Propoxur Human Health Risk Assessment DP No. D414135 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 22, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Propoxur: Human Health Draft Risk Assessment for Registration Review 

PC Code: 04 7802 

Decision No.: 482010 

Petition No.: NIA 

DP Barcode: 0414135 

Registration No.: NIA 

Regulatory Action: Registration Review 

Risk Assessment Type: Preliminary Risk Assessment Case No.: NIA 

TXR No.: NIA CAS No.: 114-26-1 

MRID No.: NIA 40 CFR: NIA 

FROM: 

THROUGH: 

Shalu Shelat, Industrial Hygienist/R· s ss "sor 

Mohsen Sahafeyan, Chemist 4--?ft-~~1'~'---

Christopher Schlosser, Toxicologist . . ~-:;;a. ---r-7'~--· 

Cassi Walls, Ph.D., Senior Biologist C:o•'l;. J.. L..1<£1?.c. 

Risk Assessment Branch VI 

Health Effects Division (7509P) ~ 

Risk 

Health 

Donna 

Assessment 

Effects 

S. Davis

Division 

, Acting 

Branch 

(7509P) 

Branch 

VI 

Chief ~~ 

And 

Donald Wilbur, RARC Designated Reviewer 

Alexandra Gavelek, RARC Designated Reviewer 

Risk Assessment and Review Committee (RARC) 

TO: Brittney Pruitt, Chemical Review Manager 

Avivah Jakob, Team Leader 

Kelly Sherman, Acting Branch Chief 

Risk Management and Implementation Branch III 

Pesticide Re-Evaluation Division (7508P) 

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Propoxur Human Health Risk Assessment DP No. D414135

The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with 

estimating the risk to human health from exposure to pesticides. As part of Registration Review, 

the Pesticide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the hazard 

and exposure data and conduct occupational and residential exposure assessments, as needed, to 

estimate the risk to human health that will result from the registered uses of propoxur. This Draft

Risk Assessment (DRA) serves as HED’s Registration Review assessment of the dietary, 

occupational, and residential exposure and risk as well as the aggregate risk assessment for the 

registered uses. 

The HED team members contributing to this risk assessment include Mohsen Sahafeyan (residue 

chemistry and dietary exposure assessment), Cassi Walls (occupational and residential exposure 

assessment), Shalu Shelat (risk assessment), and Christopher Schlosser (hazard assessment). 

Note: This memorandum was reviewed by the Risk Assessment Review Committee on 

February 4, 2015.

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Propoxur Human Health Risk Assessment DP No. D414135

1.0 Executive Summary........................................................................................................... 5

2.0 HED Recommendations.................................................................................................... 8

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.3 Label Recommendations................................................................................................ 8

3.0 Introduction........................................................................................................................ 9

3.1 Chemical Identity ........................................................................................................... 9

3.2 Physical/Chemical Characteristics ............................................................................... 9

3.3 Pesticide Use Pattern.................................................................................................... 10

3.4 Anticipated Exposure Pathways................................................................................. 10

3.5 Consideration of Environmental Justice.................................................................... 10

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 10

4.1 Summary of Toxicological Effects.............................................................................. 11

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 12

4.2.1 Completeness of the Toxicology Database.............................................................. 13

4.2.2 Evidence of Neurotoxicity........................................................................................ 13

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 13

4.2.4 Residual Uncertainty in the Exposure Database ................................................... 14

4.3 Toxicity Endpoint and Point of Departure Selections.............................................. 14

5.0 Dietary Exposure and Risk Assessment......................................................................... 18

5.1 Residues of Concern Summary and Rationale.......................................................... 18

5.2 Food Residue Profile .................................................................................................... 18

5.3 Water Residue Profile.................................................................................................. 18

5.4 Dietary Risk Assessment.............................................................................................. 19

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 19

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 19

5.4.3 Acute Dietary Risk Assessment............................................................................... 19

5.4.4 Chronic Dietary Risk Assessment........................................................................... 20

5.4.5 Cancer Dietary Risk Assessment............................................................................. 21

5.4.6 Summary Tables....................................................................................................... 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 23

6.1 Residential Handler Exposure .................................................................................... 23

6.2 Post-Application Exposure.......................................................................................... 25

6.3 Residential Risk Estimates for Use in Aggregate Assessment.................................. 27

6.4 Residential Bystander Post-application Inhalation Exposure ................................. 29

6.5 Spray Drift.................................................................................................................... 29

7.0 Aggregate Exposure/Risk Characterization.................................................................. 29

7.1 Acute Aggregate Risk................................................................................................... 29

7.2 Short-Term Aggregate Risk........................................................................................ 29

7.3 Chronic Aggregate Risk .............................................................................................. 30

7.4 Cancer Aggregate Risk ................................................................................................ 30

8.0 Cumulative Exposure/Risk Characterization ............................................................... 31

9.0 Occupational Exposure/Risk Characterization ............................................................ 31

9.1 Short-/Intermediate-Term and Cancer Handler Risk.............................................. 31

9.2 Short-/Intermediate –Term and Cancer Post-Application Risk.............................. 36

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9.2.1 Dermal Post-application Risk.................................................................................. 36

9.2.2 Inhalation Post-application Risk............................................................................. 36

10.0 Incident Report and Epidemiology............................................................................. 36

11.0 References......................................................................................................................... 37

Appendix A. Physiochemical Properties.................................................................................. 38

Appendix B. Registered Labels and Current Use Pattern for Propoxur.............................. 39

Appendix C. Toxicology Profile and Executive Summaries .................................................. 42

C.1 Toxicology Data Requirements................................................................................... 42

C.2 Toxicity Profiles............................................................................................................ 43

C.3 Executive Summaries................................................................................................... 49

Appendix D. Review of Human Research................................................................................. 62

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Propoxur Human Health Risk Assessment DP No. D414135

1.0 Executive Summary

Propoxur [2-(1-methylethoxy)phenyl methylcarbamate] is a carbamate insecticide registered for 

use by pest control operators (PCOs) to control ants, roaches, hornets, and other pests in and 

around commercial, industrial, and institutional buildings, as well as in food handling 

establishments (FHEs) and outside residences. Propoxur is currently formulated as liquid 

concentrate, ready to use (RTU) liquid in aerosol cans, bait in bait stations, impregnated shelf 

paper, and impregnated insect tape. It was first registered in 1963. Exposures to propoxur can 

be expected to occur via the dietary as well as through the occupational and residential handler 

and post-application pathways of exposure.

Propoxur is part of the common mechanism group for the N-methyl carbamate (NMC) 

insecticides. An important aspect of the NMCs toxicity is the rapid inhibition of 

acetylcholinesterase (AChE) (15-45 minutes) through carbamylation of the serine hydroxyl 

group located in the active site of the enzyme. AChE recovery is also very rapid and typically 

occurs within minutes to hours. For propoxur, AChE data are available from multiple studies in 

adults as well as for different life stages (i.e., developmental, and juvenile rats). A non-guideline 

oral comparative cholinesterase assay (CCA) is available for propoxur which measures AChE 

inhibition at the time of peak effect (15-30 minutes) in both adult and post-natal day 11 (PND 

11) rats. The toxicology database is therefore complete for propoxur. 

For propoxur, the most sensitive indication of toxicity is inhibition of red blood cell (RBC) 

AChE following oral exposure and brain AChE inhibition following inhalation exposure. Since 

peak inhibition of cholinesterase is rapid (15-30 minutes) with recovery occurring within hours 

(2.76 to 3.4 hours) acute/daily exposure to propoxur is the primary non-cancer toxicological 

duration of concern. Therefore, based on this cholinesterase inhibition mode of action, only 

acute effects (AChE inhibition) were selected as points of departure for dietary, incidental oral, 

dermal, and inhalation Points of Departure (PODs).

The Agency used an exponential dose-time-response model to develop benchmark dose (BMD) 

estimates at a level estimated to result in 10% cholinesterase inhibition (i.e., a benchmark dose 10 or 

BMD10) to assess the dose response for propoxur. A BMD analysis was conducted for both oral 

and inhalation endpoints. The acute dietary and incidental oral point of departures (POD) are

based on a BMDL10 (BMD lower limit of a one-sided 95% confidence interval) of 0.038

mg/kg/day for RBC AChE inhibition at the peak time of inhibition (30 minutes) in male and 

female post-natal day (PND) 11 pups (combined) in the acute CCA. For dietary assessment, the 

endpoint used is based on data from the pups as it based on the most sensitive lifestage and 

protective for all age groups. However, in order to estimate adult-specific aggregate risks, the 

BMDL10 of 0.339 mg/kg/day for RBC AChE inhibition in male and female rats (combined) from 

the CCA study has been selected as an adult oral POD. The inhalation POD is based on a 

BMDL10 of 0.0076 mg/L for brain AChE inhibition in female adults in a chronic inhalation 

toxicity study. Using the methods and dosimetry equations described in EPA’s reference 

concentration (RfC) guidance (1994), a Human Equivalent Concentration (HEC) and Human 

Equivalent Dose (HED) based on the inhalation toxicity POD were derived for use in the 

Margins of Exposure (MOE) calculations. No dermal risk estimates were determined from 

dermal exposure of any duration because no adverse effects were observed at the highest dose 

tested (1000 mg/kg/day) in a 90-day dermal toxicity study. Propoxur is classified as a Group B2: 

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Propoxur Human Health Risk Assessment DP No. D414135

Probable human carcinogen by the U.S. EPA with a linear low-dose approach for quantification 

of risk using the oral slope factor (Q1*) of 3.52 × 10-3 (mg/kg/day)-1. 

The recently submitted acute CCA study indicates that PND 11 pups are approximately 9-fold 

more sensitive than the adult rats for brain and RBC cholinesterase inhibition (combined sex 

data). However, there is no evidence of increased quantitative susceptibility in the rat and rabbit 

developmental toxicity studies or the 2-generation reproductive studies. Although PND11 pups 

had greater RBC and brain AChE inhibition in the CCA study, HED’s degree of concern for the 

susceptibility observed is low because the oral regulatory endpoints for propoxur are based on 

the rat PND 11 pup BMDL10 for RBC AChE inhibition. Therefore, HED concluded that the 10X 

Food Quality Protection Act (FQPA) Safety Factor (SF) could be reduced to 1X for oral 

exposures. As a result, the UF for oral exposure is 100X (10X intraspecies, 10X interspecies, 

and 1X FQPA SF). For residential inhalation exposures, HED is applying a data-derived 9x

FQPA SF based on the relative sensitivity of pups versus adults for RBC AChE inhibition in the 

CCA study. This factor is necessary to protect sensitive lifestages because the inhalation POD is 

based on brain AChE inhibition in adult animals. Additionally, for studies in this risk assessment 

with inhalation animal data, uncertainty factors are based on the RfC methodology. Since the 

RfC methodology takes into consideration the pharmacokinetic (PK) differences but not 

pharmacodynamic (PD) differences, the UF for interspecies extrapolation may be reduced to 3X 

(to account for the PD differences) while the UF for intraspecies variation is retained at 10X. 

Thus, the UF when using the RfC methodology is customarily 30X and is applicable to adult 

inhalation exposures in this risk assessment. However, when considering the application of the 

FQPA SF, a total MOE of 270 (3X interspecies, 10X intraspecies, and 9X FQPA SF) defines 

HED’s LOC for residential/non-occupational inhalation exposures to children.

Currently, the only registered food use for propoxur is crack and crevice treatment to food areas 

of FHEs; however, no tolerances have been established for those uses. A study elucidating the 

potential for propoxur residues on food in a FHE set up was submitted previously and showed 

detectable residues of propoxur on food. A metabolism study on food samples which were 

fortified with [14C] propoxur and subjected to various food processing procedures showed that 

the major residue of concern is propoxur only. During registration review, the Agency has 

evaluated the available residue data relevant to the crack and crevice use and concluded that 

tolerances are required to support the FHE uses. There is no direct applications of propoxur to

raw agricultural commodities, and the outdoor non-agricultural registered uses of propoxur are 

discontinuous, non-broadcast in nature, and in relatively limited volume; therefore, there is no 

concern for propoxur residues in drinking water, and drinking water was not included in the 

dietary assessment. HED selected use in a restaurant setting as the FHE scenario likely to result 

in the highest potential acute dietary exposure. Additionally, HED ran multiple scenarios which 

assumed a range of exposures in a restaurant setting from all consumed foods bearing propoxur 

residues to just the items on a salad bar bearing propoxur residues. The results of the refined 

acute dietary analysis (food only) conducted to support the continued registration of the FHE 

uses showed that the dietary risk estimates exceed HED’s level of concern for the U.S. general 

population and all population subgroups for all scenarios assessed. There is no chronic dietary 

non-cancer endpoint, therefore a quantitative chronic dietary non-cancer risk assessment was not 

conducted. A chronic cancer dietary risk assessment was conducted; the cancer risk for the U.S.

general population is 2 x 10-7

. Subsequent to completion of the dietary risk assessment, the 

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Agency has received notification from the registrant for voluntary cancellations of liquid spray 

formulations. Should all indoor spray and liquid formulations be cancelled, there will not be any 

exposure from the dietary route associated with propoxur uses.

Residential handler inhalation non-cancer and cancer exposure and risks were estimated for 

propoxur handlers treating outdoor crack and crevice, spot, and perimeter sites using RTU

aerosol cans. All handler inhalation scenarios resulted in MOEs that do not exceed HED’s Level 

of Concern (LOC) (MOE ≥ 30 for adults) and, therefore, are not of concern. The resulting 

dermal and inhalation combined cancer risk estimate for adult handlers is 2 × 10-7

. 

Although propoxur may be used as a spray in outdoor residential settings, potential residential 

post-application exposure is negligible since the likelihood of contacting treated spots, structural 

foundations, and the perimeter of patios, driveways, and sidewalks is low. Therefore, only postapplication exposure to the bed bug treatment in institutional settings (i.e., dormitories) and crack 

and crevice/perimeter treatment in institutional settings such as hospital waiting areas were

quantitatively assessed. All post-application inhalation scenarios result in MOEs that do not 

exceed HED’s LOC (MOE ≥ 30 for adults and MOE ≥ 270 for children). The children’s (1<2 

years old) incidental oral MOE resulting from contact with carpeted surfaces in institutional 

settings (i.e., hospital waiting rooms) is 60 and exceeds HED’s LOC (MOE < 100), however, the 

MOE for hard surfaces is greater than the LOC (MOE ≥ 100). The resulting dermal and 

inhalation combined post-application adult cancer risk estimate for adults from the propoxur 

bedbug use is 5 × 10-7

. While residential post-application risks of concern were not identified for 

all indoor spray use sites, given the persistence and mobile nature of propoxur, there is potential 

for transfer of residues from the indoor use sites to food located in a nearby untreated indoor 

location where food may be handled. HED determined that propoxur is not registered on use 

sites that are likely to result in spray drift. Therefore, a quantitative spray drift assessment was 

not conducted for propoxur.

The acute aggregate risk assessment by definition, includes only dietary (food only) exposure, 

and resulted in risk estimates of concern for all population subgroups. The short-term aggregate 

assessment includes residential post-application inhalation exposure combined with background

dietary (food only) exposures. Short-term aggregate risk estimates were calculated using the 

Aggregate Risk Index (ARI) approach. The adult and children (11<16) scenarios do not exceed 

HED’s LOC (ARIs ≥ 1), however, the children (1<2) short-term aggregate assessment does 

result in risk estimates of concern (ARI <1). For the adult cancer aggregate risk assessment, 

dermal and inhalation exposures were combined with background dietary (food only) exposures 

and resulted in a cancer aggregate risk estimate for the U.S. general population of 7 × 10-7

. 

Occupational non-cancer inhalation exposure as well as combined dermal and inhalation cancer 

exposure and risk estimates were derived for propoxur handlers treating insect mounds/nests, 

FHEs, warehouses, and institutional settings using RTU aerosol cans and manually pressurized 

handwand equipment. All of the non-cancer inhalation baseline scenarios (e.g., no respirators)

resulted in MOEs that do not exceed HED’s LOC (MOEs ≥ 30). The baseline cancer risks for 

the private handler ranged from 2 × 10-7 to 6 × 10-6

. The baseline cancer risks for the 

commercial handler ranged from 6 × 10-7 to 2 × 10-5. The cancer risks for the commercial 

handlers wearing a PF5 respirator ranged from 5 × 10-7 to 1 × 10-5. 

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Based on the use profile of propoxur, the potential for post-application dermal exposure to occur 

for occupational handlers is not expected; further there is no dermal risk identified for propoxur. 

Therefore, a quantitative occupational post-application dermal exposure assessment was not 

conducted.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for propoxur at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for propoxur.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical which have received an ethics review, and 

are compliant with applicable ethics requirements. 

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies relating to toxicology, residue chemistry, or occupational and 

residential exposure associated with this action.

2.2 Tolerance Considerations

Currently, the only registered food use for propoxur is crack and crevice treatments to food areas 

of FHEs. No tolerances have been established for residues of propoxur in raw agricultural 

commodities or processed foods and feeds as a result of this use. The registrant has proposed a 

tolerance of 0.2 ppm (parent only) in/on all food commodities. The registrant previously filed a 

food additive petition (9H5199, 10/16/78) to the Food and Drug Administration (FDA) under 

section 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA) which included residue data 

that indicated the potential for residues in food adjacent to areas subjected to spot or crack and 

crevice treatment. Due to the enactment of FQPA in August 1996, all tolerances are now 

required to be established under section 408 of the FFDCA. At this time, dietary risks exceed 

HED’s level of concern; therefore we are not recommending the establishment of tolerances to 

support the FHE uses and we note that the Agency has received notification from the registrant 

for voluntary cancellations of all FHE uses.

2.2.1 Enforcement Analytical Method

There are no tolerances currently established for propoxur, and a safety finding cannot be made 

to establish new tolerances; therefore a discussion of an analytical enforcement method is not 

relevant to this action.

2.3 Label Recommendations

Although the indoor spray labels state that indoor sprays can only occur in settings where 

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children will not reside, it is not possible to restrict or prohibit children from some of the use 

sites on the registered indoor spray labels (i.e., dormitories, hospitals, and nursing homes). This 

label statement is not enforceable and cannot prevent the potential for children’s post-application 

exposure to propoxur, and as such, exposure scenarios for children 1 to 2 years old and 11 to 16 

years old were included in this assessment. 

In addition, there were several inconsistencies noted during the label review process:

EPA Reg No. 279-3395: The use site section should be updated to remove the use of the product 

in “Schools” since the label specifically prohibits the use in schools by stating “Do not spray this 

product on indoor residential use sites, schools, day care facilities, motels, hotels, and other 

indoor locations where children may be present.”

EPA Reg No. 86244-1: The use site section should be updated to remove “Indoors: Kills Insects 

in Homes, Apartments..” since the label specifically states “Do not spray this product on indoor 

residential use sites, schools, day care facilities, motels, hotels, and other indoor locations where 

children may be present.”

