### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460

MEMORANDUM

Date : 

### February 10 ,2 013 OFFICE OF CHEMICAL SAFET Y AND
POLLUTION PRE V ENTION



### SUBJECT: Fluop icolid e 

### Human Health Risk Assessment Seeping D ocument in Support of

R egistration Review.

PC Code : 027412 (F lu o pic o l ide), 027402 (B AM) D P Ba rc ode: 0405060

Registration N o. : NA Decision No .: 469292

Pe titi on No .: NA Regulatory Actio n: Registrat i on Review

Risk Ass essm ent Ty pe: Si n g l e C h e mical Aggregate Case No.: NA

TXRNo .: NA

MRIDNo

. :NA



### FROM:



### THROUGH:

TO : CAS No.: 239110 -1 5-7

40 CF R : 180.627



### Danette Dr ew, Chem i st/Risk Ass

. essor**?"'1-~L.L-~......-** '--J"'-- 

### A l exan dra LaMay, Biologist 

### c::{..=:::z;;.-z!IV'

John Liccione

, Toxicolog i st**5~~~~~L.,.___.....e** 

### Risk Assessment Branch V 

### N

Heal th Effects Division (7509P)

Mic h ael S. Metzger, Chief 

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Risk Assessment Branch V

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Hea l th Effects D i vision (7509P

Russell Wasem, Chemical Review Manager

Pesticide R e-Eva luation Division (7508 P )

Office of Pe st i c ide Programs

Attached is the H ea lt h E ffects Divisi on's ( HED) human health ri sk assessment seeping (s tatus update ) document for fluopicolide to support the registration review process.

Pa ge 

### 1 of 35

### Page 2 of 35

Executive Summary

EPA’s Health Effects Division (HED) has evaluated the avail able data and the most recent

human health risk assessments for the herbicide fluopicolide, 2,6

- dichloro

- N

- [3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridylmethyl]benzamide, to determine the scope of work necessary to support the registration review process. HED has considered the current ly labeled use patterns (labels) as well as the available toxicity and exposure information for fluopicolide

. The most

recent human health risk assessment for fluopicolide was performed on 12/9/10 to support the

then

- proposed use s on b rassica l eafy greens
, p otatoes, s ugar b eets, and ca rrots a nd to allow crop rotation to wheat (D 384431 ).

Fluopicolide is formulated as a liquid/suspension concentrate and is registered for use on a wide variety of food crops. Fluopicolide is also re gistered for use on non

- agricu ltural sites such as ornamental plants , lawns, recreational areas, parks, golf courses, athletic fields, commercial and

industrial areas. P ermanent tolerances for residues of fluopicolide are established under 40 CFR

180.627

. The r esidue of concern for tolerance enforcement is parent fluopicolide. Residues of

concern for risk assessment include parent fluopicolide and, depending on the crop, one or more of the following metabolites: PCA, P1X and BAM. Residues of concern in livestock commodities and in drinking water are fluopicolide and BAM . (S ee Table 1. Summary of Fluopicolide Residues of Concern and Table A.3 Chemical Names and Structures of Regulated Fluopicolide Metabolites. )

The Codex and U.S. residue definitions for fluopicolide are harmonized and both express determination of parent fluopicolide. The Codex maximum residue levels (MRLs) and U.S.

tolerance levels for many commodities are not harmonized, mainly because of differences in commodity group definitions.

BAM ( 2,6

- dichlorobenzamide ; PC code 027402 ) , the toxic degradat e/metabolite of fluopicolide is also a degradate/metabolite of the herbicide dichlobenil (2, 6

- dichlorobenzonitrile; PC code

027401 ). The risk from exposures to BAM through the use of both dichlobenil and fluopicolide

is assessed separately from either of these active ingredients because it has its own toxicity

database , toxic effects and points of departure. The most recent hazard and exposure estimates for BAM are summarized within this fluopicolide scoping document . More information regarding BAM hazard and exposure , including outstanding data requirements, can be found in the 5/16/12 dichlobenil registration review scoping document ( D396248).

The fluopicolide toxicology database is sufficient for the characterization of a wide variety of toxic effects, including potential carcinogenic, mutagenic, developmental, and reproductive. However, immunotoxicity testing is required for fluopi colide as part of the new data requirement

under 40 CFR Part 158

.

The BAM toxicology database is adequate except for a special study to evaluate olfactory toxicity following oral administration of BAM ( f or details, see D396248

, Dichlobenil

, Human

Health Assessment Scoping Document in Support of Registration Review ). Once outstanding data are received for BAM the 10X FQPA safety factor (retained for oral exposures) for the lack of this special study will be reevaluated.

### Page 3 of 35

The HED Hazard and Science Policy Council (HASPOC ; TXR. 0056544 ) recently met (12/19/12) to discuss the need for a 28

- day inhalation study for fluopicolide; previous assessments used toxicity points of departure (PODs) from an oral study to assess inhalation

exposure

. The HASPOC determine d that, based on a weight of evidence ( WOE) approach, a 28

- day inhalation toxicity stu dy is not required at this time and that the use of the oral study POD is protective for assessing inhalation exposures to fluopicolide.

The residue chemistry database i s incomplete. Residue chemistry studies are required for storage stability, processing, and field rotational crops (see “ Data Requirements for Fluopicolide” section of this document)

.

Currently there are no dietary (food and water) risk estimates of concern for fluopicolide or the

metabolite BAM . Updated dietary exposure assessments for fluopicolide or BAM may be necessary under registration review if the toxicological PODs

, FQPA safety factors or other uncertainty factors change, or percent crop tre ated estimates increase significantly , or there are significant changes in the estimated drinking water concentrations based on the Ecological Fate

and Effect Division ’s (EFED) updated drinking water assessment

.

The residential exposure database for fluopicolide is complete , with the exception of a requirement for a chemical specific turf transferable residue (TTR) study (i n accordance with the updated Part 158 data requirements ). Previous residential handler and post

- application

exposures assessment s for fluopicolide used default TTR values and did not result in risk

estimates of concern. However, the residential post

- application Margins of Exposure ( MOEs )

for adults and children contacting a treated lawn were not at lea s t 10 times the level of conc ern (i.e. MOEs were <1000 and the LOC is 100), thus triggering the need for a chemical specific TTR study (as per the Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council ).

Residential handler exposure was not evaluated for BAM because the metabolite BAM is believed to form slowly in plants and soil after the product containing the parent (fluopicolide) has been applied. However, t here is a potential for dermal (adults and children) and incidental

non

- dietary ingestion (for children) exposure to BAM during post

- application activities on fluopicolide

- treated lawns. The short

- /intermediate

- term dermal MOEs for adults and children

and incidental oral MOE for children are greater than the ir respective LOCs ( dermal MOEs >

100 and oral MOEs >1000) and are therefore not of concern.

An updated residential handler (fluopicolide) and post

- application (fluopicolide or BAM) assessment may be required under registrati on review as a result of the 2012 revisions to HED’s Residential Exposure Standard Operating Procedures (SOPs ). In addition, revised residential assessments may be needed if toxicological PODs or uncertainty factors change or other new

data are received by the Agency that impact exposure estimates.

In addition, a quantitative residential post

- application exposure assessment has not been performed as a result of pesticide drift or volatilization from neighboring fluopicolide

- treated

### Page 4 of 35

agricultural fields; s pray drift and volatilization assessments may be necessary under registration

review.

There were no aggregate ( combined food, drinking water, and residential exposures ) risks of concern for fluopicolide or for BAM. If significant changes are made to th e previous fluopicolide or BAM residential or dietary risk assessments, revised aggregate risk assessments may be performed under registration review.

The occupational exposure database for fluopicolide is complete. There were no occupational

risk estima tes of concern. An u pdated handler and post

- application assessment may be necessary under registration review of fluopicolide or BAM if warranted by any significant changes in exposure assessment metho dology, toxicological PODs or uncertainty factors.

Chemical Use Profile

Fluopicolide is a fungicide intended for the control of plant diseases caused by Oomycetes

. Fluopicolide controls a wide range of Oomycete (Phycomycete) diseases including downy mildews ( Plasmopara

, Pseudoperonospara

, Peronospora , a nd Bremia ), late blight ( Phytophthora ), and some Pythium species. Fluopicolide appears to interfere with mitosis and cell division resulting in the rapid destabilization of fungal cell structures; this pesticidal mode of

action has been characterized as n ovel and unique and unlike the known modes of action of other registered fungicides. In the plant, fluopicolide is a mesosystemic fungicide; it translocates toward the stem tips via the xylem but it does not translocate toward the roots.

