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

POLL U TION PREVENTION

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

PC Code: 04 7802

Decision No.: 482010

Petition No.: N I A DP Barcode: 0414135 Registration No.: N I A Regulatory Action: Registration Review

Case No.: N I A Risk Assessment Type : Preliminary Risk Assessment

TXR No.: N I A CAS No.: 114-26-1

MRID No.: N I A 40 CFR: N I A

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)**~**

Donna S. Davis

, Acting Branch

# Chief**~~** Risk Assessment Branch VI

Health Effects Division (7509P)

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)

Page 1of62Propoxur Human Health Risk Assessment DP No. D 414135

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 propo xur. This Draft Risk Assessment ( D RA) 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.

Page 2 of 62Propoxur Human Health Risk Assessment DP No. D 414135

1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Recommendations

................................ ................................ ................................ .... 8
2.1 Da ta 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 an d 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

Page 3 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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

Page 4 of 62Propoxur Human Health Risk Assessment DP No. D 414135

1.0 Executive Summar y

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

- m ethyl 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 cholin esterase 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 mos t 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 h ours (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 depar ture 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

BMD 10 ) 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 departure s ( POD ) are based on a BMDL 10 (BMD lower limit of a one

- sided 95% confidence interval) of 0.0 38 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 use d 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

BMDL 10 of 0.339 mg/kg/day for RBC AChE inhibition in male and female rats (co mbined) from the CCA study has been selected as an adult oral POD

. The inhalation POD is based on a

BMDL 10 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 estimate s 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:

Page 5 of 62Propoxur Human Health Risk Assessment DP No. D 414135

Probable human carcinogen by the U.S. EPA w ith a linear low

- dose approach for quantification of risk using the oral slope factor (Q 1 *) 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 b rain and RBC cholinesterase inhibition (combined sex data). However, there is no evidence of i ncreased quantitative susceptibility in the rat and rabbit developmental toxicity studies or the 2

- generation reproductive studies. Although PND11 pups had greate r 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 BMDL 10 for RBC AChE inhibition. Therefore, HED concluded th at the 10X Food Quality Protection Act ( FQPA) Safety Factor (SF) could be reduced to 1X for oral

exposure s

. As a result, the UF for oral exposure is 100X (10X intraspecies, 10X interspecies, and 1X FQPA SF). For residential inhalation exposures, HED is a pplying 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 ad ult 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, w hen 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 inhala tion 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 m etabolism study on food samples which were fortified with [ 14 C] 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 t he FHE uses. There is no direc t application s 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 d rinking 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

ass umed a range of exposures in a restaurant setting from all consumed foods bearing propoxur residues to just the ite ms on a salad bar bearing propox ur 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

- c ancer 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 di etary risk assessment, t he

Page 6 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 a ssociated with propoxur use s

.

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 handler s is 2 × 10

- 7

.

Alt hough propoxur may be used as a spray in ou tdoor 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 post

application 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 w ere

quan titatively assessed. All post

- applicat ion 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., hos pital waiting rooms) is 60 and exceeds HED’s LOC (MOE < 100) , however, the

M OE for hard surfaces is greater tha n 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 r esidues from the indoor use site s 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 l ikely to result in spray drift. Therefore, a quantitative spray drift a ssessment was not conducted for propoxur.

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

, and resulted in risk estimates of conce rn for all population subgroups. The short

- term aggregate
assessment includes r esidential 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 exce ed

HED’s LOC ( ARIs ≥ 1) , however, the children (1<2) short

- term aggregate assessment does result in risk estimates of concern (ARI <1)

. For t he adult cancer aggregate risk assessment,
dermal and inhalatio n exposures were combined with background dietary (food only) exposures
and resulted in a c ancer aggregate risk estim ate 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 d erived for propoxur hand lers 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 t he commercial handlers wearing a PF5 respirator ranged from 5 × 10

- 7 to 1 × 10

- 5

.

Page 7 of 62Propoxur Human Health Risk Assessment DP No. D 414135

Based on the use profile of propoxur, the potential for p ost

- 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

- applicat ion inhalation exposure assessment was not perfo rmed 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 Reco mmendations

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 secti on 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 volunta ry 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 enforc e ment metho d 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

Page 8 of 62Propoxur Human Health Risk Assessment DP No. D 414135

children will not reside, it is not possible to restrict or prohibit children from some of the use
site s on the registered indoor spray labels (i.e., dormitories, hospitals, and nursing homes ). This
label statement is not enforceable and cann ot prevent the potential for children’s post

- application exposure to propoxur, and as such, exposure scenarios for c hildren 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 t he 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 In troduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C 11 H 15 NO 3

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 sol vents. 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.