3.0 Introduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C11H15NO3

Common Name Propoxur

Company experimental name N/A

IUPAC name 2-isopropoxyphenyl methylcarbamate

CAS Name 2-(1-methylethoxy)phenyl methylcarbamate

CAS Registry Number 114-26-1

End-use product/EP varies

Chemical Class N-Methyl Carbamate

Known Impurities of Concern propoxur

3.2 Physical/Chemical Characteristics

Propoxur is solid at room temperature with a melting point of around 90°C. It is only slightly 

soluble in water and n-hexane but readily soluble in methanol, acetone, dichloromethane, 2-

propanol, toluene, and many other organic solvents. Propoxur has a vapor pressure at 20oC of 

1.29 mPa (9.7 × 10-6 mm Hg). See Appendix A for detailed physiochemical property 

information.

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3.3 Pesticide Use Pattern

Propoxur is registered to control ants, roaches, hornets, and other pests in and around 

commercial, industrial, and institutional buildings, as well as in FHEs and outside residences. 

Propoxur is currently formulated as liquid concentrate, RTU aerosol cans, bait in bait stations, 

impregnated shelf paper, and impregnated insect tape. A summary table of the registered labels 

and existing use pattern for propoxur is provided in Appendix B. 

3.4 Anticipated Exposure Pathways

Adults and children may be exposed to propoxur in their food, since propoxur is applied in 

FHEs. While propoxur may be used outdoors, the use pattern and the limited application pattern 

makes it unlikely that residues of propoxur will be present in drinking water. Adults may be 

exposed to propoxur during outdoor applications in residential settings and adults and children 

may be exposed to propoxur entering into and contacting treated areas after application. Workers 

may be exposed to propoxur while handling and applying the pesticide. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA’s 

NHANES/WWEIA and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups

4.0 Hazard Characterization and Dose-Response Assessment

The toxicology database for propoxur is complete as described in 40 CFR, Part 158, and includes 

a recently submitted acute CCA study and an immunotoxicity study. The available toxicology 

studies for propoxur are listed in Tables C.2.1 and C.2.2 in Appendix C. The following 

toxicology studies have been submitted in support of registered of propoxur:

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• Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and 

dermal sensitization) 

• Dermal toxicity- rat (90-day dermal toxicity and dermal penetration) 

• Oral developmental (rat and rabbit) and reproductive toxicity (rats) studies

• Chronic oral toxicity studies (rat and dog)

• Carcinogenicity studies (rat and mouse)

• Chronic inhalation study (rat)

• Metabolism studies (rat) 

• Acute and subchronic neurotoxicity studies (rat)

• Immunotoxicity study (rat)

• Mutagenicity battery

• Comparative Cholinesterase Assay studies (CCA) (rat)

4.1 Summary of Toxicological Effects

Propoxur is a member of the common mechanism group of N-methyl carbamate (NMC) 

insecticides which function by inhibiting acetylcholinesterase (AChE) through carbamylation of 

the serine hydroxyl group located in the active site of the enzyme. Inhibition of AChE leads to 

accumulation of acetylcholine and ultimately to neurotoxicity. Propoxur, like other NMCs, 

rapidly inhibits cholinesterase (peak inhibition within 15 and 30 minutes in adult and PND 11 

rats, respectively), with recovery in pups occurring in hours after exposure (2.76 and 3.4 hours

for RBC and Brain ChEI, respectively). This rapid toxicity profile is supported by the propoxur 

database, which indicates that the most sensitive effect is AChE inhibition following oral gavage 

in the acute CCA study. The magnitude of AChE inhibition does not increase following repeat 

dosing if measurements were taken within the peak time of inhibition. Furthermore, a bolus dose 

given via gavage typically results in faster and greater magnitude of AChE inhibition compared 

to propoxur consumed via diet throughout the day. Therefore, the daily exposure to propoxur is 

the main non-cancer toxicological duration of concern. 

As stated previously RBC and brain AChE data are available from multiple studies and the more 

sensitive compartment should be considered for single chemical assessments. For propoxur, red 

blood cell (RBC) AChE is the more sensitive compartment following oral exposure while brain 

AChE inhibition was more sensitive following inhalation exposure. Acute and subchronic 

neurotoxicity studies showed evidence of neurotoxicity manifested as brain and RBC AChE 

inhibition, functional observational battery (FOB) changes, motor and locomotor activity 

changes and reduced pupillary reflex. However, there were no indications of any dose-related 

microscopic effects in skeletal muscle tissues or neural tissues. Clinical signs were observed at 

doses 10-fold higher than AChE inhibition in the CCA study. 

In the CCA study, PND 11 pups were found to be more sensitive to both RBC and brain AChE 

inhibition than adult rats following a single dose (approx 9-fold). There was evidence of a partial 

recovery for RBC and brain AChE inhibition by 4 hours post-dosing in both adults and PND 11 

pups exposed to 5 and 3 mg/kg, respectively. The half-life of RBC and brain AChE inhibition for 

PND 11 pups was calculated from the CCA data to be 2.76 and 3.40 hours, respectively. This is 

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consistent with the PND17 half-life calculated from the NMC CRA for propoxur of 2.69 hrs 

(2007 Revised N-methyl Carbamate Cumulative Risk Assessment1).

Following a dermal absorption study in rats, 50 to 65% of the total radioactivity was found to be 

absorbed following a single application. However, at all measured time points blood 

concentrations of propoxur did not exceed 1% of the total radioactivity indicating that the rate of 

dermal absorption does not exceed the rapid rate at which propoxur is metabolized. This supports 

the findings of the 90-day dermal toxicity study in rabbits, in which AChE inhibition was not 

observed at various time points following 6 hours of exposure. In a human penetration study, it 

was reported that the total amount of propoxur absorbed after application of 4 μg/cm2 to the 

ventral forearm of human volunteers was 19.6% (±5.2%)2. This is consistent with the findings 

observed in the animal studies as human skin is generally 3 to 10 times less permeable than rats. 

There is no evidence of increased quantitative susceptibility in the rat and rabbit developmental 

toxicity studies, or the 2-generation reproductive studies. However, the results of the recently 

submitted acute CCA study indicate that PND 11 pups are quantitatively more sensitive than the 

adult rats (9x) to AChE inhibition (combined sex data) (See Table C.2.3).

In the chronic rat inhalation study, brain AChE inhibition was more sensitive than RBC 

inhibition. In the oral combined chronic and carcinogenicity study, there was a dose-related and 

highly significant increased incidence of urinary bladder papillomas and carcinomas in both 

sexes of rats. There also was a borderline statistically significant increased incidence of uterine 

carcinomas in high-dose females from a 1984 chronic feeding study with rats (MRID 00142725). 

In the mouse carcinogenicity study, propoxur was associated with statistically significant 

increases in hepatocellular adenomas in males. Propoxur is classified as a Group B2: Probable 

human carcinogen, with a linear low-dose approach for quantification of risk using the oral slope 

factor (Q1*) of 3.52 x 10-3 (mg/kg/day) -1

. Propoxur was not mutagenic in bacteria. It was also 

not mutagenic or clastogenic in cultured mammalian cells (Chinese hamster ovary cells). 

Similarly, there was no evidence of a clastogenic and/or aneugenic effect in bone marrow cells 

from either Chinese hamsters or male and female NMRI mice. 

In lethality studies, propoxur is in the Toxicity Category II by oral routes, and Toxicity Category 

III by dermal, inhalation, and eye irritation. Propoxur is a mild irritant to the eyes of rabbits 

(Toxicity Category III), but is not a dermal irritant (Toxicity Category IV), or dermal sensitizer. 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the required 10X FQPA Safety Factor for the protection of infants and 

children be reduced to 1X for oral exposures because of the following reasons: (1) the endpoint 

used for the dietary assessment is s based on the most sensitive compartment of the most 

sensitive effect (RBC AChE inhibition) and lifestage (PND 11 pups) in the database, (2) the 

POD is based on the lower limit or BMDL10 of the central estimate (BMD10) and is health 

1 U.S. EPA. 2007. Revised N-Methyl Carbamate Cumulative Risk Assessment. 

http://www.epa.gov/pesticides/cumulative/common_mech_groups.htm#carbamate

2 Feldman, R.J. and Maibach, H.I. (1974). Percutaneous Penetration of some Pesticides and Herbicides in Man. 

Toxicology and Applied Pharmacology 28, 126-132

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Propoxur Human Health Risk Assessment DP No. D414135

protective; (3) there is a complete toxicity database that evaluates all lifestages for propoxur, and 

(4) the exposure estimates are unlikely to underestimate exposure. 

For inhalation exposures, available toxicity studies only assess exposure to adults Therefore, 

HED recommends that a data-derived FQPA Safety Factor of 9x be applied as the results of the 

CCA study show that PND 11 pups were more sensitive to RBC and brain AChE inhibition than 

adults (combined male/female data). In the pup BMD analysis, data from the definitive doseresponse study were combined with the CCA range-finding study to improve fit and convergence 

(See Appendix C, Table C.2.3). This FQPA SF is only necessary when assessing inhalation 

exposures for children. There is no dermal hazard or POD identified, and thus dermal risk 

estimates were not quantified. 

4.2.1 Completeness of the Toxicology Database

The toxicology database is complete for propoxur. The toxicity profile can be characterized for 

all effects, including potential neurotoxicity, developmental and reproductive toxicity, and 

immunotoxicity. Acceptable studies for developmental toxicity in rats and rabbits, 2-generation 

reproduction in rats, an acute CCA, and acute and subchronic neurotoxicity are available.

4.2.2 Evidence of Neurotoxicity

Propoxur is a member of the common mechanism group known as the NMCs. As with other 

NMCs, propoxur causes neurotoxicity through the inhibition of AChE leading to clinical signs of 

neurotoxicity. Neurotoxicity in the form of gait abnormalities, involuntary clonic motor 

movements, labored breathing, decreased activity, impaired righting reflex, decreased responses 

to auditory and tail pinch stimuli and decreased grip strength was observed at higher doses in 

several of the toxicity studies for the active ingredient. However, the endpoint of concern for risk 

assessment is AChE inhibition which is protective of the clinical signs observed in the database.

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased quantitative susceptibility in the rat and rabbit developmental 

toxicity studies, or the 2-generation reproductive studies. However, the recently submitted acute 

CCA study indicates that PND 11 pups are quantitatively more sensitive (~9x) than the adult rats 

for brain and RBC AChE inhibition (combined sex data). 

Although the AChE inhibition was greater in PND11 pups than adults in the CCA study (9x 

RBC AChE), HED concluded that there is a low concern and no residual uncertainties for preand/or postnatal toxicity for oral exposure because: 1) the oral POD is based on the most 

sensitive life stage (PND11) and compartment (RBC AChE) in the CCA study, and thus are 

protective of infants and children, and 2) the oral POD is based on the BMDL10 for RBC AChE 

inhibition, which is health protective for all of the effects observed in the database. Thus, the

oral regulatory endpoint for propoxur is protective of the AChE inhibition observed in PND11 

pups in the CCA study, and there are no residual concerns for these effects.

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Propoxur Human Health Risk Assessment DP No. D414135

4.2.4 Residual Uncertainty in the Exposure Database

The exposure database for propoxur is considered to be adequate for risk assessment. The FHE 

dietary analysis was based on the upper-bound estimated anticipated residue (0.05 ppm) and a 

conservative estimate of 5% treated FHEs. The residential and occupational exposure 

assessment also incorporates conservative assumptions in the assessment of adults and children. 

HED concludes that the exposure estimates in this analysis are unlikely to underestimate actual 

exposure. 

4.3 Toxicity Endpoint and Point of Departure Selections

As discussed previously, since peak inhibition of cholinesterase occurs rapidly (within 15-30 

minutes) with recovery occurring within minutes to hours (2.76 to 3.40 hours for propoxur), the 

daily exposure to propoxur is the main non-cancer toxicological duration of concern. This is 

supported by the toxicity database for propoxur, which indicates that the most sensitive 

toxicological effect is inhibition of AChE following acute exposure. As discussed above, the 

magnitude of AChE inhibition does not increase over repeated administration. Therefore, based 

on this mode of action and time course for inhibition and recovery, the endpoints selected are 

protective for acute and repeat exposure assessment.

HED performed BMD analyses of the CCA study on propoxur in order to establish an acute 

POD for the single-chemical risk assessment (TXR #0057134). Based on the analyses, it is 

concluded that the use of a BMDL10 of 0.038 mg/kg/day for RBC AChE inhibition in male and 

female PND 11 pups (combined) at the time of peak effect (30 minutes) will provide a healthprotective and scientifically supportable approach for an acute oral POD. As this endpoint based 

on the most sensitive lifestage it is considered protective for all age groups.

For incidental oral exposure, the BMDL10 of 0.038 mg/kg/day for RBC AChE inhibition in male 

and female PND 11 pups (combined) was selected as it is appropriate to the population of 

concern (children) and protective of all other effects observed in the database. 

For propoxur, short-term aggregate risks have been calculated based on food and residential 

exposure (see Section 7.2). In order to estimate adult-specific aggregate risks, the BMDL10 of 

0.339 mg/kg/day for RBC AChE inhibition in male and female adult rat (combined) from the 

CCA study has been selected as an adult oral POD as it is appropriate to the population of 

concern (adult), and is protective of all other adult-specific effects observed in the database. 

The inhalation POD is based on a BMDL10 of 0.0076 mg/L for inhibition of brain AChE in 

female adults in a chronic inhalation toxicity study. Using the methods and dosimetry equations 

described in EPA’s reference concentration (RfC) guidance (1994), a Human Equivalent 

Concentration (HEC) and Human Equivalent Dose (HED) based on the inhalation toxicity point 

of departure (BMDL) were derived for use in MOE calculations (see Table 4.3.2). The regionaldeposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median 

aerodynamic diameter [MMAD] and geometric standard deviation [σg] of aerosols), can be used 

to estimate the different dose fractions deposited along the respiratory tract. The RDDR is also 

based on interspecies differences in ventilation and respiratory-tract surface areas. Thus, the 

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Propoxur Human Health Risk Assessment DP No. D414135

RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the 

predicted inhalation exposure for a human. For propoxur, a RDDR was estimated at 3.413 based 

on systemic effects (inhibition of brain AChE) and a MMAD of 1.4 μm and σg of 1.4. The 

HEC/HED values are presented below in Table 4.3.2.

No dermal risk assessment is required as no adverse effects were observed at the highest dose 

tested (1000 mg/kg/day) in the 90 day dermal toxicity study in the rabbit with AChE 

measurements, and dermal absorption data indicate that the rate of absorption does not exceed 

the rapid rate of propoxur metabolism. 

The 10x intraspecies and 10x interspecies factors are applicable. In addition, the Agency reduced 

the FQPA SF to 1x for oral exposures, but has applied a data-derived 9x a FQPA SF for 

residential/non-occupational inhalation exposures to children based on quantitative sensitivity in 

the young. When conducting inhalation risk assessments, the magnitude of the UFs applied is 

dependent on the methodology used to calculate risk. As discussed above, studies in this risk 

assessment use inhalation animal data and UFs are based on the RfC methodology developed by 

the Office of Research and Development (ORD) for the derivation of inhalation RfCs and HECs 

for use in MOE calculations. Since the RfC methodology takes into consideration the 

pharmacokinetic (PK) differences but not pharmacodynamic (PD) differences, the UF for 

interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF 

for intraspecies variation is retained at 10X3

. Thus, the UF when using the RfC methodology is 

customarily 30X. When considering the application of the FQPA SF, a total margin of exposure 

(MOE) of 270 defines HED’s LOC for residential/non-occupational inhalation exposures to 

children. The LOC for adults is 30.

While propoxur is classified as a Group B2: Probable human carcinogen by the U.S. EPA with a 

linear low-dose approach for quantification of risk using the oral slope factor (Q1*) of 3.52 x 10-3

(mg/kg/day) -1, this linear low-dose approach was based on concentrations of exposure that were 

orders of magnitudes greater than what is currently allowable, and thus is considered to be 

conservative and health protective.

Table 4.3.1 Summary of Toxicological Doses and Endpoints for Propoxur for Use in the Human Health 

Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(all 

populations)

BMDL10 = 

0.038 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

aPAD 

=0.00038 

mg/kg/day

Acute comparative cholinesterase assay 

(MRID 48784802, 48784803)

BMD10 = 0.049 mg/kg/day 

BMDL10 = 0.038 mg/kg/day based on 

RBC AChE inhibition in male and 

female PND11 pups (combined) 

3 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans 

which are not accounted for in the RfC methodology. 

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Table 4.3.1 Summary of Toxicological Doses and Endpoints for Propoxur for Use in the Human Health 

Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Chronic 

Dietary (all 

populations)

No chronic dietary endpoint has been selected. The acute dietary endpoint is based on 

cholinesterase inhibition observed in the acute CCA study, the most sensitive non-cancer 

endpoint in the database, and therefore the protective of all longer-term exposures.

Incidental 

Oral 

BMDL10 = 

0.038mg/k

g/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

aPAD 

=0.00038 

mg/kg/day

Acute comparative cholinesterase assay 

(MRID 48784802, 48784803)

BMD10 = 0.049 mg/kg/day 

BMDL10 = 0.038 mg/kg/day based on 

RBC AChE inhibition in male and 

female PND11 pups (combined) 

Adult Oral 

(Aggregate)

BMDL10 = 

0.339 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

aPAD 

=0.000339 

mg/kg/day

Acute comparative cholinesterase assay 

(MRID 48784802, 48784803)

BMD10 = 0.474 mg/kg/day 

BMDL10 = 0.339 mg/kg/day based on 

RBC AChE inhibition in male and 

female rats (combined) 

Dermal 

A risk assessment for dermal exposure of any duration is not required as no adverse effects 

were observed at the highest dose tested (1000 mg/kg/day) (MRID 41066001), and dermal 

absorption data indicate that the rate of absorption does not exceed the rapid rate of propoxur 

metabolism.

Inhalation 

BMDL10

F= 0.0076 

mg/L

UFA = 3X

UFH = 10X

FQPA SF= 9X 

Residential 

(children) 

LOC= 270

Residential & 

Occupational

(adult) 

LOC= 30

Chronic inhalation study - Rats (MRID 

42648001; 40836402)

BMD10 F= 0.0095 mg/L

BMDL10 F= 0.0076 mg/L based on 

inhibition of AChE in the brain

BMD10 M= 0.016 mg/L

BMDL10 M= 0.011 mg/L based on 

inhibition of AChE in the brain

Cancer (oral, 

dermal, 

inhalation)

Classification: Group B2; “ Probable Human Carcinogenic ” based on dose- related and highly

significant increased incidence of urinary bladder papillomas and carcinomas in both sexes, and 

a borderline statistically significant increased incidence of uterine carcinomas in high- dose 

females (MRID 00142725). The Q1* is 3.52 x 10-3 (mg/kg/day).

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

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Table 4.3.2 Summary of HEC/HED values for Propoxur

Population Scenario

Tox Duration 

Adjustment HEC HED(mg/kg-day; breathing rate specific)

hr/day day/wk mg/L mg/m3 8.3 L/min 16.7 L/min 29 L/min

Occupational Handler 8 5 0.0195 19.5 1.1 2.2 3.9

Residential

Handler N/A N/A 0.0259 25.9 N/A 0.74 N/A

Outdoor postapplication N/A N/A 0.0259 25.9 N/A N/A N/A

Indoor postapplication N/A 7 0.019 19.0 N/A

Bystander 24 7 0.0046 4.6 N/A

HEC =human-equivalent concentration; HED =human-equivalent dose.

