### Triflumizole Human Health Risk Assessment DP No. 420633

UNITE D STAT E S ENVIRONMENTAL PRO T EC T ION AG E NCY



## WAS HIN G T ON

, D.C. 20460

MEMORANDUM

Date: June 0 5

, 2014 OFFICE O F

CHEM ICAL SAFETY AND

POL LUTI ON PREVEN TION

SUBJECT: Triflumizole: Human Hea l th Risk Assessment for Registration Review

PC Code: 1288 79

Decision No

. : 491745

Petition No.:

Risk Assessment Type: Registration Re v i ew
TXRNo.:

MRIDNo.: NA

FROM : Seyed T a da yon
, Risk**Assessor ~~~** **-:>- ""X'/**  

### John Liccione, Ph.D

. , Toxicologis

William D o no va n
, Ph.D., Chemis

Risk Assessment Branch V

H ealth Effects Di vision (7509P) DP Barcode: D 420633 Registration No.: Regulatory Action: Registration Review

Case No

. : NA

CAS No.: 68694-11-1

40CFR: § 180.4 76



# . /



### Office of Pesticide Programs



### T H ROUGH: Michael S Metzger, Branc h Chief 1

# ~ /) 

# P. [ iJ----

. Risk Assessment Branch V 

# L{**~** 

# v( ' 

# U

Health Effects Division (7509P)

Office of Pesticide Programs

TO: Steven Snyderman, Chemical Review Manager

R i sk Ma n ageme n t and Im plementat i on Branch III

Pe sticide Re-evaluation Division (7508P)



### This is a revision of the original Human**Hea~th** 

### Risk Assessment for Registration Review

, (S. 

### Tadayon May 0 2

, 2 01 2

, D393221). This document has been revised to address changes in

Re

- Entry Inter v als (REI) for grape and hop. The changes are on pages 3, 14 and 30.

Page 1 of30

### Triflumizole Human Health Risk As sessme nt DP No. 420633

This document provides the Health Ef fects Division's (HED's) risk assessment conducted in

support of registration review for triflumizole. The emphasis of the present memo is on changes

since the mos t recent assessments. The su pporting documents are listed below.

Triflumizole- Human Health Risk Assessment. W. Cutchin, D363719, 4/1109.

Triflumizole- Residue Chemistry Assessment. W. Cutchin, D346779, 10 /1108.

Triflumizole- Seeping Assessment. C. Eiden, D332497, 4/2/07.

Triflumizole

- Drinking Water Assessment, C. Koper

, D395021, 1/9/12.

T riflum izol e- Dietary Exposure Assessment, W. Donovan, D397935, 3/28112.

T riflum i zo le SLUA, BEAD, 9/2/11.

Triflumizole- Results of th e MARC Meeting, J. Tyler, 3/12/02.

1.0 Executive Summary

T r iflumizole 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 so luble 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, ornamentals in greenhouses/shade houses, interior scapes, and

Christmas trees/conifers on nurseries and plantations. It 

### is used as a pre-plan t seed piece

treatment on pineapples. Triflumizole can also be applied to trees, shrubs, and vines. There are

no registrations on turf and garden vegetable us es.

HED reviewed the toxicity database for triflumizole, as well as the most recent risk assessment (DP 363719, Cutchin, W., 4-1-09), and concluded that no changes in point of departures (PODs), endpoints of concern or FQP A Safety Factors are warranted. Since the last risk assessment

, a n immunotoxicity study in mice was submitted and reviewed. The results of this study did not impact the overall risk assessment.

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-hydroxy6-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 -trifluoromethylaniline moiety.

Adequate res idue chemistry data have been provided for all crop uses oftriflumizole. However, previously recommended changes to 40 CFR 180.476 are still needed (see Recommended Tolerances).

Revised dietary exposure assessments were conducted to incorporate updated percent crop treated information from the Biologic and Economic Analysis Division (BEAD) and updated

estimated drinking water concentrations (EDWCs) from the Envi ronmental Fate and Effects

Division (EFED). Drinking water was incorporated directly in the dietary assessments.

Page 2 of30

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 3 of 30 The acute dietary (food + water) exposure assessments used tolerance level residues and 100% crop treated ( CT ) for all registered uses. These assessments demonstrate that the acute dietary

risk estimates are not of concern for the general U.S. population ( 26 % aPAD , 0.065598 mg/kg/day ) and all population subgroups. Children 1

- 2 years old was the most highly exposed population subgroup at 39% aPAD and 0.096453 mg/kg/day. Exposure was equivalent to 0.068075 mg/kg/day or 68 % of the aPAD for females 13

- 49 years old.

The chronic dietary exposure assessment used anticipated residues ( ARs ) from average field trial

result s and the most recent % CT information from BEAD . This assessment shows that the chronic dietary exposure estimates are not of concern for the general U.S. population (19 % cPAD) and all population subgroups. The most highl y exposed population subgrou p is children

1

- 2 years old at 32 % cPAD. A cancer assessment was not performed because triflumizole is not carcinogenic.

