UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

DATE: 15-SEPT-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT : P rofenofos: Human Health Draft Risk Assessment (DRA) for Registration 

Review. 

PC Code: 11 1401 DP Barcode:}}4 14 150 

Decision No.: 482022 Registration No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 2540 

TXR No.: NA CAS No.: 41 198-08-7 

MRID No.: NA 40 CFR: § 180.404 

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Kelly M. Lowe, Senior Ehvironm ntal Sc nti st~~~ Risk Assessment Branch 1 (RAB I) V 

Health Effects Division (HED; 7509P) 

::hael Meuger, RARC Reviewerv{,{J JA 

Alexandra Gavelek, RARC Reviewer V1 

TO: Christina Scheltema 

Patricia Parrott 

Pesticide Re-Evaluation Division (PRO) (7508P) 

This document provides the HED's human health risk assessment for the Registration Review of 

profenofos ( 0 -( 4-bromo-2-chlorophenyl)-O-ethyl S-propyl phosphorothioate). The hazard 

characterization, endpoint selection, and risk assessment were provided by Monique Perron 

(RAB l ); the residue chemistry assessment and dietary exposure assessments were provided by 

Sarah Levy (RAB 1 ); and the occupational and residential exposure assessment was provided by 

Kelly Lowe (RABI). 

Page I of 57 
Page 2 of 57

Table of Contents

1.0 Executive Summary............................................................................................................. 4

2.0 HED Recommendations....................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................. 7

2.2 Tolerance Considerations................................................................................................. 7

2.2.1 Enforcement Analytical Method............................................................................... 7

2.2.2 International Harmonization ..................................................................................... 8

2.2.3 Revisions to Established Tolerances......................................................................... 8

2.3 Label Recommendations.................................................................................................. 9

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 ........................................................................ 11

4.0 Hazard Characterization and Dose-Response Assessment................................................ 11

4.1 Toxicology Studies Available for Analysis ................................................................... 11

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME) ...................................... 12

4.2.1 Dermal Absorption.................................................................................................. 13

4.3 Toxicological Effects ..................................................................................................... 13

4.3.1 Critical Durations of Exposure ............................................................................... 13

4.4 Literature Review on Neurodevelopment Effects.......................................................... 15

4.5 Safety Factor for Infants and Children (FQPA SF)........................................................ 20

4.5.1 Completeness of the Toxicology Database............................................................. 20

4.5.2 Evidence of Neurotoxicity ...................................................................................... 20

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 20

4.5.4 Residual Uncertainty in the Exposure Database..................................................... 21

4.6 Toxicity Endpoint and Point of Departure Selections.................................................... 21

4.6.1 Dose-Response Assessment.................................................................................... 21

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment........ 24

4.6.3 Cancer Classification and Risk Assessment Recommendation.............................. 24

4.6.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ............................................................................................................................ 24

4.7 Endocrine Disruption ..................................................................................................... 26

5.0 Dietary Exposure and Risk Assessment ............................................................................ 27

5.1 Metabolite/Degradate Residue Profile ........................................................................... 27

5.1.1 Summary of Plant and Animal Metabolism Studies............................................... 27

5.1.2 Summary of Environmental Degradation ............................................................... 28

5.1.3 Comparison of Metabolic Pathways....................................................................... 28

5.1.4 Residues of Concern Summary and Rationale........................................................ 29

5.2 Food Residue Profile...................................................................................................... 29

5.3 Water Residue Profile .................................................................................................... 29

5.4 Dietary Risk Assessment................................................................................................ 30

5.4.1 Description of Residue Data Used in Dietary Assessment..................................... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 31

5.4.3 Acute Dietary Risk Assessment.............................................................................. 31
Page 3 of 57

5.4.4 Steady-State Dietary Risk Assessment ................................................................... 32

5.4.5 Cancer Dietary Risk Assessment............................................................................ 34

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 34

6.1 Residential Handler Exposure........................................................................................ 34

6.2 Post-Application Exposure............................................................................................. 34

7.0 Residential Bystander Post-Application Inhalation Exposure........................................... 35

8.0 Spray Drift ......................................................................................................................... 35

9.0 Aggregate Exposure/Risk Characterization....................................................................... 39

10.0 Cumulative Exposure/Risk Characterization..................................................................... 39

11.0 Occupational Exposure/Risk Characterization .................................................................. 39

11.1 Short- and Intermediate-Term Handler Risk.............................................................. 39

11.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates...................... 41

11.2.2 Occupational Post-Application Dermal Exposure/Risk Estimates......................... 42

12.0 References............................................................................................................................. 45

Appendix A. Toxicology Profile.................................................................................................. 47

A.1 Toxicology Data Requirements...................................................................................... 47

Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling................... 52

Appendix C. Summary Tables of Benchmark Dose (BMD) Analyses ....................................... 53

Appendix D. Physical/Chemical Properties................................................................................. 56

Appendix E. International Residue Limits................................................................................... 57
Page 4 of 57

1.0 Executive Summary

Background

Profenofos is an organophosphate (OP) insecticide-miticide used for insect and mite control on 

cotton. There is only one end-use product label registered with profenofos as the active 

ingredient (ai) (EPA Reg. #100-669; Curacron® 8E Insecticide-Miticide). This product is 

formulated as an emulsifiable concentrate (EC), containing 73% ai or 8 lb ai/gallon, and is a 

restricted use pesticide. The product label indicates that a closed mixing/loading system and 

enclosed cab groundboom equipment are required. The maximum single application rate is 0.5 

lb ai/A. The maximum seasonal rate is 5 lb ai/A/season, with a 5 day minimum retreatment 

interval (RTI). 

Based on the registered use pattern for profenofos, humans may be exposed to profenofos in food

(from cottonseed oil as well as secondary residues in milk and meat byproducts) and drinking 

water since profenofos may be applied directly to growing crops and application may result in 

profenofos reaching surface and ground water sources of drinking water. Dermal and inhalation 

exposures are anticipated for occupational handlers as well as dermal exposures for postapplication workers. There are currently no registered residential uses of profenofos; however, 

there is the potential for non-occupational exposure as a result of spray drift. 

Hazard Assessment

Profenofos is a member of the OP class of pesticides. Like other OPs, the initiating event in the 

mode of action (MOA)/ adverse outcome pathway (AOP) for profenofos involves inhibition of 

the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine residue at the active 

site of the enzyme. This inhibition leads to accumulation of acetylcholine and ultimately to 

neurotoxicity in the central and/or peripheral nervous system. For profenofos, AChE inhibition 

is the most sensitive endpoint in the toxicology database in multiple species, durations, 

lifestages, and routes. Profenofos does not require metabolic activation to an oxon metabolite to 

inhibit AChE (i.e., the parent compound is the active form inhibiting AChE). OPs also exhibit a 

phenomenon known as steady-state AChE inhibition. After repeated dosing at the same dose 

level, the degree of inhibition comes into equilibrium with the production of new, uninhibited 

enzyme. Therefore, steady-state exposure assessments of 21 days and longer were conducted 

instead of the traditional chronic or long-term assessments. 

The toxicology database for profenofos is considered adequate for risk assessment. There are 

acceptable studies available for toxicity endpoint selection. Profenofos has high-quality doseresponse data across multiple lifestages, durations, and routes for both red blood cell (RBC) and 

brain AChE inhibition. Dermal and inhalation studies allow for route-specific evaluation. 

Clinical signs of neurotoxicity can be found throughout the database following acute exposures 

at doses much higher than those causing inhibition of AChE. None of the submitted studies in 

the toxicology database for profenofos suggest increased sensitivity to profenofos based on 

AChE inhibition; however, the Food Quality Protection Act (FQPA) Safety Factor (SF) has been 

retained for infants, children, youths, and women of childbearing age for all exposure scenarios 

due to uncertainty in the human dose-response relationship for neurodevelopmental effects (see 
Page 5 of 57

Section 4.4). Additionally, for inhalation exposures, a database uncertainty factor was applied 

for extrapolation from a lowest-observed adverse-effect level (LOAEL) to a no-observed 

adverse-effect level (NOAEL) (UFL). For all exposure scenarios, interspecies (10X) and 

intraspecies (10X) uncertainty factors were applied. As a result, a total uncertainty factor of 

1000X was applied for all exposure scenarios, except dietary exposures for the adult population 

subgroup 50-99 years old where the FQPA SF does not apply (total uncertainty factor = 100X) 

and inhalation exposures (maximum total uncertainty factor of 3000X). 

Profenofos is classified as a “Group E Chemical – evidence of non-carcinogenicity for humans” 

based on lack of evidence of carcinogenicity in rats and mice. A quantitative cancer risk 

assessment is not required.

Dietary (Food and Water) Exposure and Risk

The existing residue chemistry database for profenofos is adequate for risk assessment purposes. 

An unrefined acute dietary exposure assessment was conducted to estimate the dietary exposure 

and risk associated with Registration Review. The acute dietary exposure assessment 

incorporated tolerance level residues, DEEM default processing factors, and 100% crop treated 

(PCT). The Environmental Fate and Effects Division (EFED) provided a surface water 

estimated drinking water concentrations (EDWC) of 5.92 ppb from the Tier 2 Surface Water 

Concentration Calculator (SWCC) version 1.106 (EFED, 2014). The unrefined acute aggregate 

dietary (food + drinking water) exposure estimates are below HED’s level of concern [<100% 

the acute population adjusted dose (aPAD)] for the U.S. population and all population subgroups

at the 95th percentile. Combined dietary exposure from food + drinking water is 38% of the 

aPAD for the U.S. population and 80% of the aPAD for children 1-2 years old, the highest 

exposed population subgroup.

The DEEM acute module was used to conduct refined two-day (steady-state) average 

assessments using the steady-state endpoint, 2-day average dietary exposure, and 21-day rolling 

water averages. Steady-state assessments were conducted for drinking water alone, food alone, 

and food + drinking water. The steady-state dietary exposure assessments assumed, where 

applicable, an average field trial value for cotton, a cottonseed oil processing factor, and 

tolerance-level and processing factors for meat and milk commodities. The cotton PCT was 

applied to cotton and all meat/milk commodities; therefore, results are discussed at the 99.9th

percentile of exposure. However, when discussing drinking water only, results are discussed at 

the 95th percentile of exposure as PCT was not applied to drinking water. EFED provided daily 

time-series outputs that simulate 29 years of residues of profenofos in drinking water for 5 cotton 

application scenarios (TX, MS, NC, CA cotton reservoir, and MS cotton pond). These 

distributions were used as a residue-distribution file (RDF) in DEEM for direct all sources and 

indirect all sources. For the partially-refined food alone steady-state assessment, children 1-2 

years old are the highest exposed subpopulation at 350% ssPAD at the 99.9th percentile of 

exposure. Four out of the five drinking water only scenarios had at least one subpopulation that 

was >100% aPAD at the 95th percentile (CA cotton scenario had estimates <100% for all 

populations at the 95th percentile). For the partially-refined food + drinking water exposure 

estimates at the 99.9th percentile, all five scenarios are of concern to HED (>100% ssPAD). The 

TX drinking water scenario had the overall highest risk estimates (all infants <1 year old (1600% 
Page 6 of 57

ssPAD)). The CA cotton scenario had the overall lowest risk estimates (children 1-2 years old 

was the highest exposed population subgroup at the 99.9th percentile at 350% ssPAD)). The 

other three food + drinking water scenarios were similar to (but lower than) the TX scenario. 

Residential (Non-Occupational) Exposure and Risk

There are currently no registered residential uses of profenofos; therefore, a quantitative 

residential handler and post-application assessment was not conducted. 

Spray Drift

A quantitative non-occupational spray drift assessment was conducted for the registered uses of 

profenofos. Risk estimates related to spray drift are of concern at various distances from the 

edge of the field for adults and children (1 to <2 years) depending on the spray drift scenario. 

For adults, the screening level scenario of a high boom and very fine to fine spray requires a 

distance of over 300 feet to reach a dermal margin of exposure (MOE) ≥ 1000. For children, the 

screening level scenario also requires a distance of over 300 feet to reach a combined (dermal 

and incidental oral) MOE ≥1000. Drift reduction technologies, such as using coarser sprays and 

lowering boom height for groundboom sprayers, reduces risk concerns; however, there are still 

risk estimates of concern at the field edge. 

Occupational Exposure and Risk

Occupational handler dermal and inhalation exposure and risk estimates were calculated for the 

registered uses of profenofos. Dermal and inhalation risk estimates were combined in this 

assessment since the toxicological effects for these exposure routes were the same. A total 

aggregated risk index (ARI) was used to combine dermal and inhalation risk estimates since the 

level of concern (LOC) values for dermal exposure (1000) and inhalation exposure (3000) are 

different. The target ARI is 1; therefore, ARIs of less than 1 are risk estimates of concern. The 

occupational handler exposure and risk estimates indicate that the steady-state dermal and 

inhalation combined ARIs are of concern to HED (i.e., ARI ≤ 1) for all scenarios. Occupational 

post-application dermal exposure and risk estimates were assessed for the registered cotton use 

of profenofos using submitted chemical-specific dislodgeable foliar residue (DFR) data and 

dislodgeable cotton boll data. Based on the current exposure assessment, post-application risk 

estimates remain a concern (i.e., MOEs <1000) up to 4 days after application for hand weeding 

and up to 9 days after application for scouting activities. Post-application risk estimates 

associated with harvesting activities are a concern (MOEs <1000) 14 days after treatment, which 

would be the earliest harvesting could occur after application based on the current pre-harvest 

interval (PHI). An additional calculation was performed to estimate post-application exposure 

and risk using the cotton boll residue data from the day of sampling (day 44); however, there 

were still risk estimates of concern for all harvesting activities even 44 days after application at 

which point residue values were less than the limit of quantification (LOQ) in the study. 

 

The current product-label restricted entry interval (REI) is specified as 48 hours (72 hours in 

areas that receive less than 25 inches of rain per year). The REI on the registered label is in line 

with the Worker Protection Standard [40 CFR 156.208(c)(2)] assignments for ais that are 

classified as Toxicity Category I for acute dermal, eye irritation, or primary skin irritation, and 

for organophosphates in particular. However, there were risk estimates of concern related to all 

activities associated with cotton at the current label-prescribed REI.
Page 7 of 57

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

inhalation exposure assessment was not performed for profenofos 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 profenofos.

Environmental Justice:

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

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf.

Human Studies Review:

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 Handler Exposure Database (PHED) 1.1, the Agricultural Handlers Exposure Task 

Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) 

subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are 

compliant with applicable ethics requirements. For certain studies, the ethics review may have 

included review by the Human Studies Review Board. Descriptions of data sources, as well as 

guidance on their use, can be found at the Agency website1

. 

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review eligibility of profenofos.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Profenofos is adequately recovered using the Food and Drug Administration (FDA) protocol 

multiresidue methods (MRMs) D and E (PAM Volume 1, Sections 302, 303 and 304). The plant 

and livestock data collection methods for profenofos were submitted to FDA as confirmatory 

(lettered) methods for inclusion in PAM Volume II. Independent laboratory and EPA method 

validation are not required for these confirmatory methods. The FDA PESTDATA database 

dated 1/94 (PAM Volume I, Appendix I) indicates that profenofos is completely recovered 

(>80% using multiresidue method Section 302 (Luke method; Protocol D) and partially 

recovered (50-80%) using Sections 303 (Mills, Olney, Gaither method; Protocol E, nonfatty) and 

304 (Mills fatty food method; Protocol E, fatty).

 1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Page 8 of 57

2.2.2 International Harmonization

U.S. permanent tolerances are summarized in Appendix E along with International Maximum 

Residue Limits (MRLs) established by Codex Alimentarius Commission. Mexico adopts the 

U.S. tolerances and/or Codex MRLs for its export purposes. Canada has not established MRLs 

for profenofos. Codex has a maximum residue limit (MRL) for “cotton seed” at 3 ppm. For 

purposes of harmonization, HED recommends increasing the existing U.S. cotton, undelinted 

seed tolerance of 2.0 ppm to 3.0 ppm. 

2.2.3 Revisions to Established Tolerances

Adequate field trial data have been submitted and reviewed for cotton undelinted seed and cotton 

gin byproducts. Field trials reflected use of the registered EC formulation at the maximum 

registered use patterns. Permanent tolerances are established for profenofos residues under 40 

CFR §180.404 in/on cotton, undelinted seed at 2.0 ppm; cotton gin byproducts at 55.0 ppm; milk 

at 0.01 ppm; and the fat, meat, and meat byproducts of cattle, goat, horse, and sheep at 0.05 ppm. 