Fluopicolide is formulated as a liquid/ suspension concentrate and is registered for use on currants, grapes, huckleberries, nut trees, pome fruits, flavoring and spice crops, cucurbits, eggplant, tomatoes and other fruiting vegetables, leafy and stem vegetables (like spin ach , broccoli etc), root crop vegetables, okra, onions, sugar beets and turnips. P ermanent tolerances

for residues of fluopicolide are established under 40 CFR 180.627

.

Fluopicolide is also registered for use on non

- agricultural sites such as forest trees, herbaceous plants, ornamental plants, ornamental lawns and turf, ornamental woody shrubs and vines, ornamental trees, lawns, recreational areas, parks, golf courses, athletic fields, commercial and

industrial areas. Fluopicolide may be applied by a ir or ground equipment.

The nomenclature and physiochemical properties of fluopicolide can be found in Appendix A.

Hazard Identification/Toxicology

Fluopicolide

The toxicity database for fluopicolide is complete except for immunotoxicity testing. This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses).

### Page 5 of 35

Te chnical grade flu opicolide has low acute toxicity via oral, dermal and inhalation routes of

exposure. Flu opicolide is not a dermal sensitizer, primary eye irritant, or primary skin irritant.

The subchronic and chronic oral toxicity studies in rats and mice revealed liver toxicity in both species. Kidney and thyroid toxicity were observed in rats only. Flu o picolide is not neurotoxic, carcinogenic , n or mutagenic. Developmental toxicity in the rabbit occurred only at doses that caused severe maternal toxicity (including death). In the rat, developmental effects were seen only at high dose levels (700 mg/kg/d ay) in the presence of maternal toxicity. Similarly, offspring effects (body weight, kidney) occurred only at levels causing toxicity in parents of the

multi

- generation reproductive toxicity study. There is no evidence of increased quantitative susceptib ility of rat or rabbit fetuses to in utero or post

- natal exposure to flu opicolide

.

No toxic effects were observed in studies in which flu opicolide was administered by the dermal routes of exposure . An inhalation toxicity study is not available. The Hazard and Science Policy Council (HASPOC ; TXR. 0056544 ) met on December 19, 2012 to discuss the need for this inhalation study. The HASPOC has determined that , based on a weight of evidence ( WOE) approach, a 28

- day inhalation toxicity study is not require d at this time. This approach considered all of the available hazard and exposure information including (1) the physical/chemical properties of fluopicolide , including its potential to volatilize (8.03 x 10 - 7 

### Pa vapor pressure); (2) the low acute inhalati on toxicity; (3) the primary target organs of fluopicolide are the liver and hematopoietic system following repeat oral exposure; (4) the use of an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs >40,000

.

No a ppropriate endpoint was identified for the acute dietary (general population, including infants and children) exposure scenarios. The toxicological profile for fluopicolide suggests that

incr eased durations of exposure do not significantly increase th e s everity of observed effects. Therefore, t he rabbit developmental and rat chronic/carcinogenicity studies were considered co

critical for endpoint selection for all routes ( dietary , incidental oral, dermal and inhalation) and

durations of exposure (with the exception of acute exposures)

.

The Agency considers it appropriate to reduce the Food Quality Protection Act (FQPA) safety

f actor to 1X because the toxicity database is sufficient for endpoint selection, t here is no

evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2

- generation rat reproduction study , t here is low

concern for the qualitative susceptibility observed in the rat developmental toxici ty study because the offspring effects (reduced growth and skeletal defects) and late

- term abortions are well characterized and accompanied by maternal toxicity near the limit dose , and the exposure

assessment s are unlikely to underestimate risk

.

The toxi city profile and summary of toxicological endpoints for fluopicolide are provided in Appendix B.

BAM

In the subchronic and chronic oral toxicity studies in the rat and dog, respectively, body weight change was the toxicological effect most often observed at the LOAEL. In the combined chronic

### Page 6 of 35

toxicity/carcinogenicity study in the rat, toxicologically sign ificant changes in body weight were also observed at the LOAEL, as were eosinophilic foci in the liver. BAM

- mediated olfactory toxicity was observed in one study reported in the open literature (Brittebo et al. 1991). There

was n o evidence of increased susceptibility to offspring following pre

- natal exposure to rabbits in a developmental toxicity study with BAM.

Appropriate endpoints were identified for the acute dietary (general population, including infants and children) from a single oral dose in the in vivo mouse erythrocyte micronucleus assay; acute dietary for females 13

- 49 based on effects observed on a developmental toxicity (rabbit) study; chronic dietary based on a chronic toxicity (dog) study; incidental oral based on a 90

- day oral study in rat; inhalation and dermal endpoints are based on the dichlobenil toxicity studies (in the absence of route specific studies for BAM, studies from parent compound dichlobenil were selected)

.

The 10X FQPA s afety f

actor has been reta ined as a database uncertainty factor for acute dietary, chronic dietary and incidental oral exposures to account for the lack of a special oral toxicity study with thorough examination of the olfactory system. An oral toxicity study in the rat with a

foc us on the examination of the olfactory system after 1, 7, 14 and 28 days of exposure will be required to assess the potential of olfactory toxicity following acute and subchronic oral

exposure ( D396248

, Dichlobenil

. Human Health Assessment Scoping Document in Support of Registration Review ) . The FQPA factor has been reduced to 1X for dermal and inhalation exposures, since the olfactory endpoint of concern has been measured in dermal and inhalation

studies.

BAM is not mutagenic or clastogenic in submitted genotoxicity studies. EPA has assumed that BAM’s potential for carcinogenicity is similar to parent dichlobenil (Group C, possible human carcinogen) and therefore has determined that the cPAD will adequately account for all chronic effects, including carci nogenicity, likely to result from exposure to BAM.

The toxicity profile and summary of toxicological endpoints for BAM are provided in Appendix

B.

Conclusions: The fluopicolide toxicology database is sufficient for the characterization of a wide variety of toxic effects, including potential carcinogenic, mutagenic, developmental, and reproductive. However, immunotoxicity testing is required as part of the new data requirement

under 40 CFR Part 158

. For BAM, o utstanding data requirements (special olfactory toxicity

st udies) and associated rationale can be found in D396248

. Once outstanding data are received for BAM the 10X FQPA safety factor for the lack of the special study will be reevaluated.

Dietary Exposure

Residu e Chemistry

The residue database is incomplete. Additional storage stability data are required to support the

Brassica head and stem, bulb, and root vegetable, and leafy vegetable crop field trials

. A processing study is required for aspirated grain fra ctions. Limited field rotational crop studies

### Page 7 of 35

are required for small grains, soybean, corn, rice and oilseed. See the “Data Requirements for Fluopicolide ” section of this document for details.

Dietary Assessment

The fluopicolide residues of concern for primary and rotational crops, livestock and drinking

water are shown in Table 1. S eparate risk assessments were conducted for the fluopicolide metabolite, BAM. There is a complete hazard database available for BAM and separate endpoints for risk assessment have been selected from that data. All other metabolites referenced below are assumed to have equivalent toxicity t o the parent compound and are included with the parent compound in dietary risk assessment.

Table 1. Summary of Fluopicolide Residues of Concern.

Matrix Residues included in

Risk Assessment Residues included in Tolerance Expression

Plants Primary Crops

All primar y crops except Tuberous and Corm Vegetables Fluopicolide (parent) and

BAM Fluopicolide

Tuberous and Corm Vegetables Fluopicolide (parent), PCA, and BAM

Rotational Crops

All rotational crops except cereal grains Fluopicolide (parent) and

BAM

Fluopicolide Cereal grains

- grain for

human food Fluopicolide (parent), PCA, P1X and BAM

Cereal grains

- forage/hay/straw and grain for livestock feed Fluopicolide (parent) and

BAM

Livestock Fluopicolide (parent) and

BAM Fluopicolide

Drinking Water Fluopicolide (parent) and

BAM Not applicable



### Fluopicolide

The most recent dietary assessment for fluopicolide , which included parent fluopicolide plus

metabolites indicated in Table 1 above except BAM ( the BAM metabolite was assessed separately ), was performed in 2010 to support the established uses and Section 3 requests for use

on Brassica Leafy Greens Subgroup 5B, Potatoes , Sugar Beets, Carrots and to Allow Rotation to

Wheat ( D381050, D. Davis, 8/19/10 ). An acute dietary assessment was not conducted because an endpoint attributable to a single dose has not been identif ied for fluopicolide. A chronic dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 2.03. That assessment is considered

### Page 8 of 35

highly conservative as it included tolerance level residues or maximum field trial residue levels for all crops, assumed 100% crop treated and used empirical or default DEEM processing

factors. Estimated drinking water concentrations (EDWCs) from the last fluopicolide Drinking Water Assessment (DWA) ( R. Miller, D370764, 6/20/10) were incorporated directly into the dietary assessment. Chronic surface water and groundwater EDWCs were based on

PRZM /EXAM and SCI

- GROW models, respectively, and reflected aerial application to Florida

carrots (the use pattern resulting in the highest EDWCs)

.

