Triflumizole Human-H e alth Risk Assessment DP# 407679

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C

. 20460

MEMORANDUM

Da t e : October 29,2013 OFFI C E OF
CH EM I C AL S AFE TY AND PO LL UTI ON P REVE N T IO N

SUBJECT: Tri fl umizole: Human-Health Risk Assessment fo r the Proposed Uses on Greenhouse-Grown Tomato and Cucumber ; Pome Fru i t G r oup 11- 1 0, Small Fruit

Vine Climbing except Fuzzy Kiwifruit Subgroup 13-07F and L ow Growing Berry Subgrou p 13-07G

, Except C r anber r y

.

PC Co d e: 128879

De c isi o n N o .: 4 72282

Pet it ion No. : 2E81 1 9

R i s k Assess m e n t Type : Single Chemical Aggregate

TXRNo. : NA

M RI DNo. : NA DP B arco d e: D407679

R e g i s t ration N o

. : 400- 4 36,

- 5 1 8,

- 521 Reg ul a t ory A cti on : Sect i on 3

Case No. : NA

CAS No.: 6869 4

- 1 1- 1
4 0 CFR: 

### § 180.476

FR O M : Seyed Tadayon, Risk Assessor

## ~""~~"'V-?~-~---­ John Liccione, P h .D

. , Tox i colog i

William Donovan

, Ph.D.

, Chem i s Ri sk Assessment Branch V

H ealth Effects Div i sion (HE D ; 7509P)

THROUG H : MichaelS. Metzger, Branch Chief 

# jf/ /}17 /) }**--** Risk Assessment Branches V & V II

## ~**·** 

# 1/ l)

HED (75 0 9P)

TO : Barbara Madden/Andrew Ertman

, RM 05
Risk I ntegration, M i nor Use, a n d Eme r ge n cy Response B r anch Registration Division (RD; 7505P)

The Registrat i o n d i v i sio n has reques t ed that HED evaluate hazar d and exposure data a n d conduct dietary

, occupational

, residential, and aggregate exposure assessments

, as needed

, to estimate the

risk to human health that will result from the proposed Section 3 registration uses of the ac t ive ingredien t (a i ) tr iflumizo l e ( 1-[( 1 E)

- 1-[[ 4-chloro-2-(trifluorome th y l )phe n yl]im i no ]- 2 propoxyethy l ) -1 H-imidazole)

, on tomato and cucumber (grow n i n green house)

, pome fruit

group 11-10, small fruit vine climbing except fuzzy kiwifruit subgroup 13-07F and low grow i ng berry subgroup 13-070, except cranberry.

The most recent human

- health risk assessment for triflumizole was completed for registration
review on 02-May-20 12 (Memo

, S

. Tadayon, et al.; D393221 ). Page 1 of 44Tritlum i zole Human-Health Risk Assessment DP # 407679



### Table of Contents
1 .0 Executive Summary

.. .. .. . .. .. . .. . ..... . .. . . ... .. . .. .. ................ . ... .. .. . ... . ............ .. ... . .. .. ... . .. . ......... . . . .. 4
2

. 0 HED Recommendations

........... . ... . .. . ... .. ........... . .. . ... . .. .. .. .. ............. .. . . . .. .. . ... .. ............... .. .. .. 8
2.1 Data Deficiencies

.......... ... . .. .. ... . . ........... . .. .. .. .. .. .. . .. ...... . ... . ... ... . ... . .. .. .. .... . ....... . . ... .. .. .. .. .. ... 8
2.2 Tolerance Considerations

............ . .. .. .. . ... . ............... .. . ... .. .. . . ....................... .. .. .. .............. 8
2.2

. 1 Enforcement Analytical Method

........ .. . . . .. .. ... . .............. . . . . .. . ... .. .. . ... .............. ... . ... . ... . 8
2.2

. 2 Recommended Tolerances

.. . .. .. .. .. ..................... ... .. .. . . . ....................... .. . ... . ... .. .. .... . ..... 8
2.2

. 3 Revisions to Petitioned-For T olerances

. .. .. ................... . .. .. . . .. .. .. . ... . . . ........... .. .. ... . ... . . 9
2.2.4 International Harmonization

.. .. .. .. . ......... . .......... . . . .... . .. .. .. .. .. .. ................... . . . ... .. .. .. .. .. . 9
3.0 Introduction

.............. . ... . .. . . .. .. .. .. . .. . ................ . .. . ... . .. .. . . . . . . ... ...................... . .. ... . ... .. . ... . ......... 9
3.1 Chemical Identity

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


### 3

. 2 Physical/Chemical Characteristics

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


### 3.3 Pesticide Use Pattern

....... .. .. .. .. .. .. . . . ... . . . . ........ . ...... .. .. . ... . ... .. .. .. .. .. .. . ... .. . .......... .. ... ... . ... .. . 1 1


### 3.4 Anticipated Exposure Pathways

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


### 3.5 Consideration of Environmental Justice

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


### 4.0 Hazard Characterization and Dose-Response Assessment

...... .. .. .. . . . . .. .. .. . ................... 13
4.1 Toxico l ogy Studies Available for Analysis

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


### 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

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


### 4

. 2

. 1 Dermal Absorption

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


### 4.3 Toxicological Effects

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


### 4.3.1 Summary of Toxicological Effects

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


### 4.4 Safety Factor for Infants and Children (FQPA SF)

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


### 4.4.1 Completeness of the Toxicology Database

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


### 4.4.2 Evidence of Neurotoxicity

... . .... :

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


### 4

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

.. . ... 17


### 4.4.4 Residual Uncertainty in the Exposure Database

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


### 4.5 Toxicity Endpoint and Point of Departure Selections

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


### 4.5.1 Dose-Response Assessment

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


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

.. ... 19


### 4

. 5.3 Cancer Classificat i on and Risk Assessment Recommendation

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


### 4

. 5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

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


### 5.0 Die t ary Exposure and Risk Assessment..

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


### 5.1 Residues of Concern Summary and Rationale

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


### 5.2 Food Residue Profile

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


### 5.3 Water Residue Profile

. ...... .. . .. . . .. .. .. . . .. . .. .. .. .. ... . .. . . . . .. . .... . ...................................... . . . ...... 23


### 5

. 4 Dietary Risk Assessment

. .. . ...... . ........................ . ........ . . . ... .. ..... . .. .. .. .. . . .. .. ... . .. .. ... .. .. .. .. .. . 23


### 5.4

. 1 Description of Residue Data Used in Dietary Assessment

. .. . . .. . .. . ... . .. .. ............... . . 23


### 5.4

. 2 Percent Crop Treated Used in Dietary Assessment

........................................ .. ... . 24
5.4.4 Chronic Dietary Risk Assessment

.............. . ...... . ... .. . . ... .. . . .. . . . . . . .. .. .. . ... .. .. .. .. ... .. . ... . . . . 24
5.4

. 5 Cancer Dietary Risk Assessment..

.. .. .. .. .. .. .. .. . ... .. .. .. .. .. .. . .... . . . .... . .............................. 25
6.0 Residential (Non-Occupational) Exposure/Risk Characterization

....... . ...... . ... .. . .. . . . . .. 25

6.1 Residential Bystander Post

- Application Inhala t ion Exposure

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

6

. 2 Spray Drift

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


### 7

. 0 Aggregate Exposure/Risk Characterization

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


### 7

. 1 Acute Aggregate Risk

. .. .. . ............ . ....... . ........ . ............ . .......................... . ....................... 27 Page 2 of44Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 3 of 44 7.2 Shor t

- Term Aggregate Risk

................................ ................................ ........................ 27
7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 27
7.4 Chronic Aggregate Risk

................................ ................................ .............................. 27
8.0 Cu mulative Exposure/Risk Characterization

................................ ............................... 28
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 28
9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 28
9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 29
9.2.2 Inhalation Post

- Application Risk

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

................................ ....................... 32 Appendix B. Review of Human Research

................................ ................................ ................ 37 Appendix C. Residential Exposure Tables.

................................ ................................ ................ 38 Appendix D. International Residue Limits Table

................................ ................................ ........ 44Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 4 of 44 1.0 Executive Summary

Triflumizole is a broad spectrum, imidazole fungicide (group 3) that inhibits ergosterol biosynthesis in fungi. In the U.S., triflumizole is registered to Chemtura USA Corporation and is formulated as 50% water soluble packets (WS), 50% water dispersible granules (WDG), and as 480SC (suspension concentrate) at approximately 42% active ingredient (ai). It is registered for use on many agricultural crops, orna mentals in greenhouses/shade houses, interior scapes, and Christmas trees/conifers on nurseries and plantations. It is also used as a pre

- plant seed piece treatment on pineapples. Triflumizole can also be applied to trees, shrubs, and vines in
residential settings . There are no registrations on turf and garden vegetable uses.

HED has reviewed residue chemistry database relevant to t he proposed uses and has conducted dietary, occupational

, and residential exposure assessment s as part of an aggregate assessment to support the proposed uses of the active ingredient (a.i.) triflumizole on greenhouse

- grown cucumber and t omato , pome fruit group 11

- 10, small fruit vine climbing except fuzzy kiwifruit subgroup 13

- 07F and low growing berry subgroup 13

- 07G, ex cept cranberry. The end

- use product s are Procure ® 480 SC and Terraguard ® SC (EPA Reg # 400

- 518 and EPA Reg# 400

- 521 , respectively ), at 4 lb ai/gallon liquid formulation s . The maximum single application rate proposed is 0.5 lbs. ai/A via ground and aerial a pplication to pome fruit

.

In conjunction with this petition, IR

- 4 has requested the establishment of permanent tolerances
for the residues of the triflumizole, including its metabolites and degradates, in or on the
commodities summarized in Table 2.2.2

.

For plant commodities, the tolerance expression and risk assessments include parent and all metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety. For livestock commodities, the tolerance expression and risk assessments include parent, the metabolite 4

- chloro

- 2

- hydroxy

6

- trifluoromethylaniline sulfate, and other metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety. The drinking water risk assessment includes parent and all metabolites containing the 4

- chloro

- 2

- trifluoromethy laniline moiety. Tolerances are currently established in/on a variety of crops (40 CFR §180. 476 ).

Hazard Assessment :

T he toxicology database for triflumizole is complete

. The database of laboratory animal studies spans multiple routes of exposure (oral, dermal, inhalation) and animal species (rat, mouse, dog) and consists of studies ranging from a single exposure (acute) to subchronic and chronic exposures. Additionally, there are developmental toxicity studies in rats and rabbits, a rat reproducti ve toxicity study, an immunotoxicity study

, and acute and subchronic neurotoxicity
studies. A 28

- day inhalation study was identified as a data gap but a waiver request for the 28

- day inhalation toxicity study was granted (September 2004)

. A summary of th e current toxicity data available for triflumizole is included in the toxicity profile in Appendix A.

The liver is the primary target organ of triflumizole in the rat, mouse, and dog as evidence d by increased liver weight, hepatocyte fatty vacuolization , hypertrophy, inflammation, fatty degeneration, and necrosis. Specific s ubchronic effects included increased absolute and relative liver weights, accumulation of fat droplets, and slight hepatocyte centrilobular swelling. C hronic effects included hepatoc yte fatty vacuolization; hepatocyte hypertrophy, focal inflammation, and necrosis; fatty degeneration; eosinophilic foci of hepatocyte alteration; hepatic nodules; bile ductTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 5 of 44 hyperplasia; and hyaline degeneration/fibrosis of the bile duct. Liver effects we re seen in rat and mouse subchronic and chronic/carcinogenicity studies.

Triflumizole is classified as not likely to be carcinogenic to humans, based on a weight of evidence determination including the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a mutagenicity concern.

Clinical signs of neurotoxicity ( neuromuscular impairment and decreased locomotor activity ) were noted in the acute neurotoxicity study at mid and high doses. There was no evidence of neurotoxicity in the subchronic neurotoxicity stud y in the rat with triflumizole

. In oral rat developmental studies, fetal effects (decreased numbers of viable fetuses, increased dead or resorbed fetuses, increase d numbers of late resorptions, decreased fetal body weight and increased incidences of cervical ribs) were seen in the fetuses at the same doses at which maternal toxic effects were noted. Reproductive toxicity, manifested as increased gestation length, w as observed at the high dose. There is no evidence for quantitative or qualitative susceptibility following in utero exposure or following pre

- and post natal exposure.