HED has recently revised the Agricultural Re

- entry Task Force (ARTF) and Pesticide Handler Exposure Database (PHED) , and has conducted new occupational risk assessments for triflumizole. Based on this updated occupational exposure and risk assessment, HED is recommending the following label revisions:

When applying sprays with open cab air blast equ ipment on apple, pear and cherry

, handlers

must wear a chemical resistant hat to achieve the target MOE ≥ 300

. The MOE with the current

label PPE recommendations (single layer and glove) is 230. The Restricted Entry Interval ( REI ) for grapes (table and ra isin) should be extended from the current REI (zero days) to 1 day , and for hops to 3 days to achieve the target MOE ≥ 1 00

. The current 12

- hour REI for wine grapes is adequate. The restricted reentry interval for hops may not be necessary since the longer PHI (7 days) would provide the necessary restricted entry for this activity

.

Data Deficiencies

HED has examined the toxicology and residue chemistry databases for triflumizole and found both to be complete.

Tolerance Considerations

Enforcement Analyt ical 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 ).

International Harmonization

Codex has not established Maximum Residue Limits (MRLs) for residues of triflumizole in/on various raw agricultural and processed commodities. Tolerance definitions are harmonized between Canada and the U.S. Additionally, all Canadian MRLs are harmonized with the corresponding US tolerance levels (see Appendix B ).

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 4 of 30 Recommended Tolerances

HED recommends that the residue definition for the tolerance expression for triflumizole be modified in accordance with current policy on tolerance definitions (S. Kni zner, 5/27/09), to

read as follows for 40 CFR § 180.476(a)(1):

“Tolerances are established for residues of triflumizole (1

- [(1 E )

- 1

- [[4

- chloro

- 2

- (trifluoromethyl)phenyl]imino]

- 2

- propoxyethyl]

- 1 H

- imidazole) , including its metabolites and degradates, in or o n the commodities in the table below. Compliance with the tolerance levels specified is to be determined by measuring only those triflumizole

residues convertible to 4

- chloro

- 2

- trifluoromethylaniline , expressed as the stoichiometric equivalent of triflumiz ole, in or on the commodity.”

Similarly, 40 CFR § 180.476(a)(2) should be revised to:

“Tolerances are established for residues of triflumizole (1

- [(1 E )

- 1

- [[4

- chloro

- 2

- (trifluoromethyl)phenyl]imino]

- 2

- propoxyethyl]

- 1 H

- imidazole) , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified i s to be determined by measuring those triflumizole residues

convertible to 4

- chloro

- 2

- trifluoromethylaniline plus the metabolite 4

- chloro

- 2

- hydrox y

6

- trifluoromethylaniline sulfate , expressed as the stoichiometric equivalent of triflumizole, in or on the commodity.”

No changes to tolerance levels have occurred as a result of this registration review. However, some recommendations for changes made in a previous review are not currently reflected in the

40 CFR § 180.476 (D346779, W. Cutchin, 10/1/08). T he following tolerances should be deleted from 180.476(a)(1): apple, dry pomace; apple, wet pomace; grape, dried pomace; grape, raisin, waste; and g rape, 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; poultry, 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 commodit ies should be lowered from 0.5 to 0.20 ppm: meat byproducts of cattle, sheep, goat, and horse.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 5 of 30 Chemical Identity

Table 3.1 Trifumizole and Metabolite Nomenclature



### Chemical 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 common moiety

structure

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 Service

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 6 of 30 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 Not available

Bulk Density 0.50

- 0.70 (at 20oC)

Water solubility (g/L at 20oC) 0.0125 (at pH 5.9)

Solvent solubility (g/100 mL at 20oC) Chloroform 222

Acetone 144

n

- Hexane 1.76

Methanol 49.6 Xylene 63.9

Vapor pressure (at 25oC) 1.4 x 10

- 6 mmHg

Dissociation constant, pK
a 3.7

Octanol/water partition coefficient, Log(K OW ) at 25oC 25

UV/visible absorption spectrum Not available



### T oxicology A ssessment

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 expos ure (acute) to subchronic and chronic exposures. Additionally, there are developmental toxicity studies in rats and rabbits, a rat reproductive toxicity study, an immunotoxicity study and acute and subchronic neurotoxicity

studies. A summary of the curren t 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 hepatocyt e centrilobular swelling. C hronic effects included hepatocyte fatty vacuolization; hepatocyte hypertrophy, focal inflammation, and necrosis; fatty degeneration; eosinophilic foci of hepatocyte alteration; hepatic nodules; bile duct hyperplasia; and hyaline degeneration/fibrosis of the bile duct. Liver effects were seen in rat and mouse subchronic and chronic/carcinogenicity studies.

Triflumizole is classified as not likely to be carcinogenic to humans, based on the lack of evidence of carcinogenicity in s tudies in rats and mice and the absence of a mutagenicity

concern.

There was no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies in the

rat with triflumizole.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 7 of 30 I n oral rat developmental studies, fetal effects (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) were seen in the fetuses at the same doses at which

maternal toxic effects were noted. Re productive toxicity, manifested as increased gestation length, was increased at the high dose. T here 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/da y. The results of the immunotoxicity study do not impact the point of departures (PODs) selected for dietary and

non

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

.

