5d/wk- 14 wks of F0; 17 wks F1 premating period 6h/day, 7d/wk –during mating gestation and lactation periods Subchronic Oral Toxicity

Subchronic Toxicity, Rats, Antonova et al. 1981 (as cited in WHO, Doses (drinking NOAEL: 0.0052 mg/kg/day LOAEL: 0.052 mg/kg/dayPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 19 of 38 Strain not specified, 26-
weeks 1985) water): 0, 0.00052, 0.0052, 0.052, 0.52 mg/kg/day Mild hematological abnormalities At highest dose, polyuria, hematological abnormalities, decreased serum albumin, increased serum-beta-globulin levels and increased activity of gastrointestinal mucosal enzymes Acceptable/Non-Guideline ?

Subchronic 24 days
Females rats Rowe et al. 1956 (as cited in EPA, 1987) Doses (oral): 0, 100, 200, 300 mg/kg NOAEL: 0.2 mg/kg LOAEL: 0.3 mg/kg Slight decrease in body weight, gastric irritation, and slight liver damage Acceptable/Non-Guideline? 18 doses in 24 days Subchronic Inhalation Toxicity

Subchronic Neurotoxicity,
Fischer 344 Rats, 24 weeks Young et al., 1985

45292801 Doses (inhalation): 0, 30, 100, 300 ppm NOAEL: 300 ppm LOAEL: >300 ppm No systemic and neurologi cal effects at the HDT Acceptable/Non-Guideline (motor activity tested only at the end of treatment; only one sex tested) 6h/day, 5d/week (14 wk), 7d/wk (remainder of the study) 30/group males only
Subchronic Neurotoxicity, Wistar Rats, 7
weeks Ohnishi et al., 1988 (IRIS) 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 7 th week; histo: axonal degeneration of the hindleg nerve and fasciculus gracilis and myelinated fibers in the sacral spinal root Acceptable/Non-Guideline 6h/day, 5d/week 11/sex/group

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 Dyspnea, hypoactivity, gaspin g, ataxia, and diarrhea were observed at the highest dose; 20% mortality in
males

6h/day, 5d/week Range finding test 5/sex/group

Subchronic Toxicity, B6C3F1Mice, 12-14 days NTP, 1985 Doses (inhalation): 0, 20, 47, 99, 196, 487

ppm NOAEL: 99 ppm LOAEL: 196 ppm Dyspnea at 196 and 487 ppm; less active at 487 ppm Acceptable/Non-Guideline 6h/day, 5d/week Range finding test 5/sex/group

Subchronic Toxicity,
Fischer 344/N Rats, 13 weeks NTP, 1985 Doses (inhalation): 0, 31, 63, 125, 250, 500 ppm NOAEL: 250 ppm LOAEL: 500 ppm Decreased body weight Acceptable/Non-Guideline 6h/day, 5d/week Range finding test 5/sex/group

Subchronic Toxicity, NTP, 1985 Doses (inhalation): NOAEL: 250 ppm LOAEL: 500 ppmPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 20 of 38 B6C3F1Mice,
13 weeks 0, 31, 63, 125, 250, 500 ppm Decreased body weight (12.9% in males and 14.6% in females) Acceptable/Non-Guideline 6h/day, 5d/week Range finding test 5/sex/group

Subchronic

870.3465 Rats (Strain not specified), 16-
31 weeks Rowe, 1956 (as cited in WHO, 1985 and EPA, 1987) Doses (inhalation): 0, 102, 195, 457 ppm NOAEL: 195 ppm LOAEL: 457 ppm irritation of the eyes and respiratory passages, decreased body weight and increased mortality rate ; histo changes in liver such as alveolar edema and hemorrhage and hyperaemia of the lungs after 5
weeks Acceptable/Non-Guideline 10-20 rats of both sexes/group, (number of animals per sex not specified) 7h/d, 5d/wk

Subchronic

870.3465 Guinea Pigs (Strain not specified), 22-
26 weeks Rowe, 1956 (as cited in WHO, 1985 and EPA, 1987) Doses (inhalation): 0, 102, 195, 457 ppm NOAEL: Not Established LOAEL: 195 ppm increased lung weight in females HDT-irritation of the eyes and respiratory passages and decreased bw, fatty degeneration of the liver, increased lung weight in both sexes; histo changes in liver such as alveolar edema and hemorrhage and hyperaemia of the lungs; Acceptable/Non-Guideline 8 guinea pigs of both sexes/group (number of animals per sex not specified) 7h/d, 5d/wk