Chronic dietary (food and water) risk estimates were not of concern for fluopicolide . The

established and then

- proposed uses of fluopicolide resulted in an estimated exposure to the general U.S. Popula tion which is equivalent to 7.9% of the chronic population adjusted dose (cPAD). The most highly exposed subgroup is children 1

– 2 years of age with an estimated exposure equivalent to 13% of the cPAD.

BAM

BAM (2,6

- dichlorbenzamide) is a metabolite o f concern for two active ingredients, fluopicolide and dichlobenil; therefore, the BAM dietary assessment includes residues of BAM in food and drinking water from uses of both pesticides

. The last dietary assessment for BAM was conducted to support new us es of fluopicolide (D. Davis, D 381051, 09/09/2010 ). The assessment was partially refined : residue values for BAM from field trials conducted either with

flu opicolide or dichlobenil were incorporated into the risk assessment and percent crop treated data, where available, were used. The EDWC for BAM used in the dietary assessment was modeled from the established dichlobenil uses since these provide d higher residue levels than those from fluopicolide uses ( EFED, D 340773, J. Angier , 8/29/07 ). T he EDWC for groundwater (which was higher than the surface water) was based on SCIGROW modeling of dichlobenil use

on turf/ nutsedge.

A cute and chronic dietary (food and water) risk estimates for BAM are not of concern. For the acute dietary assessment the estimated risk is 12% of the aPAD for the general U.S. population. All infants and females, the two population subgroups with the highest estimated risk had exposures that resulted in estimated acute dietary risks equivalent to 28% of the aPAD for each subgroup. F or the chronic dietary assessment the U.S. population has an estimated risk of 30% of the cPAD. All infants, the most highly exposed population subgroup, had a chronic dietary (food and water) exposure that resulted in an estimated risk of 93% of the cPAD. A significant portion of that risk comes from the drinking water component of the assessment which is based on conservative modeled water residues. The population subgroup, all infants has a chronic dietary exposure from food alone that is equivalent to only 6.5% of the c PAD.

C onclusions : Currently there are no dietary (food and water) risk estimates of concern for fluopicolide or the metabolite BAM. Updated dietary exposure assessments for fluopicolide and BAM may be necessary under registration review if the toxicological PODs or FQPA safety

factor s change , percent crop treated estimates increase significantly , or there are significant changes in the estimated drinking water concentrations based on EFED’s updated drinking water

assessment to be perform ed under registration review.

### Page 9 of 35

The residue chemistry database is incomplete. Residue chemistry studies are required for storage stability, processing, and limited field rotational crops. See the “Data Requirements for Fluopicolide ” section of this document for details.

Residential Exposure

Fluopicolide

Residential Handler Exposure

Fluopicolide is a fungicide registered for use on herbaceous plants, ornamental plants, ornamental lawns and turf, ornamental woody shrubs and vines, ornamental trees, recreational areas, parks, athletic fields, and golf courses. The uses on turf and orna mental plants do not prohibit homeowners from using the products, therefore, residential handlers may apply the products; short

- term dermal and inhalation exposure to fluopicolide while mixing, loading, and applying products may occur. MOEs for residentia l lawn application were not of concern (MOEs > LOC).

Since the previous 2010 fluopicolide assessment, the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure

assessment methodol ogy for residential exposure scenarios, including methodology for adult handler exposure assessment. An updated residential handler assessment may be needed under registration review as a result of these revisions.

Residential Post

-

A pplication Exposure

For post

- application exposure, dermal exposure is likely for adults and children entering treated lawns and playing golf or contacting treated plants; children may also experience incidental oral exposure during post

- application activities on treated tur f. Post

- application exposure and risks for treated lawns were previously assessed for fluopicolide (D384431). No turf transferable

residue ( TTR) data are available; therefore default estimates of transfer were used in the

assessment. Risks were not of concern for all scenarios. It was concluded that recreational exposures to turf (including playing golf) are expected to be similar or less th an exposure assessed for treated lawns , and are therefore not of concern.

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue (TTR) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed all of the available TTR data and selected new liq uid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR 

### ). This default is 1% for formulations applied as liquids which are the case with fluopicolide . Of the available TTR

studies subm itted to the Agency, the maximum F AR 

### value seen using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 10 times higher than the level of concern (e .g., an MOE > 1,000 if the LOC = 100) using the default residue transfer values would provide an adequate

### Page 10 of 35

margin of safety for any potentially higher residues seen in a chemical

- specific TTR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council ). A TTR study is required for fluopicolide at this time since the dermal MOEs for adults and children contacting a

treated lawn are <1,000.

Since the previou s 2010 fluopicolide assessment, the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure assessment methodology for residential exposure scenarios, including adult and children

expo sure to treated turf and golf courses

. An updated residential handler assessment may be

needed under registration review as a result of these revisions.

Residential bystander inhalation exposures resulting from off

- site transport ( e.g., spray drift or volatilization) may occur as a result of agricultural applications of fluopicolide

. The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessments. The need for a bystander

inhalation risk assessment for fluopicolide will be based on the specifics of these policies

.

Although a quantitative r esidential post

- application inhalation exposure assessment has not been performed as a result of pesticide drift from neighboring fluopicolide

- treated agricultural fields, an inhalation exposure assessment should be performed for flaggers, and may be consi dered representative of a worst

- case inhalation (drift) exposure.

BAM

Residential handler exposure was not evaluated because the metabolite BAM is believed to form slowly in plants and soil after the product containing the parent (fluopicolide) has been applied. There is a potential for short

- term non

- occupational exposure to BAM during post

- application

activities. Dermal exposure is possible for adults and children entering treated lawns; children may also experience exposure via incidental non

- dietary ingestion during post

- application activities on treated turf. These scenarios were previously assessed for BAM (D345920). Since

BAM is a m etabolit e/degradate which forms slowly, these scenarios were assessed assuming that BAM is present at levels which r eflect high

- end measurements observed in the plant metabolism

studies (instead of “Day 0” levels typically used) in order to provide a protective assessment.

The short

- /intermediate

- term dermal MOEs for adults and children and incidental oral MOE for

chi ldren are greater than the ir respective LOCs ( dermal MOEs > 100 and oral MOEs >1000) and

are therefore not of concern.

Conclusions: The residential exposure database for fluopicolide and BAM is complete , with the exception of the TTR study data requirement for fluopicolide . Previous residential handl er and

post

- application exposure (fluopicolide and BAM) assessments did not result in risk estimates of

concern.

An updated residential exposure assessment may be needed during registration review as a result of the 2012 revisions to HED’s Residential Exposure Standard Operating Procedures (SOPs ). In

### Page 11 of 35

addition, revised residential assessments may be needed if toxicological POD s change or other new data are received by the Agency that impact exposure estimates.

In addition, a quantitative residential post

- application exposure assessment has not been performed as a result of pesticide drift or volatilization from neighboring fluopicolide

- treated agricultural fields; spray drift and volatilization asse ssments may be necessary under registration

review. An inhalation exposure assessment should be performed for flaggers, and may be considered representative of a worst

- case inhalation (drift) exposure.

Aggregate Risk Assessment

Fluopicolide

A ggregate ( food, drinking water, and residential exposures ) exposure assessments were performed for fluopicolide in the 2010 risk assessment . An acute aggregate assessment was not conducted because an endpoint attributable to a single dose was not identified for fluopicolide. A chronic aggregate dietary (food and drinking water only) assessment was performed and there

were no risk estimates of concern.

Short

- and intermediate

- term aggregate risks assessments were performed which combined residential exposures to fluopicolide from lawn uses with average dietary exposure estimates. The lawn uses are expected to result in higher exposures than the other turf uses (e.g. golf course use). The short

- and intermediate

- term aggregate risk estimates (for adult handlers and for both adults and children contacting treated lawns) for fluopicolide were below HED’s level of

concern

.

BAM

Aggregate (food, drinking water, and residential exposures) exposure assessments were performed for BAM in 2008 BAM risk assessment (D354 111)

. The acute and chronic aggregate dietary (food and drinking water only) assessments were performed and there were no risk

estimates of concern.

Short

- and intermediate

- term aggregate risks assessments were performed which combined

residential post

- application exposures to BAM (from lawn uses of fluopicolide) with average BAM dietary exposure estimates. The lawn uses are expected to result in higher exposures than the other turf uses (e.g. golf course use). The short

- and intermediate

- term aggre gate risk estimates (for adults and children) for BAM were below HED’s level of concern.

