### UNITED STATES ENVIRON M E N TAL PROTECTION AGENCY

WASHINGTON, D

. C. 20460

MEMORANDUM

Date: January 6, 2015 O FFI CE OF
CHEMICAL S AFETY AND
POLLUTION PREVENTION



### SUBJECT: 

### Forch lorfenuron. Preliminary Human He a lth Risk Assessment for Registration

Review.

PC Code: 1 28819
Decision No.: 494704

Petition No.: NA

Risk Assessment Ty pe: Single Chemical



### TXRNo.: NA

MRIDNo.: NA DP Barcode: 0422 527 Registration No.: NA Regulatory Ac tion: Registration Review



### C ase No.: 7057

CAS No.: 68157-60-8

40 CFR: 180.569



### FROM: 

# t 1 P

_ A 

# 11 /.

. /

Alexandra LaMay

, Biologist

.

## no.**~** 

# ......**~** William Dono va n
, Chemist

# (;V/Jt**'£** Matt Lloyd, Indus tr i al Hygienist**~** 

## I**_,~** 

### Linda Taylor, Ph

. D. Toxicologist**V~** 

### Risk Assessment Branch VII

Health Effec ts Division

## (7509P**~** 

# -(&

THROUGH: Ronnie Bever,

# Tox**icologist ~**  f 

# (AD \ry

Michael Metzger, Chief

# ~**~,** 

# I '-

R isk Assessment Branch VII

Health Effects Division (7509P)

TO: Wilhelmena Livingston, Chemical Review Manager

Pesticide Re-evaluation Division (7508P)

### Forchlorfenuron H um an Health Risk Assessment DP No

. D422527



### 1.0 Executive Summary

........ . .. ..... .. .. ......... .. .......... .. .. .............. ................................ . ............... 4

2.0 HED Recommendations

.... .. .. ......... ............... . ... . .. ... .............................................. ....... ..... 6

2.1 Data Deficiencies

. . .... .. . ..................... ................ ........... .. .. .. .. .. ... . .. .. ....... . ... . .... . ... . ........ ... . 6

2.2 Tolerance C onsiderations

....... . . ....... . ....... . ......... .. ..... .. ................................................... 7

2.2.1 Enforcement Analytical Method

...... .. ..... .. ... .. .. ...... ...................................... ... .. .. ...... 7

2.2.2 Recommended Tolerances

.......... . ........................................... . ... . ... . ......................... . 7

2.2

. 3 International Harmonization

............... .............................. ....................... ............... . . 8

2.3 Label Recommendations

.. . ............................................................................... .... .......... 8

3.0 Introduction

..... . .. .. ..... .. .................... ........... .................. ........................ .... ........... ........... .. .. 8

3.1 Chemical Identity

....................................................................... . .............. .. .. .... .. .. ......... 8

3.2 Physical/Chemical Characteristics

. ... . ... . ............. . . . ... . .. .. .. ............... .. .. .. .. .. ... ... . .. .......... 9

3.3 Pesticide Use Pattern

......................................................................... . ........... ....... ... . .. .. .. 9

3.4 Anticipated Ex posure Pathways

..................... .. .. .. . ............................ . ..... .. .. .. .. .. ......... 10



### 3.5 Consideration of Env ironmental Justice

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



### 4.0 Hazard C harac te rization and Dose-Response Assessment.

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



### 4

. 1 Toxico l ogy Studies Available for Analysis

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



### 4.2 Absorption, Distribut i on, Metabolism, & 

### Ex cretion (ADME)

................................. 1 2



### 4.2.1 Derma l A bsorption

.. ......... ....... . ......................... .. .. .. .................................... . ............ 12



### 4.3 Toxicologica l E ffects

............................. ........................................... .. ............. ............. 12



### 4.4 Safety Factor for Infants and Children (FQPA Safety Fa ctor)

.. . ............................ 1 3



### 4.4.1 Completeness of the Toxico l ogy Database

........... .. ..... .. .. .. .......... ... .......... ....... .. .. .. .. 13



### 4.4

. 2 Evidence of Neurotoxic i ty

............................ .. .. .. .. .. . . .. . . ... .......... ...... . ... . .... . .. ... .. ........ 1 3



### 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.

....... 14



### 4

. 4

. 4 Residual Unce rta i nty in the Ex posure Database

..... .......................... .. . ................. 1 4



### 4.5 Toxicity E ndpoint and Point of Departure Selections

.......................... .. . ........ ......... 14



### 4

. 6 Endocrine Disruption

................................................................................................... 16



### 5.0 Dietary Exposure and Risk Assessment

................. ............................ ............................ 17



### 5

. 1 Residues of C oncern Summary and Rationale

.. ....... .. .. .............................. .. ............. 17



### 5.2 Food Residue Profile

.................... ..................... ....................... .'

............ ................... .... 18



### 5.3 Water Residue P rofile

... ..... . . . .. ............. ............ .. . .. . .. .. .. .. .............................................. 18



### 5.4 Dietary Risk Assessment..

........................................................................... .... . .. .......... 1 9



### 5.4

. 1 Description of Residue Data Used in Dietary Assessment..

.................................. 1 9



### 5.4.2 Percent Crop Treated Us ed in Dietary Assessment

.......................... .. . ............ ..... 19



### 5.4.3 Acute Dietary Ri s k Assessment

...... .. ...... ............................. ..................... ............... 19



### 5.4.4 Chronic Dietary Risk Assessment

........................................................................... 20

5.4.5 Cancer Dietary Risk Assessment..

........................ .. ................................................. 20

5.4

. 6 Summary Ta ble

........................... ...... .................... . . .. .. .. .. .......................................... 20

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

............................. 20

6.1 Residential Handler Exposure

... . .. .. .. .................... ....... .................. ... . ... .. ... . .. . . ... .. .. . ... . 2 1



### 6.2 Post-Applicat i on Exp osure

..... ............. ...... .. .. . ... .. . ....................................... .. . . . .. ......... 21



### 6

. 3 Residential Bystander Post

- applic at ion Inhalation Exposure

................................. 21



### 6.4 Spray Drift

.................. ..... .. .. ..................................................................... .. . ... .. ... . ... ..... 2 1



### 7. 0 Aggregate Exposure/Risk Characterization

......... .. .. ... ............................. :

.. ..... ......... .... 26

7

. 1 Acute Aggregate Risk

.. ...... ........................................................................................... 26

7.2 Short-Te r m Aggregate Risk

..................... ...... . .. .. ... .. .. .. .. ....................... . ... . .. ... . . ........... 26

7.3 Intermediate-Term Aggregate Risk

.................................. .............. .. .......... ....... ........ 26

P age 2 o f 40

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 3 of 40 7.4 Chronic Aggregate Risk

................................ ................................ .............................. 26

7. 5 Cancer Aggregate Risk

................................ ................................ ................................ 26

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 26

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 27

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 27

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 30

9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 30

9.2.2 Inhalation Post

- Application Risk

................................ ................................ ............ 32

10.0 References

................................ ................................ ................................ ......................... 32 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 34

A.1 Toxicology Data Requirements

................................ ................................ ................... 34

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 35 Appendix B. Forchlorfenuron International Residue Limits Table

................................ ..... 39 Appendix C. Review of Human Research

................................ ................................ ................ 40

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 4 of 40 1.0 Executive Summary

HED has conducted a human health risk assessment to support registrations review for the active ingredient, forchlorfenuron, a plant growth regulator used to incre ase fruit set and size.

Forchlorfenuron is registered for use on grapes, bushberries, blueberries, kiwi, almond, sweet cherry, fig, pear, pistachio, and plums/prunes. It is formulated as a soluble concentrate and a wettable powder and applied via groun d equipment. There are no non

- agricultural uses registered for forchlorfenuron.

The toxicological database for forchlorfenuron is considered complete for characterization of potential developmental, reproductive, carcinogenetic, mutagenic, neurotoxic, an d immunotoxic effects. Forchlorfenuron is rapidly absorbed following oral exposure, with the majority of the dose being recovered in the urine within 24 hours. Forchlorfenuron is not acutely toxic via the oral, dermal, and inhalation routes. It produces mild eye irritation, is not a dermal irritant, and is negative for dermal sensitization. Dose

- related effects noted in the dog following subchronic and chronic exposure were generally limited to decreased body weight and body weight gain. In the rat, the only organ that appeared to be affected was the kidney, which showed suppurative inflammation, suppurative pyelonephritis, non

- suppurative interstitial nephritis, and cortical cysts following chronic exposure. The prenatal developmental studies in rabbits and rats and the

two

- generation reproduction study in rats showed no indication of increased susceptibility to

in utero and/or postnatal exposure to forchlorfenuron. Developmental toxicity occurred in the rat only at a maternally toxic dose level and was not observed in the rabbit. Reproductive toxicity was not observed. There is no concern for immunotoxicity or neuroto xicity following exposure to forchlorfenuron. Forchlorfenuron has been classified as not likely to be a human carcinogen, and there is no concern for mutagenicity.

