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

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 Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 042501 DP Barcode: 414670 

Decision No.: 476419 Registration No.: NA 

Petition No.: NA Regulatory Action: NA 

Risk Assessment Type: Scoping Case No.: NA 

TXR No.: NA CAS No: NA 

MRID No.: NA 40 CFR: 180.491 

FROM: Thurston 

Angela Howard, 

G. Morton, 

Ph.D., 

Risk 

DABT

Assessor , Toxicot6gist -"/~~r __A,~~ v\~ Susan V. Hummel, Ph.D, Senior Chemist 

Ivan Nieves, Chemist 

Risk Assessment Branch 4 (RAB4) 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, PhD., Branch Chief ~)k Risk Assessment Branch 4, Health Effects Division, 7509P 

TO: Garland Waleko, Risk Manager Reviewer 

Andrea Mojica, Risk Manager Reviewer 

Pesticide Re-evaluation Division 

Risk Management and Implementation Branch IV (7508P) 

-

Attached is HED's human-health risk assessment scoping document for Propylene Oxide to 

support registration review. 

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Executive Summary 

Propylene oxide (PPO) is used as an insecticidal fumigant on several food items such as 

processed spices, cocoa (beans and powder), in-shell and processed nutmeats (except peanuts). 

In addition, there is a label claim of aiding in the control of microbiological spoilage. PPO also 

has nonfood uses for cosmetic articles, gums, ores, packaging, pigments, pharmaceutical 

materials, and discarded nut shells prior to disposal. The assessment of the food use of PPO as 

an insecticidal fumigant will cover the antimicrobial 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. HED has also considered 

the most recent human health risk assessments for propylene oxide with respect to toxicity, 

exposure, and usage databases, and the most updated 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 issued. An updated dietary exposure analysis was 

conducted in October 2011 to address pine nuts. 

Propylene oxide (PPO) is a highly reactive gas and is rapidly taken 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 properties to eyes and skin and is 

classified as Class I for both tissues. PPO has shown 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 and DNA and is classified as a probable human 

carcinogen. 

Propylene chlorohydrin (PCH) is a reaction product of PPO. It is formed in PPO-fumigated 

commodities whenever chloride ion is present. PCH is moderately toxic via the oral route. A 

two-generation reproductive toxicity study in rats showed systemic, reproductive and offspring 

toxicity. PCH showed evidence of mutagenicity. There was no evidence of carcinogenicity via 

the oral route. 

The toxicity database for propylene oxide is inadequate for Registration Review. A special acute 

inhalation toxicity study is needed 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). 

 
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The following data deficiencies were identified for propylene oxide: 

 Toxicology: a special acute inhalation toxicity study is required for 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/Residential 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 use region, frequency, and application 

equipment. 

o 875.2500 Post-Application Inhalation Exposure Study - outdoor. This study is 

required to assess post-application exposures for workers or bystanders near 

fumigation facilities/operations, or for those 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 occupational 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/Residential Exposure: None 

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

 Toxicology: 

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

 Residue Chemistry: None 

 Dietary Exposure: 

o New dietary exposure and risk assessments may be required during Registration 

Review to incorporate potential changes to the propylene oxide and/or PCH 

toxicological PODs. In addition, the assessment should include updated 

consumption information and utilize the newest version of DEEM-FCID. 
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 Occupational/Residential 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 exposure data, Agency policies, or if the 

toxicological reevaluation results in changes to the endpoints. 

1.0 Introduction 

Propylene oxide (PPO) is used as an insecticidal fumigant on several food items such as 

processed spices, cocoa (beans and powder), in-shell and processed nutmeats (except peanuts). 

In addition, there is a label claim of aiding in the control of microbiological spoilage. PPO also 

has nonfood uses for cosmetic articles, gums, ores, packaging, pigments, pharmaceutical 

materials, and discarded nut shells prior to disposal. Currently, there are three registered 

products for PPO. Both the technical and an end-use product contain 100% a.i. An additional 

end-use registration product, Propoxide 892, which contains 8% PPO and 92% carbon dioxide 

(CO2) is being proposed for uses on dried fruits such as figs, raisins, and prunes. 