### Page 12 of 35

Conclusion: There were no aggregate ( food, drinking water, and residential exposures ) risks of concern for fluopicolide or for BAM. If significant changes are made to the previous fluopicolide or BAM residential or dietary risk assessments, revised aggregate risk assessments may be performed under registration review.

Cumulative Risk Assessment

Unlike other pesticides for which EPA h as followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluopicolide (parent) and any other substances

. For the purposes of this tolerance action, therefore, EPA has not assumed that fluopicolide (parent) 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 concerning common mechanism determinations and procedures for cumulating effects from substances found to have

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Occupational Exposure

Fluopicolide

Occupational Handler Exposure

Fluopicolide is a fungicide registered for use on currants, grapes, huckleberries, nut trees, pome fruits, flavoring and spice crops, cucurbits, eggplant, tomatoes and other fruiting vegetables, brassica vegetables (leafy and stem vegetables like spinach , broccoli etc), leafy vegetables, root crop vegetables, bulb vegetables, okra, onions, sugar beets and turnips. Fluopicolide is also registered for use on forest trees, Christmas tree plantations, herbaceous plants, ornamental plants, ornamental lawns and turf, ornamental woody shrubs and vines, ornamental trees, recreational areas, parks, athletic fields, golf courses , commercial and industrial areas. Fluopicolide is formulated as a suspension concentrate. Occupational handler exposure

scenarios include mixing/loading, applying by aerial, groundboom, airblast, or handheld equipment, mixing/loading/applying with handheld equipment, and flagging. These handler scenarios have been previously assessed in D347228 and D326082. Handler risks were not of

concer n with label

- required PPE (baseline plus chemical

- resistant gloves).

Recommended unit exposures for occupational handler assessments have generally been derived only from the Pesticide Handlers Exposure Database ( PHED ). However, recently both the

Outdoor Residential Exposure Task Force ( ORETF ) and the Agricultural Handler Exposure Task Force ( AHETF ) have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ). As more reliable data become available, the Agency will cont inue to replace existing data. Reviewers should incorporate new exposure monitoring data, as necessary, dur ing r egistration

r eview.

### Page 13 of 35

An updated occupational handler assessment may be required under registration review if warranted by any significant changes in exposure assessment methodology, toxicological PODs or uncertainty factors.

Occupational Post

-

A pplication Exposure

Dislodgeable foliar residue (DFR) data are available for fluopicolide (MRID 46708641) use only

on lettuce. These data were used to assess post

- application exposure for workers entering treated

fields and satisfy the DFR data requireme nt under 40 CFR Part 158. All worker risks were not of concern on the day of application.

Recommended transfer coefficients for occupational post

- application assessments are derived

from Agricultural Reentry Task Force ( ARTF) exposure monitoring studie s ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer coefficients have been updated in 2012 based on a reanalysis and submission of new monito ring data. Reviewers should incorporate new exposure monitoring d ata, as necessary , during

r egistration r eview.

An updated occupational post

- application assessment may be required under registration review if warranted by any significant changes in exposure assessment methodology, toxicological endpoints or points of departure

, or uncertainty factors.

BAM

Handler exposure was not evaluated because the metabolite BAM is believed to form slowly in plants and soil after the product containi ng the parent (fluopicolide) has been applied.

There is a potential for short

- and intermediate

- term occupational dermal exposure to BAM during post

- application activities. These scenarios were previously assessed. P lant metabolism

data were available w hich include surface residues of BAM. These residues, which were assumed to be dislodgeable, were used in conjunction with the fluopicolide DFR data (MRID 46708641) to provide residue estimates for BAM on crops and ornamentals. Because turf

transferable residue (TTR) data were not available, turf residues were estimated using default assumptions. Since BAM is a metaboli te/degradate which forms slowly

, post

- application worker MOEs were calculated assuming that BAM residues are at levels which reflect high

- end measurements observed in the plant metabolism studies in order to provide a protective

assessment. The results of the occupational post

- application exposure and risk assessment indicate that for potential BAM exposure as a result of fluopicolide use, MOEs for agricultural, turf, and ornamental uses are greater than 100 and therefore, are not of concern (D345920 and D347230).

Recommended transfer coefficients for occupational post

- application assessments are derived

from Agricultural Reentry Task Force ( ARTF) exposure monitoring studies ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring

### Page 14 of 35

data. Reviewers should incorporate new exposure monitoring d ata, as necessary , during

r egistration r eview.

Conclusions: The occupational exposure database is complete. There were no occupational risks

of concer n. An updated handler and post

- application assessme nt may be necessary under registration review of fluopicolide or BAM if warranted by any significant changes in exposure assessment methodology, toxicological PODs o r uncertainty factors.

Public Health and Pesticide Epidemiology Data

For fluopicolide, the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for

incident data ( D 405059 , 10/16/12)

.

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study evaluating the link between pesticide use and various health outcomes includ ing cancer. Fluopicolide is not included in the AHS, and therefore this study does not provide information for this report.

Because there are no incident cases reported for fluopicolide in either the Main or Aggregate IDS, no cases are identified in the SENSOR database, and f luopicolide is not included in the

AHS

, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered,

additiona l analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, the tolerance expression for fluopicolide is expressed as “ fluopicolide [2,6

- dichloro

N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide] ”. HED has recommend ed that the tolerance expression for fluopicolide be revised under 180.627(a)(1) to read as follows ( D 3 84663, 12/9/10) :

Tolerances are established for residues of the fungicide fluopicolide [2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide], including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be det ermined by measuring only fluopicolide [2,6

- dichloro

N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide] in or on the commodity.

T he Codex and U.S. residue definitions are harmonized and both express determination of parent fluopicolide. The C odex maximum residue levels (MRLs) and U.S. tolerance levels for grapes and cucurbit vegetables are harmonized. The residue levels are not harmonized for brassica vegetables, bulb vegetables, fruiting vegetables or leafy vegetables

. Much of this discrepa ncy is because of differences in commodity definitions (e.g. U.S. tolerances are established at 5.0 ppm on Brassica, head and stem, subgroup 5A whereas C odex MRLs are established at 2 ppm on Flowerhead brassicas (includes broccoli; broccoli, Chinese and ca uliflower), 7 ppm on cabbages,

### Page 15 of 35

head, and 0.2 ppm on brussel sprouts). Canada also has MRLs established for residues of fluopicolide on several commodities, many which are harmonized with U.S. tolerances, and a

few which have lower values. See Appendix C for a table of U.S. tolerances and Codex and

Canada MRLs.

Human Studies

Past fluopicolide risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide expo sure databases such as the PHED, the Agricultural Reentry Task Force (ARTF)

Database , and the Outdoor Residential Exposure Task Force (ORETF) Data base . EPA has

reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to th e ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued relianc e on these studies.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology,

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA secti on 408(p), Flupicolide is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

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

- tiered approach to making the statutorily required

determinations. Tier 1 co nsists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine rel ated effects caused by the substance, and

establish a dose

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

### Page 16 of 35

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

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Flupicolide is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.

A ccordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for f lupicolide

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Data Requirements for Fluopicolide

Toxicology

870.7800

- Immunotoxicity testing

- This study is a new data requirement under 40 CFR Part

158.

Residue Chemistry

8 60.1380 Storage Stability

Additional storage stability data are required to support the Brassica head and stem, bulb, and root vegetable, and leafy vegetable crop field trials

. S torage stability stud ies with a representative root or tuber vegetable (reflecting analysis of roots and tops) and a Brassica vegetable must be conducted . The requested dat a for a root or tuber vegetable may be translated to bulb vegetables. T he required stud ies should reflect the storage conditions of samples from the crop field trials and should include storage intervals of up to 47 months for the root or tuber vegetable and 45 months for the Brassica vegetable. Additional ly, storage stability data are needed for celery and spinach reflecting a storage interval of 38 months. One study should be conducted on any representative leafy vegetable. If residues are found to be unstable in any representative commodity, additional storage stability data studies will normally be required on additional commodities of that group [see OPPTS 860.1380(c)(5)(ii)(D)].

860. 1520 Processed Food and Feed

Since residues concentrate in whe at milled byproducts, residue data and a tolerance are required for aspirated grain fractions (AGF) . The Agency had recommend ed setting the AGF tolerance at 0.07 ppm based on the wheat processing data; however, confirmatory residue data on AGF is required

.

860.1900 Field Accumulation in Rotational Crops Limited field trials at two sites per crop as described in OCSPP Guideline 860.1900 Field Accumulation in Rotational Crops should be conducted on the following crops:

Small Grain

– the registrant has pr oposed conducting a limited field rotational crop study in wheat. HED concurs that a study should be conducted in a small grain. Data from the wheat rotational crop study can be translated to other small grains (oats, barley, etc.).