Based on the toxicity, duration of exposure, and uses of forchlorfenuron, the following t oxicity endpoints were selected: Acute dietary (all populations) : No appropriate toxicity endpoint attributable to a single dose (exposure) could be identified from the available toxicology data base. Chronic dietary: cRfD = 0.07 mg/kg/day derived from a NOAEL of 7 mg/kg/day in a chronic oral toxicity study in the rat. LOAEL = 93 mg/kg/day based on decreased body weight parameters and kidney toxicity. Dermal, inhalation , and incidental oral exposures (short

- term): NOAEL = 100 mg/kg/day from data of the main and range

- finding developmental toxicity studies in the rabbit. LOAEL = 125 mg/kg/day based on body weight loss. Dermal, inhalation

, and incidental oral exposures (intermediate

- term): NOAEL = 87 mg/kg/day from a chronic oral toxicity in the dog. LOAE L = 195 mg/kg/day based on decreased body weight

, body weight gain , and food consumption.

For dermal exposure and risk assessments, 100% absorption was assumed ; inhalation toxicity was assumed to be equivalent to oral toxicity . For the occupational and r esidential risk assessments the level of concern (LOC) is for MOEs less than 100. The FQPA safety factor has been reduced to 1X since the database is complete, there is no evidence of pre

- or post

- natal

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 5 of 40 sensitivity/susceptibility, there is no evidence of neurotoxicity, and exposure estimates are not likely to underestimate risk.

T he residue chemistry database for forchlorfenuron is complete. Validated analytical methods are available for both data collection and enforcement purposes. Sufficient storage stability data were submitted to support sample storage intervals in the magnitude of the residue studies, which supported the established tolerance levels in registered crops. The nature of the residue in plants is adequately understood

, and the residue of concern in plants is forchlorfenuron only for both risk assessment and tolerance setting. As a 40 CFR §180.6(a)(3) situation exists, no residue

definition is needed for livestock. The residue of concern in drinking water is forchlorfenuron only

.

T he Environmental Fate and Effects Division (EFED) has developed estimated drinking water concentration (EDWC) values for use in human health risk assessment using the PRZM/EXAMS

and PRZM

- GW models for surface and ground water, respectively. For the chronic dietary analysis, the maximum annual mean EDWC value of 7.3 μg/L, derived from the PRZM

- GW

model

, was used as a point estimate to represent chronic drinking water concentration. The EDWC of 7.3 μg/L is a post

- breakthrough mean that occurs after 88 years of annual use. The PRZM/EXAMS (surface water) EDWCs were considerably lower than the PRZM

- GW EDWC (groundwater). No new drinking water assessment is required for this risk assess ment.

An acute dietary endpoint was not selected since there were no effects seen in the toxicological database that were attributable to a single dose of forchlorfenuron; therefore, quantification of acute dietary exposure and risk assessment is not requ ired. A highly conservative chronic dietary risk assessment was conducted using tolerance level residues, assuming 100% c rop treated for all commodities, and using default concentration values ( or actual processing study

information when available ) for pr ocessed commodities. For the U.S. general population and for all subpopulations, risks were <1% of the cPAD, and are, therefore

, not of concern. Since forchlorfenuron has been classified as not likely to be carcinogenic, quantification of dietary

cancer risk assessment is not required.

Quantification of acute aggregate risk assessment is not required since forchlorfenuron does not

pose an acute hazard . Since there are no uses of forchlorfenuron existing tha t would result in residential (non

- occupational) exposure to the pesticide, short

- and intermediate

- term aggregate
risk assessment are not required.

The chronic aggregate risk assessment includes only food and drinking water exposure, and is equivalent to the chronic dietary (food and water) risk assessment . The chronic dietary risk estimates are not of concern for the general population and all population subgroups. Quantification of aggregate cancer risk assessment is not required.

A spray drift assessment was completed for forchlorfenuron. The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Children’s (1 to < 2 year old) derm al and incidental oral risk estimates from indirect exposure to forchlorfenuron, related to spray drift, result in no buffers for

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 6 of 40 groundboom or airblast applications. Risk estimates from ground boom and airblast applications

are not of concern at the field edge for all situations considered.

EPA has not assumed that forchlorfenuron has a common mechanism of toxicity with other

substances , and thus cumulative risk characterization is not required

HED conducted occupational handler and post

- application exposure and risk assessments for all registered uses . Short

- and intermediate

- term MOEs for handlers (mixers/loaders and applicators) were not of concern to HED as they significantly exceeded the target MOE of 100. Total MOEs for the occupational handle r a ssessment range from 3,300 to 180 ,000. The occupational post

- application exposure and risk estimates indicate that short

- and intermediate

term MOEs are not of concern to HED

, also significantly exceeding the targe t MOE of 100. MOEs for the occupatio nal post

- appl ication assessment range from 720 to 20 0,000

, depending on the crop/activity combination

.

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. 1 

### ”

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their exposure. Appendix C provides additional information on the review of human research used to complete the r isk assessment. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been

satisfied.

2.0 HED Recommendations

During the conduct of the forchlorfenuron PRA, HED did not identify any data deficiencies or

label recommendations.

2.1 Data Deficiencies

The toxicity, exposure and residue chemistry data base s are considered complete for the purpose

of registration review . No additional data are required to support the registration review of

forchlorfenuron

.

Although HED would typically require dislodgeable foliar residue (DFR) studies based on the existing use pattern, no studies are required due to forchlorfenuron’s risk estimates exceeding the criteria laid out in HED’s guidance on waiving DFR data 2



### .

1 http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf

. 2 Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Resid ue (DFR)

Studies

. 10 / 23 /201 4 , Exposure Science Advisory Council

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 7 of 40 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

HPLC/UV method CCRL

- MTH

- 029, Analytical Method for the Determination of Forchlorfenuron In/On Grapes, Gra pe Juice and Raisins , (D344334, D. Davis, 2/13/08) is available for enforcing the tolerances for forchlorfenuron on plant commodities. For this method, residues are extracted with methanol or acetone, diluted with water, and partitioned against hexane. R esidues remaining in the aqueous fraction are then partitioned into dichloromethane (DCM)

, and if necessary

, further purified using a silica SPE cartridge. Residues are determined by HPLC/UV using external standards

, and residues are confirmed by

LC/MS/MS analysis. This method has been adequately validated by the registrant and the Agency. The validated limit of quantitation (LOQ) is 0.01 ppm for forchlorfenuron in fruit and nut crops, and the reported limits of detection (LOD) are 0.002

- 0.003 ppm.

Va lidated analytical methods are available for both data collection and enforcement purposes.

Tolerances are not required for livestock commodities; therefore, an enforcement analytical method in livestock commodities is not required.

2.2. 2 Recommend ed Tolerances

Permanent and temporary tolerances are currently established under 40 CFR §180.569(a)(1) and 180.569(a)(2) for residues of forchlorfenuron in or on several commodities. HED recommends

that the residue definition for the forchlorfenuron tolerance expression retain its current wording

as:

“Tolerances are established for residues of the plant growth regulator forchlorfenuron, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance lev els specified below is to be determined by measuring only forchlorfenuron (N

- (2

- chloro

- 4

- pyridinyl)

- N’

- phenylurea), in or on the commodity”.

The expiration date of the temporary tolerances is 12/31/2015. Upon expiration, section §180.569(a)(2) may be rem oved from the CFR

, as all the commodities with temporary tolerances also have permanent tolerances listed in §180.569(a)(1).

Table 2.2.2 . Tolerance Summary for Forchlorfenuron

. Commodity Established Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Commen ts

(C orrect C ommodity D efinition )

Almond 0.0 1 0.01 Almond
Almond, hulls (processed commodity) 0.15 0.15 Almond, hulls

Bushberry subgroup

13

- 07B 0.01 0.01 Bushberry subgroup 13

- 07B

Cherry, sweet 0 .01 0.01 Cherry, sweet Fig 0.0 1 0.01 Fig Grape 0.03 0.03 Grape Grape, raisin 0.06 0.06 Grape, raisin

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 8 of 40 Kiwifruit 0.04 0.04 Kiwifruit

Pear 0.01 0.01 Pear

Pistachio 0.0 1 0.01 Pistachio Plum, prune , fresh 0.0 1 0.01 Plum, prune , fresh



### 2.2.3 International Harmonization

No Codex or Canadian Maximum Residue Limits (MRLs) have been established for forchlorfenuron. At this time, there are no international harmonization issues for

forchlorfenuron.