The Health Effects Division (HED) has evaluated the status of the human health assessments for 

PPO to determine whether sufficient data are available to support Registration Review. HED has 

also considered the most recent human-health risk assessments for PPO with respect to toxicity, 

exposure, and usage databases, along with the most updated Agency science policy and risk 

assessment methodologies to determine the scope of work necessary to support Registration 

Review. The assessment of the food use of PPO 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. Additional product and residue chemistry data 

received since 1989 have been reviewed by the Agency. PPO has a tolerance of 300 ppm for 

processed spices, cocoa (beans or powder), edible gums, and processed nutmeats (except 

peanuts) under 40 CFR 180.491. 

The requirement for the series of acute toxicity studies on PPO has been waived in the past based 

on available information in the literature, consideration 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 Administration (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 carcinogens, which includes PPO. The ACGIH 

(American Conference of Governmental Industrial Hygienists) recommends a TLV-TWA 

(Threshold Limit Value – Time Weighted Average) of 2 ppm for PPO. The exposure limits from 

NIOSH and ACGIH are recommended levels and are not enforceable. The California Division 

of Occupational Safety and Health (Cal/OSHA) has established an exposure limit value for PPO 
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as 20 ppm. The current EPA label for PPO requires respiratory protection if PPO concentrations 

exceed 20 ppm. 

2.0 Hazard Identification/Toxicology 

The toxicology database for PPO is not complete. Based on a weight of evidence (WOE) 

approach, a special acute inhalation toxicity study should 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 inhalation toxicity study should include 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 sublethal 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 data and the weight of 

the evidence, the following studies 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 literature 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 minutes following inhalation 

exposure. PPO is metabolized via conjugation with glutathione and hydrolysis by epoxide 

hydrolase to 1,2-propanediol (propylene glycol), which is subsequently metabolized to lactic and 

pyruvic acids. 

 

The available evidence from the open literature suggests that PCH is widely distributed to 

tissues, metabolized and excreted following inhalation in animals. Most of the administered 

radioactivity appears to be excreted in urine as glutathione conjugates. Also, biliary excretion is 

reported in rats exposed to PCH by inhalation. Following oral exposure, PCH is eliminated as 

glucuronic acid and glutathione conjugates. 

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 severe irritant properties to eyes and skin and is 

classified as Category I for both tissues. PPO has shown neurotoxicity in rats at a high dose 

level (1500 ppm or 3.6 mg/L) including: awkward gait/ataxia and axonal degeneration of the 

hindleg nerve. Decreased survival in conjunction 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 mice (2-year inhalation study; 200 

ppm). 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 (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 purpose of risk characterization, a low dose 

extrapolation model was applied to the animal data for the quantification of human risk (Q1*), 

based on the total incidence of hemangiomas and hemangiosarcomas in the nasal cavity of male 

mice (Q1* = 1.3x10-2). PPO is classified as a probable human carcinogen (B2). 

Attachment 2 provides a summary of the acute, subchronic, and chronic toxicity profiles for PPO 

and PCH. 
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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 assessment (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 7th cervical rib) which were observed at the LOAEL of 500 ppm 

(349 mg/kg/day). To assess the short- and intermediate-term occupational inhalation scenario, 

an inhalation POD of 75 ppm (180 mg/m3) was selected based on decreased body weight and 

body weight gain in both F0 and F1 males and 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 occupational 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 between animals and humans for systemic effects 

(100 ppm x 6h/8h =75 ppm). 

 

To assess the long-term occupational inhalation scenario, an inhalation POD of 5.2 ppm (12.5 

mg/m3) was selected based on decreased survival, increased incidences for basal cell 

hyperplasia, and nest-like infolds of the respiratory epithelium. The study NOAEL and LOAEL 

were adjusted to human equivalent doses for the occupational scenario only, e.g., animal 

NOAEL of 30 ppm (6h/day, 5d/week) was adjusted 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 was a margin of exposure (MOE) < 300 (UFH=10, a UFA=3 

and a UFL=10)1

. The level of concern (LOC) for short-, intermediate- and long-term exposures 

was a margin of exposure (MOE) < 30 (UFH=10 and a UFA=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, developmental, reproduction, immunotoxicity or 

chronic toxicity studies) have been submitted to agency for PCH. The available data from the 

open literature indicate that PCH is Category II or III by the oral route (D316547, 2006). 