### Page 17 of 35

Soybean

- the registr ant is proposing to conduct a limited rotational crop study in soybeans. HED concurs that a limited field rotation study in soybeans should be conducted and that this data may be translated to other legumes.

Corn

– the registrant has proposed to submit da ta reflecting a 30

- day PBI in corn and to establish tolerances for inadvertent residues in corn if required. HED has no objection to submission of data on corn to support a 30

- day PBI, however if the registrant decides not to pursue a 30

- day PBI in corn, a limited field rotational study for corn will be required to determine the appropriate PBI which is ≤ 12 months.

Rice

– a limited field rotational study for rice is required. Alternately, in lieu of generating data, the registrant may chose to prohibit rotation to rice on the label.

Oilseed

– a limited field rotational study in a representative oilseed is required. The registrant may conduct the study in rape (canola varieties only), sunflower, or cotton.

Occupational and Residential Exposure

875.2100

- T urf transferable residue (TTR) data for fluopicolide.

Data Requirements for BAM (From D396248)

Special Oral Toxicity Study (including examination s at 1, 7, 14 and 28 days ) in the rat. The study should address olfactory toxicity for both dichlobenil and BAM

. [ See Appendix C of

memo D3962 48 for Data Requirement Rationale

. ]

References

S. Recore, 10/16/12, Fluopicolide: Review of Human Incidents, D 405059

.

I

. Negrón

- Encarnación , 5/16/12, Dichlobenil. Human Health Assessment Scoping Document in

S upport of Registration Review, D396248

.



### D. Davis, 3/23/11, Fluopicolide. Confirmatory Data Requirements and Revised Label Recommendation to Support Proposed New Uses on Potatoes, Sugar Beets, and Carrots and

Addition of Rotational Wheat Use with a 30

- Day PBI. D387817

.

D. Davis et al , 12/9/10, Fluopicolide and its Metabolite, 2,6

- Dichlorobenzamide (BAM). Amended Human Health Risk Assessment to Support New Section 3 Uses on Brassica Leafy Greens Subgroup 5B, Potatoes, Sugar Beets, Carrots a nd to Allow Rotation to Wheat, D 384431

D. Davis, 9/9/1 0 , 2,6

- Dichlorobenzamide (BAM) Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment to Support New Section 3 Uses of Fluopicolide on Brassica Leafy Greens Subgroup 5B, Potatoes, Sugar Beets, and Carrots, and to

Allow Rotation to Wheat.; D 381051, D381052

### Page 18 of 35

D. Davis, 8/19/10, Fluopicolide Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment to Support New Section 3 Uses on Brassica Leafy Greens Subgroup 5B, Potatoes, Sugar Beets, Carrots and Ro tational Wheat. D381050.

K. O’Rourke, 10/9/07, Occupational and Residential Risk Assessment to Support Request for Registration of Fluopicolide on a Variety of Crops, Residential Turf and Ornamentals, D326082

.

K. O’Rourke, 10/9/07, Occupational and Resi dential Risk Assessment of Metabolite BAM ( to Support Request for Registration of Fluopicolide on a Variety of Crops, Residential Turf and Ornamentals) . D345920.

K. O’Rourke, 12/13/07, Occupational and Residential Risk Assessment to Support Request for

R egistration of Fluopicolide on Brassica, Bulb Vegetables, and Root and Tuber Vegetables.

D347228.

K. O’Rourke, 12/13/07, Occupational and Residential Risk Assessment of Metabolite BAM (to Support Request for Registration of Fluopicolide on Brassica, Bulb Vegetables, and Root and Tuber Vegetables )

, D347230

.

BEAD Chemical Profile for Registration Review: Fluopicolide (027412). C. Chen, J. Alsadek,

and S. Smearman.

J. Angier, 8/29/07, Drinking Water Assessment for the BAM (2 ,6

- Dichlorobenzami de) Degradate of Dichlobenil, D 340773.

### Page 19 of 35

Appendix A

Table A

. 1 Fluopicolide Nomenclature

. Chemical structure

Empirical Formula C 14 H 8 Cl 3 F 3 N 2 O

Common name Fluopicolide

Company experimental name AE C638206

IUPAC name 2,6

- dichloro

- N

- [3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridylmethyl]benzamide

CAS name 2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide

CAS Registry Number 239110

- 15

- 7

End

- use products (EPs) V

- 10161 4SC Fungicide (39.5% fluopicolide; EPA File Symbol No. 59639

- RUN)

V

- 10161 Premix Fungicide (5.54% fluopicolide and 55.4% propamocarb; EPA File Symbol No. 59639

– RUE)

Chemical Class Fungicide

Known Impurities of Concern None

Table A.2 BAM Nomenclature

Chemical Structure

Empirical Formula C 7 H 5 C l2 NO

Common Name 2,6

- dichlorobenzamide

Company experimental name AE C653711

IUPAC name 2,6

- dichlorobenzamide

CAS Name 2,6

- dichlorobenzamide

CAS Registry Number 70852

- 53

- 8

End

- use product/EP Not applicable

Chemical Class amide; benzamide

Known Impurities of Concern Not applicable

### Page 20 of 35

Table A.3 Chemical Names and Structures of Regulated Fluopicolide Metabolites.

Common name/code Chemical name Chemical structure

BAM

AE C653711 2,6

- dichlorobenzamide

PCA

AE C657188 3

- chloro

- 5

- trifluoromethylpyridine

2

- carboxylic acid

P1X

AE 1344122 3

- methylsulfinyl

- 5

- trifluoromethylpyridine

- 2

- carboxylic

acid

Table A.4 Physicochemical Properties of Fluopicolide.



### Parameter Value Reference

Molecular Weight 383.59 *

Melting point/range 149 C MRID 46474015

pH 6.5 at 22.0 C ( 1% suspension) MRID 46474013

Density 1.65 g/cm 3 (30 °C) MRID 46474016

Water solubility (20 C) 2.86 mg/L at pH 4 2.80 mg/L at pH 7 2.80 mg/L at pH 9 MRID 46474021

Solvent solubility (g/L at 20 C) n

- Hexane: 0.20

Ethanol: 19.2

Toluene: 20.5 Ethyl acetate: 37.7

Acetone: 74.7

Dichloromethane: 126 Dimethyl sulfoxide: 183 MRID 46474022

Vapor pressure (25 C) 6.02 x 10 - 9 mm Hg MRID 46474023

Dissociation constant (pKa) No evidence of ionization in the pH range of 1.9 to

9.8 MRID 46474017

Octanol/water partition coefficient Log(K OW ) Log P OW = 3.26 at pH 7.8 and 22 ± 1 C MRID 46474018

Log P OW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 C MRID 46474019

UV/visible absorption spectrum Absorption maxima wavelengths (nm):

In methanol: 203 and 271

In methanol/HCl: 202 and 270

In methanol/NaOH: 219 and 271 MRID 46474014

*The molecular weight was calculated from the Periodic Table.

### Page 21 of 35

Table A.5

. Physiochemical Properties of BAM.

Parameter Value References*

Molecular Weight 190.03 g/mol Product Chemistry (HSDB, 2002)
Melting point/range Not available

pH Not available

Density Not available

Water solubility (pH 7, 20°C) 2700 mg/L Product Chemistry (HSDB, 2002)
Solvent solubility (20°C to 25°C) Not available

Vapor pressure (25 C) 3.26 x 10 - 5 mm Hg Product Chemistry (HSDB, 2002)
Dissociation constant, pKa Not available
Octanol/water partition coefficient, logPOW (25°C) Kow = 30 mL/g** HSDB, 2002

UV/visible absorption spectrum Not available

### Page 22 of 35

Appendix B: Toxicity Profile for Floupicolide and BAM

Table B.1 Acute Toxicity Profile of Fluopicolide Technical, and Selected Metabolites and

Formulations

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] Fluopicolide

Technical 98.3% (AE C638206) Formulation SC 40 (AE C638206) Formulation SC61 (AE B066752) 46708601

46709903

46709803 LD 50 ≥ 2000 mg/kg (f)

LD 50 ≥ 2000 mg/kg (m/f)

LD 50 ≥ 2000 mg/kg (m/f) III

III

III

870.1100 Acute oral [rat] Metabolites

2,6

- dichlorobenzamide (BAM) 1,3

- chloro

- 5 (trifluoromethyl) pyridine

- 2

- carboxylic acid (PCA) 42940201
46708602
46708603 LD 50 ≥ 1538/1144 mg/kg (m/f)

LD 50 ≥ 2000/300 mg/kg (m/f)