HEC =rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR*

HED = HEC*relative activity factor*human-specific conversion factor*daily duration

4.4 Endocrine Disruption

As required by FIFRA and 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 reregistration decision for propoxur, 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), propoxur 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. A second list of chemicals 

identified for EDSP screening was published on June 14, 20134 and includes some pesticides 

4 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

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Propoxur Human Health Risk Assessment DP No. D414135

scheduled for registration review and chemicals found in water. Neither of these lists should be 

construed as a list of known or likely endocrine disruptors. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

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

website5.

5.0 Dietary Exposure and Risk Assessment 

HED completed a dietary analysis in order to assess the currently registered propoxur FHE uses. 

The registrant has recently notified the Agency of their intent to voluntarily cancel the FHE uses 

for propoxur. Should all FHE uses be formally cancelled, there will be no exposure from the 

dietary route associated with propoxur use.

5.1 Residues of Concern Summary and Rationale

HED previously reviewed a study with food samples fortified with [14C] propoxur and subjected 

to various processing procedures which showed that the major residue is parent only. Based on 

this study, HED concluded that the residue of concern is the propoxur per se (Olinger, C., 

D178313, 11/3/1992).

5.2 Food Residue Profile

Currently the only registered uses of propoxur that may result in residues in/on food are crack 

and crevice treatments to food and non-food areas of FHEs including institutional establishments 

that have areas where food is handled. In a pilot study conducted by Mobay Chemical 

Corporation in 1973, twelve foods in a cafeteria were analyzed before and after crack and crevice 

applications at 3X the maximum labeled rate. Detectable residues up to 0.15 ppm were found in 

the study. In other studies, propoxur residues persisted in air even after 48 hours, detectable 

residues of propoxur did incur on foods in dairy, milling and packaging type FHE facilities, and 

propoxur residues survived extreme processing conditions including high temperatures as in 

frying of hamburgers, boiling of potatoes, and pasteurization of milk. Based on the use pattern 

and the available residue data, residues of propoxur are expected to be on the surface of foods 

and detectable residues are possible. However, in the event that the indoor spray formulations 

are cancelled, there would be no remaining registered food uses, therefore, no food residues 

would be expected.

5.3 Water Residue Profile

There is no direct applications of propoxur to raw agricultural commodities and the outdoor nonagricultural registered uses of propoxur are discontinuous, non-broadcast in nature, and in 

relatively limited volume; therefore, there is no concern for propoxur residues in drinking water 

and drinking water was not included in the dietary assessment (H. Yingling, G. Rothman, 

D414136, 8/6/2014).

5 http://www.epa.gov/endo

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5.4 Dietary Risk Assessment

HED conducted a highly refined probabilistic acute dietary assessment to support the registered 

FHE uses of propoxur. Propoxur is registered for use in a variety of FHE facilities from food 

processing plants and food storage facilities to food servicing establishments. For the dietary 

assessment, HED considered a food servicing establishment where all foods contained residues 

of propoxur. This was assumed to be the scenario most likely to represent the greatest estimated 

exposure and risk and therefore would be protective of all other FHE uses including institutional 

establishments that have areas where food is handled. An acute dietary (food only) exposure 

assessment was conducted using the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

5.4.1 Description of Residue Data Used in Dietary Assessment

The dietary exposure from propoxur use is limited to food only; exposure from drinking water is 

not expected. Anticipated residues were used in the dietary risk assessment based on a pilot 

study in which propoxur was applied as a crack and crevice treatment at 3X the maximum rate. 

The maximum residue of 0.15 ppm in that study was extrapolated to 0.05 ppm for a 1X rate and 

used for all foods. Processing factors were not used since the analysis was for food servicing 

establishments; i.e., residues are assumed to incur on foods after being processed.

5.4.2 Percent Crop Treated Used in Dietary Assessment

A value of 5% for treated FHE facilities was used for all analyses. This value was provided by 

the Biological and Economic Analysis Division and is the probability that a food has come into 

contact with any pesticide in any facility along any food path from farm gate to consumers

(Becker, J., D413125, 10/7/2014). The 5% value is believed to be a conservative probability of 

the presence of pesticide residue as a result of FHE treatment. 

5.4.3 Acute Dietary Risk Assessment

The results of the refined acute dietary analysis for food servicing establishments and 5% 

probability of residue showed that the risk estimates at the 99.9th percentile of exposure are 

above HED’s level of concern for U.S. general population and all population subgroups, with the 

highest risk estimate for children 1-2 years old at 1400% of the aPAD.

Toxicological characteristics of propoxur, like the other NMCs, involve rapid AChE inhibition, 

reactivation, and recovery. In other words, after each ingestion of a NMC-containing food, the 

toxic effect of the NMC in the body dissipates, usually in a matter of a few hours. In a typical 

acute (one-day) dietary analysis, the residues in meals which are taken a few hours apart, are 

added together and compared to a total daily reference dose. However, in the case of assessing a 

chemical with rapid dissipation and recovery, the typical acute dietary analysis would be an 

overestimation. To estimate the acute dietary risk more accurately for NMCs, a “eating 

occasion” analysis was performed. Such analyses take into account the time between eating 

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occasions and the corresponding recovery rate, an AChE inhibition half-life of 2.76 hours for 

propoxur. Therefore, in addition to a refined acute dietary analysis, an “eating occasion” dietary 

exposure analysis was conducted for children 1-2, the population subgroup with the highest 

exposure.

The results of the refined acute “eating occasion” dietary analysis showed that the risk estimates 

at the 99.9th percentile of exposure are above HED’s level of concern for U.S. general population 

and all population subgroups, with the highest risk estimate for children 1-2 years old at 940% of 

the aPAD. A series of sensitivity/characterizing analyses were conducted which showed that 

there is still an estimated risk of concern even with exclusion of foods which contribute most to 

the dietary exposure for children 1-2 years old. Additionally, consumption of even a few 

common fruits and vegetables in a food servicing setting lead to acute dietary estimated risks that 

are of concern. A summary of the analyses are provided below in Table 5.4.6.2 and as part of 

the final dietary memorandums for propoxur (M. Sahafeyan, D421691, 7/24/2014 and D425959, 

3/12/2015). 

Additional refined dietary analyses were conducted in order to determine the maximum propoxur 

residues on food which would result in dietary risks below HED’s level of concern. Only when 

residues were reduced to 0.004 ppm for all foods listed in DEEM did the acute dietary risk 

estimate based on the “eating occasion” analysis drop to below HED’s level of concern (<100% 

aPAD) for children 1-2 years old. HED notes that the residue value of 0.004 ppm is significantly

lower than the typical limits of quantitation of enforcement methods. Detailed results are shown 

in Tables 5.4.6.1 and 5.4.6.2, below.

Although several different approaches to quantifying the acute dietary exposure were modeled, 

there are additional characteristics of propoxur that have been considered. Other studies indicate 

that 1) propoxur residues persist in air even after 48 hours and one study has shown that 

propoxur residues can travel from treated to non-treated areas, 2) detectable residues of propoxur 

do incur on foods in dairy, milling, and packaging type of FHEs, 3) propoxur survives extreme 

processing conditions including high temperatures as in frying of hamburgers, boiling of 

potatoes, and pasteurization of milk, and 4) commodity specific (CS) analysis, indicate that for 

any child 1-2 years old, any typical one-time consumption of many fruits and vegetables result 

in dietary risk much above HED’s level of concern. Furthermore, the anticipated residues 

reported from a 1973 study have associated uncertainties as the study itself indicated that there 

was a +20% uncertainty with some of the results. These points are discussed in separate 

memorandums (M. Sahafeyan, D421691, 7/24/14, C. Smith, D390098, 9/15/11). Due to the 

nature of propoxur, as stated, there is concern for exposure to propoxur on food from indoor 

spray/aerosol applications in food and non-food areas of any FHEs including institutional 

establishments that have areas where food is handled.

5.4.4 Chronic Dietary Risk Assessment

A chronic non-cancer dietary exposure assessment is not warranted since, as with other NMCs, 

propoxur neurotoxicity is considered reversible. Propoxur AChE inhibition and reactivation is 

rapid, therefore, every day is considered a new day for exposure and a chronic assessment would 

not be appropriate. Although a chronic dietary risk assessment is not required, exposures to 

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propoxur residues estimated from a chronic analysis were used as average background dietary 

exposure values for estimating aggregate risk. The results are shown below in Table 5.4.6.1.

5.4.5 Cancer Dietary Risk Assessment

A chronic cancer dietary risk assessment was conducted assuming that all foods in DEEM

contained the anticipate residue value of 0.05 ppm and incorporating the 5% FHE treated value. 

The cancer risk for U.S. general population was 2 × 10-7. The resulting risk estimate is shown 

below in Table 5.4.6.1.

5.4.6 Summary Tables

Table 5.4.6.1 Summary of Dietary (Food Only) Exposure and Risk for Propoxur 

Population Subgroup

Acute Dietary

(99.9th Percentile)

“Eating Occasion”

Acute1 (99.9th Percentile) Average2 Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

Estimate

General U.S. Population 0.002072 550 ----------- --------- 0.000054 2 × 10-7

All Infants (<1 year old) 0.00395 1000 0.000096

NA

Children 1-2 years old* 0.005503 1400 0.003572 940 0.000227

Children 3-5 years old 0.003048 800 ----------- ----------- 0.000153

Children 6-12 years old 0.001868 500 ----------- ----------- 0.000087

Youth 13-19 years old 0.001072 280 ----------- ----------- 0.000045

Adults 20-49 years old 0.000762 200 ----------- ----------- 0.000038

Adults 50-99 years old 0.000664 170 ----------- ----------- 0.000036

Females 13-49 years old 0.000808 210 ----------- ----------- 0.000037

1. Half-life for “Eating Occasion” Acute Dietary Analysis = 2.76 hours

2. Average exposures to propoxur residues are those estimated from chronic analysis; they are used as background exposure for 

estimating aggregate risk.

*The subpopulation with the highest risk estimates.

Further “Eating Occasion” sensitivity/characterization analyses were conducted for children 1-2 

years old since they were the population subgroup with the highest exposures. The result of all 

the analyses with their assumptions are summarized in Table 5.4.6.2 below.

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Table 5.4.6.2 Summary of “Eating Occasion” Acute Dietary characterization analyses (Food 

Only) Exposure and Risk for Propoxur1

Run # Population Scenario

Acute 

95%ile

(%aPAD)

Acute 

99%ile

(%aPAD)

Acute 

99.9%ile

(%aPAD)

1 Children

1-2 years old

All foods included with residues at 

0.05 ppm and

5% FHE treated.

200 410 940

2 Children

1-2 years old

Uncooked milk (water, fat, solids), 

all uncooked juices and all baby 

foods were zeroed out; all other 

commodities were assumed to have 

residues at 0.05 ppm and 5% FHE 

treated.

89 170 340

3 Children

1-2 years old

Only Uncooked, Fresh food forms 

of apple, banana, grapes, pear, 

peach, lettuce, tomato, carrots, 

cauliflower and broccoli are 

included with residues at 0.05 ppm

and 5% FHE treated.

1 100 200

4 Children

1-2 years old

All foods included with residues at 

0.004 ppm2 and

5% FHE treated.

16 33 75

1 All analyses were conducted in eating occasion mode with half-life of 2.76 hours, holding daily residues constant, and with 1000 iterations. 2 Residues were sequentially reduced in order to determine the maximum propoxur residues on food which would result in dietary risks below 

HED’s level of concern. Only when residues reduced to 0.004 ppm for all foods listed in DEEM did the dietary risk estimate (eating occasion 

analysis) dropped to below the HED’s level of concern (<100% aPAD) for children 1-2 years old. 

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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Propoxur is currently registered for outdoor residential areas such as around foundations, patios, 

driveways, sidewalks, and surfaces of buildings as a spot spray. Propoxur is also formulated as 

bait in bait stations, impregnated shelf paper, and impregnated insect tape. Additionally, nonoccupational post-application exposures may occur for those entering into institutional areas (i.e., 

dormitories and hospital waiting areas) that have been previously treated with propoxur. Noncancer dermal risk estimates have not been quantified because of the lack of a dermal hazard in 

the subchronic dermal study. These uses have been assessed to reflect the updates to HED’s 2012 

Residential SOPs6 along with policy changes for body weight assumptions. 

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

Based on a review of the most recent active labels, only the following propoxur formulations are 

currently registered for use in residential sites: enclosed/containerized bait stations, impregnated 

shelf paper, and outdoor perimeter sprays. The quantitative exposure and risk assessment 

developed for residential handlers is based on the following scenarios: 

• Applicator of RTU aerosol can for outdoor crack and crevice and perimeter treatment.

Handler exposure to the enclosed/containerized bait stations and impregnated shelf paper 

products is considered to be negligible and therefore, a quantitative residential handler 

assessment for these uses was not conducted.

Residential Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

handler risk assessments. Each assumption and factor is detailed in the Propoxur. Revised 

Occupational and Residential Exposure Assessment for Registration Review (D425960, February 

12, 2015) Memorandum.

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

All residential handler inhalation scenarios resulted in risk estimates that do not exceed HED’s

LOC (MOE ≥ 30) and therefore, are not of concern. Table 6.1.1 summarizes the residential 

handler inhalation exposure and risk estimates from the outdoor use of propoxur.

6 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html

Page 23 of 62

 
Propoxur Human Health Risk Assessment DP No. D414135

Table 6.1.1. Residential Handler Non-Cancer Exposure and Risk Estimates for Propoxur

Exposure 

Scenario Crop or Target LOC

Inhalation 

Unit Exposure

(μg/lb ai)1

Maximum

Application 

Rate2

Amount 

Handled 

Daily1

Inhalation

Dose

(mg/kg/day)3 MOE4

Applicator

RTU Aerosol 

Can

Outdoor

Insect 

mounds/nests

30 3000 0.013 lb ai/can 1 can 0.00049 1,500

Outdoor

Perimeter of 

gardens, lawns, 

etc. 

30 3000 0.013 lb ai/can 2 cans 0.00098 760

1 Based on the 2012 HED’s Residential SOPs

2 Based on registered label (Reg. No 655-796) with the maximum application rate.

0.013 lb ai/can = 1% ai x 20 oz/can x 1 gal/128 oz x 0.834 lb product/gal (assuming the product has the same specific gravity as water)

3 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/ can) × Amount Handled 

Daily (cans/day)/BW (80kg).

4 Inhalation MOE = Inhalation HED (0.74 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Summary of Residential Handler Cancer Exposure and Risk Estimates

Residential handler cancer exposure and risk estimates were estimated for propoxur handlers 

treating outdoor surfaces and perimeters using RTU aerosol cans. Although a non-cancer dermal 

risk assessment was not performed due to the lack of an adverse effect in the subchronic dermal 

study, it is assumed that dermal and inhalation exposures both potentially contribute to the 

overall cancer risk for propoxur. The combined inhalation and dermal cancer risk estimate for 

the residential handler is 2 × 10-7. Table 6.1.2 summarizes the residential handler cancer risk 

estimates from the outdoor use of propoxur.

Table 6.1.2. Residential Handler Cancer Exposure and Risk Estimates for Propoxur

Exposure 

Scenario

Dermal 

Unit 

Exposure

(μg/lb ai)1

Inhal 

Unit 

Exposure

(μg/lb 

ai)1

Maximum

Application 

Rate2

Amount 

Handled 

Daily1

Dermal 

Dose

(mg/kg/day)

3

Inhal Dose

(mg/kg/day)

3

LADD

(mg/kg/day) 4

Risk5

Applicator

RTU Aerosol 

Can use on 

Outdoor

Perimeter of 

gardens, 

lawns, etc.

0.37 3000 0.013 lb 

ai/can 0.1 can 0.0012 0.000049 0.000066 2 × 10-7

1 Based on the Residential Exposure Joint Venture (REJV) survey where homeowners apply 2oz of aerosol spray during a single treatment

(assuming 20 oz can).

2 Based on registered label (Reg. No 655-796) with the maximum application rate.

0.013 lb ai/can = 1% ai x 20 oz/can x 1 gal/128 oz x 0.834 lb product/gal (assuming the product has the same specific gravity as water)

3 Dose = Unit Exposure (μg/lb ai/m3

) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/ can) × Amount Handled Daily (cans/day) x 

Dermal absorption 19.6% (if applicable)/BW (80 kg).

4 Lifetime Average Daily Dose (LADD) (mg/kg/day) = [Inhalation Dose (mg/kg/day) + Dermal Dose (mg/kg/day)] × [Days per year of 

exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

5 Cancer risk estimates = LADD (mg/kg/day) × Q1

*

, where Q1

* = 3.52 × 10-3

(mg/kg/day)-1

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Propoxur Human Health Risk Assessment DP No. D414135

6.2 Post-Application Exposure

There is the potential for post-application dermal, inhalation, and incidental exposure for 

individuals exposed as a result of being in an environment that has been previously treated with 

propoxur. The quantitative exposure and risk assessment for residential post-application 

exposures is based on the bed bug use in institutional settings (e.g., adult correctional facilities, 

military barracks, university dormitories, etc.) and the crack and crevice use in institutional 

settings, such as hospital waiting areas. Although propoxur may be used as a perimeter spray in 

outdoor residential settings, the potential post-application exposure is expected to be negligible 

since the likelihood of contacting structural foundations, and the perimeter of patios, driveways, 

sidewalks is low. In addition, post-application exposure is expected to be negligible from the use 

of propoxur impregnated shelf paper and baits. Therefore, only the indoor post-application 

inhalation exposures to the crack and crevice and spot treatments for control of bed bugs in 

institutional settings were quantitatively assessed. Furthermore, incidental oral exposures via 

hand to mouth activities were also assessed for children 1<2 years old present in treated 

institutional settings such as hospital waiting areas. Additionally, given the persistence and 

mobile nature of propoxur, there is potential for transfer of residues from treated indoor use areas 

to nearby or adjacent untreated indoor areas (C. Smith, D390098, 9/15/2011).

This assessment considers post-application inhalation exposure to adults and children (11<16 

years old and 1<2 years old). Although the label states that the bed bug treatment can only occur 

in institutional settings where children will not reside, children 11<16 years old were included in 

the assessment since there is a potential for them to reside in university dormitories (for example 

during summer camps). Children 1<2 years old were included since there is a potential for them 

to be present in treated commercial/institutional settings that are currently registered for crack 

and crevice applications, such as hospital waiting areas.

Residential Post-application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessments. Each assumption and factor is detailed in the Propoxur. 

Revised Occupational and Residential Exposure Assessment for Registration Review (D425960, 

February 12, 2015) Memorandum.

Summary of Residential Post-application Non-Cancer Inhalation Exposure and Risk Estimates

All post-application inhalation scenarios resulted in risk estimates greater than the Agency’s 

level of concern (LOC = MOE ≥ 30 for adults and LOC = MOE ≥ 270 for children) and 

therefore, are not of concern. Table 6.2.1 summarizes the post-application inhalation exposure 

and risk from the limited indoor use of propoxur.