Since the last risk assessment, an immunotoxicity dietary study in female BALB/c mice has been submitted and reviewed. The study revealed a significant decrease in the anti

- SRBC IgM response at a dose level of 285.7 mg/kg/day. The NOAEL was 28.6 mg/kg/day. The results of the immunotoxicity study do not impact the point of departures (POD s) selected for dietary and

non

- dietary exposure risk assessments (W. Cutchin, D363719, 4/1/09).

The toxicological endpoint selected for dietary and non

- dietary risk assessments are presented in Appendix A. Separate acute endpoints and PODs were selected for females of child

- bearing age (13

- 49) and the general population including infants and children

. For females 13

- 49, a developmental endpoint was selected with a NOAEL = 10 mg/kg/day and a LOAEL = 35 mg/kg/day . For the general population the P OD was the NOAEL = 25 mg/kg/day and a LOAEL = 100 mg/kg/day at which functional observational battery ( FOB ) findings (neuromuscular impairment) and decreased locomotor activity were observed following a single exposure

. An uncertainty factor of 100x (10x for inter

- species extrapolation and 10x intra

- species variation) was applied to derive the acute Reference Doses ( a RfD) and the acute Population Adjusted Dose (aPAD) for these population groups. The chronic dietary endpoint is liver toxicity observed at
3 .5 mg/kg/day, the lowest dose tested in the c ombined c hronic t oxicity/ c arcinog enicity s tudy in

r at s; a NOAEL was not established. An uncertainty factor of 300x (10x for inter

- species extrapolation, 10x intra

- species extrapolation and 3x for the use of a L OAEL (UF L 

### )) was used to
derive the chronic RfD and chronic population adjusted dose . An oral NOAEL of 3.5 mg/kg/day for offspring toxicity seen at 8.5 mg/kg/day from a two

- generation reproduction study was used for assessing dermal and inhalation risk resu lting from short

- term exposures. A Margin of Exposure (MOE) of 100 is adequate for these exposure scenarios. An oral LOAEL of 3.5 mg/kg/day based on liver toxicity in the combined chronic toxicity/carcinogenicity was used for assessing dermal and inhalati on risks resulting from intermediate

- and long term exposures. Since a LOAEL was used, the target MOE is 300 for these scenarios. An upper

- bound estimate of dermal absorption of 3.5% was calculated by comparing the maternal LOAEL from the rat developmenta l study with the NOAEL from the rat dermal study. Since oral doses were used, a dermal (3.5%) absorption factor was used for route

- to

- route extrapolation , and inhalation toxicity was assumed to be equivalent to oral toxicity

.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 6 of 44 The toxicology data base i s complete and there are no residual uncertaint ies for pre

- and post natal toxicity. The o ral rat developmental stud y showed an increased qualitative susceptibility of
the fetus to triflumizole in utero

, however, the use of the rat developmental NOAEL for the
derivation of the aRfD for females 13

– 49 would be protective of potential pre

- natal toxicity following an acute dietary exposure. Likewise, the use of the NOAEL for offspring and reproductive effec ts for incidental oral and short

- term dermal and inhalation exposure scenarios would address concerns for the increased qualitative susceptibility noted in the 3

- generation reproductive toxicity study. The FQPA Safety Factor is reduced (1x) for acute dieta ry and short term (dermal and inhalation) exposure scenarios. However, a 3X FQPA Safety Factor is retained in the form of a LOAEL to NOAEL factor (UF L 

### ) for assessing chronic dietary and intermediate

and long term dermal and inhalation risks from occupat ional use. The Agency has determined that a 3x for the use of a LOAEL (as opposed to the default 10x) is adequate b ased on the following weight of evidence considerations :

o The most sensitive endpoint in the target organ (liver) for this chemical and cla ss of compounds (conazole fungicide) is used for assessing chronic risk

.

o There is low concern for the observed effects since the observed lesions ( eosinophilic foci in male rats and fatty vacuolation and inflammation and necrosis in female rats) did
not pr ogress into malignancy

.

o The extrapolated NOAEL of 1.2 mg/k g /d ay (3.5/3 = 1.2) is supported by a comparable NOAEL (2.5 m g /k g /d ay ) used for deriving the chronic RfD for a structurally

- related chemical (Imazalil).

Based on these factors, the Agency is confi dent that the risk assessment would not under estimate dietary and non

- dietary risk s from chronic exposure to triflumizole

.

Food Residue Profile: Adequate residue chemistry data have been provided in support of the triflumizole petition. The nature of the residue in plants and livestock is adequately understood. The requested pome fruit crop group tolerance is supported by previously submitted data for the representative crops of apple and pear. Tolerances for crop subgroups 13

- 07F and 1 3

- 07G, except cranberry are supported by translation from grape and strawberry, respectively. Organization for Economic Co

- operation and Developme nt (OECD) tolerance calculation procedures were used to c ompute the HED

- recommended tolerance for greenhouse

- grown

tomato. For greenhouse

- grown cucumber, the recommended tolerance was based on the results
of the OECD calculator and international harmonization considerations. There is an adequate residue analytical method for the purposes of tolerance enforcemen t. T here are no residue chemistry issues that would preclude establishing tolerances for residues of triflumizole and its metabolites, as outlined in Table 2.2.2.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 7 of 44 Exposure/Risk Assessment Characterization: Acute and chronic risk assessments were
conduct ed for dietary exposure based on the existing and proposed uses. The acute and chronic assessments directly incorporated drinking water estimates. Assumptions for the acute
assessment included tolerance

- level residues for all foods, Dietary Exposure Eval uation Model (DEEM) 7.81 default processing factors (where appropriate ), and 100% crop

- treated (CT). Assumptions for the chronic dietary assessment included average field trial residues and average percent crop treated information . Some empirical process ing factors were used in the chronic assessment along with DEEM 7.81 default processing factors

, where applicable . All exposure
and risk estimates were not of concern. A quantitative cancer dietary assessment was not
conducted because triflumizole is cla ssified as “not likely to be carcinogenic to humans.”

The registered non

- occupational uses of triflumizole include a foliar spray by home owner and commercial applicators to landscape grown trees, shrubs and vines. Triflumizole is also registered for use on residential/non

- commercially grown bearing apples, pears and grapes. Though not a restricted use pesticide, the product is intended for “commercial” use and “private
residential” use. These label statements are not considered sufficient to preclude use by homeowners; therefore, these uses were assessed. There are no registered uses on lawns or turf.
S hort

- term r isk estimates to residential handlers do not exceed HED’s level of concern (i.e.,
MOEs > 100 ) for the residential scenarios assessed. Estimates for residential handlers margins of exposure ( MOEs) for these scenarios range from 200 to 8,200

.

T he acute and chronic aggregate risks are made up o f dietary sources (food and drinking water).
Short

- and intermediate

- term assessments, which ar e used to evaluate aggregate dietary and residential exposure s, were performed. Because t riflumizole is not carcinogenic, quantitative cancer aggregate risk assessments were not performed.

The occupational handler and post

- application assessments were co mpleted assuming the maximum label application rate. Based on the proposed use pattern s, there is potential for short

and intermediate

- term occupational exposure to triflumizole during mixing, loading, applying, and other handling tasks; and during post

- application activities. Additionally, since the same endpoint and point of departure (POD) were selected for intermediate

- term and chronic durations, intermediate

- term exp osure a nd risk estimates are protective of chronic exposure and risk. Chronic exposure is only expected for greenhouse uses o n cucumber and tomato . The level of concern (LOC) for short

- term and intermediate

- term occupational dermal and inhalation

exposures are margins of exposure (MOEs) <100 and < 300 , respectively . With the exception of grapes while performing short

- term girdling activity, the short

– te r m post

- application risk estimates did not exceed HED’s LOC (i.e., MOEs ≥ 100) on day 0 using the highest relev ant transfer coefficient ; t he intermediate

- term post

- application risk estimates did not exceed HED’s LOC (i.e., MOEs ≥ 300) on day 0 using the highest relevant transfer coefficient. The activit y with the highest estimated risk is girdling for grapes. The short

- term MOE’s for girdling grapes

are 79 on day zero and 100 on day 1 ; intermediate

- term risks are not of concern (MOEs>300)

. HED is recommending that the REI be revised on the label to address risk concerns related to girdling grapes.

T he triflumizole label includes a personal

- protective equipment (PPE) requirement that applicators and other handlers wear long

- sleeved shirts, long pants

, chemical

- resistant gloves and shoes plus socks

.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 8 of 44 2.0 HED Recommendations

Pending submission of a revis ed Section B as described in Section 2.3, there are no residue chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of permanent tolerances for residues of triflumizole and it metabolites and degradates as outlined in
Table 2.2.2.

2.1 Data Deficiencies

860.1200 Directions for Use

None

860.1550 Proposed Tolerances

Proposed and r evised tolerance levels and commodity definitions a re presented in Table
2.2.2.

860.1650 Submittal of Analytical Reference Standards

An a nalytical standard for triflumizole is currently available in the EPA National Pesticide Standards Repository ( personal communication with Ther esa Cole

, 8/20/2013 )

, the reference
standard was received on 8/16/2013 and will expire on 01/31/2018

.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A dequate plant and livestock analytical enforcement method s are available to enforce tolerances
for residues of triflumizole ( D346779, W. Cutchin, 10/1/08 ). The appropriate analytical standards have been submitted to the BEAD standards repository.

2.2.2 Recommended Tolerances

The proposed tolerances and commodity definitions are appropriate

. However , some recommendations for changes made in a previous re view are not currently reflected in the 40 CFR § 180.476 (D346779, W. Cutchin, 10/1/08). The following tolerances should be deleted from 180.476(a)(1): apple, dry pomace; apple, wet pomace; grape, dried pomace; grape, raisin, waste; and grape, wet pomace . The commodity listed as “cilantro, leaves” should be changed to “coriander leaves.” Also, the following tolerances should be deleted from 180.476(a)(2): cattle, meat; egg; goat, meat; hog, fat; hog, meat; hog, meat byproducts; horse, meat; milk; poult ry, fat; poultry, meat; poultry, meat byproducts; and sheep, meat. Tolerance levels for the following commodities should be lowered from 0.5 to 0.10 ppm: fat of cattle, sheep, goat, and horse. Tolerance levels for the following commodities should be low ered from 0.5 to 0.20 ppm: meat byproducts of cattle, sheep, goat, and horse.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 9 of 44 Table 2.2.2. Tolerance Summary for Triflumizole 1

. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

Tomato 1.5 1.5 Greenhouse tomatoes only. Fruit, pome, group 11

- 10 0.5 0 0.5 0 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 2.5 2.5

Berry, low growing, subgroup 13

- 07G , except cranberry 2.0 2.0

Vegetable, cucurbit, group 9 0.5 0 2 0. 5 0 Includes established field uses for cucurbits and the proposed greenhouse use on cucumber.

1 Th ese tolerance s should be established under 40 CFR §180. 476.

2 The established and proposed tolerances for crop group 9 are identical and cover the proposed use on greenhouse grown cucumber.



### Note to RD: Upon establishment of the recommended tolerances listed above, tolerance listings
for the following individual cr ops should be revoked since they will be included in the new crop group and crop subgroup s listings : apple, pear, grape, and strawberry.

2.2.3 Revisions to Petitioned

- For Tolerances

None

2.2.4 International Harmonization

Codex has not established Maxi mum Residue Limits (MRLs) for residues of triflumizole in/on raw agricultural or processed commodities. Tolerance definitions are harmonized between Canada and the U.S. Additionally, all Canadian MRLs are harmonized with the corresponding
US tolerance le vels (see Appendix D ). Triflumizole is not registered for use in Canada. The Canadian MRLs for triflumizole were set to support the import of treated commodities.

2.3 Label Recommendations

HED is recommending that the REI be revised on the label to address risk concerns related to girdling grapes (i.e., one day) . Intermediate

- term post

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

- application activities assessed

.

HED recommends that the rotation al crop restriction be omitted from the greenhouse grown cucumber and tomato use directions since soils in greenhouses are not typically reused.