Codex has a MRL for “cotton seed” at 3 ppm. For purposes of harmonization, HED 

recommends increasing the existing U.S. cotton, undelinted seed tolerance of 2.0 ppm to 3.0 

ppm. 

Based on the available cottonseed processing study which demonstrated that residues of 

profenofos do not concentrate in cottonseed meal or oil (refined, bleached, and deodorized), and 

concentrate marginally (1.4X) in hulls, tolerances are not required for these processed 

commodities.

The tolerance expression for profenofos has been reviewed and should be updated as follows 

based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

“Tolerances are established for residues of the insecticide profenofos, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only 

profenofos (O-(4-bromo-2-chlorophenyl)-O-ethyl S-propyl phosphorothioate) in or on the 

commodities:”

Table 2.2.3.1. Tolerance Summary for Profenofos.

Commodity Established 

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Cattle, fat 0.05 0.05

Cattle, meat 0.05 0.05

Cattle, meat byproducts 0.05 0.05

Cotton, gin byproducts 55.0 55 Correct number of significant figures to 

be consistent with HED policy

Cotton, undelinted seed 2.0 3.0 Increase in tolerance level for purposes 

of harmonization.

Goat, fat 0.05 0.05

Goat, meat 0.05 0.05

Goat, meat byproducts 0.05 0.05
Page 9 of 57

Horse, fat 0.05 0.05

Horse, meat 0.05 0.05

Horse, meat byproducts 0.05 0.05

Milk 0.01 0.01

Sheep, fat 0.05 0.05

Sheep, meat 0.05 0.05

Sheep, meat byproducts 0.05 0.05

2.3 Label Recommendations

No label recommendations have been identified. Current tolerances need to be updated as 

discussed in Section 2.2.3. A summary of the risk estimates has been provided, and shows that 

there are risk estimates of concern for registered uses of profenofos based on the use information, 

label-required personal protective equipment (PPE; i.e., engineering controls), and REIs.

3.0 Introduction

3.1 Chemical Identity

Table 3.1.1. Test Compound Nomenclature.

Compound

Common Name Profenofos

Chemical Class Organophosphate, OP

Molecular Formula C11H15BrClO3PS

Molecular Weight 373.65 g/mole 

IUPAC Name (RS)-(O-4-bromo-2-chlorophenyl O-ethyl S-propyl phosphorothioate)

CAS Name O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate

CAS Registry Number 41198-08-7 

PC Code 111401

3.2 Physical/Chemical Characteristics

Technical profenofos is a pale yellow liquid with a boiling point of 100°C (1.8 Pa) and a density 

of 1.46 g/cm3 at 20°C. Its molecular weight is 373.65 g/Mole. Pure profenofos is an ambercolored oily liquid with a boiling point of 110°C (0.001 mm Hg). Profenofos has limited 

solubility in water (20 ppm), but is soluble in organic solvents (acetone, ethanol, toluene, noctanol, and n-hexane) at 25°C. It has a log octanol-water partition coefficient of 4.83. 

Profenofos is stable under neutral and slightly acidic conditions, and is unstable under alkaline 

conditions. It has a low vapor pressure (9.001 x 10-7 mm Hg). A summary of physical/chemical 

properties for profenofos can be found in Appendix D.
Page 10 of 57

3.3 Pesticide Use Pattern

There is only one end-use product label registered with profenofos as the ai (EPA Reg. #100-

669; Curacron® 8E Insecticide-Miticide). This product is formulated as an EC, containing 73% 

ai or 8 lb ai/gallon, and is a restricted use pesticide. The product label indicates that a closed 

mixing/loading system and enclosed cab groundboom equipment are required. The maximum 

single application rate is 0.5 lb ai/A. The maximum seasonal rate is 5 lb ai/A/season, with a 5 

day minimum RTI. 

The Curacron® 8E product label indicates that a closed mixing/loading system and enclosed cab 

are required. Mixer, loaders, applicators, and other handlers using a closed system must also 

wear long sleeved shirt, long pants, shoes plus socks, chemical-resistant gloves, chemicalresistant apron (for mixing and loading), and protective eyewear. The label recommends a REI 

of 48 hours (72 hours in areas where rainfall is less than 25 inches per year). 

Table 3.3.1. Summary of Registered Use Directions for Profenofos.

Application 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. No.]

Maximum 

Application 

Rate

Max No. 

Applications 

per Season

Max Seasonal 

Application 

Rate

Use Directions and Limitations

Cotton

Enclosed cab 

Groundboom

Make 1st

application 

when pest 

populations 

reach 

economic 

thresholds

Emulsifiable 

Concentrate

100-669

73%ai

8 lb ai/gal

Curacron® 8E 

InsecticideMiticide

0.5 pt 

product/A

0.5 lb ai/A

Based on max 

single rate and 

max seasonal 

rate, up to 10 

applications 

per season (not 

specified on 

label).

5 pt/A/season

5 lb 

ai/A/season

• Restricted Use Pesticide.

• Closed system mixing and 

loading and enclosed tractor 

cab required.

• REI = 48 hours (72 hours in 

areas that receive 25 inches or 

less of rain).

• Do not apply by aerial or 

chemigation application.

• Loaders/mixers not allowed to 

handler more than 10 

gallons/day.

• Hand harvesting is prohibited.

• Repeat applications at 5-7 

days intervals as needed.

• Apply in minimum of 5 

gallons/A.

• PHI = 14 days when diluted 

with water; 30 days when 

diluted with oil.

• PBI = 30 days.

REI = restricted-entry interval, PHI= pre-harvest interval, PBI = plant back interval

3.4 Anticipated Exposure Pathways

Humans may be exposed to profenofos in food and drinking water since profenofos may be 

applied directly to growing crops and application may result in profenofos reaching surface and 

ground water sources of drinking water. There are no residential uses of profenofos; however, 

there is the potential for short-term non-occupational exposure (dermal and incidental oral) as a 

result of spray drift. Based on the registered use pattern for profenofos, dermal and inhalation 

exposures are anticipated for occupational handlers and post-application workers. 
Page 11 of 57

3.5 Consideration of Environmental Justice

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

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

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

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

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

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

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

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

National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are 

used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is 

able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Profenofos is a member of the OP class of pesticides. Like other OPs, the initiating event in the 

MOA/AOP for profenofos involves inhibition of the enzyme AChE via phosphorylation of the 

serine residue at the active site of the enzyme. This inhibition leads to accumulation of 

acetylcholine and ultimately to neurotoxicity in the central and/or peripheral nervous system (see 

Figure 1). For profenofos, AChE inhibition is the most sensitive endpoint in the toxicology 

database in multiple species, durations, lifestages, and routes. AChE inhibition is the focus of 

this hazard characterization; the availability of reliable AChE inhibition dose response data is 

one of the key determinants in evaluating the toxicology database. 

Figure 1. AOP for OPs.

4.1 Toxicology Studies Available for Analysis

The toxicology database for profenofos is complete for risk assessment. The acceptable 

profenofos studies available for risk assessment include: 

Target 

Tissue 

Dose

Phosphorylation 

of the active site 

of AChE

Neurotoxicity

Accumulation 

of 

acetylcholine
Page 12 of 57

• subchronic oral toxicity studies in rats and dogs;

• chronic oral toxicity studies in rats and dogs;

• carcinogenicity studies in rats and mice;

• developmental studies in rats and rabbits;

• multigenerational reproduction toxicity study in rats;

• acute and subchronic neurotoxicity studies in rats;

• acute and repeated comparative cholinesterase assays (CCA) in juvenile and adult 

rats;

• acute delayed neurotoxicity study in hens;

• subchronic dermal toxicity study in rabbits;

• subchronic inhalation toxicity study in rats;

• mutagenicity and genotoxicity studies;

• metabolism studies in rats and monkeys;

• immunotoxicity study in mice;

• developmental neurotoxicity (DNT) study with AChE measurements in nonpregnant females, pregnant females, fetuses, and juvenile rats.

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Some OPs require metabolic activation to the oxon metabolite; however, for profenofos, the 

parent compound is responsible for AChE inhibition activity (see chemical structure in Table 

3.1.1). Generally, absorption and distribution are rapid with extensive metabolism and no 

accumulation in the tissues for OPs. 

In a rat metabolism study (MRID 42334301), recovery of radioactivity for combined fecal and 

urine samples ranged from 97-108% of the administered dose, with >97% of the radioactivity 

excreted in the urine within 48 hours. Less than 0.2% of the radioactivity was expired as 

volatiles. Insignificant amounts of radioactivity were retained in tissues after 7 days postexposure. Analysis of fecal material indicated that <4% of the parent compound or its 

metabolites remain unabsorbed or are excreted via the biliary system into the intestinal tract. 

Profenofos appears to be metabolized by hydrolysis of its thiophosphate ester followed by 

dephosphorylation to form 4-bromo-2-chlorophenol (CGA-55960), which undergoes sulfate or 

glucuronide conjugation. Metabolites were identified as unconjugated 4-bromo-2-chlorophenol 

(CGA-55960), O-ethyl-O-(2-chloro-4-bromo-phenyl)-phosphate (CGA-47196), and 

thiophosphoric acid O-(4-bromo-2-chloro-phenyl) ester O ́-ethyl ester (CGA-65867). There 

were no apparent dose or sex-related differences in the absorption, distribution, metabolism, or 

excretion of profenofos.

In a metabolism/pharmacokinetic study with rhesus monkeys, young adult males were 

administered a single oral dose via capsule at 2.4 mg/animal (approximately 0.5 mg/kg). The 

test material was rapidly absorbed with significant concentrations measured in the blood and 

plasma by the first blood measurement (30 minutes post-dose). The time to reach maximum 

concentration in the blood (Tmax) was reached by 1 hour post-dose and rapidly declined 

thereafter. The terminal phase elimination half-life (t1/2) was estimated to be 4 hours in this 

study. Approximately 68% of the administered dose was recovered in the excreta (urine, feces, 

and cage wash after 168 hours) with the majority recovered in the urine (49%). Excretion was 
Page 13 of 57

nearly complete by 24 hours following treatment. CGA-55163 was identified as the major 

urinary metabolite, which is the glucuronide conjugate of the phenol analog (CGA-55960).

4.2.1 Dermal Absorption

There are no dermal penetration studies available for profenofos; however, a dermal absorption 

factor is not needed because a route-specific dermal toxicity study was used to assess dermal 

exposure scenarios (see Section 4.5).

4.3 Toxicological Effects

Profenofos has high-quality dose-response data across multiple lifestages, durations, and routes 

for both RBC and brain AChE inhibition. In the case of profenofos, RBC AChE inhibition was 

more sensitive than brain AChE inhibition and provides the basis for human health risk 

extrapolations. Using AChE inhibition as the critical endpoint for risk assessment protects for 

other cholinergic effects, such as clinical signs, which are seen at doses much higher than those 

causing inhibition of AChE. Clinical signs indicative of neurotoxicity seen following a single 

oral dose included compulsive licking, abnormal gait, salivation, lacrimation, impaired 

respiration, ataxia, impaired reflexes, tremors, and decreased arousal, rearing, and motor activity. 

In general, these clinical signs of toxicity were observed at doses approximately 100-200X 

higher than the AChE inhibition used as the basis for the acute oral point of departure (POD). 

There were no clinical signs noted in repeated exposure studies; however, body weight 

decrements were noted in several studies. 

Many of the studies have been evaluated using benchmark dose (BMD) modeling techniques. 

Based on BMD modeling results (M. Perron; 15-SEP-2015; TXR# 0057250 and Appendix C), 

RBC AChE inhibition is remarkably similar across oral studies for adult rats. Available studies 

with adult animals show similar findings in gavage and dietary studies. Studies via the dermal 

and inhalation routes allow for route-specific evaluation; however, data from these route-specific 

studies were not amenable to BMD modeling (see Section 4.5.1). In acute and repeated studies, 

AChE inhibition in juvenile rats was seen at or above dose levels eliciting inhibition in adults. In 

the DNT studies, the adults were found to have considerable AChE inhibition at relatively low

doses, while little or no inhibition was seen in fetuses and young juvenile rats except at the 

highest doses tested. As a result, no dose response was observed and BMD estimates were not 

calculated. Pregnant females were also not found to be more sensitive than non-pregnant 

females.

Profenofos is classified as acutely toxic via the oral (Toxicity Category II) and dermal routes 

(Toxicity Category I or II) and classified as having low acute toxicity via the inhalation route 

(Toxicity Category IV). It was found to be a minimal eye irritant and moderate dermal irritant 

(Toxicity Category III). It was also found to be a dermal sensitizer.

4.3.1 Critical Durations of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between 

the exposure and hazard assessments. One advantage of an AOP understanding is that human 
Page 14 of 57

health risk assessments can be refined to focus on the most relevant durations of exposure. The 

following text provides an analysis of the temporal pattern of AChE inhibition from acute 

(single) and repeated dosing studies in laboratory animals for profenofos. This analysis provides 

the basis for determining which exposure durations are appropriate for assessing human health 

risk. Table 4.3.1.1 provides a summary of the selected results from experimental toxicology 

studies with profenofos. 

Table 4.3.1.1. Profenofos BMD10 and BMDL10 Results (mg/kg/day) for RBC AChE Inhibition Over Time 

in Adult Rats.

Days of Dosing

Males Females

BMD10 BMDL10 BMD10 BMDL10

1a 13.49 11.24 3.17 1.99

10b NMF NMF 0.38 0.17

35c NA NA 0.32 0.19

90d 0.33 0.29 0.66 0.54

91e 0.14 0.12 0.13 0.12

364e 0.17 0.15 0.22 0.18

BMD10 = estimated dose where AChE is inhibited by 10% compared to background.

BMDL10 = lower confidence bound on the BMD10.

NMF = no model fit.

NA = not applicable.

a MRID 46025406 – acute CCA study in rats(gavage). b MRID 46025403– repeat CCA study in rats (gavage). c MRID 46025401 – DNT study in rats (dietary). d MRID 00105255 – subchronic oral toxicity study in rats (dietary). e MRID 00081685 – combined chronic/carcinogenicity study in rats (dietary) – interim (91 days) and terminal measurements 

(364 days).

As shown in Table 4.3.1.1, the acute BMD values are the largest in the table, whereas BMD 

values from repeated dosing exposures are remarkably similar. OPs exhibit a phenomenon 

known as steady-state AChE inhibition. After repeated dosing at the same dose level, the degree 

of inhibition comes into equilibrium with the production of new, uninhibited enzyme. At this 

point, the amount of AChE inhibition at a given dose remains consistent across duration. In 

general, OPs reach steady-state within 2-3 weeks, but this can vary among OPs. In the case of 

profenofos, the results in Table 4.3.1.1 show a clear pattern of steady-state reached by 10 days of 

exposure. In addition to the consistency across durations, the data across multiple studies in rats 

are similar. Given the results in Table 4.3.1.1 (and Appendix C) for profenofos, acute (singleday) and steady-state durations are appropriate for human health risk assessment. As such, the 

endpoint selection discussed below focuses on acute (single-day) effects and steady-state effects. 

Although there are data at a shorter time period than 21 days (i.e., 10 days), exposure 

assessments of 21 days and longer will be conducted for all routes of exposure (i.e., oral, dermal 

and inhalation) for all single chemical OP assessments. Although the durations of the toxicity 

and exposure assessments may differ, an exact match is not necessary and would suggest a level 

of precision that the toxicity data do not support. Given this, the 21-day and longer exposure 

assessment is scientifically supportable and also provides consistency with the OP cumulative 

risk assessment (OP Cumulative Risk Assessment (CRA); 2002, 2006) and across the single 

chemical risk assessment for the OPs. 
Page 15 of 57

4.4 Literature Review on Neurodevelopment Effects

For the OPs, historically the Agency has used inhibition of AChE as the POD for human health 

risk assessment; at present time, this policy continues. This science policy is based on decades 

of work which shows that AChE inhibition is the initial event in the pathway to acute cholinergic 

neurotoxicity. The use of AChE inhibition data for deriving PODs was supported by the FIFRA 

SAP (2008, 2012) for chlorpyrifos as the most robust source of dose-response data for 

extrapolating risk and is the source of data for PODs for profenofos. A detailed review of the 

epidemiological studies used in this review can be found either in the 2014 chlorpyrifos revised 

draft human health risk assessment (D. Drew; 29-DEC-2014; D424485) or in the 2015 literature 

review for other organophosphates (OPP/USEPA; 15-SEP-2015; D331251). 

