Flurprimidol Human H ealth Draft Ri sk Assess ment DP No. D427106

UN ITED S TATES EN VIRONM E NTAL PR OT E CT IO AGENCY

W J\S Hf NGTON. D.C. 20460



### MEMORAND U M

Dat e : June 4

, 2015 OFF I C E OF

C llE\ll C \I. S
.- \F ET\

. \:'\O

POI.LI TIO:'\**PIU t;:;\**  1'1 0'1



### SUBJECT: F l urprimido l : Human He a lth Draft Ri sk A ss essment fo r Registrati o n R eview.



### P C Co d e: 1 2570 

### I

D ecis i o n No.: 503929



### P e tition No.: N I J\



### R i s k Assessme nt Type: Sing l e
Chemical/ Aggregate



### TXR No

. : N I A



### M RID No.: N I A 

### DP Bar co d e: 427106



### Re g i s tration No.: N I A



### Re g ul a tory Act i o n : Registrat i on Review



### Case No.: 

### N / A

CAS No .: 56425-91

- 3 '



### 40 

### CF R : N I A



### FROM: Chris Schlosser, Ri s k Assessor, Toxic o l og i s t

# ~~**~,?,;' ~**  M o nica Ha wk in s, Ph

. D.

,

### .P.H.**,** Pl:lvironmenta l He a lth Scientist

### ~**~** S h e ila Pip er
, C hemist 

## 6**~~ ~,._,,;**  Ri s k Assessment Branch Vf



### THROUGH : D on n a Da v i s
, Act ing Bran c h

# hief**~l.C'c_.J a~**  Ri sk Assessment Branch VI

H ea lth Effects Division



### TO: K e ll y Ballard

, C h e mical R eview Manager

Neil Anderson

, Branch Chief

Ri s k Management and 

### J mp l eme ntation Branch I

Pe s ticide Re- eva lu ation Di vision (7508P)

The Health Effec t s Di v ision ( HED ) of th e Office of Pesticide P rograms ( OPP ) i s charged with

es tim a ting the ri s k to human h ea lth from ex posure to p es t i cides. A s part of Registration R ev i e w
, th e P es ticide R e

- e valuation Divis i on ( PR O) of OPP h as r equested that HED eva lu ate the ha za rd

and expos ure d ata a nd conduct di e tar y, occ upational

, residentia l

, and aggregate ex posure

assessme nts

, as n eeded, t o est imat e the ri sk t o human he a lth that w ill r esult from th e r eg ist e r ed

u ses of flurprimid o l.

H E D h as evaluated the toxicity and expo s ure database s fo r the act i ve ingredient

, flurprimid o l

,

a nd h as conducted a hum a n h ea lth ri s k assessment in sup port of R eg i s tration Re v i ew.

P age 1 of 48Flurprimidol Human H ea lth Draft Ri sk Assessment DP No. D42710 6

A summary of the findings and a n assessment of hum a n h ea lth ri sk r es ultin g from th e currently registered uses of flurprimidol are provided in th i s document. The H E D team members

contribut in g to thi s ri s k assessmen t include C hri s Schlosser ( ri s k and hazard asse ss ment ),

Monica H awk in s (occupatio n a l and reside n t i a l assessment)

, and S h ei la Pip e r (d i eta r y

assess m e nt). James W o lf of th e Environmental F ate and Effec ts Di v i s ion (EFED) performed th e drinking wate r assess m e nt.

Pa ge 

### 2 of 48

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 3 of 48 1.0 Executive Summary

................................ ................................ ................................ ........... 5

2.0 HED Recommendations

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

2.1 Data Deficiencies

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

2.2 Tolerance Considerations and International Harmonization

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

2.3 Label Recommendations

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

2.3.1 Recommendations from Occupational/Residential Assessment

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

3.0 Ingredient Profile

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

3.1 Ch emical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Toxicology Studies Available for Analysis

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

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

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

4.2.1 Dermal Penetration

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

4.3 Toxicological Effects

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

4.4 Safety Factor for Infants and Children

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

4.4.1 Completeness of the Toxicology Database

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

4.4.2 Evidence of Neurotoxicity

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

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

......... 14

4.4.4 Res idual Uncertainty in the Exposure Database

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

4.5.1 Dose

- Response Assessment

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

...... 16

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints

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

4.6 Endocrine Disruption

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

5.0 Dietary Exposure and Risk Assessment

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

5.1 Food Residue Profile

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

5.2 Summary of Environmental Degradation

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

5.3 Water Residue Profile

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

5.4 Dietary Risk Assessment

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

5.4.1. Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Dietary Summary Table

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

6.0 Residential Exposure and Risk Estimates

................................ ................................ ..... 22

6.1 Residential Handler Exposure/Risk Estimates

................................ ............................. 22

6.2 Residential Post

- application Exposure/Risk Estimates

................................ ................ 24

6.3 Spray Drift

................................ ................................ ................................ ........................ 25 6.3.1 Combined Risk Estimates From Lawn Deposition Adjacent to Applications

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

6.4 Residential Bystander Post

- Application Inhalation Exposure

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

7.0 Combined Exposure/Risk Characterization

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

8.0 Cumulative Exposure/Risk Characterization

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

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 4 of 48 9.0 Occupational Exposure and Risk Estimates

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

9.1 Occupational Handler Exposure/Risk Estimates

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

9.2 Occupational Post

- application Exposure/Risk Estimates

................................ ............ 35

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

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

................................ ................... 37

A.1 Toxicology Data Requi rements

................................ ................................ ....................... 37

A.2 Toxicity Profiles

................................ ................................ ................................ ............... 38

A.3 Hazard Identification and Endpoint Selection

................................ .............................. 43 Appendix B. DEEM

- FCID Model Inputs and Outputs for Acute and Chronic Dietary Exposure Estimates.

................................ ................................ ................................ ......... 46

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 5 of 48 1.0 Executive Summary

Flurprimidol is a turf grass and woody

- plant growth regulator that belongs to the pyrimidine

class of chemicals and has multiple end

- use products that are r egistered for use on perennial turfgrass (cool and warm season) on golf cour ses and turf, landscape/woody ornamental plants,

ornamental trees

, and ornamental plants grown in containers in nurseries, greenhouses, and

shadehouses. Most of the flurprimidol product labels direct mixers, loaders, applicators, and

other handlers to wea r long

- sleeved shirt, long pants, shoes and socks, and chemical

- resistant gloves. Flurprimidol is marketed as a wettable powder in water

- soluble packets, liquid concentrate, granule, and soluble concentrate. There are currently no registered food uses for flurprimidol.

The toxicology database for flurprimidol is complete and provides sufficient information to adequately identify hazards for risk assessment purposes. In mammals, f lurprimidol targets the adrenal gland in dogs and the liver in rats. There are no concerns for neurotoxicity or susceptibility to the young. Based on the available data, no evidence of genotoxic, or

immunotoxic effects were identified in the database. In the 2005 Human Health Risk Assessment, flurprimidol was classified “not like ly to be carcinogenic to humans

. ”

For acute dietary assessment of the general population , the acute neurotoxicity study in rats was selected with a NOAEL of 70 mg/kg/ based on treatment related findings at the mid

- dose (285 mg/kg), includ ing gait abnormality in both sexes, low arousal and impaired righting reflex in males, and hunched body in females, 7

- 8 hours after dosing. For females 13

– 49 years old , the developmental toxicity study in rats was selected with a NOAEL of 10 mg/kg/day for dams and pups. Skeletal abnormalities seen at the study LOAEL of 45 mg/kg/day could be from a single exposure during pregnancy and are

, therefore

, considered a potential acute effect, and appropriate for the acute dietary endpoint scenario for females of c hild

- bearing age. For chronic dietary exposure and risk assessment, the chronic toxicity study in rats was selected with a

NOAEL of 3.6 mg/kg/day. The LOAEL is 12.1 mg/kg/day based on increased incidences of focal atypia, fatty change , and hepatocellular e osinophilic change in the liver of males. A dermal assessment is not required for flurprimidol since this chemical does not pose a dermal hazard

. For short and intermediate

- term inhalation exposure, the 13

- week inhalation toxicity study in rats

was selecte d with a NOAEL of 0.1 mg/L based on nasal hyperplasia observed at the next highest dose (0.4 mg/L)

. A human equivalent concentration (HEC) was calculated from the inhalation study. For inhalation exposure, the standard interspecies extrapolation uncertain ty factor can be reduced from 10X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences. The intraspecies uncertainty factor remains at 10X.

For all other routes of exposure a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X).

Food Quality Protection Act (FQPA) considerations do not apply to flurprimidol since currently registered use patterns are all non

- food uses. While there are potential exposures to infants and children from turf use patterns of flurprimidol, there are adequate pre

- and/or postnatal toxicity studies that demonstrate no residual uncertainties to infants and children for pre

- and/or postnatal susceptibilities. These studies have clearly defined NOAEL/LOAELs and the selected points of

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 6 of 48 departure (PODs) are protective of all observed adverse effects, including clinical signs indicative of neurotoxicity that were observed in the ACN.

Flurprimidol is mobile and resistant to degradati on in the soil and stable to hydrolysis suggesting the potential for leaching and movement to roots for uptake in water by growing plants. Based on the environmental fate parameters, there is the potential for flurprimidol to reach drinking

water resource s. The Environmental Fate and Effects Division (EFED) performed Tier 2 surface water and groundwater modeling using the highest application rates. The highest estimated drinking water concentrations were from groundwater.

No exposure fr o m food is expe cted. A dietary assessment was conducted for drinking water only. The acute drinking water risk estimates are below HED’s level of concern (<100% of the acute population adjusted dose (aPAD) ) for the general U.S. population and all population subgroups ; the population subgroup with the highest risk estimate is females 13 to 49 years old

which utilize 38% of the aPAD

. The resulting drinking water chronic exposure estimates were less than HED’s level of concern (<100% cPAD) for the general U.S. population and all population subgroups; the most highly exposed population subgroup was all infants (<1 years old) with an estimated risk of 89% of the cPAD.

Residential handler short

- term exposure is anticipated from the registered uses. The residential

handler exposure and risk estimates indicate that the inhalation margins of exposure ( MOE s ) are greater than HED’s LOC ( i.e., MOEs are ≥ 30). The MOEs range from 2,000 to 1,300,000. Residential post

- application dermal exposure for adults or children was not quan titatively assessed for flurprimidol because there is no identified dermal hazard. Also, residential post

application incidental oral exposure for children was not assessed based on the registered use

sites. Combined exposure assessments were not conduct ed since exposures should not be combined across routes of exposure for this chemical, and there is only a single source of oral exposure from drinking water. A quantitative spray drift assessment was conducted. Risk estimates from groundb oom applications are not of concern from the field edge for all scenarios

considered.

Occupational handler short

- and intermediate

- term exposure is anticipated from the registered

uses. The occupational handler exposure and risk estimates indicate that the short

- and

intermediate

- term inhalation MOEs are not of concern to HED (i.e., MOEs ≥ 30) at the baseline

attire (i.e. , no gloves and no respirator). The MOEs range from 1,100 to 900,000. Occupational
post

- application dermal exposure was not quantitativ ely assessed since there is n o dermal hazard for flurprimidol.