Page 9 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 can s, 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

FHE s. 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 ma y be exposed to propoxur during outdoor application s 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 A ddress 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 accor ding 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 b y 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

co mmitted 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 i mmunotoxicity 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:

Page 10 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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

• 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 inhala tion 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 ho urs 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 comp ared 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

se nsitive 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 in dications 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 b oth 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, respective ly. 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

Page 11 of 62Propoxur Human Health Risk Assessment DP No. D 414135

consistent with the PND17 half

- life calculated from the NMC CRA for propoxur of 2.69 hrs ( 2007 Revised N

- me thyl Carbamate Cumulative Risk Assessment 1 )

.

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 d id not exceed 1% of the total radioactivity indicating that the rate of dermal absorption does not excee d the rapid rate at which propoxur is metabolized . This supports the findings of the 90

- day dermal toxicity study in rabbits, in which A ChE inhibition w as 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/cm 2 to the ventral forearm of human volunteers was 19.6% (±5.2%) 2 . Thi s 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 i ncreased 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 sensitiv e than the adult rats (9x) to AChE inhibition (combined sex data) (See Table C .2.3).

In the chroni c 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 i n 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 associ ated 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 (Q 1 *) 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

fr om either Chinese hamsters or male and female NMRI mice.

In lethality studies, p ropoxur 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 rab bits (Toxicity Category III), but is not a dermal irritant (Toxicity Category IV), or dermal sensitizer.

4. 2 Safety F actor 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 compa rtment 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 BMDL 10 of the central estimate (BMD 10 ) 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 He r bicides in Man. Toxicology and Applied Pharmacology 28, 126

- 132

Page 12 of 62Propoxur Human Health Risk Assessment DP No. D 414135

protective; (3) there is a complete toxicity database tha t evaluates all lifestages for propoxur, and ( 4 ) the exposure estimates are unlikely to underestimate exposure.

For inhalation exposures , available t oxicity stud ies only assess exposure to adult s 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 dose

response 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 w ere not quantified.

4.2.1 Completeness of the Toxicology Databas e

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, a n acute CCA, and acute and subchronic neurotoxicity are available.

4.2.2 Evidence of Neurotoxicity

Propoxur is a member of the commo n 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 stud ies 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 i ncreased 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 i nhibition (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 pre

and/or postnatal toxicity for oral exposu re 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 BMDL 10 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.

Page 13 of 62Propoxur Human Health Risk Assessment DP No. D 414135

4.2.4 Resid ual 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. T he 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

expos ure.

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, t he 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 a ssessment.

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 BMDL 10 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 health

protective and scientifically supportable approach for an acute oral POD. As this endpoint based on the most sensitive lifestage it is consi dered protective for all age groups.

For incidental oral exposure, the BMDL 10 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 BMDL 10 of 0.339 mg/kg/day for R BC 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 BMDL 10 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 Hum an 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 regional

deposited

- dose ratio (RDDR), which accounts for the parti culate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [ σ g ] 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

Page 14 of 62Propoxur Human Health Risk Assessment DP No. D 414135

RDDR can be used to adjust an obse rved inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For propoxur, a RDDR wa s estimated at 3.413 based on systemic effects (inhibition of brain AChE) and a MMAD of 1.4 μ m and σ g 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 ind icate 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

- deriv ed 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 calculat e 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 calcula tions. 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 intras pecies variation is retained at 10X 3 . 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 ex posures 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 (Q 1 *) 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) BMDL 10 = 0.038 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD =

aPAD

=0.00038 mg/kg/day Acute comparative cholinesterase assay ( MRID 48784802, 48784803)

BMD 10 = 0.049 mg/kg/day

BMDL 10 = 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.