Newer lines of research on OPs in the areas of potential AOPs, in vivo animal studies, and 

notably epidemiological studies in mothers and children, have raised some uncertainty about the 

agency’s risk assessment approach with regard to the potential for neurodevelopmental effects in 

fetuses and children. Many of these studies have been the subject of review by the agency over 

the last several years as part of efforts to develop a risk assessment for chlorpyrifos (D. Drew; 

29-DEC-2014; D424485). Initially, the agency focused on studies from three US cohorts: 1) 

The Mothers and Newborn Study of North Manhattan and South Bronx performed by the 

Columbia Children’s Center for Environmental Health (CCCEH) at Columbia University; 2) the 

Mt. Sinai Inner-City Toxicants, Child Growth and Development Study or the “Mt. Sinai Child 

Growth and Development Study;” and 3) the Center for Health Assessment of Mothers and 

Children of Salinas Valley (CHAMACOS) conducted by researchers at University of California 

Berkeley. The agency has evaluated these studies and sought external peer review (FIFRA SAP 

reviews in 2008 and 2012; federal panel, 20132

) and concludes they are of high quality. In the 

three US epidemiology cohort studies, mother-infant pairs were recruited for the purpose of 

studying the potential health effects of environmental exposures during pregnancy on subsequent 

child development. Each of these cohorts evaluated the association between prenatal chlorpyrifos 

and/or OP exposure (with adverse neurodevelopmental outcomes in children through age 7 

years). For the 2014 chlorpyrifos revised human health risk assessment (D. Drew; 29-DEC2014; D424485), EPA included epidemiologic research results from these three US prospective 

birth cohort studies but primarily focused on the results of CCCEH since this cohort has 

published studies on the association between cord blood levels of chlorpyrifos and 

neurodevelopmental outcomes. The agency retained the FQPA 10X Safety Factor (SF) in the 

2014 chlorpyrifos revised risk assessment, in large part, based on the findings of these studies.

In the 2015 updated literature review (OPP/USEPA; 15-SEP-2015; D331251), the agency 

conducted a systematic review expanding the scope of the 2012/2014 review focused on US 

cohort studies with particular emphasis on chlorpyrifos. The expanded 2015 review includes 

consideration of the epidemiological data on any OP pesticide, study designs beyond prospective 

cohort studies, and non-U.S. based studies. The updated literature review identified seven studies 

which were relevant (Bouchard et al., 2010; Fortenberry et al., 2014; Furlong et al., 2014; 

Guodong et al., 2012; Oulhote and Bouchard, 2013; Zhang et al., 2014; Shelton et al., 2014). 

These seven studies have been evaluated in context with studies from the 2012/2014 review (D. 

Drew; 29-DEC-2014; D424485). Only a brief summary is provided below.

 2 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0170
Page 16 of 57

The OP exposure being assessed in many of these studies used concentrations of urinary dialkyl 

phosphate metabolites (DAPs) as the urinary biomarker. Total DAPs is a non-specific measure 

of OP exposure and is the sum of six separate molecules - three dimethyl alkylphosphate 

(DMAP) molecules of DMP, DMTP, DMDTP, and three diethyl alkylphosphate (DEAP) 

molecules of DEP, DETP, and DEDTP. Each metabolite is a breakdown product from multiple 

OPs (Table 4.4.1; CDC, 2008)3

. Specifically, DMP, DMTP, and DMDTP are associated with 

18, 13, and 5 OPs, whereas DEP, DETP, and DEDTP are associated with 10, 10, and 4 OPs, 

respectively. Thus, using urinary DAPs alone as an exposure measure, it is not possible to 

separate the exposure and associated effects for single, specific OPs. 

Table 4.4.1.CDC Table of organophosphate pesticides and their dialkyl phosphate metabolites (2008). 

Pesticide DMP DMTP DMDTP DEP DETP DEDTP

Azinphos methyl X X X

Chlorethoxyphos X X

Chlorpyrifos X X

Chlorpyrifos methyl X X

Coumaphos X X

Dichlorvos (DDVP) X

Diazinon X X

Dicrotophos X

Dimethoate X X X

Disulfoton X X X

Ethion X X X

Fenitrothion X X

Fenthion X X

Isazaphos-methyl X X

Malathion X X X

Methidathion X X X

Methyl parathion X X

Naled X

Oxydemeton-methyl X X

Parathion X X

Phorate X X X

Phosmet X X X

Pirimiphos-methyl X X

Sulfotepp X X

Temephos X X

Terbufos X X X

Tetrachlorviphos X

Trichlorfon X

DMP = dimethylphosphate; DEP = diethylphosphate; DMTP = dimethylthiophosphate; DMDTP = 

dimethyldithiophosphate; DETP = diethylthiophosphate; DEDTP = diethyldithiophosphate.

 3 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdf
Page 17 of 57

For studies which measured urinary 3,5,6-trichloro-2-pyridinol (TCPy) (e.g., Fortenberry et al., 

2014; Eskenazi et al., 2007; Whyatt et al., 2009), this metabolite can be derived from 

chlorpyrifos, chlorpyrifos-methyl, and the herbicide triclopyr. TCPy is also the primary 

environmental degradate of chlorpyrifos, chlorpyrifos-methyl, and triclopyr; thus exposure can 

be found directly on food treated with these pesticides. CCCEH studies have largely used 

chlorpyrifos measured in cord blood as the specific biomarker (e.g., Lovasi et al., 2010; Whyatt 

et al., 2004; Rauh et al., 2011). The CHARGE study (Shelton et al, 2015) did not measure 

biomarkers but instead used geospatial analysis to focus on the residential proximity to OP 

exposure using data from the California Department of Pesticide Regulation, with five OPs 

accounting for a total of 73% of the pesticide applied near residential settings (chlorpyrifos, 

acephate, diazinon, bensulide, and dimethoate). 

Similarly, DAPs can be found directly on food following OP applications (Zhang et al, 2008; 

Chen et al, 2012). Specifically, studies have shown that DAPs may form as environmental 

degradates from abiotic hydrolysis, photolysis, and plant metabolism (Zhang et al, 2008; Chen et 

al, 2012; Racke et al, 1994). Furthermore, since these DAPs are excreted more rapidly and 

extensively than the parent OPs (Zhang et al, 2008; Forsberg et al, 2008), direct exposure to 

DAPs may lead to an overestimate of OP exposure when using urinary DAPs as a biomarker of 

OP exposure. The agency recognizes that this is a source of uncertainty when using DAPs for 

assessing OP exposure and will continue to monitor this issue in future assessments. 

With respect to neurological effects near birth, the CHAMACOS and Mt. Sinai cohorts measured 

neurological effects at birth, and observed a putative association with total DEAP, total DMAP, 

and total DAP exposure (Engel et al., 2007; Young et al., 2005). Similarly, a Chinese study 

(Zhang et al., 2014) reported statistically significant associations between total DEAPs, total 

DMAPs, and total DAPs from prenatal OP pesticide exposure and neonatal neurodevelopment 

assessed 3 days after birth. However, another cross-sectional Chinese study, Guodong et al 

(2012), observed no association with urinary DAPs and a developmental quotient score for 23-25 

month old children.

The 3 US cohorts (CCCEH, Mt. Sinai, CHAMACOS) each reported evidence of impaired mental 

and psychomotor development, albeit not consistent by age at time of testing (ranging from 6 

month to 36 months across the three cohorts). Attentional problems and ADHD were reported 

by three prospective cohorts [Rauh et al, 2006; Eskenazi et al., 2007; Marks et al, 2010; and 

Fortenberry et al (2014)] investigators with additional support from a case control study, 

Bouchard et al. (2010). The exposure metric varied among these studies. Specifically, 

Fortenberry et al (2014) found suggestive evidence of an association with TCPy and ADHD in 

boys whereas statistically significant associations were observed by Rauh et al (2006) with 

chlorpyrifos exposure and ADHD. Eskenazi et al (2007) reported associations with total 

DMAPs and total DAPs and ADHD; Marks et al (2010) reported associations with total DEAP, 

DMAP, and total DAP exposure and ADHD. In a national cross-sectional study of Canadian 

children, using 2007-2009 data for children age 6-11 years (Oulhote and Bouchard, 2013), there 

were no overall statistically significant associations observed between child urinary DEAP, 

DMAP, or total DAP metabolite levels and parentally reported behavioral problems. In contrast, 

Bouchard et al. (2010), looking at U.S. children age 8-15 years in the 2000-2004 National Health 

and Nutrition Examination Survey (NHANES), observed a positive association between 
Page 18 of 57

attention and behavior problems and total DAPs and DMAPs, but not DEAPs. As part of their 

analysis, Oulhote and Bouchard (2013) noted that their outcome assessment for behavioral 

problems may not have been as sensitive as Bouchard et al (2010), which may in part account for 

the difference in the observed results from these studies. 

In addition, the three US cohorts and the CHARGE study have reported suggestive or positive 

associations between OP exposure and autism spectrum disorders (Rauh et al., 2006; Shelton et 

al., 2014; Eskenazi et al, 2007; Furlong et al., 2014). Specifically, Furlong et al (2014) 

documented suggestive evidence of an association between total DEAP exposure and reciprocal 

social responsiveness among blacks and boys. Eskenazi et al (2007) reported a statistically 

significant association between pervasive developmental disorder (PDD) and total DAP 

exposure, whereas Eskenazi et al (2010) reported non-significant, but suggestive, increased odds 

of PDD of 2.0 (0.8 to 5.1; p=0.14). Rauh et al (2006) documented a significant association 

between PDD and specifically chlorpyrifos exposure. Both PDD and reciprocal social 

responsiveness are related to the autism spectrum disorder. Using a different exposure 

assessment method (geospatial analysis and residential proximity to total OP exposure), Shelton 

et al (2014) also showed statistically significant associations between total OP exposure and 

ASD. While these studies vary in the magnitude of the overall strength of association, they have 

consistently observed a positive association between OP exposure and ASD. Finally, CCCEH, 

Mt. Sinai, CHAMACOS have reported an inverse relation between the respective prenatal 

measures of chlorpyrifos and intelligence measures at age 7 years (Rauh et al., 2011; Engel et al., 

2011; Bouchard et al., 2011). 

Across the epidemiology database of studies, the maternal urine, cord blood, and other 

(meconium) measures provide evidence that exposure did occur to the fetus during gestation but 

the actual level of such exposure during the critical window(s) of susceptibility is not known. 

While significant uncertainties remain about the actual exposure levels experienced by mothers 

and infant participants in the children’s health cohorts, it is unlikely that these exposures resulted 

in AChE inhibition. As part of the CHAMACOS study, Eskenazi et al. (2004) measured AChE 

activity and showed that no differences in AChE activity were observed. The biomarker data 

(chlorpyrifos) from the Columbia University studies are supported by the agency’s dose 

reconstruction analysis using the PBPK-PD model (D. Drew; 29-DEC-2014; D424485). 

Following the recommendation of the FIFRA SAP (2012), the agency conducted a dose 

reconstruction analysis of residential uses available prior to 2000 for pregnant women and young 

children inside the home. The PBPK-PD model results indicate for the highest exposure 

considered (i.e., indoor broadcast use of a 1% chlorpyrifos formulation) <1% RBC AChE 

inhibition was produced in pregnant women. While uncertainty exists as to actual OP exposure 

at (unknown) critical windows of exposure, EPA believes it is unlikely individuals in the 

epidemiology studies experienced RBC AChE inhibition.

A review of the scientific literature on potential modes of action/adverse outcome pathways 

(MOA/AOP)4 leading to effects on the developing brain was conducted for the 2012 FIFRA SAP 

meeting (USEPA, 2012) and updated for the December 2014 chlorpyrifos revised risk 

assessment (D. Drew; 29-DEC-2014; D424485). In short, multiple biologically plausible 

 4 Mode of action (MOA) and adverse outcome pathways (AOPs) describe a set of measureable key events that make 

up the biological processes leading to an adverse outcome and the causal linkages between such events. 
Page 19 of 57

hypotheses and pathways are being pursued by researchers that include targets other than AChE 

inhibition, including cholinergic and non-cholinergic systems, signaling pathways, proteins, and 

others. However, no one pathway has sufficient data to be considered more credible than the 

others. The fact that there are, however, sparse AOP data to support the in vitro to in vivo

extrapolation, or the extrapolation from biological perturbation to adverse consequence 

significantly limits their quantitative use in risk assessment. The SAP concurred with the agency 

in 2008 and 2012 about the lack of definable key events in a MOA/AOP leading to 

developmental neurobehavioral effects. However, since the 2014 literature review, there are no 

substantive changes in the ability to define and quantitate steps in an MOA/AOP leading from 

exposure to effects on the developing brain. Published and submitted guideline DNT laboratory 

animal studies have been reviewed for OPs as part of the 2012/2014 review (D. Drew; 29-DEC2014; D424485) and the updated 2015 review (OPP/USEPA; 15-SEP-2015; D331251). 

Neurobehavioral alterations in laboratory animals were often reported, albeit at AChE inhibiting 

doses, but there was generally a lack of consistency in terms of pattern, timing, or dose-response 

for these effects, and a number of studies were of lower quality. However, this information does 

provide evidence of long-lasting neurodevelopmental disorders in rats and mice following 

gestational exposure.

At this time, a MOA(s)/AOP(s) has/have not been established for neurodevelopmental outcomes. 

This growing body of literature does demonstrate, however, that OPs are biologically active on a 

number of processes that affect the developing brain. Moreover, there is a large body of in vivo

laboratory studies which show long-term behavioral effects from early life exposure, albeit at 

doses which cause AChE inhibition. EPA considers the results of the toxicological studies 

relevant to the human population, as qualitatively supported by the results of epidemiology 

studies. The agency acknowledges the lack of established MOA/AOP pathway and uncertainties 

associated lack of ability to make strong causal linkages and unknown window(s) of 

susceptibility. These uncertainties do not undermine or reduce the confidence in the findings of 

the epidemiology studies. The epidemiology studies reviewed in the 2012/2014 and 2015 

literature reviews represent different investigators, locations, points in time, exposure assessment 

procedures, and outcome measurements. Despite all these differences in study design, with the 

exception of two negative studies in the 2015 literature review (Guodong et al, 2012; Oulhote 

and Bouchard, 2013), authors have identified associations with neurodevelopmental outcomes 

associated with OP exposure across four cohorts and twelve study citations. Specifically, there is 

evidence of delays in mental development in infants (24-36 months), attention problems and 

autism spectrum disorder in early childhood, and intelligence decrements in school age children 

who were exposed to OPs during gestation. Investigators reported strong measures of statistical 

association across several of these evaluations (odds ratios 2-4 fold increased in some instances), 

and observed evidence of exposures-response trends in some instances, e.g., intelligence 

measures.

As section 408(b)(2)(C) of the FFDCA instructs EPA, in making its “reasonable certainty of no 

harm” finding, that in “the case of threshold effects, an additional tenfold margin of safety for the 

pesticide chemical residue and other sources of exposure shall be applied for infants and children 

to take into account potential pre- and postnatal toxicity and completeness of data with respect to 

exposure and toxicity to infants and children.” Section 408 (b)(2)(C) further states that “the 

Administrator may use a different margin of safety for the pesticide chemical residue only if, on 
Page 20 of 57

the basis of reliable data, such margin will be safe for infants and children.” Given the totality of 

the evidence, there is sufficient uncertainty in the human dose-response relationship for 

neurodevelopmental effects which prevents the agency from reducing or removing the statutory 

10X FQPA Safety Factor. For the profenofos DRA, a value of 10X has been applied. Similarly, 

a database uncertainty factor of 10X will be retained for occupational risk assessments. The 

agency will continue to evaluate the epidemiology studies and pursue approaches for quantitative 

or semi-quantitative comparisons between doses which elicit AChE inhibition and those which 

are associated with neurodevelopmental outcomes prior to a revised human health risk 

assessment. 

4.5 Safety Factor for Infants and Children (FQPA SF)

As noted above, the lack of an established MOA/AOP makes quantitative use of the 

epidemiology studies in risk assessment challenging, particularly with respect to determining 

dose-response, critical duration of exposure, and window(s) of susceptibility. However, 

exposure levels in the range measured in the epidemiology studies are likely low enough that 

they are unlikely to result in AChE inhibition. Epidemiology studies consistently identified 

associations with neurodevelopmental outcomes associated with OP exposure such as delays in 

mental development in infants (24-36 months), attention problems and autism spectrum disorder 

in early childhood, and intelligence decrements in school age children. Therefore, there is a need 

to protect children from exposures that may cause these effects; this need prevents the agency 

from reducing or removing the statutory FQPA Safety Factor. Thus, the FQPA 10X Safety 

Factor will be retained for profenofos for the population subgroups that include infants, 

children, youths, and women of childbearing age for all exposure scenarios. 

4.5.1 Completeness of the Toxicology Database

The existing toxicological database is complete and adequate for characterizing profenofos 

toxicity. Available profenofos studies for FQPA evaluation include developmental studies in the 

rat and rabbit, reproductive toxicity studies, comparative cholinesterase studies, and 

neurotoxicity studies (acute, subchronic, and developmental).