870.3465 Sprague Dawley rats, 30 days Sellakumar et al., 1987 (as cited in IARC, 1994) Doses (inhalation): 0, 435, 870, 1740 ppm ( 8 days

exposure only for the HDT) NOAEL: 870 ppm LOAEL: 1740 ppm
Decreased survival in the HDT Male rats only
All rats were observed for life 50 rats/ group except controls had 98 rats. 6h/day, 5 d/wk
Cancer effects 2 mid dose animals had lung adenomas Chronic Oral Toxicity

870.4100
ChronicToxicitySpragueDawley Rats 2 years Dunkelberg, 1982 Doses (oral): 0, 0(vehicle),

15 or 60 mg/kg in
salad oil

Gavage NOAEL: 15 mg/kg/day LOAEL: 60 mg/kg/day 30% mortality at 104 weeks

Cancer Effects Forestomach tumors-primarily squamous cell carcinoma (no of animals with forestomach tumors were 0/50 for both controls, 2/50, and 19/50 for low and high dose groups Combined incidences of hyperkeratosis, hyperplasia and papillomas were 0/50, 7/50, and 17/50) Highest dose also had one adenocarcinoma of the pylorus 50 rats/group, gavaged twice/week Females only
It is not clear if rats were treated for 150 weeks or rats
were treated for 112 weeks and observed until 150 wks. No exposure from 79-82 weeks due to an outbreak of pneumonia Limited histopathology (liver, kidney and thyroid etc. not examined)Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 21 of 38 No statistical analysis Chronic Inhalation Toxicity

870.4300
Combined/
Chronic Toxicity/ Carcinogenicity Study, Wistar

Rats
123 weeks (Females)
124 weeks (Males) Kuper et al. 1988
and 42039901 (Reuzel and Kuper, 1983) Doses (inhalation): 0, 30, 100 or 300 ppm -(0, 71, 238, 713 mg/m3) Systemic NOAEL: Not Established Systemic LOAEL: 30 ppm (HED 2.9 mg/m3) Nest-like in folds of the nasal respiratory epithelium
at 28 months At 300 ppm- increased mortal ity (increased mortality ( 79% vs 46% in males and 79% vs 43% in females) and decreased absolute body weight and body weight gain; decreased food consumption, increased incidence of olfactory epithel ium atrophy at 12 and 28 months and basal cell hyperplasia of the olfactory epithelium at 12, 18 and 24 months,
-increased incidence of nest-like in-folds of respiratory epithelium at 12, 18, 24 and 28 months; possibly, increased incidence of thrombi in the heart
in males and increased incidence of adrenal enlargement in females and myocardial degeneration
in females.

At 100ppm - increased mortality (61% versus 43% in females)

, slight basal cell hyperplasia of the olfactory epithelium, and nest-like in folds of the respiratory epithelium from 18 months onward Acceptable/Guideline Study -100 rats/sex/group -6h/day, 5d/wk 70rats/sex/group in the main study 10rats/sex/group the groups killed at 12, 18, or 24
months
-123 weeks -duration adjusted conc based on data on males. 0, 13, 43, and 127 mg/m3 -interim sacrifice at 12, 18 and 24 months and final 28
months survival, clin chem. and pathology determined

Nasal cavity- No significant nasal tumors. 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). Five males in the
HDT had a carcinoma in th e larynx or pharynx, trachea or lungs.