In a rat two generation reproductive toxicity study (oral drinking 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 (F1 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/day and decreased pup weights (F1 9% and 20%) were observed at 

≥ 65 mg/kg/day. The NOAEL for parental systemic toxicity is 65 mg/kg/day, the NOAEL for 

reproductive toxicity was not established, but the NOAEL for offspring was 30 mg/kg/day. This 

study was used to derive a chronic RfD based on the offspring NOAEL of 30 mg/kg/day and 

1000x UF (cRfD = 0.030 mg/kg/day). A suitable endpoint 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

 UFH – Uncertainty factor intraindividual variability; UFA–Uncertainty factor interspecies variability; UFL – 

Uncertainty factor LOAEL to NOAEL extrapolation 
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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-propanol). This was a drinking 

water study in rats (0, 15, 30, or 65 mg/kg/day during the beginning months and 0, 8, 17, or 34 

mg/kg/day during the remaining months) and mice (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) and did not report any treatment-related cancer or non-cancer effects 

in either species. 

Conclusions: The toxicity database for PPO is inadequate for Registration Review. During 

Registration Review, the Agency will reevaluate the points of departure (PODs) and uncertainty 

factors (UFs) for the residential and occupational exposure assessments 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 toxicity test (Attachment 4: Justification for Special Acute 

Inhalation Toxicity Study with PPO), 

The following toxicological studies 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 oxide is adequate for Registration Review. PPO 

and PCH are considered separately as residues of concern for tolerance assessment. Residue 

data from the commodity sterilization study indicates both PPO and 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 relative to PCH residues. 

Based on current information from the spice industry 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 reregistration. Tolerances for PPO 

range from 1 ppm on raisin to 300 ppm on a number of commodities including herbs and spices. 

Tolerances for PCH range from 3 ppm on fig to 6000 ppm on a number of commodities. 

Conclusions: The residue chemistry database for propylene oxide is adequate for Registration 

Review. The tolerance expression for propylene oxide will be reviewed during registration 

review to ensure that it appropriately covers the metabolites and degradates of propylene oxide 

and that it specifies the residues to be measured for each commodity. Modifications will be 

made as needed. 

4.0 Dietary Exposure 

The most recent dietary exposure and risk assessment was performed in conjunction with the 

October 2011 request from PRD to assess pine nuts. Refined acute and chronic dietary risk 

assessments were conducted using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, 

Version 2.03), and the Lifeline Model Version 3.0 which use food consumption data from the 
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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 PPO sterilization studies were used for the acute dietary analysis 

of propylene oxide. Average residues from the sterilization study were used for the chronic and 

cancer assessments of propylene oxide. Tolerance level residues were used for the chronic 

dietary analysis of PCH. Percent crop treated data provided by BEAD were used for the acute 

and chronic analyses. A drinking water exposure assessment was not conducted for this 

assessment because the Environmental Fate and Effects Division (EFED) expects that uses of 

propylene oxide for indoor and outdoor food and nonfood uses will result in insignificant 

exposure to drinking water resources. 

The refined probabilistic acute dietary exposure assessment for the population subgroup females 

13-49 concluded that for all supported commodities, the acute dietary exposure estimates for 

PPO were below HED’s level of concern. The assessment 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 for propylene oxide were below HED’s level of 

concern. An acute RfD was not established for PCH because an endpoint attributable to a single 

(or few) day exposure was not identified from the 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 adequate to support the existing registrations. 

However, a new dietary exposure and risk assessment may be required during Registration 

Review to incorporate potential changes to the propylene oxide and PCH toxicological PODs. In 

addition, the assessment should include updated consumption information and utilize the newest 

version of DEEM-FCID. 