The toxicological endpoint selected for dietary and non

- diet a ry risk as s essments are presented in Append ix A. Separate 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 O D 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 followin g 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 (RfD) for these population groups. The chronic dietary endpoint is based

on liver toxi city 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 extrapolati o n and 3x for the use of a LOAEL (UF L 

### ) ) was used to derive the chronic RfD

. 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 resulting from short

- te rm 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 inhalation risks resulting f rom intermediate

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

- bound estimate of dermal absorption of 3.5% was calculated by comparing the maternal LOAEL from the rat developmental study with the N OAEL from the rat dermal study. Since oral dose s were used, dermal ( 3.5% ) and inhalation (100%) absorption factor s are used for route

- to

- route extrapolation.

The toxicology data base is complete and there are no residual uncertainty for pre

- and post na tal toxicity. The FQPA Safety Factor is reduced (1x) for acute dietary 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 i ntermediate

- and long term dermal and inhalation risks from occupational 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 sensi tive endpoint in the target organ (liver) for this class of compounds (conazole fungicide) is used for assessing chronic risk

.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 8 of 30 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 progress into malignancy

.

o The available data do es not show this chemical to be a potent toxicant following short and long

- term dietary exposure since clear NOAELs were established in all the other

stu dies such as the reproduction (3.5 m/k/d), subchronic rat (15.3 m/k/d) , subchronic mouse (33.1 m/k/d); chronic dog 10 m/k/d) and the mouse carcinogenicity (16.2 m/k/d)

studies.

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

- related chemical (Imazalil).

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

- dietary risk s from chronic exposure to triflumizole

.

Endocrine Disruption Screening Program

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the sta tutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 scr eening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is desi gned to identify any adverse endocrine related effects caused by the substance, and

establish a dose

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

Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the fir st group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Although triflumizole is not among the group of pesticide active ingredients on the initial list to be screened under the EDSP, it i s included in a second lists of chemicals considered for Tier 1 screening. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins for all pesticide active ingredi ents. For further information on the status of the EDSP, the policies and procedures, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 9 of 30 R esidue Chemistry As sessment

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 adequate storage stability data. S ufficient processing studies were

submitted to elucidate the fate of triflumizole in processed commodities. Wet apple pomace and pineapple processed residue are the only livestock feedstuffs. As neither is fed to poultry or swine, all poultry and hog tol erances should be revoked. Finite residue levels of triflumizole are possible in fat and meat byproducts of ruminants, and these tolerances should be retained, but at lower levels than currently listed in 40 CFR 180.476

. Lower livestock commodity toleran ce levels are appropriate because of the lower dietary burden recently determined (D346779, W. Cutchin, 10/1/08). Confined rotational crops studies show that the metabolism of triflumizole in rotated crops is similar to that in primary crops, although rel atively less parent and more

metabolites were found. Results from the limited rotational crop field trials also indicated that the following current plant

- back intervals are appropriate for rotated crops: 30 days for leafy and fruiting vegetables; 60 day s for root and tuber vegetables; and 1 year for cotton, small cereal grains, and any other crops without registered uses for triflumizole.

D ietary Exposure Assessment

Revised dietary exposure assessments were conducted to incorporate updated percent cr op treated information from BEAD and updated EDWCs from EFED. Drinking water was incorporated directly in the acute and chronic dietary assessment s.

Drinking Water Residue s D395021, C. Koper, 1/9/12

EFED provided ground and surface water EDWCs for triflumizole. 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; the 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 provide d since there are no comprehensive monitoring data for triflumizole in ground or surface

water.

Table 1 summarizes the maximum EDWCs for triflumizole. In order to account for degradates containing the 4

- chloro

- 2

- trifluoromethylaniline moiety, EFED used t he total toxic residue approach to account for both triflumizole and the residues of concern

. Detailed information on how the individual modeling input parameters were derived can be obtained from the “Tier I Estimated Drinking Water Concentrations for Triflumizole Including Degradates” memo (S. Ramasamy, March 3, 2002) (D281356).

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 10 of 30 Table 1

. Summary of Estimated Surface Water and Groundwater Concentrations for Triflumizole

. 

### Scenario Surface Water Conc., ppb a 

### Groundwater Conc., ppb b

Acute 85 3.1

Chronic (non

- cancer) 21 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.



### 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, p umpkins, squash, strawberries, and watermelons in a Screening Level Usage Analysis (SLUA) dated 02

- SEP

2011. Although BEAD provided maximum and average %CT information, only the chronic dietary risk assessment required the percent crop treated refinement; therefore, only the average %CT values were utilized in the dietary exposure analysis.