Page 15 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 BMDL 10 = 0.038mg/k g/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD =

aPAD

=0.00038 mg/kg/day Acute comparative cholinesterase assay ( MRID 48784802, 48784803)

BMD 10 = 0.049 mg/kg/day

BMDL 10 = 0.038 mg/kg/day based on
RBC AChE inhibition in male and female PND11 pups (combined)

Adult Oral (Aggregate) BMDL 10 = 0.339 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD =

aPAD
=0.000339 mg/kg/day Acute comparative cholinesterase assay ( MRID 48784802, 48784803)

BMD 10 = 0.474 mg/kg/day

BMDL 10 = 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 BMDL 10 F= 0.0076

mg/L UF A = 3X

UF H = 10X FQPA SF= 9X Residential (children)

LOC= 270

Residential & Occupational (adult)

LOC= 30 Chronic inhalation study

- Rats (MRID 42648001; 40836402)

BMD 10 F= 0.0095 mg/L

BMDL 10 F = 0.0076 mg/L based on
inhibition of AChE in the brain

BMD 10 M= 0.016 mg/L

BMDL 10 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 Q 1 * is 3.52 x 10

- 3 (mg/kg/day ).

Point of Departure (PO D) = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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.

Page 16 of 6 2Propoxur Human Health Risk Assessment DP No. D 414135

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 post

application N/A N/A 0.0259 25.9 N/A N/A N/A

Indoor post

application 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 toxi city, 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 histo pathology, 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 an d 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 re quired 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 a re 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 iden tify 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, 2013 4 and in cludes some pesticides

4 See http://www.regu lations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

Page 17 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 proce dures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website 5

.

5.0 Dietary Exposure and Risk Assessment

HED completed a dietary analysis in order to assess the currently registered propoxur FHE uses. T he 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 s tudy with food samples fortified with [ 14 C] propoxur and subjected to various processing procedure s which showed that the major residue is parent only. Based on this study, HED con cluded 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 applica tions 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 expec ted.

5.3 Water Residue Profile

There is no direct application s 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; therefor e, 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

Page 18 of 62Propoxur Human Health Risk Assessment DP No. D 414135

5.4 Dietary Risk Assessment

HED conducted a highly refined probabilistic acute dietary assessment to support the regist e red 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 consider ed 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 includi ng institutional
establishments that have areas where food is handled

. An a cute 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. T his 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

Th e d ietary 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 p ropoxur was applied as a crack and crevice treatment at 3X the maximum rate.

T he ma ximum 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 assume d to incur on foods after being processed.

5.4.2 Percent Crop Treated Used in Dietary Assessment

A value of 5% for treated FHE facilit ies 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., D 413125, 10/7/2014) . The 5% value is believed to be a conservative probability of the presence of pesticide resid ue 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 99.9 th 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 1 4 00% of the aPAD.

Toxicological characteristics of propoxur, like the other NM Cs, 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

. I n a typical acute (one

- day) dietary anal ysis, 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 a n overestima tion

. 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

Page 19 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 99.9 th 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 94 0% 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. Additional ly , consumption of even a few common fruits and vegetables in a food servicing set t ing le a d 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 fo r propoxur (M. Sahafeyan, D 421691, 7/24/2014 and D 425959,

3/12 /2015).

Additional r efined 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 di etary 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 no tes that the residue value of 0.004 ppm is significantly
lower than the typical limit s of quantitation of enfor cement 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,

t here are additional characteristics of propoxur that have been considered

. O ther studies indicate that 1) propoxur residues persist in air even after 48 hours and one study ha s shown that propoxur residues can travel from treated to no n

- treated areas, 2) detectable residues of propoxur do incur on foods in dairy, milling

, and pack aging 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 o ld, 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 application s 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 r eversible. Propoxur A ChE 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

Page 20 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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

. genera l population was 2 × 10

- 7

. The resulting risk estimate is shown
below in Table 5.4.6.1.

5.4.6 Summary Table s

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

Population Subgroup Acute Dietary (99.9th Percentile) “ Eating Occasion ”
Acute 1 (99.9 th Percentile) Average 2 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* 0.005 5 03 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

- l ife 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 O ccasion ” 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.

Page 21 of 62Propoxur Human Health Risk Assessment DP No. D 414135

Ta ble 5.4.6.2 Summary of “Eating Occasion” Acute Dietary characterization analyses (Food Only) Exposure and Risk for Propoxur 1

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 ppm 2 and
5% FHE treated. 1 6 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 resu lt in dietary risks below HED’s level of concern. Only when residues reduced to 0.00 4 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.

Page 22 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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. P ropoxur is also formulated as bait in bait stations, impregnated shelf paper, and impregnated insect tape. Additionally, non

occupational post

- application exposures may occur for those entering into institutional areas (i.e.,
d ormitories and hospital waiting areas ) that h a ve been previously treated with propoxur. N on

cancer 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 SOPs 6 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 relat ed 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 equip ment.