5.0 Residential Exposure 

For most fumigants, the Agency has historically assumed that, provided adequate aeration of 

structures is completed prior to re-entry, exposure to owners of fumigated structures is expected 

to be negligible; however, there is the potential for bystander exposures, which can occur from 

emissions during treatment and aeration of commodities and structures. In the most recent 

exposure/risk assessment for PPO (Memo, M. Crowley; 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 identified 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, Crowley; D316539; 4/9/09), and 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 process of reviewing a new set of PERFUM data 

that have been submitted along with other suggested modifications to the existing registered 

product label of Propoxide 892. The proposed label amendments would greatly alter the use 

pattern for PPO because use would be permitted on much larger structures (i.e., 1,000,000 ft3

structure size with a 10 ft buffer zone). Currently the maximum structure size is 10,000 ft3 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 more 
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refined analysis would be possible if additional data were available. Types of information that 

could be used to refine the bystander assessment include: information on treatment conditions 

such as building/structure types, volumes treated, 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 assessment during registration review is recommended. 

Bystander risk from PPO emissions from treated commodities and structures will need to be 

evaluated based on PPO emissions, the label prescribed 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 exposure from food only for PPO during the RED. 

Residential exposure and dietary exposure from water was not expected 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 used both to control bacterial 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 applied 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 days per year for occupational workers were 

provided. According to the Reregistration Eligibility 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 Industrial Hygienists (ACGIH), was protective of all potential 

exposure durations. Dermal exposure risks 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 activities (i.e. aerators, fork-lift operators, etc.). 

Potential exposures due to off-gassing will also be assessed for workers conducting postapplication activities near treatment operations. 
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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 exposures (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, and 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 terms of the variety of post-application 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 conducting post-application activities need to be 

submitted to the Agency (i.e., aeration conditions, 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 use region, frequency, and application 

equipment. 

o 875.2500 Post-Application Inhalation Exposure Study - outdoor. This study is 

required to assess post-application exposures for workers or bystanders near 

fumigation facilities/operations, or for those 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 occupational 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 identified in IDS(January 1, 2008 to February 19, 

2013) or SENSOR (1998-2009)-Pesticides. For this reason there does not appear to be a concern 

at this time that would warrant further investigation. The Agency will continue to monitor the 

incident information; and, if a concern is triggered, additional analysis will be included in the 

risk assessment. 

 

2

 Details to be determined based on protocol discussion with Agency. 
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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 only 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 degradates. Compliance with the tolerance levels specified in this 

paragraph is to be determined by measuring only 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 the 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 covers the metabolites and degradates of propylene oxide and that it 

specifies the residues to be measured for each commodity. Modifications will be made as 

needed. 
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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 Mexico2 Codex3

40 CFR 180.491 

Plant: propylene oxide and separately, 

propylene chlorohydrin (2-chloroethanol)

PPO Plant: 

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US4 Canada Mexico2 Codex3

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 commodity, 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, second 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 justice concerns, to the extent possible, were considered in the 

most recent PPO human health risk assessment, in accordance with U.S. Executive Order 12898, 

“Federal Actions to Address Environmental Justice in Minority Populations and Low-Income 

Populations,” (http://www.hss.energy.gov/nuclearsafety/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 variability of diets within the 

U.S., and people who may be exposed when harvesting crops. Should these 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. 
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11.0 Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to PPO and any other substances. For the purposes of this assessment, therefore, EPA has not 

assumed that PPO has a common mechanism of toxicity with other substances. For information 

regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity 

and to evaluate the cumulative effects of such chemicals, see the policy statements released by 

EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/. 

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 reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

which may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of its most recent reregistration decision, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), propylene oxide 

is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether 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 other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects 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 ingredients 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 Registration Review, EPA will 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 procedures, the list of 67 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website: http://www.epa.gov/endo/. 
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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 adult human subjects were 

intentionally exposed to a pesticide 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) Database. EPA has reviewed all the studies supporting 

these multi-pesticide generic exposure databases, 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 prevailing at the time the research was conducted. All 

applicable requirements of EPA’s Rule for the Protection of Human Subjects 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 study and 870.3700a and b Developmental 

toxicity studies in rats and rabbits 

 Residue Chemistry: None

 Dietary Exposure: None 

 Occupational/Residential 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 use region, frequency, and application 

equipment. 

o 875.2500 Post-Application Inhalation Exposure Study - outdoor. This study is 

required to assess post-application exposures for workers or bystanders near 

fumigation facilities/operations, or for those 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 occupational 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. 
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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/dose 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 potential changes to the propylene oxide and/or PCH 

toxicological PODs. In addition, the assessment should include updated consumption 

information and utilize the newest version of DEEM-FCID. 