Acute Dietary Risk Assessment D397935, W. Donovan, 3/ 28 /12

The results of the acute dietary risk analysis are reported in Table 2

. The acute dietary (food + drinking water) exposure assessment used tolerance

- level residues and 100% CT for all registered crops; thus, the acute dietary analysis may be considered an unrefined assessment. Drinking water was incorporated directly in the dietary assessment using the maximum concentration for surface water generated by the PRZM/EXAMS model. These assessments demonstrate that the acute dietary risk estimates (95 th 

### percentile) are not of concern (<100% aPAD) for the general U.S. population ( 26 % aPAD , 0.065598 mg/kg/day ) and all population subgroups. Children 1

- 2 years old was the most highly exposed population subgroup at 39% aPAD and 0.096453 mg/kg/day. Exposure was equivalent to 0.068075 mg/kg/day or 68 % of the

aPAD for females 13

- 49 yea rs old.

Chronic Dietary Risk Assessment D397935, W. Donovan, 3/ 28 /12

The results of the chronic dietary exposure analysis are reported in Table 2

. The chronic dietary exposure assessment used anticipated residues (ARs ; average field trial values) for most crops

and tolerance level residues for hazelnuts. The assessment used % CT information for apples, cantaloupes, cherries, cucumbers, grapes, hazelnuts (filberts), honeydew melons, pears, pumpkins, squash, strawberries, and watermelons ; and 100% CT for all other crops. Thus, the chronic dietary analysis may be considered a partially refined assessment. The chronic dietary (food + drinking water) risk assessment was conducted for the general U.S. population and various population subgroups. Drin king water was incorporated directly into the dietary assessment using the chronic (annual average) concentration for su rface water generated by the

PRZ M/EXAMS model. This assessment concludes that the chronic dietary risk estimates are

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 11 of 30 below the Agency’s level of concern (<100% cPAD) for the general U.S. population (19% cPAD) and all population subgroups. The most highly exposed population subgroup is children

1

- 2 years old at 32% cPAD.

Table 2 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Triflumizole.

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

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

General U.S. Population 0.065598 26 0.002274 19

N/A N/A All Infants (< 1 year old) 0.041970 17 0.002517 22

Children 1

- 2 years old 0.096453 39 0.003785 32

Children 3

- 5 years old 0.086183 34 0.003259 28

Children 6

- 12 years old 0.067224 27 0.002189 19

Youth 13

- 19 years old 0.055321 22 0.001771 15

Adults 20

- 49 years old 0.065771 26 0.002211 19

Adults 50+ years old 0.060108 24 0.002236 19

Females 13

- 49 years old 0.068075 68 0.002168 19

a 

### Because triflumizole is not a carcinogen, no cancer risk assessment was conducted.

R esidential Risk Assessment

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

- commerc ially 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 Handler Exposure

Residential short

- term (1

- 30 days) dermal and inhalation exposures are expected for triflumizole handler activities associated with use on ornamental plants. The results of the residential handler exposure and risk assessment are presented in Appendix C. The total s hort

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

sleeves, shoes and socks). For triflumizole the dermal and inhalation endpoints are based on the same toxicological effect, therefore the MOEs are combined to determine a total risk estimates

.

Post

- Application Exposure

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 12 of 30 Post

- application exposure from triflumizole use on landscape ornamentals 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) If present, leaf to skin residue transfer would be negligible because of the minimal frequency and duration of contact

. Based on the low frequency of application and low likelihood for significant post

- application exposure, there are no residential risk concerns for post

- application exposure. Therefore, a quantitative post

- application residential exposure and risk assessment was not conducted.

A ggregate Risk Assessment

In accordance with the FQPA, HED must consider and aggregate triflumizole exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Acute Aggregate Risk

In examining acute aggregate risk, HED has assumed that the only pathway of exposu re 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 2 above

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

Short

- Term Aggregate Risk

The residential handler exposure from applying triflumizole using a h and held pump sprayer was the exposure scenario with the highest estimated risk, 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 d eveloping these estimates, the MOE is above the LOC of 100, and is not of concern (Table 3 )

.

Table 3

. 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 0.002274 0.025 0.027 130

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 Exposu re].

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

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



### Intermediate

- Term Aggregate Risk

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 13 of 30 There are no current residential uses which result in intermediate

- term exposure. Therefore, an

intermediate

- term aggregate risk assessment was not performed nor required.

Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure

rele vant to th is time frame is dietary exposure. Therefore, chronic aggregate risk is comp ri sed of exposures to tri f

lumizole residues in food and drinking water and is equivalent to the chronic dietary risk summarized in Table 2 above

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

assessment was conducted.

O ccupational Risk Assessment

Short

- /Intermediate

- term Handler Risk

Triflumizole products can be applied to apples, pears, cherries, cucurbit vegetables, grapes, strawberries, hazelnuts, b rassica leafy greens and for pre

- plant treatment of pineapple seed pieces for foliar disease control via airblast, groundboom, aircraft, dip tank, or chemigation

. Handler exposure is expected to be short

- or intermediate

- term based on information provided on the

label s . The label s state that all handlers must wear the proper personal protective equipment (PPE): a long

- sleeved shirt, long pants, chemical resistant gloves, shoes, and socks. Based on this

assessment, triflumizole ’s labels need to be amended to include a requirement to wear chemical

resistant hat for application with open cab air blast equipment in order to meet the target MO E of

3 00

. The MOE with the current label PPE recommendations (single layer and glove) is 230.