Mammary gland- Significant tumors in high dose
females Fibroadenomas: 32/69, 30/71, 39/69, 47/70 in control, low, mid and high dose groups respectively (p<0.04). Historical control incidence of mammary tumors in the lab ranges 0-15% (0/30 to 15/99); Tubulopapillary adenocarcinoma- 3/69, 6/71, 5/69 8/70 (p<0.01)

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, survival, increased hemoglobin, extra thoracic (nasal suppurative rihinitis), and
thoracic effects

300 ppm- decreased body weight and survival,Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 22 of 38 increased hemoglobin, nasal suppurative rhinitis and complex epithelial hyperplasia 0/76, 2/77, 11/78, skeletal muscle myopathy (25/78 versus 7/77 controls) Other non-neoplastic changes at both dose levels include pulmonary pneumonia, and edema,; tracheitis, bronchial lymph node hyperplasia, and multifocal myopathy of skeletal muscle -7 h/day, 5d/week -80 rats/group -duration adjusted concn. (0, 49, 150 mg/m3) -mycoplasma contamination in all groups

Cancer Effects Adrenal phaechromocytoma 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 (HEC, 16 mg/m3) extra thoracic respiratory effects Acceptable/Non-Guideline -(6h/day, 5d/week)
-50animals/sex/treatment Duration adjusted dose (0, 85, 170 mg/m3) -No significant changes in survival or body weights -Increase in suppurative inflammation of the nasal cavity: 7/50, 19/50, 33/50 in respective males and 3/50, 5/50, 20/50, in respective females -Increase in epithelial hyperplasia (0/50, 1/50, and 11/50 in respective males and 0/50, 0/48 and 5/48 in respective females -Increase in squamous metaplasia (1/50, 3/50, 21/50 in respective males and 1/50, 2/48, 11/48 in respective females)

Cancer Effects: At 400 ppm, 2/50 (m) and 3/50 (f) had papillary adenomas of the respiratory epithelium and submucosal glands of the na sal turbinates compared to none in low and control groups. A dose related 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 as some evidence of carcinogenicity for PPO in rats.

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 (HEC, 16 mg/m3) extrathoracic respiratory effects Acceptable/Non-Guideline -400 ppm decreased survival in males and females, decreased body weights in both sexes, sporadic metaplasia and hyperplasia ; histo lesions mainly in nasal cavity

Chronic inflammation of the nasal cavity (1/50, 13/50, and 38/50 in male mice and 0/50, 13/50 and 17/50 in
female mice -(6h/day, 5d/week)
-50animals/sex/treatmentPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 23 of 38 Duration adjusted dose (0, 85, 170 mg/m3)

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 sig), adenocarcinomas in nasal cavity ( 2 females, not sig)
Other tissues: Possible adenocarcinomas of the mammary gland (within historical controls)
NTP concluded as clear ev idence of carcinogenicity
for PPO in mice.

870.4100
ChronicToxicitycynomolgus Monkeys 2 years Sprinz et al. 1982 Doses (inhalation): 0, 100 or 300

ppm NOAEL: Not established LOAEL: 100 ppm
Increased incidence for ax onal dystrophy in the medulla oblongata and in the most distal portions of the fasciculus gracilus in all treated monkeys (2/2) as compared to one (1/2) in controls. No dose related
lesions between the treatments. Acceptable/Non-Guideline Study? 2/group 7h/day, 5d/week 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 transsferase 2) hydrolysis by epoxide hydrolase to 1,2 propanediol (propylene glycol??). Propane diol can be excreted as such or metabolized to lactic and pyruvic acid -Propylene oxide is a direct acting agent. Forms DNA(N-2-hydroxypropyl-guanosine, N-2-hydroxypropylguanosine and protein adducts (hemoglobin alkylation at the cysteine, histidin e 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 The half-life of propylene oxide in stomach conditions (pH1 and 37°C) is reported approximately one
minute. Mutation/Genotoxicity WHO, 1985 - 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.

Human Studies Case–control Ott et al., 1989 ( as - Cohort from two chemical manufacturing facilities inPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 24 of 38 Study cited in IARC, 1994) US died during 1940-1978 were identified (52 cases of non-Hodgkin’s lymphoma, 20 multiple myeloma, 39 non-lymphatic leukaemia and 18 lymphatic leukemia). Controls were se lected from the cohort in a ratio of 5:1 and were matched to cases by sex, decade of first employment and survival to the start of the same five year period. Exposures were inferred from the recorded job history. Odds Ratios for menexposed versus not exposed are: 1.5 for nonHodgkin’s lymphoma (4 cases), 3.4 for multiple myeloma ( 3 cases), 1.3 for non lymphatic leukemia (3 cases) and zero lymphatic leukemia (0 case). None of these ratios were found significant. No quantifiable information on the levels of propylene oxide exposure or on possible confounding effects from other chemical exposures.