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 

population subgroups that include infants, children, youths, and women of childbearing age for 

all exposure scenarios.

4.5.2 Evidence of Neurotoxicity

Profenofos is an OP with an established neurotoxic AOP. Neurotoxicity is the most sensitive 

effect in all species, routes, and lifestages and is being used in deriving the PODs. 

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

There is no evidence of increased quantitative or qualitative sensitivity/susceptibility to offspring 

following exposure to profenofos in submitted studies.
Page 21 of 57

As discussed in Section 4.4, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the 

population subgroups that include infants, children, youths, and women of childbearing age for 

all exposure scenarios.

4.5.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to the exposure databases. The acute dietary 

assessment incorporated tolerance level residues, default processing factors and 100 PCT. 

Although data were used to partially refine the steady-state dietary exposure assessments, the 

assessments are not expected to underestimate dietary (food and water) exposures. 

4.6 Toxicity Endpoint and Point of Departure Selections

4.6.1 Dose-Response Assessment

Table 4.5.4.1 summarizes the profenofos toxicity endpoints and PODs selected from an 

evaluation of the database. This endpoint selection was based on a weight of the evidence 

evaluation using the following considerations:

• Relative sensitivity of the brain and RBC compartments: For profenofos, across most 

studies, durations, lifestages, and routes, RBC is similarly or more sensitive than the 

brain. As such, OPP has utilized the RBC data in POD derivation.

• Potentially susceptible populations (fetuses, juveniles, pregnancy): The available AChE 

data across multiple lifestages (adults, pregnant adults, fetuses, juveniles) show no 

quantitative lifestage sensitivity for profenofos. After single dose exposures, females 

were more sensitive than males based on RBC AChE inhibition. Consequently, data 

from females were used as the basis for POD derivation for acute dietary exposures.

• Route of exposure: It is preferred to match, to the degree possible, the route of exposure 

in the toxicity study with that of the exposure scenario(s) of interest. There are oral, 

dermal, and inhalation studies with profenofos which contain high-quality dose-response 

AChE data for endpoint selection.

• Duration of exposure: It is preferred to match, to the degree possible, the duration of 

toxicity study with that of the exposure duration of interest. There are single day and 

steady-state oral studies, but only steady-state dermal and inhalation studies are available. 

• Consistency across studies: In cases where multiple datasets are available for a single 

duration, it is important to evaluate the extent to which data are consistent (or not) across 

studies. The profenofos database has striking consistency across studies, which allows 

the PODs to be derived from multiple critical studies, thereby increasing the confidence 

in such values. 

Summary tables of BMD analyses can be found in Appendix C and the technical details of the 

analysis can be found in the BMD analysis memo (M. Perron; 15-SEP-2015; TXR# 0057250). 
Page 22 of 57

Consistent with risk assessments for other AChE-inhibiting compounds, OPP has used a 

benchmark response (BMR) level of 10% and has thus calculated BMD10 and BMDL10 values 

(See Appendix B for summary of OPP’s ChE policy). The BMD10 is the estimated dose where 

AChE is inhibited by 10% compared to background. The BMDL10 is the lower confidence 

bound on the BMD10. As a matter of science policy, the Agency uses the BMDL, not the BMD, 

for use as the POD (USEPA, 2012). All BMD/BMDL modeling for all individual datasets was 

completed using USEPA BMD Software to fit an exponential model to the data. BMD results 

from the OP CRA (2002, 2006) were included in the endpoint selection weight-of-evidence 

evaluation. 

Acute Dietary (all populations) 

A POD for the acute dietary (all populations) exposure scenario was derived from the results of a 

high-quality, well-conducted CCA rat study (MRID 46025406). A BMDL10 of 1.99 mg/kg/day 

associated with RBC AChE inhibition following a single oral exposure in adult females (day 42) 

was selected as a suitable POD for the acute dietary (all populations) exposure scenario. The 

corresponding BMD10 was 3.17 mg/kg/day. 

RBC AChE inhibition was selected for the POD since RBCs are a principal target for OP 

pesticides and the RBC AChE data were more sensitive than the brain AChE data. Data from the 

adult females represent the lowest BMD10 and BMDL10 values obtained following a single dose 

compared to juveniles (both sexes) and adult males. This endpoint is considered protective of all 

populations, including children, since there was no quantitative lifestage sensitivity seen in the 

database.

An uncertainty factor of 1000X (10X to account for interspecies extrapolation, 10X for 

intraspecies variation, and 10X for FQPA SF due to uncertainty in the human dose-response 

relationship for neurodevelopmental effects (see Section 4.4)) is applied to the BMDL10 to obtain 

an aPAD of 0.00199 mg/kg/day for exposure scenarios with infants, children, youths, and 

women of childbearing age. The only population subgroup for which the FQPA SF is not 

retained is adults 50-99; therefore, the aPAD for this population subgroup is 0.0199 mg/kg/day.

Steady-State Dietary (all populations)

There is remarkable similarity in BMD estimates across multiple studies, durations, and 

compartments in studies 10 days and longer in adult rats (Table 4.3.1.1 and Appendix C). There 

was no evidence of increased quantitative susceptibility to offspring. AChE inhibition in 

juvenile rats was seen at or above dose levels eliciting inhibition in adults. In the DNT studies, 

little or no inhibition was seen in fetuses and young juvenile rats at doses causing considerable 

AChE inhibition in adult rats. Additionally, pregnant females were not found to be more 

sensitive.

Of the repeated dosing studies, data from the rat combined chronic/carcinogenicity study (MRID 

00081685) was found to be the most robust taking into consideration dose spacing and BMD 

model results. A BMDL10 of 0.12 mg/kg/day associated with RBC AChE inhibition in male and 

female adult rats at the 13 week interim measurement was selected as a suitable POD for the 
Page 23 of 57

steady-state dietary (all populations) exposure scenario. The corresponding BMD10 was 0.14 

mg/kg/day and 0.13 mg/kg/day in males and females, respectively. Similar BMDL10 values were 

obtained in the repeat CCA study, in non-pregnant females in the DNT studies, and at terminal 

measurements in the rat chronic/carcinogenicity study. Although lower values were obtained in 

the rat subchronic neurotoxicity and mouse carcinogenicity studies, poor dose spacing forced 

extrapolation to much lower doses in order to obtain BMD10 estimates. The subchronic oral dog 

study also provided a lower BMD estimate; however, there was large variability noted at all 

doses and inspection of the data found no AChE inhibition at the BMD10 estimates generated. 

As a result, the BMD estimates from these studies were not considered appropriate for endpoint 

selection.

An uncertainty factor of 1000X (10X to account for interspecies extrapolation, 10X for 

intraspecies variation, and 10X for FQPA SF due to uncertainty in the human dose-response 

relationship for neurodevelopmental effects (see Section 4.4)) is applied to the BMDL10 to obtain 

a ssPAD of 0.00012 mg/kg/day for exposure scenarios with infants, children, youths, and women 

of childbearing age. The only population subgroup for which the FQPA SF is not retained is 

adults 50-99; therefore, the ssPAD for this population subgroup is 0.0012 mg/kg/day.

Incidental Oral, Steady-State

For the purpose of assessing potential risk associated with incidental oral exposure from steadystate durations, OPP selected the dose and endpoint from the combined chronic/carcinogenicity 

study in rats for the reasons outlined above for steady-state dietary exposures. The selected 

study is protective of all populations since there was no evidence of increased quantitative 

susceptibility in repeated dosing studies. A total uncertainty factor of 1000X is appropriate for 

incidental oral exposures (10X for interspecies extrapolation, 10X for intraspecies variation, and 

a 10X FQPA SF due to uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4)). 

Dermal, Steady-State

A dermal POD was selected from a 21-day dermal toxicity study (MRID 44999101) in rabbits 

based on RBC AChE inhibition. The data were not amenable to BMD modeling5; therefore, the 

NOAEL of 1 mg/kg/day was selected as the POD for dermal exposures. The LOAEL was 10 

mg/kg/day based on RBC AChE inhibition. This study is appropriate for the route and duration 

of exposure. A total uncertainty factor of 1000X is appropriate for dermal exposures (10X for 

interspecies extrapolation, 10X for intraspecies variation, and a 10X FQPA SF for residential 

assessments or a database uncertainty factor in occupational assessments due to uncertainty in 

the human dose-response relationship for neurodevelopmental effects (see Section 4.4)). 

Inhalation Steady-State

 5 Data were not amenable to BMD modeling due to a flat dose response with a decrease only at the highest dose 

tested and relatively large variability noted at all doses.
Page 24 of 57

An inhalation POD was selected from a 21-day inhalation (aerosol) toxicity study based on RBC 

AChE inhibition. This study is appropriate for the route and duration of exposure. The data 

were not amenable to BMD modeling6; therefore the LOAEL of 68 mg/m3 was selected as the 

POD for inhalation exposures. The NOAEL was not established. Due to insufficient 

characterization of particle sizes in the study, the mass median aerodynamic diameter (MMAD) 

and geometric standard deviation (GSD) could not be determined. As a result, human equivalent 

concentrations could not be estimated for the systemic effects (AChE inhibition) from inhalation 

exposure. For occupational scenarios, duration adjustments were made to extrapolate exposure 

in the animal study (6 hours/day, 5 days/week) to a typical occupational exposure (8 hours/day, 5 

days/week). The resulting duration adjusted value for occupational exposures is 51 mg/m3. For 

estimating occupational inhalation risks from different occupational activities, inhalation doses 

of 2.90, 5.84, and 10.14 mg/kg/day corresponding to the breathing rates of 8.3, 16.7, or 29 L/min 

were calculated using this duration adjusted value. For occupational inhalation exposures, the 

maximum total uncertainty factor of 3000X was applied (10X for interspecies extrapolation, 10X 

for intraspecies variation, and 30X database uncertainty factor to incorporate uncertainty in the 

human dose-response relationship for neurodevelopmental effects (see Section 4.4) and the UFL

due to lack of a NOAEL).

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources (oral, dermal, and inhalation) and 

determine whether the individual exposures can be combined if they have the same toxicological 

effects. PODs for the incidental oral, dermal, and inhalation routes are all derived from RBC 

AChE inhibition. As a result, exposure from all routes can be combined. 

4.6.3 Cancer Classification and Risk Assessment Recommendation

Profenofos is classified as a “Group E Chemical – evidence of non-carcinogenicity for humans” 

based on lack of evidence of carcinogenicity in rats and mice. Therefore, a quantitative cancer 

risk assessment is not required.

4.6.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.6.4.1. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario POD UFsa LOC Study and Toxicological Effects

Acute Dietary 

(all populations

except adults 

50-99 years)

BMDL10 = 

1.99 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 10X

aRfD = 0.00199

aPAD = 0.00199

Acute CCA study in rats 

(MRID 46025406)

BMD10 = 3.17 mg/kg/day.

 6 Mortality at the highest dose tested left only two treatment groups for modeling and dose selection forced 

extrapolation to a much lower value from the lowest dose to obtain a BMD10.
Page 25 of 57

Table 4.6.4.1. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario POD UFsa LOC Study and Toxicological Effects

Inhibition of RBC AChE in adult female 

rats.

Acute Dietary 

(adults 50-99 

years)

BMDL10 = 

1.99 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = 0.0199

aPAD = 0.0199

Acute CCA study in rats 

(MRID 46025406)

BMD10 = 3.17 mg/kg/day.

Inhibition of RBC AChE in adult female 

rats.

Steady-State 

Dietary

(all populations 

except adults 

50-99 years)

BMDL10 = 

0.12 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 10X

ssRfD = 0.00012

ssPAD = 0.00012

Combined chronic oral 

toxicity/carcinogenicity study 

(MRID 00081685)

BMD10 = 0.14/0.13 mg/kg/day 

(males/females).

Inhibition of RBC AChE in adult rats at 13 

week interim measurement.

Steady-State 

Dietary

(adults 50-99 

years)

BMDL10 = 

0.12 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

ssRfD = 0.0012

ssPAD = 0.0012

Combined chronic oral 

toxicity/carcinogenicity study 

(MRID 00081685)

BMD10 = 0.14/0.13 mg/kg/day 

(males/females).

Inhibition of RBC AChE in adult rats at 13 

week interim measurement.

Incidental Oral

Steady-State

BMDL10 = 

0.12 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 10X

Residential LOC 

for MOE <1000

Combined chronic oral 

toxicity/carcinogenicity study 

(MRID 00081685)

BMD10 = 0.14/0.13 mg/kg/day 

(males/females).

Inhibition of RBC AChE in adult rats at 13 

week interim measurement.

Dermal

Steady-State

NOAEL = 

1 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 10X

Residential LOC 

for MOE <1000

21-day rabbit dermal toxicity 

(MRID 41644501)

LOAEL = 10 mg/kg/day.

Inhibition of RBC AChE in adult rabbits.

Cancer (oral, 

dermal, 

inhalation)

Classification: Group E Chemical – evidence of non-carcinogenicity for humans.

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

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

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

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

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, ss = steady-state). RfD = reference dose (a = acute, ss = steady-state). MOE = 
Page 26 of 57

margin of exposure. LOC = level of concern. BMD = benchmark dose. BMDL = lower 95% confidence interval 

for benchmark dose. 

a FQPA SF retained for infants, children, youths, and women of childbearing age for all exposure scenarios due to 

uncertainty in the human dose-response relationship for neurodevelopmental effects (see Section 4.4). This includes 

all exposure scenarios, except the dietary exposure scenarios for the population subgroup adults 50-99 for which the 

FQPA SF has been reduced to 1X. 

Table 4.6.4.2. Summary of Toxicological Doses and Endpoints for Profenofos for Use in Occupational Human 

Health Risk Assessments.

Exposure/

Scenario POD UFs LOC Study and Toxicological Effects

Dermal

Steady-State

NOAEL = 

1 mg/kg/day

UFA = 10X

UFH = 10X

UFDB = 10Xb

Occupational 

LOC for MOE 

<1000

21-day rabbit dermal toxicity 

(MRID 41644501)

LOAEL = 10 mg/kg/day.

Inhibition of RBC AChE in adult rabbits.

Inhalation 

Steady-State

LOAEL =

68 mg/m3

/daya

UFA = 10X

UFH = 10X

UFDB = 30Xc

Occupational 

LOC for MOE 

<3000

21-day inhalation rat study

(MRID 00082079)

LOAEL = 68 mg/m3

/day.

Inhibition of RBC AChE in adult rats.

Cancer (oral, 

dermal, 

inhalation)

Classification: Group E Chemical – evidence of non-carcinogenicity for humans.

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

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

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

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

sensitivity among members of the human population (intraspecies). UFL = database uncertainty factor for 

extrapolation from a LOAEL to NOAEL. MOE = margin of exposure. LOC = level of concern. BMD = 

benchmark dose. BMDL = lower 95% confidence interval for benchmark dose. 

a Inhalation doses corresponding to the breathing rates of 8.3, 16.7, and 29 L/min were calculated as 2.90, 5.84, and 

10.14 mg/kg/day, respectively, for occupational activities using a duration adjusted value of 51 mg/m3

. b UFDB for occupational dermal exposures = database uncertainty factor for uncertainty in the human dose-response 

relationship for neurodevelopmental effects (see Section 4.4). c UFDB for occupational inhalation exposures = database uncertainty factor incorporating uncertainty in the human 

dose-response relationship for neurodevelopmental effects (see Section 4.4) and the UFL due to lack of a NOAEL in 

the subchronic inhalation toxicity study.

4.7 Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

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

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

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

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

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

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

acute tests and chronic studies that assess growth, developmental and reproductive effects in 
Page 27 of 57

different taxonomic groups. As part of its reregistration decision for profenofos, 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), profenofos is 

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

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

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

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

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

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

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

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

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 20137 and includes some 

pesticides 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.

Profenofos is on List 2. List 2 represents the next set of chemicals for which EPA intends to 

issue test orders/data call-ins in the near future. For further information on the status of the 

EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the 

Tier 1 screening battery, please visit our website.

8

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The requirement for plant metabolism is fulfilled based on acceptable cotton metabolism studies 

depicting the metabolism of profenofos in cotton following foliar treatment. Profenofos is 

metabolized in cotton primarily to a glucosyl sulfate conjugate of 4-bromo-2-chlorophenol. 

Profenofos and the glucosyl sulfate conjugate of 4-bromo-2-chlorophenol are the predominant 

residues of profenofos in cotton. The results of the cotton metabolism study were presented to 

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

chemicals.