The maximum application rate for each exposure scenario is presented as the worst case scenario. All handler scenarios (mixer/loader, applicator, and flagg er) are considered to be short

and intermediate

- term. Both short

- and intermediate

- term total (dermal and inhalation ) MOEs were above the target exposure levels of 100 and 300, respectively, and therefore do not exceed
HED’s level of concern (Appendix C)

.

Short

- /Intermediate

- Term Post

- Application Risk

HED default assumptions

, triflumizole

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

- entry Task Force (ARTF) data base were u s ed in assessing post application

activities

. The short

- term Restricted Entry Interval ( REI) for grapes (table and raisin) should be extended from the current REI (zero days) to 1 day, and 3 days for hops to achieve the target
MOE ≥ 100.

Inhalation Postapplication Risk

Although a quantitative occ upational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 14 of 30 hig her exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational postapplication inhalation exposure scenarios. Since handler inhalation exposure is not of concern, post

- application inhalation exposure is not of concern.

Restricted Entry Interval

For grapes (table and raisin) the short

- term post

- application risk estimates did not exceed HED’s

LOC (i.e., MOEs ≥ 100) on day one . For wine grape reentry is acceptable on day zero

. This is a change from the previous risk assessment due to revised ARTF data which was used to calculate exposure and risk at various reentry intervals

. The activities with the highest estimated risk ar e mechanically assisted harvesting for hops and g irdling for table and raisin grapes

. The label

REIs are currently based on the acute toxicity of technical chemical material. Under the Worker

Protection Standard WPS, active ingredients classified as acu te toxicity category III or IV for acute dermal and primary skin irritation are assigned a 12

- hour REI. Thus, with the exception of hops and grapes (raisin and table only ) the 12

- hour REI on the triflumizole label is acceptable. The post

- application occupational exposure exceeds the Agency’s level of concern for grapes (raisin and table only) at day zero

. F or all types of grapes and hops the t arget MOE ≥ 1 00; therefore, the current REI of zero days fo r table and raisin grapes and hops must be extended to 1 day and 3 days respectively to achieve risks below the Agency levels of concern. Hops has a seven day P re Harvest Interval (PHI), t he restricted entry interval (3 days) for mechanically assisted harvesting may not be necessary since the longer PHI w ould provide the necessary restricted entry for this activity

.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 15 of 30 Appendix A. Toxicity Profile and Endpoint Selection

Acute Toxicity Profile

– Triflumizole

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



### Subchronic, Chronic and Other Toxicity Profile

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

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 16 of 30 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/

Classification /Doses Results

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 assigned

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. Developmenta l 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 incidences 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), bas ed 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, reduc ed 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.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 17 of 30 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/

Classification /Doses Results

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 LOAEL

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.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 18 of 30 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/

Classification /Doses Results

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 NA

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 sulfation 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 det ectable in all tissue, organ, and blood samples collected 2 days (10 mg/kg group) or 4 days (300 mg/kg group)
post

- dose with tissue concentrations generally higher in males than females. The metabolite profile in the excreta was quantitatively and qualita tively 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

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 19 of 30 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/

Classification /Doses Results

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 activities 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).

Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary and Non

- Occupational Human

Health Risk Assessments 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 Popula tions) LOAEL=3

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

UF H = 10x FQPA:UF

LOAEL→NOAEL = 3x Chronic RfD =

0.0 117 mg/kg/day

cPAD = 0.0117mg/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).

Dermal Short

- Term (1

- 30 days) NOAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x Residential and

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 (NOAEL = 3.5 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 (NOAEL = 3.5 mg/kg/day).

Dermal Intermediate

and Long

- Term (1

- 6

months and 6 months and longer) LOAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x

UF LOAEL→NOA

EL = 3x Residential and

Occupational L OC

for MOE = 300 Combine d Chronic Toxicity/Carcinog. Study

-

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

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 20 of 30 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary and Non

- Occupational Human

Health Risk Assessments

Inhalation Short

Term (1

- 30 days) NOAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x Residential and

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

o bserved at 8.5 mg/kg/day (NOAEL = 3.5 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 (NOAEL = 3.5 mg/kg/day).

Inhalation

Intermediate

- and Long

- Term (1

- 6
months and 6 months and longer) LOAEL=

3.5 mg/kg/day UF A = 10x

UF H = 10x

UF LOAEL→NOA

EL = 3x Residential and

Occupational L OC

for MOE = 300 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 on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 21 of 30 A ppendix B : International Harmonization

Summary of US and International Tolerances and Maximum Residue Limits : Triflumizole (PC Code 128879)
Residue Definition : US Canada Mexico 1 Codex
40 CFR §180.476 Plant: 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

compou nd. 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 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex Apple 0.5 0.5 Apple, dry pomace 2.0

Apple, wet pomace 2.0 Brassica,head and stem, subgroup

5A 8.0

Brassica, leafy greens, subgroup

5B 40

Canistel 2.5 Cherry, sweet 1.5 1.5 Cherry, tart 1.5 1.5
Cilantro, leaves 35 Grape 2.5 2.5 Grape, dried pomace 15 Grape, raisin, waste 10 Grape, wet pomace 15

