### Date :

S u b j ect: UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, 

### D

. C

. 20460

l 5-SE P- 2015 OF F ICE OF C HE M I CA L SA F ETY
A ND P O LL U TION PR EV ENTI O N



### Profenofos. Occupational a n d R es idential Exposu re and Ri s k Assessment for

Re gistrat ion Review.

P C Co d e: 111401 DP Barcode: 0427268 Regi str at i on N umbe r : N I A Reg ul ato r y Act i on: N I A

Case N umber: 2540 Deci s i o n N umb e r: 482022

P e titi o n N u mb e r: NA

R i s k A ssess m e nt T ype: NA

TXR N u m ber: NA C AS Number: 41198-08-7

40CFR: § 180.404 MR ID N umb e r s: NA



### From:

T hr o u g h :

To:

Introd u ct i on Kelly M. Lowe, E n vironmental Sc i e nti st**/? ~~**  Ri sk Assessment Branch I (RAB 1)

, Health Effects Di v i sio n (HED; 7509P) 

# /'J 

# # 

# ll.1 / 

# r

Thu rston Morton

, Acting Branch Chief ( 

# j/J

. rv

HED (7509 P )

and

Matthew Crow l ey, R eviewer

# ~ 

# J---

·- Shalu Shelat

, R ev i ewer 

# '1\f**~ ~hl.-4-** **--** Exposure Science Advisory Co mmitte e (ExpoSAC) I HED

C h ristina Sche l tema
Patricia Parrott

P esticide R e-Evaluation Divi s ion (PRD) (7508 P )

As part of R eg i strat i o n Review

, the Pesticide Re-evaluation Di v i s ion ( PRD ) of OPP has requested that HED eva lu ate the hazard and ex po s ure data and conduct occupatio n al a nd

re s idential exposure as sess ments

, as needed

, to est i mate the risk to human hea lt h that wi ll result

from the current ly regi ste red uses of pe s ticides

. This memorandum serves as H E D 's

Re g i s tration R ev i ew assessment of the occupational and re siden tial hand l er and post-application

exposure and risk from the current l y register e d u ses of profenofo s

.

Page I of35It is HED policy to use the best available data to assess expos ur e. Several sources of generic

data we r e used in this assessment as surrogate data in the absence of chemical-specific data

, including Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1 ); the Agricu l tural

Handler Exposure Task Force (AHETF) database; and the Agr i cultural Reentry Task Force (A R TF) database. Some of these data are proprieta r y, and subject to the data protection provisions of the Federal Insecticide

, Fungicide

, and R odenticide Act (FIFRA).

Note: This m e m orandum was reviewed by the Exposure Science Advisory Committee (ExpoSAC) on 02-APR

- 2015.

Page 2 of35Page 3 of 35 

### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ............. 4
2.0 Risk Assessment Conclusions and Recommendations

................................ ........................ 7
2.1 Summary of Risk Estimates

................................ ................................ ............................. 7
2.2 Label Recommendations

................................ ................................ ................................ .. 7
2.3 Data Deficiencies and Requirements

................................ ................................ ............... 7
3.0 Hazard Characterization

................................ ................................ ................................ ....... 7
4. 0 Exposure and Use Profile

................................ ................................ ................................ ... 11
5.0 Residential Exposure and Risk Estimates

................................ ................................ .......... 12
5.1 Spray Drift

................................ ................................ ................................ ...................... 12
5.2 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 16
6.0 Occupational Exposure and Risk Estimates

................................ ................................ ...... 16
6.1 Occupational Handler Exposure/Risk Estimates

................................ ............................ 16
6.2 Occupational Post

- application Exposure/Risk Estimates

................................ .............. 20
6.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

...................... 20
6.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

.......................... 20 Appendix A. Summa ry of Occupational and Residential Non

- cancer Algorithms

..................... 26 Appendix B. Summary of Available DFR Data for Profenofos

................................ .................. 28Page 4 of 35



### 1.0 Executive Summary

Profenofos

, [O

- (4

- bromo

- 2

- chlorophenyl) O

- ethyl S

- propyl phosphorothioate], is an organophosphate (OP) insecticide

- miticide used for insect and mite control on cotton. This document assesses exposures and risk es timates from the registered use of profenofos required during Registration Review

. There are current ly no registered residential uses . T here is the potential for non

- occupational exposure as a result of spray drift

.

U se and Exposure Profile
There is only one end

- use pro duct 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 pestic ide

. The product label indicates that a closed mixing/loading system and enclosed cab groundboom equipment are required

. T he 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 , dermal and inhalation exposures are anticipated for occupational handlers and post

- application workers. 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, chemical

- resistant apron (for mixing and loading), and protective eyewear. The label recommends a restricted entry interval (REI) of 48 hours (72 hours in areas where rainfall is less than 25 inches per year). A s noted above, t here are currently no registered residential uses ; however, there is the potential for non

- o ccupational exposure (dermal and incidental oral) as a result of spray drift

.

Hazard Profile and Dose Response 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 irrita nt and moderate dermal irritant (Toxicity Category III). It was also found to be a dermal sensitizer.

Profenofos is an OP with a neurotoxic adverse outcome pathway ( AOP ) ; neurotoxicity is the most sensitive effect in all species, routes, and lifestages, and is being used in deriving points of departure ( PODs ) . Profenofos

, as the parent ai

, is an acetylcholinesterase ( AChE ) inhibiting chemical. Profenofos has high quality dose response data across multiple lifestages, durations,
and routes for both red blood cell ( RBC ) and brain AChE inhibition. RBC AChE inhibition was
similar or more sensitive t han the brain AChE inhibition across most studies, durations, lifestages, and routes. For human health risk assessment, studies have been evaluated using benchmark dose ( BMD ) modeling techniques. 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.

The steady

- state dermal POD was selected from a 21

- day dermal toxicity study in rabbits based on RBC AChE inhibition. However, the data w ere not amenable to BMD modeling; thereforePage 5 of 35



### the no observed adverse effect level (NOAEL) of 1 mg/kg/day was selected as the POD for dermal exposures. The lowest observed adverse effect level (LOAEL) was 10 mg/kg/day. The steady

- state inhalation POD was s elected from 21

- day inhalation toxicity study based on RBC AChE inhibition. The data were not amenable to BMD modeling; therefore, the LOAEL of 68 mg/m 3 

### was selected as the POD for inhalation exposures. The NOAEL was not established. For occupational sc enarios, 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/m 3 

### . Fo r estimating occupational inhalation risks from different occupational activities, inhalation doses corresponding to the breathing rates for each activity (8.3, 16.7, or 29 L/min) were calculated using this duration adjusted value ; 2.90, 5.84, and 10.14 mg /kg/day, respectively

.