3.0 Introduction

Triflumizole is a broad spectrum, imidazole fungicide (group 3) that inhibits ergosterol
bio synthesis in fungi. In the U.S., triflumizole is registered to Chemtura USA Corporation and is formulated as 50% water soluble packets (WS), 50% water dispersible granules (WDG), and as 480SC (suspension concentrate) at approximately 42% active ingredient (ai). It is approved for broadcast foliar applications to a variety of agricultural crops

, ornamentals in greenhouses/shadeTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 10 of 44 houses, interior scapes, pre

- plant treatment of pineapple seed pieces and Christmas trees/conifers on nurseries and plantations. There are no registrations on turf or g arden vegetable uses.

3.1 Chemical Identity

Structure

Empirical f

ormula C 15 

### H 15 

### N 3 

### OCl F 3 

### Common name Triflumizole

IUPAC 1 

### name ( E )

- 4

- chloro

- α,α,α

- trifluoro

- N

- (1

- imidazol

- 1

- yl

- 2

- propoxyethylidene)

- o

- toluidine

CAS 2 

### name 1

- [(1 E )

- 1

- [[4

- chloro

- 2

- (trifluoromethyl)phenyl]imino]

- 2

- propoxyethyl]

- 1 H

- imidazole CAS registry number 68694

- 11

- 1

End

- use products (EPs) Procure ® 

### 50WS; EPA Reg. No. 400

- 431

Procure ® 

### 480SC; EPA Reg. No. 400

- 518
Chemical c lass Imidazole

Common moiety structure

Common name FA

- 1

- 1

IUPAC name 4

- chloro

- 2

- trifluoromethylaniline

Livestock metabolite

Common name FA

- 1

- 5

IUPAC name 4

- chloro

- 2

- hydroxy

- 6

- trifluoromethylaniline

Livestock metabolite

Common name FA

- 1

- 5

- S

IUPAC name 4

- chloro

- 2

- hydroxy

- 6

- trifluoromethylaniline sulfate

1 IUPAC = International Union of Pure and Applied Chemistry

2 CAS = Chemical Abstracts ServiceTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 11 of 44 3. 2 Physical/Chemical Characteristics

Triflumizole’s physical and chemical properties are summarized below in Table 3.2.

TABLE 3 .2. Physicochemical Properties of Triflumizole

Parameter Value Reference Melting point/range 63.5 °C DEB # 6410, J. Smith, 1/7/92 pH N/A

Bulk Density (at 20 o C) 0.50

– 0.70 Water solubility (g/L at 20 °C) 0.0125 (at pH 5.9) Solvent solubility (g/100 mL at 20 o C) Chloroform 222
Acetone 144

n

- Hexane 1.76
Methanol 49.6 Xylene 63.9 Vapor pressure (25 °C) 1. 4 x 10 - 6 mmHg Dissociation constant (pK

a at 25 ° C) 3.7 Octanol/water partition coefficient K OW at 25

o C 25

UV/visible absorption spectrum

max = 204, 230, and 308 nm (acidic)

max = 204, 236, and 300 nm (neutral)

max = 232 and 292 nm (basic) D368710, P. Savoia, 09

- NOV

- 2009



### 3.3 Pesticide Use Pattern

T he proposed uses of active ingredient (a.i.) triflumizole are f or greenhouse grown t omato and cucumber, p ome f

ruit g roup 11

- 10, s mall f

ruit v ine climbing except fuzzy kiwifruit s ubgroup
13

- 07F and l ow g rowing b erry s ubgroup 13

- 07G , except cranb er ry

. The end

- use product s are Procure ® 

### 480 SC and Terraguard ® 

### SC (EPA Reg # 400

- 518 and EPA reg# 400

- 521 ), a t 4 lb ai/gallon liquid formulation s. The maximum single application rate proposed is 0.5 lbs. ai/A via ground and aerial application. The summary of use information is presented in T able 3.3.1.

Table 3.3.1. Summary of Directions for Proposed Uses of Triflumizole.

Applic. Timing; Type; and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Pome fruits Crop group 11

- 10 proposed
Broadcast foliar;
At first indication of disease;
Ground or aerial equipment 4 lb/gal FlC

[400

- 518] 0.5 4 2.0 14 A minimum RTI of 10 days is specified. Apply in a minimum of 50 gal/A for ground applications.

Grapes (Small fruit vine climbing crop subgroup 13

- 07F, Except fuzzy Kiwifruit) Proposed

Strawberries (low growing berry crop subgroup 13

- 07G)

Broadcast foliar;
At first indication of disease;
Ground and Aerial equipment 4 lb/gal FlC

[400

- 518] 0.25 4 1.0 14 A minimum RTI of 21 days is specified. Apply in a minimum of 50 gal/A for ground applications. (aerial application for gra pe is prohibited)
Greenhouse grown vegetable (Cucumber and Tomato ) ProposedTriflumizole Human

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### Page 12 of 44 Table 3.3.1. Summary of Directions for Proposed Uses of Triflumizole.

Applic. Timing; Type; and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Manually and mechanically pressurized hand

gun sprayer 4 lb/gal SC

[400

- 521] 0.25 5 1.25 0 Do not plant leafy or non

- leafy Brassica vegetables or fruiting vegetables within 30 days after application. Do not plant bulb vegetables or root vegetables within 60 days after application. Do no plant cotton, small cereal grains and all other crops not registered on the label within one year after application.

REI: 12 hours.
Minimum R TI: 7 days.



### The use directions are adequate to allow evaluation of the residue data relative to the proposed uses. The proposed maximum application rates, RTIs, and PHIs are supported by the submitted field trial data. Because greenhouse soils are not reused, there is no need for a rotational crop restriction for greenhouse grown vegetables. HED recommends removal of the proposed rotational crop restriction for greenhouse cucumber and tomato.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of hu man

- health risk to suppor t the IR

- 4 proposed new uses

o n greenhouse

- grown t omato and cucumber, p ome f ruit g roup 11

- 10, s mall fruit vine climbing except fuzzy k iwifruit s ubgroup 13

- 07F and l ow g rowing b erry s ubgroup 13

- 07G

, except cranberry.

Humans may be exposed to triflumizole in food and drinking water, since triflumizole may be applied directly to growing crops and application may result in triflumizole reaching surface and ground water sources of drinking water. There are residential uses of triflumizole to trees, shrubs, and vines. There are no registrations on turf and garden vegetable uses. Residential uses could lead to potential residential handler and post

- application dermal and inhalation exposure. In an occupational setting, applica tors may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

- application exposure
for workers re

- entering treated fields.

This risk assessment considers all of the aforemention ed exposure pathways based on the proposed new uses of triflumizole , but also considers the existing residential registered uses as well, particularly for the dietary exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of en vironmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). As a part of everyTriflumizole Human

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### Page 13 of 44 pesticide risk assessment, OPP considers a large variety of consumer subgroups according to
well

- established procedures. In line with OPP policy, HED estimat es risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumpti on 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 used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments ar e performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifesty le 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 triflumizole is complete and is adequate for characterizatio n of its hazard, toxicity endpoint selection, and FQPA SF consideration. In the last registration review risk assessment ( S. Tadayon et

. al.

, 02

- May

- 2012; D393221 ), it was acknowledged that an immunotoxicity dietary study in female BALB/c mice ha d been su bmitted and reviewed. The study revealed a significant decrease in the anti

- SRBC IgM response at a dose level of 285.7 mg/kg/day. The NOAEL was 28.6 mg/kg/day. The results of the Immunotoxicity study do not impact endpoint selection or safety factors.

HED considered the toxicity database for triflumizole including this new Immunotoxicity study, the only new toxicity data submitted, as well as the most recent risk assessment (D363719, W. Cutchin, 4/1/09), to determine whether changes were needed to the e ndpoint selection, to safety factors including the FQPA factor, or to the cancer classification as part of the registration review assessment. HED concluded that no changes are required.

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

T hree metabolism studies in the rat s have been conducted. No significant sex

- related differences were observed in the absorption, metabolism, distribution, or excretion of triflumizole. Maximum concentrations of radioactivity in plasma were attained withi n 1 hour of dosing in both sexes. Excretion of the administered dose of the compound occurred primarily via the urine (74.0

- 78.9% dose), with the feces accounting for 14.6

- 20.5% of the dose. In both sexes, tissue radioactivity concentrations were highest in the liver

. Based on a one

- compartment model with a
first

- order process, the half

- time for elimination was 13.2 and 14.8 hours for male and female rats, respectively, from the 10 mg/kg dose group.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 14 of 44 Based on the metabolic profile, biotransformation in rat s primarily involves oxidation of the parent followed by sulfate and glucuronic acid conjugation. Hepatic microsomal enzyme induction was shown to occur in rats following oral administration.

4.2.1 Dermal Absorption

A dermal absorption study on triflu mizole is not available. An upper

- bound estimate of dermal absorption of 3.5% was calculated by comparing the maternal LOAEL from the rat developmental study with the NOAEL from the rat dermal study.

4.3 Toxicological Effects

4.3.1 Summary of Toxicolo gical Effects

The liver is the primary target organ of triflumizole. Liver effects were seen in rat and mouse subchronic and chronic/carcinogenicity studies. Subchronic effects included increased absolute and relative liver weights, accumulation of fat droplets, and slight hepatocyte centrilobular swelling. With increased length of exposure, the types of microscopic lesions noted increased in number and severity. Chronic effects included hepatocyte fatty vacuolization; hepatocyte hypertrophy, focal inf

lammation, and necrosis; fatty degeneration; eosinophilic foci of hepatocyte alteration; hepatic nodules; bile duct hyperplasia; and hyaline degeneration/fibrosis of the bile duct. The dog was less sensitive to the effects of triflumizole. In the dog chr onic study, effects included increased liver weights, increased serum alkaline phosphatase levels, and a macroscopic hepatic lobular pattern and granular texture. A very mild, macrocytic anemia was also noted and was most likely secondary to liver effects

.

A special microsomal enzyme induction study showed that triflumizole can induce hepatic microsomal enzymes when administered orally at high doses. Kidney weights were increased in the rat and mouse also, but the only pathology seen microscopically wa s in the rat chronic/carcinogenicity study in which cortical cysts were noted. Other organ effects were observed microscopically at the highest dose tested in the chronic rat study, which mainly involved cystic or hyperplastic lesions in endocrine glands and/or lymph nodes. Body weight decrements were noted in the rat and/or mouse subchronic, chronic and carcinogenicity studies and the developmental and reproduction studies.

Long

- term dietary administration of triflumizole did not result in an overall tr eatment

- related
increase in incidence of tumor formation in rats or mice. The former RfD/Peer Review Committee classified triflumizole as a “Group E” (evidence for non

- carcinogenicity for humans) chemical by all routes of exposure based upon lack of evide nce of carcinogenicity in rats and
mice. The risk assessment team concurs with that evaluation.

Triflumizole did not show evidence of mutagenicity in in vitro or in vivo studies.

The o ral rat developmental stud y showed an increased qualitative susceptibility of the fetus to
triflumizole in utero . Decreased numbers of viable fetuses, increased dead or resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight and increased incidences of
cervical ribs was seen in the fetuses at the same doses at which maternal toxic effects were noted. In addition, increased incidences of 14 th 

### rudimentary ribs were observed at the next highest dose. Maternal toxic effects in the rat were decreased body w eight gain and decreased foodTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 15 of 44 consumption, increased placental weight, and increased maternal spleen and liver weights. The use of the rat developmental NOAEL for the derivation of the aRfD for females 13

– 49 would be protective of potential pre

- natal tox icity following an acute dietary exposure.

No increased susceptibility of the fetus was noted in utero in the rabbit developmental study. Fetal effects included increased fetal and litter incidences of lumbar ribs and decreased placental weights, which was also included as a maternal toxic effect. Maternal toxic effects in the rabbit
included decreased b ody weight gain, decreased food consumption, and decreased placental weights.