 Occupational/Residential 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 exposure data, Agency policies, or if the 

toxicological reevaluation 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, Chronic 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 References
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Attachment 1: Chemical Identity Table. 

 

Table 2. Nomenclatures and Physical/Chemical Properties of Propylene 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 C3H6O C3H7ClO C3H7BrO 

Molecular Weight 58.080 94.541 138.992 

IUPAC Name - - - - - 

CAS Name Propylene oxide; 1,2-

epoxypropane 1-chloro-2-propanol 2-chloro-1-propanol 1-bromo-2-

propanol 2-bromo-1-propanol

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

PC Code 042501 NA NA NA NA 

Melting Point/range 

oC - - - - - 

Boiling Point oC 34.2 oC 126-127 oC 130 oC 145-148 oC NA 

Density or Specific 

Gravity 

at 20 oC (g/cm3) 

0.829- 0.831 1.115 1.09 1.53 NA 

Water Solubility 

(20 oC) 

39.5 g/100 mL NA NA NA NA 

Solvent Solubility 

at 25 oC 

Miscible with acetone, 

benzene. carbon 

tetrachloride, diethyl 

ether, and methanol. 

NA NA NA NA 

Vapor Pressure at 

20 oC 

440 mm Hg NA NA NA NA 

Dissociation 

Constant, pKa 

NA NA NA NA NA 

Octanol/Water 

Partition Coefficient 

(Kow) 25 oC 

Kow 0.03 NA NA NA NA 

UV/vis Absorption 

Spectrum 

NA NA NA NA NA 

NA = not available 

 

O

CH3

OH

Cl

Cl

HO

OH

Br

Br

HO
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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) 

LD50 520-1140 mg/kg bw 

LD50 630 mg/kg bw (males) 

LD50 660-690 mg/kg bw 

Category III 

Category III 

Category III 

870.1200 

Acute Dermal, Rabbits 

No study identified 

870.1300 

Acute Inhalation, Rats 

Mice 

 

NTP, 1985 

NTP, 1985 

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

(3207-3444 ppm) 

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

(1008- 1475 ppm) 

Category IV 

Category IV 

870.2400 

Primary Eye Irritation, Rabbits 

Weil et al., 1963 

(As cited in WHO, 

1985) 

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 ppm 
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SpragueDawley 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 weight, decreased crown rump 

length in males and females and possibly increased 

fetal and litter incidence for the reduced ossification 

of the vertebra. 

Unacceptable/Guideline 

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/day 
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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 neurological 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 7th 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, gasping, 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 ppm 
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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 

Chronic 

ToxicitySpragueDawley 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) 
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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 mortality (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 epithelium 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 the 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, 
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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 nasal 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/treatment 
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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 evidence of carcinogenicity 

for PPO in mice. 

870.4100 

Chronic 

Toxicitycynomolgus 

Monkeys 

2 years 

Sprinz et al. 1982 Doses 

(inhalation): 

0, 100 or 300 

ppm 

NOAEL: Not established 

LOAEL: 100 ppm 

Increased incidence for axonal dystrophy in the 

medulla oblongata and in the most distal portions of 

the fasciculus gracilus in all treated monkeys (2/2) 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, histidine or valine) residues. 

-Assuming a 100% alveolar absorption and first-order 

kinetics, a half-life of 40 minutes was estimated for 

the elimination of PPO in rats 

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 in 
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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 selected 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 men 

exposed 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 LD50 = 220 mg/kg 

Oral LD50 = 580 mg/kg 

Oral LD50 = 720 mg/kg 

At 200 mg/kg one of seven dogs 

died while 250 mg/kg or above 

was lethal to all six treated dogs 

Category II 

Category III 

Category III 

870.1200 

Acute Dermal, Rabbits Smyth et al., 1969 

Weisbrod, 1981 

(as cited in BIBRA 

International, 1994) 

LD50 = 528 mg/kg 

LD50 = 440 mg/kg 

Category II 

Category II 

870.1300 

Acute Inhalation, Rats 

Smyth and Carpenter, 

1969 

(as cited in SRC 

Report for US EPA, 

1980) 

LC50 = ~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 - - 
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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. 
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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 vacuolization 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 cytoplasmic 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/group
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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 of 
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Page 28 of 38 

references 

(as cited in 

NTP, 1998) 

S9 

Positive in TA1535 with or without S9. 