2.0 HED Recommendations

2.1 Data Deficiencies

No toxicology, residue chemistry or occupational/residential data deficiencies were identified for flurprimidol.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 7 of 48 2.2 Tolerance Considerations and International Harmonization

There are no food uses for flurprimidol at this time ; t herefore

, a discussion of tolerances and

international harmonization is not relevant to this chemical.

2.3 Label Recommendations

2.3. 1 Recommendations from Occupational/Residential Assessment

The Registration Division (RD) should ensure that the proper personal protective equipment (PPE) is listed on all flurprimidol labels. There are several labels that do not contain this

information. For example, EPA Registration # 67690

- 34 (Flurprimidol Solution) and 67690

- 68 (Cutless 0.67G) do not contain any PPE information

.

3.0 Ingredient Profile

3.1 Chemical Identity

Table 3.1 Compound Structure and Nomenclature

Chemical Structure

Empirical Formula C 15 H 15 F 3 N 2 0 2 Common name Flurprimidol Company experimental

name N/A

IUPAC name alpha

- (1

- methylethyl)

- alpha

- [4

- (trifluoromethyoxy) phenyl]

- 5

- pyrimidinemethanol

CAS name alpha

- (1

- methylethyl)

- alpha

- [4

- ( trifluoromethyoxy) phenyl]

- 5

- pyrimidinemethanol CAS Registry Number 056425

- 91

- 3

End

- use product/EP Topflor

Chemical Class pyrimidine plant growth regulator Known Impurities of

Concern N/A

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 8 of 48 3.2 Physical/Chemical Characteristics

Flurprimidol is a white to pale yellow crystalline solid under normal temperature and mostly odorless. Flurprimidol is not expected to be volatile, has a moderate solubility in water, and a low potential to bioaccumulate as demonstrated by its relatively low Kow. Flur primidol is resistant to degradation (e.g., half

- life > 400 days) in the soil and stable to hydrolysis

.

Table 3.2. Physical and Chemical Properties of Flurprimidol



### Parameter Value Reference
Molecular Weight 312.3 US EPA Pesticide Fact

Sheet 1989 Melting point/range 93

- 95  C pH 6.5

- 8.9 in D

- H 2 0 Density 0.83 to 0.88g/cc Water solubility (20 C) 120

- 140 ppm Vapor pressure (25 C) 3.64 x 10

- 7 mmHg Octanol/water partition coefficient, logP OW (25 C) Kw = 9.33



### 3.3 Pesticide Use Pattern

Flurprimidol has multiple end

- use products that are r egistered for use on perennial turfgrass (cool and warm season) on golf courses and turf, landscape/woody ornamental plants,

ornamental trees and ornamental plants grown in containers in nurseries, green houses, and shadehouses. Flurprimidol is marketed as a wettable powder in water

- soluble packets, liquid concentrate, granule, and soluble concentrate. For most use sites, baseline attire (i.e., long

sleeved shirt, long pants, shoes

, and socks) and chemic al

- resistant gloves are required

.

Table 3.3 provides a summary of the highest application rate of the registered uses for flurprimidol

.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 9 of 48 Table 3.3. Summary of Registered Uses for Flurprimidol

Crop/Use Site Type of

Application Register

ed

Formula

tions Maximum Application

Rate PPE Use Directions and

Limitations

Turf

Golf Course

Turf broadcast

treatment for golf courses, backpack sprayer for edging/bandi ng, hand

- held equipment WP in

Water

Soluble

Packets 1.5 lb ai/A

(Edging/Ban ding) (0.008 lb

ai /gallon,

0.000034 lb

ai/f t2 );

0.75 lb ai/A (Fairways)

0.25 lb ai/A (Greens, Tees Only) Long

- sleeved

shirt, long pants, shoes, socks,

chemical

resistant gloves Do not apply through any type

of irrigation system. Can be applied to turfgrass in edging

and banding applications along the perimeter of lawns, landscape beds, sidewalks, curbs, parking lots, driveways, posts, mailboxes, building structures, gravestones, and

fences.

Landscape ornamentals, Woody

ornamental

shrubs and hedges 1 Rotary

- type,

gravity

- f ed,

airflow

driven spreader G 1.5 ai/A

(0.000034 lb

ai/f t2 ) for landscape

ornamentals Long

- sleeved

shirt, long pants, shoes, socks,

chemical

resistant gloves Do not apply to annual bedding plants.

Golf Course

Turf Drop, rotary

type spreader G 1.0 lb ai /A for fairways,

0.75 lb ai/A for greens,

tees Long

- sleeved

shirt, long pants, shoes, socks,

chemical

resistant gloves, protective

eyewear Do not apply this product to be

inadvertently applied to non

- turf

areas such as flowerbeds or ornamental shrubs as gr owth inhibition may occur.

Ornamental

Plants Grown

in Commercial Nurseries, Greenhouses,

Shadehouses Spray,

Drench/Soil/

Ground

Directed, Chemigation Foliar

Spray 0.55 lb ai/A

(.00165 lb ai/gallon,

0.00001275

lb ai/ft 2 ) Long

- sleeved

shirt, long pants, sh oes, socks,

chemical

resistant gloves,

coveralls For commercial use. In New

York the product can be used for greenhouse applications only. Do not apply through any type of chemigation in California or

New York.

Landscape

Ornamentals (Shrubs, Bushes) Hand

- held WP in

Water

Soluble

Packets 1.08 lb ai/A

(0.000024 lb ai/square feet; 0.005 lb ai/gallon) SL w/CR

gloves, coveralls, and protective

eyewear (goggles or face shield) Do not apply through any type

of chemigation. Do not apply to annual bedding pla nts. Do not

use for treatment of trees. Do not use on plants from which fruits, nuts or other commodities may be produced for human consumption or livestock feed. Landscape Ornamentals, Hand

- held

for container

G 1.5 lb ai/A Long

- sleeved shirt, long For perennial landscape

ornamentals the label states the

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 10 of 48 Table 3.3. Summary of Registered Uses for Flurprimidol

Crop/Use Site Type of

Application Register

ed

Formula

tions Maximum Application

Rate PPE Use Directions and

Limitations

Container

Grown Ornamentals, Woody

Ornamental Shrubs, Plants, Flower s grown

ornamentals, push type spreader, belly grinder spreader pants, shoes, socks,

chemical

resistant gloves product is not for use by

homeowners. Do not apply to annual bedding plants or areas intended for annual bedding plants within 6 months of application of Cutless 0.33G. The product is not suitable for

treatment of ornamental trees.

Turf Hand

- held,

push type spreader G 1.5 lb ai /A Long

- sleeved shirt, long pants, shoes, socks,

chemical

resistant gloves Apply the product along the

perimeter of lawns, landscape beds, sidewalks, curbs, driveways, fences, mailboxes, building structures, and light

posts.

Ornamental

Trees Injection Ready

to

- Use Liquid 1.46 lb ai/day NS Do not inject food bearing trees.

Ornamental

Trees Implant Ready

to

- Use Liquid 1.5 g/tree Long

- sleeved shirt, long pants, shoes, socks,

chemical

resistant gloves For a 30

- inch diameter tree

apply 45 implants which is equivalent to 1.5 g/tree.

NS = Not Specified; G = granul ar

. 1 Note: This product is an impregnated fertilizer that could be applied by a tractor

- drawn spreader. Therefore, the assessment addresses occupational handler exposure from the tractor

- dra wn spreader.



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to flurprimidol in drinking water, as the registered uses may result in flurprimidol reaching ground water. In a residential setting, adults applying the pesticide may be exposed, howev er, application is limited to the edges of turf; therefore significant exposure to adults and children resulting from contact with treated turf is not anticipated. Workers may be exposed occupationally during the mixing, loading, and apply of the pesticid e.

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,” ( h ttp://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ) . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pestic ide use in a residential

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 11 of 48 setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008) and are u sed in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categor ized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or pl aying on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm wor kers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for flurprimidol is complete and provides sufficient information to adequately identify hazards for risk assessment purposes. Since the last risk assessment acute and subchronic neurotoxicity, immunotoxicity, and subchronic inhalati on studies have been

submitted to the A gency and incorporated into this assessment. The database includes the following studies:

 90

- Day oral toxicity studies in the rat, mouse and dog,

 21

- Day dermal toxicity in the rabbit,

 90

- Day inhalation toxicity in t he rat,

 Developmental toxicity in the rat and rabbit,

 2

- Generation reproductive toxicity in the rat,

 Chronic toxicity in the rat and dog,

 Carcinogenicity in rat and mouse

,

 Genetic toxicity battery,

 Acute and subchronic neurotoxicity in the rat,

 Metabolis m study in the rat, and

 Immunotoxicity study in the rat.

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

Flurprimidol is rapidly (peak plasma levels occur at 5

- 10 hours after dose in both sexes) and highly ( 84

- 99 %) absorbed following a single oral dose at low and high doses (2.5 and 50 mg/kg/day).

Following a single dose, tissue distribution studies demonstrated no significant accumulation 48 hours after dosing in the low or high dose groups. However, minor accumulation was observed in the liver (0.7%). Following multiple doses (low dose only), no significant tissue accumulation

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 12 of 48 (0.1% in the liver) was observed. Based on the available information, n o evidence of

bioaccumulation was identified.

Flurprimidol was extensively metabolized into over 30 metabolites with less than 2.5% of the

u nchanged parent being identified in the feces. The primary metabolite was identified (β

hydroxy

- α

- methyl

- β

- [4

- (trifluoro

- methoxy)phenyl]

- 5

- pyrimidinepropanoic acid) and was present

at 10

- 20% dose, mainly in the urine. Other metabolites individually accounted for less than 6%

of the dose. Major metabolic pathways include oxidation of the isopropyl group and the pyrimidine ring. Oxidation of the carbinol

- carbon atom and dehydration between the carbinol

carbon atom and isopropyl group were also observed.

The ma jority of the dose was excreted within 2 days (90

- 96% at the low dose and 78

- 80% at the high

- dose)

. The elimination half

- life was reported as 31 to 42 hours. At the low dose, excretion occurred primarily in the urine (61 to 74%) with the remaining dose b eing excreted in the feces (25 to 34%). At high doses, lower amounts were excreted in the urine (52

- 59%) indicating a saturation of the absorption processes. Biliary excretion studies in rats indicated most of the radioactivity eliminated in the feces was absorbed from the gastrointestinal tract and eliminated through the bile.

No significant sex

- dependent pharmacokinetic differences were identified at either low

- or high

doses.

4 .2.1 Dermal Penetration

A dermal penetration study was conducted in rhesu s monkeys but was unacceptable for risk
assessment purposes. However, using a NOAEL/LOAEL extrapolation, the upper bound limit for dermal absorption can be estimated as 6% based on comparison of the 60 mg/kg/day LOAEL in rabbits from the developmental stu dy for decreased body weight gain and the 1,000 mg/kg/day NOAEL in rabbits from the dermal toxicity study.