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 ba it 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 Re view (D 425960

, 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 c oncern. 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 62Propoxur Human Health Risk Assessment DP No. D 414135

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

Rate 2 Amount

Handled

Daily 1 Inhalation

Dose (mg/kg/day) 3 MOE 4

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 regist ered 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 exposure s both potentially contrib ute 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
estimate s 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

Rate 2 Amount

Handled

Daily 1 Dermal

Dose (mg/kg/day)

3 Inhal Dose (mg/kg/day)

3 LADD (mg/kg/day)

4 Risk 5

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 regist ered 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/m 3 ) × 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) × Q 1 * , where Q 1 * = 3.52 × 10

- 3 (mg/kg/day)

- 1

Page 24 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 residenti al 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 exposure s to the crack and crevice and spot treatments for control of bed bugs in institutional settings were quantitatively ass essed. 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 prop oxur, 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 i n university dormitories (for example during summer camps) . C hildren 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 (D 425960

, February 12, 2015 ) M emorandum

.

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 inh alation 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 M Label (mg) a ACH (1/hr) k (1/hr) b Vol (m 3 ) ET (hr) IR (m 3 /hr) Inhalation

Dose (mg/kg/day) c TWA

over ET (mg/m 3 ) d ST Inhal
MOE e

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

Page 25 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 C sat = [Vapor pressure (9.7x10

- 6 mmHg) * Conversion factor (atm/760 mm Hg) * Molecular Weight (g/mol) * Conversion factor (10 3 mg/g) * Conversion factor (10 3 L/m3)] / [R (0 .0821 L

- atm/mol

- K)* Temperature (296 K)]

c Note: the se 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 f actor (unitless) / Body Weight (kg). Exposure (mg/day) = IR*M Label * 1

- [((ACH * e

- k*ET )

– (K e - ACH ET

))]

ACH * V

room ACH

- k

d TWA (mg/m 3 ) = M Label * 1

- [((ACH * e

- k*ET )

– (K e - ACH ET

))]

ACH * V

room ACH

- k

. ET

e Inhalation MOE = HEC ( 19 mg/m 3 ) / TWA (mg/m 3 ).

Summary of Residential Post

- application Non

- Cancer Incidental Oral Exposure and Risk
Estimates

The incidental oral scenari o 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

- appli cation inci dental 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 F aihands Dermal Exp (mg) a Surface
area of
1 hand (cm 2 ) Hand
residue loading b (mg/cm 2 ) 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
MOE d

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 = Fai hands x Dermal exposure (mg) / Surface area of 1 hand (cm 2 ) x 2

c Dose = HR x (F M x SA H ) x (ET x N_Replen) x (1

– (1

– SE ) (Freq_HtM / N_Reple n) )) BW (11 kg)

d Inc Oral MOE = Inc Oral BMDL 10 (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 beca use propoxur is not mutagenic 7

. As presented in Table 6.2. 3 , t he 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
Estimate 5

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 Carc inogens” (U.S. EPA, 2005): http://www.epa.gov/ttnatw01/childrens_supplement_final.pdf

Page 26 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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
Estimate 5

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 pe r lifetime of

exposure (yrs) ÷ Lifetime expe ctancy (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 × Q 1 * , where Q 1 * = 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 applicati on 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 instituti onal 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 exposur e 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 T able 6.3. 1 and 6.3.2 for the recommend ed exposure and risk estimates to be include d in the
propoxur aggregate assessment

.

Page 27 of 62Propoxur Human Health Risk Assessment DP No. D 414135

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 Post

application Total Exposure (mg/kg/day) Residential Post

application

Total MOE 6 Dermal Inhalation Dermal Inhalation Oral

Short

- Term

Adult s 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 repres ents high

- end handler exposure (6.1.1) for the handler scenario

. 3 F or adults, r esidential total exposure reflects the high

- end inhalation exposure s ( 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 di fferent LOCs and may be combined only via the agg regate 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 LADD 5 (mg/kg/day)

Dermal Inhalation Dermal Inhalation

LADD

Adult s 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 F or adults, r esidential 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
aggregat e risks were assessed only for adults because propoxur is not mutagenic.