Hazelnut 0.05 Hop, dried cones 50 Leafy greens subgroup 4A, except spinach 35

Mango 2.5 Papaya 2.5

Pear 0.5 0.5 Pineapple 4.0 Sapodilla 2.5 Sapote, black 2.5 Sapote, mamey 2.5 Star apple 2.5 Strawberry 2.0 2.0

Swiss chard 18 Turnip,greens 40 Vegetable, cucurbit, group 9 0.5 0.5 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, cucumbers, edible gourds (other than those listed in this item), muskmelons (other than those listed in this item) pumpkins, summer squash, watermelons, west Indian gherkins, winter squash

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 22 of 30 Summary of US and International Tolerances and Maximum Residue Limits : Triflumizole (PC Code 128879)
Residue Definition : US Canada Mexico 1 Codex
40 CFR §180.476

Liv estock: parent compound triflumizole, 1

- (1

- ((4

- chloro

- 2

- (trifluoromethyl)phenyl)imino)

- 2

- propoxyethyl)

- 1 H

- imidazole, the metabolite

4

- chloro

- 2

- hydroxy

- 6

- trifluoromethylaniline sulfate, and other metabolites containing the 4

- chloro

- 2

- trifluoromethylanili ne moiety, calculated as the parent compound None None

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

US Canada Mexico 1 Codex
Cattle, fat 0.5
Cattle, meat 0.05 Cattle, meat byproduct 0.5 Egg 0.05
Goat, fat 0.5
Goat, meat 0.05 Goat, meat byproduct 0.5 Hog, fat 0.5 Hog, meat 0.05 Hog, meat byproduct 0.5
Horse, fat 0.5
Horse, meat 0.05 Horse, meat byproduct 0.5

Milk 0.05 Poultry, fat 0.05 Poultry, meat 0.05 Poultry, meat byproduct 0.1 Sheep, fat 0.5 Sheep, meat 0.05 Sheep, meat byproduct 0.5 Completed: : M. Negussie; 02/16/2012

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

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 23 of 30 Appendix C

. Residential and Occupational Exposure and Risk Estimates for Triflumizole

a. Based on registered labels

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/da y) x DAF (3.5%)/BW (80 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 gal lons/day) /BW (80 kg)

f. Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/k g/day) g Total MOEs =1/[(1/Dermal MOE) + (1/Inhalation MOE)]. Level of concern = 100 Table 1: Short

- Term Residential Handler Exposure and Risk Estimates for Triflumizole

Exposure Scenario Target

MOE Dermal

Unit Exposure Inhalatio

n 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

Mixer/Loader/Applicator

M/L/A Broadcast Hand Held Pump Sprayer (Gardens) 100 38 0.0027 1 (lb ai/A) 1 A 0.017 210 0.000034 100,000 210

M/L/A Broadcast Application Hand Held Pump Sprayer (Fruit Trees and Ornamentals) 100 56 0.0038 1 (lb ai/A) 1 A 0.025 140 0.000048 7,4000 140

M/L/A Spot Treatment Hand Held Pump Sprayer for (Gardens) 100 38 0.0027 1 (lb ai/A) 0.023 A 0.00038 9,200 7.8E

- 07 4,500,000 9,100

M/L/A Spot Treatment Hand Held Pump Sprayer (Fruit Trees and Ornamentals) 100 56 0.0038 1 (lb ai/A) 0.023 A 0.00056 6,200 0.0000011 3,200,000 6,200

M/L/A Hand Held Pump Sprayer (Gardens) 100 38 0.0027 0.0025 (lb ai/gal) 5 gal 0.00021 17,000 4.2E

- 07 8,300,000 17,000

M/L/A Hand Held Pump Sprayer (Fruit Trees and Ornamentals) 100 56 0.0038 0.0025 (lb ai/gal) 5 gal 0.00031 11,000 5.9E

- 07 5,900,000 11,000

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 24 of 30 Table 2: Short

- /Intermediate

- 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

Mix ing/Loading Liquids for

Aerial Applications Broccoli; Chinese Broccoli,

Brussels Sprouts, Cabbage, Chinese Cabbage (Napa), Chinese Mustard Cabbage, Cauliflower, Cavalo Broccoli, And Kohlrabi, Cucumber, Gherkin, Gourds, Melons, Pumpkin, Squash ,Apples, Pear, Cherry Leafy Greens(excep t spinach) 0.22
( s ingle layer/no glove 0.000219 0.25 350 0.00 84 420 0.00024 15,000 400

Hops 0

. 0376

s ingle layer/glove 0.375 0 .0022 1,600 0.00036 9,700 1,400

Strawberry 0.22
( s ingle layer/no glove 0.125 0.0042 830 0.00012 29,000 810

Hazelnut 0.19 0.0064 550 0 .00018 19,000 530
Mixing/Loading Liquids for Chemigation Applications Strawberry 0.125 0.0042 830 0.00012 29,000 810