Acute Toxicity of PCH

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 BIBRA International, 1994) Oral LD 50 = 220 mg/kg

Oral LD 50 = 580 mg/kg

Oral LD 50 = 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 BIBRA International, 1994) LD 50 = 528 mg/kg

LD 50 = 440 mg/kg Category II

Category II

870.1300

Acute Inhalation, Rats Smyth and Carpenter,

1969 (as cited in SRC Report for US EPA, 1980) LC 50 = ~500 ppm ( 1.94 mg/L) Category III

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

PCH

870.2500 Primary Skin Irritation,
Rabbits Smyth et al 1969 (as cited in BIBRA International, 1994) Limited data-No irritation 24 hr following application of 0.01 ml
PCH in a rabbit

870.2600 Dermal Sensitization, Guinea pig No study identified - -

870.6200 Acute Neurotoxicity, Rats No study identified - -Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 25 of 38 PCH Subchronic, Chronic Toxicity Studies

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

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:30 mg/kg/day Parental LOAEL: 65 mg/kg/day Decreased body weight of dams during gestation and during lactation, PND 0-14 Reproductive NOAEL: 65 mg/kg/day 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 pup weight for males and females
at PND 14 and 21 Acceptable/Non-Guideline 130 mg/kg/day : also had decreased body weight during gestation period and lactation, PND 0-21. 20 pairs/group except controls had 40 pairs/group F0 parents (F1 pups) had five litters Note: F2 generation had only controls and high dose group (i.e., 300 and 650 ppm F1 adults were not continued for F2 generation) Subchronic Oral Toxicity 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 At 3300 and 10000

ppm- Decreased body weight and body weight gain, decreased water consumption cytoplasmic alteration and degeneration of the acinar cells and fatty change in the pancreas, atrophy of the bone marrow, and atrophy and hematopoiesis of the spleen in males and females At 10,000 ppm- - 20% mortality of the females, decreased absolute as well as relative (to body weight) thymus weight Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol 10/sex/group Note: The dose in the 3300 ppm is not different from the10,000 ppm group due to significant differences in water consumption between the
two groups.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 26 of 38 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 vacu olization of cytoplasm of hepatocytes in both males and females 3300 ppm- Dec water consumption 10000 ppm –Dec body weight, decreased water consumption, 10% mortality of the males, dec thymus weight Both 3300 and 10000 ppm-Hepatocellular cytoplasmic vacuolization, and cytoplasmic alteration of acinar cells of pancreas. Degeneration of the acinar cells of pancreas (3300 ppm) and atrophy of the spleen in males and females (HDT only). Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol 10/sex/group 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 (330 ppm) LOAEL: 100 mg/kg/day (1000 ppm)
Increased incidences of the acinar cell degeneration, fatty change of the pancreas in males and females and cytoplasmic vacuolization of the liver in males, and mild anemia in females At 3300 ppm decreased body weight, body weight gain, decreased water consumption in
males and females and minimal to mild anemia in females, and decreased weights of cauda epididymis and epididymis, inc percent of abnormal sperm in males. Also,
increased incidences of the acinar cell degeneration, fatty change of the pancreas, focal metaplasia of the pancreatic islets (females only), cytoplasmic vacuolization of the liver and renal tubule epithelium degeneration (females).

Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol 10/sex/group 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: Not Established mg/kg/day LOAEL: 7 mg/kg/day Inc liver weight and cyt oplasmic vacuolization of hepatocytes in females 1000 ppm- inc liver and thymus weight in females,and inc incidence of the renal tubule cytoplasmic vacuolization in males 3300 ppm – decreased water consumption, in both sexes minimal anemia, inc epididymis, and kidney weight in males, and inc incidences of pancreatic acinar cell degeneration and fatty change in both sexes and cytoplasmic
vacuolization of the liver in females Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol 10/sex/groupPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 27 of 38 Subchronic (22 weeks)

Rats USFDA,
1969 (as cited in

BIBRA
Internationa l, 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 75 mkd-decreased bw, Unacceptable/Nonguideline 10/sex/group Another group given increasing concn of 100-250 mg/kg bw/day for 19 weeks: weight loss at 200 mg/kg/day, and 100% mortality at 250 mg/kg/day within 3 weeks Mixture or pure isomer (no information) Subchronic (25 weeks)