Table 6.2.1: Post-application Inhalation Exposure and Risk Estimates for Children and Adults

Lifestage MLabel

(mg)a

ACH 

(1/hr) k (1/hr)b Vol (m3)

ET 

(hr)

IR

(m3/hr)

Inhalation 

Dose 

(mg/kg/day)c

TWA 

over ET 

(mg/m3)

d

ST Inhal 

MOEe

Adult

2,270 0.45 4.26×10-5 33 16

0.64 0.00072

0.0056 3,400

Child 

11 to < 16 0.63 0.0010

Child

1 to <2 0.33 0.0027

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Propoxur Human Health Risk Assessment DP No. D414135

a

 Mass of active ingredient applied determined from product label (mg). b

 k (1/hr) = [ln(0.1)*CF1] /EvapT, where EvapT = 10[7.3698-0.9546*log10(Csat)] and Csat = [Vapor pressure (9.7x10-6 mmHg) * Conversion factor 

(atm/760 mm Hg) * Molecular Weight (g/mol) * Conversion factor (103 mg/g) * Conversion factor (103 L/m3)] / [R (0.0821 L-atm/mol-K)* 

Temperature (296 K)]

c Note: these inhalation dose values are used in non-cancer aggregate assessments for adults and children, and the adult cancer assessment : 

Inhalation Dose (mg/kg/day) = Exposure (mg/day) * Inhalation absorption factor (unitless) / Body Weight (kg).

Exposure (mg/day) = IR*MLabel * 1 - [((ACH * e-k*ET) – (K e-ACHET))]

 ACH * Vroom ACH-k

d TWA (mg/m3

) = MLabel * 1 - [((ACH * e-k*ET) – (K e-ACHET))]

 ACH * Vroom ACH-k .

ET

e Inhalation MOE = HEC (19 mg/m3

) / TWA (mg/m3). 

Summary of Residential Post-application Non-Cancer Incidental Oral Exposure and Risk 

Estimates

The incidental oral scenario for hard surfaces resulted in a risk estimate greater than the 

Agency’s level of concern (LOC = MOE ≥ 100 for children) and therefore, is not of concern. 

However, the incidental oral risk estimate for carpeted surfaces is 60 and, therefore, below the 

LOC of 100. Table 6.2.2 summarizes the post-application incidental oral exposures and risk 

estimates from the institutional crack and crevice (i.e., hospitals) use of propoxur.

Table 6.2.2: Post-application Incidental Oral Exposure and Risk Estimates for Children (1 to <2 yrs old).

Exposure 

Scenario Faihands

Dermal 

Exp 

(mg)a

Surface 

area of 

1 hand 

(cm2)

Hand 

residue 

loading b

(mg/cm2)

Fraction 

of hand 

mouthed

ET

(hr/day)

Replen.

interval 

(min)

No.

Replen SE

Freq of 

HtM 

activities 

(event/hr)

Dose 

(mg/kg/

day)c

Inc. 

Oral 

MOEd

Crack and Crevice Treatment in Institutional Settings (hospitals)

Carpet 0.15 0.046 150 0.000023 0.13 4 15 4 0.48 20 0.00063 60

Hard 

Surfaces 0.15 0.031 150 0.000015 0.13 2 15 4 0.48 20 0.00021 180

a See Table C.1; Details on the dermal exposure component are provided in Appendix C (D425960; 02/12/15) b HR = Faihands x Dermal exposure (mg) / Surface area of 1 hand (cm2

) x 2 c Dose = HR x (FM x SAH) x (ET x N_Replen) x (1 – (1 – SE )(Freq_HtM / N_Replen)))

BW (11 kg) d Inc Oral MOE = Inc Oral BMDL10 (0.038 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Summary of Residential Post-application Cancer Exposure and Risk Estimates

Although a non-cancer dermal risk assessment was not performed due to the lack of an adverse 

effect identified in the subchronic dermal study, it is assumed that dermal and inhalation 

exposure both potentially contribute to the overall cancer risk for propoxur. It should be noted 

that cancer risks were not assessed for children because propoxur is not mutagenic7

. As 

presented in Table 6.2.3, the resulting cancer risk for adults from the propoxur bedbug use is 

5x10-7

.

Table 6.2.3 Residential Post-application Cancer Exposure and Risk Estimates for Propoxur

Lifestage Post-application Exposure Scenario Daily Dose

(mg/kg/day) 1

LADD 

(mg/kg/day)2,3

Total LADD 

(mg/kg/day)4

Cancer Risk 

Estimate5

Adult Indoor Sprays Perimeter - Dermal 0.00088 0.000051 0.00015 5×10-7

7 “Guidelines for Carcinogen Risk Assessment” (U.S. EPA, 2005): http://www2.epa.gov/sites/production/files/2013-

09/documents/cancer_guidelines_final_3-25-05.pdf and “Supplemental Guidance for Assessing Susceptibility from 

Early-Life Exposure to Carcinogens” (U.S. EPA, 2005):

http://www.epa.gov/ttnatw01/childrens_supplement_final.pdf

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Propoxur Human Health Risk Assessment DP No. D414135

Table 6.2.3 Residential Post-application Cancer Exposure and Risk Estimates for Propoxur

Lifestage Post-application Exposure Scenario Daily Dose

(mg/kg/day) 1

LADD 

(mg/kg/day)2,3

Total LADD 

(mg/kg/day)4

Cancer Risk 

Estimate5

Bedbug Mattress - Dermal 0.00091 0.000053

Inhalation 0.00072 0.000042

1 Dermal Daily Doses are presented in Appendix C (Tables C1 and C2); Inhalation Daily Dose is presented in Appendix D (Table D1)

(D425960; 02/12/15)

2 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of 

exposure (yrs) ÷ Lifetime expectancy (yrs)].

3 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of 

exposure (yrs) ÷ Lifetime expectancy (yrs)].

4 Total LADD (mg/kg/day) = Perimeter Dermal LADD (mg/kg/day) + Mattress Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day).

5 Cancer risk estimates = Total LADD × Q1

*

, where Q1

* = 3.52 × 10-3

(mg/kg/day)-1

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Exposure scenarios considered for adults and children (both 1<2 and 11<16), were selected for 

use in the short-term aggregate risk assessment. For adults the representative handler scenario is 

the RTU aerosol can application and the post-application scenario is the inhalation exposure 

following a bed bug treatment in institutional settings. The children (11< 16) post-application 

scenario is also representative of inhalation exposure following bed bug treatment in institutional 

settings. The children (1<2) post-application scenario is based on inhalation and incidental oral 

exposure following crack and crevice treatment in institutions such as hospital waiting rooms 

and contacting hard surfaces. The incidental oral exposure following contact with carpeted 

surfaces is not included because the risk estimates are of concern (MOEs < 100) and, therefore, 

cannot be used as part of the aggregate risk assessment. 

The adult cancer scenarios considered for use in the cancer aggregate risk assessment are the 

handler RTU aerosol can application and the post-application exposure following bed bug 

applications in institutional settings.

See Table 6.3.1 and 6.3.2 for the recommended exposure and risk estimates to be included in the 

propoxur aggregate assessment.

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Propoxur Human Health Risk Assessment DP No. D414135

Table 6.3.1 Recommendations for the Short-Term Residential Exposures for the Propoxur Non-cancer Aggregate Assessment 1

Lifestage

Handler Exposure 

(mg/kg/day) 2

Residential 

Handler Total 

Exposure 

(mg/kg/day) 3

Residential 

Handler 

Total MOE 4

Post-application Exposure 

(mg/kg/day) 5

Residential Postapplication Total 

Exposure 

(mg/kg/day)

Residential Postapplication 

Total MOE6 Dermal Inhalation Dermal Inhalation Oral

Short-Term

Adults N/A 0.00098 0.00098 760 N/A 0.00072 N/A 0.00072 3,400

Child (11<16) N/A N/A N/A N/A N/A 0.0010 N/A 0.0010 3,400

Child (1<2) N/A N/A N/A N/A N/A 0.0027 0.00021 0.00291 N/A 1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Handler exposure represents high-end handler exposure (6.1.1) for the handler scenario. 3 For adults, residential total exposure reflects the high-end inhalation exposures (Table 6.1.1) for the handler scenario. For young children, handler exposure is not expected. 4 Total MOE = Inhalation MOE

5 Post-application exposure represents post-application inhalation exposure for the relevant exposure duration for both adults and children (Table 6.2.1). 6 Total MOE = Inhalation MOE; Total MOE was not provided for the Child 1<2 scenario because the incidental oral and inhalation routes of exposure have different LOCs and 

may be combined only via the aggregate risk index (ARI) approach which is detailed in Section 7.0 for the aggregate risk assessment.

Table 6.3.2 Recommendations for the Residential Exposures for the Propoxur Cancer Aggregate Assessment 1

Lifestage Handler Exposure (mg/kg/day) 2 Residential Handler Total LADD

(mg/kg/day) 3

Post-application LADD 

(mg/kg/day) 4

Residential Post-application 

Total LADD5

(mg/kg/day)

Dermal Inhalation Dermal Inhalation

LADD

Adults 0.000063 0.0000026 0.000066 0.000104 0.000042 0.00015 1 Bolded risk estimates should contribute to the residential exposure portion of the cancer aggregate assessment. 2 For adults, residential total exposure reflects the high-end dermal and inhalation exposures (Table 6.1.2) for the handler scenario. 3 Total LADD = Dermal LADD + Inhalation LADD 4 Post-application exposure represents post-application dermal and inhalation exposure for the relevant exposure duration for adults (Table 6.2.2). It should be noted that cancer 

aggregate risks were assessed only for adults because propoxur is not mutagenic. 5 Total LADD = Dermal LADD + Inhalation LADD

Page 28 of 62
Propoxur Human Health Risk Assessment DP No. D414135

6.4 Residential Bystander Post-application Inhalation Exposure

A quantitative residential post-application inhalation exposure assessment was not performed for 

the uses of propoxur in impregnated shelf paper, in baits, or as a spot spray to outdoor residential 

areas as inhalation exposure is expected to be negligible from these types of applications. 

However, an inhalation exposure assessment was performed for both handlers and following 

indoor spray applications and these exposure scenarios should be considered protective of any 

potential low-level post-application inhalation exposure that could result from the remaining

registered uses.

6.5 Spray Drift

Based on the currently registered uses, HED determined that propoxur is not registered on use 

sites that are likely to result in spray drift. Therefore, a quantitative spray drift assessment was 

not conducted for propoxur.

7.0 Aggregate Exposure/Risk Characterization

HED must consider and aggregate (add) pesticide exposures and risks from three major sources: 

food, drinking water, and residential exposures. In an aggregate assessment, exposures from 

relevant sources are added together and compared to quantitative estimates of hazard (e.g., a 

NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and 

risks from various sources, HED considers both the route and duration of exposure. Based on the 

current use profile for propoxur, an aggregate assessment is necessary due to the dietary 

exposure from the currently registered FHE use.

7.1 Acute Aggregate Risk

Acute aggregate risk from propoxur exposure is limited to food only; exposure from drinking 

water is not expected. The results of the refined acute dietary analysis shows that the risk 

estimates at the 99.9th percentile of exposure exceed HED’s level of concern for U.S. general 

population and all population subgroups, with the highest “eating occasion” risk estimate for 

children 1-2 years old at 940% aPAD. 

7.2 Short-Term Aggregate Risk

Short-term aggregate risk from propoxur exposure includes background food exposures as well 

as short-term residential exposures. In order to calculate the MOE for the background dietary 

exposure, HED has compared the background dietary exposure values with the oral POD that 

was derived from male and female rats (combined) (adult = 0.339 mg/kg/day; children = 0.038 

mg/kg/day). The scenarios appropriate for the aggregate assessment are provided in Section 6.3. 

Since the level of concern for the dietary, inhalation, and incidental oral routes are different, an 

ARI approach was used to calculate the aggregate risk estimates. An ARI of less than 1 results in 

risk estimates of concern. The results of the short-term aggregate assessment are provided below 

in Table 7.2.1 and show that there are no aggregate risk estimates of concern for adults and 

children (11<16), however, the ARI is below 1 for children (1<2). 

Page 29 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table 7.2.1 Short-Term Aggregate Risk Calculations1

Population

Short-Term Scenario

Dietary Exposure2 Inhalation Residential 

Exposure3

Incidental Oral 

Residential 

Exposure4

Aggregate ARI 

(food and 

residential)5

MOE ARI MOE ARI MOE ARI

Adults 8900 89 760 25 n/a n/a 20

Child (11<16) 840 8.4 3,400 13 n/a n/a 5.0

Child (1<2) 170 1.7 3,400 13 180 1.8 0.8 1 An ARI less than 1 results in risk estimates of concern. (ARI = Aggregate Risk Index.) 2 MOE dietary = [(short-term oral POD (child = 0.038 mg/kg/day; adult = 0.339 mg/kg/day))/(average dietary 

exposure (adults = 0.000038 mg/kg/day; children (11<16) = 0.000045 mg/kg/day; children (1<2)= 0.000227) See 

Table 5.4.6.1)]. ARI dietary = [(MOE dietary)/(MOE target (100))]. 3 MOE inhalation = [(short-term inhalation MOE (See Table 6.3.1)]. ARI inhalation = [(MOE inhalation)/(MOE 

target(adults = 30; child = 270))]. 4 MOE incidental oral = [(short-term incidental oral MOE (See Table 6.3.1)]. ARI incidental oral = [(MOE 

incidental oral)/(MOE target (child = 100))]. 5 ARI Aggregate = 1/[(1/ARI dietary) + (1/ARI inhalation)+(1/ARI incidental oral)]

7.3 Chronic Aggregate Risk

A chronic non-cancer dietary exposure is not warranted since as with other N-methyl carbamates, 

propoxur neurotoxicity is considered reversible, i.e., ChE inhibition and reactivation is rapid, 

therefore every day is considered a new day for exposure.

7.4 Cancer Aggregate Risk

A cancer aggregate risk assessment was completed for propoxur. The exposure includes 

background dietary exposure from the FHE use and the LADD from the residential uses. Based 

on the registered uses, the residential LADD included in the aggregate assessment includes the 

dermal and inhalation routes. The scenarios appropriate for the aggregate assessment are 

provided in Section 6.3. The results of the cancer aggregate assessment are provided below in 

Table 7.4.1.

Table 7.4.1 Aggregate Cancer Risk Estimates

Population Cancer Slope 

Factor (Q1*)

Food Only

Exposure 

(mg/kg/day)1

Residential Exposure 

(LADD)

mg/kg/day2

Aggregate Cancer 

Risk3 

(food and residential)

US Population 3.52 × 10-3 0.000054 0.00015 7 × 10-7

1 Average Food (dietary) exposure as provided in Table 5.4.6.1 2 Residential post-application cancer exposure values used in aggregate assessment (Table 6.3.2). 3 Aggregate Cancer Risk = (Q1*) × (Food Exposure + LADD)

Page 30 of 62
Propoxur Human Health Risk Assessment DP No. D414135

8.0 Cumulative Exposure/Risk Characterization

Propoxur is a member of the N-methyl carbamate common mechanism group for purposes of 

cumulative risk assessment and was included in the 2007 N-methyl carbamate cumulative risk 

assessment. Prior to the completion of registration review, EPA’s Office of Pesticide Programs 

will update the cumulative risk assessment to incorporate toxicity and exposure information 

submitted since 2007. 

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term and Cancer Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the registered uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

• Applicator of an RTU aerosol can for treatment in FHEs, warehouses, institutional 

settings;

• Applicator of an RTU aerosol can for treatment of insect mounds/nests;

• Mixer/loader/applicator of liquids for treatment in FHEs, warehouses, institutional 

settings via manually pressurized handwand; and

• Mixer/loader/applicator of liquids for treatment of insect mounds/nests via manually 

pressurized handwand.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed in the Propoxur. Revised 

Occupational and Residential Exposure Assessment for Registration Review (D425960, February 

12, 2015) Memorandum.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

All of the inhalation MOEs estimates do not exceed HED’s LOC of 30 and are therefore not of a 

concern. A summary of the exposure and risk estimates are provided in Table 9.1.1.

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Propoxur Human Health Risk Assessment DP No. D414135

Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Propoxur.

Exposure Scenario Crop or 

Target

Level of 

Concern

Inhalation Unit 

Exposure

(μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated 

or 

Amount 

Handled 

Daily3

Inhalation

Baseline

(no respirator)

Dose

(mg/kg/day)4 MOE5

Applicator

RTU Aerosol Can

FHE,

Warehouse,

Institutional 

settings,

Insect 

mounds/nests

30 1300 0.013 lb ai/can 2 cans 0.00042 9200

Mixer/Loader/Applicator

Manually 

pressurized 

Handwand

FHE,

Warehouse,

Institutional 

settings,

30 1100 0.094 lb ai/gal 40 gal 0.052 75

Insect 

mounds/nests 30 30 0.094 lb ai/gal 40 gal 0.0014 2800

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2014); Level of mitigation: Baseline

2 Based on registered label (Reg. No 655-796) with the maximum application rate.

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/ gal or can) × Area Treated 

or Amount Handled Daily (gal or cans/day).

5 Inhalation MOE = Inhalation HED (3.9 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Occupational Handler Cancer Exposure and Risk Equations

Although a non-cancer dermal risk assessment was not performed due to the lack of an identified

adverse effect in the subchronic dermal study, it is assumed that dermal and inhalation exposure 

both potentially contribute to the overall cancer risk for propoxur. 

Summary of Occupational Handler Cancer Exposure and Risk Estimates

Occupational handler cancer exposure and risks were estimated for propoxur handlers treating 

FHEs, warehouses, institutional settings, and insect mounds/nests using RTU aerosol cans and 

manually pressurized handwand equipment. The cancer risks for the private handler wearing 

labeled PPE ranged from 2 × 10-7 to 6 × 10-6. The cancer risks for the commercial handler 

wearing labeled PPE ranged from 6 × 10-7 to 2 × 10-5

. These cancer risks for the commercial 

handlers wearing labeled PPE and a PF5 respirator ranged from 5 × 10-7 to 1 × 10-5. All 

occupational handler cancer risks are presented in Tables 9.1.2, 9.1.3, and 9.1.4.