4.3 Toxicological Effects

Flurprimidol is a turf grass and woody

- plant growth regulator that belongs to the pyrimidine

class of chemicals. I ts pesticidal mode of action is to inhibit the early stages of gibberellin biosynthesis. The mammalian mode of action has not been elucidated. In mammals, flurprimidol targets the adrenal gland in dogs and the liver in rats. No adverse effects were obser ved throughout the database in the mouse. In rats, liver effects were only observed following chronic exposure and were evidenced by increased liver weights and histopathological changes including focal atypia, fatty change, and eosinophilic change in bot h sexes. Adrenal effects in dogs included decreased plasma cortisol levels and adrenal gland weights, adrenal cortical vacuolation, slight cortical atrophy, and eosinophilic change in both sexes. The effects were observed at similar doses following both 14

- day, sub

- chronic

, and chronic exposure and did not show progression of toxicity over time. The lack of progression over time is further supported by the metabolism data indicating that flurprimidol does not bioaccumulate in tissues.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 13 of 48 In the 2

- generatio n reproductive toxicity study no qualitative or quantitative susceptibility was observed. Reproductive effects included decreased fertility and fetal survival. In the offspring, effects included decreased survival and body weights observed in the presence of overt maternal toxicity. In the developmental studies, qualitative susceptibility was seen in the rat offspring,

based on an increased incidence of microphthalmia, a developmental disorder of the eye where one or both of the eyes are abnormally small, and skeletal anomalies in the vertebrae (extra) and

ribs (extra, rudimentary, cervical). These effects were observed in the presence of significantly decreased body weights gains (up to 138%) in maternal animals on gestation days 6

- 10. In the

rabbit deve lopmental study, anorexia, increased abortions, weight loss, and decreased food consumption were observed at highest tested dose.

Potentially neurotoxic effects were observed at high doses (≥ 285 mg/kg) in the ACN study including: gait abnormalities, low arousal, impaired right ing reflex, and hunched body posture. However, no neurotoxic effects were observed in the SCN at doses up to 77 mg/kg/day.

Based on the available data, no evidence of genotoxic or immunotoxic effects were identified in

the databas e.

In the 2005 Human Health Risk Assessment, flurprimidol was classified as “not likely to be carcinogenic to humans.” For more detail on cancer classification see Section 4.5.3.

The acute toxicity data indicate that flurprimidol has low toxicity ( Toxicity Category III and IV) via oral, dermal, and inhalation routes of exposure. It is slightly irritating to the skin ( Toxicity Category IV) and moderately irritating ( Toxicity Category III) to the eye. Flurprimidol is not a sensitizer in a guinea pig skin sensitization study.

4.4 Safety Factor for Infants and Children

HED does not recommend any additional safety factors for infants and children. No evidence of increased quantitative susceptibility was observed. In the rat developmental study, qualitative susceptibility was observed. However, the effects observed in the rat and rabbit developmental,

and rat 2

- generation reproduction studies occur in the presence of maternal toxicity. Additionally, these studies have clearly defined NOAEL/LOAELs and the selected points of departure (PODs) are protective of all observed adverse effects, including clinical signs indicative of neurotoxicity that were observed in the ACN.

4.4.1 Completeness of the Toxicology Database

The toxicology database for flurprimidol is complete and there are no residual uncertainties with regard to assessment of pre

- and/or postnatal susceptibility. Acceptable developmental toxicity

studies in rats and rabbits are available , i n addition to an acceptable reproduction study in rats.

4.4.2 Evidence of Neurotoxicity

Clinical signs of neurotoxicity w ere observed at high doses in the ACN. However, no neurotoxic

effects were obse rved in the SCN, or throughout the rest of the flurprimidol database. Based on

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 14 of 48 the available data, selected PODs are protective of any potential neurotoxic effects that may result from flurprimidol exposure.

4.4.3 Evidence of Sensitivity/Susceptibility i n the Developing or Young Animal

The available data do not provide evidence of any increased quantitative susceptibility in the offspring . In the rat developmental study, increased qualitative susceptibility was observed, characterized by fetal skeletal abnormalities in the presence of significantly decreased maternal body weight gain. However, these effects have clearly defined NOAEL/LOAELS and selected PODs are protective of all adverse effects observed in the developing or young animal.

4.4.4 Residu al Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database since adequate exposure data are available to assess the occupational and residential exposure resulting from the registered uses.

4 .5 Toxicity Endpoi nt and Point of Departure Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and PODs for various exposure scenarios is presented in Appendix A and summarized in Table 4.5.4.

For acute dietary assessment of the general population , the acute neurotoxicity study in rats was selected with a NOAEL of 70 mg/kg/day. The LOAEL is 285 mg/kg/day based on treatment related findings at the mid

- dose included gait abnormality in both sexes, low arousal

, and impaired righting reflex in males, and hunched body in females, 7

- 8 hours after dosing . No other effects attributable to a single dose relevant to the general population were observed.

For acute dietary assessment of females 13

– 49 years old , the developmental toxicity study in rats was selected with a NOAEL of 10 mg/kg/day for dams and pups. The LOAEL is 45 mg/kg/day for dams and pups based on decreased body weight gain (138%) in dams and skeletal

abnormalities in fetuses. Skeletal abnormalities could be from a single exposure during pregnancy and are therefore considered a potential acute effect, and therefore, appropriate for the acute dietary endpoint scenario for females of child

- bearing age. These effects are also protective

of abortions observed in the developmental rabbit study.

For chronic dietary exposure and risk assessment, the chronic toxicity study in rats was selected

with a NOAEL of 3.6 mg/kg/day. The LOAEL is 12.1 mg/kg/day based on increased incidences

of focal at ypia, fatty change, and hepatocellular eosinophilic change in the liver of males. The chronic toxicity study in rats is appropriate for the populations and duration of concern, and is protective of all other adverse effects observed within the database.

For short

- term incidental oral exposure (1

- 30 days), the 2

- generation reproductive toxicity study

in rats was selected with a NOAEL of 7.3 mg/kg/day. The LOAEL is 74 mg/kg/day based on

decreased pup survival and body weights (20

- 39%)

. The POD in this stu dy ( survival and

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 15 of 48 bodyweight) is appropriate for the age of the population (infant and children) and the duration of

concern. It is protective of all other short

- term effects observed in the database. Intermediate and long

- term incidental oral exposure asse ssment are not required because these exposure lengths are not expected based on current use patterns.

A dermal assessment is not required for the flurprimidol . No toxicity was observed up to the limit dose in the dermal toxicity study. No quantitative susceptibility was observed in any study. Qualitative susceptibility was observed in the rat developmental study, however; as the effects occurred in the presence of decreased maternal body weights the available dermal toxicity study is considered to be p rotective as no decreased body weights were observed in that study

. Additionally, applying the estimated upper bound dermal absorption value to the developmental

LOAEL would result in an estimated dermal LOAEL near the limit dose (~750 mg/kg/day).

For s hort and intermediate

- term inhalation exposure, the 13

- week inhalation toxicity study in rats was selected with a NOAEL of 0.1 mg/L. The LOAEL is 0.4 mg/L based on results in the range

finding study (MRID 49007302) where goblet cell hyperplasia was observ ed in nasal level II, III, IV, V, and VI of male rats (nasal passages of females were not examined microscopically). The inhalation toxicity study was chosen as it is a route

- specific study, is protective of all developmental and reproductive effects, and appropriate for the duration of concern. L ong

- term
inhalation asse ssment is not required because this exposure lengt hs are not expected based on
current use patterns.

The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) are suited for calculating HECs based on the inhalation toxicity point of departure ( N OAEL, LOAEL, or BMDL) for use in MOE calculations. The regional

- deposited

dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [  g 

### ] of aerosols), can be used to estimate

the different dos e fractions deposited along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas. Thus, the RDDR can be

used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the subchronic inhalation toxicity study with flurprimidol,

an RDDR wa s estimated at 0.223 based on portal

- of

- entry effects ( goblet cell hyperplasia was observed in nasal level II, III, IV, V, and VI) at the LOAEL of 0.4 mg/L and a MMAD of 2.62

 m and  g 

### of 1.7

.

HEC and HED calculations are summarized in Table 4.5.1. The standard interspecies extrapolation uncertainty factor can be reduced from 10X to 3X due to the HEC calculation accounting for pharmacoki netic (not pharmacodynamic) interspecies differences. The intraspecies uncertainty factor remains at 10X.

For all other routes of exposure a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X).

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 16 of 48 Table 4.5.1: Inhalation HEC and HED Calculation Summary

Population Scenario Tox duration adjustment HEC HED (mg/kg

- day; breathing rate specific)
hr/day day/wk mg/L mg/m3 8.3 L/min 16.7 L/min 29 L/min

Occupational Handler 8 5 0.0167 16.73 0.952 1.915 3.326

Residential Handler NA NA 0.0223 22.3 NA 0.638 NA

Outdoor
post

application NA NA 0.0223 22.3 NA NA NA

Indoor Post

application NA 7 0.016 15.93 NA

Bystander 24 7 0.004 3.98 NA



### 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

T he risk assessment must address exposures from three major sources: incidental oral, dermal,

and inhalation and the appropriateness of combining these exposures

. These exposure from

these three routes cannot be combined for flurprimidol as no dermal hazard was identified and

the inhalation POD is based on route

- specific portal of entry effects in the nasal passage.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In the 2005 Human Health Risk Assessment, flurprimidol was clas sified as “not likely to be a human carcinogen

. ” Carcinogenicity studies were performed in the rat and the mouse and there was no evidence of an increased incidence of tumors in animals treated with flurprimidol. In addition, the test article was conside red non

- mutagenic in 8 genotoxic studies.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 17 of 48 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Flurprimidol for Use in Human Health

Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty/

Safety Factors RfD/PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population NOAEL = 70 mg/kg/day UF A 10x

UF H 10x aRfD = 0.7

mg/kg/day

aPAD = 0.7 mg/kg/day Acute Neurotoxicity Study (rats)

MRIDs: 48897501

LOAEL = 285 mg/kg/day, based on based on treatment related findings at the mid

- dose included gait abnormality in both sexes, low arousal and impaired righting reflex in males,

and hunched b ody in females, 7

- 8 hours after dosing.

Acute Dietary (Females 13 to 49 years of age) NOAEL = 10 mg/kg/day UF A 10x

UF H 10x aRfD = 0.1

mg/kg/day

aPAD = 0.1 mg/kg/day Developmental Toxicity (rat)

MRIDs: 00147301

LOAEL = 45, based on increased incidences of skeletal anomalies in the vertebrae (extra) and ribs (extra, rudimentary, cervical).

Chronic Dietary (All populations) Parental

NOAEL= 3.6 mg/kg/day UF A 10x

UF H 10x cRfD = 0.04

mg/kg/day

cPAD = 0.04 mg/kg/day Chronic Toxicity (rat)

MRIDs: 40486003

LOAEL = 12.1, based on increased incidences of focal atypia, fatty change, and hepatocellular eosinophilic change in the liver of males.

Incidental Oral

Short

- Term (1

- 30 days) Offspring

NOAEL = 7.3 mg/kg/day UF A 10x

UF H 10x LOC = 100x 2

- Generation Reproductive Toxicity

MRIDs: 00162770

Offspring LOAEL = 74 mg/kg/day, based on decreased survival and body weights (20

- 39%) in the pups.