For residential incidental oral and dermal scenarios, a total uncertainty factor of 1000X was applied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 10X FQPA safety factor due to uncertainty in the huma n dose

- response relationship for neurodevelopmental
effects 1 

### ). For occupational dermal scenarios, a total uncertainty factor of 1000X was applied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 10X database uncertainty factor due to uncertainty in the human dose

- response relationship for neurodevelopmental effects ). For occupational inhalation scenarios, a total uncertainty factor of 3000X was applied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 3 0X database uncertainty factor incorporating uncertainty in the human dose

- response relationship for neurodevelopmental effects and the uncertainty due to lack of a NOAEL in the subchronic inhalation toxicity study ). Resulting occupational dermal and inha lation risk estimates were combined using the aggregated risk index (ARI) approach since the same effects were observed for both routes of exposure ( RBC AChE inhibition ), but the levels of concern (LOCs) are different. Residential post

- application dermal and incidental oral risk estimates were also combined since the same effects were observed for both routes of exposure ( RBC AChE
inhibition ).

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

.

Residential Exposure and Risk
There are currently no registered residential uses of profenofos ; therefore a quantitative residential handler and post

- app lication 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 3 00 feet to reach a dermal MOE ≥ 100 0 . For children, the screening level
scenario also requires a distance of over 3 00 feet to reach a combined (dermal and incidental oral) MOE ≥100 0

. Drift reduction technologies, such as using coarser sprays and lowering boom

1 For more details, see Section 4.4 in the human health risk assessment: Memo, M. Perron et al , 15

- SEP

- 2015, D416010.Page 6 of 35



### 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 . 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

.

O ccupational 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

applica tion 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 pre

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

- application exposure
and risk using the cotton boll residu e 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 c urrent 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 ai ’ s that are
classified as Toxicity Category I for acute dermal, eye irritation

, or primary skin irritation , and for organophosphates in particular . H owever, there were risk estimates of concern related to all
activities associated with cotton at the current label

- prescribed REI.

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 p ut into place, the Agen cy may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for profenofos

.

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 inc lude studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are comp liant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 2



### .

2 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

exposure

- data.htmlPage 7 of 35



### 2.0 Risk Assessment Conclusions and Recommendations

2.1 Summary of Risk Estimates

 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) using closed systems f or mixing/loading and applying . ARIs range from 0.08 to 0.14 using HED defaults for area treated per day, and from 0.1 to 0.17 using an adjusted area treated per day to account for a label restriction on the maximum amount of ai that can be handled per da y.

 Occupational post

- application dermal exposure and risk estimates are a concern for all activities associated with cotton. A REI of 4 days is necessary to reach acceptable MOEs (i.e., MOEs ≥ 1000) for hand weeding and a REI of 9 days is necessary for scouting. Activities associated with harvesting do not reach acceptable MOEs up to 44 days after

treatment.

 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) depend ing 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 30 0 feet to reach a dermal MOE ≥ 100 0 . For children, the screening
level scenario also requires a distance of over 3 00 feet to reach a combined (dermal and incidental oral) MOE ≥100 0

. 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

.

2.2 Label Recommendations

No label recommendations have been identified. A summary of the risk estimates has been provided

, and shows that there are risk estimate s of concern for registered uses of profenofos
based on the lab el

- required personal protective equipment (i.e., engineering controls) and restricted entry intervals (REIs)

.

2.3 Data Deficiencies and Requirements

There are no data deficiencies for profenofos at this time related to non

- dietary exposure.

3 .0 Hazard Characterization

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. Table 3.0.1 provides a summary of the acute toxicity of profen o fos.Page 8 of 35

Table 3.0.1. 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

-



### Profenofos is an OP with a neurotoxic AOP; neurotoxicity is the most sensitive effect in all species, routes, and lifestages, and is being used in deriving PODs. Profenofos

, as the parent active ingredient

, is a n AChE inhibiting chemical. Profenofos has high quality dose response data across multiple lifestages, durations, and routes for both RBC and brain AChE inhibition.
RBC AChE inhibition was similar or more sensitive than the brain AChE inhibition across m ost studies, durations, lifestages, and routes. For human health risk assessment, studies have been evaluated using BMD modeling techniques. 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.

OPs exhibit a phenomenon known as steady state AChE inhibition. After repeated exposure at the same dose, 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 pattern of steady state is reached at or near 10 days of

exposure. In addition to the consistency across durations, the data across multiple repeat dosing
studies in rats are similar. For the purposes of the occupational and residential risk assessment, only the steady

- state d uration is relevant to the exposure scenarios.

Consistent with risk assessments for other AChE

- inhibiting compounds, OPP has used a benchmark response (BMR) level of 10%, and has thus calculated BMD 10 

### and BMDL 10 

### values.
The BMD 10 

### is the estimated dose wh ere AChE is inhibited by 10% compared to background.Page 9 of 35



### The BMDL 10 

### is the lower confidence bound on the BMD 10 

### . As a matter of science policy, the Agency uses the BMDL, not the BMD, for use as the POD (USEPA, 2012 3 

### ).

The steady

- state incidental oral POD ( BMDL 10 

### = 0.12 mg/kg; both sexes) was selected from the rat combined chronic/carcinogenicity study (13 week interim measurement). The corresponding

BMD 10 

### was 0.14 mg/kg and 0.13 mg/kg in males and females, respectively, based on RBC
AChE inhibition.

The steady

- state dermal POD was selected from a 21

- day dermal toxicity study in rabbits based on RBC AChE inhibition. However, the data were not amenable to BMD modeling 4 

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

The steady

- state inhalation POD was selected from 21

- day inhalation toxicity study based on RBC AChE inhibition. The data were not amenable to BMD modeling 5 

### ; therefore, the LOAEL of 68 mg/m 3 

### 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 con centrations could not be estimated for the systemic effe c ts (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/m 3 

### . For estimating occupational inhalation risks from different occupational activities, inhalation doses corresponding to the
bre athing rates for each activity (8.3, 16.7, or 29 L/min) were calculated using this duration adjusted value ; 2.90, 5.84, and 10.14 mg/kg/day, respectively

.

For residential incidental oral and dermal scenarios, a total uncertainty factor of 1000X was appl ied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 10X FQPA safety factor due to uncertainty in the human dose

- response relationship for neurodevelopmental
effects 6 

### ). For occupational dermal scenarios, a total uncertainty facto r of 1000X was applied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 10X database uncertainty factor due to uncertainty in the human dose

- response relationship for neurodevelopmental effects ). For occupational inhalation scena rios, a total uncertainty factor of 3000X was applied ( 10 X for interspecies extrapolation, 10X for intraspecies variation, and a 3 0X database uncertainty factor incorporating uncertainty in the human dose

- response relationship for neurodevelopmental effect s and the uncertainty due to lack of a NOAEL in the subchronic inhalation toxicity study ).

3 USEPA (U.S. Environmental Protection Agency). 2012. Benchmark Dose Technical
Guidance. http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf

4 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.

5 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 BMD 10

. 6 For more details, see Section 4.4 in the human health risk assessment: Memo, M. Perron et al , 15

- SEP

- 2015, D416010.Page 10 of 35



### 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 quan titative cancer risk assessment is not required

.