Page 32 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table 9.1.2. Occupational Private Handler Cancer Exposure and Risk Estimates for Propoxur at Labeled PPE

Exposure 

Scenario Use Site

Private Handler

PPE

ADD (mg/kg/day)1 LADD (mg/kg/day) Total 

LADD4

Cancer Risk 

Estimate5 Dermal Inhalation Dermal2 Inhalation3

Applicator of 

RTU Aerosol Can

FHE,

Warehouse,

Institutional 

settings,

Insect 

mound/nest

Single Layer, Gloves

No respirator 0.0052

0.00042

0.000064

0.0000052

0.000069 2 × 10-7

Double Layer, Gloves

No respirator 0.0041 0.000050 0.000055 2 × 10-7

M/L/A of 

Manually 

pressurized 

handwand

FHE,

Warehouse,

Institutional 

settings

Single Layer, Gloves

No respirator 0.079

0.052

0.00097

0.00064

0.0016 6 × 10-6

Double Layer, Gloves

No respirator 0.057 0.00070 0.0013 5 × 10-6

Insect 

mound/nest

Single Layer, Gloves

No respirator 0.00040

0.0014

0.000049

0.000017

0.000066 2 × 10-7

Double Layer, Gloves

No respirator 0.0034 0.000041 0.000059 2 × 10-7

1 Average Daily Dose (ADD) see Appendix E (D425960; 02/12/15)

2 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

3 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure (days/yr) / 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

4 Total LADD (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day).

5 Cancer risk estimates = Total LADD × Q1

*

, where Q1

* = 3.52 × 10-3

(mg/kg/day)-1

Table 9.1.3. Occupational Commercial Handler Cancer Exposure and Risk Estimates for Propoxur at Labeled

PPE

Exposure 

Scenario Use Site

Commercial Handler

PPE

ADD (mg/kg/day)1 LADD (mg/kg/day)

Total 

LADD4

Cancer Risk 

Estimate5 Dermal Inhalation Dermal2 Inhalation3

Applicator of 

RTU Aerosol Can

FHE,

Warehouse,

Institutional 

settings,

Insect 

mound/nest

Single Layer, Gloves

No respirator 0.0052

0.00042

0.00019

0.000016

0.00021 7 × 10-7

Double Layer, Gloves

No respirator 0.0041 0.00015 0.00017 6 × 10-7

Page 33 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table 9.1.3. Occupational Commercial Handler Cancer Exposure and Risk Estimates for Propoxur at Labeled

PPE

Exposure 

Scenario Use Site

Commercial Handler

PPE

ADD (mg/kg/day)1 LADD (mg/kg/day)

Total 

LADD4

Cancer Risk 

Estimate5 Dermal Inhalation Dermal2 Inhalation3

M/L/A of 

Manually 

pressurized 

handwand

FHE, 

Warehouse, 

Institutional 

settings

Single Layer, Gloves

No respirator 0.079

0.052

0.0029

0.0019

0.0048 2 × 10-5

Double Layer, Gloves

No respirator 0.057 0.0021 0.0040 1 × 10-5

Insect 

mound/nest

Single Layer, Gloves

No respirator 0.00040

0.0014

0.00015

0.000052

0.00020 7 × 10-7

Double Layer, Gloves

No respirator 0.0034 0.00012 0.00018 6 × 10-7

1 Average Daily Dose (ADD) see Appendix E (D425960; 02/12/15)

2 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

3 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure (days/yr) / 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

4 Total LADD (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day).

5 Cancer risk estimates = Total LADD × Q1

*

, where Q1

* = 3.52 × 10-3

(mg/kg/day)-1

Table 9.1.4. Occupational Commercial Handler Cancer Exposure and Risk Estimates for Propoxur at Labeled

PPE and a Respirator

Exposure 

Scenario Use Site

Commerical Handler

PPE

ADD (mg/kg/day)1 LADD (mg/kg/day) Total 

LADD4

Cancer Risk 

Estimate5 Dermal Inhalation Dermal2 Inhalation3

Applicator of 

RTU Aerosol Can

FHE,

Warehouse,

Institutional 

settings,

Insect 

mound/nest

Single Layer, Gloves

PF5 respirator 0.0052

0.00085

0.00019

0.0000031

0.00019 7 × 10-7

Double Layer, Gloves

PF5 respirator 0.0041 0.00015 0.00015 5 × 10-7

M/L/A of 

Manually 

pressurized 

handwand

FHE,

Warehouse, 

Institutional 

settings

Single Layer, Gloves

PF5 respirator 0.079

0.010

0.0029

0.00038

0.0033 1 × 10-5

Double Layer, Gloves

PF5 respirator 0.057 0.0021 0.0025 9 × 10-6

Insect 

mound/nest

Single Layer, Gloves

PF5 respirator 0.00040 0.00028 0.00015 0.000010 0.00016 6 × 10-7

Page 34 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table 9.1.4. Occupational Commercial Handler Cancer Exposure and Risk Estimates for Propoxur at Labeled

PPE and a Respirator

Exposure 

Scenario Use Site

Commerical Handler

PPE

ADD (mg/kg/day)1 LADD (mg/kg/day) Total 

LADD4

Cancer Risk 

Estimate5 Dermal Inhalation Dermal2 Inhalation3

Double Layer, Gloves

PF5 respirator 0.0034 0.00012 0.00013 5 × 10-7

1 Average Daily Dose (ADD) see Appendix E (D425960; 02/12/15)

2 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure (days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

3 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure (days/yr) / 365 days/year] × [Years per lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

4 Total LADD (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day).

5 Cancer risk estimates = Total LADD × Q1

*

, where Q1

* = 3.52 × 10-3

(mg/kg/day)

-1

Page 35 of 62
Propoxur Human Health Risk Assessment DP No. D414135

9.2 Short-/Intermediate –Term and Cancer Post-Application Risk

9.2.1 Dermal Post-application Risk

Based on the use profile of propoxur, post-application dermal exposures for occupational 

workers are expected to be negligible. Further, there is no non-cancer dermal risk identified for

propoxur. Therefore, an occupational non-cancer post-application dermal risk assessment was 

not conducted. As there is no post-application exposure expected for occupational workers, a 

post-application cancer assessment was also not assessed.

9.2.2 Inhalation Post-application Risk

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

Furthermore, commercial applicators do not typically return to the treated areas after an indoor 

commercial pesticide application (sites such as warehouses, FHEs, and hotels, etc.) and thus an 

occupational post-application inhalation exposure assessment was not performed for commercial 

applicators.

10.0 Incident Report and Epidemiology

For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease 

Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) 

Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) database were 

consulted for pesticide incident data on the propoxur. The purpose of the database search is to 

identify potential patterns in the frequency and severity of the health effects attributed to 

propoxur exposure. The incidents reported for propoxur to both OPP IDS and NIOSH 

SENSOR-Pesticides were low in frequency and severity. HED found that the health effects 

reported to the incident databases queried suggest that acute health effects of propoxur are 

consistent with carbamate toxicity and include neurological, respiratory, and gastrointestinal 

effects primarily. Many products implicated in the reported incidents were cancelled either in 

2007 (indoor residential products) or 2015 (pet collars). Incidents due to these products are 

expected to decrease as existing stocks are depleted. Therefore, there does not appear to be a 

concern at this time that would warrant further investigation.

In addition to acute poisoning events reported to the OPP IDS and SENSOR-Pesticides, HED is 

also aware of results from epidemiological studies regarding the potential developmental 

neurotoxicity of the chemical, however, this information is limited. In a study conducted in the 

Philippines, researchers evaluated both fetal growth (birth weight and length, head 

circumference), and also delayed motor development in association with prenatal propoxur 

exposure (Ostrea et al., 2011). While researchers did not observe an association with fetal 

Page 36 of 62
Propoxur Human Health Risk Assessment DP No. D414135

growth, they did report a link with delayed motor development among infants exposed to 

propoxur during development. EPA notes that in a US based birth cohort study, the Columbia 

Center for Children’s Environmental Health cohort study, researchers did not observe a 

significant association with propoxur (Rauh et al., 2006). There are uncertainties surrounding 

the comparability of pesticide use pattern and conditions of chemical application in the non-U.S. 

cohort. HED will continue to monitor epidemiological information concerning propoxur through 

the Registration Review process. 

The Agency will continue to monitor the incident and epidemiological information and if a 

concern is triggered, additional analysis will be conducted.

11.0 References

1. Sahafeyan, M., Propoxur - Acute and Chronic Cancer Dietary (Food only) Exposure and 

Risk Assessment to Support Crack and Crevice Use in Food Handling Establishments 

(FHE), D421691, 7/24/2014.

2. Sahafeyan, M., Propoxur - Revised Acute and Chronic Cancer Dietary (Food only) 

Exposure and Risk Assessment to Support Crack and Crevice Use in Food Handling 

Establishments (FHE), D425959, 3/12/2015.

3. Walls, C., Propoxur. Revised Occupational and Residential Exposure Assessment for 

Registration Review, D425960, 2/12/2015.

4. Becker, J., Upper Bound Estimate of the Likelihood of Insecticide Residues on Food 

Resulting from Treatment in Food Handling Establishments, D413125, 10/7/2014.

5. Rossi, L., Reregistration Eligibility Decision (RED), Propoxur, 8/1/1997

6. Olinger, C., Reregistration of Propoxur: Plant Metabolism Data, D178313, 11/3/1992.

7. Recore, S., Evans, E., and Christensen, C., Propoxur: Updated Tier I Review of Human 

Incidents, D425958, 3/10/2015

8. Schlosser, C. 2015. Revised Propoxur BMD Memo. TXR #0057134

9. U.S. EPA. 2007. Revised N-Methyl Carbamate Cumulative Risk Assessment. 

http://www.epa.gov/pesticides/cumulative/common_mech_groups.htm#carbamate

10. C. Smith, S. Shelat., The Health Effects Division’s Review of the Office of Research and 

Development’s Study Entitled, The Spatial and Temporal Variability of Select 

Insecticides in the U.S. EPA IAQ Research House Following a Simulated Crack and 

Crevice Application., D390098, 9/15/2011

Page 37 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Appendix A. Physiochemical Properties

Propoxur is solid at room temperature with a melting point of around 90°C. It is only slightly 

soluble in water and n-hexane but readily soluble in methanol, acetone, dichloromethane, 2-

propanol, toluene, and many other organic solvents. Propoxur has a vapor pressure at 20oC of 

1.29 mPa (9.7 × 10-6 mm Hg).

Table A.1. Physicochemical Properties of the Technical Grade Propoxur

Parameter Value Reference

Melting point/range ~ 90oC Myers, T., The HED 

chapter of RED for 

propoxur, July 31, 1996

http://www.who.int/whopes

/quality/en/propoxur_eval_s

pec_WHO_October_2005.p

df

http://chem.sis.nlm.nih.gov/

chemidplus/

Density NA 

Water solubility Only slightly soluble (0.2% at 20oC)

Solvent solubility Readily soluble in methanol, acetone, 

dichloromethane, 2-propanol, toluene, and 

many other organic solvents; only slightly 

soluble in n-hexane and water. 

Vapor pressure 1.29 mPa (20oC)

Octanol/water partition coefficient, 

Log(KOW)

1.52 (20oC)

Page 38 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Appendix B. Registered Labels and Current Use Pattern for Propoxur

Table B.1. Summary of Directions for Registered Uses of Propoxur

Applic. Timing, 

Type, and 

Equip.1

Formulation 

[EPA Reg. No.]

Maximum Applic. 

Rate Personal Protective Equipment1 Use Directions and Limitations

Bait and Bait Stations

Bait station 1663-32 5.2 × 10-5

 lbs 

ai/station n/a

Apply indoors (under sinks, on counters, behind 

appliances, and along ant trails) and outdoors (surround 

house)

Bait station 3095-25 8.75 × 10-5 lbs 

ai/station n/a Use between 2 to 6 bait stations per room

Bait station 9688-304 0.00021 lbs 

ai/station n/a Use 4 to 6 trays per room

Bait station 9688-305 2.6 × 10-5 lbs 

ai/station n/a

Indoors: Place bait where ants are numerous (under 

sinks, stoves, refrigerators and cabinets); Outdoors: Place 

bait near ant colonies and along trails

Bait Station 51311-4 8.75 × 10-5 lbs 

ai/station n/a

Use all 12 to 18 roach discs at one time; do NOT use this 

product in food areas of food handling establishments, 

restaurants, or other areas where food is prepared or 

processed

Impregnated Materials

Shelf paper 62577-6 1% ai/ roll n/a

Do NOT place wrapped or unwrapped food or utensils 

on impregnated paper. Do NOT store linens, toweling, 

clothing or any other material that may come into contact 

with the skin on this paper

Insecticidal 

Strip/Insect Patch 8730-49

10% ai 

(0.0.31 oz ai or 

0.89 gm ai/6 strips)

Wear gloves when cutting the 

strips

For indoor and outdoor use in telecommunication 

equipment; do not use more than 12 strips in 48 sq inches

Insect Tag 13283-26

9.4% ai

(0.026 oz or 0.75 

grams ai/tag)

ns

For use only in and around telecommunications, power, 

utilities and railroad systems equipment; Do not apply 

more than two tags per 3 cubic feet

Liquid/Spray Formulations

Low pressure 

handwand, high 

pressure 

655-546 ns1

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves, apron

Apply as a coarse spray to cracks and crevices indoors; 

apply to surfaces outdoors; do NOT apply as a trigger 

spray; do NOT use on indoor residential use sites; do 

NOT apply as landscape treatment

Page 39 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table B.1. Summary of Directions for Registered Uses of Propoxur

Applic. Timing, 

Type, and 

Equip.1

Formulation 

[EPA Reg. No.]

Maximum Applic. 

Rate Personal Protective Equipment1 Use Directions and Limitations

handwand, 

backpack

Low pressure 

handwand, high 

pressure 

handwand, 

backpack; 

655-796 0.375 lbs ai/gallon

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves, apron

Apply as a coarse spray to cracks and crevices indoors; 

apply to surfaces outdoors; apply with most types of 

hand or power operated sprayers; do NOT apply as a 

trigger pump sprayer; do NOT spray on indoor 

residential use sites

RTU crack and 

crevice spray 47000-102 0.5% ai/ can ns

For indoor use in commercial sites; do NOT use on 

indoor residential sites; For outdoor use (spray surfaces 

of residential and commercial buildings and (b) around 

patios, driveways, sidewalks, and foundations

Low pressure 

handwand, high 

pressure 

handwand, 

backpack;

86244-1 

(422-18)

0.09375 lbs 

ai/gallon

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves, apron

Do not spray product on indoor residential use sites; For 

outdoor use spray surfaces of buildings, porches, 

driveways, sidewalks as a spot treatment; apply with 

most types of hand or power operated sprayers; do NOT 

apply as a trigger pump sprayer

RTU crack and 

crevice injection 279-3395 1.0% ai/can

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

Use only with injector tube and for injecting into cracks 

and crevices; only for use in hospitals, supermarkets, 

transportation equipment, meat packing and food 

handling establishments; Do not spray product on indoor 

residential use sites

RTU crack and 

crevice injection 

and perimeter

499-501 1.0% ai/can

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

For use in and around outside perimeters of hospitals, 

supermarkets, transportation equipment, meat packing 

and food handling establishments; Do not spray product 

on indoor residential use sites

RTU Spray 2724-819

0.5% ai/can 

(1 can per 1000 sq 

ft)

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

For use in non-food areas of kennels, commercial 

buildings, hospitals, warehouses, office buildings, 

restaurants, and food processing facilities; do not spray 

on indoor residential use sites

RTU Spray for 

crack and crevice 

and spot treatment

3862-135 6 lb product per 

1000 sq ft

Goggle or face shield, coverall 

worn over short-sleeve shirt and 

short pants, chemical resistant 

gloves

Applicators using a high 

pressured handwand must wear at 

Do not use on indoor residential use sites; intended for 

commercial/industrial use; only for indoor use in food 

handling establishments, restaurants, and other 

institutional and Industrial Establishments

Page 40 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table B.1. Summary of Directions for Registered Uses of Propoxur

Applic. Timing, 

Type, and 

Equip.1

Formulation 

[EPA Reg. No.]

Maximum Applic. 

Rate Personal Protective Equipment1 Use Directions and Limitations

least a NIOSH approved 

respirator

Concentrated 

liquid for surface 

spray spot 

treatment with low 

pressure 

handwand, 

backpack high 

pressure handwand 

(do not use trigger 

pump sprayers)

4972-30

5%

Mix 1 part to 9 

parts water

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves, goggles or face

shield

For commercial, industrial, and institutional use only. 

Includes commercial buildings, warehouses, non-food 

areas of food handling establishments; Do not use on 

indoor residential use sites

RTU crack and 

crevice and 

spot/perimeter 

treatment; may be 

applied with 

power-operated or 

hand sprayers

6218-24 1%

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

For commercial, industrial, and institutional use; food 

processing plants, restaurants, warehouses; Do not use on 

indoor residential use sites; Do not use as a space spray

RTU crack and 

crevice spray only 

to be used with 

injector tube

9444-204

10807-457

1% Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

For use in hospitals, supermarkets, transportation 

equipment, utilities, meat packaging and food handling 

establishments, warehouses, restaurants, and other 

commercial buildings; Do not use on indoor residential 

use sites

RTU crack and 

crevice and 

spot/perimeter 

spray and must be 

applied with either 

power operated or 

hand pressurized 

sprayers

84396-12 1%

Long pants, long sleeved shirts, 

shoes and socks, chemical 

resistant gloves

For use in food and meat processing plants, commercial 

building warehouses, and outdoors around the perimeter 

of structures for industrial and commercial use; Do not 

use on indoor residential use sites

1. n/a = not applicable; ns = not stated; RTU= ready to use

Page 41 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Appendix C. Toxicology Profile and Executive Summaries

C.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for propoxur are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity ...............................................

870.3465 90-Day Inhalation Toxicity ...........................................

Yes

Yes

Yes

Yes

yes

Yes 

Yes

Yes

Yes

yes

870.3700a Prenatal Developmental Toxicity (rodent) ....................

870.3700b Prenatal Developmental Toxicity (nonrodent) ..............

870.3800 Reproduction and Fertility Effects ................................

Yes

Yes

Yes

Yes

Yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity ...............

Yes

Yes

Yes

Yes

yes

Yes

Yes

Yes

Yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

Yes

yes

yes

yes

Yes

Yes

Yes

Yes

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

Yes

Yes

CR

yes

yes

not required

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

Yes

CR

yes

Yes

Yes

Yes

CR- conditionally required

Page 42 of 62
Propoxur Human Health Risk Assessment DP No. D414135

C.2 Toxicity Profiles

Table C.2.1 Acute Toxicity Profile

Guideline No. Study Type Results Toxicity Category

870.1100 Acute oral [rat] LD50 (M) = 94 

mg/kg

LD50 (F) = 68 

mg/kg

II

870.1200 Acute dermal [rabbit] LD50: >2000 

mg/kg

III

870.1300 Acute inhalation [rat] LC50 >0.498 mg/L III

870.2400 Acute eye irritation [rabbit] Mild Irritant III

870.2500 Acute dermal irritation [rabbit] No Irritation IV

870.2600 Skin sensitization [guinea pig] Non sensitizer N/A

Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3250

90-Day Dermal Toxicity

(rat)

41066001

Acceptable guideline

0, 50, 250, or 1000 

mg/kg

NOAEL =1000 (HDT)

LOAEL =not identified.

870.3465

Chronic Inhalation 

Toxicity (rat)

42648001, 43398501, 

and 40836402

Acceptable nonguideline

0 (vehicle: a 1:1 mixture 

of propylene glycol and 

ethanol), 2, 10 and 50 

mg propoxur/meter3

. 

Corresponding analytical 

concentrations were 0, 

2.2, 10.4 and 50.5 

mg/meter3 

BMD10 F= 0.0095 mg/L

BMDL10 F= 0.0076 mg/L based on ChE inhibition in 

the brain

BMD10 M= 0.016 mg/L BMDL10 M= 0.011 mg/L 

based on ChE in the brain

870.3700a

Prenatal developmental in 

(rodent)

41061101

Acceptable guideline

0, 3, 9, or 27 mg/kg

Maternal NOAEL = 3 mg/kg/day

LOAEL =9 mg/kg/day based on increased cleaning 

activity, chewing motions, grinding of teeth, reduction 

in food consumption, and a marginal (-7.1%) decrease 

in mean body weight gain for days 6-16.