Rats USFDA,
1969 (as cited in

BIBRA
Internationa l, 1994) Doses: 0, 1000, 2500, 5000 or 10000 ppm in diet (estimated as 0, 100, 250,
500 1000 mg/kg/day) NOAEL: 100 mg/kg/day LOAEL: 250 mg/kg/day
Decreased bw Unacceptable/Nonguideline 10/sex/group Poor recovery of 10,000 ppm diet – 3568 ppm on immediate analysis and 838 ppm after 7 days (mixture, 73% 1-CP, 27% 2-CP) 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 Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol 50/sex/group
No treatment related cancer or non-cancer effects

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 Acceptable/Non-Guideline 75%1-chloro 2-propanol and ~25%2-chloro 1- propanol

Mutation/Genotoxicity Multiple - -Weakly mutagenic in TA100 in the presence ofPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 28 of 38 references (as cited in NTP, 1998) S9
Positive in TA1535 w ith 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 reci procal 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 PCH
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 betacholoroacetate 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.

Human Studies No study
identified - -Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 29 of 38 

### Attachment 3: Propylene Oxide Endpoint Selection Tables.

Table 6: Summary of Toxicological Doses and Endpoints for Propylene Oxide and the Metabolite, Propylene Chlorohydrin) for Use in Human Risk Assessments

Exposure
Scenario Dose Used in
Risk Assessment,

UF 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 = 0.21 mg/kg/day Developmental Toxicity, Rats (MRID 41750801) Developmental LOAEL: # 349 mg/kg/day (500 ppm ) Increased litter incidence of an accessory 7th cervical
rib

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

Chronic Dietary (All populations) † BMDL 10 = 1.4 mg/kg/day

UF = 1000
Chronic RfD = 0.001 mg/kg/day FQPA SF = 1X

cPAD = 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 OralExposure, ShortTerm (1 - 30 days)
Intermediate-Term (1 - 6 months) No hand to mouth exposure is expected for children. Therefore, this scenario is not applicable.

Dermal, ShortTerm, IntermediateTerm, and LongTerm (> 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 = 500ppm

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 = 500ppm

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/m 3 )
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/m 3 )
Decreased body weight and body weight gain in both

F 0 and F 1 males and females during premating periodsPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 30 of 38 Table 6: Summary of Toxicological Doses and Endpoints for Propylene Oxide and the Metabolite, Propylene Chlorohydrin) for Use in Human Risk Assessments

Exposure
Scenario Dose Used in
Risk Assessment,

UF FQPA SF and
Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation Long-Term
(> 6 months) § NOAEL = 5.2

ppm (12.5 mg/m 3 )

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

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

§ LOAEL = 17.3 ppm (41.5 mg/m 3 )
Decreased survival, increased incidences for basal cell hyperplasia, and nest-like infolds of the respiratory epithelium
Cancer (Oral) Traditional cancer slope f actor (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 ( μ g/m 3) -1

Note: if a proposed MOA is a ccepted, inhalation cancer risks will be significantly reduced – likely equal to non-cancer risks.

Propylene chlorohydrin

Acute Dietary (Females, 13-49 years) and (General populations) No endpoint of concern is found suitabl e 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 = 0.030 mg/kg/day Two-Generation Reproduction Study, Rats (NTP, 1998) Offspring LOAEL: 65 mg/kg/day
Decreased F 1 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 adve rse effect level, LOAEL = lowest observed adverse effect level, PAD = popula tion 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 we ight 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; simila rly 300 ppm corresponds to 209 mg/kg/day. In the equation the default value of 1 is us ed for both absorption factor and animal activity factor.
† Study gavage doses of 15 and 60 mg/kg/day administered twi ce 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, respect ively. These adjusted doses were used for bench mark dose modeling (BMDL 10 ; Log Logistic Model had a good fit of the data).
¶ Study NOAEL and LOAEL are adjusted to human equivalent doses for occupational sc enario only. e.g., animal NOAEL of 100 ppm (6h/day, 5d/week) is adjusted to hum an NOAEL of 75 ppm (8 h/day, 5d/wee k), assuming the regional gas dose ratio (RGDR) is similar between anim als and humans for systemic e ffects (100 ppm x 6h/8h =75 ppm ); In case of continuous exposures (e.g. RfC), rat NOAEL of 100 ppm would be converted to human equivalent dose of 18 ppm [100 ppm x (6h/24h) x (5days in week/7days in week) =18 ppm] assuming similar RGDR between animals and humans for systemic effects