A dermal assessment is not required for the flurprimidol. No toxicity was observed up to the limit dose in the dermal toxicity study. No quantitative susceptibility was observed in any study. Qualitative susceptibility was observed in the rat developmental study , however; as the effects occurred in the presence of decreased maternal body weights the availab le dermal toxicity study is considered to be protective as no decreased body weights were observed. Additionally, applying the estimated upper bound dermal absorption value to the developmental LOAEL would result in an estimated dermal LOAEL near the limi t dose (~750 mg/kg/day).

Inhalation

Short

- Term (1

- 30 days) and

Intermediate

- Term (1

– 6 months) NOAEL = 0.1 mg/kg/day

See Table 4.5.1

for HEC/HED

values. UF A 3x

UF H 10x

FQPA SF = 1X LOC = 30x 13

- Week Inhalation Toxicity (rat) MRIDs: 49007301, 49007302

LOAEL = 0.4 mg/L based on results in the

range

- finding study (MRID 49007302) where goblet cell hyperplasia was observed in nasal level II, III, IV, V, and VI of male rats (nasal passages of females were not examined microscopically).
Cancer (oral) Classification: "Not likely to be a human carcinogen

. "
Point of Departure (POD) = A data point or an estimated point derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animals to humans (interspecies). UF H = potential variation in sensitiv ity among members of the human population (intraspecies). UF DB = Data base Uncertainty Factor. aPAD = acute population adjusted dose. cPAD = chronic population adjusted dose. RfD = reference dose.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 18 of 48 4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, 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 maturat ion, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for flurprimidol, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), flurp rimidol is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interac t with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effect s 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 1 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

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. 2

1 

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the

final second list of chemicals.

2 

### 2 http://www.epa.gov/endo/

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 19 of 48 5 .0 Dietary Exposure and Risk Assessment

5.1 Food Residue Profile

There are no currently registered food uses for flurprimidol.

5.2 Summary of Environmental Degr adation

The environmental fate data indicates that flurprimidol is mobile and resistant to degradation ( e.g ., half

- life > 400 days) in the soil and stable to hydrolysis suggesting the potential for leaching and movement to roots for uptake in water by growing plants as suggested by the terrestrial field dissipation studies.

For the tree injection use, it is assumed that flurprimidol will be translocated to the leaves, which will degrade, releasing flurprimidol, after falling to the ground. Flurprimidol is stable to hydrolysis and resistant to degradation in both aerobic and anaerobic terrestrial systems. Field dissipation data for cropped turf plots sugg est that much more rapid dissipation was found than might be expected from the laboratory studies.

T his could be due to significant volatilization is observed from the plant surfaces than from soil.



### A lthough vapor pressure and Henry’s law constant would s uggest that volatilization would not be an important dissipation process. Field dissipation data on bare ground sites yields much longer dissipation times that are comparable to laboratory estimates, suggesting that plant uptake via transpiration or absorp tion through plant or root surfaces is influencing the dissipation in the

field.

5.3 Water Residue Profile

The estimated drinking water concentrations (EDWCs) used in the dietary risk assessment were provided by EFED and were generated using computer mo deling methods. EDWCs were calculated using the screening models PRZM

- GW (Pesticide Root Zone Model for Groundwater, version 1.0, August 31, 2012) for groundwater and Surface Water Concentration Calculator (SWCC, version 1.106) for surface water. The mode ls and the descriptions are available at the

EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

The EDWCs for parent flurprimidol are based upon the maximum rate and number of applicati on(s) to obtain the yearly maximum application rate of 3.0 lb a.i./A/year (Table 5.3 ). The recommended EDWCs for groundwater containing flurprimidol are 707 ppb for acute exposure and 656 ppb (post

- breakthrough average) for chronic exposure. Groundwater estimates are higher than previously estimated with the Screening Concentration in Ground Water ( SCI

GROW ) model. A major reason for the difference in estimated concentrations is that PRZM

- GW

c onsiders multiple applications over 30 years, whereas SCI

- GROW only considers a single year of application. The highest EDWCs estimated using the SWCC for surface water containing flurprimidol is 110 ppb for acute exposure, and 19.1 ppb for chronic exposu re. Note: The tree injection/tree implant uses were not considered in the drinking water assessment, because any residues in water from these uses are expected to be lower than the foliar applications of flurprimidol.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 20 of 48 The highest EDWCs were from groundw ater ; therefore, the acute and chronic assessments used the groundwater EDWCs of 707 ppb and 656 ppb, respectively.

Table 5.3 Maximum Surface and Ground Water Tier 2 EDWCs from the Maximum Use Rates of Flurprimidol

Drinking water source (model) 1

- in

- 10 year 30

- year simulation

Acute Chronic Cancer

(μg/L)

Surface Water (Surface Water Concentration Calculator, SWCC) a 110 19.1 11.1

Groundwater (PRZM

- GW b ) Peak Post

Breakthrough

Ave Simulation

Ave

(μg/L)

707 c 656 c 326

Florida nursery scenario

. b WI Central Sands Scenario.

c Bold values are the recommended EDWCs.



### 5 .4 Dietary Risk Assessment

5.4.1. Description of Residue Data Used in Dietary Assessment

U pdated acute and chronic dietary (drinking water only) exposure and risk assessments were conducting using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food c onsumption

data from USDA’s NHANES/WWEIA. The drinking water estimates provided by EFED are modeled estimates, and were generated using the most conservative model available for the existing uses. The unrefined acute and chronic approach using tolerance l evel residues to dietary

risk exposure analysis will not underestimate risk to the general U.S. population or any population subgroup

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not used in this assessment.

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary (drinking water only) analysis for flurprimidol was conducted that directly incorporated potential drinking water residues . The resulting acute drinking water risk estimates are below HED’s level of concern (<100% aPAD) at the 95 th 

### percentile of the exposure distribution for the general U.S. population 6% aPAD, and all population subgroups. The aPAD

is lower for females 13 to 49 years old . Although all infants have the highest exposure estimate (0.120747 mg/kg/day; 17% aPAD), the population subgroup with the highest risk estimate is

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 21 of 48 females 13 to 49 years old, which utilize 38% of the aPAD (0.038477 mg/kg/day) at the 95 th



### p ercentile of exposure. The detailed results for the general population and all population subgroups are shown below in Table 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

The unrefined chronic dietary (drinking water only) risk estimate utilizes 34% of the cPAD for the U.S. population. The estimated risk for the most highly exposed population subgroup all infants <1 year is 86% of the cPAD. Thus, chronic dietary exposure to flurprimidol for all population subgroups is not of concern. The detailed re sults for the general population and all population subgroups are shown below in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Flurprimidol currently has no registered food uses and flurprimidol was classified as “not likely to be a human carcinogen ” ; therefore a cancer dietary (drinking water only) assessment is not required.

5.4.6 Dietary Summary Table

The acute and chronic dietary exposure and risks for flurprimidol are summarized below.

DEEM

- FCID Model i nputs and o utputs for a cute and c hroni c d ietary e xposure e stimates are attached in Appendix B.

Table 5.4.6 . Summary of Dietary (Drinking Water Only) Exposure and Risk for Flurprimidol 1

Population Subgroup aPAD (mg/kg /day) Acute Results

95 th Percentile Chronic Results 

### Cancer Results

Exposure (mg/kg/day) %

aPAD Exposure (mg/kg/day) %

aPAD 

### Exposure

(mg/kg/day) %

aPAD

General U.S. Population

0.7 0.038551 6 0.013736 34



### Not Applicable All Infants (<1 year old) 0.120747 17 0.035418 89

Children 1

- 2 years old 0.059446 8 0.019815 50

Children 3

- 5 years old 0.048236 7 0.016695 42

Children 6

- 12 years

old 0.036856 5 0.012040 30

Youth 13

- 19 years old 0.032105 6 0.010017 25

Adults 20

- 49 years old 0.037936 5 0.013705 34

Adults 50

- 99 years old 0.033793 5 0.013548 34

Females 13

- 49 years

old 0.1 0.038477 38 0.013654 34

1 Values for the population with the highest risk are bolded

.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 22 of 48 6.0 Residential Exposure and Risk Estimates

T here are existing re sidential uses that have been assessed in this document to reflect updates to
HED’s 2012 Residential SOPs 3 

### along with policy changes for body weight assumptio ns.

6.1 Residential Handler Exposure/Risk Estimates

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application proc ess. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The flurprimidol quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

 Mixing/loading/applying liquids with a manually

- pressurized handwand,

 Mixing/loading/applying liquids with a hose

- end sprayer,

 Mixing/loading/applying liquids with a backpack,

 Mixing/loading/applying liquids with a sprinkler can,

 Mixing/loading/applying wettable powders in water

- soluble packaging with a manually

p ressurized handwand,

 Mixing/loading/applying wettable powders in water

- soluble packaging with a hose

- end

sprayer,

 Mixing/loading/applying wettable powders in water

- soluble packaging with a backpack,

 Mixing/loading/applying wettable powders in water

- soluble packaging with a sprinkler can,

 Loading/applying granulars with a push

- type spreader,

 Loading/applying granulars with a belly grinder,

 Loading/applying granulars with a spoon,

 Loading/applying granulars with a cup,

 Loading/applying granulars with hand dis persal, and

 Loading/applying granulars with a shaker can.

HED anticipates that residential handler exposure from mixing/loading liquids for tree injection

use is less than would be anticipated from occupational handler exposure for tree injection. It is not anticipated that as many trees would be treated per day in a residential setting than in an occupational setting. The refore, the occupational handler assessment that was conducted for this

chemical is considered protective of the residential handler exposures and, accordingly, a quantitative residential handler assessment for this scenario was not conducted.

Table 6 .1.1 provides a summary of the residential hander exposures and risk estimates for flurprimidol. All inhalation exposure risk estimates are greater than HED’s LOC (MOEs ≥ 30) at baseline attire (i.e., no respirator)

.