2.3 Label Recommendations

No revisions to the labels are required.

3.0 In troduction

Forchlorfenuron (N

- (2

- chloro

- 4

- pyrindinyl)

- N

- phenyl urea) is a plant growth regulator used to increase fruit set and size. Forchlorfenuron is registered for use on almonds, sweet cherries, figs, pears, pistachios, kiwifruit, grapes, bushberries, and plum s/prunes. The agricultural products are generally formulated as wettable powder and soluble concentrates. There are no forchlorfenuron products registered for residential use sites (e.g.

, lawns or turf).

The most recent risk assessment was performed for the then

- proposed use s of forchlorfenuron on almonds, sweet cherries, figs, pears, pistachios, and plums/prunes (A. LaMay, D407226; 2/6/14 ).

3.1 Chemical Identity

Table 3 .1 Forchlorfenuron Nomenclature

Chemical Structure

Empirical Formula C 12 H 10 ClN 3 O

Common Name Forchlorfenuron

Company experimental name CPPU

IUPAC name 1

- (2

- chloro

- 4

- pyridyl)

- 3

- phenylurea

CAS Name N

- (2

- chloro

- 4

- pyridinyl)

- N’

- phenylurea

CAS Registry Number 68157

- 60

- 8

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 9 of 40 3.2 Physical/Chemical Characteristics

Forchlorfenuron is a lipophilic compound with a low vapor pressure (not volatile) and has low water solubility. The physicochemical properties for forchlorfe nuron are summarized in Table

3.2 , below.

Table 3 .2 Physicochemical Properties of Forchlorfenuron Technical

. Parameter Value Reference

State Crystalline solid

D309772, L. Kutney,

12/20/2004 Color Off white Melting point/range 165

- 170°C Molecular Weight 247.67
pH 6.7 Density 1.44 g/cm 3 at 21 °C Water solubility 39 mg/L Solvent solubility 17g/100 mL in acetone Vapor pressure (25°C) 3.5 x10

- 10 torr Dissociation constant, pK

a pKa 1 = 2.5; pKa 2 = 12.3 Octanol/water partition coefficient, Log(K OW ) 3.2 @ 20 °C

UV/visible absorption spectrum pH < 2: A 1 = 2.18 × 10 4 @ 202 nm; A 2 = 1.47 × 10 4 @ 279 nm pH =7: A 1 = 1.93 × 10 4 @ 205 nm; A 2 = 1.51 × 10 4 @ 261 nm pH >10: A 1 = 2.24 × 10 4 @ 207 nm; A 2 = 1.89 × 10 4 @ 261 nm



### 3.3 Pesticide Use Pattern

The registered use directions for forchlorfenuron are summarized in Table 3.3 below.

Table 3.3. Summary of Directions for Use of Forchlorfenuron Application Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Almond

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during early nut development. Apply in 100

– 200 gallons spray/acre. Sweet Cherry

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 7 Apply in 100

– 200 gallons spray/acre.

Fig

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during early fig development. Apply in

100

– 200 gallons spray/acre.

Pear

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 10 of 40 Table 3.3. Summary of Directions for Use of Forchlorfenuron Application Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply 25

- days post

petal fall. Apply in 100

– 200 gallons spray/acre.

Pistachio

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply at beginning of kernel formation. Apply

in 100

– 200 gallons spray/acre.

Plum /Prune

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during bloom. Apply in 100

– 200 gallons spray/acre.

Bushberry subgroup 13

- 07B

Ground application 98% SC/S

[71049

- 1] 0.07 lb/gal

SC/L [71049

- 3] 0.0044

-

0.022 1 0.022 NS Apply from early flowering to 14 days after petal fall. Apply in a minimum of 50 gal/A.

Grape

Ground application 98% SC/S

[71049

- 1] 0.07 lb/gal

SC/L [71049

- 3] 0.0044

-

0.022 1 0.022 NS Apply early post

- bloom, or at bloom for grapes grown for raisins. Apply in a minimum of 200 gallons of water/A.

Kiwifruit

Ground application 98% SC/S

[71049

- 1] 0.07 lb/gal

SC/L [71049

- 3] 0.0044

-

0.018 1 0.018 NS Apply 2

- 3 weeks post bloom. Apply in a minimum of 200 gallons

of water/A.



### For all labeled crops except sweet cherry, the directions permit a single application at specific

fruit and nut formation stages in lieu of specifying a PHI. Since the Agency recognizes that different varieties mature at different rates, HED considers it appropriate to specify timing based on growth stage instead of specific PHI for these crops.

3.4 Anticipated Exposure P athways

PRD has requested an assessment of human health risk to support Registration Review of all existing r egistered uses of forchlorfenuron. Humans may be exposed to forchlorfenuron in food and drinking water, since forchlorfenuron may be applied dire ctly to growing crops and application may result in forchlorfenuron reaching surface and ground water sources of drinking water. There are no residential uses of forchlorfenuron, so there is not likely to be exposure in

residential or non

- occupational set tings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 11 of 40 potential for post

- application exposure for workers re

- entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the existing uses of forchlorfenuron

.

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://www.eh.doe.gov/oepa/guidance/justice/eo12898.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 ri sks 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 pa tterns are compiled by the USDA under the National Health and Nutrition Examination 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 categori zed by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or

circumstances war rant. 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 consider ations 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 specif ic subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

No new toxicity and/or rat metabolism data have been received since the last risk assessment, which did not identify any data deficiencies with respect to toxicology. Based on the cur rent 40 CFR Part 158 data requirements, an immunotoxicity study, subchronic dermal and inhalation toxicity studies, and acute and subchronic neurotoxicity studies are required for forchlorfenuron. However, the Hazard and Science Policy Council (HASPOC) con cluded that these studies

should be waived for forchlorfenuron (TXR No s . 0056596 and 0056795 )

. This assessment includes summaries of prior assessments (D341628 , 3/11/08 ).

4.1 Toxicology Studies Available for Analysis

The toxicology database for forchlorfenuron is complete for risk assessment. There are acceptable studies available for toxicity endpoint selection; they include:

 subchronic oral toxicity studies in rats and dogs

 chronic oral toxicity studies in rats and dogs

 carcinogenicity stud ies in rats and mice

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 12 of 40  developmental studies in rats and rabbits

 reproduction study in rats

 complete mutagenicity study battery

 metabolism study in rats

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

Metabolism studies in rats indicate that forchlorfenuron is rapidly and almost entirely absorbed and metabolized, tissue residues are minimal, and excretion is almost complete. Overall recovery of the radioactive dose was 97%. The majority of the dose was recovered in the urine within 24

ho urs (62

- 74% dose). Fecal excretion accounted for 16

- 28% dose, and 20

- 23% of the dose was found in the bile. At 168 hours post

- dose, excluding the GI contents and the carcass, the highest concentrations of radioactivity were found in the kidney and liver i n both sexes. The elimination

half

- life was 13.1

- 16.2 hours. There were no sex

- related differences.

The metabolism of forchlorfenuron in rats includes conjugation with sulfate at the phenyl ring (major pathway) before or after hydroxylation of the phenyl ring, hydroxylation of the phenyl ring (major pathway), conjugation with glucuronide at the phenyl ring, methylation of the hydroxy group of hydroxyl CPPU

- sulfate, and hydroxylation of both the chloropyridinyl and phenyl rings.

4.2.1 Dermal Absorption

A dermal absorption study is not available for forchlorfenuron, and 100% dermal absorption is

used for risk assessment.

4. 3 Toxicological Effects

Forchlorfenuron is a plant growth regulator that is absorbed by leaves, stem, cotyledon, and germinated seeds. It promotes cell division, differentiation, and development; induces budding of callus; controls apical dominance; breaks dormancy of lateral bud s; promotes germination; delays the aging process; maintains chlorophyll in excised leaves; regulates the transport of nutrients; and promotes fruit formation. In the submitted studies, there were no apparent effects

observed consistent with th is mode of action.

Dose

- related effects noted in the dog following subchronic and chronic exposure were generally limited to decreased body weight and body weight gain. In the rat, the only organ that appeared to be affected was the kidney, which showed suppurative inflammation, suppurative pyelonephritis, non

- suppurative interstitial nephritis, and cortical cysts following chronic

exposure.

Developmental toxicity was not observed in the rabbit but was observed in the rat (decreased fetal body weight and delayed o ssification of the sternebrae ) only at a maternally

- toxic dose level (decreased body weight and death). Forchlorfenuron did not induce any signs of reproductive toxicity or neurotoxic potential. The developmental toxicity studies in rats and rabbits, as well as the reproductive toxicity study in rats, did not demonstrate any pre

- or postnatal sensitivity.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 13 of 40 There is no evidence of immunotoxicity, and the requirement for an immunotoxicity study has

been waived ( TXR No. 0056795)

.