8 http://www.epa.gov/endo/
Page 28 of 57

the HED Metabolism Committee (7/28/95) which concluded that profenofos per se is the residue 

of concern in cotton for tolerance enforcement and risk assessment purposes. 

The requirements for livestock metabolism are fulfilled. Acceptable ruminant and poultry 

metabolism studies have been submitted and evaluated. The HED Metabolism Committee 

(7/28/95) concluded that profenofos per se is the compound of toxicological concern in milk and 

ruminant tissues. The Committee also concluded that there is no reasonable expectation of finite 

residues of profenofos in poultry tissues or eggs. Residues of profenofos were not present in any 

of the poultry tissues analyzed (meat, fat, or eggs), even at exaggerated dosing levels. Thus, 

there is presently no need to establish tolerances for residues of profenofos in poultry tissues or 

eggs.

The requirement for a confined rotational crop study is fulfilled. An acceptable study was 

submitted that adequately demonstrates residues of concern are not likely to be found in 

appreciable concentrations in crops planted in as little as 30 days after treatment. The 30-day

plant back interval (PBI) on the label is adequate. 

5.1.2 Summary of Environmental Degradation

Profenofos degrades primarily by microbial metabolism as well as the abiotic process of 

hydrolysis. Aerobic and anaerobic soil metabolism half-lives are similar, 2.3 and 2.1 days 

respectively. Degradation due to hydrolysis varies with pH, with half-lives ranging from 107-

475 days for acidic (pH 5) waters, 24.4-69.9 days for waters with neutral pH (pH 7), and 0.32-

0.43 days for alkaline waters (pH 9). The half-life of profenofos, under anaerobic aquatic 

conditions, due to metabolism is 3.8 days at 25 °C. The values of the photolysis half-life were 

compared to the hydrolysis half-lives at pH 5. The dark corrected photolysis half- life was found 

to be 266 days. An available laboratory study indicates that profenofos has a slight mobility 

potential to leach in soils. 

The predominant degradate of profenofos observed in laboratory studies (including hydrolysis, 

photolysis, and metabolism) was 4-bromo-2-chlorophenol, which was formed by hydrolysis of 

the organophosphate group from the phenyl ring of profenofos. Also formed in equimolar parts 

with degradate O-ethyl-S-propyl phosphorothioate; however, profenofos, is the only residue of 

concern for the human health risk assessment. 

5.1.3 Comparison of Metabolic Pathways

In plants, profenofos is metabolized primarily to a glucosyl sulfate conjugate of 4-bromo-2-

chlorophenol. In goat and poultry tissues and in rats, residues consist primarily of 4-bromo-2-

chlorophenol and its sulfate. None of the primary metabolites in either plant or goat and poultry 

tissues; e.g., 4-bromo-2-chlorophenol, 4-bromo-2-chlorophenol sulfate and 4-bromo-2-

chlorophenol sulfate glucosyl conjugate, are AChE inhibitors. Furthermore, metabolism and 

feeding studies indicate that residues of profenofos are found in the milk, fat, and liver of 

ruminants, only. No profenofos is found in poultry tissues or eggs even at exaggerated feeding 

levels.
Page 29 of 57

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance

Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants

Primary Crop Profenofos per se Profenofos per se

Rotational Crop Profenofos per se Profenofos per se

Livestock

Ruminant Profenofos per se Profenofos per se

Poultry Not Applicable1 Not Applicable1

Drinking Water Profenofos per se Not Applicable

1

 CFR 180.6(a)(3) (Category 3). If new uses are registered that would result in a higher dietary burden, Category 3 may 

no longer apply (Results of Metabolism Committee, 28-JUL-1995; No DP#).

5.2 Food Residue Profile

HED has previously evaluated residue data depicting the magnitude of profenofos residues of 

concern in/on cottonseed and cotton gin byproducts. The application rates represent 1X the 

maximum registered rates and the minimum PHI of 14 days. Profenofos residues in/on treated 

cottonseed ranged from <0.05 ppm (nondetectable) to 1.1 ppm. Residues were observed to 

concentrate marginally 1.4X in cottonseed hulls, and no concentration of residues were observed 

in cottonseed meal and refined, bleached, and deodorized oil. 

5.3 Water Residue Profile

The residues of concern in drinking water for purposes of risk assessment are profenofos. EFED 

provided EDWCs for profenofos in the following drinking water assessment, “Drinking Water 

Assessment for Profenofos for Registration Review (M. Colletti; D425755). EFED noted that no 

current monitoring data are available for profenofos. The current drinking water assessment 

relies on modeled estimates. The recommended EDWCs for profenofos are based on the only 

currently registered use site, cotton, which is grown in several states. The percent cropped area 

(PCA) for cotton, 0.21, was used for a national assessment. 

EFED provided both surface (from the SWCC version 1.106 (EFED, 2014) model) and 

groundwater (Pesticide Root Zone Model for Groundwater (PRZM-GW), version 1.0, August 

31, 2012) EDWCs. EFED stated that the surface water EDWC was appropriate to use in the 

acute dietary exposure assessment. For the steady-state dietary exposure assessment, EFED 

provided daily time-series outputs that simulate 29 years of residues of profenofos in drinking 

water. These distributions were adjusted so that the data points were 21-day rolling averages. 

These values were incorporated into RDFs for use in DEEM.

Surface Water Modeling for Acute Assessment

For Tier 2 surface water assessments, the SWCC model was used to calculate the EDWCs of the 

active ingredient profenofos in surface waters. The Tier 2 assessment reports the EDWCs for 

profenofos that are expected once every ten years. The estimates are generated using 30-years of 

meteorological data, encompassing the years from 1961 to 1990. For further information on 
Page 30 of 57

these models see: http://www.epa.gov/oppefed1/models/water/index.htm. The profenofos 

concentrations simulated by SWCC assume that 100% of the watershed is planted to the 

simulated crop. The raw SWCC concentrations (output) are then multiplied by the PCA factor 

for cotton to account for the less than 100% coverage by the crop in a watershed large enough to 

support a drinking water facility. The SWCC output concentrations multiplied by the PCA are 

the EDWCs. PCAs are the maximum proportion of a drinking water basin that might be planted 

with a specific crop (EFED, 2014). The PCA for cotton was determined to be 0.21. 

The recommended EDWCs modeled using the Tier II SWCC for the surface water drinking

water exposure assessment for Registration Review are 5.92 μg/L (ppb) for the peak 

concentration, 0.283 μg/L for the annual mean concentration, and an overall mean concentration 

of 0.167 μg/L. The highest peak concentration, the highest annual, and overall mean values 

occurred with the Texas cotton OP scenario.

Table 5.3.1. EDWC of Profenofos Residues for Cotton in an Index Reservoir with the SWCC Model. 

1-in-10 year Profenofos Concentration (μg/L) Concentration (μg/L)

Scenario -State Crop1,2 Peak Annual Mean Overall Annual Mean

CA - Cotton 0.527 0.0382 0.0365

MS – Cotton 4.87 0.214 0.113

NC - Cotton 4.43 0.206 0.0945

TX - Cotton 5.92 0.283 0.167 1 The bold value represents the recommend EDWCs to be use in the acute drinking water assessment. 2 The simulations used the maximum labeled number (10) of applications and application rate (0.5 lb 

ai/A/application), and a maximum seasonal application rate (5 lb ai/A). The concentrations have been 

adjusted with the Percent Cropped Area (PCA) of 0.21 for cotton for a national assessment.

Drinking Water Estimates for Steady-State Assessment

For the steady-state assessments, EFED provided daily time-series outputs that simulate 29 years 

of residues of profenofos in drinking water for the following 5 cotton application scenarios: TX 

cotton reservoir; MS cotton reservoir; MS cotton reservoir; NC cotton reservoir; and CA cotton 

reservoir. Each scenario was run individually in DEEM. These distributions were adjusted so 

that the data points were 21-day rolling averages and these values were incorporated into RDFs 

for use in DEEM for “water direct all sources” and “water indirect all sources.” In the 21-day 

rolling average distributions, the first data point is the average of days 1-21, the second data 

point is the average of days 2-22, the third data point is the average of days 3-23, etc. The 21-

day rolling average continues until the last 20 days of residues of the final distribution year 

(1990). For these residues, the average was taken only of the remaining days, resulting in 

residue values that are not 21-day averages. This is not expected to have a large impact on the 

dietary exposure assessment since the data points which are not true 21-day rolling averages 

represent only 20 days out of 29 years and the simulated drinking water estimates do not include 

applications at the end of the year. 

5.4 Dietary Risk Assessment

Profenofos acute and steady-state dietary exposure assessments were conducted using DEEMFCID, Version 3.16, which incorporates consumption data from USDA’s NHANES/WWEIA. 
Page 31 of 57

This dietary survey was conducted from 2003 to 2008. The analyses were performed to support 

the Registration Review of profenofos. 

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute dietary exposure assessment was conducted using tolerance level residues (HED’s 

recommended 3.0 ppm for cottonseed for purposes of harmonization), DEEM default processing 

factors, and assumed 100% CT. The steady-state dietary exposure assessment assumed an 

average field trial value for cotton (Memo, C. Eiden, 01-AUG-1995; D217739), cottonseed oil 

processing factor (Memo, C. Eiden, 01-AUG-1995; D217744), and tolerance level residues and 

DEEM default processing factors for meat and milk commodities. The cotton PCT was applied 

to cotton and all meat/milk commodities. RDFs were used for milk and meat commodities. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

A Screening Level Usage Analysis (SLUA) memo was provided by BEAD; however, HED did 

not use the PCT in the acute assessment as the unrefined results were <100% aPAD at the 95th

percentile of exposure. The acute aggregate dietary analyses were performed assuming 100% of 

each commodity was treated with profenofos. For the steady-state assessments (food only and 

food + drinking water), PCT for cotton (1%) was applied to cotton and all meat and milk 

commodities. Results are therefore presented up to the 99.9th percentile of exposure. PCT was 

not applied to drinking water; therefore when drinking water only is discussed, results are 

discussed at the 95th percentile of exposure.

5.4.3 Acute Dietary Risk Assessment

The acute assessment is not considered to be a refined assessment as anticipated residues, 

monitoring data, PCT data, empirical processing factors, cooking factors derived from literature 

studies, or refined drinking water values were not incorporated. Tolerance level residues (HED’s 

recommended 3.0 ppm for cottonseed for purposes of harmonization), DEEM (ver. 7.81) default 

processing factors, and 100% CT data were utilized. 

The unrefined acute dietary (food + drinking water) exposure analysis is <100 % aPAD at the 

95th percentile of exposure for the general population and all population subgroups (Table 

5.4.3.1). Children 1-2 years old was the population subgroup with the highest exposure (80% of 

the aPAD at the 95th percentile).

Table 5.4.3.1. Summary of Acute Dietary (Food + Drinking Water – TX Cotton Reservoir Scenario) 

Exposure and Risk for Profenofos1.

Population Subgroup aPAD (mg/kg/day)

2 95th Percentile

Exposure (mg/kg/day) % aPAD

General U.S. 

Population

0.00199

0.000746 38

All Infants (<1 year 

old) 0.001311 66

Children 1-2 years 

old 0.001595 80
Page 32 of 57

Table 5.4.3.1. Summary of Acute Dietary (Food + Drinking Water – TX Cotton Reservoir Scenario) 

Exposure and Risk for Profenofos1.

Population Subgroup aPAD (mg/kg/day)

2 95th Percentile

Exposure (mg/kg/day) % aPAD

Children 3-5 years old 0.001306 66

Children 6-12 years 

old 0.000907 46

Youth 13-19 years old 0.000574 29

Adults 20-49 years 

old 0.000527 26

Adults 50-99 years 

old3 0.000461 2.3

Females 13-49 years 

old 0.000524 26

1 Highest exposure at the 95th percentile is in bold. 2 aPAD = acute population-adjusted dose. 3 Subpopulation adults 50-99 years old: aPAD = 0.0199 mg/kg/day.

5.4.4 Steady-State Dietary Risk Assessment

Steady-state assessments were conducted in the DEEM acute module using the steady-state 

endpoint and 21-day rolling water averages to provide an estimate of 21-day (“steady-state”) 

average daily exposures. Steady-state assessments were conducted for drinking water alone, food 

alone, and food + drinking water. These steady-state assessments are not considered to be highly 

refined assessments as they did not incorporate monitoring data or empirical processing/cooking 

factors. Cottonseed oil is considered a blended commodity; therefore, HED utilized an average 

field trial residue, an average processing factor, and PCT. Meat and milk commodities are not 

considered blended commodities; therefore, the tolerance level, along with PCT were 

incorporated into an RDF that was used in DEEM for the appropriate meat and milk 

commodities. EFED provided daily time-series outputs that simulate 29 years of residues of 

profenofos in drinking water for 5 different cotton application scenarios. These distributions 

were converted into 21-day rolling averages and incorporated into RDFs that were used in 

DEEM for direct all sources and indirect all sources.

For the steady-state food alone exposure estimates, results are shown at the 99.9th percentile as 

PCT was incorporated into the food residue files. Children 1-2 years old are the highest exposed 

subpopulation at 350% of the ssPAD (99.9th percentile of exposure). For drinking water only, 

the 95th percentile is shown as no PCT was incorporated. EFED provided a total of five drinking 

water scenarios. Four out of the five drinking water only scenarios had at least one 

subpopulation that was >100% ssPAD at the 95th percentile (CA cotton scenario had estimates 

<100% for all populations at the 95th percentile). The subpopulation “all infants (<1 year old)” 

was the highest exposed population for all five drinking water only scenarios at all percentiles. 

For CA cotton (the lowest exposure scenario), all infants (<1 year old) utilized 52% of the 

ssPAD and for TX cotton (the highest exposure scenario), all infants (<1 year old) utilized 220% 

of the ssPAD at the 95th percentile. For the food + drinking water exposure estimates, results are 

shown at the 99.9th percentile as PCT was incorporated into the food residue files. All five food 

+ drinking water scenarios are of concern to HED (>100% ssPAD). The TX scenario had the 

overall highest exposure estimates (all infants (<1 year old) as the highest exposed population

subgroup at the 99.9th percentile with 1600% of the ssPAD). The CA cotton scenario had the 
Page 33 of 57

overall lowest exposure estimates (children 1-2 years old was the highest exposed population 

subgroup at the 99.9th percentile with 360% of the ssPAD). The other three food + drinking 

water scenarios were similar to (but lower than) the TX scenario.

The results for all population subgroups and drinking water scenarios (general U.S. population, 

all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, 

adults 20-49, and adults 50-99 years) are summarized in the most recent dietary exposure 

assessment memorandum (S. Levy; 15-SEP-2015; D427269). 

Table 5.4.4.1. Summary of Steady-State Dietary (Food Only) Exposure and Risk for Profenofos1.

Population 

Subgroup

ssPAD 

(mg/kg/day)

2

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mg/kg/day)

% 

ssPAD

Exposure 

(mg/kg/day)

% 

ssPAD

Exposure 

(mg/kg/day)

% 

ssPAD

General 

U.S. 

Population

0.00012

0.000003 2.2 0.000025 21 0.000115 96

All Infants 

(<1 year 

old)

0.000002 1.3 0.000034 29 0.000217 180

Children 

1-2 years 

old

0.000013 11 0.000162 130 0.000421 350

Children 

3-5 years 

old

0.000009 7.9 0.000091 76 0.000232 190

Children 

6-12 years 

old

0.000006 4.9 0.000051 42 0.000144 120

Youth 13-

19 years 

old

0.000003 2.2 0.000026 21 0.000084 70

Adults 20-

49 years 

old

0.000002 1.7 0.000019 16 0.000067 56

Adults 50-

99 years 

old3

0.000002 <1.0 0.000017 1.4 0.000055 4.6

Females 

13-49 

years old

0.000002 1.6 0.000019 15 0.000064 53

1 Highest exposure at the 99.9th percentile is in bold. 2 ssPAD = steady-state population-adjusted dose. 3 Subpopulation adults 50-99 years old: ssPAD = 0.0012 mg/kg/day.
Page 34 of 57

Table 5.4.4.2. Summary of Steady-State Dietary Exposure and Risk for Profenofos1.