3 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 23 of 48 Table 6 .1.1 Residential Handler Non

- cancer Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Inhalation Unit Exposure (mg/lb ai) Maximum

Application

Rate 1 Area

Treated or

Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

M/L/A liquids with a manually

pressurized

handwand Gardens/Trees 0.018 0.000024 lb

ai/ft 2 1200 ft 2 0.0000065 99,000

M/L/A liquids with

a hose

- end sprayer Gardens/Trees 0.0014 0.000024 lb

ai/ft 2 1200 ft 2 0.0000005 1,300,000

M/L/A liquids with

a hose

- end sprayer Turf 0.022 1.5 lb ai/A 0.5 acres 0.00021 3,100

M/L/A liquids with a manually

pressurized

handwand Turf 0.018 0.008 lb ai/gallon 5 gallons 0.000009 71,000

M/L/A liquids with a backpack Gardens/Trees 0.14 0.000024 lb

ai/ft 2 1200 ft 2 0.00005 13,000

M/L/A liquids with Sprinkler can Gardens/Trees 0.0014 0.000024 lb

ai/ft 2 1200 ft 2 0.0000005 1,300,000

M/L/A liquids with sprinkler can Turf 0.022 0.000034 lb

ai/ft 2 1000 ft 2 0.0000094 68,000

M/L/A liquids with backpack Turf 0.14 0.008 lb ai/gallon 5 gallons 0.00007 9,100

M/L/A wettable powders in water

soluble packaging with a manually

pressurized

handwand Gardens/Trees 0.018 0.000024 lb

ai /ft 2 1200 ft 2 0.0000065 99,000

M/L/A wettable powders in water

soluble packaging

with a hose

- end

sprayer Gardens/Trees 0.034 0.000024 lb

ai/ft2 1200 ft 2 0.000012 52,000

M/L/A wettable powders in water

soluble packaging

with a hose

- end

sprayer Turf 0.034 1.5 lb ai/A 0.5 acres 0.00032 2,000

M/L/A wettable powders in water

soluble packaging with a manually

pressurized

handwand Turf 0.018 0.008 lb ai/gallon 5 gallons 0.000009 71,000

M/L/A wettable powders in water

soluble packaging

with a backpack Turf 0.018 0.008 lb ai/gallon 5 gallons 0.000009 71,000

M/L/A wettable powders in water

- Gardens/Trees 0.034 0.000024 lb

ai/ft 2 1200 ft 2 0.000012 52,000

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 24 of 48 Table 6 .1.1 Residential Handler Non

- cancer Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Inhalation Unit Exposure (mg/lb ai) Maximum

Application

Rate 1 Area

Treated or

Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

soluble packaging with Sprinkler can

M/L/A wettable powders in water

soluble packaging with Sprinkler can Turf 0.034 0.000034 lb

ai/ft 2 1000 ft 2 0.000014 44,000

M/L/A wettable powders in water

soluble packaging with a backpack Gardens/Trees 0.018 0.000024 lb

ai/ft 2 1200 ft 2 0.0000065 99,000

M/L/A granulars with a push

- type spreader Gardens/Trees 0.0026 0.000024 lb

ai/ft 2 1200 ft 2 0.00000094 680,000

M/L/A granulars with a push

- type spreader Turf 0.0026 1.5 lb ai/A 0.5 acres 0.000024 26,000

M/L/A granulars with a belly grinder Turf 0.039 0.000034 lb

ai/ft 2 1200 ft 2 0.00002 32,000

M/L/A granulars with a spoon Gardens/Trees 0.087 0.000024 lb

ai/ft 2 1200 ft 2 0.000031 20,000

M/L/A granulars with a spoon Turf 0.087 0.000034 lb

ai/ft 2 100 ft 2 0.0000037 170,000

M/L/A granulars with a cup Gardens/Trees 0.013 0.000024 lb

ai/ft 2 1200 ft 2 0.0000047 140,000

M/L/A granulars with

a cup Turf 0.013 0.000034 lb

ai/ft 2 100 ft 2 0.00000055 1,200,000

M/L/A granulars with hand dispersal Gardens/Trees 0.38 0.000024 lb

ai/ft 2 1200 ft 2 0.00014 4,700

M/L/A granulars with hand dispersal Turf 0.38 0.000034 lb

ai/ft 2 100ft 2 0.000016 40,000

M/L/A granulars with

a shaker can Gardens/Trees 0.013 0.000024 lb

ai/ft 2 1200 ft 2 0.0000047 140,000

M/L/A granulars with

a shaker can Turf 0.013 0.000034 lb

ai/ft 2 100 ft 2 0.00000055 1,200,000

1 Based on registered labels (See Table 3.3 ).

2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).

3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ BW (80 kg).

4 Inhalation MOE = Inhalation NOAEL (HED = 0.638 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 6.2 Residential Post

- application Exposure/Risk Estimates

Residential post

- application dermal exposure for adults or children was not assessed for flurprimidol because there is no identified dermal hazard. Also, residential post

- application incidental oral exposure for children was not assessed because flurprimidol label directions

indicat e that it is applied to turf for edging/banding applications along the perimeter of lawns, landscape beds, sidewalks, curbs, parking lots, driveways, posts, mailboxes, building stru ctures, gravestones, and fences. As detailed in the Lawns/Turf 2012 Reside ntial SOPs, residential post

application assessments do not need to be performed if label directions indicate that the turf use

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 25 of 48 is an edging use (e.g., along fence rows), a foundation perimeter treatment, or a specific spot treatment. These types of uses may result in residues on turf; however, because of the low potential for contact, the residential exposure is expected to be negligible.

Turf Transferable Residue (TTR): In accordance with the updated Part 158 data requirements, TTR data are required f

or all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. Since there is no hazard via the dermal route of exposure, a non

- cancer dermal post

- applicat ion risk assessment

was n ot performed for flurprimidol. Further, no incidental oral assessment for the registered turf uses is required for the reasons described above. Therefore, TTR studies are not needed for flurprimidol at this time.

6. 3 Spray Dri ft

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 can eventually lead to exposures (e.g

. , children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from

these residues can be calcu lated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment include assessing exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. Aside from the predicted residues available for transfer, the routes of exposure and assessment methodology is 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 wa s utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of flurprimidol . 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. Exposures were considered for 50 feet wide lawns where the nearest side of the property was directly adjoining th e treated field (at field edge) and at varied distances up to 300 feet downwind of a treated field. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in th e recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed for situations where specific label guidance for application parameters is not available. 4

, 5 

### AgDrift ® 

### is appropriate fo r use only when applications

4 http://www.agdrift.com/

5 Note that for many cases the scenario s outlined in the screening approach represent actual use practice so risk assessors should be aware and characterize these appropriately.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 26 of 48 are made by aircraft, airblast 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 u nder 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. In all cases, each sc enario 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). S ection 6.4.1 provides the screening level drift related risk estimates. These drift estimates represent plausible options based on the available pesticide

labels.

6

. 3 .1 Combined Risk Estimates From Lawn Deposition Adjacent to Applications

The spray drift risk estimates are base d on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Flurprimidol is used on perennial turfgrass (cool and warm season) on golf courses and turf, landscape/woody ornamental plants,

ornamental trees and ornamental plants grown in containers in nurseries, greenhouses, and shadehouses. The spray drift assessment was conducted using the highest registered application rate of 1.5 lb ai/A for use on golf courses. The recommended drift sc enario 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.

There are no short

- or intermediate

- term dermal PODs. Only incidental oral risk estimates were evaluated. The total applicable LOC is 100, so MOEs <100 would be of concern. Children ( 1 to <2 years old ) incidental oral risk estimates from exposure to flurprimidol related to spray drift

result in no risks o f concern at the field edge for groundboom applications (Table 6.4.1 ).

Table 6 .4.1. Children (1 to < 2 years old) Incidental Oral Risk Estimates (MOEs) Related to Spray Drift Exposure for Flurprimidol

. 1

Crop/Rate Group Spray Type/ Nozzle

Configuration Application

Rate (lb ai/A) Estimated

or Adjusted

TTR t (ug/cm2) At Edge

HtM MOE

Golf Courses

Groundboom High Boom Very fine

to Fine 1.5 0.166725 1,700

1 The spray drift assessment was conducted using the highest registered application rate of 1.5 lb ai/A for use on golf courses.



### 6. 4 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The A gency 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

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 27 of 48 A gency 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, route

- specific inhalation toxicological studies) or further analysis is required for flurprimidol.

7.0 Combined Exposure/Risk Ch aracterization

R outes of exposure cannot be combined for flurprimidol as no dermal hazard was identified and

the inhalation POD is based on route

- specific portal of entry effects in the nasal passage. Additionally, as discussed in Section 6.2, residential post

- application incidental oral exposure for

children was not assessed as residential post

- application exposure is expected to be negligible based on the use pattern ; therefore there is only one source of oral exposure (drinking water)

. Therefore , no assessment for combined routes of exposure was conducted at this time.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to flurprimidol and any other substances. For the purposes of this assessment , ther efore, EPA has not assumed that flurprimidol has a common mechanism of toxicity with other substances. For information regarding E PA’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 Pesticide Programs concerning common mechanism

determinations 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 and Risk Estimates

9.1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered uses. The quantitativ e exposure/risk assessment developed for occupational handlers is based on the following scenarios:

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 28 of 48  Mixing/loading granulars to support tractor

- drawn spreader applications,

 Mixing/loading liquids for aerial applications,

 Mixing/loading liquids for groundboom applications,

 Mixing/loading liquids for airblast applications,

 Mixing/loading liquids for chemigation applications,

 Mixing/loading liquids for tree injection applications,

 Mixing/loading wettable powders in water

- soluble packets for groundboom applications,

 Applying sprays for aerial applications,

 Applying sprays for airblast applications,

 Applying sprays for groundboom applications,

 Applying granulars for tractor

- drawn spreader applications,

 Flagging to support aerial spray applications,

 Mixing /loading/applying liquids for backpack applications,

 Mixing/loading/applying liquids for manually

- pressurized handwand applications,

 Mixing/loading/applying liquids for mechanically

- pressurized handgun applications,

 Mixing/loading/applying wettable powders in water

- soluble packets for backpack applications,

 Mixing/loading/applying wettable powders in water

- soluble packets for manually

pressurized handwand applications,

 Mixing/loading/applying wettable powders in water

- soluble packets for mechanically

pressu rized handgun applications,

 Loading/applying granulars for backpack applications

,

 Loading/applying granulars for belly grinder applications,

 Loading/applying granulars for rotary spreader applications.

Tree injection is not typically assessed by HED because the Agency has no exposure data for the

tre e injection application scenario. In this assessment, however, HED did assess exposure from mixing/loading for the tree injection scenario. Use information specific to this chemical was not

available for this scenario; therefore, HED used available tree injection assumptions from a previous ORE assessment for dinotefuran (O’Keefe, B., D378123, 2/28/2011) to represent the

same scenario. The registered label (Reg. No. 67690

- 34) specifies 2 ml per injectio n site (or 0.0024 lb ai/injection site) for trees with diameters over 12 inches as the maximum application

rate. Based on assumptions used in the dinotefuran tree injection assessment, it is assumed that one applicator can make 600 trunk injections per da y. This assessment assumes then that the maximum amount of product handled would be 1.46 lb ai/day (0.0024 lb ai/injection hole x 600 injection holes/day) by one applicator.

In this assessment, the tree implant application scenario was not assessed becau se little to no exposure is expected from this use. The label states that each implant should be firmly seated

into the tree trunk one

- inch below the bark. Holes should be drilled with a 3/8” self

- centering (brad point) spiral bit. Stop collars or tape can be used to set hole depths (1 inch plus bark thickness) on the drill bit. Each hole should be filled or flushed with water from a squirt bottle prior to implant insertion. Direct exposure to this substance is minimal because the product is in

a self

- contained device.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 29 of 48 The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has chan ged dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily
from the mid 1990’s. Over the same ti me period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to

best asses s and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve d shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term inhala tion MOEs are greater than HED’s LOC (i.e., MOEs > 30) with baseline attire. .

Table 9.1 provides the worst

- case scenarios for the registered uses for flurprimidol. The MOEs range from 1,100 to 900,000.

Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

Mixer/Loader

M/L Granules for Aerial Applications Nursery 1.7 1.5 60 0.00191 1,700

M/L Granules for

Tractor

- Drawn Spreader Application Golf Course

(fairways, tees, greens) 1.7 1.0 40 0.00085 3,900

M/L Granules for

Tractor

- Drawn Spreader Application Golf Course (tees and greens only) 1.7 0.75 5 0.0000798 42,000

M/L Granules for

Tractor

- Drawn Spreader Application Nursery 1.7 1.5 60 0.00191 1,700

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 30 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

M/L Granules for

Tractor

- Drawn Spreader Application Greenhouse 1.7 1.5 60 0.00191 1,700

M/L Liquids for Aerial Application Nursery 0.219 0.55 60 0.0000904 21,000

M/L Liquids for Airblast Application Nursery 0.219 0.55 20 0.0000301 64,000

M/L Liquids for Chemigation Application Greenhouse 0.219 0.55 60 0.0000904 21,000

M/L Liquids for Chemigation Application Nursery 0.219 0.55 60 0.0000904 21,000

M/L Liquids for

Groundboom Application Golf Course

(tees and greens only) 0.219 0.25 5 0.00000343 560,000

M/L Liquids for

Groundboom Application Golf Course

(fairways, tees, greens) 0.219 0.75 40 0.0000821 23,000

M/L Liquids for

Groundboom Application Nursery 0.219 0.55 60 0.0000904 21,000

M/L Liquids for

Groundboom Application Greenhouse 0.219 0.55 60 0.0000904 21,000

M/L Liquids for Tree Injection Trees 0.219 1.46 lb ai/day 1 day 0.000004 480,000

M/L Wettable Powders

in Water

- Soluble

Packets for

Groundboom Application Golf Course

(tees and greens only) 0.24 (EC) 0.25 5 0.00000375 890,000

M/L Wettable Powder

in Water

- Soluble

Packets for

Groundboom Application Golf Course

(fairways, tees, greens) 0.24 (EC) 0.75 40 0.00009 37,000

Applicator

Applying Sprays for Aerial Application Nursery 0.0049 (EC) 0.55 60 0.00000203 470,000

Applying Sprays for Airblast Application Nursery 4.71 0.55 20 0.000648 1,500

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 31 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

Applying Sprays for

Groundboom Application Golf Course

(tees and greens Only) 0.34 0.25 5 0.00000531 180,000

Applying Sprays for

Groundboom Application Golf Course

(fairways, tees, greens) 0.34 0.75 40 0.000128 7,400

Applying Sprays for

Groundboom Application Nursery 0.34 0.55 60 0.00014 6,800

Applying Sprays for

Groundboom Application Greenhouse 0.34 0.55 60 0.00014 6,800

Applying Granules for

Tractor

- Drawn Spreader Application Greenhouse 1.2 1.5 60 0.00135 2,500

Applying Granules for Aerial Application Nursery 1.3 (EC) 1.5 60 0.00146 2,300

Applying Granules for

Tractor

- Drawn Spreader Application Golf course (fairways,

tees, greens) 1.2 1.0 40 0.0006 5,500

Applying Granules for

Tractor

- Drawn Spreader Application Golf course, (tees and greens only) 1.2 0.75 5 0.0000563 59,000

Applying Granules for

Tractor

- Drawn Spreader Application Nursery 1.2 1.5 60 0.00135 2,500

Flagger for Aerial Application for Liquids Nursery 0.35 0.55 60 0.000145 23,000

Flagging for Aerial Application for

Granules Nursery 0.15 1.5 60 0.000169 20,000

Mixer/Loader/Applicator M/L/A Foliar Spray for Backpack Application (Broadcast) Greenhouse 140 0.00165 lb ai/gallon 40

gallons 0.000116 17,000

M/L/A Foliar Spray for Backpack Application (Broadcast Foliar) Greenhouse 140 0.00165 lb ai/gallon 40

gallons 0.000116 17,000

M/L/A Foliar Spray for Backpack Application Nursery 140 0.00165 lb ai/gallon 40

gallons 0.000116 17,000

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 32 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

M/L/A Foliar Spray for Backpack Application,

Ground/Soil

- Directed Nursery 2.58 0.00165 lb ai/gallon 40

gallons 0.00000213 900,000

M/L/A Foliar Spray for Backpack Application Landscaping,

trees/shrubs/bushes 140 0.005 lb ai/gallon 40

gallons 0.00035 5,500

M/L/A Foliar Spray for Backpack Application Landscaping, plants/flowers 140 0.005 lb ai/gallon 40

gallons 0.00035 5,500

M/L/A Liquids with Backpack for Spot

Treatment Landscaping, turf

(lawns, athletic fields, parks, etc.) 2.58 0.008 lb ai/gallon 40

gallons 0.0000103 190,000

M/L/A Liquids with Manually

- Pressurized

Handwand Greenhouse

30 0.00165 lb ai/gallon 40

gallons 0.0000248 130,000 M/L/A Liquids with Manually

- Pressurized

Handwand Nursery

M/L/A Liquids with Manually

- Pressurized

Handwand Landscaping,

trees/shrubs/bushes

30 0.005 lb ai/gallon 40

gallons 0.000075 44,000 Landscaping, plants/flowers

M/L/A Liquids with Manually

- Pressurized

Handwand Landscaping, turf

(lawns, athletic fields, parks, etc.) 30 0.008 lb ai/gallon 40

gallons 0.00012 28,000

M/L/A Liquids with Mechanically

Pressurized Handgun

for Broadcast Application Greenhouse 120 0.00165 lb ai/gallon 1,000

gallons 0.00248 1,300

M/L/A Liquids with Mechanically

Pressurized Handgun

for Drench/Soil

- /Ground

- directed Greenhouse 120 0.00165 lb ai/gallon 1,000

gallons 0.00248 1,300

M/L/A Liquids with Mechanically

Pressurized Handgun Golf course (tees and greens only) 1.9 0.25 5 0.0000298 64,000

M/L/A Liquids with Mechanically

Pressurized Handgun Golf course (fairways, tees, greens) 1.9 0.75 5 0.0000891 21,000

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 33 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

M/L/A Liquids with Mechanically

Pressurized Handgun

for Broadcast Application Nursery 3.9 0.00165 lb ai/gallon 1,000

gallons 0.0000805 41,000 M/L/A Liquids with Mechanically

Pressurized Handgun

for Drench/Soil

- /Ground

- directed M/L/A Liquids with Mechanically

Pressurized Handgun Landscaping,

trees/shrubs/bushes 3.9 0.005 lb ai/gallon 1,000

gallons 0.000244 14,000

M/L/A Liquids with Mechanically

Pressurized Handgun Landscaping, turf

(lawns, athletic fields, parks, etc.) 1.9 1.5 5 acres 0.000179 11,000

M/L/A Wettable

Powders in Water

Soluble Packets with Backpack Landscaping,

trees/shrubs/bushes

140 0.005 lb ai/gallon 40

gallons 0.00035 5,500 Landscaping, plants/flowers

M/L/A Wettable

Powders in Water

Soluble Packets with Backpack for Spot

Treatment Landscaping, turf

(lawns, athletic fields, parks, etc.) 2.58 0.008 lb ai/gallon 40

gallons 0.0000103 190,000

M/L/A Wettable

Powders in Water

Soluble Packets with Manually

- Pressurized

Handwand Application Landscaping,

trees/shrubs/bushes

30 0.005 lb ai/gallon 40

gallons 0.000075 44,000 Landscaping, plants/flowers

M/L/A Wettable

Powders in Water

Soluble Packets with Mechanically

pressurized Handgun Golf course (tees and greens only) 18 0.25 5 0.000281 6,800

M/L/A Wettable

Powders in Water

Soluble Packets with Mechanically

pressurized Handgun Golf course (fairways, tees, greens) 18 0.75 5 0.000844 2,300

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 34 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

M/L/A Wettable

Powders in Water

Soluble Packets with Mechanically

pressurized Handgun Landscaping,

trees/shrubs/bushes 3.9 0.005 lb ai/gallon 1,000

gallons 0.000244 14,000

M/L/A Wettable

Powders in Water

Soluble Packets with Mechanically

pressurized Handgun Landscaping, turf

(lawns, athletic fields, parks, etc.) 18 1.5 5 0.00169 1,100

Loading/Applying Loading/Applying Granules for Backpack

for Ground/Soil

Directed Application Greenhouse

23.8 1.5 1 0.000446 4,300 Loading/Applying

Granules for Backpack

for Ground/Soil

Directed Application Nursery

Loading/Applying Granules for Belly Grinder Application Greenhouse 62 1.5 1 0.00116 2,900

Loading/Applying Granules for Belly Grinder Application Nursery 62 1.5 1 0.00116 2,900

Loading/Applying Granules for Belly Grinder Application Landscaping,

trees/shrubs/bushes

62 1.5 1 0.00116 2,900 Loading/Applying Granules for Belly Grinder Application Landscaping, plants/flowers

Loading/Applying Granules for Belly Grinder Application Landscaping, turf

(lawns, athletic fields, parks, etc.)

Loading/Applying Granules for Rotary Spreader Application Greenhouse

(ornamentals, roses, cut flowers, container stock, vegetables) 10 1.5 5 0.000938 2,000

Loading/Applying Granules for Rotary Spreader Application Golf course (tees and greens only) 10 0.75 5 0.000469 4,100

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 35 of 48 Table 9.1 . Short

- and Intermediate

- term Occup ational Handler Exposure and Risk Estimates for Flurprimidol.

Exposure Scenario Crop or Target Baseline

Inhalation

Unit Exposure 1 μg/lb ai Maximum

Application

Rate 2

lb ai/A (unless

otherwise noted) Area

Treated

or Amount

Handled Daily 3

Acres (unless

otherwis e noted) Dose 4

mg/kg/day Short

- and

Intermediate

- term
Inhalation

MOE 5

LOC = 30

Loading/Applying Granules for Rotary Spreader Application Golf course (fairways, tees, greens) 10 1.0 5 0.000625 3,100

Loading/Applying Granules for Rotary Spreader Application Landscaping, turf

(lawns, athletic fields, parks, etc.) 10 1.5 5 0.000938 2,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, Eng. Controls.

2 Based on registered labels (See Table 3

. 3 ).

3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A or gallon) x Area treated or Amount Hand led (A/day or gallons/day) / Body Weig ht (80 kg). 5 Inhalation MOE = Inhalation NOAEL (0.952, 1.92, or 3.92 mg/kg/day)/Inhalation Dose (mg/kg/day).



### 9.2 Occupational Post

- application Exposure/Risk Estimates

Occupational post

- application dermal exposure was not assessed for flurprimidol because there is no identified systemic dermal hazard. Based on the Agency 's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for flurprimidol

at this time

.

Dislo dgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. Since there is no hazard via the dermal route of exposure, a non

- cancer dermal post

- application risk assessment was not performed for flurprimidol. Therefore, DFR studies are not needed for flurprimidol at this time. If the PODs change, the need for DFR studies may be reevaluated in the future to refine the post

application assessment.