A repeated exposure study vi a either the dermal or inhalation routes of exposure is not available

for forchlorfenuron ; however, these studies have been waived by HASPOC ( TXR No. 0056596 )

. No neurotoxicity studies are available on forchlorfenuron, but there was no evidence of

neuroto xicity in any of the submitted studies and these studies have been waived by HASPOC ( TXR No. 0056596 )

.

The database for carcinogenicity is complete, and forchlorfenuron is classified as not likely to be a human carcinogen. The mutagenicity/genetic toxicity database is considered complete, and there is no concern for mutagenicity.

Forchlorfenuron is not ac utely toxic via the oral, dermal, and inhalation routes. It is not a dermal sensitizer or dermal irritant, but it is a mild eye irritant.

4. 4 Safety F actor for Infants and Children (FQPA Safety Factor)

The Food Quality Protection Act (FQPA) safety factor for the protection of infants and children has been reduced to 1X. There are no concerns and no residual uncertainties with regard to pre

and/or postnatal toxicity. An FQPA Safety Factor of 1X is appropriate for the following reasons:

The database for prenatal developmental and reproductive toxicity is considered adequate to assess safety for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and rabbit studies or in the rat 2

- generation reproduction study. These studies have clearly defined NOAEL/LOAELs. There is a lack of evidence of neurotoxicity in any study on forchlorfenuron.

Exposure estimates (food and water) are not likely to underestimate risk.

Further details may be found in the following sections.

4. 4 .1 Completeness of the Toxicology Database

The toxicology database for forchlorfenuron is complete. Acceptable rat and rabbit developmental toxicity studies and a rat 2

- generation reproduction study are available. The HASPOC determined that the acute and subchronic neurotoxicity studies and the immunotoxicity study may be waived (TXR No s . 0056596 and 0056795 ). All other required toxicology studies have been submitted and are considered acceptable.

4. 4 .2 Evidence of Neurotoxicity

There is no concern for neurotoxicity resulting from exposure to forchlorfenuron based on a lack of evidence of neurotoxicity in any study on forchlorfenuron. There is not a concern for developmental neurotoxicity.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 14 of 40 4. 4 .3 Evidence of Sen sitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility ( qualitative or quantitative ) following in utero exposure to forchlorfenuron in either the rat or rabbit developmental toxicity study, and there is no evidence of increased susceptibility ( qualitative or quantitative ) following in utero and/or pre

- /post

- natal exposure in the 2

- generation reproduction st udy in rats.

Forchlorfenuron has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included death of one dam and significantly decreased body weight in the rat and was not observed in the rabbit. Decreased fetal body weight and a slight increase in the incidence of delayed ossification were observed in the rat at the same dose

level at which the maternal effects were seen , whereas there were no developmental effects in the

rabbit. Retarded growth was observed in the F1 and F2 offspring in the 2

- generation reproduction study at a dose level where clinical signs of toxicity and decreased body weight occurred in the parental rats.

4. 4 .4 Residual Uncertainty in the Exposure Database

There ar e no residual uncertainties in the exposure database. The dietary exposure estimates are

unrefined and reflect tolerance

- level residue in food, 100% crop treated, and upper

- bound drinking water estimates based on modeling. These assumptions and refinemen ts are detailed in

the Section 5.4.1. There are no non

- occupational exposures for forchlorfenuron.

4. 5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

There have been no changes , except as noted below, to the prior dose

- response assessment, recommendations for combining routes of exposure

, and/or cancer classification. I ncidental oral exposure endpoints and points of departure have been added.

Refer to Table 4. 5 .1 for the summary of the toxicological doses and endpoints for

forchlorfenuron.

Table 4. 5 .1 Summary of Toxicol ogical Doses and Endpoints for Forchlorfenuron for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (All Populations) No appropriate endpoint attributable to a single exposure (dose) was identified from oral

toxicity studies, including the developmental studies; therefore an acute endpoint was not selected and an acute dietary risk assessment is not required.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 15 of 40 Table 4. 5 .1 Summary of Toxicol ogical Doses and Endpoints for Forchlorfenuron for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Chronic Dietary (All Populations) NOAEL =

7 mg/kg/day UF A = 10x

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

= 0.07 mg/kg/day

cPAD = 0.07 mg/kg/day Chronic oral toxicity study

– rat

LOAEL = 93 mg/kg/day, based on decreased body weight

, body weight gain , and food consumption, and kidney toxicity (suppurative inflammation in males; nonsuppurative interstitial nephritis in females)

Dermal Short

Term (1

- 30 days) oral

NOAEL =

100 mg/kg/day

(dermal absorption

rate = 100%) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 125 mg/kg/day, based on body weight loss during dosing period in the

range

- finding study

Dermal

Intermediate

Term (1

- 6 months) oral

NOAEL =

87 mg/kg/day

(dermal absorption

rate = 100%) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Chronic oral toxicity study

- dog

LOAEL = 195 mg/kg/day based on decreased body weight

, body weight gain , and food consumption

Inhalation

Short

- Term (1

- 30 days) oral

NOAEL=

100 mg/kg/day

(inhalation toxicity

assumed to

be equivalent

to oral ) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 125 mg/kg/day based on body weight loss during dosing period in the

range

- finding study

Inhalation

Intermediate

Term (1

- 6 months) oral

NOAEL =

87 mg/kg/day

(inhalation toxicity

assumed to

be equivalent

to oral ) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Chronic oral toxicity study

- dog

LOAEL = 195 mg/kg/day based on decreased body weight

, body weight gain , and food consumption

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 16 of 40 Table 4. 5 .1 Summary of Toxicol ogical Doses and Endpoints for Forchlorfenuron for Use in Dietary and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Incidental

Oral Short

Term (1

- 30 days) oral

NOAEL=

100 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 125 mg/kg/day based on body weight loss during dosing period in the

range

- finding study

Incidental

Oral

Intermediate

Term (1

- 6 months) oral

NOAEL =

87 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Chronic oral toxicity study

- dog

LOAEL = 195 mg/kg/day based on decreased body weight

, body weight gain , and food consumption

Cancer (oral, dermal, inhalation) Classification: not likely to be a human carcinogen, based on two adequate rodent

carcinogenicity studies.

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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern.



### 4. 5 .2 Recommendation for Combining Routes of Exposure for Risk Assessment

The toxicity endpoints (based on body weight effects) for the incidental oral, inhalation, and

dermal routes are similar and need to be combined

.

4. 5.3 Cancer Classification and Risk Assessment Recommendation

The database for carcinogenicity is complete , and forchlorfenuron is classified as “ not likely to be carcinogenic to humans ” , based on the lack of evidence of tumors in two animal species . The mutagenicity database is considered complete, and there is no concern for mutagenicity.

4.6 Endocrine Disr uption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neur otoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual m aturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 17 of 40 taxonomic groups. As part of its preliminary re

- registration decision for forchlorfenuron, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However , as required by F FDCA section 408(p),

forchlorfenuron 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) ma y 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

determin ations. 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 hav e 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 advers e endocrine

- related effects caused by the substance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 3 

### and includes some

pe sticides 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. List 2 represents the next

set of chemicals for which EPA intends to issue test orders/da ta 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 4



### .

5.0 Dietary Exposure and Risk Assessment

For this risk assessment, a new drinking water and dietary exposure assessment s were not required

. The most recent di etary assessment is summarized below

.

5.1 Residues of Concern Summary and Rationale

The qualitative nature of the residue in plants is understood, based on acceptable apple and kiwifruit metabolism studies and supportive grape metabolism data. The residue of concern for both tolerance expression and risk assessment is parent forchlorfenuron.

The nature of the residu e in livestock and rotational crops has not been determined. Since there is no reasonable expectation of finite residues in livestock and there are no rotational crop uses since all registered crops are perennials, n o additional data are required at this time. However, if

3 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.

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

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 18 of 40 any future uses are proposed for annual crops or result in significant residues in feedstuffs, additional data may be required t o determine the residue definition in these matrices.

HED has determined that the residue of concern in dr inking water is parent forchlorfenuron only.