In the 3

- generation reproductive toxicity study in the rat, o ffspring effects included decreased pup weights, survival indices, and litter sizes in both F 3 

### litters, reduced li tter size in the F 1a 

### litter,
increased total

- litter mortality in the F 3a 

### litter, and developmental effects in the F 1b 

### and F 2b 

### progeny. Reproductive toxicity, manifested as increased gestation length, was increased in the

F 0 

### dams which were pregnant with F 1 

### offspring. Since the increased gestation length can be due to either effect in the dams and/or the offsprings, offspring sensitivity should be assessed relative
to the F 0 

### dams. In rats, this alteration in normal reproductive function can result in adv erse consequences in both dams and offspring. Based on this comparison, there is no increased quantitative susceptibility of the fetus. There is increased qualitative susceptibility in pups ; however, the use of the NOAEL of 3.5 mg/kg/day (offspring and re productive effects) for
incidental oral scenarios and short

- term dermal and inhalation scenarios would be protective of potential toxicity following pre

- and post

- natal exposures.

In acute oral toxicity studies in the rat and mouse and an acute inhal ation study in the rat, animals developed neurotoxic signs within 30 to 60 minutes of administration, which resolved within 24 hours in surviving animals. Signs included ataxia, hypotonia, ventral positioning, urinary incontinence, decreased respiration a nd heart rates, decreased locomotor movement, lacrimation, salivation, ptosis and/or rhinorrhea. No treatment

- related histopathological effects were found in surviving animals. In the chronic rat study, convulsions were observed sporadically in all dosag e groups, but the incidences were significantly higher in the high

- dose females. The majority of the convulsions were noted within the first year. Cholinesterase activity was also affected during the first year of the study, but not in a consistent manne r. High

dose males had decreased plasma and erythrocyte cholinesterase activity while high

- dose females had decreased plasma cholinesterase activity only. There were no treatment

- related effects on cholinesterase activity in the brain in either sex at an y dose and no neuropathology was noted. No neurotoxic effects were observed in the rat subchronic oral toxicity study or the mouse subchronic oral toxicity and carcinogenicity studies.

The lack of acute and subchronic neurotoxicity studies at the time of previous risk assessments triggered the application of a UF DB 

### of 3x for lack of acute and subchronic neurotoxicity studies (DP 361545; March 4, 2009 memo from ARIA team, RD) . Signs of neurotoxicity were seen in the acute oral and inhalation studies in the rat and mouse, although neurotoxicity studies were not submitted until 2003 (acute) and 2004 (subchronic). The submitted studies were reviewed in 2005 (R. Fricke, 6/1/05, DP Num: 304654). S igns of neurotoxicity ( neuromuscular impairment and decreased locomotor activity ) were noted in the acute neurotoxicity study at mid and high doses. As a result, the endpoint from this study was used to assess acute dietary risks from one

day exposures to triflumizole in the diet of the general population. No evidence of neurotoxicity was seen in the submitted subchronic neurotoxicity studies (R. Fricke, 6/1/05, DP 304654). Based upon the acute and subchronic neurotoxicity studies, th e 3x UF DB 

### was reduced to 1x.Triflumizole Human

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### Page 16 of 44 The evidence does not support the need for a DNT study. This conclusion is supported by lack of neurotoxic signs noted in the rat subchronic study at any dose, and in the adult or offspring in the developmental and reproduc ti ve toxicity studies in the rat. In an immunotoxicity dietary study in female BALB/c mice, a significant decrease in the anti

- SRBC IgM response was observed at a dose level of 285.7 mg/kg/day. The NOAEL was 28.6 mg/kg/day.

4.4 Safety Factor for Infa nts and Children (FQPA SF)

The risk assessment team has re

- evaluated the exposure and hazard data and, based on these data, recommended that the FQPA SF for acute risk assessment , incidental oral (short

- and intermediate term), and short

- term dermal and inhalation exposure scenarios remain at 1x , and
for chronic risk assessment remain at 3X . The se recommendation s are based on the following:

The toxicity database is complete for FQPA assessment. There was no quantitative or qualitative evidence of incr eased susceptibility in the rabbit fetuses following in utero exposure. There was evidence of qualitative susceptibility in the developmental rat study, however, there are no residual uncertainties, and the use of the developmental NOAEL and the endpoint for the aRfD for females 13

- 49 would be protective of the

pre

- natal toxic ity following an acute dietary exposure. There was evidence of qualitative susceptibility in the 3

- generation reproductive toxicity study in the rat, but there are no residual uncertainties, and the use of the offspring NOAEL for the incidental oral, and short

- term dermal and inhalation exposure scenarios would be protective of potential pre

- and post

- natal toxicity. The chronic dietary food exposure assessment is somewhat refined and utilizes ARs and % CT data for some existing uses ; however, this assessm ent is still considered conservative since it incorporates field trial data and some default processing factors

. For all proposed uses, tolerance

- level residue and 100% CT is assumed.

The dietary drinking water assessment utilizes water concentration values generated by models for which the model input parameters provide conservative, health protective, high

- end estimates of water concentrations that are not likely to be exceeded.

A 3x FQPA SF is retained for the chronic RfD because it is derived from the use of a LOAEL established in the combined chronic toxicity/carcinogenicity study in rats. A 3x FQPA SF for use of LOAEL instead of a NOAEL (as opposed to a 10x) is viewed to be adequate because:

o The most sensitive endpoint in the target organ (liv er) for this chemical and class of compounds (conazole fungicide) is used for assessing chronic risk.

o There is low concern for the observed effects since the lesions did not progress into malignancy.

o The extrapolated NOAEL of 1.2 mg/k g /d ay (3.5/3 = 1.2) i s supported by a comparable NOAEL (2.5 m g /k g /d ay ) used for deriving the chronic RfD for a structurally

- related chemical (Imazalil).Triflumizole Human

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### Page 17 of 44 4.4.1 Completeness of the Toxicology Database

The toxicology data for triflumizole are sufficient and are of good quality for selecting toxicity endpoints and points of departure for risk assessment. The database includes acceptable studies on developmental, reproductive/fertility, neurotoxic, subchronic, chronic, carcinogenic, immunotoxic, and mutagenic effects, as well as information on the metabolism and pharmacokinetics of triflumizole. A special study on hepatic enzyme induction is also available.

4.4.2 Evidence of Neurotoxicity

Signs of neurotoxicity were seen in the acute oral and inhalation studies in the rat and mouse. S igns of neurotoxicity ( neuromuscular impairment and decreased locomotor activity ) w ere noted in the acute neurotoxicity study at mid and high doses. As a result, the endpoint from this study was used to assess acute dietary risks from one

- day exposures to triflumizole in the diet of the general population. There were no treatment

- related neuropathological findings observed in
either sex in the acute ne urotoxicity study. No evidence of neurotoxicity was seen in the submitted subchronic neurotoxicity study. Likewise, neuropathological evaluation of study animals in the subchronic neurotoxicity study did not reveal any treatment

- related histological
effe cts of the central and peripheral nervous systems.

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

There is evidence of increased qualitative susceptibility following in utero exposure to rats in a developmental study. D evelopmental toxicity resulted in fetal death as compared to maternal toxicity which included decreases in body weight gain and food consumption and increases in placental, spleen and liver weights.

No quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rabbits in a developmental study

. In the rabbit developmental study, the endpoint relating to 24

- hour fetal survival after cesarian section is not a robust parameter since it is
associated with a confounding factor . This endpoint involves removal of pups from the dams and maintaining them under artificially controlled conditions that deviates from normal pup developmental conditions. Pups treated i n this fashion are no longer subject to maternal care which is critical to the survival of the pups, and hence it is difficult to discern if the decreased
24

- hour fe tal survival is treatment

- related or due to the lack of critical maternal care.

Evidenc e of increased qualitative susceptibility in pups was evident in the 3

- generation reproductive toxicity study in the rat (discussed in Section 4.3.1); however, the use of the NOAEL of 3.5 mg/kg/day (offspring and reproductive effects) for incidental oral s cenarios and
short

- term dermal and inhalation scenarios would be protective of potential toxicity following

pre

- and post

- natal exposures.

The uncertainties associated with the lack of acute and subchronic neurotoxicity studies have
been resolved. Foll owing the review and acceptance of those studies, 1) an acute endpoint for the general U.S. population (including infants and children) was selected; and 2) the 3x UF DB 

### FQPA SF was removed.

4.4.4 Residual Uncertainty in the Exposure DatabaseTriflumizole Human

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### Page 18 of 44 The acute dietary food exposure assessment utilizes established and recommend ed tolerance

level residues, DEEM 7.81 default processing factors (where available ), and 100% CT information for all commodities. By using these screening

- level assessments, actual

exposu res/risks will not be underestimated.

The chronic dietary food exposure assessment utilizes average field trial residues, and percent crop treated information , where available . Some empirical processing factors were used in the chronic assessment along w ith DEEM 7.81 default processing factors (where available ). The
chronic assessment is partially refined; however

, since it is based on reliable , high

- end data, it will not underestimate exposure/risk.

The dietary drinking water assessments utilize water concentration values generated by the

PRZM

- EXAMS model . The resulting screening

- level estimated drinking water concentrations (EDWCs) provide conservative, health

- protective, high

- end estimates of water concentrations that will not likely be exceeded.

4. 5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human

health risk assessment . Acute and chronic dietary and short

- and intermedi ate

- term inhalation and dermal exposure scenarios were assessed.

Acute Dietary Endpoint s : Separate acute endpoints were selected for females of child

- bearing age (13

- 49) and the general population. For females 13

- 49, a developmental endpoint was selected with a NOAEL = 10 mg/kg/day and a LOAEL = 35 mg/kg/day . For the general population the PoD was the NOAEL = 25 mg/kg/day and a LOAEL = 100 mg/kg/day at which FOB findings (neuromuscular impairment) and decreased locomotor activity were observed

. Thus, the acute reference dose (aRfD) and population

- adjusted dose (aPAD) are e quivalent at 0.25 mg/kg bw for general population and 0.1 mg/kg bw for female 13

- 49 years.

Chronic Dietary (All Populations ) : This dietary endpoint was based on liver toxicity in rats at the LOAEL of 3.5 mg/kg bw/day (NOAEL not determined)

. The standard combined UF of
100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation and (3X) for the la ck of NOAEL. Thus, the chronic reference dose ( c RfD) and population

- adjusted dose ( c PAD) are e quivalent at 0.01 2 mg/kg bw for all populations

Dermal and Inhalation [Short

- term (1

- 30 days)

- Occupational : The NOAEL of 3.5 mg/kg/day was based on decreased pup body weight, mortality, reduced litter size and increased incidence of hydroureter and space between the body wall and organs at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a 

### , F 2a 

### , and F 3a 

### interval s at the LOAEL of 8.5 mg/kg/day.

Dermal and Inhalation [

Intermediate

- term ( 30

- 180 days)

- Occupational : The LOAEL of 3.5 mg/kg/day was based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and inflammation and necrosis in female rats). The NOAEL is <3.5 mg/kg/day
because the lowest dose tested is the LOAEL. A 300

- fold UF (10x for interspecies extrapolation, 10x for intraspecies variation, and 3x for lack of a NOAEL) is required.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 19 of 44 A DAF of 3.5 % was estimated based on comparing the maternal LOAEL from the rat developmental study with the NOAEL from the rat dermal study.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposure, dermal and inhalation exposures will be combi ned since the toxicological effects of concern are the same and were identified from the same study.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Triflumizole is classified as not likely to be carcinogenic to humans, based on a weight of evidence determination including the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a mutagenicity concern.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Tabl e 4 .5. 4.1 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary , and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors RfD, PAD, Level

of Concern for
Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including
Infants and Children) NOAEL=

25 mg/kg/day UF A = 10x

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

0.25 mg/kg/day

aPAD = 0.25 mg/kg/day Acute Neurotoxicity Study

– Rat

LOAEL = 100 mg/kg/day based on FOB findings (neuromuscular impairment) and decreased locomotor activity.

Acute Dietary (Females 13

- 49 years of age) NOAEL =

10 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD = 0.1

mg/kg/day Developmental Toxicity Study

– Rat

Developmental LOAEL = 35 mg/kg/day
based on decreased numbers of viable fetuses, increased dead or resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight,
and increased incidences of cervical ribs.
Chronic Dietary (All Populations) L OAEL=3.5

mg/kg /day UF A = 10x

UF H = 10x FQPA SF= 3 x Chronic RfD =

0.0 12 mg/kg/day

cPAD = 0.012 mg/kg/day Combined Chronic Toxicity/Carcinog. Study

- Rat Based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and
inflammation and necrosis in female rats).