Table 3.0.2 . Summary of Toxicological Doses and Endpoints for Profenofos for Use in Human Health Risk

Assessments.

Exposure/
Scenario Point of

Departure (POD) Uncertainty

Factors a Level of Concern

(LOC) Study and Toxicological Effects

Incidental Oral Steady State BMDL 10 =

0.12 mg/kg/day UF A = 10X

UF H = 10X FQPA SF =

1 0 X Residential LOC for

MOE = 100 0 Combined chronic oral toxicity/carcinogenicity study (MRID 00081685)

BMD 10 = 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 UF A = 10X

UF H = 10X FQPA SF /

UF DB = 10x Occupational /

Residential LOC for

MOE = 1000 21

- day rabbit dermal toxicity (MRID 41644501)

LOAEL = 10 mg/kg/day

Inhibition of RBC AChE in adult rats.

Inhalation Steady State LOAEL =

68 mg/m 3 /day a UF A = 10X

UF H = 10X

UF DB = 30x Occupational LOC for

MOE = 3 000 21

- day inhalation rat study (MRID 00082079)

LOAEL = 68 mg/m 3 /day

Inhibition of RBC AChE in adult rats. Cancer (oral, dermal, inhalation) Classification: Group E Chemical

– Not likely to be carcinogenic to humans

a. For residential incidental oral and dermal scenarios, 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 of the human health risk assessment, D416010). For occupational dermal scenarios, UF DB = database uncertainty factor for uncertainty in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4 of the human health risk assessment, D416010). For occupational inhalation scenarios, UF DB = database uncertainty factor incorporating uncertainty in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4 of the human health risk assessment, D416010) and the

UF L due to lack of a NOAEL in the subchronic inhalation t oxicity study.
b. 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/m 3

.

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

- effec t level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exp osure. LOC = level of concern. BMD = benchmark dose. BMDL = lower 95% confidence
interval for benchmark dose.



### Absorption : Since the dermal and inhalation POD s were based on route

- specific toxicity studies

, absorption factor s w ere not necessary to es timate exposure.

Body Weight : For adults, when an endpoint is not sex

- specific (i.e., the endpoints are not based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment;Page 11 of 35



### 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

- re sponse relationship f or neurodevelopmental effects 7



### . A body weight of 11 kg was used to assess exposure to children (1 to <2 years old) from spray drift.

4 .0 Exposure and Use Profile

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

.

Based on the registere d use pattern for profenofos, dermal and inhalation exposures are anticipated for occupational handlers and post

- application workers. The Curacron® 8E product label indicates that a closed mixing/loading system and enclosed cab are required. Mixer,
loade rs, 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. The label recommends a REI of 48 hours (72 hours in areas where rainfall is less than 25 inches per year). As noted above, t here are currently no registered
residential uses ; however, there is the potential for non

- occupational exposure (dermal and incidental oral) as a result of spra y drift

.

Table 4.1 . 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 1 st application when pest populations
reach
economic
thresholds Emulsifiable

Concentrate

100

- 669

73%ai 8 lb ai/gal

Curacron® 8E
Insecticide

Miticide 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 receiv e 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

 Pre

- harvest Interval ( PHI ) = 14 days when diluted with water; 30 days when diluted

7 For more details, see Section 4.4 in the human health risk assessment: Memo, M. Perron et al, 15

- SEP

- 2015, D416010.Page 12 of 35

Table 4.1 . 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

with oil.



### 5 .0 Residential Exposure and Risk Estimates

There are no residential uses currently registered for profenofos ; therefore, a quantitative
residential handler and post

- application assessment was not conducted

.

6.0 Non

- Occupational Spray Drift Exposure and Risk Estimates

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 a nd do not deposit in the application area end up off

target 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 re gulatory requirements intended to prevent them. 8 

### 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 res idential 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

expo sure 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 evaluat e 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 deposi ted 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: Con sideration 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 Residen tial Risk Assessment (SOPs)

.

8 This approach is consistent with the requirements of the EPA’s Worker Protection Standar d.Page 13 of 35



### 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 deve loped based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available. 9 

### AgDrift is appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and ground boom 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 m ethodology 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 ri sk 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 ap plied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed). Table 5. 1.1 provides the screening level drift related risk estimates. In many cases, risk estimate s 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 plausib le 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 90 th 

### 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 c onditions (e.g., boom height and crop canopy conditions).

Dermal risk estimates were calcu lated for adults. 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 100 0

, so MOEs <
100 0 repres ent 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

9 http://www.agdrift.com/Page 14 of 35



### risk estimates are sum marized in Table 5.1.1. For adults, the screening level scenario of a high boom and very fine to fine spray requires a distance of over 30 0 feet to reach a dermal MOE ≥

100 0 . For children, the screening level scenario also requires a distance of over 3 00 feet to reach a combined (dermal and incidental oral) MOE ≥100 0

. D rift 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

. C hemical

- specific TTR data could be submitted to help refine the spray drift assessment.Page 15 of 35

Table 6.0 .1. Spray Drift Risk Estimate Summary for Profenofos

.

Crop / Application Type Spray Type/

Nozzle Configuration Application

Rate
(lb ai/A) Estimated

TTRt (ug/cm 2 ) MOE at Different Distances from Edge of Field
(Dermal MOE for Adults;
Dermal + Incidental Oral MOE for Children 1 to <2 years)

LOC = 100 0

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 2,300Page 16 of 35



### 7.0 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk
Estimates

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 Federal Inse cticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and h as developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the Agency will utilize this analysis to determine if data (i.e ., flux studies) or further analysis are required for profenofos

.

8 .0 Occupational Exposure and Risk Estimates

8 .1 Occupational Handler Exposure/Risk Estimates

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 t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios whi ch cover all the registered use of profenofos :

 Mixing/loading liquids using closed loading systems to support groundboom applications, a nd

 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. Each assumption and factor is detailed below on an individual basis.

Application Rate : The application rate used in this assessment is provided in Section 4.0 (Table 4.1)

.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), a nd subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in thePage 17 of 35



### “Occupational Pesticide Handler Unit Exposure Su rrogate Reference Table 10 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 11



### .

Syngenta had previously submitted a biomonitoring study which examined the potential exposure of mixers/loaders and applicators handling profenofos during aerial applications 12



### . This study wa s reviewed by EPA and found to be unacceptable for risk assessment purposes. A summary of the study and the reasons why it was not used in risk assessment is provided in Appendix B.