Table 5.1. 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 Forchlorfenuron Forchlorfenuron

Rotational Crop Not Determined Not Determined

Livestock Ruminant Not Determined Not Determined

Poultry Not Determined Not Determined

Drinking Water Forchlorfenuron Not Applicable



### 5 .2 Food Residue Profile

B ased on acceptable apple and kiwifruit metabolism studies and supportive grape metabolism

data , the nature of the residue in plants is adequately understood

, and the residue of concern is

forchlorfenuron. Available metabolism data shows that for chlorfenuron does not significantly

translocate ; therefore

, residues from foliar application are likely to be surface residues.
However, as forchlorfenuron is used at relatively low application rates, the submitted field trial

studies demonstrate that

, am ong registered crops , quantifiable residues are expected only in the following commodities: almond hulls, grape, raisin, and kiwifruit. Sufficient storage stability data are available to support the sample storage intervals reported in the magnitude of th e residue studies. Further, validated analytical methods were used for data collection purposes. As forchlorfenuron has been registered for use only on perennial crops, no rotational crop studies

have been submitted. T he only animal feedstuff associated with forchlorfenuron is almond hulls. Due to the low dietary burden and limited residue transfer to livestock commodities, there is no reasonable expectation of finite residues to livestock (40 CFR §180.6(a)(3)).

5.3 Water Residue Profile

For the chronic dietary analysis, the maximum annual mean chronic estimated drinking water concentration (EDWC) value (7.3 μg/L) derived from the PRZM

- GW model was used as a point estimate to represent chronic drinking water concentration. The EDWC of 7.3 μg/L is a post

breakthrough mean that occurs after 88 years of annual use. This maximum post

- breakthrough average value was from the WI corn modeled scenario. The PRZM/EXAMS (surface water) EDWCs were considerably lower than the PRZM

- GW EDWC (groundwate r).

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 19 of 40 Table 5.3

. Summary of Estimated Surface Water and Groundwater Concentrations for

Forchlorfenuron

.
Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 0.6 8.8

Chronic (non

- cancer) 0.21 7.3

a From the Tier II PRZM

- EXAMS

- Index Reservoir model; 34% PCA

b From the Tier I PRZM

- GW model.

Source: G. Orrick, D 407227, 3/11/13

.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Tolerances are established for residues of forchlorf enuron in/on grapes at 0.03 ppm; raisins at 0.06 ppm; kiwifruit at 0.04 ppm; the bushberry subgroup 13

- 07B at 0.01 ppm ; and on almonds, sweet cherries, figs, pears, plums and pistachios at 0.01 ppm [40 CFR §180.569(a)]. There are

no forchlorfenuron tolerances es tablished for animal commodities.

HED has determined that the residues of concern in plants include only the parent compound for purposes of both the tolerance expression and risk assessment. No animal commodity tolerances are required to support the exi sting uses for forchlorfenuron.

Tolerance level residues and 100% crop treated was assumed for all existing uses. HED notes that the temporary tolerances in or on olive and apple have expired; thus, these commodities

were not included in the assessment. DEEM (Version 7.81) default processing factors were used for dried pears, prune juice, cranberry juice and grape juice. A processing factor was not used for raisins because a separate tolerance has been established for that commodity. In addition, a

pro cessing factor was not used for prunes (dried plums)

, because data show that residues of forchlorfenuron in prunes are not likely to exceed 0.01 ppm, the tolerance established for fresh plums. A processing factor was also not used for dried figs

, because data show that residues of forchlorfenuron in dried figs are not likely to exceed the tolerance for fresh figs ( D414083, D. Davis, 9/12/13 ). Lastly, the maximum annual mean groundwater concentration from the PRZM

GW model was incorporated into the assessme nt.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated (%CT) data were not applied to the chronic assessment; 100% CT was

assumed for all commodities.

5.4.3 Acute Dietary Risk Assessment

An acute dietary endpoint was not selected

, since there were no effects seen in the toxicological database that were attributable to a single dose of forchlorfenuron; therefore, quantification of acute dietary exposure and risk assessment is not required.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 20 of 40 5.4.4 Chronic Dietary Risk Assessment

HED conducted a Tier 1, screening level chronic dietary (food and drinking water) risk

assessment. The assessment assumed that all commodities will contain residues of forchlorfenuron at the tolerance level. When available, data from processing studies w ere used to estimate residue in processed commodities; however, in the absence of data, DEEM default processing factors were incorporated into the assessment. Lastly, the highest modeled estimate of the exposure to drinking water concentrations was used i n this assessment. Based on the conservative inputs into the analysis, it is unlikely that the assessment will underestimate chronic dietary risks from the existing uses of forchlorfenuron.

HED is concerned when dietary risk exceeds 100% of the PAD. Th e dietary analysi s estimates the dietary exposure of the U.S. population and various population subgroups. The results are reported for the 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 forchlorfenuron, the U.S. population and all population subgroups had dietary risk (food and drinking water) estimates that were below 1% of the cPAD. The general population had an

exposure of 0.000175 mg/kg/day . The most highly exposed subpopulation, all infants, had an

exposure of 0.000447 mg/kg/day . The results of the chronic dietary exposure analysis for all subpopulations are summarized in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Forc hlorfenuron has been classified as not likely to be carcinogenic; therefore

, quantification of cancer dietary exposure and risk assessment is not required.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and

Risk for Forchlorfenuron.

Population Subgroup Chronic Dietary Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population 0.000175 <1

All Infants (<1 year old)* 0.000447 <1

Children 1

- 2 years old 0.000346 <1

Children 3

- 5 years old 0.000261 <1

Children 6

- 12 years old 0.000165 <1

Youth 13

- 19 years old 0.000122 <1

Adults 20

- 49 years old 0.000167 <1

Adults 50

- 99 years old 0.000168 <1

Females 13

- 49 years old 0.000167 <1
*The subpopulation(s) with the highest risk estimates.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 21 of 40 6.1 Residential Handler Exposure

There are no registered

, non

- occupational uses for forchlorfenuron; therefore

, a residential handler exposure and risk assessment is not required.

6.2 Post

- Application Ex posure

There are no registered uses for forchlorfenuron which would result in residential (non

occupational) post

- application exposures; therefore

, a post

- application exposure and risk assessment is not required.

6.3 Residential Bystander Post

- applicatio n 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 Federal Insecticide, 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 has 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 and route

- specific inhalation toxicological studies) or fu rther analysis is required for

f orchlorfenuron

.

6.4 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 off

target and can lead to exposures to those it may directly contact. They can also deposit on

surfaces where contact with residues ca n 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 met hods 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 e xposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 5 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thoug ht 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 assume d to have deposited via spray drift

, thus resulting in an indirect

5 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 22 of 40 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 agricultu ral applications of forchlorfenuron

. 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 speci fied in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parame ters is not available. 6

, 7 

### 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 cas es, 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). Section 6 .4.1 pr ovides the screening level drift

- related risk estimates.

In many cases, risks 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

man agement options

, additional spray drift deposition fractions were also considered. These drift estimates represent plausible options for pesticide labels

.

6 .4.1 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. Forchlorfenuron is used on orchard and field crops and can be applied via groundboom and airblast equipment. The

r ecommended 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.

 Orchard airblast applications are b ased on the AgDrift option for Sparse (Young/Dormant) tree canopies.

6 http://www.agdrift.com/

7 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors sho uld

be aw are and characterize these appropriately.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 23 of 40 In addition to the screening level spray drift scenarios described above, results are provided which represent viable drift reduction technologies (DRTs) that represent potential risk

ma nagement 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 and incidental oral risk estimates were combined

, because the toxicity endpoint for each route of exposure is the same . The total applicable Level of Concern is 100

, so MOEs < 100 would be of concern. Children’s (1 to < 2 year old) dermal and incidental oral risk estimates from indirect exposure to forchlorfenuron

, related to spray drift

, result in no buffers for groundboom or airblast applications

.

Exposures were considered for 50 feet wide lawns where the nearest side of the property was directly adjoining the treated field (at field edge) and at varied distances up to 300 feet downwind of a treated field. Results are presented in Table s 6.4.1 and 6.4.2 ; no risk estimates of concern were identified at field edge or any distance downwind of the treated field

. The spray drift assessment presented below is protective of the use on kiwifruit, which is registered at a lower application rate than the scenarios assessed

.

Risk estimates from ground boom and airblast applications are not of concern at the field edge

for all situations considered. U sing coarser sprays and lowering boom height for groundboom sprayers or applications to denser crop canopies with airblast sprayers lowers risk estimates

.

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 24 of 40 Table 6 .4.1 Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Forchlorfenuron for the Dermal Route of Exposure

Crop/Rate

Group Spray Type/

Nozzle Configuration Appl.