5 Total LADD = Dermal LADD + Inhalation LADD

Page 28 of 62Propoxur 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 th e s e exposure scenario s should be considered protective of any potential low

- level post

- application in halation exposure that could result from the remaining registered uses.

6.5 Spray Drift

Based on the currently registered use s , HED determined that propoxur is not registered on use sites that are likely to result in spray drift. Therefore, a quantitati ve 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 aggre gate 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

. T he results of the refi ned acute dietary analysis shows that the risk
estimates at the 99.9 th percentile of exposure exceed HED’s level of concern for U.S. general population a nd all population subgroups, with the highest “ eating occasion ” risk estimate f or children 1

- 2 years old at 94 0% aPAD.

7.2 Short

- Term Aggregate Risk

Short

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

as short

- term r esidential exposure s

. In order to calculate the MOE for the background dietary exposure, HED has compared the background d ietary 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 assess ment are provided in Section 6.3

. Since the leve l of concern for the dietary, inhalatio n , and incidental oral routes are different, an ARI approach was used to calculate the aggregate ris k 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), ho wever, the ARI is below 1 for children (1<2)

.

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

Table 7.2.1 Short

- Term Aggregate Risk Calculations 1

Population Short

- Term Scenario

Dietary Exposure 2 Inhalation Residential Exposure 3 Incidental Oral
Residential Exposure 4 Aggregate ARI (food and residential) 5 MOE ARI MOE ARI MOE ARI

Adults 89 00 89 760 25 n / a n / a 20 Child (11<16) 84 0 8.4 3,400 13 n / a n / a 5.0

Child (1<2) 1 70 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 = 0.0 38 mg/kg/day ; adult = 0.339 mg/kg/day ) )/(average dietary

exposure (adults = 0.0000 38 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 i ncidental oral = [(short

- term incidental oral MOE (See Table 6.3.1)]. ARI incidental oral = [(MOE
incidental oral )/(MOE target (child = 1 00))].

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 re versible, 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

, t he residential LADD included in the aggregate assessment includes th e dermal and inhalation routes. The scenarios appropriate for the aggregate assessment a re provided in Section 6.3 . The results of the cancer aggregate assessment are provided below in
Table 7.4.1

.

Table 7.4 .1 Aggregat e Cancer Risk Estimates

Population Cancer Slope Factor (Q 1 *) Food Only Exposure (mg/kg/day) 1 Residential Exposure (LADD ) mg/kg/day 2 Aggregate Can cer Risk 3 (food and residential) US Population 3.52 × 10

- 3 0.000054 0.000 15 7 × 10

- 7

1 Average Food (dietary) exposure as provided in Table 5.4.6.1

2 R esidential post

- application cancer exposure values used in aggregate assessment (Table 6.3

. 2 ).

3 Aggregate Cancer Risk = (Q 1 *) × (Food Exposure + LADD)

Page 30 of 62Propoxur 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 O ffice of P e sticide P rograms 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 handl ers 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 anticipa ted 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 bas ed on the following scenarios:

• Applicator of an RTU aeroso l 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, Februar y 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.

Page 31 of 62Propoxur 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
Co ncern Inhalation Unit Exposure
(μg/lb ai) 1 Maximum
Application

Rate 2 Area

Treated

or Amount

Handled

Daily 3 Inhalation

Baseline
(no respirator) Dose (mg/kg/day) 4 MOE 5

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: Base line

2 Based on regist ered 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 a nd 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

F HEs, 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 c ommercial 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 62Propoxur 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
LADD 4 Cancer Risk
Estimate 5 Dermal Inhalation Dermal 2 Inhalation 3

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 lifeti me 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 pe r 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 × Q 1 * , where Q 1 * = 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
LADD 4 Cancer Risk
Estimate 5 Dermal Inhalation Dermal 2 Inhalation 3

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 62Propoxur 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
LADD 4 Cancer Risk
Estimate 5 Dermal Inhalation Dermal 2 Inhalation 3

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 lifeti me 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 pe r 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 × Q 1 * , where Q 1 * = 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
LADD 4 Cancer Risk
Estimate 5 Dermal Inhalation Dermal 2 Inhalation 3

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 62Propoxur 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
LADD 4 Cancer Risk
Estimate 5 Dermal Inhalation Dermal 2 Inhalation 3

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 lifeti me 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 pe r lifetime of exposure (yrs) ÷ Lifetime expectancy (yrs)].