Drinking Water 

Scenario 

Steady-State DRINKING WATER ONLY 

(All Infants <1 year old)

Steady-State FOOD + DRINKING WATER 

Highest Exposure Estimate

95th 99.9th

Population 

Subgroup2

99.9th

Exposure 

(mg/kg/day) % ssPAD Exposure 

(mg/kg/day) % ssPAD Exposure 

(mg/kg/day) % ssPAD

MS Cotton reservoir 0.000227 190 0.001577 1300 All infants 0.001577 1300

TX Cotton Reservoir 0.000262 220 0.001919 1600 All infants 0.001922 1600

MS Cotton pond 0.000153 130 0.001525 1300 All infants 0.001527 1300

NC Cotton 0.000130 110 0.001352 1100 All infants 0.001342 1100

CA Cotton3 0.000064 523 0.000318 2803 Children 1-2 

years old 0.000429 360

1 ssPAD = steady-state population-adjusted dose. 2 The results for all population subgroups (general U.S. population, all infants (<1 year old), children 1-2, children 3-

5, children 6-12, youth 13-19, females 13-49, adults 20-49, and adults 50-99 years) for all runs are summarized in 

the dietary exposure assessment memorandum (S. Levy; 15-SEP-2015; D427269). 3 For reference, drinking water exposure for children 1-2 years old was 140% at the 95th percentile and 160% at the 

99.9th percentile. 

5.4.5 Cancer Dietary Risk Assessment

Profenofos is classified as a Group E Chemical based on lack of evidence of carcinogenicity in 

rats and mice. Quantitative risk assessment for profenofos using the reference dose approach 

will adequately account for all chronic toxic effects, including carcinogenicity. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

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

application process. There are currently no registered or proposed residential uses for 

profenofos; therefore, a residential handler assessment was not performed. 

6.2 Post-Application Exposure

There are currently no registered or proposed residential uses for profenofos; therefore a 

residential post-application assessment was not performed. The potential for indirect exposure 

from spray drift has been assessed below in Section 6.4. 
Page 35 of 57

7.0 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010.

9

 The Agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis.

10 During Registration Review, the Agency will utilize this 

analysis to determine if data (i.e., flux studies) or further analyses are required for profenofos.

8.0 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.11 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to <2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of profenofos. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift® (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the recently 

revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs). 

 9 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 10 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219

11 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.
Page 36 of 57

For profenofos, chemical-specific turf transferable residue (TTR) data are not available, 

therefore, the estimated TTR are based on a default assumption from the 2012 Residential SOPs 

that the transferable residue available for exposure is 1% of the total deposited residue, which is 

assumed to be equivalent to the maximum application rate. 

A screening approach was developed based on the use of the AgDrift® model in situations where 

specific label guidance that defines application parameters is not available.12,13 AgDrift® is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift® was developed, a series of screening values (i.e., the Tier 

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Table 6.4.1 provides the screening level drift related risk estimates. In many 

cases, risk estimates are of concern when the screening level estimates for spray drift are used as 

the basis for the analysis. In order to account for this issue and to provide additional risk 

management options, additional spray drift deposition fractions were also considered. These 

drift estimates represent plausible options for pesticide labels.

Combined Risk Estimates from Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Profenofos is registered on 

cotton, and can only be applied via enclosed cab groundboom equipment at a rate of 0.5 lb ai/A. 

The recommended drift scenario screening level options are listed below: 

• Groundboom applications are based on the AgDrift® option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

In addition to the screening level spray drift scenarios described above, additional results are 

provided which represent viable drift reduction technologies (DRTs) that represent potential risk 

management options. In particular, different spray qualities have been considered as well as the 

impact of other application conditions (e.g., boom height and crop canopy conditions).

Dermal risk estimates were calculated for adults. For adults, when an endpoint is not sexspecific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is 

typically used in risk assessment; however, in this case, a female-specific body weight of 69 kg 

was used. While the endpoint of concern, RBC AChE inhibition, is not sex-specific, the femalespecific body weight was used to protect for pregnant women due to uncertainty in the human 

 12 http://www.agdrift.com/ 13 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors should 

be aware and characterize these appropriately.
Page 37 of 57

dose-response relationship for neurodevelopmental effects (see Section 4.4). Dermal and 

incidental oral risk estimates for children (1 to <2 years old) were combined because the toxicity 

endpoint for each route of exposure is the same (RBC AChE inhibition). The total applicable 

LOC is 1000, so MOEs <1000 represent risk estimates of concern. 

Risk estimates related to spray drift are of concern at various distances from the edge of the field 

for adults and children (1 to <2 years) depending on the spray drift scenario. Adult and children 

risk estimates are summarized in Table 8.0.1. For adults, the screening level scenario of a high 

boom and very fine to fine spray requires a distance of over 300 feet to reach a dermal MOE ≥ 

1000. For children, the screening level scenario also requires a distance of over 300 feet to reach

a combined (dermal and incidental oral) MOE ≥1000. Drift reduction technologies, such as 

using coarser sprays and lowering boom height for groundboom sprayers, reduces risk concerns; 

however there are still risk estimates of concern at the field edge. Further, chemical-specific 

TTR data could be submitted to help refine the spray drift assessment.
Page 38 of 57

Table 8.0.1. Spray Drift Risk Estimate Summary for Profenofos.

Crop / 

Application 

Type

Spray Type/ 

Nozzle 

Configuration

Application 

Rate 

(lb ai/A)

Estimated 

TTRt 

(ug/cm2)

MOE at Different Distances from Edge of Field

(Dermal MOE for Adults;

Dermal + Incidental Oral MOE for Children 1 to <2 years)

LOC = 1000

At 

Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 feet 150 feet 200 feet 250 feet 300 feet

Children (1 to <2 years) 

Cotton / 

Groundboom

Screening Level

High Boom Very 

fine to Fine

0.5 0.056

12 25 41 66 92 110 140 160 210 290 330

Low Boom Very 

fine to Fine 27 72 110 180 230 290 330 380 460 570 770

High Boom Fine 

to Medium / 

Coarse

47 120 180 260 330 380 460 460 570 770 770

Low Boom Fine 

to Medium / 

Coarse

70 190 290 380 460 570 770 770 1,100 1,100 1,100

Adults

Cotton / 

Groundboom

Screening Level

High Boom Very 

fine to Fine

0.5 0.056

25 49 82 130 180 230 270 330 420 570 660 

Low Boom Very 

fine to Fine 54 140 230 350 460 570 660 770 920 1,100 1,500 

High Boom Fine 

to 

Medium/Coarse

94 240 350 510 660 770 920 920 1,100 1,500 1,500 

Low Boom Fine 

to 

Medium/Coarse

 140 380 570 770 920 1,100 1,500 1,500 2,300 2,300 2,300 

Bolded values are below the LOC of 1000.
Page 39 of 57

9.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. The registered uses of profenofos are not anticipated to result in residential 

exposure and thus the acute and steady-state dietary exposure estimates provided in Section 5.4.3 

and 5.4.4 represent the acute and steady-state aggregate exposure.

Profenofos is classified as a Group E Chemical based on lack of evidence of carcinogenicity in 

rats and mice. Quantification of risk using a non-linear approach will adequately account for all 

chronic toxicity, including carcinogenicity that could result from exposure to profenofos.

10.0 Cumulative Exposure/Risk Characterization

OPs, like profenofos, share the ability to inhibit AChE through phosphorylation of the serine 

residue on the enzyme leading to accumulation of acetylcholine and ultimately cholinergic 

neurotoxicity. This shared MOA/AOP is the basis for the OP common mechanism grouping per 

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common 

Mechanism of Toxicity (USEPA, 1999). The 2002 and 2006 CRAs used brain AChE inhibition 

in female rats as the source of dose response data for the relative potency factors and PODs for 

each OP, including profenofos. Prior to the completion of Registration Review, OPP will update 

the OP CRA on AChE inhibition to incorporate new toxicity and exposure information available 

since 2006. 

As described in Section 4.4, OPP has retained the FQPA Safety Factor for OPs, including 

profenofos, due to uncertainties associated with neurodevelopmental effects in children and 

exposure to OPs. There is a lack of an established MOA/AOP for the neurodevelopment 

outcomes which precludes the agency from formally establishing a common mechanism group 

per the Guidance For Identifying Pesticide Chemicals and Other Substances that have a 

Common Mechanism of Toxicity (USEPA, 1999) based on that outcome. Moreover, the lack of a 

recognized MOA/AOP and other uncertainties with exposure assessment in the epidemiology 

studies prevent the agency from establishing a causal relationship between OP exposure and 

neurodevelopmental outcomes. The agency will continue to evaluate the epidemiology studies 

associated with neurodevelopmental outcomes and OP exposure prior to the release of the 

revised DRA. During this period, the agency will determine whether or not it is appropriate to 

apply the draft guidance document entitled, Pesticide Cumulative Risk Assessment: Framework 

for Screening Analysis for the neurodevelopment outcomes. 

11.0 Occupational Exposure/Risk Characterization

11.1 Short- and Intermediate-Term Handler Risk

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

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

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

(amount of chemical used in each application), the kinds of equipment used, the target being 
Page 40 of 57

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

manner specific to each application event. 

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

following scenarios which cover all the registered use of profenofos: 

• Mixing/loading liquids using closed loading systems to support groundboom 

applications, and

• Applying sprays with closed cab groundboom equipment.

Occupational Handler Exposure Data and Assumptions

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

handler risk assessments. Assumptions and factors, as well as algorithms used to estimate noncancer exposure and dose for occupational handlers are detailed in the most recent occupational 

and residential exposure (ORE) assessment memo (K. Lowe; 15-SEP-2015; D427268). 

The steady-state approach is appropriate for profenofos given the toxicological and exposure 

profile. The steady-state endpoint selection for profenofos overlaps with HED’s traditional 

short-term exposure duration endpoint selection and is considered health protective for 

occupational handlers that apply commercially over longer periods of time (i.e., intermediateterm exposures).

The registered profenofos label requires a closed mixing/loading system and an enclosed cab. In 

addition, mixer, loaders, applicators, and other handlers using a closed system must also wear 

long sleeved shirt, long pants, shoes plus socks, chemical-resistant gloves, chemical-resistant 

apron (for mixing and loading), and protective eyewear. Estimates of dermal and inhalation 

exposure were calculated assuming the use of engineering controls as required by the label. 

For adults, when an endpoint is not sex-specific (i.e., the endpoints are based on developmental 

or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, 

a female-specific body weight of 69 kg was used. While the endpoint of concern, RBC AChE 

inhibition, is not sex-specific, the female-specific body weight was used to protect for pregnant 

women due to uncertainty in the human dose-response relationship for neurodevelopmental 

effects (see Section 4.4). 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

A total ARI was used since the LOC values for dermal exposure (1000) and inhalation exposure 

(3000) are different. The target ARI is 1; therefore, ARIs of less than 1 are risk estimates of 

concern. The ARI was calculated as follows.

Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE)+ (Inhalation LOC ÷ Inhalation MOE)]

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

The occupational handler exposure and risk estimates indicate that the dermal and inhalation 

combined MOEs are of concern to HED (i.e., ARI <1) for all scenarios. ARIs range from 0.08 to 

0.14 using HED defaults for area treated per day (i.e., 200 acres for high-acreage crops such as

cotton), and from 0.1 to 0.17 using an adjusted area treated per day (160 acres) to account for the 

label restriction on the maximum amount of ai that can be handled per day (10 gallons of product 

or 80 lb ai per day; see Table 3.3.1). Table 11.1.1 provides a summary of the occupational 

handler risk estimates. 
Page 41 of 57

Table 11.1.1. Summary of Occupational Handler Risk Estimates for Profenofos.

Exposure 

Scenario

Crop / 

Target 

Category

App 

Rate2

Area 

Treated3

Engineering Control 

Unit Exposure 

(ug/lb ai)1

Engineering Control 

Dose (mg/kg/day)

Engineering Control 

MOE Engineering 

Control 

ARI8

Dermal Inhalation Dermal4 Inhalation6 

Dermal5

(LOC = 

1000) 

Inhalation7 

(LOC = 

3000)

Mixing / 

loading 

liquids for 

groundboom 

application

Cotton 0.5 lb 

ai/A

200 

acres

8.6 0.083 0.0125 0.00012 80 85,000 0.08

Applying via 

groundboom 5.1 0.043 0.00739 0.0000623 140 160,000 0.14

Mixing / 

loading 

liquids for 

groundboom 

application

160 

acres

8.6 0.083 0.00997 0.0000962 100 110,000 0.1

Applying via 

groundboom 5.1 0.043 0.00591 0.0000499 170 200,000 0.17

Bolded values are below the LOC (dermal = 1000 and inhalation = 3000) or the combined ARI estimate is <1.

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013]); Level of mitigation: Eng. Controls.

2 Based on registered label (Reg. No. 100-669).

3 Exposure Science Advisory Council Policy #9.1 and information provided on labels regarding maximum amount of product that can be 

handled by mixers/loaders per day (10 gallons). More detailed information regarding the acres assessed can be found in the most recent ORE 

memo (K. Lowe; 15-SEP-2015; D427268)

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ 

BW (69 kg).

5 Dermal MOE = Dermal POD (1 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated 

(A/day) ÷ BW (69 kg).

7 Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation PODs (2.90, 5.84, and 10.14 mg/kg/day) related to 

breathing rates (8.3, 16.7, or 29 L/min).

8 ARI = Aggregate Risk Index = 1 ÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].

11.2 Short-/Intermediate-Term Post-Application Risk

11.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 

2, 201014. The Agency has evaluated the SAP report and has developed a Volatilization 

Screening Tool and a subsequent Volatilization Screening Analysis15. During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies) or further 

analysis is required for profenofos.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by ARTF. Given these two efforts, the Agency will continue to identify 

 14 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 15 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219. 
Page 42 of 57

the need for and, subsequently, the way to incorporate occupational post-application inhalation 

exposure into the Agency's risk assessments.

11.2.2 Occupational Post-Application Dermal Exposure/Risk Estimates

Occupational Post-application Dermal Exposure Data and Assumptions

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

post-application risk assessments. Assumptions and factors, as well as the algorithms used to 

estimate non-cancer exposure and dose for occupational post-application workers are detailed in 

the most recent ORE memo (K. Lowe; 15-SEP-2015; D427268). 

The steady-state approach is appropriate for profenofos given the toxicological and exposure 

profile. The “steady-state” endpoint selection for profenofos overlaps with HED’s traditional 

short-term exposure duration endpoint selection as well as being appropriately health protective 

for workers that are exposed over longer periods of time (i.e., intermediate-term exposures).

Chemical-specific DFR and dislodgeable cotton boll data have been submitted for profenofos. 

Three DFR studies were submitted that examined residues of profenofos on cotton foliage in 

various locations: California (MRID 4281303), Texas (MRID 4281303), and North and South 

Carolina (MRID 4281302). One of these studies (MRID 4281302) also examined residues of 

profenofos on cotton bolls collected after treatment. All three studies have been reviewed by 

HED and found to be acceptable for risk assessment. 

A summary of the results of the available studies and a description of how the DFR and cotton 

boll data were used is discussed in the most recent ORE memo (K. Lowe; 15-SEP-2015; 

D427268).

For adults, when an endpoint is not sex-specific (i.e., the endpoints are based on developmental 

or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, 

a female-specific body weight of 69 kg was used. While the endpoint of concern, RBC AChE 

inhibition, is not sex-specific, the female-specific body weight was used to protect for pregnant 

women due to uncertainty in the human dose-response relationship for neurodevelopmental 

effects (see Section 4.4). 

Occupational Post-application Non-Cancer Dermal Risk Estimates

Tables 11.2.2.2 and 11.2.2.3 provide summaries of the exposure and risk estimates for postapplication activities associated with cotton. Even though the profenofos label requires 

mechanical harvesting, there are post-application activities associated with mechanical 

harvesting that can result in potential exposure. These activities have been assessed using the 

available cotton boll residue data.

Based on the current exposure assessment, post-application risk estimates remain a concern (i.e., 

MOEs <1000) up to 4 days after application for hand weeding and up to 9 days after application 

for scouting. Post-application risk estimates associated with harvesting activities are a concern 

(MOEs <1000) 14 days after treatment, which would be the earliest harvesting could occur after 

application based on the current PHI (see Table 3.3.1). An additional calculation was performed 

to estimate post-application exposure and risk using the cotton boll residue data from the day of 

sampling (day 44); however, there were still risk estimates of concern for all harvesting activities 

even 44 days after application at which point residue values were less than the LOQ in the study. 
Page 43 of 57

Table 11.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Profenofos on 

Cotton.