§ Study NOAEL and LOAEL are adjusted to hum an equivalent dose for o ccupational scen ario only. e.g., animal NOAEL of 30 ppm (6h/day, 5d/week) is adjusted to human NOAEL of 5.2 ppm, after correcting fo r the duration (8 h/day, 5d/week) and regional gas dose ratio (RGDR) of 0.23 for extrathoracic effects in rats (30 ppm x 6h/8h =22.5 ppm; 22.5 ppm x 0.23= 5.2 ppm); In case of continuous exposures (e.g. RfC) , rat NOAEL of 30 ppm is adjusted to human NOAEL of 1.2 ppm, after correcting for the duration (8 h/day, 5d/week) and regional gas dose ratio (RGDR) of 0.23 for extrat horacic effects in rats (30 ppm x 6h/24h x 5days in week/7days in week =5.4 ppm; 5.4 ppm x 0.23=1.2 ppm]. ** Slope factor used for dietary exposure assessment 

### Attachment 4: Justification for Studies with PPOPropylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 31 of 38 

### Special Study: Special Acute Inhalation Toxicity Study in Rodents with PPO

Rationale for Requiring the Data

Like other fumigants, as part of the risk assess ment for PPO, the Agency will need to conduct an acute worker and an acute bystander assessment. Several other fumigants have a special acute inhalation study in rats which evaluates histopathology of the respiratory tract including incidence and severity at multiple tested c oncentrations, GSH measurements (i.e. nose), pharmacokinetics/tissue dosimetry including time c ourse, and sublethal portal of entry effects (i.e. within the respiratory tract) along with information on dose response, incidence and severity. The currently available acute inhala tion toxicity studies for PPO only provide LC 50 

### values, and do not have additional respirat ory tract histopathology information. This special study has been shown to be useful in fumigant risk assessment. Available inhalation studies have shown that the nasal cavity is a ta rget organ for PPO. Therefore, there is a reasonable likelihood that a special acute inhalation toxicity study would identify a more sensitive endpoint than the current acute endpoi nt, which was obtained from a developmental toxicity study and used to evaluate acute worker and acute bystander exposure to PPO. Practical Utility of the Data

How will the data be used?

There is a potential for exposure and risk for non-occupational/residential bystanders as a result of commodity fumigations. The MOEs calcula ted using the monitoring data collected for almond/walnut fumigation workers exceed th e Agency’s level of concern for acute, short/intermediate term and long-term exposure via the inhalation route. These data will be used to reevaluate the current point of depart ure for the acute worker and acute bystander

assessments.



### How could the data impact the Agency’s future decision-making?

The absence of the special acute inhalation toxicity study with comprehensive evaluations of the respiratory tract may result in increased uncertain ty around the acute endpoint. These data will allow the Agency to fully characterize the eff ects that occur following acute exposure. In addition, more precise information will allow the Ag ency to refine its pr evious risk assessment and to defend challenges to the propylene oxide decision.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 32 of 38 

### Guideline Number: 875.1400 Study Title: Inhalation Exposure Study for Applicators Rationale for Requiring the Data The inhalation exposure route is ve ry important for exposure scenarios such as fumigation activities where gases will be generated. However, very limited worker exposure monitoring data are available for workers 

### involved in the fumigation of commodities, other materials, and/or structural facilities . These data do not address the breadth of possible activities associated with propylene oxide uses that are of potential risk concern. Traditional sources of worker expos ure information (e.g., Pesticide Handlers Exposure Database or PHED) have not been used to supplem ent the existing data and do not apply because of the highly volatile nature of propylene oxide.