Rate (lb ai/A) TTR (ug/cm2) At Edge 10 Feet 25 Feet 50 Feet 75 Feet 10 0 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

Almond, Cherry, Fig, Pear, Pistachio, Plum/Prune, Grape, Bushberry (Covers use on Kiwifruit)

Groundboo m High Boom Very

fine to Fine

0.022 0.00245 56,000 110,000 190,000 300,000 420,000 520,000 610,000 750,000 950,000 1,300,000 1,500,000
Low Boom Very fine

to Fine 120,000 330,000 520,000 800,000 1,000,000 1,300,000 1,500,000 1,700,000 2,100,000 2,600,000 3,500,000
High Boom Fine to Medium/Coarse 210,000 550,000 800,000 1,200,000 1,500,000 1,700,000 2,100,000 2,100,000 2,600,000 3,500,000 3,500,000

Low Boom Fine to Medium/Coarse 320,000 870,000 1,300,000 1,700,000 2,100,000 2,600,000 3,500,000 3,500,000 5,200,000 5,200,000 5,200,000

Airblast Sparse 73,000 130,000 240,000 520,000 950,000 1,500,000 2,300,000 3,300,000 5,800,000 9,500,000 13,000,000

Normal 3,500,000 5,200,000 8,000,000 12,000,000 17,000,000 21,000,000 26,000,000 35,000,000 35,000,000 52,000,000 52,000,000

Dense 250,000 370,000 600,000 1,000,000 1,600,000 2,100,000 2,700,000 3,300,000 4,500,000 5,800,000 7,000,000

Vineyard 1,300,000 2,500,000 4,800,000 8,700,000 13,000,000 17,000,000 21,000,000 26,000,000 35,000,000 52,000,000 52,000,000

### Forchlorfenuron Human Health Risk Assessment DP No. D 422527

Page 25 of 40 Table 6 .4.2 Children (1< 2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Forchlorfenuron for the Combined Dermal and Oral Routes of Exposure

Crop/Rate

Group Spray Type/

Nozzle Configuration Appl.

Rate (lb ai/A) TTR (ug/cm2) At Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

Almond, Cherry, Fig, Pear, Pistachio, Plum/Prune, Grape, Bushberry (Covers use on Kiwifruit)

Groundboom High Boom

Very fine to

Fine

0.022 0.00244 32,000 64,000 110,000 170,000 240,000 300,000 350,000 430,000 550,000 750,000 860,000

Low Boom Very

fine to Fine 71,000 190,000 300,000 460,000 600,000 750,000 860,000 1,000,000 1,200,000 1,500,000 2,000,000
High Boom Fine

to Medium/Coarse 120,000 320,000 460,000 670,000 860,000 1,000,000 1,200,000 1,200,000 1,500,000 2,000,000 2,000,000

Low Boom Fine

to Medium/Coarse 180,000 500,000 750,000 1,000,000 1,200,000 1,500,000 2,000,000 2,000,000 3,000,000 3,000,000 3,000,000

Airblast Sparse 42,000 72,000 140,000 300,000 550,000 880,000 1,300,000 1,900,000 3,300,000 5,500,000 7,500,000

Normal 2,000,000 3,000,000 4,600,000 6,700,000 10,000,000 12,000,000 15,000,000 20,000,000 20,000,000 30,000,000 30,000,000

Dense 140,000 210,000 340,000 600,000 900,000 1,200,000 1,500,000 1,900,000 2,600,000 3,300,000 4,000,000

Vineyard 750,000 1,500,000 2,700,000 5,000,000 7,500,000 10,000,000 12,000,000 15,000,000 20,000,000 30,000,000 30,000,000

### Forchlorfenuron Human Health Risk Assessment DP No . D422527

Page 26 of 40 7.0 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.

7.1 Acute Aggregate Risk

An acute endpoint was not selected; therefore

, quantification of acute aggregate risk is not required.

7.2 Short

- Term Aggregate Risk

Since there are no uses for forchlorfenuron that would result in residential (non

- occupational)

exposure , a short

- term aggregate risk assessment is not required.

7.3 Intermediate

- Term A ggregate Risk

Since there are no uses for forchlorfenuron that would result in residential (non

- occupational)

exposure, an intermediate

- term aggregate risk assessment is not required.

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment in cludes food and water exposure only

. The chronic food plus drinking water risk estimates are not of concern to HED for the general population and all population subgroups. Refer to section 5.4.4 for a detailed discussion of the chronic dietary risk

asses sment.

7.5 Cancer Aggregate Risk

Since forchlorfenuron has been classified as not likely to be carcinogenic, quantification of aggregate cancer risk is not required.

8.0 Cumulative Exposure/Risk Characterization

EPA has followed a cumulative risk approach for other pesticides based on a common mechanism of toxicity

. EPA has not made a common mechanism of toxicity finding as to forchlorfenuron and any other substances . F orchlorfenuron does not appear to produce a t oxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that forchlorfenuron has a common mechanism of toxicity with other

substances

, and a cumulative risk approach is unnecessary . For inform ation regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of

### Forchlorfenuron Human Health Risk Assessment DP No . D422527

Page 27 of 40 Pesticide Programs concerning common mechanism de terminations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment wa s completed to include all registered uses of

forchlorfenuron.

9.1 Short

- /Intermediate

- Term Handler Risk

HED uses the term “ handlers ” to describe those individuals who are involved in the pesticide application process. HED has determined that there are pote ntial exposures to handlers during application of forchlorfenuron. Scenarios assessed include mixing/loading wettable powders and

soluble concentrate formulations for groundboom and airblast applications and applying sprays with groundboom and airblast equipment

. No chemical

- specific data for assessing human exposures during pesticide handling activities were submitted to the Agency; therefore, handler exposure was assessed using the Pesticide Handlers Exposure Database version 1.1 (PHED V.1.1). The fo rchlorfenuron product labels direct mixers, loaders, applicators and other handlers to wear baseline PPE plus chemical

- resistant gloves. The occupational handler exposure and risk

estimates indicate that short

- and intermediate

- term MOEs are not of concer n to HED (i.e.,

MOEs > 100) with label

- specified PPE. Total MOEs for the occupational handler assessment range from 3

, 300 to 180 ,000. While the assessment has been completed for both the short

- and

intermediate

- term exposure durations, the 1 application p er season make the short

- term exposure duration risk estimates more probable from a risk management perspective.

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 28 of 40 Table 9 .1.1. Occupational Handler Short

- Term Non

- Cancer Exposure and Risk Estimates for Forchlorfenuron

.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Total

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

SC

- Airblast applications Orchard 37.6

– SL/G 0.219 0.03 40 0.000564 180,000 0.00000329 30,000,000 180,000

WP

- Airblast applications Orchard 170

– SL/G 43 0.03 40 0.0026 39,000 0.000645 160,000 31,000

SC

- Groundboom applications Field Crops 37.6

– SL/G 0.219 0.03 80 0.00113 88,000 0.00000658 15,000,000 87, 000

WP

- Groundboom applications Field Crops 170

– SL/G 43 0.03 80 0.005 20,000 0.00129 78,000 16,000

Applicator

Liquid

- Airblast applications Orchard 1770

– SL/no G 4.71

– no

- R 0.03 40 0.0265 3

, 300 0.0000706 1

, 200

, 000 3

, 300

Liquid

- Groundboom applications Field Crops 78.6

– SL/no

- G 0.34

– no

- R 0.03 80 0.00236 37

, 000 0.0000102 8

, 500

, 000 37

, 000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 ); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (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 or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/ day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 29 of 40 Table 9 .1.2. Occupational Handler Intermediate

- Term Non

- Cancer Exposure and Risk Estimates for Forchlorfenuron

.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation Total

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

SC

- Airblast applications Orchard 37.6

– SL/G 0.219 0.03 40 0.000564 150,000 0.00000329 26,000,000 150,000

WP

- Airblast applications Orchard 170

– SL/G 43 0.03 40 0.0026 34,000 0.000645 130,000 27,000

SC

- Groundboom applications Field Crops 37.6

– SL/G 0.219 0.03 80 0.00113 77,000 0.00000658 13,000,000 77, 000

WP

- Groundboom applications Field Crops 170

– SL/G 43 0.03 80 0.005 17,000 0.00129 67,000 14,000

Applicator

Spray

- Airblast applications Orchard 1770

– SL/no G 4.71

– no

- R 0. 0 3 40 0.0265 3

, 300 0.0000706 1

, 200

, 000 3

, 300

Spray

- Groundboom applications Field Crops 78.6

– SL/no

- G 0.34

– no

- R 0. 0 3 80 0.00236 37

, 000 0.0000102 8

, 500

, 000 37

, 000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 ); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Am ount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Do se = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Trea ted or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 To tal MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 30 of 40 9.2 Short

- /Intermediate

- Term Post

- Application Risk

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 previousl y 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 on 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.