Area Treated or Amount Handled : The inputs for area treated were based on information in ExpoSAC Policy 9.1 , as well as information provided on the label

. The label indicates that the product is sold in a container containing no more than 10 gallons of the product. In addition, the
label includes a restriction that mixers/loaders are not allowed to handle more than 10 gallons of product per day. Since the product contains 8 lb ai/gal, this equates to a total of 80 lb ai that can be handled per day. Policy 9 .1 recommends 200 acres for high acreage crops like cotton, which with an application rate of 0.5 lb ai/A, equates to 100 lb ai handled per day. Estima tes of exposure using our default Policy 9.1 assumptions have been presented, as well as those assuming only 10 gallons of product are handled per day. The following summarizes the inputs used for estimating handler exposures:

 200 acres for ground applica tion to high acreage crops (from Policy 9.1)

, and

 160 acres for ground application ( based on label restriction of 8 0 lb ai handled per day; 80 lb ai/day ÷ 0.5 lb ai/A = 160 acres)

Exposure Duration: HED typically classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the
pest icide, and the cultural practices surrounding that use site. For the organophosphate pesticides, the match between the toxicological endpoint selection and the exposure duration is different than HED’s approach for conventional chemicals. The endpoint sel ection for organophosphate pesticides involves a “single day” and “steady state” approach based on an
individual chemical’s cholinesterase inhibition. T he steady state approach is appropriate for profenofos given the toxicological and exposure profile. The “steady state” endpoint selection
for profenofos overlaps 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., intermedia te

- term exposures).

For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicator s who may apply a produ ct over a period of weeks ( e.g., completing multiple applications for mult iple clients within a region). The available product label for profenofos indicate s that the product can be applied up to 10 times per season given the maximum single rate and the maximum seasonal rate

.

10 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

11 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

12 “Determination of Exposure during the Mixing, Loading, and Application of Curacron 8E (Profenofos) by Air thro ugh the Use of Biological Monitoring” (MRID 46204902; D363390; 26

- MAR

- 2009)Page 18 of 35



### Mitigation/Personal Protective Equipment: 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 loa ding), and protective

eyewear

. Estimates of dermal and inhalation exposure were calculated assuming the use of engineering controls as required by the label

.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix A.

Combining Ex posures/Risk Estimates
A total ARI was used since the LOC values for dermal exposure (100 0 ) and inhalation exposure ( 3 000 ) 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, and from 0.1 to 0.17 using an adjusted area treated per day to account for a label restriction on t he maximum amount of ai that can be handled per day. Table 8 .1.1 provides a summary of the occupational handler risk estimates.Page 19 of 35

Table 8 .1.1. Summary of Occupational Handler Risk Estimates for Profenofos.

Exposure
Scenario Crop /

Target Category App

Rate 2 Area

Treated 3 Engineering Control Unit

Exposure (ug/lb ai ) 1 Engineering Control Dose (mg/kg/day) Engineering Control MOE Engineering
Control ARI 8

Dermal Inhalation Dermal 4 Inhalation 6 Dermal 5 (LOC = 100 0 ) Inhalation 7

(LOC = 3 000) Mixing / loading liquids for groundboom application

Cotton 0.5 lb
ai/A 200 acres 8.6 0.083 0.0125 0.0001 2 80 85 ,000 0.0 8

Applying via groundboom 5.1 0.043 0.00 739 0.0000 623 1 4 0 1 6 0,000 0.1 4

Mixing / loading liquids for groundboom application 160 acres 8.6 0.083 0.00 997 0.0000 962 1 0 0 1 1 0,000 0.1

Applying via groundboom 5.1 0.043 0.005 9 1 0.00004 99 170 20 0,000 0.17

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 gall ons)

. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treate d (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 ) rela ted 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)].Page 20 of 35



### 8

. 2 Occupational Post

- application Exposure/ Risk Estimates

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend o n such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

8

. 2 .1 Occupational P ost

- 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 volatilizat ion 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 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Ad visory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a su bsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this a nalysis 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 the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

8

. 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. Each assumption and factor is detailed below on an individual
basis.

Exposure Duration: The endpoint selection for organophosphate pesticides involves a “single day” and “steady state” approach based on an individual chemical’s cholinesterase inhibition.

T he steady state approach is appropri ate for profenofos given the toxicological and exposure profile. The “steady state” endpoint selection for profenofos overlaps HED’s traditional short

term exposure duration endpoint selection as well as being appropriately health protective for
workers th at are exposed over longer periods of time (i.e., intermediate

- term exposures).Page 21 of 35



### Transfer Coefficients : It is the policy of HED to use the best available data to assess post

application exposure. Sources of generic post

- application data, used as surrogate data in the
absence of chemical

- specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment,
known as “transfer coefficien ts”, are presented in the ExpoSAC Policy 3 13 

### ” which, along with additional information about the ARTF data, can be found at the Agency website 14



### .

It is noted that the Registrant had previously submitted a worker reentry exposure study from
which chemical

- specific transfer coefficients were calculated. This study was reviewed and found acceptable for risk assessment 15 

### . However, this study has not been used as an independent
chemical

- specific study since it has been incorporated into EPA’s Science Advisory Council for Exposure (ExpoSAC) Policy 3 ( http://www.epa.gov/pesticides/science/exposac

- policy

- 3

- march2013.pdf

). The recommended transfer coefficients from this policy ar e recommended for use in the profenofos risk assessment , and these are provided in Table 8 .2.2.1 below

.

Table 8 .2.2.1. Anticipated Post

- Application Activities and Dermal Transfer Coefficients.

Crop Policy Crop

Group Category Crop

Height Foliage

Density Transfer Coefficients Activities

Cotton Field / row crop,

low / medium Low Min/Full 70 cm 2 /hr Hand weeding

210 cm 2 /hr Scouting

High Min 900 gm cotton boll/hr Mechanical Harvesting (Module Builder Operator)

2400 gm cotton boll/hr Mechanical Harvesting (Picker Operator and Raker)

5050 gm cotton boll/hr Mechanical Harvesting (Tramper)



### Application Rate: The application rate used in this assessment is provided in Section 4.0 (Table 4.1)

.

Exposure Time : The average occupational workday is assumed to be 8 hours.

Chemical

- specific Residue Data :

DFR: Chemical

- specific DFR data have been submitted for profenofos

. Three 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 428130 2 ). All three st udies have been reviewed by HED and found to be acceptable for risk assessment. All of t he cotton foliage data represent DFR lev els obtained at an application rate of 1.0 lb ai/ A . The DFR residues (μg/cm 2 

### ) were adjusted

13 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

14 Available: http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

15 “ Worker Reentry Exposure to Profenofos in Cotton Treated with Curacron® 8E” ( D429108 ; MRID 4281302; 15

- SEP

- 2015).Page 22 of 35



### to account for the difference in application rate for the registered crop (cotton @ 0.5 lb ai/A)

. For more information on the study and results, see Appendix B.

Cotton bolls: One of the studies (MRID 428130 2 ) also collected dislodgeable residue data on cotton
bolls. Cotton boll samples were collected at 44

– 70 days after treatment ( DAT ), and
were less the level of quantification ( LOQ

, 0.75 ug). Each sample co nsisted of 5 cotton bolls, and weigh ed a total of 1.44 g per sample , resulting in a residue value of 0.52 ug/g at the LOQ . One

- half the LOQ was used in calculating dislodgeable residue, which resulted in a residue value of 0.26 ug/g on Day 44 after applic ation.