To protect workers from inhalation exposure to p esticides, the Agency requires inhalation exposure monitoring data. These data will ensure that the Agen cy has the most accurate information possible to assess exposures for those involved in the fumigation pr ocess. In addition, these data will be used during registration review to evaluate the potential for prop ylene oxide occupational exposure to fumigators who treat structural facilities, commodities, and other ma terials, and will inform the Agency as to how to manage any risks which may be identified based on th ese data which will reflect the current use practices for propylene oxide. Practical Utility of the Data

How will the data be used?

The inhalation exposure data will be used to assess oc cupational risks for workers involved in fumigation activities during treatment of commodities, materials and/or structural facilities.

How could the data impact the Ag ency’s future decision-making?

The inhalation exposure data will be used to determine the accuracy of the inhalation risks to occupational applicators during fumigation activities based on modern fumigation practices. If future risk assessments are performed without these data, the Agency will have to factor a significant degree of uncertainty into its regulatory decision-making process and that the curre nt mitigation measures (i.e., personal protective equipment) may not provide adequate protection fo r workers applying propylene oxide in structural facilities and/or during the treatment of commodities and other materials.

The lack of these data will limit the flexibility of the Ag ency and registrants with respect to the ability to evaluate risks associated with the modern use practices associated with propylene oxide. It will also allow the Agency to refine its previous risk assessment and could be used to defend ch allenges to the propylene
oxide decision and to consider additional sources of e xposure to those involved in the fumigation process.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 33 of 38 

### Guideline Number: 875.1700 Study Title: Product Usage Information Rationale for Requiring the Data The Agency’s understanding of propylene oxide products and usage is limited to the directions found on pesticide labels and estimates of the amounts used to treat certain commodities or structures. The Agency, believes that the current understanding of the propylen e oxide usage pattern is not sufficient to assess the full range of potential exposure associat ed with its use because how it is applied, how much is applied, and associated fumigation practices (e.g., aeration methods) can impact exposures and these data are not available in a systematic manner.

Additional data are necessary to u nderstand propylene oxide usage in terms of both commodity and facility fumigations and the potential exposures as a result of th ese uses. These data will ensure that the Agency has the most accurate information possible to assess product usage parameters by major use region, frequency, season, maximum and typical rates, and application equipment/procedures. In addition, these data will be used during registration review to eval uate the potential exposure for workers and the general public. Practical Utility of the Data

How will the data be used?

This information will be used to confirm the e nd-use products, use patterns, usage assumptions and parameters to determine exposures to propylene oxide for humans or provide the basis for possible refinements to the process based on a more thorou gh understanding of modern fumigation practices.

How could the data change the Agency’s decision?

Additional precautions and/or restrictions may be n ecessary to protect workers and the general public from exposures to propylene oxide as a consequence of co mmodity/material fumigations and/or fumigation of structural facilities. These data will allow the Agency to refine its previous risk assessment and could be used to defend challenges to the propylene oxide decision.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 34 of 38 

### Guideline Number: 875.2500 

### Study Title: Post-Application Inhalation Exposure Study Rationale for Requiring the Data

Post-application inhalation exposure to propylene oxide is predicted to occur as a result of the registered uses of propylene oxide, including commodity/material fumigation and/or structural fumigations. The existing data for exposure to prop ylene oxide are limited in terms of the variety of post-application activities and the potentia l exposures due to off-gassing from treated
structural facilities and commodities.

The original data requirements were not broa d enough to assess risks to occupational workers near fumigated facilities treated with propylene oxide or who have to work directly with propylene oxide treated commodities/materials th at could result in post-application exposures which may be a concern. These data will ensure that the Agency has the most accurate information possible to assess post-application e xposures for workers near fumigation structural facilities/operations or who work with treated co mmodities/materials. In addition, these data will be used in registration review to determine if the potential for post-application occupational exposure for workers near fumigation facilities/opera tions is below the Agency’s level of concern or establish further risk management needs that would apply to the use of propylene oxide. Practical Utility of the Data

How will the data be used?

These data will be used to determine inhalation exposure to propylene oxide for workers conducting a variety of post-application activiti es near fumigated facilities/commodities or who work directly with treated commodities/materials.

How could the data impact the Agency’s future decision-making?