Incidental Oral
Short

- Term (1

- 30 days) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential LOC

for MOE = 100 Multi

- generation Reproduction Study

- Rat
LOAEL = 8.5 mg/kg/day based on decreased pup body weight, mortality,
reduced litter size and increased incidence of hydroureter and space between the body wall and organs were observed at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5

mg/kg/day.Triflumizole Human

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### Page 20 of 44 Tabl e 4 .5. 4.1 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary , and Non

Occupational Human Health Risk Assessments
Incidental Oral
Intermediate

Term (1

- 6 months) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x Residential LOC

for MOE = 100 Multi

- generation Reproduction Study

- Rat

LOAEL = 8 .5 mg/kg/day based on
decreased pup body weight, mortality,
reduced litter size and increased incidence of hydroureter and space between the body wall and organs In addition, gestation length was increased in the dams
of F 1a , F 2a , and F 3a animals

. Dermal Short

Term (1

- 30 days) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x Residential LOC

for MOE = 100 Multi

- generation Reproduction Study

- Rat
LOAEL = 8 .5 mg/kg/day based on decreased pup body weight, mortality,
reduced litter size and increased incidence of hydroureter and space between the body wall and organs were observed at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5

mg/kg/day.

Dermal
Intermediate

and Long

Term (1

- 6
months and 6
months and longer) L OAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x
UF DB = 3 x Residential LOC

for MOE = 3 00 Combined Chronic Toxicity/Carcinog. Study

- Rat Based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and inflammation and necrosis in female rats).

Inhalation
Short

- Term (1

- 30 days) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x Residential LOC

for MOE = 100 Multi

- generation Reproduction Study

- Rat

LOAEL = 8 .5 mg/kg/day based on decreased pup body weight, mortality,
reduced litter size and increased incidence of hydr oureter and space between the body wall and organs were observed at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5

mg/kg/day.

Inhalation
Intermediate

and Long

Term (1

- 6
months and 6
months and longer) L OAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x
UF DB = 3 x Residential LOC

for MOE = 3 00 Combined Chronic Toxicity/Carcinog. Study

- Rat Based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and
inflammation and ne crosis in female rats).

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based a weight of evidence

determination including the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a mutagenicity concern.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF =
uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a
NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of keyTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 21 of 44 date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of co ncern. N/A = not applicable.

Table 4 .5. 4. 2 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors RfD, PAD, Level

of Concern for
Risk Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x Occupational

LOC for MOE =
100 Multi

- generation Reproduction Study

- Rat
LOAEL = 8 .5 mg/kg/day based on decreased pup body weight, mortality,
reduced litter size and increased incidence of hydroureter and space between the body wall and organs were observed at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5

mg /kg/day.

Dermal
Intermediate

and Long

Term (1

- 6
months and 6
months and longer) L OAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x

UF DB = 3 x Occupational

LOC for MOE =
3 00 Combined Chronic Toxicity/Carcinog. Study

- Rat Based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and inflammation and necrosis in female rats).

Inhalation
Short

- Term (1

- 30 days) NOAEL=

3 .5 mg/kg/day UF A = 10x

UF H = 10x Occupational

LOC for MOE =
100 Multi

- generation Reproduction Study

- Rat

LOAEL = 8 .5 mg/kg/day based on decreased pup body weight, mortality,
reduced litter size and increased incidence of hydroureter and space between the body wall and organs were observed at 8.5 mg/kg/day. In addition, gestation length was increased in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5

mg/kg/day.

Inhalation
Intermediate

and Long

Term (1

- 6
months and 6
months and longer) L OAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x

UF DB = 3 x Occupational

LOC for MOE =
3 00 Combined Chronic Toxicity/Carcinog. Study

- Rat Based on liver toxicity (eosinophilic foci in male rats and fatty vacuolation and inflammation and necrosis in female rats).

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based a weight of evidence

determinat ion including the lack of evidence of carcinogenicity in studies in rats and mice and the absence of a mutagenicity concern.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The Metabolism Assessment Review Committee (MARC) determined that residues of concern should include parent triflumizole and all metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety (D280869, J. Tyler, 3/13/02). Based on structural consider ations,Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 22 of 44 parent triflumizole and m etabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety are assumed to have similar toxicity. As they were found to comprise >10% TRR in the plant metabolism studies, it is appropriate to include these compoun ds in the risk assessment. Further, it is also appropriate to include these metabolites in the tolerance expression since a common moiety enforcement method is available.

Table 5.1 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Triflumizole and all metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety Triflumizole and all metabolites containing
the 4

- chloro

- 2

- trifluoromethylaniline

moiety

Livestock Triflumizole, 4

- chloro

- 2

- hydroxy

- 6

-

trifluoromethylaniline sulfate, and other metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety Triflumizole, 4

- chloro

- 2

- hydroxy

- 6

- trifluoromethylaniline sulfate, and other metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety
Drinking Water Triflumizole and all metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety Not Applicable



### 5.2 Food Residue Profile

D4 1369 8, W. Donovan, 29

- OCT

- 2013



### Adequate residue chemistry data have been provided for triflumizole . Field trials are of adequate number and geographic representation. Data analyses employed validated analytical methods and are supported by ade quate storage stability data. Residues of triflumizole demonstrated stability in frozen storage except for fortified samples of cucumber , where residues declined 38 %

over 832 days . Accordingly, magnitude of the residue data for cucumber was corrected for degradation during frozen storage. No tomato processing studies were submitted because triflumizole use is limited to greenhouse tomato varieties, and these are not expected to be processed for economic reasons.

The recommended tolerances for triflumizole were derived by 1) use of the OECD MRL calculation procedures for tomato, and 2) direct translation for crop group 10

- 11, and crop subgroups 13

- 07F and 13

- 07G. The computed tolerance level for greenhouse

- grown cucumber was 0.80 ppm, based on OECD MRL calculation procedures. However, HED concludes that the established tolerance of 0.5 ppm for cucurbit vegetables group 9 is adequate to cover greenhouse cucumber for the following reasons: 1) the greenhouse cucumber HAFT is 0.34 ppm (less th an the crop group 9 tolerance), and 2) keeping the established crop group 9 tolerance at 0.5 ppm
retains harmonization with the PMRA MRL

.

To reiterate conclusions from previous triflumizole reviews (D346779, W. Cutchin, 10/1/08), the following tolerances should be deleted from 180.476(a)(1): apple, dry pomace; apple, wet pomace; grape, dried pomace; grape, raisin, waste; and grape, wet pomace. The commodity listed as “cilantro, leaves” should be changed to “coriander, leaves.” Also, the following
tolera nces should be deleted from 180.476(a)(2): cattle, meat; egg; goat, meat; hog, fat; hog, meat; hog, meat byproducts; horse, meat; milk; poultry, fat; poultry, meat; poultry, meat byproducts; and sheep, meat. Tolerance levels for the following commodities should be loweredTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 23 of 44 from 0.5 to 0.10 ppm: fat of cattle, sheep, goat, and horse. Tolerance levels for the following commodities should be lowered from 0.5 to 0.20 ppm: meat byproducts of cattle, sheep, goat,
and horse.

The following PBIs are appropria te for rotated crops: 30 days for spinach and fruiting vegetables; 60 days for root and tuber vegetables; and 1 year for cotton, small cereal grains, and any other crops without re gistered uses for triflumizole. No rotational crop restrictions are
needed for greenhouse grown crops because the soils are not reused.

5.3 Water Residue Profile

EFED provided ground and surface water EDWCs for triflumizole ( D 407680 , C. Koper et. al.

, 5/20/13 ) Updated EDWCs were provided to include the use on ornamentals. The highest ground water EDWCs were based on the aerial use pattern for cherries, consisting of 6 applications at 0.5 lb ai/A, with a 7

- day retreatment interval (RTI). This same use pattern was selected for calculation of the chronic surface water EDWC; t he acute surface water EDWC was modeled on the use pattern for ornamentals [FL nursery]: 3 applications at 1.0 lb ai/A, with a 7

- day RTI. Model ed values were provided since there are no comprehensive monitoring data for triflumizole in ground or surface water.

Table 5.3 summarizes the maximum EDWCs for triflumizole. In order to account for degradates containing the 4

- chloro

- 2

- trifluoromethylaniline moiety, EFED used the total toxic residue approach to account for both triflumizole and the additional res idues of concern

. Detailed information on how the individual modeling input parameters were derived can be obtained from
the memo “ Tier II Drinking Water Assessment to Establish Tolerances of Triflumizole on Greenhouse Vegetables (Cucumber and Tomato), Pome Fruit Subgroup 11

- 10, Small Fruit Vine Climbing Subgroup 13

- 07F and Low Growing Berry Subgroup 13

- 07G (excluding Cranberry) 

### ” 5/20/13, C.M. Koper, S. Sankula, and E. Odenkirchen, D407680.

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations for Triflumizole.



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

Acute 98 3.1

Chronic (non

- cancer) 22 3.1

Chronic (cancer) 15 3.1

a From the Tier II PRZM

- EXAMS

- Index Reservoir model.

b From the SCI

- GROW model.

Bolded values selected for use in the dietary exposure assessments.



### 5.4 Dietary Risk Assessment

D 4 13699, W. Donovan, 22

- AUG

- 2013



### 5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary

- exposure (food plus water) and risk assessments were conducted using

DEEM

- FCID, Version 3.16, which uses food consumption data from the USDA’s NHANES/WWEIA survey from 2003 through 2008. The assessments were performed for the

gen eral U.S. population and all population subgroups. Assumptions for the acute assessment
included tolerance

- level residues for all foods, DEEM 7.81 default processing factors (whereTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 24 of 44 applicable ), and 100% CT. Assumptions for the chronic dietary assessment included anticipated residues (average field trial values) for most crops and average percent crop treated information as available (see Section 5.4.2). Thus, the chronic dietary analysis may be considered a partially
refined assessment

. Some empirical p rocessing factors were used in the chronic assessment along with DEEM 7.81 default processing factors (where applicable ). Drinking water estimates were provided by EFED. The EDWC values were generated using the ornamental and cherr y use pattern s for acut e and chronic exposures, respectively

. The resulting screening

- level EDWC
estimate s of 0. 0 98 and 0.022 ppm w ere used for the acute and chronic assessments , respectively

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Updated percent crop treated (%CT) information was provided by the Office of Pesticide Program’s (OPP’s) Biological and Economic Analysis Division (BEAD) for apples, cantaloupes, cherries, cucumbers, grapes, hazelnuts (filberts), honeydew melons, pears, pu mpkins, squash, strawberries, and watermelons in a Screening Level Usage Analysis (SLUA) dated 30

- JAN

2013. Although BEAD provided maximum and average %CT information, only the average %CT values were utilized in the dietary exposure analysis.

The foll owing average percent crop treated estimates (30

- JAN

- 2013 Triflumizole SLUA) were used in the chronic dietary risk assessments for the following crops that are registered for triflumizole: apple: 25%; cantaloupe: 10%; cherry: 25%; cucumber: 2.5%; filbert: 5%; grape: 5%; honeydew: 15%; pear: 45%; pumpkin: 5%; squash: 5%; strawberry: 25%; and watermelon:
5%.

5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern for the general population or any other population subgroup. The assessment was unrefined and the highest exposure estimate was for the population subgroup children 1

- 2 years old, w hich utilized 40 % of
the aPAD for triflumizole . The acute exposure estimate for the general U.S. population utilized
25% of the aPAD. The acute exposure estimate for females 13

- 49 was based on a lower POD than for other population subgroups, and utilized 66% of the aPAD. A summary table of dietary exposure and risk for triflumizole is provided in Section 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general population or any other population subgroup. The assessment was partially refined and the highest exposure and risk estimates were for the population subgroup children 1

- 2 years old,
which utilized 3 9 % of the cPAD for triflumizole . The chronic exposure estimate for the general U.S. population utilized 2 1 % of the cPAD. A summary table of dietary exposure and risk for
triflumizole is provided in Section 5.4.6. Although further refinement to the analysis is not required at this time, future assessments could be refin ed through the incorporation of monitoring
data.Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 25 of 44 5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because triflumizole was classified as “not likely to be carcinogenic to humans.”