Since profenofos has a pre

- harvest interval ( PHI ) of 14 days, it would be possible for harvesting activities to occur on DAT 14; therefore, a back

- calculation was performed to estimate a residue value on Day 14 (assuming there had been 10% dissip ation per day
which i s HED’s default dissipation assumption for post

- application assessments ) . This
calculated value (4.54 ug ai/g cotton) was use d in calculating post

- application exposure resulting from application of profenofos to cotton during harvesting activities (e.g., module builder, picker operator, raker, tramper)

.

Occupational Post

- application Non

- Cancer Dermal Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for occupational post

- applica tion workers can be found in Appendix A

.

Occupational Post

- application Non

- Cancer Dermal Risk Estimates
Tables 8 .2.2.2 and 8 .2.2.3 provide summaries of the exposure and risk estimates for post

application activities associated with cotton. Even though the profenofos label requires mechanically 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 resid ue data.

Based on the current exposure assessment, post

- application risk estimates remain a concern (i.e.,
MOEs < 100 0 ) up to 4 days after application for hand weeding and up to 9 days after application for scouting. Post

- application risk estimates ass ociated 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 estima te 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

.

Table 8 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Profenofos on Cotton.

Activities Transfer

Coefficient (cm 2 /hr) Site Days after application DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(LOC = 100 0 )

Hand weeding 70 CA 0 (12 hours) 1.72 0.0121 83

1 0.45 0.0031 320Page 23 of 35

Table 8 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Profenofos on Cotton.

Activities Transfer

Coefficient (cm 2 /hr) Site Days after application DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(LOC = 100 0 )

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

Chesterfield, SC 0 (12 hours) 2.99 0.073 14Page 24 of 35

Table 8 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Profenofos on Cotton.

Activities Transfer

Coefficient (cm 2 /hr) Site Days after application DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(LOC = 100 0 )

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

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/cm 2 ) × Transfer Coeffici ent × 0.001 mg/μg × 8 hrs/day ]  BW ( 69 kg).
3 MOE = POD ( 1 mg/kg/day) / Daily Dermal Dose.

Table 8 .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 TC 1 (g cotton/hr) Days After

Treatment Cotton boll

residue 2 ( ug ai/g cotton) Daily Dose

(mg/kg/d ay ) 3 MOE 4

(LOC = 1000)

Cotton 0.5 Harvesting
Mechanical (Module Builder) 900

14 (pre

- harvest interval) 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) 0.26 0.0 27 37

Harvesting
Mechanical (Picker Operator; Raker) 2400 0.0 72 14

Harvesting
Mechanical (Tramper) 5050 0.1 52 6 .6

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, r esidues 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 pre

- harvest interval) residu es were back

- calculated assuming 10% dissipat ion 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)Page 25 of 35



### 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 fo r acute dermal, eye irritation or primary skin i rritation are assigned a 48

- hour REI. In addition, for organophosphates that may be applied outdoors in an area where the average annual rainfall for the site is less than 25 inches per year, the REI shall be 72 hours. However, b ased on the current
post

- applica tion 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 L OC.Page 26 of 35



### Appendix A. Summary of Occupational and Residential Non

- cancer Algorithms

OCCUPATIONAL NON



### - CANCER HANDLER ALGOR ITHMS



### Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

where:

E = exposure (mg ai/day),

UE = unit exposure (μg ai/lb ai),

AR = maximum application rate according to proposed label (lb ai A or lb ai/gal), and

A = area treated or amount handled (e.g., A/day, gal/day).

The daily doses are calculated using the following formula:

ADD= E * AF

BW

where:

ADD = average da ily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (dermal and/or inhalation), and

BW = body weight (kg).

Margin of Exposure: Non

- cancer risk estimates for each application handler scenario are
calcul ated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD to assess the risk to occupation al handlers for each exposure route. All MOE values are calculated using the following formula:

MOE= POD

ADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),
POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).Page 27 of 35

OCCUPATIONAL NON



### - CANCER POST



### - APPLICATION ALGORITH MS



### Potential daily exposures for occupational post

- application workers are calculated using the following formulas

. DFR from chemical

- specific studies were used in the post

- application
calculations.

P ost

- application exposure was calculated using the following formula:

E=TC * DFR t 

### * ET * 0.001 mg

ug

where:

E = exposure (mg ai/day),
TC = transfer coefficient (cm 2 

### /hr ),

DFR t 

### = dislodgeable foliar residue on day “t” (μg/cm 2 

### ), and

ET = exposure time (hours/day).

The daily doses are calculated using the following formula:

ADD= E * AF

BW

where:

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (dermal and/or inhalation), and

BW = body weight (kg).

Margin of Exposure: Non

- cancer risk estimates for each scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal dose received by occupational post

- application workers is compared to the appropriate POD to assess the risk to occupational post

- application workers. All MOE values are calculated using the following formula:

MOE= POD

ADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),
POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).Page 28 of 35



### Appendix B. Summary of Biomonitoring Study Available for Profenofos

Syngenta submitted a biomonitoring study ( Determination of Exposure during the Mixing, Loading, and Application of Curacron 8E (Profenofos) by Air through the Use of Biological Monitoring (MRID 46204902 ) which examined the potential profenofos exposure to mixers/loaders and applicators handling the pesticide product Curacron 8E. Thi s study was initially reviewed by HED in February of 2007 and HED requested additional information
related to several questions identified during the review (D301892). In a 2008 document, HED commented on the responses received by Syngenta, and noted issu es that were still unresolved (D349260). In 2009, HED provided a final review of the biomonitoring study, noting the unresolved issues and reasons for finding the study unacceptable for use in risk assessment (D363390). A summary of the study, as well as the conclusions reached by HED

, is provided
below.

The b iomonitoring study was designed to examine the absorbed dose of handlers using a closed mixing/loading system and aerial application (enclosed cockpit fixed

- wing aircraft) of profenofos. Sixteen mixing/loading replicates and sixteen applicator replicates were monitored in Texas, Mississippi, and Louisiana. The test substance was packaged in 2.5 gallon jugs that were specially designed to work with the Securalink

- G closed transfer handling system. T he pilots treated approximately 400 to 480 acres of cotton at an application rate of 1 lb ai/A, which involved the mixer/loaders handling between 50 and 60 gallons of test product (2 spray cycles).

Twelve

- hour composite urine samples were collected fro m each handler starting from 24

- hours prior to the time of monitoring through 72 hours after application. In the analysis phase of the study, profenofos and all urinary metabolites were converted to 4

- bromo

- 2

- chlorophenol (4,2

- BCP) for quantitation. Acco rding to the study author, the predominate form of metabolized profenofos in urine is the glucoronic acid conjugate of 4,2

- BCP (CGA

- 55163). The study author

converted the 4,2

- BCP residues detected in the samples to proposed profenofos equivalent

absorbed doses.