Broccoli; Chinese Broccoli, Brussels Sprouts, Cabbage, Chinese Cabbage (Napa), Chinese Mustard Cabbage, Cauliflower, Cavalo Broccoli, And Kohlrabi], Cucumber, Gherkin, Gourds, Melons, Pumpkin, Squash, Leafy green (except spinach) 0.25 350 0.0084 420 0.00024 15,000 400

Mixing/Loading Liquids for

Groundboom Applications Broccoli; Chinese Broccoli,

Brussels Sprouts, Cabbage, Chinese Cabbage (Napa), Chinese Mustard Cabbage, 0.25 80 .0019 1,800 0.000055 64,000 1,800

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 25 of 30 Table 2: Short

- /Intermediate

- 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

Cauliflower, Cavalo Broccoli, And Kohlrabi, Cucumber, Gherkin, Gourds, Melons, Pumpkin, Squash Strawberry 0.125 0.00096 3,600 0.000027 130,000 3,500
Mixing/Loading Liquids for

Airblast Applications Apples, Pear, Cherry 0.5 40 0.0019 1,800 0.000055 64,000 1,800

Canistel, Mango, Papayas, Sapodilla, Sapote, Star apple 0.31 0.0012 2,900 0.000034 100,000 2,900

Hazelnut (filbert) 0.19 0.00073 4,800 0.000021 170,000 4,700
Hops 0.375 0.0014 2,400 0.000041 85,000 2,400
Grape 0.25 0.00096 3,600 0.000027 130,000 3,500
Pineapple 0.005/lb/gal 100 gals 0.00048 73,000 0.0000014 2,600,00

0 71,000

Mixing/Loading

Wettable Powders (W SP)

for Aerial Applications Apples, Pear 0.0098
( s ingle layer/no glove with

water
soluble packages 0.00024 0.5 350 0.00075 4,700 0.00053 6,700 2,700

Mixing/Loading

Wettable

Powders for

Airblast Applications Grape 0.17
Single layer/glove 0.0434 0. 2 5 40 0.00 75 4800 0.0055 640 600

Mixing/Loading

Wettable

Powders for Apples, Pear 0.17

s ingle layer/glove 0.0434 0.25 0.0007 4700 0.0054 650 600

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 26 of 30 Table 2: Short

- /Intermediate

- 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

Airblast Applications

Mixing/Loading

Wettable Powders (WSP)

for Aerial Applications Apples, Pear, Cherry 0.0098

w ater
soluble packages 0.00024 0.5 350 0.00075 4,700 0.00053 6,700 2,700

Cucumber, Gherkin, Gourds,
Melons, Pumpkin, Squash,

Strawberries 0.25 0.00038 9,300 0.00026 13,000 5,500

Hazelnut 0.19 0.00029 12,000 0.0002 18,000 7,200

Hops 0.375 0.00056 6200 0.00039 8,900 3,700

Mixing/Loading

Wettable Powders(WSP)

for Airblast Applications Grape 0. 25 40 0.0000 43 82 ,000 0.0000 3 116,000 48,000

Hazelnut 0.19 0.000033 110,000 0.000023 150000 63,000

Apples, Pear, Cherry 0.50 0.000086 41000 0.00006 58,000 24,000

Mixing/Loading

Wettable Powders (WSP)

for

Groundboom Applications Cucumber, Gherkin, Gourds,

Melons, Pumpkin, Squash,

Strawberries 0.25 80 0.000086 41000 0.00006 58,000 24,000

Mixing/Loading

Wettable powder (WSP)

v ia Dip Pineapple 0.005lb ai/gal 100gals 0.000021 160,000 0.000015 230,000 96,000

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 27 of 30 Table 2: Short

- /Intermediate

- 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

Mixing/Loading Dry Flowables

for Airblast Applications Apples, Pear 0.227 0.00896 0.25 40 0.0010 3,500 0.0011 3,100 1,700

Applicator
Applying Sprays via

Aerial Equip ment Broccoli; Chinese Broccoli,

Brussels Sprouts, Cabbage, Chinese Cabbage (Napa), Chinese Mustard Cabbage, Cauliflower, Cavalo Broccoli, And Kohlrabi, Cucumber, Gherkin, Gourds, Melons, Pumpkin, Squash ,Apples, Pear, Cherry , Leafy Greens(except spinach) , strawberry 0.005

e ng. control 0.000068 0.25 350 0.000 19 18,000 0.000074 47,000 13,000

Hops 0.375 0.00029 12,000 0.00011 31,000 8,800

Hazelnut 0.19 0.00015 24,000 0.000057 62,000 17,000
Applying Sprays via

Groundboom Equipment Broccoli; Chinese Broccoli,

Brussels Sprouts, Cabbage, Chinese Cabbage (Napa), Chinese Mustard Cabbage, Cauliflower, Cavalo Broccoli, And Kohlrabi, Cucumber, Gherkin, Gourds, Melons, Pumpkin, Squash , Strawberry 0.0786

o pen c ab 0.00034 0.25 80 0.0007 5,100 0.000085 41,000 4,500

Applying Sprays via Apples, Pear, Cherry 0.215
glove/ chemi 0.00471 0.5 40 0.0019 1,900 0.0012 3,000 1,100