5.4.6 Summary Table of Dietary Exposure and Risk

Table 5.4.6 : Summary of Dietary 

### (Food and Drinking Water) Exposure and Risk for
Triflumizole

.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.06 3555 2 5 0.002571 21

N/A N/A All Infants (< 1 year old) 0.04 6533 19 0.002625 22

Children 1

- 2 years old 0.099738 40 0.004641 39

Children 3

- 5 years old 0.0 90227 36 0.003741 31

Children 6

- 12 years old 0.0 58912 24 0.002281 19

Youth 13

- 19 years old 0.0 48310 19 0.001728 14

Adults 20

- 49 years old 0.06 2830 25 0.002563 21

Adults 50

- 99 years old 0.06 2045 25 0.002602 22

Females 13

- 49 years old 0.06 6279 6 6 0.002531 21



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

The registered non

- occupational uses of triflumizole include a foliar spray by home owner and commercial applicators to landscape grown trees, shrubs and vines. Triflumizole is also registered for use on residential/non

- commercially grown bearing apples, pears and grapes. Though not a restricted use pesticide, the product is intended for “commercial” use and “private residential” use. There are no registered uses on lawns or turf.

Residential short

- term (1

- 30 days) dermal and inhalation exposures are expected for triflumizole handler activities associated with use on ornamental plants and bearing pome fruit trees

. For
triflumizole the dermal and inhalation endpoints are ba sed on the same toxicological effect,
therefore the MOEs are combined to determine a total risk estimates

. The results of the residential handler exposure and risk assessment are presented in Appendix C . The total short

term margins of exposure (MOEs) ar e not of concern (i.e. an MOE > 100) with baseline attire (shorts, short

- sleeves, shoes and socks).

Post

- application exposure from triflumizole use on landscape ornamentals for children (1

- 2 years) is expected to be negligible based on the following factors : 1 ) Children young enough to
exhibit hand

- to

- mouth behavior would not typically play in ornamental beds or tree plots ; 2) IfTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 26 of 44 present, leaf to skin residue transfer would be negligible because of the minimal frequency and
duration of cont act

. There is also the potential for post

- application exposure for adult and children (6

- 11 years old), exposed as a result of being in an environment that has been previously
treated with triflumizole

. All the short

- term dermal post

- application MOEs fo r each scenario are greater than the LOC of 100, and are not of concern.

6. 1 Residential Bystander Post

- A pplication Inhalation Exposure

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

- application inhalation exposure assessment was not performed for triflumizole at this time. However, volatilization of pesticides may be a source of post

- application inhalation exposure to indivi duals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subse quently, the way to incorporate post

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

- application inhalation exposure assessment

6. 2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground appl ication method employed for triflumizole . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Ag ency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labe ls/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific prod ucts with significant risks
associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a
worse case inhalatio n (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios ; flagger risks were
not of concern

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HE D must consider and aggregate triflumizole exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregateTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 27 of 44 assessment, exposures from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

In examining acute aggregate risk, H ED has assumed that the only pathway of exposure relevant

to the acute time frame is dietary exposure. Therefore, the acute aggregate risk is comp ri sed of exposures to triflumizole residues in food and drinking water and is equivalent to the acute dietary risk estimates summarized in Table 5.4.6

. T he acute risk estimates are well below HED’s level of concern for all population subgroups.

7.2 Short

- Term Aggregate Risk

The residential post

- application exposure for adults exposed to home garden and trees

r epresent the highest estimated risk (children 6

- 11 show lower exposure due to shorter time spent in the garden) , and was therefore combined with the chronic dietary exposure for adults (General US population), to estimate the highest aggregate exposure and risk

. Despite the numerous conservative assumptions in developing these estimates, the MOE is above the LOC of 100, and
is not of concern (Table 7.2.1)

.

Table 7.2.1 . Short

- Term and/or Intermediate Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and
Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male 3.5 100 0.035 0.00257 0.0165 0.0191 180 Child (6

- 11 yrs) 3.5 100 0.035 0.00281 0.003 0.00581 600

1 The LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100. The FQPA Safety
Factor has been reduced to 1X.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure + Inhalation Exposure].

4 Total Exposure = Avg Food + Drinking Water Exposure + Residential Exposure).

5 Aggregate MOE = NOAEL of 3.5 mg/kg/day / (Avg Food + D rinking Water Exposure + Residential Exposure)



### 7.3 Intermediate

- Term Aggregate Risk

There are no current residential uses which result in intermediate

- term exposure. Therefore, an
intermediate

- term aggregate risk assessment was not performed nor required.

7.4 Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure
relevant to th is time frame is dietary exposure. Therefore, chronic aggregate risk is comp ri sed of exposures to tri f

lumizole resi dues in food and drinking water and is equivalent to the chronic dietary risk summarized in Table 5.4.6

. T he chronic risk estimates are below HED’s level of concern for all population subgroups. Because triflumizole is not a carcinogen, no cancer risk

as sessment was conducted.Triflumizole Human

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### Page 28 of 44 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 triflum izole and any other substances

, and tri f lumizole does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that tri f lumizole has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs c oncerning 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/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in a HED
memorandum dated 2 9

- OCT

- 2013 (S. Tadayon; D 414029 ). For the proposed use sites, there is a potential for short

- and intermediate

- term occupational exposure to triflumizole duri ng mixing, loading, applying, and other handling tasks; and during post

- application activities . Additionally, since the same endpoint and point of departure (POD) were selected for intermediate

- term and
chronic durations, intermediate

- term risk estimates are protective of chronic exposure and risk. Chronic exposure is only expected for the proposed green house uses of cucumber and tomato.

9.1 Short

- and Intermediate

- Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loa ding liquids to support aerial, airblast, groundboom, and chemigation applications, applying sprays with aerial, airblast, groundboom equipment, hand held equipments and flagging for liquid aerial applications.

It is the policy of HED to use the best av ailable data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) da tabase, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table 1 

### ,” which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 2



### .

Estimates of dermal and inhalation exposure were calculated for various levels of PPE . Results are presented for “baseline,” defined as a single layer of clothing consisting of a long

- sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline
with various levels of PPE as necessary (e.g., glo ves, respirator, etc.). The triflumizole product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirts, long

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

- exposure

- table.pdf

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

- exposure

- data.htmlTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 29 of 44 pants, chemical

- resistant gloves, shoes plus socks, and protective eyewear.

The occupational handler exposur e and risk estimates indicate that short

- and intermediate

- term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOEs > 100 for short

– term and MOEs > 3 00 for intermediate

- term ) with baseline and label recommended attire. T he dermal plus inhalation MOEs range from 3 50 to 2 8 ,000 (see Appendix C ). 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 usi ng the engineering control (enclosed cockpits) and baseline attire (long

- sleeved shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of concern for applicators

.

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 changed dramaticall y over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid 1990s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor
all available information sou rces to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- Application Risk

HED expects that post

- application exposure will occur since triflumizol e is applied as a foliar

spray. B ased on the proposed uses, short

- and intermediate

- term exposures are expected since there is the potential for multiple applications at the maximum application rate for most crops.

. Additionally , since the same endpoint and point of departure (POD) were selected for
intermediate

- term and chronic durations, intermediate

- term exposure and risk estimates are protective of chronic exposure and risk.

HED default assumptions, triflumizole

- specific DFR data (MRID # 45375401) and the revised Agricultural Re

- entry Task Force (ARTF) data base were used in assessing exposure from post

application activities. The standard values recommended for use in predic ting post

- application exposure that are used in this assessment, known as “transfer coefficients,” are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along wit h additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.

The short

- and intermediate

- term post

- applica tion exposure scenarios associated with the proposed uses for triflumizole are summarized in Appendix C

.Triflumizole Human

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### Page 30 of 44 Table 9.2.1 : Summary of Short

- term Occupational/Commercial Post

- application Risk Estimates for Triflumizole.

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Day zero

Tomato and cucumber (greenhouse) All activities (except irrigation) 1200

0.563 0.002742 1,300
Irrigation (Hand set) 1900 0.00434 800

Irrigation (Hand Watering) 230 0.000525 7,000
Fruit, small vine climbing, except fuzzy

kiwifruit Scouting, Hand pruning, Hand weeding 640 0.001462 2,400

Irrigation 1,900 0.004341 800
Tying/training/Leaf pulling 5,500 0.012566 300 Hand harvesting 10,100 0.023075 150

Girdling 19,300 0.044094 79

0.0354 (day 1) 100

Pome fruit crop group

11

- 10 Orchard maintenance 100 0.000228 15,000 Scouting, Hand pruning 580 0.001325 2,600 Hand harvesting 1,400 0.003198 1,100 Thinning fruit 3,600 0.008225 400

Berry (13

- 07G) Hand weeding 70 0.00016 22,000 Transplanting 230 0.000525 7,000 Irrigation 1,900 0.004341 800

1. DFR = Chemical

- specific DFR = day zero predicted grape vine DFR data (0.563 ug/cm 2 ) for short

– term exposure estimate

2. Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (69kg). 3. Dermal MOE = POD (3.5 mg/kg/day) / Daily Dermal Dose. LOC=100

Table 9.2.2 : Summary of Intermediate

- term Occupational/Commercial Post

- application Risk Estimates for Triflumizole.

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Tomato and cucumber (greenhouse) All activities (except irrigation) 1200

0.130 0.000546 6,400 Irrigation (Hand set) 1900 0.000865 4,000 Irrigation (Hand Watering) 230 0.000105 33,000

fruit, small vine climbing, except fuzzy

kiwifruit S couting, Hand pruning, Hand weeding 640 0.000291 12,000

I rrigation 1,900 0.000865 4,000

T ying/training/Leaf pulling 5,500 0.002503 1,400

H and harvesting 10,100 0.004596 800

G irdling 19,300 0.008782 400

Pome fruit crop group

11

- 10 O rchard maintenance 100 4.55E

- 05 77,000

S couting, Hand pruning 580 0.000264 13,000

H and harvesting 1,400 0.000637 5,500

T hinning fruit 3,600 0.001638 2,000

Berry (13

- 07G) H and weeding 70 3.19E

- 05 110,000

T ransplanting 230 0.000105 33,000 Irrigation 1,900 0.000865 4,000

1. DFR = DFR = Chemical

- specific DFR = average 21 days residue (0.130 ug/cm 2 ) data for intermediate

- term exposure estimate for all crops.

2. Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (80kg). 3. Dermal MOE = POD (3.5 mg/kg/day) / Daily Dermal Dose. LOC=300



### The 12

- hour REI specified on the proposed label is based on the acute toxicity of triflumizole.
Triflumizole is classified as Toxicity Category III for acute oral and Category IV for acute dermal toxicity, Toxicity Category IV for acute inhalation toxicit y, and Toxicity Category III for primary eye irritation. Triflumizole is not an irritant to the skin of rabbits (Toxicity CategoryTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 31 of 44 IV), but was shown to be a mild skin sensitizer in mice. Short

- term post

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

- application activities except for girdling of grapes (acceptable MOE reached 1day after treatment). Therefore, HED is recommending that the REI be revised on the label to address risk concerns
related t o girdling grapes. Intermediate

- term post

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

- application activities assessed”

9.2.2 Inhalation Post

- Application Risk

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

- application inhalation exposure assessment was not performed for triflumizol e . However, there are multiple potential sources of
post

- application inhalation exposure to individuals performing post

- application activities in

pr eviously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 

### . The Agency is in the process of evaluating the SAP report as well as available post

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

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

- application inhalation exposure assessment
for triflumizole

.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios ; handler inhalation risk estimates are not of concern

.

10.0 References

Previous Risk Ass essments: S

. Tadayon

, et al., 02

- May

- 20 1 2; D393221. Chemistry Memo: W. Donovan ; 29

- OCT

- 2013; D 413698

. Drinking Water Memo: C

. Koper ; 20

- May

- 201 3 ; D 407680 Dietary Memo: W. Donovan ; 2 2

- Aug

- 2013; D 413699. Occupational Exposure Memo: S

. Tadayon ; 29

- OCT

- 2013; D 414029

List of Appendices: Appendix A. Toxicology Profile and Executive Summaries Appendix B . Review of Human Research Appendix C

. Occupational and Residential Exposure Tables Appendix D

. International Residue Limits Table

3 Available: http://www.epa.gov/scip oly/SAP/meetings/2009/120109meeting.htmlTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 32 of 44 

### Ap pendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158. 476 ) for Food Use for triflumizole are presented below.