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

5 Cancer risk estimates = Total LADD × Q 1 * , where Q 1 * = 3.52 × 10

- 3 (mg/kg/day )

- 1

Page 35 of 62Propoxur 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 quantita tive 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 resu lt 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 appli cators.

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 Sy stem 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

prop oxur 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). In cidents 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 62Propoxur 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 condu cted.

1 1 .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)

, D 421691, 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) , D 425959, 3/12/2015

. 3. Walls, C., Propoxur. Revised Occupational and Residential Exposure Assessment for Registration Review

, D 4 25960

, 2/12/2015

. 4. Becker, J., Upper Bound Estimate of the Likelihood of Insecticide Residues on Food Resulting from Treatment in Food Handling Establishments

, D 413125, 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 Ap plication

., D390098, 9/15/2011

Page 37 of 62Propoxur 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.ni h.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(K OW ) 1.52 (20oC)

Page 38 of 62Propoxur 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 Equipment 1 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 equip ment; Do not apply more than two tags per 3 cubic feet
Liquid/Spray Formulations

Low pressure handwand, high

pressure 655

- 546 ns 1 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 62Propoxur 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 Equipment 1 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

tri gger 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 62Propoxur 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 Equipment 1 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 b e 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 r esidential 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, transpo rtation 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 str uctures 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 62Propoxur 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

....................... Ye s

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 62Propoxur 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] LD 50 (M) = 94 mg/kg

LD 50 (F) = 68 mg/kg II

870.1200 Acute dermal [rabbit] LD 50 : >2000 mg/kg III

870.1300 Acute inhalation [rat] LC 50 >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 non

guideline 0 (vehicle: a 1:1 mixture of propylene glycol and ethanol), 2, 10 and 50 mg propoxur/meter 3

. Corresponding analytical concentrations were 0, 2.2, 10.4 and 50.5 mg/meter 3 BMD 10 F= 0.0095 mg/L

BMDL 10 F = 0.0076 mg/L based on ChE inhibition in

the brain

BMD 10 M= 0.016 mg/L BMDL 10 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

LOAE L = >27 mg/kg/day (no effects noted)

Page 43 of 62Propoxur 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 Materna l 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.

. Developmenta l 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 nu mber 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 l evels 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),

Page 44 of 62Propoxur 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,
42.0 3 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

Page 45 of 62Propoxur 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 requirem ent (84

- 2) for an in vitro mammalian cell chromosome

aberration test

.

Page 46 of 62Propoxur 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 42005 101

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 sacrifi ce 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 prop oxur 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 inhibiti on.

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; M 6 = 2

- isopropoxy

- 5

- hydroxyphenyl

- methylcarbamate; M7 = 2

- isopropoxy

5

- hydroxyphenyl carbamic acid; M8 = 2

- isopropoxy

- 5

- hydroxyphenylhydroxymethyl carbamate; M9 = 1,5

- dihydroxy

- 2

- isopropoxybenzene.

Page 47 of 62Propoxur 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

870.7485
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

radio labeled 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

- 8 6% 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

- hydroxyphenyl

- hydroxymethyl carbamate, and M7A (= 2

- isopropoxy

- 3

- hydr oxyphenyl

- 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 tra ct 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/cm 2 (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

- 0.1 8%) 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 solve nt.

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. BMD 10 F+M= 0.04 9 mg/kg /day

BMDL 10 F+M = 0.0 3 8 mg/kg /day based on RBC ChE

inhibition in PND 11 pu ps

Page 48 of 62Propoxur Human Health Risk Assessment DP No. D414135

Table C .2.3 Summary of Benchmark Dose (BMD) Analyses for RBC and Brain AChE
inhibition from Acute CCA Studies

Source

Sex Target Organ Adult B

(MRID 48784802 Range Finding Study) PND 11 Pups B

(MRID 48784803 Dose Response Study) PND 11 Pups B

(MRID 48784802 Range Finding Study)

BMD 10 BMDL 10 BMD 10 BMDL 10 BMD 10 BMDL 10

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

BMD 10 BMDL 10
RBC 0.474 0.339 0. 0 49 0. 0 38

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 exhibi ted 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 se xes (males:

- 18%; females:

- 21%) 45

Page 49 of 62Propoxur 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 decre ased 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 h igh

- 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 tissue s 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 neurotoxicit y 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

Page 50 of 62Propoxur Human Health Risk Assessment DP No. D414135

Battery (FOB) and Motor and Locomotor observ ations at pretreatment and weeks 4, 8, and 13. Epileptoid seizures were observed in 5/24 8000 ppm females during FOB

testing. It is hypothesized that these were due to acetylcholine accumulation in the brain and a genetic disposition of these rats. In m ales, 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 reduce d 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 betwe en 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 non

recovery 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 inhi bition 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 m ales 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 i n 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.