Grape 0.25 0.00095 3,800 0.0006 6,000 2,200

### Triflumizole Human Health Risk Assessment DP No. 420633

Page 28 of 30 Table 2: Short

- /Intermediate

- 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

Open Cab Air

blast Equipment Canistel, Mango, Papayas,

Sapodilla, Sapote, Star apple cal resistant

hat 0.31 0.0012 3,000 0.00073 4,800 1,800

Hazelnut (filbert) 0.19 0.00071 4,900 0.00045 7,800 3,000

Flagger

Flagging for Aerial Sprays Applications All Crops 0.011 0.00035 0.5 350 0.0084 4,200 0.0077 4,600 2,200

Mixer/loader/Applicator
Mixing/Loading /App Mixing/Loading /App Wettable

Powder with Mechanically

pressurized Handgun (ORETF) Ornamentals 1.3
single layer/glove 0.0039 0.005lb ai/gal 1000gals 0.0028 1200 0.0002 11000 1100

Orchard crops 0.5 40 acres 0.011 310 0.0010 3600 300

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 Treat ed (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) 

### Applicator with open cab air blast equipment on grapes, apple, pear and cherry must wear a chemical re sistant hat to achieve the target MOE ≥ 300. The MOE with the current label PPE recommendations (single layer and glove) is 230.

### Triflumizole Human He alth Risk Assessment DP No. 4 20633

Page 29 of 30 Table 3: Dermal Post

- application Exposure and Risk Using Chemical

- Specific DFR Data.

Crop Group Proposed

Crop Highest Transfer

Coefficient for Crop (cm 2 /hr)

and Associated Activity Days after

Treatment Study

Test

Site Chemical

- specific DFR a

(ug/cm 2 ) Dermal Dose b (mg/kg/day) Short

Term

MOE c Intermediate

Term MOE c

Short

- Term Intermediate

Term Short

-

Term Intermediate

Term

Deciduous

tree fruit Apple, Pear,

Cherry Thinning fruit

(3600) 0 CA

0.563 0.130 0.014 0.003 250 1100

Evergreen

tree fruit Canistel,

Mango, Papayas, Sapodilla, Sapote, Star apple Thinning fruit

(3600) 0 CA 0.009 0.002 400 1700

Brassica Broccoli;

Chinese Broccoli,

Brussels Sprouts, Cabbage,

Chinese Cabbage (Napa),

Chinese

Mustard Cabbage, Cauliflower,

Cavalo Broccoli,

And

Kohlrabi Hand harvesting

(4200) 0 CA 0.0083 0.0019 420 1800

Cucurbit vegetables Cucumber,

Gherkin, Gourds, Melons, Pumpkin, Squash Irrigation

(1900) 0 CA 0.0037 0.0009 930 4000

### Triflumizole Human He alth Risk Assessment DP No. 4 20633

Page 30 of 30 Table 3: Dermal Post

- application Exposure and Risk Using Chemical

- Specific DFR Data.

Crop Group Proposed

Crop Highest Transfer

Coefficient for Crop (cm 2 /hr)

and Associated Activity Days after

Treatment Study

Test

Site Chemical

- specific DFR a

(ug/cm 2 ) Dermal Dose b (mg/kg/day) Short

Term

MOE c Intermediate

Term MOE c

Short

- Term Intermediate

Term Short

-

Term Intermediate

Term

Leafy vegetable Leafy

Vegetable (except spinach) Hand weeding

(4200) 0

CA 0.0083 0.0019 420 1800

Berry low Strawberry Irrigation (1900) 0 0.004 0.001 930 4000

Tree nut Hazelnut

(filbert) Thinning

(3600) 0 0.005 0.001 650 2800

Bunch and

bundle Hops Mechanically

assisted harvesting(19,300) 3 d 0.034 0.011 100 Day 3 330

Day 1

Vine/trellis Grapes Girdling, Turning(19,300) for

table and raisin

grapes 1 0.035 0.009 100 Day 1 400

Day 0

Tying/Training/Hand harvesting for wine

grapes (10

, 100) 0 0.023 0.005 150 Day 0 760

Day 0

a. Chemical

- specific DFR = day zero predicted grape vine DFR data adjusted for application rate ( 0 .375 for hops) are 0.563 ug/cm 2 and 0.84 ug/cm 2 and used

for short

– term exposure estimate s. The predicted grape vine average

- 21 days residue data was adjusted for application rate (0.375 lb ai/A for hops and 0.25 lb ai/A for grapes ) are 0. 130 ug/cm 2 for grapes and 0.20 ug/cm 2 for hops used for intermediate

- term exposure estimate s

. b. Dermal Dose = [DFR (ug/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/ ug x DAF (3.5%) x 8 hrs/day]  body weight ( 69 kg short

- term, 80 kg Intermediate term ). c. MOE = NOAEL (3.5 mg/kg/day)/ Dermal Dose (mg/kg/day).

d 

### Hops has a seven day Pre Harvest Interval (PHI), the restricted entry interval (3 days) for mechanically assisted harvesting may not be necessary since the longer PHI would provide the necessary restricted entry for this activity.