LD 50 ≥2000 mg/kg (m/f) III
II
III

870.1200 Acute dermal [rat]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708605

46709904

46709804 LD 50 ≥ 5000 mg/kg

LD 50 ≥ 4000 mg/kg

LD 50 ≥4000 mg/kg IV

III

III

870.1300 Acute inhalation [rat]

Technical (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708606

46709905

46709805 LC 50 ≥ 5.16 mg/L

LC 50 ≥ 1.789 mg/L

LC 50 ≥ 3.195 mg/L IV

III

IV

870.2400 Acute eye irritation [rabbit]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708607

46709906

46709806 slight conjuctival irritation

chemosis/corneal opacity in both

studies IV

III

III

870.2500 Acute dermal irritation [rabbit]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708650

46709907

46709807 None (PDII = 0.00)

slight (PDII = 0.08) slight (PDII = 0.25) IV

IV

IV

870.2600 Skin sensitization [guinea pig]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708608

46709908

46709808 Negative (Magnusson

- Kligman)

Negative (Buehler) Negative (Modified Buehler) non

sensitizer

Table B.2 Acute toxicity profile for metabolite 2,6

- dichlorobenzamide (BAM)

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100 /Acute oral toxicity (mouse) 42940201 LD 50 ≥ 1538/1144 mg/kg (M/F) III

870.1100 /Acute oral toxicity (rat) 46708602 LD 50 ≥ 2000 mg/kg (M) and

LD 50 ≥ 300 mg/kg (F) II

### Page 23 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3050 28

- day dietary

toxicity (mouse) 46708609 (2000)

Acceptable/Guideline

M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129, 980/1242 mg/kg/day NOAEL = 980/1242 mg/kg/day; the limit dose).

The LOAEL was not observed.

870.3050 28

- day dietary

toxicity (rat) 46708610 (2000)

Acceptable/Guideline

M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day NOAEL = 17.4/17.9 mg/kg/day in males/females).

The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain and food conversion in females and nephrotoxicity in

males.

870.3050 28

- day dietary

toxicity (rat)

AE 1344122 (Fluopicolide metabolite) 46708611 (2003)

Acceptable/Guideline

M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day NOAEL = 151.6/167.1 mg/kg/day. LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body weight gains in both sexes, and nephrotoxicity in females.

870.3050 28

- day dietary

toxicity (rat)

AE C657378 (a Fluopicolide metabolite) 46708612 (2003)

Acceptable/Guideline

M/F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6,

and 1775.0/1930.8 mg/kg/day NOAEL = 159.2 /230.6 mg/kg/day

.
LOAEL = 1775.0/1930.8 mg/kg/day based on decreases in body weight and body weight gain (males); increased absolute (females) and relative liver weight (both sexes) and relative kidney weight (males); increased cholesterol (both sexes); and histopathological effects in the liver (females), the kidneys (males), and thyroid (both sexes)

.
870.3050 28

- day oral

toxicity (dog) 46708613 (2000)

Acceptable/Non

- guideline

0, 10, 100, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (limit dose).

LOAEL was not observed.

870.3100 90

- Day oral

toxicity (rat) 46474112 (2000)

Acceptable/guideline M: 0, 7.4, 109, 1668 mg/kg/d F: 0, 8.4, 119, 1673 mg/kg/day NOAEL = 109 mg/kg/day for males; 8.4 mg/kg/day for females LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on hypertrophy of the zona glomerulosa in the adrenal gland (M/F), decreased cellularity of the bone marrow (M/F), and trabecula r hyperostosis of the bone joint (M)

870.3100 90

- Day oral

toxicity (mouse) 46474114 (2000)

Acceptable/guideline M/F: 0, 5.5, 53, 545 or 1092 mg/kg/day NOAEL = 1092 mg/kg/day (M/F)

LOAEL = not identified

### Page 24 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral

toxicity (mouse) 46474116 (2001)

Acceptable/guideline M: 0, 10.4, 37.8, 161, 770 mg/kg/d F: 0, 12.6, 52.8, 207, 965 mg/kg/day NOAEL = 770 mg/kg/day for males; 207 mg/kg/day for females LOAEL = not identified for males; 965 mg/kg/day for females based on increased

incidence of liver oval cell proliferation

870.3150 90

- Day oral

toxicity (dog) 46474118 (2000)

Acceptable/guideline M&F: 0, 5, 70, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F) LOAEL = not identified (M/F)

870.3200 21/28

- Day dermal

toxicity (species) 46708614 (2003)

Acceptable Guideline 0, 100, 250, 500, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day No local or systemic toxicity observed

870.3700a Prenatal

developmental in (rat)

Pilot study 46708615 (2000)

Acceptable/non

- guideline F: 500, 1000 mg/kg/day (GD 7

- 20) NOAEL/LOAEL not determined. Only four animals/group. Purpose of study was to determine high

- dose level for 46474120.

870.3700a Prenatal

developmental in (rat) 46474120 (2001)

Acceptable/guideline F: 0, 5, 60, 700 mg/kg/day (GD 7

- 20) Maternal NOAEL = 60 mg/kg/day LOAEL = 700 mg/kg/day based on decreased body weight gain Developmental NOAEL = 60 mg/kg/day LOAEL = 700 mg/kg/day based on delayed fetal growth and delayed ossification

870.3700b Prenatal

developmental in (rabbit)

Pilot study 46708616 (2000)

Acceptable/non

- guideline F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day (GD 6

- 28) Materna l NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on reduced defecation and abortion in a single dose Developmenta l NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b Prenatal

developmental in (rabbit) 46474122 (2001)

Acceptable/guideline F: 0, 5, 20, 60 mg/kg/day (GD 6

- 28) Materna l NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on death, late

term abortion /premature delivery, decreased

food consumption and weight gain Developmenta l NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased fetal body weight and crown

- rump length

### Page 25 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3800 Reproduction and

fertility effects (rat) 46474124 (2003)

46474125 (additional data, 2004) 46474126 (range

- finding, 2002) Acceptable/guideline M: 0, 7.4, 36.4, 144.6 mg/kg/d F: 0, 8.1, 41.0, 159.7 mg/kg/day Parental/Systemic NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males and females and decreased weight gain in females. Reproductive mg/kg/day (M/F)

LOAEL = not identified. Offspring NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and weight gain

.

870.4100b Chronic toxicity

(dog) 44674128 (2002)

Acceptable/guideline M&F: 0, 70, 300, 1000 mg/kg/day mg/kg/day (F) LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not identified (F)

870.4200b Carcinogenicity

(mouse) 46474130 (2003)

Acceptable/guideline M: 0, 7.9, 64.5, 551.0 mg/kg/d F: 0, 11.5, 91.9, 772.3 mg/kg/day NOAEL = 64.5/91.9 mg/kg/day (M/F) LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and weight gain and

liver lesions. no evidence of carcinogenicity

870.4300 Chronic/

Carcinogenicity (rat) 46474139 (2003)

Acceptable/guideline M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day NOAEL = 31.5/41.0 mg/kg/day (M/F)

LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F) and thyroid toxicity (M). no evidence of carcinogenicity

### Page 26 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5100 Gene Mutation

( Salmonella typhimurium ) 46474146 (2001)

Unacceptable/guideline

1.6

- 5000 μg/plate

46474202 (2001) Acceptable/guideline

1.6

- 5000 μg/plate

46474148 (2001) Acceptable/guideline

1.6

- 5000 μg/plate

46474144 (2001) Acceptable/guideline

1.6

- 5000 μg/plate

46474142 (2004) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024)

5

- 5000 μg/plate negative (non

- mutagenic) Upgradeable if purity for test material is given.

negative (non

- mutagenic)

negative (non

- mutagenic)

negative (non

- mutagenic

positive (mutagenic)

870.5300 Gene mutation

(Chinese hamster lung cells) 46474204 (2000)

Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024)

1.2

- 3820 μg/mL negative (non

- mutagenic)

870.5375 Cytogenetics 46474208 (2001) Acceptable/guideline 1.22 to 625 μg/mL

46474206 (2004) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 3.2 to 100 μg/mL negative for chromosome aberrations

positive for aberrations without S9 activation

### Page 27 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5395 Micronucleus

(mouse) 46474214 (2003)

Acceptable/guideline 150, 300 or 600 mg/kg/day

46474210 (2005) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 200, 600 or 2000 mg/kg/day

46474212 (2005) Acceptable guideline AE C638206 (Batch No. OP

2050046 at 2000 mg/kg/day negative at doses up to 600 mg/kg

negative at doses up to 2000 mg/kg

negative at dose of 2000 mg/kg

### Page 28 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5550 Unscheduled

DNA Synthesis (rat hepatocytes) 42169839 (1989)

Acceptable/guideline negative at concentration up to 300 μg/mL in cultured rat hepatocytes

(no OPPTS

no./ FIFRA

test guideline

84

- 2) Other

Genotoxicity

Unscheduled DNA synthesis (rat hepatocytes) 46474216 (2000)

Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 600 or 2000 mg/kg negative at concentrations up to 2000 mg/kg in hepatocytes from treated rats

870.6200a Acute

neurotoxicity screening battery (rat) 46474218 (2002)

46474219 (range

- finding, 2002) Acceptable/guideline M/F: 0, 10, 100, 2000 mg/kg NOAEL = 100 mg/kg (M/F) LOAEL = 2000 mg/kg (M/F) based on transiently lowered body temperature.