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- app lication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatiliza tion 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 A gency has

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 3 6 of 48 evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!dock etDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for flurprimidol

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorpo rate occupational post

- application inhalation exposure into the A gency's risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupati onal/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 protec tive of most occupational post

- application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through t he use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 37 of 48 Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for the Non

- Food Use of flurprimidol are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test 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 28

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation cr

cr

nr

yes

cr yes

yes

yes no (a)

yes 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) cr

cr

cr yes

yes

yes 870.5100 Mutagenicity

— Gene Mutation

– bacterial 870.5300 Mutagen icity

— Gene Mutation

- mammalian 870.5375 Mutagenicity

— Structural Chromosomal 870.5395 Mutagenicity

— Other Genotoxic Effects 870.5550 Mutagenicity

— Unscheduled DNA Synthesis yes

yes

yes

yes

no yes

yes

yes

yes

yes 870.6100a Acute Delayed Neurotox. (hen) 870.6200a Acute Neurotox. Screening Battery (rat)

870.6200b 90

- Day Neuro. Screening Battery (rat) 870.6300 Develop. Neuro cr

yes

yes

cr no

yes

yes

no
870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity Y es

cr

yes yes

yes

yes (a) The 21 day dermal study is suitable for risk assessment based on the current use pattern, and a 90

- day dermal study is

n ot required. (b) N ot required at this time.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 38 of 48 A.2 Toxicity Profiles

Table A.2.1 Acute toxicity Profile

– Flurprimidol

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

870.1100 Acute oral

- rat 00117933 LD 50 = 914 (M) or 709 (F) mg/kg III

870.1200 Acute dermal

- rabbit 00010214 LD 50 = >500 mg/kg III

870.1300 Acute inhalation

- rat 40401009 LC 50 = >5.231 mg/L IV

870.2400 Acute eye irritation

- rabbit 00248752 Moderate eye

irritant III

870.2500 Acute dermal irritation

- rabbit 40401008 Slight dermal

irritant IV

870.2600 Skin sensitization

- guinea pig 00162766 Not a sensitizer N/A

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

870.3100 1982

- 90

- Day oral

toxicity

- rat

Acceptable/Non

guideline 0, 0.0025, 0.009, 0.03,

0.1% mg/kg/day = M: 0, 1.68, 6.04, 20.39, 68.34 F: 0, 1.98, 7.13, 24.37,

78.47 00117945 NOAEL (mg/kg/day): 68.34 LOAEL (mg/kg/day): not

determined

870.3100 1982

- 90

- Day oral

toxicity

- mouse

Unacceptable/Guideline 0, 0.010, 0.045, 0.20% mg/kg/day= 0, 15, 67.5, 300 00162767 NOAEL (mg/kg/day): 300 LOAEL (mg/kg/day): not

determined

870.3150 1986

- 90

- Day oral

toxicity

- dog

Acceptable/Guideline mg/kg/day= 0, 0.5, 1.5, 30 00162768 NOAEL (mg/kg/day): 1.5 LOAEL (mg/kg/day): 30 based on decreased adrenal weights, increased incidences of eosinophilic degeneration and vacuolation in the

zona fasciculata in both sexes and increased cortical atrophy as well as incidences in eosinophilic degeneration in the zona reticularis

in males.

870.3150 1986

- 90

- Day oral

toxicity

- dog

Acceptable/Guideline mg/kg/day= 0, 2, 10, 80 00158239 NOAEL (mg/kg/day): 2 LOAEL (mg/kg/day): 10

based on small adrenals in males, decreased adrenal weights in both sexes, and increased incidences of

adrenal cortical vacuolation in

females.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 39 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

870.3200 1986

- 21

- Day dermal

toxicity

- rabbit

Acceptable/Guideline mg/kg/day= 0, 500, 1000 00162769 Systemic NOAEL (mg/kg/day):

1000 Systemic LOAEL (mg/kg/day): not

determined

Dermal NOAEL (mg/kg/day): not

determined Dermal LOAEL (mg/kg/day): 500

based on transient dermal irritation

in the males.

870.3465 13

- Week Inhalation

–

Rat

Acceptable/Guidelin e 0, 0.010, 0.035, or 0.1 mg/L 49007301

49007302 NOAEL = 0.1 mg/L

LOAEL = 0.4 mg/L based on results in the range

- finding study (MRID 49007302) where goblet cell hyperplasia was observed in nasal level II, III, IV, V, and VI of male rats (nasal passages of females were not examined microscopically).

870.3700a 1985

- Prenatal

developmental

- rat

Acceptable/Guideline mg/kg/day= 0, 2.5, 10, 45, 200 00147301 Maternal NOAEL (mg/kg/day): 10 Maternal LOAEL (mg/kg/day): 45

based on decreased body weight gains and food consumption.

Developmental NOAEL (mg/kg/day): 10 Developmental LOAEL (mg/kg/day): 45

based on increased incidences of microphthalmia, and skeletal anomalies in the vertebrae (extra) and ribs (extra, rudimentary,

c ervical).

870.3700b 1985

- Prenatal

developmental

- rabbit

Acceptable/Non

guideline Main Study mg/kg/day: 0, 1.7, 9.0, 45 Range

- finding study mg/kg/day: 0, 2.5, 7.5, 20, 60 00147300 Maternal NOAEL (mg/kg/day): 45 Maternal LOAEL (mg/kg/day): 60

based on the results of a range

finding study in which anorexia, abortion, weight loss, and decreased food consumption was observed.

Developmental NOAEL (m/kg/day):

45 Developmental LOAEL (mg/kg/day): 60 based on abortion

870.3800 1986

- Reproduction and

ferti lity effects

- rat 0, 25, 100, 1000ppm mg/kg/day = 0, 1.8, 7.3, 74 00162770 Parental NOAEL (mg/kg/day): 7.3 Parental LOAEL (mg/kg/day): 74

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 40 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

Acceptable/Guideline based on clinical signs of toxicity in the P females during gestation and lactation, decreased body weights, decrease relative liver weights, hepatocellular hypertrophy, and increased incidence of fatty change

and vacuolation in the liver in males.

Reproductiv e NOAEL (mg/kg/day):

7.3 Reproductive LOAEL (mg/kg/day): 74 based on decreased mating, fertility, and fetal survival (stillbirths) in both generations and increased incidence of persistent vaginal estrous and no corpora lutea.

Offspring NOAEL (mg/kg/day ): 7.3 Offspring LOAEL (mg/kg/day): 74

based on decreased survival and body weights in the pups.

870.4100b 1987

- Chronic toxicity

-

dog

Acceptable/Guideline mg/kg/day= 0, 0.5, 1.5, 7.0, 30.0 40486001 NOAEL (mg/kg/day): 7.0 LOAEL (mg/kg/day): 30.0 based on microscopic lesions in the adrenal glands, reduced response to ACTH in both sexes, and decreased adrenal weights in males.

870.4200b 1988

- Carcinogenicity

- mouse

Unacceptable/Guideline 0, 10, 80, 600 ppm mg/kg/day= M: 0, 1.3, 9.8, 75.7 F: 0, 1.4, 11.2, 84.0 40513701 NOAEL (mg/kg/day): 75.7 LOAEL (mg/kg/day): not

determined.

No evidence of carcinogenicity

870.4300 1987

-

Ch ronic/Carcinogen

icity

- rat

Unacceptable/Guideline 0, 1000 ppm mg/kg/day= M: 0, 43.1 F: 0, 51.7 40486002 NOAEL (mg/kg/day): not

determined LOAEL (mg/kg/day): 43.1/51.7 based on increased liver weights and

increased incidences of focal basophilic atypia, fatty change, and hepatocellular eosinophilic change in

the liver of both sexes

No evidence of c arcinogenicity

870.4300 1987

-

Chronic/Carcinogen

icity

- rat 0, 25, 90, 300, 1000

ppm mg/kg/day= 40486003 NOAEL (mg/kg/day): 3.6 LOAEL (mg/kg/day): 12.1

based on increased incidences of focal atypia, fatty change, and

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 41 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

Acceptable/Guideline M: 0, 1.0, 3.6, 12.1,

41.2 F: 0, 1.2, 4.4, 14.5,

49.3 hepatocellular eosinophilic change in

the liver of males.

No evidence of carcinogenicity

870.5100 1987

- Bacterial Gene

Mutation

Acceptable/Guideline 312.5, 625, 1250, 2500, 5000 μg/plate 40184406 NEGATIVE

There was no evidence of induced mutant colonies over background in the presence or absence of S9.

870.5100 1987

- Bacterial Gene

Mutation

Acceptable/Guideline 312.5, 625, 1250, 2500, 5000 μg/plate 40184407 NEGATIVE

There was no ev idence of induced mutant colonies over background in the presence or absence of S9.

870.5100 1984

- Bacterial Gene

Mutation

Acceptable/Guideline 100, 500, 1000, 2500, 5000 μg/plate 00154366 NEGATIVE

There was no evidence of induced mutant colonies over background in the presence or absence of S9.

870.5100 1982

- Bacterial Gene

Mutation

Acceptable/Guideline 0.1

- 1000 μg/mL (gradient plate) 00117939 NEGATIVE

There was no evidence of induced mutant colonies over background in the presence or absence of S.

870.5300 1 982

- In Vitro Forward

Mutation

Acceptable/Guideline 1, 25, 50, 75. 100, 125, 150, 175 μg/mL 00154365 NEGATIVE

There was no concentration

- related positive response of induced m utant colonies over background.

870.5375 1987

- In Vitro

Chromosome Aberration

Acceptable/Guideline 37.5, 50, 75, 125, 250, 375, 500 μg/mL 40401010 NEGATIVE

There was no evidence that flurprimidol induced a clastogenic effect in the presence or absence of

S9

- activation.

870.5550 1982

- Unscheduled DNA

Synthesis

Acceptable/Guideline 0.5, 1, 5, 10, 50, 100, 500, 1000 nmol/mL 00117938 NEGATIVE

There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts) was induced

870.5915 1982

- In Vivo Sister

Chromatid Exchange

Acceptable/Guideline 50, 100, 200, 300 mg/kg 00117937 NEGATIVE

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 42 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

There was no concentration

- related positive response of SCE induced over background.

870.6200a Acute Neurotoxicity

Acceptable/Non

guideline 70, 285, and 500 mg/kg 48897501 NOAEL = 70 mg/kg/day

LOAEL = 285 mg/kg/day based on based on treatment related findings

at the mid

- dose included gait abnormality in both sexes, low arousal and impair ed righting reflex in males, and hunched body in females, 7

- 8 hours after dosing.

870.6200b Sub

- Chronic

Neurotoxicity

Acceptable/Non

guideline 0, 8, 43, 73 mg/kg/day 49167101 NOAEL = 77 mg/kg/day

No effects observed.

870.7485 1987

- Metabolism and

Pharmacokinetics

- rat

Acceptable/Guideline mg/kg/day = 2.5, 50 40184408

- 40184412, 40401002,

and

40401003 Absorption was rapid (beginning

within an hour of administration) and extensive (> 80% dose).