-No mutagenic activity in TA97, TA98, and 

TA1537 with or without S9 extract. 

-CHO cells- caused high levels of chromatid 

exchanges and chromosomal aberration in the 

presence or absence of S9 extract. 

-No chromosomal aberrations in vivo. 

-Induced sex-linked recessive lethal mutations in 

Drosophila in injection but not by feed 

-Negative for germ cell reciprocal translocation in 

Drosophila 

-Negative for micronuclei formation in vivo in 

mice 

Metabolism 

 Multiple 

references 

(as cited in 

NTP, 1998) 

- Absorption: No data 

Metabolism: Following inhalation, PCH was 

widely distributed to tissues, rapidly metabolized 

and eliminated. 

Excretion: Following oral administration of 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 

- - 

 
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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 = 

0.21mg/kg/day 

Developmental Toxicity, Rats (MRID 41750801) 

Developmental LOAEL: #

349 mg/kg/day (500 ppm) 

Increased litter incidence of an accessory 7th cervical 

rib 

 

Acute Dietary 

(General 

populations) 

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

Chronic Dietary 

(All populations) 

†BMDL10= 1.4 

mg/kg/day 

UF = 1000

Chronic RfD = 

0.001 

mg/kg/day 

FQPA SF = 1X

cPAD = 0.001 

mg/kg/day 

Chronic carcinogenicity study, Rats (Dunkelberg, 

1982) 

†Systemic LOAEL = 2.6 mg/kg/day 

Increased combined incidence for hyperkeratosis, 

hyperplasia and papillomas. 

Incidental Oral 

Exposure, 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/m3

)

Inhalation 

Absorption 

Rate = N/A 

Residential 

MOE =N/A 

Occupational 

MOE = 30

Two-generation Reproduction Study in Rats (MRID 

45292701) 

¶LOAEL = 225 ppm (540 mg/m3

) 

Decreased body weight and body weight gain in both 

F0 and F1 males and females during premating periods 
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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/m3

)

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/m3

)

Decreased survival, increased incidences for basal cell 

hyperplasia, and nest-like infolds of the respiratory 

epithelium 

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

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

Cancer (Inhalation) Traditional cancer slope factor (inhalation - hemangioma and hemangiocarcinoma in mice) = 

3.5x10-6 (μg/m3) -1 

Note: if a proposed MOA is accepted, inhalation cancer risks will be 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 suitable to assess risk for these populations 

Chronic Dietary 

(All populations) 

NOAEL= 30

mg/kg/day 

UF = 1000

Chronic RfD = 

0.030 

mg/kg/day 

FQPA SF = 1X

cPAD = 0.030 

mg/kg/day 

Two-Generation Reproduction Study, Rats (NTP, 

1998)

Offspring LOAEL: 65 mg/kg/day

Decreased F1 male and female pup weights at PND 14 

and 21.

Cancer (Oral and 

Inhalation) 

Data is inadequate to determine the carcinogenic effects. 

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest 

observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of 

exposure, LOC = level of concern, NA = Not Applicable 

#

Extrapolation from inhalation to oral route: mg/kg/day = (mg/L x absorption factor x respiratory volume in L/hr x duration of 

daily animal exposure x activity factor) /mean body weight in kg; The oral equivalent dose for 500 ppm =[ (500x 

(58.08/24.4)x1000) mg/L x 1x 6.06 L/hr x 6 h/day x 1 / (0.124 kg)] = 349 mg/kg/day; similarly 300 ppm corresponds to 209 

mg/kg/day. In the equation the default value of 1 is used for both absorption factor and animal activity factor. 