Page 51 of 62Propoxur Human Health Risk Assessment DP No. D414135

c. Chronic Toxicity and Carcinogenicity

In a carci nogenicity 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 th ere 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 minima l 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 t he 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 animal s/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 co ntrols (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. F emales 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 m yelin alterations, such as vacuolization, myelinovoid formation, and occasional phagocytes). Additionally, there was an increased incidence of slight muscular atrophy of the rear extremities.

Page 52 of 62Propoxur 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
ob served 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).

Th e 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,

an d 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 propyle ne glycol and ethanol), 2, 10 and 50 mg propoxur/meter 3

. Corresponding analytical concentrations were 0, 2.2, 10.4 and 50.5 mg/meter 3 . There were frequent occurrences of significant cholinesterase inhibition (plasma, RBC and brain) at 10 and 50 mg/m 3 . S tatistically significant RBC cholinesterase depressions at 2 mg/m 3 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 /m 3 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/ m 3 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/m 3 . 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/m 3 groups respectively, while for hepatocellular adenomas in males the incidences were 2/58, 0/60, 2/59 and 6/59]. The only o ccurrence 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/m 3 groups respectively]. For the females, there was a weak (not statistically signific ant) trend involving uterine adenocarcinomas [incidences of 0/47, 2/45, 2/50 and 3/47 for the 0, 2, 10 and 50 mg/m 3 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).

Page 53 of 62Propoxur 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
wit h 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 dos e level, one male died at week 50. After week 20, highest

dose 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 grou p 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 high

dose dogs had an increased incidence of vomiting; some also showed more frequent
salivation. Most als o 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 consis tently (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 fro m 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 high

dose 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 r eceiving 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 (high

dose dogs: 0.892 gm; controls: 8.69 gm). Mean kidney and mean adrenal wei ghts 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 choles terol levels)

Page 54 of 62Propoxur Human Health Risk Assessment DP No. D414135

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 f eeding 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% cremop hor 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 administra tion 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 con sumption (

- 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 satisf ies 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 distil led 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) matern al 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 statistic ally 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 ra tios. 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 grou ps 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 sacrif iced. 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. Th e 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 R BC 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 s ignificantly 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 (ma les: 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 compound

related 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) a nd 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 in hibition.

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

Page 56 of 62Propoxur Human Health Risk Assessment DP No. D414135

gavage (5 mL/kg) adult male or PND 11 male pups to determi ne 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 toxi city 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 cli nical 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. Overal l 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 t ime

- 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 compara ble 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

w as 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 ra nged 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 g roups 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

Page 57 of 62Propoxur Human Health Risk Assessment DP No. D414135

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 r eduction 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 dos e 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 decre ased 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 (BM D) 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 BM D 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 signi ficant 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

va riability 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 n ot 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.

Page 58 of 62Propoxur Human Health Risk Assessment DP No. D414135

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 TA 1538), 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 ge ne 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/m L 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 absen ce 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 interact ions 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 (MRI D 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

Page 59 of 62Propoxur Human Health Risk Assessment DP No. D414135

aberrations in bone marrow cells following oral gavage dosing of the te st 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 d ose, 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 indica te 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

- isopropo xyphenol; M3 = 2

- hydroxyphenyl methylcarbamate; M4 = 2

- isopropoxyphenylcarbamic acid; M5 = isopropoxyphenyl

hydroxy(

- ) 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, mi ce, 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 radio labele d 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 metaboli tes 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

- hydroxyphenyl

hydroxymethyl 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 pharyng eal 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 combin ation 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 stud y, a mixture of 50% ethanol and 50% water was used as solvent, with doses of 0.648, 6.91, 69.5, or 692 μg/cm 2 (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, th e 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 Heb icides 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/cm 2 to the ventral forearm was 19.6% (±5.2%). Absorption in the 8

- hour and 12

- hour p eriods 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 absorpti on 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 Ha ndler 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., Post

application exposure in indoor environments, Residential Handle rs) 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. Descr iptions of data sources, as well as guidance on their use, can be found at the Agency website.

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