Developmental NOAEL = 27 mg/kg/day

LOAEL = >27 mg/kg/day (no effects noted) 

Page 43 of 62
Propoxur Human Health Risk Assessment DP No. D414135

Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700b

Prenatal developmental in 

(nonrodent)

41061102 Acceptable 

guideline

0, 3, 10, or 30 mg/kg

Maternal NOAEL = 10 mg/kg/day

LOAEL =30 mg/kg/day based on mortality (3/16 dams 

died during the dosing period) and clinical signs 

(dyspnea and restlessness), and slight decreases in 

mean body weight and food consumption. .

Developmental NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day based on slight (not 

statistically significant) post-implantation loss (17.7% 

at 30 mg/kg/day, as compared to 10.1% in vehicle 

control animals), and a corresponding reduction in the 

mean number of pups per dam. 

870.3800

Reproduction and Fertility 

Effects (rat)

MRIDs 41817501 and 

42615403

Acceptable guideline 

(both studies together)

0, 100, 500 and 2500 

ppm (P1 females: 0, 9.7, 

48.1 and 238.9 

mg/kg/day; F1 females: 

0, 8.8, 43.7, and 228.3 

mg/kg/day)

0, 30 or 80 ppm (males: 

0, 2, or 7 mg/kg/day; 

females: 0, 3, or 8 

mg/kg/day)

Parental/Systemic NOAEL = 2.5 mg/kg/day

LOAEL = 7 mg/kg/day based on RBC ChE inhibition.

Reproductive NOAEL =500 ppm (approximately 45 

mg/kg/day) mg/kg/day

LOAEL = 2500 ppm (approximately 233 mg/kg/day) 

mg/kg/day based on a reduced mean number of 

implantation sites/dam and a reduced mean number of 

pups/dam at 2500 ppm in the F1 females .

Offspring NOAEL =500 ppm (45 mg/kg/day) 

mg/kg/day

LOAEL = 2500 ppm (233 mg/kg/day) mg/kg/day 

based on reduced mean F1 and F2 pup body weights at 

birth at 2500 ppm

870.4100b

Chronic toxicity (dog)

00149040 and 42041601

Acceptable guideline 

both studies together

0, 200, 600 or 1800 ppm 

(0, 6.77, 22.0, and 98.2 

mg/kg/day). 

Bridging study: 0 and 70 

ppm (2.46/2.71 

mg/kg/day males and 

females, respectively)

NOAEL = 2.46 mg/kg/day

LOAEL =6.77 mg/kg/day based on elevated mean 

cholesterol level.

870.4200b

Carcinogenicity (mouse)

42597701 

Acceptable guideline

0, 500, 2000 and 8000 

ppm reported as: males: 

0, 114.3, 472.4 and 

2080.6 mg/kg/day; 

females: 0, 150.4, 591.4 

and 2671.1 mg/kg/day.

NOAEL = 114/150 mg/kg/day for males/females, 

respectively

LOAEL = 472/591 mg/kg/day for males/females, 

respectively based on increased mean liver weights in 

both sexes, increased incidence of liver nodules in 

males, increased levels of alanine aminotransferase 

activity, increased incidence of ovarian nodules in 

females, increased incidence of urinary bladder 

hyperplasia in both sexes).

evidence of tumors as there was a dose-related trend 

of increasing incidence of hepatocellular adenomas in 

male mice (10/49, 10/49, 15/49, and 21/50),

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Propoxur Human Health Risk Assessment DP No. D414135

Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.4300

Combined Chronic 

Toxicity/Carcinogenicity

(rat)

00142725

Acceptable guideline

0, 200, 1000 or 5000 

ppm propoxur (0, 8.23, 

42.03 or 222.3 

mg/kg/day for males; 0, 

11.02, 56.16 or 292.72 

mg/kg/day for females)

NOAEL = 8/11 mg/kg/day for males/females, 

respectively

LOAEL = 42/56 mg/kg/day for males/females, 

respectively based on reduced weight gains and the 

occurrence of hyperplasia of the urinary bladder in both 

sexes. 

evidence of carcinogenicity based on highly 

significant increases in incidences of urinary bladder 

papillomas and carcinomas in both sexes

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Propoxur Human Health Risk Assessment DP No. D414135

Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Gene Mutation

870.5100

MRID 00147479

Gene mutation in S. 

typhimurium

dose levels: with or 

without metabolic 

activation up to 12,500 

μg/plate

Not mutagenic up to 12,500 μg/plate. There was 

cytotoxicity at highest dose tested. 

Gene Mutation

870.5100

MRID 00147479 or 

MRID 00149043

Gene mutation in S. 

typhimurium or E. Coli

dose levels: with or 

without metabolic 

activation up to 25,000 

μg/plate

Acceptable guideline

Not mutagenic up to 25,000 μg/plate. There was 

cytotoxicity at highest dose tested. 

Gene Mutation

870.5375

MRID 40836403

Gene mutation in 

Chinese hamster ovary 

cells

Acceptable guideline

No evidence of mutagenic activity at doses of 25, 50, 

75, 100 and 125 μg/mL in the absence of S9, or at 600, 

800, 900 or 1000 μg/mL with S9 

in vitro test for 

clastogenicity 

chromosomal aberration 

study with Chinese 

Hamster Ovary (CHO) 

cells

MRID 40953501

157, 313, 625 and 1250 

μg/mL without S9 mix 

and at 625, 1250, 2500 

and 5000 μg/mL in the 

presence of S9 mix.

Acceptable guideline 

with MRID 41724601

At 2500 and 5000 μg/mL the test material precipitated 

out. There was no indication of a clastogenic effect at 

any of the levels evaluated (at 1250 μg/mL without S9 

mix there was an insufficient number of metaphase 

spreads for analysis due to cytotoxicity), either in the 

absence or presence of S9 mix. However, the 10-hour 

post-treatment harvest time for cells exposed to 2500 

and 5000 μg/mL +S9 was not supported by results from 

the cell cycle assay

in vitro test for 

clastogenicity 

chromosomal aberration 

study with Chinese 

Hamster Ovary (CHO) 

cells

MRID 

625, 1250, 2500 and 

5000 μg/mL +S9 with 

20-hour post-treatment 

harvest. 

Acceptable guideline 

with MRID 

40953501

At 2500 and 5000 μg/mL there were significantly (p ≤

0.01) increased incidences of cells with chromosomal 

aberrations, but at these doses there was also 

precipitation of the test material. The EPA test 

requirements specify that testing a substance in the 

absence of marked cytotoxicity is necessary only up to 

solubility limits, as the presence of particulates may 

result in aberrations from mechanisms other than 

interactions of the test substance (and/or its 

metabolites) with chromosomes. The combination of 

these two studies meets the Guideline data requirement 

(84-2) for an in vitro mammalian cell chromosome 

aberration test.

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Propoxur Human Health Risk Assessment DP No. D414135

Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.5395

in vivo cytogenetics assay.

MRID 41008701

in vivo chromosomal 

aberration assay in 

Chinese hamster bone 

marrow at 75, 150 or 300 

mg/kg and sacrificed at 

48 hours. 

MRID 42005101

in vivo chromosomal 

aberration assay in 

Chinese hamster bone 

marrow at

75, 150 or 300 mg/kg 

with sacrifice at 6 and 24 

hours

Acceptable guideline 

together 

No evidence of a mutagenic response. Significant 

symptoms of toxicity (including death in 2/12 animals) 

at 300 mg/kg indicates this was an adequately high 

dose. There was no evidence of a mutagenic response 

in animals sacrificed at 6 and 24 hours after dosage, but 

these hamsters received only a dose level of 150 mg/kg. 

In a subsequent in vivo chromosomal aberration assay 

there was no indication of an increased incidence of 

chromosomal aberrations in bone marrow cells 

870.5395

in vivo cytogenetics assay

MRID 00149041

mouse micronucleus 

assay

Acceptable guideline

No mutagenic effect was observed in male and female 

NMRI mice following doses at up to and including 20 

mg/kg (administered as two 10 mg/kg doses, 24 hours 

apart, with sacrifice 6 hours after the last dose). 

Although sacrifice was only 30 hours after the first oral 

dose, metabolism data show that propoxur is rapidly 

and extensively metabolized within a few hours of 

dosage 

870.6200a

Acute Neurotoxicity 

Screening Battery

43445701 Acceptable 

guideline

0, 2, 10 and 25 mg/kg

NOAEL = not identified

LOAEL =2 22 mg/kg/day based on significant branch 

ChE inhibition.

870.6200b

Subchronic Neurotoxicity 

Screening Battery

43445701

Acceptable guideline

0, 500, 2000 or 8000 

ppm propoxur equivalent 

to 0, 33, 132 and 543 

mg/kg/day of for males, 

and 0, 39, 163, and 703 

mg/kg/day for females

NOAEL = 33 mg/kg/day for females, not identified for 

males

LOAEL =33 mg/kg/day for males and 163 mg/kg/day 

for females based on brain CHE inhibition.

870.6300

Developmental 

Neurotoxicity

Not required

870.7485

Metabolism and 

Pharmacokinetics

MRID 00142731

Rats fed 8000 ppm 

propoxur for 13 weeks:

The following metabolites were identified in the urine 

of rats: M1 = 1,2-dihydoxybenzene (= catechol); M2 = 

2-isopropoxyphenol; M3 = 2-hydroxyphenyl 

methylcarbamate; M4 = 2-isopropoxyphenylcarbamic 

acid; M5 = isopropoxyphenyl-hydroxy(-) 

methylcarbamate; M6 = 2-isopropoxy-5-

hydroxyphenyl-methylcarbamate; M7 = 2-isopropoxy5-hydroxyphenyl carbamic acid; M8 = 2-isopropoxy-5-

hydroxyphenylhydroxymethyl carbamate; M9 = 1,5-

dihydroxy-2-isopropoxybenzene. 

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Table C.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

Pharmacokinetics

MRID 00165000

groups of 5 female rats 

received 50, 250 or 500 

ppm unlabeled propoxur 

in their diets for 5 

months, then received 

(by oral gavage) a single 

dose of 1 mg/kg 

radiolabeled material. 

Urine samples taken in the period from 0 to 24 hours 

after dosage had 87.9 to 99.8% of the total radiolabel; 

by thin layer chromatography it was found that 97-98% 

of the activity remained at the origin, and was 

contained in conjugated metabolites and/or extremely 

polar metabolites of unknown structure. By enzymatic 

cleavage 80-86% of the activity was identified as 

specific metabolites including M1, M2, M3, M4, M5, 

M6, M7, M8, as well as M6CII (= 2-isopropoxy-5-

hydroxyphenyl carbamic acid), MS3 (= 2-isopropoxy5-hydroxyphenyl-hydroxymethyl carbamate, and M7A 

(= 2-isopropoxy-3-hydroxyphenyl-methyl carbamate). 

870.7485

Metabolism and 

Pharmacokinetics

MRID 41345801

seven male rats were 

used; one received only 

non-labeled propoxur; 

the others received 1 

mg/kg C14-labeled (ring) 

with sacrifice at 1, 4, 8, 

24, 48 and 72 hours. 

The rats were sagitally sectioned and exposed (29-124 

days) in direct contact with X-ray film. At 1 hour 

radioactivity was detectable in all organs (particularly 

intestines) except bone; 24 hours: there were high 

concentrations in the gastrointestinal tract and bladder, 

also the mucous membranes of the pharyngeal region; 

48 and 72 hours: some radioactivity was still detectable 

in the liver, kidneys and mucous membranes of the 

pharyngeal system. Propoxur (and/or its metabolites) 

was shown to be distributed via the lymph system. 

870.7600

Dermal penetration 

MRID 40953502

A mixture of 50% 

ethanol and 50% water 

was used as solvent, with 

doses of 0.648, 6.91, 

69.5, or 692 μg/cm2

(corresponding nominal 

doses: 0.009875, 0.105, 

1.0625 and 10.5 mg, 

respectively) 

radiolabeled propoxur. 

The highest values for absorption (50 to 64.9%) were 

observed with the two lowest dose levels, with the 

highest percentages of radioactivity (0.1-0.18%) in the 

blood occurring at these dose levels at 0.5 to 1.0 hour 

after dosage. Because propoxur was applied in a 

mixture of ethanol and water, the values obtained for 

dermal absorption were probably somewhat higher than 

if water alone had been the solvent.

870.7800

Immunotoxicity

48759401 Acceptable 

Guideline

Immunotoxicity NOAEL= 362/342 mg/kg/day (M/F) 

(Highest dose tested)

Special studies 

Acute Comparative 

Cholinesterase Assay 

(CCA)

MRID 48784801, 

48784802, 48784803

Acceptable nonguideline

Dose Range-Finding 

Study Adults: 1, 2, 3, 5, 

or 10 mg/kg; PND 11 

pups: 0.3, 0.5, 1, 2, or 3 

mg/kg

Dose-Response Study in 

PND 11 Pups: 0, 0.1, 

0.3, or 1.0 mg/kg.

BMD10 F+M= 0.049 mg/kg/day

BMDL10 F+M= 0.038 mg/kg/day based on RBC ChE 

inhibition in PND 11 pups

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Table C.2.3 Summary of Benchmark Dose (BMD) Analyses for RBC and Brain AChE 

inhibition from Acute CCA Studies 

Source

Sex Target

Organ

AdultB

(MRID 48784802 

Range Finding Study)

PND 11 PupsB

(MRID 48784803 

Dose Response Study)

PND 11 PupsB

(MRID 48784802 

Range Finding Study)

BMD10 BMDL10 BMD10 BMDL10 BMD10 BMDL10

HED 2012 

BMD 

Memo 

(D404194, 

TXR

0056440)

Male

Brain 1.26 1.09 0.13 0.12 0.14 0.11

RBC 0.73 0.498 0.094 0.075 0.1 0.08

Female

Brain 0.88 0.76 0.08 0.06 0.1 0.08

RBC 0.55 0.46 0.02 0.01 0.088 0.067

Combined 

Sexes

Brain 1.29 1.04 Combined Study Data

BMD10 BMDL10

RBC 0.474 0.339 0.049 0.038

A Adult BMDs based on data in MRID 48784802; PND 11 pup BMDs based on data in MRID 48784802, and MRID 48784803. 

C.3 Executive Summaries

a. Acute Neurotoxicity: 

In an acute neurotoxicity study in rats, propoxur (99.4%) was administered by single 

dose oral gavage to 12 Wistar rats/sex/dose at 0, 2, 10 and 25 mg/kg with polyethylene 

glycol 400 (5 ml/kg) as the vehicle. Functional Observational Batteries (FOB) and Motor 

and Locomotor Activity measurements were conducted on days -7, 0, 7 and 14. 

Treatment-related effects were observed in the FOB on day 0 in all treated groups, but 

effects were minimal at the low dose. For low-dose males, there was a significantly 

increased incidence of sitting or lying (rather than standing) during open field 

observation, a marginally decreased incidence of rearing, and a slightly decreased tail 

pinch response. Two low-dose females exhibited slight repetitive chewing and the 

incidence of rearing was marginally decreased in this group. Low-dose animals also had 

slightly (not significantly) lower mean body temperatures (males: 37.8° vs 38.0° for 

controls; females 38.3° vs 38.6°) which were part of dose-related trends. On day 0 in the 

10 and 25 mg/kg groups there were gait abnormalities, involuntary clonic motor 

movements, labored breathing, decreased activity, impaired righting reflex, decreased 

responses to auditory and tail pinch stimuli and decreased grip strength. Mean body 

temperatures were significantly reduced in both sexes (males: controls: 38.0°; 10 mg/kg: 

37.4°; 25 mg/kg: 35.8°; females: controls: 38.6°; 10 mg/kg: 37.9°; 25 mg/kg: 36.6°). 

Satellite groups of 6 rats/sex received 0, 2, 10 or 25 mg/kg (4/6 high-dose males received 

35 mg/kg) propoxur, with sacrifice about 45 minutes after dosing. Low-dose males and 

females had significant (p ≤ 0.01) brain cholinesterase (ChE) inhibition (-18% and -21% 

respectively); at 10 mg/kg both sexes had significant (p ≤ 0.01) RBC (males: -72%; 

females: -63%) and brain (males: -47%; females: -49%) ChE inhibition.

A neurotoxic NOEL was not determined. The neurotoxic LOEL is 2 mg/kg, based on 

significant (p ≤ 0.01) brain ChE inhibition in both sexes (males: -18%; females: -21%) 45 

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Propoxur Human Health Risk Assessment DP No. D414135

minutes after dosage. On day 0, in low-dose males, there was an increased incidence of 

sitting or lying (rather than standing) in open field observation, a marginally decreased 

incidence of rearing, and a slightly decreased tail pinch response. In females, two rats 

exhibited repetitive chewing and the incidence of rearing was marginally decreased. On 

day 0 in the 10 and 25 mg/kg groups there were gait abnormalities, involuntary clonic 

motor movements, labored breathing, decreased activity, impaired righting reflex, 

decreased responses to auditory and tail pinch stimuli and decreased grip strength. Mean 

body temperatures were significantly reduced in both sexes. With the exception of lower 

body weights in high-dose males, there was no evidence of toxicity at 7 days after 

dosage.

There were no significant differences between groups with respect to mean body and/or 

brain weights at termination. There were no indications of any dose-related gross or 

microscopic findings in high-dose animals at termination.

A NOEL could not be determined for this study. However, the Guidelines for this study 

specify that: "The lowest dose shall produce minimal effect...or alternatively, no effects." 

This study satisfies the guideline requirement (81-8) for an acute neurotoxicity screening 

study (MRID 43445701).

b. Subchronic Toxicity

In a 13-week subchronic dermal toxicity study in rabbits groups of 10 male and 10 

female New Zealand rabbits received dermal applications of 0, 50, 250, or 1000 mg/kg 

propoxur suspended in cremophor (2% v/v). Dosing was administered for 6 hours/day, 5 

days/week for a total of 65 treatments over a 90-day period. Animals were examined 

daily, dermal observations were recorded 24 hours post each treatment, body weights and 

food consumptions were measured weekly, hematology and clinical chemistry effects, 

cholinesterase activity, and liver enzyme induction were studied at termination, all 

animals underwent complete gross examinations at sacrifice, and tissues from the control 

and the high-dose (1000 mg/kg) groups underwent histopathological examination. No 

dermal irritation was observed, and no treatment-related effects were observed in body 

weight, food consumption, hematology, clinical chemistry parameters (including plasma, 

erythrocyte and/or brain cholinesterase activities), liver enzymes, and gross or 

histopathology. The NOEL is 1000 mg/kg/day which was the highest dose tested (MRID 

41066001). This study satisfies the guideline requirement (82-3) for a subchronic dermal 

toxicity study for propoxur. The lack of toxic effects observed in this study is indicative 

of the low rate of dermal absorption across the skin and the rapid rate at which propoxur 

is metabolized.