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 21

- Day Dermal
870.3250 90

- Day Dermal
870.3465 90

- Day Inhalation yes

no
yes

no

no yes

- 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)
870.4100b Chronic Toxicity (nonrodent)
870.4200a Oncogenicity (rat)
870.4200b Oncogenicity (mouse)
870.4300 Chronic/Oncogenicity yes
yes
yes
yes
yes yes

yes
yes
yes
yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial
870.5375 Chromosome aberration 870.5395 Micronucleus assay
870.550 0 DNA Damage
870.55 5 0 Unscheduled DNA Synthesis yes
yes
yes
yes
yes yes

yes
yes
yes
yes 870.6100a Acute Delayed Neurotox. (hen)
870.6100b 90

- Day Neurotoxicity (hen)
870.6200a Acute Neurotox. Screening Battery (rat)
870.6200b 90

- Day Neuro. Screening Battery (rat)
870.6300 Develop. Neurotoxicity no

no
yes
yes

no -

- yes
yes

- 870.7485 General Metabolism
870.7600 Dermal Penetration yes

no yes

- Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

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

no

no -

-

-Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 33 of 44 A.2 Toxicity Profiles
Table A.2.1. Acute Toxicity Profile

– Triflumizole Technical.

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

870.1100 Acute oral [rat] 00144463 LD 50 = 1362 mg/kg III

870.1200 Acute dermal [rat] 00144465 LD 50 > 5000 mg/kg IV

870.1300 Acute inhalation [rat] 00144466 LC 50 > 3.2 mg/L IV

870.2400 Acute eye irritation [rabbit] 00144467 Slight ocular irritant III

870.2500 Acute dermal irritation [rabbit] 00144468 Not a dermal irritant IV

870.2600 Skin sensitization [Guinea pig] 00144469 Mild dermal sensitizer N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Triflumizole Technical.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 45498001 (1980)

Acceptable/guideline 0, 20, 200, 2000 ppm M: 0, 1.4, 15.3, or 176.5 mg/kg/day F: 0, 1.8, 17.2, or 217.9 mg/kg/day NOAEL = Males: 15.3 mg/kg/day; Females: 17.2 mg/kg/day LOAEL = Males: 176.5 mg/kg/day; Females: 217.9 mg/kg/day based on increased kidney and liver weights and the accumulation of fat droplets in the liver.

870.3100 90

- Day oral

toxicity rodents (mouse) 45498002 (1980)

Acceptable/guideline 0, 20, 200, 2000 ppm M: 0, 3.2, 33.1, or 380.7 mg/kg/day F: 0, 4.2, 42.6, or 466.2 mg/kg/day NOAEL = Males: 33.1 mg/kg/day; Females: 42.6 mg/kg/day LOAEL = Males: 380.7 mg/kg/day; Females 466.2 mg/kg/day based on reduced growth.

870.3150 90

- Day oral

toxicity (nonrodents) NA NA

870.3200 21/28

- Day dermal

toxicity (rat) 41706601 (1990)

Acceptable/guideline 0, 10, 100, or 1000 mg/kg/day 6 hr/day, 7
d/week NOAEL ≥1000 mg/kg/day
LOAEL = not identified

870.3250 90

- Day dermal

toxicity NA NA

870.3465 90

- Day inhalation

toxicity NA NA

870.3700a Prenatal develop

mental in rodents (rat) 00157075 (1986)

Acceptable/non

- guideline (complimentary) F:0 or 3 mg/kg/day Must be considered with MRID 45458001

LOAELs/NOAELs not assigned

870.3700a Prenatal develop

mental in rodents (rat) 00164384 (1986)

Acceptable/non

- guideline (repeat) F: 0, 3, 7, or 35 mg/kg/day Must be considered with MRID 45458001

LOAELs/NOAELs not assignedTriflumizole Human

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### Page 34 of 44 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Triflumizole Technical.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.3700a Prenatal develop

mental in rodents (rat) 45458001 (198 3 )

Acceptable/non

- guideline F: 0, 10

, 35 , or 120 mg/kg/day Maternal NOAEL = 10 mg/kg/day
LOAEL = 35 mg/kg/day based on decreased body weight gain and food consumption,; increased placental weight, and increased maternal spleen and liver weights. Developmental NOAEL = 1 0 mg/kg/day
LOAEL = 35 mg/kg/day based on decreased numbers of viable fetuses, increased dead or resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight,and
increased incidences of cervical ribs

.

870.3700b Prenatal develop

mental in nonro

dents (rabbit) 00156546 (1985)

Acceptable/guideline F: 0, 50, 100, or 200 mg/kg/day Maternal NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day based on decreased body weight gains, food consumption, and placental weights. Developmental NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day based on decreased
24

- hour survival, decreased placental weights,
and increased fetal and litter i ncidences of
lumbar ribs.

870.3700b Prenatal develop

mental in nonro

dents (rabbit) 40752003 (1988)

Unacceptable/guideline F: 0, 5, 25, or 50 mg/kg/day Must be considered with MRID 00156546

Maternal NOAEL = 50 mg/kg/day
LOAEL = not identified Developmental NOAEL = 50 mg/kg/day
LOAEL = not identified

870.3800 Reproduction and

fertility effects (rat) 00162176 (1986)

00156548 (1984) 40301602 (1987) Acceptable/guideline with
MRID 156547 0, 30, 70, or 170 ppm P: 0, 1.5, 3.5, or 8.5 mg/kg/day Parental/Systemic NOAEL = 8.5 mg/kg/day
LOAEL = not established Reproductive NOAEL = 3.5 mg/kg/day (reproductive NOAEL), based upon increased gestation length in the dams of F 1a , F 2a , and F 3a intervals at the LOAEL of 8.5 mg/kg/day.

Offspring NOAEL = 3.5 mg/kg/day LOAEL = 8.5 mg/kg/day based on decreased pup weights, survival indices, and litter sizes in
both F 3 litters, reduced litter size in the F 1a litter, increased total

- litter mortality in the

F 3a litter, and developmental effects in the F 1b and F 2b progeny.

870.4100a Combined chronic

toxicity/carcinoge nicity (rats) 00156545 (1 984)

Acceptable/guideline 0, 100, 4 00, or 1 6 00 ppm M: 0, 3. 5

- 3.7

, 14.1

- 15.1

,
or 59.4

- 62.0 mg/kg/day F: 0, 4.5

- 4.6

, 18.0

- 18.1 , or 77.0

- 78.0 mg/kg/day LOAEL = 3.5 mg/kg/day, based on liver toxicity (eosinophilic foci in male rats and fatty
vacuolation and inflammation and necrosis in female rats). NOAEL is <3.5 mg/kg/day because the lowest
dose tested is the LOAELTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 35 of 44 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Triflumizole Technical.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.4100b Chronic toxicity

(dog) 00149848 (1984)

Acceptable/guideline 0, 100, 300, or 1000 ppm M: 0, 3.33, 10.00, or 34.10 mg/kg/day F: 0, 3.27, 10.69, or 35.17 mg/kg/day NOAEL = Males: 10.00 mg/kg/day; Females: 10.69 mg/kg/day LOAEL = Males: 34.10 mg/kg/day; Females: 35.17 mg/kg/day based on increased alkaline phosphatase activity and a mild, macrocytic anemia in males, increased absolute and relative liver weights in both sexes, and on macroscopic findings in the liver of both sexes.

870.4200 Carcinogenicity

(rat) NA; see 870.4300 NA

870.4300 Chronic Toxicity/

Carcinogenicity (mouse) 00156544 (1984)

Acceptable/guideline 0, 100, 400, or 1600 ppm M: 0, 16.2, 67.4, or 296.1 mg/kg/day F: 0, 21.7, 86.1, or 362.2 mg/kg/day NOAEL = Males: 16.2 mg/kg/day; Females: 21.7 mg/kg/day
LOAEL = Males: 67.4 mg/kg/day; Females: 86.1 mg/kg/day based on microscopic lesions
of the liver. No evidence of carcinogenicity

870.5100 Bacterial reverse

mutation 40494409 (1987)

Acceptable
seven concentrations ranging from 5 to 5000 μg/plate Negative with or without S9 activation at 5000 μg/plate and less.

870.5100 Bacterial reverse

mutation 45502203 (1983)

Acceptable concentrations ranging from 8 to 8000 μg/plate Negative with or without S9 activation at 8000 μg/plate and less.

870.5375 In vitro

mammalian
chromosome abberation (CHL) 40494408 (1987, 1988)

Acceptable 5 to 40 μg/mL Negative with or without S9.

870.5395 In vitro

mammalian cytogenetics (mouse bone marrow) 00160620 (1986)

Acceptable M&F: 160, 533 and 1600 mg/kg (single oral dose) Negative. Not clastogenic for the production of micronuclei in bone marrow polychromatic erythrocytes in mice at single oral doses up to 1600 mg/kg.

870.5500 DNA

damage/repair
REC assay 45502204 (1983)

Unacceptable concentrations range from 24 to 24,000 mg/disk Negative. No evidence of DNA damage up to 24,000 mg/disk. Study is unacceptable because a metabolic activation system was not used.

870.5550 UDS in primary

rat hepatocytes 45502205 (1984)

Acceptable 12.5 to 30 μg/mL Negative. No evidence of unscheduled DNA synthesis up to cytotoxic concentrations.

870.6200a Acute

neurotoxicity screening battery 46202502 (year) NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day, based on FOB findings (neuromuscular impairment, as evidenced by decreased hind

- and fore

- limb grip strength, impaired gait and mobility, abnormal righting reflex) and decreased locomotor activity

870.6200b Subchronic

neurotoxicity screening battery 46202502, 46259401

Acceptable/guideline NOAEL = 2000 ppm (133.3 mg/kg bw/day)

, HDT

.

870.6300 Developmental

neurotoxicity NA NATriflumizole Human

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### Page 36 of 44 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Triflumizole Technical.

Guideline No. Study Type MRID No. (year)/
Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (rat) 40789101 (1988)

Acceptable/guideline with
41606201 and 41606202 M&F: 10 mg/kg as single
oral dose Following oral treatment of rats with [phenyl

U

14 C]

- NF

- 114, no sex

- related differences were observed in absorption, metabolism,
distribution or excretion. Maximum concentrations of radioactivity in plasma were attained within 1 hour of dosing in both sexes. Low levels of radioactivity were detectable in all tissue, organ, and blood samples. Radioactivity in urine accounted for 69.5

- 74.4% of the dose and feces accounted for
21.7

- 21.9% of the dose. Based on the metabolite profile, the metabolism in rats primarily involves oxidation to FM

- 8

- 1 and
FA

- 1

- 5, followed by s ulfation and glucuronidation.

870.7485 Metabolism and

pharmacokinetics (rat) 41606201 (1983)

41606202 (1984) Acceptable/guideline with
40789101 M&F: 10 or 300 mg/kg as single oral dose Following oral treatment of rats with [phenyl

U

14 C]

- NF

- 114, approximately 93.8

- 100.6% of
the administered dose was recovered. Urine was the major route of excretion. Low levels of radioactivity were detectable in all tissue, organ, and blood samples collected 2 days (10 mg/kg group) or 4 days (300 mg/kg group)

po st

- dose with tissue concentrations generally higher in males than females. The metabolite profile in the excreta was quantitatively and qualitatively similar between the sexes and dose groups. Based on the metabolite profile,
the biotransformation of NF

- 114 in rats primarily involved oxidation of parent to FM

- 8

- 1 and FA

- 1

- 5, followed by conjugation yielding sulfate and glucuronic acid conjugates.

870.7600 Dermal

penetration NA NA

Hepatic enzyme
induction Special studies 40830401 (1988) Acceptable/nonguideline M&F: 0 or 200 mg/kg/day
as oral dose for five consecutive days The study provides evidence that triflumizole induces hepatic microsomal enzymes when administered orally. However, no correlation between the increased enzyme activiti es and hepatic lesions observed following chronic
administration was made since no histopathology was performed.