9 .2.1 Dermal Post

- A pplication Risk

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). HED has determined that there are potential exposures to persons entering treated sites (e.g., harvesters) after application of forchlorfenuron is complete. Since no post

application data were submitted in support of this registration action, dermal expos ures during

post

- application activities were estimated using (1) dermal transfer coefficients from the Science Advisory Council for Exposure Standard Oper ating Procedure (SOP) Number 3 : Agricultural Transfer Coefficients, March 2013 ; (2) the standard assu mption that 25 percent of the application rate is initially available to dislodge from foliar surfaces ; and (3) the standard assumption that residues dissipate at a rate of 10 percent per day. The application rate is 0.022 lb

ai/acre. The results of the post

- application occupational exposure and risk assessment indicate that risk estimates are not a concern on the day of application (12 hours following the end of the application). HED concurs with a 12

- hour REI for all crops.

The table below summarizes the occupational post

- application risk estimates for the registered applications of forchlorfenuron. The occupational post

- application exposure and risk estimates

indicate that short

- and intermediate

- term MOEs are not of concern to HED (i.e., MOEs > 100). MOEs for the occupational post

- application assessment range from 720 to 20 0 ,000. The crops assessed cover the use on kiwifruit, which has a lower application rate.

Table 9.2.1. Occupational Post

- A pplication Non

- Cancer E xposure and Risk Estimates for F orchlorfenuron.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Short

- term

Grape Turning/ Girdling 19

, 300

0.06 0.13807 720

Grape Tying/ Training /

Hand harvesting/ Leaf pulling 10

, 100 0.07226 1,400

Grape Tying/ Training/

Hand harvesting/ Leaf pulling 5

, 500 0.03935 2,500

Cherry/ pear/ plum Thinning fruit 3

, 600 0.02575 3,900

Blueberry/ grape Irrigation 1

, 900 0.01359 7,400

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 31 of 40 Table 9.2.1. Occupational Post

- A pplication Non

- Cancer E xposure and Risk Estimates for F orchlorfenuron.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Short

- term

C herry/plum/pear/fig / blueberry/ pistachio Hand harvesting /

Pollination 1

, 400 0.01 10,000

Blueberry Hand harvesting/

Scouting 1

, 100 0.00787 13,000

Blueberry/ grape Scouting/ Hand

pruning/ Hand weeding 640 0.00458 22,000

C herry/plum/pear/fig / almond/ pistachio Hand pruning /

Scouting/ Training 580 0.00415 24,000

F ig / almond/ pear/ blueberry/ cherry/ grape/ pistachio T ransplanting 230 0.00165 61,000

Almond/pistachio Mechanical

H arvesting 190 0.00136 74,000

Almond/pistachio / cherry/ fig/ pear/ plum Orchard

maintenance / Hand weeding/ Propping 100 0.00072 140,000

Blueberry Hand Weeding/

Hand Pruning 70 0.0005 200,000

Intermediate

- term

Grape Turning/ Girdling 19

, 300

0.06 0.12 730

Grape Tying/ Training /

Hand harvesting/ Leaf pulling 10

, 100 0.0 62 1,400

Grape Tying/ Training/

Hand harvesting/ Leaf pulling 5

, 500 0.03 3 2,500

Cherry/ pear/ plum Thinning fruit 3

, 600 0.02 2 3,900

Blueberry/ grape Irrigation 1

, 900 0.01 1 7,400

C herry/plum/pear/fig / blueberry/ pistachio Hand harvesting /

Pollination 1

, 400 0.0 08 10,000

Blueberry Hand harvesting/

Scouting 1

, 100 0.00 679 13,000

Blueberry/ grape Scouting/ Hand

pruning/ Hand weeding 640 0.00 395 22,000

C herry/plum/pear/fig / almond/ pistachio Hand pruning /

Scouting/ Training 580 0. 00358 24,000

F ig / almond/ pear/ blueberry/ cherry/ grape/ pistachio T ransplanting 230 0.001 42 61,000

Almond/pistachio Mechanical

H arvesting 190 0.001 2 74,000

Almond/pistachio / cherry/ fig/ pear/ plum Orchard

maintenance / Hand weeding/ Propping 100 0.000 62 140,000

Blueberry Hand Weeding/

Hand Pruning 70 0.000 43 200,000

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]  BW (kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal
absorption factor (%)]  BW (kg).

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 32 of 40 Restricted Entry Interval

The REI specified on the label s is based on the acute toxicity of forchlorfenuron.

F orchlorfenuron is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours following application) for all

post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), active ingredient’s classified as Acute III or IV for acute dermal, eye i rritation and primary skin irrit ation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protecti on Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to forchlorfenuron.

9.2.2 Inhalation Post

- A pplication Risk

Based on the Agency's current practices, a quantitative post

- application inhala tion exposure assessment was not performed for forchlorfenuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 3.5 x 10

- 5 

### torr (25°C) ), and the low use rate (0.025 lb ai/A). However, there ar e 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 particula tes 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 Advisory Panel (SAP) in December 2009 and received the SAP’s f inal report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report

, as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post

- a pplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inha lation exposure assessment for

forchlorfenuron

.

Alth ough a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

Davi s, D. 3/11/08. D341628. Forchlorfenuron: Human Health Risk Assessment for Proposed Uses on the Bushberry Subgroup 13 B and to Support a Requested Experimental Use Permit on Almonds, Sweet Cherries, Figs, Pears, Pistachios and Plums/Prunes. PC Code: 128 819, Petition No: 7E7228, DP Barcode: D341628.

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 33 of 40 Davis, D. 9/12 /13. D414083. Forchlorfenuron (CPPU). Petition for the Establishment of Permanent Tolerances and Registration for Use on Almond, Cherry (Sweet), Fig, Pear, Pistachio, Plum/Prune. Summary of A nalytical Chemistry and Residue Data.

Orrick, G. 3/11/13. D407227. Forchlorfenuron: Drinking Water Exposure Assessment for Proposed New Uses on Almonds, Sweet Cherries, Figs, Pears, Pistachios, and Plums Including

Prunes

Lloyd, M. 1/23/13. D407548. Forchlorfenuron (CCPU)

- Occupational/Residential Exposure/Risk Assessment for the Use of Forchlorfenuron on Figs, Plums, Pears, Sweet Cherries, Almonds and Pistachios.

LaMay, A. 2/6/14

. D414331. Forchlorfenuron

- Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Almonds, Sweet Cherries, Figs, Pears, Pistachios and Plums/Prunes

LaMay, A. 2/6/14. D407226. Forchlorfenuron. Human Health Risk Ass essment for Proposed Uses on Almond, Sweet Cherry, Fig, Pear, Pistachio and Plum/Prune.

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 34 of 40 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for forchlorfenuron are in T able 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ................................ 870.1200 Acute Dermal Toxicity

................................ ........................... 870.1300 Acute Inhalation Toxicity

................................ ....................... 870.2400 Primary Eye Irritation

................................ ............................. 870.2500 Primary Dermal Irritation

................................ ....................... 870.2600 Dermal Sensitization

................................ .............................. yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ........................ 870.3150 Oral Subchronic (nonrodent)

................................ .................. 870.3200 21/28

- Day Dermal

................................ ................................ .. 870.3250 90

- Day Dermal

................................ ................................ ....... 870.3465 90

- Day Inhalation

................................ ................................ ... yes

yes

yes

no CR yes

yes

--- A

---

--- A

870.3700a Developmental Toxicity (rodent)

................................ ............ 870.3700b Developmental Toxicity (nonrodent)

................................ ...... 870.3800 Reproduction

................................ ................................ ........... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ ........................ 870.4100b Chronic Toxicity (nonrodent)

................................ .................. 870.4200a Oncogenicity (rat)

................................ ................................ .... 870.4200b Oncogenicity (mouse)

................................ ............................. 870.4300 Chronic/Oncogenicity

................................ ............................. yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.............................. 870.5300 Mutagenicity

— Gene Mutation

- mammalian

......................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

............ 870.5395 Mutagenicity

— Other Genotoxic Effects

................................ yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ............... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .................... 870.6200a Acute Neurotox. Screening Battery (rat)

................................ . 870.6200b 90 Day Neurotox. Screening Battery (rat)

............................... 870.6300 Develop. Neurotoxicity

................................ ........................... no

no

yes

yes CR ---

---

--- A

--- A

---

870.7485 General Metabolism

................................ ............................... 870.7600 Dermal Penetration

................................ ................................ . 870.7800 Immunotoxicity...................................................... yes CR

yes yes

---

--- B

Non guideline Thyroid MOA Investigation Study no

---

A Waived by HASPOC (TXR# 0056596 )

B Waived by HASPOC (TXR# 0056795 )

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 35 of 40 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

- Forchlorfenuron

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [ rat ] 44394609 LD 50 (mg/kg) = M = 4904