The post-application inhalation exposure study w ill provide data to support and fully characterize and quantify the exposure and risks of workers exposed to this pesticide. Due to the lack of data, the Agency has used assumptions in developing the risk assessment. Th ese data will allow the Agency to refine its previous risk assessment and could be used to defend challenges to the propylene oxide decision.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 35 of 38 

### Special Study : Ambient air monitoring

Rationale for Requiring the Data

Post-application inhalation exposure from ambient ai r to propylene oxide is predicted to occur as a result of the registered use of propylene oxi de on multiple fumigated structures and/or commodities during the season of use in high areas of use which can result in community based exposures from multiple sources. The existing data fo r ambient air concentrations are limited for communities in proximity to areas where commodity /material fumigations may occur, as well as where facilities themselves may be treated.

These data will ensure that the Agency has the most accurate information possible to protect communities near fumigation facilities/operations. In addition, these data will be used to determine if the potential for post-applica tion exposure for communities near commodity fumigation facilities and treated structures is be low the Agency’s level of concern. Practical Utility of the Data

How will the data be used?

These data will be used to evaluate: (1) post-a pplication inhalation exposure to propylene oxide for communities near fumigated facilities/co mmodities, (2) potential maximum peak air concentrations in areas of high seasonal use, and (3 ) potential community-level air concentrations in areas of high propylene oxide use.

How could the data impact the Agency’s future decision-making?

The post-application inhalation exposure study w ill provide data to support and fully characterize and quantify the exposure and risks of communities exposed to this pesticide. These data will allow the Agency to: (1) evaluate whether the mitigation measures such as good agricultural practices can effectively reduce ambient air c oncentrations, (2) determine post-application inhalation exposure to propylene oxide for co mmunities near fumigated facilities/commodities, (3) refine its previous risk assessment, and (4 ) to defend challenges to the propylene oxide
decision.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 36 of 38 

### Special Study: Monitoring data on fumi gated commodities with Propylene Oxide.

Rationale for Requiring the Data

The potential post-application exposures associ ated with commodity fumigation were not quantitatively assessed when these u ses were established. The Agency did not have monitoring data to directly measure emissions of propylene oxide from fumigated commodities/materials.

These data will ensure that the Ag ency has the most accurate in formation possible on exposure to evaluate emission rates from treated commodities. Post-application risks estimates will be calculated for workers exposed to propylene oxide and will be used to determine if the potential for occupational exposure due to those emissions (i.e., for post-application workers who must handle or receive treated commodities) is be low the Agency’s level of concern. Practical Utility of the Data

How will the data be used?

These data will be used to determine if the e xposure to propylene oxide from handling treated commodities/materials is below the Agency’s leve l of concern. In addition, these data will be used to inform emissions factors and buffer zone estimates during the treatment and aeration phases of the fumigations for propylene oxide commodity uses.



### How could the data impact the Agency’s future decision-making?

These monitoring data are needed to fully char acterize emissions from fumigated commodities. These data will allow the Agency to refine its previous risk assessment in terms of model parameterization (i.e., buffer zones, emissions and other factors). In addition, more precise information appropriate for parameterization of th e exposure models could be used to refine the previous risk assessment and to defend cha llenges to the propylene oxide decision.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 37 of 38 

### Attachment 5: Propylene Oxide Literature Study 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 nButyl 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 identifica tion 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 Toxi cology 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 H ealth 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. Propyl ene oxide causes central-peri pheral 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.Propylene Oxide Registration Review Human-Health Assessment Scoping Document

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Page 38 of 38 TNO BIBRA International Limited. 1994. Toxicity Profile. Propylene chlorohydrins. 1st edition, p1-6

USEPA (US Environmental Protection Agency), 1987. Summa ry review of the health effects associated with propylene oxide. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-86/007F

USEPA (US Environmental Protection Agency), 1994. Integrated Risk Information System. http://www.epa.gov/iris/subst/0403.htm

U.S. EPA (Environmental Protection Agency). (2005a) Gu idelines for carcinogen risk assessment. EPA/630/P03/001F. Available at: www.epa.gov/cancerguidelines

.

U.S. EPA (Environmental Protection Agency). (2005b) Supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. EPA/630/R-03/003F. Available at: www.epa.gov/cancerguidelines.

WHO (World Health Organization), 1985. Propylene Ox ide. Environmental Health Criteria, 56, Geneva.