Activities

Transfer 

Coefficient 

(cm2/hr)

Site Days after 

application DFR/TTR1 Dermal Dose

(mg/kg/day)2

MOE3

(LOC = 1000)

Hand weeding 70

CA

0 (12 hours) 1.72 0.0121 83

1 0.45 0.0031 320

2 0.22 0.0015 650

3 0.17 0.0012 830

4 0.13 0.0009 1,100

TX

0 (12 hours) 2.44 0.020 51

1 0.33 0.003 380

2 0.11 0.001 1,200

Cheraw, SC

0 (12 hours) 2.25 0.018 55

1 0.46 0.0037 270

2 0.094 0.00076 1,300

Chesterfield, SC

0 (12 hours) 2.99 0.024 41

1 1.20 0.0098 100

2 0.483 0.0039 260

3 0.194 0.0016 640

4 0.078 0.00063 1,600

NC

0 (12 hours) 2.69 0.022 46

1 0.26 0.0021 480

2 0.02 0.00020 5,000

Scouting 210

CA

0 (12 hours) 1.72 0.0362 28

1 0.45 0.0094 110

2 0.220 0.0046 220

3 0.171 0.0036 280

4 0.133 0.0028 360

5 0.104 0.0022 460

6 0.081 0.0017 590

7 0.063 0.0013 760

8 0.049 0.0010 970

9 0.038 0.0008 1,300

TX

0 (12 hours) 2.44 0.059 17

1 0.33 0.008 130

2 0.11 0.003 390

3 0.08 0.002 510

4 0.06 0.001 670

5 0.05 0.001 880

6 0.04 0.059 1,200

Cheraw, SC

0 (12 hours) 2.25 0.055 18

1 0.46 0.011 89

2 0.094 0.0023 440

3 0.019 0.00047 2,100
Page 44 of 57

Table 11.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Profenofos on 

Cotton.

Activities

Transfer 

Coefficient 

(cm2/hr)

Site Days after 

application DFR/TTR1 Dermal Dose

(mg/kg/day)2

MOE3

(LOC = 1000)

Chesterfield, SC

0 (12 hours) 2.99 0.073 14

1 1.20 0.029 34

2 0.483 0.012 85

3 0.194 0.0047 210

4 0.078 0.0019 530

5 2.99 0.00076 1,300

NC

0 (12 hours) 2.69 0.066 15

1 0.26 0.0063 160

2 0.02 0.00060 1,700

Bolded values are below the LOC of 1000.

1 DFR = Predicted profenofos residues (based on a biphasic regression analysis) adjusted to account for application rate differences. See 

Appendix C for more information on DFR study and regression analysis.

2 Daily Dermal Dose = [DFR (μg/cm2

) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day] ÷ BW (69 kg).

3 MOE = POD (1 mg/kg/day) / Daily Dermal Dose. 

Table 11.2.2.3. Post-Application Exposure and Risk Estimates for Use of Profenofos on Cotton During 

Harvesting Activities.

Crop

Proposed 

Maximum 

Seasonal 

Application Rate

(lb ai/A)

Activity

TC1

(g cotton

/ hr)

Days After 

Treatment

Cotton boll 

residue2

(ug ai/g 

cotton)

Daily Dose 

(mg/kg/day)3

MOE4

(LOC = 

1000)

Cotton 0.5

Harvesting 

Mechanical 

(Module Builder)

900

14

(PHI) 4.54

0.474 2.1

Harvesting 

Mechanical (Picker 

Operator; Raker)

2400 1.264 0.79

Harvesting

Mechanical 

(Tramper)

5050 2.661 0.38

Harvesting 

Mechanical 

(Module Builder)

900

44

(sampling 

day in 

submitted 

study)

0.26

0.027 37

Harvesting 

Mechanical (Picker 

Operator; Raker)

2400 0.072 14

Harvesting 

Mechanical 

(Tramper)

5050 0.152 6.6

Bolded values are below the LOC of 1000.

1. Transfer Coefficients from HED Policy No. 3.0., Non-Foliar Transfer Coefficient Table, March 2012 (p 122). 

2. Residue value from MRID 4281302. On sampling day 44, residues reported as <LOQ (75 ug) and cotton boll sample weighed 

1.44 g; therefore, residues = 0.52 ug/g. Per HED policy, 1⁄2-LOQ value used in calculations (0.26 ug/g). Day 14 (the PHI) 

residues were back-calculated assuming 10% dissipation had occurred per day from day 14 to day 44.

3. Dermal Dose (mg/kg/day) = [Cotton Boll residue, ug ai/g cotton) x TC (g cotton/hr) x hr/day (8 hrs/day)] / BW (69 kg).

4. Dermal MOE = NOAEL (1 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 1000.

Restricted-Entry Interval (REI)

The current product-label REI is 48 hours (72 hours in areas where rainfall is less than 25 inches 

per year). Under 40 CFR 156.208 (c) (2) (i), ai’s classified as Acute toxicity category I for acute 

dermal, eye irritation or primary skin irritation are assigned a 48-hour REI. In addition, for 

organophosphates that may be applied outdoors in an area where the average annual rainfall for 
Page 45 of 57

the site is less than 25 inches per year, the REI shall be 72 hours. However, based on the current 

post-application dermal exposure assessment, a REI of at least 9 days is necessary for scouting, 

and a REI of 4 days is necessary for hand weeding. In addition, activities associated with 

harvesting of cotton are of concern at the current PHI. Increasing the PHI is unlikely to impact 

the risk estimates since MOEs for activities associated with mechanical harvesting using the Day 

44 residue value from the submitted study are still less than the LOC.

12.0 References

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Organophosphate Pesticides and IQ in 7-Year-Old Children. Environ Health Perspectives. 

2011;119:1189-1195.

Bouchard M.F., Bellinger D.C., Wright R.O., Weisskopf M.G., (2010). Attention-Deficit/Hyperactivity

Disorder and Urinary Metabolites of Organophosphate Pesticides. PEDIATRICS

DOI:10.1542/peds.2009- 3058.

Chen L, Zhao T, Pan C, Ross JH, Krieger RI. (2012) Preformed biomarkers including dialkylphosphates 

(DAPs) in produce may confound biomonitoring in pesticide exposure and risk assessment. J 

Agric Food Chem. 2012 Sep 12;60(36):9342-51. doi: 10.1021/jf303116p. Epub 2012 Sep 4.

Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. 

Prenatal Organophosphate Metabolite and Organochlorine Levels and Performance on the 

Brazelton Neonatal Behavioral Assessment Scale in a Multiethnic Pregnancy Cohort. American 

Journal of Epidemiology. 2007;165:1397-1404.

Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, Wolff MS. Prenatal Exposure to 

Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood. Environmental 

Health Perspectives. 2011;119:1182-1188. 

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong CE, Holland NT. 

Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of 

Gestation in an Agricultural Population. Environmental Health Perspectives. 2004;115:792–798.

Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. 

Organophosphate Pesticide Exposure and Neurodevelopment in Young Mexican-American 

Children. Environmental Health Perspectives. 2007;115:792–798.

FIFRA Scientific Advisory Panel. (2012). Transmittal of the Meeting Minutes from the FIFRA Scientific 

Advisory Panel Meeting of April 10-12, 2012. FIFRA Scientific Advisory Panel, Office of 

Science Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances, U.S. 

Environmental Protection Agency. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/meetings/2012/041012meeting.htmll

Fortenberry, GZ, Meeker, JD, Sánchez, BN, Barr, DB, Panuwet, P, Bellinger, D, Schnaas, L, SolanoGonzález, M, Ettingera, AS, Hernandez-Avila, M, Hu, H, Tellez-Rojoj, MM. Urinary 3,5,6-

trichloro-2-pyridinol (TCPY) in pregnant women from Mexico City: Distribution, temporal 

variability, and relationship with child attention and hyperactivity. International Journal of 

Hygiene and Environmental Health 217 (2014): 405–412.

Forsberg ND, Rodriguez-Proteau R, Mab L, Morréc J, Christensen JM, Maierc CS, Jenkins JJ, Anderson

KA. Organophosphorus pesticide degradation product in vitro metabolic stability and timecourse uptake and elimination in rats following oral and intravenous dosing. Xenobiotica, 2011; 

41(5): 422–429. 

Furlong, Melissa A., Engel, Stephanie M., Boyd Barr, Dana, Wolff, Mary S. Prenatal exposure to 

organophosphate pesticides and reciprocal social behavior in childhood. 2014. Environment 

International 70:125-131.

Guodong, Ding, Pei, Wang, Ying, Tian, Jun, Zhang, Yu, Gao, Xiaojin, Wang, Rong, Shi, Guoquan, 

Wang, and Xiaoming, Shen. Organophosphate Pesticide Exposure and Neurodevelopment in 

Young Shanghai Children. Environmental Science and Technology 46:2911-2917, 2012.
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Marks AR, Harley K, Bradman A, Kogut K, Barr DB, Johnson C, et al. Organophosphate Pesticide 

Exposure and Attention in Young Mexican-American Children: The CHAMACOS Study. 

Environmental Health Perspectives. 2010;118:1768-1774.

Oulhote, Youssef and Bouchard, Maryse F. Urinary Metabolites of Organophosphate and Pyrethroid 

Pesticides and Behavioral Problems in Canadian Children. Environmental Health Perspectives. 

121:1378-1384 (2013) 

Racke J.D. Degradation of organophosphorous insecticidesin environmental matrices. In: 

Organophosphates Chemistry, Fate and Effects. Academic Press, Inc., San Diego, CA, 1992, pp 

47–72.

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt 

RW. Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life 

Among Inner-City Children. Pediatrics. 2006;18(6): 1835-1859.

Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. 2011. Seven-Year 

Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural 

Pesticide. Environmental Health Perspectives. 2011;119:1196-1201.

Shelton, Janie F., Geraghty, Estella M., Tancredi, Daniel J., Delwiche, Lora D., Schmidt, Rebecca J., 

Ritz, Beate, Hansen, Robin L., and Hertz-Picciotto, Irva. Neurodevelopmental disorders and 

prenatal residential proximity to agricultural pesticides: The CHARGE Study. Environmental 

Health Perspectives 122:1103–1109, 2014.

U.S. Environmental Protection Agency. (2008). Draft Science Issue Paper: Chlorpyrifos Hazard and 

Dose Response Characterization. 

http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm

U.S. Environmental Protection Agency. (2012). Draft Issue Paper: Scientific Issues Concerning Health 

Effects of Chlorpyrifos. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2012-

0040-0002

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, 

Holland NT. Association Between In Utero Organophosphate Pesticide Exposure and Abnormal 

Reflexes in Neonates. NeuroToxicology. 2005;26:199–209.

Zhang, Ying, Han, Song, Liang, Duohong, Shi, Xinzhu, Wang, Fengzhi, Wei Liu, Zhang, Li, Chen, Lixin, 

Gu, Yingzi, Tian, Ying. Prenatal exposure to organophosphate pesticides and neurobehavioral 

development of neonates: A birth cohort study in Shenyang, China. PlosOne 47:80–85, 2014.

Zhang X, Driver JH, Li Y, Ross JH, Krieger RI. (2008) Dialkylphosphates (DAPs) in fruits and 

vegetables may confound biomonitoring in organophosphorus insecticide exposure and risk 

assessment. J Agric Food Chem. 2008 Nov 26;56(22):10638-45. doi: 10.1021/jf8018084. 

RDI: RAB1 (9/15/15)

cc: M.M. Perron

M.M. Perron: S10955:PY-S:(703)347-0395:7509P:RAB1
Page 47 of 57

Appendix A. Toxicology Profile 

A.1 Toxicology Data Requirements

Study requirements (40 CFR 158.340) for profenofos are presented below. 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

no

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

yes1

yes2

yes1

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5xxx Mutagenicity— Structural Chromosomal Aberrations..

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

yes

yes

yes

yes

yes

yes

yes

yes

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

--

yes 1 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.

2 Subchronic 90-day and 6-month studies are available; therefore, a longer term study is not required.
Page 48 of 57

A.2. Toxicity Profiles

Table A.2.1. Acute Toxicity Profile for Technical Profenofos.

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral (rat) 41714801

LD50 = Males: 492 (363-666) mg/kg

 Females: 809 (600-1090) mg/kg

 Combined: 630 mg/kg

II

870.1100 Acute oral (mouse) 00105226 LD50 = 298 (268-332) mg/kg II

870.1100 Acute oral (rabbit) 00105228 LD50 = 300 mg/kg II

870.1200 Acute dermal (rat) 00105231 LD50 = 1610 (1073-2415) mg/kg II

870.1200 Acute dermal (rabbit) 00109427

LD50 = Intact skin –

 Males: 146.8 mg/kg

 Females: 143.4 mg/kg

 Abraded skin-

 Males: 97.5 mg/kg

 Females: 15.9 mg/kg

I

870.1300 Acute inhalation (rat) 00109428 LC50 = 3.36 mg/L IV

870.2400 Acute eye irritation 

(rabbit) 00109429 Minimal irritation, reversible within 7 days; no corneal opacity III

870.2500 Acute dermal 

irritation (rabbit) 41714802 Moderately irritating at 72 hours III

870.2600 Skin sensitization 

(guinea pig) 00109431 Sensitization was induced -

Note: Studies have not been updated to reflect current HED policy. Endpoint selection was 

driven by BMD modeling of the AChE activity to obtain BMD10 and BMDL10 values. As a 

result, updates to NOAEL/LOAEL values (or NOEL/LOEL values) in these studies would not 

ultimately impact current PODs or risk estimates. Consequently, the Agency did not find it 

necessary to update these studies at this time.

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile - Profenofos.

Guideline No. Study Type MRID No./Doses Results

870.3100

90-Day Oral 

Toxicity in Rodents 

(rat)

00105255

0, 0.2, 2, or 20 mg/kg/day

NOEL = not established.

LOEL 0.2 mg/kg/day based on RBC, plasma and 

brain AChE inhibition.

870.3150

Subchronic Oral 

Toxicity in NonRodent (dog)

90 days

00108016

0, 0.05, 0.5, or 5 

mg/kg/day

Systemic NOEL = 5 mg/kg/day.

Systemic LOEL = not established.

Plasma AChE inhibition NOEL = not established.

Plasma AChE inhibition LOEL = 0.05 mg/kg/day.

RBC AChE inhibition NOEL = 0.05 mg/kg/day.

RBC AChE inhibition LOEL = 0.5 mg/kg/day.

Brain AChE inhibition NOEL = 0.5 mg/kg/day.

Brain AChE inhibition LOEL = 5 mg/kg/day.
Page 49 of 57

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile - Profenofos.

Guideline No. Study Type MRID No./Doses Results

870.3150

Subchronic Oral 

Toxicity in NonRodent (dog)

6 months

00081687

0, 0.005, 0.05, 2.5, or 12.5 

mg/kg/day 

NOEL = 0.005 mg/kg/day.

LOEL = 0.05 mg/kg/day based on AChE inhibition 

in plasma.

870.3200 21-Day Dermal 

Toxicity (rat)

41644501

0, 0.05, 1, or 10 mg/kg/d

Acceptable/guideline

NOEL = 1 mg/kg/day.

LOEL = 10 mg/kg/day based on significant 

decreases in AChE in RBC, serum, and brain.

870.3700a

Prenatal 

Developmental in 

Rodent (rat)

00045031

0, 10, 30, or 60 mg/kg/day

Maternal NOEL = 30 mg/kg/day.

Maternal LOEL = 60 mg/kg/day based on decreased 

food consumption and slightly decreased body 

weights.

Developmental NOEL = 60 mg/kg/day.

Developmental LOEL = not established.

870.3700b

Prenatal 

Developmental in 

Non-Rodent (rabbit)

00128870

0, 30, 60, 90, or 175 

mg/kg/day

Maternal NOEL = 30 mg/kg/day.

Maternal LOEL = 60 mg/kg/day based on decreased 

body weight gain.

Developmental NOEL = 175 mg/kg/day.

Developmental LOEL = not established.

870.3800 Reproduction and 

Fertility Effects (rat)

43213308, 43213309

0, 0.36, 7.3, or 29 

mg/kg/day

Parental NOEL = 7.3 mg/kg/day.

Parental LOEL = 29 mg/kg/day based on decreased 

body weight, body weight gain, and food 

consumption.

Offspring NOEL = 7.3 mg/kg/day.

Offspring LOEL = 29 mg/kg/day based on 

decreased pup body weight and body weight gain.

Reproductive NOEL = 29 mg/kg/day.

Reproductive LOEL = not established.

870.4100a Chronic Toxicity

(rat) See 870.4300 See 870.4300

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity 

(mouse)

00082901

0, 0.15, 4.5 or 15 

mg/kg/day

NOEL = 0.15 mg/kg/day.

LOEL = 4.5 mg/kg/day based on AChE inhibition 

in plasma and RBC.

No evidence of carcinogenicity.

870.4300

Combined Chronic 

Toxicity/

Carcinogenicity (rat)

00081685

0, 0.015, 0.5, or 5 

mg/kg/day

NOEL = 0.015 mg/kg/day.

LOEL = 0.5 mg/kg/day based on AChE inhibition 

in RBC and plasma.

No evidence of carcinogenicity.

870.5100 Bacterial reverse 

mutation 41866901 No increases in revertant colonies were observed in any strain up to 5000 μg/plate.