Excretion of the administered dose was nearly complete (>82% dose) within 7 days, and was recovered predominantly in the urine (53

- 75% dose), but also in the feces (17

- 34% dose). At 7 days post

- dose, the liver

contained a mean value of 0.1% of the administered dose; all other

tissues contained <0.1%. Consequently, bioaccumulation is not expected to occur. The terminal

half

- life of radioactivity in plasma is

31

- 32 hours in males and 41

- 42

hours in females at both doses. In general, the highes t tissue concentrations of radioactivity were found in the adrenals, liver, and kidney. Unchanged parent was present in the feces in minor amounts <2.5% dose, as the parent was extensively degraded into over 30 metabolites. The primary

metabolite was ide ntified (β

hydroxy

- α

- methyl

- β

- [4

- (trifluoro

methoxy)phenyl]

- 5

- pyrimidinepropanoic acid) and was present at 10

- 20% dose, mainly in

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 43 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Flurprimidol

Guideline Study Type Dose Levels MRID Results

the urine. Other metabolites individually accounted for less than

6% of the dose. Eleven of these

metabolites were tentative ly identified. Major metabolic pathways include oxidation of the isopropyl group and the pyrimidine ring. Oxidation of the carbinol

carbon atom and dehydration

between the carbinol

- carbon atom and isopropyl group were also

observed. The absorption,

dist ribution, excretion, or metabolite profiles were not dependent on sex, dose concentration, or the number of

doses received.

870.7800 Immunotoxicity 10, 56, 95 mg/kg/day 49167201 NOAEL = 95 mg/kg/day

Non

guideline 1987

- Dermal

Penetration

- Monkey

Unaccep table/Non

guideline mg/kg/day =

1.0 40184413 Dermal absorption rate not

determined



### A.3 Hazard Identification and Endpoint Selection

3.1 Acute Reference Dose (aRfD) (General Population)

Study Selected: Acute Neurotoxicity Study in Rats

MRIDs: 48897501 Dose and Endpoint for Risk Assessment : NOAEL= 70 mg/kg/day based on based on treatment related findings at the mid

- dose included gait abnormality in both sexes, low arousal and impaired righting reflex in males, and hunched body in females, 7

- 8 h ours after dosing at LOAEL of 285 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor ) Comments on Study/Endpoint/Uncertainty Factors: This study is considered to be the most appropriate for acute dietary dose and endpoint selection. No other studies in the database were available which contained acute effects relevant to the general population.

Acute RfD = = 0.7 mg/kg/day

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 44 of 48 A.3.2 Acute Reference Dose (aRfD) (Females 13

- 49 years old)

Study Selected: Developmental Toxicity in rats

MRIDs: 00147301 Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg/day based on increased incidences of skeletal anomalies in the vertebrae (extra) and ribs (extra, rudimentary , cervical) at a LOAEL of 45 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor ) Comments on Study/Endpoint/Uncertainty Factors: This study is considered to be the most appropriate for acute dietary dose and endpoint selection. Skeletal abnormalities could be from a single exposure during pregnancy and are therefore considered a potential acute effect, and therefore, appropriate fo r the acute dietary endpoint scenario for females of child

- bearing age.

Acute RfD = = 0.1 mg/kg/day

A.3.3 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity Study in Rats

MRIDs: 40486002 Dose and Endpoint for Risk Assessment : NOAEL= 3.6 mg/kg/day based on increased incidences of focal atypia, fatty change, and hepatocellular eosinophilic change in the liver of males at a LOAEL of 12.1 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x int raspecies variability, 1x FQPA Safety Factor ) Comments on Study/Endpoint/Uncertainty Factors: The chronic toxicity study in rats is appropriate for both the population of concern (adults) and the duration of exposure.

Chronic RfD = = 0. 0 4 mg/kg/day

A.3.4 Incidental Oral Exposure (Short

- term, 1

- 30 days)

Study Selected: 2

- Generation Reproduction Toxicity Study in Rats

MRIDs: 00162770 Dose and Endpoint for Risk Assessment : Offspring NOAEL= 7.3 mg/kg/day based on decreased survival and body weights (20

- 39%) in the pups at the LOAEL of 74 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 45 of 48 Comments on Study/Endpoint/Uncertainty Factors: T he endpoint of concern in this study is appropriate for the population (infant and children) and the duration of concern.

A.3.5 Dermal Exposure (Short

- , Intermediate

- Term)

A dermal assessment is not required for the flurprimidol. No toxicity was observed up to the limit dose in the dermal toxicity study. No quantitative susceptibility was observed in any study. Qualitative susceptibility was observed in the rat developmenta l study, however; as the effects occurred in the presence of decreased maternal body weights the available dermal toxicity study is considered to be protective as no decreased body weights were observed. Additionally, using the estimated upper bound derma l absorption value would result in a dermal LOAEL near the limit dose (~750 mg/kg/day).

A.3.6 Inhalation Exposure (Short

- , and Intermediate

- Term)

Study Selected: 13

- Week Inhalation Toxicity Study in Rats

MRIDs: 49007301, 49007302 Dose and Endpoint for Risk Assessment : NOAEL= 0.1 mg/L based on results in the range

finding study (MRID 49007302) where goblet cell hyperplasia was observed in nasal level II, III, IV, V, and VI of male rats (nasal passages of females were not examined microscopically) at a

LO AEL of 0.4 mg/L. Comments on Study/Endpoint/Uncertainty Factors: The inhalation toxicity study was chosen

as it is a route

- specific study and appropriate for the duration of concern. Long

- term inhalation assessment is not required because this exposure length is not expected based on current use
patterns.

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 46 of 48 Appendix B

. DEEM

- FCID Model Inputs and Outputs for Acute and Chronic Dietary Exposure Estimates.

Acute DW Analysis

- DEEM Input File

US EPA Ver. 3.18, 03

- 08

- d

DEEM

- FCID Acute analysis for FLURPRIMIDOL

Residue file name:

C: \ Users \ spiper \ Documents \ DEEM_version316 \ Flurprimidol \ Flurprimidol_acute.r08 Analysis Date 03

- 19

- 2015 Residue file dated: 03

- 19

- 2015/09:05:27

Reference dose: aRfD = 0.7 mg/kg bw/day NOEL = 70 mg/kg bw/day Comment: Drinking Water Assessment Only

---------------------------------------------------------------------------------- EPA Crop Def Res Adj.Factors Comment Code Grp Food Name (ppm) #1 #2

---------- ---- ------------------------------- ---------- ------ ------ ------- 8601000000 86A Water, direct, all sources 0.707000 1.000 1.000 8602000000 86B Water, indirect, all sources 0.707000 1.000 1.000

Acute DW Analysis

- DEEM Output File

US EPA Ver. 3.18, 03

- 08

- d

DEEM

- FCID ACUTE Analysis for FLURPRIMIDOL NHANES 2003

- 2008 2

- Day

Residu e file: Flurprimidol_acute.r08 Adjustment factor #2 NOT used. Analysis Date: 03

- 19

- 2015/09:08:56 Residue file dated: 03

- 19

- 2015/09:05:27 NOEL (Acute) = 70.000000 mg/kg body

- wt/day Acute Pop Adjusted Dose (aPAD) varies with population; see individual reports

RAC/FF intake summed over 24 hours Run Comment: "Drinking Water Assessment Only"

=====================================================================

==========

Summary calculations

-- per capita:

--- 95th Percentile

---- --- 99th P ercentile

---- --- 99.9th Percentile

---- Exposure % aPAD MOE Exposure % aPAD MOE Exposure % aPAD MOE

---------- ------- -------- ---------- ------- -------- ---------- ------- -------- Total US Population:

0.038551 5.51 1815 0.063571 9.08 1101 0.120761 17.25 579

All Infants:

0.120747 17.25 579 0.163551 23.36 428 0.239703 34.24 292

Children 1

- 2:

0.059446 8.49 1177 0.089514 12.79 781 0 .220448 31.49 317

Children 3

- 5:

0.048236 6.89 1451 0.073875 10.55 947 0.118579 16.94 590

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 47 of 48 Children 6

- 12:

0.036856 5.27 1899 0.060486 8.64 1157 0.093227 13.32 750

Youth 13

- 19:

0.032105 4.59 2180 0.052878 7.55 1323 0.079837 11.41 876

Adults 20

- 49:

0.037936 5.42 1845 0.056455 8.07 1239 0.082132 11.73 852

Adults 50

- 99:

0.033793 4.83 2071 0.051239 7.32 1366 0.080769 11.54 866

Female 13

- 49:

0.038477 38.48 1819 0.056580 56.58 1237 0.079349 79.35 882

Chronic DW Analysis

- DEEM Input File

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysi s for FLURPRIMIDOL

Residue file:

C: \ Users \ spiper \ Documents \ DEEM_version316 \ Flurprimidol \ Flurprimidol_chronic.r08 Adjust. #2 NOT used Analysis Date 03

- 19

- 2015 Residue file dated: 03

- 19

- 2 015/09:11:33 Reference dose (RfD) = 0.04 mg/kg bw/day Comment:Drinking Water Assessment Only

---------------------------------------------------------------------------------- Food Crop Residue Adj.Factors EPA Code Grp Food Name (ppm) #1 #2

---------- ---- ------------------------------- ---------- ------ ------ 8601000000 86A Water, direct, all sources 0.656000 1.000 1.000

8602000000 86B W ater, indirect, all sources 0.656000 1.000 1.000

Chronic DW Analysis

- DEEM Output File

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for FLURPRIMIDOL NHANES 2 003

- 2008 2

- day

Residue file name:

C: \ Users \ spiper \ Documents \ DEEM_version316 \ Flurprimidol \ Flurprimidol_chronic.r08 Adjustment factor #2 NOT used. Analysis Date 03

- 19

- 2015/09:13:57 Residue file dated: 03

- 1 9

- 2015/09:11:33 Reference dose (RfD, Chronic) = .04 mg/kg bw/day COMMENT 1: Drinking Water Assessment Only

=====================================================================

==========

Total exposure by population subgroup

----------- --------------------------------------------------------------------

Total Exposure

### F lurprimidol Human Health Draft Risk Assessment DP No. D 427106

Page 48 of 48 ----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.013736 34.3% Hispanic 0.013115 32.8%

Non

- Hisp

- White 0.014128 35.3%

Non

- Hisp

- Black 0.011334 28.3%

Non

- Hisp

- Other 0.015832 39.6% Nursing Infants 0.012427 31.1%

Non

- Nursing Infants 0.045687 114.2%

Female 13+ PREG 0.012934 32.3%

Children 1

- 6 0.017593 44.0%

Children 7

- 12 0.011452 28.6%

Male 13

- 19 0.009442 23.6%

Female 13

- 19/NP 0.010581 26.5%

Male 20+ 0.012797 32.0%

Female 20+/NP 0.014427 36.1%

Seniors 55+ 0.013281 33.2%

All Infants 0.035418 88.5%

Female 13

- 50 0.013670 34.2%

Children 1

- 2 0.019815 49.5%

Children 3

- 5 0.016695 41.7%

Children 6

- 12 0.012040 30.1%

Youth 13

- 19 0.010017 25.0%

Adults 20

- 49 0.01 3705 34.3%

Adults 50

- 99 0.013548 33.9%

Female 13

- 49 0.013654 34.1%

-------------------------------------------------------------------------------