In a 13-week subchronic neurotoxicity study in rats groups of 12 male and 12 female 

SPF-bred Wistar rats were fed diets containing 0, 500, 2000 or 8000 ppm propoxur 

(99.5%) for 13 weeks. These exposure levels were equivalent to 0, 33, 132 and 543 

mg/kg/day of for males, and 0, 39, 163, and 703 mg/kg/day for females. Additional 

groups of 12 male and 12 female rats were fed diets containing 0 or 8000 ppm propoxur 

for 13 weeks, followed by a 4-week recovery period. There were Functional Observation 

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Battery (FOB) and Motor and Locomotor observations at pretreatment and weeks 4, 8, 

and 13. Epileptoid seizures were observed in 5/24 8000 ppm females during FOBtesting. It is hypothesized that these were due to acetylcholine accumulation in the brain 

and a genetic disposition of these rats. In males, 1/12 at the 2000 ppm (but 0/24 at 8000 

ppm) showed epileptoid seizures during FOB-testing; this one occurrence was not 

considered to be related to treatment. Slightly decreased grip strength and foot splay in 

males and females at 2000 and 8000 were considered to correlate with body weight 

retardation at these dietary exposure levels. Motor and locomotor activity were not 

affected in males of any dose level or in females exposed to 500 or 2000 ppm; activity 

was extremely low in individual females at 8000 ppm that had epileptoid seizures during 

FOB testing which was immediately prior to motor and locomotor activity measurements. 

There were no other indications of neurological effects observed in testing. Week 13 

ophthalmic examination showed a reduced pupillary reflex in 4/24 males and 2/24 

females exposed to 8000 ppm, presumably due to cholinesterase (ChE) inhibition. There 

were no significant differences between groups with respect to mean brain weights. 

There were no significant differences between controls and 8000 ppm rats (6/sex/group 

examined) with respect to microscopic neurology findings. At week 13, 2000 ppm and 

8000 ppm males had significantly lower mean body weights (-12% and -21% 

respectively); as did 2000 and 8000 ppm females (-7% and -20%). Plasma and Red 

Blood Cell (RBC) cholinesterase measurements were taken from 6/sex/group of the nonrecovery rats at weeks 4 and 14, and brain ChE was measured at week 14. For males, 

RBC ChE was significantly reduced at 2000 and 8000 ppm for week 4, and at 8000 ppm 

for week 14. For females, plasma ChE was significantly reduced at 8000 ppm for week 

4. Brain ChE was significantly reduced at week 14 in 2000 and 8000 ppm males and 

females (2000 ppm: males: -24%; females: -18%; 8000 ppm: males: -28%; females: -

19%), and "marginally" (but with p ≤ 0.01) in 500 ppm males (-14%). Cholinesterase 

inhibition associated with exposure to carbamates is reversible, and so these measured 

cholinesterase activities may not fully indicate the maximum levels of inhibition that 

occurred, as presumably some time elapsed between blood or brain collection and 

measurement of ChE activities.

The NOEL for FOB and motor and locomotor activity changes is 163 mg/kg/day for 

females, with a LOEL of 703 mg/kg/day; the NOEL in males is 543 mg/kg/day (HDT). 

The NOEL for ophthalmic changes is 132 mg/kg/day for males and 164 mg/kg/day for 

females, with a LOEL (reduced pupillary reflex in some rats) of 543 mg/kg/day for males 

and 703 mg/kg/day for females. The NOEL for reduced ChE in females was 39 

mg/kg/day, and the LOEL was 163 mg/kg/day (reduced brain ChE activity, with reduced 

plasma ChE at 703 mg/kg/day); for males the NOEL was below 33 mg/kg/day (lowest 

dose tested); the LOEL was 33 mg/kg/day (reduced brain ChE activity at all dietary 

exposure levels; reduced RBC ChE at 132 and 543 ppm). There were no indications of 

any dose-related microscopic effects in skeletal muscle tissues or neural tissues; the 

NOEL for microscopic lesions (and histoneurological effects) is 543 mg/kg/day for males 

and 703 mg/kg/day for females. This was the highest dose tested (MRID 43445701). 

This study satisfies the guideline requirement (82-7) for a subchronic neurotoxicity 

screening study in rats.

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Propoxur Human Health Risk Assessment DP No. D414135

c. Chronic Toxicity and Carcinogenicity

In a carcinogenicity study, propoxur (99.6%) was given in Altromin diet at 0, 500, 2000 

and 8000 ppm to groups of 50 male and 50 female B6C3F1 mice, with an additional 10 

animals/sex/ dietary dose level sacrificed at 1 year. Propoxur intake values are reported 

as: males: 0, 114.3, 472.4 and 2080.6 mg/kg/day; females: 0, 150.4, 591.4 and 2671.1 

mg/kg/day. However, these values are based on what appear to be relatively high food 

consumption values (males: 7.0-7.2 gm/animal/day; females: 8.1-8.5 gm/animal/day), 

and there may have been considerable wastage. If food consumption values had been 3 

gm/animal/day, then propoxur intake would have been: males: 0, 47.6, 202.5, or 879.1 

mg/kg/day; females: 0, 53.1, 219.0, or 977.2 mg/kg/day.

There was a dose-related trend of increasing incidence of hepatocellular adenomas in 

male mice (10/49, 10/49, 15/49, and 21/50), but no other indication of any neoplastic 

effect. Non-neoplastic effects included an increased incidence of bladder epithelial 

hyperplasia (classified as minimal and diffuse in all instances) in both sexes at 2000 and 

8000 ppm; there was also a significantly increased incidence of ovarian hemorrhage (and 

thrombus formation) in 8000 ppm females. Mean liver weights (and liver-to-body weight 

ratios) were increased (usually significantly) in both sexes at 2000 and 8000 ppm. Mean 

body weight gains were decreased by about 20% in 8000 ppm males, and 33-50% in 

8000 ppm females. The NOEL in this study was 500 ppm (males: 114.3 mg/kg/day; 

females: 150.4 mg/kg/day), and the LOEL (increased mean liver weights in both sexes, 

increased incidence of liver nodules in males, increased levels of alanine 

aminotransferase activity, increased incidence of ovarian nodules in females, increased 

incidence of urinary bladder hyperplasia in both sexes) was 2000 ppm (males: 472.4 

mg/kg/day; females: 591.4 mg/kg/day) (MRID 42597701). This study satisfies the 

guideline requirement (83-2) for a mouse carcinogenicity study.

In a combined chronic toxicity/carcinogenicity study, groups of 50 SPF strain 

BOR:WISW rats/sex/dietary exposure level was fed 0, 200, 1000 or 5000 ppm propoxur 

(0, 8.23, 42.03 or 222.3 mg/kg/day for males; 0, 11.02, 56.16 or 292.72 mg/kg/day for 

females) in Altromin 1321 diet. Satellite groups of an additional 10 animals/sex/group 

were sacrificed after one year. At 5000 ppm there were significantly (p ≤ 0.01) lower 

mean body weights in both sexes throughout the study (week 13: males -16.1% from 

their controls; females -15.2%), and reduced food consumption relative to controls 

(males: 16 gm/day vs 17 gm/day; females: 11 gm/day vs 14 gm/day). At 1000 ppm 

males tended to have a significantly (p ≤ 0.05) lower mean body weight relative to their 

controls through the first 66 weeks of the study, and sporadically thereafter. Females 

usually had significantly (p ≤ 0.05, often ≤ 0.01) lower mean body weight throughout the 

study.

In both sexes at 5000 ppm there were increases in incidence and degree of what was 

described as slight peripheral neuropathy (mainly characterized by myelin alterations, 

such as vacuolization, myelinovoid formation, and occasional phagocytes). Additionally, 

there was an increased incidence of slight muscular atrophy of the rear extremities.

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Propoxur Human Health Risk Assessment DP No. D414135

At 1000 and 5000 ppm there were highly significant increases in hyperplasia of the 

urinary bladder in both sexes (males: 1/50, 1/50, 10/50 and 44/100 for the 0, 200, 1000 

and 5000 ppm groups; females: 0/50, 0/50, 5/50, 4/48).

At 5000 ppm there were highly significant increases in incidences of urinary bladder 

papillomas and carcinomas in both sexes (papillomas: males: 0/50, 0/50, 1/50, 25/50 for 

the 0, 200, 1000 and 5000 ppm groups respectively; females: 0/50, 0/50, 0/50, 28/50; 

carcinomas were present in 8/50 males and 5/50 females at 5000 ppm, but were not 

observed in controls or any of the lower-dose groups). Females at 5000 ppm showed an 

increased incidence (not quite statistically significant) of carcinoma of the uterus (3/50, 

4/50, 3/50 and 8/50 for the 0, 200, 1000 and 5000 ppm groups respectively).

The LOEL is 42.03 mg/kg/day (1000 ppm) for male rats and 56.16 mg/kg/day (1000 

ppm) for female rats, based on reduced weight gains and the occurrence of hyperplasia of 

the urinary bladder in both sexes. The NOEL is 8.23 mg/kg/day (200 ppm) for male rats, 

and 11.02 mg/kg/day (200 ppm) for female rats (MRID 00142725). This combined 

chronic toxicity/carcinogenicity study satisfies the guideline requirements (83-1 and 83-

2) for a combined rat chronic toxicity and carcinogenicity study.

In a chronic inhalation toxicity study groups of 50 Wistar rats/sex/exposure level received 

whole body exposure for 6.3 hours/day, 5 days/week over a 2-year period followed by an 

exposure-free period of 5 months. Nominal exposure levels were 0 (vehicle: a 1:1 

mixture of propylene glycol and ethanol), 2, 10 and 50 mg propoxur/meter3

. 

Corresponding analytical concentrations were 0, 2.2, 10.4 and 50.5 mg/meter3

. There 

were frequent occurrences of significant cholinesterase inhibition (plasma, RBC and 

brain) at 10 and 50 mg/m3

. Statistically significant RBC cholinesterase depressions at 2 

mg/m3 at weeks 25-26 and 51 were not part of dose-related trends and/or were probably 

within the limits of normal variation. There were only slightly (4%) lower mean body 

weights in 10 and 50 mg/m3 females at 52 weeks. There were no dose-related effects 

involving mortality, clinical signs, hematology, clinical chemistry (other than 

cholinesterase activities), and a number of respiratory functions, urinalyses or organ 

weights. The LOEL is 10 mg/m3 based on significant plasma, RBC and brain 

cholinesterase inhibition at this exposure levels for both sexes on a number of occasions 

when these measurements were made. The NOEL is 2 mg/m3

. There were some slight 

dose-related increases in tumor incidences [the incidences of urinary bladder papillomas 

in males were 0/58, 0/60, 1/59 and 2/60 for the controls, 2, 10 and 50 mg/m3 groups 

respectively, while for hepatocellular adenomas in males the incidences were 2/58, 0/60, 

2/59 and 6/59]. The only occurrence of a papilloma of the urinary bladder in females 

occurred in the highest exposure group [incidences of 0/60, 0/57, 0/60 and 1/59 for 

controls, 2, 10 and 50 mg/m3 groups respectively]. For the females, there was a weak 

(not statistically significant) trend involving uterine adenocarcinomas [incidences of 0/47, 

2/45, 2/50 and 3/47 for the 0, 2, 10 and 50 mg/m3 groups respectively]. An apparent 

dose-related increased incidence in pituitary adenomas in males was probably due to an 

unusually low (3%) incidence of this tumor type in controls (MRID 42648001 and 

43398501).

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Propoxur Human Health Risk Assessment DP No. D414135

While this chronic inhalation study does not satisfy the 83-1 Guidelines data requirement, 

the findings (particularly the occurrence of urinary bladder papillomas) are consistent 

with what was observed in the 2-year rat chronic feeding study.

In a one-year dog feeding study groups of 6 male and 6 female thoroughbred beagles 

received 0, 200, 600 or 1800 ppm propoxur (99.4%) in their diet for a period of 12 

months. The high dose dogs received 1800 ppm during weeks 1-40, 3600 ppm for weeks 

41-44, and 5400 ppm for weeks 45-52. The mean quantities of propoxur consumed per 

animal were 0, 62.4, 186.3, and 780.7 mg/day; or values about 0, 6.77, 22.0, and 98.2 

mg/kg/day. At the highest dose level, one male died at week 50. After week 20, highestdose dogs of both sexes had lower mean body weights than their corresponding controls; 

at week 41 and thereafter their weights were significantly lower. At week 41 three dogs 

in the high-dose group showed an increased incidence of vomiting (after the level of 

propoxur was raised from 1800 to 3600 ppm). One high-dose female had poor weight 

gain in the first 40 weeks, and appeared emaciated at the end of the study. This dog was 

one of those vomiting more frequently after week 41, and had gone from 6.6 kg at week 

40 to 6.0 kg at week 52. After the level was raised to 5400 ppm, almost all of the highdose dogs had an increased incidence of vomiting; some also showed more frequent 

salivation. Most also had spasms throughout their entire bodies after feeding, while two 

"exhibited an uncertain gait with slightly bent joints." One dog "temporarily showed 

aggressive behavior" and another "exhibited circular movements." Mean thrombocyte 

counts were consistently (and significantly) elevated in high-dose dogs, and there was an 

additional increase in this parameter after week 40 (when the propoxur concentration was 

increased). Mean cholesterol levels were significantly elevated in mid- and high-dose 

dogs from week 6; mean cholesterol levels were consistently elevated, sometimes 

significantly so, (relative to control values) in 200 ppm dogs from week 6 to termination. 

At termination, mean N-demethylase activity was significantly elevated in mid and highdose dogs; cytochrome P450 was elevated (but not significantly) in high-dose dogs only. 

Plasma cholinesterase activities tended to be lower in high-dose dogs relative to control 

values, and RBC ChE activities tended to be lower (relative to controls) in dogs receiving 

1800 ppm one hour after feeding. Mean liver weights and mean thyroid weights were 

elevated at termination in the high-dose dogs, and the organ-to-body weight ratios were 

significantly elevated. However, the high mean thyroid weights were due to findings 

from only two of the high-dose dogs, one of which had a thyroid cyst; without these dogs 

the mean thyroid weight from high-dose dogs was comparable to that of controls (highdose dogs: 0.892 gm; controls: 8.69 gm). Mean kidney and mean adrenal weights were 

somewhat elevated in the high-dose dogs. Mean thymus weights in high-dose dogs were 

significantly lower (4.07 gm vs. a control value of 8.69) and the thymus-to-body weight 

ratio was significantly lower in high-dose dogs (0.479 gm/kg vs. 0.872 gm/kg).

Since the low-dose dogs showed an elevated mean cholesterol level which was part of a 

well-defined dose trend, a NOEL was not observed in the study in the original one-year 

study (MRID 00149040). Subsequently, in a bridging study (MRID 42041601), groups 

of 4 male and 4 female beagle dogs were fed diets containing 0 or 70 ppm propoxur for 6 

months (males: 0 and 2.46 mg/kg/day; females: 0, 2.71 mg/kg/day). In this 6-month 

study, there was no indication of any effect (including an elevation of cholesterol levels) 

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on animals receiving the diet containing 70 ppm propoxur. This establishes a NOEL in 

the dog of 2.46 mg/kg/day. The combination of the two studies (MRIDs 00149040 and 

42041601) satisfies the guideline 83-1 requirement (83-1) for a chronic feeding study in 

non-rodents.

d. Developmental Toxicity

In a developmental toxicity study in rats, groups of 25 mated female Wistar/HAN rats 

received oral administrations of 0, 3, 9, or 27 mg/kg propoxur (99.4%) in distilled water 

mixed with 0.5% cremophor daily during days 6 through 15 of gestation; dams were 

sacrificed on day 21. No maternal toxicity was observed at the low dose (3 mg/kg/day). 

At the mid dose (9 mg/kg/day) maternal toxicity was evident in increased cleaning 

activity, chewing motions, grinding of teeth, reduction in food consumption, and a 

marginal (-7.1%) decrease in mean body weight gain for days 6-16. At the high dose (27 

mg/kg/day), signs of maternal toxicity included mortality (3/25 dams, with one death 

after the first administration on day 6, and two deaths after the second administration on 

day 7), symptoms similar to those observed in the mid-dose group and, additionally, 

tremors and ventral recumbency. In addition, there was a significant (p ≤ 0.05) reduction 

in mean food consumption (-14.6%) for days 6-16, and a decrease (-26.2%) in mean body 

weight gain from day 6 through day 16. There were no indications that propoxur was 

embryotoxic, fetotoxic, or teratogenic at doses up to and including 27 mg/kg, Under the 

conditions of this study, the NOEL was 3 mg/kg/day for maternal toxicity, and 27 

mg/kg/day (highest dose tested) for developmental toxicity. The LOEL for maternal 

toxicity was 9 mg/kg/day and >27 mg/kg/day for developmental toxicity (MRID 

41061101). This study satisfies the guideline requirements (83-3) for a developmental 

toxicity study in rats.

In a developmental toxicity study in rabbits, groups of 16 mated female chinchilla rabbits 

received oral administrations of 0, 3, 10, or 30 mg/kg propoxur (99.4%) in distilled water 

mixed with 0.5% cremophor daily during days 6 through 18 of gestation; dams were 

sacrificed on day 28. No maternal, embryo, fetal or developmental toxicity was observed 

at the 3 or 10 mg/kg/day dose levels. At the high dose (30 mg/kg/day) maternal toxicity 

was characterized by mortality (3/16 dams died during the dosing period) and clinical 

signs (dyspnea and restlessness), and slight decreases in mean body weight and food 

consumption. Embryo/fetotoxicity was suggested by a slight (not statistically significant) 

post-implantation loss (17.7% at 30 mg/kg/day, as compared to 10.1% in vehicle control 

animals), and a corresponding reduction in the mean number of pups per dam. No 

treatment-related effects were observed on fetal body weights or sex ratios. Propoxur did 

not induce any external, visceral or skeletal malformations at any of the doses tested. 

Under the conditions of this study, the no-observed-effect-level (NOEL) was 10 

mg/kg/day for maternal and developmental toxicity. The LOEL was 30 mg/kg/day for 

both maternal and developmental toxicity (MRID 41061102). This study satisfies the 

guideline requirements (83-3) for a developmental toxicity study in rabbits.