870.5375 In vitro mammalian

cytogenetics 41945103 No aberrations reported up to cytotoxic levels (37.5 to 75 μg/mL).

870.5385 In vivo bone marrow 

cytogenetics (rat) 41945102 No induction of micronuclei up to a dose causing 

death (200 mg/kg).

870.5550

Unscheduled DNA 

synthesis (UDS) in 

mammalian cells

41945101 No increased grain count up to a dose producing 

50% cytotoxicity (highest dose = 2.91 μg/mL).
Page 50 of 57

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile - Profenofos.

Guideline No. Study Type MRID No./Doses Results

870.6100 Acute Delayed 

Neurotoxicity (hen) 00126485

NOEL = 52 mg/kg.

100% mortality at next highest dose of 104 mg/kg

LD50 = 56.3 mg/kg.

No delayed neurotoxicity.

870.6200a

Acute Neurotoxicity 

Screening Battery 

(rat)

42939801, 42939802

0, 95, 190, or 380 mg/kg

NOEL = not established.

LOEL = 95 mg/kg based on AChE inhibition in 

plasma and RBC.

870.6200b

Subchronic 

Neurotoxicity 

Screening Battery 

(rat)

43213303, 43213304

0, 1.70/1.84, 7.7/8.4, or 

36.0/37.9 mg/kg/day 

(M/F)

Systemic NOEL = 7.7 mg/kg/day.

Systemic LOEL = 36 mg/kg/day based on slight 

decreases in body weight.

Plasma and RBC AChE inhibition NOEL = not 

established.

Plasma and RBC AChE inhibition NOEL = 1.7 

mg/kg/day.

Brain AChE inhibition NOEL = 7.7 mg/kg/day.

Brain AChE inhibition NOEL = 36 mg/kg/day.

870.6300 Developmental 

Neurotoxicity (rat)

46025401, 46025402

0, 0.3, 5.1, or 50.6 

mg/kg/day

Maternal Systemic NOAEL = 5.1 mg/kg/day.

Maternal Systemic LOAEL = 50.6 mg/kg/day based 

on decreases in body weight, body weight gain, and 

food consumption.

Maternal Cholinesterase NOAEL = 0.3 mg/kg/day.

Maternal Cholinesterase LOAEL = 5.1 mg/kg/day 

based on AChE inhibition in RBC and brain.

Offspring Systemic NOAEL = 5.1 mg/kg/day.

Offspring Systemic LOAEL = 50.6 mg/kg/day 

based on decreases in body weight, body weight 

gain, and food consumption.

Offspring Cholinesterase NOAEL = 0.3 mg/kg/day.

Offspring Cholinesterase LOAEL = 5.1 mg/kg/day 

based on AChE inhibition in RBC, plasma, and 

brain.
Page 51 of 57

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile - Profenofos.

Guideline No. Study Type MRID No./Doses Results

870.7485

Metabolism and 

Pharmacokinetics

Rat

42334301

-Single oral dose of 1 or 

100 mg/kg of phenyl-UL- 14C-labeled profenofos

- Pre-exposed to 1 

mg/kg/day oral gavage of 

non-radiolabeled 

profenofos for 14 days 

before a single oral dose 

of 1 mg/kg 14C-profenofos

Recovery of radioactivity ranged from 97%-108% 

of the administered dose for combined fecal and 

urine samples, with >97% of the radioactivity 

excreted in the urine within 48 hours. Less than 

0.2% of the radioactivity was expired as volatiles. 

Insignificant amounts were retained in any tissue 

after 7 days post-exposure. Analysis of fecal 

material indicated that <4% of the parent compound 

or its metabolites are unabsorbed or excreted via the 

biliary system into the intestinal tract. Profenofos 

appears to be metabolized by hydrolysis of its 

thiophosphate ester followed by dephosphorylation 

to form 4-bromo-2-chlorophenol (CGA-55960), 

which undergoes sulfate or glucuronide 

conjugation. Metabolites were identified as 

unconjugated 4-bromo-2-chlorophenol (CGA55960), CGA-47196, and CGA-65867. There were 

no apparent dose or sex-related differences in the 

absorption, distribution, metabolism, or excretion of 

profenofos.

870.7485

Metabolism and 

Pharmacokinetics

Young adult male 

monkeys

46224401

single oral dose via 

capsule at 2.4 mg/animal 

(approximately 0.5 

mg/kg)

The test material was rapidly absorbed with 

significant concentrations measured in the blood 

and plasma by the first blood measurement (30 

minutes post-dose). Tmax was reached by 1 hour 

post-dose and rapidly declined thereafter. The 

terminal phase elimination half-life was estimated 

to be 4 hours in this study. Approximately 68% of 

the administered dose was recovered in the excreta 

(urine, feces, and cage wash after 168 hours) with 

the majority recovered in the urine (49%). 

Excretion was nearly complete by 24 hours 

following treatment. CGA-55163 was identified as 

the major urinary metabolite, which is the 

glucuronide conjugate of the phenol analog (CGA55960).

870.7800 Immunotoxicity

48785801

0, 0.2, 6.4, or 67.6 

mg/kg/day

Systemic NOAEL = 67.6 mg/kg/day.

Systemic LOAEL = not established.

Immunotoxicity NOAEL = 67.6 mg/kg/day.

Immunotoxicity LOAEL = not established.

Special Studies

Acute Comparative 

Cholinesterase 

Study

46025405, 46025406

0, 1, 5, 25, or 100 mg/kg

RBC AChE inhibition NOAEL = 1 mg/kg/day.

RBC AChE inhibition LOAEL = 5 mg/kg/day.

Brain AChE inhibition NOAEL = 5 mg/kg/day.

Brain AChE inhibition LOAEL = 25 mg/kg/day.

Repeated 

Comparative 

Cholinesterase 

Study

46025403, 46025404

0, 0.5, 5, or 50 mg/kg/day

RBC AChE inhibition NOAEL = not established.

RBC AChE inhibition LOAEL = 0.5 mg/kg/day.

Brain AChE inhibition NOAEL = not established.

Brain AChE inhibition LOAEL = 0.5 mg/kg/day.
Page 52 of 57

Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling

OPP’s ChE policy (USEPA, 200016) describes the manner in which ChE data are used in human 

health risk assessment. The following text provides a brief summary of that document to provide 

context to points of departure selected. 

AChE inhibition can be inhibited in the central or peripheral nervous tissue. Measurements of 

AChE or ChE inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung, etc.) are rare. 

As such, experimental laboratory studies generally measure brain (central) and blood (plasma 

and red blood cell, RBC) ChE. Blood measures do not represent the target tissue, per se, but are 

instead used as surrogate measures for peripheral toxicity in studies with laboratory animals or 

for peripheral and/or central toxicity in humans. In addition, RBC measures represent AChE, 

whereas plasma measures are predominately butyryl-ChE (BuChE). Thus, RBC AChE data may 

provide a better representation of the inhibition in target tissues. As part of the dose response 

assessment, evaluations of neurobehavior and clinical signs are performed to consider the dose 

response linkage between AChE inhibition and apical outcomes.

Refinements to OPP’s use of ChE data have come in the implementation of BMD approaches in 

dose response assessment. Beginning with the OP CRA, OPP has increased its use of BMD 

modeling to derive PODs for AChE inhibiting compounds. Most often the decreasing 

exponential empirical model has been used. 

OPP does have not a defined BMR for OPs. However, the 10% level has been used in the 

majority of dose response analyses conducted to date. This 10% level represents a 10% 

reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls). 

Specifically, the BMD10 is the estimated dose where ChE is inhibited by 10% compared to 

background. The BMDL10 is the lower confidence bound on the BMD10. 

The use of the 10% BMR is derived from a combination of statistical and biological 

considerations. A power analysis was conducted by ORD on over 100 brain AChE datasets 

across more than 25 OPs as part of the OP CRA (USEPA, 2002). This analysis demonstrated 

that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In 

addition, the 10% level is generally at or near the limit of sensitivity for discerning a statistically 

significant decrease in ChE activity in the brain compartment and is a response level close to the 

background brain ChE level. With respect to biological considerations, a change in 10% brain 

AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes. 

With respect to RBC AChE inhibition, these data tend to be more variable than brain AChE data. 

OPP begins its BMD analyses using the 10% BMR for RBC AChE inhibition but BMRs up to 

20% could be considered on a case-by-case basis as long as such PODs are protective for brain 

AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.

 16 USEPA (2000) Office of Pesticide Programs, US Environmental Protection Agency, Washington DC 20460. 

August 18, 2000 Office of Pesticide Programs Science Policy of The Use of Data on Cholinesterase Inhibition

for Risk Assessments of Organophosphorous and Carbamate Pesticides.
Page 53 of 57

Appendix C. Summary Tables of Benchmark Dose (BMD) Analyses 

Toxicity studies with AChE data were analyzed using the most recent version of EPA’s 

Benchmark Dose Software (Version 2.4). In Tables C.1-C.3, results have been summarized. 

Full results and technical details for these analyses can be found in the latest BMD analysis 

memo (M. Perron; 15-SEP-2015; TXR# 0057250). 

Table C.1. Summary of BMD Results Following Acute Exposures to Profenofos.1

Study Age Compartment

Males Females

BMD10

(mg/kg/day)

BMDL10

(mg/kg/day)

BMD10

(mg/kg/day)

BMDL10

(mg/kg/day)

Rat Acute 

Comparative 

Cholinesterase 

Assay - Gavage

(MRID 46025406)

D12

RBC NMF NMF 13.68 9.31

Brain 9.57 7.75 10.29 7.16

D22

RBC 7.43 4.60 14.99 12.06

Brain 20.2 14.4 31.12 14.92

D42

RBC 13.49 11.24 3.17 1.99

Brain NMF NMF NMF NMF

Rat Acute NonGuideline Oral 

Study - Gavage 

(MRID 43213302)

Adult RBC 26.1 3.46 8.78 4.45

BMD10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL10 = lower 95% 

confidence interval for BMD10. NMF = no statistical or visual model fit. D = day. 1 The acute neurotoxicity study is not shown. The data were not found to be amenable to BMD modeling because 

rats were dosed too high (95-380 mg/kg) causing extrapolation to much lower doses to obtain BMD10 estimates.

Table C.2. Summary of BMD Results Following Repeated Exposures to Profenofos.

Study Age Compartment

Males Females

BMD10

(mg/kg/day)

BMDL10

(mg/kg/day)

BMD10

(mg/kg/day)

BMDL10

(mg/kg/day)

Rat Studies

Rat Repeat Comparative 

Cholinesterase Assay -

Gavage

(MRID 46025403)

D12 post-partum

RBC 0.69 0.51 0.49 0.24

Brain NMF NMF 6.26 5.81

D42 post-partum

RBC NMF NMF 0.38 0.17

Brain NMF NMF 18.18 7.22

Rat Developmental 

Neurotoxicity Study –

Dietary

(MRID 46025401)

Fetus (GD22)

RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D5 post-partum

RBC NDR NDR NDR NDR

Brain NDR NDR 37.09 16.16

D12 post-partum

RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D22 post-partum

RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

Pregnant Dams 

(GD22)

RBC - - 0.51 0.37

Brain - - 46.31 7.63

Non-pregnant females 

(D22 post-partum)

RBC - - 0.32 0.19

Brain - - 42.57 5.19

Fetus (GD22) RBC NDR NDR 22.38 12.31
Page 54 of 57

Range-Finding Rat 

Developmental 

Neurotoxicity Study –

Dietary

(MRID 46025402)

Brain NDR NDR NDR NDR

D5 post-partum

RBC NDR NDR NDR NDR

Brain NDR NDR NDR NDR

D12 post-partum

RBC NDR NDR 94.6 40.5

Brain NDR NDR NDR NDR

D22 post-partum

RBC 15.51 12.34 NMF NMF

Brain 42.81 20.41 43.65 27.96

Pregnant Dams 

(GD22)

RBC - - 1.78 1.09

Brain - - NDR NDR

Non-pregnant females 

(D22 post-partum)

RBC - - 0.53 0.31

Brain - - 13.7 7.99

Subchronic Oral Rat –

Dietary 

(MRID 00105255)

Adult RBC 0.33 0.29 0.66 0.54

Rat Subchronic 

Neurotoxicity Study –

Dietary

(MRID 43213303)

Adult RBC 0.12a 0.05a 0.23a 0.19a

13 Week Interim 

Measurement in Rat 

Chronic/Carcinogenicity 

Study– Dietary

(MRID 00081685)

Adult RBC 0.14 0.12 0.13 0.12

Terminal Measurement 

in Rat 

Chronic/Carcinogenicity 

Study– Dietary

(MRID 00081685)

Adult RBC 0.17 0.15 0.22 0.18

Dog Studies

Subchronic Oral Dog –

Dietary 

(MRID 00108016

Adult RBC NMFb NMFb NMFb NMFb

Mouse Studies

Mouse Carcinogenicity 

Study – Dietary

(MRID 00081686)

Adult RBC 0.21a 0.08a 0.78a 0.57a

a Poor dose spacing forced extrapolation to a much lower value to obtain BMD10 and BMDL10 values. b Large variability noted at all doses and ground truthing found no AChE inhibition in the raw data for the BMD10

values generated.

BMD10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL10 = lower 95% 

confidence interval for BMD10. NMF = no statistical or visual model fit. NDR = no dose response. D = day.
Page 55 of 57

Table C.3. Summary of BMD Results for Route-Specific Studies.

Study Age Compartment

Males Females

BMD10 BMDL10 BMD10 BMDL10

Rabbit Dermal 

Toxicity Study 

(MRID 41644501)

Adult RBC NMFa NMFa NMFa NMFa

Rat Inhalation 

Toxicity Study 

(MRID 00082079)

Adult RBC NMFb NMFb NMFb NMFb

a Flat dose response with a decrease only at the highest dose tested and relatively large variability noted at all doses.

b Mortality at the highest dose tested left only 2 treatment groups for modeling and poor dose selection forced 

extrapolation to a much lower value from the lowest dose to obtain a BMD10 and BMDL10 values.

BMD10 = benchmark dose where AChE is inhibited by 10% compared to background. BMDL10 = lower 95% 

confidence interval for BMD10. NMF = no statistical or visual model fit. 
Page 56 of 57

Appendix D. Physical/Chemical Properties

Table D.1. Physicochemical Properties of Technical Grade Profenofos.

Parameter Value Reference

Melting Point/Range N/A MRID 42030301, 42854201

pH 3-5

Specific Gravity 1.46 g/cm3 at 20oC

Solvent Solubility (at 25oC) Completely miscible in 

ethanol, acetone, toluene, 

n-octanol, and n-hexane 

Vapor Pressure (20oC) 9.001 x 10-7 mm Hg

Dissociation Constant (pKa) N/A

Octanol/Water Partition Coefficient (Log[KOW]) 4.83
Page 57 of 57

Appendix E. International Residue Limits

Table E.1. Summary of US and International Tolerances and Maximum Residue Limits (MRLs) for 

Profenofos.

Commodity Tolerances or MRLs (ppm)

US Canada Mexico1 Codex2

Residue Definition:

40CFR180.404

profenofos (O-(4-bromo-2-chlorophenyl)-

O-ethyl-S-propyl phosphorothioate)

None Profenofos

Cattle, fat 0.05

Cattle, meat 0.05 0.05 (*) meat (from mammals 

other than marine mammals)

Cattle, meat byproducts 0.05 0.05 (*) edible offal 

(mammalian)

Cotton, gin byproducts 55.0

Cotton, undelinted seed 2.0 3 cotton seed 

Goat, fat 0.05

Goat, meat 0.05 0.05 (*) meat (from mammals 

other than marine mammals)

Goat, meat byproducts 0.05 0.05 (*) edible offal 

(mammalian)

Horse, fat 0.05

Horse, meat 0.05 0.05 (*) meat (from mammals 

other than marine mammals)

Horse, meat byproducts 0.05 0.05 (*) edible offal 

(mammalian)

Milk 0.01 0.01 (*)

Sheep, fat 0.05

Sheep, meat 0.05 0.05 (*) meat (from mammals 

other than marine mammals)

Sheep, meat byproducts 0.05 0.05 (*) edible offal 

(mammalian)

MRLs with NO US Equivalent

Eggs 0.02 (*)

Mango 0.2

Mangostan 10

Peppers, chili 3

20 peppers Chili, dried 

Poultry meat 0.05 (*)

Poultry, edible offal of 0.05 (*)

Spices, fruits, and berries 0.07

Spices, roots and rhizomes 0.05

Teas (tea and herb teas) 0.5

Tomato 10

Completed by: M. Negussie; 04/09/15

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.