870.7800 Immunotoxicity 48086101 Acceptable/guideline LOAEL = 2000 ppm (285.7 mg/kg/day) based

on significant decrease in the anti

- SRBC IgM

response

. NOAEL = 200 ppm (28.6 mg/kg/day)Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 37 of 44 Appendix B . Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 4



### .

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

- exposure

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

- app

- exposure

- data.htmlTriflumizole Human

- Health Risk Assessment DP# 407679



### Page 38 of 44 

### Appendix C

. Occupational and Residential Exposure Tables.

a) B ased on registered labels ( Procure 480SC, EPA REG Number 400

- 518) b) Exposure Science Advisory Council Policy #9.1 c) Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/A or gal) x Amount Treated or Handled (A or gallons/day) x DAF (3.5%)/BW (69 kg) d) Dermal MOE = Dermal NOAEL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day) e) Inhalation Dose = Inhalation Unit Exposure (mg/kg) x Application Rate (lb ai/A or gal) x Amount Treated or Handled (A or gall ons/day) /BW (69 kg) f) Inhalat ion MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day) g) Total MOEs =1/[(1/Dermal MOE) + (1/Inhalation MOE)]. Level of concern = 100 Short

- Term Residential Handler Exposure and Risk Estimates for Triflumizole

Exposure Scenario Target
MOE Dermal

Unit Exposure Inhalation

Unit Exposure Maximum

Application
Rate a Amount Treated

or Handled Daily

b Dermal Inhalation Total

Dose c MOE d Dose e MOE f MOE g

M ixer/Loader/Applicator
Manually

- pressurized handwand
Broadcast (Gardens /Trees ) 100 63 0.018 0.05lb ai/gal 5gals 0.007989 440 6.5E

- 05 54,000 440

Manually

- pressurized handwand Spot treatment (Gardens /Trees ) 100 63 0.018 0.000012lb ai/ft 2 1200ft 2 0.00046 7600 3.8E

- 06 932,000 7,500

Hose end sprayer Spot treatment(Gardens/Trees) 100 58 0.0014 0.000012lb ai/ft 2 1200ft 2 0.000424 8300 2.9E

- 07 1,198,000 8,200

Hose end sprayer Broadcast (Gardens /Trees ) 100 58 0.0014 0.05 lb ai/gal 11 0.016181 2 20 1.1E

- 05 314,000 220

Back Pack sprayer Broadcast(Gardens/Trees) 100 130 0.14 0.05 lb ai/gal 5 gals 0.016486 200 5.1E

- 04 6,900 200

Back Pack sprayer Spot

treatment (Gardens /Trees ) 100 130 0.14 0.000012lb ai/ft 2 1200ft 2 0.00095 3700 2.9E

- 05 120,000 3,500Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 39 of 44 Residential Post

- application Non

- cancer Exposure a nd Risk Estimates for Triflumizole

.
Lifestage Post

- application Exposure Scenario Application Rate 1 Dose (mg/kg/day) 2 MOEs 3 Use Site Route of Exposure

Adult Gardens Dermal

1lb ai/A 0.005 660
Child (6

- 11 yrs) 0.003 1,100

Adult Fruit Trees Dermal 0.0005 7,200 Child (6

- 11 yrs) 0.00029 12,000

1 Based on the proposed tree use on registered labels for tree and garden use

. 2 Dose (mg/kg/day) equations: See Appendix A
3 Dermal MOE = Dermal NOAEL ( 3.5 mg/kg/day) ÷ Dermal Dose (mg/kg/day).Triflumizole Human

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### Page 40 of 44 Short

- Term Occupational Exposure and Risk Estimates for Triflumizole
Exposure Scenario Crop or Target Dermal Unit Exposure 1

mg /lb ai Inhalation

Unit Exposure 1

mg /lb ai Application

Rate 2

lb ai/A Amount

Treated Daily 3

Acre or Gallon Dermal Inhalation Total

Mitigation
Level Mitigation

Level Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/Loader Mixing/Loading Liquids for Aerial Applications Pome fruits (subgroup11

- 10) 0.0376

SL/G 0.000219 0.5 350 0.00334 1,000 0.00056 6300 900

Strawberry(subgroup
13

- 07G) and tomato 0.22

SL/NG 0.000219 0.25 350 0.0098 360 0.00028 13,000 350

Mixing/Loading Liquids for Chemigation Applications Strawberry(subgroup
13

- 07G) 0.25 350 0.0098 360 0.00028 13,000 350

Mixing/Loading Liquids for Groundboom Applications Strawberry(subgroup
13

- 07G) and tomato 0.25 80 0.0022 1,600 0.000063 55,000 1,500

Mixing/Loading Liquids for Airblast Applications Pome fruits (subgroup11

- 10) 0.5 40 0.0022 1,600 0.000063 55,000 1,500

Grape (Subgroup 13

- 07F) 0.25 40 0.0011 3,100 0.000032 110,000 3,000

Applicator Applying Sprays via Aerial Equipment Pome fruits (subgroup11

- 10) 0.00208

Eng. control 0.0000049 0.5 350 0.000248 14,000 0.0000124 282,000 14,000

Strawberry(subgroup
13

- 07G) and tomato 0.25 350 0.000496 28,000 0.0000249 564,000 28,000

Applying Sprays via Open
Cab Air blast Equipment Pome fruits (subgroup11

- 10) 0.141
G, DL,
chemical
resistant hat 0.0041 0.5 40 0.0014 2,400 0.0014 2,600 2,400

Grape (subgroup 13

- 07F) 1.77 0.0041 0.25 40 0.009 390 0.0007 5,100 360

Applying Sprays via Open Cab groundboom Equipment Strawberry(subgroup

13

- 07G) and tomato 0.079 0.00034 0.25 80 0.0008 4,400 0.0001 36,000 3,900

Flagger

Flagging for Aerial Sprays Applications All Crops
Except grapes 0.011 0.00035 0.5 350 0.0010 3,600 0.0009 3,900 1,900Triflumizole Human

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### Page 41 of 44 Short

- Term Occupational Exposure and Risk Estimates for Triflumizole
Exposure Scenario Crop or Target Dermal Unit Exposure 1

mg /lb ai Inhalation

Unit Exposure 1

mg /lb ai Application

Rate 2

lb ai/A Amount

Treated Daily 3

Acre or Gallon Dermal Inhalation Total

Mitigation
Level Mitigation

Level Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/loader/Applicator
Mixer/Loader/Applicator, Backpack Sprayer Green house grown vegetable (Tomato and Cucumber) 13.2 0.140

0.00125 gal 40 0.0003 10,000 0.0001 35,000 8,000

Mixer/Loader/Applicator, Manually

- pressurized
handwand 100 0.03 40 0.0025 1,400 0.00002 160,000 1,400

Mixer/Loader/Applicator, Mechanically

- pressurized Handgun Sprayer 3.5 0.120 1000 0.0022 1,600 0.0022 1,600 800

1 PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls)

2 Based on registered or proposed label

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) x DAF (3.5%)/BW (6 9kg)

5 Dermal MOE = Dermal NOA EL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day)

6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (69kg)

7 Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day)

8 Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 42 of 44 Intermediate

- Term

/ Occupational Exposure and Risk Estimates for Triflumizole.

Exposure Scenario Crop or Target Dermal Unit Exposure 1

mg /lb ai Inhalation

Unit Exposure 1

mg /lb ai Application

Rate 2

lb ai/A Amount

Treated Daily 3

Acre or Gallon Dermal Inhalation Total

Mitigation
Level Mitigation

Level Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/Loader Mixing/Loading Liquids for Aerial Applications Pome fruits (subgroup11

- 10) 0.0376

SL/G 0.000219 0.5 350 0.002881 1,200 0.000483 7,200 1,000

Strawberry(subgroup
13

- 07G) and tomato 0.22

SL/NG 0.000219 0.25 350 0.008453 400 0.000242 14,500 400

Mixing/Loading Liquids for Chemigation Applications Strawberry(subgroup
13

- 07G) 0.25 350 0.008453 400 0.000242 14,500 400

Mixing/Loading Liquids for Groundboom Applications Strawberry(subgroup
13

- 07G) and tomato 0.25 80 0.001898 1,800 5.43E

- 05 64,000 1,800

Mixing/Loading Liquids for Airblast Applications Pome fruits (subgroup11

- 10) 0.5 40 0.001898 1,800 5.43E

- 05 64000 1,800

Grape (Subgroup 13

- 07F) 0.25 40 0.000949 3,700 2.76E

- 05 127,000 3600

Applicator Applying Sprays via Aerial Equipment Pome fruits (subgroup11

- 10) 0.00208

Eng. control 0.0000049 0.5 350 0.000214 1,6000 1.07E

- 05 327,000 16,000

Strawberry(subgroup
13

- 07G) and tomato 0.25 350 0.000428 8,000 2.15E

- 05 163,000 8,000

Applying Sprays via Open
Cab Air blast Equipment Pome fruits (subgroup11

- 10) 0.141
G, DL,
chemical
resistant hat 0.0041 0.5 40 0.001208 3,000 0.001208 2,900 1,500

Grape (subgroup 13

- 07F) 1.77 0.0041 0.25 40 0.007763 450 0.000604 6000 400

Applying Sprays via Open Cab groundboom Equipment Strawberry(subgroup

13

- 07G) and tomato 0.079 0.00034 0.25 80 0.000690 5,000 8.63E

- 05 41,000 4,500

Flagger

Flagging for Aerial Sprays Applications All Crops Except Grapes 0.011 0.00035 0.5 350 0.000863 4,000 0.000776 4,500 2,100Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 43 of 44 Intermediate

- Term

/ Occupational Exposure and Risk Estimates for Triflumizole.

Exposure Scenario Crop or Target Dermal Unit Exposure 1

mg /lb ai Inhalation

Unit Exposure 1

mg /lb ai Application

Rate 2

lb ai/A Amount

Treated Daily 3

Acre or Gallon Dermal Inhalation Total

Mitigation
Level Mitigation

Level Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/loader/Applicator
Mixer/Loader/Applicator, Backpack Sprayer Green house grown vegetable (Tomato and Cucumber) 13.2 0.140

0.00125 gal 40 0.000259 13500 8.63E

- 05 4,1000 10,000

Mixer/Loader/Applicator, Manually

- pressurized
handwand 100 0.03 40 0.002156 1600 1.73E

- 05 203,000 1,600

Mixer/Loader/Applicator, Mechanically

- pressurized Handgun Sprayer 3.5 0.120 1000 0.001898 1800 0.001898 1,800 900

1 PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls)

2 Based on registered or proposed label

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) x DAF (3.5%)/BW (80kg)

5 Dermal MOE = Dermal NOAEL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day)

6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (80kg)

7 Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day)

8 Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)Triflumizole Human

- Health Risk Assessment DP# 407679



### Page 44 of 44 

### A ppendix D . International Residue Limits Table

Triflumizole (128879; 09/12/2013)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex

40 CFR 40 CFR §180.476
Plants : parent compound triflumizole, 1

- (1

- ((4

- chloro

- 2

- (trifluoromethyl)phenyl)imino)

- 2

- propoxyethyl)

- 1 H

- imidazole, and its metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety, calculated as stoichiometric equivalent of the parent compound. 1

- [1

- [[4

- chloro

- 2

- (trifluoromethyl)phenyl]imino]

- 2

- propoxyethyl]

- 1 H

- imidazole, including metabolites containing the 4

- chloro

- 2

- trifluoromethylaniline moiety, expressed as triflumizole None



### Commodity 1 

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

US Canada Mexico 2 

### Codex

Tomato 1.5 Fruit, pome, group 11

- 10 0.50 0.5 apples, pears Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 2.5 2.5 grapes

Berry, low growing, subgroup 13

- 07G, except cranberry 2.0 2 strawberries

Vegetable, cucurbit, group 9 0.5 0 0.5 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, cucumbers, edible gourds, muskmelons (other than those listed in this item) pumpkins, summer squash, watermelons, west Indian gherkins,
winter squash Completed: M. Negussie; 09/13/13

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

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