† Study gavage doses of 15 and 60 mg/kg/day administered twice a week (corresponding average total doses are 2714 and 10798 

mg/kg bw) are adjusted for experimental duration of 150 weeks to 2.58 and 10.28 mg/kg/day, respectively. These adjusted doses 

were used for bench mark dose modeling (BMDL10; Log Logistic Model had a good fit of the data). 

¶

Study NOAEL and LOAEL are adjusted to human equivalent doses for occupational scenario only. e.g., animal NOAEL of 100 

ppm (6h/day, 5d/week) is adjusted to human NOAEL of 75 ppm (8 h/day, 5d/week), assuming the regional gas dose ratio 

(RGDR) is similar between animals and humans for systemic effects (100 ppm x 6h/8h =75 ppm); 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 human equivalent dose for occupational scenario only. e.g., animal NOAEL of 30 

ppm (6h/day, 5d/week) is adjusted to 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); 

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

Rationale for Requiring the Data 

Like other fumigants, as part of the risk assessment 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 concentrations, GSH measurements (i.e. nose), 

pharmacokinetics/tissue dosimetry including time course, 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 inhalation toxicity studies for PPO only provide LC50

values, and do not have additional respiratory 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 target 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 endpoint, 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 calculated using the monitoring data collected for 

almond/walnut fumigation workers exceed the 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 departure 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 uncertainty around the acute endpoint. These data will 

allow the Agency to fully characterize the effects that occur following acute exposure. In 

addition, more precise information will allow the Agency to refine its previous risk assessment 

and to defend challenges to the propylene oxide decision.
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Guideline Number: 875.1400 

Study Title: Inhalation Exposure Study for Applicators 

Rationale for Requiring the Data 

The inhalation exposure route is very 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 exposure information (e.g., Pesticide Handlers Exposure 

Database or PHED) have not been used to supplement the existing data and do not apply because of the 

highly volatile nature of propylene oxide. 

To protect workers from inhalation exposure to pesticides, the Agency requires inhalation exposure 

monitoring data. These data will ensure that the Agency has the most accurate information possible to 

assess exposures for those involved in the fumigation process. In addition, these data will be used during 

registration review to evaluate the potential for propylene oxide occupational exposure to fumigators who 

treat structural facilities, commodities, and other materials, and will inform the Agency as to how to 

manage any risks which may be identified based on these 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 occupational risks for workers involved in fumigation 

activities during treatment of commodities, materials and/or structural facilities. 

How could the data impact the Agency’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 current mitigation measures (i.e., personal protective 

equipment) may not provide adequate protection for 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 Agency 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 challenges to the propylene 

oxide decision and to consider additional sources of exposure to those involved in the fumigation process. 

 
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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 propylene oxide usage pattern is not sufficient to assess the 

full range of potential exposure associated 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 understand propylene oxide usage in terms of both commodity and facility 

fumigations and the potential exposures as a result of these 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 evaluate 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 end-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 thorough understanding of modern fumigation practices. 

How could the data change the Agency’s decision? 

Additional precautions and/or restrictions may be necessary to protect workers and the general public from 

exposures to propylene oxide as a consequence of commodity/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. 

 
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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 propylene oxide are limited in terms of the variety 

of post-application activities and the potential exposures due to off-gassing from treated 

structural facilities and commodities. 

The original data requirements were not broad 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 that 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 exposures for workers near fumigation structural 

facilities/operations or who work with treated commodities/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/operations 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 activities 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 will 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. These data will allow the 

Agency to refine its previous risk assessment and could be used to defend challenges to the 

propylene oxide decision. 
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Special Study : Ambient air monitoring

Rationale for Requiring the Data 

Post-application inhalation exposure from ambient air to propylene oxide is predicted to occur as 

a result of the registered use of propylene oxide 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 for 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-application exposure for communities near commodity 

fumigation facilities and treated structures is below 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-application inhalation exposure to propylene oxide 

for communities near fumigated facilities/commodities, (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 will 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 concentrations, (2) determine post-application 

inhalation exposure to propylene oxide for communities near fumigated facilities/commodities, 

(3) refine its previous risk assessment, and (4) to defend challenges to the propylene oxide 

decision. 