870.6200b Subchronic

neurotoxicity screening battery 46474221 (2002)

46474222 (positive control, 2002) Acceptable/guideline M: 0, 15.0, 106.6, 780.6 mg/kg/day F: 0, 18.0, 125.2, 865.8 mg/kg/day NOAEL = 106.6/18.0 mg/kg/day (M/F)

LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food consumption, and food efficiency.

870.6300 Developmental

neurotoxicity None

870.7485 Metabolism and

pharmacokinetics (rat) 46474242 (2004)

- main

studies 46474241 (2001) 46474244 (2003) 46474226 (2003) 46474239 (2003) rapid absorption, metabolism and excretion;

main metabolites were oxidative N

dealkylation cleavage products. Primary route of excretion is fecal and urinary with little

accumulation in the tissues.

870.7485 Metabolism and

pharmacokinetics (rat) 46708632 (2002)

Acceptable Non

- guideline Most of the metabolites observed were derivatives of AE C638206 fitting well with the prior known metabolites, implying cysteine or

N

- acetyl

- cysteine introduction on the phenyl ring from gluthione conjugation, hydroxylation, or other conjugations.

870.7485 Metabolism and

pharmacokinetics (rat)

AE C657188 (PCA) 46708636 (2002)

Acceptable Guideline AE C657188 (PCA) showed high (87%) absorption but low (14

– 21%) metabolism.

Excretion is mainly through the urine, with a minor portion in the feces.

### Page 29 of 35

Table B.3 Subchronic, Chronic and Other Toxicity Profile for Fluopicolide

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (rat)

AE C653711 (2,6

- dichloro

benzamide 46708633 (2003)

46708634 (2003) 46708635 (2003) Acceptable Guideline Absorption: 50

- 79%. Metabolized extensively to 18 identified compounds. The majority of the radioactivity was associated with a mercapturic acid conjugate of hydroxyl

chlorobenzamide (15

- 5

- 26.2%), present in the

urine Excretion mainly through urine and

feces.

870.7600 Dermal

penetration (rat) 46708638 (2003)

Acceptable Guideline 1.43, 659 ug/cm 2 skin In vivo study

Dermal Penetration rate: 37%

870.7600 Dermal

penetration

(comparative) 46708637 (2003)

Acceptable Non

- guideline

1.9, 744 ug/cm 2 skin In vitro study Rat skin dermal penetration rate is 7.8 times greater than human skin.

Table B.4 S ubchronic , C hronic

, Other Toxicity P rofile for metabolite, 2,6

- dichlorbenzamide (BAM)

Guideline No./ Study Type MRID No. (Year)/Doses/

Classification Results

870.3100

90

- day oral (rat; dietary) 00067654 (1967)

0, 50, 180, 600, or 2300 ppm (equal to 0, 4, 14, 49, or 172 mg/kg/day)

Acceptable/G uideline NOAEL = 14 mg/kg/day LOAEL = 49 mg/kg/day based on decreased body weight gain (M) and reduced skeletal muscle tone (M&F)

870.3150

90

- day oral (dog; dietary) 00067655 (1967)

0, 100, 300, or 2000 ppm (equal to 0, 7.5, 22.5, or 150 mg/kg/day)

Unacceptable/G uideline due to parasitic infections (ascariasis) in most animals NOAEL = 22.5 mg/kg/day LOAEL = 150 mg/kg/day based on clinical signs (thin appearance, dull coat, hair loss) and increased liver weight

and serum alkaline phosphatase concentrations (F) and clinical signs (thin appearance, dull coat, hair loss) (M)

870 .4700

Chronic toxicity oral (dogs; dietary) 42940203 (1971)

0, 60, 100, 180, or 500 ppm (equal to 0, 1.5, 2.5, 4.5, or 12.5 mg/kg/day)

Acceptable/Guideline NOAEL = 4.5 mg/kg/day LOAEL = 12.5 mg/kg/day based on decreased body weight and body weight gain

870.4300

Combined 42940202 (1971), 44043601

(1996), 44052901 (1996) NOAEL = 6.5 (M) and 4.7 mg/kg/day (F) LOAEL = 19 mg/kg/day (M) and 8.5 mg/kg/day (F) based on

### Page 30 of 35

Table B.4 S ubchronic , C hronic

, Other Toxicity P rofile for metabolite, 2,6

- dichlorbenzamide (BAM)

Guideline No./ Study Type MRID No. (Year)/Doses/

Classification Results

Chronic Toxicity/ Carcinogenicity oral (rat; dietary) 0, 60, 100, 180, or 500 ppm

[equal to 0, 2.2/2.8, 3.6/4.7, 6.5/8.5, or 19/25 mg/kg/day (M/F)]

Acceptable/Guideline decreased body weight and body weight gain (≥ week 26) and an increased incidence of hepatocellular alteration (eosinophilic foci)

Borderline statistically significant (P=0.049) increased incidence of hepatocellular adenomas at 25 mg/kg/day (F only); dosing considered adequate (M&F)

870.3700 Developmental toxicity oral (rabbit; gavage) 43003601 (1986), 43265201

(1994)

0, 10, 30, or 90 mg/kg/day

Acceptable/Guideline Maternal NOAEL= 30 mg/kg/day Maternal LOAEL= 90 mg/kg/day based on increased incidences of clinical signs (late abortion, thin appearance) and decreased (severe) body weight gain and food consumption during dosing

Developmental NOAEL = 30 mg/kg/day Developmental LOAEL = 90 mg/kg/day based on increased incidences of late abortion and skeletal ( bipartite interparietal bone) and visceral (postcaval lung lobe agenesis) anomalies

870.3800

3

- generation reproduction oral (rat; dietary) 42940204 (1971)

0, 60, 100, or 180 ppm (equivalent 0, 4.5, 7.5, or 13.5 mg/kg/day)

A cceptable/ Non

- Guideline (upgradable if individual

animal data is included) Parental NOAEL = 13.5 mg/kg/day

Parental LOAEL was not observed.

Reproductive NOAEL = 13.5 mg/kg/day Reproductive LOAEL was not observed.

Offspring NOAEL = 13.5 mg/kg/day

Offspring LOAEL was not observed.

Non

- guideline (literature)

Adult mouse olfactory study (single injection; i.p.) Brittebo et al. (1991); no

MRID

0, 25, 50, or 100 mg/kg/day (i.p.)

Acceptable/Non

- guideline Decreased periodic acid

- Schiff (PAS) staining of contents of Bowman’s glands (measure of mucus production) observed at ≥25 mg/kg/day (reversible); degeneration of olfactory epithelium and necrosis of Bowman’s glan ds observed at 100 mg/kg/day (sustained)

870.5100

In vitro

bacterial

reverse mutation (Ames test) 43003603 (1992)

At concentrations up to 5000 g/plate (

- /+ activation) in S. typhimurium

Acceptable/Guideline Negative with or without activation.

870.5395

In vivo mouse erythrocyte

micronucleus

assay 43003602 (1993), 43747101

(1995)

0, 250 mg/kg Acceptable/Guideline Negative.

Lethargy observed in dose

- range finding (pilot) study at 100 mg/kg/day (=LOAEL; NOAEL not observed); clinical signs worsened with increasing dose

870.5550

In vitro 43003604 (1993) Negative.

### Page 31 of 35

Table B.4 S ubchronic , C hronic

, Other Toxicity P rofile for metabolite, 2,6

- dichlorbenzamide (BAM)

Guideline No./ Study Type MRID No. (Year)/Doses/

Classification Results

Unscheduled DNA synthesis (rat hepatocytes) At concentrations up to 1000

μg/ml

Acceptable/Guideline

Table B.5 Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary

Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

A ssessment Study and Toxicological Effects Acute Dietary (all populations) An endpoint attributable to a single dose was not identified from the available data.

Chronic Dietary (all populations) Maternal

NOAEL=20 mg/kg/day UF A =10x

UF H =10x FQPA SF = 1X Chronic RfD =

0.2 mg/kg/day

cPAD = 0.2 mg/kg/day Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Co

- critical: Chronic/Oncogenicity Study

in Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.