The concerns that HED had regarding the study include d the following:

1) A c oncern was identified over different closed systems used between the study and those currently used. The test product was packaged in 2.5 gallon containers with a permanentl y installed special valve mounted in the container opening. The special adaptor caps were designed for a closed transfer handling system called Securalink

- G. The study author states that since this study was conducted, Syngenta has discontinued selling t he 2.5 gallon containers and only sells Curacron in 15

- gallon mini

- bulk
containers with the Micro MaticTM closed mixing/loading system . Syngenta has not
submitted data indicating how exposures resulting from the use of a Micro MaticTM packaging system relat e to exposures resulting from the use of the Secur a Link

- G packaging . Therefore, there are no data indicating that exposure data from the
Secur a Link

- G biomonitoring study would be appropriate as surrogate data for exposures resulting from the use of a Micr o MaticTM packaging system.Page 29 of 35



### 2) There was concern over whether 72 hours was sufficiently long enough to recover urinary metabolites given the high percentages of profenofos spikes in urine in the 36

- to
72

- hour collection periods, and the relatively significan t levels of profenofos equivalents recovered up to and including the 60

- to 72

- hour collection period. In 12 out of 14 (86%) of the mixer/loader replicates and in 10 out of 14 (71%) of the applicator replicates, urine samples indicate an increase in profe nofos during the second 36 hours of collection.

3) The monkey pharmacokinetic study involved 5 monkeys and included concerns about incomplete urine collection in the first collection period. The study was classified as acceptable/nonguideline by EPA. HED is concerned that the pharmacokinetic study may

not have a dequately measured the profenofos metabolites excreted in monkey urine a nd questions using that study as the pharmacokinetic basis for the human biomonitoring study.

4) HED raised a question regarding the adjustment factor for absorbed profenofos. HED
noted that i t was necessary to use an adjustment factor in the absorbed dos e calculation to estimate the amount of profenofos and all metabolites that are eliminated in urine in the
first 72

- hours following a single oral dose (from the monkey pharmacokinetic study )

.

5) HED questioned whether an additional adjustment factor was necessary to estimate absorbed profenofos from the measured absorbed metabolite. Since the pharmacokinetic study reports that an average of 74% of the metabolites excreted in urine was CGA

55163, H ED believes that profenofos equivalents should be adjusted to reflect that only 74% of the profenofos equivalents are CGA

- 55163.

6) HED questioned whether an additional adjustment factor was necessary to account for the percent of one of the metabolites that was not converted to 4,2

- BCP and not detected as potential exposure to profenofos. In the pharmacokinetic study, 12.7% of CGA

- 55163 was not converted to 4,2

- BCP. Therefore, it is of potential concern that not all of the
CGA

- 55163 was detected and quantif ied in the biomonitoring study

. However, as laboratory and field fortification samples were prepared in the biological monitoring study it can be assumed that corrections for these recoveries will account for the
conversion of CGA

- 55163 to 4,2

- BCP. Beca use the field fortification samples in this study were not run concurrently with the actual sample analysis (they were analyzed approximately one year after the study was completed), the laboratory fortification
recoveries were assessed

. Average laborator y recoveries were greater than 90% in the biomonitoring study; therefore, an additional correction for laboratory recovery was not
used.

7) HED ha d concerns over the representativeness of 400

- 480 acres treated for handler s per day for cotton, and whether han dling such relatively small quantities of profenofos for relatively short periods of time can be accurately extrapolated to reflect potential exposure for a full 8

- hour workday.

8) HED had concerns about whether the study represented a full day of work for t hePage 30 of 35



### handlers. During the study, the mixer/loaders handled profenofos an average of only 1 hour and 17 minutes and the pilots applied profenofos an average of only 1 hour and 29
minutes.

9) HED had concerns that the field recovery samples were conducted 1 ye ar after the conduct of the study and cannot adequately fulfill the intent of field recovery sampling.

10) Profenofos residues were detected in pre

- exposure samples in approximately one

– half of handlers (15 of the 32 handlers). Each handler claimed not to hav e used or handled Curacron for the week prior to the study. It is possible that the handlers received exposure to the chemical but did not report it.Page 31 of 35



### Appendix C. Summary of Available DFR Data for Profenofos

“Dissipation of Dislodgeable Foliar Residues of Profenofos (Curacron ® 8E) Applied to Cotton in
California” MRID 42851303

This study was designed to determine the dissipation of dislodgeable foliar residues (DFRs) of the active ingredient (ai) profenofos from treated cotton foliage. The t est product was a 73% ai emulsifiable concentrate (EC) formulation. One test site was examined in Madera, CA (NAFTA Region 10) during the 1991 growing season. Geographical and climatic conditions were relevant to the use pattern proposed. The trial site consisted of one control plot and one treatment plot, with the treatment plot receiving six foliar broadcast spray applications of the test substance via tractor

- mounted groundboom sprayers at a nominal rate of 1.0 lb ai/A/application. Applications were made using a spray volume of approximately 30 gallons per acre, at retreatment intervals of 5

- 6 days.

Single control plot and triplicate treated plot DFR samples were collected using a Birkestrand leaf punch sampler prior to and after the first, third, and sixth (last) application, and at the following intervals after the last application: 1, 2, 3, 7, 14, 21, 28, and 35 days. EPA calculated DFRs in μg/cm2, correcting for
field fortification recoveries and a leaf surface area of 400 cm2.

The highest average DFR was 1.66 μg/cm2, which occurred immediately after the first application (14.8% of application rate). The average DFR immediately prior to the last (sixth) application was 0.120 μg/cm2. The maximum average DFR after the last application occurred at the first sampling interval (after spray dried) with a value of 1.38 μg/cm2 (12.3% of application rat e). DFRs declined rapidly in the first three days to 0.162 μg/cm2 (1.4% of application rate) at 3DAT6, and reached equilibrium at 21DAT6 with a value of 0.010 μg/cm2 (0.09% of application rate). DFRs on 28DAT6 and 35DAT6 were 0.011 and 0.0081 μg/cm2, resp ectively.

The Registrant assumed first

- order dissipation kinetics to generate dissipation curves for profenofos. The Registrant conducted linear regression analyses using the natural logarithm of average DFR values from the following sampling intervals : 1) 0DAT6 through 35DAT6 (all sampling intervals after the last application), 2) 0DAT6 though 21DAT6 (sampling intervals through the point of equilibrium), 3) 0DAT6 through 3DAT6 (first part of bi

- phasic pattern), and 4) 3DAT6 through 35DAT6 (second part of bi

- phasic pattern). The Registrant’s calculated half

- lives for these intervals, respectively, were 5.4 days (R 2 = 0.816), 3.4 days (R 2 = 0.881), 1.0 days (R 2 = 0.942), and 7.9 days (R 2 = 0.848). Additionally, the Registrant generated a decline curve fi t using an equation representing the data specifically (y=a+bexp

- x), as determined by Table Curve Fitting Software. The half

- life calculated was 0.7 days (R 2 = 0.993).