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e. Reproductive Toxicity

In a 2-generation reproduction toxicity study groups of 25 male and 25 female Wistar rats 

were fed propoxur (99.4%) at concentrations of 0, 100, 500 and 2500 ppm (P1 females: 

0, 9.7, 48.1 and 238.9 mg/kg/day; F1 females: 0, 8.8, 43.7, and 228.3 mg/kg/day) in their 

diet for a 70-day pre-mating period, then through mating, gestation and lactation. Four 

groups of 25 males and 25 females (the F1 generation) were selected and maintained on 

their respective parental diets while producing F2 litters. On day 21 post partum, all F2 

pups and F1 parents were sacrificed. The reproductive NOEL was 500 ppm 

(approximately 45 mg/kg/day), and the LOEL was 2500 ppm (approximately 233 

mg/kg/day) based on a reduced mean number of implantation sites/dam and a reduced 

mean number of pups/dam at 2500 ppm in the F1 females. The fetotoxicity NOEL is also 

500 ppm (45 mg/kg/day) and the LOEL 2500 ppm (233 mg/kg/day) based on reduced 

mean F1 and F2 pup body weights at birth at 2500 ppm (F1: 2500 ppm: 5.3 gm; controls: 

5.8 gm; F2: 2500 ppm: 5.3 gm; controls: 5.7 gm). Other effects noted were body weight 

reductions in 500 ppm P and F1 males and F1 females. Dose-related urothelial 

hyperplasia was observed at 2500 ppm (P: 2/25 males and 6/25 females; F1: 8/25 males 

and 7/25 females). A NOEL for parental toxicity was not observed as RBC ChE was 

significantly (p ≤ 0.01) reduced (-21%) in 100 ppm males of the P generation; it was 

reduced (not significantly) in 100 ppm males of the F1 generation (-12%); brain ChE was 

significantly (p ≤ 0.01) reduced in F1 females (-12%). Plasma ChE was significantly 

reduced in 500 and 2500 ppm F1 females; RBC ChE was significantly reduced in both 

sexes of the P and F1 at 500 and 2500 ppm, and brain ChE was significantly reduced in P 

males at 500 and 2500 ppm, in P females at 2500 ppm, in F1 males at 2500 ppm, and in 

100, 500 and 2500 ppm F1 females (MRID 41817501.

In a subsequent 2-generation study (MRID 42615403), propoxur (99.8%) was 

administered (in Kliba 343 diet) to groups of 25 male and 25 female Wistar rats at 

concentrations of 0, 30 or 80 ppm (males: 0, 2, or 7 mg/kg/day; females: 0, 3, or 8 

mg/kg/day), with selection for an F1 generation (25 males and 25 females per group) 

which were maintained on their respective parental diets while producing F2 litters. On 

day 21 post partum, all F2 pups and their F1 parent were sacrificed. No compoundrelated reproductive toxicity was observed; for F1 males there was a significant (p ≤

0.01) decrease (-22%) in mean RBC ChE activity. The NOEL for ChE inhibition then 

was approximately 2.5 mg/kg/day (30 ppm) and the LOEL was 7 mg/kg/day. The two 

studies together (MRIDs 41817501 and 42615403) adequately satisfy the 83-4 data 

requirement for a 2-generation study in rats with propoxur.

f. Comparative Cholinesterase Assay (CCA)

This series of non-guideline cholinesterase (ChE) inhibition studies (MRID 48784801-48784803) 

was undertaken to evaluate any differences between postnatal day 11 (PND 11) pups and adult rats 

(approximately 7-8 weeks of age) with regard to cholinesterase inhibition. 

Time-Course Study (MRID 48784801): The study was divided into 3 phases (Phase I, Phase II 

and Phase III). Propoxur (98.6% a.i.; Lot #: 1104080407) in corn oil was administered once via

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gavage (5 mL/kg) adult male or PND 11 male pups to determine the time of peak cholinesterase 

inhibition. Dosing was as follows: (1) Phase I dosing was to 40 adult Crl: CD (SD) rats at a dose 

of 5 mg/kg; (2) Phase II consisted of 12 male PND 11 Crl: CD (SD) rats at a dose of 3 mg/kg to 

assess signs of overt toxicity and guide dose selection for Phase III; (3) Phase III consisted of 40 

male PND 11 Crl: CD (SD) rats at a dose of 3 mg/kg . RBC and brain cholinesterase activities 

were determined at 15, 30, 60, 120, and 240 minutes after dosing in the adult 5 mg/kg and PND 

11 pup 3 mg/kg groups (controls evaluated at 15 or 240 minutes). 

Results: All rats (both age groups) survived to scheduled sacrifice. In phase III PND 11 pups, 

tremors were noted for 12/40 males receiving 3 mg/kg, while no treatment-related clinical findings 

were noted in adult males in Phase I or PND 11 male pups in Phase II. Maximal RBC (63%) and 

brain (46%) inhibition was observed at 15 minutes at 5 mg/kg in adult males. In the PND 11 male 

pup, maximal RBC (74%) and brain (64%) inhibition was observed at 30 minutes at 3 mg/kg. 

However, RBC and whole brain cholinesterase activity in the 3.0 mg/kg group increased from 0.5-

to 4-hours post-dosing (l06% and 83%, respectively, at 4 hours), providing evidence of partial 

recovery in brain. Overall results from the doses evaluated in the time course study suggest that 

the time of peak inhibition occurred slightly faster in adults (15 minutes) than in PND11 pups (30 

minutes), but the PND11 pups took longer to recover. Based on the results of this time-course 

study, 15 minutes and 30 minutes were selected as the time of peak cholinesterase determination 

in the definitive dose-response study for adults and PND 11 pups, respectively. Following acute 

oral exposure to propoxur, brain weights were comparable among the groups in both age groups. 

Dose Range-Finding Study (MRID 48784802): This study was performed to determine the dose 

levels for use in the definitive dose-response study (MRID 48784803). Adult Crl: CD (SD) rats 8 

weeks of age (1, 2, 3, 5, or 10 mg/kg) and PND 11 pups (0.3, 0.5, 1, 2, or 3 mg/kg) were 

administered single doses of propoxur in corn oil 5 ml/kg via gavage (6/sex/dose for both age 

groups). At 15 and 30 minutes post dose for adults and pups, respectively cholinesterase activity 

was assessed in the RBC and brain compartments. 

Results: No test substance-related clinical signs were observed in the adult rats at time of dosing 

(clinical signs were not recorded in pups due to technician error). A dose-related reduction in ChE 

activity (both compartments) was observed at all dose levels in both sexes and age groups. In adult 

rats, mean RBC cholinesterase inhibition (ChEI) ranged from 15% to 84%, while mean whole 

brain ChEI ranged from 3% to 53%. In PND 11 pups, mean RBC ChEI ranged from 36% to 82%, 

while mean whole brain ChEI ranged from 22% to 64%. At the common dose of 1.0 mg/kg, RBC 

cholinesterase was reduced 15-16% in the adult rats compared to 57-58% in the PND 11 pups. 

Since significant ChE inhibition was observed at the lowest dose in PND11 pups, dosage levels of 

0.1, 0.3, and 1.0 mg/kg were selected to further elucidate ChE inhibition at low doses for 

benchmark analyses in the definitive dose-response study. Brain weights were comparable among 

the groups in both age groups and sexes. 

Dose-Response Study in Pups (MRID48784803): In the definitive dose response study, propoxur 

(98.6% a.i.; Lot #: 1104080407) was administered once via gavage in corn oil (5 ml/kg) to 11 PND 

11 pups/sex/dose at dose levels of 0, 0.1, 0.3, or 1.0 mg/kg. Adults were not evaluated since the 

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range-finding study resulted in adequate inhibition of RBC and brain ChE. RBC and brain ChE 

were evaluated at the pre-determined time of peak effect of 30 minutes. 

Results: Clinical signs. There were no treatment-related effects on mortality in either age group. 

Clinical signs were not recorded for any of the treated pups as per the protocol prior to euthanasia 

due to technician error. Brain weights were comparable among the male and female PND 11pups. 

RBC Cholinesterase Results. As suggested in the dose range-finding study, PND 11 pups were 

more sensitive than the adult rats based on a comparison of RBC cholinesterase inhibition. In the 

PND 11 pups, both sexes displayed a dose-related reduction in RBC cholinesterase activity, with 

females being more sensitive than males. The magnitude of RBC inhibition being 33-49% at 0.3 

mg/kg and 64-66% at the highest dose tested (1.0 mg/kg) in both male and female PND11 pups. 

At 0.1 mg/kg (lowest dose tested), 31% RBC cholinesterase inhibition was observed in the female 

and 12% in male PND 11 pups. 

Brain Cholinesterase. PND 11 pups were more sensitive than the adult rats, based on a 

comparison of brain ChE inhibition. Brain ChE activity was decreased at all doses in the PND 11 

pups (both sexes). The magnitude of the decrease was 7.7 % (M) and 8% (F) at 0.1 mg/kg, 23% 

(M) and-31% (F) at 0.3 mg/kg, and 55% (M) and 48%(F) at 1.0 mg/kg in the PND11 pups (both 

sexes). 

HED conducted BMD analyses on the propoxur comparative cholinesterase data (CCA) for both 

adults (MRID 48784802) and PND 11 pups (MRID 48784803) for both RBC and brain 

compartments. In addition, HED considered the registrant’s submitted benchmark dose (BMD) 

analysis of the cholinesterase findings (Mihlan and Sheets (2012). Estimation of Benchmark Dose 

for Propoxur Based on RBC Cholinesterase Activity in Post-Natal Day 11 and Adult Rats; MRID 

48784804). HED was able to reproduce most of the registrant’s BMD analyses for the male and 

females. In addition, HED evaluated the male and female pup RBC data from the dose response 

study to see if it was appropriate to combine these data for BMD analysis. Although the statistical 

tests that show a borderline significant difference in these datasets (p=0.067), HED concluded that 

these datasets can be combined to provide more robust ChE measures as there is no biological 

basis to support sex-differences for PND 11 pups, and the observed difference is likely due to 

variability in the RBC ChE measurements. Details of Agency’s BMD analysis are presented in a 

separate BMD memo (D404194 memo from J. Liccione/ B.Sarkar August 2012 TXR 0056440

. 

These studies are classified as acceptable/non-guideline. These studies do not satisfy a guideline 

requirement for propoxur. They satisfy the generic data call-in requirement for propoxur for a 

comparative cholinesterase study in adult rats versus postnatal day (PND) 11 pups. 

g. Mutagenicity

In a Salmonella typhimurium (Ames) assay no mutagenic activity was observed with or 

without metabolic activation (S9 from rat liver) in replicate studies with doses of up to 

12,500 μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. 

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At the highest dose level used there was cytotoxicity in all strains of S. typhimurium used 

(MRID 00147479).

In a second Salmonella typhimurium (Ames) assay no mutagenic activity were observed 

with or without metabolic activation (S9 from rat liver) at doses of up to 25,000 μg/plate, 

with cytotoxicity at highest dose levels in all strains of S. typhimurium used (TA98, 

TA100, TA1535, TA1537 and TA1538), as well as E. coli strain Wp2 hcr (MRID 

00149043). Either of these studies (MRID 00147479 or MRID 00149043) satisfies the 

Guideline requirement (84-2) for a Salmonella typhimurium reverse mutation assay.

In an in vitro CHO (hgprt) assay there was no evidence of mutagenic activity at doses of 

25, 50, 75, 100 and 125 μg/mL in the absence of S9, or at 600, 800, 900 or 1000 μg/mL 

with S9 (MRID 40836403). This study satisfies the Guideline requirement (84-2) for a 

mammalian cells in culture forward gene mutation assay.

In a chromosomal aberration study with Chinese Hamster Ovary (CHO) cells propoxur 

(97.8%) was tested at 157, 313, 625 and 1250 μg/mL without S9 mix and at 625, 1250, 

2500 and 5000 μg/mL in the presence of S9 mix. At 2500 and 5000 μg/mL the test 

material precipitated out. There was no indication of a clastogenic effect at any of the 

levels evaluated (at 1250 μg/mL without S9 mix there was an insufficient number of 

metaphase spreads for analysis due to cytotoxicity), either in the absence or presence of 

S9 mix. However, the 10-hour post-treatment harvest time for cells exposed to 2500 and 

5000 μg/mL +S9 was not supported by results from the cell cycle assay (MRID 

40953501).

In a second CHO chromosomal aberration assay propoxur (98.4%) was tested at 625, 

1250, 2500 and 5000 μg/mL +S9 with 20-hour post-treatment harvest. At 2500 and 5000 

μg/mL there were significantly (p ≤ 0.01) increased incidences of cells with chromosomal 

aberrations, but at these doses there was also precipitation of the test material. The EPA 

test requirements specify that testing a substance in the absence of marked cytotoxicity is 

necessary only up to solubility limits, as the presence of particulates may result in 

aberrations from mechanisms other than interactions of the test substance (and/or its 

metabolites) with chromosomes (MRID 41724601). The combination of these two 

studies meets the Guideline data requirement (84-2) for an in vitro test for clastogenicity.

In an in vivo chromosomal aberration assay in Chinese hamster bone marrow no 

evidence of a mutagenic response was observed in animals which had been orally dosed 

with technical propoxur (several batches: 99.6-99.9%) at 75, 150 or 300 mg/kg and 

sacrificed at 48 hours. Significant symptoms of toxicity (including death in 2/12 animals) 

at 300 mg/kg indicates this was an adequately high dose. There was no evidence of a 

mutagenic response in animals sacrificed at 6 and 24 hours after dosage, but these 

hamsters received only a dose level of 150 mg/kg (MRID 41008701).

In a subsequent in vivo chromosomal aberration assay in Chinese hamsters with technical 

propoxur (99.4%) there was no indication of an increased incidence of chromosomal 

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aberrations in bone marrow cells following oral gavage dosing of the test material at 75, 

150 or 300 mg/kg with sacrifice at 6 and 24 hours (MRID 42005101). The combination 

of these two studies satisfies the 84-2 Guideline requirement for an in vivo cytogenetics 

assay.

In an acceptable mouse micronucleus assay no mutagenic effect was observed in male 

and female NMRI mice following doses at up to and including 20 mg/kg (administered as 

two 10 mg/kg doses, 24 hours apart, with sacrifice 6 hours after the last dose). Although 

sacrifice was only 30 hours after the first oral dose, metabolism data (see below) show 

that propoxur is rapidly and extensively metabolized within a few hours of dosage 

(MRID 00149041). This study satisfies the 84-2 Guideline requirement for an in vivo

cytogenetics assay.

Overall, these results indicate propoxur has little, if any, genotoxic activity. The studies 

cited above (MRID 00147479, MRID 00149043, MRID 40836403, MRID 40953501, 

MRID 41724601, MRID 41008701, MRID 42005101, and MRID 00149041) adequately 

satisfy the mutagenicity data requirements (Guideline 84-2) for propoxur.

h. Metabolism

In a metabolism study (MRID 00142731), the following metabolites were identified in 

the urine of rats which had been fed 8000 ppm propoxur for 13 weeks: M1 = 1,2-

dihydoxybenzene (= catechol); M2 = 2-isopropoxyphenol; M3 = 2-hydroxyphenyl 

methylcarbamate; M4 = 2-isopropoxyphenylcarbamic acid; M5 = isopropoxyphenylhydroxy(-) methylcarbamate; M6 = 2-isopropoxy-5-hydroxyphenyl-methylcarbamate; 

M7 = 2-isopropoxy-5-hydroxyphenyl carbamic acid; M8 = 2-isopropoxy-5-

hydroxyphenylhydroxymethyl carbamate; M9 = 1,5-dihydroxy-2-isopropoxybenzene. In 

additional studies (MRID 40629703; MRID 40629702, MRID 40629704), M6 (= 2-

isopropoxy-5-hydroxyphenyl-methylcarbamate) was identified as a principle metabolite 

in hamsters, mice, and humans. The nitrosated compound M9A ( = 1-hydroxy-2-

isopropoxy-4-nitrobenzene) has been identified as a metabolite in rats and mice (MRID 

40629702), the rhesus monkey (MRID 40629706), and humans (MRID 40629704). It is 

suggested in the human study (MRID 40629704) that M9A is synthesized in the stomach.

In a second metabolism study, groups of 5 female rats received 50, 250 or 500 ppm 

unlabeled propoxur in their diets for 5 months, then received (by oral gavage) a single 

dose of 1 mg/kg radiolabeled material. Urine samples taken in the period from 0 to 24 

hours after dosage had 87.9 to 99.8% of the total radiolabel; by thin layer 

chromatography it was found that 97-98% of the activity remained at the origin, and was 

contained in conjugated metabolites and/or extremely polar metabolites of unknown 

structure. By enzymatic cleavage 80-86% of the activity was identified as specific 

metabolites including M1, M2, M3, M4, M5, M6, M7, M8, as well as M6CII (= 2-

isopropoxy-5-hydroxyphenyl carbamic acid), MS3 (= 2-isopropoxy-5-hydroxyphenylhydroxymethyl carbamate, and M7A (= 2-isopropoxy-3-hydroxyphenyl-methyl 

carbamate) (MRID 00165000).

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In a third metabolism study, seven male rats were used; one received only non-labeled 

propoxur; the others received 1 mg/kg C14-labeled (ring) with sacrifice at 1, 4, 8, 24, 48 

and 72 hours. The rats were sagitally sectioned and exposed (29-124 days) in direct 

contact with X-ray film. At 1 hour radioactivity was detectable in all organs (particularly 

intestines) except bone; 24 hours: there were high concentrations in the gastrointestinal 

tract and bladder, also the mucous membranes of the pharyngeal region; 48 and 72 hours: 

some radioactivity was still detectable in the liver, kidneys and mucous membranes of the 

pharyngeal system. Propoxur (and/or its metabolites) was shown to be distributed via the 

lymph system (MRID 41345801).

In general, the metabolism studies show that propoxur is rapidly absorbed following 

ingestion, and that it is readily metabolized. The combination of studies cited above 

(MRID 00142731, MRID 00165000, MRID 40629702, MRID 40629703, MRID 

40629704, MRID 40629706, MRID 41345801) adequately satisfy the metabolism data 

requirements (Guideline 85-1).

i. Dermal absorption

In a dermal absorption study, a mixture of 50% ethanol and 50% water was used as solvent, with 

doses of 0.648, 6.91, 69.5, or 692 μg/cm2 (corresponding nominal doses: 0.009875, 

0.105, 1.0625 and 10.5 mg, respectively) radiolabeled propoxur. The highest values for 

absorption (50 to 64.9%) were observed with the two lowest dose levels, with the highest 

percentages of radioactivity (0.1-0.18%) in the blood occurring at these dose levels at 0.5 

to 1.0 hour after dosage. Because propoxur was applied in a mixture of ethanol and 

water, the values obtained for dermal absorption were probably somewhat higher than if 

water alone had been the solvent (MRID 40953502).

In a study in the open literature (Feldman, R.J. and Maibach, H.I. (1974). Percutaneous 

Penetration of some Pesticides and Hebicides in Man. Toxicology and Applied 

Pharmacology 28, 126-132) it was reported that the total amount of propoxur absorbed in 

the 120-hour period after application of 4μg/cm2 to the ventral forearm was 19.6% 

(±5.2%). Absorption in the 8-hour and 12-hour periods immediately following 

application was 4.2% and 9.0% of the initial dermal dose. The test material was applied 

in a small amount of acetone. The acetone evaporated after a few seconds. These values 

are more indicative of the normal dermal absorption potential of propoxur than the study 

utilizing an ethanol-water solvent.

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Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

Pesticide Handlers Exposure Database (PHED )1.1; the Agricultural Handler Exposure Task 

Force (AHETF) database; Outdoor Residential Exposure Task Force (ORETF) database, the 

Residential Exposure Joint Venture (REJV) survey; and the Residential SOPs (e.g., Postapplication exposure in indoor environments, Residential Handlers) are (1) subject to ethics 

review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with 

applicable ethics requirements. For certain studies, the ethics review may have included review 

by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their 

use, can be found at the Agency website. 

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