Incidental

Oral

Intermediate

Term (1

- 6 months) Maternal

NOAEL = 20 mg/kg/day UF A =10x

UF H =10x FQPA SF = 1X MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Dermal Short

Intermediate

and Long

Term (1

- 30 days, 1

- 6 months, and >6 months) Maternal

NOAEL = 20 mg/kg/day UF A =10x

UF H =10x FQPA SF = 1X

37% dermal absorption MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Co

- critical: Chronic/Oncogenicity Study

in Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.

### Page 32 of 35

Table B.5 Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary

Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

A ssessment Study and Toxicological Effects

Inhalation

Short

Intermediate

and Long

term (1

- 30 days, 1

- 6 months, and >6 months) Maternal

NOAEL = 20 mg/kg/day UF A =10x

UF H =10x FQPA SF = 1X

(inhalation and oral toxicity are

assumed to be equivalent) MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Co

- critic al: Chronic/Oncogenicity Study

in Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Humans”

.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table B.6 Summary of Toxicological Doses and Endpoints for 2,6

- Di chlorobenzamide (BAM) for Use in Dietary, Residential, and Occupational Human Health Risk Assessments
Exposure Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological

Effects

Acute Dietary (General population, including infants and children) LOAEL = 100

mg/kg/day UF A = 10X

UF H = 10X FQPA SF 4 ,5 = 10X (includes UF L and

UF DB ) aRfD = aPAD =

0.1 mg/kg/day Dose

- range finding assay for

in vivo mouse erythrocyte micronucleus assay LOAEL = 100 mg/kg/day based on lethargy after a single oral dose

Acute Dietary (Females 13

- 49 years of age) NOAEL = 30

mg/kg/day UF A = 10X

UF H = 10X FQPA SF 4 = 10X (includes UF DB ) aRfD = aPAD =

0.03 mg/kg/day Developmental toxicity

(rabbit) Offspring LOAE L = 90 mg/kg/day based on increased

incidences of late abortion and skeletal ( bipartite interparietal bone) and visceral (postcaval lung lobe agenesis) anomalies

Chronic Dietary (All populations) NOAEL = 4.5

mg/kg/day UF A = 10X

UF H = 10X FQPA SF 4 = 10X (includes UF DB ) cRfD = cPAD =

0.0045 mg/kg/day Chronic toxicity (dog) LOAEL

= 12.5 mg/kg/day based on decreased body weight and body weight gain

### Page 33 of 35

Incidental Oral

Short

- and

Intermediate

- Term (1

- 30 days and 1

- 6 months) NOAEL = 14

mg/kg/day UF A = 10X

UF H = 10X FQPA SF 4 = 10X (includes UF DB ) Residential

LOC for MOE

= 1000 90

- day oral (rat) LOAEL = 49

mg/kg/day based on decreased body weight gain (M) and

reduced skeletal muscle tone (day 4 only in males; days 91 and 92 only in females)

Dermal

Short

- , Inter mediate

- , and Long

- Term (1

- 30 days, 1

- 6 months, and >6 months) NOAEL = 25

mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X (residential uses only) Residential and

Occupational

LOC for MOE

= 100 5

- day dermal using dichlobenil 6

(mouse; literature study 1 )

LOAEL = 50 mg/kg/day based on olfactory epithelial damage

Inhalation

Short

- , Intermediate

- , and Long

- Term (1

- 30 days, 1

- 6 months, and >6 months) NOAEL = 3.1

mg/kg/day 2 UF A = 10X

UF H = 10X

FQPA SF = 1X (residential uses only) Residential and

Occupational

LOC for MOE

= 100 28

- day inhalation using

dichlobenil 6 (rat) LOAEL = 5.5 mg/kg/day 3 based on nasal degeneration

Cancer Classification: u nclassified; parent herbicide dichlobenil classified as “Group C, possible

human carcinogen” with RfD approach utilized for quantification of human risk Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety Factor,

UF L = use of a LOAEL to extrapolate a NOAEL, UF DB = to account for the absence of key data, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, RfD = reference dose (a = acute, c = chronic), PAD = population adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A = Not Applicable

1 Deamer NJ

, O'Callaghan JP

, Genter MB . (1994). Olfactory toxicity resulting from dermal application of 2,6

- dichlorobenzonitrile (dichlobenil) in the C 57Bl mouse. Neurotoxicology 15(2):287

- 93

2 Calculated as follows: [(NOAEL) x (m 3 / 1000 L) x (10.26 L / hr) x 6 hr/day x (1 / 0.236 kg)], where NOAEL= 12 mg/m 3 from 28

- day inhalation toxicity study (Sprague Dawley rat)

3 Calculated as follows: [(LOAEL) x ( m 3 / 1000 L) x (10.26 L / hr) x 6 hr/day x (1 / 0.236 kg)], where LOAEL= 21 mg/m 3 from 28

- day inhalation toxicity study (Sprague Dawley rat)

4 The FQPA SF has been retained in the form of a UF DB for the lack of neurotoxicity data, including olfactory

toxic ity data.

5 The FQPA SF has been retained in the form of a UF L and UF DB for the use of a LOAEL to extrapolate a NOAEL and for the lack of olfactory toxicity data.

6 In the absence of route

- specific data, endpoints for all dermal and inhalation exposure sce narios were identical to those for dichlobenil (parent), since olfactory toxicity has been observed following i.p. administration of BAM in mice [ Brittebo EB

, Eriksson C

, Feil V

, Bakke J

, Brandt I . (1991). Toxicity of 2,6

- dichlorothiobenzamide (chlorthiamid) and 2,6

- dichlorobenzamide in the olfactory nasal mucosa of mice. Fundam Appl Toxicol 17(1):92

- 102].

### Page 34 of 35

Appendix C : International Residue Limits Fluopicolide (PC Code 027412 ; 10/15 /12)
Summary of US and International Tolerances and Max imum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

40 CFR 180.627

(a) fluopicolide [2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide] 2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benza

mide Fluopicolide . The

residue is fat soluble.

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

US Canada Mexico 1 Codex 2

Brassica, head and stem, subgroup 5A 5.0 2 Flowerhead brassicas (includes broccoli; broccoli, Chinese and cauliflower)

7 cabbages, head 0.2 brussel sprouts Grape 2.0 1.4 2 grapes 7 grape pomace, dry Grape, raisin 6.0 4.1 raisins 10 dried grapes (=currants, raisins and sultanas) Potato, processed waste 0.05 Vegetable, brassica (cole) leafy subgroup 5B 18 30 leafy vegetables

Vegetable, bulb, crop group

3

- 07 7.0 1 onion, bulb 10 onion, Welsh Vegetable, cucurbit, group 9 0.50 0.5 balsam apples, balsam pears, cantaloupes, chayote fruit, Chinese cucumbers, Chinese waxgourds, citron melons, cucumbers, edible gourds and muskmelons (other than those listed in this item)

, pumpkins, summer squash, watermelons, west Indian gherkins, winter squash 0. 5 Fruitng vegetables,

cucurbit s

Vegetable, fruiting, group 8 1.60 1.6 African eggplants, bell peppers, bush tomatoes,

co conas, currant tomatoes, eggplants, garden

huckleberr ies, goji berr ies ; groundcherries, martynias, naranjilla s, nonbell peppers, okras, pea eggplants, pepinos, roselles, scarlet eggplants

, sunberr ies, tomatillos,

tomatoes, tree tomatoes 1 Fruitng vegetables,

other than cucurbit s

7 peppers chili, dried

Vegetable, leafy, except brassica, group 4 25 16 head lettuce, leaf lettuce 20 celery 30 leafy vegetables

### Page 35 of 35

Summary of US and International Tolerances and Max imum Residue Limits Residue Definition :

US Canada Mexico 1 Codex 2

Vegetable, leaves of root and tuber, group 2 15.0 30 leafy vegetables

Vegetable root, subgroup 1A 0.15 Vegetable, tuberous and corm subgroup 1C 0.02 0.02 arracacha, arrowroot, cassava roots, chayote roots, Chinese artichokes, chufa, edible canna, ginger roots, Jerusalem artichokes, lerens, sweet potato roots, tanier corms, taro corms, turmeric roots, true yam tubers, yam bean

roots

Completed: M. Negussie; 10/18/2012

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

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.

(d) Indirect or inadvertent residues. Tolerances are established for residues of the fungicide fluopicolide [2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzam ide], including its metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels specified below is to be determined by measuring only fluopicolide [2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl )

- 2

- pyridinyl]methyl]benzamide] in or on the commodity.

Commodity Parts per

million

Wheat, aspirated grain fractions 0.07

Wheat, forage 0.20

Wheat, grain 0.02

Wheat, hay 0.50

Wheat, milled byproducts 0.07

Wheat, straw 0.50