 
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Special Study: Monitoring data on fumigated commodities with Propylene Oxide. 

Rationale for Requiring the Data 

The potential post-application exposures associated with commodity fumigation were not 

quantitatively assessed when these uses 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 Agency has the most accurate information 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 below 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 exposure to propylene oxide from handling treated 

commodities/materials is below the Agency’s level 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 characterize 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 the exposure models could be used to refine the 

previous risk assessment and to defend challenges to the propylene oxide decision. 

 
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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 identification V 82.215/280853, March 2, 1983.. Unpublished. 

MRID 45292701 

Hayes, W., T. Gushow, H. Kirk, et al. 1985. Propylene oxide: Two generation inhalation reproduction study in 

Fischer 344 rats. Mammalian and Environmental Toxicology Research Laboratory, Dow Chemical, Midland, MI, 

Laboratory report number, D-001784, June 19, 1985. Unpublished 

MRID 45292801 

Young, J.T., Mattsson, J.L., Albee, R.R., and Schuetz, D.J. 1985. Propylene oxide: assessment of neurotoxic 

potential in male rats. Mammalian and Environmental Toxicology Research Laboratory, Health & Environmental 

Sciences, U.S.A., Dow Chemical U.S.A., Midland, MI 48640. Study No. D1831, October 24, 1985. Unpublished. 

Cal/OSHA. Occupational Safety and Health Standards Board (OSHSB). Public meeting/public hearing/business 

meeting of the OSHSB on General Industry Safety Orders, Section 5155 – Airborne Contaminants. June 17, 2004. 

Dunkelberg, H. 1982. Carcinogenicity of ethylene oxide and 1,2-propylene oxide upon intragastric administration to 

rats. Br. J. Cancer. 46: 924- 933. 

Faulkner, John. Ethylene Oxide Quantitative Usage Analysis. Biological and Economic Analysis Division, 

USEPA/OPPTS/OPP. 

IARC (International Agency for Research on Cancer) 1994. World Health Organization, IARC Monographs on the 

evaluation of carcinogenic risks to humans. Vol. 60. Some industrial chemicals. p181-213. 

Kuper, C.F., P.G.J. Reuzel, V.J. Feron et al. 1988. Chronic inhalation toxicity and carcinogenicity study of 

propylene oxide in Wistar rats. Food Chem. Toxicol. 26: 159-167. 

Lynch, D.W., T.R. Lewis, W.J. Moorman et al. 1984. Carcinogenic and toxicologic effects of inhaled ethylene 

oxide and propylene oxide in F344 rats. Toxicol. Appl. Pharmacol. 76: 69-84. 

Morris, Mark. USEPA/OAQPS/ESD. Memorandum to Dave Guinnup, USEPA/OAQPS/ESD: Residual Risk 

Assessment for the Ethylene Oxide Commercial Sterilization Source Category. February 25, 2005. 

NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of propylene oxide (CAS No. 

75-56-9) in F344/N rats and B6C3F1 mice (Inhalation studies). NTP-TR-267. 

NTP (National Toxicology Program). 1998. Toxicology and carcinogenesis studies of 1-chloro-2-propanol (CAS 

No. 127-00-4) in F344/N rats and B6C3F1 mice (Drinking Water Studies). NTP-TR-477. 

Ohnishi, A., T. Yamamato, Y. Murai, et al.. 1988. Propylene oxide causes central-peripheral distal axonopathy in 

rats. Arch. Environ. Health. 43:353-356. 

Setzer, J.V. W. S. Brightwell, J.M. Russo et al. 1996. Neurophysiological and neuropathological evaluation of 

primates exposed to ethylene oxide and propylene oxide. Toxicol. and Indust. Health 12:667-682. 
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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. Summary review of the health effects associated with 

propylene oxide. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-86/007F 

USEPA (US Environmental Protection Agency), 1994. Integrated Risk Information System. 

http://www.epa.gov/iris/subst/0403.htm

U.S. EPA (Environmental Protection Agency). (2005a) Guidelines for carcinogen risk assessment. EPA/630/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 Oxide. Environmental Health Criteria, 56, Geneva.