EPA first assumed first

- order dissipation kinetics and conducted a linear regression analysis using the corrected average DFRs from immediately after the last application (0DAT6) through the last sampling interval (35DAT6), and determined a half

- life of 5.4 days (R2 = 0.8212). However, the regression analysis did not appear visually to be a good fit for the data, and a comparison of the 0DAT6 actual and predicted DFRs show that the actual DFR (1.38 μg/cm 2 ) is ~4x higher than the linear regression predicted DFR (0.3357 μg/cm 2 ). Therefore, EPA did additional analysis and conducted a biphasi c regression analysis using Excel’s Solver, and the corrected average DFRs from immediately after the last application through the last sampling interval. This regression analysis appears (visually) to be a better fit of the data, and provides a predicted Day 0 value of 1.74 μg/cm 2

.

No major issues were identified during review of this study and the results are considered acceptable for risk assessment purposes. There were some issues noted regarding the field fortification recoveryPage 32 of 35

samples: (1) only on e field fortification level was used in the study, and the EPA guideline recommends a minimum of two field fortification levels; (2) the level chosen was below most of the field samples (10 ug/sample for the field fortification samples vs a maximum of 648 ug/sample for the field samples); and (3) several recoveries were outside the guideline range of 70

- 120%. However, the study report did provide additional information with respect to laboratory recovery samples, which included concentrations up to 1000 ug /sample, with recoveries ranging from 88

– 121%; therefore, it is unlikely that the field fortification issues would impact the utility of the study for risk assessment.

Summary of DFR Values and EPA Regression Analysis Results for Treated Cotton with Profenofos (MRID# 42851303).

Cotton; Site: Madera, CA

Study Target Rate (lb ai/A) 1.00 lb ai/A

Spray Volume (GPA) 30

Measured Average Day 0 Residue (μg/cm 2 ) 0DAT6: 1.38

Linear Regression Predicted Day 0 Residue (μg/cm 2 ) 0DAT6: 0.336

Slope

- 0.129

Half

- life (days) 5.4

R 2 0.8212

Biphasic Regression Predicted Day 0 Residue (ug/cm 2 ) 0DAT6: 1.74

Slope

- 1.345,

- 0.251

Inflection Point (day) 1

“Dissipation of Dislodgeable Foliar Residues of Profenofos (Curacron® 8E) Applied to Cotton in
Texas” MRID 42851304

This study was designed to determine the dissipation of dislodgeable foliar residues (DFRs) of the active ingredient (ai) profenofos from treated cotton foliage. The test product was a 73% ai emulsifiable concentrate (EC) formulation. One test site was examined in Snook, Texas (NAFTA Region 6) during the 1991 growing season. Geographical and climatic conditions were relevant to the use pattern proposed. The trial site consisted of one control plot and one treatment plot, with the treatment plot receiving six foliar broadcast spray applications of the test substance via tractor

- mounted groundboom sprayers at a nominal rate of 1.0 lb ai/A/application. Applications were made using a spra y volume
between 19.4

- 21.5 gallons per acre, at retreatment intervals of 5

- 7 days.

Single control plot and triplicate treated plot DFR samples were collected using a Birkestrand leaf punch sampler prior to and after the first, third, and sixth (last) application, and at the following intervals after the last application: 1, 2, 3, 7, 14, 21, 28, and 35 days. EPA calculated DFRs in μg/cm2 using the same field fortification correction factor, and used a leaf surface area of 400 cm2.

The highest average DFR was 2.11 μg/cm2, which occurred immediately after the first application (20.4% of a pplication rate). The average DFR immediately prior to the last (sixth) application was 0.054 μg/cm2. The maximum average DFR after the last application occurred at the first sampling interval (after spray dried) with a value of 1.74 μg/cm2 (16.0% of appl ication rate). DFRs declined rapidly in the first three days to 0.076 μg/cm2 (0.7% of application rate) at 3DAT6, and reached equilibrium atPage 33 of 35

21DAT6 with a value of 0.0086 μg/cm2 (0.08% of application rate). DFRs on 28DAT6 and 35DAT6
were 0.0066 and 0.0086 μg/cm2, respectively.

The Registrant assumed first

- order dissipation kinetics to generate dissipation curves for profenofos. The Registrant conducted linear regression analyses using the natural logarithm of average DFR values from the following sampl ing intervals: 1) 0DAT6 through 35DAT6 (all sampling intervals after the last application), 2) 0DAT6 though 21DAT6 (sampling intervals through the point of equilibrium), 3) 0DAT6 through 3DAT6 (first part of bi

- phasic pattern), and 4) 3DAT6 through 35DAT6 (second part of bi

- phasic pattern). The Registrant’s calculated half

- lives for these intervals, respectively, were 5.7 days (R 2 = 0.659), 3.4 days (R 2 = 0.723), 16 hours (R 2 = 0.924), and 10.8 days (R 2 = 0.731).

EPA first assumed first

- order dissipation kinetics and conducted a linear regression analysis using the corrected average DFRs from immediately after the last application (0DAT6) through the last sampling interval (35DAT6), and determined a half

- life of 5.7 days (R2 = 0.6694). However , the regression analysis did not appear visually to be a good fit for the data, and a comparison of the 0DAT6 actual and predicted DFRs show that the actual DFR (1.74 μg/cm 2 ) is ~4x higher than the linear regression predicted DFR (0.2005 μg/cm 2 ). Therefo re, EPA did additional analysis and conducted a biphasic regression analysis using Excel’s Solver, and the corrected average DFRs from immediately after the last application through the last sampling interval. This regression analysis appears (visually) t o be a better fit of the data, and provides a predicted Day 0 value of 2.4 μg/cm 2

.

There were some issues noted regarding the field fortification recovery samples: (1) only one field fortification level as used in the study, and the EPA guideline recomme nds a minimum of two field fortification levels; (2) the level chosen was below most of the field samples (10 ug/sample for the field fortification samples vs a maximum of 648 ug/sample for the field samples); and (3) several recoveries were outside the gu ideline range of 70

- 120%. However, the study report did provide additional information with respect to laboratory recovery samples, which included concentrations up to 1000 ug/sample, with recoveries ranging from 88

– 121%.