F = 4899 III

870.1200 Acute dermal [ rabbit ] 44394611 LD 50 (mg/kg) = >2000 III

870.1300 Acute inhalation [ rat ] 44394608 LC 50 (mg/L) = >3.0 IV

870.2400 Acute eye irritation [ rabbit ] 44394607 Mild eye irritant III

870.2500 Acute dermal irritation [ rabbit ] 44394610 Non

- irritant IV

870.2600 Skin sensitization [ guinea pig ] 44394606 Non

- sensitizer

-



### Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity ( F i s ch e r 34 4 r a ts ) 44394614 (1987)

Acceptable/Guideline

0, 200, 1000, 5000 ppm M: 0, 16, 79, 400 mg/kg/day F: 0, 17, 84, 428 mg/kg/day NOAEL =  400 (male)

LOAEL = no adverse effe c ts observed (male) NOAEL = 84 mg/kg/day (female) LOAEL = 428 mg/kg/day (female), based on

decrease d body weight

, body weight gain , and food efficiency

870.3150 Sub c hroni c or a l

tox i c i t y (Beagle dog) 44394615 (1987/1993)

Acceptable/Guideline

0, 50, 500, 5000 ppm M: 0, 1.8, 16.8, 162.4 mg/kg/day F: 0, 1.8, 19.1, 188.7 mg/kg/day NOAEL = 16.8/19.1 mg/kg/day (male/female)

LOAEL = 162.4/188.7 mg/kg/day
(male/female), based on decreases (  10%) in body weight gain, food consumption , and food efficiency

870.3700a Developmental

toxicity
(Sprague Dawley

Crl:CD ®BR rat)

(GD 6

- 15) 44394612 (1986)

45840123 (2002) Acceptable/Guideline

0, 100, 200, 400 mg/kg/day

45840113 (2002) analytical information Maternal NOAEL = 200 mg/kg/day

Maternal LOAEL = 400 mg/kg/day, based on death of one dam, increased incidence of alopecia; significantly decreased body weight (BW) an d body weight gains Developmental NOAEL = 200 mg/kg/day Developmental LOAEL = 400 mg/kg/day,

based on decreased mean fetal BW and a slight increase in the incidence of delayed ossification

of the sternebrae

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 36 of 40 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Prenatal

developmental in (New Zealand White rabbit)

GD 6

- 18 44394613 (1986)

45840122 (2002) Acceptable/Guideline

0, 25, 50, 100 mg/kg/day

44359526 (1985)

- range finding 0, 125, 250, 500, 1000 mg/kg/day 45840113 (2002) analytical information Maternal NOAEL = 100 mg / k g /day

M a t e rn a l L O A EL not determined

D e ve l op m en t a l N O A EL = 100 m g/kg/d a y Develo p mental LOAEL not determined

870.3800 Reproduction and

fertility effects (Sprague Dawley

Crl:CD ®BR rat) 44394616 (1997)

Acceptable/Guideline

0, 150, 2000, 7500 ppm

F 0 M: 0, 11, 144, 544 mg/kg/day

F 0 F: 0, 13, 169, 701 mg/kg/day

F 1 M: 0, 13, 168, 829 mg/kg/day

F 1 F: 0, 15, 202, 926 mg/kg/day Parental NOAEL = 11 mg/kg/day. Parental LOAEL = 144 mg/kg/day, based on decreased food consumption (F 0 & F 1 males), clinical signs of toxicit y [ dried tan or yellow staining around the anogenital, urogenital, and

abdominal areas ; brown staining the entire length of the tail (both sexes); an unkempt appearance and pale extremities ( F 0 females )

, and dried red material around the nose ( F 0 and

F 1 fe males )] , and lower BW in F 1 males and

females

At highest dose tested ( HDT ) , decreased body weight and kidney lesions (suppurative

inflammation in F 0 rats; suppurative pyelonephritis in F 1 rats)

Reproductive N OAEL = 7500 ppm (544/701 mg/kg/day (HDT). Reproductive LOAEL not determined.

Offspring NOAEL = 11 mg/kg/day Offspring LOAEL = 144 mg/kg/day based on growth retardation in F 1 and F 2 pups.

At HDT , increased pup mortality (F 1a , F 1b &

F 2a ), growth retardation in F 1b , and decrease in

F 2 pups/litter

870.4100b Chronic toxicity

(dog) 45840105 (1998)

Acceptable/Guideline

0, 150, 3000, 7500 ppm M: 0, 5, 87, 195 mg/kg/day F: 0, 5, 91, 246 mg/kg/day NOAEL = 87/91 mg/kg/day (male/female)

LOAEL = 195/246 mg/kg/day (male/female), based on decreases in BW, BW gains , and FC

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 37 of 40 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity

(Crl:CD

- 1®(ICR) BR mouse) 45840106 (2002)

Acceptable/Guideline

M: 0, 10, 991.4 mg/kg/day F: 0, 9.9, 1001.8 mg/kg/day NOAEL = 10.0/9.9 mg/kg/day (male/female)

LOAEL = 991.4/1001.8 mg/kg/day (male/female), based on decreases in body weight and body weight gains (both sexes)

no evidence of carcinogenicity

870.4300 Combined

Chronic Toxicity/ Carcinogenicity

(Crl:CD®BR rats) 44394617 (1996)

Acceptable/Guideline

0, 150, 2000, 7500 ppm M: 0, 7, 93, 352 mg/kg/day F: 0, 9, 122, 518 mg/kg/day NOAEL= 7/9 mg/kg/day (male/female) LOAEL= 93/122 mg/kg/day (male/female),

based on reduced BW

, BW gain , and food consumption ; kidney toxicity (suppurative inflammation in males; no n

- suppurative interstitial nephritis in females) no evidence of carcinogenicity

870. 5100 Salmonella /

mammalian activation gene mutation assay 44394621 (1985)

Acceptable/Guideline

10

- 1000  g/plate +S9

2

- 200  g/plate

- S9 Evidence of induced mutant colonies over background in tester strain TA1535 in absence of S9 (repeat of MRID 44394620).

There is no evidence of reproductive effects (no decrease in fertility; no increase in dead implants/fetuses) to suggest a genetic

component

870. 5100 Salmonella /

mammalian activation gene mutation assay 44394620 (1985)

Acceptable/Guideline

10

- 1000  g/plate +S9

2

- 200  g/plate

- S9 Evidence of a positive response in tester strain TA1535 in absence of S9 at 50, 100, and 200

 g/plate; negative ± S9 at all other doses and strains (see above)

870.5375 In vitro

mammalian

chromosome

aberration test in

Chinese Hamster

CHO

- KI cells 44394618 (1985)

Acceptable/Guideline

10, 20, 40, and 80  g/mL ±

S9 activation No increase in chromosomal aberrations over background ± S9

870.5550 Unscheduled DNA

synthesis in

mammalian cell

cultures ( primary rat hepatocytes ) 44394619 (1985)

Acceptable/Guideline

0.1 to 60  g/mL Negative for induction of unscheduled DNA synthesis

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 38 of 40 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (Sprague Dawley rat) MRID 45840107 (2002)

Acceptable/Guideline

100 mg/kg (acute) Forchlorfenuron is rapidly and almost entirely absorbed and metabolized, tissue residues are minimal, and excretion is almost complete. Overall recovery was 97%. The majority of the

dose was recovered in the urine within 24 hours (62

- 74% dose). Fecal excretion accounted for

16

- 28% dose, and 20

- 23% of the dose was found in the bile. At 168 hours post

- dose, the highest concentrations of radioactivity were found in the kidney and liver. The eli mination

half

- life was 13.1

- 16.2 hours. There were no

sex

- related differences.

The metabolism of forchlorfenuron in rats includes conjugation with sulfate at the phenyl ring (major pathway) before or after hydroxylation of the phenyl ring, hydroxylation

of the phenyl ring (major pathway), conjugation with glucuronide at the phenyl ring, methylation of the hydroxy group of hydroxyl CPPU

- sulfate, and hydroxylation of both the chloropyridinyl and phenyl rings.

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 39 of 40 Appendix B

. Forchlorfenuron International Residue Limits Table

Table B.1 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 

### Codex

40 CFR 180.569:

Plant: forchlorfenuron ( N

- (2

- chloro

- 4

- pyridinyl)

- N'

- phenylurea) None None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 

### Codex

Almond 0.01
Almond, hulls 0.15 Bushberry subgroup 13

- 07B 0.01 Cherry, sweet 0.01 Fig 0.01 Grape 0.03 Grape, raisin 0.06

Kiwifruit 0.04

Pear 0.01

Pistachio 0.01 Plum, prune, fresh 0.01



### Completed: M. Negussie; 11/17/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Forchlorfenuron Human Health Risk Assessment DP No. D422527

Page 40 of 40 Appendix C

. Review of Human Research

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 PHED 1.1; the AHETF database; the Outdoor Residential Exposur e Task Force (ORETF) database; and the 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 include d 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 8



### .

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

- exposure

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

- app

- exposure

- data.html