Summary of DFR Values and EPA Regression Analysis Results for Treated Cotton with Profenofos (MRID# 42851303).
Cotton; Site: Snook, TX

Study Target Rate (lb ai/A) 1.00 lb ai/A

Spray Volume (GPA) 19.4

- 21.5

Measured Average Day 0 Residue (μg/cm 2 ) 0DAT6: 1.74

Linear Regression Predicted Day 0 Residue (μg/cm 2 ) 0DAT6: 0.2005

Slope

- 0.121

Half

- life (days) 5.7

R 2 0.6694

Biphasic Regression Predicted Day 0 Residue (ug/cm 2 ) 0DAT6: 2.4

Slope

- 2.015,

- 0.272

Inflection Point (day) 1Page 34 of 35

“ Worker Reentry Exposure to Profenofos in Cotton Treated with Curacron® 8E” MRID 42851302

The study was conducted during the 1992 growing season at three test sites located in NAFTA Region 2. Test sites 1, 2, and 3 were located in Cheraw, SC, McFarlan, NC, and Chesterfield, SC, respectively. The sites were approximately 2 to 8 miles from each other. Geographical and climatic conditions were relevant to the use pattern proposed. The trial sites consisted of one control plot and o ne treatment plot, with the treatment plot receiving s ix foliar broadcast applications of profenofos, formulated as an emulsifiable concentrate (EC) containing 73% of the active ingredient (ai) profenofos. Applications were
made to cotton via tractor

- moun ted groundboom sprayers at a target rate of 1 lb ai/A/application. The applications were made at 5

- 8 day re

- treatment intervals using a spray volume of 15

- 17 gallons of water per acre ( GPA).

Duplicate control plot and treated plot DFR samples were collec ted using a Birkestrand leaf punch sampler prior to and after the first application, after the second application, prior to and after the third application, after the fourth and fifth applications, prior to and after the sixth (last) application, and at th e following intervals after the last application: 1, 2, 3, 7, 14, 21, 28 and 35 days.

EPA calculated DFRs in μg/cm 2 (based on a 250 cm 2 leaf surface area) with correction for the average low and high field fortification recoveries of each site separately

. In general, DFRs at all sites declined rapidly within the first week after the last application, and then remained at low levels through the end of the sampling period. Residues did not decline to <LOQ ( 0.003 μg/cm 2 ) by 35DAT6.

The average DFR (and percent of application rate) at the Cheraw, SC, site was the highest at the 0DAT5 interval (2.83 μg/cm 2 ; 26.5%). After the last application, the average DFR was a maximum of 1.74 μg/cm 2 (16.3%) at 0DAT6, declined to 0.40 μg/cm 2 (3.8%) at 1DAT6, and continued to decline to 0.0047 μg/cm 2 (0.04%) at 35DAT6.

The average DFR (and percent of application rate) at the McFarland, NC, site was the highest at the 0DAT2 interval (3.99 μg/cm 2 ; 29.7%). After the last application, the average DFR was a maximum of 1.82 μg/cm 2 (17.1%) at 0DAT6, declined to 0.251 μg/cm 2 (2.4%) at 1DAT6, and continued to decline to 0.0046 μg/cm 2 (0.04%) at 35DAT6.

The average DFR (and percent of application rate) at the Chesterfield, SC, site was the highest a t the 0DAT5 interval (5.19 μg/cm 2 ; 44.5%). After the last application, the average DFR was a maximum of 2.48 μg/cm 2 (23.3%) at 0DAT6, declined to 1.54 μg/cm 2 (14.4%) at 1DAT6, and continued to decline to 0.0056 μg/cm 2 (0.05%) at 35DAT6. Actual DFRs on 0 DAT6 were 7 to 12 times higher than the predicted DFRs on 0DAT6.

The Registrant assumed first

- order dissipation kinetics to generate dissipation curves for profenofos, using the natural log of average DFR values. Using the 0DAT6 to 35DAT6 data, the Regis trant calculated half

- lives of 5 days (r =

- 0.85) for Site 1, 4.9 days (r =

- 0.77) for Site 2, and 4.6 days (r =

- 0.79) for Site 3. The Registrant also performed regressions using the 0DAT6 through 7DAT6 data only, which assumes a biphasic curve. The Regis trant calculated half

- lives of 1.2 days (r =

- 0.91) for Site 1 (Cheraw, SC), 1.1 days (r =

- 0.80) for Site 2 (Chesterfield, SC), and 0.86 days (r =

- 0.95) for Site 3 (McFarlan, NC).

EPA first assumed first

- order dissipation kinetics and conducted linear r egression analysis using the natural logarithm of the average DFR values from 0DAT6 to 35DAT6. EPA's estimated half

- life values were 5.1 days (R 2 = 0.7132) for Site 1, 5.7 days (R 2 = 0.6351) for Site 2, and 4.7 days (R 2 = 0.6271) for Site
3. However, the reg ression analysis did not appear visually to be a good fit for the data, and t he actualPage 35 of 35

DFRs on 0DAT6 were 7 to 12 times higher than the predicted DFRs on 0DAT6. Therefore, EPA did additional analysis and conducted a biphasic regression analysis using Exce l’s Solver, and the corrected average DFRs from immediately after the last application through the last sampling interval. This regression analysis appears (visually) to be a better fit of the data , and provides predicted Day 0 value s of
2. 3 μg/cm 2 , 3.0 μg/cm 2 , and 2. 7 μg/cm 2 , for Site 1 (Cheraw, SC), Site 2 (Chesterfield, SC) , and Site 3 (McFarlan, NC) , respectively.

There were some issues noted with respect to the DFR study. However, these are not anticipated to impact the validity of the data or it s use in risk assessment. These issues included: (1) o nly duplicate DFR samples were collected at each interval; the guidelines recommend the collection of triplicate DFR samples; (2) two field fortification levels were used (200 μg and 20,000 μg), as rec ommended in the EPA guidelines; however, the high fortification level was significantly higher than the treated samples; and (3) the EPA guidelines recommend a sample surface are of 400 cm 2 ; however, in this study, the total leaf surface was only 250 cm 2

, as reported in the main text of the study. It should also be noted that the study actually used a surface area of 227 cm 2 to calculate DFRs, based on a punch diameter of 1.7 cm. The Rabbit Tool website (the manufacturer of Birkestrand punches) states that the 2.5 cm 2 punch has a
diameter of 1.784 cm 2 , thus it appears that the surface area of 227 cm 2 is incorrect.

Summary of DFR Values and EPA Regression Analysis Results for Treated Cotton with Profenofos (MRID# 42851302).

Site Cheraw, SC Chesterfield,
SC McFarland,

NC
Study Target Rate (lb ai/A) 1 lb ai/acre

Spray Volume (GPA) 15

- 17

Measured Average Day 0 Residue (μg/cm 2 ) 0DAT6: 1.74 0DAT6: 2.48 0DAT6: 1.82

Linear Regression Predicted Day 0 Residue (μg/cm 2 ) 0DAT6: 0.234 0DAT6: 0.296 0DAT6: 0.146

Slope

- 0.135

- 0.149

- 0.121

Half

- life (days) 5.1 4.7 5.7

R 2 0.7132 0.6271 0.6351

Biphasic Regression Predicted Day 0 Residue (ug/cm 2 ) 0DAT6: 2.3 0DAT6: 3.0 0DAT6: 2.7

Slope

- 1.587,

- 1.587

- 0.912,

- 1.588

- 2.345,

- 1.588

Inflection Point (day) 12 12 12